Podcasts about so greg

Welcome! Today we have a special guest, UNI Alumni and human extraordinaire Katie Grassi. August is a weird month. As an academic it has the melancholy feel of the end of the summer. But it is also a fresh start. My kiddo, Harper, is starting kindergarten and we get to create back-to-school traditions. What were your favorite back to school traditions growing up?Speaking of fresh starts, Katie might need a fresh start after this week's episode. The episode begins with her hometown date with Blake. He “takes” her to Canada where they go to a cabin, take shots of maple syrup, ride a moose, and play street hockey. Justin's hometown is next. It begins by us learning that his parents will not be coming because they do not support the show. Greg's hometown begins with a ride on a tandem bike. She talks about how much fun they have together. They play basketball and he talks about his dad. He makes it rain again. Then things go South. They are having a heartfelt conversation in which Greg expresses his love for Katie. She responds with, “you seem sad.” Things get tense. She tells him he needs to trust their relationship and not give up on them. He's like, I just expressed my love for you, you barely responded and now you think I'm giving up on you.So Greg goes to see her the next day. He tells Katie that he felt like he was really vulnerable but didn't get anything in return. She apologizes but her apologies are enough for greg. Then Greg pretty much gaslights her. Was this gaslighting? History- the movie with the lightbulbHe walks out. She cries and then follows him. He tells her he's not happy and is leaving. She says if he leaves, she is going too. He leaves. She cries in the bathroom. Kaitlyn talks to Katie and she says she wants to go home. Preview to next week: Katie seems to go home. But then maybe goes back. Katie any shout outs? Last words? Buzzsprout - Let's get your podcast launched! Start for FREEInstacart - Groceries delivered in as little as 1 hour. Free delivery on your first order over $35.Disclaimer: This post contains affiliate links. If you make a purchase, I may receive a commission at no extra cost to you.

This week, we have a special podcast: the interviewers become the guests! Join Digital Strategies Editor Amit Khera as he interviews Carolyn Lam, Greg Hundley, and Managing Editor David "Augie" Rivera as they provide a behind-the-scenes look at how Circulation on the Run comes to you each and every week. Come meet your favorite podcast hosts! Dr. Amit Khera: Hi, this is Amit Khera. I'm digital strategies editor for Circulation, and boy, do I have a treat today? I get to step in for Carolyn Lam and Greg Hundley, but wait, I actually get to interview Carolyn Lam and Greg Hundley today. So we have a very special Circulation on the run. Well, the interviewer becomes the interviewee. These two you get to hear every week and hear this amazing back and forth and deep insight into Science and Circulation. But, who are these folks behind the Circulation on the Run podcast? And boy, what interesting life stories they have and how they work through this. And wait, we also have a third joining us today, and that is Augie Rivera, who is the managing editor of Circulation. So we get to see the mastermind behind how all this runs. Well, Carolyn, Greg, Augie, welcome you three. Dr. Carolyn Lam: Thanks, Amit. Feels weird. Dr. Amit Khera: Good. Then mission accomplished this week. Well, first let me start with you, Carolyn. I know you and I started this long ago, with help from so many folks. People hear you every week and I'm sure many people know you quite well. I will say you have one of the most interesting backgrounds, incredible scientific and personal accomplishments, professional accomplishments. So we're very fortunate to have you as leading this podcast in the beginning, but a lot of people may not know your background story about sort of your training and your day job, because you do have a day job outside of podcasting. So tell us a little bit about yourself, about how you got here in life. Dr. Carolyn Lam: Oh my gosh. Amit, I'm humbled by your question. My goodness. I feel just very lucky to be part of the Circulation editors. And I humbly did my med school in Singapore, and did cardiology here, and traveled and lived overseas for the first time. Guess where, in Rochester, Minnesota. Tropical Singapore island to refrigerator state. Other than that, it was absolutely the most pivotal moment of my life. Met my first female mentor and Dr. Margaret Redfield. Really, really just came into my own and got involved in population-based research. And then hopped on over to Boston where actually I was working at the Framingham Heart Study. So continuing sort of the epidemiologic work, but then I think another mentor I really have to call out too is Dr. Scott Solomon, who kind of took me under his wing a little bit and showed me a little bit of the world of clinical trials. And boy, all I can say is I haven't looked back. And so here I am. Dr. Amit Khera: I think you took a detour in the Netherlands too. Am I right to say that? Dr. Carolyn Lam: Oh yes, but that was quite a late detour in life. I was really, really fortunate meet Dr. Adrian Voris who supervised my own PhD. That was a really interesting thing because I come from a family of a pediatrician in my mom, and a scientist, a biologist really, specialized in fish, in my father. And I'm saying this because my father told me never ever follow his footsteps and do a PhD. Make sure I follow my mom's footsteps and be a clinician, and go into private practice. Dr. Amit Khera: Well, it looks like you followed both of their footsteps, maybe the best of both, so they're very proud of you for that. We recently had the privilege of having you give us grand rounds and get to hear your impressive work in clinical trials. And I have to say, the work you're doing in half half and really with some great clinical trial and cohort data involving Asian populations was quite inspiring and impressive. How did you sort of get things going? You've traveled around and moved back and how did you start getting your career going and the momentum you've had so far, incredible success? Dr. Carolyn Lam: Oh goodness. Thanks for letting me share. Amit, honestly, I don't know. And I can only look back and be on my knees and be grateful for being at the right place at the right time. I think it's a combination of taking what I had learned in Olmsted County and Framingham. Coming back to Singapore and realizing that there was a need for similar epidemiologic studies. I firmly believe if I didn't do it, someone else would. I'm not that brilliant. I just get things done. And so that's what I did. I started that. And one thing led to another. It's having really friends as well. And so I really, really want to say big thanks to my mentors who have become my friends and colleagues. And to people listening. This is really, really from the heart. You don't plan these things. You just go the next step that you see, and you go with all your heart. And you make sure that you've got your eyes open to see the next opportunity, and have the energy to seize that one when it comes by as well. I think that's how it all happened. Dr. Amit Khera: Well, that is a good pivot because one of the next opportunities that came up in Circulation on the Run after you'd done it for a while, was to bring in this gentleman, Greg Hundley. And so we're so glad that you two partnered. Now, Greg, you and I have a little bit of a shared background. You were at UT Southwestern for a period of time, where I am currently. Well, tell us your story, Greg. Tell us a little bit about your background and training and where you are currently. Dr. Greg Hundley: Sure. Thanks so much, Amit. Again, I think like Carolyn, we really feel this is an incredible opportunity. The journal is a wonderful blend of collecting impactful science, both clinically and pre-clinically. And trying to bring that to the forefront. It's just been a fantastic opportunity to participate on the editorial side, but then after that, share with the rest of the world, the findings that we really develop each week. And it is truly a team effort. All the way from identifying impactful science, discussing it, preparing it, and then sharing it. And so I think like Carolyn, I just feel very privileged to have this opportunity. Now, my path, listening to Carolyn, and for listeners, you kind of move with it a little bit, and follow along seeking, I don't know, new opportunities, but also being very humble. And as they approach you, and doing kind of the best that you can in the situation. Dr. Greg Hundley: So my career path started at what was Medical College of Virginia, but is now VCU in Richmond, Virginia, and medical school there. And then, at Southwestern, did my internship, residency, and cardiology fellowship. And I would say, probably my first strong mentors was really a mentor team. There was expertise there. Jim Willerson had brought Ron P Shock and Craig Malloy on the magnetic resonance imaging side. So for those that are listening, I'm more of an imager in cardiovascular medicine. But also a key fundamental pivotal figure or figures were David Hillis, and Rick Lang in the cath lab. And at the time, magnetic resonance imaging, we were trying to figure out, well, could this noninvasive methodology help us understand problems related to cardiovascular disease that came along maybe before, or we needed to go to an interventional situation, or how they would relate to an interventional situation. Dr. Greg Hundley: And then was briefly a faculty member at Southwestern, and then recruited back to the East Coast to Wake Forest. Another really pivotal figure for me was Dr. Bill Little at Wake Forest. Now, he's passed away, but bill had again, that great insight and excellence in science, and performing research and investigations, but also clinical expertise and emphasize the world... We haven't talked a lot about this, but education. How we take the information that we gather and educate others. Began working with the American Heart Association, with the American College of Cardiology in that realm. Then after 22 or three years, another opportunity came up actually to return back to VCU, and be the director of the heart center. And so now have that position here in Richmond, Virginia. Again, very excited to be working here with Circulation on the Run. Dr. Amit Khera: Well, I hear some amazing themes from both of you about mentoring and people along the way. It's a great story obviously for our younger listeners that are thinking about life and careers and opportunity sort of finding where life takes you. I think those are great themes for both of you. Now, we won't have as much time for this story, but Greg, you and I spoke recently. You told me this most amazing story of how you were going to be an interventional cardiologist, walked over to drop off something. A patient had an MRI machine and saw this MRI and fell in love. Dr. Amit Khera: I'll paraphrase about staying up all night, drinking soda and coding zeros and ones since that's the technology back then, but what an amazing story. We'll have to do that for our next podcast. All right. I'm going to bring in Augie Rivera. Now, he is the managing editor of Circulation. Meaning he really keeps everything going, and is the engine and brains behind the operation. And one of the many things he does, is the podcast. And we'll talk more about the logistics of that. But Augie, people never get to hear your voice. So tell us a little bit about how you got into this medical publishing and circulation in the pacific, sort of your background. David “Augie” Rivera: Well, thanks, Amit. Also thanks to Carolyn and Greg for inviting me as well to participate. This is going to be shocking and maybe scary, but I only have a couple of years of scientific journal publishing experience, and that's with the Circulation family. My background for my entire career has been in educational school publishing, specifically in mathematics. And mainly grade K to 12 mathematics. So making the jump over to scientific publishing seemed a bit daunting, but after like 20 plus years, I was looking to do something else. And I was grateful that I saw something on LinkedIn. I interviewed for the position and I was very fortunate the American Heart Association that ended up hiring me. In a sense I always say, "Taking a chance on the long shot." And so that's what brought me here. So a lot of this has been very, very new to me, but at the same time, all the Circulation editors have been so helpful, as well as my staff that I work with. They've been so beneficial to me in learning the side effects. So, that's a little bit about me. Dr. Amit Khera: We're very glad that the DHA found you, Augie, and you've been obviously this incredible resource for us. I'm glad you brought up the staff because there's so many people on Circulation that make it run and we're very grateful for all their efforts, including those who help us put on this podcast. Well, I want to dig into the podcast. Carolyn, we haven't told the story in a long, long time. I think you told it on the very first podcast, but Circulation on the Run. For those that missed in earlier days, remind us how you came up with that name. Dr. Carolyn Lam: Okay, very quickly. I'm a runner, and I know a lot of us are. It's just on one of my runs that I realized, "My goodness, wouldn't it be great to be able to just feed my mind at the time?" I was on a treadmill actually, and I was trying to read, and it occurred to me, "It is impossible. I'm getting a serious headache to try to read while you're trying to run." And so I thought, "Wow, wouldn't it be great if somebody just read that to me, so I could just read the journal while I was running?" Yeah, you can join the dots. So that was exactly the idea. That, "No, I'll do that for someone. I'll give them the nuts and bolts of that issue." Dr. Carolyn Lam: At least the main papers. The way it's grown since then, it's frankly thanks to Greg. I need to make a plug here. Greg has admitted that he's humble. And in fact, that's why I need to drag this out of him. I did not realize until I interviewed him on one of the podcasts, that he is totally gifted at interviewing. And then he tells me just, by the way, in the usual Greg way, he has a history and thick experience in this. He had done the interviews like... Greg, you have to tell me, but he had done several of these. He had a show, he had ideas. He used to do it. And I was like, "Why are you hiding all this? You got to come do this with me." But he hides it. So Greg, now you have to fess up. Dr. Greg Hundley: Oh gosh. And now Carolyn, she's too kind. So Carolyn, listeners as you can tell, just has a very warm, inviting personality. And she so couples that with just brilliance and interest in science. I mean, I can't take credit for the things, but she's also open to listening. And I think one of the really exciting things, this sort of team of three with Augie and Carolyn, we have great discussions behind the scenes on how we can bring the information in the journal to you as listeners, in a way that is inviting, engaging, and educational. It's really being part of a team, that has that common goal in mind and in thought. Carolyn and Augie, I just treasure the opportunities that we get to work together every several weeks and putting together the most exciting science that our journal really brings forth. So it's a team effort for the listeners. And just to maybe anticipate the next question, how do we do that? Dr. Greg Hundley: We do get the joy of reading the journal every week, and we spend some time each of us, on our weekends and late at nights reading thoroughly the journal. And Carolyn and I kind of divide up the articles. Both of us taking and becoming enthralled with areas of expertise that we may have. Again, we've talked about Carolyn in heart failure expertise and maybe me a little bit more on the imaging side and cardio oncology and the like. And then in any way we divide up the articles, we read them thoroughly, and then we produce a script. So one of the fun parts of this is working with Augie. We're producers as well as editors, as well as the spokespersons. Dr. Greg Hundley: So it's kind of all done in one shop and put together, and interactive, if you will. And then we are able to record that in sessions with Augie, coordinating them, and involving some of our authors, editorial experts. And then other experts that we gather from around the world that are also involved in the science. And the goal is to create discussions in addition to presenting the information that's in the journal, but to create meaningful, thoughtful discussions regarding this impactful science, so that we can actually take it in as practitioners or other researchers and scientists in the field quickly. And that's sort of the general concept. Dr. Amit Khera: You jumped right in there, Greg. And that's exactly what we want to dive into, which is sort of the behind the scenes, the mechanics about the why. Now, you two have an incredible chemistry. I will say since you two have been doing this together, it's really been a joy listening to you two. Carolyn, just maybe the dovetail on what Greg just talked about, about sort of the chemistry. That back and forth that you two do, the preparation behind that. Tell us a little bit about how that works out. Dr. Greg Hundley: Oh, absolutely. I've been dying to share. You should hear the bloopers. It's hilarious. So after a while, we just totally like... We have the fun doing this. And we realize it's very serious science that we're talking about. We're so solidly proud of circulation, but it's okay to have fun. It's okay by the way, to mispronounce some of these basic science words and to call Joe Hill, which I've done by the way, literally called him to ask him how to pronounce certain things. And you know what? And have fun at the same time. And so Greg starts these quizzes. Now, that is all Greg, okay. This Carolyn quizzes and... So after a while, we started to try to hide little quizzes inside our script with the answers given just in case. But it sometimes catches us unaware, and it's just really hilarious. Dr. Greg Hundley: And once or twice, I think Greg and I have tried to quiz Augie as well. But Augie never allows us to do that. So it's really great when we're having fun. And that is exactly what I'm so grateful for Greg to showing me that. He's the one who had the experience with the back and forth and gave us the idea. He's the one who push to say, "Look beyond the original articles, I really like as a listener, to have an overview of every single article." That was Greg. He's the one who initiated the sort of forum type discussions and double bill discussions, because he got feedback and acted on it, that people really, really enjoy listening to the authors too. And finally, we're really trying to make it even more useful for the audience based on feedback by seeing if we can get CME accreditation, seeing if we can be more responsive. I just want to let people know, even if we don't manage to achieve it, that we're listening, and we're trying, and we're constantly trying to improve. And that's what I really, really thank both Greg and Augie for. Dr. Amit Khera: Thanks for that. Listen, I want to just pick up on many things that you just said. First, I think what people may not appreciate is how much work goes into this. You read all of the articles and prepare with the featured articles. You create a script, and you have fun doing it, which is the most important thing. You record and have to coordinate. Takes a lot of time. I've seen this too, then people don't realize afterwards, you listen to the entire thing and edited again. This is impressive. And it shows, because it's a fantastic product. I want to talk a little bit about some of the deeper features. So you two obviously summarized in the beginning, the original research and we talked a little bit about the back and forth. I want to talk about the featured articles and the interviews of these different folks. Tell me a little bit about that and how that goes. What do you enjoy about the interview part of that. Greg, you want to start? Dr. Greg Hundley: Well, I thoroughly enjoy what we call the feature discussions, where we bring together the authors of the paper, editorial experts that... With Circulation, there's a team of associate editors that process the papers. And actually, when you as a listener submit an article, we review these in a discussion format. And one of the associate editors is leading that through a discussion group. And so we bring in that expert. And then oftentimes, we have an editorialist, or an expert from the world, and bringing together a discussion and focusing on the content, not only in that article, but how that article pertains to the world's literature, and then where we really want to go next with research. Dr. Greg Hundley: And I think that's sort of our objective, is to bring a living discussion for us as listeners, with authors, the active researchers, with the editorial team and the experts. Why of all the papers you get did this impactful science really come to the forefront for you? And then from the editorialists, how do we take this information and put it in the context of the world's research that's going on in cardiovascular medicine? So those are sort of the main insights and as listeners, just as Carolyn said, we really enjoy receiving feedback from you, and how we can perfect that further. One of the things we've started thinking about is, if we have a basic paper and a clinical paper on the same topic, is really having even a broader discussion, a forum discussion, where we talk about several papers at one time and really embrace a topic. And I love what Carolyn said about providing not only continuing medical education credits, but for those in the United States or maybe North America in particular, maintenance of certification credit, and something we're actively looking at, trying to work through right now. Dr. Amit Khera: Thank you for that. And Carolyn, do an add to the features and the interviewing these folks and some of the... what it is that's most interesting to you in doing that process and what you've learned. Dr. Carolyn Lam: Yeah. I certainly want to add, but probably in an angle you would not expect. And here, I really, really want to point out the tremendous work of coordinating this, that Augie takes care of. It is incredible. When we have an editor in Europe, a author in California, a me in Singapore, himself in another part of the US. I do not know how Augie does it. And not only does he do it super well, it's always with a smile. Augie, you truly are amazing. Your positivity has honestly kept me going many times, when I just came on the recording half dead. Kudos to you, truly. Dr. Amit Khera: Thank you, Carolyn, because I wanted to bring in Augie back again now. Augie, it must be amazing for you. I mean, first, the logistics. Maybe you can tell us about coordinating people from all over the world, different time zones, every single week and obviously people that are quite busy and show what a hard thing to do. And then maybe seeing the process. Boy, from seeing these papers come through our meeting, to the selection, to coordinating, to seeing the final product at the end, it must be a pretty satisfying process for you. Tell us a little bit about the mechanics and what this is from your vantage point. David “Augie” Rivera: Well, indeed, it is very interesting. It's something that I did a little bit of production back in college when I did college radio, way back in the day, but I never do. I would end up doing this again, but I think as far as the logistics are concerned, I'm not by myself in this at all. I mean, a big shout out to Sarah O'Brien who trained me when I took on this job because she was covering Circulation on the Run while there was a search for a managing editor. So she was the one who taught me all the tricks of the trade, on how to make some of this happen. But also it's the two assistants for Carolyn and Greg, Afshaan and Angela, who I contact and I go, "Please let me know what their availability is, when, and what can we fit here? And what can we fit there? And can we try to move a meeting?" David “Augie” Rivera: In fact, I get to tell Greg that we were successful in moving a meeting for tomorrow, and we have another one scheduled. So we made it work. So really Afshaan and Angela really help out with those logistics as well. We also have to thank you Ishara and her team over at Learner's Digest. They're the masters who put together all of our raw audio files, and cut them all together, to make the final product of the podcast. And not only does her team do that flawlessly, but it also coordinates with having those reviewed and approved by the editors as well. So there is no way that we would ever be able to get any of our podcasts out and delivered without their awesome help and support. So a big shout out to Ishara and team. And most importantly, and the viewers can't see this, but also to the authors and associate editors, editorialists. Augie Rivera: First of all, we're grateful that they've sent and submitted their articles to circulation for peer review, and then eventual publication, but their flexibility, because I know that they are very busy during their time too, and trying to make things work. I have had an author say, "Oh yeah, 12:30 in the morning, past midnight? Oh totally. I can totally do that. No problem." Or an associate editor who says, "Yeah, I can probably do that for 5:00 AM in the morning." So the flexibility of the authors, the editorialists and the associate editors is also what makes the logistics and everything work out. So it's not me, but it's completely a team effort. And it's also thanks to Carolyn and Greg for finding those pockets of time while they're doing their day job, to also take the time to be prepped and interview our authors and editorialists. So on that end, like I said, it's not me, it's a team of all of us that put this together. Dr. Amit Khera: Well, I appreciate everyone's humility, including yours, Augie. And you are right, there's a broader team and I appreciate you calling them out, but we certainly acknowledge you're at the center of that, and appreciate all your work to make this come to fruition. Well, we're winding down. I have maybe one last question for you two, Carolyn and Greg. Tell us about the future of Circulation on the Run. Where do we go from here? What's the future of this specifically? Or maybe podcasting and Circulation in general. Dr. Carolyn Lam: Well, what I can say is, it is continuously going to improve. You've heard us commit to that. We will and promise to try to make it as short and snappy as we can. So for those of you listening, who kind of don't get to the end, please hang in there with us. We're continuously getting better. Dr. Greg Hundley: Yeah. I would just want to echo that. If listeners have suggestions and there's a pathway to gather that information from you, we are all ears. We're listeners, and we would love to shape and mold this further based on your suggestions, because really, your suggestions have shaped a lot of where we are today. Dr. Carolyn Lam: And Amit, if I could, because the podcast is only one cog in the whole wheel of what you do as overall strategy for us, digital strategy. Could I ask you to give us that last word? I have to be the interviewer again. Dr. Amit Khera: You can't get it out of your system. This one is not about me. I'll give two seconds on my role specifically, but I have a neat role. We purposefully chose the term, digital strategies, because we appreciate there's so many different things behind getting medical literature out there, including website, working with traditional media, social media, podcast, and whatever else comes in the future. Dr. Amit Khera: So I'm very lucky because I get to work with you all plus a ton of other folks to really bring this material to life. And the coolest part is, you all are so easy to work with and so creative, and have done so many amazing things with this podcast. And it's been real privilege just to watch this grow and develop. What I love that you both said, and I hope the listeners heard this, that have hung on with this, you're appreciated for feedback and you always have been. Have made tweaks along the way to make this better and better. And so if anybody has any, feel free to email any one of us, and we welcome that feedback to make this even better. Listen, I want to say what a treat this has been to interview the interviewers. Amazing, and certainly did not disappoint learning about your backgrounds and a little bit more about all of you, and about what makes Circulation on the Run come to life. Dr. Amit Khera: So that's it. There's another rap. I'm Amit Khera, stepping in and interviewing Carolyn Lam and Greg Hundley, who will join you again next week. Thank you. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

Had to do an episode sort of on the fly this week. So Greg and I pulled out our bag of tricks and decided to do a show on euphemisms, mostly ones we don't like and why you shouldn't use them, unless in some cases you're part of the disabled community. Like us on Facebook: https://www.facebook.com/We.R.In.Pod Follow us on Twitter: https://twitter.com/We_R_In_Pod Join us on Discord: https://discord.gg/Sag7UCyfxJ Credit to Blues Traveler for "Go Outside and Drive" in the intro

When you're pitching your startup you have one shot to get the attention of people who listen to pitches every, single day. These people finely-tuned machines, and they can detect greatness, weakness, flaws & bulls#!+ in an instant. Greg White has been there – and done it, and he's discovered the secrets to this finely honed craft. So Greg shares what you need to do to get the attention of the people that can provide you the funds to make YOUR dream a reality, and so you can project your startup's value without sounding like an infomercial So, Listen UP! It's competitive out there. There are a lot of startups, so you need to know how to effectively pitch. In this episode, you'll not only know the 7 elements required to construct a pitch that tells your story in just 3 minutes, but you'll also learn a bit about the complex psyche of venture capitalists, and what they're looking for when they sit down to evaluate your life's dream in soundbites. Plus, Greg tells you why you should never try to bullshit a venture capitalist & what happens if you do. Additional Links & Resouces: Learn more about TECHquila Sunrise: https://supplychainnow.com/program/techquila-sunrise/ Subscribe to TECHquila Sunrise and all other Supply Chain Now programs: https://supplychainnow.com/subscribe This episode was hosted by Greg White. For additional information, please visit our dedicated show page at: https://supplychainnow.com/techquila-sunrise-41. FXe5QxovSmNZgKfujeJA

Haim are today’s judges in our search for Radio 1’s funniest listener and Spanner treats them to a live, on air milking. Also, we create a Radio 1 monster from listeners with “body part” names and Helen (due to lockdown) has never met her work colleagues. So Greg plays a game of Taller or Smaller with them.

So Greg and Val planned to go take photo's, Greg buddy calls and he decides to meet up with him, forgetting he already told Val they could go....

Electricity and trees seldom mix. But that doesn't mean they can't be good neighbors. Across the city of Ottawa, there are an estimated 185,000 trees in proximity to Hydro Ottawa's 2,800 kilometers of overhead high-voltage power lines. The lines run to all neighborhoods bringing electricity to over 340,000 homes and businesses. As a utility, the goal is to balance power supply reliability with environmental concerns, such as respecting the natural beauty of our community’s tree canopy. In this episode, Nick Levac, Supervisor of Distribution Operations at Hydro Ottawa, and Greg Tipman, Forestry Inspector at Hydro Ottawa, share all about their efforts in striking this balance. Related Content & Links: Hydro Ottawa Tree Planting Advice [PDF]: https://static.hydroottawa.com/documents/publications/safety/tree_planting_advice-EN.pdf Greg Tipman’s favourite trees: Eastern white pine - https://www.ontario.ca/page/eastern-white-pine  The monkey puzzle tree - https://en.wikipedia.org/wiki/Araucaria_araucana  Giant Sequoia - https://en.wikipedia.org/wiki/Sequoiadendron_giganteum  Charlie Brown Christmas tree - https://en.wiktionary.org/wiki/Charlie_Brown_tree Transcript: Dan Seguin  00:42 Hey, everyone, welcome back. This is the ThinkEnergy podcast. Dr. Thomas Fuller said it best, "He that plants trees loves others besides himself." And that dates back to 1732. Now let's fast forward to today. Based on aerial imagery and laser sensory technology, the National Capital Commission reported in a recent study that nearly half of the National Capital Region is under the cover of trees: 46% to be precise. Given Dr. Fuller's memorable quote, it looks like Ottawa-Gatineau has a lot of love for its residents. And if you know anything about electricity, you know that electricity and trees seldom mix. But that doesn't mean they can't be good neighbors. Across the city of Ottawa, there are an estimate of 185,000 trees in proximity to Hydro Ottawa's has 2800 kilometers of overhead high-voltage power lines. The lines run to all neighborhoods bringing electricity to over 340,000 homes and businesses. As a utility, the goal is always to balance reliability of the power supply with the environmental concerns such as respecting the natural beauty of your community’s tree canopy. Trees provide all sorts of environmental and energy saving benefits from absorbing CO2 to releasing oxygen back into the air, to providing shade from the sun and reducing excess heat in our home if they're planted in the right place. But, that being said, during storms, broken tree branches can bring down power lines and create serious public safety concerns like damaged equipment, fires, and power outages. Vegetation management, commonly known as tree trimming, identifies hazards and fixes them by pruning trees and redirecting growth away from power lines. All the while, making every effort to ensure trees remain healthy. Highly skilled arborists trim and cut trees near electrical equipment and wires based on tree species growth patterns, geography and line voltage. This work has resulted in reducing power outages by 40% in Ottawa. In fact, between 2019 and 2020, tree contact with power lines was the cause of only 7% of all outages. This is in large part thanks to the preventive measures that utilities like Hydro Ottawa take all year long, with the extreme weather events we've witnessed in the past years, and as climate continues to change, the outcomes will create more problems for utilities to provide reliable power to customers without extended outages. So here's today's big question: In the age of climate change and environmental responsibility, how can utility companies strike a balance between maintaining reliable service, minimizing outages and maintaining a healthy and vibrant urban forest? To help us better understand this balancing act, I've invited our Supervisor of Distribution Operations at Hydro Ottawa Nick Levac and one of the Forestry inspectors, Greg Tipman. Welcome to you both. Greg, I'll start with you. Can you tell us a bit about your work and what the biggest misconceptions are about tree trimming and vegetation control programs when it comes to electricity?   Greg Tipman  05:06 For sure, Dan, and just again, thanks for having us on your podcast this morning. It's getting kind of meat potatoes, you know, my daily job encompasses speaking with customers, addressing the vegetation concerns around power lines, auditing of the contractor we use, which is Asplundh Tree Service. There's also coordinating of our jobs, our time and material jobs. So it's stuff that I look at and deal with the customer and then gets delegated directly to a secondary crew to do that specific work for the customer. There's also writing of prescriptions for any work for other jobs for the customers. So specific work they want Hydro Ottawa to do that's outside of our regular trim program. Some of the biggest misconceptions that I've run into is that a lot of the public thinks that our tree work is just a hack and slash that there's no thought or science put into the tree trimming that's actually going on, when in actuality, we have a whole set of standards for proper pruning, and tree trimming of the species around the Hydro wires. And that kicks back to our working procedures or our lifeline clearing techniques. And then there's another misconception that I've run into quite a bit: a lot of people think that for us, or for our contractor to do the tree trimming, the power has to be shut off every single time. And that's, that's not the case. We like to keep it as a very rare scenario when we do have to shut the power off. And that's usually just for a safety issue for the for the tree trimmers.   Dan Seguin  06:56 Okay, Nick, we often say that trees and electrical wires don't mix. What types of dangerous situations can occur if they come into contact with one another? Is there maybe a recent example you can share with us?   Nick Levac  07:14 Yeah, so I mean, first in mine is obviously power outages. That's kind of the first thing that we hear about when a tree comes down on our conductors. But, you know, the power outages can vary from a whole circuit right back to a substation to just a localized outage in your community or along your streets. The other thing, if the tree does come down on the line, and our in our system doesn't experience an outage, oftentimes trees can catch on fire. So we've had, we've had examples over the years where a tree is rested on a line, nobody notices it, and then eventually, it'll catch on fire, which, which obviously can cause other issues. And especially in the summertime with dry conditions. If that does come down to the ground, I could, you know, start forest fires, which, unfortunately, our neighbors in the south of us have experienced down in California and stuff, but there was one larger outage. And I think it was a start in November, November 2, where a spruce tree that was quite a bit away from the line did fail, and it came down and took down two conductors out at the end of my road, I believe it was and it caused a large outage. In a sense, those are almost better to have because it's easier to find that tree and where the problem is, and we can get crews out to fix it in a quick manner. But that's probably the most recent one that we found that had a major outage and a big impact on system.   Dan Seguin  08:49 So we're clear, Nick, what are the guidelines that determine if tree trimming or vegetation management near power lines is required? What does sufficient clearance from electrical equipment look like?   Nick Levac  09:06 Yeah, so like Greg mentioned in the first question there, we have our arbors going through our system, and we're looking at standards that we trim to the city is divided up into about 30 vegetation management zones. And they're divided into either a two or three year trim cycle, which means you'll see arborist in your backyard or on the streets, trimming out to our guidelines, either every second year or third year. Our main goal, there's a couple of them. But our main goal when we're trimming to our standards that we have is when we come back and either two or three years, the vegetation that we trimmed out is still three feet away. There's different zones that we have from 10 feet back to the conductor or the live overhead wire, and from the wire out to three feet is called the restricted zone. And as I mentioned that that's where we do not want the vegetation to get into. Because if we, if it does get in there creates a bunch of different problems for our, for our tree arborist to go in there. And as Greg mentioned, outages is the last thing we want to do when we're trimming trees. And if that vegetation does get into that restricted zone, increased outages for trimming, there is an option that we have to look at which we're trying to avoid. So that's, that's kind of our main goal. We look at the species of tree and how much it would grow in a year. And as the arborist comes through, they're going to trim back that many feet. So if we have a fast growing species that grow, say, three or four feet a year, and we're going to be back in two years, we're going to trim that back three feet times two, plus the additional three feet. So we're looking at about a 10 foot trim on that.   Dan Seguin  10:49 Nick, pruning, and especially removal of interfering trees, often causes controversy. In an age of climate change and environmental responsibility, what do you tell folks that object to or have concerns about the important work you do to help keep the lights on and the trees safe?   Nick Levac  11:15 Yeah, that's a great question. We, you know, I think you hit the last word there. And your question kind of hits on our main goal of everything that we do here at hydro is safety. So not only we're looking out for the public safety, ensuring that trees aren't coming down on the line and staying energized. But we're also looking to know for worker safety. So as we're going through, we try to do preventative maintenance, so to speak. So very much like you get your oil change in a car, or you put your winter tires on this time of year, we're trying to trim trees away from the lines to make sure they don't come in contact that avoids outages, unplanned outages, especially because, you know, it's one thing to get a phone call to say, Hey, your power is going to be out because we're doing preventative maintenance, whether it's tree trimming, or upgrading electrical system, it's another thing to wake up at two o'clock in the morning, after lights out, heat off and everything and it's unexpected, and you're trying to get ready, your kids are at home or whatever. So preventative maintenance is the big thing. And we try to educate our customers that what we're doing out there is really just to make sure that we can decrease outages and especially those unplanned outages. The other thing that we look at when we're pruning trees is the tree health. And I know Greg's going to get into this I think a little bit later on. But just looking at the species a tree and how we trimmed them to make sure that the health of the tree is also a huge interest for our arborists that are up there. They're all certified trained arborist with some extra training on the electrical side, because obviously we're turning around live electrical lines. But when they get up into a tree, they're looking at the health of the tree. There's a lot of stuff once they get up into the canopy of the tree that they notice that you can't see from the ground. So they're taking into account and they're taking out any deadwood or anything in there and tried to not only like I mentioned before getting those clearances that we need for the electrical side, but also trying to enhance the tree growth away from our lines and looking at the health of the tree by taking the deadwood or anything out of it.   Dan Seguin  13:16 Okay, so back to you, Greg. I know you trim trees on public property that are within three meters of an overhead line. But what about on a private property? Trees near utility lines inherently carry serious risk to property owners who may be injured or killed when working on trees near power lines. What are homeowners responsible for? And when should they call us, the utility, to arrange for their help? Like a planned outage? Basically, what do homeowners need to know?   Greg Tipman  13:57 Yeah, Dan. So when you're speaking about kind of responsibilities on vegetation maintenance, Hydro Ottawa was responsible for the pole, the pole wire, and vegetation maintenance. The area around the high voltage wire that hydro trims as part of our responsibility is 10 feet from the primary which is usually the very top wire running pole, as well as about a three foot clearance around our low voltage or secondary wires. And again, that's the pole the pole wires just want to make that a bold statement. That's Hydro's responsibility as part of our maintenance package. Kind of like Nick was touching up on and that's that that happens, pending what grid what year, you know, two to three years central, within kind of the city core versus the outer rural areas. If a customer is looking to have work done on their tree which is growing out into their private property, and it's near our overhead wires, Hydro comes in free of charge, we get it clear 10 feet 10 feet back debris would stay on site. And then it would be the homeowners responsibility to either cut the tree down themselves hire private tree contractor, or if they wanted, they could also hire Hydro Ottawa, do our work for others program, and we would write them out a formal tree quote. And they would, they would pay an additional cost for that, that work that's outside of our regular maintenance scope. Now in regards to the wires running pole to house service wire, or if you're in a rural area, and it's a private primary wire, there's a couple options that they have for having those what those wires that vegetation trimmed out, they can either hire a private tree contractor, and Hydro Ottawa, or service department provides one free disconnect a year for any tree work. Little bit more legwork for the customer or the contractor to do, but it's an entirely viable option. The second option is they can again hire Hydro, to trim out their service wire to whatever specs we normally recommend it you know, it's a low voltage secondary wire to have about a three foot clearance on it, they want us to go with that option. I would write them out a formal tree quote, have all the details, proof of payment beforehand would be had. And then we would schedule in the customer an exact date. And they would essentially have the work done to what the quote was that they're paying for the work to be done and, and go from there. It's quite effective. We've gotten a lot of feedback from the customers about having their service wire trimmed down. And there's been a lot of good things to have come from having us on site. And just doing it all and not having to worry with them having to organize an outage on their house. So it's, it's been a good go.   Dan Seguin  17:03 Here's another one for you, Greg, went planting a young sapling, it's often difficult to imagine that in as few as 10 years, it could have a significant impact on the landscape with an expanding canopy as a homeowner or a landscaper. If you're planting a new tree, how important is it to contact your utility service provider? To discuss your plan? Do you have any tree planting advice? Or some good resources on what to plant? And where?   Greg Tipman  17:40 Yes, yes. So basically, Hydro Ottawa has a really good source on our internet page. Basically, just type in Google Hydro Ottawa Tree Planting Advice, and it's a pamphlet that's been put on to the internet and it has everything for suggestions of where the tree should be planted, what type of species is it? How tall? Will it grow? How wide will the canopy grow? How many feet back from an overhead wire should be planted? It has a breakdown of you know, species names, what soils are best to be planted in? You know, like I said, their typical growth structure in relation to overhead wires. And there's also advice given on planting around underground wires, which a lot of people you know, you don't see them, you don't really think they're there. But they are, you know, most people just see the, you know, the green box, the ground transformer, if you will, but where are the wires going? Which, which way Can I can I plant and whatnot. So it's a really great resource has a lot of information, a lot of diagrams. Definitely check it out. And then another great option would be just put a call in, have myself or Nick show up. And, you know, we can tell you, you know, basically where, what, what's the lay of the land? What is your yard showing you? You know, are there other trees in the neighborhood or in your yard, you can get a very good look just from seeing what's out there, what to expect. And then and then go from there.   Dan Seguin  19:29 Okay, we'll actually have for our listeners in the show notes. We'll have links to all of these publications and the actual section on the website. So definitely we'll drive traffic there. Because the last thing I think we want is for me to put your extension number, your mobile number and have 100 calls tomorrow.   Greg Tipman  19:51 There we go. I like push it all in there.   Dan Seguin  19:56 Okay, Nick. This next question might be in your wheelhouse. A power outage occurs when there's a direct contact between two conducting lines with face to face. Or by providing a path for electricity to travel to the ground. There are several other ways that vegetation, trees in particular, can cause power outages, wondering if you could expand on those causes and how utilities and folks in your profession mitigate that?   Nick Levac  20:35 Yeah, it's an interesting question. It's obviously something we look at all the time. And that's our biggest goal within our department is to mitigate those outages. And I actually came from a background in the lines department as a power line maintainer for 10 years and swung over and got into working with the veg. management program. And, you know, I'd say it's a really good partnership that we have right now, not only with, with Greg and our other utility forestry inspectors, but along with our contractor Asplund who's doing the work for us. And, you know, that's a constant conversation that we're having weekend week out. And not only are we reviewing any outages that might have occurred the week before and trying to follow up on those to see why those power outages occurred and how we can hopefully prevent them from reoccurring. But within the system itself, the electrical system, we have, it's very much like your house where it's set up where we have different circuits all the way through the city. And within each circuit, we have different fusing, the further you get away from the substation. So the fuse in coordination can really help out if you have a tree that falls at the very end of that circuit, we have the fusion set up in a way that it's only going to go back to the next device downstream. And if everything is working properly, that fuse will open up and it'll really shrink the size of that outage rather than going all the way back to the substation. So if you can imagine if you have 1000 customers on a circuit, and you have 10, different fuses all the way down, and that last one blows, you're going away affect 100 people instead of 1000 people. Also, within our system, we have devices called reclosers. So I'm sure many listeners have had their lights flicker on and off two or three times. And then unfortunately, after that third flicker, the power does stay off permanently. That means that there's a bigger issue on the line and that reclosure could self-clear. So those devices are there. For momentary outages, when they see a spike in amperage, they'll open up the circuit and give time for that tree or whatever that foreign interference is to clear itself. And then close back in with the hopes that once it closes back in that power will stay on. If it senses that it's still there, it'll open back up again. Hopefully allow it to clear a little bit longer closed back in again. And hopefully the second time's a charm. Unfortunately, sometimes that doesn't work. And then you experienced that outage, kind of the last kind of protection in the whole stream of protection devices is that circuit breaker back at the station. That's kind of the worst case if we see a circuit open up. That means that there's a major problem. Usually, like you mentioned there, there's a phase two phase kind of issue where two conductors have slapped together. And that's kind of what causes the biggest outage, that's when we know we have a large problem. And the other issue with that is because our circuits are so long, some of them you know, in the downtown core where we have more substations, it's a little bit easier to find because you know, the circuit might only be say a kilometer or two long, but if you get out into the rural Orleans, Kanata, down south - though, manotick, nepean area, you can have, you know, 10-15-20 kilometers a line. So, if your circuit breaker and your station opens up, that means that somewhere between your station and the end of the line is your problem. So there are fault indicators and stuff on your line that can help pinpoint it. But it definitely can make it more challenging when you're when you're starting back at your substation not having to patrol 20 kilometers a line versus if that fuse opens at the very end of your line, you know, okay, it's the last section within that line. The other thing that can really help us out is the customers in the field. So a lot of times we'll get calls in and it's great to get that information and Hydro Ottawa is very active on social media and that that definitely helps if, if a customer sees a problem if they see a line down if they see a bright blue flash if they hear a large loud bang. You know, first and foremost, let us know don't ever approach downed wires Stay away, even trees that could be leaning up against the wire. But I and I mentioned this before, just because the trees against the wire if that wire still energized that could potentially energize that trees, we want to make sure we stay back, you know. Stay back 10 meters from that tree stay back 10 meters from that electrical line because you don't know if it's on, or if it's still alive. So your safety is first and foremost, call in, call 911, if there's any, you know, immediate hazard fire, police can come in and assist, they will get a hold of our system office right away and direct us to that. Or if it's something that's, you know, a little bit less and you think that hydro should know, we have lots of different social media channels you can reach out on. And let us know. And that really does help because that information does find its way down to the crews in the fields. And it helps us get to the outage and find that problem that's causing the damage that much quicker.   Dan Seguin  25:51 Yeah, for sure. I know, historically, we've had customers actually send us photos on Twitter. Yeah, that we could actually send systems office so they can actually identify, they would know exactly where that is. And they helped out the guys on like the field workers.   Nick Levac  26:06 Yeah, no, that's, that's great. And I mean, I was, I was on that first response truck there 24/7crew for multiple years. And it was great. I mean, you know, when the days are getting darker and the nights it's in the middle of night, the last thing you want to do is be trying to find, find an outage and or the cause of an outage. And it's kind of like finding a needle in a haystack sometimes out there. So anything from the customers is a great help.   Dan Seguin  26:35 Yeah, definitely. Okay, in addition to being a qualified arborist, Greg, you also have extensive knowledge about electricity. Can you talk about this dual role and special qualifications that you have? How dangerous is your job? And do you work around live electricity at high voltage?   Greg Tipman  26:59 Yeah, Dan. So just a little background on my schooling and qualifications. I did my forestry technologist diploma at Algonquin - a two year program. And then from there, I moved out to BC to work on some really big trees. And while out there, I morphed into the utility side of tree work. And that's where I went and did my apprenticeship program. From there, you need approximately 4000 hours just to qualify, the program's a two year program, you've accumulated about 6000 hours around of live line clearing, working around the wires, you'll learn how it looks just all the basics, electricity, how it works, how to identify the equipment, that coupled with your actual tree work in the tree, the tools, special tools you'll be using, so dielectrically tools, how to operate bucket trucks, so on and so forth. Rigging big chunks of wood down in trees, how to do it safely, and all the while in close proximity to these overhead high voltage wires. It's very dangerous. I mean, you couple your, you know, 30-40-50-60 feet up hanging by ropes, you're using a chainsaw to cut wood. Plus, you have a live line that's, you know, five, six feet away from you. So it's definitely very dangerous. But the schooling, the on the job training that you get just, you know, old hands, showing you the techniques, the up to date, safety standards, and whatnot. It makes your comfort level something that would never, you know, come natural to you become second nature. So it's, it's definitely a process, it's definitely building the confidence over time. And then, you know, taking classes, learning whether it's through the International Society of arboriculture on the tree side of things for tree health, you know, one of the tree species tree biology pests, you know, a lot of times customers will ask, you know, why is my tree dying? What Why is it declining? A lot of times people will think, Oh, it's Hydro Ottawa you trimmed the tree incorrectly. Well, no, it's, you know, a pest infestation or you did some landscaping or whatnot, the roots have been killed and whatnot. So it's learning all that you know, information and coupling it and pairing it with the electrical side of things that it really makes for a harmonious job and, you know, a great aspect to keep learning There's always new information, new research coming out on trees and the electrical side of things you know, and then just basically, you know, having the resources also at Hydro Ottawa, it makes that partnership that much better for getting the work done and done safely.   Dan Seguin  30:24 So Greg, I've seen some amazing footage of folks in your profession climbing pretty high in trees. So besides not having a fear of heights. What's that like? And what's your favorite thing about your job? Have you ever been surprised by some birds or squirrels? Or, you know, have they surprised you? Or have you surprised them?   Greg Tipman  30:49 Yeah, so kind of, like I was touching on there. I mean, the fear of heights is not was never really the big deal. It was more trusting your gear. Knowing that you know what a 10-12 millimeter diameter rope is going to hold you and your gear. You know, it's going to hold, you know, wood swinging around and whatnot, it's not going to break off, you know that your knots have been tied correctly, they're not going to come undone, you're going to fall to your death and get injured or whatnot. Those were kind of the first fears to really get over. But once you get that it's practice, the more you do it, the more you get comfortable doing it. The more you feel safe and secure. I've definitely had some weird, interesting animal encounters while working in the trees. I've had birds land on my head and stay there while working. I've had raccoons, you know, climb out of hollows. I've had bats, you know, fly out from underneath bark. But probably the scariest was wasn't in the tree yet. But we're doing some ground slash in BC and probably 10-12 feet away. A black bear just goes running right by and yeah, it was exhilarating. But it was done in a flash and yeah, nothing. Nothing more. But you know, it definitely, you know, could have been a different interesting situation had it been a, you know, an angry bear, if you will. Yeah, for the most part. It's the job. You get to see nature all the time. And there's always something great to see, animal wise.   Dan Seguin  32:33 Cool. Okay, both. Are you ready to tag team here and close us off with some rapid fire questions?   Greg Tipman  32:43 Definitely.   Nick Levac  32:43 Yep.   Dan Seguin  32:45 Greg, what is your favorite tree?   Greg Tipman  32:48 Can I give you four Dan?   Dan Seguin  32:51 Sure. Why not?   Greg Tipman  32:53 So Eastern white pine. The monkey puzzle tree. Giant Sequoia and the Charlie Brown Christmas tree.   Dan Seguin  33:03 Okay, that's good. Yeah, we I might ask you to provide the links. So I can direct listeners to those trees. Nick, what is one thing you can't live without?   Nick Levac  33:18 That's an easy one. It's got to be my family. My two girls at home my lovely wife and, and probably a good cup of coffee or a nice Americano in the morning just to get things going.   Dan Seguin  33:29 Cool. Greg, what habit or hobby? Have you picked up during shelter in place?   Greg Tipman  33:37 Probably flying and crashing my drone.   Dan Seguin  33:43 Okay, yeah.   Greg Tipman  33:44 A little more practice.   Dan Seguin  33:47 Yeah, more practice! Nick, if you could have one superpower, what would it be?   Nick Levac  33:56 Ah, you know what I think never to age physically. Only in wisdom. The body's getting a little bit older and every you know, every time I go out and try to play hockey or do something now I wake up a little bit sore in the morning so I could keep my physical health. Maybe back when I was in my 20s. That would be amazing.   Dan Seguin  34:17 And what about you, Greg?   Greg Tipman  34:25 Maybe just unlimited superpowers.   Dan Seguin  34:28 All of them,   Greg Tipman  34:29 All of them!   Dan Seguin  34:30 Okay. Back to you, Nick. If you could turn back time and talk to your 18 year old self. What would you tell them?   Nick Levac  34:40 You know, I'd probably try to let them in on a couple of neat, you know, world events that were going to take place between then and then when they're my age now and just make Tell him to go there. Make sure he's present and no matter what the cost is. Sometimes you only get a once in a lifetime chance to see things and make sure he gets there to experience that life live.   Dan Seguin  35:05 Okay. And lastly, this one is for both. What do you currently find most interesting in your sector? I'll start with Greg.   Greg Tipman  35:15 It's a, it's really the day to day change, there's always a different challenge that's coming up, you're always in a different location dealing with different people. So it's never, you know, a monotonous job, it's, it's always fluid, there's always something new.   Dan Seguin  35:34 Okay, what about you, Nick.   Nick Levac  35:35 I, what excites me the most coming down the pipe, I think is the technology that hopefully we're going to be exposed to, I mean, Greg mentioned, crashing his drone, but you know, just even stuff like that, and us being able to fly over our overhead lines and really take a good snapshot of what that vegetation looks like within our city. And, and what we can do to kind of have a good mix between, you know, maintaining that urban canopy in Ottawa, and then also at the same time keeping the electricity on and if we can use different types of technology that's coming down the pipe to find a balance between the two that we can get out and, and proactively trim trees because we know exactly where they are. And also keep that urban canopy for that for customers here in Ottawa. I think there's a there's an interesting mix coming down, how we can leverage that technology to our advantage.   Dan Seguin  36:27 Okay, Nick, Greg, we reached the end of another episode of The ThinkEnergy podcast. I hope you had a lot of fun. And thank you very much for joining me today. I hope you I hope you enjoyed it.   Greg Tipman  36:42 Thanks again for having us, Dan.   Nick Levac  36:44 Yes, thank you, Dan.   Dan Seguin  36:48 Thank you for joining us today. I truly hope you enjoyed this episode of The ThinkEnergy podcast. For past episodes, make sure you visit our website hydroottawa.com/podcast. Lastly, if you found value in this podcast, be sure to subscribe. Anyway, this podcast is a wrap. Cheers, everyone.  

Greg plans out an entire GDMS, and then immediately takes Patrick and Miranda long a trip way OFF THE RAILS. Listen in for talk about The Mandalorian, The Batman, a free refrigerator, and some actual wrestling with Adam Pearce. The Trios Champions of Pro Wrestling Podcasting are live as Patrick O'Dowd, Miranda Morales, and Greg DeMarco present another engaging edition of... The Greg DeMarco Show! This week's Greg DeMarco Show topics include... So Greg won a refrigerator? Why do we care?Then the NFL comes up, so get ready for that!Somehow the show goes into Sasha Banks in The Mandelorian...And then The Batman comes up!You should probably listen to Bandwagon Nerds and A Winner Is You, plus The #Miranda Show.Wrestling does come up, when they talk about "the anti-Vince promo" getting old...AND HOW GREAT IS ADAM PEARCE?!?!? Follow the Trios Champions on Social Media @WrestlngRealist@TheHashtagMiranda@ChairshotGreg@ChairshotMedia About the Chairshot Radio Network Created in 2017, the Chairshot Radio Network presents you with the best in wrestling and wrestling crossover podcasts, including POD is WAR, Chairshot Radio, The #Miranda Show, Badlands’ Wrestling Mount Rushmores, The Outsider’s Edge, DWI Podcast, Bandwagon Nerds, the Greg DeMarco Show, and more! You can find these great shows each week at theChairshot.com and through our distribution partners, including podcasting’s most popular platforms.

This week’s episode includes author Charlotte Andersson and Associate Editor Naveed Sattar as they discuss familial clustering of aortic size, aneurysms, and dissections in the community. TRANSCRIPT: Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke national University of Singapore. Dr Greg Hundley: And I'm Greg Hundley, director of the Pauley Heart Center at VCU health in Richmond, Virginia. Well, Carolyn, our feature this week has to do with aortic size, aneurysms, and predilection to dissection. But before we get to that, how about if we grab a cup of coffee and go through some of the other articles in the issue? Dr Carolyn Lam: I got my coffee, Greg, and you know what? I'm going to start with quiz for you. Dr Greg Hundley: All right. Dr Carolyn Lam:  True or false, in the setting of obesity and/or diabetes, cardiac substrate metabolism shifts towards increased fatty acid oxidation, while lipid accumulates in the heart? True or false? Of course, you're right. Oh, but there's a part two. Can you guess, by increasing fatty acid oxidation, will we induce or prevent obesity-induced lipotoxic cardiomyopathy? Dr Greg Hundley: I'm going to say, because you asked it in the way you asked it, prevent. Dr Carolyn Lam: Wow. All right. Well, the truth is we didn't really know before today's paper. The specific link between cardiac metabolism and lipotoxic cardiomyopathy was elusive and there was no specific therapy available for this condition. And these authors, Dr Rong Tian from University of Washington and colleagues, hypothesized that cardiac pathology-associated obesity would be attributable to the imbalance of fatty acid supply and oxidation. So using a diet-induced obesity model in the current study, they demonstrated that enhancing fatty acid oxidation through deletion of acetyl-CoA carboxylase 2, was sufficient to prevent obesity-induced cardiomyopathy. So, increasing cardiac fatty acid oxidation alone does not cause cardiac dysfunction, but instead protects against cardiomyopathy in chronically obese mice. The cardiac-protective effect of increasing fatty acid oxidation and obese mice is through maintenance of Parkin-mediated mitophagy, and thus preventing mitochondrial dysfunction. These findings indicate that impaired mitophagy contributes to mitochondrial dysfunction in obese mice, and that targeting the Parkin-dependent pathway is a viable therapeutic intervention for obesity-induced cardiomyopathy. Dr Greg Hundley: Very nice. Carolyn. Dr Carolyn Lam: I'm going to be greedy and go on to my next paper. So Greg, do you think cardiac regeneration is possible? Dr Greg Hundley: Well, Carolyn, I would have said, several years ago, no, but that trip that we took to China with Joe Hill and Hesham Sadek, our Associate Editor and our Chief Editor, convinced me otherwise. So I'm going to definitely answer yes on this one. Dr Carolyn Lam: Oh, Greg, you're just too smart. And speaking of China, this next paper is from there, from co-corresponding authors, Dr Nie and Hu, from Fuwai Hospital National Center for Cardiovascular Disease and Chinese Academy of Medical Sciences and Peking Union Medical College. So, using seven genetic mouse lines, they identify that Oncostatin M is the top upregulated cytokine during neonatal heart regeneration. Oncostatin M is a pleiotropic secretory protein that belongs to the interleukin 6 family, and associates with the pathological process of dilated cardiomyopathy. And these authors found that macrophages promote heart regeneration by secreting Oncostatin M, which promotes cardiomyocyte proliferation via a co-receptor, gp130. Employing RNA-seq and functional screening, they further found that Src-mediated gp130 triggered cardiomyocyte proliferation by activating the downstream signaling pathway involving Yap, with Y357 phosphorylation independent of the Hippo pathway. So the last thing that they did was show that gene therapy with adenovirus-associated virus and coding this activated gp130 improved heart regeneration and pumping function, thus serving as a potential therapeutic target. An amazing paper. Dr Greg Hundley: Very nice, Carolyn. What a great summary and so much detail. Well, Carolyn, I'm going to turn our attention to catecholaminergic polymorphic ventricular tachycardia. And this article comes to us from Dr Jason Roberts, from the Western University. Carolyn, genetic variants in calsequestrin 2 can cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia, though isolated reports have identified arrhythmogenic phenotypes among heterozygotes. So in this study, a total of 112 individuals, including 36 catecholaminergic polymorphic ventricular tachycardia probands, 24 were homozygotes for compound heterozygotes, and 12 were pure heterozygotes, against 76 family members possessing at least one presumed pathogenic calsequestrin 2 variant. These were all identified. Dr Carolyn Lam: Wow, a very precious cohort. So what did they find, Greg? Dr Greg Hundley: This international multicenter study of calsequestrin 2 catecholaminergic polymorphic ventricular tachycardia really redefined its heritability and confirmed that pathogenic heterozygous calsequestrin 2 variants may manifest with a catecholaminergic polymorphic ventricular tachycardia phenotype, indicating a need to clinically screen these individuals. Among individuals heterozygous for a pathogenic calsequestrin 2 rare variant, medical therapy and exercise restriction are likely not necessary in the absence of the catecholaminergic polymorphic ventricular tachycardia phenotype. Though, you have to be certain over time, an intermittent clinical screening to ensure they remain phenotype-negative should be obtained. Dr Carolyn Lam: Wow, Greg, clinically important study there. Well, I'm going to go back to the basic science world and talk about calcineurin. Now, calcineurin has long been implicated in the induction of pathological cardiac remodeling but has not been therapeutically targetable for the prevention of heart failure because of its pleiotropy and our lack of understanding of its specific protein-protein interactions and compartmentation within the cardiomyocyte. Dr Greg Hundley: Okay. Carolyn, do you want me to give background on calcineurin? Dr Carolyn Lam: No, Greg, you're off the hook. I'm going to give you some background on calcineurin. So, calcineurin is the calcium-calmodulin-dependent phosphatase that exists as a heterodimer, consisting of a catalytic subunit and a regulatory subunit. Now, of the three catalytic subunit isoforms, alpha, beta, gamma, it's the beta isoform that appears to be the most important for the development of cardiac hypertrophy. Binding of calcium to the calcineurin regulatory subunit enables binding of the calcium-calmodulin complex, thereby releasing auto-inhibition and freeing the enzyme to dephosphorylate downstream substrates. That's the background. Now, in today's issue, we have this great paper from co-corresponding authors, Dr Kapiloff from Stanford University, and Dr Nikolaev from University Medical Center Hamburg. And, with their colleagues, they described the discovery of a calcineurin catalytic subunit beta binding protein Cdc42-interacting proteins 4, and I'm going to call that CIP4, which functions as a scaffold to sequester the pool of calcineurin near the sarcolemma of cardiomyocytes, where it regulates pro-hypertrophic signaling. These findings have really important implications for understanding how cardiac calcineurin is selectively activated by stress signals, as opposed to the pleiotropic second messenger, calcium, that really floods the cardiomyocytes during each contractile cycle. Furthermore, the data provide proof of concept for an innovative therapeutic approach, whereby CIP4-anchoring activity is selectively inhibited to block the action of a small pathogenic pool of calcineurin as a means of treating heart failure. How about that? This is really discussed in an elegant editorial by doctors, Woulfe, Travers, and McKinsey. Dr Greg Hundley: Very interesting, Carolyn. Sounds like another possibility for treating and managing heart failure. Well, let me share with you some of the other findings in our mailbag this week. First, I've got, from Professor Lang Li and Stephen Wiviott, they swap research correspondence regarding the prior publication entitled, Effect of Dapagliflozin on Atrial Fibrillation in Patients with Type 2 Diabetes Mellitus, Insights from the DECLARE-TIMI 58 Trial. And then Professor Laszlo Littmann has a nice ECG challenge for us related to a high-risk ECG that exposed some downstream worrisome vital signs. Dr Carolyn Lam: In addition, there's a perspective piece by Dr Nambi discussing the fact that a zero-calcium score is desirable, but isn't enough to defer therapy, given that up to one-third of events will occur in this group. There's also an In Depth paper by Dr Borlaug, entitled, “Altered Hemodynamics and End Organ Damage in Heart Failure, The Impact on the Lung and Kidney,” and oh boy, this one is so beautifully illustrated. Just a must read for the understanding of the hemodynamics in the lung and kidney and heart failure. Next is a research letter by Dr Loeys on enrichment of rare variants in the Loeys-Dietz syndrome genes in spontaneous coronary artery dissection, and not in severe fibromuscular dysplasia. And finally, another research letter by Dr Arora on racial differences in serial NT-proBNP levels in heart failure management with insights from the GUIDE-IT Trial. What a rich issue, but let's move on to our future discussion, shall we? Dr Greg Hundley: You bet, Carolyn. Well, listeners, we're now getting to our feature discussion and it's very interesting this week where we're going to evaluate aortic aneurysms. And we have with us one of the lead authors of this paper, Dr Charlotte Andersson from Boston Medical Center, and our own Associate Editor, Naveed Sattar from Glasgow, Scotland. Charlotte, welcome to our feature discussion. Could you tell us a little bit about the background and the hypothesis that you put forward with this study? Dr Charlotte Andersson: The background for this study was based on clinical work and what we observed in clinic. We had a few patients where we had been stricken by the fact that they came in with an acute aortic syndrome and they had a first-degree relative themself with the condition, but they did not look syndromic at all. And we started to wonder, what is the actual risk in the community, in people without obvious syndromic features of suffering from an aortic event itself. And although there are quite a few studies out there that have, to some degree, focused on the familial clustering of aortopathies, there is not a lot of information based on communities and whole entire populations. So we wanted to, frankly, estimate what is the incidence rates of aortic dissections and aortic aneurism in the community if you have a first-degree relative that has suffered from the disease themselves. Dr Greg Hundley: How you organize your study and what was your population and what was your design? Dr Charlotte Andersson: This study was actually based on two independent samples. First, we used the Framingham Heart study population that is very densely phenotypes over many years of spanning three generations of participants, where we looked at people who had at least one parent who had an aortic size in the upper quartile index to body-surface area and adjusted for age and sex. And we saw what's the risk of you, as a child, having an aortic size in the same upper quartile. And second, we looked in the general Danish population, the Danish healthcare system is, as you probably know, governmental funded and we have very good registries of all hospitalizations, all outpatient visits, and so we were able to link more hard clinical events in people with and without a first-degree relative. What we did was we started time when people had an aortic dissection, we identified all the first-degree relatives in these people, and we matched them with up to 10 sex and age match controls from the general population without a first-degree relative with the disease. Dr Greg Hundley: What did you find? Dr Charlotte Andersson: We found that in the Framingham sample, if you had at least one parent who belongs into the upper quartile of aortic size, you had an odds ratio of two to three, adjusted for various clinical risk factors, such as hypertension and smoking yourself. And in Danish population, we found that if you had a first-degree relative with an aortopathy, the hazard rates for you developing the disease yourself was almost a tenfold-increase compared to age and sex match controls. And importantly, seemed like hazard ratios use were, more or less, unchanged when we start adjusting various known risk factors, such as bicuspid aortic valve, Marfan syndrome, and Ehlers-Danlos syndrome, normally those kinds of things. And we also found that the younger your proband were at the time of an acute event, the higher was your relative risk yourself. So among people who were below the age of 50 when they suffered an event, the hazard ratios were up to a 50-fold increase. Dr Greg Hundley: Very nice. Naveed, what attracted you to this article as it was coming through the editorial process? And then second, how do we take the information that Charlotte's just conveyed and will be published here today, how do we take this in the context of what we already know about aortic aneurysms? Dr Naveed Sattar: I think it's a beautiful study, so well done, Charlotte. I think it's a beautiful fusion. As Charlotte said, an in-depth cohort study, which has got very well-measured parameters of systematic points and a fantastic population-based data set from Denmark, which Sweden shares and Scotland shares and relatively small countries like us share. So small countries like Denmark punch above their weight in these kinds of studies, which is fantastic. But there's a rich seam of research that comes from these, and this is one of them. So I think that fusion of two data sets with different strengths and limitations combined giving off same signals is good. I think, as Charlotte said, this is the first major population study to look at this question. So there's been people around the world who have got this sense that the aortic aneurism may well be familial, this provides, probably, some of the best data to suggest, yes, it definitely is. Now the questions going forward is, okay, at what point do you screen everybody's got a family history with a proband, or do you screen those who've got a family history of younger probands? And I think what Charlotte and the team and other people around the world thar are going to look at this say, "Okay, we now think, in addition to screening, for example, in the UK and the US we probably screen just men above 65, where most of the disease is, do we also then implement screening in younger people with family histories? And who do we screen, and when and how? And do we need to develop some kind of risk score?" And then when we do that screening, what do we do about it? Is going to be the questions and I'm sure Charlotte and her colleagues have thought about these things and it'd be interesting to see what her view is on those things. But I think it was a beautiful study in every sense. Dr Greg Hundley: So Charlotte, he's really set you up nicely, what study do we need to perform next in this area? What are you and your group thinking about? Dr Charlotte Andersson: Yeah, I think there are two implications of this study. First, clinical, as Naveed says. They already had a sense that aortic diseases were heritable, and I think these data definitely support that we should probably screen first-degree relatives. And I think, at some extent, this is what the guidelines already encourage us to do. So I'm not sure it would be feasible to randomize people or do a clinical trial where we screen some but not others. I'm not sure that would be ethical. I think the evidence is too strong for familial clustering and that we should probably screen these people. But I think also, our estimates, they are so strong that I suspect that there are likely more genetic variants associated with non-syndromic aortopathies that we are not aware of just yet. So I think the next step would be to try to disentangle the genetics a little bit more. I have seen some preliminary analysis based on the UK Biobank, for instance, and I think there are more genetic variants to come up with also, more common genetic variants, at least, that we are not aware of just yet. So that would be the next step as I see it. Dr Naveed Sattar: And that might particularity in younger probands. Dr Charlotte Andersson: Right. Dr Naveed Sattar: Those with the younger probands, because it looks like, as you said, the hazard ratio, the risks, are so high, it could also potentially be monogenic, but anyway. Dr Charlotte Andersson: I agree. Dr Greg Hundley: Well, Charlotte, Naveed, we really appreciate your time and taking this opportunity to discuss these really interesting findings and helping us understand that, truly, there may be a familial component to understanding this disease process, particularly in patients with aortic aneurysms that may go on to develop aortic dissections. Well listeners, we hope you have a great week and on behalf of Carolyn and myself, catch you on The Run next week. This program is copyright, the American Heart Association, 2020.  

