Podcast appearances and mentions of amit khera

Roxana Mehran gets a preview from Keith Churchwell and Amit Khera.

Ron takes a look at honesty, lovable people, pandemic results, dogs, facebook, chicadas, knowing when to shut up, and other unrelated stuff.... Guest: Dr. Amit Khera of the Family Heart Foundation

JAMA Associate Editor Gregory Marcus, MD, a cardiologist and professor of medicine at the University of California San Francisco, speaks with American Heart Association Scientific Sessions 2023 conference chair Amit Khera, MD, MSc, a professor in the department of internal medicine at UT Southwestern Medical Center and the director of preventive cardiology. Related Content: Highlights From AHA 2023—New Risk Calculator, Semaglutide and CVD, and More

Roxana Mehran gets a sneak peak at AHA 2023 from Amit Khera.

On today's episode, financial journalist Govindraj Ethiraj talks to Amit Khera, Senior Partner at Consulting firm Mckinsey & co as well as Amit Prothi, Director General of The Coalition for Disaster Resilient Infrastructure (CDRI).SHOW NOTES[00:50] Empowerment, the new way of measuring economic security at $12 per person with Amit Khera[08:14] China's Missing Data & India's Too[12:31] Govt suspects exporters of selling non basmati rice as basmati rice, clamps down[16:57] A new global disaster resilience coalition sets up shop in India with Amit ProthiFor more of our coverage check out thecore.inSubscribe to our NewsletterFollow us on:Twitter | Instagram | Facebook | Linkedin | Youtube | Telegram

This week, please join authors Marc Sabatine and Prakriti Gaba, as well as Associate Editor Amit Khera, as they discuss the article "Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE." Dr Greg Hundley: Welcome listeners, to this April 18th issue of Circulation on the Run and I am Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Peder Myhre: And I'm Dr. Peder Myhre, Social Media Editor from Akershus University Hospital and University of Oslo. Dr Greg Hundley: Peder, today's feature discussion, very interesting. We're going to evaluate the association between what's achieved with LDL cholesterol lowering, and then also long-term cardiovascular and safety outcomes. But before we get to that, how about we grab a cup of coffee and discuss some of the other articles in the issue? Would you like to go first? Dr Peder Myhre: Yes, Greg. I would love to. And the first paper is from the World of Preclinical Science and it comes to us from corresponding author, Jan Magnus Aronsen from University of Oslo in Norway. And perhaps, as you know, Greg, cardiomyocyte contraction and relaxation depend on the activity of the sarcoplasmic reticulum CA+2 ATPase 2, abbreviated SERCA2, and lowered levels or reduced activity of SERCA2, as seen in chronic heart failure, weakens contractile force and delays relaxation and no available therapy involves direct manipulation of the SERCA2 activity. And Greg, phosphodiesterase 3A is proposed to be present in the SERCA2 interactome limit SERCA2 activity and disruption of phosphodiesterase 3A from SERCA2 might thus be a strategy to develop SERCA2 activators. And in this study, the authors investigated and mapped SERCA2 and phosphodiesterase 3A and assessed this in experiments assessing the binding between these two in cardiomyocytes and in vesicles. Dr Greg Hundley: Wow Peder, sounds very interesting. So what did they find and how about the clinical implications of the findings? Dr Peder Myhre: So Greg phosphodiesterase 3A bounded directly to SERCA2 in the cardiomyocyte. So that's the first finding. Second, they demonstrated that SERCA2 phosphodiesterase 3A disruption increased SERCA2 activity independently of the catalytic activity of phosphodiesterase 3A in both normal and failing cardiomyocytes. And third, SERCA2 activity by the optimized SERCA2 phosphodiesterase 3A disruptor peptide OPT F reduced mortality and improved contractility after aortic binding in mice. So the clinical implication is that direct targeting of phosphodiesterase 3A binding to SERCA2 could be a novel approach to increase SERCA2 activity and thus cardiac contractility in patients with heart failure. Dr Greg Hundley: Very nice Peder. What a great new finding in the world of preclinical science. Well my paper is going to delve into the world of clinical science and involves patients with stroke. So Peder in this study led by corresponding author, Dr. Dileep Yavagal from University of Miami Miller School of Medicine performed a survey in 75 countries through the Mission Thrombectomy 2020+ Global Network between November of 2020 and February of 2021 to determine the availability of mechanical thrombectomy for large vessel occlusion in patients with stroke. Now Peder, the primary endpoints were the current annual mechanical thrombectomy availability, the mechanical thrombectomy operator availability and the mechanical thrombectomy center availability. All of these availabilities were defined as the proportion of estimated large vessel occlusion for patients receiving mechanical thrombectomy in a given region annually. Dr Peder Myhre: Okay, Greg, so this is really an access question. So in essence, what is the availability of mechanical thrombectomy worldwide? So what did they find? Dr Greg Hundley: Right, great Peder. So what they found, the authors received 887 responses from 67 countries and low-income countries had 88% lower mechanical thrombectomy availability compared to high-income countries. The global mechanical thrombectomy operator availability was 16.5% of optimal, and the mechanical thrombectomy center availability was only 20.8% optimal. And with these results, the authors indicate that global cooperation and targeted region-specific public health interventions, including all stakeholders involved in stroke care delivery, are really needed to rapidly increase access to this brain-saving and disability-sparing treatment with mechanical thrombectomy really worldwide. Dr Peder Myhre: Oh wow. What a beautiful summary, Greg. Thank you so much. And we also have some other interesting papers in the mailbag today. We have an exchange of letters between Dr. Yang and Dr. O'Donoghue regarding the article “Long Term evolocumab in Patients with Established Atherosclerotic Cardiovascular Disease.” Dr Greg Hundley: Great Peder, and also Professor Perera has a Frontiers article entitled “Unloading the Left Ventricle in Venoarterial ECMO in Who, When and How?” and then finally there's a Research Letter from Professor Verma entitled “Prevalence of Diabetes and Cardiovascular Risk in the Middle East and Africa: The Primary results of the PACT-MEA Study.” Well Peder, how about we jump to that feature discussion? Dr Peder Myhre: Can't wait. Dr Greg Hundley: Welcome listeners to this feature discussion on April 18th and we have with us today Prakriti Gaba and Marc Sabatine from Brigham and Women's Hospital and our own associate editor, Dr. Amit Khera. Welcome everyone. Well Marc, we'll start with you. Can you describe for us some of the background information that really helps constitute the preparation of your study and what was the hypothesis that you wanted to address? Dr. Marc Sabatine: Yeah, thanks Greg and thanks for having us. So we've seen in a variety of epidemiologic cohorts the association between LDL cholesterol and the risk of adverse cardiovascular events like in Framingham Heart Study and UK Biobank. But in those cohorts, in these industrial societies, we don't have the benefit of lots of data in individuals with very low levels of LDL cholesterol and so we had the opportunity with the FOURIER study that was the randomized comparison of evolocumab PCSK9 inhibitor versus placebo to get patients down to extremely low levels of LDL cholesterol and evolocumab. We were able to get individuals down to about 30 mg/dL. And so in addition to all the studies we've done showing the comparison of evolocumab to placebo, we also then had the chance to use FOURIER, and as you'll hear from PK, FOURIER-OLE, the open-label extension, as a cohort to then examine patients' new baseline, if you will, their new achieved LDL cholesterol and then it's association not only with cardiovascular events but safety events. And so the hypothesis is that there would be a relationship with the lower the LDL cholesterol, the lower the risk of cardiovascular events and we wanted to explore how far down that went. And then the second one for safety would be that there wouldn't be any association between low levels of LDL cholesterol and a variety of safety outcomes that rightly or wrongly people have ascribed to low levels of LDL cholesterol. Dr Greg Hundley: Thanks so much, Marc. Well listeners, now we're going to turn to PK, the first author, on this very interesting paper and PK, Marc mentioned to us the FOURIER-OLE study. Maybe describe for us here your study design and then what specifically was your study population? Dr. Prakriti Gaba (PK): Yeah, definitely. Thanks so much for the introduction. So the study population included 27,564 patients with stable atherosclerotic cardiovascular disease and LDL cholesterol levels that were greater than or equal to 70 mg/dL or non-HDL cholesterol greater than or equal to a 100 mg/dL on statin therapy. The patients who then went on to the FOURIER-OLE or the open-label extension part of the trial consisted of about 6,635 patients. And so in this study we essentially evaluated the combination of those populations in 2 separate analyses. We then categorized patients according to 6 pre-specified bins based on their achieved LDL cholesterol levels at designated time points and those ranged from LDL levels of less than 20 mg/dL all the way up to 100 mg/dL. And then we looked at their baseline characteristics and evaluated the cardiovascular and safety outcomes that Dr. Sabatine mentioned earlier. Dr Greg Hundley: Very nice PK. Well we've got a great listening audience today and they're anxious to hear your study results, so can you share those with us please? Dr. Prakriti Gaba (PK): Definitely. So over the course of more than 77,000 patient years of follow-up, we found that there was a monotonic relationship between achieving lower LDL cholesterol levels down to very low levels of less than 20 mg/dL and a lower annualized risk of the primary efficacy endpoint, which was a composite of 5 individual endpoints. We also found that there was a similar relationship observed between lower LDL achieved, LDL cholesterol levels and a lower annualized risk of the secondary efficacy endpoint, and then when we looked at safety, there were actually no clear monotonic trends between lower achieved LDL levels and the risk of any of the 8 adverse events and these included things like serious adverse events, hemorrhagic stroke or muscle related events. Dr Greg Hundley: Very nice PK and I'm sure our listeners are wanting to know, did you find any discrepancy in your results based on either age or gender? Dr. Prakriti Gaba (PK): That's an excellent question, and we did look at age and gender throughout. I think across the board the results were pretty consistent, but additional subanalyses will further address this question. Dr Greg Hundley: Very good. Well listeners now we're going to turn to one of our associate editors, Dr. Amit Khera, who has helped move this article through the process of evaluation with the editorial team. Amit, you have many papers come across your desk, what attracted you to this paper and then how do we put this study's results really in the context of other studies that have sought to dramatically lower LDL cholesterol? Dr. Amit Khera: Well first thanks a lot Greg for allowing me to participate today. I want to congratulate Drs. Gaba and Sabatine on a fantastic paper and the minute I saw it, and you know can tell when you've done this for a while what's a great paper, and this one certainly is and we work closely with them to try to make it better and enhance the analyses and as a group, I think we achieved that. I was fortunate to write an accompanying editorial that you'll see. So I got to take a pretty deep dive in this paper and I want to just talk about sort of what's important here, why is this important, and I think as Dr. Gaba mentioned, there's two sides to this. There's the efficacy side where you talk about LDL lowering and getting to very low levels. Now mind you, they got to, what I call, ultra low levels, even explored for a down to a median of 7 mg/dL, so really, really low. And first I think what our listeners need to know when we look at guidelines, these numbers of 70 or 55, these are completely arbitrary and they're based on what was observed in clinical trials, what was achieved in high intensity versus moderate intensity statins in IMPROVE-IT. There's no biology behind that, and I think what this study does is reminds us there is no biology behind how low we need to go. This group previously published their shorter-term data approximately 2 years with this construct of lower is better and I think that's fine, but people worry, particularly on the safety side about extension, and we'll get to that in a minute, so where this fits is it gives us even more reassurance that lower is better, reminds us there's no biologic basis of that even down to very low levels. And so what does that mean? I think that comes back to guidelines. We have some discrepancy between European, ACC, Multisociety Guidelines that are around 55 and so from a guideline perspective, I think we'll see a little bit more enthusiasm about lower cut points or lower thresholds. And from a clinical standpoint, as a clinician it reminds me that when I see someone that's very high risk, there's no magic to achieving a number that if the risk is high, we need to be quite intensive and get their LDL down as low as possible and as safely as possible. I do want to also acknowledge, there's not, to your point about context, the IMPROVE-IT study also showed very low levels show additional efficacy and there's also a lot of other data, genetics and ecologic data supporting this. So this is... we look at Bayesian analysis that this is consistent that we're seeing across different platforms. I do want to talk about safety too, Greg. That's really important because honestly this is when it comes to patient level, the safety part of it. We as clinicians may have comfort with very low levels, but the safety is important. I also want to, just from a steady design, this is post-hoc, so those that achieve very low levels are different. You can see that in their table 1, but these investigators did lots of things. They did pretty extensive multi-variable analysis, they looked at time-dependent LDLs, they looked at it multiple different ways, but as mentioned, there really did not seem to be a safety signal. And this is where time matters. Safety in two years, interesting, but safety 5 to 8 years really offers us much more reassurance. So I think that's where this really comes in about that safety piece with the extended analysis. So again, I think from a guideline perspective, from a clinical perspective, there's so many implications from this paper and I really hope people take the time to take a deep dive and also put it in context, like you said, to the other literature where this is not standalone, but it's corroborating what we're seeing. Dr Greg Hundley: Very nice, amit. Marc, I want to come back to you, just two quick questions thinking about the preparation of your study. One, did you sample cognition? One thing we hear about frequently in dramatic lowering of LDL cholesterol are questions around cognition, particularly in the elderly? Dr. Marc Sabatine: Yeah, it's a great question Greg. So first of all, in the FOURIER study itself, there was an embedded study called EBBINGHAUS that Bob Giugliano from our group led that actually did formal neurocognitive testing in individuals using basically a iPad-like test. We also collected the usual neurocognitive adverse events as part of safety collecting. So 2 ways, the general asking about any adverse events and then the specific neurocognitive testing. We had previously reported out the results of EBBINGHAUS that there wasn't any relationship between evolocumab and the low LDL cholesterol and the risk of any neurocognitive AEs. We just were able to recently do this OLE analysis over time for the major adverse cardiovascular events and for the general safety events including cognition, so all that looked good. As PK indicated, we're now digging into the EBBINGHAUS formal neurocognitive testing, which was also extended out. So stay tuned for those results. Dr Greg Hundley: Very nice. And then eligibility, maybe just walk us through that really quickly. Patients that are going to be randomized to this form of therapy, were they already on high-dose statins? Who exactly did we randomize in this trial? Dr. Marc Sabatine: Yeah, so at the get-go, as PK indicated, these are patients with atherosclerotic cardiovascular disease, so they had a prior MI, prior stroke, symptomatic PAD. They were to be on an optimized lipid-lowering regimen, optimized statin therapy, so for close to 70%, that was a high-intensity statin. We had a small percentage on ezetimibe, but that's because we hadn't yet published the results of the IMPROVE-IT trial that Amit mentioned when we were enrolling in FOURIER, but it was a well-treated population on statin therapy. So these results would apply to your typical patient with ASCVD who's on a good statin regimen. Dr Greg Hundley: Very nice. Well, listeners now we're going to go back to both of our authors and investigators, as well as Dr. Khera. PK we'll start with you. What do you see as the next study to really be performed in this sphere of research? Dr. Prakriti Gaba (PK): I think that's an excellent question. I think with the data presented here now we know that the lower the LDL, the lower the risk of adverse cardiovascular events and that having a low LDL is safe in the long term. I think moving forward, as Dr. Khera mentioned, there needs to be a shift of these recommendations into the guidelines. So I think additional studies confirming these findings is what we need, but we do have the evidence available. Dr Greg Hundley: Very nice. And Marc? Dr. Marc Sabatine: Yeah, and I agree with PK of course. I think there's a couple things that we want to look at. We had looked in the parent FOURIER trial and found some groups who were higher risk, who seemed to have a bigger benefit early on, and those by and large were people who had a lot of athero. But as Amit indicated that the parent FOURIER trial was relatively short at about in two and a quarter years median follow up, and so now we have the benefit of an additional half decade of follow up in a subset of people and so now we're starting to look through and see the subgroups where we saw some differential benefit and this was a paper we published in circulation soon after we published the primary results of FOURIER. Now we have the ability to go through and look at those same subgroups and see what happens now with an additional 5 years. And so that'll be quite interesting, I think, to see how those groups play out now over time. I think as Amit indicated, time is critical. We know the benefit of lipid lowering really tends to grow with time. We saw that in FOURIER, we saw that in FOURIER-OLE and then as Amit indicated, I think for safety also it's now very reassuring, being able to go out to not two and a half years, but 5, 6, 7, 8 years of safety follow up. Dr Greg Hundley: Very nice. Well, listeners we're next going to turn to Dr. Khera. I'm going to put him on the spot a little bit. I don't know if many of you know he's a cardiologist with expertise in primary prevention. So here we've really focused today, I think, on a very unique set of results in secondary prevention. Amit, as you think about studies to be performed in the future, is there a role for really lowering LDL cholesterol as a primary prevention target? Dr. Amit Khera: The short answer is absolutely. I think, to be fair, you can't necessarily directly extrapolate these results 'cause it's a secondary prevention population, but I think if we step back for a second, is there any reason I think this wouldn't work in primary prevention, there's not, and I think there's tons of genetic data, tons of other long-term data that suggests that lower is better than primary prevention. I think the challenge, as you know, is just from primary prevention is it's just about the number that you need to treat and primary prevention is pretty profound in terms of to lower events. So this is where the trade-off comes. I think even in their study, we do have to appreciate while lower is better, when you have very low levels and you're going to even lower, let's say when you go from in secondary prevention from 50 to 40, as much as that sounds valuable, that delta's pretty small and then the absolute risk reduction is still going to be pretty small for those individuals and that's only magnified in primary prevention. So the short answer is I have no reason to believe that lower is better is not applicable in primary prevention, but I do know that the cost and what entails to get there, you don't get as much return on investment. I do want to say one last thing though. We're talking about lower is better, and I know these investigators know this well, but it's not only just how low but how long and I think that's where primary prevention about to go to clinic and I play the long game for primary prevention that we know we've magnified these benefits over the long term and even a little bit early in life can pay off long dividends. So that's how I look at it. Dr Greg Hundley: Very nice. Well, listeners we want to thank Dr. Prakriti Gaba, Dr. Marc Sabatine, both from Brigham and Women's Hospital and also our own associate editor, Dr. Amit Khera from University of Texas Southwestern Medical Center for bringing us this study involving patients with arteriosclerotic cardiovascular disease indicating that long-term achievement of lower LDL cholesterol levels down to values less than 20 mg/dL was associated with a lower risk of cardiovascular outcomes and not and not an increase in the risk of significant safety related events. Well, on behalf of Peder, 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 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.

Please join author Pieter Martens and Associate Editor Justin Grodin as they discuss the article "Decongestion With Acetazolamide in Acute Decompensated Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Prespecified Analysis From the ADVOR Trial." Dr. Greg Hundley: Welcome listeners to this January 17th issue of Circulation on the Run. And I am Dr. Greg Hundley, Director at the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Peder Myhre: And I'm Dr. Peder Myhre from Akershus University Hospital and University of Oslo, in Norway. And today, Greg, we have such an exciting feature paper. It comes to us from the ADVOR trialists. And the ADVOR trial examined the effect of acetazolamide in acute decompensated heart failure. And in this paper we're going to discuss how that treatment effect was across the left ventricular ejection fraction, across the spectrum. Greg, what do you think? Dr. Greg Hundley: Oh, wow. Sounds very interesting. But we might have some other articles in the issue. How about we grab a cup of coffee and Peder maybe this week, I'll go first and we'll start with preclinical science. How about that? Dr. Peder Myhre: Let's do preclinical science, Greg. Dr. Greg Hundley: Well, Peder, this particular paper focuses on the relationship between cardiac fibroblasts and cardiomyocytes. Remember that myocytes sit on a lattice of network of fibroblasts. And when the myocytes die, the fibroblasts then proliferates, secrete collagen and form this thick scar. Now, if we're going to try to regenerate, how are we going to get myocytes to get back into that thick scar when there's really a complete absence? And so as adult cardiomyocytes have little regenerative capacity, resident cardiac fibroblasts synthesize extracellular matrix, post myocardial infarction to form fibrosis, leading to cardiac dysfunction and heart failure. And therapies that can regenerate the myocardium and reverse fibrosis in the setting of a chronic myocardial infarction are lacking. Now, these investigators led by Professor Masaki Ieda from University of Tsukuba, were going to evaluate this process. The overexpression of cardiac transcription factors, including Mef2c, Gata4, Tbx5, Han2, all combined as MGTH. They can directly reprogram cardiac fibroblasts into induced cardiomyocytes and improve cardiac function in and under the setting of an acute myocardial infarction. However, the ability of an in vivo cardiac reprogramming to repair chronic myocardial infarction with established scars, well, that is really undetermined. Dr. Peder Myhre: Oh, what a wonderful introduction, Greg. And the way you described to us how cardiomyocytes and fibroblasts interact was really fascinating. Thank you. And now let's hear what the authors found and don't forget the clinical implications. Dr. Greg Hundley: Thanks, Peder. So these authors developed a novel transgenic mouse system where cardiac reprogramming and fibroblasts lineage tracing could be regulated spatiotemporally with tamoxifen treatment to analyze in vivo cardiac reprogramming in the setting of chronic MI. Then with this new model, the authors found in vivo cardiac reprogramming generates new induced cardiomyocytes from resident cardiac fibroblasts that improves cardiac function and reduces fibrosis in chronic myocardial infarction in mice. Wow. And additionally, they found that overexpression of cardiac reprogramming factors converts profibrotic cardio fibroblasts to a quiescent state, and that reverses fibrosis in chronic myocardial infarction. And therefore, Peder, direct cardiac reprogramming may be a promising therapy for chronic ischemic cardiomyopathies and heart failure. Really exciting work, converting scar tissue to actual functional cardiomyocytes. Dr. Peder Myhre: That was such a fantastic summary, Greg, and a very interesting paper. And I'm now going to take us back to clinical science and epidemiology. Because Greg, we all know that social and psychosocial factors are associated with cardiovascular disease risk. But the relative contributions of these factors to racial and ethnic differences in cardiovascular health has not been quantified. So these authors, led by the corresponding author, Nilay Shah from Northwestern University Feinberg School of Medicine in Chicago, used data from NHANES to examine the contributions of individual level social and psychosocial factors to racial and ethnic differences in population cardiovascular health. And that was measured by something called the cardiovascular health score, CVH score, which ranges from zero to 14, and it counts for diet, smoking, physical activity, body mass index, blood pressure, cholesterol, and blood glucose. Dr. Greg Hundley: Wow, really interesting, Peder. So what did they find here? Dr. Peder Myhre: So Greg, among males, the mean cardiovascular health score was 7.5 in Hispanic, 8.7 in non-Hispanic Asian, 7.5 in non-Hispanic black, and 7.6 in non-Hispanic white adults. And the authors found that the education explained the largest component of cardiovascular health differences among males. And now what about females? In females, the mean score was 8.0 in Hispanic, 9.3 in non-Hispanic Asian, 7.4 in non-Hispanic black, and 8.0 in non-Hispanic white adults. And for women, education explained the largest competence of cardiovascular health difference in non-Hispanic black. And place of birth, and that is US born versus born outside the US, explained the largest component of cardiovascular health difference in Hispanic and non-Hispanic Asian females. So Greg, the authors conclude that education and place of birth conferred the largest statistical contributions to the racial and ethnic differences in cardiovascular health among US adults. Dr. Greg Hundley: Very nice, Peder. What a beautiful description and outline that so well highlighting the differences in men versus women. Well, now we're going to turn back to the world of preclinical science, listeners. And we will continue with the paper by Dr. Amit Khera from Verve Therapeutics. Now, Peder, VERVE-101, this is an investigational in vivo CRISPR base editing medicine designed to alter a single DNA base in the PCSK9 gene. And that permanently turns off hepatic protein production and thereby, durably lowers LDL cholesterol. In this study, the investigators tested the efficacy, durability, tolerability, and potential for germline editing of VERVE-101 in studies of non-human primates and also in a murine F1 progeny study. Dr. Peder Myhre: So more on PCSK9s, and this time CRISPR technology. Very exciting. Greg, what did they find? Dr. Greg Hundley: Right, Peder. So VERVE-101 was well tolerated in non-human primates and led to, listen to this, an 83% lower blood PCSK9 protein and 69% lowering of LDL-C with durable effects up to 476 days following the dosing. These results have supported initiation of a first inhuman clinical trial. That's what needs to come next in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease. Wow. Dr. Peder Myhre: Even greater reductions from this therapy on PCSK9 than the previous PCSK9 inhibitor therapies. Wow. Okay, Greg, and now we go from one fascinating study to another. And this time we actually have the primary results from a large randomized clinical trial, Greg. Isn't that exciting? Dr. Greg Hundley: Yes. Dr. Peder Myhre: And this paper describes the primary results of a trial testing in Indobufen versus aspirin on top of clopidogrel in patients undergoing PCI with drug-eluting stent DES who did not have elevated troponin. So that is patients without mycardial infarction. And in fact, fact, this is the first large randomized control trial to explore the efficacy and safety of aspirin replacement on top of P2Y12 inhibitor in patients receiving PCI with death. And Greg, I suppose you like I wonder what Indobufen is, and I just learned that that is a reversible inhibitor of platelet Cox-1 activity and it has comparable biochemical and functional effects to dose of aspirin. And previous data indicate that Indobufen could lessen the unwanted side effects of aspirin and that includes allergy intolerance and most importantly, aspirin resistance, while it retains the antithrombotic efficacy. Dr. Greg Hundley: Wow, Peder. Really interesting and great explanation. Indobufen. So how did they design this trial and what were the primary results? Dr. Peder Myhre: So Greg, the investigators of this trial, called OPTION, led by corresponding authors, Drs. Ge, Quian, and Wu from Fudan University in Shanghai, randomized 4,551 patients from 103 center to either indobufen based DAPT or conventional, and that is aspirin based DAPT for 12 months after DES implementation. And the trial was open label and with a non-inferiority design, which is important to keep in mind. And the primary endpoint was a one year composite of cardiovascular death, non-fatal MI, ischemic stroke, definite or probable stent thrombosis or bleeding, defined as BARC criteria type 2, 3, or 5. And now Greg, the primary endpoint occurred in 101, that is 4.5% of patients in the indobufen based DAPT group compared to 140, that is 6.1% patients, in the conventional DAPT group. And that yields an absolute difference of 1.6%. And the P for non-inferiority was less than 0.01. And the hazard ratio was 0.73 with confidence intervals ranging from 0.56 to 0.94. And Greg, the occurrence of bleeding was particularly interesting and that was also lower in the indobufen based DAPT group compared to the conventional DAPT group. And that was 3.0% versus 4.0% with the hazard ratio of 0.63. And that was primarily driven by a decrease in BARC type two bleeding. So Greg, the authors conclude that in Chinese patients with negative cardiac troponin undergoing DES implementation, indobufen plus clopidogrel DAPT compared with aspirin plus clopidogrel DAPT significantly reduced the risk of one year net clinical outcomes, which was mainly driven by reduction in bleeding events without an increase in ischemic events. Dr. Greg Hundley: Very nice, Peder. So another reversible inhibitor of platelet COX-1 activity, indobufen. And seems to be very, have high utility in individuals of Chinese ethnicity and Asian race. Well, perhaps more to come on that particular drug. Peder, how about we dive into some of the other articles in the issue? And I'll go first. So first, there's a Frontiers article by Professor Beatty entitled “A New Era and Cardiac Rehabilitation Delivery: Research Gaps, Questions, Strategies and Priorities.” And then there's a Research Letter by Professor Zuurbier entitled, “SGLT-2 inhibitor, Empagliflozin, reduces Infarct Size Independent of SGLT-2.” Dr. Peder Myhre: And then Greg, we have a new ECG challenge by Drs. Haghighat, Goldschlager and Oesterle entitled, “AV Block or Something Else?” And then there is a Perspective piece by Dr. Patrick Lawler entitled, “Models for Evidence Generation During the COVID-19 Pandemic: New Opportunities for Clinical Trials in Cardiovascular Medicine.” And Greg, there's definitely so much to learn from all the research that has been done through the pandemic. And finally, we have our own Molly Robbins giving us Highlights from the Circulation Family of Journals. And first, there is a paper describing the characteristics of postoperative heart block in patients undergoing congenital heart surgery described in Circulation: Arrhythmia Electrophysiology. Next, the impact of socioeconomic disadvantages on heart failure outcomes reported in Circulation: Heart Failure. Then there is social and physical barriers to healthy food explored in circulation, cardiovascular quality and outcomes. And then there is the association of culprit-plaque morphology with varying degrees of infarct, myocardial injury size reported in Circulation: Cardiovascular Imaging. And finally, the impact of optical coherence tomography on PCI decisions reported in circulation cardiovascular interventions. Dr. Greg Hundley: Fantastic, Peder. Well, how about we get off to that feature discussion? Dr. Peder Myhre: Let's go. Dr. Mercedes Carnethon: Well, thank you and welcome to this episode of the Circulation on the Run Podcast. I'm really excited today to host this show. My name is Mercedes Carnethon. I'm an associate editor at Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine. I'm really excited to learn from the lead author of a new study on decongestion with Acetazolamide and acute decompensated heart failure across the spectrum of LV ejection fraction. And I've got the lead author with me today, Pieter Martens, as well as my colleague and associate editor Justin Grodin, who handled the paper. So I'd love to start off with just welcoming you, Dr. Martens. Dr. Pieter Martens: Thank you for having me. It's a pleasure to be here today. Dr. Mercedes Carnethon: Yes. And thank you so much for submitting your important work to the journal, Circulation. I'd love to start to hear a little bit about what was your rationale for carrying out this trial and tell us a little bit about what you found. Dr. Pieter Martens: So the ADVOR trial was a double blind placebo controlled randomized trial, which was performed in Belgium. And it set out to assess the effect of acetazolamide in acute decompensated heart failure and this on top of standardized loop diuretic therapy and patients with heart failure. And the goal of the current analysis was to assess whether the treatment effect of acetazolamide in acute heart failure differs amongst patients with a different ejection fraction at baseline at randomization. So we looked specifically at patients with heart failure, reduced, mildly reduced and preserved ejection fraction to determine whether acetazolamide works equally well in those patients. Dr. Mercedes Carnethon: Well, thank you so much. Tell me a little more. What did you find? Did your findings surprise you? Dr. Pieter Martens: All patients that were randomized in the ADVOR trial, we registered a baseline left ventricular ejection fraction at baseline. And what we saw was at the multiple endpoints that we collected in the ADVOR trial, that randomization towards acetazolamide was associated with a pronounced and preserved treatment effect. And different endpoints that we looked at was a primary endpoint which was successful, which is an important endpoint, which we all strive towards in acute decompensated heart failure. And we saw that irrespective of what your baseline ejection fraction was, that randomization towards acetazolamide was associated with a higher odds ratio for having successful decongestion. And also looking at other endpoints which we find important in the treatment of patients with acute compensated heart failure, such as renal endpoints such as the diuresis, the amount of urine that they make, or the natruresis, the amount of sodium that they excrete, we again saw that randomization towards acetazolamide was associated with a higher treatment effect, so more diuresis, more natruresis, which was not effective, whether you had heart failure, reduced, mildly reduced or preserved eject fraction. We did see a slight increase in the creatinine, which was a little bit more pronounced in patients with heart failure with reduced ejection fraction. Dr. Mercedes Carnethon: Thank you so much for that excellent summary. I'm an epidemiologist, so I'm certainly aware that of the cardiovascular diseases and their changes over time, heart failure is one that is going up over time and affecting more of the population. So I know I really enjoyed hearing about an additional therapy that helps to improve quality of life and improve clinical outcomes in individuals who are experiencing heart failure. And I'm really curious as I turn to you, Justin, what attracted you to this particular article and why did you find it to be such a good fit for our audience here at Circulation? Dr. Justin Grodin: Well, Mercedes, I mean, I think you hit the nail on the head with your comment. And clearly when we look at Medicare beneficiaries in the United States, hospitalization for decompensated heart failure is the number one or most common cause for hospitalization. And up to this time, we really haven't had any multi-center randomized control clinical trials that have really informed clinical care with a positive result or a novel strategy that says, "Hey, this might be a better way to treat someone in comparison with something else." And so when we have a clinical trial like ADVOR, one of the crucial things that we want to understand is how does this work and does it work for everybody? And now when we look at the population hospitalized with heart failure, we know that approximately half of them have a weak heart or low ejection fraction, and the other half have a stiff heart, a normal ejection fraction. And so since we've got this 50/50 makeup, it is a crucially important question to understand if we have an important study like ADVOR, does this apply? Are these benefits enjoyed by all these individuals across the spectrum? Dr. Mercedes Carnethon: Thank you so much for really putting that in context. And I believe you had some additional questions for Dr. Martens. Dr. Justin Grodin: Yes. Yeah, thank you. So Pieter, I mean obviously this was a terrific study. One question I had for you guys is, you and your colleagues and the ADVOR research team is whether you had expected these results. Because we know at least historically, that there might be different cardiorenal implications for individuals that have a weak heart or heart failure with reduced ejection fraction in comparison with a stiff heart or heart failure with preserved ejection fraction. Dr. Pieter Martens: Thank you for that comment. And thank you also for the nice feedback on the paper. I think we were not really completely surprised by the results. I think from a pathophysiologic perspective, we do wonder whether heart failure with reduced ejection fraction from a kind of renal perspective is different from heart failure with preserved ejection fraction. Clearly, there are a lot of pathophysiological differences between heart failure with reduced, mildly reduced and preserved ejection fraction. But when it comes to congestion and acute heart failure, they seem to behave, or at least similarly in terms of response to acetazolamide, which was very interesting. We do think there are neurohormonal differences between heart failure reduced ejection fraction, preserved ejection fraction. But at least how acetazolamide works seems relatively unaffected by the ejection fraction. Dr. Justin Grodin: And Pieter, another question that comes to mind, and this is getting a little bit technical, but there have been studies that have shown that people that present to the hospital with decompensated heart failure, that have HFpEF, have a very different perhaps congestion phenotype where they might not have as much blood volume expansion. And so I, for one, was pretty curious as to how these results were going to play out. And I wonder what your thoughts are on that, or maybe that's perhaps more niche and less widely applicable than what you observed. Dr. Pieter Martens: Now, I can completely agree that when we are thinking about congestion, the congestion itself is a sort of pressure based phenomenon. And the pressure based phenomenon is based on what your volume is and the compliance within your cardiovascular system. But I think one of the important things to remember is that how we enrolled patients in the ADVOR trial was that we enrolled patients who had clear signs of volume overload. Remember, we used a volume score to assess clinical decongestion or actually getting rid of the volume. Volume assessment isn't really necessarily a pressure based assessment. And pressures might be the genesis of elevated pressures might be different amongst heart failure with reduced versus preserved ejection fraction. But what was really clear was that all these patients were volume overloaded. And when you think about the volume axis, then it's really about getting rid of that additional sodium, water, and that's where really acetazolamide works. So I do think we differ a little bit from historical acute decompensated heart failure trials in which they sometimes use signs and symptoms of more congestion, a pressure based phenomenon, where our endpoint was truly at volume endpoint. And we do believe that diuretics work really on a volume component of heart failure. Dr. Mercedes Carnethon: Thank you so much, especially for explaining that in a way that even non-clinicians such as myself can understand the potential implications. A big picture question that I have, and I really enjoy these discussions because they give us an opportunity to speculate beyond what we read in the paper. And that question is we do clinical trials and we identify effective therapies. And one of the bigger challenges we often face is getting those therapies out to the people who need them. Do you perceive any barriers in uptake of the use of acetazolamide in clinical practice? Dr. Pieter Martens: That's an excellent question. So one of the, I think beauties about acetazolamide is that this drug has been on the market for about 70 years. So I think everybody has access to it. This is not a novel compound which needs to go through different steps of getting marketing approval and getting a sort of reimbursement before it becomes available in clinical practice. And in theory, everybody should have access to this relatively cheap agent and can use it in its clinical practice. And I think it was very interested when we came out with the initial paper. I think already the day afterwards, we were getting messages from across the world that people have been using acetazolamide. So I think it is an agent which is available in current clinical practice and should not be too many barriers to its current implementation and clinical practice. Dr. Mercedes Carnethon: Well, that's fantastic to hear. So I hope Justin, that you will certainly help to ring the bell to get the information out about this wonderful study. I do want to turn to you, Pieter, to find out whether or not there are any final points that you didn't have an opportunity to discuss with us today. Dr. Pieter Martens: Think some of the other end points we didn't discuss were the effect, for instance, on length of stay. I think length of stay is a very important endpoint because hospital admissions, like Justin said, heart failure is the number one reason why elderly patients are being admitted. And just shortening the length of stay from a financial perspective might be important. So it was also very interesting to see that the use of acetazolamide in the study also translated into a shorter length of stay, which was also was unaffected, whether you had heart failure, reduced, mildly reduced or preserved ejection fraction, Dr. Mercedes Carnethon: Well, I certainly know people appreciate being in their own homes and being able to discharge is certainly a major benefit. So thank you so much for sharing that final point. I really want to thank you so much for a stimulating discussion today. I know that I learned a lot from you, Pieter, and the hard work of your research team as well as from you, Justin, for putting these findings in context and really helping our listeners and the readers of our journal understand why this paper is so important and how it's really moving the field forward for a clinically important problem. So thank you both so much for joining us here today on Circulation on the Run. Dr. Justin Grodin: Thank you. Dr. Pieter Martens: Thank you for having me. Dr. Mercedes Carnethon: I really want to thank our listeners for joining us today for this episode of Circulation on the Run. I hope you will join us again next week for more exciting discussions with our authors. 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.

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O podcast Health Innovation dessa semana aborda a possibilidade de evitar doenças a partir do estudo genético de pacientes. Contudo, há questões éticas a serem estudadas. No episódio desta semana do Podcast Health Innovation, Laura Murta, Camila Pepe e Jonas Sertório discutem a descoberta do cardiologista Amit Khera. O médico encontrou uma maneira de testar o DNA e desvendar as chances de pacientes terem determinadas doenças. No entanto, essa tecnologia pode levar à classificação de pessoas por divisões genéticas ao nascer. Esse podcast é um oferecimento da Sociedade Beneficente Israelita Brasileira Albert Einstein.

