Podcast appearances and mentions of sandeep das

Guest Suggestion Form: https://forms.gle/bnaeY3FpoFU9ZjA47Disclaimer: This video is intended solely for educational purposes and opinions shared by the guest are his personal views. We do not intent to defame or harm any person/ brand/ product/ country/ profession mentioned in the video. Our goal is to provide information to help audience make informed choices.Order 'Build, Don't Talk' (in English) here: https://amzn.eu/d/eCfijRuOrder 'Build Don't Talk' (in Hindi) here: https://amzn.eu/d/4wZISO0Follow Our Whatsapp Channel: https://www.whatsapp.com/channel/0029VaokF5x0bIdi3Qn9ef2JSubscribe To Our Other YouTube Channels:-https://www.youtube.com/@rajshamaniclipshttps://www.youtube.com/@RajShamani.Shorts

The Two Crew continue the fight! Music: "Thumri" by Sandeep Das "Northbound Along the 25th" by Robbie Whiplash All other music by Tabletop Audio Thanks for listening! You can find us on Twitter @25northpodcastYou can join our Discord community with this invite code "nBTZzTGZdA"You can send us an email at 25northpodcast@gmail.com if you wish

Tabla virtuoso Sandeep Das and conductor James Ross preview a varied SSO program

Check out my latest episode! This episode is dedicated to the Afghanistan cricket team who had a fantastic ICC ODI WORLD CUP. Back ground music track taken from YOUTUBE Audio Library Album credits: RAAG PAHADI by Sandeep Das, Mayank Raina & Bivakar Chaudhuri

Join Instagram Growth Masterclass Here: https://hi.switchy.io/FFAFOrder 'Build, Don't Talk' (in English) here: https://amzn.eu/d/eCfijRuOrder 'Build Don't Talk' (in Hindi) here: https://amzn.eu/d/4wZISO0--------------Subscribe To Our Other YouTube Channels:-https://www.youtube.com/@rajshamaniclipshttps://www.youtube.com/@RajShamani.Shorts----------------In this video we are in conversation with Sandeep Das. He is a business storyteller and Global Foresight Lead (Emerging Countries) for Mars Wrigley. He is also an author of 4 successful books - 'How Business Storytelling Works', ‘Hacks for Life and Career', ‘Satan's Angels' &‘Yours Sarcastically'.In this podcast we have discussed the emerging markets, like Mexico, South Korea, South Africa and also discussed why China is not a competition to India. Sandeep also shared how gen z's are different from millennials and how gen z's think about relationships. He shared why people should focus on themselves instead of seeking a relationship. Then he discussed the future of relationships and shared how relationships and the marriage market is in danger because of AI. At the end of the podcast we discussed why storytelling is number 1 skill and everyone should learn it. Watch this podcast till the end for an insightful conversation on different countries, India-China debate, relationships and power of storytelling.Follow Sandeep Das OnLinkedin: https://www.linkedin.com/in/sandeep-das-1b343719/Twitter: https://twitter.com/SandyDasAuthorCheck Out His Book - How Business Storytelling Works: https://amzn.eu/d/7dXgEz4-----------------Timestamps:00:00 - Introduction02:59 - Role of Global Foresight Lead05:16 - Shocking facts about Mexico08:04 - How did South Korea become a soft power?11:19 - How is South Africa similar to India?14:42 - Is China a global threat?20:22 - Are China & India competitors?22:08 - Biggest opportunities in India24:43 - House of X26:49 - Role of family in India34:16 - Scientific reason behind prayers38:30 - Gen Z vs millennials45:44 - Gen Z's take on relationship55:08 - Digital companion56:51 - Top 1 skill everyone should learn1:02:49 - Conclusion---------------

In this captivating solo episode, join your host Piyushi Sharma as she dives into the enchanting world of communication skills with a review of the highly acclaimed book, "How Business Storytelling Works" by renowned author Sandeep Das. Effective communication is a vital skill in the world of business, and Sandeep Das's book offers invaluable insights and techniques for mastering the art of storytelling to captivate audiences, influence decision-making, and inspire action. Whether you're a seasoned professional seeking to refine your communication prowess or an aspiring entrepreneur looking to convey your vision persuasively, this episode offers an engaging review of "How Business Storytelling Works." Get ready to unlock the secrets of powerful storytelling and revolutionize the way you communicate in the business world. So, grab your headphones, sit back, and join us for an insightful solo episode filled with inspiration and practical wisdom from Sandeep Das's groundbreaking book on communication skills.

This week, please join author Xuerong Wen, Associate Editor Sandeep Das, and Guest Host Mercedes Carnethon as they discuss the article "Comparative Effectiveness and Safety of Direct Oral Anticoagulants and Warfarin in Patients With Atrial Fibrillation and Chronic Liver Disease: A Nationwide Cohort Study." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass of 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 Poly Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, I'm so excited about today's feature paper. It deals with the important condition where atrial fibrillation exists in patients with chronic liver disease and what do we do for anticoagulation in these patients. It's a comparative effectiveness and safety study of direct oral anticoagulants compared with warfarin in these patients. A huge, wonderful, important study that we're going to discuss. But before we get there, I'd like to tell you about some papers in this issue and I'd like you to tell me about some too. You got your coffee? Dr. Greg Hundley: Absolutely. Dr. Carolyn Lam: All right. I'll go first In this paper that describes a quantitative prognostic tool for the mitral valve prolapse spectrum and it's derived from the new mitral regurgitation international database quantitative or MIDA-Q registry, which enrolled more than 8,000 consecutive patients from North America, Europe, Middle East. And these were patients all diagnosed with isolated mitral valve prolapse or MVP in routine clinical practice of academic centers, all of which also did prospective degenerative mitral regurgitation quantification. The MIDA-Q score was calculated based on characteristics collected in routine practice combining the established MIDA score, which integrated guideline based markers of outcomes like age, New York Heart Association status, atrial fibrillation, LA size, pulmonary artery pressure left ventricular and systolic, I mentioned, and ejection fraction. Integrating that with scoring points based on the degenerative mitral regurgitation quantitation that is measuring effective regurgitant orifice and volume. Dr. Greg Hundley: Very interesting Carolyn. So a scoring system that combines clinical information with what we might assess with echocardiography like regurgitant volume or regurgitant orifice area. So how well did this mortality risk score perform? Dr. Carolyn Lam: So the new score was associated with an extreme range of predicted survival under medical management and that ranged from 97% to 5% at five years for the extreme score ranges. And it was strongly, independently and incrementally associated with long-term survival over all the markers of outcomes. So the authors concluded, and these by the way were authors led by Dr. Maurice Serrano from Mayo Clinic, Rochester, Minnesota. These authors concluded that the score should allow integrated risk assessment of patients with mitral valve prolapse to refine clinical decision making in routine practice and ultimately reduce degenerative mitral regurgitation under treatment. Dr. Greg Hundley: Wonderful description Carolyn. Well I'm going to switch to the world of electrophysiology, Carolyn. And so as you know, the Brugada syndrome is an inherited arrhythmia syndrome caused by loss of function variants in the cardiac sodium channel gene SCN5A and that occurs in about 20% of subjects. And these authors led by Dr. Dan Roden at Vanderbilt University School of Medicine identified a family with four individuals diagnosed with Brugada syndrome, harboring a rare missense variant in the cardiac transcription factor, TBX5, but no SCN5A variant. And upon identifying these individuals, their objective was to establish TBX5 as a causative gene in Brugada syndrome and to define the underlying mechanisms by which it would be operative. Dr. Carolyn Lam: Oh wow. So a new gene variant. So what was the relationship? Dr. Greg Hundley: Right Carolyn? So using induced pluripotent stem cell derived cardiomyocytes from members of the affected family, multiple electrophysiologic abnormalities were detected in these cardiomyocytes including decreased peak and enhanced late cardiac sodium current. In these cells these abnormalities were entirely corrected by CRISPR/Cas9 mediated editing of that TBX5 variant and transcriptional profiling and functional assays in unedited and edited pluripotent stem cell derived cardiomyocytes showed direct SCN5A down regulation caused decreased peak sodium current and that reduced PDGF receptor expression and blunted signal transduction to phosphoinositide-3-kinase. And interestingly, PDGF receptor blockade markedly prolonged normal induced pluripotent stem cell derived cardiomyocyte action potentials. And also Carolyn interestingly in this study they did a separate analysis. It reviewed plasma levels of PDGF in the Framingham Heart Study and they found that they were inversely correlated with the QT corrected interval. And so Carolyn, these results established decrease SCN5A transcription by the TBX5 variant as a cause of Brugada syndrome and also reveal a new general transcriptional mechanism of arrhythmogenesis of enhanced late sodium current caused by reduced PDGF receptor mediated phosphoinositide-3-kinase signaling. Dr. Carolyn Lam: Wow. Wow, that's significant. Thanks Greg. So this next paper is also really important and could change the practice in the field of cardiac resynchronization therapy or CRT. You see, it suggests that the practice of what we do now, which is combining right bundle branch block with intraventricular conduction delay patients into a single non-left bundle branch block category when we select patients for CRT, that this may not be the way to go. So let's go back a bit and remember that benefit from CRT varies with QRS characteristics and individual trials are actually underpowered to assess the benefit for relatively small subgroups. So the current authors led by Dr. Friedman from Duke University Hospital and colleagues, therefore performed a patient level meta-analysis of randomized trials of CRT to assess the relationship between QRS duration and morphology with outcomes. Dr. Greg Hundley: Very interesting Carolyn. So another wonderful paper from the world of electrophysiology in trying to understand optimal mechanisms to resynchronize the ventricle in patients with differing bundle branch blocks or intraventricular conduction delays. So what did they find? Dr. Carolyn Lam: They found that patients with intraventricular conduction delays and a QRS duration of 150 milliseconds or more, CRT was associated with lower rates of heart failure hospitalizations and all cause mortality. The magnitude of CRT benefit among these patients with the interventricular conduction delay of 150 milliseconds or more and those with the left bundle branch block of 150 milliseconds or more were similar. In contrast, there was no clear CRT benefit for patients with a right bundle branch block of any QRS duration, although the authors could not rule out the potential for benefit at a markedly prolonged QRS duration. So they concluded that the practice of combining right bundle branch block with intraventricular conduction delay patients into a single non-left bundle branch block category when we make patient selections for CRT is not supported by the current data. And in fact, patients with an intraventricular conduction delay of 150 milliseconds or more should be offered CRT as is done for patients with a left bundle branch block of 150 milliseconds or more. Dr. Greg Hundley: Wow, Carolyn, so really interesting point. No clear CRT benefit for patients with right bundle branch block regardless of the QRS duration. Well we've got some other articles in the issue. I'll describe a couple from the mail bag. There's a Research Letter from Professor Lassen entitled "Risk of Incident Thromboembolic and Ischemic Events Following COVID-19 Vaccination Compared with SARS-COV2 Infection." Also Bridget Kuhn has a wonderful Cardiology News piece entitled "Collaborative Care Model Helps Heart Failure Patients Meet End-of-Life Goals." Dr. Carolyn Lam: There's an exchange of letters between Doctors Donzelli and Hippisley-Cox regarding that risk of myocarditis after sequential doses of COVID-19 vaccine, there's an AHA Update by Dr. Churchwell on continuous Medicaid eligibility, the lessons from the pandemic. There's an On My Mind paper by Dr. Parkhomenko on Russia's war in Ukraine and cardiovascular healthcare. Wow, what an issue. Thanks so much, Greg. Shall we go on to the feature discussion? Dr. Greg Hundley: You bet. Dr. Mercedes Carnethon: Well welcome to this episode of Circulation on the Run podcast. I'm Mercedes Carnethon, associate editor of the journal Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine. I'm very excited to be here today with Xuerong Wen and Sandeep Das, my fellow associate editor here at Circulation to talk about a wonderful piece by Dr. Wen and colleagues from the University of Rhode Island. So welcome this morning Xuerong and thank you so much for sharing your important work with us. Dr. Xuerong Wen: Thank you Dr. Carnethon. It was great meeting you all and I'm the Associate Professor of Pharmacoepidemiology and Health Outcomes at the University of Rhode Island. I'm happy to introduce my study to everyone. Dr. Mercedes Carnethon: Well thank you so much and thank you as well Sandeep for identifying this fantastic article and bringing it forth. Dr. Sandeep Das: Thanks Mercedes. It's great to be with you. Dr. Mercedes Carnethon: Great. Well let's go ahead and get into it. There's so much here to talk about. So Dr. Wen and colleagues studied the comparative effectiveness and safety of direct oral anticoagulants or DOACs and warfarin in patients with atrial fibrillation and chronic liver disease. So this is such an important topic. Can you tell us a little bit about what your study found? Dr. Xuerong Wen: So our study is a comparative effectiveness and the safety analysis using a national health administrative data from private health plans. So we compared the risk of hospitalized ischemic stroke, systemic embolism and major bleeding between DOACs and warfarin in patients with atrial fibrillation and chronic liver disease. So we also had to had compare to these primary outcomes between apixaban and rivaroxaban in the study population. So our studies show that among patients with atrial fibrillation and chronic liver disease, DOACs as a class was associated with lower risk of hospitalization of ischemic stroke and systemic embolism and major bleeding, compared with warfarin. And when compared risk outcomes between individuals apixaban has lower risks as compared to rivaroxaban. So that's our study results. Dr. Mercedes Carnethon: Well thank you so much. This seems like such an important question. We hear a lot about DOACs and some of their risks as well as their considerable benefits. I think what leaves me the most curious is why did you choose to pursue this question and in particular in patients with both atrial fibrillation and liver disease. So why was the intersection of these two particular conditions of interest to your study team? Dr. Xuerong Wen: That's a great question. So the liver actually plays a central role in both the synthesis of coagulation factors and the metabolism of anticoagulant drugs. And the clearance of the anticoagulants in liver ranges from 20% to 100% for DOACs and warfarin. So in clinical practice anticoagulation abnormalities and elevated risk of spontaneous or unprovoked venous thrombotic complications have been reported in patients with liver disease. While these patients with cirrhosis were excluded from the clinical trials of DOACs and also population based, the real world experience is very limited. So that is why we initiated this retrospective cohort study and based on the real world data in this specific population. Dr. Mercedes Carnethon: Oh, thank you so much for explaining that. I definitely learned a lot and really enjoyed reading the piece. I think it was very well organized and well written and I know that our readership will appreciate it. It obviously stood out to you as well, Sandeep. Can you tell me a little bit about why you thought that this would be an excellent piece for circulation? Dr. Sandeep Das: Yeah, absolutely. Thanks for the question. So in the broad field of what we call observational comparative effectiveness research, so basically that's using large observational data sets to try to answer important clinical questions and it's a really challenging thing to do. I mean we're all very familiar with the idea of using randomized trials to assess important clinical questions because of the structure of that design allows you to mitigate some of the effects of confounding. Here, it has to be done analytically. So what's the important factor that really drives you towards a great observational comparative effectiveness piece? So first the clinical importance. I feel a little guilty because I'm old enough to remember when warfarin was the only option available, but really as a clinician, or every patient, I really prefer DOACs over warfarin just for ease of use and lifestyle. So there's a huge sort of importance to the question. Second, the patients with chronic liver disease were excluded from the larger RCTs and the DOAC trials. So really we don't have the answer to the question already. It's an important question. Obviously the bleeding risk is tied up with the liver, warfarin directly antagonizes vitamin K, so there's real questions about safety and so this is the perfect storm and then on top of it was a really well done and well executed study. So when this came across my desk, the very first thing I thought was not, "Is this something that we're interested?" But rather, "How do we make it better? How do we make it more useful to the reader?" This had me from hello. Dr. Mercedes Carnethon: Well thanks so much. We rarely have the opportunity when we read an article to be able to ask the authors questions. So Sandeep, I know that you had mentioned that you had some follow up questions as well. Dr. Sandeep Das: Yeah. So the real thought that I have then is would you argue based on this that we know enough that we should change our practice? And that do you feel comfortable advocating that people now prescribe DOACs to these patients? Dr. Xuerong Wen: I would say yes. Okay. Although this is not a clinical trial, but our study is actually systematically compare the effectiveness and safety between DOAC users and also the warfarin users. And if you look at our table one, we compare with so many variables between these two users and we use the propensity score adjustment and we after propensity score weighting and the two control group almost balanced. And I know right now FDA actually suggested that emulate the trial using the large real world data to do the emulated trial. So our study actually conducted is based on the large population using large data and we use the propensity score weighting to control all this potential compounding factors. Although there are still some limitations in this study. I think we mentioned that in the discussion section and we discussed all potential compounding factors that still may exist. And also there are some misclassifications and out of all this limitations and we still found the two drugs performed differently in this specific population. So we feel that comfortable to say that a DOAC drug performs better than warfarin. And also I think based on other studies that based on the clinical trial in the general population, DOAC drug is performs much better than warfarin and considering that the clearance in liver for DOAC is less than warfarin. So plus all this information together, I think DOAC may be safer than wafarin in the patients with AF and chronic liver disease. Dr. Sandeep Das: Yeah, I would say that I agree that these data, even if you're skeptical about observational CT generally, which I admit that I tend to be, these are really reassuring data that at least the DOACs are... There's absolutely nothing that suggests that they're any worse than warfarin and all of the sort of soft indications for ease of use and patient happiness really would seem to favor DOACs. So I think this is the sort of rare observational CT paper that may actually change my practice. Dr. Mercedes Carnethon: I have a follow-up question, Xuerong, related to the design and as well your strategy to address differences between the groups. So inverse probability weighting is certainly a standard in the field to be able to manage differences between groups when you have a situation where can't, where it's not a randomized trial. Do you as well, and educate me, I admit I'm an epidemiologist whose methodological skills are sometimes challenged. Do you have the opportunity using this design and with inverse probability weighting to evaluate subgroup effects? So my specific question is were you able to determine whether or not these associations were similar based on age and gender in particular? Dr. Xuerong Wen: That's a great question. We did conducted a lot of subgroup study but not by age or gender. We conducted I think this study in a lot of subgroups using the propensity score weighting, but the subgroup that I think we did a subgroup like a patient with a different chronic liver disease. So that's what we did. And we also tested different methods inverse probability score weighting. So we did trimming and we used a different percentage of trimming and to see how that affect the study results. So we have done a lot of subgroup studies. We did not check the age and the gender, but that's a very good point. Maybe later, well I'll ask my student to do that. Dr. Mercedes Carnethon: Well, you're a good mentor. So I think that is a really certainly an appropriate approach. Sandeep, did you have additional questions? Dr. Sandeep Das: No, I wish I had thought of yours before you did. I think exactly the older age, women, racial ethnic groups that are underrepresented historically in trials. I think that that's really, again, the sweet spot of this observational research. We definitely, and NH definitely working on trying to increase enrollment of all these groups in our CTs. However, while we wait for that, I think that's exactly what we should be doing. Dr. Mercedes Carnethon: Well that's great. And Xuerong, you really alluded to really, I think what is one of my final questions related to what do you think based on what you have observed in this study, what do you see as the next steps in the research field for your team, your students, or other people who are carrying out this type of work? Dr. Xuerong Wen: Well, that's a great question. We currently have a couple of more manuscripts ongoing in this field, and we will continue conducting the comparative effectiveness and analysis to compare drugs head to head as well as developing and implementing new methodologies to this field. And we hope our study provides real world evidence for clinical decision making, prescribing anticoagulants to patients with atrial fibrillation and chronic liver disease. We also expect the physicians and researchers more and more value the real world data studies, especially when clinical trials are not feasible or ethical. Dr. Mercedes Carnethon: Well, thank you so much. That was such an excellent vision that you provided us with and we're just very grateful that you submitted this fantastic work to the journal Circulation. I know that our readers will enjoy really digging in. The podcast is meant as a teaser to bring you to the journal so that you can read about this wonderful work by Dr. Wen and colleagues. So again, thank you. I'm Mercedes Carnethon, joined with my associate editor partner here, Dr. Sandeep Das. And thank you very much for spending your time with us today, Dr. Wen. Dr. Xuerong Wen: Thanks for this great opportunity to disseminate my study with us, thank you. Dr. Sandeep Das: Thanks Mercedes. Dr. Mercedes Carnethon: Thank you for joining us for this episode of Circulation on the Run. 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.

Over the past years, technology has grown from simple spreadsheets to precision surgeries. What's next? Should we be fearful or hopeful about the future of AI?  In this episode, global foresight leader Sandeep Das dives into the current and future developments of AI. Joining him are experts in the technology industry: Global Chief Digital Officer at Mars Inc., Sandeep Dadlani, and Partner at Bain & Company, Rahul Shah.  Together, they give their insights into the future of AI and how it can change the world. They discuss the differences between AI applications, particularly in the East and West. According to Rahul, data regulation and privacy still need to grow. A global guideline won't be present soon, as all governments have different concerns and cultures. They also address digital detox and how to think about technology. Sandeep shares that every new technology will compete for our time and focus. It is important to retain what makes you human.  Remember, AI is ultimately a tool. Human experience and values are far more important than technology.  Want to know how AI will shape our future? And how we can be aware of exciting breakthroughs? Tune in to find out why we're barely scratching the surface of AI and how much more it can change. Learn how we can harness AI to create better products and experiences for everyone.  ––– https://www.linkedin.com/in/sandeep-das-1b343719/ (Read more from Sandeep Das on LinkedIn) https://www.linkedin.com/in/sandeepdadlani/ (Read more from Sandeep Dadlani on LinkedIn) https://www.linkedin.com/in/rahulvshah/ (Read more from Rahul Shah on LinkedIn) ——— All views are those of the podcast hosts and guests only and do not necessarily reflect the views of their employer(s).