This week’s episode of Circulation on the Run has 2 Feature Discussions. Associate Editor Ntobeko Ntusi discusses the article "Prevalence of Infectove Encocarditis in Streptococcal Bloodstream Infections is Dependent on Streptococcal Species." Then, author Anumpam B. Jena and Associate Editor Sandeep Das discuss trends in new diagnoses of atrial fibrillation after the release of an ECG-capable smartwatch. TRANSCRIPT: Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature this week involves infective endocarditis and looking at that in streptococcal bloodstream infections. Are they dependent on the different species of streptococci? But before we get to that, how about we grab a cup of coffee and start off and discuss other papers in the issue. You want to go first? Dr Carolyn Lam: Sure, Greg. I got my coffee, but I want to start with a quick question. So do you think it's safe and efficacious to prescribe SGLT2 inhibitors to patients with Type 2 Diabetes and concomitant peripheral artery disease? Dr Greg Hundley: Ah, Carolyn, very good question. I don't know if it's right or wrong. A little bit of controversy here. Dr Carolyn Lam: Let's explain that controversy. So patients with peripheral artery disease are at heightened risk of cardiovascular complications. However, there's also an increased risk of amputation that was observed with canagliflozin in one prior trial. Now, the SGLT2 inhibitor dapagliflozin was shown to reduce the risk for hospitalization for heart failure and kidney events in patients with Type 2 Diabetes in the DECLARE–TIMI 58 trial. So authors Dr Bonaca from University of Colorado School of Medicine and colleagues examined the cardiovascular and kidney effects and the risk of limb related events in patients with and without peripheral artery disease in the huge DECLARE–TIMI 58 trial, including more than a thousand patients with peripheral artery disease. Dr Greg Hundley: So this could be really helpful to answer this question. What did they find, Carolyn? Dr Carolyn Lam: Well, patients with versus without peripheral artery disease were indeed at higher risk of major adverse cardiovascular events, cardiovascular death, or heart failure, hospitalization and kidney events. They also had consistent benefits for the outcomes of cardiovascular death or heart failure hospitalization as well as progression of kidney disease with dapagliflozin. Now ,patients with peripheral artery disease also had a higher risk of limb events, but there was no consistent pattern of incremental risk observed with dapagliflozin. So the take home, diabetes patients with peripheral artery disease are at risk of heart failure and kidney events and dapagliflozin is beneficial with no patterns of increase limb risk. Dr Greg Hundley: Very nice, Carolyn. Boy, that is very helpful and a nice take home message for all of us administering these agents. Well, Carolyn, my first study comes from Professor Magnus Bäck from the Koralinska Institute. And the aim of this study was to identify the role of omega−3 polyunsaturated fatty acids, derived specialized pro resolving mediators, or SPMs, in relation to the development of aortic valve stenosis. The synthesis of specialized pro resolving mediators are potent beneficial anti-inflammatory agents. They have pro resolving and tissue modifying properties that are useful in managing patients with cardiovascular disease. Dr Carolyn Lam: Interesting. So what did these authors find? Dr Greg Hundley: This study showed that human stenotic aortic valves contain decreased levels of n-3 PUFA, and that n-3 PUFA treatment decreased aortic valve calcification, and aortic valve leaflet area in murine models’ concomitant with improved aortic valve hemodynamics. The pro resolving lipid mediator, resolvin E1, which is derived from the n-3 PUFA enoic acid, or EPA, exerted protective effects on valvular interstitial cell calcification and valvular inflammation through its receptor, chemR23. And therefore Carolyn, further clinical evaluation of n-3 PUFA treatment may open up novel therapeutic opportunities for preventing the progression of aortic valve stenosis. Dr Carolyn Lam: Wow, really interesting, Greg. Just more and more data on these omega−3 PUFAs, huh? So cool. Well, the next paper is kind of related in the lipid world. Do you think treating to a low LDL cholesterol target of less than 70 milligrams per deciliter may impact carotid plaque evolution? Dr Greg Hundley: I would think so. It seems like that target is beneficial in many ways. Dr Carolyn Lam: Well, good guess, Greg. But I'm going to tell you about a study that actually looked at that. First of all, recall that the treat stroke to target, or TST trial, showed the benefit of targeting an LDL cholesterol concentration of less than 70 in terms of reducing the risk of major cardiovascular events in 2,860 patients with ischemic stroke with atherosclerotic stenosis of the cerebral vasculature. Now, today's paper describes results of the parallel TST plus study, which included 201 patients assigned to an LDL cholesterol concentration of less than 70 versus 212 patients assigned to a target of a hundred. To achieve these goals, investigators led by corresponding author, Dr Amarenco from Bichat Hospital in Paris, France, allowed investigators use the statin and dosage of their choice, and added ezetimibe as needed. After certification of ultra-sonographers, carotid ultrasound examinations were performed at baseline and at two, three, and five years, and blindly analyzed at a central core laboratory. Dr Greg Hundley: Very nice, Carolyn. So what did they find? Dr Carolyn Lam: After a median follow-up of 3.1 years, patients in the lower target group had a similar incidence of newly diagnosed carotid plaque compared to the higher target group, but significantly greater regression of carotid atherosclerosis as measured by the common carotid intima media thickness. So this really further strengthens the concept that the lower the LDL cholesterol, the better the clinical and atherosclerosis outcomes. Dr Greg Hundley: Very nice, Carolyn. Another study emphasizing that very important point. Well, Carolyn, my next study comes from Professor Abdelkarim Sabri from the Temple University School of Medicine. So studies suggest that cardiac rupture can be accelerated by thrombolytic therapy, but the relevance of this risk factor remains controversial. In this study, the authors analyzed protease activated receptor or PAR4 expression in mouse hearts with myocardial infarction, and investigated the effects of PAR4 deletion on cardiac remodeling and function post demise by echocardiography, quantitative immunohistochemistry, and flow cytometry. Dr Carolyn Lam: Oh, okay. What did they find, Greg? Dr Greg Hundley: Three things. First, PAR4 deficiency leads to cardiac hemorrhage and increases the rates of cardiac rupture following chronic myocardial infarction. PAR4 deficiency in neutrophils, but not in platelets, impairs inflammation resolution and myocardial healing after myocardial infarction. And finally, adoptive transfer of neutrophils can be used as a novel therapy to modulate the inflammatory response and improve cardiac remodeling and function following myocardial infarction. Dr Carolyn Lam: Okay, what's the take home message? Dr Greg Hundley: It's a little tricky. So acute transient administration of par four inhibitors may provide a new approach to prevent early inflammation and myocyte loss immediately after ischemic injury. The keyword is immediately. But importantly, prolonged P4 inhibition strategies could impair myocardial healing and increased cardiac hemorrhage and the rates of myocardial rupture following infarction. PAR4 inhibition therapies should be limited to the acute phases of the ischemic and fault, and it should be avoided for the chronic treatment post myocardial infarction. Really intriguing, Carolyn. Dr Carolyn Lam: Very nice and elegant results, kind of like yin and yang, huh? Dr Greg Hundley: You bet. Dr Carolyn Lam: All right. Let's sum up with the other papers in the issue. There's a white paper by Dr Psotka on challenges and potential improvements to patient access to pharmaceuticals with examples from cardiology. There's a perspective by Dr Armstrong comparing the benefit of novel therapies across clinical trials, and that provides important insights from the VICTORIA trial. There's an ECG challenge by Dr Chu regarding a young male with incessantly alternating tachyarrhythmias. Dr Greg Hundley: Very nice, Carolyn. Well, in my mail bag, I have an on my mind piece from Dr Jamil Tajik relating to, our favorite, the art and science of occultation. Well, Carolyn, how about we get on to that feature article and talk a little bit more about those little devils, the streptococci? Dr Carolyn Lam: Yeah, let's go, Greg. Infective endocarditis is the topic of our feature paper today. Now, we all know it's a life threatening disease, and despite its relative rarity, it's still consumes a disproportionate share of healthcare resources, and its annual mortality is still really high, exceeding 20%. Now, I think we all recognize that improved outcomes are critically dependent on a timely diagnosis and early investigation. The problem is the clinical presentation is less and less likely that classical textbook presentation, and the clinical suspicion is often triggered after microbiological identification of potential causative organisms in the blood. And while we as a medical community are usually aware of the dangerous of staphylococcal bacteremia, I think there's a lot less appreciation of the propensity of different streptococcal species to cause infective endocarditis. Greg, my dear partner, greatest friend, and colleague, do you agree? Dr Greg Hundley: Yes, Carolyn. So this paper and this feature addresses bacterial endocarditis and focuses on streptococcal infections just as you've described. Now, streptococci I frequently cause infective endocarditis. Yet, the prevalence of infective endocarditis in patients with bloodstream infections caused by different streptococcal species is unknown. So in this study, Dr Shamat and associates aim to investigate the prevalence of infective endocarditis at species level in patients with streptococcal bloodstream infections. Dr Carolyn Lam: Now, we're taking a lot of pains to describe this paper, Greg and I, because we didn't manage to get hold of the authors this time. We certainly have our editor who managed the paper and that's Ntobeko Ntusi from University of Cape Town. So welcome Ntobeko, and thank you so much for discussing this paper with us. But before we get to that, I think Greg and I are going to try to, in our usual fashion, get to the bottom of describing. Here's something I learned that I didn't know before. That the ESC guidelines for example, are primarily based on the modified Duke criteria, which include blood cultures, mentioning viridians streptococci. Remember those? Viridians streptococcus, or strep bovis, as a diagnostic major criterion for streptococcal infective endocarditis. And yet, the term viridians is based on bacterial culture using green hemolysis on blood agar plates, which is outdated. So I didn't realize that. It's outdated and inconsistent because some of the included streptococcal species do not even cause hemolysis, and other species are able to produce different kinds of hemolysis. And thus, we really need more details on specific streptococcal types that are much more current. And when we face these different streptococcal species, they're not mentioned in the guidelines and so we need more data. So that's why this paper is so important. So Greg, now over to you. Do you mind to describe what the authors did? Dr Greg Hundley: Sure, Carolyn. So these investigators identified and assessed all patients with streptococcal bloodstream infections from the period of time of 2008 to 2017 in the capital region of Denmark. And data were cross-linked with Danish nationwide registries for identification of concomitant hospitalization with infective endocarditis. In multi-variable logistic regression analyses, the authors investigated the risk of infective endocarditis according to some of those species that you just mentioned. And they adjusted their analyses for age, sex, greater than or equal to three, positive blood culture bottles, native valve disease, prosthetic valves, prior episodes of infective endocarditis, and whether or not they may have had an implanted cardiac device. Dr Carolyn Lam: Great, great. So tell us the results, Greg. Dr Greg Hundley: So Carolyn, they had 6,500 plus cases with streptococcal bloodstream infections. And the average age of the patients was 68 years, and a little more than half. So 52% to 53% were men. The prevalence of infective endocarditis overall was 7%. Now, the lowest infective endocarditis prevalence was found with strep pneumoniae and strep pyogenes, ranging from 1.2% to 1.9%. the highest infective endocarditis prevalence, and that was found with strep mitis or oralis at 19%. Streptococcus gallolyticus, formerly known as strep bovis, at 30%. Strep sanguinis at 35%, and strep mutans at nearly 50%, at 48% overall. So in multi-variable analysis, using the strep pneumonia at 1.2% as a reference, all species except strep pyogenes were associated with a significantly higher infective endocarditis risk. Again, the highest with the odds ratio of strep gallolyticus is at an odds ratio of 31 ranging up to straight mutans with an odds ratio of 81.3. Dr Carolyn Lam: Whoa, Greg, that was beautifully summarized, and frankly, beautifully pronounced. I don't think I could have done that with all the species. That is so cool. And in case everyone didn't get it, I strongly suggest you refer to figure three of this beautiful paper. It shows the prevalence of infective endocarditis in bloodstream infections with the different streptococcal species, all in one figure. And Ntobeko, with that introduction, if you may, by both Greg and I, could you please let us behind the scenes? Tell us what you first thought when this paper came across your desk and perhaps what the editors’ thought was so important about this paper. Dr Ntobeko Ntusi: Thank you very much, Carolyn and Greg. So this is an important paper coming out of circulation. And while infective endocarditis may not be so harmonic in North America and western Europe, in many parts of the world, including where I come from in Sub-Saharan Africa, with a high prevalence of rheumatic heart disease, it remains an important cause of morbidity and mortality. And we forget that it's a disease with very high inpatient mortality of up to 50% in many countries. And of course in those with rheumatic heart disease, streptococcal bloodstream infections remain an important cause of infective endocarditis. So when I saw this paper, I very much enjoyed reading it. I thought it was well written and beautifully illustrated. In some ways, even though I say it's an original paper, it has a feel of a review because the discussion, as well as the figures and tables, are quite instructive. And the comments from the reviewers were very much aligned with my own thinking that there were a number of important new learnings coming out of this paper. The first important message for me was that the distribution of streptococcal infections in the population was not uniform and I had assumed infections to be broadly the same across the population. And contrary to what I thought, the risk of infective endocarditis was inversely related to the frequency of streptococcal bloodstream infections in the population. In other words, the most common streptococcal blood infections that are very low prevalence of infective endocarditis. And that leads to the second important learning from this paper, which is that if you are a clinician evaluating a patient with suspected infective endocarditis, the risk of infective endocarditis should be evaluated on a species level, as the species from Greg's description is probably the most important determinant of the likelihood of developing infection. And then the other important, I think, take home message from this paper, I'm looking at the results of multivariate regression analysis, is that it confirms much of what we know from studies with older patients studies focusing primarily on staphylococcal bloodstream infections as well as studies focusing on device therapies. And that message is that the risk of developing infective endocarditis, even with streptococcal blood infections is related down to presence of native or valve disease. Those with trust that tech devices, intracardiac devices, and of course, the number of fat blood culture bottles that are positive, which is something that is well accepted and established in clinical practice. Thank you, Carolyn. Dr Carolyn Lam: I just love those three take home messages. So beautiful. And I really also love that you invited this fantastic editorial, Dr Prendergast, Dr Allen, and Dr Klein. I thought it was wonderful the way they summarized the paper, put it into context, and perhaps, I could borrow their words and also explaining that they pointed out that we do need to be cautious about interpreting this being a retrospective series classified by diagnostic coding. And of course, by design, because of that, we can't fully attribute causal associations. They also pointed out that this paper, I believe did not include echocardiographic data as one of the variables. And so of course, that could be something that could be further explored in future studies. And I'd love your thoughts on what they also said about before we extrapolate regional data, I mean, it's all from Denmark after all, to other regions, this work should probably be considered something that should inspire extension of further studies and prospective evaluations in other areas, and yet never losing sight of the fact that this informative paper will of course be of considerable interest to not just cardiologists, but also infectious disease specialists, because we're often called to sort of assess, "All right, how much do you need to work up for infective endocarditis if you see this specific streptococcal bacteremia?" And this paper definitely puts us strides ahead in this area. Would you agree with that, Ntobeko, and anything to add? Dr Ntobeko Ntusi: Indeed, Carolyn. So I was delighted that the review, the editorial, was co-authored by cardiologists and infectious disease specialists. We might view as they balanced in as one of the modifications to the original submission. We actually posed that question to the office that how can we be certain in the absence of echocardiographic data that the diagnosis was in fact infective endocarditis in patients? And so they went back and performed a sensitivity analysis and triangulated the principle diagnosis of infective endocarditis with the treatment of patients in the duration in hospital. And that sensitivity analysis in fact strengthened our believe that this wasn't fit the diagnosis of infective endocarditis. And I think your point is well taken that similar studies need to be conducted in different regions of the world and this field will be strengthened by large amount of prospective studies on top of the plethora of retrospect data that we have. Dr Greg Hundley: Well listeners, we have a second feature discussion this week. A very interesting article pertaining to the use of smartwatches and detection of atrial fibrillation. And to present this work, we have Dr Bapu Jena from the Harvard Medical School, and our own associate editor from University of Texas Southwestern Medical Center in Dallas, Dr Sandeep Das. Welcome gentlemen. And Bapu, perhaps, could you tell us a little bit about the hypothesis and the background of this material? Dr Anupam B. Jena: Sure. So you probably are aware that in December of 2018, Apple released this new watch and this watch made a lot of buzz in part because it featured this single lead EKG that the company said would be able to detect atrial fibrillation. And there was this question among many, at least certainly among clinicians, as to whether or not we would see a large increase in atrial fibrillation diagnoses after this watch was released onto the market. And then the second question was, would we be picking up worrisome cases of atrial fibrillation that we needed to act on, or would we be picking up cases that patients probably would have been okay living with and would never have known that they were living with? We were lucky to be able to work with a company called Athenahealth. Athenahealth is a nationwide cloud-based healthcare information technology company. What that allowed us to do was to do a very early analysis of the change in atrial fibrillation diagnosis after the Apple Watch was approved on the market. So that's the data we use is from small physician practices. It's not nationally representative, but these practices are all across the US. The data from Athenahealth have been used in other studies, including some by myself and other colleagues. In terms of the method that we applied; it was pretty straight forward. So what you basically want to see is before and after December of 2018, do we see a market spike in the diagnosis for atrial fibrillation? Again, these are diagnoses that physicians who are in these offices would be making and that we would be seeing in the electronic health records of their practices. Now, the problem is, is suppose over time, atrial fibrillation diagnoses are going up. So if we looked at the first six months of 2019 compared to the last six months of 2018, and we saw an increase, we obviously wouldn't want to attribute that solely to the Apple Watch because atrial fibrillation diagnoses may be going up for a lot of other reasons. What we said as well, let's at least try to account for the possibility that there are seasonal trends at play in the diagnosis of atrial fibrillation. Dr Greg Hundley: Very nice. What did you find? Dr Anupam B. Jena: So the basic finding is as follows that we didn't really see a differential increase in atrial fibrillation diagnoses. So for example, in the months before the watch was released, in this population, about 0.4% of all visits had an atrial fibrillation diagnosis. 0.4%. If you look at the year after the app release, about 0.4% of visits have the diagnosis. If you look one year back, you also find that one year before in the pre period, there is about 0.36% of visits were for atrial fibrillation, and that increased the 0.39%. So the difference in difference change is basically about zero. Meaning, we found that there was no increase in atrial fibrillation diagnoses. The second thing that we did is we looked at high income zip codes, and we looked at zip codes with the population of individuals would be such that we might expect an increase. And we found no changes in either one of those two subgroups. Dr Greg Hundley: Very good. Well, Sandeep, help us put this in the context of using these watches and then also using these watches to identify patients with atrial fibrillation. Dr Sandeep Das: Absolutely. So let me first just add a comment that Bapu was a little too modest to blow his own horn, but he's really built a lovely research program of identifying and answering really interesting questions in large datasets. So the fundamental question here about whether the use of the Apple Watch and these detection algorithms would be associated with a big spike in diagnosis of atrial fibrillation was extremely important or is extremely important. So that was really the hook. I knew it was going to be something interesting. In our heart of hearts, we're all a little worried that people are going to have wearables. There's going to be an 8 million people presenting with abnormal findings on their watch and it's going to break medicine. So that was really kind of the context and the key for what made it interesting to us. Dr Greg Hundley: Very nice. And so what do you think, maybe start with Babu, and then come back to Sandeep. What do you think will be the next study in this area using these devices as they pertain to patients with atrial fibrillation? Dr Anupam B. Jena: Yeah. Great question. So I think there's two things that come to mind. So first is this was really an early analysis. I do expect that as the Apple Watch grows in popularity and as other similar such devices get introduced to the market, that we probably will pick up patients with atrial fibrillation who otherwise wouldn't have been diagnosed. I think that's less likely, but would be diagnosed earlier than they otherwise would have. So I think that if we look a couple of years out, we probably will find different answers that we found here. But as Sandeep said, at least in the first year after the watch was introduced to the market, we didn't break the bank. So I think this first natural question is to look longer out. And I think the second thing, which is particularly interesting to me at least, is that this potentially gives us a nice natural experiment to understand whether or not all patients with atrial fibrillation or what are the other factors that we should be thinking about in terms of benefits? Dr Greg Hundley: Very good. Sandeep, do you have anything to add? Dr Sandeep Das: So I agree with that answer entirely. I think that one of the things that really is going to be the $64,000 question is what does wearable diagnosed atrial fibrillation mean? So we were pretty good. As Bapu said, we have well established history of understanding what to do with patients that have atrial fibrillation that we diagnose in conventional ways. People either present with symptoms or are diagnosed externally in the hospital. But what does it mean if you're perfectly fine and you just have a watch that gives you an alarm? What are the implications of that? Because there are therapies generally revolve around anticoagulation in a large fraction of patients with atrial fibrillation. And that's the big deal. If we're going to commit people to lifelong anticoagulation, based on what they're watch told us, is that the right thing to do? So I think that to me, the most important question going is what does a diagnosis of a-fib by wearable mean for downstream treatment implications and outcomes? And then the larger scope is also how can we then incorporate the data that we're going to continue to get from wearables into practice? So studies on sort of the practical downstream implications of wearable technology on utilization are also going to be super important and interesting. Dr Greg Hundley: Very good. Well, I want to thank you Bapu, and also thanks Sandeep for your time today. And just sharing this new research using Apple smartwatches and trying to diagnose atrial fibrillation and compared it at least in this first year to, I guess, historical controls, not an overabundance or mass increase in the diagnosis of atrial fibrillation. And as you both have identified more to come with research on using these watches in the future for management, and then how we might improve therapeutic interventions through the use of these devices. Well, listeners, we hope that you have a great week and we look forward to catching you on the run next week. Take care. This program is copyright of the American Heart Association, 2020.  

DISCLAIMER: Always drink responsibly. Always follow laws and restrictions in your area. Do not drink and drive. Love a good drink? So do we! So Greg and Kierston are tackling the history of alcohol. Come enjoy (responsibly) with us!

Today’s episode discusses issues pertaining to the management of ST-elevation myocardial infarction in low and middle-income countries. Dr Carolyn Lam and Dr Greg Hundley also discuss the following: Mechanism of Eccentric Cardiomyocyte Hypertrophy Secondary to Severe Mitral Regurgitation by Sadek et al. Autoantibody Signature in Cardiac Arrest by Li et al. Cardiovascular Risk of Isolated Systolic or Diastolic Hypertension in Young Adults by Kim et al. TRANSCRIPT Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article this week is a little bit different from what we've done in the past with original manuscripts, we're going to focus on issues pertaining to the management of ST-elevation myocardial infarction in low- and middle-income countries. Oh my Carolyn, there's so many different things to consider. There are knowledge gaps, how we manage patients, how we get from one center to another, even just defining those centers. And this could be a very nice blueprint for future governments to use in managing these patients. But before we get to that feature, how about we have a little bit of a chat on some of the other articles in the issue? Dr Carolyn Lam: You bet, Greg. Now, have you ever wondered why do some but not all patients with severe aortic stenosis develop otherwise unexplained reduced systolic function? Dr Greg Hundley: Yes, I have Carolyn. And I wonder if it happens to do with one of our favorite magnetic resonance spectroscopy measurements, including creatine kinase. Dr Carolyn Lam: You are just too smart, Greg Hundley! Dr Greg Hundley: I had the opportunity to manage this one through the whole editorial board review. Dr Carolyn Lam: Well, Dr Ryder and colleagues from University of Oxford hypothesized that reduce creatine kinase capacity and or flux would be associated with the transition to reduce systolic function in severe aortic stenosis. So they looked at 102 participants recruited into five groups. One, those with moderate stenosis. Two, severe aortic stenosis with ejection fraction above 55%. Three, severe aortic stenosis with ejection fraction less than 55%. Four, healthy volunteers with non-hypertrophied hearts with normal systolic function. And five, patients with non-hypertrophied, non-pressure loaded hearts with normal systolic function who are undergoing cardiac surgery and donating left ventricular biopsies. Now, all these groups underwent CMR, cardiac magnetic resonance imaging, and 31 phosphorous magnetic resonance spectroscopy from myocardial energetics. And they also had left ventricular biopsies. So Greg, I know you know what they found, and so let me lunge right into it. They found that total creatine kinase capacity was reduced in severe aortic stenosis with median values lowest in those with systolic failure, consistent with reduced energy supply reserve. Despite this, in vivo magnetic resonance spectroscopy measures of resting creatine kinase flux suggested that ATP delivery was reduced earlier at the moderate aortic stenosis stage, but where left ventricular functions still remain preserved. These findings thus suggest that significant energetic impairment is already established in moderate aortic stenosis and a fall in creatine kinase flux is not per se the cause of transition to systolic failure. However, as ATP demands increase with aortic stenosis severity, this could increase susceptibility to systolic failure. As such, targeting creatine kinase capacity and our flux may be a new therapeutic strategy to prevent or treat systolic failure in aortic stenosis. Dr Greg Hundley: Very nice, Carolyn. That is a very challenging explanation. And boy, you walked us through it just perfectly. And I'm so glad you're here as an expert in heart failure and transplantation to get us through this next quiz. So Carolyn, can you name several of the primary causes of heart transplant related mortality? Dr Carolyn Lam: All right. Rejection, infection, malignancy and allograph vasculopathy, of course. Dr Greg Hundley: Thank you very much, Carolyn. What a wonderful job. So this paper comes from Dr Alexandra Loupy, and the study focused on the etiology of transplant related vasculopathy, the last one that you just named, from a population-based perspective. So 1,310 heart transplant recipients from four academic centers spread across Europe and the United States underwent prospective protocol-based monitoring consisting of repeated coronary angiographies together with systematic assessments of clinical histological and immunological parameters. The main outcome was prediction for cardiac allograph vasculopathy trajectory. Dr Carolyn Lam: Interesting. So what did they find? Dr Greg Hundley: So Carolyn, over a median follow-up post-transplant of about six and a half years, 4,710 coronary angiograms were analyzed, and four distinct profiles for allograph vasculopathy trajectories were observed. These four trajectories were characterized by one, patients without allograph vasculopathy at one year and non-progression over time. And that was about 56% of the patients. Second, patients without allograph vasculopathy at one year and late onset slow allograph vasculopathy progression. And that was about seven and a half percent of patients. Third, patients with mild allograph vasculopathy at one year and mild progression over time. And that was about 23% of patients. And finally, a fourth category, patients with mild allograph vasculopathy at one year and accelerated progression. And that was about 13% of patients. Dr Carolyn Lam: Huh? So what most predictive? Dr Greg Hundley: Well Carolyn, six early independent predictors of these trajectories were identified. One, donor age. Second, donor male gender. Third, if the donor used tobacco. Fourth, recipient dyslipidemia. Fifth, class two anti-HLA donor-specific antibodies. And finally, acute cellular rejection greater than 2R. The four allograft trajectories manifested consistently in the US independent cohort with similar discrimination, and in different clinical scenarios, and showed gradients for all caused mortality. Dr Carolyn Lam: Wow. Okay. So what's the take home message, Greg? Dr Greg Hundley: Well, because this study identified these four trajectories and their respective independent predictive variables, they provide the basis for a trajectory-base assessment of heart transplant patients for early risk stratification. And therefore, we might be able to develop monitoring strategies and form clinical trials around those to determine the efficacy of perhaps these predictive models. Dr Carolyn Lam: Thanks. Okay. Well, this next paper focuses on Tet-methylcytosine dioxygenase 2, or TET2. Dr Greg Hundley: Carolyn, what is that? Dr Carolyn Lam: Well, I'm glad you asked me before I asked you. So TET2 is a key enzyme in DNA demethylation. And the gene TET2 encodes an epigenetic regulator that demethylates cytosine. Somatic mutations of TET2 occur in cardiovascular disease and are associated with clonal hematopoiesis inflammation and at first vascular remodeling. The current paper by Dr Archer from Queens University Kingston in Ontario, Canada, and colleagues, is novel because it's the first to examine the role of TET2 in pulmonary arterial hypertension. And they did this by evaluating exome sequencing data from the largest PAH cohort assembled to date, including 2,572 patients in the PAH Biobank. Unlike prior genetic studies, the biobank includes patients with associated PAH. Now, this is important. This is the category that includes patients with connective tissue disease such as scleroderma. This biobank also included non-European ancestry. So these are the novel aspects. The authors performed gene-specific rare variant association analyses using up to 1,832 cases of European origin from the PAH Biobank, and transcriptomic analysis in an independent cohort to assess TET2 expression. Dr Greg Hundley: Carolyn, so what did they find regarding to TET2? Dr Carolyn Lam: In the entire cohort, they identified 12 predicted deleterious variants of TET2 novel to PAH. 75% predicted germline and 25% predicted somatic variants. None of the variant carriers were responsive to acute vasodilator challenge. Now, this is the first time that putative germline TET2 mutations have been associated with a human disease. They also identify ubiquitous downregulation of the expression of TET2 in the peripheral blood mononuclear cells of idiopathic PAH and associated PAH patients. Finally, they evaluated TET2 depleted mice and demonstrated that they spontaneously developed inflammation, pulmonary vascular obliteration and pulmonary hypertension, thus providing biological plausibility that disorders in this pathway can indeed cause PAH. This is discussed in an editorial by Dr Soubrier from INSERM, entitled, TET2: A Bridge Between DNA Methylation and Vascular Inflammation. Dr Greg Hundley: Oh wow, Carolyn. Well, let me tell you about a couple other articles in our issue. First, Dr Amr Abbas has a letter to the editor regarding actuarial versus echocardiographic outcomes following TAVR, evaluating gradients, leaks, areas and mortality with responses by Flavin Vincent and from Laurent Fauchier. We have Dr Miguel A. Arias again presenting another EKG challenge for us. Next, professor Giovanni Esposito has a research letter involving PCI rates for ACS during this COVID-19 pandemic. Next, Dan Roden from Vanderbilt has a consensus report related to QTC prolongation during the coronavirus pandemic. And finally, professor Marco Roffi has an on my mind piece related to STEMI and COVID-19 pandemics. Dr Carolyn Lam: Oh, there is a series of on my mind papers in this week's issue. “The Future of Cardiovascular Prevention: Unprecedented Times,” by Laurence Sperling. “Primary and Secondary Prevention Of Cardiovascular Disease in the Era of Coronavirus Pandemic,” by Erin Michos. “Reperfusion of STEMI in the COVID-19 Era: Is it Business as Usual?” by Dharam Kumbhani. And finally, we also have a research letter by Dr Lili Jong, addressing immune checkpoint inhibitors which are increasingly applied to a broader range of cancers and their potential toxicity causing myocarditis. And this letter describes the association of timing and dose of cortical steroids in immune checkpoint inhibitor associated myocarditis and cardiac outcomes. Dr Greg Hundley: How about we discuss how we might want to manage ST-elevation myocardial infarctions in low- and middle-income countries? Dr Carolyn Lam: You bet. Let's go, Greg. Dr Greg Hundley: Well listeners, now we get to turn to our feature article. And we're very privileged today to have Dr Chandrashekhar from The University of Minnesota. And he and a large group of authors have put together a paper discussing the resources and infrastructure really necessary to manage ST-elevation myocardial infarction in low- and middle-income countries. Welcome Chandra. So we're going to call him Chandra for short as he is known internationally. Chandra, can you tell us a little bit about this prevalence of STEMI in low- and middle-income countries, and then also about the constitution of your writing group and what you were trying to do to address this issue? Dr Chandrashekhar: The issue we are trying to address is, as you know, the low- and middle-income countries, there are about 80 plus countries constituting this group, and they account for something like 5.8 billion people around the world. And it's so interesting that 80% of the MIs that happen on the face of this earth are probably happening there, in areas which don't have resources to effectively deal with this condition, unlike the US or European countries and developed countries. So this group got together to create some outlines of how to optimize care in low- and middle-income countries. And we got together groups which have extensive experience in dealing with this problem. It was a coalition of frontline clinicians as well as major organizations, including the Indian Council of Medical Research, the premier research body in India, a public health foundation of India which is a nongovernmental organization extensively involved in this, The Population Health Research Institute in Canada, the Latin America Telemedicine Infarct Network called LATIN, The Pan African Society of Cardiology and The South African Society of Cardiac Interventions, and an NGO in India called STEMI India. So we took experienced people from a number of different countries and created this group. Dr Greg Hundley: Very good. Now, were there knowledge gaps or implementation gaps, maybe help distinguish those two terms for us, that you had to address when just starting your effort? Dr Chandrashekhar: Yeah, absolutely. So let's start with the knowledge gap. As you know, there are excellent guidelines both in the United States, as well as Europe. Of course, there are STEMI guidelines in the UK and Australia and New Zealand, but these guidelines are not very applicable to low and middle income countries due to a number of reasons, due to porosity of resources, due to poverty, overcrowding, lack of infrastructure, and a bunch of other reasons that you can imagine. So if we recommend somebody needs total balloon time under certain threshold, it's nearly impossible to meet this in most places in the low- and middle-income countries. And so there is a significant amount of implementation gap as well as knowledge gap, because the guidelines that are tailored to Western societies don't fit very easily in low- and middle-income countries. It's like fitting a round peg in a square hole. So that's why we thought we should create something very focused, right? And there are implementation gaps in the sense infrastructure-based as well as resource-based. And knowledge gaps, for example, we don't know what the dose of dual antiplatelet therapy is optimal in these patients, for example, ticagrelor may have a higher effect in some Asian populations with small body habitus. Similarly, as you know, statin doses, especially in the far east are much lower than what are prescribed here. So these are the kinds of challenges that we are applying and try to suggest some solutions. Dr Greg Hundley: It sounds like definitions could differ, management strategies could differ, pharmacologic versus invasive, even centers that would manage the patients. Can you describe some of those issues for us? Dr Chandrashekhar: Right. So that was the biggest challenge we had. So we had to create some resource infrastructure appropriate management paradigms for low- and middle-income countries. To give you an example, primary PCI, which is something we take for granted within our milieu, if you think about it, you and I probably didn't give thrombolytic therapy in the last 15 years. So this is a day-to-day thing in low- and middle-income countries. Most of the patients either they come so late that they don't get any reperfusion therapy for STEMI, or if they do, thrombolytic therapy is are very common mode of treatment there. And so we had to create a way for them to get the optimized care. And so we divided the localities into different levels, from level one to level five. Level one being the most remote area and five being the one which is most equipped and can implement all the Western standards and guidelines. And so we suggest a system of hub and spoke to transfer people from the smaller centers to the big centers, and outline what therapies need to be done at what stage. And one of the things that we emphasize so much is called pharmaco-invasive therapy, where you give thrombolytic therapy if you cannot reach a PCI center in time, and then in the next three to 24 hours, you transport the patient to a center where they can do PCI. And this has been studied in a number of trials showing that it's a very effective strategy. And so these are the kinds of solutions that we try to emphasize. Dr Greg Hundley: And how about the patients themselves and the doctors that would implement, in terms of education, does your document cover how to reach out to both patients and physicians in these countries to emphasize these new protocols that you and your group have developed? Dr Chandrashekhar: Absolutely. That's the crucial issue, right? No matter how many guidelines we create, if we can't implement it, they're useless, right? And so we have two parts to this guideline. There's a section devoted to governmental agencies as well as NGOs interested in improving care, STEMI care in low and middle income countries, as well as a section for frontline clinicians, which includes very focused flashcards with definitions and what exactly each level of this center in the hub and spoke model should be doing and how do they transport patients and how do they ensure that adequate pharmacotherapy is instituted? And so we keep repeating this and we also provide some other options of how to communicate with the hub facilities, from the spoke facilities, including use of mobile and social media apps like WhatsApp. Dr Greg Hundley: Do you have certain recommendations that physicians in the field and patients at home should be aware of, for example, administration of aspirin and things like that? Dr Chandrashekhar: Absolutely. These are all codified in flashcards, which are going to be printed for distribution to the frontline physicians. And they are also created as wall posters and plastered in this peripheral health centers where essentially the only thing they may have is an old EKG machine and a few drugs like aspirin. And so we have tried to cater to each of this, both in the informational material and what basic pharmacotherapies and equipment these centers should be having. And that's where the governmental part comes. So when governments have to decide how they invest their scarce dollars, they can divide it appropriately based on these recommendations. Dr Greg Hundley: I like that last statement, it sounds like in addition to physicians and patients that your document may even be useful for governments and organizations delivering the care in these countries, do you want to talk a little bit about where you think this document may go next in that regard? Dr Chandrashekhar: The best use of this document would be for agencies in different parts of the countries to take this up. And at the last count, there are at least five or six governments which are actively looking at the blueprint that is provided from this document, and to see what parts of this are locally implementable within their environment. And eventually, if it appears that it's applicable to multiple jurisdictions, then perhaps something like WHO could take this and modify it suitably for different localities. We see a lot of potential in this. Dr Greg Hundley: Well, we are very privileged to have the opportunity to publish this important work. And I wonder here, just in closing, on behalf of your entire author group, are there any words you'd like to leave us with regarding this just monumental effort? Dr Chandrashekhar: The thing that we can say is we should thank Circulation and its editorial board for working with us. It went through, I think, three revisions and it really made the document much better. And we really thank all of you for allowing us this platform. As you know, this is going to reach a huge part of the medical establishment as an open access article. And hopefully it will help us implement some progressive changes in healthcare in the low- and middle-income countries. And so we really thank Circulation for providing us this platform. Dr Greg Hundley: Well, listeners, we're going to wrap up here and we're most appreciative to Chandra from The University of Minnesota and his entire author group. On behalf of Carolyn and myself, we wish you a great week and look forward to chatting with you next week. This program is copyright to The American Heart Association, 2020.  

Greg still collects comic books. Greg's wife is annoyed at the money he spends on them. So Greg's sister thought it would be funny to #PhoneTap his wife!!

Dr Carolyn Lam: Welcome to circulation on the run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU health in Richmond, Virginia. Well Carolyn, our feature this week really examines long-term efficacy of drug eluting stents versus coronary artery bypass grafting in those patients with left main disease. Really looking at long-term extended follow up from the PRECOMBAT trial but before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? And I'll start off. My first article is a basic science paper looking at catecholamine sensitive and ventricular tachycardia in ARVC. And it comes from Dr Long-Sheng Song from the University of Iowa Carver College of Medicine. So, the study from Dr Song used protein mass spectrometry analyses and that identified integrin beta one is downregulated in those patients with arrhythmogenic right ventricular cardiomyopathy hearts without changes to calcium handling proteins as adult cardiomyocytes express only the beta-1 D isoform, they generated a cardiac specific beta-1 D knockout mouse model and perform functional imaging and biochemical analyses to determine the consequences from integrin beta-1 D loss of function in hearts in vivo and in vitro. Dr Carolyn Lam: Nice, very elegant design. So what were the results Greg? Dr Greg Hundley: Well Carolyn, the authors found that integrin beta- 1D deficiency and RyR2 serine 2030 hyper phosphorylation were detected by Western blotting in left ventricular tissues from patients with ARVC but not in patients with ischemic or hypertrophic cardiomyopathy. And in the mouse experiments, beta-1 D negative or knockout mice exhibited normal cardiac function and morphology, but presented with catacholamines sensitive polymorphic ventricular tachycardia consistent with increased RyR2 serine 2030 phosphorylation and apparent calcium handling in beta-1 D knockout cardiomyocytes. So Carolyn, in conclusion, the authors found their data suggest that integrin beta-1D deficiency represents a novel mechanism underlying the increased risk of ventricular arrhythmias in patients with ARVC. Dr Carolyn Lam: Okay. You told us about integrin beta-1 D and I'm going to tell you about apolipoprotein M. So Greg, what do you know about apolipoprotein M? Dr Greg Hundley: Well, Carolyn, at seven o'clock the morning, I seem to have forgotten a little bit about that. Can you remind me what apolipoprotein M is? Dr Carolyn Lam: Sure Greg, very happy to. So apolipoprotein M or apoM mediates the physical interaction between high density lipoprotein particles and sphingosine 1-phosphate and exerts an anti-inflammatory and cardio-protective effects in animal models. Now listen on, listen on. So authors, Dr Chirinos from Perelman Center for Advanced Medicine, University of Pennsylvania and Dr Javaheri from Washington University School of Medicine and co-authors hypothesized that reduced levels of apoM would be associated with worse outcomes in human heart failure. Specifically, they tested the hypothesis that reduced circulating apoM would be associated with the risk of death, a composite of death, ventricular assist, device implantation or heart transplantation and a composite of death, heart failure related hospitalization among adults with heart failure and rolled in a large multicenter Penn heart failure study. They did stratified analysis in patients with heart failure with reduced and preserved ejection fraction and even replicated these findings in two independent cohorts, the Washington University heart failure registry and a subset of the TOPCAT trial. What they found was that reduced apoM plasma protein levels indeed were associated with adverse outcomes in heart failure including both HFpF and HFrF. The relationship between reduced apoM and outcomes and heart failure was particularly pronounced when concentrations of its binding partner sphingosine 1-phosphate were also reduced. ApoM protein levels were associated with inflammation in human heart failure and thus the conclusion being that apoM represents a risk marker in human heart failure. Further studies are of course needed to assess whether it could be a therapeutic target as well. Dr Greg Hundley: Very good. Carolyn. So more information for the world of heart failure isn't it. I'm going to sort of switch over to coronary artery disease and talk about low attenuation non-calcified plaques that are sometimes appreciated on cardiac computed tomography scans. And in this study, Dr Michelle Williams from the University of Edinburg evaluated the results from the multi-center SCOT-HEART trial or the Scottish computed tomography of the heart. So Carolyn, the future risk of myocardial infarction is commonly assessed using cardiovascular risk scores, coronary artery calcium score or coronary artery stenosis severity and the authors assessed in 1,769 patients about 56% men and the average age 58 years and they followed them up for a median of 4.7 years and looked at whether noncalcified low attenuation plaque burden on coronary CT angiography might be a better predictor of the future risk of myocardial infarction. Dr Carolyn Lam: Interesting. So what did they find? Dr Greg Hundley: Well, low attenuation plaque burden was the strongest predictor of myocardial infarction irrespective of cardiovascular risk score, coronary artery calcium score or coronary artery area stenosis. And patients with low attenuation plaque burden greater than 4% were nearly five times more likely to have subsequent myocardial infarction and the hazard ratio was 4.65 with a confidence interval of two to more than 10 and a half. So in conclusion, Carolyn in patients presenting with stable chest pain, low attenuation plaque burden is the strongest predictor of fatal or nonfatal myocardial infarction and these findings may add to classical risk predictors of myocardial infarction. Dr Carolyn Lam: Wow. Important findings. Okay, let's go onto what else is in this week's journal issue. There's an online mind by Dr Jaffe. It's on the universal definition of myocardial infarction. It talks about both present and future considerations. There's an ECG challenge by Dr Arias and what's described as spontaneous wide QRS complex rhythm in a patient with wide QRS complex tachycardia. Dr Greg Hundley: Very good, Carolyn. Well, I've got two other articles. Another on my mind piece from Professor Peter Nagele from the University of Chicago Medicine and it discusses a simplified proposal to redefine acute MI versus acute myocardial injury. Looking at that troponin question. And then finally Dr Fabian Hoffman from the Heart Center and University of Cologne has a research letter on providing new data regarding the evolution of pulmonary hypertension during severe sustained hypoxia. Well Carolyn, how about we get onto that feature discussion looking at left main disease and whether we should place an intercoronary stent or undergo coronary artery bypass grafting. Dr Carolyn Lam: Important question. Let's go, Greg. Dr Greg Hundley: Welcome everyone to our feature discussion today that really pertains to interventional cardiology and we're very fortunate to have Duk-Woo Park from Asian Medical Center in Seoul, South Korea and our own associate editor, Dr Manos Brilakis from the Minneapolis Heart Institute. Well Duk-Woo, we'd like to get started with you and could you tell us a little bit about the background data and the hypothesis related to your research study? Dr Duk-Woo Park: Our research, it was the 10-year report of the PRECOMBAT trial. If I'm going to first introduce the background over the last half of a century bypass surgery, it was a mainstream, the number one choice of on protecting the main disease. Yeah. Did you know unprotected left main disease, the one were very high risk of coronary artery disease and owing two and the supply, the large burden of myocardium. But the last two decades, 20 years. Their remarkable evolution in PCI field including development adaption of a drug eluting stent and the adaption of intravascular ultrasound as well as experience of intervention or catalyst expertise. So on the basis of such evolution, many interventional cardiologists think about that, a PCI with a drug eluting stent. Will it be non-inferior to a standard type A surgery? Sometime for single region PCI could be very nice alternative option for unprotected left main disease that the reason why we're going to start quick on the trial. This trial already done 15 years ago at the time. We designed this PRECOMBAT trial on the basis of that background. Dr Greg Hundley: Very good. Well can you tell us a little bit about the study population of this trial and what was your study design? Dr Duk-Woo Park: This is a open library trial design and we at first time we evaluated the noble unprotected left main disease and the for considerable for clinical and ethic eligibility, initially assessed by intervention or cardiologists as you as a cardiac surgeon and the reason why we try to pick up the post treatment eligible population and then at the screening initial re-screen the nearly 1,400 patient and then finally 600 of patient who was our individuation one arm is drug eluting stent, first-generation ciphers 10 versus another arm is convention or a coronary artery bypass stent grafting. Dr Greg Hundley: What were you looking for your outcome measures and how long did you follow these patients? Dr Duk-Woo Park: Initially and the BDN two year follow and are published in England, the journal of medicine nearly eight years ago. And then we did five year follow-up at the publish the JAG in five years ago and the this time is a, we did complete that 10 year follow up all the render mutation population and the median follow-up duration is nearly more than 11 years and we complete 10 year follow-up and the key outcome was PCI is a comparable apart from surgery for treatment of left main disease. Dr Greg Hundley: And were there other outcomes that you were looking for? Dr Duk-Woo Park: We evaluated several important clinical outcomes. We primary end the point we select competent outcome compass of all cause of mortality by myocardial infarction, stroke, or ischemia-driven target vessel revascularization. Secondary outcome was each component of a primary outcome all-cause mortality as you raise the harder clinical and the point like compost outcome like this am I sure. So finally we did not any statistical difference with the regard to primary composite outcome as well as a hard clinical compost outcome as death or stroke. Finally, we did not detect all-cause mortality. One exception or difference was a target vascularization as well as a repeat rebase collateralization was a much higher after PCI than after bypass surgery. Dr Greg Hundley: So overall, in this more lengthy follow up of 10 years. The primary outcomes were similar between the two interventional arms, but there was a difference in target vessel revascularization. With that being more frequent after PCI as compared to bypass, were there any other subgroups that tended to have distinctions or discrepancies between your primary outcome? Dr Duk-Woo Park: As the sensitive to analysis, in circulation we supply the subgroup analysis or more, we did not find any differential treatment. IPEC according to subgroup in age group, diabetes and clean-cut presentation or in environmental coronary embolism shock versus application. We didn't find any interaction effect, just the except the extent of disease vessel, left or main. We the three best three digit bypass surgery was better than PCI. However we did not do any P value. Adjust them on. So interpretation is should it be cautious. Dr Greg Hundley: Well you know as an interventional cardiologist, what new information does this bring and how do you interpret the results of this study relative to other studies that have been published in the past? Dr Emmanouil Brilakis:  I think this is a very timely study, especially since about a year ago we did have the five-year outcomes from two other similar trials, the Excel file and the Nobel trial which say randomized patients with unprotected left main disease to either PCI or bypass. And actually those studies had some differences which are also relevant to the present study. So for example, Excel overall the outcomes were similar. There was a higher all-cause mortality in the PCI where normal had better outcomes in terms of death, MIT VR, but there was no difference in mortality. So I think the natural question that comes up from the studies was whether mortality is different with PCI versus coronary bypass and you know the PRECOMBAT, the 10 years. It's really suiting in that respect because it doesn't show any difference in the overall mortality. So I think this comes very timely and the answers a lot of questions. Of course there's limitations with the sample size and the number of patients treated, but I think although it's a very timely result. Dr Greg Hundley: Maybe I'll start first with you, Manos and then I'll circle back to you. Duk-Woo. Manos what do you see is the next important study to perform in this field? Dr Emmanouil Brilakis:  I think the natural question here is these outcomes which are similar but use first generation drug eluting stents, which we no longer use. He did use high proportion of five which is an excellent feature in, again congratulate Duk-Woo and the other co-investigators for doing such a high rate of follow-up. But we now know that the techniques, for example, for bifurcations, maybe the DK crush or double DK crush might be a better technique to do. So in my mind, the next question would be if who use the current, a much improved the drug eluting stent and state of the art bifurcation techniques. For example, DK crush where the double-kiss crush bifurcation would, the outcomes have been different and perhaps PCI will be similar, even better than bypass in long-term outcomes. So for me this next study will be state of the art techniques, state of the art materials and long-term for follow-up as in frequently. Dr Greg Hundley: Duk-Woo. How about from your perspective? Dr Duk-Woo Park: You know, a future perspective is a very difficult to expect. Our trial is the longest to follow-up trial. We have the nation are insurance support and we nearly a hundred percent pop picked up fighters status, but I think most of them interventional cardiologists as well as a cardiac surgeon. One true additional longest follow-up Excel and Noble trial. The reason why we didn't do additional random trial using additional second generation drug eluting stent. We already do exit trial approximately 2000 and noble trial and more than thousand patients we already do and the two trial a complete five-year follow and most of the trial is as well as the clinician want to extend the follow-up of Excel and Noble trial but I don't know how much that extended of a follow-up would be possible. Dr Duk-Woo Park: The next step as you know the intervention or cardiac surgeon still debate about the long-term mortality issue after release of exited five-year-old research and the data peak issue, European association cardiac thoracic group. We did draw the endorsement of a guideline so I think an additional stem we require the individual patient level data analysis involving, Excel, Nobel, Syntech and PRECOMBAT trial would be required to provide the more definite compelling evidence for mortality difference as well as the have the end point and including or so some end point to repeat revascularization. We do allow individual patient data analysis. That would be next. The short step, next the long step, we definitely require extended follow-up, Excel and Noble trial. Dr Greg Hundley: Very good. Well listeners, this has been another very informative feature discussion where we've compared PCI and coronary artery bypass grafting in those with left main disease. And now from this PRECOMBAT trial, 10 years of follow up showing very similar outcomes related to death, myocardial infarction and stroke in the two randomized arms. We want to thank Dr Duk-Woo Park and Dr Manos Brilakis for presenting this information and as we move forward, their insights as to next studies with newer technologies and different examinations of stents. More long-term follow-up from ongoing trials and then individualized patient assessments. Listeners, we hope you have a great week and hope everyone is staying safe in this COVID crisis. Take care. This program is copyright of the American Heart Association 2020.  

Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article today looks at the use of Apixaban versus Warfarin, so a trial between the two in patients with atrial fibrillation and advanced kidney disease. But before we get to that, how about if we break away, grab a cup of coffee and go through some of the other important papers in this issue? Dr Carolyn Lam: Yeah, and why not start with talking about our gut and fiber in the diet. Now, we know that a diet poor in fiber is associated with the prevalence of hypertension, but what are the underlying mechanisms? Well, this first paper I want to talk about is from Dr Marques from Baker Heart and Diabetes Institute in Australia and colleagues who basically performed a nice series of mouse experiments and found that a diet lacking prebiotic fiber led to a gut microbiome that was pro hypertenenogenic facilitated the development of cardiac hypertrophy in germ free mice. Even in the absence of fiber, gut metabolites called short chain fatty acids usually produce from the fermentation of prebiotic fiber by the gut microbiota, but they were able to protect against the development of hypertension, cardiac hypertrophy and fibrosis in a preclinical model. This cardioprotection involved short chain fatty acid receptors, and a decrease in the ratio of sodium to potassium excretion and changes in genome white methylation that supported higher levels of T regulatory cells. Dr Greg Hundley: Oh my goodness, Carolyn. So I need to know what I eat for lunch? What's the take home message here? Dr Carolyn Lam: Lots of fiber and definitely not the low fiber westernized diet, which may underlie hypertension. And how? Through deficient short chain fatty acid production and thus the take home is maintaining a healthy, short chain fatty acid producing microbiome is important for the cardiovascular health. Dr Greg Hundley: Wow, Carolyn. I love that article because it really helps provide some perspective on all the diet information that we've been receiving lately. Well, my paper is from doctor ... another Carolyn, but this is Carolyn Ho from Brigham and Women's Hospital- Dr Carolyn Lam: I love her. Dr Greg Hundley: ... And it involves hypertrophic cardiomyopathy and left ventricular systolic dysfunction. So Carolyn, the term end-stage has been used to describe hypertrophic cardiomyopathy with left ventricular systolic dysfunction. And that's defined when someone has hypertrophic cardiomyopathy and the LVEF is less than 50%. The prognosis of patients with this condition has been reportedly poor, but it's very rare in occurrence and therefore, the natural history really remains incompletely characterized. So what did the authors do in this study? They evaluated more than 500 patients from 11 high volume hypertrophic cardiomyopathy specialty centers comprising the international Sarcomeric Human Cardiomyopathy Registry or SHaRe registry. And they were used to describe the natural history of patients with hypertrophic cardiomyopathy and left ventricular systolic dysfunction. Dr Carolyn Lam: Interesting. So what did they find, Greg? Dr Greg Hundley: Number one, first overall, this group of patients, hypertrophic cardiomyopathy with left ventricular systolic dysfunction occurs in about 8% of those with hypertrophic cardiomyopathy. Although the natural history of left ventricular systolic function and hypertrophic cardiomyopathy is variable, 75% of those that have this condition experience adverse events including 35% experiencing a death equivalent at a medium of 8.4 years after developing their systolic dysfunction. In addition to clinical features, the genetic substrate appears to play a role in both prognosis, so there are multiple sarcomeric variants, and in the risk for incident development of left ventricular systolic function with hypertrophic cardiomyopathy due to variance in the thin filaments within those myocytes. Dr Carolyn Lam: Nice. Thanks for that Greg. My next paper is a really interesting secondary analysis if you may, of the EXSCEL study. As a reminder, the Exenatide Study of Cardiovascular Event Lowering or EXSCEL assessed the impact of once weekly exenatide versus placebo in patients with type two diabetes and showed non-inferiority but not superiority for the primary MACE outcome. Now, during this trial, while aiming for glycemic echo-poise, a greater drop-in of open label glucose lowering medications occurred in the placebo group, thus prompting the current authors, which is Dr Rury Holman from University of Oxford and their colleagues to really explore the possible impact of unbalanced open labeled drop-in of glucose lowering medication on EXSCEL outcomes. To our modern diabetes trial, they used three methodologies. One, drop-in visit, right censoring. Two, inverse probability for treatment waiting. And three, applying drug class risk reductions. Now, Greg, I could either quiz you on these methods or summarize the results, which would you prefer? Dr Greg Hundley: Well, Carolyn, this calls for the infamous phone a friend. So one of the nice things we have at Circulation is a wonderful group of statisticians that really help us go through all the papers. But I sure would like to pick up the phone and call one of those folks now. But I think what I'm going to do ... maybe just give me the results of this study. That's what I prefer. Dr Carolyn Lam: I thought you might say that. So the EXSCEL observed has its ratios for MACE remained robust after right censoring or application of the literature derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by the inverse probability treatment waiting approach. So I think the take home is that effects of open label drop in cardioprotective medications do need to be considered carefully when designing, conducting and analyzing cardiovascular outcome trials of glucose lowering agents. Do we have the perfect solution? Perhaps not, but this was a really important paper to just look at and study. So Greg, I can see that you are stats out, so I'm going to tell you a little bit more about other papers in this week's issue. There's a research letter by Dr Zhang on transcription factor Kruppel-like factor 15 and how it regulates the circadian susceptibility to ischemia-reperfusion injury in the heart. Dr Greg Hundley: Very good, Carolyn. Well, I've got a couple of other papers. There's a nice in-depth piece from Dr Gregory Marcus from the University of California, San Francisco on how we evaluate and manage patients that have premature ventricular contractions. Dr Mori Krantz from Denver Health and Hospital Authority gives us an EKG challenge in someone that's had a needle stick. And then finally, there's a nice perspective piece from Dr Paul Armstrong from the Canadian VIGOUR Centre, department of medicine cardiology at the University of Alberta. And he really goes over nicely how we're going to do global collaboration to enhance cardiovascular care. What a great issue. And now onto that feature where we're going to hear a little bit about Apixaban and Warfarin in those individuals with atrial fibrillation and chronic kidney disease. Dr Carolyn Lam: Let's go, Greg. Today's feature paper really represents the first randomized data on NOAC versus warfarin in a very important group of patients, that is those with atrial fibrillation and advanced chronic kidney disease. So happy to have with us the corresponding author, Dr John Stanifer from Munson Healthcare, Traverse, Michigan. As well as our associate editor, Dr Chang-Sheng Ma from Beijing Anzhen Hospital in China. Welcome, welcome. So John, could you tell us the inspiration if you may, or the rationale, for doing this study? Dr John Stanifer: This is a population that's near and dear to my heart as a practicing nephrologist. We care for so many patients with atrial fibrillation, particularly those on dialysis or those with advanced kidney disease. And as other practitioners and people taking care of this population will tell you, this is just such a confusing and challenging clinical problem to try to deal with. And then really this stems from that important clinical need that we recognize almost on a daily basis. Dr Carolyn Lam: I just love that you shared that John, because coming from a nephrologist, and we're usually talking to cardiologists where we think about this all the time and have no idea what to do. So tell us about your study and what you found. Dr John Stanifer: As you know, these were data that were taken from the Aristotle trial that was finished in 2011, that was really a landmark study that established the real superiority of Apixaban compared with Warfarin and the general population. And it happened that within the study, there were several patients, 269 that had a creatinine clearance of between 25 and 30 milliliters per minute. We then took those data from those patients and compared really in this study, the safety of Apixaban compared with Warfarin within that subpopulation, and then compared that as an interaction with the safety of Apixaban versus Warfarin in patients with creatinine clearance of greater than 30. Dr Carolyn Lam: And what did you find? Dr John Stanifer: Well, in conclusion, we really found that among these patients with a creatine clearance of 25 to 30 MLs per minute in atrial fibrillation that Apixaban did cause less bleeding than Warfarin. And it appeared to be an even greater relative risk reduction when you compare that with the safety of Apixaban versus Warfarin and those with a less severe kidney disease. Dr Carolyn Lam: It's truly the first time I've seen data like this. So congratulations John and thank you so much for publishing this paper with us at Circulation. Chang-Sheng, Circulation seems to be publishing a lot in the space of combined renal and cardiac disease, which is very interesting. Why was this paper so important to us as well? Dr Changsheng Ma: It's a very important question for a clinical practice. The anticoagulation therapy in patient with advanced CKD. And observation or analysis have demonstrated inconsistent of findings regarding the net clinical benefit of warfarin in reducing the risk for stroke in patients with advanced CKD. The problem of Warfarin treatments in this patient group is dramatically higher bleeding risk. The current study also show that the bleeding risk was three- to four-fold higher in patient with advanced CKD compared to that in patient with creatinine clearance more than 30 milliliters per minute when treated with a Warfarin. So these studies are our first randomized data for NOAC compared with warfarin in patients with advanced CKD. The results provide important information as to the safety of Apixaban in this special patient group with high risk of bleeding. With reduced risk of bleeding, we may expect net clinical benefits of Apixaban in preventing stroke in patients with advanced CKD. Dr Carolyn Lam: Indeed. John, did you demonstrate that net clinical benefit or could you perhaps explain if future steps are needed to look at that a bit better? Dr John Stanifer: Well, I think absolutely future studies are needed. You have to keep in mind that these were pre-specified groups within Aristotle. These are still post-trial data from this study and that absolutely we need studies that are powered to really compare the safety. I would add not just apixaban with warfarin, but I would also add placebo to that. Dr Carolyn Lam: Interesting. Changsheng, you had some questions for John as well. Dr Changsheng Ma: Yes. John, I had questions for you. If you take a randomized trial for the answer for this question, how many cases do you think? Dr Carolyn Lam: How many cases of? Dr Changsheng Ma: How many cases should there be for a sample size for a trial? Dr John Stanifer: Well, you're really putting me on the spot here. I'll have to go back to my statistical days. Well, I think the easy part in the design of a trial for a question like this is that the event rates are so high. Whether that be for both safety outcomes related to hemorrhage and bleeding risks or primary benefit outcomes. So that would be very beneficial with that respect. But I think the key to designing a study ... and I know that there are several ongoing RENAL-AF and several others that are trying to examine this very question, but I think as a nephrologist, what we would kind of push back on a little bit is that there's no placebo arm to these trials. And I actually think that that would be a step forward even though that would be a very challenging thing, I think at this point to push for ... I think the nephrologist has kind of continued to push for that a little bit. Dr Carolyn Lam: So John, that was beautifully answered. If I could ask you then, have these results influenced your practice even now? Dr John Stanifer: Well, prior to this, we've been a little bit nervous with Apixaban, even though observational data may suggest that it would be safer or potentially usable in patients with advanced kidney disease. But part of the real conundrum and some of the challenges that come up are really around dosing of Apixaban. And they say, "Well, gosh, if they're in stage renal disease, yeah, maybe it's too bad. Maybe the kidney function is way too low and we need to kind of reduce it based just on that one criterion as opposed to the three criteria laid out in Aristotle." So I think that was some of the challenges. but I think after seeing these data and seeing the safety relative to Warfarin was really there in this patient group, yeah, it has influenced me a little bit. I am a little more adamant about switching patients. Dr Carolyn Lam: Yep. Chang-Sheng, do you agree with that? What do you think are next steps here? Dr Changsheng Ma: Because clinical practice is different, apparently, more evidence is badly needed to guide the future clinical practice because the patients with creatinine clearance even less than 25 milliliters per minute. And those in dialysis were not included in any of the pivotal studies of NOAC. Dr John Stanifer: Absolutely. Dr Changsheng Ma: It is still uncertain whether this patient will benefit from Apixaban or other NOACs. So in this study, even the significant less measured bleeding events were observed. I think the all-cause mortality was not different between the two groups. So the next step we should design a new trial to confirm whether Apixaban will really improve the prognosis of the patient with advanced CKD and AF. Dr John Stanifer: I will second that. For sure we want to answer that very important efficacy question related to this class of medications. Dr Carolyn Lam: Efficacy and patients on hemodialysis. Wow. This really just opens up a lot, but you're right. It's such tantalizing information that you see in ... so thank you so much John, for publishing this paper with us. Chang-Sheng, it's such a great paper. I remember the discussions we had during our editors’ discussions and it's so nice to see it out in print. I'm telling you, audience, you have to get hold of this paper. It will change this field I think and will lead to further trials exactly like you've heard here, and that we've put John on the spot to describe. Dr Carolyn Lam: Thank you very much gentlemen for a wonderful discussion. Thank you, audience, for joining us. You've been listening to Circulation On The Run. Join us again next week. Dr Greg Hundley: This program is copyright the American Heart Association, 2020.  

