Podcast appearances and mentions of ben levine

Republished with permission from Nutrition Without Compromise and ORLO NutritionGuest: Ben Levine, Co-Founder of Rasa & Clinical HerbalistIn this enlightening episode, we meet Ben Levine, a clinical herbalist and co-founder of Rasa, a sustainable adaptogenic coffee alternative brand. Ben shares his journey from corporate herbal sourcing to founding Rasa, revealing the darker side of the herb trade, the pitfalls of commoditization, and the powerful role of regenerative and responsible sourcing practices.You'll learn how Rasa supports farmers and wildcrafters through boots-on-the-ground sourcing, why certifications like Fair Trade and Fair for Life aren't always enough, and how adaptogens like ashwagandha and rhodiola can help combat modern stress. We also explore the future of plant-based nutrition, climate-resilient herbs, and how reconnecting with even a single plant can shift consumer behavior.Topics Covered:[00:01:04] Introduction to Ben Levine and his path from Celestial Seasonings to founding Rasa[00:02:57] Disillusionment with the commercial herb industry & the commodification of plants[00:04:41] The impact of popularity on wildcrafted adaptogens like rhodiola and eleuthero[00:06:21] Visiting ashwagandha farms in India and how Rasa builds sourcing relationships on the ground[00:08:17] Certifications like Fair for Life vs. direct trade: Are labels enough?[00:10:14] How certification programs can be co-opted by corporations[00:13:56] The case for paying more for responsibly sourced coffee and tea alternatives[00:14:26] How Rasa formulations address daily stress with adaptogens[00:15:35] Why ritual matters—building healthy habits into your daily routine[00:18:13] How adaptogens work: Partial cortisol agonists and stress modulation[00:20:32] Adaptogens at altitude: Helping the body acclimate to high elevations[00:23:38] The evolutionary intelligence of plants and why they thrive in extreme climates[00:25:12] The growing disconnect in modern diets: Nature deficit and phytochemical diversity[00:28:05] Coffee vs. herbal alternatives: Water use, land use, and regenerative potential[00:30:03] Fermentation teas, compost brews, and the Jeewamrutha system in India[00:31:01] Why rainwater catchment systems are essential in regions affected by climate variability[00:32:26] How regenerative practices spread farmer-to-farmer[00:33:33] The one action you can take today: Build a relationship with a single plant[00:34:56] Why sourcing matters more than ever—and how you can vote with your dollars[00:35:58] Discount code & final thoughts: Try Rasa and support responsible sourcing

Are You Overlooking This Critical Factor in Real Estate Investing?   Plumbing issues can turn into costly surprises for real estate investors. In this episode, I sit down with Ben Levine, President of Levine Brothers Plumbing, to break down what every investor should know about property plumbing. We discuss how to identify potential risks, the impact of outdated systems, and key maintenance strategies that can save you thousands down the line.   Ben shares insights from running a fourth-generation plumbing business, covering everything from galvanized pipes to lead water entries, main drains, and automation sensors. Whether you're buying your first property or managing a portfolio, understanding plumbing fundamentals is essential to protecting your investments.   Tune in to learn how proactive maintenance and the right upgrades can prevent major headaches and unexpected expenses. If you own real estate, this episode is a must-listen.   What you will learn if you listen to the episode:   - Common plumbing problems real estate investors should watch for - How outdated plumbing systems affect property value and repairs - Key plumbing inspections before buying a rental property - Signs of plumbing issues that could cost thousands to fix - Best maintenance tips to avoid major plumbing disasters - How plumbing automation can save money and prevent damage - Why upgrading pipes and drains is crucial for long-term investments   SUPPORT US ON PATREON!    patreon.com/realestateeffect and become a part of our real estate family! You'll get access to exclusive content, monthly virtual meetings [Ask me anything!], special events, and more!   And please subscribe to the show, share it with a friend and send us feedback. Visit www.realestateeffect.ca and follow me on IG @monsaxel   Connect with Axel Monsaingeon:   Linkedin - https://www.linkedin.com/in/axel-monsaingeon-42577b28/ Website - https://www.realestateeffect.ca/ Facebook - https://www.facebook.com/realestateeffect/ Instagram - https://www.instagram.com/veryrealestateeffect/ Youtube - https://www.youtube.com/channel/UCc8EYrmO1aVvVIgwT7AfNFw   Connect with Ben Levine:   Website: https://levinebros.ca/ Instagram: @levinebros   Do you have any questions about your real estate journey?   Whether you're curious about navigating the complexities of development projects, dealing with financial challenges, or anything in between, I'm here to delve into the topics that matter most to you.    I invite you to submit your questions by visiting our website at https://www.realestateeffect.ca/ and clicking on the 'Send Voicemail' widget on the right side.   Your inquiries will help shape our upcoming episodes, ensuring we cover the real estate issues you're most interested in. 

In this episode of Gathering the Kings, Chaz Wolfe and guest Ben Levine discuss the plumbing service business, inspiring future tradesmen, and the importance of growth within a company. They cover topics like legacy, brand identity, networking, coaching, and diversifying in business. Additionally, they delve into emotional intelligence and decision-making, followed by a speed round of key business insights.

Prepare for an invigorating journey into the success story of Ben Levine, the man behind the 7-figure success in the plumbing industry. Ben, the driving force of Levine Bros. Plumbing, has been serving the Greater Montreal region since 2004. As the fourth-generation steward of this family business, Ben has catapulted it into the limelight with 49 strong employees and 22 trucks, continually transforming and uplifting the plumbing industry.In this episode, host Chaz Wolfe probes into the dynamic realm of trade enhancement, the unique challenges and perks of inheriting a 4th generation business, and the essence of leadership through Ben's lens. Also, gain insights into diversifying your business portfolio. Uncover the layers of Ben's expansive knowledge and apply the nuggets of wisdom to accelerate your business growth. So, what are you waiting for? Ignite your entrepreneurial spirit and press play now!#entrepreneur #podcast #businessowner #entrepreneurmindset #plumbingDuring this episode, you will learn about;[01:33] Intro to Ben and his business[02:54] Why Ben continues to push[09:42] How Ben moved into entrepreneurship[14:55] Ben's move into the family business[18:35] How Ben earned the trust to take over the family business[22:10] A good decision Ben made[28:07] A bad decision Ben made[29:49] Ben's approach to decision-making[34:40] One metric Ben would use[35:10] Ben's book recommendation[36:48] Ben's thoughts on masterminding[38:26] If Ben lost it all, what would he do?[40:36] How to connect with Ben[41:23] Info on Gathering The Kings MastermindNotable Quotes“We provide a level of service beyond what the customers even knows to ask for.” - Ben Levine“Customer experience is the new speed.” - Chaz Wolfe (Host)“I realized that I don't want “Elliot's son” running the company, I want “Ben” running the company.” - Ben Levine“Plumbing is more than just a plunger. We need to elevate that.” - Ben Levine“We deserve to be paid like experts.” - Ben Levine“Pay attention to the people. Pay attention to what's currently happening. Identify areas of opportunity. Don't go changing things too quick.” - Chaz Wolfe (Host)“Respond, but don't react. Make sure emotions are completely out of decision-making.” - Ben Levine“Once you're going to mastermind, you're going to like-minded people who elevate each other.” - Ben Levine“I don't care if you are that one client with 60% of my business, our plumbers are above you. That's our goal in the office, is to serve them properly.” - Ben LevineBooks and Resources Recommended:The E-Myth by Michael Gerberhttps://www.amazon.com/Myth-Most-Businesses-Dont-About/dp/0887303625Think and Grow Rich by Napoleon Hillhttps://www.amazon.com/Think-Grow-Rich-Landmark-Bestseller/dp/1585424331The Power of Why: Ted Talk by Simon Sinekhttps://www.ted.com/talks/simon_sinek_how_great_leaders_inspire_action?language=enThe Slight Edge by Jeff Olson

Overview Ben joins us from New Jersey where he goes to college. Ben may be young and isn't known, but he is an experienced author with several books under his belt already with many planned in the future. Ben has also talked with an author, Sue Bentley, that he admires and got her permission to use some of the animals names from her book in his book. Listen to what Ben shares about his books and his advice for writing. Book Favorites Website http://benlevinauthor.com/ YouTube https://youtu.be/OGYibEJBE8Q Transcript Stephen: today on Discovered Wordsmiths, I want to welcome Ben Levine. Ben, good morning. How are you doing Levin? Let me rewind and back that up. I'm messing this all up today. Alright, so today on Discover Wordsmith, let me welcome Ben Levin. Ben, how are you doing today? Good morning. I'm doing all right. Ben: Thank you, Stefan. And you, Stephen: You're doing all right. As long as I keep getting things correct instead of messing things up on what we're talking about. Sorry. That's okay. All right. So Ben tell us a little bit about who you are, where you live, what you like to do, some things you outside of writing. I'm currently going Ben: to college at Fairleigh Dickinson University, and I am, I live in Mottville, New Jersey. In addition to writing, I like to read, relax, sometimes go on walks and do active stuff, even though I don't do it as often as I'd like. Stephen: Gotcha. And being in school that keeps you pretty busy. Anyway. Yeah, I remember. Yeah, it's a fun time. Good time. You like to read, we're gonna talk a little bit about some of your favorite books and stuff later, but what are you studying in college? Creative writing. Okay. It fits right in. How's that going? You enjoying it? Yes. Yeah. We'll assume you're doing well 'cause I don't want you to embarrass yourself if you're not. So we'll just say, Ben, I'm glad you're doing so well in college. That's good. But let, we're gonna talk about that too, also a little bit about what it's like to write while still in school. And you started writing before college, so we'll talk a little bit about that too. Let's talk about your latest books. You've got several books out in a series. Tell us a little bit about that. You mean about Nellie's friends? Nellie's friends? Yes. Ben: What exactly do you want to know Stephen: about it? Sorry. Tell us what the series is about. What it is it's about healthy. Is it mystery? Little bit of it's a. Ben: Okay. It's a kid series, a little girl series about a girl named Nelly who moves to Illinois from New York. And after she leaves all her friends behind her favorite hobby becomes making new ones. Each book is about a new friend she makes and the adventure they have together. Stephen: Okay, nice. So why did you wanna write a series of books about a girl who's trying to make friends? Ben: The idea initially came to me in fourth grade, a time when I was obsessed with things stereotypically meant for girls, like dolls and girl books, and part of me wanted to explore this interest more. Okay. And Nelly's friend seemed like the right way to do it. Stephen: Nice. Okay. You know what are you using any of these books for part of your schoolwork, creative writing, or is this all on the side? All on the side. Okay. So are you picking up some things in college that are helping with the writing? Or are you Yes. Okay. Like what have you learned in school that's helped with your latest writing? I have to think. Okay. Yeah. Sorry. Throwing 'em at you, you're not ready for, got it. Ben: I've never really thought of it that way but I'm almost certain I've learned Stephen: something. Yeah. I hope, yeah. You're spending a lot of time and money there, so I hope they're giving you something right. That's true. How many books do you have in the series right now? Ben: Published or in general

Hello and welcome to the first episode of: We talk, UDance episode of 2024!! Today we are joined with the previous Co-Executive directors of UDance 2023 (Caroline Stevenson and Adam Bungarden), the previous Entertainment Director (Josie St. Claire), the new Co-Executive directors (Jen Moran and Alex Kinsey), and the new Entertainment director (Ben Levine)! --- Send in a voice message: https://podcasters.spotify.com/pod/show/udance-executive-board/message

Mushrooms are suddenly everywhere. Products ranging from functional beverages to mood-changing supplements have popped up in media, online, and in-market. What's the difference between functional mushrooms and adaptogens? Do they really work? On this episode of Tech Bites, host Jennifer Leuzzi talks with Charlotte Cruze, Co-Founder and COO of Alice Mushrooms, a functional mushroom chocolate, and Ben LeVine, Co-Founder and Chief Herbalist of Rasa, an adaptogen coffee alternative, about how mushrooms work and what consuming them can do. Interested in the mushroom trend? Listen to Tech Bites Episode 286 with Meati Foods, the mycelium mushroom root steaks.Heritage Radio Network is a listener supported nonprofit podcast network. Support Tech Bites by becoming a member!Tech Bites is Powered by Simplecast.

Does Altitude Training make you a slower cyclist? You may be missing an essential ingredient in the recipe for successful adaptations to altitude. From the Institute for Exercise and Environmental Medicine (IEEM), Nurse Practitioner, Shannon Grappe, and Dr. Benjamin Levine reveal what might be missing and how we can prepare for altitude, allowing us to reap the rewards of altitude training.    TOPICS COVERED IN THIS EPISODE:    (0:00) Welcome! (1:15) How altitude training is theorized to improve performance  (11:29) The role of iron in red blood cell production (13:47) Iron in endurance athletes (19:56) Optimal levels of iron in elite and amateur athletes  (22:05) Optimal iron levels for men vs. women (28:04) Iron injection through IV (34:35) How to get more iron   • Continue the discussion on the TrainerRoad Forum: https://trainerroad.cc/3HsexjP • Submit a study, researcher or topic to be covered on the Science of Getting Faster Podcast: https://www.TrainerRoad.com/SOGF  ----------------------------------------- ABOUT TRAINERROAD — CYCLING'S MOST EFFECTIVE TRAINING SYSTEM TrainerRoad makes cyclists faster. Athletes get structured indoor workouts, science-backed training plans, and easy-to-use performance analysis tools to reach their goals • Introducing Adaptive Training: https://bit.ly/3qb8KDn  • Build Your Custom Plan: https://bit.ly/3rbc0jM  • Train Together with Group Workouts: https://bit.ly/3r8PRlQ   • Get Started: https://bit.ly/302vUkW  ------------------------------------ SCIENCE OF GETTING FASTER PODCAST The Science of getting Faster Podcast cuts through the noise and talks directly to the scientists doing the latest research into how to become a faster cyclist, stronger athlete, and healthier person. Join Sarah Laverty of TrainerRoad as she interviews a new researcher every month about their latest studies, what questions they were hoping to answer, what they observed and what they are still hoping to learn.  • Subscribe to the Science of Getting Faster Podcast on iTunes: https://www.TrainerRoad.com/SOGF  -------------------------------------- FOLLOW TRAINERROAD   • Facebook: https://www.facebook.com/TrainerRd     • Instagram: https://www.instagram.com/trainerroad/   • Twitter: https://twitter.com/TrainerRoad  • Strava Club: https://www.strava.com/clubs/trainerroad    

I thought it timely to look deeply into the heart of the older athlete.  I think about my heart a lot.  I am constantly monitoring my resting heart rate, my training heart rate, my HRV, how my heart feels when I am going all out, and I think hard about how to make my heart work better today and tomorrow and long into the future.  I thought it was time to talk to the one and only Benjamin Levine, MD, a practicing cardiologist and researcher with an amazing track record in Sports cardiology and cardiovascular physiology and exercise.   Dr. Levine is also the founder and Director of the Institute for Exercise and Environmental Medicine at Texas Health Presbyterian Hospital Dallas, Professor of Internal Medicine/Cardiology and Distinguished Professor of Exercise Sciences at the University of Texas Southwestern Medical Center. Dr Levine is the real deal, and this short conversation is so chock full of useful information you'll want to listen twice.  All right let's talk to dr Benjamin Levine. https://www.texashealth.org/ieem/About-Us/Directors-Letter IEEM: https://www.texashealth.org/ieem BIO: https://www.texashealth.org/ieem/Faculty/Benjamin-Levine Institute for Exercise and Environmental Medicine: https://www.texashealth.org/ieem

Please join Guest Host Maryjane Farr, authors Sarah Franklin and Stavros G. Drakos, as well as Associate Editor Hesham Sadek as they discuss the article "Distinct Transcriptomic and Proteomic Profile Specifies Heart Failure Patients With Potential of Myocardial Recovery on Mechanical Unloading and Circulatory Support." 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 in Duke National University of Singapore. Dr. Peder Myhre: And I'm Dr. Peder Myhre, social media editor from Akershus University Hospital and University of Oslo. Dr. Carolyn Lam: Peder, today's featured paper is very, very important in the heart failure world. It is such a deep dive into the transcriptomic and proteomic profile that specifies heart failure and the potential of myocardial recovery with mechanical unloading and circulatory support. Dr. Peder Myhre: Can't wait for that feature discussion today, Carolyn. Dr. Carolyn Lam: But you have to wait because I insist on telling you about yet another really important paper, of course in my favorite subject, heart failure with preserved ejection fraction or HFpEF. Now you know that exercise intolerance is a defining characteristic of HFpEF and a marked rise in pulmonary capillary wedge pressure during exertion is pethepneumonic for HFpEF and it's thought to be a key cause of the exercise intolerance. Now if that is true, acutely lowering the wedge pressure should improve exercise capacity, right? Well, don't assume this because to test this hypothesis, authors led by corresponding author Dr. Ben Levine from UT Southwestern evaluated peak exercise capacity with and without nitroglycerin, which was used to acutely lower pulmonary capillary wedge pressure during exercise in patients with HFpEF. Dr. Peder Myhre: Oh, that's so cool. What an amazing research question and Carolyn, you're the best to summarize this. Please tell us what did they find? Dr. Carolyn Lam: Well, they studied 30 patients with HFpEF and get this. They underwent two bouts of upright seated cycle exercise dosed with sublingual nitroglycerin or a placebo every 15 minutes in a single blind randomized crossover design. So really well done. Wedge pressure, VO2 and cardiac output were assessed at rest with 20 watts exercise and at peak exercise during both the placebo and nitroglycerin conditions and the principle finding of the study (singing) acutely lowering pulmonary capillary wedge pressure during upright exercise with nitroglycerin in HFpEF did not improve peak exercise performance. So peak VO2 was practically identical with a 1% difference despite a 17% drop in peak wedge pressure. Peak cardiac output and peak peripheral oxygen extraction were unchanged, again, despite the drop in peak wedge pressure suggesting that oxygen delivery and utilization were unaffected. Exercise performance variables including peak wattage, peak ventilation and peak RER were unchanged, suggesting that again, reductions in peak wedge were insufficient to improve exercise tolerance. All these results suggest acute reductions in wedge pressure are insufficient to improve exercise capacity and provide convincing evidence that a high wedge during exercise by itself is an epiphenomenon perhaps rather than a primary limiting factor for exercise performance in patients with HFpEF. Now of course this is incredibly interesting contrary to hypothesis and so please read the paper. The discussion is very rich. Dr. Peder Myhre: Oh wow, Carolyn. That is such a great paper. I can't wait to pick it up and read it from start to finish and now Carolyn, we're going to look into research within cardiovascular disease from COVID-19 and we have learned so much and so quickly about COVID-19 and its effects on the heart and we have really come a long way from the first case reports reported in the beginning of the pandemic and this paper, which comes to us from corresponding author Professor JP Greenwood, really adds important knowledge to this field. The COVID heart study was a prospective longitudinal multi-center observational cohort study of patients hospitalized with COVID-19 and at elevated serum troponin levels across 25 hospitals in the UK and these investigators aim to characterize myocardial injury, its association and sequela in convalescent patients following hospitalization with COVID-19 utilizing appropriately matched contemporary controls. Dr. Carolyn Lam: Ooh, important stuff. So what did they find? Dr. Peder Myhre: So these authors included in total 519 patients comprising 342 patients with COVID-19 and an elevated troponin, 64 patients with COVID-19 and a normal troponin and 113 age and comorbidity matched controls without COVID-19 and the frequency of any heart abnormality defined as left or right ventricular impairment, scar or pericardial disease was two full greater in patients with COVID positive and troponin positive, so 61% compared to the control groups and that is 36% for COVID positive and troponin negative and 31% for COVID negative and comorbidity positive and the myocardial injury pattern was different for these patients with COVID and an elevated troponin more likely than controls to have infarction and micro infarction. But there was no difference in non-ischemic scar and using the late MRI criteria, the prevalence of probable recent myocarditis was almost 7% for those with COVID and elevated troponin compared to only 2% for the controls without COVID-19 and myocardial scar is but not prior COVID-19 infection or troponin was an independent predictor of MACE. So Carolyn, these authors discussed their findings in light of previously reported studies and these authors identified a lower prevalence of probable recent myocarditis than previously described and a higher proportion of myocardial infarction and this newly described pattern of micro infarction following COVID-19 and Carolyn, there is a brilliant editorial really summarizing this by Dr. Stuber and Baggish entitled "Acute Myocardial Injury in the COVID Heart Study Emphasizing Scars While Reassuring Scarce." I really recommend everyone to pick this up and read the editorial as well. Dr. Carolyn Lam: Very clever title. Thank you. For the last original paper in today's issue, it focuses on the crosstalk between sterile metabolism and inflammatory pathways, which have been demonstrated to significantly impact the development of atherosclerosis. Authors today are featuring and focusing on 25 hydroxy cholesterol, which is produced as an oxidation product of cholesterol and belongs to a family of bioactive cholesterol derivatives produced by cells in response to fluctuating cholesterol levels and immune activation. So these authors with co-corresponding authors, Dr. Suárez and Fernández-Hernando from Yale University School of Medicine, they showed beautifully that first, 25 hydroxy cholesterol accumulates in human coronary atherosclerosis. Next, that 25 hydroxy cholesterol produced by macrophages accelerated atherosclerosis progression and promoted plaque instability by promoting the inflammatory response in macrophages and also via paracrine actions on smooth muscle cell migratory responses. Dr. Peder Myhre: Wow, that is so interesting, Carolyn. What are the therapeutic implications of these findings? Dr. Carolyn Lam: Yes, I'm glad you asked because it was summarizing a lot of work in those findings with the very important implications that inhibition of 25 hydroxy cholesterol production might therefore delay atherosclerosis progression and promote plaque stability. So this study actually opens a door to explore the role of 25 hydroxy cholesterol as a target to control inflammation and plaque stability in human atherosclerosis. Dr. Peder Myhre: Oh, that is so important. Thank you so much and there is more in this issue as well, Carolyn. We have another issue of Circulation Global Rounds and this time we're going to France in a paper written by Dr. Danchin and Bouleti. We also have an exchange of letters by Dr. Yang and Dr. Schultze regarding the article, "Deep Lipidomics in Human Plasma: Cardiometabolic Disease Risk and Effect of Dietary Fat Modulation" and an ECG Challenge by Drs. Manickavasagam, Dar and Jacob entitled "Syncope After Transcatheter Aortic Valve Implantation: Pace or Not." Dr. Carolyn Lam: Interesting. There's a Frontiers paper also by Dr. Dimopoulos on “Cardiovascular Complications of Down Syndrome: Scoping Review and Expert Consensus,” a Research Letter by Dr. Kimenai on the impact of patient selection on performance of an early rule out pathway for myocardial infarction from research to the real world. Nice. Well let's carry on to that feature discussion on heart failure, transcriptomics and proteomic, shall we? Dr. Peder Myhre: Can't wait. Dr. Maryjane Farr: Welcome everybody to Circulation on the Run. We are so pleased to be talking with Dr. Stavros Drakos and Dr. Sarah Franklin from the University of Utah. My name is Maryjane Farr and I am the heart failure section chief at UT Southwestern and Digital Strategies editor for circulation. Myself and Hesham Sadek will be talking with them about their new paper and circulation called "Distinct Transcriptomic and Proteomic Profile Specifies Heart Failure Patients with Potential of Myocardial Recovery Upon Mechanical Unloading and Circulatory Support." Just briefly, Dr. Stavros Drakos is the director of cardiovascular research for the division of cardiology at Utah and co-director of the Heart Failure Mechanical Circulatory Support and Heart Transplant Program. Dr. Sarah Franklin is associate professor of medicine at the University of Utah whose lab has a specific expertise in the applications of proteomics to heart disease. Welcome, Stavros and Sarah. Dr. Sarah Franklin: Thank you. Dr. Stavros Drakos: Thank you. Thank you for having us. Dr. Maryjane Farr: This paper is exciting for clinicians. It's exciting for translational scientists. Hesham, why don't you start digging into this paper and tell us one or then the other of you tell us what this paper is about, what's the background and let's get into the science. Let's go there and then we'll pull back and look at some of the big picture stuff. Hesham. Hesham Sadek: Well, thank you. So I've been fascinated by the field of cardiac recovery for some time now and obviously Stavros is as an expert and one of the leaders of that field and what struck me about this is that we are starting to see some distinct molecular signature of patients that can experience recovery as opposed to patients undergoing the same procedures with the same profile that do not manifest evidence of myocardial recovery and specifically, the study was conducted very rigorously and the signature was very clear in that they saw primarily interest for someone like me who's interested in cardiac regeneration, a signature of cell cycle in the patients that experience recovery as well as ECM signature which could suggest reverse remodeling and also there's some evidence that ECM might impact cardiomyocyte and myocardial regeneration. So my interest in this for selfish reasons is primarily that this supports the hypothesis that perhaps there is a molecular signature of regeneration that occurs in patients that experience myocardial recovery with LVAD. Dr. Maryjane Farr: So Stavros, let's start with you. Give us the reason why to do this study. You mentioned some of the background. It'd be great to sort of talk for a moment about re-stage heart failure and then how it brought you to this study. Dr. Stavros Drakos: Thank you, Jane. So again, thank you for the opportunity to talk about the findings and the implications of this study. I like the way you are asking us to look a little bit at what led to this study and as you mentioned, the re-stage is a multi-center study that was performed in six US sites which showed in a reproducible fashion now given that we had single center studies from all over the world suggesting that, advanced heart failure is not an irreversible process that has to lead to end stage, an irreversible disease and what a re-stage demonstrated was that there is a subset of patients which if you select them based on clinical characteristics that we derived from other studies that were performed previously, you can achieve reverse remodeling, essentially a bad heart looking much better by every clinical, functional, structural characteristic in up to 50% of the selected patients. That's what re-stage showed. So having this finding now in a multicenter study, what made this study very timely was to be able to understand what drives this remarkable response. What are some of the mechanisms, as Hesham said, that we can if uncover take advantage of and expand this paradigm and enhance it and achieve reverse remodeling and recovery of even more patients and even go earlier in the disease process. So that's kind of how I would link the clinical findings that preceded this study with the motivation to perform the study and the implications of these findings for the ongoing translational and basic science research. Hesham Sadek: I'd like to ask a question here. So Stavros, do you think it's too early to sort of redefine the term reverse remodeling in this context to include perhaps some evidence of regeneration? Is there evidence of regeneration in this field or that's too premature to say? Dr. Stavros Drakos: I think the data are directing us towards the direction you just mentioned. I think that we can begin talking about it and planting the seed. We do have other evidence from work that you and others have performed indicating that this indeed is one of the mechanisms that drives this phenomenon and I think that the findings, especially in the cell cycle that we identified add to and contribute even more to that body of work that you and others have done. At this point, I will turn it to Sarah who can talk a little bit more about the findings related to the cell cycle that we identified in our study and I think that these may complete the answer to you, Hesham. Dr. Sarah Franklin: Yeah, I would love to comment. I think it's a really interesting phenomenon and really in these patient samples we were trying to understand molecularly what the difference is between individuals that respond positively to therapy and individuals that receive the same exact therapy and do not respond positively. So these are termed responders and non-responders and in our analysis we combined two platforms where we could molecularly interrogate what's different in these two tissues and try to see what is differentiating these populations. So what's consistent and reproducible different in responders and non-responders on a molecular level and in both the transcriptomic data and the phospho proteomic data, we saw clear patterns with cell cycle regulation and extracellular matrix or focal adhesion molecules and the interesting thing about cell cycle is cardiomyocytes have typically been thought to exit the cell cycle not long after birth and we see some interesting phenomenon either in humans or mice where we can have nuclei that have either multiple sets of chromosomes or multiple nuclei and there's some differences that have been observed in the nucleus with regards to disease, so hypertrophy, heart failure. So the molecules that we've identified, we saw a large difference in proteins involved in cell cycle regulation. Now the interesting thing is not all of those molecules are increasing or decreasing. We see a combination of molecules that are increasing or decreasing. But I think the other thing that's interesting is that these molecules, even though we are seeing changes in expression or changes in phosphorylation, exactly how that contributes to either cell cycle or cell cycle reentry or just nuclear function and transcription of proteins or genes or DNA regions is still what we need to continue to study. So exactly how these changes in proteins or transcripts related to the cell cycle, how they are exactly contributing to the physiological improvements that we're seeing is something that still needs to be investigated but is really important that that is a highlight of this study and as Stavros mentioned of previous work. Dr. Maryjane Farr: Stavros, tell us the design of the study. Dr. Stavros Drakos: Okay. So this study was performed in 93 patients that were prospectively enrolled in the Utah transplant affiliated hospitals here in Salt Lake City between the University of Utah, Intermountain Medical Center and the VA and these people came from all over the mountain west, the surrounding states of Utah and through our VA, through the state, from all over the west and south, from Alaska and Hawaii to Texas and we think it's a very representative population of our country's patient population and then we followed prospectively these people with serial echocardiograms so we can tell who will respond as Sarah said before, which essentially means which hearts are going to get better by echocardiographic criteria functionally and structurally, the dimensions of the heart shrinking and the ejection fraction improving to more than 40% and the dimension shrinking to normal range and then we compare these people, the subset of patients that have responded to the majority of patients actually that they have not responded. As we know these are advanced end stage patients and there is only a subset of those that they will favor respondents. As we said earlier, these subset can increase if you go selectively and pick these patients based on baseline characteristics. So then we analyze the tissue we got from these people when the LVAD went in, which is the core of the apex of the heart and compare that to the tissue we receive when the patients got transplanted and we got the whole heart. So in the meantime, as we just discussed, we phenotyped these people so we knew who were responders and non-responders and then we went back in the lab and tried to marry two basic processes, analyzing the transcriptome and the proteome and by doing that we were able to see some overlapping changes between the transcriptome and the proteome and we felt that by doing this overlapping analysis, we will increase the likelihood that what we are seeing, exponential mechanistic drivers will be the real mechanism and not just associations that you can frequently find when you do studies in humans and that's kind of a rough, brief summary of the design. Sarah, would you add something to that? Dr. Sarah Franklin: No, I think that's a great overview of it. I think what excites me about it is that this was first clinically observed that these patients were recovering and so I think the exciting part is the hypothesis was that there was some molecular underpinnings that could molecularly define these patients that were responding or not responding and so with that hypothesis we then carried out these analyses hoping that we would see a difference and we're very excited. It's very successful in that we found very clear, molecular differences that are reproducible between these patient populations. Dr. Maryjane Farr: So obviously there's lots of implications. Let me start with one very simple clinical one and that is, so based on some of the differences in the signatures and pathways that you saw for the next patient who needs LVAD therapy and you're trying to predict in some way whether they may be a responder or a non-responder, could you look at a biopsy sample and try to make some sort of prediction based on some of your findings so that they can choose a VAD over a transplant? That's a very clinical question and then I guess the second question is would it have to be a left ventricular myocardial sample? So are the differences? What do you think about that question? Or it's just too much too, far beyond? This is obviously a mechanistic study. But I'm just asking. Dr. Stavros Drakos: No, that's a great question and I'll start and Sarah can add later. So obviously it will be great if we can have a practical way to predict before the intervention who are the people that they will respond and that's one of the motivations for this study. It was not just to find the mechanism so we can make this phenomenon better and enhance it and find the mechanism, create new therapies. It was also the practical approach that you suggested, Jane, and I think that yes, this adds to the clinical predictors that we have already identified from other studies and yes, we could theoretically take the tissue and do this analysis. Is this the most practical thing we can say to the patient to biopsy the heart, right? It would've been better to be able to identify a biomarker in the plaque and we've done that. We started in other studies, identifying what's going on in the tissue and then going targeted in the blood and that's how we identified two cytokines and a two cytokines model, interferon gamma and TNF alpha being predictive as circulating biome. In this study we identify changes that can also inform future studies of biomarkers in the blood. But if we had a way to easily get the tissue and analyze the genes, yes, we could have done that as a predictor as well. The practical issue is that asking a patient for a biopsy just to predict the response to therapy may be something that most patients and most clinicians will consider way too advanced and complicated, right?that's why more work should and could be done to identify circulating biomarkers or other modalities that can help us interrogate what's going on in the heart related with these findings. But not that we cannot also do what you said. It's just more complicated. I don't know if Sarah would like to add to this. Dr. Sarah Franklin: I'd love to. I think that's a great overview. I think the only thing that I would add is that there are a number of conditions whether in the heart or otherwise in the body that you can use a single biomarker and it can be very predictive of conditions. Heart failure is so complex that often individual biomarkers are not sufficient enough to cover an entire population and all the nuances that can go into heart failure symptoms or syndromes and I think the exciting part about this study is it is one of the largest cohorts of patients that have been examined in this manner, which is exciting, but also that we have a multi-factor panel that is made up of multiple biomarkers that with the number of individuals that we examined is completely predictive of all of these patients. So these biomarkers are consistent and reproducible across all of these patients between responders and non-responders regardless of some of the nuances in the heart failure that they have and so it's very exciting because it's possible that a multifactorial panel could be much more applicable and last the test of time more so than an individual biomarker. I think the one other thing that is exciting like Stavros mentioned is that we did initially identify these in the left ventricle and it will be really exciting to see how far these biomarkers can be used if they can be used in potentially other aspects of the heart or blood, which obviously is less invasive and so that's not something that we've applied this panel to yet, but I think is a really wonderful extension of now saying, can we also identify some of these biomarkers in the blood which would be less invasive even if it's a fraction of them. That would still be wonderful. Dr. Maryjane Farr: I have so many clinical questions. But Hesham, what questions do you have? Hesham Sadek: Yeah, so the elephant in the room here obviously is that the variable is that these patients have an unloaded heart and there is evidence that unloading can reverse some of the changes that occur after birth with increasing ventricular load and initiate cascade of molecular events that may allow myocytes to proliferate. So this begs the question, is there a difference in how these ventricles of patients that recover versus those that do not recover see load? Are we able to measure load appropriately and is there a difference in load between these patients and if so, can this be improved or detection or measuring unloading or the degree of unloading clinically, can this be improved? Dr. Stavros Drakos: No, that's a great question and it provides the opportunity to talk about some of the things we can do on the clinical arena to further enhance this phenomenon. Yes, there are ways that we can use to tailor the mechanical unloading that we can provide in order to enhance this phenomenon. One way, and that's a study that we are proposing, is to use sensors, pressure sensors that can guide the way you function the machines, the devices, right? The way you remove part of the load and these sensors, some of them are clinically approved like cardioments and then without doing invasive procedures you can follow chronically how these patients are being unloaded and how the heart is responding to this unloading. We know that a lot of LVAD patients, despite doing clinically well, we know this from snapshot evaluations in right-heart cath studies, they are not optimally unloaded. They are feeling pressures left and right are not always optimized and so by doing this kind of prospective assessment of the mechanical unloading, you can tailor what you offer and the hypothesis generated is that by doing that you may be able to recover even more people. You can do this as we said, with approved sensors like cardioments or with other sensors that they are under investigation. You can also do more invasive stuff like PV loops. Of course these will require cathing these patients, which is a little bit more complicated. But it will provide more accurate assessment and it will also interrogate how the heart is improving and provide to you in-depth investigation and in-depth insights on also how the recovery process and the reverse remodeling process is being, I would say, digested by the heart and translated to functional response instead of just looking at it with an echocardiogram or the findings of a right-heart cath and these are studies that others have performed and have published and we know that they can give you a real good look into the systolic and diastolic function of the heart and how this is changing and improving down the road. So yes, that's the short answer. We can do that and we can tailor the unloading and potentially that's the hypothesis, maximize the effect that we saw here. Hesham Sadek: So this begs the question, maybe two questions here. One, is there evidence that patients who recover not from this study only but from other studies, is there evidence that patients who recover are more unloaded than patients that do not recover and the second question is: is it time to standardize assessment of mechanical load in patients with LVAD, especially those that will undergo or would be considered for recovery? Dr. Stavros Drakos: Yes. So that's a great opportunity to share with our audience what we know and what we don't know in this field in relation to your question about whether we know what is the optimum degree of unloading and the answer I think is that we need to know and understand more. What do I mean by that? There's this idea that the heart as every other organ after being unloaded and not working for some time may it lazy, may get atrophic and may need some rehab like the skeletal muscle when we put it in the cast and get atrophic and we need to rehab it when we remove the cast. So you can imagine that the LVAD and the unloading that provides, which in many cases may take over a significant part of the function of the heart may need gradual reloading as a second phase after the first phase of unloading and that's something that we've done. We have an ongoing study on this and also others have published that it may be beneficial. Of course, it needs to be validated and investigated further and to discuss about the degree of unloading in the first phase and what is the optimum degree of unloading, I would say even there, there is room for us to understand better what's going on and I think that we can investigate with ongoing studies right now whether full unloading versus partial unloading and measure the pressures using these sensors can translate to better changes functionally and structurally. I think that's something that is very doable and it would be very beneficial. What was the second part of your question, Hesham? Hesham Sadek: I was asking whether it's time to start standardizing some measure of unloading if these patients are planned for recovery? Dr. Stavros Drakos: Yes, and that's what we are doing. In all of these people, we report from the get-go what is their recovery score based on the intermixed ICARS derived score and when we have patients that they have high likelihood of recovery, we monitor them very closely and clinically what we do is just looking at the echo and whenever we do a right heart cath for clinical reasons. But in a prospective research study we could do more than just looking at the echo and occasional right heart cath and using the sensors we just discussed previously, you can tailor the unloading and begin prospectively unloading them in a more I would say well monitored wave. Yes. Hesham Sadek: So this is unloading or device specific parameters. Now are there patient specific parameters with regards to type of heart failure? So we talked initially about whether there's an element of regeneration specifically when it comes to cell cycle. But many patients with non-ischemic cardiomyopathy for example, don't have large scars and don't have lot of myocytes as the underlying cause of cardiomyopathy. Would you foresee that there is different mechanisms, for example, in these patients that don't have myocyte loss, that perhaps maybe it's not cardio myocyte proliferation and not regeneration? Dr. Stavros Drakos: Yes. So I think that the differential responses we get based on the heart failure theology warrant further investigation. Sarah and I have discussed that and actually we are following on our findings with larger number of patients so we can tease out these and I'll let Sarah talk a little bit more about it in a minute. But to answer the clinical part of this question, we don't know yet whether different parts of heart failure should be prescribed different modes of unloading. But the way you described it of course invites the hypothesis that of course different substrates, different injuries of the heart, as you said, it's a completely different failing heart if you have a big scar there versus a patient who has a mode of heart failure, another type of injury and would this be treated better and more effectively in terms of reverse remodeling by applying a different mode of unloading? That's things that we need to investigate further. But Sarah, would you like to comment on the potential on the effect of the different heart failure theologies on some of the findings we saw? Dr. Sarah Franklin: Yeah, definitely. So I think it's a really interesting question and in this analysis we included ischemic and non-ischemic samples in the patient populations and really we're just stratifying them based on responders and non-responders. When we start layering additional levels onto that, then we're effectively kind of reducing the potential numbers. So if we have 25 responders and we start breaking that down into ischemic and non-ischemic to see if there's another layer of biomarkers there, we actually did that we did not include it in this study. It's something that we're working on to add that. But we do reduce the number overall of patients in those two populations. So it would be fine to share that we were seeing stratification between ischemic and non-ischemic. But we did not feel like the numbers might be high enough within the responder and non-responder categories that warrant including that in this manuscript. So it's very intriguing that just responders and non-responders alone stratify as well as they do. They separate based on these biomarkers and it looks like it will also be possible in the future for us to even separate these samples further based on similar or additional biomarkers based on more specific factors in the etiology. So I think that will be another really exciting next step for future research. Hesham Sadek: My final question would be maybe a little bit broader than LVAD population, but definitely informed by this study. The term non-ischemic cardiomyopathy, do you think it's too broad and too vague for us to use in this setting because this encompasses many different types of cardiomyopathy that really are not nuanced enough by this definition. Dr. Stavros Drakos: Well, Jane was smiling while you were asking this question because we all as heart failure clinicians need to accept that it was not a good idea to name all of these different diseases non-ischemic cardiomyopathy when we did it or when this happened many moons ago. As you said, Hesham, and I couldn't agree more, these are completely different diseases. We need to understand them better and I think that the way we treat nowadays, chronic heart failure, many years down the road when people will look back, they will consider it a little bit, I would say, surprising that we were treating all of these the same way. We need more studies like the one we just did, that they will have enough numbers and that's when the issue becomes that you need enough numbers to be able to tell the differences between all of these non-ischemic cardiomyopathy types, theologies and if you go upstream, motivated and inspired by findings like this, we hope that we will be able to identify how to go and do a root cause analysis and treat these diseases, not down, down, downstream the same way, but going upstream, finding what really went wrong and treating them earlier in the molecular or other pathophysiological mechanism pathway that led to the heart failure and so yes, it was a bad idea to do that. But of course sometimes we do things because we don't understand it better, right? As one of our keynote speakers here in the recovery symposium said a few years ago, Jay Khan, the founder of Heart Failure Strata of America, some things look complicated until you understand them. Then when you understand them, they look simple. So here we don't really understand non-ischemic cardiomyopathy and how all these theologies lead there and I think studies like these can help us really inform the field better. But we will need, as Sarah said, more numbers. Dr. Maryjane Farr: So that was a great conversation. I wanted to just raise one last thing and that is what's so interesting about this cohort relative to re-stage heart failure is these were older patients and for re-stage heart failure, I think the average age was 35. So you would imagine there might have been one etiology for cardiomyopathy, uncontrolled hypertension or peripartum. But for cohorts in their fifties, there's probably an accumulation of different insults over many years time and so I thought that was particularly interesting from the point of view of that you were probably dealing with, again, a mixed bag of pressure overload, volume overload, maybe a genetic underpinning, whatever the life trajectory of some of these patients were and then lastly, the decision to try to go to recovery rather than to transplant, which would be the real world experience of why this wet pathway than the other. These are people truly in their fifties where they may have one or two surgeries in their lifetime left and so it's the relevant population that you're studying and so I'll leave it at that. That's a comment rather than a question, I think. But I think for heart failure clinicians, this is why the bench to bedside piece is so relevant to understanding this because it actually does change clinical practice, even if the mechanistic pathways may take still many more years to truly understand. It helps understand what's possible from an accrued clinical decision-making level. Dr. Sarah Franklin: Jane, if I might just comment on that, I actually think that's one of the most exciting parts about this dataset is that, as you mentioned, these patients have complex diseases. They are older. But yet we are still able to see consistent and reproducible differences between the patient populations that respond and don't respond and to me that suggests that at the end of the day there are consistent differences or reproducible or consistent molecular changes in cardiac tissue and in response to stress and I think that that gives us hope that we could potentially not only predict who would respond or not respond, but that as we get better at understanding the differences, that there could be potential therapeutic targets or therapies that would still be beneficial regardless of the complexity of the heart failure. Dr. Maryjane Farr: Okay. So Sarah, Stavros, thank you so much for spending time with Hesham and myself and look forward to EUCORS--I'm allowed to say that. Dr. Stavros Drakos: Of course. Dr. Maryjane Farr: Thanks so much. Bye. Dr. Greg Hundley: This program is copyright of the American Heart Association 2023. 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, please visit ahajournals.org.