The consumer experience has been described in many different ways in the past. But in general, it's all about the interaction between the brand and consumers across the world and cultures. It's the journey towards seeking a great experience with the brand in question. In this episode, our host, global foresight leader Sandeep Das invites exotic science experts Zoe Chance, Melina Palmer, and Marian St. Laurent into the discussion. They will explore key terms and concepts that will drive the future of consumer experience. They will also give insight into the opportunities and risks for companies with consumer experience moving forward with advanced technological innovation. Want to know more about how the consumer experience will evolve in the near future? Tune in to discover how brands and platforms can adapt to significant industrial changes. Learn how you can transform your approach and emerge at the top of the consumer experience battle. ––– https://www.linkedin.com/in/zoebchance (Read more from Zoe on LinkedIn) https://www.linkedin.com/in/melinapalmer (Read more from Melina Palmer on LinkedIn) https://www.linkedin.com/in/marian-st-laurent-9774394 (Read more from Marian St. Laurent on LinkedIn) ——— All views are those of the podcast hosts and guests only and do not necessarily reflect the views of their employer(s).

This week, University of Arkansas music professor Lia Uribe explores the tabla, the main percussive instrument used in Northern Indian classical music. Featuring music and performances by Nilan Chaudhuri, Dinuk Wijeratne the Boston Conservatory Orchestra, Sandeep Das, Bjork and Talvin Singh.

The Asia Society Texas presents music from Turkey and South Asia.

This conversation with Sandeep Das explores the influence of Yo-Yo Ma, the generosity of musical service and Dehli to Damascus. This centers on the notion of incompleteness, shared heritages of poetry, maqams, and the unique stories that inform a wisdom of compassion.  We enter deep notions of “surrender” in a bhajan beloved by Mahatma Gandhi and the HUM ensemble's musical realization of surrender, longing, balance, and cyclical hope.

Please join author Jonathan Newman and Associate Editor Sandeep Das as they discuss the article "Outcomes of Participants With Diabetes in the ISCHEMIA Trials." 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. Well, Carolyn, this week's feature, a couple of weeks ago, we had that feature forum on the ischemia trial. Now we're going to explore some of the outcomes in patients with diabetes, from the ischemia trial in the feature discussion today. But, before we get to that, let's grab a cup of coffee and start in on some of the other articles in this issue. So, how about if I go first, this time? This particular paper, Carolyn, we're going to start on one of your topics. I know you're a fan of diet related interventions. So high intake of added sugar is linked to weight gain and cardio-metabolic risk. And in 2018, the U S National Salt and Sugar Reduction Initiative proposed government supported voluntary national sugar reduction targets. Dr. Greg Hundley: This intervention's potential health and equity impacts and cost effectiveness are unclear. And so Carolyn, these authors, led by Dr. Renata Micha from Tufts University, incorporated a validated micro-simulation model - CVD Predict coded in C++, and used it to estimate incremental changes in type two diabetes, cardiovascular disease, quality adjusted life years, cost and cost effectiveness of this national policy. The model was run at the individual level and the model incorporated national demographic and dietary data from the National Health and Nutrition Examination Survey across three cycles spanning from 2011 to 2016, added sugar related diseases from meta-analysis and policy costs and health-related costs from established sources and a simulated nationally representative us population was created and followed until age 100 years or death with 2019 as the year of intervention start and findings were evaluated over 10 years and a lifetime from healthcare and societal perspectives. Dr. Carolyn Lam: Ooooh, You so got my attention, Greg, a very important topic and so, what did they find? Dr. Greg Hundley: Right, Carolyn. So achieving the NSRI sugar reduction targets could prevent 2.48 million cardiovascular death related events, 0.5 million cardiovascular disease deaths, and three quarters of a million diabetes cases, gain 6.7 million quality adjusted life years, and save $160.8 billion in net cost from a societal perspective over a lifetime. The policy became cost-effective, defined as less than $150,000 for quality adjusted life years at six years and highly cost-effective at seven years with a cost savings noted at nine years. And therefore, Carolyn, implementing and achieving the NSSRI sugar reformation targets could generate substantial health gains, equity gains, and cost savings. Dr. Carolyn Lam: Wow, thanks Greg. So, moving from a very publicly health focused paper to this paper that really focuses on hypoplastic left heart syndrome with very, very scientifically significant findings. Now, first, we know hypoplastic left heart syndrome is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis is unknown, but hemodynamic disturbances are assumed to play a prominent role. Authors led by Doctors Moretti and Laugwitz from Technical University of Munich in Germany, as well as Dr. Gruber from Yale University School of Medicine, and their colleagues combined whole exome sequencing of parent offspring, trios, transcriptome profiling of cardiomyocytes from ventricular biopsies and immuno-pluripotent stem cell derived cardiac progenator or cardiomyocyte models of 2D and 3D cardiogenesis, as well as single cell gene expression analysis to decode the cellular and molecular principles of hypoplastic left heart syndrome phenotypes. Dr. Greg Hundley: Wow, Carolyn, there is a lot of data, very complex preclinical science here. So what did they find? Dr. Carolyn Lam: Indeed, Greg. As I said, scientifically incredible and rigorous, and they found that initial aberrations in the cell cycle unfolded protein response, autophagy hub led to disrupted cardiac progenator lineage commitment, consequently, impaired maturation of ventricular cardiomyocytes limited their ability to respond to growth cues. Resulting in premature cell cycle exit and increase apoptosis under biomechanical stress in 3D heart structures. Together, these studies provide evidence that the hypoplastic left heart syndrome pathogenesis is not exclusively of hemodynamic origin, and they revealed novel potential nodes for rational design of therapeutic intervention. Dr. Greg Hundley: Wow, Carolyn, we really need research in this topic and this is great preclinical science that we're getting here in our journal. Congratulations to the authors and what a great presentation of that by you. Well, Carolyn and my next paper there remain major uncertainties regarding disease activity within the Retain Native Aortic Valve, as well as bioprosthetic valve durability, following transcatheter aortic valve implantation. And these authors led by Doctor Jacek Kwiecinski, from the Institute of Cardiology, aimed in a multi-center cross-sectional observational cohort study to assess native aortic valve disease activity and bioprosthetic valve durability in patients with TAVI in comparison to subjects with bioprosthetic surgical aortic valve replacement or SAVR. Dr. Carolyn Lam: Oh, very interesting. And what were the results? Dr. Greg Hundley: An interesting comparison, Carolyn. So in patients with TAVI, native aortic valves demonstrated 18 F sodium fluoride uptake around the outside of the bioprosthesis that showed a modest correlation with the time from TAVI. Next, 18 sodium fluoride uptake in the bias prosthetic leaflets was comparable between SAVR and TAVI groups. Next, the frequencies of imaging evidence of bioprosthetic valve degeneration at baseline were similar on echo cardiography 6 and 8% respectively, CT, 15 and 14% respectively, and with PET scanning. Next, baseline 18 F sodium fluoride uptake was associated with subsequent change in peak aortic velocity for both TAVI and SAVR. And on multi-variable analysis, the 18 F sodium fluoride uptake was the only predictor of peak velocity progression. And so Carolyn, therefore, in patients with TAVI, native aortic valves demonstrate evidence of ongoing active disease and across imaging modalities, TAVI degeneration is of similar magnitude to bioprosthetic SAVR suggesting comparable midterm durability. Dr. Carolyn Lam: Very nice, important stuff. Dr. Carolyn Lam: Well, thanks, Greg. Let's tell everyone about the other papers in today's issue. There's an exchange of letters between Doctors Baillon and Blaha regarding the article very high coronary artery, calcium and association with cardiovascular disease events, non-cardiovascular outcomes and mortality from MESA. There's an ECG challenge from Dr. Bell Belhassen on a left bundle branch block, tachycardia following transcatheter aortic valve replacement. And On My Mind paper by Dr. Neeland on cardiovascular outcomes trials for weight loss interventions, another tool for cardiovascular prevention, another Research Letter by Dr. Nakamura on clinical outcomes of Rivaroxaban Mono therapy in heart failure, patients with atrial fibrillation and stable coronary artery disease. So insights from the AFIRE trial, and finally, a Research Letter from Dr. Kumoro three-dimensional visualization of hypoxia induced, pulmonary vascular remodeling in mice. Dr. Greg Hundley: Great, Carolyn, and I've got an in-depth piece from Professor Jia Sani entitled breadth of life, heart disease, linked to developmental hypoxia. Dr. Greg Hundley: Well, Carolyn, how about we get onto that feature discussion and learn more about results from the ischemia trial? Dr. Carolyn Lam: Let's go Greg. Dr. Carolyn Lam: Well, we all know how important diabetes is as a risk factor for atherosclerotic coronary disease. And we know it's a very common comorbidity among patients with chronic coronary disease, but the question is do patients with diabetes and chronic coronary disease on top of guideline directed medical therapy and lifestyle interventions, of course, do they derive incremental benefit from an invasive management strategy of their coronary disease? Well, we are going to try to answer that question today in our feature discussion. Thank you so much for joining us today. The first author and corresponding author of today's feature paper, which tells us about results from the ischemia trials. And that's Dr. Jonathan Newman from New York university Grossman School of Medicine. We also have associate editor Sandeep Das from UT Southwestern. So welcome both of you. And if I could please start with Jonathan reminding us, perhaps, what were the ischemia trials and then what you tried to answer and do in today's paper, Dr. Jonathan Newman: Of course, Carolyn, and thank you so much for having me and for the discussion with Sandeep. It's a pleasure to be here. So sure has a little bit of background, as you indicated, the ischemia trials basically enrolled and for the purposes of this discussion and this analysis, I'm referring to both the main ischemia trial and the ischemia chronic kidney disease trials. So ischemia CKD under the umbrella of the ischemia trials. Ischemia stands for the international study of comparative health effectiveness with medical and invasive approaches. And the purpose of the trial was to test to see whether a routine invasive approach on a background of intensive guideline directed medical therapy for high risk patients with chronic coronary disease and at least moderate ischemia and obstructive coronary disease documented on a blinded CCTA or computed coronary tomography angiography prior to randomization was associated with benefits for a cardiovascular composite. And we looked in this analysis at whether or not there was appreciable heterogeneity of treatment effect or a difference in treatment effect for patients compared without diabetes in the ischemia trials, in ischemia and ischemia CKD. Dr. Carolyn Lam: Great, thanks for lining that up so nicely. So what, Dr. Jonathan Newman: So the results of our analysis really highlighted a couple of things that I think you touched upon initially, the first thing that I would highlight is that diabetes was very common in this high risk cohort with chronic coronary disease, over 40% of participants in the ischemia trials, 43% with obstructive coronary disease and moderate to severe, you may have had diabetes. Perhaps not surprisingly patients with diabetes had higher rates of death or MI than those without diabetes. And the rates were highest among those patients that required insulin, had insulin treated diabetes, but using really robust methods to assess for heterogeneity using a Bassen assessment of heterogeneity of treatment effect accounting for violation of proportional hazards. The fact that there was an upfront hazard and a late benefit, we really saw no difference in death or MI, between the invasive or conservative strategies for patients with, or without diabetes over about three years of follow-up. Dr. Jonathan Newman: And the results importantly were consistent for ischemia and ischemia CKD and provided the rationale for us when we started by looking to see if the distribution of risk and characteristics allowed the trials to be combined. The study really confirms this higher risk of death or a MI for chronic coronary disease patients who have diabetes extends these findings for those patients with moderate or severe ischemia. And I think really notably also adds information about chronic coronary disease patients with diabetes and CKD. That's sort of the overall findings. And I'm happy to talk in more detail about that. Dr. Carolyn Lam: I love the way you explain that Jonathan and especially, going into detail on what was so different about the paper and the really important statistical methods that made these findings robust, very important and impactful findings. If I could ask Sandeep to share your thoughts. Dr. Sandeep Das: Thanks, Carolyn. You know, I am just a big fan of everything that's come out of the ischemia group. One of the things that I really most enjoy as a consumer of the literature is when well done studies give me results that are unexpected. And I know it's become fashionable now to say that everybody knew that all along that this is what going to be the result. But honestly, I think we all sort of are many of us thought that there's going to be a subgroup somewhere that's really going to benefit from an invasive approach in terms of preventing heart outcomes. I think the key here that really jumped out at me was that this is identifying what we typically think of is a very high risk subgroup. You know, patients with diabetes patients with multi-vessel coronary disease patients with insulin dependent diabetes. Dr. Sandeep Das: And we did see the association with mortality across the increased disease severity and the increased severity of diabetes as expected. But really we didn't see a signal that revascularization, routinely revascularizing patients, even the higher risk patients led to clinically relevant heart outcome benefits. So I thought that that was a really interesting top line finding and really that's kind of. I mean, it would have been interesting if it was the other way too, but it was, it really was kind of the hook that got me into the paper. Dr. Sandeep Das: I actually have a question for Jonathan, one of the things that I think we spend a lot of time as an editorial group thinking about and talking about, and we bounce back and forth with the authors a few times was the idea that relatively few of these patients with multi-vessel CAD ended up having CABG. So, you would typically think of diabetes multi-vessel CAD as being a pretty strong signal for patients that may benefit in terms of mortality from having bypass surgery. And here it was a relatively small group about a third, or maybe even less than a third. And I realized up front, they excluded the left main and the patients that had angina had a CTA, et cetera. But what I'd be curious as to your thoughts about, the benefits of bypass surgery and diabetes, which have been established in other trials. Dr. Jonathan Newman: It's a great question. And I think we really appreciated the questions from you and from the editors to try and get at some of the nuance with this issue. As you indicated in the ischemia and ischemia CKD trials overall, and the patients in the invasive treatment arm, it was about 25% or so 26% and 15% were revascularized with CABG. Part of the issue here is that it gets a little tricky with the use of CCTA of pre randomization CTA to define coronary artery severity, which was not required in the CKD population due to impaired renal function. But what we can say is among the patients with diabetes and multi-vessel coronary disease, 29% were revascularized surgically in their combined analysis, which is comparable to the 30% in Bery 2d that were revascularized via bypass surgery, as we've discussed. And as you know, the decision for surgical versus percutaneous revascularization in ischemia, as in Barry 2d was non-randomized though we might want to, we really tried to be very, very cautious in terms of comparing revascularization strategies on outcomes for patients with diabetes and multi-vessel CAD, which has you suggested. Dr. Jonathan Newman: And as we pointed out, the proportion with multi-vessel CAD was more common amongst in patients with diabetes compared with those patients without diabetes. The other thing I would sort of say in the framework of, the revascularization and strategies for revascularization, comparing, let's say ischemia to Barry 2d or to freedom. Basically we have very little data about revascularization approaches for those patients with creatinine with impaired renal function and, patients with the crediting greater than two were excluded from Barry 2d. So while we had about 15% or so that had severe CKD. So in the GFR, less than 30 are on dialysis. And we know that's an extremely high risk group of patients with diabetes and chronic coronary disease. And we don't have great evidence on which strategy for revascularization if at all provides additional benefit. So I think it's a really a tough question to answer, and we tried to be as judicious as possible in our comments about revascularization approaches, given the nature of the trial design. Dr. Carolyn Lam: Gee, thanks so much, Jonathan, for explaining that. So, well, I actually have a related question now, referring to the medical therapy. Can I, sort of ask you about the fact that, these days that the rage is all about GLP one receptor agonist, for example, that are known to reduce the risk of atherosclerotic cardiovascular disease and diabetes. So these ischemic trials, I assume, did not have a high usage of these medications. And what do you think would be the impact, if anything, I suppose even more for guideline directed medical therapy. Huh? Dr. Jonathan Newman: Yeah. So it's a great question, Carolyn. As you know, in strategy trials and clinical trials in general, that take a while it's always a real challenge to keep the trial contemporary with current clinical practice, whether it's revascularization strategies or changes in medical therapy. And as you indicated, the real revolution and glucose lowering therapies with profound cardiovascular benefit for patients with diabetes, we worked hard to try and stay up to date and encourage sites around the world with the use of best SGLT2 inhibitors and GLP ones. The rates were very, very low and we don't actually given the fact that the ischemia trials were conducted a real multinational and is really an international trial is over 330 sites worldwide. So we really had to balance the data that we could get from sites with the reality of collecting and running this trial across the whole world. Dr. Jonathan Newman: So we don't actually know. We know insulin use or non-use or oral medication use or non-use or no medication use or non-use, but not much more than that. From what, as, you know, unfortunately, even after now, six going on seven years of impressive data for the benefit of these agents, uptake remains low for patients with diabetes, whether it's with coronary disease or heart failure. And there was certainly the case with the trial, which started back in 2015, or sorry, before 2015, even before the results of EMPA-REG. So the rates of those agents were low. I would expect as you indicated that if we did have greater use of these beneficial therapies. Medical therapy may have performed even better and potentially given an added boost potentially for our high risk, even higher risk subgroups that we'd looked at that were available in these trials. Dr. Carolyn Lam: Oh, thanks again. I wish we could go on forever, but we've got just a little bit of time left. So I'd like to ask you both for your quick take home messages for the audience. Could I start with Sandeep and then Jonathan? Dr. Sandeep Das: Yeah. You know, I think a key take home from this is that, although it may be naively intuitive that a very aggressive invasive strategy would be superior, especially in high risk patients. You know, the data are very, very convincing that it's not. And so therefore I think in an absolute minimum, you have plenty of time and ability to think about these patients carefully, to select who, if anybody would be a great candidate for revascularization, more aggressive therapy and more invasive therapy, but the most patients will do well with conservative management. Dr. Sandeep Das: And I think that that's the, that's a real key take home here. And I think that the points that Jonathan raised about, you know, poor uptake of GLP one RAs and SGLT 2 inhibitors in the community as they're so far are key, right? So we have great medicines that we just under used, and that to me is the other sort of clarion call here is that if in the context of a nice trial, that you can see similar result for invasive conservative approaches, then lets, let's get our medical therapy where it needs to be to provide our patients the best outcomes we can Speaker 3: Love it, Jonathan. Dr. Jonathan Newman: Yeah. So I'm really glad that Sandeep brought up the issue of medical therapy in the trial. And maybe I can take a minute to sort of frame what San kind of build off of what Sandeep just said, you know, we, in the context of this clinical trial, you know, Dr. Judy Hawkman, the study chair and Dr. David Marin, the co-chair and I, we worked very hard with optimizing medical therapy across the trials, for all participants. So really getting patients on the maximum tolerated doses of high-intensity statins, lowering patient's LDL as aggressively as possible evolving our systolic blood pressure targets. And it was extremely challenging. And at the end of the day, we see that patients with diabetes were more likely than those without to get to our LDL goal. We used a threshold problematic concept that that still may be to some extent, but they were less likely to achieve their systolic blood pressure goals. Dr. Jonathan Newman: And I think Sandeep was exactly right. We have a way to go with implementing existing therapies, existing medical therapy. There may be a benefit for as demonstrated in Dr. S. for patients that remain highly symptomatic to derive symptom benefit with revascularization. The other context I would sort of add with the medical therapy issue is that despite really aggressive medical therapy, and we really did as much as we could, patients with diabetes still had, a 40, 50% greater risk of death or MI than those without diabetes. So there's still this idea of kind of residual risk. And these were patients with diabetes that were very well managed from a medical and glycemic control perspective. So we still have a lot of work to do. And I think understanding ways we can benefit our patients is really that challenge. Speaker 3: Thanks so much, Jonathan, and thank you Sandeep for joining us today. Speaker 3: And thank you audience for listening from Greg and I. This has been "Circulation On The Run", please tune in again. Next week. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for more visit AHJjournals.org.

With more than half of the world's population living in cities like New Delhi, Mexico City, Beijing, São Paulo, and Kuala Lumpur, we're taking a look at what's driving the future of food in emerging markets. Taking us on a journey of future food trends is our host, Sandeep Das, Global Foresight Lead, Emerging Markets at Mars Wrigley. Joining him are Blas Maquivar, President, Global Emerging Markets at Mars Wrigley, Food Futurist Tony Hunter, and Alki Manias, Executive Vice President of the VR simulations provider StoreLab. In this episode, we discuss how emerging markets will explode in the next few decades and what that means for FMCG. To do that, we explore current consumer behaviors, the recent growth in e-commerce, and issues like sustainability that are increasingly important to younger generations. What will the food industry look like in 2050? How will retailers provide a more experiential approach to the shopping experience as economies begin to boom and technology advances? Join us as we get curious about the future nuances and opportunities for this massive area of the world. ——— All views are those of the podcast hosts and guests only and do not necessarily reflect the views of their employer(s).