Dr Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast soiree and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor for the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:            And I'm Greg Hundley, Associate Editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week we're going to talk about carotid stenosis, and you remember how we measure those a lot with ultrasound, and what that thickness is, and IMT? Well, we're going to talk about getting some thresholds and an update in that with our feature discussion today. But before we get there, how about grab a cup of coffee and we get started with other papers. Dr Carolyn Lam:               All right. Well, I've got my coffee and I'm ready to tell you about two papers. They're both on left ventricular hypertrophy. One is basic and one is clinical. I will start with the basic paper because it is a super cool one that uncovers a novel mechanism underlying myocardial hypertrophy. And this involves S-nitrosylation, a prototypic, redux-based post-translational modification, S-nitrosylation. So this is from co-corresponding authors, Drs Xie, Han, and Ji from Nanjing Medical University, who performed a series of elegant experiments using myocardial samples from patients and animal models exhibiting myocardial hypertrophy, and they demonstrated that S-nitrosylation of muscle limb protein plays a crucial role in myocardial hypertrophy. This muscle limb protein modification enhanced binding to toll-like receptor 3 and receptor interacting protein kinase 3, which stimulated NOD-like receptor pyrin domain containing 3 or NLRP3 inflammasome activation and consequent caspace-1 and interleukin 1 beta activation, ultimately promoting myocardial hypertrophy. They further showed that the deficiency of S-nitrosylated muscle limb protein governed toll-like receptor 3 really alleviates pathological myocardial hypertrophy. Okay Greg, I can see the look on your face. You're like what? That was a lot. What are the clinical implications, right? Dr Greg Hundley:            Yeah, Carolyn, you are taking me back to molecular biology course 410, that I would take as a senior in college. Wow. So tell me what are the clinical implications? Dr Carolyn Lam:               All right, here's a take-home. The data really identify that S-nitrosylated muscle limb protein is a key regulator, which together with toll-like receptor 3 made therefore serve as putative therapeutic targets in treating pathological myocardial hypertrophy in heart failure. That's the take-home. Before any further comments, let's go to the clinical study. Now, this one focuses on a malignant subphenotype of left ventricular hypertrophy in which minimal elevations of cardiac biomarkers identify individuals with left ventricular hypertrophy at high risk for developing heart failure. And this is from corresponding author Dr James de Lemos from UT Southwestern. He and his colleagues tested the hypothesis that a higher prevalence of the malignant left ventricular hypertrophy phenotype among blacks may contribute to racial disparities in heart failure risk. So they pooled data from three large multi-ethnic cohorts, that is Eric, Dallas Heart Study, and MESA, totaling more than 15,700 participants. These participants were then classified into three groups: One, those without ECG left ventricular hypertrophy; two, those with ECG left ventricular hypertrophy but normal biomarkers; and three, those with ECG left ventricular hypertrophy and at normal levels of two biomarkers, high sensitivity troponin T above six nanogram per liters, or NT-proBNP above 100 picograms per milliliter. And that last group were the malignant left ventricular hypertrophy group. They found that the prevalence of malignant left ventricular hypertrophy was threefold higher among black men and women versus white men and women. Compared to participants without left ventricular hypertrophy, the adjusted hazard ratio for heart failure was 2.8 in those with malignant ventricular hypertrophy and only 0.9 in those with left ventricular hypertrophy and normal biomarkers. And these were similar findings in each race and sex subgroups. Mediation analysis indicated that 33% of the access hazard of heart failure among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant left ventricular hypertrophy in blacks. Dr Greg Hundley:            So Carolyn, race could be a really important issue in left ventricular hypertrophy. What did the authors conclude? I mean, how should this help us perhaps manage these patients? What was the take-home? Dr Carolyn Lam:               So this really shows that a higher prevalence of the malignant hypertrophy phenotype may in part, explain the higher risk of heart failure among blacks compared to whites. And what it means too is that when left ventricle hypertrophy is detected by ECG or cardiac imaging, perhaps we should consider measuring high sensitive troponin T or NT-proBNP, which will help distinguish those in whom risk for heart failure is favorable from those at a much higher risk. Dr Greg Hundley:            Very, very interesting. Well Carolyn, I'm going to switch. I've got a basic paper and it's going to focus on dysfunctional adipocytes and how they might talk to cardiomyocytes in the situation of ischemia reperfusion injury. And the corresponding author is Xin-Liang Ma, from Thomas Jefferson University in Pennsylvania. So Carolyn, do you have any thoughts regarding how patients with diabetes might experience a greater degree of myocardial ischemia reperfusion injury in the setting of an MI? Dr Carolyn Lam:               Oh my goodness, you're really putting me on this spot here. Well, I know things that come to mind would be oxidative stress, microvascular disease. Dr Greg Hundley:            Very good. Open-ended questions for Carolyn's quiz. I'm going to give you a 90. That was very good. So Carolyn, this current study attempted to clarify whether and how small extracellular vesicles may mediate pathological communication between diabetic adipocytes and cardiomyocytes, exacerbating myocardial ischemia reperfusion injury. And to do this, adult male mice were fed a normal or high fat diet for 12 weeks. The small extracellular vesicles from diabetic serum, diabetic adipocytes, high glucose, high lipid-challenged, non-diabetic adipocytes were injected then, intramyocardially, distal of the site of a coronary ligation. Dr Carolyn Lam:               Okay. So Greg, I would not have guessed it was about extracellular vesicles, but very interesting. What did they find? Dr Greg Hundley:            Intramyocardial injection of diabetic serum small extracellular vesicles or these SEVs, in the nondiabetic heart, significantly exacerbated myocardial ischemia reperfusion injury, as evidenced by poor cardiac function recovery, larger infarct size, and greater cardiomyocyte apoptosis. And administration of small extracellular vesicles, biogenesis inhibitors, significantly mitigated the myocardial ischemia reperfusion injury in diabetic mice. And mechanistic investigations in these studies identified that MIR 130B3P is a common molecule, significantly increased in diabetic serum of small extracellular vesicles and mediated the pathological communication between the dysfunctional adipocytes and the cardiomyocytes. Therefore, if in the future, we could interfere with this molecule, that could perhaps be a novel strategy for attenuating diabetic exacerbation of myocardial ischemia reperfusion injury. Really, a clever study, I think. What else did you find in this issue of the journal? Dr Carolyn Lam:               Yeah, Greg, this week's issue is packed with other papers too. For example, there's the research priorities for HFpEF by NHLBI working group summary by Dr Shah, et al. There's a research letter by Dr Kaltman on the disparities in congenital heart disease mortality based on proximity to a specialized pediatric cardiac center. There's also another research letter by Dr Irisawa, on the impact of low-flow duration on favorable neurological outcomes of extracorporeal CPR, after out-of-hospital cardiac arrest, and this is a multicenter prospective study. Dr Greg Hundley:            It sounds like a lot's in the mailbag. In the couple of things that I wanted to talk about, Dr Giulia Rivasi from the University of Florence, and William White from University of Connecticut, exchange a series of letters back and forth regarding a previous publication on the effects of intensive versus standard ambulatory blood pressure control on cerebrovascular outcomes in older individuals. I have another research letter entitled, The Cardiac Cell Therapy Rejuvenates the Infarcted Rodent Heart via Direct Injection, but not by Vascular Infusions. And that is from Dr Jeffrey Molkentin from Cincinnati Children's Hospital Medical Center. Finally, though Carolyn, there's a very interesting piece from Dr Carl Bakker at the Ann and Robert H. Lurie Children's Hospital of Chicago, discussing are we now in a time, in the United States, where congenital heart surgery should be coalesced or regionalized? And that really comes on the back of a discussion of there have been several high-profile articles in the national media, reporting on US congenital heart surgery programs. And that's led to, the author describes, some closure of several centers and at least in five programs. So a great discussion on, should this be regionalized? But we've got a great feature article coming ahead and how about if we head to that. Dr Carolyn Lam:               Let's go, Greg. Dr Greg Hundley:            Welcome everyone, to this feature discussion where we are going to discuss the use of diagnostic ultrasound in the carotid arteries and how that pertains to selection of patients for vascular surgery. And with us today, we have Dr Jesse Columbo from the Geisel School of Medicine at Dartmouth University in Hanover, New Hampshire. We also have Dr Bob Zwolak, from the Manchester VA at the Dartmouth School of Medicine and we have our own Josh Beckman from Vanderbilt University, one of our associate editors at Circulation. And Bob, let's get started with you. Could you tell us a little bit, what was the background of this study and what hypothesis were you looking to test? Dr Robert Zwolak:           It goes without saying that stroke is still a huge health problem in the United States. If there is any good news, it's that stroke incidence is falling slightly, but there are still over 100,000 deaths from stroke each year in United States and as many as 700,000 new strokes each year, and a significant proportion of those derive from atherosclerotic plaque in the carotid bifurcations. Carotid duplex ultrasound is a fantastic way to assess the presence of plaque in the carotid bifurcations because it does not use any ionizing radiation, does not require any contrast. Ultrasound is a relatively less expensive technology than CT or MR, and the study can be repeated so we can follow people over time, who are found to have significant atherosclerotic plaque in their bifurcations. The hypothesis of our study though, was that there is variation in the diagnostic thresholds used by various carotid ultrasound testing laboratories, such that it may impact the healthcare and the treatment plans of people who undergo the studies. Jesse will tell you the details, but specifically, we hypothesized that people who undergo this carotid ultrasound test may or may not be inducted into a surveillance program and intensive therapy based on the diagnostic criteria that were used by the individuals conducting their ultrasound study. And even more substantially, we hypothesized that individuals who undergo carotid endarterectomy or potentially carotid stenting, could also have their procedure influenced, whether or not they undergo surgery or stenting based on the carotid ultrasound results. It might vary from one facility to another. So it potentially could be that an individual would be inducted into ultrasound surveillance or even undergo carotid surgery, depending on the vascular laboratory in which they were tested. Dr Greg Hundley:            Jesse, could you tell us a little bit, what was your study population and how did you design this to address the hypothesis that Bob just stated? Dr Jesse Columbo:          Sure. A review of the published literature really shows a variability in that ultrasound criteria that's used for diagnosing carotid stenosis. And so our first objective was to see if we could obtain as many in-use criteria as possible. Our first step was to partner with the Intersocietal Accreditation Commission, the commission that accredits vascular labs. We partnered with them and obtained a 25% random sample of ultrasound criteria in use across the US. And so that kind of gave us the starting point for the criteria upon which to look at. We then wanted to apply those to a couple of different groups. As Dr Zwolak mentioned, there's really two primary breakpoints here. One, you either have mild stenosis, where you get medical therapy, but no further surveillance, or moderate stenosis, at which point you then are dedicated to long-term surveillance per the AAJ recommendations, or then, the break point between moderate and severe stenosis where surgery is considered. What we wanted to do is examine the impact of moderate and severe stenosis thresholds. For the severe stenosis thresholds, we use the Vascular Quality Initiative Registry, which collects information on patients who underwent carotid endarterectomy. When we studied patients specifically that we thought the percent stenosis would be the major deciding factor in who got surgery, those are the asymptomatic stenosis and we applied the range of severe stenosis criteria from the IAC to those patients. We then wanted to study other individuals who might be committed to long-term surveillance based on the criteria used. And so for that, we used participants in the Cardiovascular Health Study, which had their induction into the study, had baseline data on carotid stenosis collected. And so that kind of formed our basis of the study, applying the criteria to those two different groups of individuals. Dr Greg Hundley:            And so how many subjects did you have in the two cohorts? And then tell us what were your study results? Dr Jesse Columbo:          Sure. Once we narrowed down that patients in the vascular quality initiative to those who underwent surgery for asymptomatic carotid stenosis, we had about 28,000 patients. And then when we examined the Cardiovascular Health Study, we had about 4,800 or 5,000 patients in that group. What we found was pretty interesting. If you look at individuals who underwent surgery, and you take the carotid threshold criteria and apply it to them, and if you say, "Well, we're going to take criteria in the fifth percentile versus criteria in the 95th percentile," what you'll find is that 10% of patients who got surgery, fall between that range. And what that means is that there are patients, approximately 10% of patients, who are undergoing surgery that may not have been offered surgery if they had gone to a different institution, which we thought a pretty important finding. The second part was studying patients who maybe committed to long-term surveillance. And if we took centers that were in the fifth percentile versus those in the 95th percentile for their carotid stenosis thresholds, we found a twofold difference in the number of patients that would be committed to long-term surveillance. And remember, this is the difference between getting aspirin and a statin and medical therapy, but no longer surveillance and getting carotid ultrasound every six months to a year for a long period of time. That twofold difference really could have a meaningful impact on patients. Dr Greg Hundley:            It sounds like we've got a variance issue here and that could really impact clinical care. So while ultrasound's very portable and advantageous, how do we use these results to more effectively select how we're going to implement ultrasound to monitor these patients? Dr Joshua Beckman:       I have to say the results of this study, when I read them the first time were eye opening. One point that doesn't come out clearly to those folks who aren't necessarily in the field, is that these are the labs that have been accredited and they are the top labs in the United States. This doesn't include at least half of the rest of the labs in the United States and suggest that if there's variation in the very best of labs, you know that there's even more variation that's being practiced routinely around the United States. So when I read this, I thought that there was a huge problem that they were uncovering. There are many, many millions of patients with atherosclerosis. And so what we have to figure out now is how to standardize the measurement and reading of these studies so that ultrasound can be deployed routinely, without a fear of your treatment varying based on which doctor you decide to see and where you decided to go. And I think the fact that these guys highlighted that in such a nice and clear way, really raises the alarm and raises the flag that attention needs to be paid here quite soon because it's quite important. Dr Greg Hundley:            So what study could we perform next? And maybe I'll ask, Bob, you just start off. What study could we perform next to help clarify and guide us to the better use of ultrasound in this situation? Dr Robert Zwolak:           Well, I think there are two issues. The first issue that this manuscript points out is the one of variation and it's real and the results speak for themselves. The second issue is the one of accuracy, and the question of what are the best thresholds? And there are several ways that this can be standardized. I'm pleased to say that the Intersocietal Accreditation Commission, the IAC, that Jesse mentioned, is actually tackling this problem. Dr Robert Zwolak:           But what's the gold standard? 40 years ago when ultrasound was developed, these thresholds that people are discussing, were related to measurements on contrast arteriograms. And the catheter-based contrast arteriogram, a relatively invasive study, was the source and we compared ultrasound velocities to the measurements on the contrast arteriograms to determine these thresholds that Jesse has investigated. That resulted in substantial variation depending on the individual authors. The question is, over time, have the machines changed? Is there really a central focus that we can look at? Most of these studies were very small and so it accounts for the variation in recommendations. Dr Robert Zwolak:           The IAC now, is going back and collecting contemporary contrast arteriograms, not so many of which are done anymore and so, it's taken a very substantial multicenter effort. But trying to look again, to see if there are more accurate results that could be published, studied in a way such that they would be universally accepted and potentially promulgated by professional societies within guidelines. And standardized such that various specialties, whether it's vascular surgeons who run the labs, or a cardiologist, or radiologist, would agree on a set of both accurate and reproducible and constant velocity thresholds to standardize this technology, which is otherwise a very, very good technology and eliminate this variation that we've seen. Dr Greg Hundley:            Well, this has been a phenomenal discussion in a very interesting piece of research. Jesse, can you give us sort of a point forward from here, how do we move forward with some of these results and what you anticipate seeing going forward? Dr Jesse Columbo:          Well, a duplex ultrasound for carotid stenosis is really important. There are lots of studies done. It's a great way to follow patients over time, in a noninvasive manner. And I might hope that this paper would open the eyes of some of the listeners as to what the carotid ultrasound really means. Instead of just looking at the percent stenosis on the report, to perhaps look at the raw velocities and interpret them in the context of the patient, because I think that has really important impact on how we might manage some of these individuals, for each person that you see. Dr Greg Hundley:            Well, listeners, we want to thank Dr Jesse Columbo, Dr Bob Zwolak, also Dr Josh Beckman, for discussing this very informative research related to the use of ultrasound for assessing carotid stenosis. Dr Greg Hundley:            On behalf of both Carolyn and myself, we wish you a great week and see you next week. This program is copyright, the American Heart Association 2020.  

Nobody ever thought Greg Porterfield (our Senior Pastor) would cancel church! Following the recommendations of public health officials, he has respectfully acquiesced to the unthinkable. Nevertheless, Pastor Greg reminds us that, though our circumstances may change how we do church, the "essence" of church extends beyond the building. So Greg offers us a morning message as a voice of hope and reason about how we may come together in the wake of all the coronavirus hysteria and be a force for God's goodness in the world.

 Announcer:                      00:05                  Welcome to what's your MO in Healthcare, the podcast that's all about understanding the core motives of the people you work with and manage in healthcare.Megan:                            00:17                  Welcome to What's your MO in Healthcare? And today I have Greg Clifford and he is a recently retired EMT who is joining me today to talk a little bit about his experience as a volunteer EMT, what that involves and what are some of the stressors and Things that may be people in the medical profession can learn from his experience, whether it comes to burnout or what drives someone to become an EMT and maybe learn some lessons from Greg. So with that, welcome.Greg                                                             Thanks for having me.Megan                                                         You bet. So Greg, let me start off. Um, you're a volunteer EMT. Recently retired. How long were you a volunteer EMT?Greg                                 01:05                  I've got 20 years at the end of this year in EMS. I started back in the 90s, but I took a few breaks and so, you know, there's actually more years since I started to now than there than I did in service.Megan:                            01:22                  And what interested you about the profession?Greg:                                01:27                  It's funny because I've sat on a lot of interview committees for new EMTs in our organization. We askthat question all the time. You know what, why do you want to be an EMT? What motivated you? Everybody gives a pat answer. I want to help people, right? What people forget to say, a lot of their motivations are beyond that. You know, it's nice to help people, but there's an excitement to it, right? There's a, maybe somebody was in a situation where they saw somebody that needed CPR or somebody who was in a car wreck. They came upon them and they felt helpless. And so for me, I had some situations like that too, where you know, that, wow, uh, I feel like I don't have anything to offer to these people that needed help. I had a landlord that was multigenerational firefighter and he invited me to come down to fire station one night, see what they did and what they were all about. And I saw that and I thought, this is so cool. These people are empowered with these new sets of skills with these tools to do something more than just stand by or call 911 So that's really above and beyond helping people why I wanted to do it.Megan:                            02:36                  So it was feeling empowerment, feeling like you could offer something and that satisfaction of building your skills. So why did you decide to do that on a volunteer basis versus making it a career?Greg:                                02:55                  I was already pretty far along in my career when I got the opportunity to try it out. But I did consider a career change at one point. But EMS is not a high paying field unless you've been in it a long time and you end up being management or something, you know, teaching you how to add things on, you know, or have lots of years of service. So it's, it's pretty low pay for what they have to do. So I stayed in the broadcast/IT world instead.Megan:                            03:30                  Yeah. It has its own stresses, I'm sure. So what does a volunteer EMT schedule look like? How does that work versus being on the payroll?Greg:                                03:44                  Different in every department. When I was in Pennsylvania, they had what they called the jolly volley slot and that was 6:00 PM to midnight. So after most people were done working, they would go and run until midnight when most people need to go to bed so they can sleep and do their day job. In Moscow here it's different. It's shift based. So you have A, B, C, D shift and you're on for 24 hours from 7:30 morning until 7:30 the next morning.Megan                             04:17                  when you say you're on, you're on call, correct?Greg:                                04:21                  Yup. So you carry a radio with you, you also have an app on your phone that will send you an alert and that's whatever you're doing, you're supposed to drop what you're doing and go answer the call.Megan:                            04:34                  So that might be one of those stressors in terms of being on call, because working in the healthcare field, I talk to practitioners and doctors and they say that's probably one of the most stressful things is being on call. So tell me why that is. Why is that stressful?Greg:                                04:51                  Yeah. You can never just truly relax, right? You can't even watch a movie at home without thinking, well, I've got to have my radio on. It's got to be loud enough that it can hear it over the movie. Um, at night when you sleep, you’ve got to balance like, well, I need this radio loud enough. It's going to wake me up, but hopefully not wake my spouse up. It's just never, you're always on alert. You're always on high alert. There's just no time to really, you know, you can't go out and eat, because your meal probably will get interrupted and you'll have to walk away from your friends that you wanted to have dinner with. Things like that. So you have to, you have to give up a lot while your on call.Megan:                            05:29                  And what are some of the other stressors that an EMT particularly volunteer EMT would experience?Greg:                                05:36                  Oh, you are going to eventually run into somebody you know and it might even be somebody that's your own family if you're in a small enough town. So you may find yourself doing CPR on your own relative or on your best friend’s relatives. It's a, yeah, that's another stressor for them.Megan:                                                        Any particular examples or stories that you're willing or able to tell that were particularly traumatic or that you remember?Greg:                                                           Well I did CPR on my own brother-in-law. That was a not a comfortable thing. And you know, we're, we're trained to just do our thing, right? We train enough, we know what to do. We just go into action. But you also look up once in a while just to see or is it still a safe place for me to be? Things like that. That's part of your training. And I remember doing CPR on my brother in law and looking up and what I saw was horrified faces of my wife and my sister in law and the grief on their faces. It was just so huge. And you know, you just feel that to the core of yourself when you see that going on. It happens with people you don't know. Yyu look up and see their grief, but when it's somebody, you know, it really strikes home.Megan:                            06:57                  How do you manage that? How do you come off of something like that?Greg:                                07:02                  It's hard. Mostly, at least for me, you just push it down deep somewhere and you try to put it away. And that's some of the motivation for me to stop doing this. I’ve pushed 20 years of it down and I'm not sure I have the resilience to keep pushing it down.Megan:                                                        How do you think it might express itself?Greg:                                                           Oh, all kinds of ways. I mean, burnout, you know, that's the thing. It's like, whether you call it burnout, compassion, fatigue, PTSD, they're all really tightly intertwined. All those terms and it expresses itself like “Ever been so tired that it hurts?”  mean, that's for me was the symptom as of late. It's just you, it doesn't matter who, if you sleep eight hours or 10 hours or 12 hours, you still just have to drag yourself out of bed the next day because it's not just a physical hurt, it's a mental hurt on top of it. It just consumes you. Just uses every bit of energy you have after a while.Megan                                                         So your colleague, some paid, some volunteers. Is it something that people talk about? Is it something that you can see maybe as someone who's maybe experiencing that have a higher awareness?Greg:                                08:28                  There is more awareness and it’s becoming more acceptable to talk about it nowadays. Um, there's a code green campaign, which is a bigger nationwide one, but even locally, we've tried to put together some peer support groups and things like that. And I think our command people are embracing it more than they used to. But in Moscow in particular, we're a very young organization as far as our EMTs. So our ratio of 20 year olds to people who are 40 plus is it's way different. So at 20, you've got a lot more resilience. I mean, these are the people that we're sending to the front lines in war and expecting to protect your country. Well, we do that because that's the age of people who, you know, charge forward. They work hard. They can go 24 hours without sleeping and still function the next day. You don't see a lot of really old EMTs and, that's why. Age has something to do with it. The physical nature of the work.Megan:                                                        But you're saying also the years of seeing things and pushing down those memories are the things that in order to keep functioning eventually does catch up.Greg:                                09:44                  Yeah. We had a, a recent college graduate who’s still with us in our EMS who said to a couple of us the other day, “I don't know how you guys do this and have full time jobs?” because now he's out of school and he's having to deal with the rigors of a full time job plus doing the volunteer work. He's only 20 somethin. It’s tough to balance it.Megan:                            10:11                  So any words of wisdom to a young person just getting into this field, maybe something around recognizing when they might be feeling burnt out or the importance of pacing yourself or anything after looking back at 25 years of doing this?Greg:                                10:31                  Yeah, I think you need to talk to people when you feel bad. It used to be everybody who is associated with fire departments, mostly with EMS and the volunteer world and they've got a way about them, you know, they eat smoke and they do brave things and run into fires and all this and that whole mindset wasn't really conducive to people saying “I don't feel good. I feel crappy after that call. I feel sad.” You just, you didn't say it. Nowadays there are different generations. We’ve got the Gen Z's and the Millennials and, and all that. They are less worried about having people judge them about mental issues and there's less stigma I think with these newer generations. I think they're more willing to talk about it. That's great. That's a positive.Greg:                                11:28                  I think it's good because you’ve got to talk it through sometimes. I'll have it build up and build up.  In a non-volunteer setting where you're running with a partner a lot and maybe the same core group of people. you talk amongst each other but in a volunteer situation, you don't often work with the same people all the time. Especially in our world (university town) where the churn happens because they graduate and they leave. So you end up always with new people and you don't have that comfort of, well this person knows me, I've been running with them for 10 years or 5 years or whatever. Right. It's a new person. So your shields are up a little bit around that new person and you're probably more in that mentor teaching role.Greg:                                12:19                  And they look to you as the wise one and you talk about positive things with them and encourage them to be better, not bring them down. So it's hard to take somebody that you're trying to mentor and, and say, “I had a really crappy call.” EMS isn't what you see on TV. It's not all emergency calls and resuscitations you know, a lot of it is nursing home calls and people who are too poor to get medical attention. So they call you because of whatever, you know, or they need to go to the ER because they can't afford a copay or if they even have insurance or they might not even have it.Megan                             13:19                  So you see a lot of cross section of people that uh, they're calling you because you're the only medical help they're going to get.  So I think what I'd like to do to end is bring it back to Color Code, which is what my podcast is based on. Remember it's a personality assessment tool. I asked you to take that test and you scored a little bit higher on Yellow, which is someone who's motivated by fun and likes that variety and excitement in their work. And that makes a lot of sense because that drew you to this field, which I imagine, you know, you never know what you're going to get into. There are folks who really like that. That's an adrenaline thing. Exciting. But you also tested fairly high on Blue, which is motivated by relationships again, makes perfect sense because you're working with people, you're motivated to help them. Those two colors happen to be very emotion-based so you can see how someone like yourself after 20 some odd years of doing this, it could be pretty draining because it's a highly emotional thing. It does make sense and helpful for people to think about that. That's why that's such an important tool because it helps you understand why you're responding the way you are and helps you make some decisions and understand how you can help yourself.Megan:                            14:52                  Well with that, Greg, I so appreciate it. Interesting topic and wish you all the best in your retirement and enjoy yourself after so many years of service that we really appreciate.Greg:                                                           Thanks. You bet. Okay. With that, this is What's your MO in Healthcare?Megan:                            15:12                  Thanks for listening to what's your MO in Healthcare? You can find us on Apple podcasts or on Podbean. If you like this podcast, we encourage you to subscribe and to let us know what you think. You can also follow us on Instagram, Twitter, and Facebook. Our website is MOinhealthcare.com

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And, I'm Greg Hundley, Associate Editor, Director of the Poly Heart Center of VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature articles, very interesting, discussing hypertrophic cardiomyopathy and sudden death in young individuals. But, let's save all the details for later and start in on our coffee chat. So, Carolyn, have you got a paper that you'd like to start with? Dr Carolyn Lam: I have, and it's a basic science paper. It's one that details the contribution of get this, M-C-U-B. Now this is a paralogue of the poor forming sub-unit MCU in mitochondrial calcium, uniporter regulation and function. Now, this paper shows, for the first time, MCUB's relevance to cardiac physiology, and it's from corresponding author Dr Elrod from Center of Translational Medicine, Louis Katz School of Medicine at Temple University in Philadelphia, and their coauthors, who showed, in a series of elegant work, that MCUB is absent from the uniporter complex in the homeostatic heart. But it's incorporated into the mitochondrial calcium uniporter following ischemic injury and thus represents an endogenous mechanism to limit mitochondrial calcium overload during stress. Interestingly, the increased incorporation of MCUB into this mitochondrial calcium uniporter is too little and too late to limit acute cell death following ischemic reperfusion injury but may limit cell loss during chronic stress. Dr Greg Hundley: So Carolyn, tell me what are the clinical implications of this important finding? Dr Carolyn Lam: Well, simply put, MCUB represents a novel therapeutic target to modulate mitochondrial calcium uptake in disease states speech during mitochondrial calcium overload such as myocardial infarction and heart failure. Dr Greg Hundley: Very nice, Carolyn. Well, I've got another basic science paper and it involves Protein Kinase N and how that promotes stress induced cardiac dysfunction through phosphorylation of myocardin-related transcription factor A and disruption of its interaction with actin. This comes from the corresponding author Mikito Takefuji from Nagoya University Graduate School of Medicine. So Carolyn protein phosphorylation of course, is a major and essential intracellular mechanism that mediates various cellular processes in cardiomyocytes, in response, extracellular and intracellular signals. The RHOA-associated protein kinase, or ROCK Rho-kinase, in effect, are regulated by the small GTPS RHOA causes pathological phosphorylation of proteins resulting in cardiovascular diseases. RHOA also activates Protein Kinase N, however, and the role of PKN in cardiovascular disease remains unclear. Dr Carolyn Lam: Ah, okay. So with that background, what did these authors find, Greg? Dr Greg Hundley: Great question, Carolyn. What they found is that PKN inhibits the binding of MRTFA to G-actin by phosphorylating MRTFA and activating SRF mediated expression of cardiac hypertrophy and also fibrosis associated genes. Also, they showed that cardiomyocyte specific PKN1 and PKN2 double deficient mice are resistant to pressure overload and ANGII induced cardiac dysfunction. Dr Carolyn Lam: Wow. There's a lot of letters in what you just said. So could you just tell us how does this impact heart failure research and management? Dr Greg Hundley: So Carolyn, this PKN family appears to play a role in regulating hypertrophy and fibrosis in the heart and therefore could serve as a unique target for therapeutic interventions for heart failure in the future. And so maybe it's going to make its way your way. Dr Carolyn Lam: Well, okay, well this next paper definitely is making its way my way and it focuses on the Sodium Glucose Co-transporter two inhibitors or SGLT-2 inhibitors, which we know lower cardiovascular events in patients with type two diabetes, but whether they promote direct cardiac effects as in that we can see in cardiac structure and function actually remained unknown until today's paper. And this is from Dr Subodh Verma and Dr Kim Connelly, these co-corresponding authors from St. Michael's Hospital and University of Toronto and their colleagues. And they sought to determine if empagliflozin causes a decrease in left ventricular mass in patients with type two diabetes and coronary artery disease. So this was a six month double blind randomized placebo controlled trial. If individuals with type two diabetes, coronary artery disease and relatively normal left ventricular mass index. The primary outcome was six month change in left ventricular mass index to body surface area from the baseline and measured by cardiac magnetic resonance imaging and they found that the empagliflozin allocated group exhibited a significant reduction in left ventricular mass index compared with the placebo group. Dr Greg Hundley: Wow, Carolyn. We have been hearing a lot about empagliflozin in the last several issues. How does this article differentiate what we do or maybe even change our practice? Dr Carolyn Lam: Well, you know what? It enhances our understanding which is important. We knew about the events. Now we perhaps understand a little bit more of what it may be doing actually to the heart in terms of cardiac structure and function. The so the decrease in left ventricular mass associated with empagliflozin may explain and contribute to the cardiovascular benefits observed in patients with type two diabetes and coronary artery disease who are treated with SGLT-2 inhibitors. Now it's interesting the way we've gone like reverse translation in this, haven't we? Observing the events and then trying to find the mechanism. And this is in fact discussing an editorial by Mark Petrie and titled SGLT-2 Inhibitors: Searching for Mechanisms in the Wake of Large Positive Randomized Trials. So Greg, after that, maybe you could tell us what else resides in this week's issue. Dr Greg Hundley: Oh my goodness, Carolyn. Well, there's quite a bit. First Paola Erba from Pisa, Italy provides a nice In-Depth review of the use of echocardiography, radioisotope imaging and computed tomography for the assessment of patients with endocarditis. In another article, Wayne Batchelor and Rebecca Ortega and their colleagues discuss a Perspective piece, several strategies to improve enrollment of racial and ethnic minorities into clinical cohorts and trials addressing cardiovascular disease. And of course we have our mailbox. And first is Dr Diamantis Tsilimigras from The Ohio State University, and he responds to a letter by Moris et al regarding the article: Effects of Arteriovenous Fistula Ligation, or cardiac structure and function in kidney transplant recipients. Barry Borlaug from Mayo clinic discusses the importance of right ventricular volume loading and high output heart failure with arteriovenous fistulas. And Carolyn, our own Joe Hill and a first author Dan Tong coauthor a letter pertaining to whether female sex is protective in a preclinical model of heart failure with preserved ejection fraction. And then finally Toby Coates from Australia responds to several inquiries related to a prior publication regarding a published article involving the effects of arteriovenous fistula ligation on cardiac structure and function, again in kidney transplant recipients. There's an On My Mind piece from Dr Heinrich Taegtmeyer from McGovern Medical School at The University of Texas Health Science Center at Houston, or UT Health, relating to characteristics of past prominent investigators. What makes them tick? What contributes to their long-term success and sharing their catch with others? And it's interesting Carolyn, because he compares the vast community of cardiovascular investigators to those that are like anglers or fisherman. Their passion is kind of like the allure of catching just one more. And in so doing, they like to share their catch with others. Dr Carolyn Lam: That is hilarious. I don't think I've ever wanted more to be a fisherman or angler myself. Well that's great, Greg. Thanks and let's carry on with our feature discussion, shall we? Dr Greg Hundley: Absolutely. Welcome everyone to our feature discussion and we're going to discuss hypertrophic cardiomyopathy and sudden cardiac death and the relationship to exercise. And our study comes from Ontario and our lead investigator is Dr Paul Dorian from St. Michael's Hospital, and we also have our associate editor Mark Link from Dallas, Texas. Welcome gentlemen. And Paul, I'll start with you, tell us a little bit, what was the hypothesis and what were the aims that you were trying to accomplish with this particular study? Dr Paul Dorian: Our hypothesis was that the likelihood of sudden death in patients with hypertrophic cardiomyopathy may be less than has previously been supposed. In brief, the community that looks after patients with HCM, we'll call it for short, is faced with a major challenge in knowing what the actual rate of sudden cardiac death is and it seems to be a little bit of a moving target. Over the last decade, I think that most clinics that look after these patients were faced with what appears to be a less and less frequent likelihood of sudden death in these mostly young patients that we follow. And because we have the opportunity to study this using a well-established prospective coroner database with autopsy results in all sudden deaths in Ontario in young individuals, that we have the opportunity to test our hypothesis that this sudden death rate is lower than had previously been suspected. Dr Greg Hundley: It sounds like younger patients and trying to investigate the cause of sudden cardiac death. Can you tell us a little bit more about your study population and what was your study design? Dr Paul Dorian: We had the fortune of being able to use the Coroner of Ontario database. Ontario has about 13 million population and by the longstanding design, almost all patients under the age of 45 who suffer out of hospital, sudden cardiac death receive a full coroner investigation and then 90% of them, it's an autopsy which includes a cardiac autopsy by a qualified forensic pathologist. And in the case of cardiac hypertrophy, the cases are re-reviewed by a specialized cardiac forensic pathologist. So we have very extensive, if you like, detective work, CSI-type information on virtually everybody who dies out of hospital suddenly including those individuals among them who have hypertrophic cardiomyopathy. And what we did was we reviewed every single case of unexpected sudden death, looking for the specific diagnosis of cardiac hypertrophy or HCM. We verified the accuracy of our numbers by also using, for at least portions of our follow-up, the complete emergency medical services database for about 7 million people, mostly from Toronto. And this included all patients who had a 9-1-1 call for documented cardiac arrest. So we were able to verify that we missed essentially no patients without a hospital cardiac arrest who then died suddenly. Dr Greg Hundley: Give us a little bit more about the numbers. So what was the age range of your study population, perhaps the gender and breakdown, things like that? Dr Paul Dorian: We looked at individuals under the age of 45 but the median age was 36 for all of our patients. About 85% of the patients with documented HCM were male, 83% to be precise. And a pretty small minority of them. Had comorbidities that we would expect including hypertension, diabetes, et cetera. 11% were on beta blockers, and a small proportion had atrial fibrillation. So these are generally healthy individuals, or at least they had had relatively little interaction with the healthcare system and about half of these individuals had previously been diagnosed clinically with HCM and the rest had not been diagnosed as far as we could tell, or at least there was no medical record of them having been diagnosed with HCM. Dr Greg Hundley: And what was the total number of individuals in this study? And then tell us a little bit about your study results. Dr Paul Dorian: The total number of individuals who had definite HCM was about 45 we had 31 patients who were not known to have HCM who had definite HCM, which we defined as having myocardial disarray on cardiac microscopy and another 13 who are not known to have HCM. And then we had about another 10 patients who we thought had possible HCM because they had autopsy with hypertrophy but didn't have disarray. And a few patients that were diagnosed with HCM but didn't have autopsy. So the total population was approximately 50 patients and this is out of a total population of estimated population of about 140,000 HCM person-years using the widely estimated prevalence of HCM of one in 500. Dr Greg Hundley: And what did you find? Dr Paul Dorian: The bottom line, if you like, is that the annual incidence of unexpected sudden death, this would be out of hospital sudden death, was many folds lower than would've been expected based on prior publications and on prior risk calculators that are used by many physicians who for these patients. If your readers or the listeners just want single numbers, the total number of both definite probable and possible HCM related sudden death, this is the most sort of conservative estimate, would be approximately 0.4 per thousand person-years. So this would be less than one per thousand. This would be one half of one 10th of 1% so less than one per thousand per year. Patients with HCM will have sudden death. If we take the most conservative definitions. Dr Greg Hundley: Now, could you tell whether these sudden deaths were related to exercise? That was sort of one of the feature questions. Dr Paul Dorian: Absolutely. That's how we were of course, very interested so we defined both exercise as somebody died or doing sport or observed during exercise. I should emphasize that the coroners do extremely careful digging if you like into the circumstances. They interview paramedics, police, they have the police and paramedic report, they interview physicians, relatives, so they do a very thorough assessment of course as best as could be told after the fact. 65% of the sudden deaths occurred at rest and 18% occurred during light activity and about 10% occurred during exercise. Dr Greg Hundley: Very good. I want to turn over to Mark now. This is Dr Mark link from University of Texas Southwestern in Dallas. Mark, how can we put the results from this study in the context of other studies relating to implementation of defibrillators in patients with hypertrophic cardiomyopathy? Dr Mark Link: This study brings up a lot of issues and I want to applaud Paul and his gang for doing this. The data is very good. The autopsies are very good. So the quality of the data is excellent and the incidence of sudden death for a hypertrophy is lower than any other study that we've seen. And there are a number of possible reasons for that. Well, you know, one is that the Toronto group was using autopsied determined HCM or most other studies were kind of a mixed bag of clinical and autopsy and newspaper reports and all sorts of things. So the Toronto data is going to be probably the most accurate. The other issue, or the other question I think that could lead to a low incidence, is the denominator, in that there were estimated to be more hypertrophy in Toronto than there actually are. They use the commonly accepted one in 500 and I think that's a reasonable number across all sorts of populations that we see, but is it possible that maybe the one in 500 number isn't true for Toronto? You know, I've heard one person explain this is that patients with HCM can't stand the cold weather. So they left Toronto, but it is a much lower number than we've seen in regards to sudden death. A couple of other things I think are very interesting in this study. One is that if you looked at the individuals that got ICD shocks for ventricular arrhythmias is there was about as many people as died suddenly, arguing that the Toronto physicians can actually in many ways predict who would benefit, predict which hypertrophy would benefit from an ICD. Since many of these hypertrophies didn't have appropriate ICD shocks. And I also found fascinating that more of the deaths occurred during rest or light activity than exercise. We all tend to think that HCM causes its sudden death with exercise. And what this study's telling us is that's not true that more sun deaths are during rest and light activity. So there's a lot of very interesting insights that come out of this manuscript in this data. Dr Greg Hundley: Just following up on your last point, are there any inferences regarding activity in this patient population that we should take away from these study results? Dr Mark Link: I think if you look at the early newspaper reports and they're in there as reports of the incidence of HCM, sudden deaths during sports. So it was because of that, that everyone associated HCM with death during sports. But you have to remember those studies didn't include athletes that died at night. Athletes that died during dinner. They only included athletes that died during sports. So we were missing a large percentage of the hypertrophs dying. And I think we sort of infer that it was exercise that was dangerous, but in fact there's really not that much data that would support that exercise is dangerous for patients with HCM. Dr Greg Hundley: Interesting. So I'll maybe ask Mark first and then come back to you, Paul. Do you think there are tools that could be available, either blood testing or perhaps other imaging that could help identify which HCM patients may benefit from a defibrillator? Do these results help us in any way make that decision? Dr Mark Link: Unfortunately, I don't think this study offers us any clues into which patients should get defibrillators. And clearly there are other data that look at risk factors for sudden cardiac death in hypertrophic cardiomyopathy. And one of the things that has come out over the last 10, 15 years is that magnetic resonance imaging, and in particular the scar burden magnetic resonance imaging may actually offer additional prognostic information to our traditional respect for stratification grade CM. Dr Greg Hundley: Paul, do you have anything to add? Dr Paul Dorian: Just a couple of things if I may. I think on that last point I completely agree with Mark. Of course we didn't have data on MRI, but the greater the scar burden, the greater our index of suspicion. It is interesting that 57% of the cases of sudden death had asymmetric septal hypertrophy, so we can at least hypothesize that it is possible that patients with septal hypertrophy as opposed to concentric hypertrophy may be at higher risk. The one thing I might want to highlight for the listeners is that it would seem to me based on our data and based on our suspicions, is that there's probably a difference in the risk in patients who are discovered incidentally. In other words, somebody has an echocardiogram or an ECG for reasons unrelated to their heart and then HCM is discovered and these might be asymptomatic patients as opposed to patients that tend to be followed in specialized clinics who often are sent there because they have some symptoms or there's some specific signal that they have a clinically evident HCM. So I wouldn't want listeners to conclude that the risk is necessarily this low in patients that are transferred to a clinic because of disarray or atrial fibrillation or electro regurgitation or some other manifestation of a hypertrophic cardiomyopathy. Dr Greg Hundley: Paul, I want to start with you first. What study do you think should follow yours? What's the next study? Dr Paul Dorian: What I'd like to see, and this is technically feasible although practically challenging, is to use the big data approach and combine in one large database, all echocardiograms done in a large geographic area. All electrocardiograms done in a large geographic area with supplemented with clinical information and do, over a long period of time, a prospective study looking at all patients with cardiac hypertrophy, particularly asymmetric hypertrophy or suspected to have HCM to look at the long-term outcomes. And this should be feasible because most echocardiograms today are uploaded if you like, into a database. Dr Greg Hundley: Very nice and Mark, how about you? Dr Mark Link: I have similar opinion. Any one of the most important things in HCM is being able to predict who would benefit from a defibrillator, and currently our ability to risk stratify is woefully inadequate. It lacks sensitivity and specificity. And so with a larger population of HCM patients, and I think Paul's correct followed prospectively, not retrospectively, with the kind of data that we would want to be complete, including echo. Now, MRIs would be fantastic, but there's just no way that's practical, but to have echoes and EKGs and clinical factors and be followed prospectively really to hone down which patients would benefit from a defibrillator, and which patients would not benefit. Dr Greg Hundley: Well listeners, this has been a great discussion and we want to thank Dr Paul Dorian from the St. Michael's hospital for providing this paper to Circulation and sharing these results with us and also our associate editor, Dr Mark Link from Dallas, Texas and both have emphasized in this study that those individuals with HCM, while we often see them on the sports programs and whatnot, having their, experiencing their event during activity, they also occur within activity. For Carolyn and myself, we wish you a great week, and we look forward to talking with you next week in our next chat. Bye now. Dr Carolyn Lam: This program is copyright American Heart Association 2019.  

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and    backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Poly Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, this issue is super exciting. It's the ESC simultaneous publication issue, isn't it? So the original papers were simultaneous publications at the European Society of Cardiology meeting this year. Dr Greg Hundley: Oh, wow. Carolyn can't wait to get to these. So Carolyn, later we're going to listen to the authors of this feature discuss the association between ICD use and all-cause mortality in a contemporary heart failure reduced ejection fraction cohort and examine relevant subgroups. So Carolyn, I'm going to get started with my first paper and it's a randomized trial of one hour, one-hour deponent T protocol and suspected acute coronary syndromes and it's a rapid assessment in emergency rooms and it's from professor Derek Chew from Flinders Medical Center. High sensitivity troponin assays promise earlier discrimination of MI, yet the benefits and harms of this improved discriminatory performance when incorporated within rapid testing protocols with respect to subsequent testing and clinical events has not been evaluated in an in-practice, patient level, randomized study. So this multicenter study evaluated the non-inferiority of a zero to one hour, zero to one-hour, high sensitivity troponin T protocol compared with a more traditional zero to three-hour mask, high sensitivity troponin T protocol in those suspected with ACS. Dr Carolyn Lam: Interesting. So what did the study show? Dr Greg Hundley: So participants in the zero to one-hour arm were more likely to be discharged from the ED quicker and that would be expected. So 45% versus the standard arm, which was 32%. Also their median ED length of stay was shorter, and we would expect that. Four and a half versus five and a half hours. Those randomized to the zero to one-hour protocol were less likely to undergo functional cardiac testing. The zero to one-hour high sensitivity troponin T protocol was not inferior to standard of care and among patients discharged from the ED, the zero to one-hour protocol had a negative predictive value of 99.6% for 30-day death or MI. So Carolyn, how about your first study? Dr Carolyn Lam: Well, from MI risk stratification to heart failure risk stratification. I'm going to tell you about a paper describing the TIMI Risk Score for heart failure in diabetes, which is a novel integer base clinical risk score for predicting hospitalization for heart failure in patients with type two diabetes. This is from Dr Mark Sabatine and the TIMI study group who developed a clinical risk score for heart failure hospitalization in more than 8,200 patients with type two diabetes in the placebo arm of saver TIMI 53, as well as externally validated this score in more than 8,500 patients with type two diabetes in the placebo arm of declare TIMI 58. They found that five clinical variables were independent risk predictors of heart failure hospitalization. These were prior heart failure, history of atrial fibrillation, coronary artery disease, estimated GFR, and urine albumin-to- creatinine ratio, a simple integer base score from zero to seven points. Using these predictors identified a more than 20 full gradient of heart failure hospitalization risk in both the derivation and validation cohorts with high SES statistics. Although the relative risk reductions with dapagliflozin were similar for patients across the risk scores, the absolute risk reductions were greater in those with higher baseline risks. Dr Greg Hundley: Wow, Carolyn. So tell us what are the clinical implications of this really thorough study? Dr Carolyn Lam: In summary, the risk score had excellent discrimination in two large clinical trial cohorts. It was well calibrated, and it identified a strong gradient of increasing absolute reduction in risk of heart failure hospitalization with the SGLT two inhibitor dapagliflozin. So by using this TIMI Risk Score for heart failure in diabetes, which is a simple validated clinical risk score, clinicians could better educate patients about their risk for heart failure hospitalizations and could perhaps better identify those patients who have a greater absolute risk reduction in heart failure risk with SGLT two inhibitors. Dr Greg Hundley: Very good, Carolyn. Well, I'm going to go back to the world of troponins and talk about a paper from Nicholas Mills from University of Edinburgh. And in this study, they evaluated the safety and effectiveness of risk stratification thresholds of high sensitivity troponin in patients with suspected acute coronary syndrome. 48,282 consecutive patients with suspected ACS were enrolled in a multicenter trial from 10 hospitals within Scotland and they're pre-specified secondary and observational analyses. They compared the performance of the limit of a detection of less than two nanograms per liter versus the optimized stratification threshold of less than five nanograms per liter using the Abbott high sensitivity troponin I assay. Patients with myocardial injury at presentation with less than two hours of symptoms or with ST segment elevation myocardial infarction were excluded and the negative predictive value was determined in all patients in subgroups for a primary outcome of MI or cardiac death within 30 days. And they had a secondary outcome that was MI or cardiac death at 12 months. Dr Carolyn Lam: Nice. So Greg, which threshold of troponin was the optimal one? Dr Greg Hundley: So the negative predictive value for the primary outcome was 99.8% and 99.9% in those with cardiac troponin I concentrations of less than five or less than two nanograms per leader respectively. At both thresholds, the negative predictive value was consistent in men and women across all age groups. Although the proportion of patients identified at low risk fell with increasing age. Compared to patients with cardiac troponin I concentrations of greater than five nanograms per liter but less than the 99th percentile, the risk of MI or cardiac death at 12 months was 77% lower in those with less than five nanograms per liter and 80% lower in those with less than two nanograms per liter. So in conclusion, use of risk stratification thresholds for high sensitivity cardiac troponin I identified patients with suspected acute coronary syndrome in at least two hours of symptoms at low risk presentation irrespective of both age and sex. Dr Carolyn Lam: Very nice. Well, more risk stratification in this next paper, which really evaluated the application of the 2018 ACC AHA Cholesterol Management Guideline recommendations for additional lipid lowering therapies in patients with established atherosclerotic cardiovascular disease and residual dyslipidemia despite maximum tolerated Statin who were enrolled in the ODYSSEY OUTCOMES trial. Now, just as a reminder, the 2018 US Cholesterol Management Guidelines recommend additional lipid lowering therapies for secondary prevention in patients with LDL above 70 or non-HDL above a hundred despite maximum tolerated Statin therapy. Such patients are considered at very high risk based on a history of more than one major atherosclerotic cardiovascular disease event or a single event and multiple high-risk conditions. So in this paper from Dr Matt Roe from Duke Clinical Research Institute and colleagues, they found that in the ODYSSEY OUTCOMES trial, patients classified as very high risk by these 2018 ACC AHA guidelines and either because of a history of multiple atherosclerotic cardiovascular events or a single event, which is a trial qualifying acute coronary syndrome and multiple high risk conditions, these very high risk patients had more than double the risk of recurrent cardiovascular events as compared to patients classified as not very high risk.  They further looked at the association of Alirocumab with outcomes and found that Alirocumab was associated with a consistent relative risk reduction in both risk categories. But the absolute risk reduction for major adverse cardiovascular events was numerically greater, although not statistically different, in the very high-risk group versus those not at very high risk and among patients at very high risks with multiple prior events versus a single prior event. Dr Greg Hundley: Wow, Carolyn. Can you put all this together? This is a lot of information in this study. Dr Carolyn Lam: Yes, so it would appear that the application of the new ACC AHA 2018 guideline recommendations for risk stratification and the use of additional lipid lowering therapies in patients with established cardiovascular disease clearly identifies patients at very high risk of recurrent cardiovascular events after an acute coronary syndrome and these patients may derive substantial benefit from additional lipid lowering therapy, for example, with a PCSK nine inhibitor. Dr Greg Hundley: Very nice, Carolyn. Well, let me just finish off with what other articles we have in this ESC featured issue of our journal. So Jonathan Stamler and John Lundberg in separate letters discuss findings related to whether hemoglobin beta 93 cystine is not required for export of nitric oxide bio activity from the red blood cell. And in additional separate letters, Doug Lewandowski and Heng-Chen Yao discuss preservation of ACL CoA and attenuation of pathological and metabolic cardiac remodeling through selective lipid trafficking. In a perspective piece, Blake Thomson from the University of Oxford discusses what Medicare for all in the United States can mean for US medical research and provides lessons from the United Kingdom. In a letter from the United States, Gregory Marcus from University of California San Francisco discusses incident atrial fibrillation among American Indians in California and then both Marco Bergonti from University of Milan and Derek Chew from University of Calgary present two separate cases in our ECG challenge feature. Well, Carolyn, what a great issue and how about we turn to our feature discussion? Dr Carolyn Lam: Yes, let's go. Thanks, Greg. Dr Greg Hundley: Welcome, everyone, to our feature discussion today we have Gianluigi Savarese from Karolinska Institute in Stockholm, Sweden and our own associate editor, Sana Al-Khatib from Duke University. We're going to be discussing implantable cardioverter defibrillators in their mortality and looking at a more recent take on this relative to some of the previous published studies. So Gianluigi, I'd like to start with you. Could you tell us a little bit about the hypothesis and why you wanted to perform your study? Dr Gianluigi Savarese: Yes. Basically we design our study based on three main considerations. First one is recent studies show that the advance in heart-failure therapies have impact patients' risk profile leading to roughly 40% reduction risk of sudden cardiac death in HFrEF and RCTs on ICD use for primary prevention of sudden cardiac death and rural patients more than 20 years ago and thus, nowadays the beneficial prognostic effects of ICD may be different due to the improved risk profile in this population. The second consideration was that efficacy of ICD patients with heart failure with non-ischemic cardiomyopathy patients receiving a contemporary heart failure therapy as being a question in Danish trial and the third consideration is that efficacy of ICD in elderly is still debated due to findings again from the Danish trial showing a significant reduction in all-cause death associated with ICD use in patients age younger versus older than 70 years old. Based on these considerations, we decided to assess the use of ICD for primary prevention propose in a contemporary and selected FRF population and to assess the association between ICD use and outcomes in such a population. Dr Greg Hundley: So it sounds like we're doing an update on the utility of ICDs. Can you tell us a little more about your study population and your study design and then let's hear a little bit about your results. Dr Gianluigi Savarese: Sure. First of all, I would like to first highlight of course the observational natural of this study. Our analysis is performed using data from the Swedish Heart Failure Registry, which is a large enough select court of heart failure patients, enrolling patients regardless of ejection fraction. So today we have roughly around 70,000 patients. And of course for the current analysis we select the patients with HFrEF. There were around 15,000 patients with the HFrEF who were eligible for ICD use for primary prevention according to the ESC guidelines. A study design, we used propensity score matching design in order to try to address the issue of potential compounders. Of course this is a very important point in observational studies. So basically, we amassed patients receiving the ICD versus those not receiving ICDs. And we assessed the association between ICD use and all-cause death and cardiovascular death and we accessed one year and five-year outcome. Dr Greg Hundley: And so what were some of those results? Dr Gianluigi Savarese: What we observed is that there was a statistically significant 25 relative risk reduction in all-cause mortality in ICD recipients versus those who didn't receive an ICD within one year and there was also a 12% reduction erased within five years. And we also serve a statistically significant 29% reduction in risk of cardiovascular mortality within one year. But we were not able to observe any association for cardiovascular mortality within five years. We thought it was particularly relevant to have subgroup analysis in our studies since there are so many questions regarding ICD use in specific subgroups, which are, for example, older versus younger patients, those with versus without ischemic heart disease, males versus the females and so on. So what we observed was that results in terms of all-cause mortality were consistent in all of the subgroups considered such as patients older versus younger than 70 years old, versus those without history of ischemic heart disease and those with versus without concurrent CRT use. Dr Greg Hundley: What about the frequency of implanting ICDs? Was the frequency expected in your results? Dr Gianluigi Savarese: We add that only 10% of our patients received an ICD at the baseline. This person's age is quite low in particular. If we compare these with other studies in US for example, or also in other European countries and basically, we can only speculate about the underuse of ICD in primary prevention propose. First of all, a certain proportion of ICD underuse may be explained by the fact that we could not assess whether life expectancy was longer than one year, and this is one of the eligibility criteria for ICD according to the guidelines. Then another point is that in Sweden, the majority of heart failure patients are seen by primary care physician and general practitioners who may have less knowledge and acceptance of device therapy and then higher perception of contraindication. In our previous analysis, we showed that patients not seen by cardiologists have lower likelihood of receiving an ICD and use of devices is higher in centers who do implants, CRT, ICD. So this may be some of the explanation that I can anticipate that some more analysis will follow where we will try to assess the predictors for an under use of ICD for primary prevention. Dr Greg Hundley: Well, thank you very much. Sana, now we're going to turn to you and help us put this study in perspective to what we have already found or observed in other prior studies related to implantation of cardio defibrillators. Dr Sana Al-Khatib: As was mentioned earlier, I was the handling associate editor for this paper, so I really enjoyed the handling it and writing an editorial on it. The main points that I wanted to touch on are number one, the significantly low or reduced utilization rate of ICDs. So as was mentioned, the 10% of this patient population received a primary prevention ICDs. Even if you account for some of the new ones is that you can't estimate life expectancy. You can't capture granular clinical data on these patients. So of course some of the non-use of ICDs may have been appropriate. I think 10% by anyone's definition is still pretty low and I'm very encouraged to hear that there are plans to look at predictors of non-use, the characteristics of those patients and hopefully the office can build on their findings and try to implement some strategies to improve the utilization of this life saving therapy. The other thing that I wanted to touch on is clearly the results are positive in favor of the implantable cardioverter defibrillator. Showing that it significantly reduces all-cause mortality within one year, within five years, certainly reduces cardiovascular mortality within one year. As was mentioned, the reduction in cardiovascular mortality within five years was not significant and to me that is probably mostly explained by competing causes of death in this patient population, but I also cannot rule out the possibility of some mis-classification of causes of death, which is not uncommon. I do want to commend the authors for the great and robust methods that they applied in their analysis. As was mentioned, this was a comparative effectiveness research using observational data. These kinds of analyses can be pretty challenging, but the authors defined their patient population very clearly. They used propensity score matching. In fact, they took it a step further by doing a negative control analysis, meaning looking at hospitalizations for renal failure, for pneumonia, respiratory infections, things like that that you don't expect to be affected by the ICD and they found no difference in that. And that is amazing to kind of see this level of analysis that I believe really lends their results more credibility. It is important though to keep in mind that when you have 10% of patients getting an ICD, I suspect that this was a highly selected patient population and most likely people who were thought to benefit the most from ICDs were implanted with an ICD. And yet, as I said, that given the robustness of the methods that they use, I actually believe the results. I think the results are credible. The one last point that I want to comment on is the subgroup analyses that were mentioned. Absolutely important subgroups to look at from a clinical perspective. But I point out the fact that when you start looking at subgroup analyses, and especially when you have a smaller sample sizes and lower event rates that it makes you start thinking about, "Well, are these results valid? Are they believable?" I mean, even honestly, in the setting of a randomized clinical trial, I look at subgroup analyses as hypothesis generating. So I liked that they included those just to kind of really emphasize the importance of looking at these subgroups. But I certainly would not put too much weight on the subgroup analysis results, but overall great results and congratulations to the authors. Dr Greg Hundley: Fantastic overview, Sana and Gianluigi. So on behalf of Carolyn Lam and myself, we wish you a great week and we look forward to speaking with you next week. Dr Carolyn Lam: This program is copyright American Heart Association 2019.  

Amazon Strategy   Links Mentioned: www.rainmakerpartner.io www.amazing.com www.smartmarketer.com www.advertisingboost.com www.collective.com.au www.GetMeToDone.com www.Productiveinsights.com www.YouTube.com/ProductiveInsights www.CallAshRoy.com www.PremiumProductivity.com Related Episode: 055. Ezra Firestone on How To Use Ecommerce To Take Your Business From Six Figures To Seven Ash Roy and Greg Cassar Video Transcript (This transcript has been auto-generated. Artificial Intelligence is still in the process of perfecting itself. There may be some errors in transcription): Greg Cassar: 00:00 Amazon doesn't allow you to track conversions like when you got a sale from an outside traffic source so it is a little bit harder and they don't allow you to do remarketing except for if you're a big seller and you're using their tools. So Amazon, the only way we do that is like we drive traffic from the videos out on social media about key products. We do like Facebook video view ads and we send them in but we can't really track and measure. We can just see that if we turn that off, their sales go down and the social buzz goes down and that kind of stuff. Ash Roy: 00:35 Welcome back. This is Ash Roy. I'm the founder of productiveinsights.com and the host of the productive insights podcast. And I'm delighted to have Greg Cassar back on the podcast from Rainmakerpartner.io. Now, Greg recently was on the podcast and he talked about some high level strategies around building a successful online business and we talked through the various kinds of business models, starting with a local business where you're trading your time for money and then a more services based business where it's a little bit higher end. Then we talked about having an information product business, which was a bit further up the line way. You're not trading time for money as much and it's a bit more leveraged. And then we talk about Amazon and SAS being at the top of that succession where you build something that is more of an asset and something that tends to generate income more on automatic. Ash Roy: 01:29 In this episode, Greg and I are gonna dig a bit deeper into the tactical aspects of building an Amazon based eCommerce business that will enable you to create a lifestyle that Greg currently enjoys, which means that he is free by 9:00 AM every morning from all his commitments that generate his income. And he is pretty much free to do whatever he wants to do with his time after that. So I'm sure all of us would like to establish that lifestyle. Uh, it isn't something that's gonna happen overnight. I'm not gonna lie to you. This is not one of these get rich quick schemes. It takes a long time to do it. It took Greg about 15 years and I suspect it would take most of us around that long. That said, Greg has worked with some of the smartest people online, including people like Ryan Deiss, Ezra Firestone, and many others, several of whom have been guests on this podcast. And so I'm delighted to have Greg back on once again from Rainmakerpartner.io. Welcome back, Greg. Greg Cassar: 02:34 Hey, thank you. Actually, it was a great introduction. I hope I can live up to it. Ash Roy: 02:39 Well, thank you so much for being on the show, Greg. I've known you for about five years and it's really been a pleasure every time we've met. Um, and so thank you for coming back on. So Greg, let's talk a bit about how you have used online strategies and really leveraged your journey of 15 years to culminate in your epic success of $1 million in revenue in the last 12 months. Can you talk to us about that journey and can you also bake in where you see yourself in two years time? Greg Cassar: 03:12 Yeah. Gotcha. So I guess it didn't, if you look at it like for example, the last that business you're talking about is, um, I've got some amazing partners in the physical products space.