In this episode of Oh My Heath ... There's HOPE! Jana talks with Ben LeVine   Sitting quietly atop a Colorado mountain peak, Ben LeVine felt a voice from his favorite herb that would define his future: “You were meant to become an herbalist. Just let the plants guide you.” That path has led him to the farthest corners of the Earth and back, driven to unravel the mysteries of the world's most powerful plants. Now as Co-Founder and Chief Herbalist of Rasa, he's using those potent herbal secrets to revolutionize your morning energy ritual with the power of adaptogens. “The difference in energy between adaptogens and coffee has everything to do with stress and our vital energy.”   This 30-minute episode is on: * Learning to deal with chronic stress? * Exactly what are adaptogens and how do they support the body? * What is the definition of an Adaptogen? * How is Rasa different compared to other alternatives * What are we going to find in Rasa that will support our wellness Journey This episode is about: In this episode, Jana and Ben discuss, learning to deal with chronic stress, and exactly what are adaptogens and how do they support the body? What is the definition of an Adaptogen? and how does Rasa compare to other alternatives.   Get in touch with Ben: https://wearerasa.com/  https://www.instagram.com/wearerasa/  https://www.facebook.com/wearerasa/  https://www.linkedin.com/in/ben-levine-b1313810/    Use Discount Code BESTHOLISTICLIFE to receive 15% off your order.   Get in touch with Jana and listen to more Podcasts: https://www.janashort.com/  Show Music ‘Hold On' by Amy Gerhartz https://www.amygerhartz.com/music.    Get Your Free Copy of Best Holistic Life Magazine! One of the fastest-growing independent magazines centered around holistic living. https://www.bestholisticlife.com/    Grab your gift today: https://www.janashort.com/becoming-the-next-influencers-download-offer/    Connect with Jana Short: https://www.janashort.com/contact/ 

When it comes to sustainability, so many industries still have a long way to go. Clinical Herbalist Ben LeVine has always felt a profound connection with nature. So much so that he set out to disrupt the system through his company, Rasa, where he stewards the development of an ethically sourced herbal coffee alternative that's helped over 100,000 people connect with mother nature, live their values, and discover plant-powered energy. In this episode, he joins Corinna Bellizzi to let us in on the wonderful work they are doing, especially when it comes to responsible sourcing. Ben shares the problems currently faced by the herbal world and how they are trying to achieve sustainability while keeping people healthy through adaptogenic coffee alternatives with herbs. Don't miss out on more great insights as Ben ultimately shows you that businesses can also become more pro planet. Key takeaways from this episode:· The problems faced by the herbal world· Achieving sustainability while supporting local economies· The idea behind making an adaptogenic coffee alternative· Benefits of adaptogens to our health· How to make businesses more pro planet Guest Social Links:· LinkedIn: https://www.linkedin.com/in/ben-levine-b1313810/· Rasa Website: https://wearerasa.com· Rasa Instagram: https://www.instagram.com/wearerasa/· Rasa Facebook: https://www.facebook.com/wearerasa/· Rasa Pinterest: https://www.pinterest.com/wearerasa/_shop/

Todays guest is the co-founder and chief herbalist of RASA FOODS: Ben LeVine Ben's story takes us into the topic plants, herbs and allyship with plants just as much as how to grow a strong business with regenerative impact and footprint in the real world. About Ben: Sitting quietly atop a Colorado mountain peak, Ben LeVine felt a voice from his favorite herb that would define his future: “You were meant to become an herbalist. Just let the plants guide you.” That path has led him to the farthest corners of the Earth and back, driven to unravel the mysteries of the world's most powerful plants. Now as Co-Founder and Chief Herbalist of Rasa, he's using those potent herbal secrets to revolutionize your morning energy ritual with the power of adaptogens. From his earliest memories of exploring his family's orchard with wonder, Ben has felt a profound connection with plants and nature. As a young man he followed this passion across the globe, working on farms from India to Alaska and learning traditional plant ceremonies from Ethiopia to Ecuador. Driven by a scientific mind that hungered for data as much as it reveled in tradition, he earned his MSc in Clinical Herbalism with a focus on adaptogens, and accepted a position at herbal tea juggernaut Celestial Seasonings. As Senior Buyer of Botanicals, Ben was charged with sourcing and purchasing over 10 million pounds of herbs each year. Unfortunately, the more he learned about the inner workings of the commercial herb industry, the more jaded he became. He watched as the world's precious botanical resources were ravaged by uncontrolled harvesting and over-exploitation. Even worse — he was part of the problem. So once again, Ben followed the call of the plants. Leaving his corporate job behind, he joined the nascent Rasa team as Employee #2 to steward the development of its ethically sourced, adaptogen-infused herbal coffee alternative as their Co-Founder and Chief Herbalist, and formulator of all their blends. Built on a foundation of plant stewardship and radical sustainability, they've helped over 100,000 people and counting reconnect with mother nature, live their values, and discover boundless, plant-powered energy. --- Support this podcast: https://anchor.fm/julian-guderley/support

In this episode we speak with herbalist, entrepreneur and teacher Ben LeVine about the science behind why and how adaptogens work, the common chemistry behind many of these herbs, about going from dumpster diving, to working at Celestial Seasonings, to co-founding Rasa, an herbal company that provides coffee alternatives that are "obsessively sustainable" - and we get into what that means, and how to actually scale up herbalism in a way that helps heal the earth. If you're interested in attending sliding-scale priced classes on herbalism with AC this month (May 2022) visit her website, www.travelingherbfarmer.com/education to learn more and register. --- Send in a voice message: https://anchor.fm/plantcunning/message Support this podcast: https://anchor.fm/plantcunning/support

Ben has always felt a profound connection with nature, a passion that lead him to earn his MSc in Clinical Herbalism and accept a position as Senior Buyer of Botanicals for tea juggernaut Celestial Seasonings. But as he watched as the world's most precious botanical resources were ravaged by uncontrolled harvesting, he had a terrible realization — he was part of the problem.  So, he set out to disrupt the system. Today, Ben serves as the Co-Founder, Chief Herbalist, and formulator of all their blends at Rasa. They are stewarding the development of an ethically sourced coffee alternative that's helped over 100,000 people reconnect with mother nature, live their values, and discover plant-powered energy. https://wearerasa.com/ use coupon code GREENLIFE15 for 15% off  Follow on social media @wearerasa If you are in need of some help reaching your goals with lifestyle change, we are here!! Head to lovethegreenlife.org/plantpower --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app Support this podcast: https://anchor.fm/lovethegreenlifeorg/support

In this episode we are very grateful to welcome Ben LeVine! Ben is the Co-Founder and Chief Herbalist of RASA, a company focused on ethically sourced, adaptogen-infused herbal coffee alternative. Please join us as we explore the deep connection between the science and spirituality of plant medicine! Ben's lifelong profound connection with plants harkens back […]

Get full show notes and more information at: http://herbswithrosaleepodcast.com/ (herbswithrosaleepodcast.com) For more behind-the-scenes of this podcast, follow https://www.instagram.com/rosaleedelaforet/ (@rosaleedelaforet) on Instagram! The secret to using herbs successfully begins with knowing who YOU are. Get started by taking my free Herbal Jumpstart course when you https://www.herbalremediesadvice.org/ (sign up for my newsletter). If you enjoy the Herbs with Rosalee podcast, we could use your support! Please consider leaving a 5-star rating and review and sharing the show with someone who needs to hear it! On the podcast, we explore the many ways plants heal, as food, as medicine, and through nature connection. Each week, I focus on a single seasonal plant and share trusted herbal knowledge so that you can get the best results when using herbs for your health. Learn more about Herbs with Rosalee at http://herbswithrosalee.com/ (herbswithrosalee.com). ---- Rosalee is an herbalist and author of the bestselling book https://www.amazon.com/gp/product/140195006X/ref=as_li_qf_sp_asin_il_tl?ie=UTF8&tag=metvalher-20&camp=1789&creative=9325&linkCode=as2&creativeASIN=140195006X&linkId=015132911186b966727b15dabec8da5d (Alchemy of Herbs: Transform Everyday Ingredients Into Foods & Remedies That Heal) and co-author of the bestselling book https://amzn.to/3a2G3R4 (Wild Remedies: How to Forage Healing Foods and Craft Your Own Herbal Medicine). She's a registered herbalist with the American Herbalist Guild and teaches many popular online courses. Read about how Rosalee went from having a terminal illness to being a bestselling author in https://www.herbalremediesadvice.org/rosalee-de-la-foret.html (her full story here). 

When we think about nature, or we talk about spirituality, it's easy to see it as something ‘other'. Something disconnected from the modern world that we have to live in, day to day. We save it for the weekend or for our morning meditation sessions, and we view the wisdom of the ancients as something quaint – but certainly not something that we should bring into the office. But this cultural disconnect could actually being doing us more harm than good. By turning our backs on nature, and creating lives that are more processed than ever in terms of what we consume – both into our bodies and our minds – we are making ourselves ill, or at the very least, living lives that are lacklustre and dull. What if, instead, we were to find a way of connecting with the spiritual wisdom of nature, of ancient cultures, and bring into our daily lives – in a way that didn't seemed perfectly, well, natural. This week I'm speaking with Ben LeVine, he is a herbalist and co-founder of Rasa. It is a coffee alternative made with adaptogenic plants, mushrooms and herbs. Designed to nourish our nervous systems, enhance and balance our energy, and calm our stress, it is based on a relationship with nature that is not exploitative as in most western industries, but instead reciprocal. It's about flavour and feeling – spiritually, emotionally and physically – as a form of communication between ourselves and our bodies, and the natural world around us. I chatted with Ben about the science behind our relationship with plants, and how we can enter into dialogues with them that are beneficial to everyone – you, me, and the planet we live on. To find out more about Rasa, and what they're all about you can find them at wearerasa.com, and listeners to the podcast can get a discount of 15% on their first order – just enter the voucher codes LIVING15

Today we have Ben LeVine who is the co-founder and chief herbalist at Rasa which makes adaptogen-rich elixirs, powders, and drinks. We talk about the benefits of adaptogens, what are adaptogens and what are not, and using adaptogens as alternatives for coffee. Rasa is here to transform the way we energize with delicious, adaptogen-packed herbal coffee alternatives. We talk about:  02:30 - My sleep has not been great recently and the sleep supplements I have been taking 14:00 - Who is Ben LeVine 16:10 - The first herb Ben used in a medicinal way 19:00 - The booming use of adaptogens and what they are  22:00 - Choosing the right adaptogen 27:30 - Plants that are not adaptogens and characteristics of adaptogens 31:00 - Adaptogens and stress 32:30 - How to start with adaptogens for beginners 34:00 - Adaptogens and probiotics 35:30 - Coffee and its side effects 41:00 - Coffee and sleep 45:30 - Is decaf coffee healthy? Let's Connect: Instagram Facebook Subscribe to my newsletter Shop my favorite health products Listen on Spotify, Apple Podcasts, Google Play Sponsors:  Use my discount code BIOHACKINGBRITTANY at Sensate for $25 off today. Shop beautiful pieces of Shungite at https://www.theshungiteshop.com

In today's episode we'll hear from herbalist Ben Levine, co-founder and chief herbalist at the adaptogenic, coffee alternative beverage company Rasa.  Listen in as Ben shares his story on how the plants called him to be an herbalist, and the evolution of how he's made his living as an herbalist.  I found his talk inspiring and informative, and especially useful for budding herbalists looking how to make it. Even if you're a seasoned herbalist you're bound to relate to Ben and have some takeaways!  Ben and Rasa are offering HerbRally podcast listeners 15% off their purchase. Just use coupon code "HERBRALLY" at checkout.  For more info about Rasa visit WeAreRasa.com.  Thanks for sharing your story with us Ben! And thanks to y'all for listening.  Also, be sure to check out HerbRally Schoolhouse for a chance to win a gift basket valued at $210 and get your first 30 days for FREE by using coupon code "FREESCHOOL".  You've got until the end of February 2022!  Learn more at HerbRally.com/schoolhouse

Aspiring podcaster Ben Levine takes The Boston Podcast Challenge.