Ep #112 with Mike Block, cellist, composer and singer-songwriter. Mike Block is an eclectic composer, singer-songwriter and cellist who performs with Yo-Yo Ma's Silk Road Ensemble. He has freed himself from the ordinary constraints of playing the cello sitting down with his innovative Block Strap which allows him to move freely and even dance while playing. This episode features some of his great compositions and improvisations with a variety of musicians including Sandeep Das on the tabla. A Worldsoul Records production derrikjordan.com Facebook: https://www.facebook.com/109866072979176/videos/298132958441160 YouTube: https://youtu.be/EYbycxQCUVU Podcast: https://soundcloud.com/hilljoy/ep-112-with-mike-block-cellist-composer-and-singer-songwriter Derrik Jordan Host and Producer of The World Fusion Show National Winner of the Best Entertainment and Arts Series 2019 on Public Access TV https://soundcloud.com/hilljoy

This week's episode features a panel discussion. Please join author Harmony Reynolds, editorialist David Newby, and Associate Editors Nicholas Mills and Sandeep Das as they discuss the articles "Natural History of Patients with Ischemia and No Obstructive Coronary Artery Disease: The CIAO-ISCHEMIA Study, "Outcomes in the ISCHEMIA Trial Based on Coronary Artery Disease and Ischemia Severity," and editorial "Forget ischemia, it's all about the plaque." Dr. Greg Hundley: Welcome listeners to this week's, September 28th, issue of Circulation on the Run. And I'm Dr. Greg Hundley, Director of the Poly Heart Center at VCU Health in Richmond, Virginia, and associate editor at Circulation. And this week, listeners, we have an outstanding feature discussion. It's actually forum where we're going to discuss from Dr. Reynolds two papers pertaining to the ischemia trial. One looking really at the functional importance of stress testing, the other looking at the anatomical importance of cardiac CT scanning. We're going to have two of the associate editors along with Dr. Reynolds, each that handled the two papers and also a guest editorialist that will help put the entire paper together. Well, before we get to that, we're going to start and review some of the other papers in this issue. And let's grab a cup of coffee and get started. Dr. Greg Hundley: The first comes to us from Dr. Maliheh Nazari-Jahantigh from Ludwig Maximilian University in Munich, Germany, and it pertains to atherosclerotic plaque rupture. So the necrotic core of an atherosclerotic plaque is partly formed by ineffective efferocytosis, which increases the risk of an atherosclerotic plaque rupture. And in cell biology, efferocytosis comes from the Latin word effero, which means to take to the grave or to bury. And it's really the process by which apoptotic cells are removed by phagocytic cells. And so therefore, it can be regarded as the burying of "dead cells." Now MicroRNAs contribute to necrotic core formation by regulating efferocytosis as well as macrophage apoptosis. We also know that atherosclerotic plaque rupture occurs at an increased frequency in the early morning, indicating that diurnal changes occur in plaque vulnerability. Now all those circadian rhythms play a role in atherosclerosis, the molecular clock output pathways that control plaque composition and rupture susceptibility are unclear. Dr. Greg Hundley: And so these authors investigated this phenomenon. And what they found, interestingly, their results suggest that the molecular clock in atherosclerotic lesions induces a diurnal rhythm of apoptosis regulated by circadian Mer 21 expression in macrophages that is not matched by efferocytosis, and thereby increasing the size of the necrotic core of these plaques. So clinically, the implications are that a macrophage death clock controlled by mer 21 may enhance lesion growth and susceptibility to plaque rupture indicating that the molecular clock can have detrimental effects under pathologic conditions. And additionally, the molecular clock in lesional macrophages may contribute to the circadian pattern of myocardial infarction, which could be a target for preventive measures to limit the mismatch between apoptosis and efferocytosis and thus reduce plaque vulnerability in the early morning. Dr. Greg Hundley: Well, our second paper comes to us also from the world of preclinical science, and it's from Professor Thomas Braun from the Max Planck Institute for heart and lung research. And this particular paper pertains to pulmonary hypertension. And as we know, pulmonary hypertension and chronic obstructive pulmonary disease, or COPD, originate from a complex interplay of environmental factors in genetic predispositions and little is known about developmental abnormalities or epigenetic dysregulation that might predisposed individuals to develop pulmonary hypertension or COPD in adults. So these authors screen a cohort of human pulmonary hypertension in COPD patients for changes of histone modifications by immunofluorescent staining. And also, they developed knockout mouse lines targeting cardiopulmonary progenitor cells and different heart and lung cell types. Dr. Greg Hundley: Now molecular, cellular and biochemical techniques were applied to analyze the function of SUV420H1-dependent epigenetic processes in cardiopulmonary progenitor cells and their derivatives. Well, what did they find? So the investigators found that loss of SUV420H1 in cardiopulmonary progenitor cells caused a COPD-like pulmonary hypertension phenotype in mice, including formation of perivascular tertiary lymphoid tissue, and goblet cell hyperplasia, hyperproliferation of smooth muscle cells and myofibroblast, impaired alveolarization and maturation of defects of the microvasculature leading to massive ripe ventricular dilation and premature death. Dr. Greg Hundley: Now mechanistically SUV420H1 bound directly to the five prime upstream in regulatory element of Superoxide Dismutase 3 gene to repress its expression and increased levels of the extracellular Superoxide Dismutase 3 enzyme in SUV420H1 mutants increased hydrogen peroxide concentration causing vascular defects and impairing alveolarization. So what can we take away, listeners, from this clinically? Well, the author's findings reveal a pivotal role of histone modifier SUV420H1 in cardiopulmonary co-development and uncover developmental origins of cardiopulmonary diseases. And now these results suggest that this study will facilitate the understanding of pathogenic events causing pulmonary hypertension in COPD and aid the development of epigenetic drugs for treatment of other cardiopulmonary diseases. Dr. Greg Hundley: Well, listeners, what else is in, we call it, the mail bag, but some of the other articles in the issue? Well, doctors Varricchi and Wang exchanged letters regarding the prior article, the role of IgE FcεRI in pathological cardiac remodeling and dysfunction. And our own Sara O'Brien highlights articles from our circulation family of journals. Professor Ross has a Research Letter regarding the effects of walnut consumption for two years on lipoprotein subclasses among healthy elders findings from the WAHA randomized controlled trial. And then finally, Dr. Maurer has a really nice On My Mind piece that raises concerns pertaining to the use of cardiac scintigraphy and screening for transthyretin cardiac amyloidosis. And now listeners, we're going to turn to that forum discussion where we have an author, our associate editors and an editorialist discussing two really important papers from the ischemia trial. Dr. Greg Hundley: Well, listeners, we are very excited today to discuss in sort of the forum feature, two papers pertaining to the ischemia trial. And with us this day, we have Dr. Harmony Reynolds from New York University Grossman School of Medicine in New York city; two of our associate editors, Dr. Nick Mills from university of Edinburgh in Scotland; and Dr. Sandeep Das from UT Southwestern; and then also an editorialist, Dr. David Newby, who's also University of Edinburgh in Scotland. Welcome to everyone. Dr. Greg Hundley: Harmony, we're going to start with you. And in the first paper, the natural history of ischemia and no obstructive coronary artery disease, can you describe for us a little bit of the context of what shaped this question for you, what hypothesis did you want to test? And then describe for us a little bit your study population and your study design. Dr. Harmony Reynolds: Sure. Thanks so much for having me here to discuss these papers. I'm really appreciative of the attention from circulation, and I'm excited for this discussion today. So in this first natural history paper, we were looking at ischemia with non-obstructive corona arteries, INOCA, the kind of thing that used to be called cardiac syndrome X. And we know this is an extremely common problem. It's defined by having signs or symptoms of ischemia and no 50% or greater lesion on coronary imaging. And we also know from prior invasive studies that the mechanisms of this are overwhelmingly microvascular coronary disease and provokable coronary spasm. Some patients prove to be normal and invasive testing, but most will have some objective abnormality. Dr. Harmony Reynolds: We know this problem is associated with a higher risk of cardiovascular events and with high costs, but what we didn't know was whether the symptoms and ischemia on stress testing are tracking together in these patients. So if we're trying to treat these patients, should we be doing serial stress testing and targeting the medical therapy to ischemia abrogation or should we just be making their symptoms go away? And would this provide any long range insights for us into when we can figure out the symptom are truly ischemic in nature? Dr. Harmony Reynolds: So we decided to use the ischemia trial, and we had a fantastic platform for that in ischemia because, as you know, patients were screened in part for randomization using coronary CT angiography. And even though these patients had moderate or severe ischemia, some had no obstructive coronary disease on that CT coronary angiogram. And those are the patients that we enrolled in CIAO-ISCHEMIA. They had an assessment of angina at baseline, and they had to be symptomatic at some point. They didn't have to be symptomatic at the moment. They were enrolled in CIAO, but they had their stress test generally to evaluate ischemic symptoms. And they had their stress echocardiogram read by a core lab. Importantly, that core lab did not know the result of that CT scan. So they read them like all the other ischemia stress echoes. And then these patients had an angina and ischemia assessment with a repeat stress echo at one year. Dr. Greg Hundley: And what did you find? Dr. Harmony Reynolds: There were a number of interesting findings from this study. The first thing was that the severity of ischemia in the CIAO patients with INOCA was very similar to the ischemia patients who had obstructive coronary disease. So that tells us that the INOCA problem can happen with quite a lot of ischemia, and that had not been as well delineated before. Another finding expected, but we did find that is that there were many more women in the INOCA group, two thirds of our child population was female. And in ischemia, overall, it was closer to a quarter. We found that the symptoms and the ischemia were quite changeable. So at one year, the stress echocardiogram was normal in half of the child participant and only 23% still had moderate or severe ischemia. Angina had improved in 43%, and it worsened in 14%. There was an awful lot of change over one year, but the change in angina and the change in ischemia did not track together. And that was a bit of a surprise to me. Dr. Greg Hundley: Very nice. Well, Nick, I know serving it as an associate editor, you see many papers come across your desk. What attracted you to pushing this paper forward for publication? Dr. Nicholas Mills: Thanks, Greg, and congratulations. Harmony, we love the papers you've been sending from ischemia trial, which genuinely is changing clinical practice all over the world. And it's been great to see the secondary analysis and follow-up papers. So this paper attracted me because it addresses an area where I still don't fully understand in clinical practice, what recommendations to make for my patients and what tests to arrange. As you say, INOCA is more common in women. I think these patients have largely been understudied over many decades, and there remains a lot of uncertainty. I liked it because you had a core lab, blinded core lab analysis with systematic follow up and it was a really well-done study. It reassured me in many ways because it told me that actually a lot of these patients, their symptoms get better, sort of irrespective of what we do. The treatments didn't seem to track within improvements of symptom, nor did the severity of ischemia, and that I think provides a lot of reassurance to our patients who are in this situation. Dr. Nicholas Mills: Of course, there is a group there who continue to have moderate to severe ischemia a year later. And I think this trial helps us understand maybe how we should study this group more, understand the heterogeneity that you've observed in this population in order to really try and resolve that and resolve their ongoing symptoms. But for the majority, four in five patients, they're going to do well and they're going to get better over time. And I think that's an important message from this study. Dr. Greg Hundley: Thank you so much, Nick. Well, Harmony, we're going to come back to you. You have a second paper, the outcomes in the ischemia trial really based on coronary artery disease and ischemia severity. Can you describe for us, again, working us back through, what were some of the constructs that you really wanted to address here? What was your hypothesis? And again, how did this study population maybe differ a little bit in this second paper? Dr. Harmony Reynolds: Thanks so much. So this paper tracked outcomes based on the severity of ischemia and the severity of coronary artery disease on the CT coronary angiogram now in randomized patients in the ischemia trial. So all of these had obstructive coronary disease and they were selected for randomization. And the premise of the ischemia trial was partly that we would be able to select patients who might benefit from revascularization and from an invasive strategy really based on how much ischemia they had on the stress test. Moderate or severe ischemia was required for randomization and for entry into the trial, but a core lab read those stress tests independently and independently assessed ischemia. And in some cases, when the site thought there was moderate or severe ischemia, the core lab did not agree. And the core lab independently decided whether it was moderate or severe. So we wanted to understand whether the ischemia severity at the time of trial entry influenced outcomes and influenced the outcomes by randomization treatment assignment. Dr. Harmony Reynolds: Similarly, about half of the patient had a CT that was interpretable for the number of vessels disease. And we wanted to understand in the context of all those prior stable ischemic heart disease trials, showing a lot of heterogeneity by the amount of coronary disease, whether in ischemia as well, there would be heterogeneity of the treatment effect based on how much coronary disease you started with. So the ischemia population, and this is almost the entire randomized cohort, but it's important to recognize for the CT analysis that only about three quarters of the patients had CT. They didn't get a CT, if your GFR was too low or if you had known coronary anatomy. And among those Cts, not every CT is perfectly interpretable for the number of vessels disease. These are sicker patients. These are not the super stable patients who have a low prevalence of disease. These were pretty sick, multi-vessel coronary disease patients, and they couldn't always hold their breast all that well. There was a lot of calcification in these. Dr. Harmony Reynolds: So for example, if there was motion artifact in the right coronary artery, we wouldn't be able to quantify the number of vessels disease. And that left us with a cohort of about half of our ischemia population, but that's still a giant cohort of several thousand patients. So that's how our study. Dr. Greg Hundley: Very good. And what did you find here? Dr. Harmony Reynolds: Here, we found that more severe ischemia was not associated with outcomes. Now that does go along with the COURAGE study in which after you adjust for clinical characteristics, ischemia was not associated with outcomes. But still it came as something of a surprise that even severe ischemia was not associated with a higher risk of outcomes than moderate or mild ischemia. We also found that in the coronary disease group, no matter how you measure the severity of coronary disease, the Duke prognostic index, the number of vessels disease, the segment involvement score, the segment stenosis score, all of these measures were very strongly associated with our outcomes, whether it was all cause mortality MI or our composite. Dr. Harmony Reynolds: When it came to treatment effect, we found that the ischemia severity were no relationship to treatment effect. There was no ischemia subgroup in which there appeared to be an advantage with an invasive strategy. But in the coronary disease group, and again taking into account the caveats of not everybody had a CT interpretable for the number of vessels disease, in those with the most severe coronary disease, that's the Duke 6 subgroup. And they had multi-vessel severe disease, either two vessel including the proximal LAD at 70% or three vessels with 70% stenosis. There was no benefit on mortality. But if we looked at the composite endpoint of cardiovascular death or MI, there appeared to be some advantage to the invasive strategy. Dr. Greg Hundley: Very good. Well, Sandeep, similar to Nick, working as an associate editor and meeting weekly, what attracted you to this particular paper? And why did you want to really see it come forward to be published? Dr. Sandeep Das: So first of all, I want to echo Nick's comments that these are great papers, and thanks very much for sending those our way and letting us have sort of first crack at them before they're released to the world. And I also want to comment on the side that Harmony and her team were just absolutely fantastic to work with in this process. From having been on the other side when you get 300 different comments from the editors and reviewers and you respond to them thoroughly and with grace, that's a feat in and of itself. So I want to shout out Harmony and her team for just being fantastic partners, because really we see ourselves as sort of the author's partners in kind of making the paper as good as it can be as the best it can be. Dr. Sandeep Das: So I'll admit upfront, I think it's kind of fashionable for people to say, well, I knew that this was going to show this, I knew this all from COURAGE, and this is not surprising to me. But I'll admit that I was surprised. And so this has been practice-changing for me, so this whole evolution post ischemia. And I really feel like a little bit of an existential crisis because I'm not sure I understand what ischemia means anymore. You ask me five years ago, I would've been very confident that I knew the answer to that. So you know what, really, as soon as this paper crossed our desk, I thought, wow, this is something we want to keep, this is something that's going to be really important to practice of cardiology. It's going to be really important to our readers. It's a great paper from a great group. This is something we want. So really it was never a question of, well, am I interested or am I not? I was interested from reading the abstract. Dr. Sandeep Das: So the question then became what are the real important questions that we need to sort of tease out and help elucidate for the clinician for the reader? And really for me, the question has always been, is there a subset of people where... So in my heart of hearts, I always kind of thought that burden of ischemia, if there was enough burden of ischemia, that it probably did help to revascularize that, right? I definitely practiced that way, right? There was some sort of number where I would start to say, that's a lot of ischemic myocardium and maybe we need to do something about that. Even though I know my intellectual brain says, no, there's no data that supports this, I really kind of thought it was true. And so Harmony and her team put another nail in that coffin here because it doesn't seem to be true, which to me was interesting and different and practice-changing. Dr. Sandeep Das: So the real questions here were sort of to tease out the interaction between anatomic severity, and we've all known that sort of anatomic burden of disease is proportional to adverse outcomes. That's not surprising. But the question then is, can we tease out a group where there may be benefit to revascularization? So there's a real interesting sort of interplay here between degree of ischemia and anatomic burden of disease. And is there a subset with enough of an anatomic burden of disease where you really may be interested in going after that to improve heart outcomes? So that's what I thought this was really fascinating paper. Dr. Greg Hundley: Very good. Well, David, we're going to turn to you next as the editorialist and asking you to sort of put the results of each of these two studies together. One, kind of highlighting for us how functional imaging might be useful to identify whether ischemia is present or not. And then the second study, really defining for us an association between anatomy and outcomes. So putting these all together, could you share your thoughts with us regarding these two papers? Dr. David Newby: Yes. Thank you. So I think that the CIAO-ISCHEMIA is very interesting, isn't it? And those clinicians were often challenged with symptoms versus our objective tests and trying to work out exactly what's going on, and it is. And such an important group as Harmony says, I can't agree more. We have a lot of morbidity here. As Nick said, I think the short term, a lot of the patients do seem to get better with just conservative management is good, but there's a core group that clearly are a problem. And as Harmony highlighted, you've got people with terrible regional wall-motion abnormalities on stress echo and yet no angina, others with no angina with no apparent difficulty on repeat testing. And then you've got a core group that has both, and it is fascinating to try and unpick that. And clearly, the symptoms are not correlating with our tests, and that's not the patient's fault. Dr. David Newby: And very often, no, no, you're wrong, can we say that to the patient? No, no, the patient is right and our tests are wrong, and we've got to work out how best to manage them. And I have a bit of analogy with Takotsubo cardiomyopathy as well, I think is at play here. I mean, here, you've got people with stable pain. We're not coming in as an acute emergency, but they're having regional wall motion abnormalities at times. They're getting a lot of symptoms. And we see similar things with Takotsubo, which is, I suppose, a much more flurry thing. I know that's something close to Harmony's his heart too. Excuse the pun. But this ischemia relationship, these regional wall motion abnormalities with chest pain, particularly in women, is something we really need to get our heads around and understand what's going on. It just reflects our ignorance, I think, of knowing exactly how to manage these patients. Dr. David Newby: And so for me, ischemia testing is about symptoms. It's about working out what's going on with the patient. It doesn't always give us the answer, but I certainly think that the role of ischemia testing is more about the symptoms. Dr. David Newby: And then when it comes to the second paper and outcomes with the ischemia trial, I absolutely was delighted to see those findings. I have to say place to what my prejudice is, I suppose, as someone that's been working with CT. And I suppose the slightly obvious thing is that the more disease you have, the more you will benefit from an intervention. And plaque and the burden of plaque is critical to that because how do you have a heart attack? Well, you have to have plaque, right? And it has to rupture. So the more plaque you have, the more likely you are. And I think that the analysis is again reinforcing what we've learned from some of the imaging trials with PROMIS and SCOT-HEART. Actually, the more plaque you have, the worse you are. Dr. David Newby: And yes, ischemia predicts risk, but ischemia predicts risk through its association with plaque burden, not through ischemia itself. And what I think we're seeing very nicely being played out in ischemia trial is the risk is definitely much stronger for CT than it is for imaging. And that's very clear, and that's exactly what PROMIS found exactly what SCOT-HEART found as well, and it's a rise robust finding. The interaction with the treatment effect that I find also fascinating and again plays to some of the bypass surgery trials that we've seen, bypass surgery tends to prevent spontaneous MIs and, even in some cases, mortality. And we're seeing trends in ischemia for mortality, can't over call them. I'd love to see what happens in 10 years. But I think in terms of the prevention of MIs, I'm putting all my money in one basket, which is the bypass surgery, 25% of course of patients revascularized that way. I don't believe that PCI is going to prevent the myocardial infarction. So I think all my money is in that box. Dr. David Newby: But it's absolutely fascinating data. It is all about the plaque if you're talking about prevention of clinical events downstream. And I think that's where the dichotomy is, scheme is about symptoms and understanding the patient's problems in terms of symptomatic improvement. If you want to improve their long term outcome, it's all about the plaque, understanding the burden of plaque and what you can do to hopefully prevent downstream event. Dr. Greg Hundley: Great. Thank you so much. And so listeners, we're going to ask each of our speakers today in really 20 or 30 seconds to go through and identify what do they think is the next study really to be performed in this space? So Harmony, we're going to start with you and then Nick, Sandeep and then finish up with David. Harmony? Dr. Harmony Reynolds: Thanks. Well, when it comes to INOCA, I would like to see more studies in the vein of CorMicA. So I'd like to see routine invasive testing to define the underlying pathophysiology problem and then targeted medical therapy interventions, and I'd like to see outcome trials. There's one outcome trial going on. It's a challenge because the event rate, though very important and higher than in the general population for sure, is low enough that these trials have to be quite large, and we look at ischemia with a relatively high event rate. And even so it's a stable population and that had to be large, this would have to be even larger. So we're going to need more mechanistic studies in order to lead to the treatment trials that will really influence practice. Dr. Harmony Reynolds: And in terms of the severity of coronary disease, this is a tough one. We felt like ischemia was a lift, and I'm not sure that there will be another huge stable ischemic heart disease trial. But sure, I'd love to see in people selected by CT for their advanced severity of coronary disease, whether an invasive management strategy makes a difference compared to medical therapy. I don't know that we'll see that one come to pass, but you never know. Dr. Greg Hundley: Nick? Dr. Nicholas Mills: Yeah. I agree. We need more mechanistic research, but I'd like to see more non-invasive methods to understand the mechanistic basis of this condition because CorMicA has caught an invasive protocol for a condition, which we know is benign and who most patients get better without any treatment. I would also like to see randomized blinded studies of treatment effects and because there are too many observational on blinded studies here. And I think the outcome has to be patient-focused and symptoms. Dr. Greg Hundley: Sandeep? Dr. Sandeep Das: Yeah. So everything that's been raised so far are fantastic comments and really on point. For me, I think if we can tease out the population that may benefit to get back to Dave's earlier comment that there's possibly not going to be a little humble here, there's possibly a population that has extensive, extensive CVD that could benefit from bypass surgery. And I think that that hasn't really been firmly demonstrated yet, although it's been suggested strongly. So that I think is an interesting study, and I hope that that gets done as a trial, but I can understand that it'd be a giant undertaking. And then the other thing I think is just algorithmic approaches that are driven by anatomical studies like SCOT-HEART and things like that, where we really try to make decisions based on the anatomical approach and pretend like the last 15 years never happened and that we kind are starting fresh with our best approach to how to treat these patients. Dr. Greg Hundley: And finally, David. Dr. David Newby: Yeah. I'm actually going to agree with everybody there, and I'm rooting for this trial actually because that's the one I want to do is look at advanced coronary disease on noninvasive imaging, irrespective of symptoms. And that's the big call actually if you've got no symptoms to put yourself through a bypass, because it's bypass, it's not standing. Bypass, we need. I'd also love to see some substudy coming out of ischemia. I think you're doing them. I hope you are looking at plaque burden and plaque characteristics because I think that's another level of complexity. We're so obsessed with stenosis, actually. And again, even anatomical and ischemia testing plays to that, it's not just about stenosis, stenotic arteries have big plaque burdens, et cetera. And it's not bypassing them, it's bypassing all the nonobstructive plaque and the obstructive plaque that has given you the benefit of revascularization with surgery. So I think you need to think about a really nice cool trial where we can do that trial even in the presence of nonobstructive disease, but big plaque burden, adverse plaque characteristics, and think about bypass. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Harmony Reynolds for bringing us these two really informative studies from the ischemia trial, and also our associate editors, Dr. Nick Mills and Dr. Sandeep Das for providing their perspective and our editorialist, Dr. David Newby, who really helped us organize our thoughts and put both of these two studies into great perspective highlighting in the first that functional testing can really help us identify the presence or absence of ischemia. And then our second study highlighting the association between CT coronary angiography and the identification of the anatomic severity of disease with cardiac outcomes. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we 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 speaker in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

In part 3 of our Author's Own series, we cover Hacks for Life and Career by Sandeep Das. The book revolves around issues faced by Millenials and Gen Z in the workforce. Sandeep Das has penned down a plethora of knowledge in his book to help these generations find their meaning and navigate success in the workplace.