Dr Carolyn Lam:                Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, associate editor from the Pauley Heart Center in Richmond, Virginia at VCU Health.                                                 Well, Carolyn, we've got a great feature article to discuss later in our interview today. We're going to compare surgical versus percutaneous aortic valve replacement, but now with coronary artery revascularization. So, very exciting results from the SURTAVI trial.                                                 So, Carolyn, do you have a couple papers to discuss? Dr Carolyn Lam:                For sure. Actually, it's exactly a couple, and it's a couple of GWAS papers. The first is a GWAS of the cardiac magnetic resonance imaging derived left ventricular phenotypes of the UK bio bank. It comprises almost 17,000 European-UK bio bank participants without prevalent myocardial infarction or heart failure. So this was led by professors Petersen and Monroe from Queen Mary University of London, and colleagues who found that prognostically important left ventricular imaging phenotypes were highly heritable, with a heritability of 22 to 39%. A total of 14 genetic susceptibility low PSI, eight of which were unique, enriched in the cardiac developmental pathways and regulation of contractile mechanisms were discovered, and the polygenic risk scores of left ventricular phenotypes were predictive of heart failure events independently of clinical risk. Dr Greg Hundley:             Well, Carolyn, knowing me and MRI, something I really am interested in. So tell us a little about what are the clinical implications? Dr Carolyn Lam:                Well, the findings not only enhance our understanding of the genetic basis of prognostically important left ventricular phenotypes in the general population, but they also underscore the intricate genetic relationship between these endo phenotypes and the pathogenesis of heart failure. The prioritized genes in the genome whites significant load size should be followed up in the functional studies to aid the development of potential novel therapies in future. The polygenic risk scores of left ventricular phenotypes may have a role in personalized risk stratification. But this, of course, is dependent on further validation of the clinical robustness in future studies.                                                 I want to skip onto my second GWAS paper, and this time dealing with bicuspid aortic valve. So, first a little reminder that bicuspid aortic valve disease is a congenital defect that affects 0.5 to 1.2% of the population, and is associated with comorbidities including ascending aortic dilatation and calcific aortic stenosis. To date, while a few causal genes have been identified, the genetic basis for the vast majority of bicuspid aortic valve cases remains unknown. Today's paper from Dr Lipschultz from Medical University of South Carolina reports novel human genetic based models, which developed bicuspid aortic valve and aortic stenosis with high penetrance. Dr Greg Hundley:             Very interesting. So, how did the authors do this, Carolyn? Dr Carolyn Lam:                Yeah, it is interesting. What they did is they performed a GWAS and replication study using cohorts of more than 2,000 patients with bicuspid aortic valve and more than 2,700 controls, which identified the primary Celia genes as associated with the bicuspid aortic valve phenotype. Specifically the most associated snips were identified in or near genes that are important in regulating Ciliogenesis through the exocyst, which is a shuttling complex that chaperone Celia cargo to the membrane. Genetic dismantling of this exocyst resulted in impaired Ciliogenesis through the XO CIS, disrupted Ciliogenic signaling, and resulted in a spectrum of cardiac defects in zebra fish and aortic valve defects including bicuspid aortic valve, valve stenosis, and Velveeta calcification in murine models as well. So this data really supports that the exocyst is required for normal Ciliogenesis during aortic valve morphogenesis and really implicates the disruption of Ciliogenesis, and its downstream pathways may contribute to bicuspid aortic valve and its associated comorbidities. Dr Greg Hundley:             Wow. Very interesting. Learning more and more about bicuspid valves through our journal. I'm going to shift Carolyn and talk about an article from Dr Marc Sabatine from the TIMI study group at Brigham and Women's hospital. This study performed a systematic review and a trial level meta regression analysis of three classes of lipid lowering therapies that reduce triglycerides to a greater extent than they do LDLC. Fibrates, Niacin, and Marine derived Omega-three fatty acids and key inclusion criteria were a randomized, controlled trial that reported on major vascular events. The study also incorporated data from a previous Meta-regression of 25 Statin trials, and the main outcome measure was the risk ratio for major, vascular events associated with absolute reductions in lipid parameters. Dr Carolyn Lam:                Oh, very interesting. So did the study show that it was beneficial to lower triglycerides or not? Dr Greg Hundley:             Let me tell you a little more about it. The study encompass 374,358 patients that sustained 46,180 major cardiovascular events, and in their multi-variable Meta-regression model, that included terms for both LDLC and triglyceride surrogates for LDL and VLDL. The risk ratio was 0.8 per one millimole per liter reduction in LDLC, and 0.84 per one millimole liter reduction in triglycerides. Therefore, a reduction in non-HDLC, a measure of atherogenic LDL and VLDL particles, is strongly associated with lower risk of major vascular events regardless of the lipid lowering drug class, and triglyceride lowering is associated with a lower risk of cardiovascular events, but to a lesser extent per absolute amount of reduction then with LDLC. Interesting, Carolyn one study reduce it and impacted the study results, and nearly all non-statin trials did not achieve significant non-HDLC lowering to detect a clinical difference in major vascular events. Now how about in regards to Omega- three dose?                                                 Well, each one gram per day of EPA administered was associated with a 7% relative risk reduction in major vascular events, whereas there was no significant reduction in major vascular events with DHA. So the benefits of Marine-derived Omega-three fatty acids, particularly high dose EPA, appear to exceed their lipid lowering effects. Dr Carolyn Lam:                Wow. Interesting. So Greg, take it home for us. What should we do clinically about this information? Dr Greg Hundley:             Carolyn, developing drugs that achieve large reductions in VLDL and triglycerides and are targeting patients with high baseline levels of triglycerides would likely increase the probability of showing a meaningful clinical benefit, and fibrates could be considered in patients needing further non-HDLC lowering, being mindful of side effects, as they should offer clinical benefit proportional to the degree of non-HDLC lowering, and if a disproportionate relationship between lipid lowering and cardiovascular risk reduction is validated in ongoing high dose Omega-three fatty acid trials, it will support the hypothesis that confers a unique benefit of this class of agents beyond simply their lipid lowering.                                                 How about that? Dr Carolyn Lam:                Very nice Greg and I think very balanced and good clinical take home messages. Tell us what else is in the mailbag. Dr Greg Hundley:             We have so many interesting articles in Circulation and let me just run through a quick list of those that are also in this issue. First, Dr Jere Mitchell, from UT Southwestern, reviews the 50th anniversary of the Dallas Bedrest Study that involve five 20-year-olds that underwent several weeks of bedrest, and he discusses how this informs many of our thoughts regarding the benefits of activity today, and one of his major coauthors is Dr Ben Levine. Our own Josh Beckman reviews the ongoing efforts of physicians to understand the role of paclitaxel coated stents for those undergoing peripheral arterial interventions. Dr Berlinde von Kemp, in our case series, identifies that not all cardiomyopathy, after delivery, is simply postpartum cardiomyopathy. In another article, Dr Anurag Agrawal discusses what's on their mind regarding the use of spirometry as a cardiovascular disease risk assessment tool, should it be incorporated into existing cardiovascular disease risk models.                                                 Then, we have a great letter back and forth discussion from Dr Junfeng Wang, Dr Daxin Wang, and our own Naveed Sattar in three separate letters that discussed the relevance of age of onset for type two diabetes relative to cardiovascular risk. Then, finally our own Carolyn Lam reviews the role of biomarkers in heart failure and preserved ejection fraction. Dr Carolyn Lam:                Let's hop on to our feature discussion, shall we? Dr Greg Hundley:             Absolutely. Dr Greg Hundley:             Welcome everyone to the discussion of our featured article today where we're going to review an excellent study comparing TAVR versus SAVR in patients with aortic stenosis, but also now considering simultaneous coronary artery revascularization. Discussing our article today we have Dr Thomas Engstrøm and then our own associate editor, Dharam Kumbhani. Well Thomas, welcome to our podcast featured article discussion. I wonder if you could start us off with a little background regarding your study. What were your hypotheses, and then tell us a little about your study population and your methods. Dr Thomas Engstrøm:     Now, as you know, up to 50% of patients that are treated for aortic stenosis have coronary artery disease, and this may be considered as a bystander disease to develop disease, but definitely also adds to the prognosis for the patients. A priority guideline recommends that if you do SAVR, you'll also have significant coronary artery disease. What we don't know is if the complete percutaneous approach is as good as a surgical approach. Maybe do TAVR plus PCI comply with fiber plus CABG. That's the background for the study.                                                 Now, the population involved in this study is the population from the search TAVR trial, which as you know compared TAVR to SAVR in patients that were clinically at intermediate risk and in patients that had severe aortic stenosis. If patient had additional coronary artery disease with a syntax called Bob 22, they were excluded from the trial. We are talking about intermediate risk patients with low syntax score. Of the patients in the TAVR trial, 20% had additional coronary artery disease and were resterilized. In the paper, we compare TAVR plus PCI versus SAVR plus CABG in those patients with significant coronary artery disease. Dr Greg Hundley:             How did you define the presence or absence of coronary disease? Just real quickly before we get to your results. Dr Thomas Engstrøm:     This was at the discretion of your operator to define where the patients had coronary artery disease or not. In the paper, patients were defined as having significant diseases. More than 70% of stenotic lesions were present in one or more coronary arteries. Dr Greg Hundley:             And so can you tell us, Thomas a little about the results of your study? Dr Thomas Engstrøm:     First of all, the patients that had additional coronary artery disease had a poor prognosis than those that only had valve substitution, which is probably not a surprise. Within those that also had coronary artery disease, TAVR plus PCI appeared to be as good as CABG plus SAVR in terms of the primary endpoint, which was all because mortality or disabling stroke after two years. Then, if you dive more deeply into the endpoint and the number of secondary endpoints were pre-specified, there were no differences regarding any stroke myocardial infraction and in total no differences between what you could call major heart end points. If you look more into detail of the secondary endpoint, there are subtle differences. Patients that were in the SAVR plus CABG had more atrial fibrillation as they also had more acute kidney injury following that treatment. Whereas, in the TAVR plus PCR, more patients had vascular complications and of course had the need for pacemaker implantation. There are differences between the outcome in the two groups, but not in regard of pre-specified primary and more important secondary endpoints. Dr Greg Hundley:             Dharam, I was wondering if you could help us think about what this means for the field in terms of both from aortic valve replacement, and then also the concomitant management of coronary disease in patients that require aortic valve replacement. Dr Dharam Kumbhani:   As Thomas just pointed out, I think this is a very important question. This comes up all the time in patients with severe aortic stenosis, being evaluated for best options, and the guidelines have stayed true to this that if somebody has concomitant coronary artery disease, then the guidelines typically would recommend SAVR as the first option because then they can have CABG at the same time. This study really seeks to address a very important knowledge gap in the field, and as he very well pointed out, this does restrict itself a little in terms of the population, because they couldn't have a high syntax score, actually an intermediate or high syntax score, and they need in the trial...I think the main syntax score was eight or nine. I think that is important, but having said that, more than 50% of the patients had multi-vessel disease, and it was really impressive that nearly 15 or 17% still had three vessel PCI even in this arm.                                                 I think it's important for people to recognize that although this was the lowest syntax score, multivessel PCI was still pursued. I think that's definitely an important takeaway from the strike. It's a really important trial. It's one of the very few pieces of information that we have that is prospectively done under the auspices of a big trial like SURTAVI, and with low risk approval in and what this means for patients going forward I think will be very exciting to see how this few devolves.                                                 Thomas, as this field matures, could you walk us through, in terms of did you do the valve first and then the coronaries, or where the coronaries worked on first and then the valve? That's sort of the first question. Can you walk us through how you make those decisions? Dr Thomas Engstrøm:     It was up to the discretion of the operator whether to do a concomitant procedure, both PCI and TAVR, or to state the procedures in that way that PCI was done first, and this could be done up to seven days before the TAVR. If you compare those two groups, and now numbers become a little bit few, so we can't be conclusive here. It appears that patients that had stage procedures did poorer than those that had concomitant procedures done. Of course, it raises some questions. The prioritization as to do it in one way or the other was that through concomitant procedure, you may introduce too much of stress to the patient. Otherwise, if you do a stage procedure, it's best to do the PCI first, because the actual appearance of the valve may make it more difficult and cumbersome to address the coronary arteries. To sum this up, in the patients that we have, it appeared that a concomitant procedure is safe. Dr Greg Hundley:             Dharam, tell us, what do you think is the next step forward for this field? What do see as the next study moving forward here? Dr Dharam Kumbhani:   I think this study really sets the stage for, I think future trials where perhaps we would have... So I'm doing this in this trial. The stratification was done based on whether or not they need to revascularization. I think going forward, again with LOTUS approval here and proliferation of the number of TAVR procedures that are being offered everywhere, I think it will be helpful. This study would set the stage for future studies, where I think you would prospectively have patients with needing an aortic valve replacement and perhaps even complex revascularization, and how that was kind of actually the randomization, which is the stratification strategy, which again was very helpful. These are really among the first few data that we have of this, but I think this kind of sets the stage for future investigations in this space. And then as I briefly alluded to, I think this may help evolve or this may help in the evolution on the guidelines as well.                                                 Thomas, would you like to add anything to that? Dr Thomas Engstrøm:     Yeah, I completely echo that. Going back to the old syntax trial, it would be very interesting to see if PCI holds through, even in high tunes, syntax scores with newer drug eluting stents, and also of course the question of the diabetics is totally unsolved in this cohort. CABG plus SAVR may turn out to be the best solution, but we still are waiting to see data that can support any of the two strategies in those patient cohorts. Dr Greg Hundley:             We want to thank Thomas Engstrøm and also our own Dharam Kumbhani. We look forward to seeing you next week. Dr Carolyn Lam:                This program is copyright American Heart Association, 2019.  

Types Of Business Models: Which Of These 5 Types Is Best For You With Greg Cassar Links Mentioned: * www.rainmakerpartner.io * www.advertisingboost.com * www.collective.com.au * The Billion Dollar Mistake * www.GetMeToDone.com * www.Productiveinsights.com * www.YouTube.com/ProductiveInsights * www.CallAshRoy.com * www.PremiumProductivity.com Related Episodes: * 170. Ryan Deiss From Digital Marketer Reveals The 5-Step Conversion Funnel That Turbo-Charges Your Business Growth * 055. Ezra Firestone on How To Use Ecommerce To Take Your Business From Six Figures To Seven * 122. Shark Tank Judge — John McGrath — On How To Cultivate A Success Mindset And Build An Enduring Brand * 001. Neil Patel (Kissmetrics Founder) On How To Make Better Decisions Around Client Selection, Branding and Investing * 044. Hiten Shah — Cofounder of Kissmetrics — How To Assess If The Software As A Service (SAAS) Business Model Is Right For You * 176. The Alter Ego Effect With Todd Herman Ash Roy and Greg Cassar Video Transcript (This transcript has been auto-generated. Artificial Intelligence is still in the process of perfecting itself. There may be some errors in transcription): Greg: 00:00 I'm kind of lucky now that I've achieved a higher level of freedom in my life at 44 then most people will ever really achieve in their lifetime. But when you talk about luck, I think luck can also be labor under correct knowledge. You can do things to engineer luck if that makes sense. Ash: 00:25 Welcome everyone. Welcome to the productive insights podcast. This is Ash Roy, your host and today's guest is Greg Cassar. Greg Cassar started selling online in 2003 after he left his fulltime role in 2009 which was in it in the corporate world. He left to run his own digital marketing agency, which specialized in traffic and conversion. Greg has invested over $250,000 in his education, has worked with 300 businesses and driven over 2 million leads. He's responsible for over $500 million in online sales and has worked with some online marketing greats who have previously been on this podcast, including Ryan Deiss. In episode 170 and Ezra Firestone and episode 55. Greg is a master at performing split tests and has recently been doing a lot of work in the ecommerce space. So Greg has some great knowledge to share with us in terms of the various business models out there and what really lends itself to creating a life of freedom. So I'm delighted to welcome Greg Cassar from collective.com.au Welcome Greg. Greg: 01:41 Hey Ash. Thank you very much for having me. It's a real pleasure. I've uh, we've known each other for many years. I've always found you to be a stand up guy. And I was talking to another guy today, guy, so home and he said, Ash, he always comes from just such a place of giving. So I think that's a, a true compliment that, you know, people talk about you like that.

Types Of Business Models: Which Of These 5 Types Is Best For You With Greg Cassar Links Mentioned: www.rainmakerpartner.io www.advertisingboost.com www.collective.com.au The Billion Dollar Mistake www.GetMeToDone.com www.Productiveinsights.com www.YouTube.com/ProductiveInsights www.CallAshRoy.com www.PremiumProductivity.com Related Episodes: 170. Ryan Deiss From Digital Marketer Reveals The 5-Step Conversion Funnel That Turbo-Charges Your Business Growth 055. Ezra Firestone on How To Use Ecommerce To Take Your Business From Six Figures To Seven 122. Shark Tank Judge — John McGrath — On How To Cultivate A Success Mindset And Build An Enduring Brand 001. Neil Patel (Kissmetrics Founder) On How To Make Better Decisions Around Client Selection, Branding and Investing 044. Hiten Shah — Cofounder of Kissmetrics — How To Assess If The Software As A Service (SAAS) Business Model Is Right For You 176. The Alter Ego Effect With Todd Herman Ash Roy and Greg Cassar Video Transcript (This transcript has been auto-generated. Artificial Intelligence is still in the process of perfecting itself. There may be some errors in transcription): Greg: 00:00 I'm kind of lucky now that I've achieved a higher level of freedom in my life at 44 then most people will ever really achieve in their lifetime. But when you talk about luck, I think luck can also be labor under correct knowledge. You can do things to engineer luck if that makes sense. Ash: 00:25 Welcome everyone. Welcome to the productive insights podcast. This is Ash Roy, your host and today's guest is Greg Cassar. Greg Cassar started selling online in 2003 after he left his fulltime role in 2009 which was in it in the corporate world. He left to run his own digital marketing agency, which specialized in traffic and conversion. Greg has invested over $250,000 in his education, has worked with 300 businesses and driven over 2 million leads. He's responsible for over $500 million in online sales and has worked with some online marketing greats who have previously been on this podcast, including Ryan Deiss. In episode 170 and Ezra Firestone and episode 55. Greg is a master at performing split tests and has recently been doing a lot of work in the ecommerce space. So Greg has some great knowledge to share with us in terms of the various business models out there and what really lends itself to creating a life of freedom. So I'm delighted to welcome Greg Cassar from collective.com.au Welcome Greg. Greg: 01:41 Hey Ash. Thank you very much for having me. It's a real pleasure. I've uh, we've known each other for many years. I've always found you to be a stand up guy. And I was talking to another guy today, guy, so home and he said, Ash, he always comes from just such a place of giving. So I think that's a, a true compliment that, you know, people talk about you like that. So it's awesome what you're doing with the group here. Ash: 02:01 That's very kind, Greg, thank you very much. And I was going to say that I've known you for about five years and I can honestly say it's always been a pleasure. You're a very down to earth person and very approachable and very honest. So thank you. Greg: 02:15 You are welcome. Ash: 02:17 So Greg, what are we going to talk about today is the different business models, particularly in the context of what we've seen happening of late, which is a little bit of a tectonic shift if you like. Amazon seems to have come to the fore and as Mike Rhodes said to me once, he talked about the four horsemen of the apocalypse and that was Amazon, Apple, Google and Facebook and we now are seeing some sort of a, maybe not resurgence but a progression of Amazon. There's a bit of a groundswell happening around that. And Greg, you were saying to me just before we started recording that by 9:00 AM in the mornings you are pretty much free of all your commitments th...

Dr Carolyn Lam:                Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam:                So Greg, have you ever wondered what is the clinical significance of exercise induced cardiac troponin eye release with regards to mortality and cardiovascular events? Dr Greg Hundley:             Well, being a runner, and you are too, I actually have wondered about that. Dr Carolyn Lam:                Well guess what? I'm not going to tell you the answer because you're going to have to wait for our feature discussion coming right up after we chat about a few wonderful papers in this week's issue. And I want to start. So the first paper I chose really sought to discover new and effective drug treatments for ischemic stroke. And it did this by integrating genetic and proteomic data through Mendelian randomization analysis. Dr Greg Hundley:             So Carolyn, what is Mendelian randomization analysis? Dr Carolyn Lam:                Well, I would have loved to quiz you on that, but since you already asked me, I'll tell you. So Mendelian randomization is a statistical genetics framework that's used to assess causality between an exposure and an outcome. So similar to how randomized controlled trials randomly allocate an intervention to test its causal effect on an outcome. Well, Mendelian randomization represents a sort of natural randomized control trial that leverages the random allocation of exposure influencing genetic alleles.                                                 Now previously, this technique of Mendelian randomization was applied in a hypothesis driven manner to assess causality of selected biomarkers on stroke risk, for example. However, there has been no systematic scan of the human proteome for novel causal mediators of stroke. And beyond drug target prioritization, Mendelian randomization can actually also be applied to predict target mediated side effects to reveal unanticipated adverse effects and opportunities for drug re-purposing. Hence, in the current paper, the authors led by Dr Paré from Hamilton Health Sciences, McMasters University and colleagues, use Mendelian randomization to firstly systematically screen 653 circulating proteins to identify novel mediators of ischemic stroke subtypes.                                                 Secondly, examine the relationship between identified biomarkers and the risk of intracranial bleeding. And thirdly, predict target mediated side effects through phenome wide analysis. They found that among these 653 proteins, seven were causal mediators of ischemic stroke, including two established targets, apolipoprotein allele and coagulation factor 11. As well as two novel mediators of cardioembolic stroke, which were scavenger receptor class A5, or SCARA5, and tumor necrosis factor weak inducer of apoptosis.                                                 They further showed that targeting SCARA5 was predicted to also protect against subarachnoid hemorrhage with no evidence of it for side effects. Some biomarkers mediate at risk of multiple non-stroke disorders. So in summary, integrating genomic, proteomic and phenomic data through Mendelian randomization facilitated discovery of drug targets and their side effects. Their findings provide confirmatory evidence for pursuing clinical trials of coagulation factor 11 and apolipoprotein allele. Furthermore, SCARA5 represents a new therapeutic target. Neat, huh? Dr Greg Hundley:             You bet. Well, my basic paper, Dr Carolyn Lam, focuses on the border zones of infarcts. And it comes to us from Vincent Christoffels from the Academic Medical Center in Amsterdam. So surviving cells in the post infarction border zone is subjected to intense fluctuations of their microenvironment. We can imagine that. And recently border zone cardiomyocytes have been specifically implicated in cardiac regeneration. Here in this study, the investigators define their unique transcriptional and regulatory properties and comprehensively validated new molecular markers, including NPB or encoding B-type natiriuretic peptide after infarction.                                                 So, in the study, transgenic reporter mice were used to identify the NPB positive border zone after mitochondrial infarction, and transcriptome analysis of remote border and infarct zones, and of purified cardiomyocyte nuclei was performed using some RNA sequencing. Top candidate genes displaying border zone spatial specificity were histologically validated in ischemic human hearts. So like these great papers we have in basic science, there is a fundamental mouse and then human subject validation. Dr Carolyn Lam:                 Nice. A lot of work. So what did they show? Dr Greg Hundley:             So Carolyn, the investigators identified the border zone as a spatially confined region transcriptionally distinct from remote myocardium. The transcriptional response of the border zone was much stronger than that of that remote ventricular wall involving acute downregulation of mitochondrial oxidative phosphorylation, fatty acid metabolism, calcium handling and sarcomere function, and activation of the stress response program.                                                 Analysis of infarcted human hearts revealed that the transcriptionally discrete border zone is conserved in humans and led to the identification of novel conserved border zone markers including NPBB and a whole list of others. So in conclusion, cardiomyocytes in a discrete zone bordering the infarct switch gene expression programs, this post switch program is conserved between mouse and humans, includes the NPPB expression, which is required to prevent acute heart failure after infarction. Dr Carolyn Lam:                Wow, really interesting. Well, my next paper is also really just novel information, and it's a promising clinically-relevant approach for immune modulation in transplantation medicine. And that is by selectively targeting notch one. Dr Greg Hundley:             Tell us a little bit about notch signaling. Dr Carolyn Lam:                Well, I'm glad you asked me before I asked you again because notch signaling is a highly conserved pathway, pivotal to T cell differentiation and function, rendering it a target of interest in efforts to manipulate T cell mediated immunity. Now this is relevant in transplantation since, despite advances in immunosuppression, long-term outcomes remain suboptimal and is hampered by drug toxicity and immune mediated injury, the leading cause of late graph loss.                                                 So, the development of therapies that promote regulation while suppressing effector immunity is imperative in improving graph survival and minimizing conventional immunosuppression. In today's paper, Dr Riella and colleagues from Brigham and Women's Hospital, Harvard Medical School in Boston, Massachusetts investigated the pattern of notch one expression and effector and regulatory T cells in both murine and human recipients of a solid organ transplant. They further examine the effect of notch one receptor inhibition in full murine cardiac and lung transplant models as well as in a humanized skin transplant model, and also in T regulatory cells. They found that notch one is a potent novel target to modulate aloe immunity. Blockade of notch one signaling prolongs allograph survival and enhances tolerance in animal transplant models in a regulatory T-cell dependent manner.                                                 So, in summary, these data suggests that notch one signaling pathway is a potentially clinically relevant target to control effector function and promote immune regulation after transplantation. Dr Greg Hundley:             Oh wow. A lot of intense work, and I learned about notch pathways. I am going to switch and talk about a clinical situation that's really emerged over the last five years, particularly in our scientific literature. And that's tricuspid regurgitation. And this paper comes to us from Dr Jeroen Bax from Leiden University Medical Center in the Netherlands. So in patients with moderate and severe tricuspid regurgitation, the decision to intervene is often influenced by right ventricular size and function. And right ventricular remodeling in significant secondary TR however been under explored. And so in this study the investigators characterize right ventricular remodeling in patients with significant secondary tricuspid regurgitation, and they investigated its prognostic implications. Dr Carolyn Lam:                 Indeed, very important topic. So please tell us what they found. Dr Greg Hundley:             Okay, so they use transthoracic echo-cardiography, and it was performed in 1,292 patients with significant secondary tricuspid regurgitation with patients having an average or median age of 71 years. Half were men, half were women. They had four patterns of right ventricular remodeling, and they were defined according to the presence of RV dilation with the tricuspid annulus of greater than 40 millimeters and RV systolic dysfunction. So pattern one was normal RV size and normal RV systolic function. Pattern two was a dilated RV with preserved systolic function. Pattern three, normal RV size with systolic dysfunction. Pattern four was a dilated RV and systolic dysfunction.                                                 So the primary end point was all caused mortality and event rates were compared across these four patterns of remodeling. So what did they show, Dr Carolyn Lam? The five-year survival rate was significantly worse in patients presenting with either pattern three or pattern four remodeling compared to pattern one, which was normal. And they were independently associated with poor outcome in multivariable analysis. Thus, in patients with significant secondary tricuspid regurgitation, patients with RV systolic dysfunction have worse clinical outcomes regardless of the presence of the magnitude of RV dilation. So really helps us as we're trying to decide what going to do with that tricuspid valve and modifying the severity of tricuspid regurgitation. Very nice work. Dr Carolyn Lam:                 Yeah. Very interesting. Now let's get to our feature discussion. Dr Greg Hundley:             You bet. Dr Carolyn Lam:                Our feature discussion today is all about cardiac troponin increases after endurance exercise. Is it a new marker of cardiovascular risk? What should we think of it? Is it associated with cardiovascular events? Now I know many of us has thought of this many times and we're going to get some beautiful answers with today's feature paper. I'm so glad to have the corresponding author, Dr Thijs Eijsvogels, from Radboud Medical Center that's in Nijmegen. And I also have our associate editor and editorialist for this paper, Dr Torbjørn Omland from University of Oslo. So welcome gentlemen, and if I could please start. Thijs, I think a good place to start would be for you to tell us about this four-day march of Nijmegen. Tell us about that and how your study builds on that. Dr Thijs Eijsvogels:           The Nijmegan four-day marches is actually the largest walking march in the world, so it's hosted every year in July in the Netherlands, and about 45,000 people walk for four consecutive days. And this gave us the opportunity to collect some research data during this great exercise event. What we did over the past couple of years is that we've collected blood samples and participants of this Nijmegan marches. We did a before exercise and also directly after exercise. Within those blood samples we determined the concentration of cardiac troponin eye, which is a marker of mitochondrial damage. And what we subsequently did is that we followed this group of walkers over time and we collected data about diverse events that occurred, and also whether they survived or whether they died over time. Dr Carolyn Lam:                Thijs, it's such a clever setup for a study. Now give us some idea though. We're saying walking for four days; how many kilometers is covered? And when you say before and after your troponin sampling, give us an idea of how many hours of walking that would be. Because I believe you did it only on the first day, right? Dr Thijs Eijsvogels:           Yeah, that's correct. So the distance that they must cover is dependent on sex and on age. So for example, if you're a male older than 50 years old, you can walk 30 kilometers per day, but then for four days in a row. But if you are a young individual like me, then you have to cover 50 kilometers per day. So that's a lot more. Typically, they walk about four to five kilometers per hour. So that means that if you walk the shorter distances then you are done within six to seven hours of walking. But if you walk for a longer period of time, then you need 10, 11, and sometimes even 12 hours to complete the distance. Dr Carolyn Lam:                Okay, there you heard it everybody. So we've got a stress test of a mean, I'm reading from your paper, 8.3 hours of walking at almost 70% of maximum heart rate. So that's really cool. Now before you go on further too, tell us a little bit about the population because everybody's wondering, oh no, does this apply to me? Dr Thijs Eijsvogels:           So the population participating in this walking event, I would almost say it's about a representation of the general population. So we have very healthy and very trained individuals. So you could say athletes. But we also have people with cardiovascular disease or cardiovascular risk factors. And even obese individuals. So it's a very mixed population, and it's not like the typical athlete population that you see at a runner’s event, for example. Dr Carolyn Lam:                Great. That's important. So now with that backdrop, please tell us your main findings. Dr Thijs Eijsvogels:           We measured this cardiac troponin and eye concentration, and we determined the number of individuals that were above the clinical threshold, which is the 99 percentile. And then we've compared the event rate. So major at first cardiovascular events and mortality with those walkers who had a cardiac troponin above the 99 percentile and those below it. And then we found that it was way higher in the walkers with the high troponin concentration. So they had an event rate of 27%, whereas the reference group they only had an event rate of 7%. So that was quite a marked difference. Dr Carolyn Lam:                That's huge. So first data of its kind and it's so scary because I think, Torbjørn, as you discussed in your editorial, a lot of us have sort of excused the rises in troponin that we know have been reported at the marathons and all that. So how do you put it all together, Torbjørn? what are your thoughts? Dr Torbjørn Omland:      So I would just like to congratulate Dr Eijsvogels with a very interesting article. And the findings are, as you say, very novel and significantly enhances our understanding of the prognostic implications of exercise induced increase in cardiac troponins. That transient increase in cardiac troponin concentrations may occur in many circumstances, and it's usually considered to reflect acute mitochondrial injury. And thus it has been considered to reflect harmful pathophysiological processes.                                                 But there has to be in one notable exception and that has been the rise in cardiac troponin after endurance exercise, which has commonly been considered a benign phenomenon. But until this study, definitive data relating post exercise troponin concentrations, or the magnitude of the cardiac troponin response following exercise have been lacking. So with Dr Eijsvogels' study we now have clear data showing that these are associated with increased risk. Dr Carolyn Lam:                That's amazing. So thank you for that in context. Thijs, do you agree? I mean that is a beautiful summary, but what is the take home for listeners? What should we be thinking about now first pertaining to our own exercise I suppose, but also then how do we interpret this clinically? Dr Thijs Eijsvogels:           I think that Dr Omland made a great point. So for a long period of time we thought that it wasn't a benign phenomenon, that everybody had those increases in cardiac proponents following exercise and also the pattern that was way different from what we see in clinical populations. So we thought, it's just a physiological phenomenon and it doesn't hurt the heart. But clearly our study now shows that there is an association between high post-exercise troponin concentrations and clinical outcomes. So this is an important finding.                                                 And basically there are two hypothesis I guess that could explain those findings. So first of all, it could be that participants with higher troponins have subclinical or underlying disease. And due to this walking exercise, that could be a stress test for the heart. And then those with vulnerable hearts, they demonstrate a greater increase in cardiac troponins. On the other hand, we should also acknowledge the hypothesis that even though it's moderate intensity exercise, it could be some damage to cardiomyocytes. And those individuals with the greatest or the highest troponin concentrations, they could have more cardiomyocyte damage compared to individuals with lower troponin concentrations. And if you then have repetitive exposures to exercise bouts, it could be harmful in the long run as well. Dr Carolyn Lam:                And so, Torbjørn, you discuss this along with several different mechanisms by which troponin could be increased. Do you have anything else to add to that? Dr Torbjørn Omland:      No, I think it's very right what the Dr Eijsvogels point out. So on one hand we can consider this like a stress test. And there are some data suggesting that that could be the main effect, in that those who had the higher baseline troponin in the trifocal study also demonstrated the highest increase. So in one way you could consider this as a long-term exercise test. Of course that makes it less applicable in clinical practice. So because we can't have exercise test that last for so many hours, but I think that should be an impetus to have more standardized tests that could be applied to the clinical practice. Dr Carolyn Lam:                There's also a comment that you made about the kind of troponin tests that we're applying here, that people should understand that we're using the high sensitivity ones, right? Is that correct? Dr Torbjørn Omland:      Actually, it is not the high sensitivity, but it is a contemporary essay, but it had quite good sensitivity even though it is not classified as a high sensitivity test. Dr Carolyn Lam:                Thank you for clarifying that. I know you made a point about that, that we should know what kind of tests we're talking about. The other thing is what are the remaining unanswered questions then? Like you said, we can't do an eight-hour walking test. Should we be measuring troponins now in our exercise stress? Which kinds? What time? No, it's not time yet? What are the next steps? I'd like to hear from both of you, actually. Dr Thijs Eijsvogels:           First of all, indeed it's not possible in clinical practice to do an eight-hour tests whatsoever. But I think that it could be interesting to explore that maybe with some small modifications to current stress tests, if we do it maybe on a little bit lower intensity. For example, moderate intensity exercise, but we do it for a fixed amount of time and then collect blood sample to determine a highly sensitive correct proponents., then maybe also the Delta, so the increase in proponents could be predictive sign of underlying disease. Because what you see in studies that have been published so far is that the duration of most stress test is too short to induce any substantial changes in aortic troponin concentrations. So I think if we modified a protocol a little bit, we can see greater increases in cardiac troponins, and that could provide us with more information, of course. Dr Torbjørn Omland:      I completely agree. And I think like all great studies, this study raises many new questions, and of course how we should use this clinically is very important one. And as such Eijsvogels pointed out, standardized tests will be required. And I think how much the Delta information we get from measuring the Delta to just the baseline should be one topic for future studies.                                                 And then of course we know that the cardiac troponin increase is a risk factor. But what we also would like to know is whether the at risk is modifiable in some way. So there are some studies that have suggested that increasing your physical activity over time can actually decrease your sort of chronic cardiac troponin concentration. And it would be interesting to see whether increased physical activity over time will also reduce the increase that you observe after a stress test like in Nijmegan march. Dr Carolyn Lam:                That's such great points. And if I could add too, not to forget that the study population here, would I be right to say the majority are middle aged individuals and they do have cardiovascular risk factors or even prior cardiovascular disease in a sizeable proportion? So to what extent these findings generalized to a really, like the young, athletic, competitive, athletic population? Could you comment on that Thijs? Dr Thijs Eijsvogels:           I think that's a very good point, that we cannot compare this population where the fit population competing in running events or cycling events or triathletes or whatsoever. So I think we definitely need follow up studies that reproduce our findings in different cohorts with different training modalities, with different age categories, and so on. So that's definitely a topic of interest for future studies. Dr Carolyn Lam:                Thank you so much. I mean, you've inspired me on so many levels. You've been listening to Circulation On The Run. Don't forget to tune in again next week. Dr Carolyn Lam:                 This program is copyright American Heart Association 2019.  

There’s a new chapter in the history books for Kentucky Peerless Distilling Company. A thriving distillery that had been lost during prohibition is now reemerging right in the heart of downtown Louisville. Corky Taylor, CEO of Peerless, joins the show to share his story. After being bored with retirement, Corky decided to risk it on building a distillery and fighting with a team of lawyers to reclaim their original DSP-50 designation. We talk more about their rye, the recent bourbon release, and some stories from when he was roommates with the Allman brothers. Show Partners: The University of Louisville now has an online Distilled Spirits Business Certificate that focuses on the business side of the spirits industry. Learn more at uofl.me/pursuespirits. At Barrell Craft Spirits, they explore whiskey in an entirely new way. The team selects and blends barrels of whiskey into something greater than the sum of its parts. Find out more at BarrellBourbon.com. The 2019 Kentucky’s Edge Bourbon Conference & Festival pairs all things Kentucky with bourbon. It takes place October 4th & 5th at venues throughout Covington and Newport, Kentucky. Find out more at KentuckysEdge.com. Central Kentucky Tours offers public and private bourbon tours for groups from 2 to 55. Learn more at CentralKentuckyTours.com. Receive $25 off your first order at RackHouse Whiskey Club with code "Pursuit". Visit RackhouseWhiskeyClub.com. Show Notes: Denny's Bourbon Menu: https://vinepair.com/booze-news/dennys-bourbon-menu-pancakes/ Sweet spot for aging bourbon: https://www.winemag.com/2019/08/12/ultra-aged-spirits-ripping-you-off/ Can liquor go bad?: https://www.bustle.com/articles/99585-does-alcohol-go-bad-yep-so-heres-how-long-you-have-to-finish-off-your-favorite This week’s Above the Char with Fred Minnick talks about marketing to children. Tell us about growing up in Hawaii. Where does the name Corky come from? What is the history of Peerless? What happened during prohibition? What made you decide to bring the brand back? Why Louisville? Tell us about getting your original DSP number back. Was it hard to make such a big investment? Why was it important to wait to release your own product vs. sourcing? What differentiates you from other brands? What systems are you investing in? If you were younger, would you have focused as much on quality as you are now? Tell us about the bottle and the price point. Why does rye age quicker than bourbon? Is the price of the rye going to go up when it is older? Tell us about the small batch and single barrel. What is your definition of small batch? Were your recipes trial and error? What other ryes do you like? Who are you teaming up with for barrels? How did you chose your Master Distiller? What's your connection to General Patton? What about the Allman Brothers? 0:00 Hey everybody. Are you interested in looking at the distilling process and pairing that with key business knowledge such as finance, marketing and operations, then you should check out the online distilled spirits business certificate from the University of Louisville. It's an online program. It can be completed in as little as 15 weeks. It's taught by both of you have all business faculty and corporate fellows. So you're getting real experience from real experts at the most renowned distilleries, companies and startups in the distilling industry. And all that's required is a bachelor's degree. Go to business.louisville.edu/onlinespirits. You know, 0:35 you play League baseball or be three core keys on two teams, you know, so to be so everybody's name. 0:43 It was the new john back then. Yeah, they will. Everybody says, everybody looks. 1:00 Welcome back. It's Episode 216. of bourbon pursuit. I'm Kenny, and we've got some news to run through. And we've got some exciting news that's coming from old forester there. 1910 old fine whiskey we talked about on the show with Jackie's I can before and it exceeded the expectations that old forester ever would have known about. It was their fourth and final expression of the old foresters, whiskey row series, and it's sold out across the nation, but it's now being announced that'll be back on shelves at the end of the month. You know, the idea of pairing bourbon and food and even infusing bourbon and food is nothing new, but some might wonder, have we gone too far? Well, the commercialization of bourbon continues as a Denny's. You know that place with moons over my hammy is announcing a new bourbon themed menu for fall. It's called Big bourbon flavors. The menu features a range of bourbon inspired dishes to enjoy throughout the day. So for breakfast, you've got the apple bourbon pancake breakfast that has two flaxseed multigrain pancakes with a caramel apple walnut bourbon sauce. And for lunch and dinner. You've got two classic bourbon dishes, the bourbon bacon burger, which is topped with a bourbon sauce. And then you've got the bourbon chicken sizzling skillet, which sees a grilled chicken breast coated in a bourbon glaze. And as with any rare bourbon release, this is a limited time offer and you can read more about this with a link to vine pair calm in our show notes. What's the sweet spot for Bourbons age? You know if you follow along with the podcast you would know after hearing all kinds of master distillers and master blenders that ages and everything and heck, we know that when we go on barrel pics, and we have this notion that higher age is better but there's a reason why you're gonna end up seeing barrels of stuff that has been rejected for last year Craig 23 that just gets dumped into standard Evan Williams tanks. And there's a new article by wine mag calm that interviewed four roses master distiller Brent Elliot, about that sweet spots, and bread said that the majority of barrels speak and around the fire 10 year range. And in this range is when all the immature character of the white dog is gone. And there's a light and bright and delicate balance of the flavors from the grains and the fermentation that had developed in the barrel. And with the barrel to create that perfect balance. And beyond the 12 year ranges, we're going to start seeing fewer and fewer of those actually, quote unquote improving each year. You can read more about bourbon rum, scotch and army sweet spots, which surprisingly, Armagnac was at 50 years old, with the article from wine mag in our show notes. Do you have an old dusty bottles still sitting on the shelf? And more importantly, have you opened it? Well, I guess this kind of goes for any bottle of bourbon that you have open. And you're now wondering, how long do I have to drink this before it goes bad or maybe just changes completely. According to researchers at Bacardi they presented their findings at the annual Tales of the cocktail convention in New Orleans, and everyday factors such as temperature fluctuations, light exposure, and oxidation can lead to rapid fire beard aggregation. And this can really severely alter both of the color and the flavor of alcohol stored in glass bottles. Bacardi flavor, scientists conducted a series of experiments on the effects of temperature fluctuations on its rum and found that temperature changes can degrade an organic molecule called Turpin. And this alters the flavor of the alcohol to by exposing various glass bottles stored to UV radiation. It actually intended to try to simulate the effects of sunlight. And researchers found that over a period of 10 days of exposure, bourbon lost 10% of its color while scotch lost 40%. But color is never just color when it comes to alcohol color changes are indicative of flavor changes to and researchers concluded that whiskey has an almost indefinite shelf life if you leave it unopened and stored in a cool space. However, once you open it, the rules of the game start changing in order to best protect the flavor profile from oxidation. If you have a bottle that is less than half, you should drink it within a year. And if you have less than a quarter of a bottle left, you have about three to four months before it starts to get questionable. You can read the entire article from bustled calm in our show notes. Are you a Patreon supporter of ours. But we had recently launched a new Discord server where everybody can come and chat daily in real time. There's a lot of talk going on about the podcast on a daily basis. And for me seriously, it's almost hourly because I'm giving updates of what's coming in through email and other kind of news that we necessarily don't always talk about on the podcast, but there's just loads of bourbon talk. So come connect your discord account to your Patreon account, and you can join in the fun with us. Now for today's podcast, you know we look back and peerless has just been a fun distillery to watch when they first launched their two year ride at $100 or more across the country. It's a major push back from whiskey geeks know until they tried it, it gets better and better every single year. This whiskey is just one aspect of the story because Corky talks a lot about how they rebuilt this brand. It's just a fantastic story here. It's always appealing to hear kind of how someone fights hard to restore history by fighting to get their original DSP. And no expense was spared when it's actually coming to the bottling and really what the end result of their whiskey is. So this is going to be a fun distillery to watch as they grow. And if you didn't know they just released their first bourbon to the world at four years old. All right, now here we go. Let's get in a quick word from Joe over a barrel bourbon. And then you've got Fred Minnick with above the char. 6:38 Hi, Joe from barrell bourbon. Here, we explore whiskey in an entirely new way. My team at barrel craft spirits, selects and blends barrels of whiskey into something greater than the sum of their parts. Find out more at barrellbourbon.com. I'm Fred Minnick, and this is above the char. I'm going to say this now and repeat it a lot. In this episode, do not market to children if you're an alcohol brand. Now with that said, we live in this beautiful bourbon lifestyle and sometimes friends by friends, baby gifts that have bourbon logos on it. Let me give you an example. A few weeks ago, a good friend brought me a baby bib with a distillery logo on it. It was for my than seven month old son and it was quite cute. And I really appreciate it. It was It was lovely. My wife laughed about it. Even my son thought it was cute. But I didn't really think anything of it from a marketing perspective because my friend actually made it this was not created by the distillery. My friend made this special embroidered baby bed. And then I started reviewing some cigarette testimony from the 1990s. You know, that's what I do. I like reading old transcripts and lawsuits to find nuggets of history and factual information. Well, this was a time when the anti smoker leagues were really dissecting the tobacco industry for having built in their schools and creating cartoon characters as the mascots for tobacco. Now the alcohol industry has always done a very good job of avoiding this, you know, marketing to children and they've really enforced that heavily within the trade. But in recent years, whiskey fans have actually gifted one another bourbon related things to celebrate newborns and even make you know, children t shirts with whiskey logos. For the most part, these are innocent homemade gifts from one friend to another. When a friend has a kid the natural instinct is to buy that friend a gift. And if your friend is a bourbon fan, you might be inclined to buy or create a bourbon one z. We may like it and think it's cute, but the rest of the world could see it as marketing bourbon to a child, which is very bad. You see, we are in this weird place in our society with how we perceive alcohol. Many of us look at bourbon as the great bourbon lifestyle and our children see our bottles all the time. And here is talking about master distillers. So for this audience, you and I, getting a bourbon baby bib is one of the greatest, most thoughtful gifts you could possibly imagine. But this is potentially a very slippery slope. If the wrong person sees my son wearing that bib, they may think it's from a brand and report it to the federal authorities. It could lead to an investigation and severe consequences and social media circles which are already cracking down on alcohol and tobacco related posts after all advocacy groups will go to the ends of the earth to protect children and they absolutely should, again, do not market to children at all, especially if you are a bourbon related brand. And nobody wants to market to children in this industry. Nobody. So as we give to our friends and celebration of their children just be cognizant of what it might look like to an outsider. And while bourbon is a long way from Joe camel, we don't want to portray our lifestyle and the wrong light. And that's this week's above the char Hey, did you know I have a second edition of my book bourbon curious coming out soon. You can find it on Amazon and Barnes and Noble search bourbon curious again that's bourbon curious until next week. Cheers 10:20 welcome back into a another episode of bourbon pursuit and here we are the second time at down one bourbon bar doing our live streaming podcast. So Happy Monday to everybody that's out there. You know hopefully we're starting to shake things up to start the beginning of the week because a lot of news kind of happens on Monday so 10:38 yeah, especially after spring break, you know, the wall everybody's having a case of the Mondays today. 10:45 I don't want to do anything 10:46 but every every comes back looking super tan though. Oh no. Yeah, 10:49 not me. I still got white farmers tan. You don't Tandy Corgi I do 10:55 if I'm in the sun. Yeah. I hear either more. Yeah, 10:59 well, yeah, this is our room now you know the Kenny and Ryan. This is our studio 11:03 so it's slowly turned it into that we got the the phones are going off the hook if anybody can hear me Yes. Good. I've got a telephone going. Yeah. So 11:12 all in for your sport. We have one a day bourbon will take your questions live. Actually, that's not a real number. Please don't call. Yeah. But you know, today is going to be a pretty fun and interesting episode because we are sitting here with Corky Taylor Corky is the chairperson, CEO as well of, of peerless distilling company. You know, this is something that you know, honestly for us it had taken a while for peerless to kind of get on the map for us even though it's kind of in our backyard. We all the time we have people that say oh, we want to go on the podcast, we're going to podcast but they don't really hit a national awareness and I think it's time now that peerless is started to break that ground and they are starting to kind of venture out and away and make themselves a nationally recognized brand at this point. 11:57 Yeah. And internationally as well. I was just talking to Cordell my good friend corps de before the show and he was telling us and tell me that how port peerless is now in 45 states and it just one like I think the British craft Producer of the Year and, and globally so I mean, that's pretty big stuff you know, coming out of you know, peerless. So I'm I'm super excited being Kenny actually Corky pride. I remember we came there last year for my birthday. We had a group of 10 and you gave a great tour. It was actually a pursuit undercover Volume One Yeah, yeah. Exactly. We were we're behind the scenes, I brought my own whiskey thief. And you know, and I was it was a lot of fun. It's a very cool place if no one's been to but excited to revisit the story and share with our audience you know, Corky background and the whole peerless brand and what they're doing to make their name in the whiskey game. 12:50 Absolutely. So I guess we should we should probably introduce our guest so today we do have Corky he is the chairman and the CEO of peerless to ceiling company so Corky aloha haha. Right. Yeah, that was one thing that I learned from you at the last Legends Series is that you grew up in Hawaii. I did. My father was in the military. So we spent I spent the first 13:13 eight and a half, nine years growing up in Hawaii. My dad was stationed over there. So actually, at one time live right on Waikiki Beach. So surfed on Waikiki Beach. And then we moved to Schofield and chapter so and then when I was older, I served 13:31 was that a huge lie down? It was 13:34 why I went 13:35 straight from Hawaii to military school now lived in Tennessee. Oh, that was a major lead. And you know, I used to serve the North Shore, Sunset Beach where the big I wouldn't serve from the 25 foot waves. But I still surfing the 10 foot waves. So but now, our family moved back to my dad's hometown, Henderson, Kentucky. 13:57 Well, what what can give us a time frame of that like the when you were growing up in Hawaii? Like what age? What age range was this? 14:03 I was about five years old. When we moved to why my brother was actually born in Hawaii on Maui. Then we moved back when I was 13 years old Henderson so 1314 right in there. 14:16 Was he given when your brother was born? Was he given like a an official like Hawaiian name that you didn't get because 14:23 he was actually named after my great grandfather? He's 14:25 not Hawaiian. 14:28 Polynesian name. Yeah. 14:29 Yeah, no, no, he was named after actually my great grandfather that started peerless. So he was he was Henry, they call it we call the man but he was Henry named after my great grandfather. So 14:42 we'll kind of talk about your name a little bit too so Corky Taylor, and this the name Corky, because it is a little bit different, right? So kind of how did this name of offer what does it come from? And I'm going to just guess it's not your actual given name, or no, it's not 14:53 okay. No, I'm, I'm Roy M. Taylor. The third course my grandfather was you know, always Roy My dad was Roy to until and then general Pat named my father a so he went by aces, you know, the whole time and I was with him. And then since they that they didn't really want to call me Roy. So I, I got the name Corky day one. So the only time I was ever named Roy was first day of school. So they'd say Roy Taylor, and I'd kind of raise my hand up, you know, no, it's Corky. So that was I could go into the year by Corky so it's I've always gone by Corky. 15:31 That's a great it's not too bad. 15:32 It was a military name. I mean, there was a lot of visit. He's something about it. I don't I don't know. But I had I had played darn it 15:39 the neighbor. 15:40 No, not really. So it was you know, you play Little League baseball and or be three core keys on two teams, you know, so it'd be so everybody's name. 15:51 It was the new john back then. 15:53 Yeah, they will. Everybody says Korea everybody looks 15:58 good. So I kind of want to kick it off and start talking a little bit about the story in the history of peerless. So before we talk about the whiskey and the bourbon that you're producing now kind of give the story of your family and how this really evolved. 16:13 Okay, how it had evolved, was obviously through my great grandfather. He was he was born in Poland. He was a Polish Jew. He moved to New York City to Manhattan. When he was five years old. He was selling papers on the corner when he was seven 810 12 years old. And when he was he saved up some money when when he was 19. He said I'm going to get on a riverboat. When I run out of money, that's where I'm going to get off. Why didn't get off in Louisville, Kentucky. I have no idea he got off in Henderson, which was a good thing. Walk up top of the hill head zero money. And he asked the bar up there called buckets. Can I sweep the floor and can I live in the attic until I get myself squared away. And about two years later, he ended up buying the bar. But what he really wanted to be was a banker, and that's what he was. He went from Henderson to St. Louis, for a short period of time because there was a lot of Jewish people from St. Louis. So they kind of took him under his wing. He became a banker and st move back to Henderson open First National Bank and an 1818. And he bought a small distillery from the worship family Mr. worship and passed away he bought a distillery. They were making about eight barrels of bourbon a day. And within two years, he was he had some weeks he was making 200 barrels a week. So he took it to a pretty good at one time, he was probably two or 222 stories in the state of Kentucky. He was probably in the top five or 10. during that era. 17:43 He looked as it purely investment or was it like something I enjoyed? 17:48 Now I think he looked at it as an investment. Yeah, I think he was pretty money driven. He built one of the largest breweries outside of the Mississippi, the Henderson Brewing Company, and a way to distributor just beer during that era was all by river boat. So your head his own river boats and went to Cincinnati to local down to St. Louis and he built that into a pretty good says brewery. But his love was Chicago. That's where all his buddies were. He couldn't do this today. But back then he said on the board of five different banks up in Chicago, but he owned the Palmer house up in Chicago is probably one of the most famous some people never heard of it. But it's the longest running Hotel in the United States first hotel to have a light bulb. Telephone elevator dishwasher. and air conditioning. 18:33 No iPhone, not the first off 18:36 iPhone. No, I think it's but but they invented the brownie. So that's what they were famous. Okay. I like brownies. Yeah, yeah. 18:44 So I guess kinda helped me through the the timetable here now was your great, great, great or great, great, great grandfather. Okay, so was this last during Prohibition or like it was okay. So you want to talk about like, how that that sort of 19:00 had it. He headed up to prohibition and he had about 63,000 barrels of bourbon he had to get rid of. He was having if you had 50,000 oh man owns borough, because they had huge warehouses or some big distilleries and, and owns burn, they had big fences with Abby on him. So he was able to had a lot of barrels. And it took him about three years to get licenses to distribute alcohol during Prohibition. So 19:26 so nobody was coming there. Day one trying to bring cameras. Yeah. And Whoa, I 19:30 think they probably were, I mean, all he is, the distillery and Henderson was pretty wide open. And that's reason why he would sneak at night over on 17. train cars don't want to keep barrels over and keep them hidden. So the government, you're right would have gone in there with access, crack them open, pour them out. So he thought he could get a license eventually. And it took him about three years to do so. So then he got a license of sable to distribute, where he distributed a lot of his alcohol and we found sad, Rocky words up in, in Chicago. It's worth distributing. That's breakthrough. But they were that it was a I guess he knew about my great grandfather. And before I got up there, he told us that my great grandfather sold the Walgreen or buys from a with Walgreens got one on every corner, right. But he sold them a little less than 40,000 barrels of bourbon during Prohibition, which was a big deal back then. So they partied pretty hard in the Palmer house. For years, not his quitting one of these two week parties. This went on for like 10 or 12 years term, prohibition but he was able to get rid of all his and he shut the distillery down. He shut it down before that. 20:44 So it was more like a like a liquidation sort of thing is what he was trying to get out of. 20:48 Yeah, he was he'd already sold his skills and 1917 probation came along in 1919. So he must have known something was coming on. So in 1917, he sold his still united distillery up in Vancouver, British Columbia. And what he did, he hired Mr. Sherman here in town that owns Vendome. They're the largest still building in the United States, probably the world hired Mr. Sherman brought his family, the Henderson his wife and four kids stayed there eight months broken down, went up to Vancouver, about a month on the train, set them up, spent eight months up there came back here. And that's where they got some of the money to continue and to build Vendome with. So I went in there and 98 years later, and they told me was your great grandfather that helped put our great grandfather and business. 21:38 So they were like, well, you need to still so we're gonna go ahead and just bump you up near towards the front of the line. This is this is your repayment 21:43 dad wouldn't really it. 21:47 So talk about the the idea now, you know, the family legacy of distilling, and having your own whiskey had been lost for a few generations. And and now you were at the point of just saying like, screw it. Like, let's let's start making whiskey again, like what was the what was that real determining factor that wanted you to start pushing towards that as 22:09 he had a legitimate story? Yeah. People are like my great grandparents. You're like, You're not even related. 22:16 It's not even clay. 22:17 Yeah, exactly. I'll tell you what, I had a big company and I had a financial services company. I sold it group at a New York fifth floor Rockefeller Center. I walked on a beach in Sarasota, Florida for a year and a half most depressed I've ever been in my life. I said, I've got to go back to work. So I came back. I had a home here in Lowell. And my youngest son Carson was a builder. And so let's let's do something I don't care what we do. Let's do something. So we had a lot of history with my great grandfather and my grandfather, running a distillery. So he said, Let's build a distillery, we went down to Vendome and walk through the door. And so we want to order a still and started looking for buildings here in town. And Carson was a builder. So we found this building, down on 10th Street did kind of lend itself to do what we wanted to do and or distills. And he started the building took us almost two years to the day to build the building or to convert the building to a distillery and 23:15 YG to that building, and that location. 23:18 Well, I just felt like that if I kept the building, and maybe when our bourbon came out in six to seven years part a little bit would be heading that direction. It was pretty pretty much gone news greatness, but there's not many places left and that into town. So I thought in 678 years, local would be heading that direction. So it was in a kind of a rough area and then it's starting to get better as we go along. And I'm going to get the park built in on river to be better yet, but I just thought it would it would work out and it had a loading dock he was about to write says we wanted so it's worked out. I think it's worked out very well for us. 24:00 Why not up? Sorry. 24:01 No, no, I was about to say I mean, do you see that as more of like, like levels having a Renaissance period because you had a choice you could have you could have gone to Bardstown you could have gone back to your hometown. 24:12 Why not be the ones bro because you know, those the dollars making a great name for themselves? Sure they are there? 24:18 Yeah. Well, Henderson, Henderson, my hometown. I mean, that's, you know, I feel like it's where everything started in Henderson. But I felt like that I like global I knew local was coming along with the bourbon Renaissance with bourbon ism and what was going on, and that was be even being talked about four or five years ago. So I felt like, you know, with brown form and being here and, you know, just a lot of things going on at downtown local, I just felt like that, I'd go ahead and take the chance. And in 567 years, it would kind of hit our direction. I'm not too far off. I mean, a lot of it has to do with luck, you know, you have to have a lot of luck doing it. But as luck would have it, I think that we're in the right place at the right time. And we made a decision that we're making our own product, I don't source anything at all. So I knew our Bourbons not even out it won't be out till June 22. So we're actually, you know, waiting a little bit over four years for it to come out. I'm holding off, I can bring it out today if I wanted to, but I'm bringing it out on my dad's birthday. That's the only generation we skipped. We skipped the third generation on the fourth, obviously Carson's a fifth. So an honor my father, I'm bringing it out on his birthday. Very cool. 25:41 So I mean, back to the global thing. I'm assuming that you are as I mean, you're going to pay a little bit more money up front to actually sit here and have your home base and being headquartered in Louisville, then then trying to go and you know, be in Owens borough or be in Bardstown or something like that, you know, did you look at this and saying, you know, this is the this is where the population is going to grow. This is where the tourism is going to expand more argument. We don't have to convince people to come like we're already just like, another.on, the map of the Louisville bourbon kind of experience, if you will. 26:11 Absolutely. I mean, with the convention center, right here, I mean, you know, you know, what's going on here with, you know, the farm machinery shows the big shows are here in local, the convention center. At that time, I didn't know it was going to be torn down and start all over. But that's okay. We got through though that two years, so did everybody else. But during that era, they were building like an unbelievable amount of hotels in this town. I think when I started, they were building like 10 hotels, and then it come with another couple years and there's 20 new hotels. So those people are going to do something they're going to go places and I wanted to be in local so people could come in and take a tour of our distillery and know the family the history because I really believe we have about as much history in the bourbon industry is any distillery in the whole state of Kentucky and it might be a might be saying a mouthful, but when you go back Red 27:09 Nose gonna have a sponsor that when you 27:11 said, 27:13 Right, right, no or any names. Well, okay, well, 27:16 Jim Beam is known as DSP number 230. We're number 50. So Oh, 27:23 I want you to I want you to also tell that story too. Because I know that you were you also thought to have your original DSP back as well 27:31 fought fought it in the word for I spent, I spent a year and a half. Getting that number back. I mean, we started from my great grandfather. I can't tell you how many attorneys in this town I went through and, and what we had to do to get that but I was bound and determined that we had DSP number 50. It took us a year and a half to get almost to the day, a year and a half to get that number. First time in history. The government's ever gone back to give a DSP number back a family. So we were able to get it and finally I called the fella when it when we got an asset. Okay, what would my number have been if I could just fill the paperwork out the way you want me to? 20,232? I said, 50 looks better up on 28:18 the building. It's hard to market out there like I have all this history. But we're DSP to 1000. Like, yeah, right. 28:25 Yeah. So the new numbers in the 20 2000s. Yeah, you know, and there's a number of them in this town that are 22,000. So, but no, I mean, when you mentioned Jim Beam there to 30 were 50. When you mentioned buffalo there 113. wild turkeys, 139. makers is for 44. I know them all. So number 50 is a big deal. It doesn't it's not such a big deal sometimes in the United States, and we do tour center. Okay, we're number 50. But you bring somebody in here from Japan, you bring them in from Scotland, from Ireland, and they see number 50. There are like, Oh, my gosh, you have got to have a lot of history with your family to have DSP number 50. 29:07 When you're going through that process at a point where you just like this is this is too much. Yes, we've we've dealt with TTP, we've dealt with the laws we've we've gone through and I don't even know, they know all the laws and all the restrictions. So at some point, did you ever think like, let's just give it up, it's going to be it's going to take way too long to get this 50 back? 29:26 You know, I did, but you have to keep in mind, we were going through the construction era, that time we were we started and it took exactly two years to go through it. So I started that process. Even before we started, when we first bought the building, and we had to get some thing we had to get permits, you know, it takes time to do. So I was I was working on 50 from day one. So yeah, I I just felt like that I'd finally get it. So and we are severe. Yeah, yeah. So we never really, you know, 30:03 I just thought I'd get 30:04 you're a financial guy. So like, when you're looking at a bird, you know, starting a distillery in in the investment it takes and the return on investment and like, like, were you like, this is this is like, what was your mindset going into this? Like, I know, you want to bring your family's history back and like that. But talk about pulling those triggers like even though your brains probably like this doesn't make much sense. Like 30:29 now I did. You know, when I first we weren't going to be and we're not we're not that big. Today, we're we're a small distillery. But when when Carson and I got into that we were thinking along the lines of a smaller about half the size we are, but then I guess my financial background kicked in, and I started figuring, you know, I've got to do X amount to make this many barrels to make this many bottles to be in so many states, this is what we need to be. And then we wanted to make it where we had complete control of what we were doing. So my mindset was, we've got to make it a certain size, we have to make it this way. And I think we had it down to a pretty good sense. People asked me Well, were you aware of the construction costs? Well, Carson having a financial background or a business background on on building, I pretty much knew what it was going to cost us to build. And you know, putting barrels away, you know, where we waited, and we waited for a rye whiskey to come out and a little over two years. And now we're waiting over four years for our bourbon. So people don't do that, you know, they go and they source it, they put it in a bottle. This is my product, you know, same old game everybody plays, but I just couldn't do it. I just, I had to, I had to do what I wanted to do and keep it and make it keep it and hold it and put it out when it's ready to go. 31:56 Why was that so important to me. 31:59 Because I'm building a distillery to stay. I'm not I'm not building this distillery to sell. We're building it. As a family. We're building it for people who work with us. And we call them family. So you know, I'm the fourth generation Carson's a fifth, he's got boys, it'll be the six. I don't do that anymore. You all know all the distilleries in the state of Kentucky, you know, so there's only one or two owned by the family. Everybody else is owned by this one. That one, we can go all over the world and talk about that. But I think in order to have respect from the big distilleries, a big what I call the big seven and to be have the respect from other distilleries around the United States, I had to do it my way. And that's make my own product. When it's ready. It's ready. And as luck would have it, that's kind of what's happening to us. 32:54 So So talk about how to say you say what you want to do it your way and your own product. How did you define that or come up with like, this is my set of these are my standards these are? This is my ethos. And don't give us some like, Oh, we source all our corn from you know, 50 miles away 33:10 else's story. You know, I think there's there's gotta be a what 33:13 is what makes when you look at a bottle of peerless What do what, what do you tell people to see in that bottle like What's in it? Well, not just whiskey. 33:24 Whiskey, we, we understand, everybody makes it the same run through the same stills I put it in a barrel, they still at 160, they put it in a barrel at 125 they watered down they put it in a bottle at 92 proof that wouldn't we we wanted to have complete control over everything that we did. And in order to do that, we had to have the right computer systems, which we did our it all our own software, we had to have a right drain opera, we had to find out what would make it the best product, it was a 1964 change from from going into barrel at 110. Proof 225 proof. So they did that for cost. But going into barrel, and 110 proof actually makes a better product. So I put it in a barrel at 107 proof because it might creep up a little bit. And then I take it straight from the barrel right to the bottle, we don't add one drop of water to it. When you take it from the barrel once its age to the bottle. So the bottles that you see right here are probably 100 and 808. Point 108.2. We wanted to give it the best flavor profiles we could possibly give it. The other. The other main reason why I think that we're making as good a product as we are is we're sweet mash. everybody's familiar with sour mash, you hold the mash back, you pull it forward, you know, that didn't away we're a military family. I want it I want this place clean up. The joke is I want a battleship clean. I want that place spotless when we when we make a product, we steam clean, we clean everything, you won't see a hose on the ground, you won't see a pressure gauge spewing, you won't see any of that everything we have is control we could cook Exactly. It was a certain temperature we ferment exactly at a certain temperature, everything is controlled. And I think that's reason why we've received accolades that we have, since we started and we're going to continue, we're not going to be cocky enough to think that we're doing it exactly right. We're doing it better every day, everything we do, we're going to we're going to get better equipment better systems to make sure that we're on top. 35:44 What kind of those better systems are you investing in? Today? Well, 35:47 we're we're, we have a continuous still. But there's you know, there's just so many ways to make that still run better run hotter, run faster. So basically pumps and gauges and things like that, that we have just exactly. complete control over so you know, we're we don't make a lot of product, we only make 1012 barrels a day, that's probably all we'll ever going to make. I don't have any aspirations of building a distillery that's going to be line up to Jim Beam or Maker's Mark and making 1000 barrels a day we're going to make, you know, we might make 1215 1618 barrels a day someday, but not today. So we just want to have control. If you can have control if you're the size distillery we are today, when you get way up there. You just you're just making product. Yeah, and don't miss it. And all bourbon coming out of Kentucky is a good product. We just want to have the best. 36:52 Do you think, you know, the decision to you know, like you said stay small, like really focused on quality? Do you think you would have made it that same decision younger in your life if you were like, start the distillery like younger and like oh, we gotta you know, make this as big as big as best, big, fast and best as possible and turn over like, like whereas this is more like a passion project. I'm sure it's giving you returns but it seems like more like you know, this is really 37:18 you know if how to stay down in Henderson. We're all my buddies are and where the some of the big buildings are. And maybe I would had aspirations of building a bigger distillery and coming out of my great grandfather's buildings or done something. But, you know, coming into Louisville, Kentucky and wanting to do it in in the city where I could I could benefit from from people taking tours and visiting us. I think and then in the timing on bourbon bourbon, it's only been hot for the last probably 810 years. I mean, you go back 20 years. I mean, everything was vodka. You know, Jen was way before that. So vodka was so hot, how the flavored vodkas, bourbon really hasn't been that strong for the last I'd say 10 years. 38:09 Now, no one cared about it. 38:12 Now they know that they care about Yeah, but they make great stuff in Bardstown. Yeah, 38:17 so I think that you know, I talked to the all the big guys and they say that the bourbon industry will be good for the next 14 to 20 years. So that's good to hear because every business has a cycle. My father was in the head of Ford dealership and every five years you know is going to go down is going to come back. So at least bourbon industry I think will be good for the next 1520 38:40 Why do they think that? 38:45 The 2019 Kentucky's edge bourbon conference and festival pairs all things Kentucky with bourbon. It takes place October 4 and fifth at venues throughout Covington in Newport, Kentucky, Kentucky's edge features of bourbon conference music tastings pairings tour and an artisan market. Kentucky's edge 2019 is where bourbon begins. Tickets and information can be found online at Kentucky'sedge.com. 39:10 If you're making plans to visit the bourbon trail, the one thing you're thinking about is how do I get around to all these distilleries? 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Use code pursuit for $25 off your first box. 40:39 So at least bourbon industry I think will be good for the next 1520 Why 40:43 do they think that? 40:45 Well, I think it's a lot of reasons i think i think they feel like that it is because it's getting to be a war worldwide drink. I mean, the Japanese love it. They even they even in the UK, they like it Australia likes it can it is drinking our product. So but the main reason is, I think women like the flavor of bourbon. They they like it. They're getting away from vodka. And I think and then I think you've got a mixologist and all the big cities are getting back to mixing the drinks. The Manhattans, you know are made with. They were made originally with rye whiskey. Now they're coming back and making with Rasul that helps us in the big cities of New York, Chicago, San Francisco, LA. So I think there's a lot of reasons but I'd say number one would be that women like bourbon, they liked it, they liked the flavor of it. And it'll hopefully it'll be a good thing. It's number one drink in the world today. 41:44 Let's keep it number one. 41:45 Yeah, it will if it's, you know, obviously we do we do our part. 41:50 Yeah, keep writing keep keep keep keep it going. Great. So the other kind of question I want to kind of talk about is is the bottling and as well as the price point, right? Because this is something that most consumers out there if they've never heard of it, they might see it on the shelf and they're gonna be like well what's that's really up there for for two three year old products are kind of talk about the cost of the bottle that goes into it because I know that you put a concern amount of effort that goes into the shape the topper and everything like that, and how that kind of falls into the ending retail price as well. 42:21 Yeah, so probably the craziest thing I've ever done, but I'll explain. We're here for what we what we, Carson and Chris Edwards and are they designed the bottle we wanted to have what we thought was one of the best bottles made in the United States and again, I wanted this bottle to be made in the United States we found a company down in right outside of Atlanta, they only make perfume bottles, they make our bottle when you pick it upside down and says Made in USA. So we wanted to have the right bottle the cap actually cost more than the bottle. So it's we wanted to have the heaviest cap, the heaviest bottle. One it has a design on it. And then the label we actually won. On December 5 repeal day in New York City, they have a contest who has the best bottle who has the best label and who has the best cap in the United States. And last year we won all three It's never happened before. So we feel like we have the right and then to put the pot product in or to put a two year old product in there. And and and retail it out for 119 or hundred and $20 was a push. But we don't make much product. We felt like it was a good product. Evidently whiskey advocate thought it was a pretty good product too, because we're ranked the 15th best whiskey in the world with a two year old product, but the number one rye whiskey in the world. On April the 18th of 18 we're ranked the number one rye whiskey in the world jack daniels Rakim and second whistle pig came in third. So it was a big gamble on our part. We have won the accolades, accolades January the 30th check and I went to New York City and whisky magazine gave us the award for the number one craft distillery in the United States out of 900 Caleb Kilburn our distiller master distiller just got back from London March he went to our March 28 we got that we want to have the number one craft distillery in the world so we must be doing something right we are getting but now we do have different price points so a lot of our rye will be more in the $89 our bourbon will come out about 1600 dollar it's still a high end but we don't make much 44:38 well oddly enough I don't know if people know that that rye whiskey actually is more expensive to to mash and to create than it is to actually make a bourbon whiskey. So 44:47 kind of talk about comes up the tanks Glen all that fun. Yeah, 44:50 it does anyway in rotten rice, you know, it's 1313 $14 a bushel and corns $3 and 68 cents so, you know, it just costs a lot more money to make Yeah, 45:02 but why is it that that rice seems to age a lot quicker and have a better approachable taste to it at a younger age and say a bourbon does what really think it counts for that. 45:13 You know, I that's probably a question more for Caleb than it is for me. I don't know why it why it ages that much faster, but it's twice as fast. I mean, so to have our now we're going to have we have a three year old out. We're going to have a four year old out probably in the next three or four months. So on a go forward basis. We won't be a two year old raw. All of our Robbie for four to seven years old and then we'll come out with a Henry Craver eight year old so it'll be hitting on a four year old here probably in the next three or four months. So we'll be strictly over for four to five year old right. 45:53 What's this Henry Craver thing you just brought up that that kind of piqued my interest that you're talking about that? 45:57 Well, we're going to honor my great grandfather we're holding about 20% of what we make for Henry Craver bourbon. So we'll have a deer will always have the peerless product out. But we're going to have a Henry Craver eight year old product and probably an eight year old rye whiskey as well hold a little bit for him for an eight year old. So we're it's more an honor my great grandma. It's all about our family, our heritage, what we're trying to accomplish here as a family. But I think our eight year old bourbon should do well for us. 46:36 Yeah, that was always one of the things that I remember. I remember when this when the two year old ry first came out and yeah, it came out with $100 price tag and I know people were talking to like, oh man, like how can they do $100 on a two year rye whiskey? And I think one of the big things that was the question that was came up was well, when the rise three years and that's four years and as five years so on and so on, like, is the price going to keep going up? Is he gonna go down as gonna say the same? Like what's what's your the long term game there? 47:04 Well, I'll tell you what the short term game was for a long time. Okay, let's go the short term, the short term, if I had to ask $39 and 95 cents a bottle, I would have just been everybody else. I'd have been Jim Beam Maker's Mark, you know what we'd have just been? We've gotten lost in the shuffle. So in order to get everybody's attention, which I think we did, we were getting $129, which everybody went Holy cow, I've got to try that. Yeah, I got I mean, $129 for two year old bottle. Let's try it. And it just so happened to taste good. So was it a gamble? You damn right? It was God. But, you know, as it turns out, the way there's come down the pike, we do realize we've got to get to a four year old, then you don't have put an age statement on the bottle once it's four years old. So it'll be five, six years old. And I think it'll get it'll get better every year, our three year old is better than the two year old. But it's, it's hard to say. I mean, if you're number one in the world at a two year old, what the hell? 48:09 Where do you go from there? 48:10 Where do you know where do you you know, 48:12 what, how much close up shop. Let's start off. 48:16 But now we know. We want to make things better all the time. We want to do a better job. We want to be proud of the product we put out. Can we want to be more cost effective? It was it was a big deal to come out over $100 with a two year old but it got people's attention. We would have never, ever gotten the accolades we got if we hadn't asked $129. Right. 48:39 Who was who was the biggest like, advocate and then like the person that was against it, like with inside of the family or inside of the company that was like this, the price point we're going with, and then somebody was like, I don't know about that. Or you just kind of like headstrong with it saying we got to do this. 48:55 You know, I don't I think everybody pretty much agreed. I mean it. We don't make much product, where I'll make it real simple. We go where the money is. The money's in New York City. The money's in Chicago, the money's in San Francisco, la Houston, Dallas, Atlanta, Miami. So, London. So if you only make 1012 barrels of bourbon a day, 49:23 you don't need to Henderson 49:24 you don't think 49:26 we got it in Henderson but only bet three places exact, you know, you don't we're not going to go down to Bardstown and put it in the bar down in Bardstown. You know, 49:34 they'll bitch like, they can't even pay for a $40 bottle. Yeah. 49:38 So So I mean, you know, if you if you if you have the history that we have, and we go to the places where the money is it and they like it, they have to like it, then we're taking a gamble, but not going with its it's going to work? 49:57 No, absolutely. And I think it seemed to work. So the doors are open, the money's still coming in, you get product and would you say 48 for how many states have 45 states the five states across the country. 50:08 And so that was kind of like the one of the big reasons we kind of want to talk to us because yeah, you're starting to get this this national presence around you. And I kind of want to also talk about like so what are the difference in the two bottles we have in front of us today? You have the two years small batch and we have a three year single barrels that would exactly and it's it's a three year single barrel and we we've, I don't course all the distilleries have a reputation of selling single barrels but for the size that we are I think it's kind of hit pretty good for us to where we are selling quite a few single barrels. I mean, last year we I think we sold over 50 which was big for us and this year we anticipating selling well over 100 and for a small distillery that's that's a good thing and that's how it helps marketing when you're 50:54 it's almost like it's almost like a month worth of inventory at this point. Yeah. 50:59 Yeah, you know, so you get in some of the big bars and you get in some of the big liquor stores in the country and they've got 30 cases your product in the center out you know, they see it and so it's kind of help us with that as well. 51:13 What's the Nashville on this this route these rye whiskey? 51:16 we don't we don't I can't tell you. 51:19 That's that's so good. 51:21 So everybody Asad now, you know it just we just we don't want to do that. Because everybody else to school disclose their we're not going to disclose our How do you like it? 51:32 I love it. 51:34 It's it's great for two years, or 32 or three? That's the two years. 51:39 That was about three. Okay, cool. This is 51:43 nice weather. 51:44 No, I mean, both great. I mean, to me taste. It tastes like a Kentucky right, like more of a lower. Rob. Like a closer to 51%. Rob, but I'm not going to prod you to give us that. 52:00 Drink the rest of it. I'll get you some of this three. 52:02 No, but I will say you know a little bit about what you said about the mash bill. No matter where we go in the country. They basically call it a bourbon drinkers rye whiskey. Yeah. So we do have enough corn in there to gives it a little bit sweeter, sweeter taste, and I don't think you quite get that burn that you would within different raw. And then we have the three different profiles. We only blend six barrels. 52:29 Three. What's 52:31 your definition 52:33 six barrel? Yeah. So we take try to take three different flavor profiles, fruits and florals, Carmine vanilla. And in the obviously the oak and pepper is the original rice with we blend those and we do it, you know, we pick our barrel. So if we can continue doing that, it's not ready, it's not ready, we put it back for another three months, six months or whatever. So we want to make sure that the barrels we put out again being small, we can do that. Obviously, we're not going to blend 500 like the big ones stood. And the other thing it's really important to to try to stay. What we feel like will be a quality product is all of our Rick houses are just going to be one floor five. So the temperature from the top to the bottom is that four degrees, you go in these big warehouses could be 40 degrees temperature from the top floor to the bottom floor. So we like the idea one floor, more control better product. So the things that we do on a continuous basis, we hope will be a better product for us. 53:45 Where did you so when you're developing, you know, Corky thing your own way whose whose recipes? Are these are like was it just trial and error? Like we're waiting on someone else to like figure it out? Or? 53:58 You got it? trial and error? Yeah, we you know, a year 54:04 trial. That's the fun part. Right. 54:06 Yeah, you know, sorry, we knew, you know, kind of what we wanted to do with flavor profiles. We had a pretty good idea what some other products close to what, you know what their mash bill. So we just came up with a magic pill that had enough corn in it that people would still think it's a good quality bourbon. And a lot of people that drink this still think it's bourbon. 54:29 It I mean, it could I mean, you can taste the right of it. It's very close. Like you said, it's a bourbon drinker bourbon, it's like you're not a barbarian bourbon bourbon drinkers. Right? We'll get there. Yeah. So talk about like, what, what are some of your favorite products that kind of like, made you determine that this is what I like, you know, some similar similar products out there that were like, this is kind of a whistle, whistle pig. 54:55 And when when we, when we looked at it, we knew who who our competition was going to be. And it seems like since we came out, whistle pig, no matter where he goes, God is going to be our competition. So, you know, but but there there's is 810 1214 years, right? So and, you know, so we we had pretty good idea that that's, that's our competition, but we wanted to make it our flavor, flavor profiles. So we couldn't sit around and wait 14 years. So we had to figure out what what we could do. And Caleb Kilburn is a is our master distiller he's been with us since day one, and he does a great job for us. But we got Chris and Tommy and Aaron Carson. So we're, we're kind of all on it trying to figure out, you know, what we can do to make it better. And obviously, going from the two year to three years better than when it come out with a four year it's going to be better and five year and then kind of hold it about two. I don't think Brad needs to be with some pig does a great job. They've got a great product, but we're not going to be up at 1214 years. Yeah, we're just not 56:10 well, who knows? That 20% you're holding back save another 2%? And then you know, you'll you'll find out later on. 56:16 I am afraid here. Yeah. 56:18 Yeah, that's me tough sell, sell, sell, 56:21 sell the other about the the flavoring aspect or not flavoring. But you know, how you how you embody and invoke the flavor of the whiskey is all done a lot through the barrel itself? It is and are who are you teaming up with to get your barrels? Or is this another? I'm not going to tell you? 56:37 No, no, no, you know, we we strictly do business with Calvin Cooper each. We like the quality of their barrels that they make. Personally, we like them. They're there, they become good friends of ours. They, you know, when we got in this business barrels were hard to come by there was a barrel shortage. So we went to some of the big barrel places and they'd say, Well, you know, we can help you with four or 500 barrels, we can give you 1200 a week, you know, we can do this or, you know, and we went to Kelvin and, and talk to them. And they said, we'll take care of you. And I'll be with Calvin Cooper each. As long as there have to always be with them. I'm not gonna I won't, I won't leave. I won't 57:20 leave. It's amazing how rich these barrels are. I mean, for three year old property, it's crazy. I mean, talk about how did you get hooked up with Caleb and why did you choose him to be your master distiller? 57:34 Well, there's, there's flavor man, the epicenter has a school, that that only lasts about six days, but it helps you gives you an idea how to become a distiller or to build a distillery. Caleb went through the school, my son Carson went through the first class. Caleb was in a second said, Mike. So we've had a number of them go through the school. And then they said, somebody said, you got to take a look at this young man, he's still a junior in college. So he came over and talk to me said, you know, I'd like to, you know, work with you. And this is even before we laid out to the story, and I said, Sure, you know, once you start shoveling gravel over there, and oh, by the way, I got a bunch of nails in his would pull nails. And he did that for the first summary was their second summer. I think he he shoveled gravel, and helped us pour concrete so and then he was able to lay out the distillery the way he wanted it laid out the kid, I say he's a kid. He's not a kid. But he's, he's literally a genius. I think he's he's very, very smart. He understands the mechanical. He understands the whole system all the way around. He's gone into big distilleries. He's followed him around, he went to the school. He's sharp, and he does a great job for us. He's helped work with Tommy and, and Nick, Chloe, and help them along. So we we have three people that can really do what we want to enter. But Caleb is the he's the lead lead pony there. So 59:07 is he like another son to you? 59:08 party? Emily, he really is. Yeah, no, he is. And you know, and I feel like a lot of men are there. You know, we're basically a big family. We don't we only have about 20 employees. Maybe we got a few part time that are you know, working in the retail part of it. But you know, we're most will have is 22 employees in there. So we're always going to be that's us distillery. 59:30 So before we kind of wrap things up, I know that I kind of want to touch back on the the history of you and your military background, because I know there was you have a title to General Patton as well. 59:42 Is that correct? My my father was General patents chief aide. So if you saw the movie Pat and the man at work was right with General Patton in real life was my father. I've got general patents gun and he carried all through the war. You saw the movie Pat, and he said pearls were for women and average for men have got to go the average handle 45 that was his shoulder harness. So my father owned it for 30 years. He passed away young and have a heart attack. I've owned this gun for 43 years. My sons alone and my grandsons, they'll own it. So the gun that General Patton carried all through the war will never leave the Taylor family. 1:00:19 And then and then so you also have like I mentioned that that military tie. When military officers or personnel come through the distillery I think you've had a few of those kind of moments as well with with some of those individuals, have you not? 1:00:33 Oh, yeah, they do. Because if you go down to the patent Museum, down in Fort Knox, there's, there's a picture about a 10 foot tall picture general Pat, and that's my father standing right next time. So all the army generals, McCaffrey just just retired two star General, he wanted to have his retirement dinner darkness story. He brought eight of the top army generals and United States Army we're in our distillery that night. So he wants us to bring the gun in so people can see the generals in the army. And the Colonel's. If there's a general or a colonel down at Fort Knox, or somebody visiting from Leavenworth or from other places, they come see me and they want to know the history about my father. And which is, which is a pretty interesting history. I mean, the story that everybody likes to hear is when I when my father sent me to military school down in castle heights, and my two roommates were the Allman Brothers. So Greg, and my roommate started that in military school. And it was a wild damn time. I'll tell you that. So we every time I've listened all in, but brother, yes. Wild. So we, we, and that's to back up just a little bit. You mentioned Freddie now. Yeah, well, Freddie. Freddie and I spoke at the convention center one time and Freddie's father Booker sent him to Castle heights. kind of straighten your career and dad, my dad said me to Castle, I straighten my rear. I work for Fred. It didn't work for me. So, so Freddie for all these years, he said, you know, the Allman Brothers went to Castle heights. So I'm 70 years old. Freddie's probably 62. So he'd been telling these people that the Allman Brothers went to Castle i. So we're speaking here to Convention Center. So Friday, you didn't know this, but I went to Castle IT can imagine what he said. Yes. No muffler. Yeah. So as I said, And oh, by the way, the Allman Brothers were my roommates. Well, he busted a good on that when he said my goddess, but Freddie, you never saw the Allman Brothers. I'm 70 year like 62 they weren't a said no, they weren't here about God. But I knew they were there. I said, I know they were to they were my roommate. So we laughed about that. And so when he does see me, so I know you're the only brothers roommate. 1:02:53 That's pretty awesome. They didn't initially I try to get you to pick up another guitar. You start playing with them or anything. 1:02:59 You know, that was that was when they were 1415 years old. They were they were Yeah, they had a guitar in the room. But they never know. I mean, they might on Sunday afternoon they play the guitar you'd sing but I mean, I didn't know what the hell's going on. You know, they weren't writing Jessica 1:03:13 they know they know they weren't they weren't a ramble man. 1:03:17 We we got a little trouble we we found out the first day we were there The girls were to Dairy Queen on Sunday night so we come busting out of there for the Dairy Queen Sunday night come back at one captain's always standing there raising like we care we want to get kicked out Yeah, exactly. 1:0