In this week's edition of Circulation on the Run, Dr. Amit Khera introduces the new Social Media Editors to our Circulation listeners. Please welcome Dr. Vanessa Blumer, Dr. Pishoy Gouda, Dr. Xiaoming (Ming) Jia, Dr. Peder Langeland Myhre, and Dr. Sonia Shah to Circulation. Dr. Amit Khera: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Amit Khera, Associate Editor from UT Southwestern Medical Center in Dallas, and Digital Strategies' Editor for Circulation. And today I have the privilege of sitting in for your usual host, Dr. Carolyn Lam, and Dr. Greg Hundley. Well, two times a year, we really have a special issue, there's no print issue for Circulation in the summer and here in that holiday time. So, fortunately, we get to use this for really whatever we want to do. Dr. Amit Khera: And today we have a very special issue. A few months ago, we transitioned over from a prior social media editor team that was Jainy Savla Dan Ambinder, and Jeffrey Hsu. We were able to recruit a fantastic group of new social media editors. You probably have seen their work behind the scenes, but you've not gotten to meet them personally. So, today I have the privilege of introducing you to our new social media editors. This group of five, that's been working for several months and we get to know them a little bit. Get to hear a little bit about their perspective on social media from fellows in training, and also what they've learned so far in their few months in working with Circulation. So, I'm going to go one by one and introduce you. And first I want to introduce you to Dr. Vanessa Blumer. Vanessa, tell us a little bit about yourself. Dr. Vanessa Blumer: Thank you so much, Dr. Khera, it is such an honor to be here. And I've had so much fun the months that I've been working for Circulation, it's truly just a privilege to work alongside this talented group. So I'm Vanessa Blumer. I am originally from Caracas, Venezuela, born and raised there, did all of my medical training back home. That included medical school, a year of rural service, or rural medicine. Then I actually did residency training in Venezuela as well. It wasn't really in my plans straight away to come to the US, but a little bit due to the political situation that we all know that Venezuela's going or suffering, I decided to come to the US. Dr. Vanessa Blumer: I did residency in the University of Miami, Jackson Memorial hospital, which I loved. Stayed there for a chief year. And then after that came to Duke University to do cardiology fellowship. I'm currently a third year cardiology fellow at Duke, doing a year of research at the DCRI, which I am enjoying a lot, and will be doing heart failure next year. I will be going to Cleveland Clinic for a year of advanced heart failure. Dr. Amit Khera: Well, you've had quite a journey, Vanessa, and congratulations, I think your match was relatively recently. So, we're excited to see where your career takes you from here and appreciate your contribution so far. Now I'm going to introduce you to Pishoy Gouda. Pishoy Tell us a little bit about yourself.     Dr. Pishoy Gouda: Morning, Dr. Khera. My name is Pishoy. I have had the privilege of doing my medical trading all over the world. I was born here in Toronto and moved to Edmonton where I mostly grew up. Since then, I traveled to Galway Ireland where I spent six years to do my undergraduate medical training. Hopped over a short flight and did my Masters in Clinical Trials in the London School of Hygiene and Tropical Medicine before returning to Canada to start my residency training. Got to work with some amazing people in Calgary while I completed my internal medicine training, and then finally returned home to Edmonton where I am in the last few months of my adult cardiology training. Dr. Pishoy Gouda: Next year, I'm really excited to start my interventional cardiology training, which is going to be really exciting. Some of my interests, working with social media, wearable technology so working with this great group has been really awesome. Dr. Amit Khera: Thank you Pishoy. Obviously lots of travels from you as well, and we definitely appreciate your expertise and interest in social media and in technology. It's been very valuable. Next someone who's closer to my backyard. Ming Jia. Ming, welcome. Dr. Xiaoming (Ming) Jia: Hello from Houston, and thank you Dr. Khera. So, it's been a great opportunity to be involved as a social media editor for Circulation. So I'm a current cardiology fellow at Baylor College of medicine in Houston, Texas. Was originally born in China, and grew up in sunny Florida. I did my medical training in Florida as well, and then moved over to Houston, Texas for residency, and now wrapping up my last year in general fellowship. Next year, I'll be staying in Houston at Baylor for interventional fellowship. Then, hopefully after that career in interventional cardiology, but as well as preventional cardiology as well, I tended to actually interest in both interventional and preventional cardiology. Dr. Amit Khera: Very cool. I know you and I were talking about this right beforehand, how that nexus of the two fields and just some of your interest in a lot of the research you've done so far. So again, offering a unique and different perspective, which we appreciate so, welcome, Ming. Next, Peder Myhre. Peder, welcome. Dr. Peder Langeland Myhre: Thank you so much, Dr. Khera. This is Peder Myhre from Norway, all the way across the pond. And it's such a great honor to be part of this podcast, which I've been a big fan since it started a couple years ago and where Carolyn Lam has been doing with it, it's been really amazing. And I've actually been promoting it to everyone I know with any kind of interest in cardiology. My position in training right now is that I'm in the last year of cardiology training and I'm also doing a 50% post-doc at the University of Oslo with Professor Torbjørn Omland as a mentor. And as a part of my training, I was one year at Harvard University at Brigham Women's Hospital to do research with Professor Scott Solomon's group a couple of years ago. Dr. Amit Khera: Well, we appreciate your affinity and now you get to be on the podcast. That's pretty exciting as well. I should say, each of you is linked to an outstanding Associate Editor at your home institution. And so we're glad you have that mentorship as well there too. And speaking of someone at home institution, someone who I've known for a very long time, Dr. Sonia Shah. Sonya, introduce yourself, please.   Dr. Sonia Shah: Thank you, Dr. Khera. No, just to echo what everyone has said already, it truly has been an honor and a privilege to work with this awesome team. And it's been a lot of fun along the way. So I'm Sonia Shah. I'm a third year cardiology fellow at UT Southwestern in Dallas, Texas. Originally from Central Florida, actually. And then did my undergrad medical school training in Chicago and then went out to the West Coast for my residency training was out at Stanford and now I'm loving being in Dallas. So it's been a lot of fun. So I particularly have an interest in women's cardiovascular health and advanced imaging. And so currently looking for jobs now. Dr. Amit Khera: Well, I can say you've been a star fellow and have a really incredible and unique skillset. And, so we look forward to seeing what your career brings and certainly you've brought a lot to our podcast. And we'll talk more about that in just a bit, since you are longest standing social media editor currently. Well, I want to now dig in a little bit and you all again, I want to thank you for what you've done for the last several months. I certainly have learned a lot from you. We've had some discussions as a group about, thoughts about social media and how social media works. Dr. Amit Khera: And so maybe we'll start with the sort of existential question about, why social media? What is the value for journals, if you think about Circulation, but really any journal. What does social media bring? And again, you all have a unique perspective as largely fellows in training and Vanessa, maybe I'll go back to you a little bit about, why social media? What's the point of relevance about all this work that you're doing? Dr. Vanessa Blumer: Yeah. Thank you so much, Dr. Khera. I think that's a great question. And I do think that that's a question that we ask ourselves every day as we're doing this. I think the way that the medical literature has been evolving, it's been evolving in a way of social media and people are consuming more and more social media daily. I think in my own daily life, I discover articles that I'm interested in through social media a lot more than I used to before. And I also discover that I'm interested in particular articles, the way that they are transmitted in social media or the way that they're presented in social media. Dr. Vanessa Blumer: So I think we're reinventing ourselves and reinventing the way that we present to the public, the articles that we have in Circulation, so that people want to read our articles or want to read the articles that authors are doing such a great job at putting together. So I think, we are coming up with creative ideas every day and it's part of what we discuss as a group of how do we present this so that people want to read the articles and discover all the hard work that authors are putting together through different social media platforms. Because we know that people consume not just one social media platform, but several. So I think there's huge potential in social media if we use it in the right way. Dr. Amit Khera: Yeah. I think your points well taken. I know we're going to talk a lot about Twitter today, but as you pointed out, there are other media as well. That's just in the sort of main, I guess, currency and in the medical and cardiovascular literature. And you mentioned value to authors and one thing you mentioned, which I'll transition a little is about the way things are presented, help you get interested in them. And so that gets to the art of the tweet. Something we've talked about a little bit and, there's a little bit of on the job training, if you will. And we've talked about is there a gold standard in terms of what makes a good frankly, a medical journal tweet. Well, Ming, what do you think? You've been toiling over this for a few months now and tell us what you think is helpful in a medical journal tweet in terms of achieving the goals that Vanessa mentioned. Getting an audience interested in reading these articles is really doing justice for the authors to transmit their research. Dr. Xiaoming (Ming) Jia: Great question, Dr. Khera, and this is something that, as a social media editor, I'm still learning. So for me, writing a concise tweet is very important. Trying to get that essence of a entire study into a very limited number of characters. Obviously having a great figure that highlights the key findings of a study is also very important as well. Now at the same time, I think the most effective posts though, are those that serve as a hook for the paper. So, while we want are tweet to stand on their own. I think the most effective tweets helped to entice the audience to want to read a little bit more and go and read the entire manuscript. So certainly there is a art and skillset in terms of writing these effective posts. Dr. Amit Khera: Yeah. You certainly bring up some key points, right? So being concise, one by definition and but two is, there are tweets that sometimes can go on and on and that comes into using some interesting hashtags and some shortcuts. But I think your point about innuendo, enticing, not giving away the whole story, but just enough to get people to want to read more. And I think that that is an art. Dr. Amit Khera: And I've certainly seen as you all have done this more and more about how your own writing and tweets have evolved. Pishoy, we've talked a little bit about, all of you are researchers, you've all done some great research, about thinking about social media, sort of a research area. Again, since there's no gold standard about what's a great tweet, just thinking about it more of a discipline as we do any other area that we want to explore scientifically. What are your thoughts about, how do we figure out more, learn more about what makes a great tweet? Dr. Pishoy Gouda: Yeah. Evidence based tweeting is something that I've been interested in. Everything that we do, we want to make sure that we do it well and that we do it effectively and the same goes with social media posts. So what works, what raises interactions with our content. And that's something that other disciplines and advertising have been doing all the time and we should be doing the same as well. If our goal is to increase interactions with our content, then we want to make sure that we are doing it in the most evidence based way. And we've learned a few things. We know that cardiologists and individuals in medicine in general have been using Twitter much more frequently as a way to consume in both your medical and research content. Dr. Pishoy Gouda: So what makes a post great and what increases its interaction and the bottom line is we don't really know. We have a few studies and a few small randomized controlled trials that have been done that give us some insight. We know that vigor, that tweets that include images might pull readers to them a little bit more. But you know what exactly works. We have a lot of observational data, but we don't have a lot of high quality data that gives us the answer to this question. So what we've learned so far is use images, use links. If you can use graphical abstracts, that seems to help as well. But, it's something that we're continuously looking at and we're really excited to put together some new evidence coming up soon in the future. Dr. Amit Khera: Evidence based tweeting. I like it. As you and I have discussed, my predecessor Carolyn Fox had a randomized trail called Intention-to-Tweet using Circulation and then a follow-up study to that. So we hope to do also some good high quality research about social media and what works. Well, that gets to who's your audience, right? I always like to think about when you start something, who's your audience. And there could be lots of people. I think probably our strike zone is researchers, scientists, clinicians, of course, there's lots of lay individuals too, that are paying attention on social media. One thing that's different about Circulation than some other journals is this melding of basic science and clinical science. Some journals are all basic science and all clinical science and Circulation's both. Dr. Amit Khera: And I mean, frankly, that's posed an interesting challenge for this group. None of you are, including myself, are card carrying basic scientists, if you will. So we've had to translate those articles. And I would consider that both a challenge, but also an opportunity because, if we're speaking to a basic science audience, of course we may have one tone we use, but we want this basic science. I think that's the purpose of Circulation is basic science applicable to the clinician and clinical researchers. So, translating that's been a real opportunity. And Peta, maybe I can ask you about that opportunity of translating basic science for clinical researchers and clinicians. Dr. Peder Langeland Myhre: Yes. I completely agree. And I've learned so much from this job as a social media editor to really try to get the essence out of a basic science paper and the translational outlook for clinicians. Because all of the papers that are basic science that at least I came across in Circulation also have a clinical implication and a translational side of it. And I think when we read these papers and try to sum it up in one tweet, we want to keep the most important essentials of the basic science, but also extend it to clinicians so that they understand in what setting and what this can potentially mean in the future. So for me, that's the biggest challenge when we review basic science papers, but it's also perhaps the part of this job that I learn the most. Dr. Amit Khera: Yeah. I agree. I think we're all learning a lot. I've certainly learned a lot by delving in deeper into the basic science papers and figuring out how to translate them appropriately. And I think this really highlights, as you mentioned, what Dr. Hill our Editor in Chief, his feeling is basic science papers in Circulation all have to have important clinical implications. That's the benchmark, if you will. So I think we've seen that shew in terms of what papers have come across for you all. Dr. Amit Khera: Well, I'm looking now at our longest standing social media editor, Sonya Shaw, she started a few months before as sort of a transition because we certainly wanted someone in place that could help bridge between the old and the new. And Sonya, you've had a decent amount of experience now with two editorial teams. Tell us what you've learned so far by working as a social media editor at Circulation. What are some of the observations you've had and some of the things you've learned in this space? Dr. Sonia Shah: Yeah, certainly. So I think a couple things. I think my ability to accurately and concisely convey the important key points from each journal has definitely improved. But I think the other unique thing, unique perspective that we gain as social media editors is getting to actually see the behind the scenes workings of how the journal works and how papers are put together and accepted. And so I think it's been interesting to see how papers are being analyzed and the teamwork that's required by the Associate Editors and the Editors and making sure to do each paper justice and properly evaluate it. So I think that's been a really cool experience. It certainly has improved my ability to write when I try to think of, what are the key points I want to include. And how to convey information in a way that will be appealing to journals. Dr. Amit Khera: Well, thank you for that. We take this job very seriously, as you all have in that point about doing each paper justice, because you've seen, one, from the author's perspective about how much work they put in and you've been an author before and want to make sure that we appropriately appreciate that. And then also the Associate Editors, there are hours and hours of work for each paper. So even though it comes out, maybe in a few characters in a tweet, we appreciate all that's going behind it. And I'm glad you've gotten to see that process through. Ming, maybe I can come back to you. What have you learned so far by working in Circulation for the last few months? Dr. Xiaoming (Ming) Jia: I do want to echo what Sonya just said in terms of really getting a glimpse of the behind the scenes work is quite amazing. The amount of work and coordination it takes to get a paper from publication to promotion. And, we don't really get that exposure as a author for a manuscript or even as a peer reviewer. So, that part has definitely been a great learning experience. On the other side, I do find it interesting that ever since taking on this role as a social media editor, my way of writing has changed as well. So, trying to be more efficient, getting key points across and really being concise and focused in my manuscript writing. So that's been very helpful from a personal level as well. Dr. Amit Khera: We're very thankful for that. I think we always want this to be bidirectional where you all are contributing in meaningful ways. But that the goal here with fellows in training in this role, social media editors. But for you all to be learning something as well. So I'm glad that that has occurred. And we'll talk more about that in just a few minutes. Dr. Amit Khera: Well, we have a couple of international social media editors and this is my intention. We want to make sure we have a diverse group of social media editors. By background, by thought, by location. And, one way that the beauty of that is again, we get different perspectives. I guess the downside is time zones. We were just joking before, as we were starting this podcast about some of us are very early in the morning and one of our social media editors unfortunately is always late at night when we have our meetings. Peta, tell us a bit about unique observations from an international perspective. You said you've been following Circ for a while, but tell us, from your perspective in Europe, the social media process and how you see it. Dr. Peder Langeland Myhre: Thank you so much. And it's actually been a really transformation for me from before I spent my year in Boston to after. Because I really learned the potential of using social media and especially Twitter to stay updated and get the latest papers and thoughts from experts in the field. And I remember before I went there, I was often very frustrated that it was so inconvenient to get across important papers that was within my field of interest. Because all the journals were not longer sent in paper to our hospital and the websites were confusing. Dr. Peder Langeland Myhre: So when Dr. Vaduganathan at the Brigham & Women's Hospital introduced me to Twitter, that really was an eye opener for me. And, ever since that, 90% of the papers that I read I first see on Twitter. Because that's the first place, the people that are within my field, publish it or tweet it. And also I'm able to, you follow a certain amount of scientists and physicians and they have the same interest as you. So it's also, most of it is relevant for what I want to read. So it's really been a revolution for me to start to use Twitter and social media for medical and scientific purposes. And not only for friends and family. Dr. Amit Khera: Yeah. I think it's some great points. One, is even simplistically just be able to access articles, which we don't always appreciate, from people from around the world. And then obviously what many can, is follow people that have similar interests and amazing to see sort of how different people consume the literature. And for you Twitter being your entry point, I guess, for how you do that, which is I'm sure many, many people do the same. And we have another international editor you met earlier. Pishoy, tell us your perspective. And obviously you're in Canada now and have moved many places. What's your perspective from an international perspective, looking at social media? Dr. Pishoy Gouda: Coming to work at Circulation, I expected a very niche editorial board, but what I'm really finding out is boy, does it take a village. And it is people from all over the world. And it really hits home that collaboration and research has become a global phenomenon. And to be able to do art well and to appropriately represent researchers from across the world. We have an editorial board and team that is global and it really does take a village to take a paper from submission all the way through the publication team, starting from the authors to the peer reviewers, editors. But then the entire post-production team, which is behind the scenes and don't get a lot of glory, but they do a lot of the heavy lifting to make sure that, the research that's submitted gets in front of readers. And that's something that I hadn't really thought of before. And it's been really interesting to see how that process unfolds. So that's definitely been eye opening for me. Dr. Amit Khera: Well, I appreciate what you said about, when it takes a village and I would be remiss if I don't always call out Augie Rivera, who is the engine and mastermind behind Circulation, who's helping us do this podcast today and every week. But the other part is the international workings I think many may not appreciate. We have editorial board meetings every other week at very different time zones on purpose because we have people in Europe and in Asia and in Africa. And as you know, Dr. Lam who's the main podcast editor is in Singapore. Dr. Amit Khera: So, this is by intention. It really gives us a wonderful international perspective. And so we're so glad to have you two as part of our international team. Well, I think that's a great transition, a little bit to just talking about fellows in training and involvement in journals for Circulation perspective, and from the AHA, I should say, getting fellows in training involved in cardiovascular research, the editorial process, this is something that's really important to us and something we continually strive to find new ways to do. So, Vanessa, I'm going to come back to you. I know, not just at Circulation, but I know at other journals you've had some responsibilities. Tell us a little bit of what you tell other fellows in training about getting involved in journal activities. How to, and what's the benefit. Dr. Vanessa Blumer: Thank you so much Dr. Khera. I think this is such an important question. First my recommendation is, get involved in one way or another. I think there's different ways of getting involved as simple as just start reviewing articles. And the reason I say this is as I aspire to become an academic, a well-rounded academic cardiologist, I think my involvement with journals has just made me a much better researcher, a much better academic cardiologist. It's made me, I think, Sonya said this so well, it's made her a better author. It's made me a better writer. So I think it compliments what you do just so much better. I think you're better at what you do when you see the behind the scenes and you understand what happens in scholarly publishing. So I think there's different ways of getting involved. I know that Circulation has many and then probably a good way is to reach out. Dr. Vanessa Blumer: I know that people can reach out to us and we can probably guide them along the way, but different journals have different ways of getting involved. But I think if you want to start, one way is start reviewing. You learn a lot through the review process in itself on how an article is structured. And there's some journal that have a little bit more of a mentorship approach towards reviewing. And, that's also a good way starting out. When we start off as residents, we get some papers get in our inbox to review and we really don't necessarily know how to approach it. So maybe a mentorship approach to it is a good way to start. But overall, I would just say, start getting involved. I think it's a great experience. Personally, I have learned so much from it and I think I'm just a better academic cardiologist because of it. Dr. Amit Khera: Thank you for that. And I think your point about just find ways to get involved. And I think our challenge is to continue to facilitate ways for trainees, fellows in training and others to get involved. But I think that that first step in finding maybe a mentor of your institution that could help guide you would be important. And I'm going to finish with Sonya. I'm going to come back to you. You've not only had the social media editor window for quite some time. Being at Circulation, you get to see behind the curtain perhaps more than others because, Circulation is such a big part of what we do at UT Southwestern. And, we've had this Fellow Reviewer Program where you've been able to participate in reviews and things like that. From your perspective, maybe telling the fellows in training, listening out there about getting involved in journal activities, the value that you've seen and how to do so. Dr. Sonia Shah: Yeah, I think that's a really important question. At the end of the day, the ability to read and interpret and take away the major conclusions and properly interpret a study is a skill. And so I think the more you do it, certainly the better you get at it. And being part of a journal being on the reviewer end, being on the end where you're creating social media posts is really an opportunity to develop and refine that skill. And so to all the fellows out there who are interested, regardless of whether you want to do academic cardiology or not, it is an important skill, even in the future, to be able to read and properly interpret studies. So I highly recommend it. I find for me, I've definitely learned a lot through the process and have certainly improved. Dr. Amit Khera: Well, there you have it, our five social media editors. First, I want to thank you all for your contributions to Circulation. You're an incredibly bright group as everyone learned about. I have future leaders in cardiology. And we're very fortunate to have you contributing to Circulation and to our authors and readers. So thankful to have you as part of Circulation and look forward to working with you and innovating and coming up with some creative, new ways to think about social media and ways to transmit research for journal. Dr. Amit Khera: Well, I think there you have it. Again, I'm Amit Khera. I'm associate editor and standing in this week for Carolyn Lam and Greg Huntley, who will join you again next week. So thank you for joining us for Circulation on the Run. Dr. Greg Hundley: This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more visit ahajournals.org.

In this AHA 2021 episode of Parallax, Dr Ankur Kalra's guest is Dr Amit Khera, Professor and Director of Preventive Cardiology at UT Southwestern Medical Center, Dallas and Vice Chair of the Scientific Sessions. For this week's show, Dr Khera selected three thought-provoking late-breaking trials that will inform or change clinical practice. Ankur and Amit discuss how the AVATAR trial will influence guidelines, and whether these findings could be translated to TAVR. Most importantly, they discuss how AVATAR's results could inform patient decisions. Next, Dr Khera highlights a randomized trial that was designed to address the needs of a larger population. The China Rural Hypertension Control Project offers exciting insights and an innovative framework for relying on social healthcare work. Lastly, Dr Kalra and Dr Khera discuss a trial that investigated the LDL-cholesterol lowering efficacy of MK-0616. This oral PCSK9 Inhibitor may open the door for more patients in the future. What were the key findings? What are the take-home messages? How will these 3 trials foster new opportunities for patients? Trials covered in detail include: • Aortic Valve Replacement versus Watchful Waiting in Asymptomatic Severe Aortic Stenosis: The Avatar Trial • A Cluster Randomized Trial of a Village Doctor-Led Intervention on Blood Pressure Control: China Rural Hypertension Control Project • The Clinical Safety, Pharmacokinetics, and LDL-Cholesterol Lowering Efficacy of MK-0616, an Oral PCSK9 Inhibitor Questions and comments can be sent to “podcast@radcliffe-group.com” and may be answered by Ankur in the next episode. Guest @dramitkhera hosted by @AnkurKalraMD. Produced by @RadcliffeCARDIO. Brought to you by Edwards: www.edwardstavr.com

TCTMD's Shelley Wood hears highlights from the 2021 TCT and AHA meetings from Ajay Kirtane and Amit Khera.

Roxana Mehran discusses the different formats for cardiology conferences with Amit Khera and Pamela Morris.

Human genetics has the power to transform the future of drug development, disease treatment, and the overall approach to healthcare. In this episode, we discuss current and future applications of -omics to clinical trials, disease risk assessment, and precision medicine with Amit Khera, a cardiologist and associate director of the Precision Medicine Unit in the Center for Genomics Medicine at Massachusetts General Hospital. Khera pioneered the use of polygenic risk scores calculated from genome-wide associate studies as a way to quantify genetic risk. His research program uses genetic variation as a tool to uncover new biology and enable enhanced clinical care informed by inherited susceptibility.   DNA Unlocked is a special edition podcast series produced by The Scientist's Creative services Team. This series is brought to you by Amgen, which is a pioneer in the science of using living cells to make biologic medicines. They helped invent the processes and tools that built the global biotech industry, and have since reached millions of patients suffering from serious illnesses around the world with their medicines. Since the initial sequencing of the human genome almost twenty years ago, researchers have been enticed by an explosion of DNA data. These sequences hold the promise of understanding human biology, transforming drug research and development, and curing diseases. However, the quest to generate insights from human genetics and -omics research has been full of twists, turns, and roadblocks. In DNA UNLOCKED, Ray Deshaies, senior vice president of Global Research at Amgen, explores the ever-evolving perception of human biology and disease processes thanks to a growing mountain of genetics and omics data. Through discussions with colleagues and other leading research experts, Deshaies unpacks how drug developers decode human genetics to solve some of the most challenging diseases.

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

CardioNerds (Carine Hamo, Amit Goyal and Daniel Ambinder) discuss personalized risk assessment for cardiovascular prevention with Dr. Amit Khera, the immediate past president for the American Society for Preventive Cardiology and Director of the Preventive Cardiology and Professor of Medicine at the University of Texas, Southwestern Medical School in Dallas, Texas. They dive into an illuminating discussion about traditional and next generation personalization of risk assessment which covers the need for personalization, traditional risk stratification, applying risk enhancing factors for decision making, biomarkers, familial hypercholesterolemia, and the use of -Omics. This episode is the 13th and final part of our in-depth prevention series produced in collaboration with the American Society for Preventive Cardiology! Stay tuned for a bonus segment at the end of the episodeas we talk to Dr. Ankur Kalra, interventionist at the Cleveland Clinic, Podcast host of Parallax by Ankur Kalra, and founder of the non-profit startup, makeadent.org for a discussion about the CHAI (Cardiovascular Health in Asian Indians) Collaborative, an initiative that aims to identify genetic markers of heightened atherosclerosis in South Asians. Episode graphic by Dr. Carine Hamo CardioNerds Cardiovascular Prevention PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll Subscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Show notes Coming soon! Cardionerds Cardiovascular Prevention Series The Cardionerds CV prevention series  includes in-depth deep dives on so many prevention topics including the ABCs of prevention, approach to obesity, hypertension, diabetes mellitus and anti-diabetes agents, personalized risk and genetic risk assessments, hyperlipidemia, women’s cardiovascular prevention, coronary calcium scoring and so much more! We are truly honored to be producing the Cardionerds CVD Prevention Series in collaboration with the American Society for Preventive Cardiology! The ASPC is an incredible resource for learning, networking, and promoting the ideals of cardiovascular prevention! This series is kicked off by a message from Dr. Amit Khera, President of the American Society for Preventive Cardiology and President of the SouthWest Affiliate of the American Heart Association. Guest Profiles Amit Khera, MD, MSc, FACC, FAHA, FASPC Dr. Amit Khera is Professor of Medicine at the University of Texas, Southwestern Medical School in Dallas, Texas where he serves as Director of the Preventive Cardiology, and holder of the Dallas Heart Ball Chair in Hypertension and Heart Disease.  He is also currently President of the American Society for Preventive Cardiology and President of the SouthWest Affiliate of the American Heart Association. His clinical and research interests include the primary and secondary prevention of coronary artery disease, focusing on risk assessment and risk factor modification in those with premature and familial disease. Dr. Khera received his undergraduate degree in American History from the University of Pennsylvania, with magna cum laude honors. He obtained his medical degree from Baylor College of Medicine where he served as class president and was inducted into the Alpha Omega Alpha honor medical society. He completed an Internal Medicine Residency at Brigham and Women’s Hospital, Harvard Medical School, followed by a Cardiology Fellowship at the University of Texas, Southwestern Medical Center. He also completed his Masters degree in Epidemiology at the Harvard School of Public Health. He has published over 150 publications in the field of preventive cardiology and has served on numerous local and national committee and leadership roles for the American Heart Association, American College of Cardiology, and American Society for Preventive Cardiology.

CardioNerds (Amit Goyal and Daniel Ambinder) are joined by Cleveland Clinic cardiology fellow Dr. Gregory Ogunnowo to discuss hypertension with Dr. Luke Laffin, cardiology faculty in the division of Preventive Cardiology and Rehabilitation and Medical Director of Cardiac Rehabilitation at the Cleveland Clinic. Part 2 of this discussion covers the evaluation for secondary causes of HTN, approach to resistant HTN, interventional anti-hypertensive procedures, and a note on cardiac rehabilitation. Part 1 covered the definition of hypertension, correct measurement of blood pressure, nonpharmacologic HTN management, initial choice of BP agents, and hypertensive disorders of pregnancy. Episode graphic by Dr. Carine Hamo CardioNerds Cardiovascular Prevention PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll Subscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Show notes Coming soon! Cardionerds Cardiovascular Prevention Series The Cardionerds CV prevention series  includes in-depth deep dives on so many prevention topics including the ABCs of prevention, approach to obesity, hypertension, diabetes mellitus and anti-diabetes agents, personalized risk and genetic risk assessments, hyperlipidemia, women’s cardiovascular prevention, coronary calcium scoring and so much more! We are truly honored to be producing the Cardionerds CVD Prevention Series in collaboration with the American Society for Preventive Cardiology! The ASPC is an incredible resource for learning, networking, and promoting the ideals of cardiovascular prevention! This series is kicked off by a message from Dr. Amit Khera, President of the American Society for Preventive Cardiology and President of the SouthWest Affiliate of the American Heart Association. Guest Profiles Dr. Luke Laffin, serves as cardiology faculty in the division of Preventive Cardiology and Medical Director of Cardiac Rehabilitation at the Cleveland Clinic. Dr. Laffin attended medical school at Vanderbilt University School of Medicine. He trained in internal medicine and cardiology at the University of Chicago where he completed a dedicated fellowship in hypertensive diseases. He is a clinical specialist in hypertension designated by the American Society of Hypertension – which has now merged with the AHA. Dr. Gregory Ogunnowo is a cardiology fellow at the Cleveland Clinic. He completed medical school at the University of South Carolina School of Medicine in Columbia, South Carolina. He went on to complete internal medicine residency at Washington University School of Medicine in St. Louis where he stayed on as faculty in the Department of Hospital Medicine for a year prior to pursing fellowship. His interests include outcomes research in interventional cardiology and medical education In his spare time, Greg enjoys traveling, exercising, and experiencing new cultures through their food. When he’s not in the hospital, you can find Greg planning a trip with close friends and family. References and Links Coming soon! Luke Laffin MDGreg Ogunnowo, MDAmit Goyal, MDDaniel Ambinder, MD

CardioNerds (Amit Goyal and Daniel Ambinder) are joined by Cleveland Clinic cardiology fellow Dr. Gregory Ogunnowo to discuss hypertension with Dr. Luke Laffin, cardiology faculty in the division of Preventive Cardiology and Rehabilitation and Medical Director of Cardiac Rehabilitation at the Cleveland Clinic. Part 1 of this discussion covers the definition of hypertension, correct measurement of blood pressure, nonpharmacologic HTN management, initial choice of BP agents, and hypertensive disorders of pregnancy. Be sure to follow-up with Part 2 to learn about evaluation for secondary causes of HTN, approach to resistant HTN, interventional anti-hypertensive procedures, and a note on cardiac rehabilitation. Episode Graphic by Dr. Carine Hamo CardioNerds Cardiovascular Prevention PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll Subscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Show notes Coming soon! Cardionerds Cardiovascular Prevention Series The Cardionerds CV prevention series  includes in-depth deep dives on so many prevention topics including the ABCs of prevention, approach to obesity, hypertension, diabetes mellitus and anti-diabetes agents, personalized risk and genetic risk assessments, hyperlipidemia, women’s cardiovascular prevention, coronary calcium scoring and so much more! We are truly honored to be producing the Cardionerds CVD Prevention Series in collaboration with the American Society for Preventive Cardiology! The ASPC is an incredible resource for learning, networking, and promoting the ideals of cardiovascular prevention! This series is kicked off by a message from Dr. Amit Khera, President of the American Society for Preventive Cardiology and President of the SouthWest Affiliate of the American Heart Association. Guest Profiles Dr. Luke Laffin, serves as cardiology faculty in the division of Preventive Cardiology and Medical Director of Cardiac Rehabilitation at the Cleveland Clinic. Dr. Laffin attended medical school at Vanderbilt University School of Medicine. He trained in internal medicine and cardiology at the University of Chicago where he completed a dedicated fellowship in hypertensive diseases. He is a clinical specialist in hypertension designated by the American Society of Hypertension – which has now merged with the AHA. Dr. Gregory Ogunnowo is a cardiology fellow at the Cleveland Clinic. He completed medical school at the University of South Carolina School of Medicine in Columbia, South Carolina. He went on to complete internal medicine residency at Washington University School of Medicine in St. Louis where he stayed on as faculty in the Department of Hospital Medicine for a year prior to pursing fellowship. His interests include outcomes research in interventional cardiology and medical education In his spare time, Greg enjoys traveling, exercising, and experiencing new cultures through their food. When he’s not in the hospital, you can find Greg planning a trip with close friends and family. References and Links Coming soon! Luke Laffin MDGreg Ogunnowo, MDAmit Goyal, MDDaniel Ambinder, MD

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.

CardioNerds (Carine Hamo, Amit Goyal, and Daniel Ambinder) discuss the obesity epidemic and how it relates to the cardiovascular system with Dr. Chiadi Ndumele, cardiologist and epidemiologist at The Johns Hopkins Hospital and chairs the obesity subcommittee of the American Heart Association (AHA). They cover obesity definitions, epidemiology, strengths and limitations of different biometrics, including BMI, impact on myocardial structure and function, and current pharmacologic & surgical options for weight loss. They also discuss the practical approach to addressing obesity with patients. This episode was produced by Dr. Carine Hamo. Show notes & references by Dr. Daniel Ambinder. Episode graphic by Dr. Carine Hamo Cardionerds Cardiovascular Prevention PageCardioNerds Episode PageSubscribe to our newsletter- The HeartbeatSupport our educational mission by becoming a Patron! Show notes Coming soon! Cardionerds Cardiovascular Prevention Series The Cardionerds CV prevention series  includes in-depth deep dives on so many prevention topics including the ABCs of prevention, approach to obesity, hypertension, diabetes mellitus and anti-diabetes agents, personalized risk and genetic risk assessments, hyperlipidemia, women’s cardiovascular prevention, coronary calcium scoring and so much more! We are truly honored to be producing the Cardionerds CVD Prevention Series in collaboration with the American Society for Preventive Cardiology! The ASPC is an incredible resource for learning, networking, and promoting the ideals of cardiovascular prevention! This series is kicked off by a message from Dr. Amit Khera, President of the American Society for Preventive Cardiology and President of the SouthWest Affiliate of the American Heart Association. Guest Profiles Dr. Chiadi Ndumele is an Assistant Professor in the Department of Medicine at Johns Hopkins University. Dr. Ndumele graduated from Harvard University School of Medicine. He completed his Internal Medicine training at Brigham and Women’s Hospital, where he also served as Chief Medical Resident. He was Chief Cardiology Fellow at Johns Hopkins University. During fellowship training, Dr. Ndumele received an MHS and Ph.D. in Epidemiology at Johns Hopkins Bloomberg School of Public Health. Dr. Ndumele’s research has been supported by career development awards from the NHLBI and Robert Wood Johnson Foundation, a Catalyst Award from Johns Hopkins, an R01 from the NHLBI and an AHA Strategically Focused Research Network Grant. He has received national recognition for his work, including a Young Physician-Scientist Award from the American Society of Clinical Investigation. He has national leadership roles including Chair of the Obesity Subcommittee of the American Heart Association (AHA) and Editorial Board membership on the journals Circulation and Circulation Research. Dr. Ndumele’s research focuses on mechanisms linking adiposity to CVD and strategies to improve prediction and prevention. References and Links Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: A report of the American College of cardiology/American Heart Association task force on practice guidelines and the obesity society. Circulation. 2014;129(25 SUPPL. 1):102-138. doi:10.1161/01.cir.0000437739.71477.ee Yu Z, Grams ME, Ndumele CE, et al. Association Between Midlife Obesity and Kidney Function Trajectories: The Atherosclerosis Risk in Communities (ARIC) Study. Am J Kidney Dis. September 2020. doi:10.1053/j.ajkd.2020.07.025 Kaze AD, Musani SK, Bidulescu A, et al. Plasma Adipokines and Glycemic Progression Among African Americans: Findings from the Jackson Heart Study. Diabet Med. November 2020. doi:10.1111/dme.14465 Cohen LP, Vittinghoff E, Pletcher MJ, et al. Association of Midlife Cardiovascular Risk Factors with Risk of Heart Failure Subtypes Later in Life. J Card Fail. November 2020.

Recombinant DNA. The double helix. Mapping the human genome. You know these are all related to our genes, but you might now know how, or what connects them. In this episode of Trailblazers, we answer those questions while exploring the world of genomics. Gain a deeper understanding of our genetic code and how that knowledge is changing how we think about our health with experts like Hallam Stevens, Glenn Cohen, Rick Myers, Eric Green, Amit Khera and Jennifer Doudna. For more on the podcast go to delltechnologies.com/trailblazers

CardioNerds (Amit Goyal & Carine Hamo) discuss the past, present, and future of Women's Heart Health & Women in Cardiology with Dr. Nanette Wenger, Professor of Medicine in the Division of Cardiology at the Emory University School of Medicine. Dr. Wenger is a true leader in the field of women’s heart health and a strong proponent for women in cardiology and medicine. Her passion, dedication, and advocacy have inspired countless trainees to carry this torch and continue to build on her truly impactful work. Special introduction by Dr. Martha Gulati and birthday wishes to Dr. Wenger by the entire CardioNerds Team! Special thanks to Dr. Kimberly Manning for her invaluable mentorship. Episode graphic by Dr. Carine Hamo The Cardionerds CV prevention series  includes in-depth deep dives on so many prevention topics including the ABCs of prevention, approach to obesity, hypertension, diabetes mellitus and anti-diabetes agents, personalized risk and genetic risk assessments, hyperlipidemia, women’s cardiovascular prevention, coronary calcium scoring and so much more! CardioNerds Episode PageCardioNerds Prevention PageCardioNerds Women's Cardiovascular Health PageCardioNerds Academy - Apply now! Subscribe to our newsletter- The HeartbeatSupport our educational mission by becoming a Patron! We are truly honored to be producing the Cardionerds CVD Prevention Series in collaboration with the American Society for Preventive Cardiology! The ASPC is an incredible resource for learning, networking, and promoting the ideals of cardiovascular prevention! This series is kicked off by a message from Dr. Amit Khera, President of the American Society for Preventive Cardiology and President of the SouthWest Affiliate of the American Heart Association. Cardionerds Cardiovascular Prevention Series References and Links 1. Wenger NK (2005) Women in cardiology: The US experience. Heart. 2. Douglas PS, Rzeszut AK, Noel Bairey Merz C, Duvernoy CS, Lewis SJ, Walsh MN, Gillam L (2018) Career preferences and perceptions of cardiology among us internal medicine trainees factors influencing cardiology career choice. JAMA Cardiol. 3. Wenger NK, Speroff L, Packard B (1993) Cardiovascular Health and Disease in Women. N Engl J Med. 4. Burgess S, Shaw E, Zaman S (2019) Women in Cardiology. Circulation. Meet Dr. Wenger! Dr. Nanette Wenger is Professor of Medicine in the Division of Cardiology at the Emory University School of Medicine. Dr. Wenger received her medical degree from Harvard Medical School in 1954 as one of their first female graduates followed by training at Mount Sinai Hospital where she was the first female to be chief resident in the cardiology department. She is among the first physicians to focus on heart disease in women with an expertise in cardiac rehabilitation and geriatric medicine. Dr. Wenger has received numerous awards including the Distinguished Achievement Award from the Scientific Councils of the American Heart Association and its Women in Cardiology Mentoring Award, the James D. Bruce Memorial Award of the American College of Physicians for distinguished contributions in preventive medicine, the Gold Heart Award, the highest award of the American Heart Association, a Lifetime Achievement Award in 2009 and the Inaugural Bernadine Healy Leadership in Women’s CV Disease Distinguished Award, American College of Cardiology. She chaired the U.S. National Heart, Lung, and Blood Institute Conference on Cardiovascular Health and Disease in Women, is a Past President of the Society of Geriatric Cardiology and is past Chair, Board of Directors of the Society for Women’s Health Research. Dr. Wenger serves on the editorial boards of numerous professional journals and is a sought-after lecturer for issues related to heart disease in women, heart disease in the elderly, cardiac rehabilitation, coronary prevention, and contemporary cardiac care. She is listed in Best Doctors in America. Carine Hamo,

The CardioNerds discuss Coronary Artery Calcium Scoring with Dr. Michael Blaha, Director of Clinical Research for the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease. Joining the discussion is Dr. Gabriel Shaya, cardiology fellow at the Johns Hopkins Hospital and prevention researcher. Carine, Heather and Dan take a deep dive into the crunchy and calcified world of coronary artery disease discussing the evidence and utility of coronary artery calcium scoring as a powerful tool for individualized risk stratification of cardiovascular disease prevention. Episode graphic by Dr. Carine Hamo The Cardionerds CV prevention series  includes in-depth deep dives on so many prevention topics including the ABCs of prevention, approach to obesity, hypertension, diabetes mellitus and anti-diabetes agents, personalized risk and genetic risk assessments, hyperlipidemia, women’s cardiovascular prevention, coronary calcium scoring and so much more! Take me to the Cardionerds Cardiovascular Prevention PageTake me to episode topics page We are truly honored to be producing the Cardionerds CVD Prevention Series in collaboration with the American Society for Preventive Cardiology! The ASPC is an incredible resource for learning, networking, and promoting the ideals of cardiovascular prevention! This series is kicked off by a message from Dr. Amit Khera, President of the American Society for Preventive Cardiology and President of the SouthWest Affiliate of the American Heart Association. Cardionerds Cardiovascular Prevention Series References and Links https://www.mesa-nhlbi.org/CAC-Tools.aspxBlaha MJ, Blankstein R, Nasir K. Coronary Artery Calcium Scores of Zero and Establishing the Concept of Negative Risk Factors. J Am Coll Cardiol. 2019;74(1):12-14. Peng AW, Mirbolouk M, Orimoloye OA, et al. Long-Term All-Cause and Cause-Specific Mortality in Asymptomatic Patients With CAC ≥1,000: Results From the CAC Consortium. JACC Cardiovasc Imaging. 2020;13(1 Pt 1):83-93. Shaya GE, Al-Mallah MH, Hung RK, et al. High Exercise Capacity Attenuates the Risk of Early Mortality After a First Myocardial Infarction: The Henry Ford Exercise Testing (FIT) Project. Mayo Clin Proc. 2016;91(2):129-139. Dr. Michael Blaha is an Associate Professor of Cardiology and Epidemiology and presently serves as the Director of Clinical Research for the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease. Dr. Blaha completed both his MD and MPH and Vanderbilt University. He then completed his Internal Medicine residency in the Osler Medical Housestaff Training Program at Johns Hopkins where he also completed fellowship training. He is an Associate Editor for the Journal of Cardiovascular Computed Tomography, Associate Editor for the Diabetes and Cardiometabolic Clinical Community on acc.org and is a standing member of the Endocrinologic and Metabolic Drug Advisory Committee (EMDAC) for the FDA. He is Principal Investigator for the Coronary Artery Calcium Consortium, co-chair of the Cross-Cohort Collaboration, and a Principle Investigator for the American Heart Association (AHA) Tobacco Regulation and Addiction Center. Dr. Gabriel Shaya earned both his Medical Degree and Masters of Public Health at the University of Miami Miller School of Medicine. He went on to complete his residency in Internal Medicine at the New York Presbyterian – Weill Cornell Medical Center. He has returned to his hometown of Baltimore for Cardiology fellowship with the intent of pursuing a career as an academic cardiologist. His clinical and research interests center on the refinement of cardiovascular risk assessment with the goal of tailoring preventive therapies to avert adverse cardiovascular events before they happen. Michael Joseph Blaha, M.D., M.P.H.Gabe Shaya, MD, MPHCarine Hamo, MDHeather Kagan, MDDaniel Ambinder, MD

The CardioNerds discuss Lipid Management with Dr. Ann Marie Navar and Dr. Nishant Shah from Duke Medical Center, Division of Cardiology. Amit, Carine and Dan take a deep dive into the greasy world of lipids and cholesterol, covering lipid metabolism, therapeutic targets, approach across the entire spectrum of predicted risk, and key common management scenarios (statin intolerance, hypertriglyceridemia, elevated LP(a)), and more. Episode 42. Lipids and Cholesterol with Drs. Drs. Ann Marie Navar and Nishant Shah Take me to the Cardionerds Cardiovascular Prevention PageTake me to episode topics page The Cardionerds CV prevention series will include in-depth deep dives on so many topics related to prevention starting with this case discussion. Stay tuned for upcoming episodes on the ABCs of prevention, obesity, hypertension, diabetes mellitus and anti-diabetes agents, personalized risk and genetic risk assessments, hyperlipidemia, women’s cardiovascular prevention, coronary calcium scoring and so much more! Key references: Toth, P. P. (2020). Familial Hypercholesterolemia and Lipoprotein(a): Unraveling the Knot That Binds Them. Journal of the American College of Cardiology, 75(21), 2694–2697.Michos, E. D., McEvoy, J. W., & Blumenthal, R. S. (2019). Lipid management for the prevention of atherosclerotic cardiovascular disease. New England Journal of Medicine, 381(16), 1557–1567. AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology, 73(24), e285–e350.Lloyd-Jones, D. M., Braun, L. T., Ndumele, C. E., Smith, S. C., Sperling, L. S., Virani, S. S., & Blumenthal, R. S. (2019). Use of Risk Assessment Tools to Guide Decision-Making in the Primary Prevention of Atherosclerotic Cardiovascular Disease: A Special Report from the American Heart Association and American College of Cardiology. Circulation, 139(25), E1162–E1177.Laufs, U., Parhofer, K. G., Ginsberg, H. N., & Hegele, R. A. (2020). Clinical review on triglycerides. European Heart Journal, 41(1), 99–109.ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology, 74(10), 1376–1414. We are truly honored to be producing the Cardionerds CVD Prevention Series in collaboration with the American Society for Preventive Cardiology! The ASPC is an incredible resource for learning, networking, and promoting the ideals of cardiovascular prevention! This series is kicked off by a message from Dr. Amit Khera, President of the American Society for Preventive Cardiology and President of the SouthWest Affiliate of the American Heart Association. Cardionerds Cardiovascular Prevention Series Dr. Ann Marie Navar is a cardiologist and epidemiologist at the Duke Clinical Research Institute focusing on cardiovascular disease prevention. She received an MD from Duke University and a PhD in Global Disease Epidemiology and Control from the Johns Hopkins School of Public Health in 2009 before completing residency in internal medicine and pediatrics and fellowship in cardiology at Duke. Dr. Navar’s research focuses on improving cardiovascular disease prevention through better identification of at-risk populations, targeted interventions to improve quality of care and patient engagement through the electronic health record, and better treatment of hypertension and cholesterol to lower CV risk. She also studies the impact of payer-imposed barriers to novel therapies. Her areas of expertise include risk prediction, patient risk communication, real world data analyses using EHR- and claims-based datasets, and registries. She is an associate editor at JAMA-Cardiology and a board membe...