This week's episode features author Benjamin Levine and Guest Editor Walter Paulus as they discuss the article "One-Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients with Stage-B HFpEF." Dr. Greg Hundley: Well, welcome listeners. This is the September 21st podcast for Circulation on the Run. Sadly, I'm without Carolyn today, but I am your host today, Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Greg Hundley: Our feature discussion today is really interesting. It's from Dr. Ben Levine, and he's evaluating the utility of exercise training and actually trying to reverse abnormal left ventricular myocardial stiffness in individuals that have stage B, it's a very early heart failure and preserved ejection fraction. But before we get to that, let's grab a cup of coffee and we're going to work through some of the other articles in this issue. Dr. Greg Hundley: So the first one comes to us from Göran Bergström from University of Gothenburg in Sweden. He and his team used coronary computed tomography angiography or CCTA to determine the prevalence, severity and characteristics of coronary atherosclerosis and its association to coronary artery calcification scores in a general population of greater than 25,000 individuals all aged 50 to 64 years and without known coronary heart disease. It really comes to us from the Swedish CArdioPulmonary BioImage Study or SCAPIS. Well, Carolyn would ask me that is a really large study, and what did they find? Well, let's get to the results. Dr. Greg Hundley: So using CCTA to detect silent coronary atherosclerosis, the investigators showed that any coronary atherosclerosis was actually quite common, 42% of individuals and significant stenosis of greater than 50% was less common, only 5% of individuals. More severe forms were rarely found, only 1.9% in this very large, random sample of middle-aged individuals. Dr. Greg Hundley: Now disease onset was delayed by 10 years in women and a higher prevalence of coronary atherosclerosis was observed with higher age and accumulation of risk factors. Interestingly, CCTA detected atherosclerosis increased with an increasing coronary artery calcium score. All those with a high CAC score of greater than 400 had atherosclerosis and 45% had significant stenosis. 5.5% of those with no coronary artery calcification had atherosclerosis and 0.4% had significant stenosis. So although there was a strong association with high coronary artery calcium scores and significant stenosis, atherosclerosis was not excluded in those with zero coronary artery calcification especially in those with high baseline risk. Dr. Greg Hundley: Well, our second article comes to us from the world of preclinical science and it's from Dr. Nathan Palpant from the University of Queensland. So the article pertains to ischemia reperfusion injury, and it's one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. Now during cardiac ischemia, the buildup of acidic metabolites results in decreased intracellular and extracellular pH that can reach as low as 6 to 6.5, and the resulting tissue acidosis exacerbates ischemia injury and significantly impacts cardiac function. Dr. Greg Hundley: So the authors today use genetic and pharmacologic methods to investigate the role of acid-sensing ion channel 1a or ASIC1a, we'll call it from now, in cardiac ischemia reperfusion injury at the cellular and whole organ level. Human induced pluripotent stem cell-derived cardiomyocytes as well as ex vivo and in vivo models of ischemia reperfusion injury were used to test the efficacy of ASIC1a inhibitors as pre-imposed conditioning therapeutic agents. Dr. Greg Hundley: So what did the authors find in this study? Well, they demonstrated for the first time that acid-sensing ion channel 1a or that ASIC1a mediates cardiac ischemia reperfusion injury. The authors identify that ASIC1a inhibition is a novel therapeutic strategy for preventing acute injury response to myocardial ischemia reperfusion injury. Dr. Greg Hundley: So what are the clinical implications of this research? Well, first there are currently no drugs in clinical use that prevent acute injury response to myocardial ischemia, despite many promising candidates identified over decades of research, all of which ultimately failed in subsequent clinical trials. Second, the identification of new therapeutic targets for preventing the injury response to myocardial ischemia reperfusion injury would therefore have profound implications in cardiovascular medicine. Therefore, the results of this study reveal that ASIC1a inhibiting drugs, they're safe and they have potential applications in heart transplant and myocardial infarction with potential use in other clinical scenarios where myocardial ischemia reperfusion injury is a risk such as those that undergo cardiac surgery. Dr. Greg Hundley: Well, our next article comes from Robin Choudhury from the University of Oxford. Have you ever wondered why cardiovascular risk and diabetes remains elevated despite glucose-lowering therapies? Well, these authors hypothesized that trained immunity in response to elevated glucose accounts for diabetic hyperglycemic "memory", we'll call it, in relation to atherosclerosis. So accordingly, the author sought to determine if hyperglycemia-induced disease relevant changes in monocyte and macrophage function and whether these changes persisted after restoration of normal glucose, thereby implying fundamental reprogramming. So the team combined studies of cellular function, metabolomics, transcriptomics and epigenomics to define how hyperglycemia altered metabolism to modulate long-term activation through epigenetic modifications. Dr. Greg Hundley: Well, what did they find? First, hyperglycemia induced a trained immunity in bone marrow progenitor cells by inducing persistent epigenetic modifications. Second, hyperglycemia-induced trained immunity persisted after differentiation into those macrophages. Finally, hematopoetic stem cells transplanted from mice with diabetes to euglycemic mice promoted exaggerated atherosclerosis. So therefore, the findings of this study may explain the resistance of macrovascular complications of diabetes to conventional glucose-lowering treatments. Dr. Greg Hundley: Well, in the mailbag this week, there are some other articles. Professor Huang has a Research Letter entitled, “Adrenergic-Thyroid Hormone Interactions Drive Postnatal Thermogenesis and Loss of Mammalian Heart Regenerative Capacity.” Dr. De Caterina has an In Depth article on coronary artery anomalies. Finally, Professor Merid has a Perspective piece entitled, “Digital Redlining and Cardiovascular Innovation.” Dr. Greg Hundley: Well, listeners, what a great group of articles, and now we're going to turn to that feature discussion with Dr. Ben Levine. Dr. Greg Hundley: Welcome listeners to our feature discussion today and we're very fortunate. We have with us, Dr. Ben Levine from UT Southwestern in Dallas, Texas and also Dr. Walter Paulus from Amsterdam. Welcome gentlemen. Dr. Greg Hundley: Ben, we'd like to start with you. Could you describe for us a little bit of the background related to your study and what was the hypothesis that you wanted to test? Professor Benjamin Levine: Sure. Oh, nice to talk with you, Greg. As you know, our lab has been very interested in the effects of both aging and physical activity on cardiac mechanics. To cut a very long story short, what we know is that sedentary aging leads to stiffening of the heart. We also know that HFpEF, heart failure with preserved ejection fraction, is a disorder predominantly of the aged. I don't know about you, Walter, but I've never seen any lead masters athlete HFpEF. Professor Benjamin Levine: What we've shown is that if you regularly exercise over a lifetime that the heart can preserve its youthful compliance and flexibility. But if you wait until somebody is older, meaning over 65, 70, regardless of how hard or intense we train, the heart seems to lose its plasticity. It can't actually get that much better. But if we start in late middle age, it turns out that you can actually reverse some of the adverse effects of sedentary aging. So we said, "Okay, we know what the dose is, how much exercise you need to do. We know what the sweet spot in time. Now how do we find those people who are most likely to go on to develop HFpEF in whom getting them on a regular exercise program might help forestall this very challenging syndrome." Professor Benjamin Levine: So as part of an AHA-funded strategically focused research network and prevention, we identified a group of patients who had left ventricular hypertrophy, but evidence that they were on the wrong path. Their biomarkers were elevated. They have an elevated NT-BNP or a high sensitivity troponin. We did a right heart catheterization and we looked at their cardiac stiffness using a technique that we've done now for the past 25 years or so, and showed that indeed those patients' hearts are clearly stiffer than healthy, but otherwise sedentary middle-aged individuals. Professor Benjamin Levine: So our key question was what happens if we put them on a long sustained high intensity exercise program? Can we reverse the effects of sedentary aging superimposed with hypertension, left ventricle hypertrophy and elevated biomarkers? Dr. Greg Hundley: Really interesting, Ben. So describe your study design for us. How are you going to set up? It sounds like a very elaborate experimental setup here. Then also, maybe just define for us your study population. Did you have men and women or- Professor Benjamin Levine: Yeah, we started by going to the Dallas Heart Study. We're blessed here in Dallas by having this room access to our remarkable population where we know a lot about them. So we picked people in late middle age of all races, both sexes, and we reached out to the members of the Dallas Heart Study if they had left ventricular hypertrophy by echo or MRI and were of the right age range. We enriched that database by going to an EKG database and looking at the Ecolab database, trying to find people who did not have heart disease already. That was important. They couldn't have had a heart attack. They couldn't have had heart failure. They couldn't have had infiltrative disease. They had to be generally healthy except had left ventricular hypertrophy. Professor Benjamin Levine: We screened a lot of patients to get there, I have to acknowledge that, almost 4,000 of them or so to get the small number who were interested in doing a one-year exercise training program. But as we eventually got a good solid number that because we use such high resolution techniques, we were able to define the key outcome variable, which is cardiac stiffness. Professor Benjamin Levine: Briefly in our lab, we put a right heart catheter in to measure wedge pressure. We use 3D-echo to measure volume and then we use something called lower body negative pressure to unload the heart. It's almost like standing up progressively or tilting upright and then we give them a rapid saline infusion, 200 mls a minute. So a lot of saline, 15 and 30 mls/kg. We can get the left atrial pressure from about three or four up until about 18 to 20 and define the entire physiologic range of left ventricular filling. We look not just at the wedge pressure of course, but the transmural pressure. Professor Benjamin Levine: John Tyberg and his colleagues in Canada have shown clearly that the pericardial pressure is pretty close to right atrial pressure. So transmural pressure, which is the distending pressure of the heart, is left atrial minus right atrial pressure. We use that as the input into a pressure volume relationship. Dr. Greg Hundley: Very nice, and then what did you find? Professor Benjamin Levine: Well, what we found is after demonstrating that these patients with LVH and elevated biomarkers have increased stiffness, what we found quite remarkably actually was that we were able to reverse that by a year of training. Professor Benjamin Levine: Now when I say training, I mean, we do use the optimal approach to training that we've demonstrated in our lab. We didn't just pick one thing, get on a bike, do that for 30 minutes three times a week, right? These were sedentary people so we built them up slowly over about seven months. We added frequency, we added duration, we added intensity. Professor Benjamin Levine: I am enamored by the four by four in old Norwegian ski team workout, which is four minutes at 95% of max followed by three minutes of recovery repeated four times. We added interval training and long slow distance battle lasting about an hour on the weekends and a little bit of strength training, too. Professor Benjamin Levine: So what we consider the ideal prescription for life, four to five days a week, one long session, one high intensity session, two or three moderate intensity sessions and a little bit of strength. We did it for a year. It took a lot of effort. We had dedicated trainers. We gave them all heart rate monitors. Each person had a trainer to follow them. Professor Benjamin Levine: We did have a control group. We randomly assign them to a group that did stretching and yoga and mindfulness and a little bit of strength training, which makes people feel better. But we know from experience, it doesn't make them fitter and doesn't change their cardiac compliance. Dr. Greg Hundley: What happened with the treatment group? Professor Benjamin Levine: Oh, they got much more compliant. They got as compliant as if they had been training most of their lives. It was quite remarkable, actually, frankly, better than we expected it to be. We check the data multiple times by multiple people to make sure that this was a real finding. We really reversed much of the effects of the adverse effects of sedentary aging plus LVH. We hope that if that would be sustained over more than a year, years of long training study, there are very few training studies that go that long. But it's not a lifetime and at least we've set the stage for the concept that if this were to be sustained over a lifetime that we think it could forestall HFpEF. Dr. Greg Hundley: Very nice. Well, Walter, I know serving as a guest editor for us at Circulation and we're most appreciative for you doing that task. What struck you about this particular article and really enticed you to want to help us move it toward publication? Professor Walter Paulus: Well, I felt that the article was very visionary. Of course, as it comes from Ben, I didn't expect anything else. But what struck me were two points. Professor Walter Paulus: First of all, he looks at patients which we would label type B HFpEF. Most of our efforts have always been focusing on sick people, stage C HFpEF, stage D HFpEF. Now Ben was so clever to go to an early stage, and I believe that many of the so-called neutral outcomes in therapy for HFpEF are related to the fact that we actually address patients population who is quite far out on its natural history. So I think this was the first point to me. He, Ben, was addressing a population at the early stages of HFpEF. Professor Walter Paulus: The second point that struck me was that the variable he was looking at is in my opinion the key variable in HFpEF. It's the main reason I appreciated that this is the disease of myocardial compliance of left ventricle stiffness, and then very nicely addressed the stiffness of the heart as its primary outcome. This is something what we miss in all the pharmacological trials. I have always been curious when are we going to see the pharmacological trial whereby somebody is going to evaluate a compound in terms of its effects on left ventricular stiffness on myocardial compliance. Professor Walter Paulus: So these were for me two very salient features and very visionary in terms of treatment of a HFpEF population. Also, a couple of things that need to be clarified for me and I did. The patient's entry criteria were very demanding, has been also already said. I have the feeling that if you have LVH and then you will try NT-proBNP to be elevated and all your required troponins to be elevated, it's probably be very hard to get such a patient population and that may be then the only remark that could come up toward an extent in such a patient population still reflective of everyday health. Dr. Greg Hundley: Very good. Well, Ben, coming back to you, what's your next study? Professor Benjamin Levine: Well, we have a large program project grant, Greg, funded by the NIH, looking at the mechanisms of dyspnea and HFpEF. We're now just entered our third year. We're looking at a strategy to try to lower cardiac filling pressures acutely to see if that improves exercise tolerance and reduce dyspnea. We're looking at peripheral mechanisms of oxygen uptake and utilization and vascular control. We're looking at autonomic function, sympathetic nerve recordings, regulation of the sympathetic nervous system. We have a group focused on pulmonary mechanics, particularly on the effects of obesity. Professor Benjamin Levine: Our team with Tom Sarma is our recruitment core expert and one of the Circulation editors and is really the lifeblood of our study and leads our effort. We have Paul Fidel from UT Arlington who's leading our peripheral function studies, Qi Fu from UT Southwestern leading our autonomic group, and Tony Babb also from Southwestern in the pulmonary division leading our pulmonary mechanics. Professor Benjamin Levine: So we're entering this phase where we're trying to say, "Are there other components?" We know myocardial stiffness is a key factor, but what else in patients with the already manifest HFpEF is causing them to be so short of breath and can we change that? Professor Benjamin Levine: So that's what we're doing next, Greg. I think that if you ask what is the next step from this study, I think it has to be population-based and pushing the concept that exercise is medicine. When you find patients who have hypertension in general, and most of these had hypertension or diabetes, I mean, Walter has led this field and in emphasizing these comorbidities and what they do to the heart and the vasculature and the rest of the body, we have to catch people early. We can't wait until they have full-blown manifest HFpEF. We have to get them to include exercise as part of their personal hygiene. Professor Benjamin Levine: I know that that's a major effort from the American Heart Association. But I think that for the long-term health of our population and preventing this disease that is so difficult to treat when it's firmly established, we have to as cardiologists and as a healthcare system, we have to start by including incentives for reducing healthcare costs to get people to use exercise as part of their personal hygiene and daily life. Dr. Greg Hundley: Very nice. Walter, from your perspective, what do you see are the next studies that need to be performed in this sphere of research? Professor Walter Paulus: Well, I will be very curious to see how many patients would actually go on to develop HFpEF in their life. It should be as if Ben's hypothesis holds, then the control group probably would have an access development of HFpEF compared to his exercise training group. I think that would really extend to study from above, from a mechanical observation to a clinically, epidemiologically more relevant endpoint. So I think that to me would be the first question, how many patients will evolve to clinical HFpEF. Professor Walter Paulus: Second point I would be very intrigued in is, are there SIP groups in the patients who have a positive response to exercise? For instance, what happens with the different ejection fractions? Because we are very intrigued at present in HFpEF that at high ejection fractions nothing seems to work. Sacubitril was notable at high ejection fractions. Empagliflozin was also neutral to ejection fractions. What would happen with exercise? Do the patients who present with the 70% ejection fraction at the angio study, do they still have a positive response? This would be a game change because this would then be the only intervention that is able to cure the HFpEF with high ejection fraction. These are some future projects that come into my mind. Professor Benjamin Levine: Let me just add that we have studied and put patients with HFpEF on a yearlong exercise program with not as much effect as we would like. I think that's one of the things that pushed us to getting earlier into the course of HFpEF, as Walter said earlier. Professor Benjamin Levine: Ambarish Pandey and Jarett Berry, also from UT Southwestern, of course are very interested in this effect of fitness at different points in the lifespan, our fitness test, for example, measured in mid-life and what means for heart failure later. I think it's hard to do the kind of studies that we do and follow patients for 20 years to see if they're going to develop heart failure, and that's where I think being creative and looking at the studies that incorporate an assessment of fitness and that follow people over time will be very informative. I hope with me, Walter's hope and hypothesis that these patients are less likely to develop HFpEF. We've got to get in there early. Dr. Greg Hundley: Very good. Well, listeners, we want to thank Professor Benjamin Levine from UT Southwestern in Dallas and also Dr. Walter Paulus from Amsterdam for bringing us this really interesting study, indicating that in patients with LVH and elevated cardiac biomarkers, sort of the stage B HFpEF that one year of exercise training reduces left ventricular myocardial stiffness. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, I want to wish you a great week and we will catch you next week on the run. 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.  

Rasa Co-Founder + Chief Herbalist Ben LeVine discusses the science of adaptogens, his journey to becoming an herbalist, and the joy and challenges of building a conscious business within a capitalist system. Find me at healingcorner.net or @healing_corner on Instagram wearerasa.com @wearerasa on IG Discount code: HEALINGCORNER15 for 15% off of your order! wearerasa.com Episode Notes • Difference between adaptogenic energy and caffeine energy • Where adaptogens grow • Ben's upbringing and background • His mystical mountain top experience • Meeting Lopa and deciding to collaborate • Signature 12 herb blend for everyday use • Adaptogen origins and American integration • Phyto-chemical diversity • Discussing contraindications • Michael Pollan "This is Your Mind on Plants" • Coffee and capitalism • Dale Pendell Ben's favorite plant poet • Network pharmacology • Triterpenoids • Sourcing and direct trade • Examples of partnership and Rasa's deep investments • Experimenting and macrodosing as an herbalist • Ben's favorite blends and his daily routine • Adaptogens vs coffee and pharma • Antiracism at Rasa • Whiteness at work • Rachel Ricketts “Spiritual Activism 101” • Herbalist specific course: "Woke Without the Work" • Ibrham Kendi How to be an Antiracist • What Ben's most proud of • Where to find Rasa • Ben's recommendations for beginners • Men vs. women customer split

Births and leprosy and emissions - oh my! Ben Levine '24 joins Rabbi Josh, Rhyan and Leah to talk about Tazria-Metzora, with a focus on the treatment of purity and impurity around menstruation and childbirth. What were the motivations of the Biblical text, and how do we feel about it today? How have women reclaimed the practices of niddah and mikvah in the 21st century? The text sheet can be found here.

This week, join author Chintan Dave and Associate Editor Naveed Sattar as they discuss the risk of cardiovascular outcomes in Type 2 Diabetes patients following the addition of SGLT2 inhibitors versus sulfonylureas to baseline GLP-IRA therapy. TRANSCRIPT BELOW: 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 Dr. Greg Hundley, Associate Editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, I love today's featured paper. It's a question everybody's asking. It's about cardiovascular outcomes, potential benefits, following the addition of SGLT2T2 inhibitors versus sulfonylureas to baseline GLP-1 receptor agonist therapy. Now, okay, I'm going to keep you waiting because that was just a hook. We got to get to us summaries first. And I'm going to start. The first original paper I want to describe is an analysis of myocardial infarction from the ischemia trial. And it looks at the impact of different definitions on the incidents, prognosis and treatment comparisons. Dr. Carolyn Lam: Because I know you're going to ask, I'm going to tell us a little bit about ischemia. So in an ischemia and initial invasive strategy did not significantly reduce rates of cardiovascular events or all-cause mortality compared with a conservative strategy in patients with stable ischemic, heart disease, and moderate to severe myocardial ischemia. The most frequent component of the composite cardiovascular end points was myocardial infarction. So in the current report from Dr. Chaitman and colleagues from St. Louis University school of medicine, the aim was to compare treatment effects on the primary and major secondary competent end points in the ischemia trial using the pre-specified primary and secondary MI definitions. Dr. Greg Hundley: So Carolyn, what were those two EBI definitions, the primary and secondary? Dr. Carolyn Lam: Right. Now, I'm going to try to simplify this. So, for procedural MI, the primary MI definition use CK-MB as the preferred biomarker, whereas the secondary definition used cardiac troponin. Dr. Greg Hundley: Great, Carolyn. So what did they find? Dr. Carolyn Lam: So procedural MI definition had an important impact on event frequency and subsequent prognosis. When the pre-specified secondary MI definition was applied, the conservative strategy had a significantly lower composite event rate for the primary and major secondary trial end points, due to an increased number of procedural MIs in the invasive strategy. Furthermore, spontaneous Type One MI events associated with increased risk of cardiovascular death were reduced with an invasive strategy, which is either PCI or CABG. Dr. Greg Hundley: Nice, Carolyn. Well, my first paper actually is a favorite topic of yours, HFpEF. And it really involves the central command and the regulation of exercise rate response. It comes to us from Dr. Ben Levine and colleagues at the University of Texas Southwestern Medical Center in Dallas. Dr. Carolyn Lam: Yay. Dr. Greg Hundley: All right, Carolyn. So chronotropic incompetence is common in HFpEF. And it's linked to impaired aerobic capacity. Whether upstream, autonomic signaling pathways are responsible for raising exercise heart rate are impaired in patients with HFpEF, That's really unknown. Dr. Carolyn Lam: Yep. It is something that we wonder. And so what did Dr. Levine find? Dr. Greg Hundley: Thanks Carolyn. So the central command, so vaguely mediated and the metabo-barrow receptor function, which is sympathetically mediated in patients with HFpEF, We're not different from healthy senior controls, despite significantly lower peak whole body exercise, heart rates. So these results, Carolyn, demonstrate key reflex autonomic pathways, regulating exercise, heart rate responsiveness are actually intact in patients with HFpEF. Great new work from Dr. Ben Levine. Dr. Carolyn Lam: And I love the way you summarized that. Thank you, Greg. Well, my next paper is the first report implicating the cross priming function of dendritic cells in immunopathology after Type Two MI. And that includes inflammation, fibrosis and functional decline. Dr. Greg Hundley: So tell us a little bit more Carolyn about these dendritic cells? Dr. Carolyn Lam: Ah-ha so I was ready for that question. So after ischemic injury to the myocardium, dendritic cells respond to cardiomyocyte necrosis present the cardiac antigen to T-cells and potentially initiate a persistent auto-immune response against the heart. So cross priming dendritic cells may have the ability to activate both CD4-positive helper and CD8-positive cytotoxic T-cells in response to necrotic cells. And may thus be crucial players in exacerbating auto-immunity targeting the heart. Dr. Carolyn Lam: So, in this study, authors led by Dr. Sattler from Imperial College, London, performed some elegant mouse experiments and showed that cross-priming dendritic cells were present in the heart and activate it after ischemic injury. Depletion of these dendritic cell cross priming function, inhibited accumulation, and activation of cytotoxic T-cells and stopped myocardial immunopathology and functional decline. So with cross-priming, these authors provided a targetable pathway to prevent activation of T-cells cyto-toxicity and persistent post Mia immunopathology exacerbating heart failure risk. Dr. Greg Hundley: Oh, beautiful. Carolyn, what a great description there. So my next paper comes to us from Dr. David Park from the New York University school of medicine. So Carolyn elevated intracardiac pressure due to heart failure, induces electrical and structural remodeling of the left atrium that begets atrial myopathy and arrhythmias. At present the underlying molecular pathways that drive atrial remodeling during cardiac pressure overload are poorly defined. So the purpose of this study for these investigators was to characterize the response of the ETV1 signaling axis in the left atrium during cardiac pressure overload in humans, as well as mouse models. And explore the role of ETV1 in atrial electrical and structural remodeling. Dr. Carolyn Lam: Ah, another study involving both animal and human models. Very important subject too. So what were the results? Dr. Greg Hundley: Well, Carolyn, evidence from both the Cleveland Clinic, Biobank Human Subjects Repository and the animal science experiments revealed that ETV1 is downregulated in the left atrium during cardiac pressure overload. Thereby contributing to both the electrical and the structural remodeling that we observe in the left atrium during cardiac pressure overload. Dr. Carolyn Lam: Nice. Well, let's quickly finish up with what's in the mailbag. We've got a research letter by Dr. Randi on the lack of evidence of AEs to expression and replicative infection by SARS-CoV-2 in human endothelial cells. There's another by Dr. Stokes on the association of cigarette and electronic cigarette use patterns with levels of inflammatory and oxidative stress biomarkers among US adults. And another research letter by Dr. Hemelsoet on screening for Fabry disease in male patients with arrhythmia requiring pacemaker or ICD. Dr. Greg Hundley: Thanks Carolyn. So I've got a paper it's a cardiovascular case series from Dr. Workman that involves a case of presyncope after transcatheter aortic valve replacement. Dr. Özeke has an ECG challenge reminding us that common things occur commonly. Dr. Zaha has a Perspective entitled, "Mending Broken Hearts, a New Treatment Paradigm for Immune Checkpoint Inhibitor Induced Myocarditis." And then finally, Dr. David Goff, the director of the NHLBI has a wonderful perspective piece (Special Report). And it really addresses some results from the Bethesda conference at the National Heart Lung and Blood Institute and the American Heart Association. And it was co-sponsored the bending curve of cardiovascular disease mortality, the Bethesda plus 40 years Symposium. Dr. Greg Hundley: The report, Carolyn, summarizes the relevant research, policy, and practice opportunities discussed at the symposium, including participant led discussion that explored the challenges and barriers in promoting cardiovascular health, across lifespan. And established a potential framework for observational research interventions that would begin in early childhood. Well, Carolyn, how about now we jump forward to that feature discussion. Dr. Carolyn Lam: All right, now we can go. Dr. Greg Hundley: Well, listeners, we are to the feature discussion today. And we have with us Dr. Chintan Dave from Rutgers University in New Jersey, and our own associate editor, Dr. Naveed Sattar from Glasgow, Scotland. Welcome gentlemen. Chintan, could you explain to us some of the background information that went into the construct of your study and then what hypothesis did you want to test? Dr. Chintan Dave: So just for background, so we know that artheriscraotic cardiovascular events in heart failure typically occur in higher prevalence in patients with type two diabetes. What's been really exciting in recent years is that certain second-line therapies, namely SGLT2 inhibitors and GLP-1 receptor agonist in these large cardiovascular outcome trials have shown to reduce the incidents of cardiovascular events. So from these trials, we can infer that SGLT2 inhibitors typically reduce heart failure hospitalizations, and also have an impact on 3P-MACE, which is just the composite of cardiovascular death, non-fatal MI and non-fatal stroke hospitalizations. While GLP-1 receptor agonist tend to reduce, also have an impact on 3P-MACE, but they also have some modest benefits in heart failure hospitalizations as well. Dr. Chintan Dave: So now that we know that these agents reduce cardiovascular risk, what's not known is, whether or not, if we can use these agents together to further maximize a reduction in cardiovascular events. So in the cardiovascular outcome trials the dual use of SGLT2 two inhibitors and GLP-1 receptor agonists was rare and ranged from between 0% to 5.3%. So as a starting point, we said, "Okay, let's look at observational data to see what happens when you add SGLT2 inhibitors to patients who are already using GLP-1 receptor agonist." And we hypothesized that, given the orthogonal pharmacodynamic effects on cardiovascular risk, adding SGLT2 inhibitors to existing GLP-1 receptor therapy should further reduce cardiovascular events. Dr. Greg Hundley: Very good. And can you describe for us your study population and study design? Dr. Chintan Dave: Sure. So we used three databases in the US. Two of these databases were commercial claims data, which is typically your employer based insurance plans, which have patients between the ages of 18 and 64. And we supplemented that data with Medicare fee for service claims, which have patients over the age of 65. So within these three databases, we identified patients who have a diagnosis of type two diabetes and are already a GLP-1 receptor therapy or GLP-1RAs and initiating either SGLT2 inhibitors or sulfonylureas. Dr. Chintan Dave: And after we identified this patient population, we controlled for several pertinent variables that could be considered confounders, including socio-demographic variables, diabetes complications, and cardiovascular conditions. And we had two primary endpoints. The first primary end point of interest was a composite cardiovascular endpoint, which is defined as the composite of non-fatal MI or nonfatal stroke hospitalizations in all cause mortality. The reason we used all cause mortality instead of cost specific mortality is basically because we didn't have information on cause of death. So we have to resort to a more generic definition of mortality in the composite cardiovascular endpoint. The second primary endpoint that we used was heart failure hospitalizations. So we then in this population, estimated hazard ratios using basically a time to event framework. Dr. Greg Hundley: Okay. And what were your results? Dr. Chintan Dave: So after applying the eligibility criteria in all three databases and after doing a one-to-one propensity score matching, we had 12,500 patients who initiated SGLT2 inhibitors and 12,500 patients in the sulfonylurea groups. For the true primary end points the addition of SGLT2 inhibitors to baseline GLP-1RA therapy was associated with a 22% decrease in the incidents of composite cardiovascular end point or an adjusted hazard ratio of 0.78. And the caught 95% confidence intervals were statistically significant. For the endpoint of heart failure hospitalizations, we noted a 36% decrease in the risk of heart failure hospitalizations with the adjusted hazard ratio being 0.64. And again, that was statistically significant as well. Dr. Chintan Dave: The CCE or the Composite Cardiovascular Endpoints was driven primarily by non-statistical decreases in the risk of MI by about 25%, in all cause mortality by about 32%. But we also found no effect on stroke, which is also in line with what others have reported. The other thing we looked at was also to look at any evidence for heterogeneity in treatment effects by presence of cardiovascular diseases. And we found no statistical significant difference in that aspect. The last thing we looked at also was to look at any evidence of heterogeneity by baseline cardiovascular disease in the patient groups. And we found no evidence to that effect. Dr. Greg Hundley: Very nice. Well, Naveed help us put this study in perspective with some of the other research that I know you're familiar with related to the use of SGLT2 inhibitors and GLP-1 receptor agonists. Dr. Naveed Sattar: Yeah. Thanks Greg. So as we all know, the biggest gains in diabetes in the last few years is these two costs of the trucks SGLT2 inhibitors and GLP-1. We believe and the evidence suggests that SGLT2s, are more cardiorenal in its benefits, and GLP-1 more atherothrombotic. So the hope is that if you combine these drugs, you get additional benefits, but there are no trials that have actually tested this. So this particular paper being kind of first observational, look at adding an SGLT2 versus another drug on top of a GLP-1, tries to get at that particular question. And it provides an early hint that yes, if you add an SGLT2 on top of the GLP-1, you get additional benefits. Giving us some insight that yes, you combine these two classes of drugs, you might get additional benefit in one drug on its own. Dr. Naveed Sattar: Of course, this is not trial. Some of our readers are going to be nihilist and will not believe the data because it's not a trial, but that's fine. But it's done as well as it possibly can. This observational propensity analysis is well matched. The data have some kind of external validity in the sense that the greatest benefits or risks reductions, but for heart failure post-acquisition, which is what we would believe ratio to inhibitors. So there is some sense of validity here, but clearly colleagues, they want to know, and I actually had a patient in the clinic on Tuesday who was on a GLP-1 and actually was an SGLT2. And I wanted to add the GLP-1. And this kind of evidence provides me some evidence of confidence that yes, by adding both drugs, I might get additional benefits in that one drug on its own. Dr. Naveed Sattar: So what you're going to ask next, Craig, and I'll give my answer first. What we really need to do now is actually do the trials. And I think the trials will predominantly work, adding GLP-1 on people who are on SGLT2, because I think more people will be initially an SGLT2 because it's a oral therapy. Then we'll add GLP-1. Although we do have a new oral GLP-1 in play as well. So, that's the kind of paradigm we're in. Some hints, the combination gives you more than the single drug and I think that's really quite promising for people. Dr. Greg Hundley: Very nice. So Naveed suggesting a clinical trial to confirm some of these results. Chintan, do you have anything to add? What study do you think or what area of investigation in this field do you feel is next in line? Dr. Chintan Dave: Yeah, I mean, I would just start by saying that I agree with everything that Naveed said in the sense that this is a starting point. And that I think the key take home from this study that sort of is going to be published is basically that not only do SGLT2 inhibitors reduce the cardiovascular events in patients using GLP-1 therapy, but the fact that the magnitude of this reduction is very similar. What was noted in cardiovascular outcome trials of SGLT2 inhibitors for GLP use was very minimal. In other words, you can super impose the cardiovascular benefit profile of the SGLT2 inhibitors, which were seen in trials two patients using GLP-1 therapy. Dr. Chintan Dave: Now the converse is what needs to be done next, basically, where we need to look at what happens when you add GLP-1 receptor agonist, to SGLT2 inhibitors, as Naveed just said. And he raised a really good point in that more patients are going to be on SGLT2 inhibitors, because they want to avoid GLP-1 receptor agonist because they don't want to use injectable therapies. Of course we have oral semaglatites maybe that may mitigate these issues. But the fact that that aspect is still unknown, could potentially be really good idea for future studies. So that potentially would be a nice, good step. Dr. Greg Hundley: Excellent. Dr. Naveed Sattar: Can I see one last thing, Greg? There is a trial coming this year called AMPLITUDE‐O, which is a GLP-1 trial, which does have a fair number of people on base than SGLT2s. We might be able to get a curly hint at that ongoing trial in the next six months to a year. Dr. Greg Hundley: Excellent. Well, we want to thank both Chintan Dave from Rutgers and our own associate editor, Dr. Naveed Sattar from Glasgow, Scotland. And really presenting information from US Claims databases highlighting the addition of SGLT2 inhibitors to GLP-1 receptor agonists and finding there was an association with a further reduction of cardiovascular risk relative to the use of GLP-1 agonists alone. On behalf of both Carolyn and myself, we want to wish you a great week. And catch you next week On the Run. This program is copyright of the American Heart Association, 2021.  