A discussion with Sandeep Das and Samina Hooda from the Lincoln Crossroads Music Festival.

A discussion with Sandeep Das and Samina Hooda from the Lincoln Crossroads Music Festival.

Host, Sister Dr. Jenna is joined by the amazing tabla maestro Sandeep Das as he shares how he was introduced to the Tabla, his love for golf & how he is supporting budding talent! Sandeep Das is a composer, educator and one of the leading Tabla maestros in the world. He leads a prolific international musical career characterized by tradition, innovation, and a passion for spreading love and joy. He is one of the unique Indian Classical Musicians to actively seek a new context for his instrument. Since his debut concert with Ravi Shankar at the age of 17, he has gone on to perform with iconic artists such as Yo-Yo Ma and Paquito D'Rivera at prestigious venues ranging from Carnegie Hall to the Royal Albert Hall. Performances for significant events such as the opening ceremony of the Special Olympics, the 150th anniversary of the United Nations and for dignitaries such as the Queen of England, the Queen of Thailand, the Pope, and various other world leaders, have established him as a highly sought-after performer all around the globe. He has made a musical and spiritual mission out of transporting the classical music of his native India to the West and around the world. Visit www.sandeepdas.com Check out Sister Jenna's Om Shanti CD on Spotify and visit www.AmericaMeditating.org.  

How are alternate business models evolving in emerging markets of the world? What role will new-age channels such as livestreaming and human-less shops play in the future?  Today's episode is hosted by Sandeep Das, Global Foresight Lead for Emerging Markets. He is joined by Jessica Southard, futurist within Mars Global Services, Salim Zanari, Human Intelligence Director for Emerging Countries for Mars Wrigley and Justin Stokes, Co-founder and Managing Partner of Ananda Partners. Together, they discuss consumer trust, human behavior patterns, unconventional partnerships and the heart of FMCG in emerging markets: traditional trade. Will traditional trade significantly lose share to e-commerce in the future? Sandeep shares his personal encounters with the shopkeepers in his youth in India and gets curious about how soon these futuristic channels will affect the emerging markets. Join us as we ponder whether or not livestreaming in China will be the premier global online shopping experience and much more! ——— All views are those of the podcast hosts and guests only and do not necessarily reflect the views of their employer(s).

What is the future of our relationship with technology and virtual versions of our lives? In this final exploration of the 5 shifts of the Transformed Next Normal we discuss Presence Free Living, with a special guest host - Sandeep Das of Mars Wrigley Global Foresight Emerging Markets.  AJ Coyne, Head of Marketing at Klarna UK talks about online shopping behaviors and changing consumer expectations. Sarah Owen, Trend Forecaster and Social Scientist at WGSN shares new trends for a low simulation society. And Manish Thapa, Senior Manager, Product & Marketing at Amazon India shares his personal views on our evolving relationship with virtual and real life experiences.  Join us as we explore what technology will replace, what it will augment and what will remain technology-free. ——— All views are those of the podcast hosts and guests only and do not necessarily reflect the views of their employer(s).

Asia Society Texas presents performances by Zeshan B and Sandeep Das.

This week feature a Double Feature of Discussions. In our first discussion, author Larry Allen and Associate Editor Justin Grodin discuss the article "An Electronically Delivered, Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure with Reduced Ejection Fraction: The EPIC-HF Trial." Then in our second discussion, author Benjamin Scirica and Associate Editor Sandeep Das discuss the Research Letter "Digital Care Transformation: Interim Report From the First 5000 Patients Enrolled in a Remote Algorithm-Based Cardiovascular Risk Management Program to Improve Lipid and Hypertension Control." 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: Dr. Greg, I really love these double features that we have in 2021. Let me tell you about the first one. We are going to be talking about the EPIC heart failure trial. That's the electronically delivered patient activation tool for intensification on medications in HFrEF. Very important results. Dr. Greg Hundley: Yes, Carolyn. And the second feature is going to evaluate an algorithm based cardiovascular risk management program to improve lipid and hypertension control. But before we get to the double feature, how about we grab a cup of coffee and start with some of the other articles in the issue? Dr. Carolyn Lam: My coffee is right here and I want to talk about, guess what? SGLT2 inhibitors again for this first paper. Dapagliflozin, as we know, reduces the risk of end stage renal disease in patients with chronic kidney disease. We saw that in the DAPA-CKD trial. However, the primary and secondary preventive effects of SGLT2 inhibitors on cardiovascular outcomes have not been studied in patients with chronic kidney disease, with and without diabetes. Dr. Greg Hundley: Well Carolyn, remind us a little bit, what were the end points in the DAPA-CKD trial? Dr. Carolyn Lam: Okay, well yes. DAPA-CKD as a reminder, randomized more than 4,000 participants with chronic kidney disease to dapagliflozin, 10 milligrams daily or placebo. The primary endpoint was a composite of sustained decline in GFR of more or equal to 50% or end stage kidney disease or kidney or cardiovascular death. The secondary end points were a kidney composite outcome, the composite of hospitalization for heart failure or cardiovascular death and all cause death. Now the current paper is a pre-specified subgroup analysis where authors led by Dr. John McMurray from University of Glasgow, divided patients into primary and secondary prevention subgroups according to the history of cardiovascular disease. And results showed that dapagliflozin reduced the risk of the primary composite outcome to a similar extent in the primary and secondary prevention groups. This was also true for the composite of heart failure hospitalization or cardiovascular death and all cause mortality. The combined cardio renal benefits of SGLT2 inhibitors in patients with chronic kidney disease with and without diabetes therefore are substantial, whether there is history of cardiovascular disease or not. Dr. Greg Hundley: Not very nice, Carolyn. Well, my paper comes from Dr. Pradeep Natarajan and his colleagues at the Massachusetts General Hospital. And Carolyn, this study evaluated whether premature menopause is associated with CHIP. For our listeners, CHIP stands for clonal hematopoiesis of indeterminate potential and it is the age related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy. And previously it's been shown associated with accelerated atherosclerosis. Dr. Carolyn Lam: Yikes. Greg, is pretty much our menopause associated with CHIP? Dr. Greg Hundley: Well Carolyn, the investigators, among 19,606 women, they identified 418 or 2.1% with natural premature menopause and 887 or four and a half percent with surgical premature menopause. Premature menopause, especially the natural premature menopause was independently associated with CHIP among post-menopausal women. Natural premature menopause, therefore may serve as a risk signal for predilection to develop CHIP and CHIP associated cardiovascular disease. Dr. Carolyn Lam: Interesting. Okay. Well, my next paper really provides the first evidence for endogenous induction of type-1 protein kinase A disulfide formation in the heart and this occurring after ischemia and re-profusion in both humans and mice. Dr. Greg Hundley: Ah Carolyn, so tell us more about this interesting paper. Dr. Carolyn Lam: Well, this is from Dr. Simon from University of Oxford and colleagues who used high spatial and temporal resolution imaging modalities in conjunction with an interesting redox dead type-1 protein kinase A knock-in mouse model and demonstrated that disulfide modification targets this type-1 protein kinase A to the lysosome where it acts as a gatekeeper for two poor channel mediated calcium release and prevents inappropriate triggering of calcium release from the sarcoplasmic reticulum. In the post ischemic heart, they found that inhibition of lysosomal calcium release by these oxidized molecules was crucial for limiting infarct size and preserving cardiac function during re-profusion. All this thus offering a novel target for the design of cardio-protective therapeutics. This is discussed in an editorial by Doctors Westenbrink, Nijholt, and deBoer from University Medical Center Groningen. Dr. Greg Hundley: Thanks, Carolyn. Very nice. Well, my last paper comes from Dr. Nicholas Marston and colleagues from the TIMI study group at Brigham and Women's Hospital of the Harvard Medical School. Carolyn, genome wide association studies have identified single nucleotide polymorphisms or SNIPs that are associated with an increased risk of stroke. The authors sought to determine whether a genetic risk score could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors across five trials involving the spectrum of cardiometabolic disease. Dr. Carolyn Lam: Interesting. And these genetic risk scores are very hot. What did they find? Dr. Greg Hundley: Thanks, Carolyn. Among 51,288 subjects across the five trials, a total of 960 subjects had an ischemic stroke over a median follow-up of two and a half years. Across a broad spectrum of subjects with cardiometabolic disease, a 32 SNIP genetic risk score was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation, but lower CHA2DS2-VASc two scores, the genetic risk score identified patients with risk comparable to those with higher CHA2DS2-VASc two scores. Dr. Carolyn Lam: Wow, that really is impressive. Well, guess what? We've got some other articles in today's issue. There's a beautiful White Paper about the definitions and clinical trial design principles for coronary artery chronic total occlusion therapies and this from the CTOARC consensus recommendations by Dr. Rinfret and colleagues from McGill University. There's a Research Letter entitled, The Randomized Control Trial to Evaluate the Effect of Dapagliflozin on Left Ventricular Diastolic Function in Patients with Type II Diabetes. And this is from Dr. Hong and colleagues from Yonsei University College of Medicine in Korea. Dr. Greg Hundley: Thanks, Carolyn. Well I have an exchange of letters from Doctors Albiero and Xie regarding the previously published paper, Patent Foramen Ovale Could be a Source of Paradoxical Embolism and Lead to Adverse Outcomes in Hospitalized Patients with COVID-19 Pneumonia and DVTs.” There's also a Perspective piece to the 2020 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease from Dr. Bavry. And finally Carolyn, Dr. Tung has an ECG Challenge entitled, “Narrowing the Differential Diagnosis for a Wide Complex Tachycardia.” Well, how about we get on to both of our double features. Dr. Carolyn Lam: Let's go, Greg. Dr. Greg Hundley: Well listeners, we are here for our first feature discussion and we have with us today, Dr. Larry Allen from University of Colorado and our own associate editor, Dr. Justin Grodin from University of Texas Southwestern Medical School in Dallas, Texas. Welcome gentlemen. Larry, could you walk us through the background that really formulated your hypothesis? And then what was the hypothesis that you wanted to test with your study? Dr. Larry Allen: Well, thanks again for having me. I'm a heart failure doctor. The research group that I work with has spent a lot of time on patient empowerment and think about medication prescribing for HFrEF as shared decision making. Thinking about this as a discussion between the patient and me, rather than me deciding what to do. As you know, patients are now coming into the office because they've seen direct to consumer advertising around medications, but typically those are very biased. They're advertisements that are for only patented drugs. And what I'm really trying to think about is what is my patient's overall regimen in terms of heart failure? Dr. Larry Allen: And so we developed a tool which was a three minute video to tell patients that they should come into their visit and be excited to have discussions about their medicines and then a one page checklist that basically said, "Here's what an optimal regimen of medicines looks like for a patient with heart failure and reduced ejection fraction and nobody's really on a perfect regimen, but these are all the possibilities that you could have." Our hypothesis was that if we delivered that to patients before the clinic visit, that it would lead to better prescribing of these drugs. Essentially we imparted on a randomized trial within our healthcare system to do that and that's what we're discussing today, the results of the EPIC heart failure trial. Dr. Greg Hundley: Very nice, Larry. Tell us a little bit, what patients did you enroll in your trial? And then what outcomes did you work to assess? Dr. Larry Allen: We're part of the UC Health System, which has 12 hospitals, but a number of cardiology clinics across the front range of Colorado. Our entire system is on a single instance of the EPIC electronic health record so we're now able to essentially automatically identify all the patients in our system who have HFrEF. We generated lists of patients who had HFrEF who were going to see a cardiology provider in clinic and then we identified them ahead of time, enrolled them in the study prospectively. And the enrollment was for them to agree to be randomized in the study and then for us to be able to collect data on them. Dr. Larry Allen: The patients were kind of a wide range of HFrEF. They were an average of 65 years old, about 70% of the patients were male and reflected the race and ethnicity of Colorado with 11% Blacks and about 7% Hispanics. And everybody in the study had an ejection fraction of 40% or less on their last echocardiogram or other recent cardiac study. And then they were randomized to either get this three minute video sent to them as an email or as a text link that kicked them over to the one page checklist. And then we had them come in. A 145 patients came to clinic having got the information and a 145 patients just came to clinic like usual. Dr. Greg Hundley: Very nice. What did you find, Larry? What were your results? Dr. Larry Allen: Yeah, so we found not surprisingly that the majority of patients who were in usual care had no change to their medical regimen. What we found in the patients who received the EPIC heart failure three minute video and checklist, we saw about a 19% absolute increase in intensification of guideline directed medical therapy. And then we found that most of that was actually an increase in beta blocker dose prescribing. To some extent, the cheapest therapy that could be increased on a drug that people are already on. Dr. Greg Hundley: Very good. Well Justin, we'll turn to you. Help us put the results from Larry's work in the context of A, management of patients with heart failure and reduced ejection fraction and then also B, tell us a little bit about what attracted you to this article and maybe even where you see some of this going next. Dr. Justin Grodin: Thanks, Greg. And Larry, obviously I want to echo Greg's comments by thanking you for your submission. This was a paper that we thought obviously very highly of. Greg, for your first point, we've got novel therapies, but really one of the major issues now is not can we find a newer, better drug? I think we've all come to this realization, it's scalability and implementing these therapies into our regular practice, like beta blockers, RAS inhibitors and mineralocorticoid receptor antagonists. And as Larry said, the problem now is not the quality of our therapies, it's really scaling it and getting it to everyone. It's also increasing these therapies to optimum dosages in patients that can tolerate it over time. Dr. Justin Grodin: And then, to answer your second question, I think some of the things that struck us by this was that this is a wonderfully simple intervention that truly does empower patients. The majority of our interventions to optimize medical therapy has been targeting the physicians, the APP, the nurses, et cetera. This is beautiful in that it empowers the patient and we are putting the ball in their court. And I think to kind of dovetail with your third question, this is a health system clinical trial and I think that tells us a few things. I think one, it provides the framework on how one could perhaps implement that in their health systems. And we'll have to see if this is something that could translate to other health systems across the country or multiple centers. But I think really the intrigue with this work is that it all comes back to empowering the patients. Dr. Greg Hundley: Very nice. Dr. Larry Allen: Greg, I wanted to just add one thing that in the heart failure community, there's this argument going back and forth about whether the lack of optimization of guideline directed medical therapies is due to intolerance or whether it's due to therapeutic inertia. And one of the things I like about this study is on face value, we're empowering patients, but the fact that by asking patients to get involved in prescribing decisions, I think one of the take home messages is that this is partially about therapeutic inertia and that as clinicians, we have a lot of things we're dealing with. And if patients come in to the clinic visit and they're motivated to make these changes actually, we can intensify the therapy. Dr. Greg Hundley: Very good. Larry and Justin, both one at a time here quickly, in the last minute that we have, what do you see as the next study, Larry, that needs to be performed in this space? Dr. Larry Allen: I see two things quickly. One is, as Justin mentioned, validating that this kind of intervention, while simple can be pragmatically deployed in other health systems and in other contexts. The second thing is how do we integrate this kind of small intervention with the larger overall care of patients? One of the concepts that I've talked a lot about over the years with others, including Len Stevenson, is this concept of an annual heart failure review, where rather than seeing people on multiple short visits where we tackle small issues, we actually create a little bit of time to stand back and take a global view of heart failure therapy and how that heart failure therapy fits into the goals of care for the patient, the other medical problems they have and where they're headed. Dr. Greg Hundley: Very good. Justin, anything? Dr. Justin Grodin: Greg, I have to agree with Larry. I think he hit the nail on the head with his first comment. At least for me from an editorial standpoint is really we like to see how generalizable this is and really this implemented in other health systems. I think that's the logical next step. I can tell you, at least from our discussions at our medical center about this manuscript since it's been published at Circulation is, is there something like this we could implement in our own health system? Or in the health systems that we're affiliated with? Dr. Larry Allen: And I would just add that this research and the intervention was funded by the American Heart Association under the strategically focused research network for heart failure and so we've made the interventions public they're online at the research website we have, patientdecisionaid.org. Dr. Greg Hundley: Well fantastic. Well listeners, we want to thank Dr. Larry Allen from University of Colorado and our associate editor, Dr. Justin Grodin from UT Southwestern, for bringing us this article, demonstrating a process that facilitates patient physician interactions to improve the administration of guideline based therapy to patients with heart failure and reduced ejection fraction. And so we're going to wind up this feature discussion and we will head to our next feature. Dr. Greg Hundley: And we have with us Dr. Benjamin Scirica from Brigham and Women's Hospital and our own associate editor, Dr. Sandeep Das from UT Southwestern. Benjamin, could you tell us a little bit about the background information that you used to formulate your hypothesis that you wanted to test for this study? Dr. Benjamin Scirica: Thanks so much first for the invitation. It's a great honor to obviously be in Circulation and to be part of this podcast. We started with the recognition that in our practice, which is similar, I think to a lot of the United States, we are not doing as good a job as we could in terms of care for a lot of the chronic cardiovascular conditions we see. And hypertension and high cholesterol are one of those clear areas where we know there are very good guidelines with clear indication for therapy in specific situations and that these drugs that are available are predominantly generic. But when we looked at our registries, we found that we were not doing as well as we thought. We felt that there are a lot of reasons for that. Dr. Benjamin Scirica: A lot of it was based on the fact that for something good to happen, the right thing to happen, you have to have a patient and a doctor in the same room, the doctor has to recognize that there's a problem. They have to know that there is something they can do about it. They have to be able to convince the patient or educate the patient that they should start this new therapy. They have to know how to start the therapy and then have the ability to follow up and make sure that there is longitudinal care for these chronic diseases. Dr. Benjamin Scirica: And that's a lot to ask for any of us when we have 15 minutes to see the patient, we may only see the patient a couple times a year at most. And so we felt that our hypothesis is, could we design a program, would be delivered remotely, that would not require a doctor in the middle of all of these decisions and that we could scale by using lower cost resources, non-licensed healthcare coordinators or navigators and pharmacists who could follow very clear treatment algorithms to be able to identify patients and prescribe the right medicines to patients at the right time, based on their cardiovascular risk. Dr. Greg Hundley: What was your study design? And what was your study population? Dr. Benjamin Scirica: This is an active, ongoing quality improvement program where our hypothesis is that by doing this, we could improve patients' lipids and cholesterol prescriptions compared to prior. And we did some analysis and we saw that a lot of these patients had not been on optimal therapy for many years, even though they've been in our system. With the limitations of not having randomization, we identified these patients and through different clinics in the different hospitals, and would either have patients referred to us by providers or more commonly go and find them within the registries and identify the patients and contact them and have them enter our program where they would usually take somewhere between eight to 12 weeks to be actively managed, to get to their goals and then they'd enter a maintenance program. The report that we do now is that the story of the first 5,000 patients who we enrolled in our program of whom about 35% were still in management at the time we presented these ongoing results. Dr. Greg Hundley: Roughly how old were these participants? And what was the breakdown in terms of gender or sex distribution? Dr. Benjamin Scirica: We found that about 12% were over 75 years old, a little over half were female. We had 71% who are non-Hispanic Caucasian and 8% who were non-English speaking. In terms of their cardiovascular risks, about a third of the patients had established cardiovascular disease, about a quarter of the patients had diabetes and about a third had an LDL of more than 190 milligrams per deciliter, but no history of ASCVD or diabetes. And then for hypertension, we really would take anybody whom the physician felt required further blood pressure management, because their blood pressure was over 130 over 85. Dr. Greg Hundley: And what did you find? Dr. Benjamin Scirica: We found that of the 5,000 patients that we enrolled, about 4,000 were in the lipid program, a little over 1,400 we're in the hypertension program, so some patients were in both programs and in the lipid patients, in those patients who achieved maintenance, we increased lipid therapy, any lipid lowering therapy, from about 78% up to 97%. And that was predominantly through statins but we doubled the use of ezetimibe from 9% to 17%. We saw a small increase in PCSK9 inhibitor use from 1% to 3%. And if we looked at LDL reductions, it was a 52 milligram per deciliter reduction in LDL from an average LDL of a 125 down to 73 in those folks who achieved maintenance. For blood pressure, again, in those patients whom we successfully treated who are about 600 patients, we saw a 14 millimeter systolic blood pressure reduction and a seven millimeter mercury diastolic blood pressure reduction. Dr. Greg Hundley: Wow. Well Sandeep, what drew your attention to this? And then also, how do you put the context of these results with others that really are working in this wing of data science in cardiovascular medicine? Dr. Sandeep Das: Great question. We have a large body of literature that suggests that the use of these fantastic evidence based therapies like statins, like blood pressure medications is poor and we really struggle to improve those numbers. I wanted to applaud Ben and his group for really taking on, in a robust way, an important topic and subject. The other thing that really attracted me to this study, there was a hypertension expert here named Ron Victor back when I first started as a fellow. Fantastic researcher and he did a project called Colloquia called the Barbershop Project about leveraging pharmacists and barbers to improve the blood pressure control of African American men in the community. Dr. Sandeep Das: The idea is that you get out there, you got to go to where the patients are rather than expecting them to come to you. And you got to figure out ways to engage them, activate them, get them to participate in their own care. A fantastic study, but the one thing that always, we discuss that study, the thing that always jumps out is, well how do you scale it? How do you use it in a real practice? To me was also a very exciting aspect to this. The goal is to take steps to generalize from clinical trials to real world practice, because we got to get this to patients. Dr. Greg Hundley: Very nice. Well Ben, coming back to you, what do you see as next steps for your research here? And then even in the field? Dr. Benjamin Scirica: The first is, are there other disease areas we can do this in? I think the second part is how to test different techniques to try to improve the ability to scale it to broader populations and keep the cost down. And I think it is a combination of trying to find the right tools, whether they're digital or not and the right techniques to be able to activate patients, educate them, such that they are asking the question, "How come I'm not on these medicines? How come I'm not on this?" And I think we could do a lot in terms of AB testing in there. The part that I think is challenging in these healthcare studies and quality improvement studies, is that randomization would be great. How can we do it streamline? Do we need to get consent? Can it just be that approved drug A can be tested against approved drug B because there is clear equipoise. And I think by doing that, we could lower the bar for really pragmatic randomization in practice and be able to have much more rapid cycles of improvement and optimization on therapy. Dr. Greg Hundley: Very good. Sandeep, do you have anything to add? Dr. Sandeep Das: I'll echo Dr. Scirica's called arms here that we need to have a way to do this, do trials in this space pragmatically. I agree with that strongly. I did have a few thoughts on next directions. I work in a population of the urban poor of Dallas County with a lot of my clinical time and these patients have poor health literacy so I think that one question, not question but suggestion or comment to Ben and his group would be to think hard about how you would expand this to lower resource setting or to people that would be a little harder to reach. And even as sort of an aspirational goal, how do you expand it into the community? The other question that I would have is how much of this can we get by with adherence interventions? It's one thing to prescribe, but it's another thing to figure out how to get people to adhere to meds. Dr. Greg Hundley: Very nice. Well listeners, we want to thank Dr. Ben Scirica for Brigham and Women's and Dr. Sandeep Das from UT Southwestern, bringing us this really interesting research that has been providing early results of a remotely delivered pharmacist led lipid and hypertension management strategy that dramatically increased medication compliance and improved hypertension control and lipid management. Dr. Greg Hundley: On behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021.  