The CardioNerds discuss Women's Cardiovascular Prevention with Dr. Leslie Cho, Interventional Cardiologist and Director of the Cleveland Clinic’s Women’s Cardiovascular Center. She is also Section Head of Preventive Cardiology and Rehabilitation in the Robert and Suzanne Tomsich Department of Cardiovascular Medicine at Cleveland Clinic. Amit, Dan and Carine take a deep dive into women's cardiovascular prevention and discuss the epidemiology, unique risk factors, different manifestations of CVD and treatment strategies to lower cardiovascular risk in women. Tune in as we discuss cases from the CardioNerds Women's Clinic to learn more! Take me to the Cardionerds Cardiovascular Prevention PageTake me to episode topics page Cardiac Consult PodcastTall Rounds Lectures Key Reference: Cho L, Davis M, Elgendy I, et al (2020) Summary of Updated Recommendations for Primary Prevention of Cardiovascular Disease in Women: JACC State-of-the-Art Review. J Am Coll Cardiol 75:2602–2618 We are truly honored to be producing the Cardionerds CVD Prevention Series in collaboration with the American Society for Preventive Cardiology! The ASPC is an incredible resource for learning, networking, and promoting the ideals of cardiovascular prevention! This series is kicked off by a message from Dr. Amit Khera, President of the American Society for Preventive Cardiology and President of the SouthWest Affiliate of the American Heart Association. Cardionerds Cardiovascular Prevention Series Dr. Leslie Cho is a professor of Medicine at Cleveland Clinic Lerner School of Medicine Case Western Reserve Medical School and serves as Director of the Cleveland Clinic’s Women’s Cardiovascular Center. She is also Section Head, Preventive Cardiology and Rehabilitation in the Robert and Suzanne Tomsich Department of Cardiovascular Medicine at Cleveland Clinic. Dr. Cho received her undergraduate degree in interdisciplinary studies from the University of California, Los Angeles, graduating cum laude. She received her medical degree from the University of Chicago Pritzker School of Medicine, and took her residency in internal medicine at the University of Washington Medical Center where she received the John Humphrey Award as Most Outstanding Internal Medicine Resident. Her clinical training continued when she accepted a fellowship in cardiology, followed by a fellowship in interventional cardiology and peripheral disease, both from Cleveland Clinic. Leslie Cho, MDAmit Goyal, MDCarine Hamo, MDDaniel Ambinder, MD

The CardioNerds discuss The 'ABC's of Cardiovascular Prevention with Dr. Roger Blumenthal, Director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease and co-chairperson of the 2019 American College of Cardiology/American Heart Guideline on prevention of cardiovascular disease. Joining the discussion is Dr. David Feldman, Osler housestaff and first author of a beautiful State-of-the-Art review in the American Journal of Preventive Cardiology discussing a comprehensive ABCs of prevention. A: Assess Risk, Anti-Inflammatory, AspirinB: Body weight, Blood PressureC: Cigarette Cessation, CholesterolD: Dream (sleep), Diet, Digital Health, DiabetesE: Exercise F: Factors of the EnvironmentG: Genetics Take me to the Cardionerds Cardiovascular Prevention PageTake me to episode topics page Key Reference: Summarizing 2019 in Cardiovascular Prevention using the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease’s ‘ABC’s Approach We are truly honored to be producing the Cardionerds CVD Prevention Series in collaboration with the American Society for Preventive Cardiology! The ASPC is an incredible resource for learning, networking, and promoting the ideals of cardiovascular prevention! This series is kicked off by a message from Dr. Amit Khera, President of the American Society for Preventive Cardiology and President of the SouthWest Affiliate of the American Heart Association. Dr. Roger Blumenthal is a Professor of Medicine and the Director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease for which he was the principal developer. He received his medical degree from Cornell Medical College, where he was awarded the Weiss Prize for Excellence in Clinical Medicine. He completed his internal medicine and cardiology fellowship training at The Johns Hopkins Hospital before joining the Johns Hopkins cardiology faculty. Dr. Blumenthal was the most recent recipient of the Landon School Anthony Kupka Distinguished Alumnus Award. He was co-chairperson of the 2019 American College of Cardiology/American Heart Guideline on prevention of cardiovascular disease. Dr. David Feldman is a Junior Assistant Resident in the Osler Medical Residency Program at the Johns Hopkins Hospital. Prior to joining the housestaff, David received his MD and MPH degrees from the University of Miami. David first joined the Ciccarone Center as a pre-doctoral fellow in 2013 under the mentorship of Drs. Roger Blumenthal and Mike Blaha. David is passionate about cardiovascular disease prevention and hopes to pursue a career in academic cardiology, with a particular interest in preventive cardiology.  Roger Scott Blumenthal, M.D.David Feldman, MDCardionerds Cardiovascular Prevention SeriesDaniel Ambinder, MDAmit Goyal, MDCarine Hamo, MD

CardioNerds Amit Goyal and returning guest Dr. Zach Il’Giovine explore the patient's perspective on cardiovascular prevention with the star patient of this series: Kanak Amin. to explore the patient perspective on cardiovascular prevention. Mr. Amin tells us about his perspectives on being a heart patient and offers important advice for both patients and providers on the. He gives us many pearls, but especially highlights the importance of diabetes education, cardiac rehabilitation, engaging loved ones, and getting to know the patient on a deeper level. Special messages from Dr. Wael Jaber and Dr. Nishant Shah, who both knew Mr. Amin as a colleague, friend, and patient. Take me to the Cardionerds Cardiovascular Prevention PageTake me to episode topics page We are truly honored to be producing the Cardionerds CVD Prevention Series in collaboration with the American Society for Preventive Cardiology! The ASPC is an incredible resource for learning, networking, and promoting the ideals of cardiovascular prevention! This series is kicked off by a message from Dr. Amit Khera, President of the American Society for Preventive Cardiology and President of the SouthWest Affiliate of the American Heart Association. Kanak Amin is the Program Manager of the Radiochemistry Nuclear Medicine program at Cleveland Clinic. His hobbies and interests include woodworking, learning Wall Street and the financial world as well as computer web design. We are so appreciative this phenomenal patient perspective on cardiovascular prevention! Dr. Zachary Il’Giovine is a general cardiology fellow at the Cleveland Clinic. He received his medical degree from the Wright State University Boonshoft School of Medicine before completing internal medicine training at Duke University. He has clinical interests in advanced heart failure and cardiac critical care. Outside of the hospital he loves playing soccer and spending time with his wife Clare and son Luca. Kanak AminNishant Shah, MDZachary Il’Giovine, MD Amit Goyal, MDCardionerds Cardiovascular Prevention Series

This is the first episode in an important series on cardiovascular prevention. It's no secret that cardiovascular disease is the #1 killer worldwide; the total impact on humanity is just staggering. A focus on preventing CVD is an impetus for every cardionerd. In this episode Dan, Amit, Carine, and Heather discuss an illustrative case discussion and review the Cardionerds 2+4 paradigm of cardiovascular prevention: 2 fundamental principles of management + 4 steps in risk stratification. The Cardionerds CV prevention series will include in-depth deep dives on so many topics related to prevention starting with this case discussion. Stay tuned for upcoming episodes on the ABCs of prevention, obesity, hypertension, diabetes mellitus and anti-diabetes agents, personalized risk and genetic risk assessments, hyperlipidemia, women's cardiovascular prevention, coronary calcium scoring and so much more! Take me to the Cardionerds Cardiovascular Prevention PageTake me to episode topics page We are truly honored to be producing the Cardionerds CVD Prevention Series in collaboration with the American Society for Preventive Cardiology! The ASPC is an incredible resource for learning, networking, and promoting the ideals of cardiovascular prevention! This series is kicked off by a message from Dr. Amit Khera, President of the American Society for Preventive Cardiology and President of the SouthWest Affiliate of the American Heart Association. TWO principles of management Emphasize healthy lifestyle for everyone regardless of riskEscalate Preventive Measures with ↑ Risk  FOUR steps of risk stratification Qualitative risk approximation - identify major risk factors and start counseling and education. Quantitative risk estimation - use a validated model to quantify a patient’s future risk of CVD. Identify Risk Enhancing Factors - personalize risk if patient is in the gray zones after step 2Measure coronary artery calcium score - selectively if risk remains uncertain Cardiovascular Prevention Amit Goyal, MDDaniel Ambinder, MDCarine Hamo, MDHeather Kagan, MD

This week’s episode is special: we have the former and current Editors-in-Chief of Circulation on Circulation on the Run. Join Dr Amit Khera, Digital Strategies Editor of Circulation, as he speaks with Dr James T. Willerson, Editor-in-Chief from 1993 to 2004; Dr Joseph Loscalzo, Editor-in-Chief from 2004 to 2016; and Dr Joseph A. Hill, the current Editor-in-Chief. They will discuss the history of Circulation and how it continues to evolve. TRANSCRIPT Dr Amit Khera: Hi, this is Amit Khera. I'm digital strategies editor for Circulation from UT Southwestern Medical Center in Dallas. Today we have a very special Circulation on the Run. We have three Editors-in-Chief from Circulation. First, we have Dr James Willerson, who was the Editor-in-Chief from 1993 to 2004. He's a President Emeritus at the Texas Heart Institute. We also have Dr Joseph Loscalzo, who was Editor-in-Chief from 2004 to 2016, the Chairman of Department of Medicine from Brigham and Women's Hospital. And finally, Dr Joseph Hill, the current Editor-in-Chief, the Chief of Cardiology at UT Southwestern Medical Center. Welcome, gentlemen. Dr Joseph Hill: Thank you. Dr James Willerson: Thank you. Dr Joseph Loscalzo: Thank you. Dr Amit Khera: Dr Willerson, I must say, looking over the tenure prior to Dr Loscalzo, you had one of the longest tenures ever as Editor-in-Chief of Circulation, and certainly a lot happened in the practice of cardiology during that period. It was a really formative period in cardiology. As you think back, what were some of the most important topics that you covered during that time as Editor-in-Chief, thinking about the evolution of cardiovascular care and science at that time? Dr James Willerson: You have to remember, there have been many editors at Circulation. We all build on the shoulders of others, certainly I did. I really wanted Circulation to be the premier cardiovascular journal in the world. I wanted it to be much like the New England Journal of Medicine, but the New England Journal of Medicine Circulation of Cardiology. I wanted to publish it every week. We got permission to do that. That wasn't easy, but we were fortunate. I've been accused of wanting to publish it every day. There's actually some truth to that. I didn't make that. I didn't try very hard. I wanted to be able to present the information, important information, to everybody who cared about cardiovascular medicine: physicians, scientists, students, nurses, those who cared for people, and I wanted to do it frequently. I wanted to publish it quickly. So, we had some success with that. There are many other things that are well-known to the other editors, all of whom have built before me and after me, and I'm very proud of them. Dr Amit Khera: Well, thanks for that. And certainly, as you pointed out, this has been an evolution where you took the gauntlet, if you will, from the people before you, and then built on that and had many advances. I guess after you, Dr Loscalzo, you I think did have the longest tenure if I saw of any of the editors and similarly, a lot of evolutions in cardiovascular care and a lot in science, particularly during your time. Tell us a little bit about any particular papers or topics that you focused on, or that really were revolutionary in the cardiovascular space during your tenure. Dr Joseph Loscalzo: I'll pick up where Jim left off and just make the case that as you're suggesting, I mean, there's sort of been a natural transition of the kind of science that Circulation has been publishing over the tenure of the three editors here today. Before Dr Willerson, it was largely physiology and excellent clinical science. Jim really expanded the scope of what Circulation published to begin to put in press in its pages, fairly basic and translational science as well. I picked up from what he'd laid the groundwork for to expand the scope of that science. And as you know, expand it to the point that we had to develop daughter journals that would pick up the mantle in each of these increasingly subspecialized areas. So, it's hard to think about those papers that I found have the greatest impact because every field had several of them in my several years as editor. As you know, the subspecialty journals that we established, which remain active to the current time, are also broad in their scope from outcomes based research to genomics and proteomics insistence, cardiovascular medicine, to everything in between, imaging, intervention, heart failure, and electrophysiology to arrhythmias. Each of these was led, and continues to be led, by outstanding leaders in their subspecialty fields. I think the beauty of Circulation in contrast to even fine journals like the New England Journal of Medicine, is that Circulation has been able to put on its pages those studies that really do span quite a spectrum. We don't shy away from very basic studies. That actually began with Jim, I must say, because that wasn't the case previously. And of course, we move right through to epidemiology and outcomes based research. And the impacts have been broad in each of those fields, as witnessed by the excitement and uptake of the journal, measured however you wish, by impact factor, or citations, or the frequency with which it's referred to in the lay press. So, I think that tradition certainly continues under the current editor with papers of extraordinary impact. Dr Amit Khera: Thanks for that. I think your point about the evolution of science over time from Dr Willerson and certainly during your tenure and beyond to the breadth of Circulation currently. You also touched on the subspecialty journals. That happened in your watch and that was quite a marked change in cardiovascular medicine to have that explosion of new journals, if you will. What do you think the impact of those subspecialty journals has been for the cardiovascular field? Dr Joseph Loscalzo: We struggled with the idea about whether or not we should pursue that kind of fragmentation. What really pushed us was the fact that the acceptance rate remains quite low, in those days, probably eight or so percent range at its nadir. So, we were rejecting a lot of really excellent papers which wound up in competitor journal pages, that we would like to have accepted and been given the scrutiny of the careful reviews and editorials that accompany papers accepted by Circulation. We felt the best way to do that under the circumstances was to create these daughter journals. They succeeded, in many respects, beyond our wildest imagination. The numbers of papers that were published in the family increased, I think in the first two or three years, by at least 2-to 3000. So, that really speaks to the fact that we kept the best papers in the family. We gave them the right kind of audience. Some of these would have been too technical or too highly specialized to have been published in Circulation proper, but certainly of the highest quality and of significant relevance to the subspecialist. So, we think that it was a successful experiment. Now it's sort of become tradition. I think that the question that will always come up, of course, is can we fragment things more? I would say one of the best reasons to make the case that this was a successful experiment is that if imitation's the sincerest form of flattery, the New England Journal is now going to start three subspecialty journals. In fact, in my role now as an editor of the New England Journal, editor-at-large, they asked my input in how to design those daughter journals and what to expect from them. Dr Amit Khera: Well, I think that's a great point. It certainly has been a resounding success and as you pointed out, imitation is the best form of flattery. I'm going to pivot now to Joe Hill. Dr Hill, you have certainly been the beneficiary of all the great work that these two editors have done in the past. You've inherited a very successful journal and also have crafted your own vision for where you want Circulation to go in your mark. Tell us a little bit about some of the new initiatives you've tried to implement, leveraging on these past successes. Dr Joseph Hill: Thank you, Amit, it's an honor and a privilege to be in this conversation, frankly. I mean, Dr Willerson made this a weekly journal. That was back in the day when FedExes were flying around. Everything was paper. That kind of volume with that technology is impressive. And Dr Loscalzo, who has been a friend and mentor for many, many years, spearheaded the subspecialty journals, as we just heard, and took the journal to yet new heights. Each of you has been a pioneer and we've been fortunate to put together a team that I think has moved in exciting directions. We've leveraged technology now, such that we have our video conference meetings. We meet in a video conference with editors from 17 different countries. We have a third of our editors in Dallas, where I live, a third in the US outside of Dallas, and another third in 16 other countries. It turns out we alternate the time of that meeting each week because there's no single hour of the day that works around the globe, so we move it around to capture Asia or to capture California in alternating weeks. That has been a thrill and, honestly, I believe a robust success. We have leaders on the ground in all these different countries. We have a highly diverse team across the different subspecialty domains of cardiology, across different geographic regions, across race and sex and gender lines. It is an amazing team. And Amit, who leads our robust digital efforts, including this podcast and our efforts on social media, again, the opportunity now in the 21st century to take these initiatives forward has been a real privilege. Dr Amit Khera: It's ironic that Circulation was doing Zoom before everybody else was in the modern era. I'm going to pivot back to Dr Willerson. As Dr Hill just mentioned during your tenure how the volume of papers was handled, FedEx and sort of the nature of the journal publishing process. And now in the modern era, we have so much different information. We have a huge volume of journals. We have online, we have Twitter, we have podcasts. We have people that are consuming information in so many different ways. Tell us from your perspective, what's the role of the scientific journal currently and how has it changed at all in the last few decades? Dr James Willerson: It's always going to continue to evolve. It's about as good as it can be right now with Dr Loscalzo and Dr Hill's leadership, and I'm really proud of them. There'll be more. We can't even imagine what it will be in two or three years. Of course, it'll be better and better, faster, almost momentary. Thank you, Dr Hill. Dr Amit Khera: Thank you for that. I think we all look forward to seeing how this evolves more rapid information, rapid turnaround. I'm certain that will change. Dr Hill, you had a comment on that? Dr Joseph Hill: We live in an era now where peer review is under attack in many ways and pre-print journals, blogs and so forth. And one of the things that I've really seen, and we've all seen, is how the peer review process, and we're all authors, right, we live on the other end of that stick, but it really is important. It makes a big difference. And people who are anxious to accelerate that process, I totally get it. We work very hard to do that. At the same time we, following the traditions here, have an intentionally redundant review process where every paper is evaluated by multiple editors and multiple peer reviewers. On a number of occasions, we've avoided a pothole, or we've improved a paper many, many times. And that is something that has really been impressed on me that I think people who aren't on this side of the editorial fence might not appreciate as much. Dr Amit Khera: I think that's an important point about sort of the rigor about the way that articles come out in Circulation. And Dr Loscalzo, maybe as an extension of the last question, what do you see as some of the challenges going forward or opportunities for Circulation? You think about where it's been, but what are some of the things that you look forward to for Circulation in the future and what are some of the things you're concerned about? Dr Joseph Loscalzo: Well, I too am concerned about this issue of peer review being under attack, and I'm particularly concerned about it for papers that have direct clinical impact. A good example of that concern, of course, are papers published, or at least publicly released, on non-peer reviewed websites like the archive sites because of their importance in the COVID epidemic, potentially. We all know of cases of drugs, at least in test tubes, with cultured cells and viruses appear to be effective that have adverse clinical consequences. So that, and more than in any other sphere of science, ensuring that proper peer review from as many perspectives as possible is always a part of the process is absolutely critical for clinical medicine. And to me, the threat that this need for acceleration and rapid peer review poses and the sort of socialization of the transmission of scientific information that we're all interested in doing really has to have the brakes put on it a bit for the clinical science that the journal represents for this very important reason. Not to say we want to slow things down, we want to make sure that the best possible reviews are performed before we release it to the public. I know that, as Joe was pointing out, one of the most exciting parts of the role of when I led the journal was the weekly meeting. We had a face-to-face meeting because all of our associate editors, save one, was actually physically proximate and they could travel to our conference room. But it's a wonderful exercise to have people of very different perspectives, from basic scientists, to clinical electrophysiologists, to outcomes researchers, make comments on papers that were completely outside their sphere. The argument, of course, is if one can write and transmit a thought with the clear intent in a way that's rigorous and logical, that any reasonably bright person with reasonable scientific background should be able to understand it. And often these folks with very different scientific backgrounds have perspectives that very clearly improved the paper when they were acted upon. That's a process that doesn't exist in many other journals, I have to say. And I would encourage Joe, which I know, well, he's doing this because he enjoys it and he recognizes its importance, and Joe's successors continue to do that as well because that will ensure the value of the journal through all of the challenges that it is going to have to face in the next decade or two. Dr Amit Khera: I think that was a great point. We're certainly seeing candy bowl examples of the importance of this rigorous process of the editors looking through it carefully and, as you both mentioned, peer review. Joe Hill, I'm going to let you maybe have the last word. I know how hard the three of you have historically worked on your craft for the journal, how much effort you've put in, but I also know it's quite a rewarding job. What would you see as the best part of being Editor-in-Chief of Circulation? Dr Joseph Hill: Oh my, I'm learning something every day. I've been on about a steep a learning curve as when I was an intern at Dr Loscalzo's hospital long ago. Under Dr Willerson's term, I imagine many, many studies came in on acute coronary syndromes and thrombolytic therapy, primary PCI, antiarrhythmic drugs. We haven't seen an antiarrhythmic drug paper except for a recent review we did, but for quite a long time. It's artificial intelligence, it's big data, it's the UK Biobank, it's Omix, it's incredibly sophisticated genetics and genomics and basic science with genetic manipulations, IPS cells. It's a very different world now than it was 10 years ago, 20 years ago and it certainly will be again, 10 and 20 years down the road. We are now approaching, I will say, 600 COVID related papers, and they're still coming in at a record pace. The world has changed. As I said before, this is the 70th anniversary of this storied journal. And it is truly my honor to be able to stand on the shoulders of Doctors Loscalzo and Willerson. Dr Amit Khera: Thank you. I think that's a great way to end this podcast and congratulations on the 70th anniversary. It truly has been a privilege to chat with the three of you today. I want to thank you not only for what you've done for Circulation, but for the field of cardiovascular medicine. This is Amit Khera, digital strategies editor for Circulation. Next week we're back to our usual podcast with Carolyn Lam and Greg Hundley. Take care. Dr Greg Hundley: This program is copyright the American Heart Association, 2020.  

In today’s episode, Dr Carolyn Lam discusses the prevalence of familial hypercholesterolemia among the general population and patients with atherosclerotic cardiovascular disease with Dr Kausik Ray (KOSH) and Dr Amit Khera. Dr Carolyn Lam: Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Greg. I'm the associate editor from the Pauley Heart Center at VCU health in Richmond, Virginia. Dr Carolyn Lam: Greg, ever wondered what's the prevalence of familial hypercholesterolemia in the general population? It's an important question, but we're going to wait to discuss that with our feature discussion coming right up. First, I want to tell you all about valvular heart disease. In a preclinical model, would you believe, but first let me just remind us all that primary valvular heart disease is a really prevalent cause of morbidity and mortality. And although the primary consequence of valvular heart disease is myocardial dysfunction, treatment of valvular heart disease has always centered around valve repair or replacement, rather than the prevention or reversal of myocardial dysfunction. In fact, have you thought about this? We know very little about the mechanisms, the actual preclinical underlying mechanisms of left ventricular dysfunction and primary severe mitral regurgitation. Well, in the first paper I want to talk about today, Dr Li from First Affiliated Hospital, Sun Yat-sen, University Guangzhou, and Dr Sadek, from UT Southwestern Medical Center and their colleagues develop the first mouse model of severe mitral regurgitation. And they did this by severing the mitral valve leaflets and chords using iridectomy scissors. Similar to the human condition, induction of mitral regurgitation was followed by gradual left ventricular dilatation and dysfunction resulting in severe systolic dysfunction. Further analysis revealed that severe mitral regurgitation resulted in a marked increase in cardiac mass, increased cardiomyocyte length, but not with, and electron microscopy evidence of sarcomere disarray and the development of sarcomere disruption. From a mechanistic standpoint, severe mitral regurgitation resulted in activation of multiple components of both the mTOR and Kelson urine pathways. Now intriguingly, inhibition of mTOR signaling even preserved sarcomeric structure and prevented left ventricular remodeling and systolic dysfunction. Finally, immunohistochemical analysis uncovered a differential pattern of expression of the cell polarity regulator CRB2, along the longitudinal axis of cardiomyocytes and close to the intercalated discs, with a similar pattern of polysome localization. And all of this suggests a potential new mechanism of longitudinal cardiomyocyte growth. Dr Greg Hundley: Well, Carolyn, there is a lot of basic science and a lot going on both histopathologically, but also mechanically with this model. What's our take home message? Dr Carolyn Lam: Well, Greg, this mitral regurgitation mouse models suggest that cardiomyocyte hypertrophy in response to mitral regurgitation is a maladaptive process that may be pharmacologically targeted by mTOR inhibitors. Dr Greg Hundley: Oh my, very nice Carolyn. Well, I'm going to bring you another kind of basic science paper as well. And it's from Dr Jin Li from the Institute of Biochemistry and Molecular Medicine at the University of Bern. And it really involves auto antibody signatures in cardiac arrests. So Carolyn, a quiz of what percentage of individuals sustaining out of hospital cardiac arrest have no known cause? Dr Carolyn Lam: You said, “Oh oh!” I’m on the spot here, Greg. Okay. What about if I start with what I do know? Coronary artery disease is the most common cause. I think that may be, I don't know, large majority, 80% of it. And then we get inherited cardiomyopathy, channelopathies. So I'm going to guess less than 10%. Dr Greg Hundley: Wow. That is why you're just the stellar extraordinaire. So it's exactly about 5% to 10%. So Carolyn this study sought to address the etiology for this out of hospital arrests in this 5% to 10% of individuals, using a peptide micro-ray designed to screen for IgG targeting epitopes from all known cardiac ion channels with extracellular domains. So plasma samples from 23 patients with unexplained cardiac arrest were compared to 22 cardiac arrest cases of ischemic origin and a group of 29 age, sex, and BMI matched healthy subjects. Dr Carolyn Lam: Wow. What did they find, Greg? Dr Greg Hundley: The auto antibody against the poor domain of the L tight voltage gated calcium channel or Cav 1.2 was consistently identified as a biomarker of idiopathic cardiac arrest and functional studies on human induced pluripotent STEM cell derived cardiomyocytes demonstrated that the anti Cav 1.2 IgG purified from patients with idiopathic cardiac arrest is pro-arrhythmogenic by reducing the action potential duration through calcium channel inhibition. Dr Carolyn Lam: Wow, that seems huge. Clinical implications? Dr Greg Hundley: I thought you'd asked me that. So the present report addresses the concept of autoimmunity and cardiac arrest and hitherto unknown auto antibodies targeting extra cellular sequences of cardiac ion channels were detected. And so moreover, this study identifies an auto antibody signature to specific patients with cardiac arrest, thereby explaining perhaps a potential etiology for this 5% to 10% of individuals that here to for, we were uncertain of that particular ideology. Dr Carolyn Lam: Wow. That clearly needs follow-up, but you know what? What also needs follow-up is a quiz question for you. What do you say to a young adult with stage one hypertension about his or her future health risks? Dr Greg Hundley: Well, how about A, see a physician, B, listen to that physician and follow their recommendations? Dr Carolyn Lam: Oh, you are brilliant. Well, guess what? I'm going to tell you a little bit more about this in the next paper from Dr Kim from Yonsei University College of Medicine and Colleagues who looked at almost six and a half million participants aged 20 to 39 years. So young, and without taking any antihypertensive medication in 2003 to 2007 in a nationwide health screening database. Now participants were categorized according to the 2017 ACCAHA guidelines as having a normal blood pressure. That is an untreated systolic blood pressure, less than 120 and diastolic blood pressure less than 80. Or stage one, isolated diastolic hypertension. So that's when systolic is less than 130 and diastolic between 80 and 89. Or stage one isolated systolic hypertension. So that's when systolic blood pressure is between 130-139 and diastolic is less than 80. Or finally, stage one systolic and diastolic hypertension. So that's when systolic is between 130-139 and diastolic is between 80 and 89. And these were followed up for the primary outcome of composite cardiovascular disease events, including myocardial infarction, stroke, heart failure, and cardiovascular related death. Dr Greg Hundley: Caroline, I am dying to hear what did they find? Dr Carolyn Lam: So over a median follow-up of 13.2 years, more than 44,000 new cardiovascular disease events occurred. Among these young adults who had a median age of only 30 years stage one, isolated systolic hypertension, isolated diastolic hypertension, and systolic and diastolic hypertension were each associated with higher cardiovascular risks compared to normal blood pressure. Cardiovascular risk of stage one systolic and diastolic hypertension was higher than the risks of stage one isolated systolic and isolated diastolic hypertension.   Dr Greg Hundley: Very good. That was an outstanding presentation and very pertinent to our younger listeners as well as young patients with hypertension. In the rest of this journal, we are jammed packed with more articles. Let me tell you about a few. First, I've got a research letter by Professor G. Kees Hovingh from Amsterdam UMC discussing Inclisiran and how that durably lowers LDLC and PCSK-9 expression in homozygous familial hypercholesterolemia. Next there's an ECG challenge from Dr Miguel Arías from Complejo Hospitalario Universitario de Toledo involving syncope and alternating QRS morphologies. Next Professor Qing Yang from Tianjin Medical University General Hospital has a perspective piece regarding anti-platelet therapy following percutaneous coronary interventions in patients complicated by COVID-19. One of our own associate editors, Dr Nicholas Mills, has a very nice on my mind piece related to the use of serum troponin and biomarkers, as well as their utility in managing patients with COVID-19. Next, Dr Courtney Campbell from Ohio State University and Wexner Medical Center has a perspective piece regarding will compliment inhibition be the new target in treating COVID-19 related systemic thrombosis. And then finally, Carolyn, there's a nice exchange of research letters regarding Orai 1 channel inhibition, preserving left ventricular systolic function, and normal calcium handling after pressure overload. And the contributing authors that provided these letters are Dr Muddassir Mehmood from University of Tennessee Medical Center and Dr Jessica Sabourin from INSERM UMR S1180. Dr Carolyn Lam: And that's not all, Greg. There's also an in-depth article on the implications of altered ketone metabolism and therapeutic ketosis in heart failure by Dr Salvaraj, Kelly, and Margulies. Now this review is a must read. It summarizes the current evidence supporting a role for ketones in heart failure and covers normal myocardial ketone utilization, alterations, and ketone metabolism in a failing heart and effects of therapeutic ketosis in both animals and humans with heart failure. There's also a research letter by Dr Susanna Larson who used the UK Biobank Cohort to perform a Mendalian Randomization investigation into the causal effects of circulating LPA levels on atherosclerotic, cerebral vascular thrombotic, and valvular disease. There's another research letter by Dr Eliseo Guallar and that's on mitochondrial DNA copy number, which is an indirect biomarker of mitochondrial dysfunction and its association with incident heart failure in the Eric study. Wow, such a full issue, but now let's go on to our feature discussion. Shall we, Greg? Dr Greg Hundley: You bet. Dr Carolyn Lam: Today's feature discussion is all about familial hypercholesterolemia. Now, recent study suggests it is more frequent than previously reported. And in fact, increasingly recognized as affecting individuals of all ethnicities and across many regions of the world. Well, today's feature paper really represents one of the most comprehensive assessments of the prevalence of familial hypercholesterolemia. More than 7.3 million individuals from 62 studies. So pleased to have with us the corresponding author of this beautiful paper, Dr Ray Kosh from Imperial College London, as well as our editor of digital strategies, Dr Amit Khera from UT Southwestern. Kosh, if I may call you that, congratulations again on another just really important paper. This systematic review and meta-analysis is really revealing. So could you tell us a little bit more of the details of what you did and just really tell us the take home messages. Dr Kausik Ray: We've been getting signals that familial hypercholesterolemia... So this is where essentially individuals inherited an abnormality that results in lifelong elevations of LDL cholesterol birth, increases risk of cardiovascular disease. The previous prevalence was believed to be about one in 500 and suggestions... It's actually not just a suggestion, there's a lot of data suggesting that it's a lot more prevalent than that. And one of the queries that we often have, if you think about global health is does it affect all regions of the world? And if we don't go out looking for it, you're not going to find it. So this is really why this was done. And we basically synthesize the global data and there was basically over 7 million people approximately from general population primary care settings, if you will. And the global prevalence for FH is one in 311. Confidence interval is between about one and 250 to one in 397. If you look at WHO regions of the world, it's equally prevalent across all regions of the world. And we know there are many regions of the world where they're not going out looking for this. So if you don't look for it, you won't find it. And we think that that should inform public health policies. The other key things about this or that because this is a condition that results in premature cardiovascular disease, there's been emerging data that actually in people with early myocardial infarction, for example, the possibility of FH may be higher. So in proportion of studies where we had participants with established cardiovascular disease, the possibility of this being present is about one in 17. Now they're not all going to be FH, but it means that actually the coronary care unit where the vast majority of these patients arose from, that's a great starting place. If you see somebody with premature MI before the age of 55, high LDL cholesterol above 190, start thinking about it. If you find one, you can think about cascade testing and finding family members because each effected individual potentially the likelihood in a first degree relative is 50%, 1 in 2. So that becomes really important. And I think those are probably where I'd stop now and maybe take a few more questions, but I think that's the take home message. Dr Carolyn Lam: Very, very important and practical take home messages. So thanks for that, Kosh. But could I just go back with one basic question? For those of us who don't think of it every day, what is the definition of familial hypercholesterolemia? There are so many definitions out there. Could you simplify it for us? Dr Kausik Ray: Yeah, so basically all the definitions, the common ones that have been used in making an early diagnosis. So met that criteria, looking at family history, looking at elevated cholesterol levels. There's the Simon-Broome criteria with some clinical signs, as well as family history and genetic mutations. And then there's the Dutch lipid criteria. That's probably the most used in the world, looking at the physical signs, LDL cholesterol levels, and also family history. And they give you essentially a score of the likelihood of this. And if you like, the gold standard really is probably genetic testing. That's not available in all regions of the world. There may be cost and other issues with that, but essentially that is giving you a diagnosis of a known variant of monogenic disorder and there's over 1,800 or so variants identified. So those are the ways that you can essentially do this. Dr Carolyn Lam: Thanks, Kosh. Amit, I have to bring you in here. Thank you so much for managing this beautiful paper and recognizing how important it is. You invited an editorial as well. Could you share some of your thoughts? Dr Amit Khera: Sure. The one thing, Kosh, as we look at this, which is so important to understand the prevalence worldwide and really glad that your group took on this project. But if you look at your figure, what's striking is how many areas are essentially white where there's no data. I mean, huge proportions of countries around the world. Why do you think that is? And how do we close that gap? Dr Kausik Ray: That becomes really important. So what I would say is this was looking at prevalence and those are areas of the world where prevalence has not been reported. So if I were to overlap that with countries, for example, where we are starting to get definitive diagnosis through gene mutations, for example, there would be fewer gaps. We don't yet have enough data in terms of prevalence in those areas. But if you look, there's a huge gap, for example, in Africa. You've got a few countries that we know that haven't reported prevalent but have published on FH. So we do know it's there. And then you've got South Africa at the bottom and you've got Nigeria now also collecting data. But part of it is, I guess, one important thing is misclassification. So if somebody dies in those regions of the world, often it's attributed to other causes. And because there is little public health information, because there hasn't been investments on thinking about cholesterol, for example, is it common in our population? If you were in sub Saharan Africa, maybe you think about infectious disease or other things, right? So it's not on the agenda. So there hasn't been that investment and therefore data is then lacking. We starting to see shifts in that, and hopefully this will move the needle a little bit more. And I think once that is done, what will then happen is we will get more reliable estimates from that part of the world. I think we've all got patients from that part of the world. And when I think about my clinical practice, I have patients from the middle of Africa, West, East, Sri Lanka, none of which is represented on that map. Dr Amit Khera: I think that's a great point. And you know, there's no reason to think that the prevalence is much different. We just have a gap in knowledge there. And I guess the next part comes to implications. As you rightfully discussed many times in your paper, less than 1% of people are diagnosed. And even if someone publishes prevalence data, a diagnosis could involve genetic testing, it could involve broad limpid screening, a combination of both. What do you think is the next step? Dr Kausik Ray: That's incredibly important. And I think you have to think about two different approaches. They're are the populations already out there living with this condition. So how do we picture those? It's going to be very difficult to think about universal screening in everybody 40-60, for example. So one way is to look at those people, the index case who comes in premature myocardial infarction in particular and use that as a source for cascade testing. We know that that is cost-effective. There've been formal evaluations of that approach. I do think with the cost of genetic testing, for example, that will make life a lot easier. And I think that that point in CCU, the elevated LDL premature MI should be the start of that thought process. What we tend to do is we have a whole list of medications. We start people on that and it's an afterthought, depending upon the post-treatment cholesterol levels. It shouldn't be. The other thing I think that you could do, there are lots of opportunities for screening. If you think about those people now, who are under the age of 10, 11, and you think about vaccination programs, you think about pre-college, pre-university health assessments that are often done in many parts of the world. Those offer opportunities to get a blood sample. David Wall did a lovely piece several years ago, looking at child parents screening, reverse cascade, if you will. And that showed that it could be cost effective. You don't need a small sample of blood. You can use DNA. And each of those interactions gives you an opportunity for screening. What I'd love to see is we all think that there will be or there could be an update of the WHO recommendations for cholesterol management. And that might advocate, for example, universal screening for cholesterol before the age of 29. If that is done, then if you think of low middle-income countries, a lot of those white gap, we will start to see those things being or this condition being picked up and potentially huge numbers of lives being saved. And because this is a genetic condition which is ultimately dominant, you find one, you can either exclude or find other people early and early diagnosis changes prognosis as you well know. Dr Amit Khera: Thank you for that, the implications and the potential profound if one could implement that broad screening. And as you pointed out early treatment, and I have one last question for you and it has to do with other part of the coin, which you touched on, which is the ASCBD. You know, your estimates of one and 17 were really helpful. I think many people aren't appreciative of how relatively common FH is in patients with coronary artery disease. And you talked about the implications being cascade screening of family members, but I know you work in therapeutics as well. There've been some data about maybe even earlier intervention or more aggressive intervention once someone's diagnosed with FH and after cardiovascular disease. What are your thoughts on that part of the investigation? Dr Kausik Ray: Yeah, no, that's a really important question. So most of the studies that have actually looked at ACVD, they didn't utilize, for example, a genetic diagnosis. So it's largely the clinical phenotype. And remember, you have an A priority bias in terms of scoring on the Dutch Lipid Network Criteria, by virtue of the fact that you've had premature disease. Some of these people will probably have elevations in LP(a) and others it could be polygenic hypercholesterolemia, which does carry an increased risk, but not as much as FA. If you could separate those three out the implications really are if you think about the ACVD patient population with true FA, you basically missed 40 years of unexposed exposure. And so in these people, I think those are people that we should be thinking about mainly more aggressive intervention with either lower LDL targets, because the absolute benefit is likely to be much, much greater. So I think that's the key implication I think of these findings. Dr Carolyn Lam: Thanks so much, Amit. Thanks so much, Kosh. As someone living in an area where there is... It's white on that map as well, but no available data in Southeast Asia, I've learned a lot. Thank you, listeners, for joining us this week. You've been listening to Circulation On the Run. Please tune in again next week. Dr Greg Hundley: This program is copyright the American Heart Association 2020.  