Dr. Ben Levine is a renowned cardiologist practicing medicine at the UT Southwestern Medical center in Dallas, Texas. His distinguished career covers broad areas in both medicine and physiology. He has the high honor of seminal contributions towards our understanding of how exercise can affect the aging athlete as well as how exercise can affect astronauts. In the endurance world, his landmark research in 1997 on ‘Live High, Train Low’ has served as the benchmark for athletes and coaches wanting to undertake altitude interventions.JAMA Statement on COVID return to play guidelinesInformation on coaching:www.trainright.comKoop’s Social Media:Twitter/Instagram- @jasonkoop

Ep. 83Cecil hotel/ Stay On Main Hotel Welcome my friends to the first episode of 2021! We hope you all enjoyed our last episode of 2020, we did! We hope you all made it to the new year safe and sound. We're alive and well and we're going to take a much needed vacation. Where are we headed you may ask? Well we are going to head to sunny Los Angeles! Hopefully you passengers hang on and come with! Los Angeles, the city of angels, and tons of weird people and rich movie types that are better than we are...eh… Fuck em. We're not headed there for a tour of stars' homes, we're not headed there to further Jeff's acting career with casting couch auctions in some seedy office with a casting couch, no my friends were heading specifically to 640 south main street l.a. california! What sits at that address you may be wondering. Well it's none other than The Cecil hotel, aka The hotel Cecil, aka The Cecil, aka The stay On Main Hotel, aka whatever the fuck the next name is gonna be. That's right, the famous, or maybe infamous Cecil hotel. If this sounds familiar but you can't quite place it, well get to what's most recently made this place famous in a bit. But first buckle up cus here we go! The Cecil was built in 1924 by hotelier William Banks Hanner with partners Charles L. Dix and Robert H. Schops. It was supposed to be a destination hotel for international businessmen and social elites. Designed by Loy Lester Smith in the Beaux Arts style, and constructed by W. W. Paden[7] the hotel cost $1.5 million to complete and boasted an opulent marble lobby with stained-glass windows, potted palms, and alabaster statuary. The three hoteliers invested about $2.5 million knowing several other similar hotels had been constructed and opened in the area. They had the utmost confidence in their venture. Unfortunately for them, only a few years after opening the hotel disaster would strike. Not only would it strike the three hoteliers, but the nation as a whole. The country was plunged into the great depression. The Great Depression started in the United States after a major fall in stock prices that began around September 4, 1929, and became worldwide news with the stock market crash of October 29, 1929, (known as Black Tuesday). Between 1929 and 1932, worldwide gross domestic product (GDP) fell by an estimated 15%. By comparison, worldwide GDP fell by less than 1% from 2008 to 2009 during the Great Recession.[4] Some economies started to recover by the mid-1930s. However, in many countries, the negative effects of the Great Depression lasted until the beginning of World War II. The Great Depression had devastating effects in both rich and poor countries. Personal income, tax revenue, profits and prices dropped, while international trade fell by more than 50%. Unemployment in the U.S. rose to 23% and in some countries rose as high as 33% While this was happening the Hotel hung on as best it could to it's roots of being a destination for wealthy socialites, unfortunately those were heard to come by at that point. As the depression wore on, the area around the hotel became the infamous Skid Row. Now we're not talking the Sebastian bach fronted band that had so many great jams back in the day. To give you an idea of the area that the hotel was in and had to deal with while trying to keep clientele, here's a brief history:     At the end of the 19th century, a number of residential hotels opened in the area as it became home to a transient population of seasonal laborers.[13] By the 1930s, Skid Row was home to as many as 10,000 homeless people, alcoholics, and others on the margins of society.[12] It supported saloons, residential hotels, and social services, which drew people from the populations they served to congregate in the area.[14] In June 1947, Los Angeles Police Department (LAPD) chief Clemence B. Horrall ordered what he called a "blockade raid" of the whole Skid Row area. Over 350 people were arrested. Assistant Chief Joseph Reed, who claimed that "at least 50 percent of all the crime in Los Angeles originates in the Skid Row area," stated that there had been no "strong arm robberies" on Skid Row as late as one week after the raid. Long time residents, however, were skeptical that the changes would last.[15] In 1956, the city of Los Angeles was in the midst of a program to "rehabilitate" Skid Row[16] through the clearance of decaying buildings.[17] The program was presented to property owners in the area as an economy measure. Gilbert Morris, then superintendent of building, said that at that point the provision of free social services to the approximately one square mile of Skid Row cost the city over $5 million per year as opposed to the city average of $110,000 per square mile annually.[16] The city used administrative hearings to compel the destruction of nuisance properties at the expense of the owner. By July 1960, the clearance program was said to be 87% complete in the Skid Row area.[17] With increased building codes during the '60s, owners of residential hotels found demolition to be more cost-effective than adhering to repairs. The total number of these buildings is estimated to have dropped from 15,000 to 7,500 over the following decade.[18] Many residents of the area found themselves homeless with the loss of half of the affordable housing provided by hotels.[18] 1970s through present EditSkid Row was established by city officials in 1976 as an unofficial "containment zone", where shelters and services for homeless people would be tolerated.[19] During the 1970s, two Catholic Workers — Catherine Morris, a former nun, and her husband, Jeff Dietrich — founded the "Hippie Kitchen" in the back of a van. Over forty years later, in March 2019, aged 84 and 72, they remained active in their work feeding Skid Row residents.[20] Throughout the 1960s and 1970s, many veterans of the Vietnam War found themselves drawn to Skid Row, due to the services and missions already in place there, and feeling outcast from other areas. Like those after World War II, many of them ended up on the streets. It was around this time that the demographics of Skid Row shifted from predominantly white and elderly to those here today Now that only takes us through the 70s but we can tell you, it didn't get any better after that.  The reason we went through a small history of Skid Row is to show how the area had changed and the type of people that inhabited the area. The reason to show this will become evident…. Right… about… Now! By  the 50s the hotel had become a place known to house transients and drug dealers and many unsavory types. This would lead to a history of murder, suicide and other tragedy. That would ultimately lead to takes of the hotel being haunted. The hotel would more recently become the location of a story that would capture the attention of the world due to its strangeness. So without further ado let's get into the craziness! Murders and murderers at the Cecil: One of several noteworthy guests of the hotel was Elizabeth Short, who you may know as the “Black Dahlia” after her 1947 murder in Los Angeles. She reportedly stayed at the hotel just before her mutilation, which remains unsolved. What connection her death may have had to the Cecil is not known, but what is known is that she was found on a street not far away on the morning of January 15 with her mouth carved ear to ear and her body cut in two. Some people say that this sorry of Short staying or being seen at the hotel are untrue but we like to think there's a connection, however we cannot confirm nor deny the validity of this claim and there is much conflicting reporting on this. There are some reports of sorry saying at a nearby hotel and just doing into the Cecil bar from time to time.  Next up a confirmed and also unsolved murder at the Cecil. Georgina "pigeon" Goldie Osgood. On June 4th a 79 year old retired telemarketer named Goldie Osgood was found in her hotel room dead. The autopsy showed that she was beaten, stabbed and choked with a rag. Her hotel room was ransacked. Friends say they talked her merely minutes before her death. She was known for feeding pigeons at a nearby park and that’s how she earned her nickname “Pigeon Goldie”. She was staying at the Cecil hotel, where she was very liked and was a long time residence. Not much information can be found about her death. Only that a man named Jacques B. Ehlinger was arrested a few hours after her body was found. He had been seen walking in the same area Ms. Osgood would feed pigeons. He was covered in blood, but was later released due to lack of evidence. Several serial killers have called the Cecil home as well. Chief among them… good ol Richard Ramirez, the fucking Night Stalker. Now if you're listening to this podcast and you don't know who Ramirez is, we question why you're here! But as a refresher:           Ramirez was a Satanist and a particularly awful human, even for a serial killer: He seemed to have no M.O. except to be as sadistic as possible.His victims — men, women, children — were chosen randomly and killed in a variety of ways, with whatever weapon was handy, often after a sexual assault. Most reports suggest that he influenced as a teenager by his cousin Mike, a Green Beret who bragged of committing horrific acts in Vietnam, and who later shot his wife to death in front of Ramirez.The Night Stalker was ultimately caught after a rape victim who’d been left alive got a look at his getaway car, a stolen Toyota that was found abandoned and connected to Ramirez by a single fingerprint. Once they had a suspect, police broadcast his name and face widely and Ramirez was recognized and beaten by a mob in East Los Angeles.He was convicted in 1989 of 13 counts of murder, five counts of attempted murder, 11 sexual assaults, and 14 burglaries, and sentenced to death. To which he said: “No big deal. Death always comes with the territory. I’ll see you in Disneyland.”Ramirez spent the next 23 years on Death Row at San Quentin, but died of Lymphoma in 2013. He was 53. “The Cecil and the Alexandria and the Twin Rosslyn hotels just become these giant coral reefs of the worst people in the world,” says Richard Schave, who runs Esotouric bus tours with his partner Kim Cooper, and makes the Cecil a featured stop on the “Hotel Horrors and Main Street Vice” package. “By 1990, the LAPD won’t go into [t hese places]. It was like, ‘If we’re called we’ll go in. But we’re not patrolling.’”That’s how a guy like the Night Stalker could operate there. Ramirez would return to the Cecil after a killing and ditch his blood-soaked clothes in the dumpsters out back, then walk into the hotel either naked or maybe in his underwear, none of which would have raised an eyebrow since the Cecil in the 1980s, as Schave put t, “was total, unmitigated chaos.”After all, that dumpster probably contained far worse things, and it wouldn’t have been weird to see a half-naked man wandering around a hotel renowned for vice and where the police rarely ventured. Drug dealers worked openly inside. The bodies of overdosed residents could linger in the hall for days. “No one wanted to be the person who called the cops,” Schave says. Another serial killer was known to live at the Cecil. In 1991, six years after Ramirez was caught and sentenced to death, a 41-year-old Austrian journalist named Jack Unterweger checked into the Cecil while he worked on a story about crime in L.A. for an Austrian magazine. Unterweger used his reporting work to secure ride-alongs with LAPD vice cops and those trips were revealed as scouting missions when it was later discovered that Unterweger was also a serial killer with a penchant for strangling prostitutes. It is suspected (but was never proven) that he chose the Cecil because of its connection to Ramirez.When Austrian police connected the strangulation deaths of three L.A. sex workers with a series of six unsolved murders back home — all of them prostitutes who’d been sexually assaulted and strangled with their own bras, using a distinct ligature — Unterweger fled and was arrested in Miami in February of 1992. Unterweger, it turns out, had started abusing prostitutes in his youth, and at age 24 he was convicted of strangling an 18-year-old German woman with her own bra, and sentenced to life in prison.Behind bars, Unterweger had been a model inmate, publishing poems, plays, and an autobiography that became a movie and his popularity made him a cause célèbre in the European arts community, which began to lobby passionately for his release. In 1990, after serving 15 years, Unterweger was granted parole, and almost overnight became a popular TV host and journalist. Within a year, he was in California, killing women again.In June 1994, an Austrian court convicted Unterweger of 11 murders and sentenced him to life with no chance of parole. That night, he killed himself in his cell — with a poetic twist. “He tied the ligature,” Schave said. “The signature ligature by which he killed all the prostitutes in Los Angeles and Vienna. That was his confession.” So those are murders and murderers connected and possibly connected to the Cecil. But the tragedy doesn't end there. There are many other crazy deaths from the Cecil. Mostly all suicides. During the Great Depression. Tens of thousands of Americans took their own lives during the late 1930s, creating the highest-recorded level ever—more than 150 per one million annually in 1937 and 1938, and In the 30s the Cecil had its share of suicides.  In 1931, a guest, W.K. Norton, 46, was found dead in his room after eating poison capsules. A week prior, he had checked into the Cecil under the name "James Willys" from Chicago.  This seems to be the earliest case of suicide at the Cecil. The following year, 25-year-old Benjamin Dodich was found by a maid in a room, dead by a self-inflicted gunshot wound to the head. In 1934, former Army Medical Corps sergeant Louis D. Borden was found with his throat slashed—he had written several notes about suicide while in the room including one that cited poor health as a reason for the suicide. In 1937, the body of Grace E. Magro was discovered wrapped in the telephone wires around the hotel. She later died at the now-demolished Georgia Street Receiving Hospital. Police were unable to determine whether Magro's death was the result of an accident or suicide.  A year later, the body of 35-year-old US Marine Roy Thompson was found on the skylight of a nearby building after he also jumped from his room. He had been staying at the hotel for several weeks.  In 1939, Navy officer Erwin C. Neblett was found dead after ingesting poison; he was 39 years old. Moving past the thirties we find more craziness and fuckery.      In January 1940, teacher Dorothy Sceiger, 45, ingested poison while staying at the Cecil and was reported by the Los Angeles Times to be "near death." No further reports were published about her condition.     In 1944, one of the youngest victims at Cecil Hotel had their life taken from them. Dorothy Jean Purcell, 19 years old, was staying as a guest at the hotel when she threw her newborn son from a window. Purcell did not know she was pregnant and woke in the middle of the night with stomach pains when she was sleeping next to her partner, 38-year-old shoe salesman Ben Levine. Not wanting to wake Levine, she went to the bathroom and delivered the baby herself. Purcell believed the boy was dead, and that’s when she got rid of the body from a great height. The lifeless baby was found on a roof adjacent to the building. Purcell was arrested, but after psychologists determined she was “mentally confused,” she was eventually found not guilty by reason of insanity. In November 1947, Robert Smith, 35, died after jumping from one of Cecil's seventh-floor windows. On October 22, 1954, San Francisco stationery firm employee Helen Gurnee, 55, jumped from the window of her seventh-floor room and landed on top of Cecil's marquee. One week prior, she had registered at the hotel under the name "Margaret Brown." On February 11, 1962, Julia Frances Moore, 50, jumped from the window of her eighth-floor room. We found the newspaper clipping announcing her death, it reads as follows:       "A woman leaped to her death from an eighth-floor window of the Cecil Hotel, 640 S Main St., early Sunday morning, her body landing on a second-floor roof in the light well of the building. Police identified her from a hotel registration card and papers in her purse as Julia Frances Moore, about 50. Det. Sgt. Paul LePage said the woman, who left no notes, had registered at the hotel on Wednesday. Her purse and a small over night bag were found in the room. Although the purse contained only 59 cents, a bank book showed she had nearly c $1,800(around $15,000 today) in a Springfield (II.) bank. Sgt. LePage said he also found a bus ticket stub in dicating she had come here from St. Louis. Other papers I containing two home ad dresses in St. Louis were also found. The officer said he would contact St. Louis police in a an effort to locate the woman's relatives." Also in 1962, October to be exact, another strange death occurred. On October 12, two bodies were found dead on the sidewalk in front of the hotel. One of the bodies was that of Pauline Otton. She was staying on the 9th floor of the hotel. She was 27 years old and had just had an argument with her estranged husband Dewey. The other body was not that of Dewey. It was the body of 65 year old George Gianinni. Initially police suspected the pair jumped together. After some investigation however there found that Ol George has his haha on his pockets and his shoes were still on. They said that if he had jumped his shoes would have fallen off during the fall or when he landed, also who jumps with their hands in their pockets? Well turns out that after her argument Pauline decided it wasn't worth living any more and jumped from the window of her room on the 9th floor. George however was just walking by the hotel about to have the worst, and last, day off his life. Pauline jumped and landed on George as he strolled by killing him. Talk about your bad luck, no wonder some people think the place is cursed. On December 20, 1975, a still-unidentified woman, approximately 23 years old, jumped from her twelfth-floor window onto the Cecil's second-floor roof. She had registered at the hotel on December 16 under the name "Alison Lowell" and was staying in room 327. On September 1, 1992, a man was found deceased in the alley behind the Cecil. Authorities believe the decedent either fell from, jumped from, or was pushed from the hotel's fifteenth floor. At the time of his death, the decedent was five feet, nine inches tall and weighed around 185 pounds. He was wearing blue sweatpants and a black sweatshirt over a gray t-shirt. The Los Angeles County Coroner's Office placed the decedent's age at twenty to thirty-two years. The decedent's true identity has never been established. On June 13, 2015, the body of a 28-year-old man was found outside the hotel. Some conjectured he may have committed suicide by jumping from the hotel, although a spokesperson for the county coroner informed the Los Angeles Times that the cause of death had not been determined. Now in between those last two there was another incident. This incident is probably the most well known one. Thanks to the internet the incident spread fast and there is tons of discussion and speculation about what really happened. The official cause of death was listed as accidental drowning although most people don't by that. If you haven't figured it out already we are talking about the death of Elisa Lam. Wwe could probably do an entire episode on this story so we'll just give you the basics and maybe hit the story a little harder in a bonus for our patreon.   On Jan. 26, 2013, Elisa Lam arrived in LA. She had just come by Amtrak train from San Diego and was headed to Santa Cruz as part of her solo trip around the West Coast. The trip was supposed to be a getaway from her studies at the University of British Columbia in Vancouver, where she was originally from. Her family had been wary of her traveling by herself but the young student was determined to go at it alone. As a compromise, Lam made sure to check in with her parents every day of the trip to let them know that she was safe. That’s why it struck her parents as unusual when they didn’t hear from their daughter on Jan. 31, the day she was scheduled to check out of her LA hotel, the Cecil. The Lams eventually contacted the Los Angeles Police Department. The police searched the premises of the Cecil but couldn’t find her. Police soon released surveillance footage taken from the cameras at the Cecil Hotel on their website. This is where things took a turn into the truly bizarre. The hotel video showed Elisa Lam in one of its elevators on the date of her disappearance acting rather strangely. In the pixelated footage, Lam can be seen stepping into the elevator and pushing all the floor buttons. She steps in and out of the elevator, poking her head out sideways toward the hotel’s hallways in between. She peers out of the elevator another few times before stepping out of the elevator entirely. The last minutes of the video show Lam standing by the left side of the door, moving her hands in random gestures. Nobody else was captured on the video, except Lam. On Feb. 19, two weeks after the video was published by authorities, maintenance worker Santiago Lopez found Elisa Lam’s dead body floating in one of the hotel water tanks. Lopez made the discovery after responding to complaints from hotel patrons about low water pressure and a weird taste coming from the tap water. According to a statement by the chief of the Los Angeles Fire Department, the tank in which Lam’s body was found had to be drained completely and then cut open from the side to remove her five-foot-four frame. Nobody knows how Lam’s corpse — floating lifelessly next to the same clothes she wore in the surveillance video — ended up in the hotel’s water tank or who else might have been involved. Hotel staff told authorities that Lam was always seen by herself around the hotel premises. At a nearby shop, eerily named The Last Bookstore, owner Katie Orphan was among the last to see Elisa Lam alive. Orphan remembered the college student buying books and music for her family back in Vancouver. When the autopsy results for Lam’s case came out, it only served to ignite more questions. The toxicology report confirmed that Lam had consumed a number of medical drugs, likely to be medication for her bipolar disorder. But there were no indications of alcohol or illegal substances in her body. Soon after the toxicology report came out, amateur sleuths began poring over any information they could find in hopes of solving the mystery behind the death of Elisa Lam. One person noted that she seemed to not be taking her medicine previous to her death. It is an important finding to note given that the use of antidepressants to treat bipolar disorder can risk inducing manic side effects if done without caution. Some sleuths have understandably latched onto this detail and suggested it was a likely explanation behind Lam’s strange behavior in the elevator. Hotel manager Amy Price’s statements in court strongly support this theory. During Lam’s stay at the Cecil Hotel, Price said that Lam was originally booked in a hostel-style shared room with others. However, complaints of “odd behavior” from Lam’s roommates forced Lam to be moved to a private room by herself. David and Yinna Lam filed a wrongful death suit against the Cecil Hotel several months after their daughter’s death was uncovered. The Lams’ attorney stated that the hotel had a duty to “inspect and seek out hazards in the hotel that presented an unreasonable risk of danger to [Lam] and other hotel guests.” The hotel fought back against the suit, filing a motion to dismiss it. The hotel’s lawyer argued that the hotel had no reason to think that someone would be able to get into one of their water tanks. Based on court statements from the hotel’s maintenance staff, the hotel’s argument is not entirely far-fetched. Santiago Lopez, who was the first to find Lam’s body, described in detail how much effort he had to exert just to find her body. Lopez said that he took the elevator to the 15th floor of the hotel before walking up the staircase to the roof. Then, he had to first turn off the rooftop alarm and climb up on the platform where the hotel’s four water tanks were located. Finally, he had to climb another ladder to get to the top of the main tank. Only after all that did he notice something unusual. “I noticed the hatch to the main water tank was open and looked inside and saw an Asian woman lying face-up in the water approximately twelve inches from the top of the tank,” Lopez said, as reported by LAist. Lopez’s testimony suggested that it would have been difficult for Lam to make it to the top of the water tank on her own. At least, not without anyone noticing. The hotel’s Chief Engineer Pedro Tovar also made it clear that it would be difficult for anyone to access the rooftop, where the hotel water tanks were located, without triggering the alarms. Only hotel employees would be able to deactivate the alarm properly. If it was triggered, the sound of the alarm would reach the front desk as well as the entire top two floors of the hotel. Los Angeles Superior Court Judge Howard Halm ruled that the death of Elisa Lam was “unforseeable” because it had happened in an area that guests were not allowed to access, so the lawsuit was dismissed. All of the talk of the difficulty on even getting to the water tanks, especially the fact that no alarms were triggered only fueled more conspiracies and speculation. We may never know what really happened and it's another feather in the crazy creepy cap of the Cecil! There are  stories of cold spots and shadowy figures. A news story went around a couple years ago of a ghost photograph, showing a shadowy figure outside of a window of the Cecil Hotel, looking like it was about to jump.There are stories of people saying that they see a woman who looks like Elizabeth Short and feeling like they’re being watched in the hotel. It’s a creepy place even though there are renovations and rebranding (the Cecil Hotel was renamed the Stay on Main), but, well, it’s hard to shake the sort of stories of the Cecil. Also early in 2021 the discovery channel is kicking off it's streaming service with a new episode of everyone's favorite… Ghost Adventures… Those idiots are at it again.   The hotel and the Elisa Lam footage was the inspiration for the Hotel season of American horror story. It was also the inspiration behind the movie Barton Fink starring John Goodman and Johnathan Turturro.  The hotel can also be seen in two popular music videos. The streets have no name by U2, where the brand performs on the roof of a building next to the Cecil. And in Blink 182 video for The Rock Show. The band is shown throwing money off of a single story building next to the Cecil, which may or may not be the same building u2 played on… Probably was though. Top hotel horror movieshttps://www.ranker.com/list/best-horror-movies-about-hotels/ranker-film

LQ (listener question) episode! First Dr. Nichols addresses the impact that elevation has on athletes and what functional ingredients can be fed to help improve oxygen carrying capacity and athletic performance. Secondly, she explains the benefits of natural vitamin E and why synthetic E should not be feared. Show Notes: A functional yeast proven to improve athletic performance by increasing packed cell volume (PCV) and blood hemoglobin can be found in the following products: · Intensify® family of horse feeds by Bluebonnet Feeds · Equilene® family of horse feeds by Bluebonnet Feeds · ADR Paste or Powder from Stride Animal Health · Transform DSI pellets from Stride Animal Health More about Dr. Ben Levine, MD can be found here: https://utswmed.org/doctors/benjamin-levine/ Natural vitamin E supplement: Vitamin E/C by Stride Animal Health Please share this episode on your favorite social media channels using #feedroomchemist so we can see which episodes you are loving! _ If you have a topic or question you would like addressed on a future episode please email info@acbluebonnet.com Dr. Jyme Nichols is Director of Nutrition for Bluebonnet Feeds and Stride Animal Health. For more information on these brands or a free virtual nutrition consult from our team just visit bluebonnetfeeds.com/nutrition-consult --- Send in a voice message: https://anchor.fm/FeedRoomChemist/message

This week’s episode of Circulation on the Run features author Ami Aronheim and Associate Editor Thomas Eschenhagen as they discuss early cardiac remodeling that promotes tumor growth and metastasis. 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 of the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, today we're taking a look at the cardio-oncology world in our feature discussion, but in a very interesting reverse way. Cardio-oncology, what would you think of? I suppose the effects on the heart of cardiotoxic drugs that we use in oncology, right? But this feature paper looks at it the other way around and says does the heart and its remodeling promote tumor growth and cancer? Terribly interesting data coming right up after we discuss a couple of papers, well, all the papers in today's issue. So I want to start. Greg, do you remember what parasites are and why they're important? Dr Greg Hundley: Well, Carolyn, this is actually one of the things that I do remember because we study the parasites when we're looking at microcirculatory dysfunction after the administration of potentially cardiotoxic agents for treatment of cancer. But how about you tell us a little bit more. Dr Carolyn Lam: This is going to be very basic just for all of us. Now, the blood vessels are composed of endothelial cells and mural cells. Endothelial cells line the vascular lumen. Whereas the mural cells, which include faster smooth muscle cells and parasites adhere to the abluminal surface of the endothelium. Parasites regulate vessels stabilization and function, and their loss has been associated in diseases such as diabetic retinopathy, vascular malformation, stroke, and cancer. Just like you said, Greg. Now here we have a series of elegant experiments by Dr Mariona Graupera from IDIBELL in Barcelona and colleagues who use genetic mouse models to identify the specific molecular signature of mural cells at early and late stages of the energetic process and unveil their biological relevance. Their results show that phosphatidyl inositol 3-kinase or PI3K-beta is the main regulator of parasite, proliferation and maturation in vessel growth. PI3K-beta deletion in parasites triggered early parasite maturation, whereas exacerbated PI3K signaling delayed parasite maturation, and thus vessel maturation during angiogenesis. Dr Greg Hundley: So clinically what's the take home message here. Dr Carolyn Lam: The proposed model of mural cell maturation together with the tools developed would be instrumental for the characterization of mural cells in pathologies associated with deregulated vessel growth, such as ischemia stroke, vascular malformation, diabetic retinopathy, and cancer. The therapeutic potential of modulating parasite biology through PI3K signaling provides a new window of clinical intervention for vascular related diseases in which parasite dysfunction contributes to their onset and or progression. Dr Greg Hundley: Very nice, a very important cell type Carolyn. Well, my paper comes from Professor Xiang Qian Lao from The Chinese University of Hong Kong. In this paper, the authors investigated in 140,072 adults all greater than the age of 18, without hypertension who joined a standard medical screening program with 360,905 medical exams that occurred between the years of 2001 and 2016. They assess the joint associations of habitual physical activity and long-term exposure to find particulate matter with the development of hypertension in Taiwan. Dr Carolyn Lam: Wow. A huge study. So what did they find Greg? Dr Greg Hundley: After adjusting for a wide range of co-variants including a mutual adjustment for physical activity or particulate matter, a higher physical activity level was associated with a lower risk of hypertension. Whereas a higher level of particulate matter was associated with a higher risk of hypertension. No significant interaction was observed between physical activity and particulate matter. So Carolyn in conclusion, a high physical activity and a low particulate matter exposure were associated with a lower risk of hypertension. What we would expect the negative association between physical activity and hypertension remain stable in people exposed to various levels of particulate matter. The positive association between particulate matter and hypertension was not modified by physical activity. Thus, Carolyn the authors believed their results indicate that physical activity is a suitable hypertension prevention strategy for people residing in relatively polluted regions. Dr Carolyn Lam: Oh, thanks for summarizing that. So well, Greg, Hey, I've got a question for you. Do you measure a high density, lipoprotein cholesterol or HDL cholesterol? Do you measure the levels or do you measure the particle concentration in your clinical practice? Dr Greg Hundley: I think just the levels Carolyn. Dr Carolyn Lam: Yeah. Same, but there's a lot of data coming out about the particle concentration. Let's review a little bit about that. So the HDL cholesterol is an established athero-protective marker, particularly for coronary artery disease, but HDL particle concentration may better predict the risk. However, the associations of HDL cholesterol and HDL particle concentration with ischemic stroke and with myocardial infarction among women and blacks has not been well defined. And so Dr Rohatgi from UT Southwestern and colleagues analyzed individual level participant data in a pool cohort of four large population studies without baseline atherosclerotic cardiovascular disease. These were the Dallas Heart Study, the ERIC study and the MISA study, as well as the PREVENT study. Dr Greg Hundley: What did they find? Were there any unique pieces of data related to either sex or those of black race? Dr Carolyn Lam: They found that HDL particle concentration is inversely associated with the specific endpoint of ischemic stroke overall and among women. Whereas HDL cholesterol was not associated with ischemic stroke. Neither HDL particle concentration nor HDL cholesterol levels were associated with myocardial infarction in blacks. Thus HDL particle concentration, but not HDL cholesterol may be a useful risk marker for ischemic stroke. HDL particle concentration may be a useful risk marker for both myocardial infarction and ischemic stroke among women. There is likely minimal utility of HDL markers for risk prediction of myocardial infarction in the black population. Dr Greg Hundley: Thanks Carolyn. That was such a great introduction and overview and then the results was so clear. Carolyn, my next paper comes from Dr Peter Willeit from the Medical University of Innsbrook. In this paper, the author systematically collated carotid intima-medial thickness data from randomized controlled trials. The primary outcome was a combined cardiovascular disease endpoint defined as myocardial infarction, stroke, revascularization procedures, or a fatal cardiovascular event. The authors estimated intervention effects on carotid intima-medial thickness progression and incident CVD for each trial before relating the two using a Bayesian eta- regression approach. Dr Carolyn Lam: Oh, this is important. So what did they find? Dr Greg Hundley: Carolyn, they're going to have 10 micrometer per year evaluations. So across all intervention, each 10 micrometer per year reduction of carotid intima-medial thickness progression resulted in a relative risk for cardiovascular disease of 0.91 with an additional relative risk for cardiovascular disease of 0.92 being achieved independent of carotid intima-medial thickness progression. So combining these results, the authors estimate that interventions reducing carotid intima-medial thickness progression by 10, 20, 30 or 40 micrometers per year would yield relative risks of 0.84, 0.76, 0.69 or 0.63 each incrementing with the magnitude of reduction in micrometers per year. Results were similar when grouping trials by type of intervention. Time of conduct, time to ultrasound follow-up, availability of individual participant data, primary versus secondary prevention trials, the type of carotid intima-medial thickness measurement, and the proportion of women in the studies. Dr Carolyn Lam: So could you summarize that Greg? Dr Greg Hundley: You bet, Carolyn. So the extent of intervention effects on carotid intimal-medial thickness progression predicted the degree of cardiovascular disease risk reduction. This provides a missing link supporting the usefulness of carotid intimal-medial thickness progression as a surrogate marker for cardiovascular disease risk prediction in clinical trials. Dr Carolyn Lam: Indeed. Thanks, Greg. It's important because it also quantifies that risk reduction. Very nice. Now let's just round up with some other papers in the issue. There is a perspective paper by Dr Bunch on Dementia and atrial fibrillation, a research letter by Dr Ellinor on myocyte specific upregulation of ACE two in cardiovascular disease, the implications for our SARS-coronavirus to mediated myocarditis. There are letters to the editor regarding the article small extra cellular macrovesicles mediated, pathological communications between dysfunctional adipocytes and cardiomyocytes as a novel mechanism, exacerbating ischemia reperfusion injury in diabetic mice. These letters were by Dr Li with response by Dr Ma. There's a research letter by Dr Natarajan on genetic variation and cardiometabolic traits and medication targets and the risk of hypertensive disorders of pregnancy. Dr Greg Hundley: Carolyn, I've got a couple other features to describe. Aaron Baggish and Ben Levine provide an On My Mind piece, related to sports after COVID-19. Jeffrey Smietana has an ECG challenge regarding an ELVAD artifact. Then finally, Bridget Kuhn has cardiology news related to an announcement from the Association of Black Cardiologists calling for an urgent effort to address health inequality and diversity in cardiology. Can't wait to get to that feature discussion and that really unique twist in cardio-oncology. Dr Carolyn Lam: Here we go. Greg. Based feature discussion. We are diving into the world of cardio-oncology. Now, usually that refers to the intersection between cancer and cardiovascular disease, where we usually talk about cancer and cancer treatment effects on the cardiovascular system. But emerging data now suggests the concept of reverse cardio-oncology, whereby heart disease potentiates cancer. Today's feature paper really provides very important and significant preclinical data to support this. I'm so pleased to have with us, the corresponding author, Dr Ami Aronheim from Israel Institute of Technology, as well as our associate editor, Dr Thomas Eschenhagen from University Hospital Hamburg Eppendorf in Germany. Ami, thank you very much for joining us today. Please. Could you walk us through your very elegance study and the results? Prof Ami Aronheim: We used a model, which is called the transfers, all the constriction, which promotes pressure overload on the heart. Actually following this procedure, we implanted cancer cells into mice and we followed the growth of these tumors. Actually we found out that the tumors of a tuck operated mice is growing much faster. Also when we used a metastatic model, namely, when we injected cells into the tail vein, we obtained more metastatic lesions in the lungs. Actually we found out that the serum from these mice is able to promote the variation of cancer cells in vitro. Then we also identified a protein, which is potentially promoting these cell proliferation in vitro. Dr Carolyn Lam: That is really significant. I mean, am I right that this is the first study to show that cardiac remodeling actually promotes tumor growth and metastasis and this is probably via secreted factor. Prof Ami Aronheim: This is the first paper showing that early events of cardiac remodeling promote cancer cell proliferation. It is known that heart failure by the work of De Boer’s group, that heart failure is promoting cancer load in mice. This paper was also published in Circulation 2018. Dr Carolyn Lam: Indeed. Thank you for reminding me about that. And I am a huge fan of Rudolph de Boer and his work. Indeed. Could I ask though, in your study, did you identify a particular secreted factor? Prof Ami Aronheim: We looked at the RNA seq from conduct remodeled heart, and we looked for secreted factors in the heart and we focused on two secreted factors CTGF and periostin, which are known to promote cancer growth. And indeed we found in our mice models that reduced in level is increased in the serum of mice of tuck operated mice. Once we deplete the serum from periostin, we ambulated this increase in cell proliferation. Dr Carolyn Lam: Wow. So periostin appears a culprit, but I'm sure the listeners are dying to know. Was there any human data that you had that supported the animal findings? Prof Ami Aronheim: The model in mice, the tack operation, it's hard to find the right model in human because the operation is really rapid. When the mice wake up, they have this pressure overload, the only disease which in human correlates or is mimicked by the tag is Altucher's stenosis, which is the restriction of the outtake evolve, the right aortic valve]. And we looked in these patients and what we found out, we looked at the echo cardiography data of a lot of patients. We actually found out that for young basically patients 40 to 60 years old, if they have moderate to severe aortic stenosis, they have higher risk to develop cancer about 1.6-fold higher than our external these patients. Although I must say with caution that this size group is quite small and it should be repeated with much higher number of patients. Dr Carolyn Lam: Wow. Thank you so much, Ami. Thomas, I have to bring you in here. Thank you for managing this very remarkable paper. Could you share some thoughts on what you think this means for the field? Thomas Eschenhagen: We all immediately as editorial team like this paper. When it came in on the background of the different paper, it really provides significant additional evidence that this interaction between cancer and the heart is two sided. And that's, as you said in the intro, that's really very important. And it's all very interesting that apparently these two different models used by Rudolf de Boer, which wasn't ischemia myocardial injury model. And here it's a hypertrophy model with early remodeling. They both do similar things, but apparently by different mechanisms. Because the number of the factors identified in the de Boer paper do not match with, with these two factors, CTGF and periostin. And for both, I think we have now convincing evidence that they may play a role, but it also shows that this is probably a quite complex interaction between the heart and the cancer. That makes it extremely interesting. Of course it's important because it's such a common comorbidity, I mean, cancer, cardiovascular diseases, are the most prevalent and the second most prevalent diseases is cancer. So this interaction must be very, very important. And it's very good that these two papers now focus of you on the reverse side and not only on the classic cardiac toxicity side, which me as pharmacologists, of course, we, I was always interested in. Dr Carolyn Lam: Yeah, indeed. I mean, Thomas me too. As a heart failure clinical trial list and epidemiologists, if I may, I always thought it was just shared risk factors, you know, age being particularly one of them. Thomas Eschenhagen:   Obviously, as you said, shared risk factors do play a role must, must their role. So it's certainly not only this direct interaction, but this new paper shows that there is in addition to this risk factor model, something specific. And that of course could be, I mean, at least theoretically be addressed. Dr Carolyn Lam: For both Thomas and Ami, what do you think are the implications now? I mean, should we be screening all patients with aortic stenosis more closely for cancers? What do you think are the clinical implications? Maybe Ami first? Prof Ami Aronheim: I think cardiovascular disease patients are already watched very carefully beforehand. But certainly I think that they should be also observed for cancer specifically. So yes I believe it should be. Also I this cardiovascular treatment should consider to make them early as possible to avoid any interaction with cancer. Dr Carolyn Lam: Yeah, that completely opens the field to, for example. Early aortic valve replacement, reducing subsequent cancer risk, like you mentioned in your paper, I mean, that's just mind blowing. Thomas, what do you think? Thomas Eschenhagen: I agree, 10 years ago, we said that more cancer patients, particularly those under treatment should be sent to the cardiologist to look for the heart. Now we will say the other way around as well. We really need to look more carefully for cancer. So I think this paper and the other one have the consequences we should do more here. There's also obviously a number of very interesting questions because one of the findings I found fascinating in this paper by Ami and this group was that this mouse strain, which finally did not show the classical science of remodeling after transverse aortic striction. So no BNP, no NP, no BDMEC increase in this small strain. There was no increase in cancer growth. Very interesting, because normally you would think somehow that these mice, which were kind of normal in the cardiac response would be worse, but in this respect they were better. So that's a very interesting aspect. The second aspect I found really fascinating is the human data suggest, I guess it's quite preliminary data, but there's a suggestion here that this interaction is mainly seen in younger patients. And I'm not quite sure what that means, but it's something to look at. Dr Carolyn Lam: Wow. Thanks for highlighting those Thomas. So Ami maybe the last word from you. Given all of this remaining questions and so on, what are your next steps? Prof Ami Aronheim: First, I wanted to comment something more wide view for this interaction that we find with cancer. I think all the organs actually communicate with one another. The fact that we are looking on a heart and cancer, this is due to the fact that it's easy. We have the models working in the lab and it's easy. But I'm sure if we're going to look to other diseases and other organs, there will be other connections of the heart with other organs and other diseases and maladies, which by conducting modeling, they will promote or maybe even reverse other maladies. So I'm sure that there is a communication between all organs, many organs altogether, and they will affect one another. Our directions currently are to look more precisely for the periostin story because we follow this mainly in vitro and would like to follow it in vivo. Also I think this mice model are nice, but to look also in human, where the periostin in aortic stenosis patients, where then, we can find out earliest in, in the serum before intervention, and to look after whether this secreted factor goes down or reduced. Also we are looking in other transgenic model that we generated along the years, which are known to result in cardiac modeling. We want to see whether these mechanisms are similar or different and whether they can promote also cancer progression. The use of these transgenic mice is very nice because we can induce them and we can shut down them so we can learn more about the kinetic, which influence one another, and exactly whether they can be reversed or not. Dr Carolyn Lam: Thank you so much Ami for sharing your thoughts on those future actions, a lot of work and such worthwhile areas to explore. Thank you too, Thomas for sharing your thoughts. Listeners. Thank you for joining us today on circulation on the run. Dr Greg Hundley: This program is copyright the American Heart Association, 2020.  