This week's episode is special: To start 2021, Circulation's Digital Strategies Editor, Amit Khera, hosts a look back at Circulation's response to the Covid-19 pandemic. Circulation's Executive Editor James de Lemos and Senior Associate Editor Biykem Bozkurt discuss the initial days of Covid manuscript submissions to Circulation. Then Amit interviews author Fatima Rodriguez and her findings of racial and ethnic differences of patients suffering from Covid-19. Finally, Amit interviews authors Nicholas (Nick) Hendren and Justin Grodin as they discuss their article, which was one of the first science outputs from this AHA COVID registry. TRANSCRIPT BELOW: Dr. Amit Khera: Well, welcome to Circulation on the Run. This is Amit Khera. I am digital strategies editor for Circulation, and I have the privilege of standing in for Carolyn Lam and Greg Hundley on this very special edition this week. We have no Circulation issue, so we get to use this and we thought we would use it for a really special look at COVID the Circulation response. It's a time to take a pause and reflect on what we've seen so far this year and what science and initiatives have come out of Circulation. And it's a real privilege today to be joined by first senior associate editor of Circulation, Biykem Bozkurt, who's professor of medicine at Baylor College of Medicine, and also James de Lemos. He's executive editor of Circulation and professor of medicine at UT Southwestern Medical Center. Welcome to you both. Dr. James de Lemos: Thank you. Dr. Biykem Bozkurt: Thank you, Amit. Dr. Amit Khera: Well, Biykem, I'm going to start with you. I remember when COVID came out, it was, we were all overwhelmed. The data were coming fast and furious. Most importantly as cardiovascular specialists we wanted to know how to manage these patients and what manifestations we're seeing. Things were coming from all over the world, and you were tasked with the challenge of, well, how do we organize and curate all this? And what can Circulation do to be most helpful in this response? And you came up with some really creative ideas that I really lodge you for. Maybe you can tell us a little bit about what was going through your mind when this was starting and what are some of the initiatives you started around that? Dr. Biykem Bozkurt: Thank you, Amit. And I really appreciate your pushing it to reflect. In early March it was clear that COVID was surging and we had to create a platform rapidly to disseminate the insights and the best practices from around the world in a timely fashion, and also inform future research for the fight against COVID. We discussed amongst the senior editors, and it was apparent early on that we would not have large-scale multicenter trials. And most of the information was going to come from site experiences and our cohorts, which were so valuable, and everybody was yearning for that information. With that framework in mind, we thought the best platform would be to do a call for submission of rapid research letters. And also we thought of interviews with experts from the hotspots, and we rapidly assembled a Circulation COVID editorial team, which comprised of me along with my colleagues, Salim Virani, Erin Michos, and then both of whom are the guest editors at Circulation, along with Mark Drazner, Darren McGuire and yourself. Dr. Biykem Bozkurt: And we created a call for rapid research letters for COVID and also started doing short video interviews from pandemic hotspots around the globe. We wanted these interviews to be dynamic, informative, conversational, both recognizing the crisis and the human factor as well as the best practices. We were so hungry for information. So we thought of a dyad approach where the interviews would be conducted by early career fellows in training, along with regional experts from the hotspots who were leading the fight formulating solutions. And we are so indebted to these experts and heroes for sharing their stories and experience on the cardiovascular presentations and the practices and how they were managing their patients. And these were called COVID updates from the front lines. Dr. Biykem Bozkurt: We had approximately 19 interviews with leaders from Seattle. That was one of the early hotspots. Then we moved on to Singapore because they were having such valuable and successful interventions. Then we went over to Madrid, Spain, where there was a huge hotspot, of course New York City. Then we interviewed with Milan, Italy, Brescia, Italy, Wuhan, China, New Orleans, South Korea, Salt Lake City, Paris, French, Houston, Texas, Atlanta, San Francisco, Delhi, India. Dr. Biykem Bozkurt: And we also try to address not only the local expert's approach to how to treat and manage and what they were seeing, but also strategically how the health disparities were being handled, how the emergency room or ICU clinicians were tackling COVID. We also try to provide a nursing perspective and even pandemic modeling. For our call for research letters we had approximately, or more than 1,000 papers submitted, 414 of those were original research letters and about 265 as research letters. So I think it was truly a gratifying experience that we were able to provide a voice for the frontline cardiovascular specialists, providing what they were seeing, what they were doing, and also a perhaps a platform that was quick enough, dynamic enough for us to disseminate information. And also a platform for publications as research letters, which are concise and addressing the issue at hand and creating a portfolio by which all the investigators could voice their observations. Dr. Amit Khera: Well, listen, first and foremost, that was a heroic effort and a huge volume of different components, both research components, regional research articles, research letters, and then the videos. And I'll say those videos included fellows. I know I watched many of them before I went on service and taking care of patients to learn what people were doing. And that's so different than what we do in a scientific journal where we peer review and all that. And I can't tell you how helpful that was. And then something else you said was the personal experience. I remember watching a few physicians talking about what it meant personally for them and their families and quarantining and how hard that was and the human toll. And boy, that was really amazing. And I know we'll look back on those years to come and as we think about what COVID was when it first started. Dr. Amit Khera: I'll pivot a little to some of the science. I think having seen this from a different vantage point, at first you weren't sure how many papers you'd get. We were all looking for sort of kernels. And then all of a sudden there's a deluge of papers, right? Can you talk to that experience about how you learned how to curate all this when it was sort of started slow and then it was overwhelming? Dr. Biykem Bozkurt: We knew we would get a lot of papers. We didn't realize the true magnitude. At the beginning we thought that the assigned group, which we call the COVID editor group would be able to handle this. And thus we were trying to triage and provide a structured approach to this. It was quickly clear with James and Joe's and Darren's help that we needed the remainder of the whole editorial board. I remember initially we started with that small group and immediately expanded it to the larger group for us to be able to tackle. Dr. Biykem Bozkurt: I think starting with March, there was a steady rise in the types of papers. The interesting concept was the observations eventually start coming with a certain repeated theme. And of course the ones who provided the initial observations usually had the innovative part of the initial, the first one to recognize it. And there was a lot of debate. For example, when we were first seeing the papers about, or the research letters about the clots we were saying, or asking the questions, "Whether these were higher than the other ICU patients and so forth?" Dr. Biykem Bozkurt: But as the numbers increased, it was the summation of the gestalt of I think what the papers were providing was also moving the field. So not only the volume, I think that was a very interesting experience. Of course how to deal with that on an operational level, at a journal level. But also cataloguing and creating these, okay, these appear to be myocarditis, these appear to be potentially the clots. And then recognizing the how the story's evolving about COVID. And of course, intermittently we had the commission request and ask individuals to provide reviews that are with the insights, creating the synthesis from this culmination of this large volume of papers. And I think we try to do that in a timely manner periodically. Dr. Amit Khera: Yeah. Dr. James de Lemos: Actually just how hard it was to evaluate science in the midst of a pandemic. You know, what these investigators were doing in the midst of their surges was frankly heroic in the beginning. They were terrified, didn't know what was happening in their sites and they were submitting research. But the challenge is that it's not the kind of research we're used to evaluating in Circulation in terms of very well controlled clinical studies with good control groups and clear experiments. We were forced to evaluate research in a war zone basically and decide when something was actionable enough that we thought the clinical community could get ahold of it. Dr. James de Lemos: And at the same time we also had to think about our mission to publish durable science that will last beyond a few weeks or few months of the pandemic. And it was a real challenge and credit to Biykem and Augie here, who's running this podcast for the nights and weekends that we're done evaluating these and the many discussions about really what's the bar for research to get published in the midst of a pandemic. None of us and any of the journalists had ever been through this before. Dr. Amit Khera: I think those are great points. And I may even add to that just as much as there was the wanting to get things out that would help clinicians on the front lines, also responsibility of not publishing something erroneous where people would do the wrong thing. And we've certainly seen that along the way. So that was an added challenge. James, I'll pivot to you a bit more on this, in reflection, if you think about the papers now that you'd be able to look back, what are some of the ones that you remember the most, or you think were most impactful published in Circulation so far? Dr. James de Lemos: Well, some of the ones at the very beginning that were really written with almost a 24 or 36 hour cycle to get information out, there was a research, a review paper rather by Nick Hendren and Les Cooper that really came out almost the first weekend after this group launched. Biykem was involved in that. It was a remarkable effort to summarize really weeks old data on the potential cardiovascular complications. And it was an instant classic. Another one I think that has been tremendously important and durable was the report from Bonnet's group in France on the MIS-C syndrome in children that has been really paradigm changing. I think it was, it won the Willerson award as our top clinical paper of the year because the editors and editorial board felt that this was the most impactful paper we published of all papers in the year. And I think it certainly was amazing work to pull together that kind of series in such a short period of time and define a syndrome really that had never been reported before. Dr. Amit Khera: Yeah. You know, I'm looking here out of the maybe near a 1,000 papers or so of different varieties that came through, those are certainly two very memorable ones and several others. Biykem, I'm thinking about some other articles and even some really interesting frame of reference pieces that people, just sort of personal reflections. What are some of the ones that you remember? Dr. Biykem Bozkurt: The sequence of how it evolved is truly, left a sort of enduring impact on me. The first one that I remember was Kevin Clarkson's paper that provided the initial review, and we all were reading that, of course. Nick Hendren and of course Mark Drazner's paper also added a larger framework of the whole spectrum of cardiovascular disease or cardiovascular abnormalities with COVID. We, I think, try to provide a right balance in terms of the research papers and have received a large scale of papers on DVT and PE. And we then clustered quite a few of those. One of which was from Wuhan, China and the others were from U.S. And that became a very nice complimentary portfolio of three DVT PE papers, which I thought was very helpful at that juncture, because that came a little bit later in the timeframe. I can't recall, I think it was around June timeframe where we were able to formulate, really, this is truly a pattern. Dr. Biykem Bozkurt: The other very interesting paper that I remember is a series of echocardiographic imaging of all hospitalized patients from Israel. This was published in July. This was one of the first structured screening by echocardiography of all comers to the hospital. And it was about a 100 patients and it was by Topilsky. If I remember correctly, it was published in July. And that was the first one stating that a large number of patients had abnormality in the cardiac structure and predominantly RV, which until that time it was anecdotal case reports. We were all hearing about the RV and PE. Dr. Biykem Bozkurt: Then I think in July we had Peter Lewis' very nice review. And of course, Damien Bonnet's the multi-system inflammatory syndrome in the pediatrics, especially how to manage it. We also had a HRS partnership on guidance for how to do EP studies during the time of COVID, and a variety of frame of references. Some of which were about certain different approaches. We had one paper about senior woman leaders as to how they were supporting their colleagues. We also had early career faculty members who had provided their frame of references about social consciousness and ethical dilemmas, all of which were a true complimentary portfolio, providing not only the scientific expertise about human factor in managing this. Dr. Amit Khera: Well, you certainly have a great perspective on all the articles that came through, Biykem, and listed several of the highlights and James, I'm going to pivot you and ask you, what comes next? As one of the senior editors along with Biykem for Circulation, what do we need to see next in cardiovascular space or literature as it relates to COVID? I appreciate there's also what's happening with COVID in general, but what do we need to know and what's the level and bar of science now? Dr. James de Lemos: The bar is back to requiring excellent science, even for COVID cardiovascular disease, really. Because we know enough about the disease that we need the best information that's clinically actionable and meet sort of usual circulation standards. And what I'd say we need next is we need long-term outcome data. So we have a lot of information about short-term cardiovascular complications of the illness, but the next wave, and we're going to get through this, right? The end, the light is on for the end of this thing. But then the next phase is what's the long-term implications of cardiac injury that occurs in the hospital? What are the cardiovascular manifestations of these long haulers? And I think that will be the kind of research that's durable really over the next few years. Dr. James de Lemos: I'm very, very hopeful that we won't be talking about hospitalized COVID in 2022, that that will run its course and not be a dominant theme in Circulation. But I do think we're going to need long-term follow-up of cardiovascular issues for these patients. Particularly given the subtle cardiac abnormalities that Biykem was talking about that we've been reporting in the hospital. Dr. James de Lemos: The other piece I would just say is that we know almost nothing about cardiovascular manifestations of non-hospitalized COVID. Almost everything that we've published and other journalists have published has been about the minority of patients that get hospitalized. But we do need to know more about the many larger proportion that never get hospitalized. Dr. Amit Khera: That's a nice segue when we talk about sort of high quality science and maybe slowing things down just a bit to make sure we're getting the best answers. And that's a pivot to the AHA COVID-19 Cardiovascular Disease Registry, something which you have co-chaired and spearheaded. And we recently had a milestone at DHA scientific sessions. We had the first output just in a few months to already have some high-quality research coming out, we're going to hear in just a bit from two of our featured articles that were leg breaking science out of that registry in shortly. Tell us a little bit about the inception of that registry, what led to it and sort of how did it form? Dr. James de Lemos: Well, the impetus was really the same as what Biykem was talking about with her nights and weekends trying to generate information for practitioners. It was that feeling of powerlessness that we all had early on, knowing that this surge was coming, developing in other parts of the country and realizing that we knew nothing and all of us felt the need to fight back. And as you know, Amit, this really grew out of work of our young people that we developed, or I should say we, meaning our fellows developed a program to teach us about COVID and to study COVID in the patients at our two teaching hospitals. And that really led us to realize that the field needed generalizable knowledge that was beyond single center experiences and their work really directly led to the idea to approach the American Heart Association about a multicenter registry and then Sandeep Das, one of our associate editors and a faculty member at UT Southwestern and I pitched this to the AHA and then we put together a great steering committee and launched this. Dr. James de Lemos: And I think the unique thing about this that we tried to do was in the same, we recognized that the window for discovery was short and the usual way of registry research wouldn't work. And so what we did is we democratized the process. So we allowed multiple teams of investigators to be doing science simultaneously on a secure platform at the AHA, the precision medicine platform. And that's allowed dozens of projects to forward in parallel so that within this six month timeframe we have these two papers published, but we've got a lot of other, what we hope will be important work that can still make a difference in the pandemic. Dr. Amit Khera: Well, thank you for that. And I won't steal this under the upcoming articles to talk more, but congratulations to you on seeing this come to fruition, all the fruits of your labor in a very short amount of time. So we look forward to seeing many, many more papers coming out of it. I want to wrap up by just saying, I know we are certainly not done with the COVID pandemic, but it is a new year by the time this podcast comes out. And so we want to make sure we have time to reflect on what lessons were learned. What we learned about scientific publishing in these really trying times. And I want to congratulate you both on coming up with some very creative strategies to be as contributory as possible to what the field needed at the time. And I think you achieved that and we look forward to continuing to learn from Circulation and from the work coming in about this pandemic and many more things to come. So thank you both for your time today. Dr. James de Lemos: Thank you. Dr. Biykem Bozkurt: Thank you. Dr. Amit Khera: So now we're moving on to the featured article. This is the first of two, and I'm fortunate to be joined by my colleague here, Dr. Fatima Rodriguez, who's an assistant professor at Stanford in the division of cardiology. Welcome, Fatima. Dr. Fatima Rodriguez: Thank you so much, Amit for the invitation. Dr. Amit Khera: Well, you had this really important article on racial and ethnic differences in presentations and outcomes in those hospitalized with COVID and certainly there's been a lot about racial and ethnic differences. Tell me a little bit about the genesis of this particular article. What made you decide to use the registry early on as one of the first studies to evaluate this registry? Dr. Fatima Rodriguez: So as you heard from Dr. James de Lemos and Sandeep Das, the American Heart Association very rapidly created this registry to democratize and accelerate the way we do research during the pandemic. And this topic of racial ethnic disparities was right off the bat selected as a priority area because of the inequities that we're seeing, and that have been magnified by the COVID-19 pandemic. Dr. Amit Khera: Well, there's so much that you found and when it came to who was affected and who ended up in hospital with COVID and then obviously exploring some outcomes, maybe tell us a little bit about what are some of the main findings of this work? Dr. Fatima Rodriguez: We had a lot of significant findings, but I would say that some of the most important findings is that black and Hispanic patients really accounted for over half of the hospitalizations and the deaths in the registry during this first data cut. A third of the patients that were hospitalized were Hispanic and a quarter were black. Asian patients that we also studied had more severe presentations when they were admitted to the hospital. We were also surprised that race and ethnicity itself was not independently associated with worse in-hospital outcomes or other adverse cardiovascular outcomes. But again, this suggests that we really need to move upstream from hospitalizations to deal with the factors that result in the higher rates of hospitalizations for these underserved communities. Dr. Amit Khera: You know, I think you just summarized it so well. And I think for many of us that saw this paper, we saw that there was no difference in in-hospital outcomes in general and after adjustment, which I think that was a little surprising. Maybe we shouldn't have been surprised. Or do you think that perhaps looking at all the sort of media and the press about adverse outcomes we should have thought differently, or do you think this is the actual finding that one can expect? Dr. Fatima Rodriguez: Yes, we were surprised as well. And our hypothesis was that race and ethnicity would be independently associated with worse in-hospital death, but also mace. But it actually turns out there have been many publications across many different sites in the United States that have documented similar findings. Again, the caveat being here is that these patients were hospitalized and as a clinician you and I know that once people get in the hospital, at least for a disease like COVID-19, the care is fairly protocolized. And more of the variation mortality has to do with where these individual patients are hospitalized. And again, not surprising with the new disease that there's a lot of in-hospital variation. So not to say that there aren't disparities, but at least the hospital itself does not seem to be a cause of disparities and outcomes by race and ethnicity. Dr. Amit Khera: I mean, that's an incredible important finding to your point about once you get to the hospital people seem to do comparably well. So I think you said this in your conclusion as well. We really need to work upstream and is also profound that 58% were Hispanic or non-Hispanic black that were hospitalized with COVID. What are some of the upstream things we could be doing? Dr. Fatima Rodriguez: Yes, and this finding has been consistent across many studies. And I think that this reflects the over representation of these communities and the essential workforce, right? People that are not able to isolate. People that need to show up to work every day. People that live in multi-generational households and therefore exposed to the virus and higher rates of transmissions. So first I would say we need to try to do things to prevent the transmission in the first place in the communities. For essential workers they need to be provided the protective gear to again prevent them from the transmission. And now things are different then when we did this study. Now we have a vaccine that's about to be rolled out that we were discussing before, and we really should prioritize these communities in the vaccine rollout as well. Dr. Amit Khera: All great points. And as we drill down a little deeper into some of your findings, I think one that really stuck out to me was how much younger the Hispanics and non-Hispanic blacks were. I think average age of 57 and 60 versus 69 in non-Hispanic whites. Tell me a little bit about your thoughts on what is driving that younger age as well? Dr. Fatima Rodriguez: Yes, I agree that that was a fairly striking finding, especially Hispanic patients were on average 57-years-old compared to non-Hispanic whites who were 69-years-old when they were hospitalized. So more than 10 year difference. Again, I think a lot of this reflects the nature of the workforce and help individuals are higher rates of getting exposed, but also likely reflect some of the underlying co-morbidities. Remember, these are patients that are sick enough to require hospitalization. And again, we know that individuals that have higher rates of diabetes, obesity, and other risk factors have a higher tendency to be hospitalized. Dr. Amit Khera: You know, you also looked a bit at Asians, I should mention that. I think some of the findings were increased respiratory complications and perhaps some issues related to delayed some of the observations around Asian patients. Dr. Fatima Rodriguez: So the Asian patients did comprise a smaller portion of our registry, but again, still a notable finding that they tended to be sicker at time of presentation. We developed a cardio-respiratory disease severity scale specific to COVID, modified from the WHO scale. And again, found that patients even after adjusting for all other factors did tend to have a higher disease severity when they came in. One of the hypothesis of why this was the case is that they tended to have longer delays from symptom onset to both hospital arrival and to the diagnosis of COVID-19. And our study didn't look up why, but there have been some other studies that have suggested perhaps that there's been some hesitation in the Asian community to seek medical care for a variety of factors. Dr. Amit Khera: You know, and I think as we try to think about what are some implications of this work and what are next steps that could be one is to how do we enhance understanding of the need for prompt care in the Asian community, that could be one take home. One other tantalizing finding was this observation of less Remdesivir use amongst non-Hispanic blacks in this study, you made a point of that. What do you make from that, and what are some of the reasons you think are for that? Dr. Fatima Rodriguez: Absolutely. And we were interested in looking at how COVID-19 specific therapies varied by race ethnicity. And of course, things have changed dramatically in this area. As an example, Hydroxychloroquine was the most frequently used drug, and we know we don't use that right now in practice because it's not recommended. However, and Remdesivir is one of those drugs that does have fairly good evidence to use. And we saw that less than 10% of patients in our registry were on Remdesivir during the study period, with black patients being the least likely to be on this drug. Part of this may be explained by the lower rates of clinical trial participation among these patients, and then the other may be just higher rates of comorbidities. But again, might preclude the use of this drug. And we actually have a paper coming out from our registry, exactly looking at the differences in clinical trial participation by race and ethnicity. Dr. Amit Khera: Well, certainly look forward to seeing that. I think that would be an important followup to this. So I guess, leaving you the last word. This was I think a really important finding, helping us understand where the problem is, if you will. Actually there's numerous problems, but your point about upstream focus. So what's next? What do we do next in this field in terms of helping eliminate these disparities that we're seeing in COVID-19? Dr. Fatima Rodriguez: Yes, our hope when we started this registry is that we would have nothing to say at this point, this far along in the pandemic. I will also say one point that we didn't discuss is that mortality was high, and it was high among all groups. So we still have work to do in the inpatient setting to lower mortality, especially as the pandemic continues. But again, our work really suggests that we need to move upstream and focus specifically on vulnerable and marginalized communities, such as racial ethnic minorities to try to prevent the high rates of COVID-19 infection, and in particular high rates of severe COVID-19 infection. Dr. Amit Khera: Well, that was a fantastic review. And congratulations again on this leg-breaking science at the AHA sessions and one of the first early manuscripts coming out of the AHA COVID-19 registry. So thank you again, Dr. Rodriguez. It was a true pleasure to have you on today. Dr. Fatima Rodriguez: Thank you so much, Amit. Dr. Amit Khera: And now for our second featured article, we have Dr. Nicholas Hendren, who's chief cardiology fellow at UT Southwestern Medical Center and Dr. Justin Grodin, who is an assistant professor in the heart failure transplant section at UT Southwestern Medical Center. Their articles entitled Association of Body Mass Index and Age With Morbidity and Mortality in Patients Hospitalized With COVID-19, also from the AHA registry and also a late breaker at the AHA scientific sessions. Welcome gentlemen, and congratulations to you both. Dr. Justin Grodin: Thank you. Dr. Nicholas Hendren: Thank you. Dr. Amit Khera: Well, I'm going to jump right in, this obviously was a really exciting article. One, because of course it's timely with COVID. Secondly because it's one of the first science outputs from this AHA COVID registry, so we're all very excited about it. And importantly, really impactful findings I felt. So maybe I'll start with you, Justin. Tell us out of all the different questions and people were working on this registry, how did this sort of move to the top? What was the impetus behind this question? Dr. Justin Grodin: Well, I mean, I think the answer really lies from clinical experience. I think as you know, Amit, and as Nick knows, we quickly understood as the pandemic evolved that in addition to what we would call more traditional risk factors like cardiovascular disease, diabetes, hypertension, et cetera, and old age, we noticed that the young individuals that were hospitalized with this disease were actually more likely to be overweight or obese in comparison with their older counterparts. So really based on those empiric clinical observations we hypothesized that that would certainly influence outcomes for those that are in the hospital or ill enough to be in the hospital with this disease. As most COVID research has gone, we're basing kind of a hypothesis based on pure clinical assertion. So that was really, the origin was very organic and really based at observations made at the bedside. Dr. Amit Khera: I think that makes a lot of sense, and as you pointed out, with COVID drinking from the fire hose initially and hearing a lot of reports about interplay of obesity. But I think the value here of the registry was which was systematic curation and acquisition of patient data. So definitely makes a lot of sense why you pursued this. And I think what you found first and foremost was that the prevalence of obesity was higher in your patients hospitalized with COVID than those from exchange of the U.S. population. And then I'll turn to you, Nick. Tell us a little about what you all discovered, what happened with these folks with obesity? What was the course? What were some of the findings? Dr. Nicholas Hendren: You know, as Dr. Grodin mentioned, we were really interested at the intersection between the obesity epidemic and the COVID-19 pandemic. And they're major questions focused on two parts initially, which is, are people who are obese at increased risk of dying in the hospital? And the second part being, if you're hospitalized and obese, are you more likely to be intubated? And the answer to both of those after adjusting for the traditional risk factors like age, renal function, et cetera, were yes. And so what we observed was that people who are younger than 50 and severely obese, that means a BMI greater than 40, were at increased risk of dying. And that includes young people who otherwise might not think that they were high risk of dying. And then we observed that your body mass index, if you're obese, again a BMI greater than 30, puts you at increased risk of ending up on the ventilator unfortunately. Dr. Amit Khera: So really I'm going to dig deeper here as you all did in this paper. At first, obviously the prevalence of obesity was higher. Secondly, as you pointed out certain complications like being on the ventilator and I think VTE and other complications, and then some really interesting finding was this interaction with age. Maybe, Nick, tell us a little bit more about that age interaction. Dr. Nicholas Hendren: I think a lot of people are familiar with that age is one of the strongest, if not the strongest risk factor for dying from COVID-19. And what we were interested in was, if you adjust for age and try and take away the association between age, what is the risk of obesity in and of itself? And so we looked at patients that were less than or equal to 50 years old, kind of 51 to 70 and older than 70 years old. And really wanted to look at for those individuals that are obese in those age groups, what are their outcomes? What is their risk? And what we observed was that if you're older than 70 and obese, your risk of dying is probably not all that different by BMI. But if you're younger than 50 and obese, your risk is significantly higher if you're obese than if you were normal weight for that age group. Dr. Amit Khera: It's pretty fascinating this age interaction, that obesity seem to be more of a bad actor, if you will, in young people than it was an older people. And Justin, why do you think you find that? What was the rationale or biology there? Dr. Justin Grodin: You know, Amit, I think that's a great question. And that's a question that we were asking ourselves. As with other diseases, individuals that are more obese tend to be younger in general. So it's very unusual to see somebody that's older that is otherwise obese. So we do see a little bit of an imbalance in the age distribution, favoring higher obese groups in those that are younger. And that certainly could have influenced some of the observations that we saw. And then I think what's perhaps more interesting is, really what makes these young people that we would otherwise think would be low risk, high risk? What is it about obesity that portends a higher risk with COVID-19? Dr. Justin Grodin: And Nick and I, we speculated in the manuscript and really the reasons are threefold. At least we think, obviously it could be more than that. But number one is that we all know that obesity can be associated with metabolic diseases, diabetes, and whether or not there's some subclinical or undiagnosed form of that that is also contributing to risk in these people mediated by obesity could be one possibility. Dr. Justin Grodin: The second is actually directly related to the SARS-CoV-2 virus itself in that the ACE2 receptor is actually abundantly expressed in adipocytes. And so we know that obese individuals have more adiposity perhaps putting them at higher risk. And then the third reason is that individuals that are more obese actually have just more mass on their thorax and that might influence some of their pulmonary dynamics and might put them at increased risk for adverse events. Dr. Amit Khera: All certainly great hypotheses, and obviously further things to test. I'm looking at your conclusions and essentially you reminded us that preventive strategies in obese people regardless of age is something we need to focus on. So I think that's a really important take home point. Last question. Do you, Nick, I want to first congratulate you. I know way back when we were just thinking about the problem of COVID and begin to collect our own data and that germ of an idea really snowballed into this idea of the AHA COVID registry, and you had a critical role in that. I remember talking to you and you were putting in data on nights and weekends. How does it feel now to see the output of your work really so quickly and so such impactful work after doing all this labor and working so hard to get this up and running? Dr. Nicholas Hendren: Well, I think anytime you're able to have at least a small amount of success or something that's felt to be valuable to the contributions, it's always a nice thing. And it was such a team effort all the way through and from the American Heart Association to our attendings, Dr. de Lemos who spoke earlier and Dr. Grodin and all of our team members. And so it's really impressive how the entire field of medicine and cardiology has come together and try and battle COVID across all lines. And so to contribute to that in even a small way is hopefully helpful. And hopefully people will read our information and make choices that will help keep them safe and keep people out of the hospital and doing well off the ventilators. Dr. Amit Khera: Well, thank you. And congratulations to you both on a really fantastic work and impactful paper. And that's it for me, I'm Amit Khera, digital strategies editor for Circulation covering for Carolyn Lam and Greg Hundley, who you'll hear from next week. Thank you all for enjoying our podcast today. Dr. Amit Khera: This program is copyright of the American Heart Association 2021.