Today we just wanted to go through some of the benefits of setting up a company for your business. Separate legal entity This is a concept that a lot of people struggle to get their heads around. But once understood it, it's really a game changer A company is a separate legal entity from the people behind it. That means that if you get sued it protects the person people behind that company. It also means that the separate legal entity has a different tax regime. And it has a separate credit with credit reporting agencies. Directors A company has directors. You can have a number of directors depending on how your business is structured. The company is a separate legal entity, and directors are not personally liable in my instance, unless they sign a personal guarantee. This allows the directors to have asset protection for them personally. Shareholders The directors have control over the company but the shareholders actually own the company. So the benefit here is that people who own the company don't necessarily have to have any exposure to the outside world. Shareholders very rarely have any liability. So that's probably the main benefit. People who own the company are separated from the risk. If you're a sole trader, if something goes wrong, then liability rests with you as the owner of the business. So Greg, there are benefits of our company.

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, also Associate Editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam:                I'm so excited about our feature discussion today, Greg, because it is about a familiar but very important problem of hypertension, and we will be looking at trial results of a new drug, a first in its class type of drug. And tackling a problem that is particularly important perhaps in black patients with hypertension. Well, more very soon. First, let's discuss some papers, shall we? Do you have one? Dr Greg Hundley:             My paper is from Joseph Burgoyne from King's College in London and pertains to resveratrol. Now, resveratrol is a non-flavonoid polyphenolic compound that has been found in the skin of several fruits, with the most notable being grapes. The compound exhibits beneficial effects, including the prevention of cardiovascular neurologic diseases, cancer, metabolic syndrome, as well as it promotes bone and eye health. And in this study, the investigative team explains how resveratrol may mediate its numerous beneficial effects including lowering of blood pressure by direct thiol oxidation. Also, they demonstrate that resveratrol can counter-intuitively induce direct protein oxidation, a process that is enhanced under pro-oxidative conditions associated with disease. The oxidation of cyclic GMP dependent protein kinase 1 alpha, or PKG1 alpha, by resveratrol lowers blood pressure in hypertensive mice. Dr Carolyn Lam:                Okay. But what does that mean for us clinically, Greg? Dr Greg Hundley:             Well, the results demonstrate how blood pressure can be lowered by using resveratrol, and targeting cysteine 42, or PKG1 alpha, may provide a new class of anti-hypertensive agents. In addition, identifying additional proteins modified by resveratrol may provide new targets for therapy to treat cardiovascular disease. Carolyn, how about your first paper? Dr Carolyn Lam:                We are going to look at the further results of the ODYSSEY OUTCOMES trial. And as a reminder, ODYSSEY OUTCOMES was a double-blind randomized comparison of the PCSK9 antibody Alirocumab with placebo in almost 19,000 patients who had an acute coronary syndrome 1-12 months previously and elevated at the atherogenic lipoproteins despite intensive statin therapy.                                                 And that trial found that Alirocumab reduced the risk of the primary composite outcome of coronary heart disease, death, ischemic stroke, myocardial infarction, or unstable angina requiring hospital admissions. The current paper looked further at the effects of Alirocumab on death. Dr Greg Hundley:             So Carolyn, what did they find? Dr Carolyn Lam:                Well, there are quite a number of findings here. The first, there were fewer deaths in total that occurred with the PCSK9 inhibitor Alirocumab versus placebo, and this resulted from a non-significantly cardiovascular and non-cardiovascular deaths with Alirocumab. The second finding was that in a pre-specified analysis of more than 8,200 patients eligible for 3 or more years of follow-up, Alirocumab reduced death.                                                 And then, the third finding was that patients with non-fatal cardiovascular events were at increased risk for both cardiovascular and non-cardiovascular deaths, and a post-Hoc analysis found that compared to patients with a lower LDL, those with a baseline LDL above 100 had a greater absolute risk of death, and a larger mortality benefit with Alirocumab. In the Alirocumab group, all cause death declined with a lower achieved LDL achieved at 4 months of treatment to a level of approximately 30.                                                 So in summary, Alirocumab added to intensive statin therapy, has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for 3 or more years, and if baseline LDL is 100 or more, or if achieved LDL is low. Dr Greg Hundley:             That's great, Carolyn. My next paper is going to talk a little bit about endothelial cells. And what I think we're going to learn is that not all endothelial cells are alike. This comes from Dr Rajat Gupta from Brigham and Women's Hospital, and I really thought this was an interesting article that used single-cell RNA sequencing to make it possible to identify and characterize cellular sub-populations. Dr Greg Hundley:             The investigative team performed enzymatic dissociation of 4 whole mouse aortas, followed by single-cell sequencing of over 10,000 cells. Dr Carolyn Lam:                Wow. What did they find? Dr Greg Hundley:             Well using cluster analysis of gene expression from the aortic cells, they identified 10 populations of cells representing each of the main arterial cell types. There were fibroblasts, vascular smooth muscle cells, endothelial cells, immune cells, including monocytes, macrophages, and lymphocytes. And importantly, there were 3 distinct endothelial cell sub-populations with differences in them driven by major functional gene programs including adhesion and lipid handling.                                                 Comparison of aortic single-cell RNA sequence data sets from normal and Western diet-fed mice suggested that these sub-populations exist under both dietary conditions and have some unified responses to diet alteration. Also, immunofluorescence using single marker genes to identify endothelial cell sub-populations showed that the VCAM1 positive population was spatially located in regions of disturbed flow like the lesser curve of the aorta. Dr Carolyn Lam:                Okay. So bring it home for us, Greg. What does this mean clinically? Dr Greg Hundley:             Yeah exactly, Carolyn. So, characterizing functional sub-populations may serve as a novel method for understanding endothelial health in patients with vascular disease. And although aortic endothelial cell sub-populations demonstrate some unified responses to vascular disease relevant stimuli, like a Western diet, functionally different sub-populations may contribute differentially to vascular diseases, enabling sub-population targeted therapies to perhaps be implemented in the future. Dr Carolyn Lam:                Cool. So Greg, cardiomyopathies have often been seen as genetic in origin, but what about potentially modifiable causes? So, this next paper that I picked looked at that, and it's from corresponding author Dr Rosengren from Sahlgrenska University in Gothenburg, Sweden, who with her colleagues, sought to investigate a potential link between obesity in adolescence and being diagnosed with cardiomyopathy in adulthood.                                                 So, this was a nation-wide register-based prospective cohort study of almost 1 million 690,000 adolescent men who were enlisted for compulsory military service from 1969 to 2005. Now at baseline, body mass index, blood pressure, and medical disorders were registered, along with test results for fitness and muscle strength. Cardiomyopathy diagnosis was then identified from the National Hospital Register and Cause of Death Register.                                                 So, they found that during a median follow-up of 27 years, 4,477 cases of cardiomyopathy were identified, of which 59% were dilated, 15% were hypertrophic, and 11% were alcohol or drug-induced. Increasing body mass index, or BMI, was strongly associated with elevated risk of cardiomyopathy, especially dilated cardiomyopathy, starting at levels considered normal, meaning a BMI of 22.5 to less than 25 kilograms per squared meters.                                                 And this was even after adjusting for age, years, center, and baseline comorbidities. There was a more than 8 fold increased risk of cardiomyopathy at a body mass index of 35 and above, compared with a BMI of between 18.5 and less than 20. Dr Greg Hundley:             So, it sounds like BMI elevations and cardiomyopathies don't go together. So, what are the clinical implications? Dr Carolyn Lam:                This really shows that even mildly elevated body weight in late adolescence may contribute to being diagnosed with cardiomyopathy in adulthood. So, the already marked importance of weight control in youth is really further strengthened by these findings, as well as the greater evidence for obesity as a potential important cause of adverse cardiac remodeling that is independent of clinically evident ischemic heart disease. Dr Greg Hundley:             Outstanding. So, BMI, not good. Dr Carolyn Lam:                Nope, Greg. High BMI, not good. That was fun, Greg. So, shall we move on to our feature discussion? Dr Greg Hundley:             Absolutely. Dr Carolyn Lam:                For our feature discussion today, we are talking about a familiar problem, but just so very important, and that is hypertension. And guess what? Our feature paper discusses a new first in class centrally-acting renin-angiotensin system blocker that has such remarkable initial results. I am so pleased to have with us the corresponding author for the paper, Dr Keith Ferdinand from Tulane University School of Medicine, as well as our Guest Editor, Dr David Calhoun from University of Alabama and Birmingham.                                                 Keith, could you start by telling us a little bit about the kinds of patients you see there in New Orleans that struggles with hypertension control perhaps? And then, please tell us about Firibastat. Dr Keith Ferdinand:         I'm in New Orleans. In fact, I'm a native New Orleans. And as you know, most of the south and southeast and part of the United States has a high proportion of African American or US blacks. This population has higher rates of hypertension, increased prevalence, more severe hypertension, and more uncontrolled hypertension.                                                 We also note in the south that there tends to be an increase in obesity, which is a powerful risk factor for all patients with hypertension, regardless of race or ethnicity. And unfortunately, the rates of obesity appear to be increasing. So based on the fact that we have an increase in obesity, we have many patients whose blood pressures are not controlled, and some of the previous data have suggested less response to first step or monotherapy with ACE inhibitors and angiotensin receptor blockers, I initiated a trial with a first in its kind oral active brain aminopeptidase A inhibitor. Dr Carolyn Lam:                Wow. Could you tell us a little bit more about brain aminopeptidase, and this new drug Firibastat? Dr Keith Ferdinand:         Most people don't know anything about this molecule, because this is something that was discovered by some French physiologists. They approached me to design the clinical trial here in the United States. And what it does is, it blocks the conversion of angiotensin II to angiotensin III in the brain. Angiotensin III is actually the active component of the renin-angiotensin system centrally, and if you block angiotensin III production, it has a triple therapy effect.                                                 One is that it causes the diuresis. It decreases sympathetic tone, and it stimulates the carotid artery, such that you have, again, a decrease in sympathetic tone. Now, why choose it for patients who are obese, and why want to include a large proportion of non-Hispanic blacks here in the United States? Well, the reasons are that when you look at some of the bench research using rats, it appears to have a more beneficial effect in DOCA-salt rats, which is a model for salt-resistant hypertension.                                                 Salt-resistant hypertension is more common in blacks, more common in patients with obesity, and may indeed be one of the reasons why monotherapy or first-step with conventional renin-angiotensin system agents, specifically ACE inhibitors and ARBs, have not been as effective in the past. Dr Carolyn Lam:                Gosh. That is so interesting, and it's really making me think about my patients too here in Asia, where we have a lot of salt-sensitive hypertension. Now, could you please tell us about the trial you did, and what you found? Dr Keith Ferdinand:         We looked at a cohort of patients. All of the patients were overweight and obese. They were washed out for 2 weeks, and had a systolic blood pressure of 145-170, and a diastolic of less than 105. We wanted to get at least 50% self-identified blacks or Hispanics, and I suspect that any patient who meets this phenotype, and that would include Asians, or even Whites, may respond similarly.                                                 We then placed them in an open label format, and I can discuss why we used an open label, with monotherapy with Firibastat. After 2 weeks, we then titrated the dose level from 250 twice daily to 500 twice daily if needed, and we had a low dose thiazide and hydrochlorothiazide 25 mg addition, if needed, for escape, if patients had a blood pressure greater than 160/100.                                                 The other thing that was interesting and unique about this particular trial is that we used the automatic office blood pressure, where the blood pressure was taken 6 times. The first time was discarded, and then averaged, without a particular doctor or a nurse being there to do the blood pressure. We felt that this was a valid means of getting blood pressure loaded. It tends to mimic, to a large extent, what you see in 24 hour inventory daytime systolic blood pressure.                                                 So, this was a valid means of measuring blood pressure loads. This was a relatively high risk patients. And these were patients whom, previously, probably would not have responded as well to monotherapy with ACE inhibitors or ARBs. Dr Carolyn Lam:                That's really clear, and clever design. I would love to hear a little bit more about why the open label, and of course, the results. Dr Keith Ferdinand:         Well, that's one of the criticisms of this study, but actually, we presented to the FDA when we were discussing designing this trial, perhaps doing a placebo control trial. And we were told by the FDA that if you use a valid means of measuring blood pressure load, so that would be ambulatory blood pressure, or automated office blood pressure, that a placebo would not be necessary, because those means of checking blood pressure load would be considered a true valid means of finding a blood pressure effect.                                                 The other thing is, dealing with minority patients, and really dealing with patients in general, for blood pressure, if they have substantial hypertension, the message has been out there that this is a killer and cause of cardiovascular disease. It would probably have been very difficult to enroll the patients, you've got 254 patients in a national study. It would have been very difficult to enroll these patients, who would have known easily that they had substantial elevation of blood pressure, and we said, "You know, 50% chance you're going to get a sugar pill that has no effect." Dr Carolyn Lam:                Right. Right. Very nice. The results? Dr Keith Ferdinand:         Well, the results were a robust 9.7 mm reduction in systolic blood pressure. At day 56, the p-value was less than 0.0001. And when you do a sub-group analysis of patients who were in the study, it was effective for persons who are under 65, or over 65, male or female. All patients were overweight, and the patients who were obese, with a BMI of 30 or above, had a trend towards even a better blood pressure effect, which again, is not seen with first step with conventional ACE and ARBs.                                                 We also did an analysis based on black and non-black, and there was no difference, again with the trend towards the black patients actually doing fairly well. So, the take home from the particular study was this is the first in its kind, new approach to central Ras blockage with aminopeptidase A inhibitor, that was effective in a population which was overweight and obese, with over 50% minority, and showed substantial blood pressure reduction using a valid means of checking blood pressure, the automated blood pressure in the clinic. Dr Carolyn Lam                  Keith, congratulations. A very important study. David, could I bring you in here? What were your thoughts as you were managing this paper, and what do you think are the future steps here? Dr David Calhoun:            Looking at the submission, I was obviously excited about the results and the potential implications. I think, like Keith, in treating a lot of resistant or obesity-related hypertension, we're frustrated that control rates are not better, that the initial response to monotherapy is not better, and that's particularly true of Ras blockers. I think many of us are investigating the initial use of Ras blockers for a variety of reasons related to outcome benefit and reduction in incident and diabetes.                                                 So, I know I like to start with such an agent. I'm particularly excited that there may be, firstly, a new opportunity to block the Ras system, and potentially comparable or even better in the most difficult patients to treat. That is, the African American and the Hispanic patients, who often have very severe hypertension. So, my initial reading was I was very excited to see the potential, and that was brought out by the reviews as well. They shared my excitement. So, I'm looking forward to Keith advancing this compound. Dr Carolyn Lam:                Indeed. Keith, I'm sure everyone's thinking now, wow, remarkable results. What's the drawbacks? How well-tolerated was this drug? Dr Keith Ferdinand:         One of the drawbacks is that the structure of Firibastat included a sulfhydryl group. And we saw with early studies with captopril, which also has a sulfhydryl group, some skin rash, and we saw those similar changes with some of the patients in this particular study. At least 2 of them were suggested to potentially have erythema multiforme, although this was not proven. This was an investigator initiated adverse event.                                                 So, I don't know if we're going to be able to structure a similar type of aminopeptidase inhibitor without a sulfhydryl group. The other thing is that in its presence formulation, it's given twice daily. We know optimally you'd like to have a long-acting agent that can be given once daily. And I don't think we need a placebo control trial, but we may need to do a trial where patients are on 2 or more medications, and then, you add the Firibastat versus adding placebo. But, I don't think at this particular point, we need to get some of these more difficult to treat patients, and just place them on placebo, and watch and see what happens.                                                 We know what happens. The blood pressure goes up. Many of them may have acute heart failure, or progression of renal failure. And I just don't think it's necessary. And the FDA doesn't think it's necessary to prove that hypothesis. Dr Carolyn Lam:                David, what do you think about that? Do we need a placebo control trial? And that use of ambulatory blood pressure, that's novel aspects of this trial too. Dr David Calhoun:            I think use of placebo comparison has been for the traditional or conventional approach. I think most investigators, most clinicians, sort of anticipate seeing the placebo corrected effect. So, I think the results would have been, or will be potentially, more compelling if that's done. But, I can also appreciate Keith's contention, and it sounds like the FDA, that in this day and age, with use of automated office blood pressure measurements tend to minimize that white coat effect, and particularly true of ambulatory monitoring, that it may be that not using a placebo comparison maybe is compelling as well. Dr Carolyn Lam:                Indeed. I really enjoy actually just digging deep into the study like this. Keith, if I could just ask for some final words from you, learning lessons, or even what have you got planned next. Dr Keith Ferdinand:         The first lesson is, we need to continue to pay attention to hypertension. It's kind of been placed on the back burner with more interest now in diabetes and sugar, a lot of interest in lipids because of some of the new agents. But if you look across the globe, Asians, blacks, whites, regardless of race or ethnicity or geography, hypertension is the most potent cardiovascular risk factor, and I think we need to continue to address that.                                                 In terms of this particular agent, I believe that we will have to have some sort of placebo arm, but again, I think it's going to be built on a conventional medication, and then randomized with Firibastat versus placebo on top of conventional medications. In a more severe or a more difficult to treat hypertension, I'm just not really convinced that we need to do a purely placebo arm. Dr Carolyn Lam:                Great, Keith. And David, how about yourself? Any take home messages? Dr David Calhoun:            I think when there's a new in-class compound, I think that's always exciting, particularly when it has the initial results, preliminary results, that Keith is reporting. As many agents as there are out there to treat hypertension, we still are not doing as well as we should be. I think it can only help to have additional classes of agents as therapeutic options, and I think that's particularly true with minority patients, who are, as Keith has indicated, are at the biggest need in terms of controlling blood pressure. Keith, these initial results are very exciting, and I look forward to future studies. Dr Carolyn Lam:                Completely sharing your enthusiasm here. Thank you so much, Keith, for publishing this remarkable paper with us at Circulation. Thank you, David, for helping us manage it.                                                 And thank you, audience, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.                                                 This program is copyright American Heart Association 2019.  

Dr Greg Hundley               Welcome back everyone from our week hiatus for this July 2nd issue of Circulation On the Run. I'm Dr Greg Hundley, from the Pauley Heart Center at VCU health in Richmond, Virginia. Dr Carolyn Lam:                And I'm Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. So good to be back, Greg. Dr Greg Hundley               Absolutely. So Carolyn, our featured articles going to focus on amyloid and transthyretin amyloid is recognized in middle age and older individuals with increases in LV mass and heart failure. And in our featured article from the United Kingdom, Dr Gilmore and colleagues are going to discuss the natural history of this disease and compare outcomes of those with acquired versus hereditary forms of the disease. But before we get to that interview, how about we discuss several other original articles? Dr Carolyn Lam:                For sure, Greg. Thanks. I want to pick two genetic papers in this issue. They're really exciting. The first one is actually the first study to consider the association between rare genetic variance in a large set of cardiomyopathy genes and the occurrence of cancer therapy induced cardiomyopathy. So this paper is from co-corresponding authors, Dr Garcia-Pavia from hospital Universitario Puerta de Hierro from Madrid, and Dr Christine Seidman from Harvard Medical School in Boston, Massachusetts. The authors studied 213 patients with cancer therapy induced cardiomyopathy from three cohorts. The first retrospectively recruited adults with diverse cancers, the second prospectively phenotyped breast cancer patients. And then the third prospectively phenotyped children with acute myeloid leukemia. They showed an increased prevalence of rare variants in cardiomyopathy genes, particularly the truncating variants of the TTN gene in both adults and pediatric cancer patients with cancer therapy induced cardiomyopathy. They confirmed the human genetic data with experimental analyses showing that anthracyclines induced protracted left ventricular dysfunction in mice with truncating variants of TTN genes but not in the wild type mice. Dr Greg Hundley               Aha. So what are the clinical implications of this study, Carolyn? Dr Carolyn Lam:                Well, the findings show that variance in cardiomyopathy genes contribute to cancer therapy induced cardiomyopathy susceptibility among adult and pediatric cancer patients. And thus the identification of genetic risk factors really opens the door to new opportunities to define patients at high risk of cancer therapy induced cardiomyopathy and associated adverse outcomes.                                                 I want to go onto the next paper because it's so related. It's another genetic paper. This time looking further at the truncating variants of the TTN genes and a very novel approach, they aim to assess a genomics first approach to assess the consequences of these TTN variants. So, this was from corresponding author Dr Zoltan Arany from Perelman School of Medicine in University of Pennsylvania where he and his colleagues reviewed whole exome sequence data for more than 71,000 individuals to identify anyone with truncating variants of TTN genes. They further selected individuals with these variants in exons highly expressed in the heart and using a linked electronic health record, they evaluated the associations of these truncating variants of TTN genes with the diagnosis and quantitative echocardiographic measures. They also reviewed data from the Jackson Heart study to validate specific analyses for individuals of African ancestry. Dr Greg Hundley               Interesting. So we're hearing a little bit about different ancestry and TTN genes. What did they find? Dr Carolyn Lam:                So, I should have first clarified that that first look was in individuals of European ancestry. And they found there that the individuals of European ancestry identified through this genomics VERSE approach had a much greater odds of developing dilated cardiomyopathy and had lower left ventricular function than their peers, whether or not a clinical diagnosis of dilated cardiomyopathy was present. They also found that the association of the TTN variants and dilated cardiomyopathy was much weaker in individuals of African ancestry. So in summary, truncating genetic variants of TTN had a measurable effect in large clinical populations with respect to both strong associations with cardiomyopathy and with associations with quantitative differences in cardiac structure and function. Given the caveat though, that these association appeared strongest in individuals of European ancestry. So Greg, what did you have? Dr Greg Hundley               Well, Carolyn, the overlap of inflammatory processes operating in atherosclerosis and the rich presence of macrophages within plaques make macrophages a strong candidate for therapeutic targeting in atherosclerosis. And so this study comes from Levent Akyürek at the Institute of Biomedicine and involves targeting filament A to reduce macrophage activity in atherosclerosis. So filament A is a large actin binding protein that has been implicated in atherosclerosis and this study tested the hypothesis that targeting filament A in macrophages would impair atherosclerosis in vivo in mice and the investigators evaluated the expression of filament A in human atherosclerotic plaques. Dr Carolyn Lam:                Huh, interesting. So what did it show? Dr Greg Hundley:             Well, in humans, expression of filament A is increased in macrophages and advanced atherosclerotic plaques of human carotid arteries. In mice, in the absence of filament A, macrophages displayed impaired migration, proliferation and lipid uptake and secreted lower levels of inflammatory IL 6, also lack of filament A and macrophages in vivo reduced aortic plaque size and atherogenic mice.                                                 There were additional mechanistic findings and that the C terminal fragment of Filament A produced by calpain cleavage regulated IL 6 secretion in macrophages and treatment with calpeptin, which inhibits calpain cleavage, reduced aortic plaque size and atherogenic mice. And so therefore, filament A might serve as a prognostic biomarker and atherogenesis and perhaps targeting the C terminal proteolytic fragment of filament A could be a strategy to reduce inflammation and atherosclerotic plaque development. Carolyn, I've got another paper, but guess what? This one has our first quiz of the academic new year. This is a paper about Nexclin, and it discusses a new component of junctional membrane complexes required for cardiac T-tubule formation. The corresponding authors are led by professor Zhou Shen from the University of California, San Diego. So, Carolyn in this quiz, what is a T-tubule? Dr Carolyn Lam:                Greg, that is mean! T-Tubules, something inside the cell. Something to do with membranes folding over. Dr Greg Hundley               Yeah, you know this is one of those, it's not multiple choice. It's an open ended question. You need your little blue book. You've got to write the answer. So T, or transverse, tubules are extensions of the cell membrane that penetrate into the center of cardiac muscle cells and interact with the sarcoplasmic reticulum to facilitate calcium release and thus help modulate myocardial contraction. T-tubule uncoupling and remodeling are known features of heart failure. Dr Carolyn Lam:                Alright, so that's T-tubules. Guess what Greg, I'm going to ask you before you ask me. So, what's Nexilin? Dr Greg Hundley               I read the paper like a good student of the American Heart Association. This was answered by the investigative team of Chen and his associates. Nexilin has been identified as an actin binding protein and multiple mutations in the nexin gene are associated with cardiac diseases. In this study, Nexilin was required for initiation of T-tubule invagination and overall T-tubule formation, with a loss of next sullen leading to impaired calcium handling. Clinically, these results identified Nexilin as a new possible target for T-tubule remodeling and provide mechanistic insight into molecular pathways leading to cardiomyopathy in patients with mutations in Nexilin. So Carolyn, great job on our first quiz of the academic new year. And how about we move on to that featured discussion? Dr Carolyn Lam:                Absolutely. Dr Greg Hundley               Welcome everyone to our featured article discussion on this July 2nd and we are going to discuss with Dr Julian Gilmore from London, and our editor Dr Justin Grodin from Dallas, regarding amyloid. And Julian, I understand this particular study you have investigated a natural history of transthyretin amyloidosis cardiomyopathy. Can you tell us a little bit about transthyretin amyloid as opposed to light chain amyloid? And then also I think there's two types of transthyretin amyloid, both a hereditary and then a wild type. Dr Julian Gilmore:            Amyloidosis is a disorder of protein misfolding, and there are in fact many different proteins that can misfold and form amyloid fibrils. When they form fibrils they become insoluble and tend to build up and cause damage to whichever organ they're depositing in. Two of the proteins that form amyloid fibrils in humans in vivo are transthyretin, known as TTR for short, or immunoglobulin light chains, known as immunoglobulin light chains, and those two proteins cause transthyretin amyloidosis and AL amyloidosis or immunoglobulin light chain amyloidosis respectively. Those are the main two types of amyloid that affect the heart or cause a cardiomyopathy and they behave very differently in terms of their natural history in that AL amyloidosis is a very aggressive, rapidly fatal cardiomyopathy if untreated. Whereas cardiac transthyretin amyloidosis tends to be a more gradual albeit progressive cardiomyopathy.                                                 Transthyretin amyloidosis, as you alluded to, can either be acquired, known as wild type or hereditary and in the hereditary version it's associated with mutations in the transthyretin gene of which there are more than 130 now that are recognized to cause disease. The wild type version of the disease, the non-hereditary version of the disease, is now an increasingly recognized cause of heart failure, mainly in older individuals and particularly older males. And the hereditary version essentially remains a rather rarer disease, although the mutation that is associated or it is associated with a risk of developing this disease occurs in certain populations and in particular occurs in 4% of people of African descent, as a particular genetic mutation that occurs in 4% of individuals of African descent. So and that is associated with risk of developing this hereditary transthyretin cardiomyopathy. Dr Greg Hundley:             And so, there's the UK National Amyloidosis Center. Tell us a little bit from that center, what did you do with this particular study in terms of its design and what were your results? Dr Julian Gilmore:            Essentially the UK National Amyloidosis Center is the single center in the UK, which is commissioned centrally to diagnose and type, stage, and provide treatment FYS for patients with amyloidosis. And that includes all parts of amyloidosis. We studied a large number of patients with cardiac transthyretin amyloidosis, so cardiac ATTR amyloidosis, who referred to our center and studied them longitudinally, if you like, over the course of many years. So this was a natural history study for a condition for which at the time of the onset of the study and until the end of the study there was no disease modifying treatment and essentially what we found is that there was a great delay in diagnosis amongst most patients diagnosed with the disease and in fact the median number of attendances in hospital for patients diagnosed with the disease before they were actually diagnosed with 17 which is quite amazing and unsurprisingly in a gradually progressive disease, by the time they were diagnosed, their quality of life was very poor.                                                 We found that their quality of life symptoms gradually progressed and that they became more and more functionally impaired and had relatively poor survival with a median survival of somewhere in the region of five years. What we did find is that patients with a particular type of hereditary, ATTR amyloidosis, the type that I alluded to earlier, the mutation for which is present in 4% of people of African ancestry, he planted the V122I mutation. Patients carrying that particular mutation actually have more aggressive disease and survive for shorter than patients with the wild type disease.                                                 So, 17 hospitalizations before diagnosis and the proceeding three years. Were there factors in your study that you could identify that we should now be looking for to try and make this diagnosis earlier?                                                 Absolutely. So one of the reasons for not diagnosing the condition is basically the poor sensitivity and specificity of echocardiography, which is generally the first investigation that a cardiologist will request when a patient presents with symptoms of heart failure. There are some particular features on echocardiography that can provide clues such as strain measurement on tissue doppler imaging, where one can get a bullseye pattern, that's been reported in the literature. So there are particular features on echocardiography that one can look at to increase the chance of picking up this disease. And in particular the big increase in the number of diagnoses over recent years has been because of cardiac MRI scanning, which has become an increasingly used tool for the investigation of heart failure in which one gets a very characteristic picture of late gadolinium enhancement when it's performed in a patient with cardiac amyloidosis, which immediately triggers people to think, ah, here it is, we've got amyloid.                                                 And the other sort of novel diagnostic technique as being bone scintigraphy. In the UK we use a bone tracer called DPD and in the US a bone tracer called PYP, and those bone tracers have exquisite sensitivity for cardiac amyloidosis. So if one injects these tracers in a patient with cardiac amyloidosis one gets cardiac uptake into the heart, which can't really be missed on a planar scan. So those two techniques basically, the increasing needs of cardiac MRI and the increasing use of bone scintigraphy to investigate patients with heart failure have resulted in a great increase in the number of diagnoses.                                                 The last thing to say is that a huge proportion of patients with amyloid or transthyretin amyloid cardiomyopathy have actually had carpal tunnel syndrome previously. The median time from carpal tunnel syndrome to presentation with heart failure is about seven years, but that is another red flag, if you like, that ought to at least trigger a doctor to think could be amyloid. A thick walled heart in the context of someone whose had previous carpal tunnel syndrome. So there are a few clues there as to how one might make an earlier diagnosis, which is absolutely necessary given the nature of our data, sharing the delays that I outlined down here. Dr Greg Hundley               And Julian, last quick question before we get with Justin here. In your data, can you describe for us the importance of that earlier diagnosis related to long-term outcomes as opposed to the group that was diagnosed much later, you know, beyond your median. What was the difference in prognosis in those two groups? Dr Julian Gilmore:            There is no doubt that if patients are diagnosed earlier, they survived for longer, reflecting the natural history of the disease. So these patients, as I mentioned earlier, did not receive any disease modifying therapy and we did divide the patients into pre 2012, when patients were essentially diagnosed by endomyocardial biopsy, or the vast majority of them were diagnosed by endomyocardial biopsy, and post 2012 by which time most patients were diagnosed via an imaging, if you like, algorithm that we published in 2016 in the same journal in circulation. And the patients who were diagnosed earlier had significantly improved survival. Just corroborating really the fact that they were actually diagnosed earlier. What's particularly relevant there, is that the treatments that have been developed for this condition, and there are some recent new potential disease modifying treatments that have been developed, they find that things seem to slow progression of the disease rather than stop it or reverse it, so that if one can diagnose a patient early when their quality of life is still good and then slow progression, there's a high chance of improving quality of life quite substantially and obviously prolonging life. Dr Greg Hundley               Thank you so much, Julian. And Justin as the managing editor of this article, what struck you most in terms of its results and conclusions, and how we should manage patients today suspected of transthyretin amyloid? Dr Justin Grodin:              Well, I would say that really there are four things that in my opinion that were quite striking. The first at least as highlighted by Professor Gilmore is that the UK National Amyloid Center, they get the national case load. So this is unlike other cohorts and other centers across the world in that this is subject to less referral bias than others. So I think that's the first thing that's quite impressive. And I think Professor Gilmore really hit the nail on the head when he highlighted that this paper, that this analysis really underscores the importance of an early efficient diagnosis. And a lot of this is really through his seminal work in achieving a non-biopsy diagnosis of ATTR amyloidosis and his findings have been replicated in other cohorts as well. So I think those, I would like to say are really one and two.                                                 And then number three, which is one that I don't think Dr Gillmor mentioned, I think he mentioned indirectly, but we were also struck by the prognostic importance or I should say the prognostic meaning of having the V122I mutation. So these are individuals like hereditary amyloidosis and they have a single mutation. This is the one that is prevalent, at least we think from population studies, in approximately 4% of the African or Afro-Caribbean population. And we really see unequivocally that the time from symptom onset to diagnosis was shorter and the prognosis was actually worse in comparison to other mutations or in individuals with wild-type amyloid. And this is an important finding really for two reasons. Number one, it is largely confirmatory from other studies, but it's important to note that those studies were subject to referral bias. And we could never ever successfully incorporate whether or not socioeconomic status had actually influenced the bad outcomes of these individuals.                                                 And I would say that Professor Gilmore's findings are quite compelling in that regard. And then the second thing for this point is really this underscores I think the importance of genetic testing. I mean I think all the readers can take that message away. And then the fourth thing, which as Professor Gilmore alluded was the striking amounts of healthcare utilization, although it was in a minority, certainly quite compelling and really what it speaks to is multiple missed opportunities. Even in the UK where they have a centralized center of excellence, just like Professor Gilmore's, that there were delays in diagnosis and then when delayed these patients are quite ill. And I think I'm making all these points because at least in 2019, the regulatory environment about amyloidosis, specifically ATTR therapies. In The United States, it's actually changed. So a disease where we had therapies that might be off label or our therapies were largely symptomatic, where we managed the patient's signs and symptoms, we now actually have disease modifying therapies.                                                 So, in the United States in 2018, there were two biological agents that actually silence the livers production of transthyretin or TTR and they were approved for hereditary ATTR polyneuropathy. But there is some suggestion from sub-studies that those will have the efficacy in cardiac amyloid. And then number two in the United States, we recently gained approval in May of a drug that actually stabilizes the transthyretin protein or tetramer. So in other words, just as Professor Gilmore had highlighted at the beginning of this call, it stabilizes the breaking up, if you will, of this protein, which is the rate limiting step of amyloid formation. So you take this pill and then the transthyretin molecule does not then deposit amyloid. So this is really exciting because professor Gilmore's cohort study really captures now at least the impact that these therapies might have, and in the United States and across the world and in the UK, these therapies are being studied for all types of ATTR amyloid and really they're on the horizon. So it's given us very deep insights into how these might impact our patient's lives with ATTR. Dr Greg Hundley               Julian, Justin, that was just such an impressive discussion of a very important topic and something that again, with echocardiography, we really need to start thinking about when perhaps we appreciate some LVH, diastolic dysfunction. We have apical sparing of systolic function, but abnormal basal systolic function. Could you just summarize one point, each of you, that we should be thinking about as we move forward and we're seeing patients in our clinic that might have this disorder. Dr Justin Grodin:              The first thing to say is that awareness is all important. You know, 25% of male individuals in autopsy studies over the age of 80 have ATTR amyloid deposits in their heart, and when one sees a thick walled heart in any situation, and particularly in an elderly individual, one needs to think, could this be, amyloid, that's the first thing. And the second thing I'd like to say is that if that thought occurs, which it should occur at a much earlier stage than it does probably in most cardiologists minds, then one should think about either a bone scan, which is a cheap, simple tests. The PYP scan in the US or DPD scan in the UK and or an MRI scan, which has a very characteristic picture in a patient with cardiac amyloidosis. So those would be my take home messages to try and improve early diagnosis.                                                 You know, I'd like to dovetail what Professor Gilmore had said cause he just about took the words out of my mouth and I would like to emphasize the first point in that the diagnosis of AL, we mentioned earlier, or an ATTR amyloidosis, really necessitates a very, very high index of suspicion. What do I mean by that? When somebody has a thick heart muscle and it's not explained by something else, in other words, they don't have a lifetime history of high blood pressure and they don't have high blood pressure seeing you, or maybe they don't respond adequately to standard heart failure therapies when something is not fitting, it's always incumbent to the treating clinician to think amyloid.                                                 I would also like to highlight some of the clues that Professor Gilmore had mentioned, that any individual with carpal tunnel syndrome or who might be hospitalized with heart failure, in other words, they have shortness of breath and swelling, and the squeeze of their heart is normal, or the ejection fraction is normal, that should increase your index of suspicion for amyloidosis. And then individuals that might've had lumbar canal surgery or really any issue impacting their tendons. And then they're now presenting with a thick heart muscle. That should be a clue. It doesn't necessarily mean it's diagnostic. In fact, the majority of those individuals might not have, or a large proportion, might not have ATTR amyloid, but it should certainly raise an eyebrow and then kind of allow the clinician to move forward with the evaluations that Professor Gilmore had mentioned. Dr Greg Hundley               Well, listeners, what a phenomenal discussion that we've had from Professor Julian Gilmore from London, and Dr Justin Grodin from Dallas, Texas, educating us on transthyretin amyloid and thinking about that early and being suspicious as we evaluate patients, particularly older individuals that are symptomatic with heart failure. Well, on behalf of Carolyn Lam, this is Greg Hundley. We look forward to seeing you next week. Have a great week. Dr Carolyn Lam                  This program is copyright American Heart Association 2019  