Jon and Bryan discuss Bob Larsen's path to becoming one of the most influential coaches in distance running, including:- His initial thoughts about Robert Lusitana's film "City Slickers Can't Stay With Me" and his reluctance to make it- His life growing up on a farm in Minnesota with no electricity or running water some 15 miles from the nearest town- The challenge of raising children when their life experiences are so different, and Bob's experience seeing his children and his runners adopt the values he tried to instill- Why you need to be able to see a person's life through their eyes if you hope to get the best out of them- His advice to his runners: if you're going to get the best out of yourself, you need to get the best out the people around you. Including your coach.- How he used moderate improvements and successes in his athletes' performance to get them to pursue success in other areas- The conflict of investing so much time in your athletes and the job of coaching--from Sunday morning runs to trips to Europe or training camps--and the challenge of balancing that with family responsibilities- His decision to de-emphasize the distance events when he became the head coach at UCLA, when many coaches gave their scholarships to distance runners in hopes of competing for Track and Cross Country titles- Why high school is the best level to be a coach, and why Bob misses it- How he handled athletes leaving his program and moving on- Why the decrease in scholarships at the NCAA level and the move to low volume training methods in the 90s caused the club scene--and American distance running--to decline- What a threshold (or tempo) run is, how it should be executed, and what the minimum length of a threshold run should be for most high school athletes- The conversation that shifted Bryan's approach to training and unlocked more of his ability- How he evaluated his success for each season by whether the year ended with a "wow factor"- How he came to believe altitude training was key, and why they chose Mammoth Lakes, CA, for their training location- His ability to be at the forefront of three critical trends--threshold training, altitude training, and group training--and why he was able to build his training program around them when so many other coaches didn't- How threshold training played a key role in Jon's breakout season, and the incredibly fast threshold run he did training for the World Cross Country Championships- Karen Hecox's surprise NCAA 3000m Championship off of a summer of training with her future husband- Why Meb didn't expand his training group in Mammoth and how he eventually prioritized the control over the workout over the benefits of having others there to push him- And finally, the secret of threshold training: it's the way runners love to run. If you liked this episode, you might also like our interviews with Merhawi Keflezighi (Meb's brother) and Ben Auerbach.Recorded July 1, 2020.References:City Slickers Can't Stay With Me - Amazon Prime VideoRunning to the Edge by Matthew Futterman - AmazonMake the Leap by Bryan Green - On sale end of summer/early fallGuest:Bob LarsenHosts:Bryan Green, @sendaibry, Go Be More BlogJon Rankin, @chasejonrankin, Go Be MoreLinks:Go Be More websiteGo Be More YouTube ChannelFeedbackSubscribe on your favorite player:Simplecast 

Today’s episode discusses the paper “Randomized Comparison of the Polymer-Free Biolimus-Coated Biofreedom Stent With the Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Orsiro Stent in an All-Comers Population Treated With Percutaneous Coronary Intervention: The SORT OUT IX Trial”   Dr Carolyn Lam and Dr Greg Hundley also discuss the following: “Incidence, Microbiology, and Outcomes in Patients Hospitalized With Infective Endocarditis” by Shah et al. “Reducing Hypermuscularization of the Transitional Segment Between Arterioles and Capillaries Protects Against Spontaneous Intracerebral Hemorrhage” by Joutel 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 Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn our feature article this week, we're going to dive into evaluating stent efficacy and looking at biodegradable stents and polymer free stents, and I can't wait to get to that feature. But before we do that, how about we get to other articles in our journal today? Would you like to start? Dr Carolyn Lam: You bet, Greg. So this paper describes temporal changes in the incidence, microbiology and outcomes of infective endocarditis and the impact of changes in national antibiotic prophylaxis guidelines on incident infective endocarditis in Scotland. Dr Anoop Shah from University Center for Cardiovascular Science at University of Edinburgh, and colleagues used a Scotland wide individual level linkage approach to identify all patients hospitalized with infective endocarditis from 1990 to 2014, and linked their records in national microbiology, prescribing and morbidity and mortality datasets. Dr Greg Hundley: Interesting, Carolyn. So what did they find in this study? Dr Carolyn Lam: The crude incidence rate of infective endocarditis hospitalizations increased from 1990 to 1995 but has remained relatively static thereafter with both short and long-term adjusted case fatality rates showing a steady decrease over the last 25 years. However, the incidence rate has doubled in the elderly. Importantly, there was no change in crude incidence following the 2008 change in antibiotic prophylaxis guidelines. The majority of patients with endocarditis in their cohort did not have positive blood cultures. However, in those that did have positive microbiology, staphylococcus and enterococcus conferred the highest risk for all-cause mortality. Dr Greg Hundley: Ah, very interesting. More in the world of endocarditis. Well, Carolyn, my paper is also interesting and it involves both mouse and human experiments to identify the etiology of deep intercranial hemorrhagic stroke. Now I'm not going to quiz you this week because I think you're going to want to quiz me in anticipation of some of these exciting study results. A little bit of background. First of all, the study comes from Dr Anne Joutel from INSERM and it has been thought that smooth muscle cell degeneration at the site of arterial wall rupture may be sufficient to cause hemorrhage. However, deep intracranial hemorrhages are rare in some aggressive small vessel diseases that are characterized by significant arterial smooth muscle cell degeneration. Therefore, the authors hypothesized that a second cellular defect may be required for the occurrence of intercranial hemorrhage. So to address this hypothesis, the author studied a genetic model of spontaneous deep intercranial hemorrhage in mice, and analyzed cerebral retinal micro vessels, performing genetic rescue experiments, vascular reactivity analysis, and computational modeling. And in the human experiments, they examined post-mortem brain tissues from patients that had sporadic deep intercranial hemorrhage. Dr Carolyn Lam: Wow, that's a lot of work from mice to men. Well, let's start with the mice. So what did they find there, Greg? Dr Greg Hundley: Right, Carolyn. So the authors identified in the normal cerebral retinal vasculature, a novel segment between arterials and capillaries herein called the transitional segment, and that is covered by neural cells distinct from smooth muscle cells and parasites. In Col4a1 mutant mice, this transitional segment was hyper muscularized with a hyperplasia of neural cells expressing more contractile proteins, whereas the upstream arterial exhibited a loss of smooth muscle cells. Moreover, the hyper muscularization of the retinal transitional zone increased its contractility in tone and raised the intravascular pressure in the upstream feeding arterial. Dr Carolyn Lam: Wow, masterful explaining, Greg. Okay. What about in the humans? Dr Greg Hundley: Well, the author similarly found that hyper muscularization of the transitional segment and focal arterial or smooth muscle cell loss in brain tissues from patients were observed in those with sporadic deep intercranial hemorrhage. Dr Carolyn Lam: Okay, so put it together for us, Greg. Dr Greg Hundley: Right. So the results suggest that hyper muscularization of this transitional segment is involved in the incurrence of intracranial hemorrhage in these studied mice, and this hyper muscularization in this zone raises the intravascular pressure in the upstream feeding arterial and promotes its rupture at the site of smooth muscle cell loss. The human data corroborate these findings indicating that these two mutually reinforcing vascular defects may represent a general mechanism of deep intercranial hemorrhage. Really interesting results. Dr Carolyn Lam: Not just interesting, but very, very nicely summarized. Thanks Greg. Well, other very interesting papers in today's issue include a research letter by Dr Tiantian Li et al, entitled Associations Between Short Term Exposure to Fine Particulate Matter and Cardiovascular Disease Hospital Admissions After Index Myocardial Infarction. A case crossover study from Beijing, China. There's also a white paper from Dr Milton Packer on the role of deranged energy deprivation signaling in the pathogenesis of cardiac and renal disease in states of perceived nutrient over abundance. This beautiful white paper presents a mechanistic framework that may explain the findings of large scale randomized trials of SGLT-2 inhibitors and the close association of ketogenesis and erythrocytosis with the cardio protective and renal protective benefits of these drugs. Interesting. There's also a series of papers on COVID-19, including an online white paper by Dr Franz Messerli on COVID-19 and renin-angiotensin blockers, current evidence and recommendations. A perspective paper by Dr Michael Givertz on the challenges in heart transplantation in the era of COVID-19. Another online paper by Dr Harsimran Singh entitled New York City innocence lost, cardiology in the COVID-19 pandemic. Dr Greg Hundley: Wow, Carolyn, this issue is just truly full of a lot of articles in addition to our original research. So I have an exchange of letters to the editor between Richard Sutton and Dr Ben Levine regarding Dr Levine's previously published tilt table manuscript. Next, Dr James Byrd from the University of Michigan offers a perspective on pausing clinical research during the COVID-19 pandemic. Dr Comilla Sasson from the American Heart Association heads a very large group of authors to provide a very nice piece on guidance for life support during the COVID-19 pandemic. Next, Professor Guilo Stefanini from Humanitas University has a research letter regarding ST elevation myocardial infarction in patients with COVID-19, both the clinical and the angiographic outcomes. And then finally, another ECG challenge from Dr Adrian Baranchuk entitled an ominous ECG sign in critical care. Well, Carolyn, what a great issue, and let's get on to that feature discussion to learn a little bit more about bio resorbable intercoronary stents. Dr Carolyn Lam: Great. Let's go, Greg. Dr Greg Hundley: Well, listeners, We're here for our feature discussion. And today we have Professor Lisette Jensen from Denmark and Dr Dharam Kumbhani from Dallas, Texas, one of our own associate editors. Lisette, could you tell us a little bit about the background for your study of intercoronary stenting and what was the hypothesis that you wanted to address? Prof Lisette Jensen: The overall background or aim for this program is that we want to have a quality control of what we put into the patients, what stent we put in, and also we wanted to do as much research as possible, and we want to do it if it's possible on a low budget. For the present study, the Sort Out IX, before we did the study, we knew that the Bio Freedom stent was doing very well with a short time of dual antiplatelet therapy in patients with high bleeding risk. At the same time, we knew that the Orsiro stent was doing very well in all common populations, we used it in Sort out VII also. We wanted to see how the Bio Freedom stent, the one you could use with a short time of dual antiplatelet therapy, how it was compared to a gold standard stent. In this study, we did not shorten the treatment time with dual antiplatelet therapy, but we followed the guidelines with six months for patients with stable angina, and 12 months for patients with acute coronary syndrome. Dr Greg Hundley: Can you just remind our listeners, what's the difference between the Bio Freedom stent and then Orsiro stent? Prof Lisette Jensen: There's several differences. The strut thickness of the two stents differs. The Orsiro stent is an ultra-thin stent strut and the Bio Freedom stent is 120 microns. Also, the Bio Freedom stent is free of a polymer, compared to the Orsiro stent where the polymer is biodegradable and is degraded in one to two years. And also the drug is sirolimus in the Orsiro stent and it is released within three months compared to the Bio Freedom stent where most of the drug biolimus is released within one month. Dr Greg Hundley: So the Bio Freedom is a stainless-steel drug coated stent, and the Orsiro stent is a biodegradable stent. So can you tell us what was the study design, and then the study population? Prof Lisette Jensen: It was a randomized trial and we enrolled 3,151 patients. They were randomized one to one, two to two stent groups, and we followed the patients. The primary endpoint was after one year, and this is what we're going to publish now in the journal, and we plan to do up to five years follow-up in the patients. Dr Greg Hundley: And what outcomes were you looking for? Prof Lisette Jensen: The primary endpoint was MACE, and that was a composite endpoint of cardiac deaths, target lesion revascularization, and myocardial infarction, not clearly related to any other segment that the index listed. Dr Greg Hundley: So 3,151 patients, so a very large study. Can you tell us a little bit about your study outcomes? Prof Lisette Jensen: The outcome was the primary end point after one year was, we saw MACE rate in the Bio Freedom treated patients was 5.0% compared to 3.7% in the Orsiro group. And the study was designed as a non-inferiority study, so with these numbers, Bio Freedom stent did not meet the criteria for non-inferiority.   Dr Greg Hundley: And were there any particular patient populations or subgroups where you saw differences in performance from one stent versus the other? Prof Lisette Jensen: We looked into several predefined subgroups, which are also in the paper as figure three where we did a force plot, and in all the pre-specified subgroups, including indication for PCI, acute coronary syndrome or stable angina, young patients, old patients, diabetic, non-diabetic, gender, we did not see any significant difference. Dr Greg Hundley: Well, Dharam, I'd like to switch over to you a little bit. Can you help us put this study in perspective to the other world's literature related to intercoronary stenting? Dr Dharam Kumbhani: You know, one of the biggest advantages of the way they enroll patients is they tend to be a lot more inclusive than many of the other trials that are done. So typically isn't all common population. So, now and again, I think it was an important trial because as she just outlined, it compares the Bio Freedom stent, which is a polymer free stent to a biodegradable stent. And this was really the first comparison of this Bio Freedom stent with a more contemporary stent that is used in clinical practice. There have been a couple of other trials like the industry three and industry two trial which have compared it with bare metal stents. We know that this stent has a better performance than that, but when you compare it with, especially the thin struts or Orsiro, the latest in this class of DES, it is the thinnest strut, one of the thinnest strut stents that is in the market. The strut thickness, we know it really correlates quite well in stent restenosis. I think this really helps move the field forward in terms of having data available for this comparison, and it suggests that perhaps in this kind of pragmatic design, that this Bio Freedom stent did not necessarily in the timeframe that they studied, meet the criteria for non-inferiority compared with the Orsiro stent. So I think there's still valuable insight. The stent is not yet approved in the US. None of the Bio Freedom stents are available in the US. This is CE Mark, but not available in the US. So I think this does add to the overall body of literature for this group of stents. Dr Greg Hundley: I would like to ask you both, perhaps one at a time. Lisette, you first. What do you see is the next research study that needs to be performed in this field? Lisette. Prof Lisette Jensen: Can I just give one more comment to what Dharam mentioned with the restenosis, because that was actually what we saw in the Sort Out IX. We had a higher rate of the target lesion revascularization rate in the Bio Freedom stent group, so the efficacy was less. It could be because of the bigger stent struts, pushing us in a direction where we should use stents with thinner stent struts. And also we saw that the safety did not differ as we saw the equal number of stent thrombosis within one year. I think what we should do next is maybe we should continue to work on the thin stent struts, and then also for the patients, the bleeding matters a lot. So it should be better to reduce the bleeding time to develop devices where we can reduce the treatment time for dual antiplatelet therapy. Dr Greg Hundley: Very good. Dharam, your thoughts? Dr Dharam Kumbhani: I would definitely agree. I think one of the most appealing aspects of this group of stents, because they don't have polymer, the ability to shorten the duration of antiplatelet therapy. And over the last couple of years, we've seen an incredible change in how we think about dual antiplatelet therapy and a number of trials have really challenged that dogma. So I really think that a stent like this, I think it will be very interesting to study this in patients who are either high bleeding risk. This does perform better than bare metal stents, we know that. So conceivably we can get away with a much shorter duration of dual antiplatelet therapy, or just a lower duration of dual antiplatelet therapy in general. So I would think that that would be one of the next areas of research in a randomized fashion for this group of stents. Dr Greg Hundley: Well, listeners, we've had a wonderful conversation here with Professor Lisette Jensen from Denmark and Dr Dharam Kumbhani from Dallas, Texas, related to some new evolutionary thoughts in intercoronary stenting. For all our listeners out there on behalf of Carolyn and myself, we wish you a great week and look forward to speaking with you next week. This program is copyright of the American Heart Association 2020.  

With our second episode back in the studio we’ve got a local comedian who we’ve been trying to get on the show for a hot minute. Then Covid-19 hit, and here we are. So we’re back and so is he, Ben Levine joins us to have a few tasty brews, and tell us how hungry he is to get back on the stage.

This week we are joined by the director of Réveil - Waking up French, Ben Levine. This documentary asks all the questions we've been asking while working on this podcast. Jesse talks to Ben about how Réveil came to be and what he learned while working on it. If you haven't seen this documentary we can't recommend it enough! Réveil - Waking up French Website - http://www.wakingupfrench.com/ Follow Ben on Facebook - https://www.facebook.com/Reveil.WakingUpFrench/ Don’t forget to check out our Patreon for extra bonus content and a way to support the show - https://www.patreon.com/fclpodcast If you’ve always wanted to have a French-Canadian Legacy t-shirt check out our merch on Teespring – https://www.teespring.com/fclpodcast

Melody is back to let you know about all the Blog and Virtual Meetups happening and then Jesse returns to preview next week's episode with Filmmaker Ben Levine. Ben is the director of the brilliant Documentary Réveil – Waking up French. For the bonus question, Jesse gets to ask Ben something that's been on his mind since his Junior year of High School. For a limited time you can watch Réveil here - https://video.maine.edu/media/Waking+up+French--!+R%C3%A9ve%C3%ADl+-+Public/1_zb73lmqz Don’t forget to check out our Patreon for extra bonus content and a way to support the show - https://www.patreon.com/fclpodcast If you’ve always wanted to have a French-Canadian Legacy t-shirt check out our merch on Teespring – https://www.teespring.com/fclpodcast

In this conversation, the third of a four-part series on mentorship, SSPI Director of Development and Innovation Lou Zacharilla speaks with two men whose careers have taken them to the top of their respective professions at some of the industry’s largest corporations. They share with us the unique advantages and challenges of mentorship “inside a giant.” Airbus is an international company and a leader in designing, manufacturing and delivering aerospace products. And with 133,671 employees, it certainly qualifies as a giant. Its US Space & Defence Group is led by Chris Emerson. Chris has served as president of the group since 2019, where he oversees the operations and strategy of all its companies in the USA. He also serves as Chairman of the Board. Founded in 1948 by David Ogilvy, this ad agency can be found in 132 offices in 83 countries around the world. Adweeks’ Agency of the Year in 2016, Ogilvy’s client list is long and ranges from American Express to Ikea to Samsung. Ben Levine serves as Executive Partner and Head of Global Partnerships from Ogilvy’s main office in New York. He is responsible for developing and growing strategic relations across the Ogilvy Group, its parent company WPP and external networks to find greater value for its clients. Ben also serves as Global Client Leader for the agency.

Introduction: Today we are fortunate to have with us none other than Ben Levine from Long Island, New York. Ben was a 2019 summer intern at Leasing REality, and is currently a sophomore at the University of Wisconsin. A random fun fact about Ben is that he used to be a black belt in karate.   Episode Notes:  At 2:01, Ben Levine touches upon his work ethic and how preparation provides him comfort. At 3:22, Ben discusses making a great first impression during an interview. At 5:50, Levine points out being a communicative and organized person. At 6:59, he talks about planning, evaluating, and simplicity. At 8:10, Ben shares being a believer in karma, and how he “makes a difference.” At 8:57, Levine provides his thoughts on Larry Haber’s “Mo Money Mo Problems” question. At 9:46, he dives into the topic of utilizing past experiences to grow. At 11:09, Ben dishes on “subscribing to a team first mantra,” as you’re only as strong as your weakest link. At 11:46, Levine notes how he goes about mastering his craft. At 13:14, Ben Levine closes out the podcast discussing his desire to teach others about his past mistakes.