With growing competition everywhere, Millennials are always under the scanners to make a difference and an identity. No one is better than to meet the person who can guide and pave the path with the real hacks of life and career. To make it easy, we have Sandeep Das enlightening us on the essential tricks to step up the ladder of success. --- Support this podcast: https://anchor.fm/secrets-of-storytellers/support

in this episode:- Why you should not do one thing for life- The next big opportunity in India- Biggest mistakes a millennial makes- What are the skills a millennial should focus on- How to find a mentor- What is the next big challenge which might be a billion dollar opportunity- Why it is important for every millennial to build a personal brand

Escuchamos los tres discos favoritos del mes de octubre, con el indio Sandeep Das y el Hum Ensemble, que reúne músicos de India y Siria; el japonés Yukihiro Atsumi, y los gambianos, lamentablemente ya desaparecidos, Dembo Konte y Kausu Kuyateh. Continuamos adelantando el nuevo disco de Sara Vidal, lo que aprovechamos para saludar a nuestros nuevos oyentes portugueses de Rádio Universidade de Coimbra. Saludamos también al canciller de la embajada de España en Lima, Antonio Moriana, que nos escucha a través de Radio Filarmonía en la capital peruana, poniendo música de la banda andaluza en cuya fundación estuvo involucrado: Andaraje Y seguimos con #Mundofonews, hablando de convocatorias inminentes y escuchando la música que está sonando en ellas: Fira Mediterrània de Manresa; WOMEX, este año en Budapest; Journey to Korean Music y PAMS, en Seúl, y la Indonesian Music Expo que se celebra en Bali. We listen to the three favorite albums of October: the one of the Indian Sandeep Das and the Hum Ensemble, which brings together musicians from India and Syria; the Japanese Yukihiro Atsumi, and the Gambians, unfortunately already passed away, Dembo Konte and Kausu Kuyateh. We continue previewing the new album by Sara Vidal and we take the opportunity to greet our new Portuguese listeners of Rádio Universidade de Coimbra. We also greet the Chancellor of the Spanish Embassy in Lima, Antonio Moriana, who tunes in to Mundofonías through Radio Filarmonía in the Peruvian capital, playing music of the Andalusian band in whose foundation he was involved: Andaraje. And we also bring our #Mundofonews, talking about imminent events and listening to the music that is performed in them: Fira Mediterrània de Manresa; WOMEX, this year in Budapest; Journey to Korean Music and PAMS, in Seoul, and the Indonesian Music Expo held in Bali. Favoritos de octubre / October favorites · Sandeep Das & The Hum Ensemble – Parvaaz-e noor: Flight of light – Delhi to Damascus · Yukihiro Atsumi – Waiha bushi – Kachofugetsu · Dembo Konte & Kausu Kuyateh – Demba Hajada – Kairaba Jabi Saludos y noticias / Greetings and news · Sara Vidal – Adelaidinha – Matriz · Andaraje – La huida a Egipto – Al grano: coplas de campo, vol. 2 · Maria del Mar Bonet – Zapateo – Ultramar · Xabi Aburruzaga – Bost – Bost · NST & The Soul Sauce meets Kim Yulhee – Joong taryeong – NST & The Soul Sauce meets Kim Yulhee · Jegog Suar Agung – Suar udaya giri – Gamelan joged bumbung · Suarasama – Zapin rindu – Fajar di atas awan Imagen / Image: Yukihiro Atsumi

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

9/21/2018 International Day of Peace with members of Silkroad Ensemble In observation of International Day of Peace, the Rothko Chapel presented a performance by members of the Silkroad Ensemble, while in residency at Rice University, in collaboration with the Aga Khan Council. Performing artists included: Shawn Conley, bass; Nicholas Cords, viola; Sandeep Das, tabla; Maeve Gilchrist, harp; Kaoru Watanabe, shinobue flutes, taiko. Set list: Taiko and Shinobue solo by Kaoru Watanabe Vaishanavi by Sandeep Das Harp Solo by Maeve Gilchrist Ostinato 4 ("Yellow Birds") by Maeve Gilchrist In Manus Tuas by Caroline Shaw Bloodlines by Kaoru Watanabe Tarang by Sandeep Das, arr. Silkroad In a Landscape by John Cage Waves of Rush by Aidan O'Rourke, arr. Maeve Gilchrist Together Alone by Kaoru Watanabe The International Day of Peace ("Peace Day") is observed around the world each year on the 21st of September. Established in 1981 by unanimous United Nations resolution, Peace Day provides a globally shared date for all humanity to commit to Peace above all differences and to contribute to building a Culture of Peace. To learn more about International Day of Peace, visit internationaldayofpeace.org. About Silkroad Ensemble: Silkroad creates music that engages difference, sparking radical cultural collaboration and passion-driven learning to build a more hopeful world. Yo-Yo Ma conceived Silkroad in 1998 as a reminder that even as rapid globalization resulted in division, it brought extraordinary possibilities for working together. Seeking to understand this dynamic, he began to learn about the historical Silk Road, recognizing in it a model for productive cultural collaboration, for the exchange of ideas and tradition alongside commerce and innovation. And in a radical experiment, he brought together musicians from the lands of the Silk Road to co-create a new artistic idiom, a musical language founded in difference, a metaphor for the benefits of a more connected world. Today, these Grammy Award-winning artists seek and practice radical cultural collaboration in many forms, creating and presenting new music, teacher and musician training workshops, and residency programs in schools, museums, and communities. Silkroad has recorded seven albums. Sing Me Home, which won the 2016 Grammy for Best World Music Album was developed and recorded alongside the documentary feature The Music of Strangers, from Oscar-winning director Morgan Neville.