LIVE on the Sport Physiotherapy Canada Facebook Page, I welcome Greg Lehman on the show to preview his lecture for the Third World Congress of Sports Physical Therapy in Vancouver, Canada. Greg is a physiotherapist, chiropractor and strength and conditioning specialist treating musculoskeletal disorders within a biopsychosocial model.  He currently teaches two 2-day continuing education courses to health and fitness professionals throughout the world.  Reconciling Biomechanics with Pain Science and Running Resiliency have been taught more than 60 times in more than 40 locations worldwide. In this episode, we discuss: -Common misconceptions surrounding the source of pain -Do biomechanics matter? -Promoting movement optimism in your treatment framework -What Greg is looking forward to at the Third World Congress of Sports Physical Therapy -And so much more!   Resources: Greg Lehman Website Greg Lehman Twitter Third World Congress of Sports Physical Therapy David Butler Sensitive Nervous System Alex Hutchinson Endure                                                                      For more information on Greg: Prior to my clinical career I was fortunate enough to receive a Natural Sciences and Engineering Research Council MSc graduate scholarship that permitted me to be one of only two yearly students to train with Professor Stuart McGill in his Occupational Biomechanics Laboratory subsequently publishing more than 20 peer reviewed papers in the manual therapy and exercise biomechanics field. I was an assistant professor at the Canadian Memorial Chiropractic College teaching a graduate level course in Spine Biomechanics and Instrumentation as well conducting more than 20 research experiments while supervising more than 50 students. I have lectured on a number of topics on reconciling treatment biomechanics with pain science, running injuries, golf biomechanics, occupational low back injuries and therapeutic neuroscience. While I have a strong biomechanics background I was introduced to the field of neuroscience and the importance of psychosocial risk factors in pain and injury management almost two decades ago. I believe successful injury management and prevention can use simple techniques that still address the multifactorial and complex nature of musculoskeletal disorders. I am active on social media and consider the discussion and dissemination of knowledge an important component of responsible practice. Further in depth bio and history of my education, works and publications.   Read the full transcript below: Karen Litzy:                   00:00                Hey everybody, welcome to the live interview tonight with Doctor Greg Lehman. And we have a lot to cover tonight. So for everyone that is on watching, oh good. And we're on. Awesome. Just wanted to make sure, for everyone that's on watching and kind of throughout the interview, if you have any comments or you have any questions or you want to put Greg on the spot, feel free to do so. We can see your comments as they come up. Greg, if you can't see them, just know I'll kind of let you know. But one thing we do want to know is if you're watching, say hi and let us know where you're watching from. And that way when you start asking questions, at least I'll have a better, kind of know who you are a little bit. Now before we get to the meat of the interview, I just want to remind everyone that if you are watching this, this is not on my page and it's not on Greg's page, but instead we are on the Facebook page for the Third World Congress in Sports Physical Therapy and that is going to be taking place on October 4th and fifth in Vancouver, Canada. Karen Litzy:                   01:20                So hopefully we're going to be doing more of these throughout the year talking to a lot of the presenters and Greg is one of the presenters at the congress. So that's why he's here. Greg Lehman:               01:31                Not just me every time Karen Litzy:                   01:35                Although I have to say, I bet people would really enjoy that. Greg Lehman:               01:39                Yeah, I'll fill in for whatever speaker it is and I'll just learn their stuff and then pretend like I know Karen Litzy:                   01:46                Okay. So I'd like to see you fill in for Sarah Haag. Greg Lehman:               01:50                Done. I’ll shake my pelvis. Karen Litzy:                   01:53                Pelvic health and stuff like that. That would be amazing. I would actually wouldn't mind seeing that. Now before we get started, Greg, can you talk a little bit more about yourself, just kind of give the listeners, the viewers here a little bit more of a background on you so that they know where you're coming from, if they are in fact not familiar with you. Greg Lehman:               02:13                Okay. Well, leading into that, I'm a generalist. I'm not a specialist. I have a background in kinesiology and then a master's in spine biomechanics and I was really into spine biomechanics for a long time. But you know, I became not, sorry, I was going to say dissolutioned. That's a little too strong. I've always been skeptical, skeptical of everything that I've known, and that's probably why I got accepted to my master's in biomechanics because they liked the questions I asked. And then my research there was in mainly exercise, like EMG and manual therapy, what manual therapy does. And I was pretty lucky because I was with Stuart McGill and two chiros named Kim Ross and Dave Breznik, who I always have to mention. And I should give a big shout out to Stu because he took on Kim Ross Dave Breznik who were chiros at the time and they did like amazing research that challenged so much of what we know about, you know, spine manipulation. Greg Lehman:               03:19                And they also challenged me to think about what I thought about low back pain at the time. So my master's was really helpful for me because it challenged so much of what I thought. And so that's when I was first introduced to the bio psycho social, not actually first, cause I used to read John Sarno when I was like 19 years old. I was a bit of a nerd when I was a kid. But definitely the occupational biomechanics at Waterloo, even though they love biomechanics, even back then they knew that psychosocial factors were important for your pain and injury. And then I went to chiro school, actually I went to, that's like in quotes. I like was registered, but I didn't go to class, but I had a research program and they were awesome. They funded me to do more biomechanical research. Then I was in practice for a long time and then I went back to physio school and then I was in practice for a long time and didn't do a lot of research. And then I just started teaching with John Sarno who's running the conference with the running clinic and they were great. And at the same time I also started teaching my course which is about biomechanics and pain science. How do we like bring them together? And you've hosted me. Karen Litzy:                   04:38                I've taken that course. Yes. Greg Lehman:               04:41                For you is like an echo chamber. Just it was confirmation bias. Yeah, yeah, yeah. We know this shit, Greg. But thanks for confirming what I already know. And my course does that a lot, which I don't mind. So that's me. There you go. That was fun. Karen Litzy:                   04:56                Excellent. Very good. And, you know, just as a side note that I spoke to John Sarno a couple of years, like when I was in the middle of like all my neck pain, I reached out to him via email and he said, you need to call me. Greg Lehman:               05:11                Oh, interesting. Karen Litzy:                   05:12                So I called him and I spoke to him. I never saw him but I spoke to him and he was like, you're a young chickadee. I was like, what? And like crying and all this neck pain. I'm like, who is this guy? And he said, well, just get my book. Read it. If it doesn't work, come in and see me. Greg Lehman:               05:30                Yeah, that's funny. I had a patient, he was very famous, very rich, and he bought like a hundred of his books and gave them out to his friends. He thought it was amazing. Sarno was interesting because and this happens, this is the issue with biomechanics sometimes is he had physios working with him for a long time and then he realized that doing physical medicine conflicted with the message he was giving about where pain came from, meaning like predominantly emotional, I'm probably bastardizing my sense in a long time since I thought about them. And so, which is funny that he had the problem that I had for a long time and so many of us do where we think it's bio-psychosocial, but often our biomechanical ideas will conflict with their psychosocial. So we have to be careful in how we navigate all the multidimensional nature of pain. Karen Litzy:                   06:26                I think that's the important part is that it's multidimensional and that you can't have that pendulum swing too far in either direction. And you know, now that we're on the topic of pain, let's go in a little bit deeper, so what would you say are the biggest misconceptions or common misconceptions around pain and it's, I'll put this in quotes, sources, quote unquote sources. Greg Lehman:               06:53                Yeah. The biggest one. And I really like to focus on this because it helps me in practice, it's this idea that, and I like this cause it's how our practice is that we don't always need to fix people, right? And I kind of mean, I don't just mean that in the biomechanical way. And I would have meant that in the biomechanical way five years ago where I would have said, well, you don't have to fix that posture. You don't have to fix that strength or that weakness or we don't fix strength. We're gonna have to fix that weakness or tightness. And I believe that although I do think strength and weakness and range of motion can be relevant sometimes, but I also don't think we need to always fix catastrophizing and depression and anxiety and worry, and so that criticism goes both ways. Greg Lehman:               07:53                It started out for biomechanical with me, but I would also say psycho social and we see that in the literature where people recover and they still have these, you know, mediators of disability and pain. It could be high catastrophizing but they still do really well because maybe they built up their self efficacy and they got a little bit of control and they were able to do something and something to control their pain or do something that they loved or they had some sort of hope. And so that's the biggest one, that idea of like fixing and if you want to be more technical or mechanical, it's the same idea. Like I don't think you have to get rid of nociception. So like your tissue irritation stuff, you can have shit going on in the tissues, but it's how you kind of respond to that stuff. That’s exciting. Karen Litzy:                   08:45                Well why would want to get rid of nociception. Greg Lehman:               08:49                Yeah. Well I mean I don't, well I know what you mean. Like, we don't, you don't want to, cause when you sit down you want to get an ass ulcer. Right. You definitely want to move around. So, but that now we get into crazy stuff with that. Karen Litzy:                   09:03                Well do you mean the sensitivity around it? Greg Lehman:               09:05                Yeah, it'd be like you definitely don't want like a raging disc herniation that's pressing on a nerve root and you have chemical inflammation, things like that. It’s worthwhile getting rid of. But you know, other things, you know, you can have tendinosis and a muscle strain and it can definitely hurt. But it's the idea that sometimes maybe what our rehab does is helps us cope with those, with those things, right? That's at a peripheral level and more central level. You can have anxiety and worry and those might magnify your pain response, but you can also cope with them as well. And so I love that message because I think it's just positive. Like people think I'm so messed up, I got scoliosis, I'll never got pain. And I'm like, dude, like it might contribute. I don't think the research actually supports that. Perhaps. Perhaps it does, but you can have that and still be doing awesome. Karen Litzy:                   10:00                Right. So just cause you have chronic, let's say persistent pain or you've had pain for x amount of time, it doesn't mean that that should be the thing that defines what you do or defines whether you're happy or sad or anxious but that it's a part of your life that perhaps you can cope with or like in my case I had many years of chronic pain. Now I have pain every once in awhile. But there are times where it's more severe than I would like it to be. And there are times when I want to fix it or I need to fix it. And then there are other times where I feel like I can cope with it and it's not horrible. Karen Litzy:                   10:45                I think it's context dependent. So like I had pain last year, like pretty severe for like a week or so, and I knew that in another couple of days I had to get on a flight to go to Sri Lanka. And so I needed it. So what I did for myself was I decided to get medication to help bring those pain levels down and that's what I needed at the time. But I felt so guilty about it. I would like say is this the bio psycho social way? Is this the way I should be handling this? Greg Lehman:               11:20                I would think so. I’m going to mansplain you for a second. Cause I'm guessing that you knew that this was just a flare it was going to go away and that you've managed it before, but you're just giving yourself a break for a few days. Yeah. I don't think there's anything wrong with taking Tylenol for a few days. I've talked off topic, but it's how you do manual therapy, I don't do a lot of manual therapy, but I don't begrudge people that do. And it's, especially at an athlete level, I brought this up with some of the people who are going to be at the congress and I'm like, I find it ironic that all of us who teach a running course, none of us really teach manual therapy at our running courses and no one would ever say that manual therapy is a strongly evidence based, you know, modality for running injury. Greg Lehman:               12:16                It's not, we would all talk about load management and exercise and blah, blah, blah, blah, blah, all of these things. Yet when you're a physio or a chiro training like elite athletes and you're working with them the day before their competition, what are you doing? You're probably doing some manual therapy. And so I just found that ironic that we do that, that when we're traveling with the team, I don't travel with teams, but I do have athletes come to see me the day before an event or I've been working with them for months and here I am doing what people would call low value care. But I'm like, no, sometimes it's a bandaid, but sometimes bandaids help and that's the only solution. Well, the solution that works then. Karen Litzy:                   13:08                Well again, it's context dependent, right? So if, and I saw this conversation on Twitter about, you know, what are we doing race day and race day yeah you probably are doing some sort of manual therapy. Greg Lehman:               13:30                You’re treating that little niggle and this things tight and sore and you treat and people feel better. And if fatigue is psychobiological, which it is, then our intervention is probably psychobiological and it could certainly be more psycho based. Yeah. Karen Litzy:                   13:48                Right, right. It’s still real. And you know, in the context of athletes and being, this is the Third World Congress in Sports Physical Therapy. So there'll be a lot of, we can assume, I don't know, physios there that probably work with an athletic population. And so I think it's important to bring that up. All right. I digress. Greg Lehman:               14:14                I did, you were the professional. Karen Litzy:                   14:20                So one common misconception is that we don't have to fix everything and not just the biological part, but the psychosocial part as well. Is there any other, maybe one other common misconception around pain and its sources that you hear a lot or you see a lot? Greg Lehman:               14:40                I mean if I had to say anything, it's like it's the relationship between bio motor abilities, which would be like strength and flexibility and pain. I think that it’s over sold. You know, I don't think posture is relevant. I don't think strength or motor control is irrelevant. I just think it gets over done in that, that to me is that kinesio pathological model, which I have a big issue with, which would be like your knee goes into Valgus, you're going to pay for it later and you're going to get knee pain or hip pain. And, I'm like, well if your knee hurts and it goes into Valgus it's certainly a reasonable option to avoid that for a little bit. And then you might recover cause it's an avoidance strategy and build yourself back up and you'll do great. But I think what often happens is we then say, well, you went into valgus and it hurt, therefore valgus is inherently wrong and we need to make rules for everyone on how they should function. I hardly saw you when we were in Denver together, but I gave that whole, I forgot about that. We just saw each other, sorry, I was with Betty the whole time. I couldn't hang out with you guys. And so that I gave that example of limping, like when you sprain your ankle. Karen Litzy:                   16:06                That example was great. Greg Lehman:               16:08                Yeah. You sprained your ankle and it feels better to limp. That's totally reasonable. But no one would then conclude that we all should be limping. That that's the right way to move. When I see like people I really respect, like Shirley Sahrmann or Jill Cook who will, you know, say avoid hip abduction, right? It's so horrible on the tendon, on the outside of the hip or is so bad on the knee. And I'm like, yeah, it's reasonable for symptom modification but I don't want to make a general rule and that happens too much and then we're too quick to be like, well just cause someone got better with exercises that try to change those movement patterns. That doesn't mean that's why that treatment was successful. Often those rehab programs that try to change movement patterns are like amazingly comprehensive and excellent rehab programs. And then you have like awesome therapists like you know, Stuart McGill or Shirley Sahrmann who just like build in this graded self efficacy and pump them up and they tell them you can do whatever you like. Let's just change your movement patterns and start doing this stuff you love again, may have nothing to do with the movements. It's just like the person was like, wow, I'm awesome, you're awesome. Let's do it. Karen Litzy:                   17:26                I think you can’t sort of parcel out one part of that complete treatment program and say this is the thing that worked. This is why this worked. I mean, you can't do that. I think that's impossible. Greg Lehman:               17:37                No. And it's certainly the same with the people who I really love, like Peter O'Sullivan and that whole group when they help people, like I don't really agree. I'm such a jerk. I don't always agree with their mechanisms because when I see Pete treat, he's just so confident. It's like, you can do this, you can do this and bend over and do this and do this. And like, and I would never practice that way. I just couldn't pull it off. But I can imagine how much he helps people. That's actually why I really respect him. What he does really well. When he tests RCTs, he doesn't test himself. He trains people and other people do it. So, I actually shouldn't, I'm not knocking his research. I can't get to his style because he's so confident. It's absolutely really honorable what he does where he's like, I'm not going to be the dude that's in the RCT and train people and then we'll do the studies on them, which is just, that's nice science. Karen Litzy:                   18:34                Yeah, for sure. And all of those people you mentioned also have great reputations. People are referred to them when nothing else works. And so as the patient, you're like, well I know this person's the expert. Karen Litzy:                   18:49                Right. So I think in the patient mind they're thinking, if anyone can fix me, yeah, it's going to be this person. And I think that that also plays into it. Greg Lehman:               19:00                I just opened my own little clinic out of my house. We have like a little gym. It used to be a workshop and now it's a clinic gym and I have nothing on the walls. And I'm like, how can I placebo the hell out of this? So that's my answer. I like art. I want to put up like, no, I should put up like placebo shit. Like what was like going to make me look amazing? Karen Litzy:                   19:25                Yeah. Well you can put up like awards you've gotten put up your degrees. People will be like, look at how many degrees he has. Look at all of his qualifications. He must be amazing. Greg Lehman:               19:37                Yeah. Maybe, I don't know. Karen Litzy:                   19:41                You see that a lot in the US like when you walk into an office, the degrees and the licenses and certifications, right? Greg Lehman:               19:46                All that weekend certifications, all that nonsense. After I teach, I always tell everyone, like, whenever you want me to write on your certificate, I will write levels six fascial blaster done, master Fascia blaster. I don't care. It's all bullshit. Karen Litzy:                   20:03                Biomechanics. Does it matter? Greg Lehman:               20:07                Since the sport conference let's start. They definitely matter for performance. We got to listen to our coaches and the physios. But biomechanics and technique matter for performance. So if you want to tell someone to sit up straight, yeah, it's totally reasonable to do that if you're thinking how they're going to function 30 years from now. So that's great advice. And then, it's like a question of when they matter after that. And so I kind of Parse it into a few different areas of when they matter. The big one for me is like what's more important, is it's not how you move, it's that you're prepared to do what you're doing. So make the mechanics and the loads on the person matter. Greg Lehman:               20:59                But it's the movement preparation. So my pithy expression is preparation trumps quality, right? Something like that. And then the other way or the other area where they matter is this symptom modifications. So if it hurts to do something, like if you're a runner and your knees hurt and you heel strike and you have a long stride, it's totally reasonable to shorten your stride, maybe changed your foot strike, although that's debatable, but it could serve it is certainly is an option. And if it feels better, keep running like that. So the mechanics there help but it doesn't prove, you know, the thesis that there's a right way of running. It's just that you're running differently cause another run or you're going to be like stop forefoot striking and actually lengthen your stride. I've done that plenty of times. So you're just symptom modifying. Greg Lehman:               21:45                So mechanics help a ton for symptom modification. And then you know there's probably under high high loads, there's probably better ways for your tissue to tolerate strain. You know, like if you're landing and cutting you can go into valgus but you probably don't want to go into Valgus if your knee's not flexed. Right. So high loads where the tissue gets overloaded matters. And then after that with that principal there, it gets more difficult because you start thinking of the spine and you're like, okay, is there a better way for the spine to tolerate loads? And that's where we have been debating biomechanical principles here because certainly the bio does drive nociception sometimes. And so those are the big areas for me where biomechanics matters. Sorry I went over that fast. Karen Litzy:                   22:39                I think that makes perfect sense. And I mean, I don't know if you saw this since you are probably more into tumbling and gymnastics than I am.  I haven't seen this yet. But did you see yesterday a gymnast broke both of her legs or something. Greg Lehman:               23:01                I saw that by accident. I won't see it again. Karen Litzy:                   23:02                But I don't know what happened there. Greg Lehman:               23:07                I think it may have been in a double Arabian or a double front tack and she landed and then hyper extended. And what freaked me out a little, only saw it once and I'm not gonna see it again, is I don't think she landed with straight knees. They were like bent and then they went into extension like, which freaks me out because my daughter's learning front and I'm doing them with her front tuck step outs, and you kind of land on that one leg and it's straight ish. And I was worried of extending. Karen Litzy:                   23:46                Yeah. I mean I haven't seen the footage of that, so I was just wondering if that would be a time when biomechanics mattered or just an accident. Greg Lehman:               23:55                It certainly did. But here's the problem with all the biomechanics mattering stuff, is it the mechanics mattered and caused the injury. It's just whether you can prevent it. Yeah. It's like so many ACLs. Someone might cut 10,000 times with their knee in valgus. Well, that's proof of principle, that they're safe and then they do it one way that's slightly different and then they tear their ACL. But it doesn't mean that the way they were doing it before was unsafe because they could have had less valgus pattern before and then they could have done that too. Like, yeah, I don't know. It's difficult. Karen Litzy:                   24:34                Yeah, and I think when you're talking about injury prevention, I mean that's a whole other conversation. But I think that so many factors go into that as well. It's sleep, it's nutrition. It's what did you do the day before or was the beginning of the game, the end of the game? Are you fatigued? Are you not? I mean, so much can go into that. So yeah, you can cut 10,000 times and one time you have an injury. It doesn't mean that the way you did it was incorrect. It doesn't mean that the preparation leading up to it, it could have been that day. It could have been what you did the night before. I mean, so many factors and elements that go into something, some sort of accident or injury like that, which is why injury prevention programs are difficult. Greg Lehman:               25:25                Yeah. And, and we see them running, you know, like we've been saying the same thing for years. So you don't have training errors, which just means don't do too much too soon. And then you try to nail it down in the research and you say, well, what's too much and what's too soon? And then there's no real good research on that, right? Because there's so many different variables that influence that. So my joke tonight, we're arguing not we were talking on Twitter about this. I'm like, well, we can probably all agree when it's like just looks ridiculously like too much too soon. And that's the pornography test, right? Which is your old Supreme Court justice is either pornography or obscenity and they're like, I can't define pornography, but I know when I see it. And so when a movement pattern or a training load is pornographic than maybe you avoid it or depending on your personality. Karen Litzy:                   26:17                Right. Well, you mean it just gets a point where it's so obscene. Greg Lehman:               26:20                It's so obscene. You say, ah, that's probably some of them. But it has to be that and who knows? That's the worst part is there's probably people who can handle that obscenity. And I stopped this analogy because I dunno, they're built for it. They prepared to handle. Karen Litzy:                   26:41                All right. Let's talk about being a movement optimist. Yes. So for those of people watching and listening that aren't familiar with this, can you talk about it a little bit more and how this came about? Greg Lehman:               27:02                Well, I mean, I have already, I've already said all the good stuff I've run out of material. Karen Litzy:                   27:08                I can't, I can't even believe for a second. That's true. You're not like your greatest hits album. Greg Lehman:               27:18                I was in Denmark and they gave me this little bobble head that you've pressed the top of and the whole thing like bounces. And it's funny, I was in Scandinavia three or four years ago and they gave me the same thing. It's like this thing that I would get there, but it's called a hop to mist. I loved it. My kids have it anyways, so what it means is like we need to stop vilifying like certain movements. You know, like when you look at someone's skateboarding, their knees are going to cave in and it's amazing and it's a successful movement pattern. If you rock climb and you were just at a birthday party. Karen Litzy:                   28:01                I was  at a rock climbing birthday party yesterday for my 10 year old niece. Greg Lehman:               28:05                Well, I doubt they were doing it, but there's something called a drop knee, which is what I do on a climb is, is you can do it. I'm not doing it. You put your foot up behind you almost and drop your knee down into valgus and then stand up on that and you go into that. Karen Litzy:                   28:24                There are actually some more like real climbers there and they were doing that. There are a couple of people doing that move. Cause I remember my friend that I was with was like, oh my God, look at that person's knee. How is she doing that? Greg Lehman:               28:37                Yeah. And so Alex Honnold is a famous rock climber. They just won the Oscar for Free Solo Yosemite without a rope. But I have sometimes he's in another documentary about Yosemite. I've filmed it when he's in it because he sits like me. He's like super hunched forward with the super forward head posture. And here he is climbing, you know, these massive granite walls and that's a movement optimists, it says you can do all these weird funny things with your body and still be fantastic. You can be a paralympian where you're missing a limb than have induced, you know, assymmetry that you can have scoliosis and make it to the Olympics. You can have scoliosis and lift five times your body weight. And so that's the optimism. It's this revolt a bit against the kinesio pathological model, which to me is certainly has value. Greg Lehman:               29:39                It's certainly has treatment efficacy because I like the treatments that are associated with it, but the fundamental ideas behind it that there's like bad ways to move or better ways to move for injury and pain, that's what I would challenge. I'd be like, let's be more optimistic about how we move, you know, we don't have to always fix these things right now is go and anytime someone like me talks and says to people, all you can move this way, you always want to look for exceptions, right? When you're in practice, like, when should I, you know, disregard what I think, like when you know, when is how someone moves. Like when is that important? You know that and that'll help him be a better clinician. I think. I always challenge challenging whatever you think is true. It makes it difficult. Karen Litzy:                   30:40                Yeah. But I think having that as a clinician, having that sense of doubt is not a bad thing. Greg Lehman:               30:48                Yeah. I mean, I'm going to want to agree with you. Sorry. It was like, why am I listening to this guy? It's like, but then there's those clinicians that get people better by sheer force of personality. They have that utmost belief in what they do, even when they may be full of shit. And so that's how it was hard. Karen Litzy:                   31:16                I have a great example of that, I'm not going to go into it right now. Greg Lehman:               31:25                Now you also have to wake up in the morning and be happy with yourself, so. Karen Litzy:                   31:29                This'll be an easy one for you. What is the most common question you get asked by other physio therapists? If you could say whether it's maybe they private message you or at your courses or lectures. What is the most common question that other physios or healthcare providers ask you? Greg Lehman:               31:59                Oh, that's funny. I didn't read this one before, but a few things. But usually it's like what's the paper that you mentioned? And then I have to like come up with a name and I usually know it, but the bigger one is this is what I do with people. This is not what you talked about, but tell me why it's helping them. That's, what I get a lot, they want validation and then they want to like, you know, tell me their theories of things, but really tell me they want me to tell them why it's great. It's like what the mechanism is. Karen Litzy:                   32:47                That's why it's okay. Looking for just your confirmation. Greg Lehman:               32:54                Confirmation and then like, and then trying to like find out why it works. Like they want me to do the research behind it, I'm going to go. Okay. So what do you say? I mean it depends. Like I probably do like the motivational interviewing thing where I roll a bit with towards distance and I just probably, it's pretty bad, but I probably just read say are actually depends if I've met them before, I'll just talk about the general things that help pain and I'll say maybe it's working this way, but I don't, that's all I do if I think they're totally off base. I don't think I ever really say that. I don't know if I've ever done that. Karen Litzy:                   33:49                Now, and you kind of alluded to this in your answer there, but if you could recommend one must read book or article, what would it be? And if you want to say one book and one article, but just one. Greg Lehman:               34:06                Yeah. You know what I'd go old sounds funny saying old school, but I would read David Butler's the sensitive nervous system. So good. Yeah, it is. Cause it's not only good in like a pain, but if when you read that he's just throwing out little ideas all the time. Like it would be nice for me to reread and just pull out his anecdotes and like little things that he says to do because there's things that I do and I thought, oh, this is kind of neat. And I thought I'd discovered them myself. I thought I'd, you know, you know, found it myself and then I'm realizing here at, he said it 20 years ago or something like that. Yeah, yeah, yeah. That, and then like his former partner would been Louie Gifford and I've only read parts of his books, but I've read some of his other writings and I like his stuff too. But David Butler's the central nervous system, which is just, and it's what, 15 years old, but it's still plenty accurate. Karen Litzy:                   35:07                Yeah. Yeah. And for people who are listening or watching, I can plug that into the comment section, when this is done. All right, so let's move on to the conference. October 4th and fifth in Vancouver, the Third World Congress is sports physical therapy. So can you give us a little bit of a glimpse into what you're going to be talking about? Greg Lehman:               35:32                Not really. I am talking with Alex Hutchinson who's kind of a friend of mine here in Toronto, like the same kind of know those same people. Karen Litzy:                   35:46                You run in the same crowd. Greg Lehman:               35:53                Like, you know, like we rock climb together. We've been to some similar weddings. I've known Alex for awhile and I love his stuff and I always pump up his stuff in my courses. That's what's funny. And then when they put him with me, I was like, this is awesome. Because I always talk about the psychobiological model of fatigue, which is that fatigue is kind of a nice analog for pain. That it's not just purely physiology, that there's a psychology component to fatigue. And I'm like, Whoa, we should talk about this because look how this area of function relates to pain. But so we're talking together on like this massive nebulous talk topic of pain science and athletes. Karen Litzy:                   36:44                Yeah. Yeah. That's a heavy one. I listening to his book Endure right now. Greg Lehman:               36:48                Yeah. See I like the breath holding stuff in there. Karen Litzy:                   36:55                That's the chapter I'm on now, which I can't even fathom. Greg Lehman:               37:13                So go, go online and find David Blaine's breath holding stuff. He needs to have the breath holding record. He did. But he could also do like eight minutes without that. I used to hold my breath in church all the time to pass the time. But breath holdings interesting because if you just hold your breath right now, you might make it 30 seconds, but you can train yourself to make it for four minutes. And so within like a few days if not an hour. So it means your physiological reaction to try to breathe is way over cooked. And that often happens with persistent pain. We do this protective response. So I've been talking about breath holding for years and then Alex's book came out and I'm like perfect. Now I can refer people to that way better down. But so like finding analogs between weird things about pain and then interesting things about performance or breath holding is really nice. Greg Lehman:               38:04                So we've been talking, we were probably going to go rock climbing and then we're going to try to maybe come up with something that parallels each other. I will probably, I'm guessing talk about like how we, I like doing something really practical, like instead of saying this, which might have a negative connotation to some patients, like set them up to have some, you know, less than good expectations say this instead. So, you know, like the diet stuff, don't eat this, eat this. Well it would be the same idea with explaining common running injuries. Which we'll probably talk about, cause Alex’s a runner and I'm a slow runner. So mine will probably be something like that. Just met her way to phrase things. And because everyone always says to me like, okay, well what the hell do I do then if I don't tell them that they have SI joint pain cause it's out of place than what the hell do I say? No, no, not yet. Yeah, I think. And then that's really fun and it's a nice end. We'll have time to talk about it too because there'll be a lot of wisdom in the room and hopefully we'll maybe pull that out. Karen Litzy:                   39:22                Yeah, that sounds great. And I really appreciate those kinds of conversations because then I know that I can kind of take that and use that with my patient population on Monday. Or Tuesday, whatever day. But you know, the next day in clinic. Greg Lehman:               39:38                That's the idea. I don't want to hammer people with research. I know I won't do that. That's for sure. That's easy. I could do that. And it'll be entertaining by your life. Go. Well I got some more research, but it'll probably be more practical. Right. And we're real, more practical story. Karen Litzy:                   39:52                Nice. And I look forward to, you know, the two of you speaking together, I think we'll be entertaining and educational and I look forward to that kind of play that you guys will most likely have off of each other. I’m reading his book and you brought the bread holding, which is exactly where I am. And it reminded like in the breath holding chapter, you know, he said like the people who had like, who broke these records or who could really hold their breath the longest are the people who knew that someone was there to pull them up if they needed it. Yeah. And so when I think about that as it compares to pain, like especially persistent pain, I wonder if you knew like you had an out, would that pain still be as persistent? So that's what got me thinking listening to this chapter was like, hmm, if you knew your pain had a safety net, how would that change your view of your pain? Greg Lehman:               41:03                Oh, that's interesting. No, and I think what you're talking about has actually more ramifications for the negative aspects, right? Because most people think, oh, this will pass, but there's some that think that this won't pass. And Yeah. And that's why there is no optimism. And that's of building that where, there's no reason for them to think that it will change. And that's kind of what we have to do is build that model that there's a possibility for change. Karen Litzy:                   41:35                Yeah. And before we're going to wrap things up in a second, but Kate Pratt said, well, I find one of the greatest sources of misinformation to patients about pain and biomechanics is their MD/ortho. As PTs we hopefully consistently educate our patients. Do you think it's possible to educate MD’s or orthos regarding pain and how would you begin to approach such a scenario? So I think she means as the individual clinician with, you know, the referring physician or the physician who's seeing that patient. Greg Lehman:               42:11                Yeah. I mean in general, I think that's a problem across the board of all professions. How we change our colleagues, view the docs, like our colleagues. And I'm not really sure cause you would assume that has to happen at a school level, right at the training there and at a conference level. So it's really conferences in schools who are open to, you know, providing the different messages there. But I would say, and we've talked a lot about this is when you do have patients who have these beliefs from their doctors or other healthcare providers, which is super common, there are routes that you can, you know, still address those beliefs without throwing the doctor under the bus and that’s what you have to figure out. So often it's more like acknowledging yeah, that's, you know, you have hip pain because he has OA or something you can say that's part of it. Greg Lehman:               43:15                This is the my optimism approach. Yeah. The hip OA is part of your hip pain, but you can still do great even though you have those changes on the scan. And that often really helps, especially with when physios and like we're navigating referral sources. And it's so funny that you bring, I just got, I just like 10 minutes ago before we started, I got a referral from a sport MD who was in the course. I taught with JFS school. On running five years ago and said, are you seeing patients? And like it was so funny that she was in the course because you don't normally see MDs. Yeah. You know, taking courses with the PTs. Great to do that. And so that's how we have to change. You use it somehow get into that educational system. Karen Litzy:                   44:01                Yeah, I agree. And from a one on one. I think it's difficult. I mean Karen Litzy:                   44:11                What I've done once that worked with the referring physician was, you know, I said, hey, you know, we're doing this, this, this and this, but I found this article, do you want to take a look and let me know what you think? Cause I'm thinking of incorporating it. And it was like an, I don't know, I think it was an article, Moseley or Peter O'sullivan. And so I sent them that and then he was like, oh yeah, that's really interesting. Yeah, definitely start doing that. So that's a way you can kind of maybe start. Greg Lehman:               44:44                Yeah. O he or she just rolled with your resistance maybe. No, I totally agree. Yeah. I think we're good. Karen Litzy:                   45:00                It's so hard, but it's a way to be diplomatic. It's a way to say, you know, I don't know. Greg Lehman:               45:08                I really liked that you just sold a good treatment plan and then you gave them other research behind it. That's nice. Yeah. That's probably better than saying you're an idiot. Karen Litzy:                   45:20                Yeah. Well, yeah. But I mean I also find that like I had one doctor that came back to him and he's also a good friend of mine. He was like, that's really interesting. Like we need to talk more about it. Oh, that's cool. Which is awesome, you know? But he's also a friend began, you know, we played softball together. So it's like the different opinions. Karen Litzy:                   46:01                Chris Johnson said to say thanks for carving out the time you need to stop picking your eye. Always exercise diplomacy and avoid creating a disconnect. It doesn't accomplish anything. And that's in regards to Kate's question that we just tried to answer. Like I'm bringing a course to New York City and we're going to have like a free two hour preview of it and just invite doctors. Greg Lehman:               46:44                Wow. Karen Litzy:                   46:45                That's, you know, one way to do it if you want to get them involved in the educational process with Physios, which I think is great. Greg Lehman:               46:52                One of my best course ever in Toronto here was, we had three physiatrists that came and they were fantastic. That's awesome. Go into this stuff. It was a bit, some of it seemed a bit new, but they're open and like, and then the email to everyone after and they share their experiences. I love when you have multi disciplinary people at the course. There are some, I mean I'm not throwing MDs under the bus. They certainly, it's so hard. I have a friend who was an MD and he's like the best motivational interviewer. He was so good. Like he knew this thing is that as patients had to do, but you know, in Canada you only have eight minutes with them. Yeah. And there or whatever. Anyways, so I'm off topic. Karen Litzy:                   47:42                So let's wrap things up here. Are there any presentations you're looking forward to seeing at the conference? Greg Lehman:               47:48                Rob Whiteley. Yeah. I really like is like career and that the stuff he's done and what he's doing there, you know. I'm a socialist I like exercise for everybody and I like the name to change things. But I have trouble like arguing with exercise. It's amazing. It's jam packed like there, there's so many. So that's one of the reasons I wanted to go cause you know, I would have, it'd be nice to go to that conference as well. Karen Litzy:                   49:22                Well, I am looking forward to your talk with Alex. I will obviously finish his book within the next week, so that's very exciting. And I've already taken your class and read your free resource. So I feel like I'm like ready for it. Greg Lehman:               49:39                I'll bring something new. Karen Litzy:                   49:42                I'll come armed with lots of questions. All right. So before we hop off, where can people find you? Greg Lehman:               49:49                Just my website I guess, which is Greglehman.ca. Which I hardly do anything on and then Twitter, same thing. Twitter is my favorite. I like the discussions on Twitter, even cultivate them, trying to keep them polite and nice and you know. So Facebook, Nah, it's for the trolls. Karen Litzy:                   50:15                I think. Yeah, I guess it depends anyway. Again, a whole other conversation. Yes. Greg Lehman:               50:21                No, I'm doing a big thing on Facebook right now. I shouldn't say that. Greg Lehman:               50:29                Yeah. Cause we have like a podcast with me and Oh, I have a podcast, I guess. Never. It's, well it's Adam, it's Meakins podcast, but I'm the cohost so I guess is mine. I don't know. When do you get part of that? I've done three with them. I'm just baggage. I'm a carry on. Karen Litzy:                   50:52                Yeah. I think, I think you need, you need a little bit more. I don't think that three really qualifies as like a permanent cohost. Greg Lehman:               51:01                Oh yeah, yeah. I don't think I want that. Karen Litzy:                   51:03                No, no, no. You're still like a guest cohost, give it a couple more and then I think you're in. Greg Lehman:               51:08                Okay. Well we're doing like a thing on neurodynamics like their dynamic techniques. And so I wanted to poll people and see what people thought. You know, I was curious what people thought, what the hell we were doing when we do them for that. Karen Litzy:                   51:27                I use them, I use them. And oftentimes in people who are a little fearful of movement. Greg Lehman:               51:33                Yeah. So what does that tell you what you're doing? Or you really like manipulating the nerve to, you know, feed them more oxygen or something. Getting someone moving again? Karen Litzy:                   51:45                I think you're getting someone moving again, I think you're taking them to a place where they can stay within a relative comfort zone and you can kind of see, I think what I use it is because you can see some changes pretty quickly. And so I think patients then get a little more confident that they can move because they can see those changes pretty quickly. So that's why I like to use them is to give people some hope. Greg Lehman:               52:15                It’s a modification. Karen Litzy:                   52:18                So that's why I use them, but I use them quite a bit just because I think, I think that they work very well. The only time I don't use them was really with like one person who said I was doing all these nerve glides and now it made my arm so much worse. Greg Lehman:               52:37                It's like everything. Karen Litzy:                   52:38                You know, but I don't know how many, what they were doing, why they were doing them, what explanation they were given. I have no idea that I just sort of held off for a little bit and had the move a different way. But yeah. So that's why I use them. Karen Litzy:                   52:59                So if no one else has any questions. So Agnes said that she'll play softball with me in Vancouver. Greg Lehman:               53:08                Tell her I’m going trampolining and rock climbing. Karen Litzy:                   53:15                I would go trampolining but I really just like bungee trampoline. Greg Lehman:               53:19                Let's do stuff. Karen Litzy:                   53:20                Well you're attached to a bungee and then you obviously go down and then you can go up and flip like two, three times in the air and come back down again. You can't twist, but I did do a double layout. Yeah, it was pretty cool. But yeah, I would definitely play softball. I will bring my glove and I can do some trampolining. I wouldn't have done it 10 years ago or five years ago because of my neck, but now I can do it. Yeah, totally can. Karen Litzy:                   54:14                Just so people know when Greg and I were at the align conference a couple of weeks ago in Denver, Colorado and he had his daughter Betty with him cause it was her birthday weekend and she was his personal photographer just so that it made him look better than everyone else because he had personal Paparazzi. And she was just super adorable and doing back walkovers and she probably would've done a lot more, but we were at a conference on the first day. Karen Litzy:                   55:21                She was very sweet and that's who we're talking about. All right. And I’m going to edit all of this out before I put it out on a podcast. Thank you everyone so much for listening and sorry for rambling at the end. If no one else has any questions, I just want to thank you all for listening and make sure you go and click on the link on this Facebook page. Should take you to the website for the Third World Conference in sports physical therapy. Again, it's October 4th and fifth, and Vancouver. Greg is speaking with Alex Hutchinson and I think that's going to be a highlight of the conference. You don't want to miss it. So Greg, thanks so much for hopping on the call and sorry for the technical difficulties. Thank you so much and we'll try and put all the information that we spoke about in the comments section here. So thanks everybody. And Greg, thanks again.     Thanks for listening and subscribing to the podcast! Make sure to connect with me on twitter, instagram  and facebook to stay updated on all of the latest!  Show your support for the show by leaving a rating and review on iTunes!

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             I'm Greg Hundley, Associate Editor for Circulation and Director of the Pauley Heart Center in Richmond, Virginia at VCU Health. Dr Carolyn Lam:                So Greg, ever wondered if prophylactic use of ICDs would help prevent sudden cardiac death in dialysis patients? Well, guess what? We're going to be discussing it in the feature discussion of the ICD II trial coming right up. First, I hear you've got a very interesting probabilistic paper. Dr Greg Hundley:             Yes. It's very sweet. This is from Renata Micha at Tusk University and it's examining the cost effectiveness of the US Food and Drug Administration added sugar labeling policy for improving diet and health. So Carolyn, in this study, investigators used a validated micro simulation US impact food policy model to estimate cardiovascular disease and type II diabetes mellitus cases averted, quality adjusted life years, policy costs, health care, informal care, and loss productivity in health related savings and cost effectiveness of two different policy scenarios.                                                 First, the implementation of the US Food and Drug Administration added to your labeling policy or just the sugar label. And second, further accounting for corresponding industry reformulation the sugar label plus reformulation. The models used nationally represented demographic and dietary intake data from the national health and nutrition examinations survey and diseased data from the centers for disease control and preventive wonder data base and policy affects in diet disease effects from meta-analysis and policy and health related costs from established sources. Probabilistic sensitivity analysis accounted for model parameter uncertainties and population heterogeneity. Dr Carolyn Lam:                Sweet indeed, so tell us all about probabilistic analysis Greg. Dr Greg Hundley:             Okay Carolyn, so between 2018 and then forecasting out into the future, so this is probabilistic, in the year 2037. The sugar label would prevent 354,400 cardiovascular disease cases, and 599,300 diabetes mellitus cases, gain 727,000 quality adjusted life years, and save 31 Billion dollars in net health care costs. Or 61.9 Billion dollars in societal costs incorporating reduce loss productivity and informal care costs and similar findings were accomplished for the sugar label plus reformulation scenario, both scenarios were estimated with greater than 80% probability to be cost saving by the year 2023.                                                 Thus, the results of this simulation exercises indicated that implementing the FDAs added sugar labeling policy could generate substantial health gains and cost savings for the US population particularly if the new label stimulates industry reformulation. The authors point out that the compliance date for updating the nutrition facts label including the added sugar perversion has been continuously delayed. And the authors believe, their findings highlight the need for timely implementation of this label so as to maximize health and economic gains.                                                 An excellent editorial was written by Elizabeth Magnuson at Saint Luke's Mid America Heart Institute revealing the strengths of this work and explains some of the variants that could occur in the results based on assumptions that were used in the authors micro simulation model. Dr Carolyn Lam:                That is so interesting Greg, thanks. So from policy to guidelines and this time on cardiopulmonary resuscitation or CPR, now we know that an out of hospital cardiac arrest, chest compression only CPR has emerged as an alternative to the standard CPR where we use both chest compressions and rescue breathes. Since 2010, CPR guidelines recommend chest compression only CPR for both untrained bystanders and trained bystanders who are unwilling to preform rescue breaths.                                                 The current study really aimed to describe the changes in the rate and type of CPR perform before the arrival of emergency medical services doing three consecutive guideline periods with gradual adoption of compression only CPR and this was in Sweden. Now these were authors led by Dr Hollenberg from The Center of Resuscitation Science, Karolinska Institute in Stockholm, Sweden and colleagues and basically, they study all bystander witness out of hospital cardiac arrest reported in the Swedish register for CPR from 2000 to 2017. They found that there was a six fold higher proportion of patients receiving compression only CPR and a concomitant almost double rate of CPR before emergency medical services arrival, and these changes occurred over time. Any type of CPR was associated with doubled survival rates in comparison with cases not receiving CPR, and this association was observed in all time periods studied. They also found a small but significantly higher chance of survival after CPR with compression and ventilation in comparison with compression only CPR. Dr Greg Hundley:             So Carolyn, does this mean we should go back to standard CPR? Dr Carolyn Lam:                Well, remember these we observational findings, albeit really amazingly done and nationwide. But the findings really support continuous endorsement of the compression only CPR as an option and that's because its associated with higher CPR rates and overall survival of the no CPR skill. The authors ended up calling for randomized controlled trials, which are really needed to answer the question of whether or not CPR with compression and ventilation is superior to compression only CPR, especially in cases where bystanders have had the previous CPR training. Now, this is discussion in a wonderful editorial by Drs. Hsu and Neumar from University of Michigan Medical School. Dr Greg Hundley:             Very nice, so you're going to tell us a little bit about troponin? Dr Carolyn Lam:                Well, the question is "Is Plasma Troponin I measured by the high sensitivity assay associated with incident cardiovascular disease in the community?" Well, Dr Ballantyne from Baylor College of Medicine and colleagues decided to answer this question by looking at the ARIC Study participants age 54 to 74 years without base line cardiovascular disease and what they found was that elevated high sensitivity troponin I was strongly associated with increased global cardiovascular disease incidents in this general population, and this was independent of traditional risk factors. They also found differences between black and white individuals and between men and women. Dr Greg Hundley:             What kind of differences? Dr Carolyn Lam:                Well high sensitivity troponin I had a stronger association with incident global cardiovascular disease events in white compares to black individuals and a stronger association with incident coronary heart disease in women than in men. The authors also did a comparative association of high sensitivity troponin I vs. troponin T, they found that the high sensitivity troponins I and T show only moderate correlation with each other but were complementary rather than redundant in risk assessment for incident cardiovascular events in individuals without known clinical cardiovascular disease at base line. The bottom line is, adding biomarkers to traditional risk prediction models presents a potentially effective approach for future risk prediction algorithms for cardiovascular disease in the general community. Dr Greg Hundley:             You know, think I might read that paper looking at that complimentary risk assessment. That sounds really interesting Carolyn. Well, I'm going to go back to the world of basic science and discuss a paper from Kun Wang discussing the long non encoding RNA regulation of cardiomyocyte proliferation and cardiac repair. Carolyn, post mitotic cardiomyocytes in the adult heart exit from the cell cycle and cease to proliferate, and that's the basis for their poor regenerative capacity and defective repair in response to say a myocardial infraction. Interestingly, the nonmammalian vertebrates such as our friend the zebra fish, their heart exhibits a robust capacity for regeneration. And it can efficiently regenerate its lost cardiac tissue throughout life due to this retain cardiomyocyte proliferation capability. Dr Carolyn Lam:                Interesting indeed Greg about our friend the zebra fish. So what did the authors find? Dr Greg Hundley:             Okay, in this study, Wang and associates investigated whether long non-encoding RNAs had a role in the regulation of cardiomyocyte proliferation and cardiac repair. Using bioinformatics and initial analysis, the identified a long coding RNA named Cardiomyocyte Proliferation Regulator or CPR that was comparatively higher in the adult heart as opposed to hearts in the fetal stage. The silencing of the Cardiomyocyte Proliferation Regulator or CPR significantly increased the cardiomyocyte proliferation in the postnatal in adult hearts, more over CPR deletion restored the heart function after myocardial injury which was evident from increased cardiomyocyte proliferation, improvement of myocardial function and reduce scar formation. Also, neonatal cardiomyocyte proliferation in cardiac regeneration where markedly suppressed in CPR overexpressing heart cells, therefore CPR acts as a negative regulator of cardiomyocyte proliferation and regeneration in fetal hearts.                                                 So, Carolyn the conclusion of this paper is that the inactivation or silencing of CPR accelerates cardiomyocyte proliferation along with significant restoration of cardiac structure and function after myocardial injury in adult hearts. And as such, further studies may investigate whether the therapeutic inter fashion of CPR could be a useful strategy to trigger the expansion of cardiomyocyte populations and myocardial repair. Dr Carolyn Lam:                Nice Greg, so we've talked about CPR as in Cardiopulmonary Resuscitation to CPR as in Cardiomyocyte Proliferation Regulator, how about that? Well, that's as much as we go for now, let’s get to our feature discussion.                                                 Dialysis patients are known to have a high mortality rate, a large proportion of which have been attributed to sudden cardiac death and yet compared to patients with heart failure, these patients with dialysis have been either excluded or only nominally enrolled in all previous trials of implantable defibrillators or ICDs. Now that's why our feature paper this week is so important, and it is the Cardioverter-Defibrillator in the prevention of sudden cardiac death in dialysis patients that prospective randomized controlled ICD to trial. So pleased to have with us, the corresponding author Dr Wouter Jukema from Leiden University Medical Center as well as associate editor Dr Mark Link from UT South Western to discuss this very important paper. Wouter, congratulations, this is a very difficult, very important to do the study though, could you tell us a bit about what you did and what you found? Dr J. Wouter Jukema:     Actually, you just referred to it as a very difficult study to perform and indeed it was. Many years ago, actually, twelve years ago, we noticed that now a lot of death in dialysis patients was attributed to sudden cardiac death, before we tried to make these type of patients better with all types of medications, but did not really work and suddenly the idea was, that came also from death certificates and death records that they have sudden cardiac death and we said we should monitor it and we should treat it in a prospective randomized study. We initiated the study after careful thoughts and we thought we would do it in 4-6 years but it took us 12. So it was quite an effort to set up this rightly and spread it around the Netherlands and activate a Nephrologist and a Cardiologist to take part in this prospective randomized controlled study in dialysis patients.                                                 Of course, you can easily imagine that you could have great benefit from this ICD devise, but you could also easily imagine that you would have complications of the implication of the device. So explaining that we should show it out, I think was the most important job we had to do and think that was a great effort, and it was not easy to do. Dr Carolyn Lam:                And that in it of itself is very important observation. Dr Mark Link:                     So you picked patients without doubts, which is great I mean this is a difficult study, but you also picked with an LDF greater than 35% and traditionally, ICDs are indicated for under 35%, can you give us a little explanation on why you chose the greater than 35% population? Dr J. Wouter Jukema:     Yeah, I think this is perhaps the most important remark on the study, because when we designed the study we had to choose at that time we had guidelines in general that under 35% of injection fraction you were entitled to receive an ICD, however of course almost never dialysis patients were included so there was no formal recommendation on that not to include them or not to exclude them, but dialysis patients have a death rate at that time to sudden cardiac death, anyway regardless of the injection fraction and we thought okay, the patient population that is first at high risk of sudden cardiac deaths so any dialysis patients but also they are entitled to have a meaningful extension of the lives because the prognosis of patients that are on dialysis with an injection fraction under 35% is in general so poor that it would be unfair to start there and most of the Nephrologists also would not allow it anyway, these patients are at the end of life and if you extended for two or three months its useless.                                                 Anyway, so we thought we'd pick the high-risk population and we prove that there were still on high risk but when we could do something meaningful to extend their lives, so we thought we do not pick the worst patients we pick the patients that we think we can really help. We screened them well, we treated them well and we see if an ICD on the patient will benefit them. And that's why we picked the over 35% rage. You need another study to do below 35%, but I don't think that our results are substantiating such an effort. Dr Mark Link:                     The population with EFs was 6-50%, which also has a high risk of sudden death in patients with dialysis but it’s still not looking with the population of less than 35%. Dr J. Wouter Jukema:     No, I completely agree, and we acknowledge that in the manuscript, it was always in the manuscript within the revision that was also pointed out to us that it should be more clearly acknowledged, why we choose this patient population and finally, we can of course not make a formal recommendation on dialysis patients with an injection fraction of less than 35%. You can extrapolate data but we have no formal prof of course for this type of population. I fully agree. Dr Carolyn Lam:                Before we go further, could you first describe, what did you find? Dr J. Wouter Jukema:     Basically, the conclusions are the prophylactic ICD therapy in patients on chronic dialysis with an injection fraction of 35% or higher was not associated with a reduced rate of sudden cardiac death nor of all cause of mortality and besides that the preference of sudden cardiac death in this type of patients on dialysis was actually significantly lower compared to its reports from literature, so that's what we very often see of course if you fill out a death certificate, you have to fill out a cause of death and of course in many patients the heart stops, and you say it's a sudden cardiac death. But that's not what this study actually showed and finally it's also no authority that this population was not too healthy to see any benefit, if you look at the results over the years, then you'll see that after five or six years more than half of the patients are dead anyway, but due to all kind of causes and not to a sudden cardiac death.                                                 So, I think that this is from a pathophysiological background, this is also a very interesting study because we now have finally data, real data on sudden cardiac deaths in these types of patients. Dr Carolyn Lam:                Indeed, and Mark, I know that you invited the editorial from Rod Passman, just discussing why did we see the results that we did. Not quite what we expected I suppose, what do you think Mark? Dr Mark Link:                     First, I want to congratulate Dr Jukema for finishing this study, this was a massive task and a difficult and long one. I think I was surprised, there has been reported to be a very high rate of sudden death in dialysis patients regardless of their LDF. The ICD is very good at preventing sudden deaths, but not good at preventing other types of deaths, so I would extrapolate to say, well you can prevent sudden death in dialysis patients, you should prolong their life and this study did not show that at all. And I was surprised, and it just goes to what Dr Jukema was telling us, that what's reported on a death certificate as sudden death is not necessarily sudden death and could be other types of death and at the end all death is sudden. Dr J. Wouter Jukema:     I fully agree with that remark because that makes is cumbersome to have the right interpretation of the data, so you have to feel like something and then finally your heart stops. Dr Carolyn Lam:                What seems that most of the reasoning seems to be maybe a lower rate of sudden cardiac death than we expected, but there were also other factors that were considered, for example, if you could clarify by dialysis did you mean both hemodialysis as well as peritoneal dialysis, do you think that made a difference? For example, do you think ICDs work differently in presence of uremic precipitant of arrhythmias vs. not and so on, what do you have to say about those factors? Dr J. Wouter Jukema:     We include on purpose both types of patients, the peritoneal dialysis and the hemodialysis patients because you could easily in-visit that there could be a difference, for instance to fluid or electrolyte sheaths that are more sudden in the hemodialysis patients than in peritoneal dialysis and we did a sub-analysis where we looked at both types, but the results are essentially the same, it doesn't seem to matter a great deal of what type of dialysis you have, the amount of sudden cardiac is lowered and expected. By the way occasionally, of course the ICD did work in sudden cardiac death, was aborted. So, it’s not that the apparatus doesn't function it does, it takes it properly and if functions properly. But finally, it doesn't prolong the life and you will die of something else, mostly infections in general well-being when finally, the nephrologist will say this is end of life you have to stop the dialysis procedures anyway. Dr Carolyn Lam:                Right, great points, now in the last few minutes, I'm dying to ask, what do you think of the next steps from here. Mark, what do you think first? And then perhaps I'll give the last word to Wouter? Dr Mark Link:                     I'll start with a question to Wouter myself, the question is what are we going to do now with the individuals on dialysis that are under 35%? I think this study has pretty clearly said that were not going to extend our CDs to people on dialysis with greater than 35%. But we still have a population that currently fits indication for a ICD if their expected longevity is greater than a year. And currently those people are included in the guidelines for ICDs, I think this study gives us some pause about what to do with our population. And many of that population are getting our CDs and I'd be curious to what Dr Jukema thinks about that population and whether that population warrants some randomized trial or whether we should continue with our current guidelines that recommend implantation of an ICD in any individual less than 35%, as long as their expected life span is greater than a year. Dr J. Wouter Jukema:     I think these are excellent questions with excellent remarks, of course, finally, we do not know because we didn't investigate it, I can only imagine the difficulties we would have if we were to do a new additional trial with injection fractions patients less than 35%. I could tell you we had great great difficulty in persuading Nephrologists to take part in the study, because many of them were very reluctant, this is their principal, these are very ill patients, and a lot of them are more or less going towards the end of their lives so you cannot do this when we have Nephrologists telling us that they considered it an unethical study. A lot of them did not want to participate they said, "You shouldn't do this to this patient, they have troubles enough, they suffer from infections and all kinds of things."                                                 Having said this, I do not advocate that you should never implant an ICD in a dialysis patient, I think in our study we also clearly show that in dialysis patients, implantation of an ICD is feasible within acceptable although better complication risk and infection risk, so if you have a patient on dialysis where you feel this patient has a good life expectancy, for instance, he already suffers an episode of arrhythmia, I think you are entitled to discuss this with the patient and have it a try, it might work and prolong their life. So I would not say never do it, I think our studies show that you can do it, yes, it sometimes works but do not expect too much of it. You will never hear me say that in general you should not do it, if you have a clear indication for it you may do it, secondary effect may require a good reason, but primary prophylactic indication, that's a difficult one I think and to do this study in patients that are even more ill, with injection fraction of less than 35%, I feel will be exceeding the difficult. Dr Mark Link:                     One other comment I have is the issue of the SUBCU ICD I think changes the equation in a bit because the risk of infection is much lower with a SUBCU IDC in patients on dialysis, did you have any SUBCU ICDs in your study or was it all transvenous? Dr J. Wouter Jukema:     We don't have any data, when we designed and the developed study, the such a device was not even there so we couldn't do that, and during the study we did not adapt that but of course there is also no formal proof yet that it's a lot safer, a lot better, and once again this time of subcutaneous ICD I think you can do it at an acceptable complication rate. But it’s not effective enough, it's not that the patients were dying from infections of their ICD, they were dying of all kinds of infections and malignancies. Infections due to the ICD were facing procedures, real complications were rare. Dr Carolyn Lam:                Great! Thank you Wouter, thank you Mark, what an important study and what a lot of lessons that we learned here.                                                 Thank you very much audience for listening as well, you've been listening to Circulation on the Run, don't forget to tune in again next week.                                                 This program is copyright American Heart Association 2019  

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. We're your co-hosts, I'm Dr Carolyn Lam, associate editor from The National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, associate editor for Circulation and director of The Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam:                Guess what Greg? Right after this we have a double feature discussion. It is all about dapagliflozin with some really, really important self-analyses from the DECLARED-TIMI 58 trial and about heart failure in Type 2 Diabetes with dapagliflozin. But, all of that coming right up only after we have our chat. So Greg, what do you have for us today? Dr Greg Hundley:             My first article is going to be from Dr Mintu Turakhia at the VA Palo Alto healthcare system at Stanford University and is going to discuss the practice variation in anticoagulation prescription and outcomes after device-detected atrial fibrillation. It's a study that has insights from the VA Health Administration. This study evaluated the relationship between oral anticoagulant prescription practice variation in response to new device detected atrial fibrillation and the association to outcomes.                                                 As you know Carolyn, there are no clearly defined thresholds of AF burden, for which to initiate oral anticoagulation. Dr Carolyn Lam:                Interesting, so what did they find, how did they do this? Dr Greg Hundley:             Carolyn, the investigators performed a retrospective cohort analysis using data from the Veterans Health Administration linked to remote monitoring data that included day level AF burden. They included patients with cardiac implantable electronic devices and remote monitoring from the years 2011 through 2014. A CHA2DS2-VASc score of greater or equal to 2, and no prior stroke or oral anticoagulant receipt in the preceding 2 years. They determined the proportion of patients prescribed oral anticoagulants within 90 days following new device-detected AFib across a range of AFib thresholds. Greater than or equal to 6 minutes, all the way up to greater than 24 hours. And they examined sight variation in oral anticoagulation prescription. Dr Carolyn Lam:                And so? What did they find? Dr Greg Hundley:             Well, you ask among 10,212 patients with defibrillators, proportion receiving oral anticoagulation varied based on device detected AF burden. For example, for those greater than or equal to 6 minutes, it was roughly 13% of individuals, for those greater than 24 hours, 27% of individuals received oral anticoagulants. Importantly, there was a substantial sight variation in oral anticoagulation prescription after device-detected atrial fibrillation, for example, greater than one hour. The median was 16%, but it ranged from as low as 3% up to highs of 67%. And so, in adjusted models, oral anticoagulant prescription after device-detected AFib of greater than 24 hours was associated with reduced stroke risk and has a ratio of 0.28, p-value's 0.02, although, the propensity adjusted model was significant when AFib lasted at least 6 minutes.                                                 So, in conclusion, among veterans with implanted devices, device-detected atrial fibrillation is common. There is large practice variation in 90-day oral anticoagulation initiation after new device-detected AFib with low rates of treatment overall, even for episodes greater than 24 hours. Remember, we said that rate was 27%. The strongest association of oral anti-coagulation with reduction in stroke was observed after device-detected Afib of greater than 24 hours. And what this study shows, is that randomized trials are needed to perform these observational findings.                                                 So, Carolyn, how about your next study? Dr Carolyn Lam:                Well, from anti-coagulants to anti-hypertensives. I'm going to tell you about the 6-month results if the RADIANCE Hypertension Solo Trial. Dr Greg Hundley:             Oh, so, what was the RADIANCE Hypertension Solo Trial? Can you remind us? Dr Carolyn Lam:                Glad you asked. So the trial was the one that demonstrated a greater reduction in daytime ambulatory systolic blood pressure at 2 months by endovascular ultrasound renal denervation compared with a sham procedure among patients who were not treated with anti-hypertensive medications. So the current paper, led by Michel Azizi from Université Paris-Descartes and colleagues, now report the 6-month results following the addition of a recommended, standardized, stepped-care anti-hypertensive treatment to the randomized endovascular procedure under continued blinding to the initial treatment.                                                 Now, remember these were patients with uncontrolled combined systolic and diastolic hypertension who were initially off medications for two months following randomization. Now, between two and five months, if the monthly measured home blood pressure was more than 135/85, the stepped-care antihypertensive treatment approach was recommended and consisted of sequential addition of, for example, amlodipine 5mg a day, then a standard dose of an angiotensin-converting-enzyme inhibitor, or an ARB, and hydrochlorothiazide at 12.5mg a day, followed by sequential uptitration of the hydrochlorothiazide and amlodipine.                                                 So, what did they find? At 6 months, 65% of the patients in the original renal denervation group were being treated by this stepped-care approach, versus 84.5 in the sham group. And the average number of antihypertension medications and defined-daily doses were all less in the renal denervation group than the sham group.                                                 Now, despite less intensive antihypertensive treatment, the renal denervation group had reduced daytime ambulatory systolic blood pressure to a great extent than the sham group. Importantly, there were no major adverse events in either group through 6 months. The blood pressure lowering effect of endovascular ultrasound renal denervation was maintained at 6 months with less prescribed antihypertension medications compared with the sham control. And what this means is if safety is maintained in larger studies with longer follow-up, renal denervation could be a promising adjunct therapy for patients with hypertension. Dr Greg Hundley:             Wow, so we're getting back toward renal denervation? How about that?                                                 Carolyn, my next paper jumps into the world of basic science. This is a study from Kari Alitalo at the University of Helsinki, and it involves endothelial cells and how they regulate physiological cardiomyocyte growth versus VEGFR2 mediated paracrine signaling. The study evaluates the role of bidirectional endothelial cells and cardiomyocyte cross-talk via cardiokine and angiocrine signaling as it pertains to the regulation of cardiac growth and homeostasis in pathological cardiac hypertrophy. The expansion of the cardiac vasculature to maintain adequate supply of oxygen and nutrients is a key determinant of whether the heart grows in a physiological compensated manner, or a pathological decompensated manner.                                                 Understanding how an excess of angiogenesis induces cardiac hypertrophy and how endothelial cells regulate cardiomyocyte homeostasis, could provide novel therapeutic targets for heart failure. Dr Carolyn Lam:                Ah, this is something very close to my heart. So Greg tell us, how did they establish the link between the endothelial cells and cardiomyocytes? Dr Greg Hundley:             The investigators demonstrated that both endothelial cell deletion of vascular endothelial growth factor receptor 1 and AAV-mediated delivery of the VEGFR1's specific ligands, VEGF-B or BGIF, into the myocardium increased the coronary vasculature and induced cardiomyocyte hypertrophy in adult mice.                                                 The resulting cardiac hypertrophy was a physiological as indicated by preserved cardiac function and exercise capacity and lack and pathological gene activation. Also, the investigators demonstrated that the reported changes were mediated by increased VEGF signaling via endothelial VEGFR2 and found that the notch and ERBb pathways are involved in transducing signals for endothelial cell cardiomyocyte cross-talk in response to angiogenesis.                                                 So clinically, the relevance of the findings are highlighted nicely in an editorial by professor Issei Komuro at the University of Tokyo Hospital. First, he emphasizes that cross-talk between the endothelial cell VEGFR2 and cardiomyocyte ErbB signaling pathways coordinates cardiomyocyte hypertrophy with angiogenesis and contributes to physiological cardiac growth. And understanding whether factors could modify this process may impact the treatment down the road of pathologic hypertrophy. Dr Carolyn Lam:                Oh interesting! Well you know what, Greg, I've got a preclinical one for you too, and this time looking at the role of inflammation in atherosclerosis and specifically at the role of the adaptive immune response and T-cells.                                                 So, Greg, let me remind you that when we looked at CANTOS and Canakinumab we were actually looking at the role of the innate immune response. And here is where I had planned this very nice, complicated quiz for you, Greg, about the innate versus the adaptive immune response in the various cells. Would you like to take the quiz? Dr Greg Hundley:             You know what? I think I'm going to pledge that I'm already going to get a D or an F, so why don't you enlighten us? Dr Carolyn Lam:                Now alright, remember that the CD4 T-cells are assumed to be activated by our antigens derived from modified proteins such as oxidized LDL, and these are presented via MHC class II molecules in the context of cytokine signaling, remember those? What I didn't realize is that it hadn't been assumed that atherosclerosis involves a loss of tolerance against these modified self-antigens, generated in response to hypercholesterolemia and that presentation of such antigens on these MHC class II cells, then lead to activation of proatherogenic Th1 cells. So, that was the assumptions, but this was really studied in detail by the authors, Dr Wigren from Scania University Hospital and Lund University in Sweden and their colleagues, who addressed the role of CD4 T-cells in a real novel, unconventional way. And they did this by crossing MHC class ii deficient mice with atherosclerosis-prone ApoE-deficient mice.                                                 Now the result of these double deficient mice was almost complete void of CD4 T-cells. However, despite the lack of these T-cells and inflammation, these mice developed larger atherosclerotic lesions in the aortic root area of the heart than their ApoE-deficient counterparts. Cell transfer and blocking antibody studies also, then supported these findings and suggested that loss of regulatory T-cells is the most important cause of aggravated atherosclerosis in the double-deficient mice.                                                 So, overall these observations demonstrate that deficiency of activation of the adaptive immune responses through MHC class ii is associated with increased development of atherosclerosis, and the findings have important implications for our understanding the possible risks and benefits of immunosuppressive therapy in patients with cardiovascular disease. Now this is discussed in a beautiful editorial by Dr Slütter and Kuiper and they are from Leiden, the Netherlands.                                                 So, Greg, interesting stuff, huh? Dr Greg Hundley:             You bet! Let's go on and here a little bit more about diabetes. Dr Carolyn Lam:                And dapagliflozin coming right up.                                                 Today's feature discussion is all about SGLT2 inhibitors both in heart failure and atherosclerotic disease. A huge discussion because we have two papers, and they're all coming from the DECLARE-TIMI 58 trial. I am so pleased to have the corresponding author, Dr Stephen Wiviott from the TIMI study group at Brigham Women's hospital in Boston, Massachusetts, as well as the first author of one of the papers, and that is Dr Eri Kato, who was at the TIMI study group and is now at Kyoto University, as well as the editorialist for these two papers, Dr Subodh Verma from University of Toronto, and our deputy editor, Dr Darren McGuire from UT Southwestern.                                                 All-star cast, all-star papers. So, Steve, could you start by telling us about the DECLARE-TIMI 58 trial, just to set the background please? Dr Stephen Wiviott:        So DECLARE, for people who don't know, was a large, randomized trial of 17,000+ patients with diabetes, comparing the SGLT2 inhibitor dapagliflozin to placebo. And the patients could be enrolled if the patients had either an established cardiovascular disease, meaning secondary prevention, or simply risk factors for cardiovascular disease with primary prevention.                                                 Patients that were treated with dapagliflozin or placebo were followed for a period of just over 4 years and there were co-primary endpoints. Those were cardiovascular death and hospitalization for heart failure, and the second co-primary endpoint was MACE, major adverse cardiovascular events, a combination of cardiovascular death, MI, or stroke.                                                 And what we saw, initially, this was a safety trial to demonstrate the safety of this diabetes agent according to worldwide guidelines. We saw that there was certainly non-inferiority for MACE, so it was safe with regard to MACE, but we did see a statistically significant reduction in cardiovascular death and hospitalization for heart failure driven predominantly by a large reduction in hospitalization for heart failure, and we also saw consistent with the other SGLT2 inhibitors, a significant reduction in the progression of renal disease. And so we had the opportunity to follow up with a couple of important papers that were published in circulation. Dr Carolyn Lam:                Thanks, Steve. And at this point I would love to invite Eri to tell us, because we just heard that the heart failure hospitalization signal is very strong. What did you do in your analysis? Dr Eri Kato:                         So previously, SGLT2 inhibitors including dapagliflozin have shown to reduce hospitalization for heart failure, now we wanted to take a step further and explore those who are at high risk. So, the aim of our study was to evaluate whether the clinical benefit of dapagliflozin is greater in patients with HFrEF, heart failure with reduced ejection fraction, compared with patients without HFrEF.                                                 So, we used data from the DECLARE-TIMI 58, which you just heard, which included a broad spectrum of patients with Type 2 diabetes, and was also unique that it is the only SGLT trial to date that has detailed the information of these ejection fractions. So, for this study, for our study trying to find patients by the presence or absence of HFrEF, which was defined as having ejection fraction less than 45%, which is pre-specified ejection fraction couplings, and the key outcome in each was cardiovascular death or hospitalization for heart failure, its components, and of course, mortality. But we also additionally looked at MACE and renal composite endpoints.                                                 There are several interesting findings. First, is that dapagliflozin reduced the risk of hospitalization for heart failure regardless of ejection fraction, including those with preserved ejection fraction.                                                 Second, is we have observed lower rates of cardiovascular death in all-cause mortality with dapagliflozin in patients with HFrEF, but not in those without HFrEF.                                                 So, in patients with HFrEF, there was a significant 45% reduction in cardiovascular death, and 41% reduction in all all-cause mortality with dapagliflozin. And I'd like to highlight that these were achieved on top of high-proportional use of conventional evidence-based heart failure therapies, and that it did not increase any adverse events.                                                 And third, and finally, there were lower rates of renal composite endpoints with dapagliflozin regardless rejection fraction, and once again, it improves patients with preserved rejection fraction.                                                 So, to summarize, our results showed a robust mortality benefit in patients with HFrEF, but also showed that dapagliflozin is beneficial in full spectrum patients with diabetes, regardless of ejection fraction. Dr Carolyn Lam:                Thank you Eri, that's beautifully summarized, but could I just clarify? These were patients not just with a reduced ejection fraction, but with heart failure? And how was that determined? Dr Eri Kato:                         We collected data at the baseline and the heart failure was collected based on the medical record. Dr Carolyn Lam:                So, I just wanted to clarify that it wasn't just rEF, but HFrEF, but the HF part was a medical record. So, Darren, I know you thought a lot about this stuff, so what do you think? Is there still equipoise for these heart failure trials, or how do you think this adds? Dr Darren McGuire:        First, as deputy editor of Circulation, I'm thrilled that were attracting these excellent diabetes-related publications, we've had a track record of several years now of capturing many of the key analyses and certainly these two papers we're talking about today qualify among the very best we've had, and I've also had the privilege of working with these investigators on the executive committee at DECLARE. And to the investigators and the credit of the sponsor, we observed these heart failure signals in other trials as DECLARE was ongoing, and we actually made a modification during the trial to begin to collect as much as we could pre-randomization ejection fraction data. And we were able to capture on roughly one-third of the patients, pre-trial EF data and we took any way it was measured and any time of when it was measured, and there are some limitations to that, but this now represents the largest data set where we can stratify the outcomes by some measure of ejection fraction.                                                 And I have to say I was really surprised by these results; that the cardiovascular death benefits were amplified in patients with heart failure with reduced ejection fraction, but not in those with heart failure with preserved ejection fraction, as these medications are relatively modest, diuretic agents I anticipated the opposite, honestly, that heart failure would preserve ejection fraction that is much more volume-sensitive may have incremental benefits from these medications.                                                 So, I was surprised by this, it was a little bit upside-down from what I expected. I know Subodh and Carolyn you've both thought a lot about this as well, I'd be interested in your opinions. Did you expect that heart failure with reduced ejection fraction would drive these clinical results? Dr Carolyn Lam:                Subodh, I'm going to let you go first. Dr Subodh Verma:           First and foremost, I appreciate the opportunity the circulation gave both myself and Professor McMurray to write the editorial to these very important pre-specified analyses from DECLARE.                                                 I actually see the results not only as interesting and tantalizing as you already discussed, but I actually see a lot of consistency between the two phenotypes, if I may, in that there is a heart failure signal or reduction in heart failure hospitalizations that appears to be consistent between the two groups, right? People with an EF of less than 45 with or without heart failure and then on the other side, people without reduced ejection fraction. They're both responsive in terms of reductions in heart failure hospitalization, so it brings into question that is this differences that we're seeing with respect to mortality, a reflection of a difference in phenotypic responsiveness to an SGLT2 inhibitor, or is this simply a reflection of increasing placebo event rates and a response based on baseline of entry in one group versus the other.                                                 So, as has been nicely outlined by the authors, the placebo event rate for CB death and heart failure and the placebo group would have pass, if I may, was about 5 times lower than those with heart failure with reduced ejection fraction. And it might be that as we go up the pyramid of risk, whether that risk is defined based on a TIMI risk score, whether it's based on a post-MI versus stable CAV risk score, or whether it's defined based on GFR, or whether, finally, it's defined based on the event rates for CV death and heart failure, that the higher the event rate, the higher the probability of demonstrating a CV death benefit, but that old strategies are actually demonstrating a consistent benefit on the overall driver of that outcome, which in this case, is a reduction in heart failure.                                                 So, that's what we sort of said in the editorial as well that we think that it may be a bit premature at this point to reach a conclusion that one group is responsive, and the other group is not responsive. But, as you rightfully said, Darren, it is entirely feasible through these analyses to hypothesize that one of the alternative hypotheses could be that there is a greater responsiveness in HFrEF compared to HFpEF. I actually don't understand the mechanisms of it, if that was the pieces I would have a difficult time explaining it based on the overall biology and sort of current understanding of these agents.                                                 But, I would say let’s wait: dapa heart failure is just around the corner. That trial will enroll people with documented heart failure with reduced ejection fraction. I think 4,774 patients that are being randomized on top of base, on top of RNA, on top of MRA, etc. who still have heart failure and who have a BP that's elevated so the definitive proof for this, at least from a rough standpoint, will be forthcoming. And then there are numerous HFpEF studies that are ongoing. There's Emperor Preserve and there's Deliver, and they have characterized the HFpEF population with a little bit more granularity and clarity. And I think we will be able to then look at, specifically, is there a HFpEF group that has the same event rate for CV death and heart failure, and compare that population to a HFrEF group at the same level of risk and whether there is differences in the responsiveness to be definitive about whether this is a matter of risk, threshold, or whether this is a true representation phenotypically. Dr Carolyn Lam:                Subodh is a hard act to follow. So, I will answer your question directly, but maybe not with so many words, because it's already been said, Darren. And I'll just say I expected this benefit to be in both, I wouldn't have said one versus the other, but because we do know that in trials and with prospective studies that HFpEF outcomes are lower, especially mortality is lower, compared to HFrEF. I do wonder if it's a power issue, but the most important message--and this is coming from me also being on the steering on the committee of both DELIVER and EMPEROR Preserve--that please, this doesn't mean that we don't need the trials. I really really think that there's equipoise there still and we need to look at the DEDICATED HFpEF trials.                                                 But, moving on from the concept of risk stratification, I would like to go on and talk about the next paper. About the DECLARE sub-study of those with a prior MI. So, Steve, could you tell us, why did you do this, and what did you find? Dr Stephen Wiviott:        I think that what we've seen as a pattern across the three SGLT2 inhibitor trials including CANVAS, EMPEROR, Outcome, and DECLARE, was that there seems to be, as Subodh has said, reductions that are relatively consistent in heart failure and renal outcomes. But there was what appears to be ischemic outcomes, the MACE outcomes, cardiovascular death, MI and stroke.                                                 In fact, in a meta-analysis that we published at the same time as the primary paper for DECLARE, we demonstrated that there was an interaction between the primary prevention in the population, those without established cardiovascular disease, and the secondary prevention population as it relates to MACE, where the benefits for MACE seem to be in the secondary prevention population.                                                 So, this was seen in DECLARE as well, and so we hypothesized that the population of patients who had myocardial infarction as their entering condition may be particularly at high risk for MACE and it may potentially be that that was driving the benefit. And so, what we did was we stratified the patients based on history of prior myocardial infarction versus none, turned out that there was about 3,500 patients in the trial who had had a prior myocardial infarction. As would be expected from what's known about the conditions, the event rates for those patients in the placebo arm were much higher, about 2.5 times higher than patients without myocardial infarction for MACE, also true for CV death and hospitalization for heart failure.                                                 And then what we saw when we looked at the treatment outcomes was that there tended to be a greater reduction in MACE for patients with prior myocardial infarction. In fact, for the MACE outcome, we saw about a 16% reduction in MACE with patients with prior MI compared to reduction with patients without prior MI. And so, the combination of this higher risk, also a tendency towards a greater relative benefit lead to a much greater absolute benefit, where, in fact, we saw about a 2.5% reduction in MACE over the four-year period for patients with prior MI, compared to a 0% reduction for patients without prior MI.                                                 And, in fact, when we broke this down to three groups: patients with prior MI, patients with atherosclerotic cardiovascular disease without prior MI, and then patients with no atherosclerotic vascular disease, essentially, we saw the same thing, which is that patients with MI were the ones who had the greatest benefit in terms of MACE. And this was almost entirely driven by reductions in myocardial infarction.                                                 Now, I would say in contradistinction, as we look at heart failure reductions, the relative benefits for heart failure were similar among these groups, but because the risk was higher in the patients with prior MI, and of course the absolute benefits were greater in the MI population, and similar for renal outcome. So, I think that this sort of extends what we have previously known that patients with atherosclerotic cardiovascular disease were at higher risk intended to have greater benefit with the SGLT2 inhibitors on MACE events that the core of that appears to be those patients with myocardial infarction. Dr Carolyn Lam:                Thanks, Steve, that was just so clearly explained. Darren, in the last couple of minutes could I ask you to give us the take-home messages from these two studies, and maybe just, what next? Dr Darren McGuire:        I think the take-home message from these two studies in the context of the overall field of SGLT2 inhibitor data, I think the picture's becoming relatively clear and Subodh stated in eloquently before and is reviewed in the editorial is that I think across the board, and independent of how you define higher versus lower risk subsets, this class of medications in general and dapagliflozin, and these studies appear to have augmented benefit, the greater the risk. Whether that greater risk is defined by prior myocardial infarction, or heart failure with reduced ejection fraction, or decreased EGFR, these are all states where various sub studies have consistently shown across the three compounds where we have outcomes data that the treatment benefits are amplified in the higher risk patients.                                                 And it's not just an absolute risk reduction that's augmented based on baseline risk, but there appears to be an interaction where the relative risk reduction is also amplified. And so, it's really a remarkable field and it's providing therapeutic options in these really high-risk subsets of patients where we've really been handicapped up until now with these antihyperglycemic therapies for type ii diabetes. Dr Carolyn Lam:                Thank you everybody for joining us today. This was truly a bonanza feature discussion, didn't I tell you?                                                 You've been listening to Circulation on the Run, thank you for listening today and don't forget to tune in again next week.                                                 This program is copyright American Heart Association 2019  