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 Centre 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. Dr Carolyn Lam: Greg, this issue is full of super interesting papers, many of which were presented as late-breaking presentations at the American Heart Association, like the feature paper that sacubitril/valsartan across the spectrum of ejection fraction in heart failure, where this was really analyzed across the landmark PARADIGM and PARAGON trials. I'm sure everyone's looking forward to hearing about it, but before we talk about that, I want to share some more very interesting results from a very important trial, the REDUCE-IT trial. So, as some background, some trials have found that patients from the United States derive less benefit than patients enrolled outside the United States. And this was the reason that there was a pre-specified subgroup analysis of the REDUCE-IT trial, which really is the reduction of cardiovascular events with icosapent ethyl-intervention trial, and this analysis was conducted to determine the degree of benefit of icosapent ethyl in the United States. So, Greg, do you remember what the REDUCE-IT trial was about? Dr Greg Hundley: Well, Carolyn, I think REDUCE-IT randomized 8,179 statin-treated patients with triglycerides between 135 and 500 milligrams per deciliter and LDL cholesterol levels between 40 and 100 milligrams per deciliter and a history of atherosclerosis or diabetes to Icosapent Ethyl, four grams per day or placebo. And the primary endpoint, I believe, was cardiovascular death, nonfatal myocardial infarction, non-fatal stroke, coronary revascularization or hospitalization for unstable angina. Hah! Dr Carolyn Lam: Wow, Greg, you pass that quiz, like maybe you had a cheat sheet answer. Dr Greg Hundley: All right, Carolyn, tell us now what did REDUCE-IT USA find? Dr Carolyn Lam: This was from a corresponding author, Dr Deepak Bhatt, from Brigham and Women's Hospital Heart and Vascular Center, and his colleagues and they found that in the United States Icosapent Ethyl at four grams a day produced large and significant reductions in multiple ischemic endpoints including cardiovascular death, myocardial infarction, stroke, coronary revascularization, and hospitalization for unstable angina. Furthermore, REDUCE-IT US demonstrated that Icosapent Ethyl provided a statistically significant 30% relative risk reduction and a 2.6% absolute risk reduction in all-cause mortality. The risk benefit profile of Icosapent Ethyl was highly favorable with an overall safety and tolerability profile virtually identical to placebo. Dr Greg Hundley: Wow, Carolyn. So, this does have important implications for us in the US, very nice. Thank you for that lovely quiz. So, Carolyn, I'm going to switch now and talk about a paper from Roddy Walsh from Amsterdam in the Netherlands. In this study, the investigators defined the frequency of rare variation in 2,538 patients with dilated cardiomyopathy across protein-coding regions of 56 commonly tested genes and compared this to both 912 confirmed healthy controls and a reference population of 60,706 individuals to identify clinically interpretable genes robustly associated with dominant monogenetic dilated cardiomyopathy. Dr Carolyn Lam: Wow, wow. That's a huge study. So what did they find? Dr Greg Hundley: Okay, Carolyn. So overall rare variants in 12 genes potentially explain 17% of cases in the outpatient clinical cohort representing a broad range of adult patients with dilated cardiomyopathy and 26% of cases in the diagnostic referral cohort enriched in familial and early onset dilated cardiomyopathy. And so, practically speaking, by analyzing two dilated cardiomyopathy cohorts with distinctive patient profiles, the authors were able to comprehensively evaluate the genetic basis of dilated cardiomyopathy and identify variant classes that were particularly associated with early-onset disease. By restricting analyses to validated and interpretable genes and variant classes, the authors hoped in this study to increase the accuracy and reduce the uncertainty associated with genetic testing in dilated cardiomyopathy. Dr Carolyn Lam: Very nice, very practical information. Well, my next paper is, I have to admit a super favorite topic of mine, and that is sex differences in heart failure. Now as a reminder to everybody, women represent over half of patients with heart failure with heart failure preserved ejection fraction, and there are multiple effective drug and device therapies for HFrEF, or heart failure reduced ejection fraction, but none approved for HFpEF. Thus, there is a greater so-called failure therapeutic deficit in women compared to men. So, does the recently presented PARAGON trial provide answers? Dr Greg Hundley: Ah, Carolyn, you were involved in the PARAGON trial. Maybe tell us a little bit about that first to help us get oriented. Dr Carolyn Lam: I would love to. So PARAGON compared sacubitril/valsartan with valsartan in patients with HFpEF. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes, and the trial overall narrowly missed this primary outcome. However, an intriguing result in PARAGON was a significant sex-by-treatment interaction. And this was explored further in the current pre-specified subgroup analysis of outcomes by sex, which was reported by John McMurray from University of Glasgow and his colleagues. Dr Greg Hundley: Ah, so I'm interested. What was this interaction? Dr Carolyn Lam: Ah, so here is how the interaction work. Now, remember this was multi-variably adjusted significant in a pre-specified large subgroup of PARAGON. And what we found was that as compared with valsartan, sacubitril/valsartan seem to reduce the risk of heart failure hospitalization more in women than in men. Now, while the possible sex-related modification of this effect of treatment has potential explanations, the current study really cannot provide a definitive mechanistic basis for this finding. Dr Greg Hundley: Very interesting. So, perhaps then, in heart failure preserved ejection fraction, sacubitril/valsartan could be very helpful in women. Dr Carolyn Lam: Yes, and perhaps especially those with each ejection fraction in the lower ejection fraction range. And that is coming up in our future discussions, so let's not preempt it. You got another paper, Greg? Dr Greg Hundley: Absolutely, Carolyn. My next paper is from Professor Irene Lang at the Medical University of Vienna, and it's related to microvascular disease and chronic thromboembolic pulmonary hypertension and hemodynamic phenotyping and histomorphometric assessments. So, Carolyn, pulmonary endarterectomy is the gold standard for treatment of patients with operable chronic thromboembolic pulmonary hypertension. However, persistent pulmonary hypertension after PEA or endarterectomy remains a major determinant of poor prognosis. Dr Carolyn Lam: Ah, so are there any possible solutions to this? Dr Greg Hundley: Well, Carolyn, today it is thought that a concomitant small vessel arteriography in addition to major pulmonary artery obstruction may play an important role in the development of persistent pulmonary hypertension and survival after pulmonary endarterectomy. One of the greatest unmet needs in the current preoperative evaluation is to assess the presence severity of small vessel arteriopathy. Dr Carolyn Lam: Huh, that makes a lot of sense. So what did the authors do? What they find? Dr Greg Hundley: Okay. Well, Carolyn, they had 90 patients with 49 of them receiving lung wedge biopsies for validation. So, in analyses incorporating receiver operating characteristic curves, pulmonary vascular resistance measures and larger arterial upstream resistance beds predicted persistent pulmonary hypertension after pulmonary endarterectomy, and certain values identified patients with poor prognosis after endarterectomy. Therefore, perhaps this form of analysis could be helpful in establishing prognosis in these patients and perhaps suitability for future interventions. Dr Carolyn Lam: Wow, very interesting. Well, we were saying this issue's full of very important papers, and that also includes research letters. There's a research letter by Dr Cannon talking about evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease according to baseline HbA1c, including those with an HbA1c less than 7%. And these are very interesting results from the CREDENCE trial that was also presented at the American Heart Association. There's a research letter by Dr Jackevicius on the population impact of generic valsartan recall in Ontario, Canada, that really highlights the potential burden and risks associated with recalls of chronic oral medications used by large populations. And in Cardiology News, Bridget Kuehn talked about cardiovascular risk biomarkers, high-sensitivity cardiac troponin T and NT-proBNP and talked about how these two biomarkers may help clinicians stratify which patients may benefit the most from therapies for hypertension or diabetes. And this was according to a pair of studies presented, again, at the American Heart Association. Dr Greg Hundley: Well, Carolyn, that's quite a nice review. I've got just a couple more papers to discuss. There's a perspective piece from Dr Ben Levine and colleagues from UT Southwestern that discusses whether a simple physical exam and maneuvers could actually supplant tilt-table testing. He provides arguments as to whether we should continue with tilt-table testing given the high rate of false positives. And then lastly, from the Mailbag, Dr Shuyang Zhang from Peking Union Medical College Hospital and the Chinese Academy of Medical Sciences provides a letter to the editors regarding a prior publication on the clinical applicability of the awareness of androgen-deprivation therapy's effects on ventricular repolarization. And Dr Joe-Eli Salem from Vanderbilt University provides his response. Well, Carolyn, how about onto that feature? Dr Carolyn Lam: Let's go. Our feature discussion today is all about left ventricular ejection fraction. Ah, that measure we both love and hate in the world of heart failure, I think. And this paper is truly remarkable, in my opinion. It is the look at the effect of sacubitril/valsartan across the spectrum of left ventricular ejection fraction in the PARADIGM and PARAGON trials. And I'm just so pleased to have none other than the first and corresponding author, Dr Scott Solomon, from Brigham and Women's Hospital and Harvard Medical School, as well as our Senior Associate Editor, Dr Biykem Bozkurt, from Baylor College of Medicine as well. Scott, could you start by telling us about this analysis and why the opportunity to do such a special analysis in this paper? Dr Scott Solomon: This was a really fantastic opportunity because, as you know, we did these two trials, PARADIGM and PARAGON, not at the same time but essentially in series. PARADIGM was a trial of patients with heart failure reduced ejection fraction, so ejection fraction of 40%, and PARAGON was a study of patients with heart failure with preserved ejection fraction. And the interesting thing is that, with the exception of ejection fraction, the criteria for enrolling patients in these trial was virtually the same. In other words, we enrolled patients with signs and symptoms of heart failure, some elevation in natriuretic peptides, and we followed them. So it's really an extraordinary dataset of 13,195 patients in whom we can look at heart failure across that full spectrum of ejection fraction. We haven't been able to do this really since the CHARM study, which enrolled about 8,000 patients across the spectrum of ejection fraction. And it gave us an opportunity to look at a number of things including the effect of sacubitril/valsartan across that full spectrum of ejection fraction. Dr Carolyn Lam: Great. And, Scott, you want to tell us what you found? Dr Scott Solomon: When we pooled 13,195 patients, and by the way, this was a pre-specified analysis that we had decided to do prior to unblinding PARAGON. We see that if we put them all together, all these patients together, and just treat them as one group, we see that for every endpoint that we looked at, whether heart failure, hospitalization and cardiovascular death, cardiovascular death, all-cause mortality, whether we look at the time to first event endpoints or the total number of heart failure hospitalizations, we see a significant benefit in patients receiving sacubitril/valsartan compared to patients receiving either enalapril in the PARADIGM study or valsartan in the PARAGON study. Now, what we also saw though, and this is probably most important, is that there appears to be an attenuation of the treatment effect as ejection fraction rises. Now we know that patients with higher ejection fractions tend to have a lower frequency of these events such as heart failure, hospitalization and cardiovascular death. But we also see here that as ejection fraction goes up that the benefit of sacubitril/valsartan appears to wane, especially when you get over about 60, an ejection fraction of about 60%. We've looked at this in categorical ways and also looking at a continuous spline analysis throughout the entire spectrum. Dr Carolyn Lam: Yeah, I love that, and I just need to point every listener right now to figures 3 and 4 of your paper. I have a feeling we're going to be seeing these figures in a lot of talks and cited everywhere. Biykem, could I bring you in on this? What are the implications of something like this? Dr Biykem Bozkurt: The interesting findings from the pooled data are, first, support of what we had seen in PARADIGM, meaning the lower the EF, the more the benefit or the higher the benefits. And as we had seen in PARAGON, which did not show an improvement in the combined endpoint with treatment with sacubitril/valsartan in patients with heart failure with preserved ejection fraction. In the pooled analysis as the EF got higher, there didn't seem to be any benefit, but the interesting, perhaps group of patients that the pooled analysis allowed us to have a deeper dive into was heart failure with mid-range EF. And we can crudely perhaps define this as ejection fraction between 40 and 50%. And by certain analyses, which again this is in the post-hoc and also in a continuous analysis and a specific analysis and a cubic spline analysis, it appeared that the benefit extended into those individuals with mid-range ejection fraction. Again, we need to keep several points in consideration. One is ejection fraction can vary over time and is not a very precise measurement. There's definitely inter-reader as well as intra-reader variability and is not a good mayor of contractile performance. And we tend to actually have a significant amount of a specific infiltrative cardiomyopathies in that EF range, which tend to be excluded from usual clinical trials. And with that caveat, having kept this in mind, it's also important to recognize from cohorts and population-based studies, about 10 to 20% of our patients currently reside in that have HeFmrEF or heart failure with mid-range EF status. And thus the findings are intriguing, hypothesis generating and also encouraging that we may see perhaps benefits with RAS antagonism in individuals that do have LV systolic dysfunction. And probably, if this is persistent and a clear reflection of a phenotype that reflects itself as reduced ejection fraction, probably the patient may benefit. Again, these results may need to be supported by future studies, and also we need to keep in mind that infiltrative cardiomyopathies, such as amyloidosis or sarcoidosis or others, were not included in these studies. Dr Carolyn Lam: Thank you, Biykem. Go ahead, Scott. Dr Scott Solomon: Carolyn, I agree with many of Biykem's points. I think that this middle range, and you and I kind of coined that term, heart failure with mid-range injection fraction, a number of years ago. The problem, of course, is knowing where that range exactly is, and I think that some people believe it's 40 to 50%, but we know that these are very arbitrary cutoffs. The data from the pooled analysis in PARAGON, in particular, do suggest that the patients who have evidence of some degree of left ventricular dysfunction seem to benefit from sacubitril/valsartan. Now, this is not a completely novel finding because we saw that in patients who received candesartan in the CHARM study and in patients who received spironolactone in the TOPCAT trial that the greatest benefit was observed in the patients in that middle range of ejection fraction, again, below what we would normally consider the normal range. Normal might be 55% or 55% in men and women. And that gets me to the other thing that I think is really worth mentioning here, which is that we found that the range of benefits does vary by sex, so that women seem to derive greater benefit to a higher ejection fraction than men. We can see that here in figure 4, looking at these two curves that there really does appear to be a difference between men and women. Women overall derive greater benefit in the PARAGON study, it appeared than in men. So I think that the fact that there's biologic plausibility here that patients with cardiac function that is not normal seem to benefit from therapies that we know benefit patients with heart failure with reduced ejection fraction, that patients with ejection fraction that was in this middle range also do appear to benefit from sacubitril/valsartan as we think they did in other studies of other agents that we know work in patients with lower ejection fraction. Dr Carolyn Lam: Indeed, Scott. You've just pointed out my favorite figure of all, that figure 4. You know how I feel about sex differences and pointing them out. I would love to ask for Biykem's thoughts on it. But in the meantime, just to emphasize how important findings like these are because it makes us question the cutoffs that we use to define heart failure groups, makes us question is midrange more mildly reduced ejection fraction like we're also writing about. And I think really makes us question, for example, the 2016 ESC Guidelines that say that mid-range ejection fraction should be treated like preserved ejection fraction. Well, maybe this could be really game changing here in that we actually think now this group should be treated more like reduced ejection fraction. So, really, congrats on this incredible paper. Biykem, what do you think of those sex differences? I have to point out, I love your editorial, which everyone should read. Dr Biykem Bozkurt: It's very intriguing, very interesting point. The benefits from sacubitril/valsartan was interestingly similar for both sexes at lower EF levels. Women's benefit compared to men's benefit for low EF was comparable; they were not different. But women seem to confer a benefit at higher EF ranges and by this continuous analysis all the way up to the 50 to 60% range, which is very, very interesting. And as to what were the phenotypes of the women compared to men at that range, women were older, had more obesity, less CAD, and of course, at all ranges they usually tend to have a higher baseline EF. And, interestingly, even though we may state that maybe women may have more systolic dysfunction at higher EF quantification ranges or may have a different phenotype than men for HFpEF, maybe a more clear or pure heart failure phenotype, heart failure with preserved EF phenotype than men. The interesting things were the NT-proBNP levels were lower for women, though the symptoms were a little bit higher, and the benefit seemed to be higher even though the KCCQ scores were not different. So, even though we did have lesser sort of filling pressures for women and perhaps other surrogates for improvement did not seem to differ, and also biological metabolites, such as urinary cyclic GMP to creatine ratios, were not different in women. So, if we were to think of whether there were biological differences, whether there were differences in NT-proBNP levels or delta changes over time or the urinary cyclic GMP levels, they were not different in women versus men. So, we still have many other substrates for neprilysin. I mean there could be other substrates, such as adrenomedullin or bradykinin or substance P that may be differentially metabolized for women compared to men, and we don't have the data on those. But again, it's very interesting to see this upper scale of EF benefit being higher in women compared to men. So, we don't have any other either biological or other surrogate markers for benefit for women, either for the HFpEF or HFrEF being than different than men. Dr Carolyn Lam: Biykem, I just love the way you so carefully dissected that, and it's so reflected in that editorial that you and Justin Ezekowitz wrote entitled Substance and Substrate. So I'm going to make sure all readers look for it. We could go on forever. I mean I just was struck, that figure 4, also is really similar if we look at what normally ejection fraction is for women versus men with increasing age. We also see that women are supposed to have higher ejection fractions as they age compared to men at any age. So it's just intriguing to me, but you're right. I think hypothesis generating. Scott, I'm going to give you the last word. Dr Scott Solomon: I'm pretty confident that there are biologic differences between men and women. I just don't necessarily know what they are with respect to heart failure, preserved ejection fraction, but I think we're going to be spending a lot of time and effort trying to sort this out. We're pretty confident that the finding of a weighing of benefit with ejection fraction is a real one and that the benefit in this middle range is an important one to pay attention to because I agree with what you said, Carolyn. If we had been thinking about heart failure with reduced ejection fraction as something that went up to a higher level 25 years ago, we would probably have treated a lot more patients with therapies that we now know to benefit patients with heart failure with reduced ejection fraction. So, I think this data helps us rethink how we parse up heart failure and hopefully, ultimately will lead to changes how we treat patients. Dr Carolyn Lam: Well, listeners, you heard it right here on Circulation on the Run. Thank you so much, Scott and Biykem, for joining us, and don't forget to tune in again next week. Dr Greg Hundley: This program is copyright The American Heart Association 2020.  

This week we’re joined Ben Levine, Executive Director of the Metrolab Network.  We chat with Ben about the partnerships that Metrolab forges between cities and academic institutions, data collection and usage, as well as the Civic Innovation Challenge. Follow us on twitter @theoverheadwire Find us online at http://theoverheadwire.com Also check out http://usa.streetsblog.org  

Dr Greg Hundley: Welcome listeners. This is Dr Greg Hundley from the VCU Pauley Heart Center in Richmond, who is in the second of his two-week stint without his dear friend, Dr Carolyn Lam who will be returning in a week or two. Our feature article this week is from Dr Mikhail Kosiborod from Saint Luke's Mid America Heart Institute and the Georgia Institute for Global Health, and University of New South Wales. And we'll review the effects of dapagliflozin on quality of life and other metrics in patients with heart failure and reduced ejection fraction. But first, let's have a look at the other articles in this issue and just like last week we've got four other original manuscripts. The first two are sort of clinically related and that very first article comes from Dr Ben Levine from University of Texas Southwestern and he serves as the corresponding author and he's examining future predictors of the development of heart failure and preserved ejection fraction or HFpEF. His team tested the hypothesis as to whether patients with LVH and elevated cardiac biomarkers would demonstrate elevated LV myocardial stiffness when compared to healthy controls as a key marker for future HFpEF. The team recruited 46 patients with LVH. The LV septum was greater than 11 millimeters and elevated cardiac biomarkers, so the NTproBNP was greater than 40 or the cardiac troponin T was greater than 0.6. And they were recruited along with 61 age and sex-matched cohort of healthy controls. To define LV pressure volume relationships, right heart catheterization and 3D echocardiography were performed while preload was manipulated using lower body negative pressure and rapid saline infusion. They found that the left ventricle was less distensible in the LVH patients relative to the controls, that is they had a smaller volume for the same filling pressure. When preload was expressed as transmural filling pressure or wedge pressure minus right atrial pressure left ventricular myocardial stiffness was nearly 30% greater in the LVH group compared to the controls. The author's note that although LV myocardial stiffness of LVH patients was greater than that of the healthy controls at this relatively early stage, further studies are required to clarify whether interventions such as exercise training to improve LV compliance may prevent the full manifestation of the HFpEF syndrome in these high-risk individuals. Well, the second paper comes from Professor John McMurry of the British Heart Foundation Cardiovascular Research Center at the University of Glasgow in the United Kingdom. And the paper is somewhat similar to our feature article because it emanates from the DAPA Heart Failure dataset that we will hear about later. So in this paper, the authors examined the effects of Dapagliflozin according to age, given potential concerns about the efficacy and safety of therapies in the elderly in the prior trial. A clinical trial that as we know, demonstrated that a reduced risk of mortality and heart failure hospitalizations occurred in patients with HFrEF. So in this current study, a total of 4,744 patients that were 22 to 94 years of age were randomized. 636 were less than 55 years of age, 1,242 we're 55 to 64 years of age 1,717 were 65 to 74, and finally 1,149 were greater than 75 years of age. Consistent benefits were observed for the components of the primary outcome of all-cause mortality and symptoms across all the age groups. Although the adverse events and the study drug discontinuation increased with age, neither was significantly more common with Dapagliflozin across any of the age groups. There was no significant imbalance and tolerability or safety events between Dapagliflozin and placebo, even in the very old population group. So we'll have more to discuss later in the feature discussion with a second paper that really looks also at the DAPA-HF study. The next original article comes from our world of Basic Science and it reports that the deficiency of circulating monocytes ameliorates the progression of myxomatous valve degeneration in the Marfan syndrome. And this paper comes from Dr Katherine Yutzey from Cincinnati Children's Medical Center. Well, first is some background, leukocytes comprised primarily of macrophages have recently been detected in myxomatous valves, but the timing of the presence and the contributions of these cells in myxomatous mitral valve degeneration is not known. So the authors found in this study that Marfan syndrome mice recapitulated the histopathologic features of myxomatous valve disease by two months of age, including mitral valve thickening, increased leaflet cellularity and extracellular matrix abnormalities characterized by proteoglycan accumulation and collagen fragmentation. Concurrently, disease mitral valves of the Marfan syndrome mice exhibited a marked increase of infiltrating and resident macrophages along with increased chemokine activity and inflammatory extracellular matrix modification. Likewise, mitral valve specimens obtained from gene-edited Marfan syndrome pigs as well as human subjects exhibited increased monocytes and macrophages detected by immunofluorescence. So remarkably deficiency of monocytes was protected against mitral valve disease progression resulting in a significant reduction of macrophages, had minimal leaflet thickening and preserved mitral valve integrity. So the authors identify for the first time in this interesting study from the world of basic science that monocytes are a viable candidate for targeted therapy in myxomatous valve degeneration. The second basic science original article in this issue is entitled "Genetic IL-6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis" and the corresponding there is Pradeep Natarajan from the Mass. General is background clonal hematopoiesis of indeterminate potential or CHIP is a term that refers to clonal expansion of hematopoietic STEM cells due to acquired leukemic mutations in genes such as DNMT3A or TET2. In humans, CHIP associates with prevalent myocardial infarction. In mice CHIP accelerates atherosclerosis and increases IL-6 and IL-1 beta expression raising the hypothesis that IL-6 pathway antagonism in CHIP carriers would decrease cardiovascular disease risk. So in this study, the authors observed some really exciting results. They analyzed over 34,000 samples from the UK Biobank and identified 1,079 individuals with CHIP, including 432 with large clones an LV fraction greater than 10%. During a 6.9-year median follow-up CHIP presence was associated with increased incidents, cardiovascular disease event risk with greater risk from large CHIP clones. IL6R attenuated cardiovascular event risk among participants with large CHIP clones but not in individuals without CHIP. This really exciting research results suggest that CHIP is associated with increased risk of incident cardiovascular disease. And among carriers of large CHIP clones, genetically reduced IL-6 signaling abdicated this risk. Really exciting results in an emerging area of science. So what else is in the issue? Well, in our in depth review feature, Professor Stephan Rosencrantz from the University of Cologne Heart Center reviews the systemic consequences of pulmonary hypertension with right side heart failure. And then an On My Mind piece, our own associate editor, Dr Vlad Zaha coupled with doctors Walter Myers and Javid Moslehi from Vanderbilt discuss the impact of evolving immunotherapies for cancer and their impact on the cardiovascular system. In our mailbag, Dr Xiayan Shen from the Medical Classification Center of the Singapore Armed Forces discusses in a research letter the prevalence of Brugada Syndrome in a large Singaporean young male population. In letters to the editor, Dr Muddassir Mehmood from University of Tennessee Medical Center in one letter and Dr Goodarz Danaei from Boston in a response letter discuss the importance of diet relative to the development of HFpEF and how heart failure may be coded in by the World Health Organization when assessing global cardiovascular outcomes. Bridget Kuhn in our cardiology news feature reports on preliminary results from the International Childhood Cardiovascular Cohort or i3C Consortium that was presented at the 2019 European Society of cardiology Congress. The i3C Consortium used data on 40,000 patients who participated in seven major longitudinal cohort studies that evaluated childhood cardiovascular risk factors from repeated measures during childhood and adolescence. And finally, our own Molly Klemarczyk at Circulation gathered and combined a very nice serial update that highlights important articles from our circulation family of journals, including electrophysiology, imaging, heart failure, and others. Well, listeners, that's a summary of what's in the journal. But let's now proceed to our feature discussion to learn more about the rapidly emerging field of SGLT2 inhibition. Well listeners, we are very excited for this feature discussion we have today, Dr Mikhail Kosiborod from Saint Luke's Mid America heart Institute and our own associate editor, Dr Justin Ezekowitz from Alberta, Canada. And we're going to be discussing the paper related to the effects of Dapagliflozin on symptoms, function and quality of life in patients with heart failure and reduced ejection fraction. They're going to be presenting results from the DAPA Heart Failure trial. Well Mikhail, I was wondering could you orient us a little bit to the DAPA heart failure trial. And then what was the hypothesis that you were trying to address in the current study? Dr Mikhail Kosiborod: DAPA-HF was the first heart failure outcome trial trying to answer two critical questions about the effects of SGLT2 inhibitors in patients with heart failure and reduced ejection fraction. We knew from prior trials, outcome trials in patients with diabetes SGLT2 agents can effectively prevent heart failure inpatients, overwhelming majority of which did not have heart failure and baseline. But what we didn't know was whether these agents can also be used as therapies for patients with established heart failure, and specifically heart failure with reduced ejection fraction. And they reduce death or worsening heart failure in the patient population. And the second question was whether that effect, if in fact this medications can significantly improve outcomes in patients with heart failure reduced ejection fraction. Can they do that even in patients who do not have type 2 diabetes? Because, in a diabetes trial it appears that that heart failure protective effect may be completely independent on the hemoglobin AONC. And so DAPA-HF was specifically designed to test those two hypotheses. It enrolled about 4,800 patients with heart failure and reduced ejection fraction about 45% of which had types 2 diabetes. And there's a majority of us, 55% did not. And the main trial results that were published prior to risk analysis showed that in fact dapagliflozin significantly reduced the risk of the composite endpoint of cardiovascular death and worsening heart failure. It was a 26% relative risk reduction and the effects were identical in patients with or without type two diabetes. So both of those hypothesis were proven to be correct. It was effective therapies for established heart failure and reduced ejection fraction, and it was equally effective regardless of diabetes status. Now what we did in this study is really trying to understand the effects not just on cardiovascular deaths and hospitalization for heart failure, but on health status, which is symptoms, physical limitations, and quality of life. He knows that heart failure is a debilitating disease, causes high burden of symptoms, and physical limitations, has adverse impact on quality of lives. We know that two key goals of managing heart failure are to; one, reduce deaths and hospitalizations for heart failure and two to reduce the burden of symptoms and physical limitations and improve the quality of life. So, that was really the focus of this specific analysis that we're talking about today. Dr Greg Hundley: Excellent. So I understand you use the KCCQ-12, maybe help us understand what that test is and then tell us a little bit about your methods and your study population. Did you use the whole study population? Dr Mikhail Kosiborod: KCCQ stands for Kansas City Cardiomyopathy Questionnaire and we actually in the study we use KCCQ-23 which is the full Kansas City Cardiomyopathy Questionnaire, consists of 23 items. And it a disease-specific tools for evaluating health status and heart failure. So it essentially assesses four key domains, which are the symptom burden, physical implementations, quality of life, and social limitations. In this particular study is a primary endpoint as a primary part of the KCCQ as KCCQ total symptom score, which is a domain that focuses on symptoms. And the idea behind KCCQ is that you have a debilitating disease, which is heart failure. That disease has impact on the patient by causing symptoms, the symptoms then translate to physical limitations. And the combination of the symptom burden physical limitations has an impact on quality of life and social limitation. So that's why are this four different domains assessing these four components of the adverse effects of the heart failure compared to health status. And just very briefly, to mention that KCCQ has been proven to be responsive to clinical change. It's highly for data predictive of death and hospitalizations from heart failure. It has been extensively validated both of them hearts failure was reduced enters and the ejection fraction. And so we essentially focused, or the primary focus of the paper was really to evaluate the effect of dapagliflozin versus placebo on a Kansas City Cardiomyopathy Questionnaire or KCCQ level symptom score. But we also looked at other domains as well. We looked at the clinical summary score, which includes both symptoms and physical limitations and we looked at the overall summary score, which includes all of the four domains that I mentioned before. Dr Greg Hundley: What did you find? Dr Mikhail Kosiborod: The patients treated with dapagliflozin had a greater improvement in health status as assessed by a KCCQ total symptom score or for that matter KCCQ clinical summary overall summary score as compared to patients treated with placebo. So if you look at the mean effect, there is some improvement in the patients taking placebo. That's what we call a placebo effect. And it's very commonly seen in clinical trials. We assessed health status, but there was a greater improvement with dapagliflozin as compared with the placebo, it was statistically significant even in four months. But as the effects were further amplified to eight months and this differences were, I would say favorable when you kind of compare the effect of Dapagliflozin versus other established heart failure therapies when you look at the effects on health status. What I think was even more important than analysis from a clinician standpoint, and then they think it's actually much more meaningful clinically is what we call a responder analysis. And that's where we look as the proportion of patients that have a clinically meaningful improvement with one type of therapy versus other in this case Dapagliflozin versus placebo. So it's been previously established that at five-point difference or a five-point change rising KCCQ is what's considered to be clinically meaningful or minimal clinically meaningful difference. So a 5.2 grade deterioration KCCQ means it's a clinically important deterioration. And a five-point or greater improvement is a clinically important improvement. And then we also looked at the proportion of patients with moderate and large improvements in health status as well defined as STEM point of grade of two, or two point a great improvement. And essentially what we found was that significantly fewer patients treated with dapagliflozin and as compared with placebo had a clinical importance deterioration. And significantly greater proportion of patients treated with dapagliflozin has small, moderate, large improvements in health status. And the numbers needed to treat to see those differences, as the small moderate large improvements was very favorable ranging typically between 12 and 18 and over eight-months-treatment period. Dr Greg Hundley: Outstanding. So both clinically relevant as well as statistically significant findings. Now we're going to bring in Justin, our associate editor. Justin, help us put these results into the just our perspective in looking at SGLT2 inhibitors, particularly for treatment for heart failure. Dr Justin Ezekowitz: This is an exciting class of medications and we're eagerly awaiting these results because we saw the DAPA-HF Overall results. The majority of us treat patients with a pretty symptomatic disease and as such this quality of life is quite an important change. There's ongoing trials we're eagerly awaiting which are also going to be using other medications in the same class, but I think one question that remained was, are these simply improving symptoms by one meaning, so the total symptom score? Or the overall quality of life? And I think you nicely, elegantly portrayed that in the figures and you have. The one other part maybe Mikhail, you could expand upon, which is when you think about DAPA-HF, and the quality of life gains and across all the three different ways of looking at quality of life, where do you see this in terms of its relationship to other things that we know improve quality of life? Where we send patients, for example, CRT or put them on an RNE. Where does this fit on top of those types of changes? Dr Mikhail Kosiborod: Thanks Justin. I think it's a really important question because it says think critical from a clinical standpoint to put it in the context of other therapies that had been previously shown to improve health status, which means again, reduced symptoms, improve physical and patient quality of life. And there are a number of perhaps the types of therapies on heart failure and LVCF that have been evaluated particularly on side this one there also have been studies with exercise training in heart failure or and the ones that you brought up, which is cardiac resynchronization therapy in patients with heart failure reduced ejection fraction and left bundle branch block. And as that perhaps, if you kind of think about it. What are some of the most effective treatments to improve the health status? That is ones that we typically would consider as such, which is CRT in patients with half RAF and a left bundle branch block. And in fact, if you look at the mean effects dapagliflozin compares very favorably even with highly effective therapies such as TRT. Relatively few studies have previously reported to this responder in analysis. But if you look at Digoxin comparing those to dapagliflozin, one of the recent ones that I can think of is [inaudible 00:20:23], again dapagliflozin compares very favorably when you look at this types of responder analysis where again you look at proportion of patients, it was a clinically meaningful change. So I think the beautiful thing about putting the study in the context of further studies looking at health status and also in the original main results that were published from a DAPA-HF early this year is that it's really kind of a full house if you will. So as the agent reduced deaths, reduced hospitalizations and made patients feel better and all of that, with very favorable safety profile. So, if you kind of think about risk benefit analysis and you look at numbers need to treat both for clinical outcomes such as CVS and hospitalizations for heart failure for example, where health status, it looks really impactful from a clinical standpoint. Dr Greg Hundley: So relevance to other therapeutic interventions for heart failure is what this whole class of agents seems to be showing? So briefly, what do you see is the next important study in the field? Dr Mikhail Kosiborod: I will waffle on this question a little bit and say there was more than one, but my views are there kind of two key components to this. One is that there are additional trials going on and heart failure with reduced ejection fraction with other agents. And so seeing what happens with those other agents in the class in a similar patient population and whether is this a class effect or not? Now the diabetes trials would suggest that these may well be class effects but I think it's nice to have validation of that. I would say that is one real important questions that hopefully we will have additional answers to in the coming year or so. And the second and perhaps I would argue even more important question is whether these agents can also be effective in improving outcomes in patients with heart failure and preserved ejection fraction. That's a patient population that has also very high debilitating burden of symptoms that has poor prognosis and for which unlike them, half rubs, there are very few, if any medications that have been proven to be disease-modifying and actually have shown outcomes and benefit. So I would say those in my mind, are the two critical developments that we'll be seeing. And the good news is, there are the trials going on with more than one agent in a class and half to half as well. Great. Dr Greg Hundley: And Justin? Dr Justin Ezekowitz: Yeah, I think that there's been an explosion of therapies and Mikhail is bang on with this is the one class where we're excited about. I think the other groups of medications include Omecamtiv Mecarbil we'll know in a year or two. We'll hear more details in the spring and then there's a few other medications that Mikhail mentioned. I think this is a real good message though, that both HFrEF and HFpEF, it's the rise of medications again. Because we were on a device track for a while, but I think the medications have such more potent effect on the underlying structure and function that it's great to see that there's been such a development and explosion of medications that may obviate the need for implanted devices or advanced therapies, so we're very excited about that. Dr Greg Hundley: Outstanding. Well, listeners, we've had the opportunity to hear from Mikhail Kosiborod from Saint Luke's Mid America Heart Institute and our own associate editor, Dr Justin Ezekowitz from Alberta, Canada, and learn more about SGLT2 inhibition and its importance in improving clinically symptomatology both in those with diabetes and heart failure, but also those with heart failure alone. On behalf of Carolyn and myself, we wish you a great week and we look forward to running and having a coffee chat next week. Take care of. This program is copyright 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 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.  