This is the full, uncut interview with Dr. Amit Khera from the University of Texas Southwestern's Preventive Cardiology Program.He discusses the great urgency of people being afraid to call 911 when they are having medical emergencies, particularly related to our hearts. This reluctance is only complicating and compounding problems that need to be dealt with sooner. He says that people are suffering irreparable harm or even death because of this new alarming trend. Also, Dr. Khera tells us how Covid-19 affects the heart, how the medical system has made adjustments to keep patients safe while getting routine treatment, the value of telemedicine, and much more. See acast.com/privacy for privacy and opt-out information.

This is the third straight Friday that Governor Abbott has released phases of Texas heading towards a "new normal." Stephen Love comments on the implications, hospital capacities and likely next steps. Also, Remdisivir is a promising new medication for COVID-19 and Stephen talks about the supply sent to North Texas hospitals as well as clinical trials underway.Dr. John Carlo, Physician CEO at Prism Health North Texas, has been on the front lines of several major outbreaks affecting our community going back to AIDS crisis of the 1980's. Dr. Carlo joins us for Part 1 of what will be a 2-part interview to discuss how residents can maintain their safety as businesses reopen.Dr. Amit Khera, director of the Preventive Cardiology Program at UT Southwestern, returns to the program to answer questions about how hospitals have adapted safety measures while treating COVID-19. He also explains how COVID-19 can potentially affect the heart.Gladys Kolenovsky, director of the Center for Dyslexia at Texas Scottish Rite Hospital for Children, will talk about her hospital's world-renown dyslexia program. She is passionate about the cause and details how the program has helped so many children and families nationwide. See acast.com/privacy for privacy and opt-out information.

DFW Hospital Council President and CEO, Steven Love, talks about the increased re-opening in North Texas this week, as Covid-19 testing numbers continue to show many cases in the area, with many still fatal. How can we make this successful? Will there be another spike? How will we know? These are all important questions that Steve addresses from his perspective working closely with the DFW area hospitals and local governing authorities. In our next two segments we address a growing problem in North Texas and around the country. Due to Covid-19 concerns, people with true medical emergencies are not calling 911. The data is clear, and this is leading to unnecessary deaths or further medical complications as a result. "Time is Brain and Time is Muscle" is the mantra you will hear from Dr. Veer Vithalani. He should know. As Interim Director of the Metropolitan Area EMS, his mission is to help people understand that it is totally safe to call 911 and get proper medical care if you are exhibiting any kind of heart, stroke, or other medical emergency symptoms. Finally, Dr. Amit Khera from the University of Texas Southwestern's Preventive Cardiology Program talks to us how Covid is affecting the heart. He underscores the critical message that if you exhibit signs or concerns of a potential heart or stroke issue, please call 911. How is Covid affecting the heart, and what can we do to stay healthy while we are sheltering at home? Dr. Khera is an expert in this area offering excellent advice whether you are dealing with cardiovascular issues or not. See acast.com/privacy for privacy and opt-out information.

Jane Ferguson:                  Hi there. Welcome to Getting Personal: Omics of the Heart, the podcast from Circulation: Genomic and Precision Medicine. I'm Jane Ferguson, and this is Episode 36 from February 2020.                                                 First up, we have “Identification of Circulating Proteins Associated with Blood Pressure Using Mendelian Randomization” from Sébastien Thériault, Guillaume Paré, and colleagues from McMaster University in Ontario. They set out to assess whether they could identify protein biomarkers of hypertension using a Mendelian randomization approach. They analyzed data from a genome-wide association study of 227 biomarkers which were profiled on a custom Luminex-based platform in over 4,000 diabetic or prediabetic participants of the origin trial.                                                 They constructed genetic predictors of each protein and then used these as instruments for Mendelian randomization. They obtained systolic and diastolic blood pressure measurements in almost 70,000 individuals, in addition to mean arterial pressure and pulse pressure in over 74,000 individuals, all European ancestry with GWAS data, as part of the International Consortium for Blood Pressure.                                                 Out of the 227 biomarkers tested, six of them were significantly associated with blood pressure traits by Mendelian randomization after correction for multiple testing. These included known biomarkers such as NT-proBNP, but also novel associations including urokinase-type plasminogen activator, adrenomedullin, interleukin-16, cellular fibronectin and insulin-like growth factor binding protein-3. They validated all of the associations apart from IL-16 in over 300,000 participants in UK Biobank. They probed associations with other cardiovascular risk markers and found that NT-proBNP associated with large artery atherosclerotic stroke, IGFBP3 associated with diabetes, and CFN associated with body mass index.                                                 This study identified novel biomarkers of blood pressure, which may be causal in hypertension. Further study of the underlying mechanisms is required to understand whether these could be useful therapeutic targets in hypertensive disease.                                                 The next paper comes from Sony Tuteja, Dan Rader, Jay Giri and colleagues from the University of Pennsylvania and it's entitled, “Prospective CYP2C19 Genotyping to Guide Antiplatelet Therapy Following Percutaneous Coronary Intervention: A Pragmatic Randomized Clinical Trial”.                                                 They designed a pharmacode genomic trial to assess effects of CYP2C19 genotyping on antiplatelet therapy following PCI. Because loss of function alleles in CYP2C19 impair the effectiveness of clopidogrel, the team were interested in understanding whether knowledge of genotype status would affect prescribing in a clinical setting. They randomized 504 participants to genotype guided or usual care groups and assessed the rate of prasugrel or ticagrelor prescribing in place of clopidogrel within each arm. As a secondary outcome, they assessed whether prescribers adhere to genotype guided recommendations. Of genotyped individuals, 28% carried loss of function alleles. Within the genotype guided group overall, there was higher use of prasugrel or ticagrelor with these being prescribed to 30% of patients compared with only 21% in the usual care group. Within genotype individuals carrying loss of function alleles, 53% were started on prasugrel or ticagrelor, demonstrating some adherence to genotype guided recommendations.                                                 However, this also meant that 47% of people whose genotype suggested reduced effectiveness were nevertheless prescribed clopidogrel. This study highlights that even when genotype information is available, interventional cardiologists consider clinical factors such as disease presentation and may weight these more highly than genotype information when selecting antiplatelet therapy following PCI.                                                 The next paper is about “Deep Mutational Scan of an SCN5A Voltage Sensor and comes to us from Andrew Glazer, Dan Roden and colleagues from Vanderbilt University Medical Center. In this paper, the team aim to characterize the functional consequences of variants and the S4 voltage sensor of domain IV and the SCN5A gene using a high throughput method that they developed. SCN5A encodes the major voltage gated sodium channel in the heart and variants in SCN5A can cause multiple distinct genetic arrhythmia syndromes, including Brugada syndrome, long QT syndrome, atrial fibrillation, and dilated cardiomyopathy, and have been linked to sudden cardiac death.                                                 Because of this, there's considerable interest in understanding the functional and clinical consequences of different variants, but previous approaches were time consuming and results were often inconclusive with many variants being classified as uncertain significance. This newly developed deep mutational scanning approach allows for simultaneous assessment of the function of thousands of variants, making it much more efficient than low throughput patch clamping. The team assessed the function of 248 variants using a triple drug assay in HEK293T cells expressing each variant and they identified 40 putative gain of function and 33 putative loss of function variants. They successfully validated eight of nine of these by patch clamping data. Their study highlights the effectiveness of this deep mutational scanning approach for investigating variants in the cardiac sodium channel SCN5A gene and suggests that this may also be an effective approach for investigating putative disease variants and other ion channels.                                                 The next article is a research letter from Connor Emdin, Amit Khera, and colleagues from Mass General Hospital in the Broad Institute entitled, “Genome-Wide Polygenic Score and Cardiovascular Outcomes with Evacetrapib in Patients with High-Risk Vascular Disease: A Nested Case-Control Study”. In this study, the team set out to probe the utility of using polygenic risk scores to predict the risk of major adverse cardiovascular events within individuals already known to be at high cardiovascular risk and to assess whether genetic scores can identify individuals who would benefit from the use of a CETP inhibitor such as Evacetrapib. They analyze data from the ACCELERATE trial which had tested Evacetrapib in a high risk population, and they found no effect on the incidents of major adverse cardiovascular events overall. Within a nested case-control sample of individuals experiencing major CVD events versus no events, they applied a polygenic risk score and found that the score predicted major cardiovascular events.                                                 Patients in the highest quintile of the risk score were at 60% higher risk of a major cardiovascular event than patients in the lowest quintile. There was no evidence of any interaction between the genetic risk score and Evacetrapib. These data suggest that genetic risk scores may have utility in identifying individuals at high risk events but may not have utility in identifying individuals who may derive more benefit from CETP inhibition. The next letter concerns “Epigenome-Wide Association Study Identifies a Novel DNA Methylation in Patients with Severe Aortic Valve Stenosis” and comes from Takahito Nasu, Mamoru Satoh, Makoto Sasaki and colleagues from Iwate Medical University in Japan. They were interested in understanding whether differences in DNA methylation could underlie the risk of aortic valve stenosis. They conducted an EWAS or epigenome-wide association study of peripheral blood mononuclear cells or PBMCs from 44 individuals with aortic stenosis and 44 disease free controls.                                                 They collected samples at baseline before a surgical intervention in the individuals with aortic stenosis and collected a follow-up sample one year later. They found that DNA methylation at a site on chromosome eight mapping to the TRIB1, or tribbles homolog one gene, was lower in the aortic stenosis group than in the controls at baseline. They replicated the association in an independent sample of 50 cases and 50 controls. TRIB1 MRNA levels were higher in the aortic stenosis group than the controls. When they looked at methylation status one year after aortic valve replacement or a transcatheter aortic valve implantation in patients with stenosis, they found that DNA methylation had increased in the cases while TRIB1 MRNA decreased. These data suggests that methylation status of TRIB1 and expression of TRIB1 may relate to the disease processes in aortic stenosis such as hemodynamic dysregulation and they can be reversed through surgical intervention. Changes in the methylation status of TRIB1 could be a novel biomarker of response to aortic valve replacement.                                                 The next letter comes from Niels Grote Beverborg, Pim van der Harst, and colleagues from University Medical Center Groningen and is entitled, “Genetically Determined High Levels of Iron Parameters Are Protective for Coronary Artery Disease”. Their study addresses the conflicting hypotheses that high iron status is either deleterious or protective against cardiovascular disease. The team constructed genetic predictors of serum iron status using 11 previously identified snips and tested the genetic association with CAD in UK Biobank data from over 408,000 white participants. Overall, the genetic score for higher iron status was associated with protection against CAD. Ten of the snips suggested individual neutral or protective effects of higher iron status on CAD, while one iron increasing snip was associated with increased risk of disease but this was thought to be likely through an iron independent mechanism. Overall, these data suggest that a genetic predisposition to higher iron status does not increase risk of CAD and is actually protective against disease.                                                 The final letter is entitled, “Confidence Weighting for Robust Automated Measurements of Popliteal Vessel Wall MRI” and comes from Daniel Hippe, Jenq-Neng Hwang, and colleagues from the University of Washington. They were interested in assessing whether images of popliteal artery wall incidentally obtained during knee MRI as part of an osteoarthritis study could be used to study the development and progression of atherosclerosis. They developed an automated deep learning based algorithm to segment and quantify the popliteal artery wall in images obtained over 10 years in over 4,700 individuals. Their approach, which they named FRAPPE, or fully automated and robust analysis technique for popliteal artery evaluation, was able to reduce the average time required for segmentation analysis from four hours to eight minutes per image. They applied weights based on confidence for each segment to automatically improve the accuracy of aggregate measurements such as mean wall thickness or mean lumen area. Their data suggest that this automated method can rapidly generate useful information on atherosclerosis from MRI images obtained as part of other studies. When combined with other data. This approach may facilitate novel discovery in secondary analyses of existing studies in an efficient and cost effective way.                                                 And that's all for issue one of 2020. Come back next time for more of the latest papers from Circulation: Genomic and Precision Medicine. Speaker 2:                           This podcast is copyright American Heart Association 2020.  

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. You know that problem we have with the development of calcification of the aortic valve, the aorta, etcetera with hemodialysis? Well, our feature is going to talk about the results of a randomized phase 2B study to address this. But first, how about if you get us started with a couple of your papers? Dr Carolyn Lam: In fact, it is a couple of papers and they're both related to hypertension. So in the first one, we know that exercise is associated with a lower incidence of hypertension, but what's the association of excessive levels of exercise in the incidence of hypertension? This question was examined by Dr Andersen from Uppsala University Hospital and colleagues, who compared the incidence of hypertension among almost 207,000 participants in a long-distance cross-country skiing event and more than 505,500 persons randomly sampled from the general population who are matched to the skiers on age, sex, and place of residence. Dr Greg Hundley: I love skiing! I want to be in the match group. Tell me, now, how long was this distance that they had to cover? Dr Carolyn Lam: Ah ha. Now the long distance event was really long. It was the Vasaloppet. I hope I pronounced that right, but it's a 45 to 90 kilometer skiing race. So participation, I'm sure you want to hear this, participation was associated with a 41% lower incidence of hypertension over the next eight years, compared to non-participation. And the better the performance in terms of percent of winning time, the lower the incidence of hypertension. If the observed associations are causal, it really adds to the list of beneficial effects of high, or even very high physical fitness. I can see you smiling, Greg. Dr Greg Hundley: This is your confirmation that the AHA wants to send us to Norway to do one of these recordings. Dr Carolyn Lam: Well, this next paper asked the question, what is the association of cumulated blood pressure exposure from young adulthood to midlife with gait and cognitive function in midlife. This is from Dr Mahinrad from Northwestern University Feinberg School of Medicine and colleagues who included 191 participants from the coronary artery risk development in young adults’ study, which is a community-based cohort of young individuals followed over 30 years. Cumulated blood pressure was calculated as the area under the curve for baseline up to year 30 exam and gait and cognition were assessed at the year 30 exam. Cerebral white matter hyperintensity was available at year 30 in a subset of participants who underwent MRI. Dr Greg Hundley: I heard that MRI word. So what did they find Carolyn? Dr Carolyn Lam: They found cumulative exposure to higher blood pressures from young adulthood to midlife, even at levels below the clinical definition of hypertension, was associated with worse gait and worse cognitive function in midlife. The impact of cumulative levels of blood pressure exposure was independent of other vascular risk factors during a follow-up period of over 30 years, and the higher burden of midlife cerebral white matter hyperintensity on MRI, Greg, moderated the association of cumulated blood pressure exposure with gait but not with cognitive function. Dr Greg Hundley: You've got me convinced we now have to go to Norway. But what did the authors think were the clinical implications of their study? Dr Carolyn Lam: Well, here it is. The deleterious effect of elevated blood pressure on brain structure and function may begin during early adulthood and this really emphasizes the need for all primordial, if you may, prevention of high blood pressure. But also reconsidering individual levels of blood pressure for the diagnosis of hypertension. Furthermore, gait may be an earlier measure of hypertensive brain injury than cognition. Now these issues are discussed an editorial by Angela Jefferson from Vanderbilt University Medical Center. Dr Greg Hundley: Very nice, Carolyn. Well, I'm going to take another sort of twist on hypertension. My paper is from Dr Thomas Thum from the Hanover Medical School and is really looking at the relationship between cardiac fibrosis and diastolic dysfunction. So the study sought to identify anti-fibrotic drug candidates by functional screening of 480 chemically diverse natural compounds found in human cardiac fibroblasts. Dr Carolyn Lam: Ooh, interesting. And what did they find? Dr Greg Hundley: What they found is using multiple in vitro fibrosis assays and stringent selection algorithms, the authors identified the steroid bufalin, also seen in Chinese toad venom, and the alkaloid lycorine, from the Amaryllidaceae species, to be effective anti-fibrotic molecules, both in vitro and in vivo, leading to improvement in diastolic function in two hypertension dependent rodent models of cardiac fibrosis. In addition, administration of these agents at effective doses did not change plasma damage markers, nor the morphology of the kidney and liver. And therefore, it's kind of an early first toxicological safety study. Dr Carolyn Lam: Fascinating. Not just in the findings and the methods, and who knew we'd be talking about Chinese toad venom on this podcast, Greg? Okay. But let me tell you about what's more in this issue. So, there is a research letter by Dr Djoussé, and it is entitled Supplementation with Vitamin D and/or Omega-3 Fatty Acids and the Incidence of Heart Failure Hospitalization. And this one is a letter from the VITAL-Heart Failure ancillary study of the parent VITAL trial. I'm sure I've got everyone's attention. (You) Got to read that letter. The next is an On My Mind, by Dr Joe Hill, and is entitled, very intriguingly, Can HFpEF and HFrEF Co-exist? Basically accumulating evidence has revealed that the pathophysiologic mechanisms driving HFrEF and HFpEF are distinct, but this On My Mind paper asks can they coexist? Is it possible to identify subjects who harbor pathophysiological elements of both syndromes simultaneously, and if so, we may find that targeting specific pathways is beneficial and in depth characterization of specific subsets of patients might help overcome the limitations of an ejection fraction driven approach. Dr Greg Hundley: Very interesting, Carolyn. I've got some letters from the mailbox, and the first letter is regarding SGLT2 inhibitors in cardiac hypertrophy and the corresponding author is Professor Kazushi Tsuda from Kansai University of Health Sciences. Another letter, from the corresponding author Dr Renato Lopes from Duke University Medical Center in Durham, evaluates stent thrombosis in patients with atrial fibrillation undergoing coronary stenting from the AUGUSTUS trial. And our own Tracy Hampton provides an update on cardiology news features. And John Warner, from UT Southwestern, the prior American Heart Association president, discusses his journey through healthcare reform. And then finally, our own Sarah O'Brian provides highlights from other journals in the Circulation family related to high points in cardiovascular disease. Well, Carolyn, how about on to dialysis and calcification? Dr Carolyn Lam: Can't wait. Let's go. Our feature discussion today, we will be focusing on patients with end-stage kidney disease. And we know that in these patients, the high cardiovascular morbidity and mortality could partially be due to extensive cardiovascular calcification. Well, our feature paper today is the first double blind placebo-controlled phase 2B trial that tests intravenous myo-inositol hexaphosphate, a novel strategy to inhibit the formation and growth of hydroxyapatite and therefore reduce calcification in these patients. I won't tell you more. I'll leave that to the corresponding author, Professor Paolo Raggi, from University of Alberta, and I'm also so pleased to have with us our editor for digital strategies and associate editor Dr Amit Khera from UT Southwestern. So Paolo, please tell us about SNF472 and your very novel trial. Prof Paolo Raggi: As you correctly stated, patients with end stage renal disease have phenomenally high morbidity and mortality, particularly cardiovascular, and they also manifest extreme calcification on the cardiovascular system. Both the valves and the vessels are very heavily calcified. There's a very clear impression throughout the literature that calcification contributes, no doubt, to the high morbidity mortality with these patients. SNF472 is a derivative of a natural product that is only present in nature in sub molecular quantities and essentially is administered intravenously and the mechanism of action is quite simple. It keeps calcium and phosphorous molecules separate. In other words, it doesn't allow crystallization of calcium and phosphate into what we call hydroxyapatite, or amorphous calcium crystals. This, hopefully, was developed, this product was developed, to inhibit the final step of calcification. Everything comes down, no matter what the promoting event is, to crystallization of calcium and phosphorus. Therefore, if we were able to stop the final event, hopefully you will be able to inhibit further calcification, and that's what we tested in this particular article, in this particular study. Dr Carolyn Lam: Oh Paolo, I just love the way you described that. Very, very crystal clear, if you don't mind the pun. But could you please let us know, so a phase 2B trial, does that mean a surrogate outcome, duration of treatment, number of patients? How about telling us a little bit about the trial? Prof Paolo Raggi: So, the trial involved recruiting three different groups of patients. One would be treated with placebo and two other cohorts would be treated with either 300 milligrams of SNF472 three times a week or 600 milligrams of SNF472 three times a week. The product is injected intravenously into the dialysis line. Therefore, the patients do not have to remember to take a pill or inject themselves. Actually, it's perfect, if you will, compliance because all they have to do is come to their dialysis session and they receive it during dialysis. The study therefore, it was a relatively small study, but enough to prove our point. Three groups were recruited, about 90 patients each, and the two treatment arms at 300 milligrams and the 600 milligrams, were combined as a single group for the purpose of reporting the primary results. The follow up was at one year, so these patients were submitted to CT scanning of the chest without contrast for measurement of calcification only at baseline and then again at 52 weeks. In the intention to treat group, patients were included if they had a baseline scan and at least one follow-up scan at some point during the study. These are very sick patients and sometimes are referred for transplant. Sometimes they withdraw from studies. So, we asked everybody to have a second scan if they needed or wanted to withdraw before the 12 month mark was reached. That's for the intention to treat analysis. And then we need some confirmatory analysis on patients who actually did have the baseline in an actual 12 months scan and received the entire year treatment with these two drugs, with a drug or placebo. Dr Carolyn Lam: That's great and please tell us the results. Prof Paolo Raggi: The results were, in our minds, very exciting. And let me first say, that in all the literature that looked at what is the average progression of calcification in the general population, it's anywhere between 10 to 15% per year. For the person with calcium in the coronary arteries, there's an expected progression about 10 to 15%. All the publications in patients with renal failure and undergoing dialysis, show the progression of anywhere between 25 and 35%, so these people are not only more calcified, these patients also progressing very fast. In the particular trial that we reported in Circulation, we demonstrated on average, a progression of 20% in the group receiving placebo and about 11% in the group receiving SNF472. So, there was about a 45% slowing of progression in the treated group compared to the placebo group.   Interestingly enough, we saw a slower progression unusual in the placebo group. As of today, many more treatments are available to patients with end stage renal disease that were not available when the original studies that I mentioned earlier were conducted. So, the 25 to 35% progression that we saw 15 years ago, it's now slowed, you notice, to a 20% progression in these patients, but SNF472 was even more effective at further slowing that progression. Dr Carolyn Lam: Well, congratulations first and foremost on a very successful and really striking and novel results. Well, Amit there's so much to discuss I don't even know where to start. But first, maybe can I bring you in by saying, so what, is Circulation now publishing renal papers? Dr Amit Khera: The answer is absolutely yes. So first I want to congratulate Dr Raggi on a fantastic paper. This was a concomitant late breaking science at the American Heart Association Sessions; so, we always try to think of timely and exciting topics and appreciate working so closely with this group to bring this across the finish line. At Circulation, one thing we've been working on is something called Bridging Disciplines, where purposefully we appreciate the heart is not in isolation and not in a box by itself, but within a larger system, a body system. So, we really enjoy these types of papers that cross disciplines and there's an outstanding editorial by Susan Hedayati, from UT Southwestern who's a nephrologist, who weighed in here as well. So we certainly really value these types of papers in Circulation. Prof Paolo Raggi: I have to say, working with Circulation was amazing. You know, you get a great job and so fast. It was an incredible, actually. Dr Amit Khera: Obviously, the results speak for themselves that the study was positive, and we certainly see this diminishing the vascular classification and certainly you've been, for decades now, an expert in vascular calcification and coronary imaging. And you know, the question that always comes up is, what are the implications here? Now, on one side, especially with the coronaries, you think this would be favorable, you get less obstructive disease, perhaps less ischemic heart disease. But there's always been this debate if calcium's a good or bad thing in terms of plaque stabilization, so what are your thoughts on what ends up being the clinical ramifications of this down the road? Prof Paolo Raggi: Well of course, as we clearly stated in the paper, this has to be followed by some sort of clinical outcome study. So, it is only speculating at this point as to what the benefit might be. But more specifically about your question, I think that there is a misinterpretation of what calcification means in general. And honestly, I would prefer not to have calcification in my cardiovascular system if I had the choice. Many believe, and it's possibly true to a degree, that calcification comes in to repair the plaque and there's some sort of repair mechanism, but we have shown very clearly that the greater the calcification burden, the higher the probability of cardiovascular morbidity mortality. And therefore, it is not benign to have cardiovascular calcification in general.   In the case of the patients with end stage renal disease, calcification is not limited to the atherosclerotic plaque. It extends to the thickness of the entire vessel wall and it's well known that patients with end stage renal disease have severe calcification of the media as well as the intima. This obviously causes a series of other problems, such as stiffening of the vessels and therefore reduce compliance and in the long run, many profusion issues to multiple organs, even in the absence of luminal stenosis. A stiff vessel does not comply with what it's supposed to be doing. It is not allowing proper profusion of an end organ and many have demonstrated that also increases the work of the heart, pumping against very rigid plumbing, if you want to put it that way and simply, and therefore may induce left ventricular dysfunction in the long run, arrhythmias if a patient develops left ventricular hypertrophy and fibrosis. So, I think that there's a cascade of events that goes beyond and above just the single plaque, atherosclerosis, calcification. I think that calcification in general, and especially in patients with end stage renal disease, is a whole marker, very high risk of complications. Dr Amit Khera: Thanks for that clarification. I think first and foremost, it's so helpful to think beyond just isolated luminal stenosis and sort of all the maladaptive aspects of vascular calcification in patients with end stage renal disease. And that leads to the next thing in your paper, which I thought was also really interesting, which was the aortic valve calcification. We certainly appreciate that focus on aortic stenosis as of late with the new therapies, but you know particularly in patients with end stage renal disease, it becomes a very complex issue. And you saw some abating of this vascular calcification in the aorta as well. Tell us a little bit about what you think the implications of that would be. Prof Paolo Raggi: So first, a word of caution that the trial was not powered to demonstrate specifically an effect on aortic valve. However, we did demonstrate a beautiful effect on the slowing of the aortic valve calcification as well. It's exciting! I think that it's something that needs to be pursued further and I hope future studies, and definitely is the first time that anything has demonstrated an effect on aortic valve calcification. I'm very well aware of other studies that have attempted, for example, use of statins to slow the progression of valvular calcification and in essence, were completely negative. Patients with end stage renal disease, very severe valvular abnormalities, very, very severe, very important valvular dysfunction as a consequence of massive calcification on the annulus and the leaflets more so of the aortic valve, but also the mitral valve. So this could definitely be a signal for an excellent potential and unexpected if you will, a secondary outcome of this treatment. I believe that in affecting valvular calcification in patients with end stage renal disease would be, could have potentially a massive effect from the point of view of lowering the cardiovascular event rate. Dr Carolyn Lam: May I chime in with a quick question? What were adverse effects like? Prof Paolo Raggi: This particular drug actually was associated with the same exact rate of adverse effect as placebo. In other words, we didn't see anything at all that was alarming. There was one patient that had been reported by the investigator as potential side effect of the drug. They reported something, I think it was like acute hepatic failure, but when the case was clearly analyzed by the DMV, we actually assessed dictation as being a case of cholecystitis had been incorrectly labeled, we believe. And except for that one case, there essentially were no side effects, no adverse effects from treatment. In fact, although it was not powered for those outcomes, there was a lower morbidity and mortality with the SNF472 and then with placebo. Dr Carolyn Lam: I really like that and was really struck by your pointing out a little bit earlier, the ease of administration as part of hemodialysis. That was very nice. Amit, I'm going to give you the final words and questions if I may. Dr Amit Khera: As expected, this has been an exciting podcast and as much as I've read this paper and looked at it in detail, I learned a lot more as I had anticipated. My question for you, Paolo, now, is what's the next step? This is a phase 2B study. What's the next step in the development or evaluation of this compound and where are you going with this? Prof Paolo Raggi: There are a few sub analysis that we haven't yet looked at in this particular study that we just reported. One of the things that we are definitely interested in is to evaluate the effect on bone. As you can imagine, it is true that this particular drug has a wonderful effect on vascular calcification, but the next question is, did it do anything adverse to the bone? It's a logical question but I feel that most likely the answer is going to be a resounding no. But, besides that, the further development of this drug is obvious in my mind. It will have to be addressed in a proper, randomized clinical trial to address some of the clinical questions that we all have. Is this reducing the cardiovascular events? Be it when we need, we will decide together what those cardiovascular events would look like. But obviously myocardial infarction, congestive heart failure, admission for unstable angina, cardiovascular deaths in general, those are going to be very important questions to be answered in a further step. Before we get there, there are a few other questions that we have for the drug itself from this particular 2B study that we can still look at. Dr Amit Khera: Excellent. Looking forward to those subsequent analyses. Dr Carolyn Lam: Thank you and we look forward to the next publication on Circulation. Dr Amit Khera: Absolutely. Dr Carolyn Lam: I'm sure the audience is actually looking forward to more such discussions as these. Remember, you've been listening to Circulation on the Run.   Dr Greg Hundley: This program is Copyright The American Heart Association 2020.  

Dr Carolyn Lam: Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: I'm Dr Greg Hundley, also Associate Editor, the Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Say, Greg, you know the feature paper this week talks about the perennially hot topic now and that is transcatheter aortic valve replacement or TAVR or TAVI. It's actually data from the France TAVI Registry comparing balloon expandable versus self-expanding transcatheter aortic valve replacement. I'm sure you want to hear more about it, but first I'm going to tell you about another paper in the same issue, this time also comparing a balloon expandable versus a self-expanding transcatheter aortic valve implantation, but data from a nationwide analysis and from corresponding author Dr Fauchier from Centre Hospitalier Universitaire Trousseau. He and his colleagues basically did a head to head comparison of the two competing transcatheter aortic valve replacement technologies that have been published but have not really been followed for long-term clinical outcomes. This was comparing balloon expandable versus self-expanding technology. They collected information from more than 31,000 consecutive patients treated with Tavern in France between 2014 and 2018 and based this on the French administrative hospital discharge database. They did propensity score matching, which was used for the analysis of outcomes according to the Sapien 3 balloon expandable versus the Evolut R self-expanding TAVR technology and studied this as nationwide level in France. Dr Greg Hundley: Wow. Carolyn, 31,000 patients. That's a really large study. What did they find? Dr Carolyn Lam: They basically found that balloon expandable TAVR was associated with lower mortality rehospitalization heart failure and pacemaker implantation compared with the self-expanding TAVR. Now, that's of course a pretty big finding and this is discussed along with the feature paper that we're going to hear about in an editorial by Drs. Abdel-Wahab and Thiele from Heart Center Leipzig. I want to tell you about another paper before I let you tell you about yours, okay? Dr Greg Hundley: Sounds great, Carolyn. Dr Carolyn Lam: Greg, what is your clinical impression of Impella use in the United States among patients undergoing PCI? Do you think it's increasing or decreasing over time? As a reminder, Impella was approved for mechanical circulatory support in 2008, so from then, what do you think? Dr Greg Hundley: You know, Carolyn, I really think it's increasing, especially used more frequently rather than an intra-aortic balloon pump. How about you? What's going on in your area of the world? Dr Carolyn Lam: My impression too, but you know, you're lucky because we now have data looking at the trends in Impella use, but in the United States, and this comes from the corresponding author, Dr Amit Amin from Washington University School of Medicine and colleagues who describe clinical outcomes and costs across U.S. hospitals in PCI patients treated with mechanical circulatory support, which is either the Impella or the intra-aortic balloon pump. They found that among more than 48,300 real world patients undergoing PCI with mechanical circulatory support at 432 hospitals between 2004 and 2016 in the Premier Healthcare Database, Impella use was indeed found to be rapidly increasing with marked variability across hospitals and not only its use, but also in its associated adverse outcomes. When analyzed by time periods or at the level of the hospitals or at the level of the patients, Impella use was associated with higher rates of adverse events and higher hospital costs. Dr Greg Hundley: You know, I wasn't thinking about the higher rate of adverse events. You wonder sometimes, are we using a technology in a sicker group of patients? Did this study shine any light on that? Dr Carolyn Lam: Those are great, great thoughts. The authors concluded that the variability in Impella use, the variability in its associated outcomes, and the association of Impella use with higher adverse events and costs really, really underscore the need for better defining of the appropriate use of mechanical circulatory devices and that was what you indicated as well, Greg, and what we need there is adequately powered randomized clinical trials and prospective real world evidence, which we don't quite have yet. Until then, perhaps a more measured approach is needed in clinical practice that balances risks versus benefits in complex patients undergoing PCI who require mechanical circulatory support. Dr Greg Hundley: That's going to be really needed, I think in this era, especially with the results from this study. Well, Carolyn, I'm going to switch over to the world of basic science and the first study I'm going to talk about is from Dr Richard Lee from Harvard University and it's a very interesting study. Just as some background, current differentiation protocols to produce cardiomyocytes from human induced pluripotent stem cells are capable of generating highly pure cardiomyocyte populations, but these cardiomyocytes remain immature and they really more closely resemble the fetal state. As a result, they have a lower maximum contractile force, slower upstroke velocity, and immature mitochondrial function compared to adult cardiomyocytes. Also, they're prone to ventricular arrhythmias. During development, cardiomyocytes undergo a shift from a proliferative state in the fetus to a more mature but quiescent state after birth. The mechanistic target of Rapamycin mTOR signaling pathway plays a key role in nutrient sensing and growth, and Dr Lee and colleagues hypothesized that transient inhibition of the mTOR signaling pathway could lead cardiomyocytes to a quiescent state and enhance cardiomyocyte maturation. Dr Carolyn Lam: Wow Greg, I really love the way you explained that. That's so interesting. What did they find? Dr Greg Hundley: Among human induced pluripotent stem cell lines, transient treatment with Torin 1, an inhibitor of the mTOR pathway, shifted cells to a quiescent state and enhanced their cardiomyocyte maturity. Also, the investigative team suggests that further testing will be necessary to evaluate whether delivery of Torin 1 treated cardiomyocytes could reduce the risk of ventricular arrhythmias in newly differentiated myocytes derived from pluripotent stem cells. Really an important advance in this whole area of developing mature cardiomyocytes from our own pluripotent stem cells. Well, Carolyn, my second basic science paper comes from Dr Calum MacRae from Brigham And Women's Hospital, also at the Harvard Medical School. Carolyn, this study used both highly purified human pluripotent stem cell derived cardiomyocytes displaying physiological and molecular characteristics of atrial cells with human MYL4 mutations in a zebrafish MYL4 knockout model, which exhibited molecular, cellular, and physiologic abnormalities that parallel those in humans bearing the cognate mutations associated with definitive genetic causes of atrial fibrillation. Dr Carolyn Lam: Oh, that's really interesting. Is this new genetic predispositions that they discovered? Dr Greg Hundley: I think the answer's yes. They found there was evidence of increased retinoic acid signaling in both human pluripotent stem cell derived cardiomyocytes and zebrafish mutant models, as well as abnormal expression and localization of cytoskeletal proteins and loss of intracellular NAD and NADH, and thereby established a mechanistic link between the transcriptional, metabolic, and electrical pathways previously implicated in the atrial fibrillation substrate of MYL4. In the future, these data could lead to novel therapies for some patients with atrial fibrillation. Dr Carolyn Lam: Wow. That really is fascinating, Greg. Well, let me round up by telling you about some of the other things in the issue. There is a research letter by Dr Parish on the effects of Omega-3 fatty acid supplements on arrhythmias and here, these authors reported more comprehensively on atrial fibrillation and other arrhythmias using additional data extracted from linked electronic health records in the ASCEND trial, remember, which was 1 gram of Omega-3 fatty acid supplementation daily in people with diabetes but without known atherosclerotic cardiovascular disease. Dr Greg Hundley: Oh wow. That's fantastic, Carolyn. I've got a couple other really interesting articles in the issue. First there's an In Depth review from Dr Yvan Devaux from Luxembourg Institute of Health, and he discusses regulatory RNAs in heart failure. In a perspective piece, Dr Alejandro Lucia from Universidad European de Madrid discusses the role of aerobic and resistance training as a therapy in addition to prescribed medications in patients with resistant hypertension. Really interesting. Then finally, Dr Ify Mordi from University of Dundee examines metformin use and clinical outcomes among patients with diabetes, with or without heart failure, kidney dysfunction observations from the SAVOR-TIMI 53 trial in which Dr Bergmark and colleagues found that metformin use was associated with a reduction in all-cause mortality and cardiovascular death, but not due to myocardial infarction or stroke, particularly in patients without a prior history of heart failure. What could the mechanism be, if not related to presumed atherosclerosis? Dr Mordi and colleagues proposed possibilities, and Dr Brian Bergmark from the TIMI study group and the cardiovascular division of Brigham and Women's hospital at Harvard Medical School and colleagues, they write a very nice response. It's really interesting listening to how could metformin reduce events but not related to atherosclerosis? How about onto our feature article? Dr Carolyn Lam: You bet. Dr Amit Khera: This is Amit Khera, digital strategies editor for Circulation from UT Southwestern Medical Center joined by my colleague, Dr Dharam Kumbhani who's also an associated editor at Circulation and we're pleased to have Dr Eric Van Belle, Professor Van Belle, from Lille University Hospital to discuss the featured article today, "Transcatheter Aortic Valve Replacement Propensity Match Comparison From the France TAVI Registry." Welcome to you both. Dr Van Belle, I'm going to start with you and we always like to hear a little bit. Perhaps you can tell us some of the background, what led up to this investigation, what led to your group pursuing this manuscript? Dr Eric Van Belle: Nowadays, the TAVI procedure, the TAVR procedure, is becoming very prominent kind of way of treating patients without stenosis, and basically we have two different type of devices that are available to treat the patients. Once series is based on the balloon expandable concept and the other one on the self-expandable concept. These two type of devices are considered to be used primarily in every kind of patient. Theoretically, we can use any of these two devices, any kind of patient, if we follow the recommendation of the manufacturer and I'll just say that that'd been done. These two devices are being validated against surgery, so basically, we could potentially use any kind of them. In today, there is no direct and there was no direct comparison between the two different kinds of concept, although they are very different. Again, the device is different. The way we implant the device is different. The major question that we had behind was to say, okay, what is the outcome? If it's a mean patient get one of the devices or can we expect or should we expect a different outcome? That was the main question behind it. Dr Amit Khera: Okay, so essentially there's two valves, they're both being used fairly regularly and without any kind of direct comparisons. Tell us a little bit about the study design and what you found in this project. Dr Eric Van Belle: For methodology, we used what is called a French study registry, basically nationwide registry with almost all patients treated in France included, and we used it as a database of patients between 2013 and 2015 with an overall group of 12,000 patients treated with either of these two kinds of devices. This is one of the aspect of this registry. The other very important aspect of this registry, and that's the mortality data survival that was obtained in all the patients in 2008 through 2016, so we have a set of 12,000 patients. It was a cool kind of device with complete mortality data by April 2016 so basically, this is the main methodological aspect. On top of this, we did the best to do some matching on the older clinical variables and all the matching valuables that we had to create pairs of patients that could be matched to one to one. We had, at the end, a group of almost 4,000 patients. Dr Amit Khera: Okay and tell us a little bit about some of your main findings of this study. Dr Eric Van Belle: The two main findings were those differences between the two groups of patients, that is a patient treated with self-expandable devices at a higher risk of valvular regurgitation. This was mainly a confirmation because this finding was already reported previously in previous studies trying to compare the two devices, but what was more striking was the difference in mortality. It was a difference mostly in hospital mortality but also in mortality after two years. That was significant with an absolute difference in mortality around 3% by two years. Dr Amit Khera: Well, obviously important, as you mentioned that paravalvular leak had been seen before and this now a long-term mortality difference. Certainly an important finding and one of the main findings of your study. One of the concerns about comparative effectiveness research, essentially you're using observational data such as this is that there still could be residual confounding. There still may be patient characteristics or decisions made by interventionalists that aren't fully accounted for. How did you all really try to account for some of these components, this residual confounding to try to get the best answer that you could? Dr Eric Van Belle: That's going to be a major comment, and everything you can do, every best way to try to control for this, there is no better answer than to do a randomized study, and probably we'll discuss on this. Let's see, indeed, we try to do our best to minimize as much as we could, all these potential confounders, so we did it in a different way, indeed. The first way to do it was to adjust all the potential differences among group but what was very also interesting to remind is that, when you look at the 25 clinical and imaging variables and creating the aortic annulus diameter that was incorporated in the matching, that actually 21 of the 25 variables were already there. We were balanced between the two groups, existing that indeed most of the case, the operators, we are not so much directing or at least if there was selecting it was not captured but all of these valuables because again, out of 25, the correction needed to do the matching was only affecting 4 variables, mainly. Those variables were already pretty well-matched between the two populations. The other way we did it was to look at what is called falsification endpoint, that it is endpoints that are supposed to be unrelated to the devices to verify that indeed, we have not selected a population that will have issues that are not related to the device itself. We look at, let's say, mortality by infection, mortality by cancer, to verify that, indeed, this kind of event where it did well balanced between the two groups suggesting that the mortality effects that we observed was not related to this kind of unbalance related to something else that was not captured by analysis. Dr Amit Khera: Yeah, I think that was quite an important observation you mentioned. The first that these two groups are generally well-balanced to begin with, even before with all the matching parameters and then certainly the falsification endpoint helped to add validity to the findings. Dharam, I'm going to turn it over to you. Maybe you can show this from an associate editor's perspective. What are some of the observations you found interesting about this study and what are some of the considerations we had in some of the discussions about it? Dr Dharam Kumbhani: I'll just remind our listeners that this was also a late breaker at AHA last year in 2019, so this is really a very important finding. As Eric briefly pointed out, there haven't really been head to head comparisons between, the two dominant valves in the market even though TAVR has pretty much become the dominant strategy for treatment of aortic stenosis. At the end of the day, it's an observational analysis. We have to take the findings with that in mind. At a minimum, it's first a lot of debate and discussion about the need to have randomized trials and our belief that, perhaps, TAVR is a class effect may not always be true. I think that hypothesis would certainly need to be tested and that's what this paper really sparks as far as discussion going forward. Dr Amit Khera: Maybe I'll ask both of you. One of the challenges of any type of observational research is time period. First there was a hint towards even maybe a greater effect in the more recent time period than the distant time period. Also, there's always commonly changes in technology, especially interventional field where a study comes out and it's already obsolete because there's some new technology. There are some newer generations of valves that have come out. Do you think that it would affect these findings in any way? Maybe we'll start with you, Eric. Dr Eric Van Belle: That's always an issue. Again, because it's a very rapidly evolving field and if you want to have strong data, you need to have really long-term follow-up. You need to have mortality data. There is some kind of contradiction between both that the field is evolving very quickly but then to have solid data, you need to have some time. What we could say, indeed, as a study period was 2013 and 2015, but the device that we are using at that time were already really well matured and also the devices that were used at that time was usually the ones that were used for the comparison with the surgical techniques. Again, these devices are not so much obsolete since they were accepted and used again, when you need this one device study to compare with surgery. Of course these devices have still had some evolution and change, and it is for the good of the patient, but again, as mentioned there, I'm seeing what is very, very important is that this finding is, in my view, intriguing enough to say, okay, even if it's difficult to conduct this kind of randomized study, it has to be done now because we need to really know. Let's say 80% of the patients could indeed be treated with any of the two device in this large margin of patients. Do we have to choose one or the other one to start with? This has already been well answered in a larger randomized trial. Dr Amit Khera: Dharam, maybe I'll ask you, do you think this large randomized trial, are you optimistic that that would happen? Certainly it sounds like it's something that would be very helpful for the field. What are your thoughts on whether that's actually going to occur? Dr Dharam Kumbhani: I know that there are some head to head trials ongoing. I don't know if they will have the sample size to really drill down, as far as hard endpoints, mortality, for example. I think the field clearly needs it. The question is, who's going to sponsor a trial like that? There's probably not much incentive for industry to sponsor something like that. Really it would fall down to whether there's a way for government agencies to partner with industry or other ways to run this. I do agree with Eric that that's really very important and hopefully we'll see that in the field going forward. I did want to comment on the next iteration of devices as far as what we may see now. The mortality signal, I know we've talked about it. It's an observation study. It's hard to know if there's confounding, and even with all the sophisticated statistical analyses that the team did, there's always a possibility that somehow there was sicker patients that received self-expanding valves. The signal for paravalvular regurgitation is not just in this study. We've observed it in many other studies and for other self-expanding platforms as well. Both the SCOPE trial and the St. Jude trial last year, both came around the same time. They were self-expanding platforms and both of them showed a higher paravalvular regurgitation rate compared to the balloon expandable rate. That may be a real thing, and I don't know if that is an inherent design flaw in the self-expanding platform or if there are ways that that could be mitigated going forward. Again, I think the trials, for it to be meaningful, it would be obviously important to collect and have short term and imaging markers. Really, what the field needs is long-term evaluation of these two strategies. Dr Amit Khera: I want to take both Dharam Kumbhani and Dr Eric Van Belle l from Lille University Hospital. Thank you both for joining today. Dr Greg Hundley: This program is copyright, the American Heart Association 2020.  