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, also associate editor from VCU Health Systems, the Poly Heart Center in Richmond, Virginia. Dr Carolyn Lam:                So arrhythmogenic cardiomyopathy that will make most of us think of right ventricular disease and fatty infiltration of the muscle, but could arrhythmogenic cardiomyopathy really be a bi-ventricular disease? Well you've got to stay tuned to find out more in a fantastic interview coming right up after our little coffee chat. So Greg, what are your picks this week? Dr Greg Hundley:             My first paper is from Chris Lim at NYU in New York. And it's looking at the relationship between Mediterranean diet, air pollution and cardiovascular events.                                                 So, it's unknown whether usual individual dietary patterns can modify the association between long-term air pollution exposure and health outcomes. And so, in this large cohort with detailed diet information at the individual level, they had 548000 individuals across six states and two cities within the U.S. and a follow up period of 17 years. And that occurred between 1995 and 2011. And they evaluated whether a Mediterranean Diet modified the association between long-term exposure to ambient air pollution and then cardiovascular disease and mortality risk. And so, the average exposures to parts per billion and nitric oxide air pollution that the residential census track level were measured, and the investigators found that for the particulate matter there were elevated significant associations with cardiovascular disease. So, a hazard ratio of 1.13, ischemic heart disease similar hazard ratio and cerebrovascular disease with also a similar hazard ratio.                                                 For the nitric oxide, there were also significant associations with cardiovascular disease, as well as ischemic heart disease. And then the analysis indicated that Mediterranean diet modified the relationships. Those with a higher Mediterranean diet score had significantly lower rates of air pollution related mortality. These results therefore indicate Carolyn, that Mediterranean diet reduce cardiovascular disease mortality related to long-term exposure to air pollutants in a large perspective, U.S. cohort. Can you believe increased consumption of foods rich in antioxidant compounds actually may aid in reducing the considerable disease burden associated with ambient air pollution? Dr Carolyn Lam:                Oh wow. That is hugely interesting. Gosh, what do we do about this clinically now?  Dr Greg Hundley:            Remember, first of all, this is an associate study, so we can't infer cause effect. And what we need next are some more independent studies from other cities around the world, prospective cohorts, examinations of clinical outcomes and randomize interventions. And so, I think the results add to a growing body of literature suggesting that dietary patterns may help reduce cardiovascular events in these high air pollution exposure areas. And how does this work? Well, potentially through augmenting antioxidants and reducing oxidative stress. Dr Carolyn Lam:                That's really cool. So from one region, talking about air pollution to another region that often reports about air pollution and that's China. But this study from China is actually the largest registry study to evaluate sex related differences and hospital management and outcomes of patients with acute coronary syndrome in China.                                                 This is from corresponding author Dr Zhao from Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease. With colleagues of the improving care for cardiovascular disease in China, Acute Coronary Syndrome project, which is an ongoing nationwide registry of the American Heart Association and the Chinese Society of Cardiology. So, the authors use data from this project and evaluate at sex differences in the acute management, medical therapies for secondary prevention and in hospital mortality in more than 82000 patients admitted for acute coronary syndrome in 192 hospitals across China from 2014 to 2018. Dr Greg Hundley:             What did they show in this study? Dr Carolyn Lam:                They showed that women hospitalized for acute coronary syndrome in China less frequently received acute treatments and strategies for secondary prevention and had a higher in hospital mortality rate than men. Now the observed sex differences in this in hospital mortality were likely due to older age, worse clinical profiles and fewer evidence base acute treatments provided to women. And that's because the sex differences were no longer observed after adjustment for these clinical characteristics and acute treatments.                                                 What this all means though is specifically targeted quality improvement programs may be warranted to narrow these sex related disparities in patients with acute coronary syndrome in China.  Dr Greg Hundley:            Very interesting. I'm going to take sort of the next paper and it's looking at a different aspect of acute myocardial infarction. And these papers from Yong Wang from the Division of Molecular and Translational Cardiology at Hannover Medical School in Hanover, Germany.                                                 Now as we know, the heart can undergo deleterious changes and left ventricular geometry and function during that vulnerable period before scar formation has stabilized the infarct area. And so inflammatory cell trafficking from hematopoietic organs like the spleen to sites of tissue injury is coordinated by chemokine chemokine receptor networks. Therapeutically modulating these chemokine chemokine receptor interactions may promote infarct healing by limiting excessive inflammation induced tissue damage or by enhancing the recruitment of angiogenic cell populations to the infarct or the wound. Inflammatory cell trafficking after a myocardial infarction is controlled by a CXC motif chemokine ligand 12 or CXCL12 and its receptor CXC motif chemokine receptor 4. CXC receptor 4 antagonists, mobilize inflammatory cells and promote infarct repair. But the cellular mechanisms are unclear.                                                 So, what do these investigators do? In mouse models, the investigators found that inflammatory cell trafficking between a hematopoietic organs and sites of tissue injury is controlled by CXCL12 and its receptor CXC receptor 4. And bolus injectives of a highly selected peptidic macrocycles CXC receptor 4 antagonist, enhanced tissue repair and functional recovery after re-perfused acute myocardial infarction in mice. And interestingly, the therapeutic effects require a dendritic cell priming and we're specifically mediated by t-regulator cells. Intermittent CXC R4 blockade mobilized the t-regulator cells from their splenic reservoir. Leading to their enhanced recruitment to the infarct region. Dr Carolyn Lam:                So bring it home for us, Greg. What does this mean clinically for MI management in humans? Dr Greg Hundley:             Right. Highlighting the translational potential. What we might infer is that CXC receptor 4 blockade reduces infarct volume and improved systolic function in a porcine close chest model of re-perfuse acute myocardial infarction.                                                 And so, the results of both the mouse experiments and this sort of translational model in pigs should stimulate further research into therapeutic potential of CXC R4 blockade after MI and in other acute conditions were excessive, innate or adaptive immune responses cause immunopathology. Dr Carolyn Lam:                Fascinating. So from one preclinical paper to another, but this time focused on heart failure. And focus specifically on titin. Titin is this giant elastic protein that spans the half-sarcomere from the Z-disk to the M band, and it acts like a molecular spring and a mechanosensor that has been linked to striated muscle disease. Now the pathways that govern tight independent cardiac growth and contribute to disease are diverse and have been really difficult to dissect. And so corresponding author Dr Gotthardt, from Max Delbruck Center for Molecular Medicine and the German Center for Cardiovascular Research and his colleagues aimed to study titin deficiency versus titin dysfunction.                                                 And how they did that is they generated and compared striatum muscles specific knockouts with progressive postnatal loss of the complete titin protein. And that's by removing Exxon 2. Or an M-band truncation that eliminates the proper structure and integration, but retains all the other functional domains. So they then evaluated cardiac function, cardiomyocytes mechanics, and the molecular basis of the phenotype. Now, what they found was that progressive depletion of titin led to sarcomere disassembly an atrophy in striated muscle. And in the complete knockout, remaining titin molecules had increased strain resulting in mechanically induce trophic signaling and eventual dilated cardiomyopathy.                                                 On the other hand, the truncated titin helped maintain passive properties and thus reduced mechanically and do signaling. In other words, truncations versus loss of titin, differentially affected cardiac pathology with atrophy versus dilated cardiomyopathy respectively. And together, these findings really contribute to the molecular understanding of why titin mutations differentially affect cardiac growth and have implications importantly for genotype, phenotype relations that support a personalized approach to the diverse titinopathy. Dr Greg Hundley:             Interesting, Carolyn. All this information on titin. So why is it clinically important? Dr Carolyn Lam:                Well, first of all, tightened mutations are the most common genetic basis of heart disease and the findings are clinically relevant, as I said, for understanding the genotype phenotype relations at the Titin mutation. But understanding the integration of Titin based signaling and sarcomere biology could indeed help personalize diagnostics by improved clinical decisions and maybe identify suitable therapeutic targets for these titinopathy. But that of course requires much further work. Well that brings us to the end of our summaries. Let's go to our feature discussion.  Dr Greg Hundley:            Welcome everyone to our second segment of our program. We're discussing an interesting paper today entitled Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy. And we want to welcome our coauthors Elijah Behr and Mary Sheppard from St George's University in London. And also, our own associate editor, Sami Viskin to discuss this paper. Mary, can you tell us a little bit about your study design here, the population and the hypothesis and some of your results? Dr Mary Sheppard:          I am a cardiac pathologist of 20 years and I have a special interest in sudden death. Over this time, I've established a national pathology database, where pathologists throughout the country when they have a sudden death, which is likely cardiac and non-ischemic, they will send the heart or tissue blocks insides to me for my opinion concerning the death. We have as a result developed a large number, over 5200 cases which has now built up to 6000. It's the largest pathological series in the world.                                                 And I was also discovering the pathologists were either under or over diagnosing all types of cardiomyopathy but particularly ergogenic cardiomyopathy. And that is why with Chris Miles, our research fellow, we looked in detail at what I had diagnosed, or the pathologist as ergogenic cardiomyopathy and we actually honed are pathological diagnostic criteria for this very important entity. Establishing that left ventricular is five and ventricular and left and ventricular is the norm almost. That right or left ventricular is unusual by themselves and even in 20%, one in five, the heart can look macroscopically normal. So that histology is essential when you're making this diagnosis. You cannot make the diagnosis pathologically without histologically examining the heart. Dr Greg Hundley:             Very good, Mary. And did you also examine some genetic markers in some of the subsets of the patients? And how did you decide who those individuals would be that received the genetic analysis? Dr Mary Sheppard:          A small subset and I will hand over to Elijah Behr, my colleague concerning that. Dr Elijah Behr:                   The genetic tissue is only available in a minority of cases. We've developed a pipeline now with the referring pathologists who are increasingly they're sending samples of spleen suitable for DNA extraction that allow us then to do a retrospective postmortem genetic testing or molecular autopsy. But unfortunately, in this particular series we only had a small proportion. I think there were roughly about 24 out of the 202 cases, so just over ten percent. And interestingly, while we didn't necessarily mirror the expected yield of genetic testing that is seen in clinical cases, where you may see about 40% carrying pathogenic variance. We certainly picked up some important pathogenic variance, particularly those that are often associated with highly penetrant and more severe disease. In particular TMEM43 and desmoplakin. These findings may reflect the small size of the sample, but it also may reflect where the greatest risk for sudden death from ergogenic cardiomyopathy lies. Dr Greg Hundley:             Elijah, getting back to some of the patients that experienced the sudden death in the study population Mary was referring to, were there characteristics that were associated with the sudden death? For example, those that might be related to gender or activity? Dr Elijah Behr:                   So the majority of the cases were male. The majority has never had prior symptoms. These were unheralded deaths. The majority did not have a family history and I think the majority were addressed, but those that were athletes, we're much more likely to have died during exertion. So as we found with ergogenic cardiomyopathy in general and exertion is a trigger to sudden death. The risk was higher and compared to the athletes in death during exertion was associated with being younger as well. I think exertion and sports clearly play a role in ergogenic cardiomyopathy. It didn't appear to play a role in whether there was left ventricular involvement or not, but certainly a role at more severe presentation.  Dr Greg Hundley:            Maybe both Mary and Elijah answering this. You found histopathological evidence of fibrosis and fatty infiltration. How extensive was that? And do you think that could be identified with a test like maybe magnetic resonance imaging? Dr Mary Sheppard:          Yes. Our diagnostic criteria which is illustrated in the addendum is that it was at least two blocks of tissue. We always look at 10 to 12 to 15 blocks of tissue from both right and left ventricle. And at least two of the blocks had to have fibrosis with fat in 20% of the area examined. We did not include inflammation because inflammation is, an important histological criterion in our experience. We were very precise about that because you need that much at least to make the diagnosis. A little bit of fibrosis or a little bit of fat is not sufficient by itself. Dr Greg Hundley:             When you mention a block, for us clinically, how much myocardium would that be? For example, on an imaging test like an echo or an MRI scan. Dr Mary Sheppard:          One to two centimeters squared. Dr Greg Hundley:             So quite a bit. Dr Elijah Behr:                   You're looking at probably around two to four millimeters of potential depth of fibrosis. And what we've seen clinically in LV involvement of MRI scans is miss two epicardial late enhancement. Now the question is whether our scans are sensitive enough to pick that up? Given the technology available or a sense to the histopathology and I think that's why maybe some of the clinical studies have tended to miss the true proportion of left ventricular involvement. Because of the relative subtlety of the fibrosis compared to the technological ability to discriminate it. I mean certainly when you look at our cases that were diagnosed previously with cardiomyopathy, either they were arrhythmogenic or dilated, many did have imaging findings if MRI was performed, that would indicate or suggest some left ventricular involvement. But as you know, the task force criteria for arrhythmogenic cardiomyopathy having very much right ventricular focus. An LV imaging findings and LV ECG findings are just not part of those at the moment. Dr Greg Hundley:             Was there a particular location within the heart where there was a predilection toward the findings of fibrosis and fat? Dr Mary Sheppard:          In the posterior basal wall particularly, transmural involves going from the epicardium to the sub endocardium and also the interior walls of the left ventricular were the predilection areas. Dr Elijah Behr:                   I think that's what we see on our MRI scans as well. When you look at these patients, that posterior basal area, is the one that tends to light up the most. Dr Mary Sheppard:          It is believed that increased stress in that area gives more damage because of the stretching away from the septum. Dr Greg Hundley:             Very interesting. So Elijah, you had mentioned task force criteria. I want to shift to Sami now and ask, Sami, can you help us put this in perspective relative to the existing task force criteria and then the findings in this study? And how that could lead to subsequent changes down the road?  Dr Sami Viskin:                 Okay, so it is difficult to place this in the context of the task force because mentioned by Elijah, the taskforce are focused on a disease that is believed to be in the right ventricle. And the study shows that many of the sudden death cases will involve the left ventricle. One of the most important messages of this paper is importance of her forensic examination. And importance of making it for anything examination in the center of expertise. We know of patients that will travel a thousand miles to undergo surgery or an ablation procedure, but families do not think that way when there is casualty or family dies. You may take a postmortem as a given, but in many countries, including my own, most cases of sudden death would not be followed by a post mortem and will not go into center of expertise. And you cannot overemphasize the importance of doing that because then you have to know what you are looking for in the remaining relatives is extremely important. Dr Greg Hundley:             Very good. How about from the perspective as an electrophysiologist? Does this impact in any way how you might evaluate a younger person with syncope? Dr Sami Viskin:                  Well, it is difficult to conclude from this paper about how to evaluate patients with syncope because most of the cases in this series don't have symptoms at all. But this paper calls to very interesting investigations by Mario del Mar and others in New York. Looking about the electrophysiology consequences of a disease like right ventricle are like a bit mechanical in [inaudible 00:21:58] The tissues becomes editing the disease, the electrical properties how the patients in brugada can cause malfunction of this sodium channel and create a disease that is more like brugada and dysplasia at the beginning. So, the entire correlation between a morphologic disease and the metrical disease and we used to think they are two different things. And now we see that we can actually put them together and you can go through stages where one disease is before an electrical disease and only at later stages it becomes a morphological evident disease.  Dr Greg Hundley:            A fantastic discussion on pathologic findings. Sami making the point that certainly in cases for young individuals having a postmortem examination performed at centers that have expertise such as what Mary's described, can be very important. And then Elijah, helping us to understand with arrhythmogenic cardiomyopathy, number one, findings are not, we shouldn't just be thinking about the right ventricle in isolation, but also the left ventricle. Fibro fatty infiltration, particularly in the posterior basal wall could be an important thing to look for, for those that are performing the magnetic resonance imaging exams. And then lastly, many of the patients in the study like this, the first presentation was of sudden death. And we need to be cognizant that this condition could be prevalent in the population and not necessarily appreciated by some of our current task force guidelines and examinations. So, what an outstanding discussion. And I think for today, we want to thank our authors and our associate editor and wish everyone a great week.                                                 On behalf of Carolyn and myself, we look forward to seeing you next week. Thank you very much. Dr Carolyn Lam:                This program is copyright American Heart Association 2019.  

So Greg decided to go walk on the ice yesterday, find out what happens!

Seventeen years ago, Greg Buzek was working as a Product Development Manager making anti-theft devices. They were the type of devices designed to deactivate if merchandise left a store without being purchased. Greg made a very good living at this, but found himself completely unfulfilled inside. Something wasn't quite right in his life. It was at a casual lunch one day with the Pastor from his church, when the first seeds would be planted. Pastor Kelly Lyons worked with small groups and missions at the church, and he needed help. He asked Greg to work in missions, and although Greg was engaged in the talk, internally, he was full of fear: "I’m a business guy, I have nothing to offer." Before he got back to his desk that afternoon, he was fired from his job! "Okay Lord, you have my attention." But now what? It kept coming back to helping the people of Liberia. Yet, Greg knew nothing about Liberia. So Greg prayed about this big decision in his life, "Lord, All I know about Liberia is that Chet’s over there, and he’s had malaria three times, been shot at, had an AK47 pointed at his chest from an 8-year-old - If I need to go to Liberia, you’ll need to make it real clear to me". As Greg was driving home, he sees a man pushing his car up the road. Something tells him to stop and help the guy out. When Greg gets out of the car, he notices a bumper sticker that might as well have been a red-neon lit sign that said: “I Support Liberia” What are the chances? This man was from Liberia. As the two men were talking, the stranger explains to Greg that Liberia is in real bad shape and going into a Civil War. Greg explains that he has had it on his heart to go to Liberia, the stranger tells Greg he is nuts! Greg Buzek was still not excited about this crazy idea of going to Liberia, but the evidence was starting to stack up against him. Chuck Smith, the Senior Pastor, explained to Greg "Beware of signs and wonders. Make sure you have scriptures backing up whatever you believe God is calling you to do". Just days later, in his studies, the first scripture presented was Genesis: 12:1; Get thee out of thy country. The next five scriptures all has a similar message. Greg Buzek's life was about to change and would never be the same again... The story continues on the Brink of Greatness Podcast… The Next Leap Forward Broken families, illness, poverty; there are over 143 million orphans around the globe. A few startling facts from UNICEF tell a story...  A Child dies every 5.2 seconds, that is over 16,000 children every single day. In the New York Foster care system, 60% of the children who age out end up in a homeless situation. More children age out of care systems in one week than are adopted in an entire year. The stats could go on forever, but they all end in one conclusion: Far too many children are suffering unnecessarily; disease, famine, lack of resources, crime, trafficking. If we are to put a dent in this worldwide problem, it will take an army of many, but it starts with one! Greg Buzek recognized this need and through his faith and trust, he took the leap forward to make that difference. Retail Orphan Initiative was born to raise awareness and provide real-life solutions by combining the resources of many with the art of streamlining to that critical moment of need. They not only do this in over 24 countries, but they also focus efforts in the United States.  Retail Orphan Initiative has interacted in over 188 Projects, raising millions of dollars, rescued 1,200 girls, helped support 1,412 Adoptions, built 19 schools, worked on brining clean water to communities. It's an impressive list of accomplishments that change on a daily basis depending on the need. The Brink of Greatness salutes our Brink Thinker Greg Buzek and the incredible team that is working for the good of humanity! For Further Insight: Website: https://www.retailroi.org/ DONATE: https://www.retailroi.org/donate/

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health, in Richmond, Virginia. Dr Carolyn Lam:                So Greg, are ARNI's now going to be used for functional, mitral regurgitation and heart failure? Well, we're going to be chatting all about that with our feature paper, coming right up after these summaries.                                                 Greg, you've got a biggie to start with, haven't you? Dr Greg Hundley:             Oh yes, Carolyn, I'm really excited about this paper. The senior author Wanpen Vongpatanasin from University of Texas Southwestern Medical Center in Dallas and looking at high phosphate diets and their relationship to exercise intolerance. I really felt this was an exceptional study and combining that key that we have, for basic science papers and translation, where we're looking at data from both human and basic science, in both in a single manuscript.                                                 So, this study focuses on inorganic phosphates and they are present in 40-70 percent of the foods, really as a preservative enhancer, in western diets. We see it in colas, meats, dry food mixes, bakery products.                                                 For the human subject component of this study, the investigators examine the relationship between physical inactivity, assessed with ActiGraphs that were worn, and serum phosphate levels. They also obtained MRI measures of cardiac function and participants were recruited from the Dallas Heart Study too.                                                 In animals, they looked at the direct effects of dietary, inorganic phosphate on exercise capacity, oxygen uptake, serum non-esterified fatty acids, and glucose was measured during exercise treadmill tests in mice fed either high inorganic phosphate diets or normal in-organic phosphate diets. And they were on that for 12 weeks.                                                 To determine the direct effect of phosphate on muscle metabolism and expression of genes involved in fatty acid metabolism, additional studies in the differentiated myotubes were conducted after subjecting those cells to media with high or low phosphate conditions. Dr Carolyn Lam:                So, what did the study show? Dr Greg Hundley:             In the human part, among 1603 participants, higher serum in-organic phosphate was independently associated with reduced time spent in moderate to vigorous physical activity and increased sedentary time. And interestingly, there was no association between serum phosphate levels and left ventricular ejection fraction or volumes.                                                 In the animal studies, mechanistic insight was obtained. Compared to controlled diets, consumption of high phosphate diet for 12 weeks did not alter body weight or left ventricular function, thereby confirming what we saw in the human subjects, but reduced maximal oxygen uptake, treadmill duration, spontaneous locomotor activity, fat oxidation, fatty acid levels, and led to down-regulations of genes involved in fatty acid synthesis.                                                 So, the take-home on this is that the results of this study demonstrate a detrimental effect of dietary, phosphate excess on skeletal muscle, fatty acid metabolism, and exercise capacity, which is independent of obesity and cardiac contractile function.                                                 And as such, dietary in-organic phosphate may represent a novel and modifiable target to reduce physical inactivity associated with the western diet. I think, Carolyn, we're going to see a large number of epidemiologic studies that are going to really look at this as something we might be able to modify in our diet to help impact some of these sedentary lifestyles and the harmful cardiovascular effects that we find associated with that lifestyle. Dr Carolyn Lam:                Yikes. Remind me again, so phosphates in colas, meats, dried food mixes, and bakery products and so on, the preservative. Wow, you're right; big paper. Dr Greg Hundley:             It's amazing. It's in 40-70 percent of the food products here in the United States. So, wow. Something really striking. So Carolyn, how about one of the papers that you liked? Dr Carolyn Lam:                Moving to related cardio metabolic disease, we know that patients with type 2 diabetes and prevalent atherosclerotic cardiovascular disease, there is a tenfold variation in future cardiovascular risk in these patients. The current paper actually analyzes data from EMPA-REG OUTCOME where the authors, led by David Fitchett from St. Michael's Hospital in Toronto, sought to investigate whether the beneficial effects of Empagliflozin, observed in the EMPA-REG OUTCOME trial, varied across the spectrum of baseline, cardiovascular risk.                                                 What they found was that in patients with type 2 diabetes and atherosclerotic cardiovascular disease, the relative reductions in risk of cardiovascular death, all-cause mortality, 3-point MACE, and heart failure hospitalizations with Empagliflozin versus placebo, were consistent in patients with and without a prior, myocardial infarction, with and without a prior stroke, and across sub-groups by the 10-point TIMI Risk Score for secondary prevention at baseline. Dr Greg Hundley:             Does this suggest, Carolyn, that we use these inhibitors in all patients with type 2 diabetes? Dr Carolyn Lam:                Remember the EMPA-REG OUTCOME; all patients had established atherosclerotic cardiovascular disease. This paper really adds to the understanding of the gradient of risk within these patients who had atherosclerotic cardiovascular disease and says Empagliflozin could be beneficial. But remember, there are patients with type 2 diabetes without established, cardiovascular disease and I think there's still equipoise in this primary prevention population. Dr Greg Hundley:             That was great, Carolyn. Now I'm going to grab another sip of coffee and go onto my next paper. Dr Carolyn Lam:                Sure, as long as it's not cola. No phosphates. Dr Greg Hundley:             Right, thank you very much, Carolyn. I'm going to talk about screening for small and medium abdominal aortic aneurysms. This particular study comes from the surveillance of the National Health Service screening program by Dr Earnshaw. Basically, population screening for abdominal, aortic aneurysms has been shown to reduce AAA-related mortality by up to 50%. Most men who screen positive have a AAA below 5.5 centimeters in diameter, and that's really our current referral threshold for treatment. When they have smaller diameter aneurysms they're entered into an ultrasound surveillance program.                                                 In this study, the investigators looked and reviewed those that had small, 3-4.4 centimeter diameter aneurysms or medium ,4.5 up to 5.4 centimeter aneurysms, and they were followed. They were looking at the risk of rupture in these under surveillance.                                                 They had a total of 18,652 men and the risk of rupture overall per annum was 0.03% for men with small, abdominal aortic aneurysms and 0.28% for medium size. That was just below the threshold for the 5-5.4 centimeters, which was 0.4% over time. The risk of abdominal aortic aneurysm surveillance is below .5% per year and that is just below our current referral threshold for surgery, which is 5.5 centimeters.                                                 This is a study that really confirms, Carolyn, that the target mark or diameter that we've selected is appropriate. Dr Carolyn Lam:                Nice. These just confirm the current guidelines? Dr Greg Hundley:             Yeah, they do and Gil Upchurch from University of Florida, a surgeon, had a very nice editorial. The point he wants to make is yep, diameter of 5.5 is the threshold, but a couple key points. As patients are coming in for these visits, we need to continue to emphasize to them other factors related to growth of abdominal aortic aneurysms and their rupture. So, tobacco cessation, treatment of your lipids, management of your hypertension.                                                 The other point that he makes, is we really don't need to be operating on those individuals with an abdominal aortic aneurysm diameter of less than 5.5 centimeters. He makes an argument here that's in some countries with fee-for-service reimbursement, up to 30% of AAA repairs are for aneurysms less than this diameter of 5.5 centimeters. This over utilization of resources can add considerable costs to the healthcare system for managing this condition and is unlikely to increase the overall survival of these patients.                                                 A nice study confirming that what we're doing, really in terms of size and diameter, is correct, but also emphasizing this patient population often has a lot of other cardiovascular co-morbidities that we need to aggressively manage. How about your next paper? Dr Carolyn Lam:                From one very clinically, applicable paper to another. This one answers the question, what's the optimal duration of emergency department and post-emergency department rhythm monitoring among patients with syncope. And the authors, led by Dr Thiruganasambandamoorthy and his colleagues from the Ottawa Hospital Research Institute, prospectively studied adults presenting within 24 hours of syncope at six emergency departments. They collected baseline characteristics, the time of syncope, the time of emergency department arrival, and the Canadian Syncope Risk Score, risk category. They followed subjects for 30 days and adjudicated the primary outcome, which was serious arrhythmic conditions and that includes arrhythmias or interventions for arrhythmias and unexplained death.                                                 Their results showed that the overall arrhythmia risk, and the risk after two hours of emergency department arrival from Canadian Syncope Risk Score, low-risk patients, was indeed very low. Similarly, the overall risk and after six hours of emergency department arrival for medium and high-risk patients was moderate and high, respectively. No low-risk patients suffered ventricular arrhythmia or unexplained death and most of the arrhythmias among the non-low-risk patients occurred within 15 days of the index syncope. Dr Greg Hundley:             Carolyn, what's the take home message here? Dr Carolyn Lam:                The results really support brief monitoring in the emergency department for two hours for Canadian Syncope Risk Score low-risk patients, and six hours for medium and high risk patients followed by selective admissions and the results also support a 15-day outpatient monitoring for medium-risk patients at a selected threshold and for all high-risk patients. So very practical advice. Dr Greg Hundley:             Very good. Until next week, I'm going to watch out for phosphates. Dr Carolyn Lam:                Indeed, and let's go on now to our featured discussion.                                                 For today's featured paper, we are discussing the results of the PRIME Study and that is Angiotensin Receptor Neprilysin Inhibitor, or ARNIs, for functional mitral regurgitation. A terribly interesting study. So pleased to have with us an author Dr Sung-Hee Shin from Inha University Medical center in Incheon, Korea as well as our associate editor Dr Victoria Delgado from University of Leiden in the Netherlands.                                                 Sung-Hee, what an interesting study. ARNI or Entresto for functional mitral regurgitation. Could you tell us what inspired this study and what did you find? Dr Sung-Hee Shin:            Our study was the designed to tell if ARNI or functional mitral regurgitation because secondary functional mitral regurgitation was developed as a result of a reduced function. Guideline-directed medical therapy for heart failure would be a mainstay for a therapy.                                                 But despite use of the traditional drugs such as BETA blocker, ACE inhibitor or angiotensin receptor blockers, you know that the functional mitral regurgitation may be common and significant in the person having this functional mitral regurgitation would be related to increased morbidity and mortality.                                                 So, that trial showed that trans-catheter mitral valve repair effectively reduced the function mitral patient and resulted in lower rate of heart related mortality among patients with heart failure and function mitral regurgitation.                                                 In our blind trial, we also tried to tell whether an ARNI is more effective in improving function mitral regurgitation and randomly assigned 118 patients with heart failure and chronic secondary function mitral regurgitation lasting more than six months despite medical therapy and ejection fraction between 25% and 50% to receive either sacubitril/valsartan or valsartan in addition to standard medical therapy for heart failure.                                                 What happened with that change of mitral regurgitation after 12 months which was assessed by means of transthoracic area ways echo. What we observed was that transthoracic area as well as the volume of mitral regurgitation saw a decrease much more effective in the sacubitril/valsartan group than valsartan group.                                                 We also looked at the various other measures of the left ventricle remodeling and showed that the valsartan group had smaller left ventricle volume at 12 months and had a greater reduction of end-diastolic volume index.                                                 Also, among the completers ARNI, for the reduced left ventricle volume and the yearly time than the control group. So, what we think is that these factors might contribute to greater reduction of function mitral regurgitation in patients in the sacubitril/valsartan group.                                                 But our study was a mechanism study, but it was not designed to see outcomes. So further research and data would be necessary to check is this transthoracic echo end point can translate into better outcome in this population. Dr Carolyn Lam:                Sung-Hee, this is just so interesting to have hypothesized this about functional mitral regurgitation. And not only that, I mean, to my mind, this is the largest echo-based studies of patients before and after Entresto that I can think of. It's nice to know, on top of knowing in paradigm that we can improve outcomes in heart failure reduced ejection fraction, that we now can look at the heart and see what happens in so many dimensions.                                                 So, congratulations.                                                 Victoria, were you surprised by these results? And do you agree with the mechanisms that Sung-Hee suggested? Dr Victoria Delgado:        I think that this study is very important because in the field of functional mitral regurgitation, there is still a lack of consensus on how to treat these patients, which are very challenging.                                                 If the patient needs revascularization they will be referred for certain. But it still should be CBR mitral regurgitation and moderate and mile mitral regurgitation are not considered.                                                 I think that we discuss often which is the optimal medical therapy or the guidelines based medical therapy but it's not really consensus because the studies before have not been like this one. That large in order to answer a specifically that question.                                                 I think that this article brings an important message and brings more evidence to our field that there is not that much data. So, I think it's very important for that research, in particularly after the research of the co-op and the mitral trial where it seems that the selection of patients is very important in order to identify the patients that will really benefit from those therapies. Dr Carolyn Lam:                That's such a good point. Going to that selection of patients, Sung-He, you mentioned very carefully the ejection fractions that you allowed up to 50% in these patients. Could you explain how you reasoned the selection of this patient cohort? Dr Sung-Hee Shin:            The reason why we chose the patients we did, the range of ejection fraction condition, was that we thought the reversibility of the left ventricle mortality and function mitral regurgitation might be more pronounced in these patients.                                                 When we considered the fraction condition in mitral regurgitation with ejection fraction used under [inaudible 00:18:17] LV dysfunction, our inclusive criteria of ejection fraction between 25 to 50% might correspond to ejection fraction of 20 to 40% in patients with mitral regurgitation.                                                 We concluded that if a patient had ejection fraction less than 25% because the reversibility of mortality and function mitral regurgitation might be smaller when all the LV dilation is too extreme and advanced heart failure is already established.                                                 So, I just thing how it can be provided to the patient who have functional mitral regurgitation associated with too extreme LV dilation and LV ejection fraction too. Dr Victoria Delgado:        I think, Carolyn, it's a very good point what she explained because we are used to select patients based on ejection fraction, in particularly patients with functional mitral regurgitation, ejection fraction is rather misleading because actually it's just a change of volume in the ventricles emptying in a low pressure chamber which is the left atrium.                                                 The moment that you correct that in mitral regurgitation sometimes then you face, or you see, the true ejection fraction of that ventricle. And if we wait too long, we may end up with ventricles that they don't have any more resource in order to improve ejection fraction after repair of the mitral valve.                                                 So, I think that this study is important to also realize that concept. That ejection fraction in patients with functional mitral regurgitation may not be the most accurate parameter to assess the function of that ventricle. Dr Carolyn Lam:                Yeah. Exactly. And I thought that was a very clever part of the design. I'm glad you explained it and also so glad, Victoria, you invited the editorial by Dr Mullens, who also commented on that. So, just for the audience to understand that ejection fraction up to 50% was included and ejection fraction less than 25% was excluded.                                                 So also, again, very consistent to your prior point, Victoria.                                                 Could I ask you, I think Dr Mullens also spent quite some time talking about the potential mechanisms. What's your take of this Victoria? ARNI for functional regurgitation. How come? Dr Victoria Delgado:        For me, I'm much more from the side of the imaging point of view. When we have patients with functional mitral regurgitation I always try to see which is the capability that that ventricle has to recover.                                                 Actually, first is always medical therapy, but we know that the [inaudible 00:20:59] only, for example, we just reduced the mitral regurgitation, but they don't really improve the function of that ventricle, while if you reduce the loading conditions of the ventricle in terms of blood pressure as well and favoring remodeling of the left ventricle, you can improve the condition of the mitral valve and reduce the mitral regurgitation.                                                 How valsartan plus sacubitril works differently than valsartan alone that I don't think that I have enough knowledge to explain why but it could be that in a way there is more effective with sacubitril on top of valsartan can improve the loading conditions of the ventricle and improve the, or facilitate, the reversing of morbidity of that ventricle, reducing the mitral regurgitation and that, by itself, could also lead to reversing morbidity.                                                 Like a little bit cardiac resynchronization we'd do, for example, in patients with an ejection fraction below 35% and based on the EEG you have the synchronous fraction of the papillary muscle or the walls of the ventricle which could lead to the mitral regurgitation at the moment that you resynchronize that mitral regurgitation can produce, you reduce part of the volume of the load of the ventricle and that can favor that reversing morbidity.                                                 So, I think that this study raises a lot of questions and I think that further research is needed in order to confirm or to know more how these treatments work. Dr Carolyn Lam:                Goodness, that was so beautifully explained and in fact, many clues from Sung-Hee's study and the reversal of left ventricle end diastolic volume index greater with those treated with ARNI, the LA size and so on.                                                 But maybe I should ask you, Sung-Hee, in line with what Victoria said, what are the next steps? Do you already know what are the next studies that you're going to be looking at in PRIME? Dr Sung-Hee Shin:            We're considering mark of monitoring such as NT pro-BNP or using auto imaging models such as echo and cardiac MRI to look at the change of mitral valve regurgitation in more detail.                                                 This kind of study might be very helpful in understanding [inaudible 00:23:15] ARNI in functional mitral patient. Dr Carolyn Lam:                Yes, that's clever, too. And Victoria, before we end could you maybe give us some take home messages? Dr Victoria Delgado:        I think that the take home message from this study is that when we have patients with functional mitral regurgitation, we need to think what we can offer to them. Not consider mitral regurgitation just as a base standard. That it's going to respond only to diuretics. No. We need to do something on that left ventricle to help it to improve the function and to avoid the progress to more reduced function.                                                 It's very important to understand the mechanism of the mitral regurgitation and to use the guidelines based medical therapy trying to go step by step in order to optimize the medication of that patient and later on, see all the potential treatments that are available right now such as cardiac synchronization therapy, which we should not forget, and then surgery if the patient needs catheterization and if the patient needs the benefit from mitral valve plasty or eventually, for example, trans catheter mitral valve therapies.                                                 But we should avoid that the patient goes further down into heart failure with very dilated ventricles and very poor function because then probably we may face a point of no return. Dr Carolyn Lam:                Thank you so much, Victoria. Both you and Sung-Hee mentioned this is a mechanistic study. So many insights. But it's not saying that everybody with functional mitral regurgitation has to be treated this way now. It's calling for more work and it's certainly very, very important study.                                                 Thank you listeners, for listening today as well. You've been listening to Circulation on the Run. Don't forget to tune in again next week.                                                 This program is copyright American Heart Association, 2019.  

So Greg took a picture of a guy taking pictures and left him a note on his car telling him to contact him if he wants the photo.....Creepy much?

Yesterday we discovered that the eighth most expensive city for housing in the world is Tauranga, where it takes more than nine times the median annual income to buy the median house. We also heard that Auckland was not too far behind. The lowest was Manawatu where the ration was five. Now, by the way, it was not widely reported that using the demographic rating system it is believed that the affordable level is three times and under.  Anything over five they class as severely unaffordable. Just about everywhere in this beautiful country is severely unaffordable. So the headlines were full of New Zealand’s housing affordability crisis.And then just like that, as I left the studio, I discovered that an Auckland councillor had come into our building and dropped off a copy of his book to every on-air staff member.The councillor’s name is Greg Sayers and his book is called "How to Fix Auckland’s Housing Crisis". But the problems he documents are spreading so I’d rename it New Zealand’s Housing crisis if you’re doing a reprint.It’s a pretty good read actually. In 166 pages it highlights the problems that have been caused by population growth, both natural and immigrated. The lack of foresight with planning and the excessive bureaucracy at both national and local level, that has made things so expensive. It also documents the social problems that come with it in terms of poverty, the elderly and the transport problems.But I think we’ve all become pretty good at talking about the problems. What we really need is a genius with some answers.So Greg’s book has four solutions in its conclusion. He wants homebuyers to be able to insure their property against poor workmanship. Which makes sense. At the moment the cautiousness of our councils over standards and consents is because they hold all the risk management.He would like to see developers given the option of developing their own infrastructure, rather than having to connect to the Council’s monopoly on services. In other words, deregulation. Whether that would create a workable citywide system is a little debatable and the other issue is whether you trust developers. Nothing personal but some developers might have been known, from time to time, to shave a little off budgets to help their margins.He’d like to see user pays infrastructure development such as at the Milldale suburb where homeowners pay a little off yearly for infrastructure to new builds rather than having it all piled onto initial purchase price. That’s a good idea. So good it’s already happening.But his main thing is getting rid of the rural-urban boundary. And that’s where he loses me. I’ve heard this trumpeted through the ages. That would make for sprawling raggedy development. Yes, it would give some short term relief but it would create long term problems. In fact, I’d argue that the transport problems we have in a number of our cities is entirely because of unfettered sprawl at the edges.  But good on Greg for raising the issues again. Councils have taken advantage of Phil Twyford’s desire to solve our housing woes singlehandedly and debates about their performance has ebbed away. The one thing I definitely know about our housing affordability crisis is that not one person caused it and not one person will solve it.

Dr Carolyn Lam:                                Welcome to Circulation on the run, your weekly podcast summary and back stage pass to the journal and its editors, and welcome to a whole new podcast format in 2019. Ha-ha, I bet that surprised you. Well guess what? This new format promises more interaction, more discussion and a whole lot more fun, and that's because to begin with, you don't have to listen to me talk to myself half the time anymore. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore, and I am simply delighted that Santa gave me a partner on this podcast, and co-hosted with me, and my gift is none other than Dr Greg Hundley, associate editor from the Pauley Heart Center, at Virginia Commonwealth University Health Sciences. Welcome Greg. Dr Gregory Hundley:                       Thank you so much Carolyn. How exciting is it to start this new year with this exciting format, where we'll take several of the key manuscripts from Circulation and discuss them? Picking five each time, and as you've alluded to, we're not going to get rid of that favorite format, where we take a select paper and interview and work with the authors. Dr Carolyn Lam:                                Exactly. In fact, maybe I could liken it to welcoming everyone to join us over a cup of coffee, each week, with the journal in the hand and we're just going to discuss it, and never forgetting that feature paper with the authors, and this week's paper is huge. I love it. We're actually going to be talking about blood pressure control in the barber shop. But before then, here's the articles that we've chosen to discuss. So Greg, you got your coffee ready? Shall we start? Dr Gregory Hundley:                       Absolutely Carolyn, and let's get going first with Gorav Ailwadi, from University of Virginia, his paper evaluating the utility of MitraClips in those with secondary mitral regurgitation. This is really a follow-up from the EVEREST study. It's not a randomized trial, but it's a longitudinal look over time, at 616 patients. Interestingly, those individuals that had class three or four heart failure, that had the MitraClip, the left ventricular volumes got smaller in a year, the hazard ratio for events became less. The magnitude of mitral regurgitation went from 4+ down to 2+. Exciting findings. Dr Carolyn Lam:                                Interesting, but you know Greg, these all sound so positive. Why is it so different in the Mitra FR study?   Dr Gregory Hundley:                       Absolutely Carolyn. So, as you know, Mitra FR, that was a randomized trial. So, this study doesn't compare, the EVEREST study in this issue, doesn't compare with conventional medical therapy, that's number one, and Mitra FR did. Also, the Mitra FR patients were a little bit sicker. The ejection fraction really was 15 to 40 percent, and in the EVEREST study, much higher, average 45 percent. In fact, many had a normal EF. So it really raises a lot of questions as to whether or not this finding will hold up in future randomized trials, which we'll be looking to see the results. Dr Carolyn Lam:                                Indeed, and it was really nicely discussing the accompanying editorial wasn't it, which I really enjoyed. Well, the paper I picked out Greg is from Dr Gatzoulis from The Royal Brompton Hospital, and it's actually the MAESTRO trial. Now, MAESTRO is a randomized control trial of the endothelin receptor antagonist macitentan in patients with Eisenmenger syndrome. Short and long of it, macitentan did not show superiority over placebo on the primary endpoint of change in baseline to week 16 in exercise capacity. And there was also no relevant trends observed for the secondary endpoints.                                                                 However, among the exploratory endpoints, macitentan did reduce Nt-proBNP in the main cohort, and improved pulmonary vascular resistant index, and exercise capacity, in a hemodynamic sub-study. Importantly also, there were no specific safety concerns with macitentan. Dr Gregory Hundley:                       Sounds really interesting, Carolyn. But how did this compare with prior studies that have really focused on endothelin? Dr Carolyn Lam:                                Great question. So, MAESTRO's only the second randomized control trial of an endothelin receptor antagonist in Eisenmenger Syndrome. BREATHE-5 was the first, and this used a different endothelin receptor antagonist that was bosentan, also in Eisenmenger Syndrome, and actually found that bosentan reduced pulmonary vascular resistance as its primary efficacy endpoint, without worsening systemic pulse of symmetry.                                                                 So, very different trials in terms of endpoints, as you can hear, but also importantly, different populations that were enrolled. MAESTRO enrolled a more heterogeneous population with more complex forms of Eisenmenger, including patients with Down syndrome, had a broader WHO functional class inclusion, and allowed the use of pre-existing therapies such as PDE5 inhibitors.   Dr Gregory Hundley:                       That's really spectacular, Carolyn. Very interesting findings for something that these vasoconstrictors, vasodilators, often very harmful. Switching over, I've got sort of another paper that is also working on vasodilation, but comes really from the world of basic science. And it's from Ingrid Fleming from Goethe University in Frankfurt, Germany, examining how does hydrogen sulfide, a common gas that we have in the environment, it smells terrible, we worry about sulfuric acid and acid rain, but how does this promote vasodilation in the system?                                                                 And so, in this basic science study, they unlocked sort of a key that this hydrogen sulfide is produced by cystathionine gamma-lyase, CSE. And why is that important, and what does it do? Well, production of H2S by CSE goes and inhibits human antigen R, or HuR, that regulates cellular proliferation and growth. And so, basically these authors have unlocked a mechanism by which hydrogen sulfide can be protective.                                                                 So, what's interesting Carolyn is that patients can have elevated levels of L-cysteine, increased expression of CSE, so you've got the components and the manufacturer of H2S, but they still have low arterial levels. Dr Carolyn Lam:                                 Hm. So, how can this be addressed then? How can we raise that H2S? Dr Gregory Hundley:                       That's what's so clever that the investigators found out, Carolyn. They found a slow-release oral active drug, a sulfide donor called sodium polysulthionate, H2R, or sulfhydration, and can inhibit atherosclerosis development or progression when these levels are low. Dr Carolyn Lam:                                Indeed. sodium polysulthionate. Awesome, Greg! That is so cool. Honestly I just loved your explanation of that. Okay. Well, I've got another paper to share. And this is from Dr Bress and colleagues from University of Utah School of Medicine. And this one is really interesting because these authors estimated the number of cardiovascular disease events that could be prevented, and the treatment-related serious adverse events that could occur over ten years, if U.S. adults with hypertension were achieving the 2017 ACC/AHA guideline recommended BP goals, compared to their current blood pressure levels, as well as compared to achieving the older 2003 JNC7 goals, or the older 2014 JNC8 goals.                                                                 Now, basically they found that achieving and maintaining the 2017 guideline blood pressure goals over ten years could prevent three million cardiovascular disease events, a greater number of events prevented compared to prior guidelines, but this could also lead to 3.3 million more treatment-related serious adverse events. Dr Gregory Hundley:                       So, Carolyn, hasn't a main concern of this type of work been that these new guidelines over-extend the reach of our treatment? Dr Carolyn Lam:                                That's a real concern that I've also heard. The lower blood pressure thresholds used to define hypertension in the 2017 guidelines could indeed lead to more diagnoses. However, this paper helped because remember that the recommendation for anti-hypertensive drug treatment in patients with the pre-treatment blood pressure of 130-139 systolic, or 80-89 diastolic, was limited to those at high cardiovascular disease risk. So not everyone, but only those at high cardiovascular disease risk.                                                                 And so, treatment under the 2017 guidelines, by these data, would lead to more health gains, while only extending treatment to 5.4% more adults with hypertension compared to JNC7. So, this paper really modeled these things out with important contemporary U.S. adult populations using a national representative, a sample of U.S. adults, and NHANES, as well as REGARDS, and they also used estimates of benefit from the recent large meta-analysis of 42 blood pressure-lowering trials.                                                                 So, important data that I think are going to be reassuring to a lot of people managing these patients. Well Greg, that really brings us to the end of our little chat. Now, let's move to our future discussion, shall we?                                                                 Could cutting blood pressure in a barber shop be the long-term solution to hypertension in African-American men? Well, the future paper of this first issue in 2019 really talks about it. Greg and I are so delighted to have with us the authors of the paper, Dr Ciantel Blyler, and Dr Florian Rader from Cedars-Sinai Medical Center, as well as our associate editor, Dr Wanpen Vongpatanasin.                                                                 So, Ciantel, can you just perhaps start by telling us what you found. Dr Ciantel Blyler:                               So, what we're talking about today are the 12-month results as a follow-up to our 6-month results that we published earlier this year. So, we took 319 African-American men in Los Angeles County, and randomized them to two groups. One group saw a clinical pharmacist who worked with them to reduce their blood pressure, and the other group just worked with their barber to talk about blood pressure, and encourage usual follow-up.                                                                 And, as we saw at the 6-month mark, blood pressure really improved in the group that was able to work with the clinical pharmacist. So, we saw an almost 29 mm Hg drop in the intervention group, as compared to only 7 mm Hg in the control group. Dr Gregory Hundley:                       Ciantel, Florian, that is really exciting results. What is a collaborative practice arrangement, and how did you affect that in Los Angeles? Dr Ciantel Blyler:                               So, collaborative practice is actually widespread in the United States. California is one particular state that is kind of ahead of the curve with respect to collaborative practice between pharmacists and physicians. But what it essentially allows a pharmacist to do is to prescribe, monitor, and adjust medications underneath a physician's supervision. So, a document is drawn up, medications are selected, and an algorithm so to speak is put together so that a pharmacist can treat a patient independently of a physician needing to be there. Dr Greg Hundley:                             Very nice. And did you find in the pharmacist-led group that these patients were taking a different anti-hypertensive regimen, or were they more compliant? What do you think was the reason for the discrepancy in this magnificent blood pressure drop in this group of hypertensive men? Dr Florian Rader:                              So clearly, there were a lot of differences between the two groups. First of all, we had a protocol with our favorite blood pressure medications that we use clinically here in the hypertension center at Cedars-Sinai. Essentially it is long-acting calcium channel blocker, specifically Amlodipine, longer-acting angiotensin receptor blockers, or ACE inhibitors, and a third line, usually a thiazide diuretic, and also a longer-acting one, not the usual Hydrochlorothiazide, but specifically Indapamide that we used for this research study. Dr Greg Hundley:                             And do you think that there was more compliance in this pharmacist-led group? Dr Florian Rader:                              One would expect that. First of all, I think that seeing the clinical pharmacist, more frequently being reminded of taking the medications, having feedback by actually seeing the blood pressure numbers in the barber shop, I think would help. But then, in addition, we choose these medications not only because they affect it, but also because they're easy to take. They're once-a-day medications with very high continuation rates in larger studies, so they're just easier to take than other medications that are oftentimes prescribed. Dr Greg Hundley:                             It sounds like also, there might have been a trust factor. Because you're seeing the same person over and over in a very nice environment. Was that a factor?   Dr Ciantel Blyler:                               Absolutely. I think there's a different level of trust that's established when you meet somebody on their own turf. So I think the fact that we met men in barber shops where they felt comfortable, where many of them had been going to the same barber for over a decade, it made all the difference in terms of establishing a rapport, and gaining their trust with respect to having them take medications. So, I think that was a huge part of why we saw increased adherence, and really sort of a commitment to the program. Dr Greg Hundley:                             And we certainly recognize how harmful hypertension is in individuals of Black race. How does this group in Los Angeles translate to perhaps other Black men in the United States? Particularly, for example, in the South. Dr Ciantel Blyler:                               I think the program could translate really anywhere. I think what makes it so tailored to African-American men is this notion of going into a barber shop, which is a very important place in the Black community. So, again, sort of going back to what I said earlier, most of these men had been seeing the same barber as frequently as almost every two weeks for over a decade. So, it really helps increase the frequency with which we could interact with the men, and it helped with continued follow-up and adherence to the program.                                                                 With respect to the area of the country again, I think it translates. Dr Carolyn Lam:                                I've got a follow-up question to that, if you don't mind. So, I'm here listening all the way from Singapore, and I'm just so impressed, and frankly just enamored by this study. And wondering what is the barber shop to my local Chinese guy? I'm actually wondering if it's the kafei dian and that stands for coffee shop, and I'm also wondering what about the women? Wanpen, do you have any insights that you want to share? Dr Wanpen Vongpatanasin:         I believe that even Dr Victor had thought about the beauty shops, that is a barber shop study in parallel, and this could very well work very well. Who knows, we could be going to massage parlor, anywhere, that when we feel relaxed and be ourselves, we go out our way, out of our regular activity, and it could really be a neat idea. And for a study, I'm not sure I could do something out of the box. I would say it must have been successful as this approach, and partly it could be because of the additional pharmacists engage likely. So, I think this is a perfect combination. Dr Greg Hundley:                             Wanpen, you had mentioned Ron Victor. Maybe Ciantel, Florian, and Wanpen, you used to work with him. What did Ron mean to this study? Ron Victor unfortunately passed away this past Fall. Dr Florian Rader:                              Ron hired me almost seven years ago now straight out of fellowship. He was personally my mentor. He taught me all the tricks when it comes to the work of the management of hypertension, so personally I owe him a lot. Regarding the study, he's been thinking about this for a long time, this approach to hypertension management. He's tried it in Dallas. It worked partially, but not very well because he didn't have a pharmacist, and he didn't have somebody that made it their goal to lower blood pressure no matter what.                                                                 And in this study, we had somebody like that, the clinical pharmacist. So, Ron Victor has thought about this for a long time, has done a lot of analysis of the Dallas hypertension study, and figured out why it didn't work out in Dallas, and really cooked up a recipe for this trial, and the results speak for themselves. Dr Greg Hundley:                             Wanpen, do you have anything to add about Ron? I think he was your mentor as well. Dr Wanpen Vongpatanasin:         Absolutely. I trained with him actually from the internship until fellowship, and I owe my career to him. And actually, I see this idea stemming from the Dallas heart study when he did the survey, and realized that if you just wait for patients to show up in the clinic, that you're not going to get anywhere, because African Americans have higher blood pressure at a younger age, and are more susceptible for target organ damage. And as we all know, by the time many presented with, they already have end-stage kidney disease or cardiovascular disease by the time first presentation. So, to avoid it, we have to go into much earlier, not wait until they come to the healthcare facility, and I'm glad to see that this idea is really becoming widely successful more than anyone can imagine. Dr Carolyn Lam:                                What a beautiful tribute. What a poignant note. Thank you, all of you, for your great input, and for publishing this amazing paper with us at Circulation!                                                                 Thank you, listeners, for joining us today on Circulation on the Run with Greg Huntley and me. Thank you, and don't forget to tune in again next week.                                                                 This program is copyright American Heart Association 2019.  