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.                                                 Our featured discussion today is really a very important message, that hospitals have the capacity to influence a patient's adherence to secondary prevention and thereby potentially impacting long-term patient outcomes. Much more on this important paper coming right up.                                                 Higher physical activity is known to be associated with lower heart failure risk. However, what is the impact of changes in physical activity on heart failure risk? The first paper in this week's journal, by first author Dr. Roberta Florido, corresponding author Dr. Ndumele from Johns Hopkins Hospital, provides us some answers. These authors evaluated more than 11,350 participants of the Atherosclerosis Risk in Communities, or ARIC, study who were followed for a median of 19 years during which there were 1,750 heart failure events.                                                 They found that, while maintaining recommended activity levels was associated with the lowest heart failure risk, initiating and increasing physical activity even in late middle age were also linked to lower heart failure risk. Augmenting physical activity may, therefore, be an important component of strategies to prevent heart failure.                                                 The next paper highlights the importance of bystander automated external defibrillator use. First author Dr. Pollack, corresponding author Dr. Weisfeldt from Johns Hopkins University School of Medicine sought to determine the association of bystander automated external defibrillator use with survival and functional outcomes in shockable observed public out-of-hospital cardiac arrests.                                                 From 2011 to 2015, the Resuscitation Consortium prospectively collected detailed information on all cardiac arrests at 9 regional centers. The exposures were shock administration by a bystander applied automated external defibrillator in comparison with initial defibrillation by emergency medical services. The primary outcome measure was discharged with near or normal functional status as defined by a modified ranking score of two or less.                                                 The authors found that among 49,555 out-of-hospital cardiac arrests, 8% were observed public out-of-hospital cardiac arrests, of which 61% were shockable. Overall bystanders shocked a remarkable 19% of shockable observed public out-of-hospital cardiac arrests. Bystander automated external defibrillation in shockable observed public out-of-hospital arrest was associated with an increased odds of survival with full or nearly full functional recovery compared to emergency medical services defibrillation.                                                 The benefit of bystander automated external defibrillation use increased as the arrival of emergency medical service was delayed. Thus, efforts to increase the availability and use of automated external defibrillators in public locations are likely the most promising immediate ways to improve survival from out-of-hospital cardiac arrests.                                                 The next paper suggests that the complement pathway may contain the secret to a successful cardiac regeneration. First author Dr. Natarajan, corresponding author Dr. Lee from Harvard University, and their colleagues performed a cross-species transcriptomic screen in 3 model organisms for cardiac regeneration, the axolotl, neonatal mice, and zebrafish, all of which underwent apical resection.                                                 RNA-seq analysis showed that genes associated with inflammatory processes were found to be upregulated in a conserved manner. Complement receptors were found to be highly upregulated in all 3 species, particularly the induction of gene expression for complement 5a receptor 1. Inhibition of this particular complement receptor attenuated the cardiomyocyte proliferative response to heart injury in all 3 species.                                                 Furthermore, following left ventricular apical resection, the cardiomyocyte proliferative response was abolished in mice with genetic deletion of complement 5a receptor 1. These data, therefore, identified the complement pathway activation as a common pathway for a successful cardiac regeneration.                                                 The final study sheds light on the association between hyperoxia exposure after resuscitation from cardiac arrest and clinical outcomes. First author Dr. Roberts, corresponding author Dr. Trzeciak from Cooper University Hospital performed a prospective multicenter protocol directed cohort study that included 280 adult postcardiac arrest patients.                                                 They found that early hyperoxia exposure, defined as a partial pressure of oxygen of above 300 millimeters mercury during the first 6 hours after return of spontaneous circulation, was an independent predictor of poor neurologic function at hospital discharge even after adjusting for a potential baseline and postcardiac arrest confounders.                                                 That brings us to the end of our summaries. Now, for our featured discussion.                                                 Medication nonadherence is a common problem worldwide and, indeed, the very topic of our featured discussion today. Our featured paper is so interesting because it tells us that hospitals may have the capacity to influence a patient's adherence to secondary preventive cardiac medications, thereby, potentially impacting long-term patient outcomes, and there are a lot of implications of that.                                                 I'm so pleased to have with us the first and corresponding author, Dr. Robin Mathews, from Duke Clinical Research Institute, as well as the editorialist for this paper, Dr. Jeptha Curtis from Yale University School of Medicine, and our associate editor, Dr. Sandeep Das from UT Southwestern. Lots to talk about.                                                 Robin, could you perhaps start by telling us what made you look at this issue of nonadherence and what did you find? Dr Robin Mathews:         The issue of medication adherence has been something that I think we've been dealing with in healthcare for some time now and, traditionally, we looked at factors that, on a patient level, you sort of also have an idea that maybe they might provider level factors that contribute to nonadherence, so we started thinking about this, what's the health system's role in adherence and is there a role? Do hospital and do providers have more of a role in promoting adherence than we acknowledged in the past?                                                 We are fortunate to have a lot of great clinical data sources available, and the one that we used for this study is the ACTION-Get With The Guidelines Registry, and this is a quality improvement registry that's been around for some time. It's a great source of research and observational studies that has produced a lot of data over the years.                                                 ACTION is a voluntary registry; there are several hundred hospitals that participate, and it gives us very good data, detailed data on the patient experience in the hospital for patients who come in with acute coronary syndrome, so we looked at patients who were enrolled in ACTION over the course of 3 years, from 2007 to about 2010, and looked at the typical patient level factors, medications that were given on admission, how they were treated and what medications they went home on.                                                 What ACTION doesn't give us is longitudinal data, which is really what we were trying to get at here, so we were able to link this clinical data set using CMS data, which is administrative data, claims data, in order to ascertain longitudinal adherence, so we ended up, after exclusions of about 19,500 patients or so, and this spanned about 347 hospitals, of patients that we followed up to 2 years out, and our objectives of the study were 2-fold, one to assess adherence at 90 days for cardio vascular medication, secondary prevention medications that are typically used, so, in this case, we looked at beta blockers, ACE inhibitors, ARB, phenoperidine, and statins.                                                 We looked at 90-day adherence, and then the question we had specifically was does adherence vary among hospitals? The second thing we wanted to knowledge was, if adherence does vary among hospitals, is there a relationship between hospital adherence and cardiovascular outcomes at 2 years, so we looked at MACE, which is MI, revascularization, readmission, stroke. We also looked at death and all-cause readmission, and also mortality.                                                                                                 What we found is that the adherence actually did markedly vary within the medication classes, but also among hospitals, and once we divided these groups into essentially high adherence hospitals, low adherence hospitals, and moderate adherence hospitals, there were these typical differences in terms of patient characteristics that one would expect in terms of comorbidity, socioeconomic status. Patients who were in the high adherence hospitals were more likely to be from ... to have a less comorbidity burden. They had higher income based on ZIP code, and they were more often represented from non-southern hospitals in the United States.                                                 When we then correlated these two outcomes, what we found is pretty interesting. Patients who were in the low adherence hospitals were more likely to have the outcomes that I mentioned earlier. That's not too surprising, yeah, because I had mentioned that the patient mix in terms of the ... their case mix varied among these hospitals, so the logical question as well, maybe the hospitals that are ... have low adherence have low adherence because the patients are generally just sicker.                                                 We know that there are certain high-risk groups and we know that the patients who are treated at some hospitals might be sicker than others, so we did our best to adjust to these, so we did a multivariable model. We adjusted for various patient differences, and we also looked at hospital-level differences, the best that we can ascertain based on the ACTION Registry. That was sort of where the interesting finding was the rates of major adverse cardiac events and death at readmission were mitigated somewhat closer to the null, but they remained significant. Dr Carolyn Lam:                What a detailed summary. Thanks so much.                                                 Jeptha, I love your editorial that accompanied it. Could you put the study into context a bit for all of us? Why are these finding so impactful? Dr Jeptha Curtis:               It's rare that you get to review and editorialize a paper that has so many implications both from a clinical practice and policy standpoint, so I think they really hit on a understudied area, and really this paper should cause people to reflect on what's going on in their practice and at the institutions that they practice in.                                                 I would say that adherence is just such a challenging problem that, as Robin articulated, has been refractory to change over 15 years. We've been studying this for a long time, and we know that the numbers had not improved over time.                                                 What's different about this paper is that it really suggests a completely different approach to addressing nonadherence among patients, and if this is ... if their findings are true, if nonadherence is really actionable at the hospital level or attributable to the hospital level, it really opens up new avenues both for research as well as for quality measurements.                                                 As I read this paper for the first time, I was really struck by thinking about how invisible adherence is to frontline clinicians. We just don't have the information to tell us are our patients taking their medications on a day-to-day basis, and we know that most of them are not because the research has consistently shown that a large proportion failed to take their medication, and Robin's paper showed that yet again, but I can't say that there's any steps that our hospitals are really doing to address that in a systematic fashion.                                                 All of our efforts for quality improvement have really been towards making sure that patients are prescribed the medication on discharge, and in the setting of readmission and trying to prevent readmission to our hospitals, we are now having follow-up phone calls with patients to assess failures to taking medications and follow-up, but it's really ... That's it. There's really no systematic way that we're trying to ... if an individual patient or a group of patients are adherent to their medications, so this is really a whole new avenue.                                                 What we don't know is how to improve it, right? I think that the first implication of this paper is that there are differences at the hospital level. Some hospitals seem to be doing this better than others. That could be driven by differences in case mix, but it could also be driven by differences in hospital practices, and I think this is a wonderful opportunity for future direction of research perhaps using positive deviance methodologies to go to those hospitals that have high adherence rates in really trying to understand what differentiates their practices from those of other hospitals. Dr Carolyn Lam:                Indeed, Sandeep, I remember some of the conversations we had as editors about this paper. We, too, were struck by the novelty, and you've mentioned before, Sandeep, that the novelty of perhaps nonadherence or adherence as a new performance measurement. Would you like to comment on that? Dr Sandeep Das:               Yeah, first thing, what was kind of interesting about the discussion surrounding this paper, there were some people who read it and just sort of read it as the message being nonadherence associated with worst outcomes, and I thought like that was pretty established, known, but then there were some people like Jeptha and Erica who really got it, who really understood what was novel and interesting about this, and I also congratulate Robin on a fantastic paper.                                                 One thing I think that's really interesting, in my day job, I wear a couple of quality hats. I am the cardiology division quality officer, and health system quality officer for UT Southwestern, so I spend a lot of time thinking about quality, and I'll tell you there's quite a bit of metrics that he ... there's just a lot of things that now you feel they're not particularly substantive and they're very difficult to change, you have, you know, if aspirin on discharge, as Robin mentioned discharge adherence, aspirin on discharge is 99% and getting people to document the last 1% rather than fail to document it, there's not really a fulfilling challenge where you think, "I'm really impacting patient endpoints."                                                 I was really struck by the opportunity here. We know that from studies like MI FREEE that adherence to medications even at a year is probably about a third of patients are not adherence, so it's really kind of interesting to take that as an opportunity. We should fixate on what are these therapeutic option or not therapeutic option can move the needle by a fraction of a percent, but these are medications that are proven to prevent MI and change lives, and there's a massive delta here that we can address. The concept that this is addressable on the hospital level is fascinating, and I'm a big fan of coming up with sort of systems level approaches to addressing problems. Dr Carolyn Lam:                Congratulations once again on this great paper. Just tell us what do you think of the next steps and what would your message be to those of us who practice outside of the US? Dr Robin Mathews:         Jeptha talked about where our focus should be in terms of what we can do on a hospital level. I think the ultimate answer is there's a lot of heterogeneity in terms of what is done, and I think that, expanding on his point about better investigating practices that currently exist, and whether that's surveying things, and we have a lot of great professional societies and registries that we can sort of reach out to these hospitals, find out what they're doing, what makes them different from the hospitals that are not doing those things and then really doing some rigorous testing to figure out if in fact these specific interventions that these hospitals have put in place are with the high likelihood leading to the effects that we've seen, so I think that surveying sort of what's out there, understanding what works in a rigorous way and then being able to systematically apply this or distribute this to other hospitals to share the knowledge and say, "Hey, this is what we think. We've actually done it."                                                 Like Sandeep said, with the inpatient management of patients who come in with acute coronary syndrome, we've done it well. I think it sort of contributed. Our guidelines and adherence to these guidelines and the metrics that we've used have really demonstrated that we've sort of achieved high levels, but we sort of reached I think the ceiling for a lot of that, and you always have to be open to novel metrics and then the idea of focusing in on the transition from hospital to home and what we can do once they leave their door, once they leave the door of the hospital, I think would be useful.                                                 In terms of the rest of the world, I mean, the US has very unique problems based on our payment models and access to care and whatnot, but I think a lot of the themes that we sort of have seen with medication nonadherence when it comes to patient-level factors and provider-level factors are sort of universal.                                                 At the end of the day, patients need to be empowered, and they also need to have the tools to allow them to be successful in my opinion. I think we've for a long time in this space often said, "Well, this is sort of a patient that there's only so much that we can do as providers," but I think that papers like this highlight the possibility that there's probably more that we can do to make these impacts. Dr Sandeep Das:               One of the comments or a question that I had was the controversial thing is to what extent hospitals should be accountable for things that happen well after discharge? I think readmission is one that always comes up. There's factors that are outside our control, so one question is kind of to what extent should we be responsible for stuff that happens forward of 6, 9 months down the road?                                                 The second question that I had or a comment that I had was I do think that there's going to be a generalizability to non-US settings because there's elements of this ... For example, this now would incentivize hospitals and discharging physicians to make sure that patient education is substantive, right? If the metric is, "Did you provide discharge instructions, yes or no?" then that's sort of trivially accomplished by handing them a piece of paper and checking a box, but, now, if we follow a metric like this, we're really going to be accountable for making sure people understand what they're supposed to be taking and have a path to get it and things like that, so it makes some of the transitions of care stuff, and that's a great point, some of the transitions of care stuff much more substantive. Dr Robin Mathews:         Sandeep's point is a very good point, and it's very difficult to come up with a clear answer for that and, like you said, the issue with readmissions and all sort of the factors that are involved from a social level and research level cloud that, so ... and, hence, I think something like readmission is controversial, and I think this sort of question will generate a lot of further questions about whether using medication adherence and holding hospitals responsible.                                                 I will say that when we looked at adherence sort of in the short term at 90 days and we looked at it in the long term at a year, we saw there was sort of a drop off, but it wasn't as substantial it was earlier, so I think a lot of adherence in the short term after hospital discharge continues to decline over time, but it doesn't drop down as precipitously downstream as it does early on, and I think that, just like with readmission, there's been some data to suggest that near term readmission are more likely things that "could be preventable" as opposed to maybe a readmission toward the end of the month.                                                 At the end of the day, it's a very difficult thing and there's a lot more discussion that needs to be had about this topic, but I think that with this, it gives me some hopefulness and I think everybody else on this call that at least we wouldn't then be able to prevent every adverse outcome that happens 2 years down the road, but we might be able to at least affect a substantial portion of them. Dr Carolyn Lam:                Listeners, you heard it. There's lots that we can do. This paper says a lot. Please do pick it up. Read the editorial as well.                                                 Thank you so much for listening today, and 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 Duke-National University of Singapore. Our feature paper today focuses on LDL cholesterol results from non-fasting samples and a personalized novel method of LDL cholesterol estimation that you will surely want to know about. So stay tuned, coming up right after these summaries.                                                 The first paper provides new evidence that RUNX1, a gene intensively studied in the cancer and blood research fields, has a critical role in cardiomyocytes following myocardial infarction. Co-first authors, Dr. McCarroll and He, corresponding author Doctor Loughrey and colleagues from University of Glasgow generated a novel tamoxifen-inducible cardiomyocyte-specific RUNX1-deficient mouse and showed that RUNX1-deficient mice were protected against adverse cardiac remodeling post-MI, maintaining ventricular wall thickness and contractile function. Furthermore, these mice lacked eccentric hypertrophy and their cardiomyocytes exhibited markedly improved calcium handling.                                                 At the mechanistic level, these effects were achieved through increased phosphorylation of phospholamban by PKA and relief of sarcoplasmic reticulum calcium pump inhibition. Thus, these data identified RUNX1 as a novel therapeutic target with translational potential to counteract the effects adverse cardiac remodeling post-MI.                                                 The next paper invites us to consider that some our resource-intensive quality improvement initiatives may not be fulfilling their intended goals or even justify their costs. In this paper by first author, Dr. Kutty, corresponding author, Dr. Chan and colleagues from St. Luke's Mid America Heart Institute, the authors evaluated the association between the implementation of pediatric medical emergency teams and the risk-adjusted mortality at the hospital level.                                                 To do this, they looked within the pediatric health information system for freestanding pediatric hospitals and calculated the annual risk-adjusted mortality rates for sites between 2000 and 2015. A random slopes interrupted time series analysis was then used to examine whether implementation of a medical emergency team was associated with lower than expected mortality rates based on the pre-implementation trends. The authors found that before medical emergency team implementation, hospital mortality rates were decreasing by 6% annually across all hospitals. After medical emergency team implementation, the hospital mortality continued to decrease by 6% annually with no deepening of the mortality slope as compared with the pre-implementation trend for the overall cohort or when analyzed separately within each of the study hospitals. Five years after implementation across study sites, there was no difference between predicted and actually mortality rates.                                                 Thus, in summary, the implementation of medical emergency teams in a large sample of pediatric hospitals in the US was not associated with a reduction in hospital mortality beyond the existing pre-implementation trends. This study's null findings on hospital mortality suggests that either medical emergency teams have no effect on mortality or are being poorly implemented in the real world. These issues are discussed in an accompanying editorial by Joshua Koch and Sandeep Das from UT Southwestern.                                                 The next study tells us that carotid stent fractures are not associated with adverse events. First and corresponding author, Dr. Weinberg from Massachusetts General Hospital and his colleagues reported the stent fracture rate and its association with instant re-stenosis and adverse outcomes in the Asymptomatic Carotid Trial 1, which was a prospective multi-center trial of standard surgical risk patients with severe asymptomatic carotid artery stenosis randomized to carotid artery stenting or carotid endarterectomy. Stent fracture occurred in only 5.4% of patients and there was no association between stent fracture and in-stent re-stenosis or with the primary endpoint, which was a composite of death, stroke or myocardial infarction during the 30 days after the procedure or ipsilateral stroke during the 365 days after the procedure.                                                 These findings suggest that routine surveillance for carotid stent fracture may be unnecessary and, if a fracture is identified in an asymptomatic patient, intervention may rarely be required.                                                 Heart rhythm disorder management procedures are increasingly being performed and the next paper tells us important information on mortality and cerebrovascular events following such procedures.                                                 Co-first authors Lee and Ling, corresponding authors Dr. Mulpuru and colleagues from Mayo Clinic in Phoenix, Arizona, performed a retrospective cohort study of all patients undergoing heart rhythm disorder management procedures between 2000 and 2016 at the Mayo Clinic from all three campuses in Rochester, Phoenix and Jacksonville. Among almost 49,000 patients undergoing a total of above 62,000 procedures, the overall mortality and cerebrovascular event rate was 0.36% and 0.12%, respectively. Lead extraction procedures had the highest overall mortality of 0.21% and the highest cerebrovascular event rates at 0.62%. However, most of the deaths and cerebrovascular events occurred after device implantation procedures due to the sheer volume of device implantation procedures, which represented 48% of all the procedures performed.                                                 The most common cause of death directly related to these procedures was cardiac tamponade, being responsible for 40% of all directly related deaths. This highlights the importance of development of protocols for quick identification and management of cardiac tamponade, even in procedures typically believed to be of lower risk such as device implantation.                                                 And that wraps it up for our summaries this week. Now, for our feature discussion.                                                 Lipid testing plays a major role in our day-to-day management of our cardiovascular patients and fasting samples have long been the standard for assessing LDL cholesterol and triglycerides since fasting is believed to reduce the triglyceride variability and allow for a more accurate derivation of the commonly used Friedewald calculated LDL cholesterol. Well, I think that's an assumption we have taken for granted, I mean, since 1972 when the Friedewald calculation was first proposed, but in this day and age, several clinical guidelines from Europe, Canada and the US have now recommended non-fasting lipid testing for routine clinical evaluations and it's time to re-evaluate perhaps the Friedewald LDL or other methods for determining LDL.                                                 Today's feature paper addresses this issue spot-on and we're thrilled to have with us the corresponding author of a very important paper and he is Dr. Seth Martin from the Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease and we also have with us Dr. Anand Rohatgi, associate editor from UT Southwestern. Welcome, gentlemen. Dr. Anand Rohatgi:          Thank you, Carolyn. Dr. Seth Martin:                Thank you. Dr. Carolyn Lam:               Seth, that was a super-long lead up from me, but I just find your paper so intriguing. Could you please paint the background of the idea behind your paper today and the rationale for questioning the Friedewald equation? Dr. Seth Martin:                Yeah, my pleasure. This was the first paper to look at directly fasting versus non-fasting using our new algorithm. To give a little background on the algorithm, we had recognized that the Friedewald equation, which had been the standard for decades as you mentioned, would really become problematic in the setting of low LDL concentrations. In fact, Dr. Friedewald himself and his co-authors said that in their original publication in 1972 because what's subtracted out is the LDL cholesterol and it's not a particularly accurate estimate by their equation, but at the time, it was viewed as acceptable because the concentrations of LDL weren't all that low.                                                 Now, in the modern era, things are different. We treat the lower LDL. We're lucky to have new drugs that allow us to achieve low LDL levels and meanwhile we have many more patients with obesity and diabetes, leading to higher triglyceride levels, so this all means that that estimated component of the equation becomes a bigger part of the equation and that's what spurred us on to say, "Well, cane we estimate that better?" And we were very lucky to have access to a huge data set that had over a million patients and had directly measured VLDL cholesterol as well as triglycerides, so that allowed us to really more specifically address this estimated component of the equation.                                                 To just give the brief details on what the equation does, is we take the original Friedewald equation from what I view is a one-size-fits-all approach where we divide triglycerides by 5 in milligrams per deciliter and now we just match the patient based on their lipid profile using the same data as the Friedewald equation with the more personalized factors, so taking it from one size fits all to a more precision or personalized fit and it's one of 180 different factors that the patient may get matched with and what we've found is that this type of approach is more flexible, so it's going ... as patients triglyceride levels go up in the setting of low LDL and as they go into non-fasting states, this type of approach can adapt to that better and provide a more reliable, accurate estimate of LDL cholesterol. Dr. Carolyn Lam:               That is so cool. It really is. It just makes so much sense in this day and age of proceeding towards personalized medicine, to make sure we apply equations that are personalized, so your paper essentially shows that applying this new equation works better than the traditional equation, particularly in the non-fasting states, right? And for states of low LDL cholesterol or perhaps high triglycerides. Would that be a good summary? Dr. Seth Martin:                Yeah, that's a great summary and this paper ... I'm really lucky. It was led by one of the fantastic Osler medical residents, Vasanth Sathiyakumar, who is going to be a future star in cardiology, I believe, and he did a great job leading our paper, which shows that in the non-fasting state, what happens is triglyceride levels are higher and this means that the Friedewald equation becomes less accurate and I think this has been a little bit overlooked in recent trends where there's been a big push to do more non-fasting lipid profiles, which really is great for patients, more convenient and it makes a lot of sense, but we have to be also, in an era of precision medicine, getting precise data and if we're going to be making clinical decisions based on LDL concentration, we want to make sure we have good information there and what our paper shows is that there should be some level of caution when using non-fasting Friedewald LDL at low levels, but our new algorithm does provide a more robust estimate in that setting. Dr. Carolyn Lam:               Anand, this is begging for the question, "What do you think are going to be the practical implications of this very important paper?" Dr. Anand Rohatgi:          I think the clinical implications are huge and I think that's why we were so excited when we received this, that sort of the potential impact was there. I can tell you personally my clinic is in the afternoon and so it's a struggle to try to get patients to get fasting lipid levels and often they can't do it when they're coming to see me and so the importance of non-fasting lipid levels is clear and what Seth's group has done is showed that we can actually accurately estimate the LDL levels. A lot of people struggle with trying to still calculate the non-HDL levels and, as Seth pointed out, oftentimes when you're non-fasting, the triglyceride levels are higher and the calculated LDL from Friedewald is artificially low, so it's very hard to combine the convenience of just looking at the lipid levels and having sort of a confidence in the actual calculated LDL, so in this case clinicians can have their patients get their lipid levels at any time and with this algorithm that's already being used by major laboratory services will have relatively high confidence that the LDL that they see is very accurate and then they can make a decision based off of that and they can counsel in real time based off of that, so it really changes the ability to engage with patients at any time and is not restrictive.                                                 I can tell you many patients sometimes won't even get their lipid levels for weeks just because they can't arrange for it to be done on a fasting state and so this really liberates patients and it really enhances the doctor-patient relationship, I think. Dr. Carolyn Lam:               I agree, Anand. I like that word that you used, "liberate" the patient. Honestly, I think some of my patients cheat a little too and they don't really fast as they should before their fasting lipids and this is going to be incredibly helpful.                                                 I have a couple of questions for you, though, Seth. In terms of understanding the limitations of what you may have tested in the current study, we all know that with triglycerides in the super-high level of more than 400, for example, the Friedewald equation breaks down. Did you test this with the new equation because I think you excluded this group as well in the current study, did you not? Dr. Seth Martin:                That's correct, yes. Traditionally, the Friedewald equation has excluded folks from calculation who have triglyceride levels, as you said, of 400 milligrams per deciliter or more and the reason for that is that's the setting where chylomicrons are more likely to be present and therefore we're trying to estimate VLDL cholesterol and it wouldn't make sense to do that if there's a lot of triglycerides and chylomicrons.                                                 That being said, we did look at this previously and found that in that setting our equation works quite a bit better than Friedewald, but it's still inaccurate I would say about a third of the time due to the presence of chylomicrons, so it's an area where we should certainly be more cautious in estimating LDL cholesterol if the triglycerides are that high, but honestly in that setting, often the clinical priority is going to revolve around triglyceride lowering and the LDL may not be the most immediate priority for clinical treatment. Dr. Carolyn Lam:               And then just another question, recognizing that our podcast is heard throughout the world, in this day and age of precision medicine, how about accounting for potential ethnic differences, possibly? Did you account for differences in race, gender perhaps in these equations? Dr. Seth Martin:                What we found is that this really is a lipid-dependent phenomenon in terms of the ratio of triglycerides to VLDL in estimating LDL. We previously looked at age and sex and found that they contributed very, very little information to actually explaining this ratio and so I think that it is something that's likely going to be preserved across different demographic groups. I can say to our listeners in places ... in Asia that the equation has been validated over there and so there's some reassurance that even around the world and other places like Brazil, that it is holding up, so I think that largely this is going to be dependent on someone's lipid profile and it is quite simple in that regard, that we don't have to likely worry about too much differences between men, women, older, younger or different ethnicities. Dr. Anand Rohatgi:          I have a question for Seth. As we mentioned, this is an international audience and guidelines do differ on their emphasis on lipid targets now as everyone is aware, some still emphasizing them and others, like the American guidelines, de-emphasizing targets, so Seth, the question i had for you is based off of your work. Where do you see that fitting in with how the different guidelines and societies are trying to emphasize or de-emphasize lipid targets. Dr. Seth Martin:                The amazing thing is we're all ... really have access to the same data. We've worked together throughout the globe to generate clinical trial evidence that guides us as well as all sorts of other type of evidence to guide us in clinical practice, so just on a very broad conceptual level, my hope is that over time with the great exchange of information around the world that we're going to converge more on consensus recommendations and then, of course, there may be needs to adapt those recommendations to different cultures and that can be taken into account, so I'm hoping there'll be a push towards more consensus and as we get our updated American guidelines, it's looking like this upcoming year, I hope that we come into even more harmony with the rest of the world.                                                 I think for a long time we've had this LDL goal in many different guidelines as less than 70, so that's part of the reason our work has focused on that level. The European guidelines have a target level for high-risk patients of less than 70 for LDL and I think what we saw in the recent consensus document on non-statins from the American College of Cardiology was a push to be thinking at that level when the LDL is 70 or above as a time to have a clinician and patient discussion about whether we should be intensifying therapy, so I guess would say the guidelines in my view, and Anand I would be curious of your view, are more alike than different, but I hope they become even more in harmony because really we're all basing our decisions on the same evidence base and I think it can be a bit confusing when we have disparate recommendations.                                                 The same can be said for the issue of recommendations for fasting versus non-fasting guidelines, which have not been harmonized either, but Anand I'd be curious to your thoughts as well on this topic. Dr. Anand Rohatgi:          I would agree with you. I think they're more alike than different. It's just what may be the high level sort of things have come out to the lay public and others, but I agree with you. If you really read them, they're emphasizing risk reduction by the therapies and by controlling the risk factors, in particular the lipid levels, so I think that's where your work is really important and insightful and I think will be incorporated in all of the respective guideline revisions. Dr. Carolyn Lam:               I completely agree and we're so proud to be publishing your excellent work in circulation. Thank you, Seth. Thank you, Anand.                                                 Thank you, listeners, for joining us today. Don't forget to tune again next week.  