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Carolyn Lam, Associate Editor from National Heart Center at Duke National University of Singapore. Dr. Greg Hundley: And I'm Greg Hundley, Associate Editor, Director of the Pauley Heart Center in Richmond, Virginia. Dr. Carolyn Lam: Greg, it is so good to be back. I just love doing these podcasts with you and what more when we get to feature a paper like the one that we have this week. It's all about high sensitivity, cardiac troponin and the universal definition of myocardial infarction, one of these evergreen topics that we truly need to understand better. But before we go onto that, I want to share my first paper. It's a preclinical paper and it provides an important breakthrough discovery that could protect the heart against progressive left ventricular systolic dysfunction following injury. Want to hear about it? Dr. Greg Hundley: Absolutely. Dr. Carolyn Lam: Okay. It's from course wanting authors, Drs Sabourin and Benitah from INSERM University, Paris, as well as Doctors Foster and Beech from University of Leeds. Dr. Carolyn Lam: Now, whereas store operated calcium entry has recently gained attention in cardiac pathophysiology, the role of the prototypic store operated channel known as Orai1 remains elusive. So these authors used a novel genetically modified mouse that specifically disrupts the Orai1 channel in cardiomyocytes and showed that functional inhibition of Orai1 preserved alterations of calcium homeostasis, fibrosis and systolic function without affecting hypertrophy. A novel in vivo small molecule Orai1 channel inhibitor, in fact, markedly improve left ventricular systolic function and calcium handling after pressure overload without causing adverse effects. Dr. Greg Hundley: Tell me, how does this help me as a clinician? Dr. Carolyn Lam: All right, you always ask the tough questions. Well, these results really suggest that Orai1 inhibition has the potential for favorable hemodynamic value in the protection of the heart from maladaptive hypotrophy, and therefore might represent a new way to provide inotropic support to help relieve systolic dysfunction. Dr. Greg Hundley: Very good. Well Carolyn, my first paper is from Dr Peter Kudenchuk from University of Washington Medical Center and this study evaluates the overall survivor after out of hospital cardiac arrest from shock refractory ventricular fibrillation or pulseless ventricular tachycardia related to the route of accessory drug administration. So to accomplish this, the investigators had 2,358 individuals that had received Amiodarone, lidocaine or placebo study drugs and randomized to an IV route. Dr. Greg Hundley: And then they also included 661 patients that received the same medications, but they were randomized to an intraosseous route. Dr. Carolyn Lam: So what were the results, Greg? Dr. Greg Hundley: Well, Carolyn, while no significant effect modification by drug administration route was observed point estimates for the effects of both drugs, both the lidocaine and the Amiodarone, compared to placebo were greater for the IV, as opposed to the intraosseous route and that was across all outcomes. And they had significant increases in survival to hospital admission and discharge and favored improved neurological outcomes with the IV administration. Dr. Greg Hundley: Unfortunately, however, the study was underpowered to examine for an interaction between the route of vascular access and drug effectiveness and thus additional studies are needed to determine whether Amiodarone in lidocaine may be lifesaving drugs in patients with shock refractory out of hospital cardiac arrest when given IV, but not necessarily intraosseous. Dr. Carolyn Lam: Very interesting. Well, my next paper is really focused on HIV infection and asks the question, is HIV infection associated with abnormal cardiac repolarization that may contribute to a greater risk for sudden arrhythmic death? Well, corresponding author Wendy Post, our very own from Johns Hopkins University School of Medicine and her colleagues studied 1,123 men, 589 of whom were HIV positive and they were from the multicenter AIDS cohort study and they were studied using the ZioXT ambulatory ECG patch. Dr. Greg Hundley: Wow. Carolyn, this study sounds like it's the largest study of QT variability in HIV today. Dr. Greg Hundley: Is that right? And what did the authors find? Dr. Carolyn Lam: Yeah, it's right. It's huge. And basically they found that HIV positive men had greater beat to beat variability in the QT interval compared to HIV negative men, especially in the setting of HIV viremia and heightened inflammation. Dr. Carolyn Lam: Among HIV positive men, a higher QT interval variability suggests ventricular repolarization lability which could increase susceptibility to arrhythmias. However, lower heart rate variability also may signal a component of autonomic dysfunction. Dr. Greg Hundley: Ah, Carolyn. My next paper goes back to the world of basic science and it's from Dr. Chen Yan from University of Rochester. And in this study, Dr. Yon and colleagues examine the role of cyclic nucleotide phosphodiesterase in isolated adult mouse cardiomyocytes and fibroblasts as well as in preclinical mouse models of hypertrophy and/or heart failure. And they found that phosphodiesterase 10A expression is significantly induced in mouse and human failing hearts. Dr. Greg Hundley: It directly promotes cardiomyocyte hypertrophic growth as well as cardio fiber-blast activation, proliferation, migration and extracellular matrix production. In addition, phosphodiesterase 10A deficiency, so not as much of it, ameliorates cardiac hypertrophy fibrosis and/or dysfunction in different preclinical mouse cardiac disease models. And finally inhibiting phosphodiesterase 10A activity with a compound labeled T P 10 effectively antagonizes the pathological cardiac remodeling in LVH. Dr. Carolyn Lam: Huh, that's interesting Greg. And now I'll ask you, so what are the clinical implications? Dr. Greg Hundley: Well, phosphodiesterase 10A inhibitors have been evaluated in phase two clinical trials for treatment of schizophrenia, suggesting that these agents are safe, druggable, if you will, targets. And therefore the results with TP 10 suggests a potential therapeutic effect of targeting phosphodiesterase 10A on antagonizing the development of pathological cardiac remodeling. Perhaps as suggested by Dr. Ezekowitz last week, this could represent another new agent in the treatment of the adverse effects of heart failure syndromes, more pharmacological agents coming to treat heart failure. Dr. Carolyn Lam: Wow. That is interesting. But okay, let's talk about what else is in this issue. So let me tell you about an online mine by Dr. Kalra and it's called the Cardiovascular Science India Tour. And what this talks about is a multi-pronged initiative bringing together professionals and diverse expertise to allow better understanding of the issues driving the ever-rising cardiovascular disease burden in South Asia. Dr. Greg Hundley: Oh, very good. And from the mailbag, I've got a research letter, Carolyn from Dr. Julian Luetkens from the University of Bond, who investigates a surrogate of frailty by examining the fat fraction within skeletal muscle at the L three L four level. So it's from an axial CT that's acquired at the time of CT scanning for TAVR pre-evaluation and uses the fat muscle fraction to forecast TAVR outcomes. Well. Carolyn, that's a great wrap up. How about we get onto our feature article? Dr. Carolyn Lam: You bet. Dr. Amit Khera: Hi, this is Amit Khera. I am digital strategies editor for circulation and today with our featured podcast we have Dr. Andrew Chapman from the university of Edinburgh, UK who is the first author of a study entitled high sensitivity cardiac proponent and the universal definition of myocardial infarction. Welcome Dr. Chapman. Thanks for joining us. Dr. Andrew Chapman: Good morning. It's a pleasure. Thank you. Dr. Amit Khera: This is obviously a very interesting study and timely and on the backs of the prior work that your group has published. Maybe we can start by you telling us a little bit about the impetus, the background which led to this work. Dr. Andrew Chapman: We've been using high sensitivity cardiac troponin in Europe now for some years, and the way that we diagnose myocardial infarction has, of course changed. We now recognize that myocardial infarction can occur in the context of an occluded coronary artery, be that a STEMI or an NSTEMI, also known as a type one myocardial infarction. Dr. Andrew Chapman: But increasingly with the use of more sensitive cardiac troponin, we're recognizing myocardial infarction can occur in other conditions. So for example, after arrhythmia or after severe infection with hypoxia. So the real rationale and background for this study is trying to understand better the different subtypes of myocardial infarction. As proposed in the universal definition. Dr. Andrew Chapman: And we were in quite a unique position to evaluate this as, when we implemented high sensitivity cardiac troponin testing in Scotland as part of a randomized controlled trial. We did so across different hospitals and two of our major cities, Edinburgh and Glasgow, and the trial which formed the basis for this study was called the high States trial and we enrolled 48,000 patients of who we initially used a contemporary sensitive cardiac troponin on an IRC and we then implemented a high sensitivity cardiac troponin IRC. Dr. Andrew Chapman: And that allowed us to evaluate what impact implementing this high sensitivity test hard firstly on the prevalence of different subtypes in myocardial infarction, but also on the investigations and the treatments received. And finally of course the clinical outcomes of these patients. Dr. Amit Khera: So obviously at a really sizable study and good forethought on your group to implement this as this step wedge type study design. As you pointed out, the goal here was to understand the different subgroups of myocardial infarction, the prevalence and implications. Tell us a little bit about what you found in this study. Dr. Andrew Chapman: As I mentioned, we had over 48,000 consecutive patients and that was the real benefit of this step wedge design is that rather than recruiting patients between say nine and five where we had research nurses available, we enrolled all consecutive patients. So we think this is quite a representative population for our area. So of those patients, we found around 10,000 had elevation in the high sensitivity cardiac troponin concentration, and we adjudicated these diagnoses in parallel. So two independent clinicians look through every case, all the clinical information. And we had a consensus from a third when there was disagreement. So in short we found that around half of all elevations in cardiac troponin in this study were to take one myocardial infarction, that is that the blocked artery phenotype and the type two myocardial infarctions or an acute or chronic myocardial injury and myocardial injury being elevation and cardiac troponin, either acute with a rise or fall or chronic with a stable concentration with no evidence of myocardial ischemia and occurred in the other 50% of patients. Dr. Andrew Chapman: So looking between the phases of the study, we found introducing high sensitivity troponin disproportionately increased the diagnosis of Type II MI or acute or chronic myocardial injury. So there's just an 11% increase in the diagnosis of Type I MI, and I think again that's highlighting that these more sensitive tests are finding myocardial damage in areas that previously it might not have been recognized. Dr. Andrew Chapman: So moving forward from that, we evaluated the primary outcome of the trial, which was future myocardial infarction or cardiovascular death by subgroup. And we also evaluated unimportant non-cardiovascular death. If I may for just 30 seconds, I'll just discuss why this is important. Dr. Andrew Chapman: So evaluating future cardiovascular events is very important and in different subgroups of myocardial infarction. However, we know patients with Type II MI and acute or chronic myocardial injury are different. So they tend to be older, they're more commonly female, they have more comorbidities, they're on more medications to start with. Dr. Andrew Chapman: And these patients are ar increased risk of a competing events to cardiovascular death or a myocardial infarction. And that is that these patients can go on and die, will primarily from their primary illness, be an infection or a pulmonary embolism or what have you. But also they are at increased risk of death from other non-cardiovascular causes. Dr. Andrew Chapman: So in this study we were able to evaluate future cardiovascular risks using quite advanced competing risks modeling. And I was very grateful for the input of a number of experts and we managed to find that actually, Type I myocardial infarction patients with occlusion or partial occlusion of the coronary artery were at the highest risk of cardiovascular events going forward. Dr. Andrew Chapman: But interestingly, even despite the vast excess in non-cardiovascular death, patients with Type II MI, and acute or chronic injury also had quite a high cardiovascular risk over three folds out of patients without myocardial injury. And we noticed that these patients did not stand to receive increases in investigations or treatments for coronary heart disease and we speculate and we hypothesize that actually in a proportion of these patients there is some clinical coronary artery disease which has manifested itself during this physiological stress test of an alternative illness. We wonder and we hope that moving forward this might be an opportunity for better targeting it in an investigation and perhaps even improving clinical outcomes. Dr. Amit Khera: Well, you just shared a ton of important findings there and I'm going to unpackage a few of them. I guess the first is this sort of type I versus type II MI, and I think one of the fears with implementing these high sensitivity troponin would be perhaps an explosion in these type II MIs. And I think, if you look, although you mentioned proportionally, the absolute numbers of increase in type I and type II MI was relatively small so it didn't seem we had this explosion that I think people had feared was implementation. Dr. Andrew Chapman: Yes, that's a fair point. And also need to bear in mind this is a population of patients from Scotland and our high sensitivity troponin testing is quite selective. You would find differences in the impact of high sensitivity if you're testing practices were different and I know there's prior work from the United States showing that less selective testing or to put it in a different way, testing troponin in more patients. Perhaps some of them may not have symptoms of chest pain or symptoms suggestive of myocardial infarction, is likely to change the prevalence of these different groups and you are likely to pick up more secondary injury or type II MI, but I think we don't need to panic. There's no need for alarm. I don't think there is going to be an explosion in recognition of these patients. If you check a temperature, you'll find a fever, but provided we're sensible and who we're testing, then I don't think practice needs to change dramatically. Dr. Amit Khera: That was a great way to say it. Unfortunately, we're always looking for fevers in the U.S. So as you pointed out, the prevalence increase may increase a bit, but definitely reassuring from what you're finding in your population was more judicious testing. Dr. Amit Khera: The second point that you brought up was the event rates, type I versus type II MI. I guess this does remind us again that patients with type II have almost comparable cardiovascular deaths and MI rates as type I, so certainly a higher risk group. As you pointed out, there's many comorbidities there and this gets to your point about treatments. I guess the question is now the event rates are higher, these are higher risk group or what to do about it I think is one of the vexing problems. As you pointed out, there's, there's not a lot of secondary prevention treatments, but what should those treatments be and where do we go from here in terms of these type II MI? Dr. Andrew Chapman: That's the million dollar question I suppose and something that we've explored in another recent circulation review under the [00:17:07] lead author is what we do for these patients. When we've looked at different strategies, it seems the most reasonable initial approach is determining, does my patient with type II MI or myocardial injury actually have a cardiac problem? Dr. Andrew Chapman: Now I don't think we have the evidence to support routine and baited testing in this population yet and indeed that might expose patients to harm and that's one of the tensions with this diagnosis. Dr. Andrew Chapman: For example, consider the patient with gastrointestinal hemorrhage and could it have gone forward for an angiogram. Giving them heparin might not be the best thing to do in their acute illness. However, whether or not these patients would benefit from noninvasive tests such as a CT scan to delineate the coronary anatomy and identify those that might benefit from an iron platelet agent or a statin or indeed an echocardiogram to determine which patients have left ventricular impairment and could benefit from the many number of treatments we have now for LV impairment and that would be my initial thinking is that we need to firstly risk profile these patients. Dr. Andrew Chapman: What is their pretest probability or likelihood of coronary artery disease? It's not intermediate or high. Let's have a think about investigating their coronary arteries. In the first instance, I think a noninvasive test is going to be most appropriate for the majority of people, but we need a personalized approach. It may be that someone's just had a very brief run of an arrhythmia and that's resulted in a disproportionate level of ischemia and a very high cardiac troponin. Dr. Andrew Chapman: Your index of suspicion for that patient having coronary disease is going to be significantly higher. So a personalized approach, I think, is where we're heading. And there are trials which are coming in this area. So yeah, two trial is being led by Derek Chu of Melbourne in Australia and they're evaluating the use of CT or invasive angiography to identify coronary disease and target treatment to see if that can improve outcomes. Dr. Andrew Chapman: And certainly here in Scotland, we're hoping to evaluate the use of a personalized approach to target treatment in patients with type II MI and again, try and improve cardiovascular outcomes. So things are coming. Dr. Amit Khera: Well, I appreciate that and I think as you pointed out, as we wait for these additional data and additional studies, sort of a thoughtful. algorithmic approach would be helpful and we certainly will make sure the readers and listeners look out for that paper that you mentioned in circulation. Dr. Amit Khera: I should also point out that your paper here is an excellent editorial by David Morrow, which has a nice figure and illustration of your central findings. So we appreciate that. As we wrap up here, maybe you can tell us what are the main take homes? What should they take away from this study? Dr. Andrew Chapman: What we've shown is that high sensitivity troponin are useful and we've shown that they increase recognition of patients who have myocardial jury or type II myocardial infarction, where in the past this may not have been found and we've shown quite clearly that these are prognostic. Not only predicting non-cardiovascular disease, but also going on to identify patients at increased risk of myocardial infarction, cardiovascular death. Dr. Andrew Chapman: So I think moving forward, clinicians using these tests and identifying these patients should be considering investigations to identify coronary or structural heart disease. And until we have that high quality randomized controlled trial data, we need to be pragmatic and we need to evaluate secondary prevention on an individual patient basis, be that an antiplatelet agent or be that a statin as the primary ones. This may even go on to include an ACE inhibitor or a beta blocker if there's LV impairment, but our aim ultimately has to be to try and reduce the cardiovascular event rates in this population who, to date, have been under investigated and undertreated. Dr. Amit Khera: That summarizes it quite well. And I want to thank Dr. Andrew Chapman for his excellent discussion today and that's why we do these backstage passes to get an inside look as to what the authors were thinking and some behind the scenes on their papers. Dr. Amit Khera: Again, I'm Omnicare digital strategies editor for circulation, and thank you for joining us on this circulation on the run podcast. Dr. Greg Hundley: This program is copyright, the American heart association 2020.

Dr Amit Khera: I'm Amit Khera, I'm digital strategies editor for Circulation and I'm standing in this week for Carolyn Lam and Greg Hunley. And I'm also doing the Circulation on the Run podcast, as well as Discover CircRes podcast with our two editors in chief. This is Jane Freedman, who recently took over as editor-in-chief of Circulation Research, and Joseph Hill, who is the editor-in-chief of Circulation. So, welcome you both. We're excited to do this. Dr Joseph Hill: Thank you. Dr Jane Freedman: Thank you. Dr Amit Khera: The idea behind this, there's this session here at sessions where we're learning a little bit about Circulation Research and Circulation, pulling back the cover, if you will, and seeing behind the cloak, as what happens in the Journal. So, Dr Freedman, I'll start with you. Tell me a little bit about, as the incoming editor of Circulation Research, some of your vision for the Journal, which you're excited about. Dr Jane Freedman: Mm-hmm (affirmative). Well, I'm thrilled to be the new editor of Circulation Research. And I've assembled a fabulous team of associate editors, deputy editors and other staff and support, that are going to continue to grow what's already a wonderful journal, to be the preeminent and primary journal for basic and translational cardiovascular sciences. And also support and interact with the other HA family of Journals. Dr Amit Khera: So obviously that starts with a great team. And it sounds like you've assembled that. Anything new that you're thinking about, and sort of the redesign of Circ Research in your term? Dr Jane Freedman: Sure. So, we're hoping to expand the original scientific content, so we can have a larger number of articles in original science. And we can have the pages to be able to handle other areas of basic cardiovascular science to include new areas, emerging areas, things like that. We're also increasing some of our early career initiatives, so that's very important to us as well. Dr Amit Khera: Fantastic. Fantastic. Can you talk about expanding for science? And Joe, that leads to you. I'm going to, in this session tomorrow, one of the goals is when people submit their science, it really goes into a black box and people don't know what happens on the editorial level. Can you maybe enlighten us a little, what happened? Dr Joseph Hill: Jane and I have been friends for 20 or more years and we now have established a bi-directional, mutually synergistic collaboration where we send papers each way. We have distinct missions, but yet with significant overlap. And I think it's an incredibly exciting time for the entire portfolio of AHA Journals. So as you say, most people that you hit send and you wait four to six weeks, and you either get a happy note or an unhappy note. And, what happens at both our Journals is we have a strategy of multiple touches on every paper. The paper that first comes in, is first touched by a senior editor, either myself or James de Lemos, and two or three others. And we will reject without review, about 50% of the papers at that point. We publish six papers a week, but we get 110 a week. So we don't need to review 50 of them to pick the top six. Out of respect to our authors to save them time, out of respect to our reviewers who devote tremendous effort to reviewing papers, we don't send them papers that we don't think have a shot. That said, if a paper makes it past that first stage, there's about a 50% chance it'll get published either in our Journal, or in one of the subspecialty journals. Probably a 50-50 chance it'll be published somewhere in an AHA family Journal. So if it makes it past that stage, we send it to an associate editor, of which you are one. And we have about 50 of them. A third are in Dallas, another third are in the U.S. outside of Dallas, and another third are in countries around the world, 17 different countries. And that person will probably reject without review, another five or 10% maybe. But he or she will dig into that paper, and in parallel send it out to two or sometimes three reviewers, who are trusted and valued advisors. They help that associate editor make a strong recommendation. He or she makes a decision to bring to the larger group, that is informed by those reviewers. So already that paper has been touched by five different investigators. Typically, that associate editor will reach out electronically within his or her affinity group. We have an affinity group in epidemiology, heart failure, intervention, basic science. Asking other AEs, "Could you take a look at this paper? One reviewer said this, one said that, I'm sort of thinking this." And then we'll have a conversation on our weekly video conference, and then a decision goes out to the authors. So every paper is touched by at least five, and sometimes 10 different editors and reviewers, which we have found has been a powerful way to really dig into and identify things that one or two people might have missed. Dr Amit Khera: One thing I note here is, if you realize how many people touch these articles, yet how efficient and how fast this process is, then that's a testament to sort of, the goals of the Journal, to be really responsive and rapid for our authors. One big part of that, and come back to Dr Freedman is peer review, right? So, associate editors have a lot of work, and were affinity groups and so forth, but really critical are these peer reviewers. And in the modern era, we're all so busy. Tell us a little bit about the value of peer review, and how we enhance the value to the peer reviewers themselves. Dr Jane Freedman: Mm-hmm (affirmative). Well, just as you said, the peer reviewers are absolutely central, valued and vital parts of making the Journal run correctly. And we, like Circulation, our associate editors send them out to three different peer reviewers, and they have a very fixed amount of time to review the articles, and they provide these wonderful comments. We also very heavily rely on our editorial board. They know the drill, that it needs to be back within a fixed amount of time. And for the most part, they do it. It's an interesting question, "What's the value to them?" I've been a reviewer too. It's part of your pay back. It's part of educating yourself about what's new and interesting. There's a lot of reasons for doing it. People enjoy being on the editorial board and interacting with the Journal. But fundamentally, as an editor, you're incredibly grateful to your reviewers. They are the unsung heroes of making a Journal work. Dr Amit Khera: You mentioned sending out to three, when you have sort of disparate reviews. It's amazing when some people love it and some people hate it. Dr Jane Freedman: Yeah. Dr Amit Khera: How do you handle that? Dr Jane Freedman: Yeah, well, sometimes it's apparent from the reviews why that happened. Someone may have focused on something, that the editorial group thinks is less important. Or they have focused on something that's addressable. The other thing we do, similar to Joe, is we have a video conference call every single week on Wednesdays, and that's a period where people can vet any concerns or questions. And then my editors, my associate and deputy editors know we have an open communication at all times. So I very frequently, when they have questions about reviews and how to reconcile disparate reviews, we'll have an ongoing conversation about that. Dr Amit Khera: It sounds like, of course you're actively engaged in how this is a dynamic process. I'll mention one thing, is digital strategies editor and I know both at Circ Research and Circulation. We're always thinking, "How do we bring these articles to life? How do we have the most people read them or engage with them?" And one is traditional social media. So Twitter and Facebook, which is incredibly important. Podcast, you have a monthly podcast. Dr Jane Freedman: Mm-hmm (affirmative). Dr Amit Khera: We have a weekly podcast and really hope that people listen to them because they're really full of important information. And finally, I think what people don't appreciate is the media. So we work with the AHA media. Some of our top stories get over a million media impressions, go all around the world and there's Professional Heart Daily. So, there's so many ways that we're bringing articles to life. Joe, I'm going to finish with you. This is a Circ family. The value of having a family of Journals and how we keep cohesion, and for authors when they're submitting to sort of a family of Journals, what's the value and how does that add? Dr Joseph Hill: Well, there has been complete turnover of all the editors in chief in the entire family of Journals, of which there are 12. And we are all quite similar in our personalities, and in our perspectives on the importance, the ultimate importance of validity. The first question we ask, "Is this true?" If it's not, it's gone. It doesn't get referred. We reject it. Even if it's going to be on the front page of the New York Times and cited 10,000 times. And all of us hold ourselves to that same standard. So our vectors are all pointed in the same direction. We also care about impact, not impact factor. But does it change the way you think? Does it matter? Is it incremental, or does it really move the needle? So we are now in a situation, I think a wonderful situation where we all sink or swim together. We send papers all around, as you know very well. We send papers to the subspecialty journals. We send 20 or 30 a week, on an extraordinarily regular basis. And we send papers horizontally to Circ Research, or Hypertension, or Stroke and so forth. So, it is a syncytium now I would say, of a family of journals where we are all looking out for each other. Jane cares about our Journal and we care about her Journal. And that's really a wonderful situation to be in. Dr Amit Khera: Well thanks. That family and how this fluidity of articles and thought and exchanges, is really part of the value. And ultimately the goal is for a great paper to find a great home. And I think in this Circ family we do that. Thank you very much. It's been a wonderful podcast. Again, I'm Amit Khera, digital strategies editor sitting in for Carolyn Lam and Greg Hundley for Circulation on the Run, as well as for Discover CircRes. Thank you. Dr Carolyn Lam: This program is copyright American Heart Association 2019.

Dr Amit Khera:                  Welcome to Circulation On The Run. Our weekly podcast summary and backstage pass to the Journal. I'm Dr Amit Khera, associate editor and digital strategies editor from UT Southwestern Medical Center in Dallas, and I had the distinct privilege of standing in for Dr Carolyn Lam and Greg Hundley this week. Twice a year, we are very fortunate to have some unique podcasts when we don't have circulation issues, and in the past we've met with many fellows in training and heard about some interesting studies that they're doing. Today we have a very special podcast we have not done before, and that is one where we had the opportunity to learn about our Circulation Family of Journals, and more importantly to hear from the dynamic editors in chief of these various journals. I think you're really going to enjoy it, we'll walk through and hear from each one of them, hear about some of the innovative things that are happening, some of the future that they see for their journal in their field, and I really enjoyed it, and I'm sure you will as well. So, without further ado, we'll start with our first editor. Dr Sunil Rao:                      I'm Sunil Rao. I'm an intervention cardiologist at Duke, and I'm the Editor-in-Chief for Circulation Cardiovascular Interventions, which is one of the daughter journals of the Circulation Family. We publish articles really related to the broad spectrum of interventional cardiology, from coronary interventions to peripheral arterial disease, and Endovascular interventions to structural heart disease interventions. We also published review articles in all of those areas, as well as any health policy or outcomes studies that are in that space. Dr Amit Khera:                  Tell us what are some of the innovative things that your journal is doing this year. Dr Sunil Rao:                      We're really excited about two things, one is our extremely successful Assistant Editor program that we launched last year at A.H.A. 2018. This is a program where we have five early career individuals that are within five years of completing their fellowship program who joined the editorial team at Circulation Cardiovascular interventions, and in that role they really learn a lot about the mechanics of how scientific publishing works, they commit to doing manuscript reviews, and receive feedback on improving their peer review process, and even independently handles some manuscripts as well, that are in their areas of interest. This is our way, I think, of encouraging the next generation to stay engaged with science, and with the scientific publishing process. It's been extremely successful. Assistant editors are part of our team for a two year term. So, in 2020, we will be selecting the next class of assistant editors, and after their term is ended, they join our editorial board as editorial board members. So, we're really excited about that, it's been an overall positive experience, for I think everybody involved. The second thing that we're really excited about is that we launched a social media presence for the journal, which it previously did not have. So, we have a very active Circulation Cardiovascular Interventions Twitter handle, I encourage all the listeners to join Twitter if you're not on Twitter, and if you are on Twitter please follow at Cirque intervened. It's " at C.I.R.C.I.N.T.V.". That is the official Twitter handle for our journal. Dave Fishman is our social media editor, and Chadi Alraies is our assistant social media editor, and we're not just tweeting out the articles, and providing summaries when the papers get published, we're holding Twitter journal clubs once a month ,and these have been extremely successful, it's an hour long Twitter journal club where the discussion gets very intense, and there's a lot of back and forth. We try to have the authors on as well, so that they can explain the rationale for their study, some of the challenges that they face when they are doing the study, and hopefully provide some implications for clinical practice, and what the next steps are. That's a way for us to engage our readership, it's almost a form of post publication peer review, which I think is becoming very popular. In addition, remember we don't have a print format of our journals, so this is a way to get the readership more engaged with the Web site, and to come to our website and learn what elsewhere publishing, and how they can get involve with the Journal as well, both as authors who submit their work, or if they want a peer review for us, please contact us and let us know. Dr Amit Khera:                  I really love hearing about the Twitter journal club, I know that they are well received, and certainly getting a lot of traction. Tell us about what initiatives or topics you're most excited about this year, and maybe some things that are coming later in the year. Dr Sunil Rao:                      We're really excited about the big areas in interventional cardiology, which are coronary physiology, we've published quite a few papers on looking at different physiological parameters, and how they can drive the appropriate use of PCI and how that affects outcomes. I think that's going to continue to be a huge topic over the next year, Certainly such a heart disease has exploded, and with the data on low risk patients undergoing TAVR, and having really good outcomes, we're seeing a lot more submissions in the low risk TAVR space, the other area that's really exploding right now is Mitral and Tricuspid Valve Interventions, one of the areas that I think has seen a tremendous amount of device innovation. So, we're seeing a lot of submissions from really high quality papers in that space, but I think it's also important to note, that unlike previous iterations of the Journal, we're actually having a review article, we're trying to have a review article every month on a major area that is burgeoning, so that the readership can understand the overall lay of the land, with respect to evidence, how that guy's clinical practice, and what's coming next. So, we've published quite a few review articles already, and there are more to come, and I think that's a really important way for the readership to keep current with what's going on in Interventional Cardiology. Dr Amit Khera:                  What about the advancing aspects of your subspecialty? There's so much going on in interventional cardiology, it's a bit dizzying, just tell us a little bit about some of the ways that your journal's helping advance that mission, not just now but perhaps in the future. Dr Sunil Rao:                      I think one of the challenges that we have at Interventional Cardiology, and maybe this is true across Cardiology, is that the evidence is developed very rapidly, and oftentimes it almost seems like the field is lurching back and forth in certain areas, a prime example of that is the drug coated balloon controversy for Peripheral Interventions. The Journal Of The American Heart Association published a meta-analysis, showing that there may be an association between the use of these devices and increased mortality, that has led to a lot of discussion in the interventional community, and quite frankly I think there's a fair amount of confusion out there about whether we should be using these devices, should we put a moratorium on these devices, is the signal real, if it is, what's the mechanism of death. So, a lot of conversation around that, in fact, it's led to what's going to be a focused FDA meeting in June, specifically on the drug coated balloon controversy. Where I see our journal playing a role is really in trying to, not only publish the latest science, which is rigorous in the field for controversial topics such as this, but also to help provide some context for that science, and I think our integrated strategy of original science review articles, and social media really helps us to communicate with the readership, and with the Interventional Cardiology community writ large, meaning not just physicians, but also Cath lab staff, nurses, noninvasive cardiologists who obviously have patients who are undergoing interventions, and even policymakers, to keep them abreast of what's going on, so that they can have the same level or base of knowledge, so that the conversation is on a level playing field. Dr Amit Khera:                  Okay, well you heard it from Dr Sunil Rao. Thank you for your time. Dr Kiran Musunuru:        I'm Kiran Musunuru, I'm the outgoing Editor-in-Chief of Circulation Genomic and Precision Medicine. Let me start by saying a little bit about the content of the journal, it considers all types of articles related to, as the name implies, Genomic and Precision Medicine, and more specifically, Clinical Genetics, the molecular basis of complex cardiovascular disorders, considered at a variety of levels, that can include a lot of different, what we would call Omics Techniques, from Genomics to Transcriptomics, Proteomics, Metabolomics, Metagenomics, and, so forth. It also deals with big data applications, that includes Electronic Health Record Data, Patient generated data combined with any of the things I've already mentioned, Genome Wide Association Studies, Pharmacogenomics, Gene Therapy, Therapeutic Gene Editing, Systems Biology. So, it's a pretty comprehensive look at all the various topics that would fall under the rubric of Genomic and Precision Medicine. Dr Amit Khera:                  Now, Dr Musunuru, you mentioned the outgoing Editor-in-Chief, let's introduce the incoming Editor-in-Chief, Thatcher Christopherson Semsarian. Dr Chris Semsarian:         I'm the incoming Editor-in-Chief. My name is Chris Semsarian, I'm a cardiologist at the Royal Prince Alfred Hospital in Sydney, Australia. Dr Amit Khera:                  What are some of the innovations you and the Journal are doing this year, or, what are some of the things you see coming in the future? Dr Kiran Musunuru:        Something I'm very excited about, is that we are just starting a pilot project with the American Heart Association's Institute for Precision Cardiovascular Medicine. The institute has a very nice platform called the Precision Medicine platform, and, in brainstorming last year, we realized there was a very nice opportunity to try to create a new type of journal article. There's also a big move in science nowadays to improve transparency, and rigor, and reproducibility, especially in science. The idea being that ideally other investigators should be able to take one team's work, and be able to run through the entire analytical process, and reproduce the original findings, and perhaps even find ways to improve upon those original findings, and, so we realized working with the institute's Precision Medicine Platform, we had the opportunity to actually make a new type of article, we think of, as the paper of tomorrow, a virtual article. The idea would be, that we would have primary data on the Precision Medicine Platform, the analytical tools used to process the data would also be on the Precision Medicine Platform, the analytical plan, in the form of a so-called Jupiter notebook, that basically takes people step by step through exactly which tools were used in which order, in which way, with which parameters, would be on the Precision Medicine Platform, and then there would be some verbal explanation, some background, to explain the context of these analysis, and to really put it into perspective, as how it fits into the body of literature, and so the idea would be, this would live on the Precision Map Platform in a virtual format, and then anyone else who is interested in this work could come, and actually directly interact with the data, and the tools, and the analytical plan, and could actually rerun the entire papers work from scratch, thus reproducing it, and then could actually tweak the analytical plan, or install tools of their own, and be able to build upon the work that had already been done. It's a very different way of thinking about journal articles, more as living entities rather than static work that just lives on a page, and is there as reported, and then never has an opportunity to be fully produced or improved upon. Dr Amit Khera:                  There's so much happening in the space of genomics, and obviously, we hear the word "Precision Medicine" so commonly. Tell us a bit about how your journal in specific is advancing the mission of your area. Dr Kiran Musunuru:        I'll say a little bit, and then maybe turn it over to Chris, give his perspective as the incoming Editor-in-Chief. I think it's a vibrant field, but it's also a very new field, it's evolving rapidly, and I think the Journal has a very important role to play, and not only reporting the results that are coming out of studies in this field, but actually having a role to play in helping to shape the field, helping to define the field, it's very exciting, it's very much in rapid evolution. Just ten years ago or so, when the Journal first started, we were just starting to see the first Genome Wide Association studies, and now we've gone so far beyond that.                                                 Now, again, we're talking about these large bio banks, we're talking about Precision Medicine, we're talking about applying this information in health care, we're talking about combining all of these various streams of data and many levels to be able to do studies, that are, I would even say, exponentially advanced beyond what we able to do just ten years ago, and so, it's very exciting times for the journal, then maybe I can ask Chris to share his thoughts on that. Dr Chris Semsarian:         Yeah Kiran, I mean, it's a great honor system to follow in your amazing footsteps, and what you've done for the Journal, and as the incoming Editor-in-Chief, I really want to sort of try, and build on the platform that you've established over the last few years, and really, one of the areas that I'm particularly interested in is the area of Translation of Genomic Findings. I mean, ultimately what we do in our lives, as clinicians, is to help patients improve diagnosis, to improve the treatment of these patients, and to be able to do studies with very basic understanding of how our genomes work, and how Narcotic Genes interact, and translating those findings into these improved diagnostic approaches, and even in guiding management is really exciting, I think, in terms of clinical medicine, and improving patient care as we look ahead. I really want to be able to continue to publish really, state of the art, novel, innovative, research areas, that you've already covered, Kiran, which would lead to better care of our patients, who are ultimately the beneficiaries of this type of amazing work.                                                 So, I'm really excited looking at the Journal, it's a tremendous area of interest and research, where there's twenty-two thousand genes approximately now genomes, and we really don't understand most of them in terms of their intricate function, and I figured it's a great time ahead, in terms of Precision Medicine. Dr Amit Khera:                  Okay, well, that was Dr Kiran Musunuru, and Christopher Semsarian, we appreciate both of your time today for Circulation on the Run. Dr Paul Wang:                   I'm Dr Paul Wang, I'm the Editor-in-Chief of Circulation Arrhythmia and Electrophysiology. Our Journal covers really the expanse of our field, going from basic mechanisms of arrhythmias, so very basic science work, to really clinical practice, clinical outcomes, to population based studies, and genetic based considerations in our field. So, we really feel we encompass the entire range, and there really isn't any topic within our area, that we don't feel is outside our realm. Dr Amit Khera:                  I know there's so many innovative things you're doing, Dr Wang, with your journal. Why don't you tell us a little bit about your plans for this year. Dr Paul Wang:                   We've been excited; our team has been at the Journal for two years now, and we focused on a number of different areas. So, I think one of our biggest advances, and we've tried to be more responsive to the authors, so we've really reduced the time to first decision very substantially, from over twenty days, to ten days or less, I think we hit a record of 7.8 days in the journal. So, really, we hope we're more responsive, we've involved the editorial board, we've substantially expanded it, so that more of our reviews of greater proportion going to our editorial board, which is a really fabulous, internationally recognized group, with really high quality reviews, so we've been very pleased, with both a level of science that we've received, as well as the level of the reviews that we have. One other area is, we really want to make sure that the reviewers, who do much of the heavy lifting, in addition to our editors for The Journal, and so we've established a new Reviewer Recognition Award System, they can be designated as silver, gold or platinum, and we've reached out to department chairs, or their deans, and recognizing that they won this prestigious award for their performance, and great work with the Journal, so there are a number of different things that, in fact, we think we've made some advances in, the other areas are really that of extending our reach, and so, one of the things we concentrated on, initially with the adding of podcasts, so we do that monthly.                                                 All the articles are now available in review, and then what we're starting at our new initiatives is, we'll be starting a Twitter Journal Club. I've been recording at least two of our articles, as the interview with the authors, and then we're going to be having a journal club, in which we will have the opportunity for people around the world to comment, and have a discussion that will really be exciting, we think. So, there are a number of other areas that we're thinking about, in terms of that kind of work. Dr Amit Khera:                  The field of Electrophysiology seems to be changing by the day, maybe you can tell us a little bit, about how the journal is advancing the mission of the field of electrophysiology. Dr Paul Wang:                   So, one of the things that we focused on is the role the Journal can play, in terms of connecting with other elements of our field, and one of the ways that we've really concentrated on is, in particular, working closely with the American Heart Association, and its committees. We're related to a number of committees, but particularly, there is a committee on Electrocardiography, Electrophysiology, part of the Clinical Cardiology Council, and so, we work very closely with that group, and, in fact, we've invited that group to create proposals for a number of review articles, state-of-the-art reviews, that we hope will come out in the next year or so. The ways in which we can tie together our committees to AHA overall, I think, is really the direction we're looking for our journal, and we feel we can play a very novel, and innovative role in that regard. We, for example, also reached out to the American Heart Association funded researchers in our area, and invited them to participate in the journal, participate in our committees, become fellows or FAHA's of the American Heart Association, so we really want to create this family, a real community, and sense of community, that we hope will stem from the Journal. So, we're very excited about the future, and what we might be able to achieve together. Dr Amit Khera:                  Thank you so much, Dr Paul Wang for your time today, and we appreciate your insights on Circulation, Arrhythmia and Electrophysiology. Dr Nancy Sweitzer:          Hi, I'm Nancy Sweitzer. I'm the Editor-in-Chief of the Journal Circulation Heart Failure. At Circ Heart Failure, we deal with all things related to heart failure. Heart failure is an expanding specialty, relatively new subspecialty in cardiology, and we're very interested in the physiology, and mechanisms of heart failure, as well as treatments of heart failure, and the innovative evolution of the specialty which includes Advanced Hemodynamics, Mechanical Circulatory Support, and transplant as therapies, as well as all Implanted Device Therapies, and new, and Innovative Pharmacologic, and Gene Therapies as well. Dr Amit Khera:                  Tell us a bit about initiatives, or features in Circulation Heart Failure, that you're planning on tackling not only this year, but into the future. Dr Nancy Sweitzer:          The effort we're most excited about at Circulation Heart Failure has been ongoing now for a little over a year, but continues, and is really focused on the emerging scientists in the Heart Failure Space; we call it our "Featured Emerging Investigator Spotlight", and this spotlight focuses on authors of manuscripts, who are within ten years of their terminal training, and can take full responsibility for the content of a manuscript. When we publish a featured emerging investigator article, which we've done more than half of the months since launching the feature in late 2017, we schedule a Twitter Journal Club with that author, where we participate, over the course of several hours, in pretty intensive conversation, about not only the science, but career development in Heart Failure Space, the importance of mentoring, and sponsorship obstacles that people are facing in development as physician scientists or scientists, and insights they may have into fostering success in the Heart Failure Space. This has been a great feature, we launched it because we feel that the emerging scientists, in the Heart Failure Space, need a virtual community in those critical years, before you have a lot of resources to start traveling, and setting up a network that's based on personal interaction, and we felt that, the modern era of social media was perfect for this. We found our emerging investigators are getting to know one another, they participate in one another's Journal Clubs, the Journal Clubs are incredibly fun, and interactive and we're getting a lot of Twitter engagement from the Heart Failure Community, there's a lot of "Twitteratti" in Heart Failure that really are engaged, and engaged with the Journal, which has really been fun for all of us, I think, so that's the thing we're most excited about. Dr Amit Khera:                  It's really wonderful to hear how you're spotlighting authors in creative ways. Tell us a bit about how your journal is advancing the mission of Heart Failure and Transplantation. Dr Nancy Sweitzer:          I see the journal as central to advancement of the subspecialty, as I mentioned earlier, Heart Failure is a relatively young subspecialty in the United States, we received a CGMC designation as a subspecialty just in 2008, just eleven years ago, and it's been a board certifiable subspecialty only since 2014. So, we're very young, and I think really developing into our own. We've seen tremendous growth in the number of people seeking subspecialty training in Advanced Heart Failure and Transplant Cardiology, and we are really enjoying helping the Journal evolve with the specialty, as it evolves, and that's happening very actively right now. So, I think what Heart Failure is in 2019 is different than what it was just five years ago in 2014. We're doing a lot more ,as I mentioned, Complex Chemo Dynamic Thinking, thinking about the path of physiology in our patients, and how we can target that effectively, not only with existing therapies, but with strategies, and, as I mentioned, the burgeoning growth of Mechanical Circulatory Support, and support devices, which the field has embraced quite actively, and The Journal is increasingly publishing content in these spaces, as well as the spaces of Advanced Heart Failure, but, I guess also, we're interested in every aspect of Heart Failure, from Complex Multidisciplinary Care Management, to Palliative Care, to the interaction of the heart with other organ systems, and Heart Failure such as the brain, we have a paper on Cognitive Function Abnormalities, and Heart Failure in this month's issue. So, the interaction with the brain, the kidney, the liver, many other organs, that are affected when the heart becomes quite ill with Advanced Heart Disease. So, basically we're interested in everything that touches Heart Failure Development Care, and treatment of patients with Heart Failure, and particularly we're interested in the newest and latest. We love publishing, and some of our highest impact papers in the last couple years have been new therapies, just being tested for the first time in patients with heart failure. Small studies that may not have large impact in terms of heart outcomes, but where we're learning about the pathophysiology of the disease, and new treatments, that's really exciting to us. We've published a couple of methods papers in the last year, really innovative models. One describing a model of pacing in mice, which has been a really challenging thing to do in Heart Failure, but several groups have now developed Tachycardia induced Cardiomyopathy models in mice, which is important for rapid discovery work, because mice have such a short reproductive span, and can be genetically altered, and then a recent publication on the methods paper, looking at a new initiative by the FDA, to potentially approve therapies based on patient reported outcomes, rather than just heart mortality and morbidity outcomes, so we're really excited about the innovations, and the Heart Failure Space, the work that describes where we're going as a field and as a profession. You'll see some features coming up in the journal, from opinion leaders across the globe on where this specialty sits in 2019, and where we, as the leaders in the field, can guide it as we move into our next decade, and I think that some of the most exciting work the journals doing. Dr Amit Khera:                  Thank you, Dr Sweitzer. We really appreciate your time today for the podcast, and your insights on the Journal. Dr Robert Gropler:          Good afternoon, I'm Rob Gropler. I'm the Editor-in-Chief of Circulation Cardiovascular Imaging. It's one of the journals within the family of Circulation Journals, and our focus is really on being the most influential source of leading edge imaging sciences, as it relates to transforming cardiovascular care, so what that means is, that we're interested in all imaging studies that are applied to the care of the cardiovascular patient, and although our primary focus is really on clinicians, and researchers, but we also want to expand our viewership, if you will, to anyone who is interested in how imaging is used to understand Cardiovascular Medicine, and to treat patients with Cardiovascular Disease. So, we are edged in all forms of imaging, this can be from MR, to echo, to nuclear, to CPT, to optical imaging, it involves all types of disease, ranging from Congenital Heart Disease, up to diseases in the elderly, it also involves not just it is in humans, but also understanding disease in the preclinical space, particularly as it helps us understand new technologies that may ultimately reach human use, either for investigational purposes, or ultimately, to be used in the treatment of a patient with Cardiovascular Disease. Dr Amit Khera:                  What are some innovative things you and the Journal are planning for this year? Dr Robert Gropler:          We're doing quite a few things. One of the first things we did, as you know, were relatively new, where we've only been an editorial team, if you will, for one year. One of the major efforts has been to increase our presence, in terms of digital media strategies, across the board. And so, this meant expand our Twitter presence, if you will. It also meant increasing our offerings in that digital space by, for example, having a journal club, what we would do is on a every other month basis, discuss a paper we published that's of significant interest via Twitter. And it would involve the authors, the associate editors who actually manage that study, as well as the editorialist who wrote about that study, and it leads to very unique insights into how that paper is being viewed by the scientific community at large, and also potentially how that information will be implemented in terms of transforming clinical care.                                                 We've added what we call a teaching file. If you think about imagers, imagers learn by seeing images. And the more they can see images, put them in the context of clinical cases, the more they understand what an image means when they see it. So, what we do now is we accept a large number of what we call imaging cases. These are specific unique cases that have a history, and then a short write up about them.                                                 And those are gathered each month, but then they're downloaded into a file. And then, anyone with access to the Journal can then look at, use to learn from, to potentially use for talks to enhance their own education the education of others. And we have found that to be, again, another offering that our readers particularly like. Dr Amit Khera:                  And how do you see Circulation Cardiovascular Imaging advancing the mission of imaging, which seems to be ever-expanding, and ever-growing? Dr Robert Gropler:          We're really in the education business. And what that means is that we're educating at a multi-scale level. Just educating a practitioner on what technology can do, how it's helping cardiovascular medicine, yes, that's important. But what we're also doing, is we're educating the scientists as to here as some of the new findings that were coming out because of imaging. And then that, in turn, will help direct them or signal them as to where is the science leading them, and what should be their next steps?                                                 We're also educating the general public as to what can imaging do, and how does imaging change cardiovascular medicine for the better, and what they can expect from that. And we're also educating the regulatory bodies, if you will, that determine what imaging can be done in the clinical environment and so on, and the importance of these imaging techniques.                                                 So number one, I think we always have to maintain that focus, as to that's our goal. Now, that being said, I think the question becomes how do you convey that concept? And where we have to continually evolve.                                                 And I think they were very smart years ago to make it a digital-only journal, as opposed to combined print and digital. So, I think that was actually very savvy. But the digital net component now has to expand. And that means our offerings have to reflect not just that people learn in different ways, that is, we have to have not just, if you will, a didactic or print equivalent component of a paper. But it also should be audio-based, such as this podcast. But they also need to be varied as in terms of the types of offerings, and their brevity or length, if you will. Dr Amit Khera:                  Thank you, Dr Robert Gropler, the Editor-in-Chief of Circulation Imaging. We really appreciate your time today. Dr Robert Gropler:          Thank you very much. You have a great day. Dr Amit Khera:                  Well, I'm sure you enjoyed this as I did. We really got incredible insight from the Editors-in-Chief of our Circulation family of journals. We learned so much about the broad array of subspecialties that they cover, and all the exciting and innovative things they're doing to really advance the missions of their fields, and also for the authors and for science.                                                 Well, again, I'm Amit Khera, associate editor from UT Southwestern, Digital Strategies editor for Circulation. And next week, you'll have your usual hosts, Carolyn Lam and Greg Hundley. Dr Carolyn Lam:                This program is copyright American Heart Association 2019.  