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:                In just a moment, we will be discussing further results from the CREDENCE trial. That's canagliflozin in patients with type 2 diabetes and chronic kidney disease, this time focusing on the cardiovascular outcomes as well as both primary and secondary prevention groups. Really exciting stuff, huh, Greg? Dr Greg Hundley:             Absolutely, Carolyn. Got any papers you want to have a coffee chat about? Dr Carolyn Lam:                Absolutely. So my first pick really tells us that allele-specific RNA silencing of human alleles may be effective in treating inherited cardiomyopathies. Want to hear more? Dr Greg Hundley:             You bet. Dr Carolyn Lam:                So, this is a study from Dr Ashley and colleagues from Stanford University School of Medicine who performed a selective allele-specific silencing of the human restrictive cardiomyopathy, a specific mutation of asparagine to lysine in the regulatory light chain, which is encoded by MYL2. So they did this in a humanized transgenic mouse model using an adeno-associated virus RNA interference approach. Using this approach, they showed that an interfering RNA treatment ameliorated disease phenotypes by specifically reducing the cardiac expression of the mutated allele, hypertrophic carb biomarkers and intramyocardial fibrosis. In fact, isolated cardiomyocytes from the treated animals showed normalization of contraction and relaxation dynamics with partial restoration of calcium re-uptake dynamics. Dr Greg Hundley:             Boy, Carolyn, sounds like improvement in cardiovascular function, but were there any adverse effects? Dr Carolyn Lam:                Great question. Well, they also performed cardiac genome-wide transcriptome profiling, which showed a reduction in the hypertrophic program without significant off-target effects, so that's important. So in summary, these results show the feasibility, efficacy, and safety of RNA interference therapeutics directed at human restrictive cardiomyopathy. A really promising step towards targeted therapy for a prevalent disease. Dr Greg Hundley:             Very nice. Carolyn. So I'm going to start my discussion also with a basic science paper that's going to focus on ischemia reperfusion injury and looking at the mechanism by which mitochondrial dysfunction can be avoided. So, the paper emanates from Dr Yu-Lin Li from Beijing Anzhen Hospital at the Capital Medical University in Beijing. The study from Dr Li identifies an important mechanism of this myocardial ischemia-reperfusion injury in a mouse model and found, in human subjects, a biomarker that was predictive of adverse cardiovascular events after those individuals had sustained an MI. Dr Carolyn Lam:                Oh, interesting. So tell us more, Greg. Dr Greg Hundley:             Yeah, so the authors utilized a dynamic transcriptome analysis of mouse hearts exposed to various myocardial ischemia-reperfusion periods to identify a new inflammatory molecule that they termed S100A8/A9, and it was an early mediator. And then they measured this new inflammatory molecule level in patients, human subjects, after myocardial infarction, before and after they had undergone percutaneous intervention. So this S100A8/A9 was identified as the most significantly up-regulated gene during the early reperfusion stage and knockout of that molecule markedly decreased cardiomyocyte death and improved heart function, whereas hematopoietic overexpression of the molecule exacerbated myocardial ischemia-reperfusion injury.                                                 The authors then demonstrated that the levels in patients significantly increased day one post-PCI in anterior MI patients and elevated molecule levels were associated with the incidents of future MACE. So perhaps, in the future, targeting this molecule-initiated signaling may represent a novel therapeutic intervention for myocardial ischemia-reperfusion injury. Dr Carolyn Lam:                Interesting and very nicely explained. Now my next paper, the title says it all. Three Public Health Interventions Could Save 94 Million Lives in 25 Years. So we know that preventable noncommunicable diseases, which are mostly cardiovascular diseases, are responsible for 38 million deaths annually. So, these authors who are Dr Danaei and colleagues from Harvard T.H. Chan School of Public Health in Boston, Massachusetts, quantified the global mortality impact of three high-impact and feasible interventions. One, scaling up treatment of high blood pressure to 70%, two, reducing sodium intake by 30% and, three, eliminating the intake of artificial trans fatty acids.                                                 So, they used global data on mean blood pressure levels and sodium and trans-fat intake by country, age and sex from a pooled analysis of population health surveys and regional estimates of current coverage of antihypertensive medications as well as cause-specific mortality rates in each country, along with projections from 2015 to 2040. They used the most recent meta-analysis of epidemiologic studies to derive the relative risk reductions for each intervention.                                                 And, in summary, they found that the combined effect of the three interventions delayed 94.3 million deaths during 25 years. Increasing the coverage of antihypertensive medications to 70% alone would delay 39.4 million deaths, whereas reducing sodium intake by 30% would delay another 40 million deaths and eliminating trans-fat would delay an additional 14.8 million deaths. Dr Greg Hundley:             Aha. So controlling blood pressure, cutting salt, eliminating trans fats, but are there any regional differences around the world, Carolyn, your part of the world versus United States? Dr Carolyn Lam:                Good question as always. So the authors also estimated the impact in different parts of the world and found that the estimated impact of trans fat elimination was largest in South Asia. Sub-Saharan Africa had the largest proportion of premature delayed deaths out of all delayed deaths. National and international efforts therefore need to scale up these interventions and this should be a focus of cardiovascular disease prevention programs. Dr Greg Hundley:             Oh, my. Really interesting. Well, I'll tell you what, Carolyn, my next article is going to take us to space, the unified efforts of all these countries in the world trying to examine the effects of prolonged space flight. So this article, it's headed up by Dr Ben Levine at University of Texas Southwestern Medical Center, but it has a very large group of coauthors and examines the impact of prolonged space flight on orthostatic tolerance as those astronauts return to earth.                                                 So, as we know, astronauts returning to earth usually demonstrate reduced orthostatic tolerance, especially when you assess them on a tilt table. But no studies to date have evaluated sort of the post-flight return to earth effects of orthostatic on activities of daily living, and those are most clinically relevant. So in this study, ambulatory blood pressure variability, that's already been known to be associated with orthostatic intolerance in other patient populations and can capture clinically significant orthostatic hypertension during activities of daily living. So, in the study, ambulatory beat-to-beat blood pressure was recorded using a portable device for multiple 24-hour time periods before, during, and after six months of space flight in 12 astronauts, four women, age averaged 48 plus or minus five years. Dr Carolyn Lam:                Fascinating. What a clever study. So what did happen to the astronauts when they returned to earth? Dr Greg Hundley:             So, in contrast to previous studies which employed the tilt tables or the stand test, no astronaut experienced orthostatic intolerance or hypertension during activities of daily living before or after space flight. 24-hour systolic blood pressure decreased in space as we might expect, but it returned to normal upon landing and diastolic blood pressure was unchanged during and following space flight. Systolic and diastolic blood pressure variability remained the same before, during, and after space flight. Given the current countermeasures that include exercise, training in flight, volume resuscitation on return, no astronauts experienced orthostatic hypertension or intolerance during routine, for landing day, activities in the initial 24 hours after landing, following six months in space. And prolonged exposure to space fight, therefore, had little impact on systolic blood pressure variability and its distribution. Though the latter showed just a transient change in space and that might be expected. It returned, however, to preflight values when we got back to earth. Very nice work. Dr Carolyn Lam:                Yes, indeed. Very clever. But let's carry on with our feature discussion, shall we? Dr Greg Hundley:             You bet. Welcome everyone to our featured article discussion, and we're going to learn more about primary and secondary cardiovascular-related events from the CREDENCE trial and we have with us, Dr Ken Mahaffey from Stanford Medical Center in California and our associate editor, Professor Naveed Sattar from Glasgow in the United Kingdom. Welcome to you both and we feel very honored to be able to discuss this paper today with you, Ken.                                                 Can you just refresh our memories a little bit about the CREDENCE trial? What were its primary results? I understand they had patients with diabetes and chronic kidney disease. Maybe tell us a little bit about how that was defined and then transition to what were the hypotheses in your study that you were going to test? Dr Kenneth Mahaffey:   So, the CREDENCE trial was a trial of an SGLT2 inhibitor, canagliflozin, in patients with diabetes who had chronic kidney disease with albuminuria. And it was the first of any of the SGLT2 inhibitor trials that was done in a dedicated renal population with a primary outcome that was a composite of renal outcomes along with cardiovascular death, and the trial was stopped early by the data safety monitoring board on an interim analysis when they found overwhelming efficacy. And, at the end of the day, the final results showed that canagliflozin compared with placebo showed a 30% reduction in the composite renal outcome as well as important reductions in cardiovascular outcomes without any evidence of increase in amputations.                                                 Now, the study that we're talking about today is a pre-specified, pre-planned subgroup analysis from CREDENCE where we wanted to look at how canagliflozin worked in people or participants who had known cardiovascular or cerebrovascular or peripheral vascular disease and those who did not. And one of the reasons this was an important analysis was that in previous studies of SGLT2 inhibitors, there has not been a consistency in the message about whether the drug worked in both primary and secondary-prevention populations.                                                 And what we found here in this analysis was that in the primary-prevention participants, which actually was 50% of the overall trial recruitment, had very similar reductions in renal outcomes and cardiovascular outcomes compared with those who were a secondary-prevention cohort. So a very different results and a very important result in this patient population. Dr Greg Hundley:             Really interesting. So in terms of the patients that you evaluated in this sub study, were they any different than the whole cohort and, in terms of participants and compliance with the therapy, was there any difference with the placebo versus the study drug that you noticed and can you infer from that any particular groups of patients that may benefit more or be able to take the therapy more? Just more about compliance. Dr Kenneth Mahaffey:   First of all, you asked how the primary and secondary-prevention groups in the study were different and they were, as one would expect. Those participants who did not have prior atherosclerotic cardiovascular disease tended to be younger. They were more often women. They had shorter durations of diabetes and they were less often treated with cardiovascular preventive medications, in terms of staph and antiplatelet therapies. All the patients were on an ACE or an ARB.                                                 In terms of overall compliance with canagliflozin, it was very good. Now, the SGLT2 inhibitors, as a class, have a number of important side effects including genital mycotic infections in both men and women. They do cause some hypovolemia and volume depletion, but we found overall in the CREDENCE trial that fewer participants stopped the study drug prematurely in the canagliflozin arm than in placebo arm. So we feel that we had a very, very good comparison of the two therapies in the overall trial and in the primary and secondary-prevention analyses. Dr Greg Hundley:             And so just general thoughts of how do you think this might impact the results of your study, or treatment, when we see patients with diabetes and chronic kidney disease? Dr Kenneth Mahaffey:   I think there's potentially a big impact moving forward. Now, the SGLT2 inhibitor classes were approved based on the early cardiovascular outcome trials, did not enroll participants with lower EGFRs. So once these data are reviewed by the FDA and if they accept these findings and change the label, then the proportion of patients with diabetes who also have EGFRs down to 30 would be potential candidates for this therapeutic intervention. And it's important to point out that the CREDENCE trial that showed this reduction in renal events in patients with type 2 diabetes and chronic kidney disease, this is the first positive trial in 20 years of an intervention and 20 years ago we had both ACEs and ARBs based on large outcome trials, but we've had nothing since then that could be a therapeutic intervention to improve outcomes in this very important patient population. Dr Greg Hundley:             Thank you so much, Ken. And, Naveed, I would like to just turn to you and ask you a couple things. One, can you put this study on the SGLT2 inhibitors with all the other information that's coming out related to potential benefits, not only in controlling blood sugar, but impacting cardiovascular disease-related events? How does this fit in to all of the other studies that we're learning about in such rapid fashion? Dr Naveed Sattar:            This comes on the back of the three major trials and extends the evidence based so that, yes, I think we now show clear evidence that these drugs work in people with impaired renal function down to a level of 30 which I think is very important, so that will extend the guidelines. Yes, they seem to work in primary prevention. Of course. I think Dr Mahaffey would accept that these are probably high-risk primary prevention individuals because you also have evidence for chronic kidney disease and I suspect a lot would probably have subclinical cardiovascular disease if we went to look for it.                                                 Nevertheless, I think it will extend the guidelines in the sense that physicians are not only going to be potentially using these drugs in people with existing cardiovascular disease but also patients like those in CREDENCE with chronic kidney disease or a very high risk of cardiovascular disease without having had an event. So I think that's also very reassuring as well and exciting. And I think also the benefits of kidney outcomes is, as we said beautifully, that this is a game changer. Over the last few decades we've not really had any major trials to excite the renal community. But now we have. This trial extends the promise that we saw in the three previous trials and takes it a bit further, that these drugs have substantial and meaningful benefits in prevention of important kidney outcomes in our patients with diabetes. It looks like those benefits appear across the spectrum of diabetes. Whether they've existing disease, chronic kidney disease, or even a primary prevention when previous colleagues looked at it in a meta-analysis.                                                 So, I think that's exceptionally exciting and I think, therefore, given the profile of these drugs and as we're improving our safety in the sense we're able to use these drugs better in groups and also advise how to reduce side effects. I think really they're changing the paradigm of how we care for many of our patients with diabetes and I'd be interested to see what Dr Mahaffey thinks about those comments. My sense is this is really exciting. Dr Greg Hundley:             Ken, any thoughts? Dr Kenneth Mahaffey:   I think it was nicely articulated, some of the important observations here. I do agree that the patient population here that has chronic kidney disease but no known atherosclerotic disease and therefore primary prevention, it had higher risk. The event rates in CREDENCE were much higher than event rates in the CANVAS trial where the mean eGFR was much higher and so I agree that these patients may have some subclinical atherosclerotic disease, but they are clearly at higher risk of developing it. Dr Naveed Sattar:            Again, this would be interesting to take Ken's take. But if people have chronic kidney disease, they are, in a sense, revealing themselves to have evidence of end organ damage or be at the level of the kidney but not necessarily the heart. So my sense is there's still people with evidence of disease and it's just that we're seeing it in a different way. I don't know what Ken thinks about that as a kind of interpretation. Dr Kenneth Mahaffey:   Again, I think they're at high risk and we know that people who have kidney disease often are at higher risk of having cardiovascular disease during their lifetime and where we are in the spectrum of those new disease processes. We don't necessarily have the data in CREDENCE to understand that at a very granular level, but I think it's an important area that we need to evaluate sooner and it raises that issue of treatment for primary prevention should occur earlier and what we're seeing now is that when people develop type 2 diabetes and we notice that they have chronic kidney disease with microalbuminuria, that is the time to intervene, intervene soon. We now have a single therapy that's safe and effective and reduces the metabolic derangements with improved glucose control, improved blood pressure control, improved weight. It also has an important impact on the renal outcomes and important impact on cardiovascular outcome. So it's really a trifecta from a single therapy that can be prescribed easily. Dr Naveed Sattar:            I agree. And all those means of treatments were very, very favorable as well across the board, which I think is also important. Dr Greg Hundley:             So, Ken, what are some key clinical aspects related to your study that you feel we need to address? Dr Kenneth Mahaffey:   What we need to think about carefully is we now have a new therapy. These types of patients are actually seen by a whole host of clinicians in our healthcare systems, at least in the United States. They're seen by diabetologists, cardiologists, nephrologists, and primary care. And we need to think of ways that we can educate all four of those groups of clinicians about these important data and provide learning and other mechanisms to integrate these therapies into clinical care. It's a message I've been trying to get out. Dr Greg Hundley:             Well, listeners, what a great discussion between Ken and Naveed on this very important topic, the emergence of SGLT2 inhibitors and the results of these primary and secondary cardiovascular prevention group analyses from CREDENCE.                                                 We want to thank each of you for listening with us this week. Carolyn and I look forward to talking with you next week. Take care 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 it's editors. We're your co-hosts. I'm 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 in Richmond, Virginia, VCU Health Sciences. Dr Carolyn Lam:                How well are we doing with guideline-directed stroke prevention therapy in atrial fibrillation? Well, there are going to be very important results that you need to hear about from Get With the Guidelines Atrial Fibrillation. That's our feature paper coming right up in a future discussion. But first, you've got Greg and I discussing really important papers that we've spotted in The Journal. Greg. Dr Greg Hundley:             Absolutely, Carolyn. And my favorite kind of follows from that 'cause it's really about left atrial electromechanical remodeling following two years of high intensity exercise training in sedentary middle-aged adults, kind of like me. The studies from Ben Levine at University of Texas Southwestern Medical Center in Dallas. So, what he's driving at here are moderate-intensity exercises associated with a decrease in incidents of atrial fibrillation. However, extensive training in competitive athletes is associated with an increased atrial fibrillation risk.                                                 So, in this study, they're looking at the effects of 24 months of high-intensity exercise training on left atrial mechanical as well as electrical remodeling in sedentary, healthy, middle-aged adults. So, he had 61 individuals, their average age was 53.5 years, quite young, who were randomized to 10 months of exercise training followed by 14 months of maintenance exercise and some stretching or stretching and balance control. He also had another group of 14 master's athletes that were added for a comparison and he looked at three of the echocardiograms to assess left atrial and left ventricular volumes and also had signal average EKG's for filtered P-wave durations and atrial light potentials. He made assessments at baseline, so before everyone started, and 10 and 24 months. Dr Carolyn Lam:                Hold on, hold on. Let's really understand here how much exercise were these sedentary middle-aged adults subjected to. Dr Greg Hundley:             So, let's talk about that because that was very interesting because a lot of us are out there exercising. So briefly the way he started this, there was an initial phase that was comprised of six months of regressive training during which an increase in the frequency, the duration, and the intensity of exercise, including two high-intensity aerobic interval sessions per week that were prescribed to peak training load. The peak training load included five to six hours of exercise per week that included two interval sessions, at least one being an hour-long session, and then two 30-minute sessions.                                                 Once you got that peak training load, that was sustained for four months and then he made these 10-month measurements as part of his study design. Now following that phase, a 14-month sort of a continuation, all of the 24 months, a 14-month period of maintenance exercise was completed where the frequency of high-intensity intervals was reduced to once per week plus continuous training all the way to that 24-month time point. And during the maintenance phase, participants performed a total of about three hours a week of aerobic exercise. Dr Carolyn Lam:                Well, don't keep us in suspense now. What did the study show? Dr Greg Hundley:             So at the 24 month time point of high-intensity exercise, it led to a disproportionate dilation of the left atrium compared to the left ventricle. So, mechanical changes, but no electrical remodeling was seen. And interesting, and remember he had that comparison cohort with master's athletes. Those participants randomized exercise training demonstrated lower absolute left atrial and left ventricular volumes, but a similar left atrial to left ventricular ratio after 24 months of exercise training.                                                 So, what's going on here, if you're middle-aged or young, some of us like to think, and you start one of these aggressive training sessions, you do have some changes mechanically in the shaping of your left atrium and left ventricle, but they're concordant, but no electrical remodeling that was observed in this situation. So, how do those elite athletes develop atrial fibrillation in the electrical remodeling? Don't know. It may be they need a longer duration of exercise. Maybe they start at a different time point because these are relatively sedentary individuals, and maybe their training regimen is very different.                                                 So, more research is needed, but it was interesting that these middle-aged folks that start with this little bit more aggressive regimen really didn't develop the electrical remodeling. So, Carolyn, you've got a couple of papers that are sort of tied together. Dr Carolyn Lam:                Indeed. A couple of papers centered on lipoprotein little A. Now, we know that lipoprotein little A levels predict the risk of myocardial infarction and this has been shown in populations of European ancestry, however there's very little data available in other ethnic groups. And so, this was addressed by Dr Paré from McMaster University and the Interheart Investigators who looked at more than 6000 cases of first myocardial infarction and more than 6800 controls, all from the Interheart study, and were stratified by ethnicity and included African, American, Chinese, European, Latin American, South Asian, and Southeast Asian ancestries.                                                 Lipoprotein little A concentration was measured in each participant, first using an SA that was insensitive to iso-form size and then iso-form size itself was also assessed by Western Blot in a subset of more than 4200 participants. So, what they found was that lipoprotein little A concentration and iso-form size varied markedly among the ethnic groups. Africans had the highest concentrations with the smallest iso-form size whereas Chinese had the lowest concentrations with the largest iso-form size.                                                 Furthermore, higher lipoprotein little A concentrations were associated with an increased risk of myocardial infarction and carried an especially high population burden in South Asians and Latin Americans. And a high concentration above 15 milligrams per deciliter was associated with significantly increased risk of myocardial infarction in all populations except Arabs and Africans. The iso-form size, on the other hand, was inversely associated with lipoprotein little A concentrations and did not significantly contribute to the risk. Dr Greg Hundley:             So, Carolyn, how do we use this clinically? I mean, do we measure this in folks? Dr Carolyn Lam:                Yeah. So, there are two take-home messages. I think one is about the monitoring or measuring and it supports a clinical use of the actual lipoprotein A concentration rather than iso-form size as a marker of myocardial infarction in this ethnically diverse population. But this is, other than Africans and Arabs where, remember that cut off did not seem to associate with a risk of MI's in these two ethnicities. The second take-home is that the effects of clinical interventions that reduce lipoprotein A should be investigated especially in South Asians and Latin Americans where the population attributable risk is really high. And that actually brings me to the second study.                                                 So, we've always been looking for intervention that can reduce lipoprotein A and this current paper is really interesting 'cause it talks about insights from the Fourier trial. So, we may finally have a therapy that can reduce it. Dr O'Donoghue from the TIMI study group and Brigham and Women's Hospital in Boston, Massachusetts and colleagues looked at the relationship between lipoprotein A levels, PCSK9 inhibition, and cardiovascular risk in the Fourier trial, which you remember is a randomized trial of Evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease.                                                 So, they found that patients with a higher concentration of lipoprotein little A were at increased risk of coronary events independent of the LDL concentration. And individuals with a higher baseline LP little A concentration tended to have a greater relative and absolute coronary risk reduction with Evolocumab and therefore a lower number needed to treat. It was as low as four T for individuals with a lipoprotein A above the median versus 105 number needed to treat for those at or below a lipoprotein A level below the median. Dr Greg Hundley:             So should we start checking this in all our patients now, these lipoprotein little A levels? Dr Carolyn Lam:                Yeah. So, this issue was discussed beautifully in a company editorial by Dr Thanassoulis from McGill University Health Center. And here he mentions that there remains tremendous clinical inertia honestly for the measurement of lipoprotein A in North America and in fact, worldwide. For this to be successful, we really need to be proactively screening our patients with myocardial infarction and stroke and especially those with premature events or a family history. And particular attention will need to be made on screening individuals with recurrent events despite adequate lipid or LDL lowering who frequently may still have high lipoprotein little A. It's encouraging to know that the most recent version of the US Lipid Guidelines has newly recommended LP little A measurements in select individuals as a risk enhancer and so this should further raise awareness of lipoprotein little A as a risk marker.                                                 Finally, the editorialist mentioned that common misconception that we have a lack of therapeutic options to lower high LP little A. Still, we need to remember that these individuals may obtain significant benefit from more aggressive lifestyle modifications. And now we have these results of this trial that suggest that PCSK9 may be one of the few drugs that can lower lipoprotein little A. And so, the editorialist actually ended with targeting therapy for lipoprotein A is around the corner and a test of this hypothesis is really imminent, so we should watch this space. Dr Greg Hundley:             Yeah, so it sounds like another wonderment of PCSK9 inhibitors. Dr Carolyn Lam:                Yeah. Dr Greg Hundley:             Well Carolyn, let me jump in and finish our chat here talking about iron. This particular paper is from Dr Jean-Sébastien Silvestre from Paris, France, and he's looking at the iron regulator Hepcidin. So, we know that iron deficiency is frequent in patients with coronary artery disease and increases morbidity in those with high risk profiles such as those with diabetes and anemia and then conversely, excess iron is also detrimental to cardiac function. We see this with iron overload cardiomyopathies and as a major co-morbidity in patients with genetic hemochromatosis.                                                 So, among the multiple regulators of iron homeostasis is Hepcidin. It plays an instrumental role in fine-tuning systemic iron trafficking by modulating the transfer of dietary, recycled, and stored iron from intracellular compartments to extracellular fluids. Hepcidin is a catatonic peptide hormone. It's produced primarily by hepatocytes, but also, it's produced in macrophages. So, given the role of Hepcidin to locally regulate cardiac function and that inflammation guides cardiac remodeling after acute MI, the investigators hypothesized that inflammatory macrophages may control cardiac repair through a Hepcidin-dependent mechanism. And until now, the role of Hepcidin in some other cardiac diseases challenged by inflammation hasn't really been explored. Dr Carolyn Lam:                Huh, interesting. So, what did they find? Dr Greg Hundley:             Great question and let's lead to the main results of this study. The hormone Hepcidin, they found, was produced by a distinct sub-population of inflammatory cardiac macrophages residing in infarcted heart tissue and the deletion of Hepcidin in macrophages improved tissue remodeling and stimulated cardiomyocyte renewal in both, just as our wonderful basic science studies have, in both adult mice with myocardial infarction, neonatal animals with apical resection and also in human subjects. And so, this study provided novel insights into the complex roles of the immune response during cardiac repair following MI and suggests and deleterious role for the macrophage-derived Hepcidin in cardiac repair.                                                 Interesting, Carolyn. Another role for iron in acute MI and more research to come. Dr Carolyn Lam:                Indeed. Well, thanks Greg. Let's move on to our feature discussion, shall we?                                                 For our feature discussion today, we are talking about the first results from the Get With the Guidelines atrial fibrillation. That is huge, and I have none other than the first author, Dr Jonathan Piccini from Duke Clinical Research Institute, as well as Dr William Lewis from Case Western Reserve University here to discuss these really important results, so listen up. I think to start with it is such an honor to have you with us, Bill. I mean, as Chair of the Get With the Guidelines atrial fibrillation work group, could you give us a background on how did this start? How far has it come? Dr William Lewis:             The Get With the Guidelines program started in 2000. Greg Fonarow figured out that if we put in place mechanisms to improve adherence, that we could get people on appropriate therapies. In 2012, there was some focus on atrial fibrillation and I had been participating in the program since 2004 and I kept telling them that A-fib was a big, big problem. And in 2012, they said, "Let's do this," so we built this program to try to improve adherence in atrial fibrillation. Get With the Guidelines is a national, hospital-based, quality improvement program that improves adherence to guidelines over time and it has been very successful at doing that.                                                 So, by 2013 we were ready to start enrolling patients and we started getting patients in the database and we're now up to about 162 hospitals nationwide, in the United States, and we've enrolled about 75000 patients in the program. So, it's been very successful from that standpoint. Dr Carolyn Lam:                Congratulation. And today we're actually going to be talking about that very question you asked. Adherence. How well are we adhering to guideline-directed stroke prevention therapy for atrial fibrillation? Jonathan, wanna share the key results? Dr Jonathan Piccini:         I think you're getting exactly to the point of what was the rationale for this study and I think most individuals that are familiar with the field and atrial fibrillation and also clinicians across the world who are treating patients with atrial fibrillation know that most large reports, most nationwide studies have shown that adherence for oral anticoagulation to prevent stroke in patients with atrial fibrillation usually ranges in the 50, 60, 70 percent range at best. And there's been some notable publications in the past several years from nationwide registries that have shown rates as low as 50 percent or lower in high-risk patients. So, one of the main goals of the program, as Bill articulated, was to try and improve the use of oral anticoagulation in patients who had a guideline recommendation. So, patients who had a CHA2DS2-VASc score of two and higher with atrial fibrillation.                                                 And so, looking at over 30000 admissions between 2013 and 2017 and the guidelines A-fib program, we saw that just under 60 percent of patients who had known AF at the time of admission were on oral anticoagulation. And not surprisingly, the patients who were on oral anticoagulation had lower rates of stroke during their hospitalization. But the major finding from the program was that in this quality improvement program, the program was able to improve adherence to oral anticoagulation at discharge from 60 percent to admission all the way up to 93.5 percent in the overall cohort. And if you looked at results over time, adherence improved from 80 percent at discharge all the way to 96 percent and those improvements were sustained in follow up as well. Dr Carolyn Lam:                Could you tell us, what do you think are the key elements that help this improvement? Is it just because there's a program and people know they're being watched? Is it that there was a change? I mean, when you say oral anticoagulants I bet you mean both Warfarin and the newer oral anticoagulants, so how much did that help? What do you think is the key ingredient here? Dr Jonathan Piccini:         It was several things. Having visited several of these hospitals and spoken with them about the impact of the program, I think you can't emphasize enough that if you don't measure something, you can't really expect to improve it. So, just the fact that hospitals were having systematic data on their atrial fibrillation patients at discharge illustrating who was and who was not getting oral anticoagulation makes a big difference. Between the program itself and the conferences affiliated with the program and teaching sessions affiliated with the program, there's a heavy emphasis on education of the importance of guideline recommended treatments for atrial fibrillation, so that's a second component.                                                 And then there's an iterative relationship between the sites and the American Heart Association where improvements in the rates of oral anticoagulation are recognized and celebrated. And I think it's not any one thing, in my opinion. I think it's all of those things taken together. And again, Bill, who's been with the program since its inception probably has additional thoughts on that as well. Dr Carolyn Lam:                Bill, did you expect such remarkable results? Dr William Lewis:             No. I actually didn't expect 96, but in a previous study where we were looking at patients who had had a stroke in the stroke database, we were able to achieve 93 percent adherence. And so, 96 is remarkable and it's the highest number that's ever been seen in any A-fib program. I was going to mention about the idea of what makes the special sauce, if you will, and I think John put forth a number of items. I think, again, celebrating success, those kinds of things, but I think that docs, by their very nature, are very competitive and when you get a data report that says you're doing x percent and somebody else is doing y percent and their percentage is higher, you tend to get motivated to actually do better. And so, we provide these reports in the program to hospitals so that they can measure their success against other institutions. Dr Carolyn Lam:                That's such a good idea. And, you know, I practice here in Asia and there aren't these very massive programs that are accepted in many places. So, what do you think is the generalizability of something like this? Dr Jonathan Piccini:         That's such a critical question because a limitation is that these are hospitals that are saying voluntarily, "We want to commit to the program because we think quality care for atrial fibrillation patients is important." And so, you could argue that, well, these results really don't generalize to your run of the mill hospital in different parts of the world. And I think while that's a limitation, it's also a call for what the next steps are. So, having visited many of these hospitals, these are real hospitals of brick and mortar that face many of the same challenges other health systems and hospitals across the world do and I think the key message is that a hospital that implements these types of interventions is very likely to see the same improvement with their patients. And so, I think that's a very important message and a very positive message for patients all over the US and all over the world. Dr William Lewis:             I agree. I think it's, not turn-key, it's much more generalizable than we had ever expected. So, community hospitals do this. The American Heart Association is using other Get With the Guidelines programs in China. I think that there is a lot that has to do with the support that's provided by the program and the tools that are made available to them to be able to make it so that you can recreate it in a hospital. I agree, it is more difficult in some hospitals than others. Dr Carolyn Lam:                John, before we end, what are the take-home messages for clinicians listening out there? Dr Jonathan Piccini:         I'd have two messages. The first message is that this study shows that with some assistance any healthcare system or hospital can achieve optimal adherence to these medications for their patients and thus in so doing achieve a significant benefit for the public health. And the second message I would have, which isn't necessarily specifically related to the paper, but I think it's equally important, that this is just the beginning for the American Heart Association and the Heart Rhythm Society Get With the Guidelines A-fib registry. Though stroke prevention is obviously just one of many different aspects of quality care for atrial fibrillation and so keep an eye out 'cause you'll be seeing a lot of studies coming out about how Get With the Guidelines A-fib is better informing care and treatment for atrial fibrillation across many different therapy domains, including catheter ablation and rate control and other interventions for rhythm control. And again, on behalf of all the co-authors and the American Heart Association, the Heart Rhythm Society sponsors, we really appreciate to have the opportunity to talk about the program. Dr Carolyn Lam:                Thank you so much for sharing that with us.                                                 Audience, you heard it right here on Circulation on the Run. Don't forget to tune in again next week.                                                 This program is copyright American Heart Association 2019.  

Ben Levine is a partner in the law firm of Gordon & Rees who has represented such high-profile sports clients as Alex Rodriguez, Jonathan Martin and Jameis Winston. Ben stops by to share his experiences as one of the up-and-coming “go-to” lawyers in sports.