This week is a fully frog podcast, dedicated to those frogs who dig. We touch on how the climate can induce fossorial adaptations and limit frog’s activity periods. Along with how some frogs manage to sustain populations despite their sedentary and subterranean lives. And look at perhaps the most bizarre looking frog ever to have graced the earth. To round off we have a newly described burrow-utilising frog for our Species of the Bi-week. FULL REFERENCE LIST AVAILABLE AT: herphighlights.podbean.com Main Paper References: Andreone, Franco, Paolo Eusebio Bergò, Vincenzo Mercurio, and Gonçalo M. Rosa. 2013. “Spatial Ecology of Scaphiophryne Gottlebei in the Canyons of the Isalo Massif, Madagascar.” Herpetologica 69 (1): 11–21.  Encarnación-Luévano, Alondra, Octavio R. Rojas-Soto, and J. Jesús Sigala-Rodríguez. 2013. “Activity Response to Climate Seasonality in Species with Fossorial Habits: A Niche Modeling Approach Using the Lowland Burrowing Treefrog (Smilisca Fodiens).” PLoS ONE 8 (11): 1–7. OPEN ACCESS Thomas, Ashish, Robin Suyesh, S. D. Biju, and Mark A. Bee. 2014. “Vocal Behavior of the Elusive Purple Frog of India (Nasikabatrachus Sahyadrensis), a Fossorial Species Endemic to the Western Ghats.” PLoS ONE 9 (2). OPEN ACCESS Species of the Bi-Week: Matsui, Masafumi, Kanto Nishikawa, and Koshiro Eto. 2014. “A New Burrow-Utilising Fanged Frog from Sarawak, East Malaysia (Anura: Dicroglossidae).” Raffles Bulletin of Zoology 62: 679–87. OPEN ACCESS Other Mentioned Papers/Studies: Andreone, Franco, Fabio Mattioli, and Vincenzo Mercurio. 2005a. “The Call of Scaphiophryne Gottlebei, a Microhylid Frog from the Isalo Massif, Southcentral Madagascar.” Current Herpetology 24 (1): 33–35. Andreone, Franco, V. Mercurio, F. Mattioli, and T. J. Razafindrabe. 2005b. “Good News for Three Critically Endangered and Traded Frogs from Madagascar.” FrogLog 72: 2–3. Biju, S. D., and Franky Bossuyt. 2003. "New frog family from India reveals an ancient biogeographical link with the Seychelles." Nature 425 (6959): 711-714. Boistel, Renaud, Thierry Aubin, Peter Cloetens, Françoise Peyrin, Thierry Scotti, Philippe Herzog, Justin Gerlach, Nicolas Pollet, and Jean-François Aubry. 2013. “How Minute Sooglossid Frogs Hear without a Middle Ear.” Proceedings of the National Academy of Sciences of the United States of America 110 (38): 15360–64. OPEN ACCESS Crottini, Angelica, Ylenia Chiari, Vincenzo Mercurio, Axel Meyer, Miguel Vences, and Franco Andreone. 2008. “Into the Canyons: The Phylogeography of the Malagasy Frogs Mantella Expectata and Scaphiophryne Gottlebei in the Arid Isalo Massif, and Its Significance for Conservation (Amphibia: Mantellidae and Microhylidae).” Organisms Diversity and Evolution 8 (5): 368–77. OPEN ACCESS Filippi, Piera, Jenna V. Congdon, John Hoang, Daniel L. Bowling, Stephan A. Reber, Andrius Pašukonis, Marisa Hoeschele et al. 2017. "Humans recognize emotional arousal in vocalizations across all classes of terrestrial vertebrates: evidence for acoustic universals." Proceeding of the Royal Society: Biological Sciences 284 (1859): 20170990 Iskandar, Djoko T., Ben J. Evans, and Jimmy A. McGuire. 2014. "A novel reproductive mode in frogs: a new species of fanged frog with internal fertilization and birth of tadpoles." PLoS One 9 (12): e115884. OPEN ACCESS IUCN SSC Amphibian Specialist Group. 2016. “Scaphiophryne Gottlebei, Malagasy Rainbow Frog.” The IUCN Red List of Threatened Species 2016: e.T57998A84182454. OPEN ACCESS Nomura, Fausto, Denise C. Rossa-Feres, and Francisco Langeani. 2009. “Burrowing Behavior of Dermatonotus Muelleri (Anura, Microhylidae) with Reference to the Origin of the Burrowing Behavior of Anura.” Journal of Ethology 27 (1): 195–201. Rosa, Gonçalo M., Vincenzo Mercurio, Angelica Crottini, and Franco Andreone. 2010. “Predation of the Snake Leioheterodon Modestus (Günther, 1863) upon the Rainbow Frog Scaphiophryne Gottlebei Busse & Böhme, 1992 at Isalo, Southern Madagascar.” Herpetology Notes 3 (1): 259–61. Wake, Marvalee H. 1978. "The reproductive biology of Eleutherodactylus jasperi (Amphibia, Anura, Leptodactylidae), with comments on the evolution of live-bearing systems." Journal of Herpetology: 121-133. Zachariah, Anil, Robin Kurian Abraham, Sandeep Das, K. C. Jayan, and Ronald Altig. 2012. "A detailed account of the reproductive strategy and developmental stages of Nasikabatrachus sahyadrensis (Anura: Nasikabatrachidae), the only extant member of an archaic frog lineage." Zootaxa 3510 (1): 53-64. Other Links/Mentions: Audio S1 from Thomas et al. 2014 - https://doi.org/10.1371/journal.pone.0084809.s001 Audio S2 from Thomas et al. 2014 - https://doi.org/10.1371/journal.pone.0084809.s002 Audio S3 from Thomas et al. 2014 - https://doi.org/10.1371/journal.pone.0084809.s003 Video S1 from Thomas et al. 2014 - http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0084809.s005&type=supplementary Audio S1 from Boistel et al. 2013 - http://www.pnas.org/content/suppl/2013/08/28/1302218110.DCSupplemental/ad01.wav Audio of Scaphiophryne gottlebei from The calls of the frogs of Madagascar by Miguel Vences, Frank Glaw and Rafael Márquez, recorded by Franco Andreone - http://www.fonozoo.com/fnz_detalles_registro_amphibia.php?id=93943&tipo_registro=1 BBC’s Life in Cold Blood, Amazing Rain Frogs - https://youtu.be/mISMwN-0ggE Music – http://www.purple-planet.com

  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. Our feature discussion today is about the validation of a novel biomarker-based stroke risk score for atrial fibrillation, the ABC stroke score. But first, here's your summary of this week's journal.     The first paper provides experimental insights into endothelial nitric oxide synthase uncoupling in endothelial dysfunction. In this paper by first author Dr. Lee, corresponding author Dr. Wong and colleagues from Qilu Hospital of Shandong University in China, authors assessed endothelial function in animal models of hyperglycemia, hyperhomocysteinemia, and a dyslipidemia. They demonstrated that GTP cyclohydrolase 1 is the target of the microRNA-133a and that it's a topic expression and endothelial cells mediates endothelial dysfunction.     Furthermore, Lovastatin up-regulated GTP cyclohydrolase 1 and tetrahydrobiopterin and re-coupled endothelial nitric oxide synthase in stress endothelial cells. These actions of Lovastatin were abolished by enforced micro RNA 133A expression and mirrored by a mir-133a-antagomir. Finally, the beneficial effect of Lovastatin in mice were abrogated by in vivo mir-133A over-expression or by GTP cyclohydrolase 1 knockdown. In summary, this paper offers a mechanistic basis for targeting micro RNA 133A as a therapeutic approach to correct endothelial nitric oxide synthase dysfunction. It also provides further support to the role of statins in combating endothelial dysfunction.     The next study shows us that in hypertrophic cardiomyopathy, calcium mishandling may be the potential link between the primary genetic cause and downstream signaling cascade that leads to hypertrophy and arrythmias. In this study, Dr. Helms and colleagues from University of Michigan analyzed gene expression, protein levels and functional essays for calcium regulatory pathways in 35 human hypertrophic cardiomyopathy surgical samples with and without sarcomere mutations and compared that with 8 control hearts. They found a marked reduction in circa2 abundance, which correlated with reduced circa2 function in hypertrophic cardiomyopathy compared to controlled hearts regardless of the underlying genetic etiology.     However, calcium calmodulin depend protein kinase type 2 or cam2, which is a calcium sensing kinase, was deferentially activated only in the sarcomere gene mutation positive samples. Activation of chem kinase 2 was associated with an increase in phospholamb and phosphorylation in hypertrophic cardiomyopathy. However, neither calcineurin MRNA nor MEF2 activity was increased, suggesting that calcineurin pathway activation was not an upstream cause of increased chem kinase 2 protein abundance or activation.     In summary, this paper demonstrated that calcium mishandling occurs through both genotype specific and common pathways in human hypertrophic cardiomyopathy. Post-translational activation of chem kinase 2 pathway is specific to sarcomere mutation positive hypertrophic cardiomyopathy. While Sarco 2 abundance and sarcoplasmic reticulum calcium uptake are depressed in both sarcomere positive and negative hypertrophic cardiomyopathy. Thus, chem kinase pathway inhibition may improve aberrant calcium cycling in hypertrophic cardiomyopathy. This is discussed further in an accompanying editorial by Dr. Jill Tardiff.     The third study suggests that in patients with a dilated aortic route and trileaflet aortic valve, a ratio of aortic route area to height provides independent and improved stratification for prediction of death. First author Dr. Masry, corresponding author Dr. Desai and colleagues from the Center for Aortic Disease, Heart and Vascular Institute of Cleveland Clinic, studied consecutive patients with a dilated aortic route of greater or equal to 4 centimeters who underwent echocardiography and gated contrast enhanced thoracic aortic computer tomography or magnetic resonance and geography between 2003 and 2007.     A ratio of aortic route area over height was calculated on tomography and a cutoff of 10 squared centimeters per meter of height was chosen as abnormal. In 771 patients with trileaflet aortic valve and concomitant aortopathy, there was incremental prognostic value for indexing aortic route or ascending aortic area to patient height rather than using an unindexed aortic diameter. Incorporation of the ratio significantly and independently reclassified the risk for death and at normal ratio was independently associated with higher long-term mortality while cardiovascular surgery was associated with improved survival. Importantly, a sizable minority of patients with aortic route diameters between 4.5 and 5.5 centimeters had an abnormal aortic route when indexed to height ratio. 78 percent of deaths in this subgroup occurred in those with an abnormal aortic route area to height ratio. Findings were similar when ascending aortic measurements were considered. The take home message is that an aortic route area to height ratio above 10 squared centimeters per meter of height has significant and independent prognostic utility and may be used to re-stratify patients with trileaflet aortic valve and a dilated aorta.     The final study provides pre-clinical data to show that Ticagrelor reduces cardio damage post myocardial infarction to a greater extent than Clopidogrel by an adenosine induced organ protective response. First author Dr. Villaher, corresponding author Dr. Bademan and colleagues from the Cardiovascular Research Center in Barcelona, Spain studied a close-chest swine model of ischemia reperfusion in which myocardial infarction was induced by 1 hour balloon occlusion of the mid-left anterior descending coronary artery followed by 24 hours of re-flow. Prior to occlusion, the animals were randomly assigned to receive either placebo, a loading does of Clopidogrel, a loading does of Ticagrelor or a loading does of Ticagrelor followed by an A1 A2 receptor antagonist. Edema infarc size left ventricular size and left ventricular function were assessed by three T cardiomagnetic resonance imaging. Inhibition of platelet aggregation was the same between the groups receiving a P2Y-12 inhibitor.     Yet, Ticagrelor reduced infarc size to a significantly greater extent than Clopidogrel, reducing it by a further 23.5 percent, an effect supported by troponin eye assessment and histopathological analysis. Furthermore, compared to Clopidogrel, Ticagrelor significantly diminished myocardial edema by 24.5 percent, which correlated with infarced mass. Administration of an adenosine A1 A2 antagonist abolished the cardio protective effects of Ticagrelor over Clopidogrel. At a molecular level, aquaporin 4 expression decreased and the expression and activation of AMP kinase cyclin and COX-2 increased in the ischemic myocardium of Ticagrelor versus Clopidogrel treated animals. In summary, this study shows that Ticagrelor exerts cardio protective effects beyond its anti-platelet efficacy by adenosine dependent mechanisms, which reduce necrotic injury and edema formation. This is discussed in an accompanying editorial by Drs. Gerbel, Jung and Tantry. That wraps it up for the summaries. Now for our feature discussion.     Today, we are going to be discussing the performance of the ABC score for stroke in atrial fibrillation. And as a reminder for all our listeners there, ABC stands for A for age, B for biomarkers, that's NT-proBNP and high-sensitivity troponin, and C for clinical history of prior stroke. And again as a reminder, this risk score was originally derived in the Aristotle trial. However, we have new results about its performance and validation today from first and corresponding author Dr. Jonas Oldgren from Uppsala Clinical Research Center in Sweden. Welcome, Jonas.   Speaker 2: Thank you very much.   Carolyn Lam: We also have today the associate editor who managed this paper, Dr. Sandeep Das from UT Southwestern. Hi Sandeep.   Speaker 3: Hi Carolyn, thanks for having me.   Carolyn Lam: So Jonas, could you start off by telling us why you did this study and what you found?   Speaker 2: We did this study to validate the recently derived ABC stroke risk score. We have had risk scores for predicting stroke in patients with atrial fibrillation derived since the late 1990's and refined later on. But those risk scores have only used clinical markers for risk. We have for several years developed new risk prediction models with biomarkers and now we are combine them in a very simple biomarker based risk score, taking into account age as a clinical variable and the clinical history of prior stroke and only two common used biomarkers. And by that we can predict the risk of stroke with better precision than previous clinical risk scores.   Carolyn Lam: Yeah, I like what you said. I mean it is literally as simple as ABC. So tell us how you validated it and what you found.   Speaker 2: It was derived in a large cohort of patients participating in a clinical trial with new or relapsed coagulant compared to Warfarin and we now validated in almost a full size group participating it another clinical trial. So we have large data sets of very well described patients where we have good outcome data. Very solid data to rely on. Now we can see that the ABC risk score is now validated but the good precision and good collaboration of the discriminatory abilities is high and better than the previously used clinical risk scores.   Carolyn Lam: Could you give us some numbers behind that that are clinically meaningful? Everyone's going to be wondering compared to the chads-vasc score for example, how does this ABC score perform in that validation test set?   Speaker 2: We can adjust that by several different aspects. One is of course to calculate the C index which is a statistical method to see how good we can predict risk and the C indices for the ABC stroke score both in the duration and now in the validation cohort is higher than for the chads-vasc and atrial risk scores. But we can also look at what we have in this paper in circulation ... we can look at predicted outcome rates and observed outcome rates and can see that they clearly overlap both in the duration and validation court. So if you predict a risk that is less than 1 percent per year, it is observed also a risk that is less than 1 percent a year. Does this always ... the thing is when you derive risk or but when you validate it in another cohort, you need to show that it's a similar result.   Carolyn Lam: Yeah, that's true. Sandeep, you are managing this paper. It's very important. How do you think that clinicians should be taking the results?   Speaker 3: I think that clearly using anticoagulation and selected patients at high risk for stroke with atrial fibrillation is one of the best things we do in cardiology. You know in terms of reducing the risk of an important harm to patients. I think there's a fair bit of dissatisfaction out there with currently sort of standard, which is chads-vasc. Especially in people with a chads-vasc ... men with a chads-vasc of 1 or women with a chads-vasc of 1 to 2 where there's a bit of struggling over how to decide. So I think that one real advantage of this score in addition to the fact that it predicts better by the higher C statistic, which is fantastic and pretty uncommon, right? Lars sort of buried the lead a little bit by not emphasizing that it's relatively rare that we're able to move a c statistic by a point of 5 in the modern era.     But the other thing is that it helps give us an ability to come up with good estimates in people at low risk, which I think has been a challenge and something that people are a little concerned clinically. So I think that this is easily available, biomarkers that we routinely check all the time and it doesn't have the sort of gender challenge with chads-vasc where you're trying to figure out whether your low risk woman really needs to be on Warfarin or anticoagulation. So I think that it has a lot of clinical utility right out of the box, which is nice.   Carolyn Lam: Actually, Jonas could you let us know is there any sex differences in the performance of the score?   [00:14:46] Speaker 2:   There are no differences in the performance of the score. So we looked ... the advantage of this score is when we derived it in the original model, we looked at all important clinical and biomarker risk factors and we can see that these were the foremost interesting markers. So we only used those. So we can predict much better and as pointed out so nicely by Sandeep, for patients at the lower end of the risk spectrum, we can find patients or have higher or lower risk even within patients with chads-vasc 1 or chads-vasc 2. And I think it's also important to see what about patients at higher risk despite proper anticoagulation. We did not know how to treat them but in the future we might perhaps tailor treatment also for those patients with residual high risk of stroke despite proper anticoagulation treatment. For instance, if the left atrial appendage occluded devices are shown in the future to be a good option for those patients, we can find them also by this risk score. So both in the higher and lower end of the risk spectrum.   Carolyn Lam: That's a really good point. On that note, I'm just curious. What do you think is in the future? What more knowledge do we need to address before we put this into practice or are you already using this? Or do you think it should enter guidelines for example? Maybe Sandeep, I could ask for your opinion first.   Speaker 3: We see a lot of biomarkers associated with increased risk kind of studies come out in the literature. You know probably every week you see several of these things come out. So what's really interesting about this is that it's obviously methodologically extremely well done but its been derived and validated in two large cohorts, which is pretty much best practice right? You want to see people validate these risk scores in large and distinct cohorts of patients to build up sort of clinical validity to the reader or consumer. So I think, from my standpoint, this is ready for prime time. I'm really intrigued by the fact that biomarkers, especially troponin, are predicting stroke in this population and there have been some observational reports out there that have showed an association between troponin and increased risk of stroke or worse outcomes after stroke. So I'd be really curious as to what Jonas thinks about why troponin would be predictive of stroke in this population.   Speaker 2: We were extremely intrigued by the finding when we first did those single observations of only troponin as a risk marker because we know that troponin is a very specific protein found in the myocardium. But the clinic predicts risk for stroke also and there are several explanations but they are mainly hypotheses about aging and myocardial function really to identify patients of risk. But the clear cut explanation is still not there.   Carolyn Lam: It's likely that these biomarkers are incorporating aspects that we don't fully understand, which is why they are better predictors isn't it? I mean to your point Sandeep.   Speaker 3: Yeah, no absolutely. And I think that's great.   Carolyn Lam: Exactly. It really opens a lot of other questions that need to be answered in the meantime. Jonas, any other last words about how you may be applying this clinically in your own patients?   Speaker 2: We have no solid data supporting the use of this clinical risk score and as already pointed out, which I think is very good, all clinic risk scores should of course be in the best world validated as useful decision support truth and really in clinics trial seeing that they improve outcomes. This is to my knowledge never been down with a clinical risk scores. We have never used them prospectively to guide treatment and to improve outcomes. Actually, we are aiming to do that. We hope to start a clinical trial next year with ABC score guided treatment compared to standard of care. But it's a very huge undertake of course to that we can improve treatment by risk or guided management.   Carolyn Lam: That's excellent. So remember everyone, you heard it right here. A new trial that they're engaging. I really congratulate you first for this study, as well as this future efforts which are clearly going to be very important.     Thank you very much both of you for joining us today and thank you listeners for listening. Don't forget to tune in next week.  

Sandeep Das (tabla) and Rajib Karmaker (sitar) perform music from India. Remarks by Anne Monius, Professor of South Asian Religions. Learn more about Harvard Divinity School and its mission to illuminate, engage, and serve at http://hds.harvard.edu/.

On this special edition podcast, join Yo-Yo and members of The Silk Road Ensemble as they explore a selection of compositions from their album “New Impossibilities.” On this episode, Yo-Yo and tabla virtuoso Sandeep Das discuss the track “Shristi.” RECOMMENDED: “New Impossibilities” Amazon.com | iTunes ADDITION INFORMATION: SilkRoadProject.org