Interview with Amit Khera, MD, MSc, author of Identifying Familial Hypercholesterolemia Using a Blood Donor Screening Program With More Than 1 Million Volunteer Donors and and Stephen Daniels, MD, author of Screening for Familial Hypercholesterolemia.

Interview with Amit Khera, MD, MSc, author of Identifying Familial Hypercholesterolemia Using a Blood Donor Screening Program With More Than 1 Million Volunteer Donors and and Stephen Daniels, MD, author of Screening for Familial Hypercholesterolemia.  

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             I'm Greg Hundley, associated editor from the Pauley Heart Center at VCU Health Sciences in Richmond, Virginia. Dr Carolyn Lam:                A big number of acute ischemic stroke patients receiving endovascular therapy in the United States are receiving this therapy only after inter-hospital transfer. What are the temporal transient outcomes following this inter-hospital transfer? Very important discussion coming right up with our featured paper. But for now, sit back, relax with us. We're going to discuss a couple of papers that we found were interesting in this week's journal. Dr Greg Hundley:             Very good, so thanks Carolyn. I'll start off, and I'm going to talk a little bit about stress induced cardiomyopathy, and we also know it as takotsubo cardiomyopathy, looking at a paper from Dana Dawson from the University of Aberdeen in the United Kingdom. Takotsubo cardiomyopathy can result in a heart failure phenotype with a prognosis comparable to myocardial infarction.                                                 In this study, the investigators hypothesize that inflammation is central to the pathophysiology in natural history of takotsubo cardiomyopathy. They prospectively recruited 55 patients with takotsubo cardiomyopathy, and 51 age, sex, and comorbidity match control subjects.                                                 During the index event, and at five months of follow-up, the patients with takotsubo cardiomyopathy underwent a cardiac MRI study in which they looked at ultra-small, super paramagnetic particles of iron oxide, or USPIOs, enhancement for detection of inflammatory macrophages in the myocardium. What would the studies show? Patients with acute takotsubo cardiomyopathy had macrophage-mediated myocardial inflammation.                                                 They also demonstrated modulation of peripheral monocyte subsets and increased systemic pro-inflammatory cytokines. This systemic inflammation persisted for five months, and then at that five-month time point, the cardiac MRI evidence of the macrophage presence was diminished. Dr Carolyn Lam:                Wow, Greg. So this is right up your wheelhouse, isn't it? Can you explain? What are the clinical implications of these MRI findings? Dr Greg Hundley:             It was really interesting. For the first time, they've linked an ongoing inflammatory process using the USPIO contrast agent with MRI actually going on or operative in the heart, and they associate that with systemic markers in the circulation.                                                 They help us elucidate the mechanisms and the pathogenesis of takotsubo cardiomyopathy, and systemic and myocardial inflammation really may start to now serve as a therapeutic target for patients with acute takotsubo cardiomyopathy. Dr Carolyn Lam:                Very interesting. From stress-induced cardiomyopathy to early onset myocardial infarction. The first paper I chose really answers the question, "What is the relative prevalence and clinical importance of monogenic mutations, that is, a single mutation that significantly increases risk, versus a polygenic score, which really measures the cumulative impact of many common variants, in early onset myocardial infarction?"                                                 The co-corresponding authors were Doctor Amit Khera and Sekar Kathiresan and both from Massachusetts General Hospital, and they performed deep coverage, whole genome sequencing of more than 2,000 patients from four racial subgroups hospitalized in the United States with early onset myocardial infarction defined as myocardial infarction before the age of 55 years, and compared this to 3,761 population base controls.                                                 What they found was that a monogenic mutation related to familial hypercholesterolemia was identified in 1.7% of the patients, and associated with a 3.8-fold increased odd of myocardial infarction. In comparison, the high polygenic score, which was composed of 6.6 million common DNA variants and defined as the top 5% of the control population distribution, now, that was identified in 10 times as many patients, so 17% of patients, and associated with a similar 3.7-fold increased odds of myocardial infarction. Dr Greg Hundley:             Interesting. How do we apply this clinically, Carolyn? Dr Carolyn Lam:                These findings really lay the scientific foundation for the systematic identification of individuals born with a substantially increased risk of myocardial infarction. The important point is both familial hypercholesterol mutations and a high polygenic score are associated with more than three-fold increased odds of an early onset myocardial infarction.                                                 However, the high polygenic score cannot be reliably identified on the basis of elevated LDL cholesterol, and yet has a 10-fold higher prevalence among patients presenting with early onset myocardial infarction. So very intriguing that both groups matter. Dr Greg Hundley:             Very good. My next paper is from Adrian Hobbs at the London School of Medicine, and is looking at the role of endothelial C type natriuretic peptide as a critical regulator of angiogenesis and vascular remodeling. We know that a central pathway coordinating both neovascularization and ischemic extremities in PAD is driven by vascular endothelial growth factor or VEGF-A4.                                                 But preclinical studies and other large scale clinical trials have been disappointing because administering or using VEGF-A to promote angiogenesis or arteriogenesis in PAD really hasn't occurred. This group focused on endothelial-derived CMP. Why? Because it plays a fundamental role in regulating vascular homeostasis. It controls local blood flow and the resistance vasculature, and systemic blood pressure, and reduces the reactivity of leukocytes and platelets.                                                 So, what were the results? Clinical vascular ischemia was associated with reduced levels of CMP and it's cognate NPR-C. Moreover, genetic and pharmacological inhibition of CNP and NPR-C reduced the angiogenic potential of the pulmonary microvascular endothelial cells and the human umbilical vein endothelial, and it isolated vessels ex vivo.                                                 So, the study really defines a central pathophysiological role for endothelium-derived C type natriuretic peptide via activation of cognate natriuretic peptide receptor C in angiogenesis and in vascular remodeling. Moreover, the work demonstrates the therapeutic utility of pharmacologically targeting NPR-C to restore deficits in these processes following ischemia and injury. Dr Carolyn Lam:                Interesting, from new mechanisms and targets to good, old, major risk factors for coronary heart disease. Back to the basics but in a really, I think, nicely done paper from Dr Pencina and colleagues from Duke Clinical Research Institute.                                                 Now, their objective in this next paper was to compare the associations of key, modifiable coronary heart disease risk factors with incident coronary heart disease events based on their prognostic performance, the attributable risk fractions and treatment benefits overall and by age.                                                 And so really aiming at quantifying the importance of these major, modifiable risk factors for coronary heart disease. What they did is they used pool participant level data from four observational cohort studies sponsored by the NHLBI, and they created a cohort of more than 22,600 individuals ages 45 to 84 years old who are initially free of cardiovascular disease.                                                 And these individuals were followed for 10 years from baseline evaluation and followed for incident coronary heart disease. They estimated that age, sex and race captured up to 80% of the prognostic performance of cardiovascular risk models. When we add either systolic blood pressure or non-HDL cholesterol, diabetes or smoking to model with the other risk factors, the prognostic performance, as measured by the C index, increased by only 0.004 to 0.013.                                                 However, if you look at it from the attributable risk and absolute risk reduction standpoint, lowering the systolic blood pressure of all individuals to less than 130, or lowering LDL cholesterol by 30% would be expected to lower a baseline, 10-year coronary heart disease risk of 10% to 7% and 8% respectively. Dr Greg Hundley:             That's a lot of data, Carolyn. Help me synthesize all that. Dr Carolyn Lam:                This is a take-home message. Although the individual modifiable risk factors contribute only modestly to the overall model prognostic performance, when we eliminate or control these risk factors, they would actually lead to a substantial reduction in total population coronary heart disease.                                                 That's because if we look at the attributable fraction and the absolute risk reductions, we see that they actually really matter. The take-home message too from Dr Pencina was that metrics used to judge the importance of these risk factors should therefore be tailored to the question being asked. Dr Greg Hundley:             Very good. That was a very nice summary, Carolyn. Dr Carolyn Lam:                Thanks. Let's move on now to our feature discussion, shall we? Dr Greg Hundley:             Very good. Dr Carolyn Lam:                Trials have established that endovascular thrombectomy dramatically reduces disability after acute ischemic stroke due to intracranial large vessel occlusion. In fact, guidelines almost immediately adopted endovascular thrombectomy as a standard of care. However, that has created some problems.                                                 The main one being that hospitals equipped to carry out this procedure are largely limited to tertiary centers in urban areas. This is, of course, important because that means that patients may need to be transferred from another center to receive such treatment.                                                 Today's feature paper discusses this very issue, a terribly important one, and I'm so pleased to have the author with us, Dr Shreyansh Shah from Duke University Medical Center. We have our editorialist, Dr James Grotta who's director of the Mobile Stroke Unit project at Memorial Herman Hospital.                                                 And we have an associate editor, Dr Graeme Hankey from University of Western Australia. So, such an important topic. I think Shrey, could you just jump right in and tell us what your study showed. Dr Shreyansh Shah:         I'm very excited to present findings of our study, and as a Carolyn mentioned, this study is going to have a very important implication in our country here in US on the creation of systems of stroke. I think the findings are already applicable to other countries also where we are seeing endovascular care getting more and more used.                                                 As Carolyn was talking, endovascular treatment is very important and lifesaving measure. But unfortunately, it is not available at every hospital. Patients are often transferred across different hospital or institution before they can receive this endovascular care.                                                 What we did in our project was we looked at the data from the hospital that's participating in Get With The Guidelines®® Stroke, which is a quality improvement program here in US. It looked at the endovascular thrombectomy used especially in relation to inter-hospital transfer.                                                 What we found was big proportion of patients receiving endovascular care, up to about 43% to 45% of patients, were getting the care after transferring across different hospital. The outcomes in this patient were worse compared to the patient who were receiving endovascular care if they had come directly to the hospital.                                                 While there was no difference in mortality between these two groups, the endovascular care, after inter-hospital transfer, resulted in a higher rate of symptomatic ICH, patients are less likely to be discharged to home, which is the preferred outcome. And patient was also less likely to be able to ambulate independently prior to the hospital discharge.                                                 There was also delay in endovascular care initiation for patient who received this after inter-hospital transfer. I think this particular study highlights the magnitude of this problem, and that's why it's going to be important for people who are studying systems of care. The fact that about 45% of patient had to get inter-hospital transfer before endovascular care tells us that we still need to take significant steps in increasing access to this lifesaving therapy. Dr Carolyn Lam:                Thank you and indeed James, I really love the editorial you wrote that accompanied this. I mean you highlighted its importance, and you also noted that what was unusual about the paper was that even after controlling for the delay in initiating endovascular thrombectomy, there was still worse outcomes in the patients who were transferred. Could you share some thoughts? Dr James Grotta:              It is a very timely issue. Now that we have a very effective treatment, the big challenge we have is getting it to the patients as fast as possible. Right now, our system, as is pointed out, means shuffling patients from one hospital to another.                                                 I think that clearly with stroke treatment, any sort of stroke treatment, the faster we deliver it, the better. Other studies have shown that transferring patients is associated with a delay of treatment, and this study showed the same thing.                                                 There was a substantial delay in getting the patients treated if they required a transfer. And as you pointed out, however, this did not explain the entire or was not at least the entire explanation for the worst outcome. So, it is a little bit of a mystery.                                                 I do know from personal experience that transferring patients from hospital to hospital, it's not exactly a black hole, but you lose control of the patient when they're being transferred. These are patients who have large artery occlusions. That means they have their middle cerebral artery is blocked.                                                 And so, the area of brain that's affected is in a very tenuous shape. So, any drop-in oxygen concentration from breathing problems or of any drop-in blood pressure might further worsen the stroke. So, this could happen in transit. So, it's possible that in the process of transfer, these sorts of things happen.                                                 I do think that we do have to be a little bit careful in that by remembering that this was not a randomized comparison, so patients that were treated directly and those that were transferred were not randomized. And so, although they appear to be balanced in a lot of the important variables like their stroke severity, there may be other things that we can't account for that could explain some of the worst outcomes.                                                 I'd like to ask Dr Shah whether he identified any things in ... well, he and his co-authors think might have contributed to some of the worst outcomes.  Dr Shreyansh Shah:        To answer Dr Grotta's question about what other factors may have played a role in the worst outcome that we saw in patients who were getting inter-hospital transfer, I think as we correctly pointed out, transferring this very sick patient is very tricky. As we know, the hemodynamic instability or variability plays an important role in outcomes of stroke patient.                                                 And it is very likely that during the transfer process, there is not adequate control of their blood pressure variability, their oxygen saturation, and this ends up affecting their brain leading to worst outcome. The other possibilities also, as Dr Grotta was explaining, this is not a randomized control trial.                                                 And although we balance for number of important factors that can affect stroke outcome, there might be a selection bias in transferring patient who are more sicker and also patients who received thrombolysis with TPA but did not improve, while the patient who were directly arriving to the hospitals and getting endovascular care, they received the TPA.                                                 It is possible that they started to improve and still received a thrombectomy at the same time. So that group may have been more favorable in that respect, which could have also played a role in better outcomes with patient who are directly arriving. Dr Carolyn Lam:                Interesting. And, you know, with the mention of TPA, I really have to bring James back. I loved your mention about potential solution using mobile stroke units. And since you direct one of them, could you tell us what you meant there? Dr James Grotta:              Yes, of course, I have to state at the outset that I have a little bit of a bias about mobile strokes, and so I do it every day. What a mobile stroke unit is, for those who don't know, it's basically taking the emergency department to the patient.                                                 It's an ambulance with a CT scanner on board and the ability to treat with TPA in the field. But in addition, it's also the CT scanner. We can do CT angio and identify large vessel occlusions on the mobile stroke unit, not to mention the fact that you have a vascular neurologist either in-person or by telemedicine examining the patient.                                                 So clinically, you can make the determination also much more accurately than any sort of pre-hospital stroke scale, whether the patient has a large artery occlusion. That way, you don't have to take the patient to the nearest hospital. You can bypass the nearest hospital, take them right to the thrombectomy center, therefore, avoiding the transfer process.                                                 We've been implementing this in Houston, and there are now about 30 mobile stroke units around the world. The innovation actually started in Germany by Dr Fassbender about a decade ago in Hamburg, Germany. We are conducting a randomized trial, comparing mobile stroke unit care to standard management to see how much better outcomes occur as a result of this faster treatment.                                                 We obviously can treat patients with TPA faster. For example, a similar study from the Get With The Guidelines® a few years ago showed that only 1% of patients treated with TPA in emergency departments get treated within the first hour after symptom onset simply because it takes an hour in the emergency room itself to do the evaluation of the patient and get them treated.                                                 Whereas on our mobile stroke unit, at least a third and probably 40% of the patients we're treating with TPA, we can get treated within that first hour where there may be an exponential better benefit. But we don't yet know really how much that translates to better benefit, and also, of course, mobile stroke units are more intensive in terms of the amount of facilities on board and costs.                                                 So, we need to look at the cost-effectiveness. If it produces only a marginal reduction in disability but costs a fortune, then it's not worth it. But in fact, in our experience, it's pretty practical. We can cover almost the entire City of Houston, which is the fourth largest city in the country, with one mobile stroke unit. When it's well-integrated, it requires careful integration with the fire department and other hospitals in the city.  Dr Shreyansh Shah:        At those two conferences, I came across a very interesting talk from Dr Grotta's group about rendezvous with the EMS which allows extending their coverage area significantly. I think we definitely need more and more innovative solutions like this where we can identify patients by their origin, whether they have large vessel occlusion or not, and then triage them appropriately at the centers that can perform endovascular therapy. So as a result, we can provide them earlier therapy and hopefully, it will lead to better outcome. Dr Carolyn Lam:                Thank you Shrey and James for these incredible insights. Now, Graeme, I want you to have the last word and reflections from down under. Dr Graeme Hankey:        Firstly, just to congratulate Dr Shrey and colleagues on this terrific study that reports a contemporary United States experience, a very broad one across the country, really highlighting how since 2012, until a year ago, there's been a six-fold increase in the number of patients being transferred for endovascular therapy.                                                 And we're all experiencing that around the world. And moreover, since the DAWN trial and the DEFUSE trial were published just over a year ago, which is when this study stopped, there's been an expansion of the window from six hours out to 24 hours.                                                 So, in the last year, which this study doesn't cover, we've seen an exponential increase in the number of people being transferred from rural and remote areas who have had a stroke up to 24 hours ago being considered for endovascular therapy if their CT angiogram at the base hospital shows a large vessel occlusion.                                                 This is likely to be not only internally valid, but externally valid to all of us around the world. It reflects our experience of this avalanche of cases coming. And it's provided a lot of challenges for those who are trying to deliver the service at the tertiary referral center.                                                 And it highlights that nearly half of the cases who are having endovascular therapy are coming from external sites. As Jim has really highlighted in his editorial, it challenges us to reassess the current practice of inter-hospital transfer. Dr Carolyn Lam:                Thank you so much for publishing this paper with us and the editorial. And listeners, don't forget to tune in again next week. This program is copyright American Heart Association, 2019.  

Dr Amit Khera:                  Welcome to Circulation on the Run, your weekly summary and backstage pass to the journal. I'm Dr Amit Khera, associate editor and digital strategies editor from UT Southwestern Medical Center in Dallas. And I have the privilege of standing in for Dr Carolyn Lam, your usual weekly podcast host. Today we have a special treat. It is our semiannual fellows and training FIT podcast. And the additional part of this treat is we have three very special FITs today. These are our assistant editors for social media for Circulation. And really I want to introduce you just a moment, but I want to thank these three for their hard work and efforts. It really is them that helped bring our social media to life. And importantly for us, we really have a commitment to enhancing fellow education involving fellows in our editorial process and really making sure that the journal is appealing to fellows in training. So we really rely on these three to help us understand what best resonates and what is most helpful for fellows in training. So without further ado, Jainy Savla from UT Southwestern. Welcome Jainy. Jainy Savla:                         Thanks for having me on the podcast today. Dr Amit Khera:                  And we have Daniel Ambinder from Johns Hopkins University. Hi Dan. Daniel Ambinder:             Hey Amit. Thanks for having me on the podcast today. Dr Amit Khera:                  Absolutely. And finally we have Jeff Hsu from UCLA. Hi Jeff. Jeff Hsu:                               Hi Amit and hi everyone. Very glad to be here. Dr Amit Khera:                  Well, Jainy, I'm going to start with you. You've been with us on the social media side the longest. I think it's maybe almost a year or a bit more that you've been working on these efforts. And again, very much appreciate all of your hard work and insight. Tell us a bit about yourself. Jainy Savla:                         So I'm currently a research fellow at UT Southwestern. So I completed my general cardiology training and I've been doing some extra research training in one of our basic science labs there. Dr Amit Khera:                  So not surprisingly with your background, do you select an article? So we've asked them each to select one article as they've been working through the social media side and see all of our articles come through. Each to select one that they found was interesting and perhaps summarize for us what it included and what appealed to them. So Jainy, tell us a little bit about the article you chose and why you chose it. Jainy Savla:                         So, I chose one of the articles that was published in April of 2018 from the Molkentin team lab. And this is a basic science article that focused on which types of cells contribute to heart regeneration. They hadn't thought that there was cardiac progenitor cell that could contribute to the development of new cardiomyocytes. And more recent data has shown that maybe that's not quite the case. So what this study did was used a lot of fancy lineage tracing models to try to figure out which types of cells we're actually contributing to the development of new cardiomyocytes. So importantly, what came from this was that one of their models, they were able to delete two transcription factors that are necessary for cardiomyocytes to develop from these progenitor cells. But they found that when they did that, they even got a higher number of cardiomyocytes that formed. And then what they were able to show in this paper was that actually comes from fusion of leukocytes to cardiomyocytes. And then interestingly, they found a role for one of these transcription factors and the development of endothelial cells. So that was kind of a new, not known function of one of these genes that was previously thought to be just contributory to cardiac development. Dr Amit Khera:                  It's really a fascinating article when you think about it. Most of the science we publish are people bringing to light new discoveries and certainly there was a component of that here. But in many ways, it was kind of a different article where there had been this a prevailing thought about these c kit positive cells and here they're actually had gone through, refuted what people had thought was happening with these in this de novo cardiomyocyte formation. So you'll see that very often where people's articles or work is headed out to sort of maybe refute or set right what's happening in the literature in the field. Can you comment on that as to that type of article and how that appealed to you in this study? Jainy Savla:                         That is interesting because previously it has meant that these cells can be used as a therapeutic option in human patients. But some of them were recent data showed that perhaps the new cardiomyocytes weren't actually coming from these cells, but it was hard to say. So the nice part about this paper was really they used a lot of important lineage tracing models to really show where these cells are coming from. And it helped clarify some of the, I guess, more confusing science that had been in the field since there were a few papers that showed these cells were contributary and then a few papers that have shown that maybe they weren't. So I think that's really helpful, particularly when you're talking about things that could be potentially used as therapeutic agents in human. And also the interesting thing is that while these cells themselves may not be useful to perhaps harvest and give to someone, you could potentially alter these cells and then they produce cells that fuse with cardiomyocytes. Or could you use this a different way? So I thought that was also interesting about this article. Dr Amit Khera:                  Great points in it. It does remind us again that in our enthusiasm for rushing things to clinical practices in some things in this field, the importance of rigorous basic science to really understand the molecular underpinnings. And as you mentioned, there's some new insights here that could be used for clinical therapeutic purposes in the future. So definitely an interesting article and glad you enjoyed it and brought it to our attention. I'm going to ask you a bit of a different question. You again have been working with this in the social media side for longer. You've seen this now for some time about the different articles that come through. I know you and I've had several conversations about our different platforms, Twitter or Facebook, and how they're different and how we engage with them and how we engage with the audience. Can you tell us a little bit just reflecting now on your time and working with social media from a journal perspective, kind of what you've learned? What are some interesting observations over this year? Jainy Savla:                         Definitely one interesting observation is just that their general usage of these social media platforms has increased significantly since I've started doing this. And you can see this with when we get articles that are accepted, how many authors have Twitter handles that they'd like to be tagged in some of these posts. And that's just gone up significantly since I've started doing this. And that also changes sort of what the comments we get on some of the posts and the back and forth discussions that we're seeing on these platforms. And then the second thing I found really interesting over time is that the way people use Facebook is really different from the way people use Twitter. And you can follow the discussions that people have linked to our posts a little bit better on Facebook. And then on Twitter, there's also a lot of similar discussions about these posts. But they kind of manifest in different ways and it's really interesting to see how that plays out. Dr Amit Khera:                  I think those are fantastic points. And from a fellow's perspective, how do you think fellows are engaging with social media now compared to maybe, I don't know, when you started your training a few years back. What have you seen in a positive light? Jainy Savla:                         I mean in general, there are more fellows on Twitter now than when I was a first-year fellow. Even myself, I've got my Twitter account when I was in fellowship. I didn't have one prior to that. I mean it's interesting because people are able to showcase their work a little bit better I think with these types of handles whereas before maybe you wouldn't know that even one of your own co fellows had published something. So it's kind of nice to see people use that kind of as a networking tool in some ways or to showcase some of their own work, which is something that when I was a first year and I didn't have a Twitter handle and there weren't as many fellows on Twitter, I didn't really notice some of the work that's being done by some of my colleagues at my level. Dr Amit Khera:                  Those are great points and I'll stoplight some of the things you just said talking about it being a way for fellows to really showcase their work, to help with networking and in some ways, it's sort of the great equalizer. So I think it's really a valuable platform specifically for fellows. Well thank you Jainy. I'm going to move on to Daniel and hear a little bit from Daniel. Tell us a bit about yourself. Daniel Ambinder:             I'm currently a second year cardiology fellow at John's Hopkins Hospital and I plan on doing interventional and structural cardiology in the future. Dr Amit Khera:                  Great and certainly a lively and growing field and so many exciting things happening. Well, it's interesting you chose an article today that is more of a clinical article and obviously quite different than the last one we heard, but equally as interesting. Tell us a little about the article you've chose and why you chose it. Daniel Ambinder:             I was very excited about this article that was published in Circulation back in July 2018. So, it's by Dr Borlaug and Reddy on how to diagnose HFpEF and what they did was they took patients with clinical dyspnea and they used invasive human dynamics to kind of assess whether or not they had HFpEF. And by doing so they were able to generate a list of clinical and eco based guidance to help us kind of identify patients with heart failure with preserved ejection fraction. So they came up with this amazing little table which was featured in Circulation and on Circulation twitter, where they have a chart that basically goes through several clinical variables including weight and hypertensiveness, atrial fibrillation, pulmonary hypertension, being elderly. And filling pressure is based on echo cardiographic information. And by that they were able to generate a score and give you a probability of if your patient has HFpEF or not.                                                 And the reason why I really enjoyed reading this article and also posting this article was because going through internal medicine and not being so fundamentally aware of echo and kind of what goes into understanding left ventricular filling pressures, it was challenging to make a diagnosis of heart failure with preserved ejection fraction. Do you just basically say, "My patient has lower extremity swelling but normal EF? They have heart failure with preserved ejection fraction and [inaudible 00:09:32] on the [inaudible 00:09:33]. And so I thought that this would be really helpful to the medical community at large. And in fact, shortly after we posted it, I saw that our cardiology console fellow is actually utilizing this exact table to help one of the medicine teams manage a patient with lower extremity swelling and come to the diagnosis of heart failure with preserved ejection fraction. So that is why I chose this article for today. Dr Amit Khera:                  That's a great article and I thought you summarized it very well. And it is a field. HFpEF you'd see a lot of articles in Circulation on this topic. We have many people that are interested from an editor’s level but also from a society level. This is a huge problem, but we know very, very little. And I'm sure you know that as well and this was a wonderful tool. Just shows you're sort of the beauty and simplicity. Although if you read it, the message were pretty rigorous and they had a lot of great work that they did to develop it. But I love that the H2 HFpEF, how they basically came up with it h for heavy and the f from fibrillation. So I thought that was incredibly creative and a very simplistic but useful score. So, you said your, tell us about yourself. Have you used the H2 of the HFpEF score yet? Daniel Ambinder:             Absolutely. I use it in clinic on a daily basis. And I actually pull up the Tweet in my office and show the patients why I think that they have heart failure preserved ejection fraction, especially since many of my patients start to get really nervous when you start talking about heart failure. But then they don't understand that they have a normal functioning heart. They can't really put those two together. And so going through this chart and going through the etiology, or at least what we know about heart failure with preserved ejection fraction, turns out to be quite helpful. Dr Amit Khera:                  And the basis of this study goes back to hemodynamics. This obviously is a cohort where they had done invasive hemodynamics to essentially diagnosed HFpEF based on pressure. So as you, as someone who's going interventional and structural where we are really seeing kind of the rebirth or refocus on hemodynamics again, tell me a little bit like what you're learning in terms of hemodynamics and how you think that importance in today's practice of cardiovascular medicine. Daniel Ambinder:             One of my passions is spending as much time as I possibly can in the cardiac ICU. And we're fortunate to meet many different patients that come in with very different kinds of cardiogenic shock for other hemodynamic compromise from other types of shock. And I have found it extremely helpful to think about either using a virtual Swan or by actually getting the measurements with a PA catheter to kind of identify where the break in the system is to hopefully provide our patients with the ability to turn them around in a fast manner before they develop metabolic compromise from prolonged hypoperfusion. Dr Amit Khera:                  Great summary of how you're using hemodynamics and the training. And I'm going to pivot. The last question for you is when we first met I think several months back and we're communicating about your interest in social media, one thing that was really interesting and fascinating was the great work you're doing on Twitter on your own account where you essentially, if I think you told me this right, you sit on your iPhone and basically in this matter of a very few minutes would construct cases and teaching points on Twitter. So tell me a little bit about that, about using Twitter for medical education and learning cardiology and cases. And I know you're passionate about that. So tell us a little bit more about that. Daniel Ambinder:             Back in May, last year, I had been in my first year of cardiology fellowship. And I was really kind of obsessed with grabbing as much imaging and cases as I could to construct them into teaching stories to share these important stories that I encounter with other people. And so also share the aha moments that I have when I'm learning from my mentors about a new clinical condition or even a clinical condition that I've encountered many times. We never thought about any unique way. And so I was putting these all together and developing somewhat of a library of cases. But I would share them with the residents that I was working with at the time. And then Dr Erin Michos was one of my mentors at Hopkins. She's an echocardiographer and she kind of exposed me to the Twitter community where you're really able to just start reaching out to different people and share the same insights that I had saved on my drive on my computer. And so I started constructing these cases, putting that together and developing them and then associating them with like a few bullet pointed tidbits of pearls that I can put on Twitter. And I quickly realized what an amazing community Twitter have to offer in terms of cardiology and in terms of the medical education community at large.                                                 At first, I realized you can't put out content and not expect to participate in a conversation. It has to be two ways. You have to really engage with others and others will engage with you. And then just a couple months later, it's really grown that you can post a case, post the teaching pearl and in about 24 hours it can be viewed thousands and thousands of times, really internationally. And generates just so much great conversation. So it's been really a tremendous way to communicate with the world, especially within the cardiovascular world. Dr Amit Khera:                  Well thanks. I think there's so much learning that can happen and I think the work you're doing with cases and with others. And I know when I've gone on Twitter, even in just two minutes you can see really fascinating things and learn a lot. So keep up the good work and appreciate your efforts there. I'm going to switch gears and finally finished with Jeff Hsu from UCLA. Jeff, tell us a bit about yourself. Jeff Hsu:                               I'm a fellow at UCLA. So I actually finished my general cardiology fellowship pretty recently and now I'm a research fellow in the STAR program here. I'm also enrolled in the PhD program at UCLA in the Department of Physiology and planning to defend in the next few months. So right now, very stressed out about that. Starting in July, I'll be starting advanced fellowship in advanced heart failure and transplant here at UCLA.                                                 Well excellent and best of luck to you in your PhD defense. Now you also chose a very interesting article that again, all of yours are a bit different. So tell us a little about the article you chose and why you chose it.                                                 When I chose this article, I was really excited by a few weeks ago. It was published in the December 4th issue of Circulation called Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human Induced Pluripotent Stem Cells. So this came out of the lab of Joe Wu at Stanford and the co first authors is Ning Ma, Joe Zhang and Ilanit Itzhaki. But I think the beauty of this article is that it really addressed this frustrating clinical scenario in question that we often encounter nowadays in this era of genome sequencing. And now that we're sequencing a lot more people, since the cost of sequencing has come down a lot, we were finding a lot of these mutations that we don't know what to do with, so I think Dr Wu's lab really try to address this question using the disease model with the cardiomyopathy. So, leveraging Dr Wu's expertise in using human induced pluripotent stem cells or iPSCs, they found a patient who is actually healthy but apparently had this mutation in this gene called MYL3 or myosin light chain 3. And so this patient had a variance of uncertain significance in this gene.                                                 Now, notably, this patient, again had no clinical phenotype, was very healthy and the patient's family members over three generations were all healthy too. But had this mutation that based on in silico analyses was thought to be likely pathogenic. So using cells from this patient that they reprogrammed into cardiomyocyte, they tested various properties of these cells from the same patient to see whether or not they thought this mutation is actually a pathogenic mutation. So again, using these reprogrammed cardiomyocytes, they tested a variety of things including gene expression, sarcomere structure, and cell contractility, action potentials, and the handling of calcium. And they saw that even with this mutation, there were no abnormal findings in vitro in their system.                                                 Now just to prove that their cell culture system and this in vitro model of testing the pathogenicity of certain mutations actually works, they actually took cells from a patient who did have the clinical phenotype as a result of a known mutation that causes hypertrophic cardiomyopathy. And found that when testing those cells in vitro, they did demonstrate abnormal phenotypes in all the parameters I mentioned before. So I thought this is really exciting. I thought this is a great way to address, potentially answer whether or not we think these variants of uncertain significance that we often encounter are indeed pathogenic because we are often just left in this situation where we don't know what to do with this information. But this potentially at least is a proof of concept for this protocol where we can finally take advantage of the ability to take cells from our patient and actually test them in the lab to see whether or not either various treatments work or whether or not these mutations that actually will results in pathology down the line. So I thought overall this was a great paper that was a great summary of how we can take the bedside to the bench actually. And I'm just really looking forward to the future where we can maybe then bring it back to the bedside. Dr Amit Khera:                  Well thanks. I think that's an excellent choice and a great summary. And this article really hit all of the kind of timely and cutting-edge topics in the era genomic medicine and precision medicine have really kind of individualized treatments. And when we get stuck, these VUSes, these are a nightmare. And also this is sort of proof of concept for extending this to other treatments and other ways to test drugs and therapies. I've heard Joe, we talk about this before and use the word disease in the dishes. He did I think in the article itself and it's exactly that. I mean the potential here is profound. I'll pivot this into the next question for you. For our roles, one thing we do is we interact a lot with media and I interact a lot with them to help translate, I guess, the articles that we have to things that would be able to be digestible for media and for lay individuals. It was interesting because it's hard for us to do that with basic science and most of the time we have some difficulty in translating that. But this one translated pretty well and I think we had done some various press releases and things because it really showed the potential of modern medicine and kind of the excitement of it.                                                 But that gets to the question I have for you, something we have discussed as well, your interest in basic science and some of the challenges of taking basic science articles and digesting them down to a couple hundred-word tweet. Even as beautiful as all the pictures are, and in this article I think there's six figures, but each panel is 10 pictures or 10 figures by themselves. And how do we digest basic science articles down to make them really appeal to people on social media and help people understand that may not be in the fields or in basic science that are clinicians, if you will. I know you've thought about that a little bit. Tell me a little bit about your thoughts on that. Jeff Hsu:                               Jainy, Dan and I have this challenge on a weekly basis, figuring out how to summarize great articles such as this one into a short tweet. And I think that is a big challenge particularly for basic science articles on social media to make it appeal to a broader audience because the audience you're seeing on Twitter and Facebook, again, they're not just basic scientists. If you want to catch people's attention, you need to find a way to really understand the big picture of the question you're answering in your basic science research. So I think that is a challenge. You're challenged to make your science appealing to a broader audience. But I think again, that's one of the advantages of social media is that you can appeal to a larger audience and have a wide range of people engage with your research and understand your research. So it is something that we work on is to try to pick out the figure that best represents the science that was done in these basic science articles.                                                 It can be quite challenging because a lot of times one picture won't do it justice. So it's tough to distill a full article in one picture. It is helpful when some articles do have a summary, a graphic or figure where they typically reserve their last figure for either a cartoon or some type of schematic that really explains either the mechanism or pathway that they explored in their article. So what we've found is that these articles that do have some of these illustrations or summary figures, they seem to engage a larger audience on Twitter and social media. So personally I find it more appealing when I do see these summary figures. So if there is one recommendation, I would have the basic science researchers, especially trainees is in this age of social media, try to come up with an illustration or summary figure for your research. I think it helps you figure out what is truly important with the research that you've done and helps you communicate this research to a broader audience. And I've seen a lot of people take advantage of a graphic designers to really help them illustrate their research. And I found that to be very effective in articles I've read on social media. Dr Amit Khera:                  Thanks Jeff. That's a great point and great suggestion. And certainly these days the most effective communicators are those they can translate their complex science into easily digestible bites and can think of ways to portray them in ways that sort of summarize, like you said, be it summary figures or otherwise. And it's a challenge and also talent. And you all are certainly perfecting that. Well, I think we've had an excellent conversation. I have to tell you, I'm so excited to get the chance to spotlight you all. You do excellent work each day. Every week you're working hard and coming up with great ideas and suggestions and we really value having your input as fellows and training and as a colleague.                                                 Thank you for joining us today on our FIT podcast. Amit Khera standing in for Carolyn Lam. We look forward to seeing you for our next edition of Circulation on the Run. This program is copyright American Heart Association 2018.  