So Greg took a tumble in the rain Saturday night dressed as Space Force, did something happen to you this weekend?

So Greg just found something out, you gotta hear this.

Our guest is Matt Dusig, Co-founder and Managing Director at InnovateMR. InnovateMR is a panel provider which has created the Pegasus Sample Access Platform, allowing users to employ a DIY sampling solution. Prior to starting InnovateMR, Matt has founded and harvested 3 other companies and invested in many others. In this interview, Matt covers building successful partnerships and teams in entrepreneurship, how he determines investment opportunities that works for him, and the what InnovateMR offers: quality, price, and trusted expertise. In hearing about his background, we learned particularly about staying ahead of the curve in technology and market research. FIND MATT ONLINE: http://www.innovatemr.com/ LinkedIn: https://www.linkedin.com/in/mattdusig/ Twitter: @mattdeuce FIND US ONLINE: www.happymr.com Facebook: https://www.facebook.com/pg/happymrxp Twitter: @happymrxp Instagram: @happymrxp LinkedIn: https://www.linkedin.com/company/happymarketresearch/ Hi, everyone, I'm Jamin Brazil and you're listening to the Happy Market Research Podcast, today my guest is Matt Dusig, co-founder and managing director at Innovate MR, Innovate MR is a panel provider who has created the Pegasus Sample Access Platform which allows users to employ a DIY sampling solution. Prior to starting innovate MR, Matt has founded and harvested three other companies and has invested in many others. Matt, thanks very much for joining us today. [00:00:28] Thanks, Jamin, excited to be here. [00:00:30] So what did you parents do and how did that affect your early career? [00:00:34] Yeah, that’s a great question, so my dad has always been an entrepreneur all through growing up. He owned various businesses, and I think what I learned from him was mostly from being scrappy, when you’re running your own company you know it’s do or die, you have to be creative, there’s no safety net, and he was just, and is, he’s still alive, is just a super creative person, always looking for solutions to problems, which my wife might tell me I shouldn’t be solving all of her problems, but that’s a whole different story. And I just think that that was a key motivator that he started businesses, and that it was possible to do it, that was what I was going to do also. [00:01:18] That’s interesting so you knew you were an entrepreneur very early on in your career? [00:01:23] Yeah, I had, in college I had a side business doing graphic design for just companies and clients, and that was how I made extra money. [00:01:34] You have a co-founder who has been with you, gosh, since your early days, right, that’s Greg? [00:01:41] Yeah. [00:01:42] Four companies together. I mean, that’s insane. [00:01:48] It’s actually five, it depends on how you’re counting. [00:01:50] I’m apparently not counting well enough. [00:01:50] There have been some failures in between. [00:01:53] Wait, say that again? [00:01:54] I said we’ve had some failures in between that we don’t always talk about but there have been five companies and in fact if you go all the way back to college there was a sixth company. So Greg and I, our relationship goes back to being six or seven years old. Our families were friends growing up, on the block, and so we’ve known each other our whole lives. My sister, his brother were friends, and then when he joined the fraternity I was in in college, we became best friends again and then college roommates, and it was in college that we actually started one of our first businesses. [00:02:31] What year was that? [00:02:33] Now you want me to age myself, OK. [00:02:37] Well, yeah, I do want you to age yourself. [00:02:39] That was 1989 that we became roommates together. In order to launch the business, we had to promote it, and in promoting it we went down to CompUSA or Circuit City, one of those stores, it had a 30 day return policy and we bought a fax machine, and we used that fax machine to send out promotions to different clients that w...

Childish Gambino's This Is America video feels like a cultural landmark in 2018. So Greg and Daniel sat down to discuss the video and song's themes of racism and violence in America. This is a special bonus episode, next time we'll be back with a full discussion. Find us on Facebook, iTunes, Google Play and Twitter. Music: https://bensound.com

The Comics Agenda Episode 60: Interview with Michael Loniewski This week Anelise is out sick. So Greg is flying solo as he interviews Michael Loniewski, Writer of the smash hit Gung Ho. Join us as we talk about what inspired Michael to pursue his dream of making his own comic. What advice he has for self-publishers, and what books he enjoys reading himself. We also get into the journey of creating and distributing Gung Ho. Gung Ho is available at Comixology for just 99 cents. So after listening to the interview head over and grab yourself a copy of Gung Ho. Listen, Enjoy and Subscribe. The Comics Agenda is hosted by Anelise (Twitter@Anelise.Farris ) and Greg (Twitter@Comicsportsgeek). We discuss several new comic book releases each week, in addition to breaking news, movies, and tv. You can reach us on Twitter @TheComicsAgenda or email us at TheComicsAgenda@gmail.com

This week, Hoss is busy with finals. So Greg has brought in another name from Corn Nation, Patrick Gerhart. Patrick specializes in #Nebrasketball, so we talk about Tim Miles’ tenure, off-season attrition and addition of personnel, and this week’s win against Number-14 Minnesota. The guys talk about Pinnacle Bank Arena and what some athletes may see in the program that would bring them to Lincoln. Since both Greg and Patrick have children under two, and since Ty just became a dad for the first time this week, the guys share some of their experiences, fond memories, and helpful hints. The Husker family.@coach_frost was greeted by former Husker players before he was introduced to media today. #GBR pic.twitter.com/GiGewSScc1 — Nebraska Football (@HuskerFBNation) December 3, 2017 Lastly, there’s a new head coach. In one of those moments that you’ll never forget where you were, Greg was on his friend’s roof hanging Christmas lights. But the Sunday of the introductory press conference, all eyes were glued. Subscribe on iTunes! The Five Heart Podcast Twitter The Five Heart Podcast Facebook Page The Corn Nation Twitter The Corn Nation Facebook Page The Jittery Monkey Facebook Page The Jittery Monkey Twitter Brian Towle Greg Mehochko Hoss Reuter Patrick Gerhart The post Corn Nation’s Five Heart Podcast Episode 47: Nebrasketball, Fatherhood, Feeling Frosty appeared first on Jittery Monkey Podcasting Network » Five Heart Podcast. The post Corn Nation’s Five Heart Podcast Episode 47: Nebrasketball, Fatherhood, Feeling Frosty appeared first on Jittery Monkey Podcasting Network » Five Heart Podcast. Learn more about your ad choices. Visit megaphone.fm/adchoices

Greg and Brian return with a bunch of topics, and in their traditional way, branch out on topics like walk-on football, Nebrasketball, the first day of the Nebraska Baseball season, Danny Woodhead, and more. Nana Atenken is mentioned as is the “basketball culture” in Illinois. It brings to light that Nebraska doesn’t have that basketball culture, but that it does have a wrestling culture. So Greg brings up the lack of wrestling coverage on Corn Nation (and may have inadvertently volunteered himself for the job). Better name: DiCaprio Bootles or Mojo Hagge? And in the “See Also” category, we mention a couple of championship-caliber Jordans…Michael Jordan and Jordan Burroughs. Plus, famous television series finales. And here are your friendly plugs and they’re grrrrrrreat! The Five Heart Podcast Twitter The Five Heart Podcast Facebook Page The Corn Nation Twitter The Corn Nation Facebook Page The Jittery Monkey Facebook Page The Jittery Monkey Twitter Brian Towle Greg Mehochko  The post Corn Nation’s Five Heart Podcast Episode 24 appeared first on Jittery Monkey Podcasting Network » Five Heart Podcast. The post Corn Nation’s Five Heart Podcast Episode 24 appeared first on Jittery Monkey Podcasting Network » Five Heart Podcast. Learn more about your ad choices. Visit megaphone.fm/adchoices

Today we have a fun episode for you. Dr. Gregory Lopez is orthopedic spine surgeon in Chicago with Midwest Orthopedics at Rush. He's a former collegiate and minor league baseball player who's experienced his fair share of injuries. It's those experiences that inspired his path toward medicine. He's also an innovator and that's where are story gets fun. As a baseball player, Greg recognized the critical importance of regular practice. During residency, Greg uncovered a real need for more hands on surgical practice. Unfortunately, time was limited and cadavers and bone models are expensive. So Greg decided to build his own surgical simulator to help his peers (and himself) improve basic psychomotor skills. Surgical simulators are complex and expensive, so where did Greg go to start his project? A large medical device company, a sawbones manufacturer, kick-starter maybe? Nope, Greg headed right over to his local Home Depot and started shopping. As we'll learn, Greg (along with several colleagues) created a simple, yet elegant system for practicing basic surgical hand skills, all for about $350 bucks! Today this system is used in teaching hospitals around the country and around the world. We're going to learn all about it and we're going to explore the broader challenges related to medical education and maintenance of skills.

One of the big things in 2017 we’ve got to deal with now, Greg Mercer, is obviously launching. In October of 2016, incentivised reviews were banned in the US, then shortly after, Germany, the UK, and the whole of Europe. How do you do an Amazon product launch now? Greg has first-hand experience with this as he has launched six or seven products since October; three or four in the last few weeks. An Amazon product launch is very different after this updated Terms of Service was released. Let’s take a 10,000 ft. look at this. In order to rank organically on Amazon, you need to have sales. There are a few ways to get sales. You can make your products really cheap, you can try to drive outside traffic, you can use deal sites like JumpSend. Without sales, you can launch your product but it will end up in the deep dark hole of Amazon and no one will find it. As Amazon sellers, we need to be thinking about how we can get sales on a product that is not organically ranking and  doesn’t have any reviews so there’s no social proof. Greg utilizes his JumpSend tool. It’s a deal site where about 30,000 people are visiting and looking for good deals. It’s no longer a place to get reviews, it’s a place to get sales. It still works, and it is completely within the Terms of Service of Amazon. So Greg puts his products on JumpSend. Then he offers it at a price people want it, which can vary. He offers about five coupons a day, maybe ten if it’s competitive. From this, he is getting sales. He will do this for about a week. After that time, the product will be ranking very well. From those sales, a few will end up resulting in a review. He will also turn on pay-per-click advertising (PPC). It’s costly, but it does get you sales. That’s what you need to get started; you have to have these sales. Where most people go wrong, is that they get scared of spending the money. Usually, Greg has to turn PPC so high that he is losing money on that sale. If he is offering 70% off, then he is likely losing money. People seem to get shy about losing money. However, that’s a part of doing business but you will recoup this money in the long-term. A big problem for people is that they’re afraid to bid the PPC that high, or they’re afraid to give that big of a discount because they’re afraid of losing money. That’s the gist of it. To do an Amazon product launch, you have to force sales somehow. The easiest way is deal sites and PPC. Then you’ll start ranking organically, and start getting reviews. Another thing is that you definitely want to have an email follow up sequence turned on. You can use any tool for that, but keep in mind that JumpSend is also a follow-up email service as well as a deal site. It’s nice that it is a full launch package. No matter what you use, before you do your first giveaway, you need to have some sort of email follow-up that asks for a review. The first email will thank them for the purchase. The second may let them know that they can contact you if you have any issues. The third could ask for a review. With an email sequence you’ll see that you can get 10-15 reviews out of 100 compared to the 3 out of 100 you may get without one. Going back to the coupons, Amazon forbids any action that tries to manipulate the sales ranking, and in a way, giving out coupons does that. It’s not so much following the letter of the law but how Amazon sees that. If you give coupons to only JumpSend users but not to the general public, is that potentially violating the Terms of Service? There is a clause in the ToS that was release in the first quarter of 2016 that said something to the effect that purposely manipulating sales rank is against the rules. It comes down to, what does this mean? It is a bit of a grey area. Greg’s personal opinion is that Amazon put that in because, at the time, sellers were doing these massive giveaways, especially in the supplement category. They were giving away about 100 units everyday for a coup...

Born in Peekskill, Darcy Parsons attended school in Buffalo before moving to New York City where she became a producer. She worked on SNL for a few years as segment producer for anything filmed outside of the show. With experience in advertising and producing Darcy eventually moved to Los Angeles and worked in commercials. She opened her own company, Brewster Parsons, which specializes in photo real visual effects, direction, design, and project management. Darcy had invested in the stock market in the late 90's and lost $10,000. She swore she would never invest in the stock market again. Instead she dappled in real estate investment. But when Darcy met someone who knew Tyrone and recommended his class, she decided it couldn’t hurt to hear his method. She was inspired by The Wealthy Investor program because there was accountability and monthly classes to make sure that the students are current with what is happening in the market. As a creative and a visual person, she enjoys that Tyrone's method simplifies something that is so extremely complex. Darcy went to the class for 6 months before making her first trade. She made her first trade with Ebay and made $750 on a volatility trade. She made $2,000 her first month and became a believer. In the Wealthy Investor Program, Tyrone and his students are simultaneously both traders, taking income in off a covered call or volatility trade, and investors who build wealth by building positions on $5 buy signals. Darcy has a few long-term positions in stocks that she uses this technique to build. This basically means that when you buy shares of a stock, you wait for it to go up five dollars to prove that it’s worthy of another round of investing. Darcy also believes that dividends are hugely important. For example, Darcy owns Macy’s stock, which has dropped, but she is still capturing the income from the dividend. She also believes that this stock is a good long-term “date” and plans to hold onto it for a while. Greg Vojtanek grew up outside of Chicago to a middle class family. The extent of his stock market education was a 45 minute lesson in high school. Greg majored in Theater at Lewis University outside of Chicago, IL. Afterwards he moved to Los Angeles to pursue in career in acting, until he moved to NYC for love. While in New York, he first began investing in real estate. He managed a small property in PA. Since he was already interested in investing and residual income, when his sister-in-law, Julie, invited him to the Wealthy Artist program (now The Wealthy Investor Program), it seemed like a natural fit. The system clicked for Greg. He really liked that it was just simple numbers on a page; there was no brick and mortar and certainly no leaky faucets to fix. He started getting really good at covered calls and discreetly started to tell people about it. Slowly he started convincing his family to let him show them his skills. He first started an account for his 13 year-old nephew and later took on his Mom’s account.  When Greg’s brother-in-law had a big break in Hollywood, he knew he was about to come into a lot of money that he didn’t know what to do with. Since Greg was the only guy who knew that could handle money, he asked Greg to move out to LA and work for him. So Greg moved back out to Hollywood and took over his finances by opening a trading account for him.  Now, between managing his own trading account and his job managing others, he is financially independent. He exemplifies this with a recent experience; “I thought I had x amount of dollars in my personal account. I logged on yesterday and it was a lot more than what I thought I had. I don’t really worry about my account value because I know it’s fine. It climbed without me even knowing it.” This has allowed Greg to get back to his creative roots. He is now a writer on a new show premiering next year. When you know you have money coming in every month from the stock market it, Greg says it is “…one less thing to worry about, and for most people that’s 50% of their worries in their life. If you can eliminate that or at least bring that down to like 10%, life becomes a lot easier.” One of the reasons Greg is still trading and taking class is because he loves helping other people, and he love’s putting other people’s minds at ease.  If you aren’t sure if you’ll find success in the stock market, Greg says, “I have met so many walks of life in six years of working with [Tyrone] of people all over the place who figure it out. It may take some people a couple more classes than others. It doesn’t matter, that’s fine. Wherever you are in your life is where you are, that’s fine. And however long it takes you to figure out the numbers or what’s going on, that’s fine. If it takes you a couple minutes, great. If it takes you a couple weeks, great. But you are on your own pace and it is really not difficult.”  To get started, take a few minutes to visit TheWealthyInvestor.net and download the free E-Book Trading Stocks For Wealth. 

Greg Vojtanek grew up outside of Chicago to a middle class family. The extent of his stock market education was a 45 minute lesson in high school. Greg majored in Theater at Lewis University outside of Chicago, IL. Afterwards he moved to Los Angeles to pursue in career in acting, until he moved to NYC for love. While in New York, he first began investing in real estate. He managed a small property in PA. Since he was already interested in investing and residual income, when his sister-in-law, Julie, invited him to the Wealthy Artist program (now The Wealthy Investor Program), it seemed like a natural fit. The system clicked for Greg. He really liked that it was just simple numbers on a page; there was no brick and mortar and certainly no leaky faucets to fix. He started getting really good at covered calls and discreetly started to tell people about it. Slowly he started convincing his family to let him show them his skills. He first started an account for his 13 year-old nephew and later took on his Mom’s account.  When Greg’s brother-in-law had a big break in Hollywood, he knew he was about to come into a lot of money that he didn’t know what to do with. Since Greg was the only guy who knew that could handle money, he asked Greg to move out to LA and work for him. So Greg moved back out to Hollywood and took over his finances by opening a trading account for him.  Now, between managing his own trading account and his job managing others, he is financially independent. He exemplifies this with a recent experience; “I thought I had x amount of dollars in my personal account. I logged on yesterday and it was a lot more than what I thought I had. I don’t really worry about my account value because I know it’s fine. It climbed without me even knowing it.” This has allowed Greg to get back to his creative roots. He is now a writer on a new show premiering next year. When you know you have money coming in every month from the stock market it, Greg says it is “…one less thing to worry about, and for most people that’s 50% of their worries in their life. If you can eliminate that or at least bring that down to like 10%, life becomes a lot easier.” One of the reasons Greg is still trading and taking class is because he loves helping other people, and he love’s putting other people’s minds at ease.  If you aren’t sure if you’ll find success in the stock market, Greg says, “I have met so many walks of life in six years of working with [Tyrone] of people all over the place who figure it out. It may take some people a couple more classes than others. It doesn’t matter, that’s fine. Wherever you are in your life is where you are, that’s fine. And however long it takes you to figure out the numbers or what’s going on, that’s fine. If it takes you a couple minutes, great. If it takes you a couple weeks, great. But you are on your own pace and it is really not difficult.”  To get started, take a few minutes to visit TheWealthyInvestor.net and download the free E-Book Trading Stocks For Wealth. 

When Jim Collins wrote "Good To Great", he did talk a fair bit about the Hedgehog Principle. But what he stresses more on, is quite another concept called "Preserving the Core and Stimulating Progress". Why does this concept matter so much? And how do you combine the Hedgehog Principle with this concept? And where does the big, hairy, audacious goal fit in with everything? This episode shows you how to tie all the elements together in a neat little bundle. Time to escalate that route to greatness, don't you think? -------------- In this episode Sean talks about Part 1: Preserving the Core + Stimulating Progress Part 2: The BHAG Part 3: Your Action Plan To Greatness Right click here and ‘save as’ to download this episode to your computer.   Useful Resources 5000bc: How to get reliable answers to your complex marketing problems Why Happiness Eludes You: 3 Obstacles That We Need To Overcome Find out: Do We Really Need To Start With Why? -------------- Preserve the Core AND Stimulate Progress Recently a client called Rosa wrote to us with a request. “I would have preferred to read the series on Dartboard Pricing in ePub,” she said. She made it clear it was a request, not a demand. Which brings up a whole new set of problems for us at Psychotactics. Most business books are designed with text in mind and may contain a few graphics. Our books aren’t designed that way at all. They have dozens of cartoons and under every cartoon is a caption. In The Brain Audit alone there are almost 100 cartoons and corresponding captions. In a PDF, this layout is easy-peasy. Create the book in InDesign and export it as a PDF and it maintains its design integrity. Try to do the same thing for an ePub and it’s like stepping in poo. It’s a tedious, frustrating process to get all the graphics to align the way they should The easier way is to just make a quick excuse, apologies and move on. After all, it isn’t like 90% of our audience is asking for an ePub. It’s just a stray request, isn’t it? It’s simple to ignore the request and get on with the important task of doing whatever it is we do. But that’s where the problem lies, doesn’t it? We’ve ignored the concept of progress. Almost all of us today read on a tablet or our phones. I know I do, my wife does, even my mother in law who ranted and raved about computers—she now loves her iPad. And PDFs work on tablet devices and phones, but they’re super clunky. Sadly that’s not the only problem Jim Collins talks about two elements: preserving the core and stimulating progress. And he goes to great lengths to stress the AND in between both of them. So all of us have to stand back and ask ourselves: What’s our core? The core of Psychotactics has been the factor of “consumption”. Any one can create attraction and conversion. It’s super-hard to get clients to consume what they’ve bought from you. Books, courses, workshops—we spend hours, days and weeks trying to figure out how to achieve a skill. The cartoons, the captions in the book—they’re not just a design concept. They’re placed there as memory hooks; as a method of summary. They need to be exactly where they are in the books and courses. We could remove them and easily create an ePub like most ePubs, but that would fit in with our core. Collins says it has to be an AND. We have to preserve the core AND stimulate progress. This principle is clearly frustrating and pulls in opposite directions. When you’re starting out, you don’t have any legacy issues in place. You create a business the way you want to shape it. And the core and the progress moves along nicely. It’s when you “grow up” that you have to worry about how all the past has to fit in with the future. The longer you’ve been in business, the greater the past, and the more the past has to merge with an ever changing future. Take Nokia for instance You can almost hear the sound of the Nokia ring, can’t you? In the early 2000s, all of us would have at one point in time run into, or owned a Nokia. Nokia was no slouch in realm of being super-progresssive. They were into paper, then electricity and bounced from there to rubber, galoshes and finally were the most dominant phone manufacturer on the planet. In the early 1990’s they had a clear and accurate vision of the future. They saw the coming of the cell phone, dumped all their businesses and stuck with the cell phone. And then, just for good measure, they invented the first smart phone. That amazing device you take photos with, use to find your way around and yes, make phone calls—Nokia was on the ball way back in 1996. They even built a prototype of an Internet-enabled phone at the end of the 90’s. And then they got stuck in a loop They failed to see the link between their core—which was to make really simple phones—and the future. The future was software. The core of their legacy was hardware. They spent millions of dollars turning out failure after failure. They believed so much in their hardware that they just couldn’t figure out the software issues. And down they went, ring and all, finally selling their company to Microsoft. To go from good to great we have to ask ourselves What’s the core of our business. What do we stand for? What will we never change, never compromise on—and yet how will we step into the future when it presents itself to us. Most of us rarely have a problem with core values. Once we’ve spent enough time in our business, we know what we stand for, but what we fail to prepare ourselves for is the oncoming storm. We keep doing things the way we’ve always done. The worst three words we repeat over and over, when faced with change is: I know that, I know that, I know that. I thought I knew a lot about podcasts After all I’d rode the early wave of podcasts when Apple first introduced them. And then in 2008/09 we decided to pull the plug on the podcast. When clients—and one client in particular—kept asking me to create a podcast, I’d ignore the comment. As far as I was concerned, podcasts were a thing of the past. I wasn’t ready to listen and the years ticked away while we busied ourselves with the core of what we’d always done. Today, the “Three Month Vacation” podcast is one of the biggest joys in my day I love writing, I love presentations, but it’s the podcast that connects me to a medium I love. And in turn the podcast connects us to our clients in ways that not possible on paper, or through books. The podcast is the closest we come to an offline workshop. But I wasn’t interested in the “future”. As far as I was concerned, podcasts were the distant past. And today we know those thoughts, that strategy was wrong. We see the enormous number of clients who find the podcast, then sign up to the newsletter. At our offline workshops over 50% of the audience listens religiously to the podcast. The podcast fit in so nicely with our core. And was the medium of the future. Even so, it’s not possible to chase every rainbow Technology moves ahead at a blinding pace. You can’t play with every new phenomenon. Which is why we have to go back to the Hedgehog principle. What can you be the best in the world in? What are you deeply passionate about? What drives your economic engine? In the subset of podcasting, we achieve all three. And this is what you’ll have to do as well. Find your core AND stimulate progress, with your eye always on the passion. The passion is what drives your business today and will continue to do so in the future. If you don’t wake up crazy with happiness, then you’re not headed towards greatness. It’s the reason I moved on from cartooning back in the early 2000s. I wasn’t waking up happy as a lark—and so I had to find something else. Which, interestingly, takes us to our third element: The hairy, audacious goal—oh, it’s big too. That makes it the BHAG (pronounced: bee-hag). The BHAG Until the moment Greig Bebner set to work on his kitchen table with a glue gun and some kite material, the basic design of the modern umbrella hadn’t changed since 1928. They come in all sorts of colours, shapes and fancy gizmos, but the core elements of the umbrella are the same—and they don’t work. The moment a gust of wind comes along, you hear cursing, then more cursing and finally the umbrella being thrown on the pavement. So Greg set about on a big, hairy, audacious goal—a BHAG. He wanted an umbrella that would stand up to the crazy wind and rain on One Tree Hill. Now if you’ve ever visited Auckland, New Zealand, you’re likely to have your hair tossed around wildly on a windy One Tree Hill day. It’s certainly no place to open an umbrella. Then to push that BHAG even further, he tested the Blunt at Force 12 (117 km/h) which is the maximum setting of the test wind tunnel. The umbrella stood up to the punishment with ease. But why did the umbrella work so flawlessly? It starts with the BHAG. It’s almost a Star Trek kind of goal—to go where no man gone before. It’s not a namby-pamby set of goals. It’s one overarching factor that scares the heebie-jeebies out of you as a business owner. A windy day on One Tree Hill in the middle of a storm. That’s a good testing ground for an umbrella. Sometimes this goal is restricted to your product, sometimes it’s a lot bigger. Like Akio Morita, the co-founder and former chairman of Sony Corporation. He was working on a revolutionary product called the Walkman. Until the Walkman was introduced on July 1, 1979. Until the Walkman showed up, portable music players were non-existent. Even though the Walkman stuttered with disappointing sales in the first month, it went on to sell over 400 million units. But Morita’s goal wasn’t just to sell a ton of Walkmans His goal was a lot loftier. Before Sony introduced a ton of extremely sophisticated equipment, Japan was considered to be a backward country. It was associated with paper parasols and shoddy imitations. Akio Morita wanted to turn that perception around so that “Made in Japan” commanded respect and was associated with high quality. And he succeeded, with Sony at the forefront of his BHAG. In 2014, A Harris poll showed Sony was the No. 1 brand name among American consumers, ahead of American companies like General Electric and Coca-Cola. At Psychotactics, we have a BHAG too The goal is to get rid of information for information sake and replace it with skill, instead. We’re drowning in information, and yet every book, every course brings even more information to the table. But is that what we really want? Or do we want the skill instead. We want to write articles, create sales pages, be able to sell at higher prices. We want to learn to cook, draw, paint or acquire skills that make us look, feel and be smarter. A BHAG has to be hairy, audacious, and bigger than anyone thinks possible. Starbucks had a BHAG too It was to open up a new Starbucks cafe every single day of the year. But soon enough, Starbucks was running into trouble. Can you see why? It’s big, hairy and audacious to open up a Starbucks every single day, but does it inspire any passion? Does it feel like you’re somehow changing the world you live in, let alone the world around you? The BHAG wasn’t to make Sony the star, but instead to make Japan and Japanese products top-notch once again. Every business should have a BHAG. Something that sits there in the corner challenging you to become better—not necessarily bigger—than you are. To create a Ferris Wheel or an Eiffel Tower. To create artworks of enduring magnificence as Michelangelo, Leonardo da Vinci and Rembrandt did. And the way to create that BHAG is to scare yourself. To know that everyone says there are things you’re not supposed to achieve. That these things are impossible. And yet, you do it, because it’s the most inspiring thing to do! Combined with the Hedgehog principle, preserving the core and stimulating progress, you have a system in place that can take your business from good to great. And even as you embark on this journey, you know that you will forever be on the road to making things better, not necessarily bigger, but always better. Better—it’s a great place to be! Action Plan: What is the one thing you can do today? Check back tomorrow. Sean is still writing it.  

There are two options in life: greatness or mediocrity. But greatness seems so elusive, even so pompous. How do you call your work "great"? How do you even know or benchmark "greatness?". And can a small business achieve greatness or do you have to be a dominant player like Apple, Disney and Walmart. In this episode we get right to the root of greatness and how the book "Good to Great" by Jim Collins changed my life. But instead of the massive journey to greatness, this episode shows you a tiny path. A path most of us can manage with just a little bit of effort. A life of mediocrity is hardly worth living. Here's the pathway to greatness. ----------  Useful Resources / To access this audio + transcript: http://www.psychotactics.com/79 / / Email me at: sean@psychotactics.com / / Twitter/Facebook: seandsouza / / Magic? Yes, magic: http://www.psychotactics.com/magic ----------  Part 1: The Hedgehog Principle Part 2: Preserving the Core + Stimulating Progress Part 3: Big, Hairy Audacious Goal—The BHAG Right click here and ‘save as’ to download this episode to your computer.   Useful Resources 5000bc: How to get reliable answers to your complex marketing problems Why Happiness Eludes You: 3 Obstacles That We Need To Overcome Find out: Do We Really Need To Start With Why? ----------------- The  Transcript “This transcript hasn’t been checked for typos, so you may well find some. If you do, let us know and we’ll be sure to fix them.”   Around the autumn of 1890, Daniel Burnham was given a project. Burnham was an architect—an extremely well known architect—in Chicago. And he’d been given a job like no other. He was expected to turn a boggy square mile into what would be the spotlight of the world. He was put in charge of the World’s Columbian Exposition. He just had one tiny problem—the Eiffel Tower. On March 31, 1889, Paris had had it’s own Exposition. And it quickly surpassed the Washington Monument to become the then tallest man-made structure in the world. Burhnam had the unenviable job of surpassing the hoopla around the Eiffel Tower, but no one had a clue what to do. “Make no little plans”, he said to his team of engineers, but they could come up with little to rival the magnificence of the Eiffel Tower. Of course there were proposals: a tower garlanded with rails to distant cities, another tower from whose top guests would be pushed off in chairs (pretty much like today’s bungee jumping). And Eiffel himself proposed an idea for the Chicago exposition—a bigger tower than the one in Paris. How could the Chicago Exposition outshine the now most famous monument in the world—the Eiffel Tower? It seemed almost impossible to come up with something that would rival the French monument. An engineer called Ferris has the answer. The ideas were going nowhere and the Chicagoans were pulling their hair out, when a 33 year old engineer from Pittsburgh came up with an idea: how about a huge revolving steel wheel? He came up with sketches, added additional specifications and then shared the idea with Burnham. But Burnham was not impressed. The slender rods of the wheel were too fragile. It would be madness to carry people to a height taller than the Statue of Liberty in such a fragile wheel. But Burnham wasn’t just dealing with any ol’ engineer. He was dealing with George Washington Gale Ferris Jr—who would forever be associated with the Ferris wheel. Ferris was so convinced his idea would work that he spent $25,000 of his own money, hired more engineers and recruited investors. And consider that $25,000 would be worth over $650,000 in today’s money. Over a 100,000 parts went into the Ferris wheel. And an 89,320 pound axle had to be hoisted onto two towers 140 feet in the air. On June 21, 1893 when it was launched, it was a stunning success. As the exposition went through the next three week, more than 1.4 million paid 50 cents for a 20-minute ride. George Washington Gale Ferris had literally reinvented the wheel. The year we moved to New Zealand, I had to reinvent my own wheel. You see, I wasn’t in marketing. I had no plans of being in marketing. I was already an established cartoonist back in Mumbai, India and when I moved to New Zealand I pretty much expected to continue to draw cartoons. In fact I was so determined to take that cartoon career forward, that when we moved I had over 100 kilos worth of books shipped. These were no ordinary books. These were the books on graphic design and cartooning that I’d accumulated over the years. Plus, there were brochures. Before I left India, I had no idea what New Zealand held for me. So I printed business cards—as you do But also lavish four colour brochures, postcards and yes, stationery that I could use when I got to New Zealand. All of this material had to be shipped by air—not by sea—because I was in a big hurry to get going in this new country. Yet, almost a year later, I had to reinvent what I was doing—and it was all because of one book. That book, “Good to Great” has sold over 2.5 million hardcover copies. But more importantly, it was the catalyst in my own reinvention. In 2000 as I got on a plane back to India (I had to go back and tidy up things I’d left undone), I had loads of time to read the book and mull over the ideas. And as I’ve mentioned before in articles and podcasts, I realised that I would never reach my greatness in cartooning. To me, the pinnacle of cartooning was the comic strip, “Calvin and Hobbes” by Bill Watterson. If I couldn’t get up to those lofty heights, it wasn’t feeding my greatness appetite. And so I turned to something I was getting exceedingly good at doing—creating taglines for small businesses. Without realising it, I was wandering down the aisle of marketing. The book—and that 19 hour flight—it did it for me. It put me on my quest for what I’d consider my “greatness journey”. But just as it set the benchmarks, it also raised a ton of questions. Are there benchmarks to know that you’re moving from good to great? How do you know what you’re choosing will end up being great? With all the stories of greatness bouncing around Apple, Boeing, Disney and Walmart, how can a small business owner get to greatness, without becoming big and dominant? Big questions—and it’s best to keep the answers simple. Deep, yet simple. Let’s take a trip and explore the three core elements required to get your own Ferris wheel going—even when the odds seem stacked against you. The three elements we’ll cover are: The Hedgehog Principle Preserving the Core + Stimulating Progress Big, Hairy Audacious Goal—The BHAG.   Avis—the car rental company—was pretty much in the doldrums. Back in 1961, it was losing $3.2 million a year and there seemed to be no way to beat the domination of their biggest rival—Hertz. And the two companies had been at each others throats since the mid-1940s, when Air Force officer, Warren Avis created a niche out of thin air. As he travelled around, Warren Avis  realized that most car companies were downtown—not a very convenient place to get a car if you just flew into a city. Business travel was growing steadily and many executives would touch down, rent a car, drive to their meetings and drop the car back at the airport on the very same day. Hertz was not impressed They continued to run their rental car business downtown, as if Avis didn’t exist. Yet, over time, they found Avis gobbling up chunks of their business. It seemed logical to simply replicate what Avis had done. With this move, Hertz signalled the start of the rivalry that exists to this day. But then, along came 1962 and an creative agency called Doyle Dane Bernbach (DDB). The copywriter team of Paula Greene and Helmut Krone created an advertising campaign that would take Avis from losing $3.2 million to earning $1.2 million. What’s more, it would rock Hertz’ smugness to its very core. From 1963 to 1966, Hertz smug look turned to paralysis The market share percentage gap between the two car companies shrunk from 61-29 to 49-36. The “We’re only No.2. We try Harder” immediately captured the attention of the public. But why did this “We try harder” campaign really work? When we look at the Hedgehog Concept outlined in “Good to Great”, the answer is more than apparent. The Hedgehog principle consists of three pertinent questions: – What can you be the best in the world at? – What drives your economic engine? – What are you deeply passionate about? Avis could easily answer those questions—but only once it had the new ad campaign going It was the best in the world at “bending over backwards” to make car customers happy. After all it was only No.2, and couldn’t afford to rest on its laurels. This concept of “trying harder” got the entire company to indeed try harder. And yes, we all know how their bleeding balance sheet made a sharp U-turn into decent profitability. They got the “best in the world” covered, the “economic engine” was purring away. Only one thing remained—the passion. The “we try harder” might have been just a slogan, but it was a slogan that drove the passion—and if the slogan is right, it often does drive the passion! Avis ticked all the three boxes, and they were well on their way to scaring the heebie-jeebies out of Hertz. Notice how money—or the economic engine—isn’t really the focus of greatness? Money is important, that’s for sure. A company gasps and coughs it’s way into oblivion if it can’t fire up that economic engine. And yet, it’s more than clear that for most of us, at least, money is not the driving factor. All those website owners that show you how their income doubled and quintupled are still sitting on the same sofa; they’re still typing on that same yellowed keyboard. Yes, they may have doubled or quintupled the size of their house or boat, but when money becomes the only focus, there’s no time to enjoy the good stuff in life. Which is why the “best in the world” journey needs to start with what makes you deliriously happy. It’s the stuff that wakes you up and keeps you going, no matter what. Your work becomes your passion and the complete opposite of trying to outsource everything and doing as little as possible. Money helps enormously in getting you to your goal, but the passion and desire is what’s behind the wheel. And this is where confusion comes bouncing through the door When I quit my career in cartooning, I was doing very well indeed. I’d moved to New Zealand and despite being in a brand new market, the profit for the first year was $75,000. Picture me sitting at my computer, drawing cartoons, listening to music and then taking a nap and you get the idea. It wasn’t exactly like I was struggling to put food on the table. Still, the moment you decide you want to change things—the moment I decided I couldn’t beat “Calvin and Hobbes”, I was in trouble. I’m good at a lot of things. I whizz my way around Photoshop, I can cook exceedingly well, you’ve probably seen my food and travel photos on Facebook—and you’re getting an idea of the looming problem, aren’t you? The moment you can do more than one thing, you’re not sure where to go. The journey to greatness seems to run right into a pool of quicksand. So how do you get yourself out of this mess and back on track? I’d decided I didn’t want to do cartooning—at least at that point in time—and I wanted to take this leap into marketing. I didn’t know much about marketing, but that minor detail wasn’t keeping me up at night. Still, I was in a fog—after all marketing is this big, nameless, faceless profession and I hadn’t a clue what the journey to greatness was going to look like, or whether one existed at all. And that’s when I ran into a subset of marketing. A subset is what starts the journey to greatness My story was quite accidental—as yours may well be. I joined this networking group called BNI. We’d meet every Friday, enjoy breakfast and hand out referrals. And crucial as all this referral giving was to me at the time, one factor was even more pivotal to help me on my journey. BNI has this strange custom called “the dance”—as in “dancing with a partner”. In this so-called “dance”, you go across to visit another of the members. For instance, I might go and meet the real estate agent at her office. Or another week I might end up talking to the financial planner in the group. Being new and enjoying this extroverted behaviour, I binged on the “dance” I started meeting several members of the BNI group in relatively quick succession. They’d tell me what they did—often spending between 10-20 minutes explaining the details. Then I’d ponder over what they just said, and boil it down to a single line. In effect, I’d given them a tagline—a working tagline that would elicit curiosity and get their prospects interested. The first time I encapsulated their 20 minute speech into a single line, I wasn’t aware of what I was doing. Twenty or thirty tagline later, with everyone telling me how “great” I was at taglines, I decided to make that my entry point into marketing. I wasn’t going to be the best in the world at marketing—and no one can ever take such a title. But I could create a subset. And that’s because a subset is simpler than a well-laid out, world domination plan. Which means that you’re going to make a career out of teaching a program like InDesign, don’t take on every tool bar in the program. Just teach clients how to create an amazing e-book in under an hour. The Hedgehog Concept If you’re going to be the best in the world at WordPress sites, you’re headed for chaos. But take on a subset and you could be the designer that gets clients to their destination in just three steps. Even the all-time greats in the history of mankind—take Michelangelo for instance—he made the statue of David his subset. He was headed towards the magnificence of the Sistine Chapel in time, but to start on that journey of greatness, he had to take on carving just the statue of David. Once you deal with a subset, passion almost force-feeds you with energy Avis found its passion once it had the subset of “trying harder” instead of the grand scheme of “trying to do everything”. I found my subset quite by accident while taking on taglines. And the moment you streamline your idea into one tiny bit, you’ll get enormous control over that bit—and the passion faucet will begin to flow. You’ll read more about the subset, practice it longer and harder and it will take over your life. Which effectively means you’re done with two elements of the Hedgehog principle all at once. You have your passion—thanks to your subset—and it’s put you well and truly on the road to personal and professional greatness. That leaves just the looming question. Will it drive your economic engine? Will it pay the bills? And how soon? I didn’t know the answer to that question of the economic engine In fact, I did something very silly in my quest for “being the best in the world”. I quit cartooning—yup, just like that. One fine day, I decided I wasn’t going to do any cartoons. And then something extremely strange happened. No one called me for a cartoon project any more. Right until that moment I’d been filling that balance sheet with a decent profit, and suddenly I didn’t get a single call or e-mail for another cartoon project. Be aware that I was drawing stuff for ad agencies, magazine covers, local councils and private clients. And yet, it stopped almost as if I had taken a full page ad in the newspaper that said, “Sean D’Souza doesn’t want to draw cartoons any more. Stop bugging him.” My dream had come true, but I didn’t have a buffer. The buffer isn’t just money It’s also the buffer of knowledge and of confidence. Remember, I wasn’t a marketing guy, I was a cartoonist. That thought stays in your head and seriously undermines your confidence. Getting to the library, stacking up 30 books at a time was top priority. We’re talking about economic engines here, and knowledge plays a big role in how you get paid. Having the skills to run a business is what allows you to make that engine vroom. I had to teach myself how to write great articles, how to create compelling copy—and yes, how to speak. That buffer was important for my economic engine, but money played its role too. I jumped right into marketing and out of a business I’d spend a chunk of time beefing up on the learning and the skills. But I hadn’t considered the factor that everything takes time to turnaround. It was a rash move, and luckily Renuka had a decent job. That paid the bills, the mortgage and let me fumble forward toward this “greatest in the world” dream. Um, Renuka also quit her job and joined Psychotactics a few months later, but that buffer was all we needed. We were now on a trajectory to align ourselves with the Hedgehog Principle. Like Michelangelo, we had to carve one David at a time. Like Avis, we had to “try harder” one car at a time. We were passionate about what we did. And the clients started to trickle in. But the Hedgehog principle itself, isn’t enough Jim Collins stresses a second more important factor. In fact, he considers this second factor to be the most important of all the material he’s written over the years. It’s called: Preserving the core AND stimulating progress. Let’s find out just what this means for you and your small business. Preserve the Core AND Stimulate Progress Recently a client called Rosa wrote to us with a request. “I would have preferred to read the series on Dartboard Pricing in ePub,” she said. She made it clear it was a request, not a demand. Which brings up a whole new set of problems for us at Psychotactics. Most business books are designed with text in mind and may contain a few graphics. Our books aren’t designed that way at all. They have dozens of cartoons and under every cartoon is a caption. In The Brain Audit alone there are almost 100 cartoons and corresponding captions. In a PDF, this layout is easy-peasy. Create the book in InDesign and export it as a PDF and it maintains its design integrity. Try to do the same thing for an ePub and it’s like stepping in poo. It’s a tedious, frustrating process to get all the graphics to align the way they should The easier way is to just make a quick excuse, apologies and move on. After all, it isn’t like 90% of our audience is asking for an ePub. It’s just a stray request, isn’t it? It’s simple to ignore the request and get on with the important task of doing whatever it is we do. But that’s where the problem lies, doesn’t it? We’ve ignored the concept of progress. Almost all of us today read on a tablet or our phones. I know I do, my wife does, even my mother in law who ranted and raved about computers—she now loves her iPad. And PDFs work on tablet devices and phones, but they’re super clunky. Sadly that’s not the only problem Jim Collins talks about two elements: preserving the core and stimulating progress. And he goes to great lengths to stress the AND in between both of them. So all of us have to stand back and ask ourselves: What’s our core? The core of Psychotactics has been the factor of “consumption”. Any one can create attraction and conversion. It’s super-hard to get clients to consume what they’ve bought from you. Books, courses, workshops—we spend hours, days and weeks trying to figure out how to achieve a skill. The cartoons, the captions in the book—they’re not just a design concept. They’re placed there as memory hooks; as a method of summary. They need to be exactly where they are in the books and courses. We could remove them and easily create an ePub like most ePubs, but that would fit in with our core. Collins says it has to be an AND. We have to preserve the core AND stimulate progress. This principle is clearly frustrating and pulls in opposite directions. When you’re starting out, you don’t have any legacy issues in place. You create a business the way you want to shape it. And the core and the progress moves along nicely. It’s when you “grow up” that you have to worry about how all the past has to fit in with the future. The longer you’ve been in business, the greater the past, and the more the past has to merge with an ever changing future. Take Nokia for instance You can almost hear the sound of the Nokia ring, can’t you? In the early 2000s, all of us would have at one point in time run into, or owned a Nokia. Nokia was no slouch in realm of being super-progresssive. They were into paper, then electricity and bounced from there to rubber, galoshes and finally were the most dominant phone manufacturer on the planet. In the early 1990’s they had a clear and accurate vision of the future. They saw the coming of the cell phone, dumped all their businesses and stuck with the cell phone. And then, just for good measure, they invented the first smart phone. That amazing device you take photos with, use to find your way around and yes, make phone calls—Nokia was on the ball way back in 1996. They even built a prototype of an Internet-enabled phone at the end of the 90’s. And then they got stuck in a loop They failed to see the link between their core—which was to make really simple phones—and the future. The future was software. The core of their legacy was hardware. They spent millions of dollars turning out failure after failure. They believed so much in their hardware that they just couldn’t figure out the software issues. And down they went, ring and all, finally selling their company to Microsoft. To go from good to great we have to ask ourselves What’s the core of our business. What do we stand for? What will we never change, never compromise on—and yet how will we step into the future when it presents itself to us. Most of us rarely have a problem with core values. Once we’ve spent enough time in our business, we know what we stand for, but what we fail to prepare ourselves for is the oncoming storm. We keep doing things the way we’ve always done. The worst three words we repeat over and over, when faced with change is: I know that, I know that, I know that. I thought I knew a lot about podcasts After all I’d rode the early wave of podcasts when Apple first introduced them. And then in 2008/09 we decided to pull the plug on the podcast. When clients—and one client in particular—kept asking me to create a podcast, I’d ignore the comment. As far as I was concerned, podcasts were a thing of the past. I wasn’t ready to listen and the years ticked away while we busied ourselves with the core of what we’d always done. Today, the “Three Month Vacation” podcast is one of the biggest joys in my day I love writing, I love presentations, but it’s the podcast that connects me to a medium I love. And in turn the podcast connects us to our clients in ways that not possible on paper, or through books. The podcast is the closest we come to an offline workshop. But I wasn’t interested in the “future”. As far as I was concerned, podcasts were the distant past. And today we know those thoughts, that strategy was wrong. We see the enormous number of clients who find the podcast, then sign up to the newsletter. At our offline workshops over 50% of the audience listens religiously to the podcast. The podcast fit in so nicely with our core. And was the medium of the future. Even so, it’s not possible to chase every rainbow Technology moves ahead at a blinding pace. You can’t play with every new phenomenon. Which is why we have to go back to the Hedgehog principle. What can you be the best in the world in? What are you deeply passionate about? What drives your economic engine? In the subset of podcasting, we achieve all three. And this is what you’ll have to do as well. Find your core AND stimulate progress, with your eye always on the passion. The passion is what drives your business today and will continue to do so in the future. If you don’t wake up crazy with happiness, then you’re not headed towards greatness. It’s the reason I moved on from cartooning back in the early 2000s. I wasn’t waking up happy as a lark—and so I had to find something else. Which, interestingly, takes us to our third element: The hairy, audacious goal—oh, it’s big too. That makes it the BHAG (pronounced: bee-hag). The BHAG Until the moment Greig Bebner set to work on his kitchen table with a glue gun and some kite material, the basic design of the modern umbrella hadn’t changed since 1928. They come in all sorts of colours, shapes and fancy gizmos, but the core elements of the umbrella are the same—and they don’t work. The moment a gust of wind comes along, you hear cursing, then more cursing and finally the umbrella being thrown on the pavement. So Greg set about on a big, hairy, audacious goal—a BHAG. He wanted an umbrella that would stand up to the crazy wind and rain on One Tree Hill. Now if you’ve ever visited Auckland, New Zealand, you’re likely to have your hair tossed around wildly on a windy One Tree Hill day. It’s certainly no place to open an umbrella. Then to push that BHAG even further, he tested the Blunt at Force 12 (117 km/h) which is the maximum setting of the test wind tunnel. The umbrella stood up to the punishment with ease. But why did the umbrella work so flawlessly? It starts with the BHAG. It’s almost a Star Trek kind of goal—to go where no man gone before. It’s not a namby-pamby set of goals. It’s one overarching factor that scares the heebie-jeebies out of you as a business owner. A windy day on One Tree Hill in the middle of a storm. That’s a good testing ground for an umbrella. Sometimes this goal is restricted to your product, sometimes it’s a lot bigger. Like Akio Morita, the co-founder and former chairman of Sony Corporation. He was working on a revolutionary product called the Walkman. Until the Walkman was introduced on July 1, 1979. Until the Walkman showed up, portable music players were non-existent. Even though the Walkman stuttered with disappointing sales in the first month, it went on to sell over 400 million units. But Morita’s goal wasn’t just to sell a ton of Walkmans His goal was a lot loftier. Before Sony introduced a ton of extremely sophisticated equipment, Japan was considered to be a backward country. It was associated with paper parasols and shoddy imitations. Akio Morita wanted to turn that perception around so that “Made in Japan” commanded respect and was associated with high quality. And he succeeded, with Sony at the forefront of his BHAG. In 2014, A Harris poll showed Sony was the No. 1 brand name among American consumers, ahead of American companies like General Electric and Coca-Cola. At Psychotactics, we have a BHAG too The goal is to get rid of information for information sake and replace it with skill, instead. We’re drowning in information, and yet every book, every course brings even more information to the table. But is that what we really want? Or do we want the skill instead. We want to write articles, create sales pages, be able to sell at higher prices. We want to learn to cook, draw, paint or acquire skills that make us look, feel and be smarter. A BHAG has to be hairy, audacious, and bigger than anyone thinks possible. Starbucks had a BHAG too It was to open up a new Starbucks cafe every single day of the year. But soon enough, Starbucks was running into trouble. Can you see why? It’s big, hairy and audacious to open up a Starbucks every single day, but does it inspire any passion? Does it feel like you’re somehow changing the world you live in, let alone the world around you? The BHAG wasn’t to make Sony the star, but instead to make Japan and Japanese products top-notch once again. Every business should have a BHAG. Something that sits there in the corner challenging you to become better—not necessarily bigger—than you are. To create a Ferris Wheel or an Eiffel Tower. To create artworks of enduring magnificence as Michelangelo, Leonardo da Vinci and Rembrandt did. And the way to create that BHAG is to scare yourself. To know that everyone says there are things you’re not supposed to achieve. That these things are impossible. And yet, you do it, because it’s the most inspiring thing to do! Combined with the Hedgehog principle, preserving the core and stimulating progress, you have a system in place that can take your business from good to great. And even as you embark on this journey, you know that you will forever be on the road to making things better, not necessarily bigger, but always better. Better—it’s a great place to be! The action plan and summary coming in the next episode. Click here to listen to part 2:  Good to Great: How To Escalate The Path To Greatness http://www.psychotactics.com/path-to-greatness/

Garagegamer 7A – Black Library Weekender (Nov. 2014) So Greg went to the weekender and comes on to talk about what they chatted about in the Warhammer seminar. Before that I complain about End Times books availability, and we start talking about that for a bit. Come to think of it, this is kind of...

A friend on IRC (Hi Greg) thought it might be neat to have an episode of post-rock / post-metal music. He might get his wish some day because apparently I can't leave well-enough alone without mixing things up with sludge, doom, desert, and black metal. So Greg, I'll get to that post-rock show sometime in the near future. But to make up for it this 90th episode is made up of 9 tracks around 9 minutes long weighing in at 90 minutes (seeing a pattern here?) Featuring music from HELA, Morgue of Saints, Anagnorisis, Allochiria, Show Me A Dinosaur, EVILHORSE, Bong Breaker, DOLMENN, and SONNÖV there's a little something for everyone in this episode. Shownotes after the break: * (00:47) Horizonte De Sucesos by SONNÖV from Hay Una Luz (BY-NC-ND) * (10:35) Grim Reaper by DOLMENN from I (BY-NC-SA) * (19:47) Mountain by Bong Breaker from MOUNTAIN (BY-NC-ND) * (30:11) The Path Must Be Walked by EVILHORSE from Cabeza de Vaca (BY-NC-ND) * (41:58) Bhopal by Show Me A Dinosaur from Dust (BY-NC-ND) * (50:10) Archetypal Attraction To Circular Things by Allochiria from Omonoia (BY-NC-ND) * (59:31) Death Mimics Life by Anagnorisis from Beyond All Light (BY-NC-ND) * (1:08:52) Desert Jam by Morgue of Saints from Monolith (BY-NC-ND) * (1:19:50) Flesh Ceremony by HELA from Broken Cross (BY-NC-ND) Please support the bands in this show! Buy a T-Shirt, head to the shows, buy some physical media from the bands, or name a winter storm after them. Whatever you can do to help these bands keep making music, please do it! Also check out the other great podcasts at Metal Injection, and be sure to listen to all of the great shows (including Open Metalcast) streaming 24/7 at Metalinjection.FM. If you have any suggestions for Creative Commons licensed metal, send me a link at craig@openmetalcast.com.

Greg pulled himself together to join Jenny O for some ear-hole magic! So Greg has been sick, watched the Super Bowl, and loves other couple drama while Jenny takes pound town to "like" town, is the bell of the ball, snorts mustard, and so much more! A very good Would You Rather with a lot of awesomely gross answers, a new caller leaves a message, and Awkward Talk about partners pressuring their significant others into things. Next weeks topic: help for Dylan. Listen to the story of Jenny's friend and help him out! Give us a LIKE on www.facebook.com/AwkwardApocalypse, a follow @AwkwardPod on twitter, send an email to awkwardpod@gmail.com, and call/sex/text (323) 379-9225! And don't forget that you can give us FIVE stars over in the iTunes store!

This is a broadcast of a Panel Session called Meeting the needs of male victims of domestic and family violence, presented at the Australian Institute of Criminology's Meeting the needs of victims of crime conference held in Sydney on 19 May 2011. Part 4 of the Panel Session features Greg Millan, director of Men's Health Services, giving an overview of his training program called Working with men affected by violence. In Australia, up to one in three victims of intimate partner violence are male. While many services have quite rightly been established over the past three decades to support female victims of family violence, the needs of male victims remain largely unmet. The issue of men affected by violence in intimate relationships has been reported for many years. Workers in the domestic violence, community and family relationship sectors are acknowledging this problem and seeking out training for their workers. There is only one training program for professionals and this talk will present an overview of this program and its evaluation. ‘Working with men affected by violence’ is a specifically designed training program for health, welfare and community workers that provides information and strategies for working with men who are affected by violence in their relationships.  Listen now (MP3) | Download PowerPoint |  Watch presentation Elizabeth Celi: Greg Millan is a social work trained health educator with over 30 years of experience with government, non-government and private sector organisations. He is an executive member of the Australasian Men’s Health Forum, which Australia’s peak body implementing a social approach to male health. And as you may be hearing we’re very much on the social psychology and social health avenue with male victims. So for over 20 years he has been working in men’s health promotion implementing different programs and professional training services, particularly for other service providers, health service providers and otherwise. So Greg will share that with us now. Thanks Greg. Greg Millan: Thanks a lot. Thank you very much for inviting me along today. This little slide starting my presentation actually is this rather interesting poster from Canada, which I think clearly talks to me about the fact that this whole issue has been silenced and that campaign was around working with those people that have been silenced, with men that have been silenced when we think about domestic violence. My background in this work, yes, I have been social worker for 30 years. I guess my clinical work in supporting male victims of domestic violence over the years. I've had some past clinical group work with men who have experienced childhood sexual assault, which is a different issue. I run a number of programs for men and have for a number of years. Two of those, ‘understanding relationships’ and ‘dealing with difficult emotions’, which are men only programs, have involved men talking about domestic violence. Just a quick scenario is that I was asked by Relationships Australia in Newcastle to run an ‘Understanding Relationships’ workshop for them, which I did. Very good workshop I ran over a number of nights, five or six nights. I think on the fifth night we actually talked about destructive relationships and I bring up the issue of domestic violence and other issues, drug and alcohol issues or mental health issues that could be destructive, and we had this lovely guy in the group in his 70s. Unfortunately his wife had passed away a couple of years ago and he was obviously still grieving her passing away. He was getting a lot out of being at the group and when I started to talk about domestic violence he said, “Well you know my wife used to hit me with a frying pan once a week, but isn’t that what love is about?” And before I had a chance to say anything the other guys turned to him and said, “No, I don’t think so. No, I think we better talk more about this.” So that was a moment I've always remembered that men pop up with these things out of the blue. It was interesting. I've been a longtime advocate for men who suffer violence and abuse in their relationships and I've worked in the men’s health area for a number of years and there is a huge growing awareness of – in both the health, welfare and in the men’s health sector of the needs of men affected by violence and in their relationships. So much so that since 2005 – we have national men’s health conferences every two years in this country. We started having papers and workshops in 2005. The last conference we had was in 2009 in Newcastle where there were 15 presentations at that conference on this issue and we’ve got our next one coming up in Perth shortly, so we’ve been tracking this for a while. I just wanted to briefly say, and my colleague Greg went through the effects on men, but I just wanted to talk about some myths about men affected by violence. Men affected by violence come from all walks of life, social backgrounds, cultures and sexualities. They suffer society’s stigma for not protecting themselves often. They become depressed in their isolation, as Greg mentioned, feel suicidal and sometimes can take their own lives without disclosure of anything that has been going on for them. They can be victimised because they fail to conform to the ‘macho man’ stereotype and as Greg mentioned, are often perceived as wimps or weak. They’re often disbelieved because they’re men. One of the difficulties I think, and this can be true for women as well, but when men say to their friends or it’s obvious that they’ve been the victim of some sort of violence and it’s within a relationship often their friends don’t know what to do or say. And they have very few support systems in place. I wanted to briefly mention men affected by violence in male to male relationships. I know this is a national conference. This is a poster from the AIDS Council of New South Wales that was released in March. They’ve had an anti-violence project running here for five of six years or more, but they’ve just had a re-release of it. Australian research shows that domestic violence is as prevalent amongst gay and lesbian communities as it is in the wider community. Having said that, I’d just like to also draw your attention to what we’re talking about today is male victims of domestic violence who would be predominately heterosexual because that is the world we live in, so the numbers of gay men affected by this are much, much smaller. The problem is often underreported as the system can be oppressive and hostile towards gay men. Gay men who experience violence report being afraid and revealing their sexual orientation or the nature of their relationship to those that are trying to help them. Something specific to gay males is that outing around sexuality or HIV status can be used as a form of control by the abusive partner. The other point is telling heterosexuals about violence in a gay relationship can reinforce the myth many believe that gay relationships are abnormal and this can further cause the victim to feel isolated and unsupported. I run a training program called ‘Working with Men Affected by Violence’ and I’ve run that here and in Perth and in a few other places. I run the only training program for workers in this country on this issue. I personally actually think that’s terrible that there is only one and I'm the person doing it and I haven’t run too many. But a typical one-day training program would include the following things: • A background to the issues and what we need to do • the effect of violence on a person • what is different for men - so we’re talking about men here, what is different for men from women • strategies for working with men from a strengths based perspective • a model for working with men affected by violence. I actually present a model that people can use to work with these men • men-friendly counselling and group work approaches • building services for male victims of violence into your agency and what you need to consider and • promoting the case for supporting male victims of violence and working with female perpetrators of violence, which is equally as important. Why I started doing this was I had received a number of calls from workers who had no idea what to do when that phone call arrives, and they’re in the business of supporting people, and they get a male victim of DV ringing up and saying ‘how can you help me’ and they almost freeze because they don’t know what to do or say. So we desperately need training of healthcare professionals in this country to be able to adequately answer those phone calls. These are some of the evaluation comments from past training program participants who’ve been through my program: • “The difficulty men have in communicating to others about domestic violence.” This was what was the most positive aspect of the program • “That domestic violence is a social problem rather than a gender problem as it is often perceived.” Now I guess to explain that, it’s my personal belief that we’re living in a far more violent world and that whatever you want to call it, domestic violence or intimate partner violence is a symptom of the fact we’re living in far more violent times and I see violence as a social problem – certainly with a gender determinate – but if I view it that way I think all violence is bad and that we should do something about all violence rather than view the whole issue as a gender problem and not a social problem. • Another comment from a past participant: “I now realise men go through the same issues as women.” • “Not looking at domestic violence from only a feminist perspective,” one of the participants said who came along. • “There is a clear need for services to help men by providing information, support and referral services” • “Networking and knowing others who are on the same page of the training.” What have you learned from this training? • “That the situation is similar for men as it is for women, however it’s hard for men due to socialisation and how society sees men,” and what this person means is, as Greg has elaborated, it’s very hard for men to talk about it to anybody or report it, so it’s very unreported because of all the reasons Greg gave. • “Men have the same responses and feelings afterwards as women.” They certainly do. •  “There is definitely a lack of services for men both in domestic violence and sexual assault areas.” • “Men underreport understandably and this hides the real problem” • And “The different situation for gay men affected by violence in their relationships.” So what do we need to do? We need to raise awareness I think as we pointed out of the issue in the community and the media. I remember distinctly the One in Three Campaign that Greg’s worked so successfully on was launched in November of 2009. It’s a great campaign, a great website, but when it was launched I was one of the people that the media could have interviewed across Australia, so the ABC as they often do if it’s a men’s health issue, I live in Newcastle, rung me up and said, “Greg, come in and let’s talk about this.” The ABC, the interview I had in the morning about this was like, “Greg, tell us about this brand new problem and what has caused it.” Oh good, you know it’s not a brand new problem, that’s good, but the ABC saw it that way. They really – it was a female journalist, I’ll put this into context – had great difficulty in getting her head around this problem. Where does it come from? Why didn’t we know about it? But as colleagues have said today, it has been around for a long time. I was working as hard as I could to talk about it and we were interrupted by a phone call from a guy who rang up to talk about his own abusive relationship and what went on in that in the middle of it and so that interviewed happened. Then we came back to me talking more about it, but that changed the whole nature of the interview. It is kind of interesting, but the interesting point was: the media don’t get their head around this either. The media, like everyone else sees domestic violence as something men do to women. They see it in that context only, so we do need to do a lot of work in the community, but also with the media. We need to provide education and training for, I think, domestic violence workers, community workers, health and welfare workers and I’d also say legal workers in there as well. We need to advocate more for resources and services for males affected by violence. We need to encourage the domestic violence area to rethink, refocus and retrain staff to provide services for male victims of violence and female perpetrators of violence as well. And we need to seek separate funding for support services for men and never, in any way, undermine the existing services for women. Thanks a lot.

*It's WrestleMania season--but does it feel like it? Plus MJF goes after Greg on Twitter and more!* Greg, Miranda, and Patrick bring you the all new Babyface Heel Podcast, where there's Two Sides To Every Storyline! Greg is the heel, Patrick is the babyface, and Miranda is stuck in the middle! This week the trio explores WrestleMania week and more! * Does it feel like WrestleMania? * How much does the build matter? How much do the matches matter? * Why did MJF go after Greg on Twitter? * So Greg hates independent wrestling, eh? * Plus a 3 Minute Warning discussing the absence of Charlotte Flair at WrestleMania 37! *Follow the Babyface Heels on Social Media* * @WrestlngRealist * @TheHashtagMiranda (just not on Twitter!) * @ChairshotGreg * @ChairshotMedia *About the Chairshot Radio Network* ----------------------------------- Created in 2017, the Chairshot Radio Network presents you with the best in wrestling and wrestling crossover podcasts, including POD is WAR, Women's Wrestling Talk, The #Miranda Show, Badlands’ Wrestling Mount Rushmores, The Outsider’s Edge, DWI Podcast, Bandwagon Nerds, the Babyface/Heel Podcast, 3 Man Weave, Five Rounds, Turnbuckle Talk, The Reaction and more! You can find these great shows each week at theChairshot.com and through our distribution partners, including podcasting’s most popular platforms. Support this podcast at — https://redcircle.com/chairshot-radio-network/donations Advertising Inquiries: https://redcircle.com/brands Privacy & Opt-Out: https://redcircle.com/privacy