Dr. Carolyn Lam:               Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I am Dr. Caroline Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.                                                 Can we reverse the cardiac effects of sedentary aging? Well if you're curious, you have to read the feature paper in this week's journal, as well as listen to the upcoming discussion of a trial that addresses this issue. All coming right up, after these summaries.                                                 Desmond mutations are known to cause skeletal and cardiac muscle disease, and also recently has been described in patients with inherited arrhythmogenic right ventricular cardiomyopathy or dysplasia. In today's first original paper, however, authors identified a novel Desmond mutation in a large Spanish family with inherited left ventricular arrhythmogenic cardiomyopathy or dysplasia, and a high incidence of, at first, cardiac events.                                                 First in corresponding author, Dr. Bermudez Jimenez from Granada, Spain, describe for the first time the largest family to date with a single Desmond mutation with a phenotype of left dominant arrhythmogenic dysplasia in the absence of skeletal myopathy symptoms and atrioventricular conduction disorders and supported by strong clinical and functional data. In a series of elegant experiments using explanted cardiac tissues and mesenchymal stem cell derived cardio myocyte from the family members, the author showed that the pathogenic mechanism probably corresponds to alteration in Desmond dimer and oligomer assembly and its connection with membrane proteins within the intercalated discs, thus Desmond mutations should be suspected in patients presenting with a cardiomyopathy characterized by mild left ventricular systolic dysfunction and/or dilatation, fibrosis, ventricular arrhythmias and a family history of sudden death.                                                 The next study is the first large scale report examining the incremental risk of surgical aortic root enlargement in patients undergoing aortic valve replacement.                                                 First author Dr. Rocha, corresponding author Ouzounian from University of Toronto and their colleagues sought to evaluate the early outcomes of patients undergoing aortic valve replacement with or without surgical aortic root enlargement.                                                 Now aortic root enlargement allows for larger prosthesis implantation and maybe an important adjunct to surgical aortic valve replacement in the transcatheter valve in valve era.                                                 Among more than 7,000 patients undergoing aortic valve replacement at a single institution from 1990 to 2014, the authors observed no incremental risk in post-operative mortality or adverse events following surgical enlargement of the aortic root as compared to aortic valve replacement alone. They therefore concluded that surgical aortic root enlargement appears to be a safe adjunct to surgical aortic valve replacement in the modern era.                                                 The next study suggests that in patients with acute coronary syndrome and an LDL cholesterol above 50 milligrams per deciliters, health care providers should consider adding ezetimibe to statins, particularly in two patient subgroups.                                                 First in corresponding author Dr. Giugliano from the TIMI study group at Harvard Medical School in Boston, Massachusetts and his colleague explored outcomes stratified by diabetes in the "improve it" trial where patients with a recent acute coronary syndrome were randomized to ezetimibe versus placebo on top of backgrounds in the statin.                                                 They found that patients with diabetes derived significantly greater relative and absolute benefit with the addition of ezetimibe relative to patients without diabetes. This enhanced benefit was driven by reductions in acute ischemic events including myocardial infarction and ischemic stroke in diabetics, while non-diabetic patients who were more than 75 years of age or who had a high risk score also significantly benefited from the addition of Ezetimibe to Simvastatin.                                                 These benefits of Ezetimibe were achieved without an increase in safety events compared to placebo. Thus, the two patient subgroups of acute coronary system who are likely to achieve greater benefits with the addition of ezitimibe include: one, patients with diabetes, and two, patients without diabetes who have a high risk score.                                                 The final study provides insight into sudden cardiac arrests in the young and the potential contribution of standard cardiovascular risk factors to this risk, even in the young.                                                 First author, Dr. Reshmy Jayaraman, corresponding author Dr. Chugh from Cedars-Sinai Medical Center in California and their colleagues, prospectively ascertained 3,775 individuals who suffered sudden cardiac arrest between the ages of 5 and 34 years in the Portland, Oregon Metropolitan area and who were also followed up for 13 years. They found that 5% of cases occurred in young residents between the age of 5 and 34 years.                                                 Among the young, there was an unexpectedly high prevalence of classical cardiovascular risk factors, such as obesity, diabetes, hypertension, hyperlipidemia and smoking. In fact, one or more risk factor was observed in 58% of cases, with obesity being the most common.                                                 Less than a third had warning symptoms prior to their lethal event and sports activity was a trigger in only 14% of young cases. Thus, standard cardiovascular risk factors, especially obesity, may play a larger role in sudden cardiac arrests in the young than previously recognized. This suggests the potential role of public health approaches that screen for cardiovascular risk factors at earlier ages.                                                 And that wraps it up for our summaries, now for our feature discussion.                                                 Oh boy, today's featured discussion is gonna make everyone listening fall in love with exercise and seriously get off your chair right now as you listen to this discussion.                                                 It's about how exercising may reverse cardiac aging and I am so delighted to have with me none other than the corresponding author, Dr. Ben Levine from the institute of exercise and environmental medicine at Texas Health Presbyterian and UT Southwestern, as well as Dr. Jarett Berry, and he's our dear associate editor from UT Southwestern.                                                 Ben, I have been dying to have you on this show, so welcome and please, tell us what you did. Dr. Ben Levine:                 Thank you very much, it's a pleasure to be here Carolyn, thanks for inviting me to talk about it. As you know, our lab has been particularly interested in the components of aging that are related to senescent versus those that are related to senescence activity.                                                 Perhaps the most dramatic reason that we're interested in this, I'm just gonna give you a little bit of background, if you don't mind, comes from one of the most important studies ever done in our field, that was done in Dallas in the mid-1960s. It's called the Dallas Bedrest and Training Study.                                                 At that time, my mentors, G Blomqvist, Jerry Mitchell, Bengt Saltin, took five young men, put them to bed for three weeks and then trained them for two months and virtually everything we know about the adaptive capacity of the circulation to exercise starts without study.                                                 I was only ten years old, so I really had nothing to do with it, but 1996, 30 years later, we found those same five guys and brought them back to Dallas to study them again.                                                 Now, these are the most intensively studied humans probably in the history of the world. 78 pages of circulation in 1968. What we found was quite amazing. We found that not a single one of those five guys was in worse shape 30 years later, than they were after three weeks of bed rest when they were in their 20s.                                                 So, three weeks of bed rest was worse for the body's ability to physically work than 30 years of aging. And so, we sort of launched off that in a series of experiments, trying to figure out when in the aging process does the shrinking and stiffening of the heart develop, that is the sine qua non. if you will, of the cardiac aging. So, when does it start? How much exercise do you have to do to prevent that?                                                 We did one interesting study where we compared a group of very highly selected seniors, all aged around 70, who were healthy, but did no exercise, compared to a group of elite Masters Athletes. Amazingly, the healthy seniors, their hearts got smaller and it shrunk and they got stiffer and the athletes had hearts that were indistinguishable from healthy 30 year olds.                                                 So, a lifelong training at the level of being an elite athlete completely prevented that aging response, which is really interesting scientifically, but not a very good public health measure.                                                 So, we then asked how much exercise do you need to do over a lifetime to preserve the compliance, the youthfulness, if you will, of the circulation, and at times, they act like you need to do about 4 or 5 days a week over a lifetime. 2 to 3 days a week didn't do anything. 4 to 5 days a week did almost as much as being an elite competitive athlete. So, now we've got the dose. 4 to 5 days a week.                                                 We said, "okay, if we do that, can we reverse cardiac aging once it's occurred?" So, we took our healthy sedentary people and we also looked at a group of HFpEF patients and we trained them for a year, at the right dose, using high intensity exercises. We made them fitter, but we couldn't touch their cardiac or vascular stiffness. Quite disappointing actually.                                                 Last thing then, we said "okay, this leads up in to our current study maybe, just maybe, if we pick the right sweet spot in time, when the heart is just beginning to stiffen in that late middle age period and deal the right dose at the right time for a long enough period, we could reverse the effects. And, that's what we did. We took 60 people, healthy, middle aged, 45-64, mean age around 50. We randomly assigned them to two years of exercise training or two years of yoga, balance, flexibility, and we did 2 light heart caths. We measured their cardiac compliance directly invasively and we showed that our 2 year training program, which included high intensity intervals, reversed the effects of decades of sedentary aging. Dr. Carolyn Lam:               Wow, Ben, you know, no one tells the story like you and I have to tell you, I've been a fan of your work, citing it since I was 10. Thank you so much for this amazing contribution to the Journal this week. I just know everybody's asking questions like "So, you've given us when to start, you given us the dose, but we want to understand a bit better, what do you mean high intensity, how many minutes and what exactly." Could you give us an idea? Dr. Ben Levine:                 Sure. There are multiple different ways to go about doing HIIT or High Intensity Interval Training. And there's no magic to intervals. Intervals just allow you to do something for a shorter period of time and harder than you could do for a longer period of time. That is the strategy that athletes use to go faster and stronger and higher, because the body adapts to the load that's placed on it.                                                 Interval training, what I like, is based on an old Norwegian ski team workout. It's called the "4x4". What that means is 4 minutes at 95% of your maximum followed by 3 minutes of recovery, active recovery, repeated 4 times. So, basically, you go as hard as you can go for 4 minutes and at the end of those 4 minutes, you should be ready to stop. Typically, your heart rate will drift up towards 95% of maximum or so. Then, at the end of the 3 minutes of recovery, you should be ready to do the next interval.                                                 As it turns out, that's extremely effective training stimulus. Not just for healthy people or athletes, for the patients with hypertension and with heart failure. Dr. Carolyn Lam:               I noticed that you have to screen over 260 individuals to finally get your 60, so how doable is this and what was the compliance? Dr. Ben Levine:                 Right. You have to remember that out of those 260 individuals that we screened, the majority of them were excluded up front because they had hypertension or if they were obese or they already had heart disease. So, the first round of screening was making sure we're getting people of the right age and were healthy. And, then another fraction, say 40 of them or so, didn't wanna undergo two light heart catheterizations. And, I get that. We were pretty pleased that somebody volunteered to do it, but you know, it's an intense commitment. People have to be willing to be randomized. So, they couldn't say "Well, I wanna do your study, but only if I get randomized to exercise", that was not acceptable.                                                 So, everybody had to be prepared to be randomized to either yoga or the fitness training and the yoga, it makes people feel better, it's relaxing. I think it provided that clinical equipoise and it ensured that even the controlled patients had close contact with our research team.                                                 Then, what we had was, on average 88% of the prescribed sessions were followed by our exercisers and a fraction of them, 15 or 20%, actually did 100% of their prescribed sessions over two years, didn't miss a single one. Dr. Carolyn Lam:               So, Jarett, have you started doing that yourself now? Dr. J Berry:                          I tell you, I pried my kids out of bed last summer, to go do 4x4s and get them ready for cross country. I talked all about Ben Levine and told my kids that we were doing what Dr. Levine recommended. That didn't help too much, they found it rather challenging. It was interesting that the VO2 plateaus a little bit at that 10 month mark, when you guys backed off on that additional interval training. Do you think that the plateau is just a limitation of the training effect or do you think that something that has to do with the lower level of interval training at that time? Dr. Ben Levine:                 You know Jarett, I think that's a fascinating question and it's one of the things that really surprised me. So, Jarett pointing to the fact that at that 10 month mark, we measured VO2 max, we didn't cath them, but we did an Echo, and it showed that from 10 months to 2 years VO2 max didn't increase very much.                                                 There was a dramatic increase from baseline to 10 months. It took 3 months at that peak dose. But then, when we dropped one interval and did the same thing every week for 2 years, there wasn't an influence of time. The heart didn't continue to get bigger, the stroke volume didn't continue to enlarge.                                                 I think it highlights a critical part, an essential element, to that exercise training and that is, doing the same thing, over and over again doesn't get you fitter. If you wanna get fitter than you are, you have to change things around, you have to increase the load. So, I think that if we had wanted to make them even fitter than they were at 10 months, we'd have had to either kept that second interval or added another one or increase the duration of some of the base training sessions.                                                 It's really interesting to me, that they didn't continue to improve simply on the basis of time. That surprised me. Dr. Jarett Berry:                Yeah, cause you wonder. You think about, the guidelines suggest moderate intensity exercise, which is obviously much lower intensity than what you're talking about with this interval training, but very little guidance with regard to interval training.                                                 Your data here obviously suggests that it's not just getting off the couch and doing something, and not just doing a decent amount, it seems to suggest that the interval training component may be a secret ingredient that might be most helpful, at least for those patients who can tolerate that level of training. Dr. Ben Levine:                 Yeah, I think that maybe it's the secret sauce, Jarett, but I think, you do have to ask yourself, what is the goal of training and what is your objective outcome? What you want is to reduce cardiovascular mortality. I think we would all agree that you get the biggest bang for your buck by going from sedentary to active. And, the mechanism of that is uncertain, but could relate to autonomic function or clotting or improving stabilization of endothelium or other risk factors, inflammation, who knows, there's a lot of different candidates. So, I think that particularly for people who are at the highest risk for heart failure, either from their family history or other risk factors, like hypertension and diabetes, those are the ones who were likely to get in a special benefit on altering cardiac structure.                                                 That's why I think our data is still an important poll. We didn't really know why do you get the biggest bank for your buck with a little training, but if you really wanna prevent heart failure, you gotta do more.                                                 In our data that we did partnered with the Cooper Clinic and looked at people who had done the same number of exercise sessions over 25 years. None, 2-3, 4-5 or 6-7, over 25 years, we saw virtually no effect of 2-3 days a week of what we call casual training on anything we could measure, related to cardiac structure. Their vascular stiffness was the same as people who were sedentary, their cardiac stiffness was the same as people who were sedentary. They were a little fitter and perhaps there were other important differences that are related to just improving immortality, but you have to get past that low to moderate dose to have the structural effects on the circulation. Dr. Jarett Berry:                These are really great points here, Ben. I want for our listeners to hear you comment a little bit more on the primary outcome and how you guys measured stiffness, because I think in addition to the level of training, it's also the approach and the phenotype that you collected to measure this and I think it would be helpful for you to walk us through that a little bit and how you guys measured stiffness. Dr. Ben Levine:                 We used an old physiological technique called "Lower Body Negative Pressure". We first let the subject settle down, we measure a variety of cardiovascular variables, cardiac output, and we do an advanced ECHO imaging and some arterial stiffness measures and after about 40-45 minutes or so, we'll measure the pulmonary capillary wedge pressure, that's what we use as an index, and plus ventricular and diastolic pressure. We'll do 3D ECHO volumes and then we unload the heart by doing Lower Body Negative Pressure. We basically seal the subject in a box at the iliac crest and turn on a vacuum cleaner and suck blood into their venous capacitance. It's a very simple way to unload the heart.                                                 In contrast to people who do put in conductants or reflectant catheters and occlude the IVC and do pressure volume rudes, we have taken a little bit of a different approach. I do steady state and diastolic pressure volume curves. So that means, we look at the pressure and volume in the heart at baseline at two different unloading levels. So, let's say the baseline ledge is 10. The first level of LBNT of minus 15 will get it down to 6 or 7. The next level of minus 30 gets it down to 2 or 3. And, so we get a nice unloading of the heart and we're able to establish a steady state, which is probably more afunctional than a release of an IVC occlusion.                                                 Then, we let go of the suction, everything returns to normal. We repeat our baseline measures and then we give the rapid saline infusion. When I say rapid saline, I mean 15 and 30 mls per kilogram, that's at 200 mls a minute. That's a big volume infusion, but we'll give those doses and we'll raise the ceiling pressure from 10 at baseline to 15 and then 19, 18, 19. So, we get a large physiologic range of the diastolic pressure volume curve, and then we'll fit that to an extremely widely accepted exponential equation, which allows us to calculate the overall stiffness of the heart, the diastolic component, and then we'll do a few other things, we'll measure distensibility , which is the volume at any given pressure and DPDV, the change in pressure for a given volume, which is the hansen float to the exponential curve fitting. Dr. Jarett Berry:                Can you comment a little bit about what this means for how this is distinguished perhaps from maybe more conventional non invasive measurements of cardiac stiffness? Dr. Ben Levine:                 I think the most important thing to realize is that, cardiac compliance is dynamic. It depends on the volume at which you're making that measurement. So, as you unload the heart, any heart, even the stiff heart, it gets more compliant, and as you load the heart, even a compliant heart, it gets stiffer. Part of that is a function of pericardial constraint, as well as myocardial stiffness.                                                 The whole idea that there is a measure of diastolic function that you can measure by ECHO that is load independent is frankly an oxymoron, because, diastole is load dependent. I think the ECHO measurements are interesting and useful, depending on what you're trying to find out, because there are many different aspects of feeling and diastolic suction and diastolic stiffness. All of which influence how well the heart feels at rest and during exercise. Dr. Carolyn Lam:               I have to ask you one last question. I am so pleased that you included at least 52% women. Were there any differences by sex? Dr. Ben Levine:                 Of course, Carolyn, it's critical to include women, since they're 50% of the population. We've been very interested in their training responses in men and women at different age groups in many of our other studies. What's interesting is that in premenopausal women, there's a quite clear distinction in how women respond to training. They don't hypertrophy as much, even for the same stimulus, heart beats a heart beat, over a year, there's a much less hypertrophic response to premenopausal women than young men.                                                 We didn't see anywhere near that difference in our mostly postmenopausal middle aged men and women. We didn't have enough power to clearly be confident that there was no difference, but when we tried to test that hypothesis, whether there was a different response in men or women, we could not detect a difference. Dr. Carolyn Lam:               That is a good thing. So, women out there, you heard it from Dr. Levine. We got to exercise too. High intensity. All the time.                                                 Thank you audience, for listening today. Don't forget to tune in again next week.  

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 Youth National University of Singapore. Coming right up, we will be discussing fascinating new data on the prevalence of subclinical coronary artery disease in masters endurance athletes but first, here's your summary of this week's journal. The first paper provides insight into ischemic cellular post conditioning. Now, we know that cardiosphere derived cell therapy has been utilized as a strategy to treat ischemic heart disease and reduce chronic scar burden when administered months after myocardial infarction. In the current study, by first author Dr. de Couto, corresponding authors Dr. Marban and Berman from Cedars-Sinai Heart Institute in Los Angeles, California, the authors used rat and pig models of myocardial infarction to show that exosomes, which are nanosize lipid bi-layer vesicles, actually mediate the cardio protective effects of cardiosphere derived cells when administered after reperfusion of myocardial infarction.                                                 They further show that treatment with either cardiosphere-derived cells or their secreted exosomes reduce infarct size and improved functional recovery. Using RNA sequencing to determine exosome content and alterations in gene expression profiles on macrophages from cardiac tissue or bone marrow, they found that a specific micro RNA species miR 181-B within the exosomes, acted on macrophages and was implicated as a key mediator of the cardio-protective benefits. Thus, this study gives new reason to test the idea that allogeneic cardiosphere-derived cells may be efficacious in preventing scar formation and improving cardiac function, when given in the earlier reperfusion period. The data further support that exosomal transfer of miR 181-B from these cardiospheric-derived cells into macrophages underlie the cardio-protective effects after reperfusion.                                                 The next study describes a potential new therapeutic strategy for vasoproliferative retinopathy which can underlie age-related macular degeneration, the leading cause of blindness in industrialized nations. First author, Dr. Bucher, corresponding authors Dr. Yea and Friedlander, from the Scripps Research Institute in La Jolla, California used rodent models of retinal neo-vascular disease to show that Tspan-12, beta-catenin signaling plays an important role in the development of vasoproliferative retinopathy. As background, Tspan-12 belongs to the Tetraspanin family, which mainly includes cell surface proteins characterized by four transmembrane domains and two extra cellular domains.                                                 Members of the Tspan family participate in a diverse cellular processes and act as signaling platforms by forming Tspan-enriched micro domains in plasma membranes. The authors went further to use a novel phage display combinatorial antibody library to specifically design a Tspan-12 blocking antibody which is capable of interacting with human and mouse Tspan-12 antigen. They then provided strong evidence that the Tspan-12 blocking antibody prevents developmental pathological neovascularization in  murine models of vasoproliferative retinopathy. Combination therapy with a known anti-VEGF agent demonstrated significant synergy supporting the potential clinical use of the anti-Tspan-12 antibody as a novel angiomodulatory agent.                                                 The next study addresses the paradox that blacks have higher coronary heart disease mortality compared with whites, but non-fatal coronary heart disease risks may be lower for black versus white men. To address this paradox, first author Dr. Colantonio, corresponding author, Dr. Safford and colleagues from Weill Cornell Medical College in New York, compared fatal and non-fatal coronary heart disease incidents and case fatality among blacks and whites in three studies. The Atherosclerosis Risk in Communities or ARIC study, cardiovascular health study, and reasons for geographic and racial differences in stroke or regards study, all stratified by gender.                                                 They found that the incidents of non-fatal coronary heart disease was consistently lower among black versus white men, although black men have a higher burden of unfavorable social determinants of health and cardiovascular risk factors and a higher fatal coronary heart disease incidents. Following adjustment for social determinants of health and cardiovascular risk factors, black men and women had a similar risk of fatal coronary heart disease, but a lower risk of non-fatal coronary heart disease compared with white men and women respectively. Finally, blacks with incident coronary heart disease had a higher case fatality compared with whites and the difference remained similar after adjustment for social determinants of health and risk factors. Thus, there is an apparent lower risk for non-fatal coronary heart disease among black versus white men and women, which needs to be further studied. Blacks have a higher risk of their initial coronary heart disease event being fatal compared with whites, highlighting the need for reinforcing primary prevention in this population.                                                 The next study provides important information on the burden of re-admissions after hospitalization for critical limb ischemia. First author, Dr. Kolte, corresponding Dr. Aronow and colleagues from Brown University in Providence, Rhode Island, used the 2013/2014 nationwide re-admissions databases to identify almost 61,0000 hospitalizations for primary diagnosis of critical limb ischemia during which patients underwent endovascular or surgical therapy. They found a 30-day re-admission rate of 20.4%. Independent predictors of 30-day re-admission included presentation with an ulcer or gangrene, age above 65 years, females, large hospital size teaching hospital status, known coronary artery disease, heart failure, chronic kidney disease, anemia, coagulopathy, obesity, major bleeding, acute myocardial infarction, vascular complications, and sepsis. Interestingly, mode of revascularization was not independently associated with re-admissions.                                                 The most common reasons for re-admissions included infections, persistent or recurrent manifestations of peripheral artery disease, cardiac conditions, procedural complications, and endocrine issues. Finally, the costs of 30-day re-admissions for critical limb ischemia during the study period were 624 million U.S. dollars. Thus, this study provide knowledge of independent predictors and reasons for re-admissions that will help clinicians and hospitals to identify, develop, and implement strategies to reduce re-hospitalizations and healthcare costs associated with critical limb ischemia. The final study tells us that there may be a direct relationship between life-long exercise volume, and coronary atherosclerosis in athletes. Dr. Aengevaeren and colleagues from Radboud University Medical Center in the Netherlands, studied 284 middle-aged men engaged in competitive or recreational leisure supports, using contrast enhanced CT to assess coronary artery calcification and plaque characteristics.                                                 Participants also reported life-long exercise history patterns and exercise volumes were quantified as metabolic equivalent of task or met minutes per week. They found that participants in the more than 2,000 met minutes per week group had a higher prevalence of coronary artery calcification and atherosclerotic plaques. The most active group did, however, have a more benign composition of plaques with fewer mixed plaques and more often, only calcified plaques. These observations may explain the increased longevity typical of endurance athletes, despite the presence of more coronary atherosclerotic plaques in the most active participants. Well, that wraps it up for your summaries. Now for our featured discussion.                                                 Our current physical activity guidelines recommend 150 minutes of moderate exercise and that's supposed to protect against cardiovascular disease and increase longevity. However, what do we really know about the dose response relationships and the effects of exercises doses that exceed current recommendations. Well, recent data, including a paper in this week's issue, suggests that long-term, high volume endurance exercise may actually accelerate, rather than reduce coronary atherosclerosis. To discuss this exciting paper, we have the corresponding author, Dr. Sanjay Sharma, from Saint George's University of London, as well as editor of digital strategies and associate editor at UT Southwestern who handled this paper, Dr. Amit Khera. Welcome, gentleman. Dr. Amit Khera:                 Good morning. Dr. Sanjay Sharma:          Thanks for having us. Dr. Carolyn Lam:               First, Sanjay, oh yikes! As a runner and as a person who strongly advocates regular exercise, please, please, put us out of our misery. Tell us what you've found and what you think are the possible explanations. Dr. Sanjay Sharma:          I'm a runner too, and I don't think anyone would argue that the benefits of exercise on the cardiovascular system are unrivaled. People who exercise regularly do reduce their risk of an adverse event from a heart attack by 50% when they're in their 5th and 6th decade and they live around three years longer than people who don't exercise at all. Now as you rightly point out, the current recommendation suggests 2 1/2 hours of moderate physical activity per week and by that I would mean, at maximum, a 15-minute mile pace. Clearly, our endurance athletes exercise much, much more than that. They exercise 10 to 20 times greater than that volume and in parallel with this has been the emergence of a large number of people participating in marathon runs. For example, in Europe, there were two million marathon runs per annum and that figure's going up by about 5%.                                                 Coinciding with this burgeoning increase in endurance exercise, is the development of several reports that show that exercise may cause release of biomarkers of cardiac damage. Animal experiments have shown that exercise may cause scaring in the heart and human studies have shown that some marathon runners have more calcium in their coronary arteries compared to relatively sedentary individuals. One of the problems with these studies is firstly, the biomarker release is very transient, it goes away after about two days. Animal experiments cannot really reflect what goes on in human beings because they're artificial and animals are forced to exercise with electrical shocks, et cetera. The studies in human beings have been conducted in runners who have been former smokers.                                                 In fact, the most commonly reported study or cited study, contained individuals of whom 50% had risk factors for coronary artery disease. What we decided to do was to do a clean study, where we took 150 individuals who had none of the risk factors for coronary artery disease and 92 relatively sedentary controls who exercise within the normal limits. We have to exclude a lot of people because we have to exclude anyone that had ever smoked, anyone that had high blood pressure, high cholesterol, or a family history of permanent cardiac disease. We actually subjected them to all sorts of investigations and we found that a small number of male runners had more calcium in their arteries compared to sedentary individuals. Dr. Carolyn Lam:               Wow! Please tell us that there's something good that you can say about that. First of all, I really want to congratulate you on this most elegant study and Amit, I'm sure you put in what the editor's thought but we're just so proud to be publishing such a high quality study here. Amit, is there anything you might want to add of what the editors thought? Dr. Amit Khera:                 Sure, I first want to congratulate Dr. Sharma and his colleagues. This was a carefully done study and we've talked a bit about the coronary calcium but there was extensive investigation and I really think this advanced the field. Sounds like all three of us are runners, so this hit home to all of us and as he mentioned, this has been a very hot area and one that's been very controversial. I think here what we have is a manuscript that really helped move the field forward, helped us better understand the biology. The one thing I'll comment on that we found very interesting was the observation that those that were the masters athletes actually had more of a calcific phenotype, where as those that were not looked like a soft plaque phenotype, if you will. Actually, if you look, we have a companion article in circulation looking at sort of dose dependent finding a similar finding. My question, now turned back to Dr. Sharma is, what do you counsel your patients now with these findings? Has it changed now how you recommend exercise or your thoughts on how you counsel them? Dr. Sanjay Sharma:          Well, we examined 152 different athletes, or masters athletes in 92 controls. These athletes were aged 56 years old, who'd been training for 36 years and had immediate marathon number of 13. Now, what we've found in these individuals is that a small number of males, that's 11%, had a coronary artery calcium score of more than 300. Some men had more plaques than sedentary individuals and these plaques were distributed throughout all three coronary arteries. When we looked at the pathology of the plaques very carefully, we found that the plaques in the athletes were calcified. Indeed, 72% of athletes had very calcified plaques. We know that such calcified plaques are stable, they're less likely to fissure and are less likely to cause coronary thrombosis and therefore, acute myocardial infarction.                                                 This led us to propose that although exercise may be causing some atherosclerosis through the sheering and stressful source during exercise of the bending and kicking of vessels, we believe that the repair mechanism here is different to that seen in people who smoke or who have high cholesterol or high blood pressure. The repair mechanism results in very calcified and stable plaques in athletes and this may actually mitigate the risk of acute myocardial infarction and may explain why the number of people who actually suffer an acute myocardial infarction during a marathon run is very small, around 1 in 50,000, and no different to the number of people who suffer a sudden cardiac arrest playing football or basketball, due to congenital or inherited abnormalities of the heart.  Dr. Carolyn Lam:               Sanjay, those are just such important points to keep in mind as we read your paper. It did strike me as a significant minority, actually, of these long term endurance athletes who develop significant coronary artery calcification and it could potentially be a clinically benign phenotype. At the end of the day, this is a cross-sectional study, isn't it? We can't, I suppose, extrapolate into the clinical events. What are your postulations there and what could be future work that you're planning? Dr. Sanjay Sharma:          Well, you make a good point. This is a cross-sectional study and the demonstration of an increased cardiopathy calcium does not necessarily reflect future cardiac events. We have followed these individuals up for the last 18 months. These masters athletes and have not demonstrated a single one to develop an acute event that would last 18 months. We really don't know what the meaning of these plaques is. I think the only thing to do now, being we've got the liberty of having so many people that do marathon runs and so many people who've been exercising for three or four decades, we can actually do a prolonged follow up study, so the answers will be a while coming. To follow these people up with high calcium, just to see whether they do go on to develop adverse events in the future. All our study has shown is that some male athletes who've exercised lifelong get an increasing number of plaques. These plaques appear to be calcified and stable and the long term effects of such  plaques is unknown. Dr. Carolyn Lam:               Sanjay, just circling back to Amit's question earlier and maybe Amit, you could take it to after this. What do we recommend to our athletes who come in and have a high coronary artery calcium score? Do we tell them to stop? Dr. Sanjay Sharma:          I certainly wouldn't and I'm much less worried about an increase coronary calcium score in a lifelong runner or cyclist than I was 10 years ago. It appears that these plaques are there in some individuals, they are calcified, they appear stable. Given the fact that we know that coronary events during marathon running in experienced runners are very, very low indeed. I don't think I would be keen to do anything about it, not even consider stacking therapy based on our findings at present. As I said before, we do need longitudinal follow up to really identify all ascertain the precise implications of these plaques in masters athletes. Dr. Carolyn Lam:               Right, and this is again recognizing that your particular population was free of traditional cardiovascular disease. Of course, if we were to find these risk factors in our athletes, we would most certainly treat the traditional risk factors. Amit, anything to add there? Dr. Amit Khera:                 I think that was an excellent point about his approach to counseling patients. I will mention on the editorial staff, we felt like this was such an interesting area with emerging data and fast moving, that it was warranting of an editorial. I recommend people to look at the one by Aaron Baggish and Ben Levine. I think they had a very similar conclusion and that was that they don't necessarily proscribe exercise in patients with high coronary calcium but rather, focus on risk mitigation strategy, focusing on risk factors as we normally would do. I think the conclusions are similar and the thoughts in that editorial were insightful, pairing both of these papers and helping us make sense out of this really evolving field. Dr. Carolyn Lam:               Well, thank you Sanjay and Amit for this wonderful discussion. I learned so much as I'm sure our listeners did. You've been listening to Circulation On The Run. Tune in next week. 

Ben Levine, MD is among the legends of exercise cardiology and altitude physiology in sport performance. It is an honor to have him join the Ultra Clan for this amazing interview, packed with heaps of evidence-based, applicable, relevant, and actionable knowledge.

If you enjoyed Part 1 of David Epstein's BJSM podcast listen to this one to hear about the genetic contribution to hypertrophic cardiomyopathy, the reason it is so hard to detect in all cases, and real life choices that some players made when offered genetic screening opportunities. We finish by discussing whether an Olympic cross-country ski champion with a hematocrit of 65 is a blood-doper or the carrier of an unusual single-gene mutation. I learned a great deal from David Epstein in both podcasts; David has put the bar very high for future podcast guests. Recorded at the Summit – Leaders in Performance – New York (June 17/18 2014); with permission from Leaders (James Worrall). David Epstein's session at Leaders was sponsored by Aspetar Orthopedic and Sports Medicine Hospital, Doha, Qatar. For more related content: Sports Cardiology module on BMJ Learning including Seattle Criteria: bit.ly/1lI8djo J Drezner, M Ackerman, J Anderson et al, Electrocardiographic interpretation in athletes: the ‘Seattle Criteria' bit.ly/1ic8P6i Advances in Sports Cardiology November 12, Volume 46: bit.ly/1pitAMf J Drezner, Standardised criteria for ECG interpretation in athletes: a practical tool, bit.ly/1lYQc5f Bruce Hamilton, Ben Levine, Paul Thompson, Greg Whyte, Mathew Wilson, Debate: challenges in sports cardiology; US vs European approaches bit.ly/1lEudzX Unravelling the grey zone: cardiac MRI volume to wall mass ratio to differentiate hypertrophic cardiomyopathy and the athlete's heart: http://bit.ly/1t1LlmQ Sudden Cardiac Arrest and Cardiac Screening: A trainee perspective: http://bit.ly/1oUOWSk Peripheral vascular structure and function in hypertrophic cardiomyopathy: http://bjsm.bmj.com/content/46/Suppl_1/i98.full Unraveling the grey zone: cardiac MRI volume to wall mass ratio to differentiate hypertrophic cardiomyopathy and the athlete's heart: http://bjsm.bmj.com/content/early/2013/06/13/bjsports-2013-092360.full Screening athletes for cardiovascular disease in Africa: a challenging experience: http://bjsm.bmj.com/content/47/9/579.full