Amit Khera breaks the Bushwick Junction mold to focus on ONE big decision: his decision to found Soul Collective, a directory of conscious community-based events in NYC.

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.                                                 Can we get better at predicting clinical benefit of PCSK9 inhibition based on the severity and extent of coronary artery disease? Well coming right up after these summaries we have an important discussion of an analysis from the FOURIER trial, so stay tuned.                                                 The first original paper this week suggests that targeting visceral adiposity may be the crucial step to limit age-related cardiac remodeling and to promote healthy cardiac aging. Co-first authors Drs Sawaki and Czibik, corresponding author Dr Derumeaux, from INSERM France, and their colleagues, hypothesize that since aging induces cardiac structural and functional changes, linked to increase deposition of extracellular matrix proteins including osteopontin, well osteopontin may play a role in myocardial aging.                                                 To test this hypothesis, they studied osteopontin-deficient mice and their wild-type litter mates at two and 14 months of age in terms of cardiac structure, function, histology and key molecular markers. They found that during aging, visceral adipose tissue represented the main source of ostepontin and altered heart structure and function via its profibrotic secretome. Furthermore, interventions targeting osteopontin, such as visceral adipose tissue removal and osteopontin deficiency, rescued the heart and induced a selective modulation of fibroblast senescence. This work uncovers ostepontin's role in the context of myocardial aging and suggests that osteopontin may be a potential new therapeutic target for a healthy cardiac aging.                                                 The next study shows that higher triglyceride rich lipoprotein cholesterol may be a risk factor for cardiovascular disease and potential therapeutic target. First author Dr Vallejo-Vaz, corresponding author Dr Ray from Imperial College London, and their colleagues assess the relationship between triglyceride-rich lipoprotein cholesterol and cardiovascular risk and whether this risk was modifiable among patients receiving statins in the TNT trial. They found that higher levels of triglyceride rich lipoprotein cholesterol were associated with a significantly higher rate of cardiovascular events among coronary patients treated with statins. Statin therapy reduced triglyceride-rich lipoprotein cholesterol and to a greater extent among those treated with a higher statin dose.                                                 Based on their post hoc analysis of the TNT trial, they found that more intensive statin therapy with atorvastatin 80 milligrams, compared to atorvastatin 10 milligrams, resulted in a significantly greater cardiovascular risk reduction among patients with higher triglyceride-rich lipoprotein cholesterol. These results were consistent for higher triglycerides and directionally concordant for non-HDL cholesterol. A higher percentage reduction in triglyceride-rich lipoprotein cholesterol was associated with lower cardiovascular risk independent of LDL cholesterol reduction. Thus, these findings suggest that triglyceride-rich lipoprotein cholesterol is not only a cardiovascular risk marker, but also potentially a therapeutic target.                                                 Late gadolinium enhancement on cardiac magnetic resonance imaging represents fibrosis and is seen in 60% of adult patients with hypertrophic cardiomyopathy. However, what about in children and adolescents with hypertrophic cardiomyopathy? First author Dr Raja from University of Copenhagen in Denmark, corresponding author Dr Ho from Brigham and Women's Hospital in Boston, and their colleagues looked at cardiac magnetic imaging data from 195 children and adolescents with hypertrophic cardiomyopathy. Late gadolinium enhancement was present in 46% of patients with overt hypertrophy as opposed to 60% typically represented in an adult population of hypertrophic cardiomyopathy. On the other hand, late gadolinium enhancement was not seen in mutation carriers without left ventricular hypertrophy.                                                 In patients who underwent serial imaging, increases in late gadolinium enhancement, left ventricular mass, and left atrial size were detected over two and a half years. Thus these findings in children provide additional insights into the biology and natural history of hypertrophic cardiomyopathy and confirmed that fibrosis is a significant part of the disease process in both children and adults.                                                 Whether the adult mammalian heart harbors cardiac stem cells for the regeneration of cardiomyocytes is an important yet contentious topic in the field of cardiovascular regeneration. This week's paper adds to the growing knowledge in this area. First author Dr Li, corresponding author Dr Zhou from Chinese Academy of Sciences and their colleagues developed a new genetic lineage tracing system to label all nonmyocyte populations that contain putative cardiac stem cells. Using dual lineage tracing system, they assessed if non-myocytes generated any new myocytes during embryonic development, adult homeostasis and after myocardial infarction. Skeletal muscles were also examined after injury and acted as internal controls.                                                 By using this stem cell marker free and dual recombinases mediated cell tracking approach, the author showed that new myocytes arose from nonmyocytes in the embryonic heart, but not in the adult heart during homeostasis or after myocardial infarction. As positive controls, the same lineage tracing system detected new myocytes derived from nonmyocytes in the skeletal muscle after injury. Thus, this study provides in vivo genetic evidence for non-myocyte to myocyte conversion in the embryonic but not the adult heart. This study also provides a new genetic strategy to identify endogenous stem cells, if any, in other organ systems for tissue repair and regeneration.                                                 Well, that wraps it up for our summaries this week, now for our feature discussion.                                                 Are there subsets of patients that derive greater clinical risk reduction with the PCSK9 inhibitors? Well we're gonna find out about that right now with a discussion of our feature paper entitled the “Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease.” So pleased to have with us Dr Marc Sabatine from the TIMI Study Group, who is the first and corresponding author of today's feature paper, as well as our editorialist, Dr Roger Blumenthal from Johns Hopkins University. And of course, we have a familiar voice, a very important editor of our digital strategies and that's Dr Amit Khera from UT Southwestern.                                                 Welcome everyone, I think I'd really like to start with maybe asking Roger to paint the background of the importance of this paper. Simply because I just love the title of your editorial, which is “Realizing the Value of PCSK9 Inhibitors: Are We Closer to Finding the Sweet Spot?” I think that really encapsulates it. So Roger, your thoughts? Dr Roger Blumenthal:     As Amit Khera knows, I'm a golfer, so when you think about the sweet spot on the club, and we know that PCSK9 inhibitors are a great story of translation from bench to bedside, and we also know that the high cost of the therapy presents a challenge. So what Dr Sabatine and colleagues did was to try to identify the sweet spot for its most effective use and that was a pleasure to comment on Dr Sabatine's excellent study. Dr Marc Sabatine:            I think taking a step back I would say from pure biologic perspective, we know that lowering LDL cholesterol will reduce events and that's true and primary and secondary prevention and so if you have therapies that were safe and inexpensive, then I think you wouldn't need to really look for that sweet spot cause it would be all sweet if you will to extend the analogy. But Roger's absolutely right that when you have therapies that are then expensive, then you have to decide, okay in which patients will I get the biggest bang for my buck? And that's a very legitimate question to ask.                                                 And so in FOURIER, overall the trial was positive but as we look for subgroups we say, "Can we find individuals who enjoy a greater absolute risk reduction?" Because therefore the benefit cost ratio is gonna be particularly favorable. And so we approach that in a couple different ways. First you can look for just predictors of baseline risk, so if someone has twice the baseline risk and the same relative risk reduction, you should get about twice the absolute risk reduction and therefore the number needed to treat would be cut in half. And so based on our experience from other TIMI trials and other datasets, we looked at three features that have identified patients with higher baseline risks.                                                 Amongst those with a history of MI which is in and of itself a heterogeneous group. And so those features were patients with a more recent MI, those with multiple prior MIs and those with known residual multivessel coronary disease. And all three features in the FOURIER dataset, not surprisingly, were predictors of risk with patients having an average about a 50% higher baseline risk. But what was particularly nice was that the subgroups also identified patients who had greater relative risk reduction. And so when you couple the two, the higher baseline risk with the greater relative risk reduction, that translated into greater absolute risk reduction then in each of these high-risk groups, the absolute risk reductions over three years or for CV death, MI, and stroke was around 3% versus around 1% for the low-risk groups.                                                 And so that changes the number needed to treat by a factor of three. Dr Carolyn Lam:                Wow, that's so cool. Amit, do you think you could just give us a sneak peek into the editors’ discussions when you saw this paper? Dr Amit Khera:                  This was an easy one, it's clearly a very important paper and if you step back 10,000-foot view, these drugs were initially approved based on LDL lowering and people were using them without knowledge of whether or not they actually lowered events. Marc's group and others have now shown us that certainly they do lower events, but really the next most important thing is application. Who should we use them in and when should they be used and where might they be most effective and I think it was said out in the introduction of this paper, this idea of personalized medicine. And I think this really is an important step forward, not just for PCSK9 field but in general, how we should be thinking about drugs, about balancing cost and benefits and who would benefit most.                                                 So maybe one analogy, I think PCSK9 was not prescribed as much as they had been predicted given costs and other considerations and maybe with analysis like this they've hit it out of the rough back on the fairway, I threw that in for you, Roger. And I do have one question for Marc, which is this is clearly important to better define who would benefit the most and I guess in terms of action abilities, the goal here to provide guidance for clinicians where, you know, if I'm seeing a patient this morning I would take this into account or is this something larger where we recently saw with alirocumab, they changed pricing based on sub-group analysis of a higher risk group. How do you think we should move forward with this type of information? Dr Marc Sabatine:            I’ll get back to the point I raised earlier, I do want to underscore that I think that the true biologic notion is that all these patients, sub-types of secondary prevention or primary prevention all benefit from LDL lowering. So I wouldn't want people to walk out with the notion that it's the only subset that would benefit and really from a population level, obviously Roger's in a better position to speak about this, but sort of shifting the population LDL lower in general would have a huge impact on the risk for cardiovascular disease. But to your question Amit, looking in for a patient in front of you, I think it's quite fair to say right now there's this kind of tug of war back and forth between payers and clinicians.                                                 Clinicians saying, "I have a patient in front of me, they have known atherosclerotic cardiovascular disease, I wanna lower their risk, I wanna manage their risk factors and I wanna get their LDL cholesterol lower and I have a bunch of great tools in front of me." Statin for sure is the foundation, maybe acetamide and PCSK9 inhibitors. And then payers saying, "Well wait a minute, these are expensive drugs and so we're gonna try to restrict that and create a lot of hoops for clinicians to jump through." And so I would rather than wasting all that time back and forth, I think it is logical to say, "What are the high-risk groups?" Where we can agree there's the large enough absolute risk reduction that for a given cost, that makes sense.                                                 Allow there to be alignment for that and have clinicians just be able to write a script and have it filled rather than wasting a lot of time with preauthorization and letters back and forth. Dr Amit Khera:                  That's a great point, maybe I'll just take one follow-up, which is now trying to sift through all the high-risk groups and they end up maybe becoming a bit of a Venn diagram. I know in Roger's editorial he talked about the other FOURIER analysis with PAD and there's more groups to come or do we have enough of a starting place where we think we have enough for decision making? Dr Marc Sabatine:            I would say there are a variety of groups, there is some overlapping even in the paper then we looked at the union of those three high-risk features, which identified about two thirds of the patients who were enrolled in the trial with a history of MI. But you're right, the other slices of the data that will also identify high risk groups, PAD is a particularly good one because most of the therapy for those patients has focused on antithrombotic therapy, which always will have some downside for increased bleeding, whereas risk factor modification in this case has no downside. So that's a very high-risk group, it certainly is important to focus on. But I think within the MI subset, this is a great place to start the other analyses we're doing.                                                 And probably after we've sort of finished the series of, if you will, these kind of univariant slices, then we'll try to put that together into a more comprehensive picture. Dr Roger Blumenthal:     We tried to say that we still need the formal cost-effective analyses in these specific high-risk groups, but it seems most reasonable to focus on engaging in shared decision making now with our patients about PCSK9 inhibitor use and those with a recent ACS and the basis of Odyssey Outcomes and we're awaiting the final publication of that. Symptomatic peripheral arterial disease, which Marc previously published in Circulation, and then looking at these high-risk features that was the subject of this article, those with a more recent MI within the past two years, multiple prior MIs and residual multivessel coronary disease.                                                 And one of the things that we especially found interesting was among the more than 8,000 individuals without a high-risk feature, the event rates were nearly unchanged in the evolocumab versus placebo groups. So I think that's very important, but one other point that we have to keep in mind is that the focus of the last set of guidelines and probably the next cholesterol guidelines that likely will be out in November, will have a large component of the shared decision making and we need to see where the cost comes down, whether these companies that make these medications will be able to significantly lower the cost in a reproduceable manner and patients and clinicians will have to jointly decide what to do, do we add acetamide? Do we add a PCSK9 inhibitor?                                                 But we finished our editorial saying that all clinicians and patients should currently pursue a comprehensive lifestyle and medical regimen for secondary prevention. We all have to remember that and if a person's LDL, a high-risk individual is at least 70 with high-risk features and certainly above 100 on maximum tolerated statin therapy, it's important to strongly consider a PCSK9 inhibition and it'll be very interesting to see what the final wording is when the ACC/AHA cholesterol guidelines come out in November. Dr Carolyn Lam:                Amit, would you like to add any further take-home for the clinicians listening in? Dr Amit Khera:                  I just first want to congratulate both of these discussions today, I think the paper was so incredibly important and I think Roger's group really helped frame it well in the field. The one thing I'd say is this is a moving target, we have some early guidance now that I do think is actionable, so I actually have clinic in about an hour and I'm sure I'll be thinking about this as I think about how to apply PCSK9. Which groups might benefit most, so I do think this is actionable now, I think the points that were made about cost effective analysis, how do we bundle all these concepts or high risk patients into maybe an algorithm and how do the guidelines interpret this as a moving target. We'll wait to see, but I do think there's some important actionable information even now for our clinical patients. Dr Carolyn Lam:                I just love that, and you know that is just so much in line with the ethos of what Circulation is about now. We really, really love the papers that you have to pick up because they're of immediate applicability to your clinical practice.                                                 Well audience, you heard it right here. Thank you so much for joining us this week and of course 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. And I am joined today by our Editor of Digital Strategies, Dr. Amit Khera from UT Southwestern, as well as three wonderful fellows in training. Yes, you've guessed it, it's our FIT Podcast and I'm just so thrilled to be here again. Dr Carolyn Lam:                Amit, any words of introduction before we start? Dr Amit Khera:                  Thank you Carolyn. I think, for both of us, this is our favorite podcast, or two podcasts, that we do, a year. It reminds us of how bright the future is, with superb cardiology fellows in training around the country, and it really is a testament to how important we find fellows in training, to Circulation, to our mission, and how much we learn from them.                                                 So we're really excited about this group, today, and thank them for participating. Dr Carolyn Lam:                Absolutely. So, why don't we start, now, with ladies first? Let's hear from Dr. Elizabeth Hill. Dr Elizabeth Hill:                Thanks for having me today. My name is Beth Hill, and I'm a first year cardiology fellow at Scripps Clinic, in La Jolla, California. I've a particular interest in sports and exercise cardiology, which brings me to the article I picked today about sudden cardiac death and hypertrophic cardiomyopathy, hot topics in the field and in general.                                                 And so, today, I'm excited to be discussing the EVIDENCE HCM study, looking at the hypertrophic cardiomyopathy of risk, sudden cardiac death model. Dr Carolyn Lam:                Nice. So tell us a little bit about what really struck you about the paper and, perhaps, how that may apply to where you practice? Dr Elizabeth Hill:                What I really liked about the paper is that, when I see patients in clinic with hypertrophic cardiomyopathy, prior to having this risk stratification tool, we didn't really have a way to objectively risk stratify our patients with hypertrophic cardiomyopathy and really guide the discussion about who may benefit from an implantable cardiac defibrillator or ICD. And so, I've been using this a little bit with my patients. While it hasn't made it fully into the AHA or ACC guidelines yet, I'm using it as a tool. Dr Carolyn Lam:                Great. You know, these are seven risk factors, isn't it? I'm always struck by that survival curve that really shows that those with a predicted 6% risk stand out. Is that what you use, as well, to guide your decisions? Dr Elizabeth Hill:                Yeah. I think, as the authors noted, they picked this somewhat arbitrarily so that they could study their risk model. But I think what they found is that it seemed to fit well with the observed high risk of sudden cardiac death cohort, such that those that were seen and observed, about 9% risk of sudden cardiac death in five years, were in that greater than 6% cohort. So I think that population should receive ICDs, and that is one factor that I used to guide my decision making as well. Dr Amit Khera:                  Beth, this sort of interest that you've had for a long time, in sports cardiology, I've noted you've done some prior work in EKG screening and other screenings. In terms of this article specifically, as you pointed out, this is a really helpful tool because I still remember back when I was a fellow in training, there was, sort of, this thought that everyone was high risk with hypertrophic cardiomyopathy, and I think we realized that's not true at all. The overall incidence of sudden death was only 2.4% in this cohort.                                                 The question I have for you, in terms of application, is, as Carolyn pointed out, these are reasonably simple variables, but as we sometimes are now using cardiac MRI and genetics and other more advanced tools, where do you think they fit in, in the current paradigm, since this is a bit of a more simplistic score? Dr Elizabeth Hill:                The seven risk factors they put into this tool were noted to be independently associated with an increased risk of sudden cardiac death, and those are well known factors, entricular tachycardia, maximum wall thickness. But I really do think that other factors will come into play soon and are part of my discussion, and colleagues' discussions, including the late gadolinium enhancement on MRI, genetic factors, and I really think this may be a place for tools like machine learning. These authors, O'Mahoney and colleagues, they really did, kind of a tour-de-force, going back to the 1970s, but there is still a decent amount of data missing. So maybe we can partner with the machines and help them go back into these records, a little bit more effortlessly, and look at genetics, maybe some wearable device data, and really refine our risk stratification tool moving forward. But that's definitely something I use in risk stratification in some of my intermediate risk patients. Dr Amit Khera:                  Those are great points. I think your point about machine learning and novel algorithms will definitely take foot in the future.                                                 Maybe a follow-up, again, given your background interest, I think it's a trade-off where we're trying to, of course, avoid sudden death, but you also don't want to overtreat. Especially, when you think about athletes getting ICDs and how that changes, or anyone, for that matter, about maybe telling someone they're at high risk, or giving them an ICD when perhaps they don't need it. I guess that comes to, what's the threshold? Here they use 6%, but that ends up being a bit arbitrary, in terms of what threshold we use. And how do we decide, when we talk to our patients, about what threshold's a right threshold to apply an ICD? Dr Elizabeth Hill:                Yeah. That's a great question. Like you mentioned, these devices come with inherent risks, such as unnecessary shocks, increased risks for infection, and sometimes there's restrictions with athletic sport, although that's been changing recently.                                                 But, I think that's where the shared decision-making process comes into play, where you put current data on the table with the patients and, perhaps, their families as well, and have a risk-benefit discussion. Perhaps gather a little bit more data about the patient, maybe follow them over time, but I guess I wouldn't jump to put an ICD in, in every patient and, especially, the lower-risk cohort. And what number that is, I'm not quite sure. Here they say maybe less than 4%, but, again, somewhat arbitrary, I think. Dr Carolyn Lam:                Thanks Beth. I mean, as Amit said, it's just so inspiring to see how the papers are being used in practice. Really loved those perspectives.                                                 Now, from sunny San Diego all the way to snowy New Zealand. We have Dr. Mesfer Alfadhel. And Mesfer, tell us a little bit about yourself, and the paper that you've chosen? Dr Mesfer Alfadhel:        Thank you very much. I'm thrilled to be part of this podcast. I'm a second-year cardiology fellow-in-training at the Needham Hospital, in Needham City, New Zealand, where it's snowing at the moment. I'm also a clinical lecturer at the University of Otago School of Medicine. I do have great interest in general cardiology, as the rest of my colleagues, but also am passionate about interventional cardiology and structural heart disease.                                                 The paper I've chosen is really quite relevant to everyone in cardiology, and perhaps extends to other colleagues in other health professions impacted by automated external defibrillator use on survival and functional outcomes in shockable observed public cardiac arrest. The aim of the study was to determine the association of bystander automated external defibrillator use, the survival and function of outcomes in shockable observed out of hospital cardiac arrests. The study was from 2011 to 2015 and the Resuscitation Consortium prospectively collected detailed information on all cardiac arrests at nine regional centers, six in the United States and three in Canada.                                                 They also found that among nearly 50,000 out of hospital cardiac arrests, 8% were observed public out of hospital cardiac arrest, of which 61% were shockable. Overall, a remarkable one in five of shockable observed public out of hospital cardiac arrest were bystander shocked. Now the bystander automated external defibrillator observed, shockable observed public out of hospital arrests were associated with increased odds of survival and full or near full functional recovery almost 2.6 and 2.7 odds ratio than when compared to emergency medical service defibrillation. What's also interesting is that the longer the wait for the emergency services, the higher the benefits from a bystander observed shock. Dr Carolyn Lam:                You know, Mesfer, I appreciate that you chose this one as well. What struck out to me immediately was that more than 60% of out of hospital cardiac arrests were shockable. And when we think about the number of lives that could potentially be saved, therefore, that's quite astounding, isn't it? But can I ask you something? So these are in the US and Canada, how applicable do you think this is to New Zealand? Dr Mesfer Alfadhel:        We do have a small population, just over four million. The number of cardiac arrests here is around 2,000 out of hospital cardiac arrests. And I think probably half of them in the latest reports were shockable. The emergency response time in the urban areas is around six minutes, which I think is acceptable, but we have about 20% of population living in rural areas. And the emergency response time exceeds 10 minutes almost all the time. I think that probably a group that we need to direct intervention to in New Zealand. Dr Amit Khera:                  It's really an important article. I should say that June for the American Heart Association is AED and CPR month so great choice to remind us of the value of these and especially, the one thing that was amazing, obviously this is an observational study, but the absolute change, not relative, was about 14% meaningful recovery and so that's quite impressive in terms of the number needed to treat if you will. Maybe an adjunct to Carolyn's question is, when we think about strategies to enhance bystander AED use for strategies, essentially get the AED there faster. As you know if the EMT time was not delayed it wasn't necessarily better for the bystander.                                                 We had a paper in Circ sometime last year looking at drones and then also geocoding and other people in some countries have looked at apps where you essentially can train a group of people and then they can be texted for a sudden cardiac arrest in their area. I'm curious about any creative things, there's always training and AEDs, I think in this place it was public areas in industry, but what do you think are some creative things or things that we need to be doing to help enhance the ability for bystander or early AED use. Dr Mesfer Alfadhel:        I think this is one area in medicine in general that where technology is really going to advance how we deal with this problem. There's an app that's available, it was launched in the UK a few years ago and it's become available in New Zealand in the last two weeks called, the Good SAM. SAM stands for smartphone activated medics. And it's become available in New Zealand two weeks ago and I downloaded it and still yet wait for it to be activated. And the way it works is you can activate a medical emergency using the app and it dials the emergency response but what it also does is it activates the nearest three people with CPR training nearest to you and it tells you how far they are from the emergency. Now if you don't have the app and you call 911 or the equivalent, the operator can activate it to the nearby personnel who have that experience. And I think it's going to reduce the time markedly.                                                 Now the other end of the question where some of what strategies could be used I think we had a good report from Denmark where they made changes in 2007 in Denmark and then followed by the rest of the country in 2010 where they made CPR or resuscitation education as compulsory at school but also when getting a driving license they made courses available for free that increased the number of defibrillators available in public places and they shared that information with public. They've redone, audited their work, and compared to prior to intervention prior to 2007 and after that and they found an increase number of using the AEDs increased from somewhere around 2% to 15%, which is really encouraging. I think we are following Denmark in that regard probably at slower rate. Dr Amit Khera:                  Thank you those are excellent insights. Dr Carolyn Lam:                Amit, don't you see that I just love learning from these fellows during these podcasts. We should do more of these. This is awesome. Dr Amit Khera:                  I completely agree. Dr Carolyn Lam:                Thank you Mesfer, enjoy the skiing. But now from snowy New Zealand we're going all the way to Nashville Tennessee. Welcome Dr. Vineet Agrawal. So tell us a bit about yourself and your paper. Dr Mesfer Alfadhel:        So my name is Vineet Agrawal. I'm a second-year cardiology fellow at the Vanderbilt University Medical Center. My background is as a physician scientist and as a general cardiologist. My long-term goals are in understanding mechanisms underlying heart failure with preserved ejection fraction.                                                 With that in mind I was really taken by an article that was recently by Margaret Redfield's group from the Mayo Clinic in Circulation, titled “Global Pulmonary Vascular Remodeling and Pulmonary Hypertension Associated with Heart Failure and Preserved or Reduced Ejection Fraction.” I found this article to be a very interesting, hypothesis-generating article.                                                 In a nutshell what they did was they took an autopsy cohort of patients in the Mayo Registry and those who had heart failure with both preserved and reduced ejection fraction, normal controls, and those who had a primary pulmonary venous occlusive disease, and looked at the lung specimens of these patients. And interestingly what they found was there was a significant amount of pulmonary venous remodeling that had occurred in patients who had both preserved and reduced ejection fraction. This correlated not only with their right heart cath findings, so those who had elevated pulmonary pressures and elevated transpulmonary gradients, but also differed from the primary pulmonary venous occlusive disease in the sense that the histologic appearance of these vessels was quite different.                                                 And while as an autopsy study this is not necessarily an article that would immediately change practice, what I think it does do though is it forces us to think about these conditions in a different context and particularly with an eye towards future therapeutics. Heart failure with preserved EF as a disease, as I'm sure we all know, is sorely missing therapies that could alter the disease progression and potentially even alter mortality in these patients. And this article in my opinion really sheds light on at least anatomically a new location for us to think about as a therapeutic target when we try to better understand this disease and find therapies for these patients. Dr Carolyn Lam:                Vineet, can I just say you're singing to the choir here. I'm such a fan of this work as well for obvious reasons. But hey, could I ask you, in your clinical practice, do you see a lot of these patients with HFpEF and pulmonary hypertension and wonder how to treat them? And along those lines, how has this paper helped you think about these patients more? Dr Mesfer Alfadhel:        I would say when I first started residency as a medical student this was not necessarily a condition that was really something that I had learned much about or felt like I had been exposed to; however, as a resident I felt like most of the patients, or at least half of the patients, I was seeing with heart failure had a component of diastolic heart failure or they had a preserved EF but very symptomatic from the standpoint of heart failure. And I struggled to treat them, particularly in some part due to the fact that many of the risk factors that contribute to HFpEF, diabetes, uncontrolled hypertension, obesity, are chronic problems that are difficult to manage as a clinician regardless.                                                 And second because I feel that there just weren't any data to support any treatments that we were pursuing at the time and so we would try and apply what we had learned in other types of heart failure to these patients with limited results. If I could talk about what I think this article may change in terms of my practice today, one thing that we've always thought about in terms of pulmonary vascular remodeling in heart failure is that it's just a passive process that as fluid builds up you back up into the lungs and as the fluid builds up and backs up into the lungs you get remodeling.                                                 I think one thing that this article shows is that it may actually be a bidirectional process, which would suggest that perhaps we may need to reconsider looking at pulmonary-specific therapies in this population. But more importantly I think it does confirm that chronic elevating filling pressures do have an effect and a deleterious effect on the pulmonary vasculature. Particularly when you look at other trials such as the CardioMEMS trial, the CHAMPION trial in which the data pretty convincingly showed that as clinicians we don't do the best job of reducing left-sided filling pressures in our patients with heart failure as much as we think we do. This article really drives home the point to me that I really need to make sure that when I see these patients that I'm doing everything I can to reduce their left-sided filling pressures because the consequences of not doing so can affect the lungs, which can then in turn affect the heart as well. Dr Carolyn Lam:                Vineet, that's really words of wisdom. Couldn't agree more. And these are the first sort of autopsy, histological evidence that we have, which is so important. I think if I could just add a couple of perspectives too, it makes me think about making sure that I rule out PVOD in these patients sometimes. We now keep thinking about HFpEF we forget that we need to also rule out PVOD and the other thing much as we now think about not just the filling pressures but the remodeling it's good to note that they found it more in the venous than the arterial system, which also comes therefore with a warning message that we can't just extrapolate I suppose all the PAH therapies that we know about. What do you think about that? Dr Mesfer Alfadhel:        I absolutely agree with that. It's really interesting that all of our therapies from heart failure standpoint and from a PAH standpoint have focused on the myocardium, the neural hormonal cascade, and then the arterials. The pulmonary main artery and arterials. I don't think anyone really understands the biology of pulmonary veins and yet they're actually a pretty significant part of our everyday practice in cardiology. Pulmonary veins are thought to be the source of atrial fibrillation. We look at pulmonary vein inflow when we evaluate patients with echoes. And yet we understand so little about the biology and the mechanisms by which pulmonary veins are affected in both diseased and healthy patients.                                                 I think this article for that reason raises a number of very interesting questions and may potentially change the way we think about these patients. Dr Carolyn Lam:                I keep learning, Amit, this is awesome. I could go on forever so you better stop me. Dr Amit Khera:                  I should probably just be a fly on the wall. You must know Carolyn is a HFpEF, HFrEF aficionado and you guys should have a side call for another hour after this. But I do have one, maybe orthogonal question which is, it's interesting because if you look at how insights were made, they're made off areas I would argue at least that we don't, modern environment uses much which is the autopsy and probably to a large degree hemodynamics as much as probably in the old days although that's changing. I'm curious in a fellowship training program your exposure to autopsy and kind of current in-depth hemodynamic-type training, what's your experience? Dr Mesfer Alfadhel:        Our experience with looking at pathological slides, getting under the microscope, seeing tissue first hand, is somewhat limited in our fellowship training program. I would say in certain subspecialties like our heart failure, advanced heart failure subspecialties we do get a chance to see more myocardial biopsy specimens, but I think increasingly the focus has been on noninvasive methods by which we can assess some of these same things that we used to do, use the microscope for. Invasive hemodynamics I think similarly we get a lot of experience in terms of spending time in the cath lab but I do kind of wonder if we don't have the same in-depth training that we used to have in understanding all the nuances of hemodynamics that used to exist in the past.                                                 Certainly, I think that while that's partially a reflection of the way and the direction in which medicine is heading, there is a little bit that's potentially lost there. That said, while we have the benefit of manuscripts like this that does do in-depth hemodynamics and looks at autopsy samples from a clinical standpoint, if we were to ever try and understand this in a larger population I think we would be required to try and find a way to noninvasively or maybe through potentially invasive hemodynamics better study this in live patients. Dr Amit Khera:                  Appreciate that answer and I'm just for all of you, this has been outstanding. You all have served as incredible expert discussants. I know Carolyn already said it multiple times but we've learned a ton about each of these articles and great to see how they come alive and are used in practice and how they're applied in your own thinking and specifically as fellows in training with these have meant to you. We thank you all for joining us and it's really been a fantastic experience. Dr Carolyn Lam:                Amit, I can only echo your thanks and thank you listeners for joining us today. Fellows out there you are so important to us. Please, please apply to join us on the next FIT podcast as you can see it's really fun.                                                 Don't forget to join us again next week.

Dr Carolyn Lam:                (Music playing)...Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and his editors I'm Dr. Carolyn Lam associate editor from the National Heart Center and Duke National University of Singapore. Today is one of my favorite podcasts as always because it is the fellows in training podcast.                                                 This is where the center stage and we're so pleased to have two brilliant fellows with us today. Dr. Tom Ford from University of Glasgow and Dr. Kevin Shah from UCLA and of course joining us today as well is our editor for digital strategies, Dr. Amit Khera. Hi everyone. Dr Kevin Shah:                   Hi Carolyn. Dr Carolyn Lam:                Hey Kevin. Since you're there in wonderful bright and sunny California and going to talk about one of my favorite topics HFpEF. Could you please tell yourself and then please tell us also about the paper you chose? Dr Kevin Shah:                   I am a third-year general cardiology fellow at UCLA. I have a career interest in advanced heart failure and transplant cardiology. I'm going to be doing a one-year fellowship in that next year at Cedars Sinai in Los Angeles.                                                 The article that I picked to discuss was the Reduced LAP Heart Failure I Trial and it was specifically testing a novel device in a small cohort of patients to see if the creation of intraatrial septal connection in patients with HFpEF can improve their filling pressures as well as their symptoms with exercise. Dr Carolyn Lam:                Yeah so Kevin what about this paper stood out to you? Dr Kevin Shah:                   The two biggest things that were impressive to me and that really stood out were 1) this concept that keeps coming up more frequently in contemporary research, which is the idea of using a sham trial. Specifically, in this study they did perform a one-to-one randomized trial. With one of the arms, if they did not receive the actual device, they underwent a complete sham undertaking including headphones in music and blind folding the patient who were not sure if they received the device or not.                                                 I think it's an important concept because it does speak to the placebo aspect of procedures. It tries to really control for that when a patient doesn't know if they received a novel device, and we can still test them and see how they feel after-the-fact. I think that's an important strategy in modern trials. Dr Carolyn Lam:                Kevin, that is such a good point and really quite novel too. So we've discussed this paper before but not quite the aspect that you point out and I couldn't agree more. The REDUCED LAP follows its pilot study results, which was open label single arm right published in the Lancet. So this is a very reassuring results since knowledge sham controlled.                                                 I suppose the lesson comes from other device trials that were sham controlled and then gave maybe slightly different results), right when we're talking about the renal innervation trials before. But you said that there were two points that stood out to you so what was the second? Dr Kevin Shah:                   The other will also be endpoints and what they chose to target. It was a small trial but I think it's important in a disease state such as HFpEF to select specific endpoint that really reflect the physiology and pathophysiology and the authors should be commended. I think for selecting primary and secondary endpoint that will primarily focus on hemodynamics as well as symptomatic relief.                                                 I know that they are working toward their stage 3 trial and I think in the vein selection of these type of endpoint. Probably more so than endpoints such as mortality are going to favor this disease state in terms of trying to carve out some sort of therapy that actually make patients feel better. Dr Carolyn Lam:                Great great points. For me to just knowing that a hemodynamic endpoint makes sense, because if we look at the Champion Trial and look at the HFpEF  subgroup of the champion trial it also seems to show that if people just treated patients with HFpEF  according to a hemodynamic guide and in the champion trial that was the pulmonary artery pressure reading. That actually appeared to keep patients out of hospital. And I have to agree with you that sometimes we forget that has HFpEF  is about pulmonary congestion and that the end of the day it is a hemodynamic disease. It is heart failure in other words.                                                 Kevin one last thing what do you think about using this sort of strategy in HFREF? Dr Kevin Shah:                   That's a good question I can't say I know at least this device has been studied in this trial like you mentioned in one prior trial that was not randomized. I'm sure it's been at least investigated. I can't say I've seen any literature on it. I like to think that it would make some sense from a physiological standpoint, but I don't know if anyone is actually gone to the task of seeing how the device performs in HFREF. Dr Carolyn Lam:                As I said I think at the end of the day I think they're all part of the same heart failure family. And left atrial hyper tension is kind of the final common pathway. So I agree with you that maybe it's worth considering in HFREF too, but then on the other hand of course and have friends HFREF you've got all this great medical therapy. Well Kevin I really, really appreciate your selection. May I now switch over to Tom? Tom would you like to tell us a little bit about yourself ,and which paper you chose. Dr Tom Ford:                      Sure thing my name is Tom Ford. I'm very interested in interventional cardiology, and my career path has been a bit unusual because I did my basic cardiology training in Sydney. And then from there I got a great opportunity to pursue a research degree, a PhD, which I'm currently halfway through. That's what Prof. Colin Berry and Prof. Keith Oldroyd here in Glasgow and that's a British Heart Foundation Fellowship so it's a great opportunity. I went out for recent WOSCOPS Trial from posthoc analysis. In this is a really interesting study a lot of the readers and listeners will be familiar with the original publication. It was actually published 22 years ago. Published in the New England Journal of Medicine.                                                 The WOSCOPS was a landmark trial that looked at statins for primary prevention. And this is the present analysis that looked at just over 2500 Mills with LDL-cholesterol above hundred and 190 mg/dL. So for those of you listeners in the UK 4.5 mmol per liter so quite the high LDL. They looked at these gentlemen without pre-existing vascular disease. There's guideline recommendation for this group but not much evidence. And what they showed was over a five-year period of follow-up that there was a reduction in cardiovascular death and all cause mortality with this treatment. That wasn't just for the period of the trial because of the study design we were able to get a legacy effect which was noted over 20 years of follow-up. So in summary a trial will show the benefits of  statins and primary prevention mortality benefit for people without very high LDL to start with. Dr Carolyn Lam:                Carolyn awesome Tom. I love that she began saying that your into interventional cardiology but you chose an article about medical therapy and the importance of it, the statins. I fully agree with you. Amit did you have some for Tom? Dr Amit Khera:                  Sure. First I want to commend you both I don't think you did this on purpose but Carolyn's heart failure HFpEF  expert. I'm sure she loved the other trial and I'm a preventative cardiologists. So we certainly love you choices this week. Tom, thanks for the summary. It's an important article and one that we did highlight on the previous podcasts. You know there's so many things to talk about but certainly remind you that we have great data sets around that can answer unique questions that maybe are unanswerable today and I think this is an example of that.                                                 Can you speak to this ideal of pulling an old 22-year-old child as you mentioned and how that provides insights and kind of as a PhD student ways to think about ways to be creative and research? Dr Tom Ford:                      One of the reasons I chose this child because it's close to my heart looking at a population in the west of Scotland. Sadly over here we've got too high prevalence of cardiovascular morbidity and mortality. So what this trial speaks to is the benefits of a really carefully planned procedure. I mean these were outstanding researchers that thought ahead of their time, and as a result of their analysis. Over two decades later they are still multiple publications and there's kind of open approach where there's different research groups that have used this data set for number of different outputs.                                                 I think a real outstanding example of what can be done with well-planned study. Dr Amit Khera:                  Sounds like were in agreement about how to use a fruitful database and continue to learn from it as time goes on. The thing about this as you pointed out is the LDL above 190 component and what the authors say this is sort of the first clinical trial evidence for treatment. In your view, does this change practices or guidelines? Was this already what we were doing? Does this support what we were already doing, or how does this impact clinical care and guidelines currently? Dr Tom Ford:                      I think it's a good point. People will say we were doing this anyways. I think now it's going to be helpful and practical inside the clinic. If you can say to a patient well actually look I know we're asking you to take this tablet you've not actually had an event but, ultimately we know the natural history of people in your position may well be unfortunately that they're high-risk, and that there is actually a mortality benefit to be had from these tablets that you don't necessarily want to take but definitely the benefit's there. Dr Amit Khera:                  The neat part as you pointed out also was dual components when they're looking at the on treatments during the trial. We see an improvement in events. What the WOSCOPS investigators have done so creatively over the years is this idea of a legacy affect.                                                 The long-term impact in preventive cardiology – certainly a space for where were going was just looking beyond the short-term. There's obviously problems there too because that was not pre specified people were necessarily on assigned therapies. Tell me when you look at this long-term legacy effect what does that mean to you? How does that add be it the way you counsel patients or how you think about this treatment in patients with high LDL? Dr Tom Ford:                      The effect of the statin assumes that all the patients are actually taking the drug. I think there has to be an analysis of these patients in this trial and obviously not everyone was compliant. So I think we can maybe extraopolate that for the that there might be in even bigger effect for those patients that were actually taking the drug. And I think if you were to take it for five year period. Obviously we don't know what happens after that. What we do know is the solid mortality data.                                                 What it speaks to me is that if you take the drug and you are at high risk to begin with then potentially it's plaque stabilization, the pleiotrophic effects of statins that we know are beneficial and the hard endpoints are definitely reduced. That persists over 20 years of follow-up. So I think that's really a great victory for preventive cardiology as you said. Dr Amit Khera:                  That's a great point about biasing towards the know when you have people crossing over and that this may be conservative of what was seeing in the long term. I think that's a really important point. One last question for you. The West of Scotland trial - generations have changed and back then obviously part of it was trial design but LDLs on average were higher. The median or mean in the group was around 192.                                                 If you look when they look above or below that 190. The people below were 178 or so - still pretty high LDL. So it does beg the question you know we have this paradigm of LDL above 190 should be treated regardless. You wonder if that should be 160 or whether the number should be lower. What are your thoughts about that? Dr Tom Ford:                      I agree with you. I think it's always a challenge to kinda pass off dichotomous endpoints when you've got continuous variable like LDL. It's just a continuum of risk and divided using the figure 190 in the study. In fact the patients with LDL less than 190 they couldn't show statistically significant reductions in all cause mortality. But I think it's again personalization of meds and we may have to discuss the risk with individual patient.                                                 Ultimately we do have to have a firm conclusion. I think in this study the data is quite clear that 190 does seem to be quite robust as the predictor who's gonna get the most benefit. Dr Amit Khera:                  Listen I think protection article that you pointed out was close to home and you certainly discuss it very well and provided lots of important insights. And again I think it was an excellent choice and one that was really highlighted in the media as well. I think there was a broad allure to this article. If we make change gears now little bit we've heard about the science part know we want to talk about what it means to be a fellow in training.                                                 I just want to say on behalf Circulation also speak for myself. It's so important for us to involve fellows in training into our activities and you're one of our major targets in terms of impact and goals for the journal. We're so delighted to do this twice a year and were always thinking about other ways we can get FITs involved. I mentioned just a couple of things the American Heart Association has of fellows in training program where people can sign up for free and get online access to the journal.                                                 So I hope all fellows are taking part in that. We're starting a new initiative called FAVES where just like you both submitted articles of interest of the fellows can do the same. On Fridays we'll post those on social media so these are a few ways that were getting FITS more involved and we really hope to continue that. Let me start by maybe asking Kevin to have a chat with you as much.                                                 Kevin in terms of journals there's some me now we're getting inundated with information. I think that's a good thing. How do you consume the medical literature? There's old print journals; there's the online journal; there's a table of contents your social media tell us a little bit about how you consume the medical literature. Dr Kevin Shah:                   I agree. We're kinda getting to a space where now the amount of information that's coming out is tremendous. I think that finding a strategy to help filter out what appeals to your clinical and research interest is becoming more challenging. For me I'll say print journals are slowly kind of falling off. I don't subscribe to too many of them but they still do come to my doorstep. The main way that I would say I'm getting access to or at least becoming aware of articles that are kinda relevant to where I am in my training and what I'm doing is the social media. Some primarily at least for me is Twitter.                                                 I'll say it's a helpful tool and that I can follow a group of individuals that have a similar professional interest as me and you can almost always rely on the fact that somebody will post an article that becomes relevant to a common interest. So between sharing on social media I think that's the primary way that I'm really catching my eyes to a major journal articles.                                                 Aside from that I still subscribe by email to a couple larger journals and see their weekly or biweekly updates about what's being published. And the last at least in my institution our division chief Dr. Gregg Fonarow; he goes out of his way to send to the fellows and faculty new articles that are kind of pertinent to clinical practice. Which is very helpful for us. Dr Amit Khera:                  That's so helpful and you know everyone has their own way of consuming the literature but I certainly appreciate your interest in social media. You know there are some luddites out there that think of it literally as just social and it really has a professional bent to it. Well rapidly you can figure out the most cutting-edge important articles in your field so I certainly appreciate your comments. Tom let me ask you now, at your stage of training. You've had an interesting training path as you said you sort of started as an interventional cardiologist and now you are doing a PhD. There so many different articles in Circulation. We have original research, state-of-the-art reviews. We have these opinion pieces and on my minds and different ones. Tell us a little bit about what articles appeal to you and which other novel formats maybe you'd be interested in seeing. Dr Tom Ford:                      I think that the original research articles are great if it's in your chosen field. Obviously this is where we're going to a great deal of detail on specific topics but outside of that I think that the review articles are great form if it's something that's a common clinical topic to kinda brush up on. Your On My Mind section I think is great because it gives you an opportunity to hear from key opinion leaders in the field. I think it was Morton Kern discussing invasive coronary physiological assessment.                                                 So I think there's different types of articles that can be quite helpful.  To start with the original research ones. I'll skim through the contents. I'll tend not to read the details if it's not in my chosen field. Dr Amit Khera:                  Yeah great point. Obviously they are topical depending on what your main interest area and we always say reading around your field to get a broader perspective in cardiovascular medicine. I think you hit on the point about on my mind ones. We really want people be able to free associate and original article are sometimes more stiff and linear. So we really like those pieces as well. Carolyn we'll give you second set ask a question or two to for today. Dr Carolyn Lam:                Actually Amit I just wanted to comment. Isn't it so encouraging to hear the variety of approaches and you know Circulation has enough that we're meeting various different needs. I really wanted to take the opportunity to thank you as editor of digital strategies for just doing so many of these initiatives for Circulation. I think it's just incredibly important for the Journal to keep up with the times in that sense. Amit, may I be cheeky ask you how do you consume the literature? Dr Amit Khera:                  Carefully. You know the neat part in being on the editorial board of Circulation and one of the associate editors we get to see so many amazing papers that come through and I think obviously I get to see, essentially and also my digital strategies role I essentially see every paper that comes through that we end up publishing.                                                 Obviously I get wide exposure to Circulation but obviously beyond that I get all the e-Table of Contents for almost every major cardiovascular Journal. Certainly looking at social media and I tend to find hotspots interventions and other areas and podcasts – let's not forget podcasts. So there's some great podcasts out there. I know of one. Dr Carolyn Lam:                Oh I love it. All right but just one last question for both Tom and Kevin from me. I honestly would love to know what do you think we could do better or what would you like to see more from Circulation? Dr Kevin Shah:                   I guess the question I have for Circulation is there any role or have fellows ever gotten involved in the review process for articles? Dr Amit Khera:                  Listen that's really important because you learn a lot from doing that and obviously in institutions similar to ours where if you asked to review a paper you have a fellow contribute. I think you might be asking something sort of more formal and systematic with Circulation. I will say that one of our Circulation journals I believe it's Circ Heart Failure or  Quality and Outcomes I'll check. It has a formal program where fellows essentially can be assistant editors if you will.                                                 We have our cardiology fellows here at UT Southwestern involved in that process. And I think part of that process is just an IT issue of how to maintain confidentiality of our papers for our authors but yet still let fellows contribute meaningfully. And also timing because you know papers have cycles where you decide if he should go out for review but it'll come back and you never know when that happens you have to make the next level decision.                                                 Then it goes potentially to a meeting and so being able to make sure that fellows can participate at every level, cause that's where the value comes in. We are certainly interested in learning from what our other Circulation of family journals is doing in that space and definitely an area that we've thought about some fellows contribute but need to do more. Dr Carolyn Lam:                And Tom how about you? Dr Tom Ford:                      Just picking up on your point on what the sister journals are doing you know I see the Outcomes Journal is looking at more visual abstracts and video abstracts. You know I think it's really important that we increase the efficiency of learning. What's your take on that? Dr Carolyn Lam:                That is the greatest suggestion. I like first of all your phrase of increasing the efficiency of learning. Amit, I'm going to turf it to you again. Dr Amit Khera:                  I'll tell you what's amazing you know when I started this role a bit ago. Both of you are obviously contributing to research and everyone on this call is and I think we forget that in the social media space we don't have a lot of data. Some things sound good or feel good. At Circulation my predecessor Carolyn Fox did a randomized trial called intention to tweet if you haven't read it. And there's a follow-up to that that was published. And essentially by randomizing articles to social media or not there was no increase in the views if you will of the article.                                                 There's always limitations to every study but the point is, as you think about novel offerings, something we struggle or something we've seen as an opportunity, what works we tried a few things we tried certain videos and we look at what's the uptake and interestingly some things we thought that would be widely of interest really weren't. Then other avenues we've tried have been.                                                   I love what you said, and as Carolyn also felt, the idea of efficiency of learning. I think we need to do frankly in the social media and journal spaces is to continue not just to innovate but to study and figure out what works and what doesn't to help different learners. Dr Carolyn Lam:                (Music playing)....Thank you very much audience for listening today as well. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and back-stage 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.                                                 What is the evidence we have for LDL-lowering therapy in primary prevention? For individuals with an LDL cholesterol above 190 mg/dL, well, you may think you know the answer, but today's featured discussion may surprise you like it did for me, and this is a must-listen in my opinion for those of us taking care of these patients. More soon right after these summaries.                                                 How can we enhance the survival and therapeutic potential of human pluripotent stem cell-derived endothelial cells? Well, the first paper in today's journal tells us how. The first author Dr. Lee, corresponding doctor Dr. Yoon, from Emory University School of Medicine in Atlanta, Georgia, developed a novel, fully-defined, cell culture system to generate endothelial cells from human pluripotent stem cells. They not only showed that these endothelial cells had pro-angiogenic activities and exerted favorable therapeutic effects in repairing limb ischemia, but also showed that encapsulation of these cells in a biocompatible peptide amphiphile nanomatrix gel improved long-term survival of these endothelial cells in an ischemic environment and improved vessel-forming properties. This novel cell culture system and gel-mediated transplantation may serve as a novel platform for cell-based therapy.                                                 The next study brings us one step closer to application of immunomodulatory therapies in pulmonary arterial hypertension. In the study, first author Dr. Saito, corresponding author Dr. Rabinovitch, and colleagues from Stanford University School of Medicine isolated lung immune complexes and pulmonary arterial hypertension target antigens from lung tissues from 16 patients with pulmonary arterial hypertension and 12 controls. SAM domain and HD1 domain-containing protein, which is an innate immune factor that suppresses HIV replication, was identified and confirmed as highly expressed in immune complexes from patients with pulmonary arterial hypertension. These immune complexes resulted from elevation in products of human endogenous retrovirus K. The human endogenous retrovirus K deoxyuridine triphosphate nucleotidohydrolase, or dUTPase, activated B cells, elevated cytokines and monocytes and pulmonary endothelial cells, and increased pulmonary arterial vulnerability to apoptosis, thus contributing to sustained inflammation, immune dysregulation, and progressive obliterative vascular remodeling. Furthermore, rats treated with the human endogenous retrovirus K dUTPase developed pulmonary hypertension. In summary, this study suggests that harnessing mechanisms that repress human endogenous retrovirus K expression and its sequelae could prevent and reverse pulmonary arterial hypertension.                                                 The next study looked at the association of timing of coronary angiography with ischemic outcomes of non-STEMI who are at high risk with a Gray score of more than 140 in the TAO Trial. In this report from first author Dr. Deharo, corresponding author Dr. Steg, and colleagues from L'Hopital Bichat from Paris, France showed that in these high risk, non-STEMI patients, a very early invasive strategy of coronary angiography within the first 12 hours was associated with a lower risk of death in MI at 180 days compared to an early strategy of between 12 to 24 hours or a delayed strategy of between 24 and 72 hours. The bleeding risk was not different between patients managed with the very early, early, or delayed strategy. These observations deserve prospective confirmation in a randomized trial.                                                 The next study provides contemporary mortality trends for STEMI and non-STEMI. In this paper from first author Dr. Puymirat, corresponding author Dr. Danchin, and colleagues from Hopital europeen Georges-Pompidou in Paris, France, the authors assess trends in the characteristics, treatments, and outcomes for EMI from five month-long registries conducted five years apart and spanning 1995 to 2015, including more than 14,000 patients admitted to cardiac intensive care units in metropolitan France. They observed major changes in the characteristics and management of both patients with STEMI and those with non-STEMI over the last 20 years. The mean age decreased in patients with STEMI and remained stable in patients with non-STEMI, whereas diabetes, obesity, and hypertension increased. At the acute stage, intended primary PCI increased from 12 to 76 percent in patients with STEMI. In patients with non-STEMI, PCI within 72 hours from admission increased from 9 to 60 percent. In parallel with these changes, six-month mortality consistently declined in patients with STEMI, whereas in patients with non-STEMI, six-month mortality reached a plateau after 2010. The authors concluded that future challenges will be to reduce pre-hospital mortality and to improve long-term survival after the acute myocardial infarction event.                                                 That wraps it up for your summaries. Now for our feature discussion!                                                 What evidence do we have from randomized trials supporting the benefit of LDL cholesterol lowering as primary prevention among patients with an LDL cholesterol above 190 mg/dL? You may be surprised to know that until today's journal, we had very little trial evidence supporting this. But I'm so pleased to have with us the corresponding author of our featured paper today, Dr. Kausik Ray from Imperial College, London, who's going tell us a bit more and discuss this very intriguing paper with our Editor for Digital Strategies, Dr. Amit Khera from UT Southwestern. Welcome, both. Dr. Kausik Ray:                  Hi. Dr. Amit Khera:                 Thanks for having us. Dr. Carolyn Lam:               Kaus, you are a familiar voice and so pleased to have you here. Please tell us, is this the first evidence we have from a randomized trial for primary prevention in those with LDL above 190? Tell us about it. Dr. Kausik Ray:                  Yeah, it is. It really came about because we were interested in familial hypercholesterolemia and we used the level of 190 to talk about either primary hypercholesterolemia, which may have a genetic basis, or not. I kept hearing that there is no trial evidence, so you're not going to be able to ethically do a trial today despite the fact there's not much evidence, because most of us think that it's a bad thing to leave people on placebo in patients above 190, so I thought the only way to do this was to go historically to the WOSCOPS Study, which is, as you remember, 6,500 people, elevated LDL cholesterol. Interestingly, you go to WOSCOPS, the median LDL in that population is very close to 190. So, that gives a good starting point, thinking that we'll have at least half the population.                                                 Now interestingly in WOSCOPS, although none of the patients had a history of myocardial infarction, a very small number of the 6,500, about 1,000 actually had evidence of some other vascular disease, so maybe a TIA, maybe angina, maybe some sort of ECG non-specific change of coronary disease. Today, you would say, well, actually, you've got to give these people a statin because there's evidence of vascular disease, PVD, et cetera. So we had to take those people out and that left us with 5,529. Once you break people down by LDLs above and below 190, you have 2,560. You could actually look at the randomized treatment effect of pravastatin, which was the statin chosen, over a five year period both above and below 190.                                                 But interestingly, this was the first study and what we showed was that in this population, even with as little as 23% reduction in LDL cholesterol, over a five year period, you saw a statistically significant 27% reduction in CHD and if you take the usual 3 point MACE of current clinical trials, there was a 25% reduction, already statistically significant. We also had the ability to link data over 20 years. Remember, after the five year randomized treatment period, it becomes observational in nature, but what it showed was that when you gave nearly 40% in each arm statins and you followed people up this legacy effect, over a 20 year period, the people with the LDL above 190, that translated into this 28% reduction in CHD death. It translated into a 25% reduction in CV death, and actually an 18% reduction in all-cause mortality, which you didn't see in the population with slightly lower LDL cholesterol.                                                 This is the best evidence we're ever going to get, really, and answer the question about what should we do in this patient population. Should we treat with lipid-lowering therapy? The answer, unequivocally, is yes, and the longer you treat, the more likely you are to see survival benefits. Dr. Carolyn Lam:               Oh, my goodness! I just love his paper. I have to humbly admit. I mean, it's in the guidelines already that we should treat these individuals with LDL above 190, and it really made me think how I'd taken for granted that there would be a whole body of evidence behind it from randomized trials, and you are right! This is the first, and likely going to be the last we're going to get, because we can't randomize them. So, congratulations. What you said just now, I can already hear myself playing this podcast to my patients. May I just ask, are there other remaining questions to answer, and then what do you also say to those that say, well what are the harms? How do you balance that with any potential harms? Dr. Kausik Ray:                  In this particular study, given there was overall safety data observed in the WOSCOPS Trial population and in their extended follow-up in the overall 6,500 person cohort, we didn't go on and look at that. There was no evidence of harm in the extended follow-up of 6.500 people, so we didn't see the potential added gain in specifically looking for that. The main question we wanted to answer, because people had always pulled primary and secondary prevention patients together, and in fact, your best evidence is actually from CTT, pooling of primary and secondary prevention patients where they break the data down by an upper limit of about 175. With patients above 175, they don't specifically answer that question. So, to answer your question, we didn't look at that in the overall WOSCOPS Trial population. There was no signal for harm that was noticed. Even things like glucose elevation, if you remember in WOSCOPS, tended to be a little bit lower. Dr. Amit Khera:                 Let me comment on a few things about this paper. First, I want to congratulate Dr. Ray and his colleagues. I was a history major and I think this is a great use of a historical tool. At this point, I think we can talk about WOSCOPS. It's 22 years old. It is part of the medical history and a very seminal article. I think they got creative because, as he mentioned. We have guidelines that support this treatment, but this is almost an unanswerable question, whether you say it's from ethics, or from equipoise, it was essentially unanswerable. So, they had to go back and take this historical study where practice patterns were different, to be able to look at this question. It was pointed out, there's pretty clear evidence in here and I think if you look at that during the five-year study period of the randomized period, pretty clear evidence that treating participants with LDLs above 190 without vascular disease certainly lowers cardiovascular disease events.                                                 One of the best things about working on the editorial board is being able to work closely with authors, and I have to also thank Dr. Ray and his colleagues for being so gracious in working with us closely in some modifications as this went along. We hope, and I hope he feels this way, too, that at the end of the day, the product ends up being even better than where we started. That's our goal is to really help and work with authors in that way and they were incredibly responsive. The two things I thought they did really well that were insightful to the US guidelines and beyond. One is they also restricted to the group without diabetes, without ASCVD less than 7.5%, and some other parameters to really hone down on what we have in the current US guidelines and still the finding was consistent that the statin therapy benefited that group.                                                 The other part was just acknowledging that the legacy part, the long-term effect, is really valuable. They published heavily in this area, but at that point, it becomes an observational component. It's not part of the randomized period. The reason that adds value, if you look at our guidelines above the age of 21, an LDL above 190 can be treated with a statin, there would be less controversy if your LDL was 200 and you're 55, but if you're 22 or 23, I think there may be more angst. That's where the long-term data is important, because we're not looking necessarily always at 10 years, but we're looking at 20 or 30 or 40 or 50 years. I think this does at least shed some light. I appreciate the study population was older, but a least it helps us look at maybe some of the long-term benefits.                                                 If I may, Carolyn, I would love to ask Dr. Ray a question. Kaus, when you guys did this, the group with the LDL less than 190 had essentially similar benefit. The p-interaction was no. I think we have to acknowledge that the LDLs were higher in that group than what would seem because the lowest level was 155. Is it above 190, or should it be above 160 where we treat patients with statins? Dr. Kausik Ray:                  Yes, and I really want to thank the editors, because there were certain things that you pushed us with analyses and I think that you could make the case that if you have a LDL cholesterol above 155, over a five-year randomized treatment period, there was a significant reduction in CHD and MACE as well. So, you could make that point that actually the cutoff should perhaps be pulled down even further to about 155. What's interesting is, these groups, when you broke them down, age was identical, BMI was identical, blood pressure, and everything else. The only thing that was different, really, was the LDL cholesterol, which impacted on total cholesterol. TGs, HDLs were absolutely identical. I think you could probably make the case.                                                 I think the one thing that we didn't see, although it's observational in those with slightly lower LDL cholesterols, is that over the 25 year period, they seem to get slightly less mortality benefits. Now, that could be a chance finding, because it's observational. We don't really know the implications of that, but I think over a five-year period, this is the best evidence you're going to get for primary prevention, right? Dr. Amit Khera:                 Agreed. The US guidelines do say above 160, it's a point of consideration. It can be a factor to consider as we think about treatment, so perhaps this helps bolster that point as well. Dr. Kausik Ray:                  It's not just the American guidelines. In the European guidelines, when they use score, if you look at LDL cholesterol levels, the European case fatality 10 year risk is 2.5%, which is equivalent roughly to 7.5% fatal and non-fatal MI in the pooled cohort equation. There they still have diet and lifestyle, but it says, "Consider pharmacological," and one of the things I thought was really interesting is if you did a 10 year risk calculation in this group, 67% of the population with an LDL above 190, you would have said the predicted 10-year risk was below 7.5%, but the 10-year observed risk was double that. It was 15%. If you did the same thing for the group between 155 and 190, your ten-year risk predicted would be in most of these people, you would have said about 90% actually are less than 7.5%, so you wouldn't have given them a statin. But, their observed event rates in the placebo group was about 11%.                                                 So, I think that it tells you if you have an isolated elevated cholesterol above 155, you're probably going to be underestimating risk if you're using global risk score, and perhaps a discussion with the patient about risks and benefits in the way that most of us try to do and citing data like this might encourage patients to actually start that therapy earlier, which most of us probably believe from genetic and legacy effect is probably beneficial. That's one of the other implications of this. Dr. Amit Khera:                 This is why one has to read not just the abstract, but all the details, because there are so many kernels of interesting findings in this paper beyond just the highlights that we hit upon. Dr. Carolyn Lam:               Thank you both for just a marvelous discussion of an incredible paper that is really, really going to be extremely clinically relevant. We're so proud to be publishing this in Circulation this week.                                                 Audience, you heard it right here. Don't forget to tune in again next week as well to Circulation on the Run for even more hot news.

Jane Ferguson:                Hello, and welcome to episode one of Getting Personal: Omics of the Heart, a podcast from the Functional Genomics and Translational Biology Council of the American Heart Association. I'm Jane Ferguson, the current chair of the FGTB Professional Education and Publications Committee. This monthly podcast will bring you up to date with the latest in genomics, other omics technologies, and precision medicine as they relate to cardiovascular and metabolic disease.                                            In each episode, we'll give you an overview of some of the latest research to be published, and delve deeper into topics of particular interest. Whether you're a clinician, researcher, genetic counselor, or other healthcare or science professional, we hope these podcasts will be informative, and help you stay up to date with the latest developments in this exciting field.                                            In this episode, my colleague Naveen Pereira talks to Amit Khera about his recent publication with Sek Kathiresan and colleagues in the New England Journal of Medicine entitled Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease, and we highlight a recent AHA scientific statement on the use of genomics. But first, Naveen and I will give you a round up of some interesting papers from the past month. Naveen Pereira:              So Jane, there was this really interesting paper in the American Journal of Medicine whether we can use gene expression signatures along with other clinical covariates to predict the presence or evaluate whether symptoms are suggestive of obstructive coronary artery disease. Jane Ferguson:                Yes. This paper was published online on the 16th of December 2016. It comes from Joseph Ladapo, Mark Monane and colleagues. They carried out this study in 566 patients from the PRESET Registry, which enrolled stable, nonacute adults presenting with typical or atypical symptoms that were suggestive of obstructive coronary disease.                                            What they did was calculate an age/sex/gene expression score, or ASGES score. They included gene expression, which they measured in a blood sample collected in a PAXgene Tube, and this score ranges from 1 to 40. They've previously validated this, and a score less than or equal to 15 indicates that a symptomatic patient is very unlikely to have obstructive coronary artery disease. The genes they measured include 23 genes that are selectively expressed in circulating neutrophils, NK cells, and B- and T-lymphocytes. Naveen Pereira:              So really, this expression reflects inflammation, and the hypothesis being perhaps these inflammatory markers are very indicative of the presence of obstructive coronary artery disease, or plaque rupture I guess, huh? Jane Ferguson:                Yes, exactly. What they actually found was that individuals with high scores were referred to cardiology or advanced cardiac testing at far greater rates, and then even of subjects with low scores who did undergo additional testing, none of them had any detectable abnormality. Then, in subjects with high scores who did undergo further testing, 14% had abnormal findings. So after a year of followup, 1.2% of patients with an ASGES score below 15 had an adverse event, compared to 4.5% of those with elevated scores. Naveen Pereira:              So a fairly high negative predictive value, huh Jane? Jane Ferguson:                Right. Right, exactly. Naveen Pereira:              Did you find any limitations, Jane, in this study? Jane Ferguson:                There were some. Well firstly, it's worth noting that the score itself, and this test, has been developed by CardioDx, and a number of authors on this manuscript are affiliated with CardioDx. In addition to that, they did not include a control group in this. That certainly is somewhat of a limitation, but the authors say that this is probably still useful, and it may have some clinical utility in guiding decision making for patients with obstructive CAD. However, whether or not this is actually true will probably require some additional testing. Naveen Pereira:              So quite a foray into using this perhaps in the emergency room or in hospital. So I guess our audience should look out for this in the American Journal of Medicine, December 2016. Jane Ferguson:                Yeah. Naveen Pereira:              So there was another paper that we kind of thought was interesting, Jane, from the European Heart Journal. Jane Ferguson:                Yes, exactly. This comes from Jozef Bartunek, and Andre Terzic, and their colleagues, and they were reporting this on behalf of the CHART Program. Naveen Pereira:              So this was published on January 15, 2017. Jane Ferguson:                Yeah. This was a prospective, randomized, double-blind, sham-controlled trial, which was the Congestive Heart Failure Cardiopoietic Regenerative Therapy, or CHART-1 trial. In this trial, they were aiming to test safety and efficacy of delivery of cardiopoietic cells. They recruited subjects who had symptomatic ischaemic heart failure, and they consented to bone marrow harvest and mesenchymal stem cell expansion. They ended up randomizing 315 subjects.                                            They received cardiopoietic cells delivered endomyocardially by a retention catheter, or either a sham procedure. The outcome that they were looking at was a hierarchical score, which is assessed 39 weeks post-procedure. That score comprised all-cause mortality, the number of worsening heart failure events, the Minnesota Living with Heart Failure Questionnaire, a difference in the six minute walk test, change in left ventricular end-systolic volume, and change in left ventricular ejection fraction. So it was interesting. They found a neutral effect on the primary end point, but they did find some evidence of benefit in subgroup analyses, which were based on baseline heart failure severity. Naveen Pereira:              But and this was not designed to show efficacy, because it was primarily a safety trial. Is that right, Jane? Jane Ferguson:                Yes, exactly. Naveen Pereira:              Right. Jane Ferguson:                Overall, they found that there were no indications for concern regarding safety, so I think they've shown that certainly this is a technique that is safe and is well-tolerated, and I think it's really quite exciting. Future studies that are adequately powered, particularly looking at subgroups of individuals, may actually identify patient populations that would derive particular benefit from cardiopoietic cell therapy. Naveen Pereira:              Fascinating, so it'll be interesting to see what the Phase III clinical trial will show. Overall, a new foray into regenerative medicine. Jane Ferguson:                Yeah, yeah. Really interesting. Naveen Pereira:              Hi everybody. My name is Naveen Pereira. I'm from the department of cardiovascular diseases at Mayo Clinic in Rochester, and on behalf of the Functional Genomics and Translational Biology Council of the American Heart Association it gives me great pleasure to interview Amit Khera. We are going to be discussing this very exciting paper that was published in The New England Journal of Medicine on November 13, 2016, titled Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease. Amit, welcome. We are so glad you could make it. We really appreciate you doing this for us. Amit Khera:                      Naveen, thank you so much for having me. It's a real pleasure. By way of introduction, as you said my name is Amit Khera, I recently joined as a staff cardiologist at Massachusetts General Hospital in Boston where I see both general cardiology patients and also work in the prevention center. But one of the things I've noticed is that many of us have heard a lot about precision medicine, and how we can incorporate genetics into some of our clinical decision making, or risk stratification. So I've really been working with Sek Kathiresan at both Mass General and the Broad Institute to get training in both genetics to complement some of the clinical medicine aspects in order to help us get at some of those questions. Naveen Pereira:              Fantastic. Amit, what got you interested in genomics? Amit Khera:                      Sure. Well, you know for a complex disease like coronary artery disease, and risk of a heart attack, we've really known for a long time, like since the 1960s that there is a familiar pattern, meaning that if your brother or your father had a heart attack at a young age, your risk of having one is increased by almost a factor of two. It's really been only recently that the technology has allowed us to get at those questions, and really isolate the exact genetic determinant.                                            So really in the last 10 years, we've been able to identify a large number of variants that influence an individual's risk of coronary artery disease. So it really an opportunity to be in a place where the technology was coming along, where we have discovered all these variants, clinical medicine of course has come a long way since the 1960s as well. So the idea was to really put these two bodies of work together, and see what we could come up with. Naveen Pereira:              Yeah. This is very exciting. Amit, I completely agree with you. In our clinical practice we see patients with strong familial history of coronary artery disease, so certainly inheritance has been suspected for some time, and in fact genome-wide association studies have been done to identify loci for coronary artery disease.                                            As you know, the effect size of these individual variants have been small. And so groups have got together to form genetic risk scores, where they take kind of an aggregate of the effect of these individual variants, and we think this is more helpful. And this is what you did for your paper, so can you describe to us a little bit about how you derived the genetic risk score that you applied in this great paper? Amit Khera:                      Sure. The first aspect of our paper involved proving basically that we could quantify someone's genetic risk for having a heart attack. So in order to do that, as you said, we took advantage of a number of previously published genome-wide association studies. There are about 50 genetic variants all across our genome and different chromosomes that we know are strongly linked to coronary artery disease from a statistical standpoint, but actually might only have a very modest impact on coronary disease.                                            So let's say any individual could have a maximum of 100 risk variants. Now, some people might have inherited just by chance 80 variants, and other people might have inherited only 20. So we basically genotyped, meaning measured all 50 genetic variants in a large number of people, and then we said, "Those who are in the top quintile," meaning the top 20% of the genetic risk score, we're going to say "those people are at high genetic risk." And by contrast, if you're in the lowest quintile, we said, "Okay, those people are at low genetic risk." Naveen Pereira:              Right. Amit Khera:                      Then the question became okay, well does that categorization actually predict your risk of having a heart attack? So in order to do that, we analyzed over 50,000 individuals from three different prospective cohort studies, and what we found actually was that if you compare the high genetic risk to the low genetic risk people, their risk for having a coronary event over prospective follow up was increased by about 91%, meaning almost two fold. Naveen Pereira:              Wow. Oh, that's amazing. So using the genetic risk score, you could almost predict a doubling of the risk for coronary events. That's fantastic. Can you describe these populations briefly, Amit? Who are these people that you applied the genetic risk score to? Amit Khera:                      Sure. So we took advantage of three prospective cohort studies. The first was a Atherosclerosis Risk in Communities study, and that was a community based population of about 8,000 people. The second was the Women’s Genome Health Study, over 20,000 women who were originally recruited as part of a randomized control trial, and the third was the Malmö Diet and Cancer Study, which again had more than 20,000 individuals.                                            The really nice thing about these studies was that they were asked questions in a similar way, and they were followed ... in each case, participants were followed for about 20 years. So we really had a long time to observe what happened to these folks over time. Naveen Pereira:              So these are really longitudinal cohorts, not specifically disease oriented cohorts, but just community based, Amit? Amit Khera:                      That's exactly right, and in fact none of the individuals had coronary disease at baseline. They were all disease free- Naveen Pereira:              I see. Amit Khera:                      ... and then we followed them over 20 years to see who developed the coronary artery disease and who did not. Naveen Pereira:              So this is really applicable to the general population. Amit Khera:                      I do believe that these risk estimates would for sure hold true. Naveen Pereira:              Okay, wonderful. So Amit, you know you have the genetic risk score for coronary artery disease, and you have some great longitudinally followed population based cohorts, and you were studying a specific phenotype, so can you describe to us the phenotype? Amit Khera:                      Well, the primary outcome phenotype was incident coronary events, and those were all adjudicated by different committees, but it basically involved individuals who had either a new heart attack or myocardial infarction, they had to have one of their vessels either stented or bypassed via revascularization, or in fact it was determined that they died from coronary artery disease. So that was the outcome which we were trying to predict. Naveen Pereira:              Amit, let's get straight into it. What did you find? Amit Khera:                      So as a preventive cardiologist, I often see patients in my clinic who come to me and they say, "You know, almost everyone in my family has had a heart attack." Oftentimes at a very young age, and in some cases that can lead to almost a sense of determinism, where they feel like maybe they are unable to control their fate. So our primary question was a really a pretty simple one, which is to what extent can a healthy lifestyle offset someone's genetic risk of coronary disease.                                            So as I mentioned, we had a way of quantifying someone's genetic risk, and then we next said, "Okay, we want to quantify someone's lifestyle risk." So for that we kept it pretty simple. We had four criteria of what makes up a healthy lifestyle. First, no current smoking. Second, avoiding obesity. Three, regular exercise, and fourth, adhering to a healthy diet. And we said, "Okay, if you have at least three out of those four," we gave you a pass and said "you had a favorable lifestyle." Now if you had only zero to one out of those four, you had an unfavorable lifestyle.                                            One of the interesting things was that actually the genetic risk and the lifestyle risk actually were totally independent. There was no association for example between those who had high genetic risk and what their lifestyle was. So it really reinforced longstanding views that genetics and lifestyle are really independent axes of someone's individual level of risk. Now- Naveen Pereira:              So both, Amit, both could contribute to your individual risk for coronary artery disease? Amit Khera:                      Exactly. As I mentioned, the high genetic risk versus low genetic risk, there was about a two fold difference in risk, and we saw an almost identical pattern versus a favorable lifestyle versus an unfavorable lifestyle. There was about a two fold risk [inaudible 00:17:08]. Naveen Pereira:              Interesting. Amit Khera:                      Then that got us to the next question, which is to say if we analyze only those at high genetic risk so everyone had a similarly increased degree of genetic risk, to what extent could that risk be offset by a favorable lifestyle? This really gets back to the questions and the conversations we have with our patients who have a family history all the time. What we found there I think was a nice message, was that if you are at high genetic risk, you could actually decrease your risk by about 50% if you adhered to a favorable lifestyle, as compared to those with an unfavorable lifestyle.                                            So for example, when we looked at it in absolute terms, in terms of a 10 year risk of having a coronary event, in one of the cohorts, those with a high genetic risk but an unfavorable lifestyle had about an 11% chance of having a coronary event, versus if you had the same high genetic risk but a favorable lifestyle, your risk was only about 5%. And we saw that, a very consistent pattern across all the cohorts and all the categories of genetic risk, that those who had a favorable lifestyle ... the risk was decreased by about 50% in those with a favorable lifestyle. Naveen Pereira:              So that's fascinating, Amit. When physicians see a patient who have a really strong history of coronary artery disease within the family, and come up to you and say, "Doc, am I destined to have a heart attack?" You know, now with the availability of genotyping, with direct to consumer testing, people can find out their genetic risk. So they may not necessarily be doomed. Their fate is not predetermined. What you're suggesting is that fate can be modifiable. Amit Khera:                      Right. I think certainly for coronary disease your DNA is not your destiny, at least for these common variants. I think we provide evidence that really lifestyle factors powerfully modify your risk, really regardless of your genetic risk profile. Naveen Pereira:              So Amit, can we make any recommendations based on the results of your paper? Amit Khera:                      Well, I think ... The American Heart Association has really endorsed these four lifestyle criteria as a way of improving the population's health in the population as a whole, and I think actually that our results actually support that. Which is to say that this really supports the fact that these healthy lifestyle parameters are critically important for everyone, and I think that's a good starting point.                                            Genomic medicine is actually in its early days, but really what we hope to do is first to identify individuals, a subset of the population, who are at increased risk for a disease like heart disease, and I think we've shown that we can actually do that reasonably well. Like 20% of the population has a double risk. And the second part is actually to disclose this risk to both the patients and their providers in a way that's meaningful. And third, is actually demonstrate that we can actually implement the therapy to mitigate this increased risk.                                            So I think we, in this paper, we provided evidence that a healthy lifestyle can mitigate that risk. Papers from our group, both published and some in press, have actually demonstrated that taking a statin can also powerfully modify this increased risk. And you might imagine that there may be other interventions that ... especially if an intervention has increased risk, you really may want to target it to those people who actually ... if a medicine has increased side effects, you may want to target it to those at the highest risk. I think that, you know, this polygenic risk score does provide at least one way of stratifying people into those high risk groups. Naveen Pereira:              Yeah. Amit, really impressive results, 50% relative risk reduction in a high genetic risk population. You make a compelling argument. Obviously, however, this is not a prospective randomized clinical trial. It's really hard to do these. You had the advantage of well designed cohorts to study this in a cross sectional way. We don't know how these behaviors change. So these are some of the limitations, but the results are quite compelling, and contribute to the literature. Any other comments, Amit? Anything else that we should take home here? Amit Khera:                      No, I think as you said, there are some limitations. I think our really goal was to lay the foundation for future efforts where we really think about what the optimal way is for genetic information to be integrated into routine clinical practice to help prevent disease, and that's really what our group is planning on focusing on for the future years. Naveen Pereira:              We look forward to hearing more exciting results from your laboratory, Amit. It's been a pleasure. We should end I guess with a quote from William Shakespeare, "It's not in the stars to hold our destiny but in ourselves." Correct? Amit Khera:                      Thank you very much. Sounds great. Naveen Pereira:              Thanks, Amit. Jane Ferguson:                So as we just heard from Naveen and Amit, the combination of genetic risk and modifiable lifestyle parameters are crucial in determining CAD risk. A recent AHA statement from the FGTB Council focused on this topic. The statement, entitled Nutrigenomics, the Microbiome, and Gene-Environment Interactions: New Directions in Cardiovascular Disease Research, Prevention, and Treatment, focused on how dietary and genetic contributors to disease have been studied in the past, and how emerging omics technologies can be used to rapidly advance these fields.                                            Genomics, transcriptomics, metabolomics, proteomics, lipidomics, epigenetic profiling, and metagenomic characterization of the microbiome can all be used alone or in combination to better understand mechanisms underlying gene-environment contributions to disease. While the ultimate goal would be the development of improved therapeutic options, including personalized and precision approaches, a considerable amount of research remains to be done before this goal can be clinically implemented. You can read this statement in the June 2016 issue of Circulation: Cardiovascular Genetics. Naveen Pereira:              So, Jane, this has been an exciting first podcast. I really look forward to doing more with you. Jane Ferguson:                Yeah. I think this is great, so thank you everyone for listening, and happy heart month. We will look forward to bringing you a podcast again next month. Naveen Pereira:              Thank you.

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

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, and I'm just so thrilled to be joined by a co-host today and that's Dr. Amit Khera. He's the Editor of Digital Strategies for Circulation from UT Southwestern. Welcome, Amit. Dr. Amit Khera:                 Hi, Carolyn. Thank you for letting me participate today and we're excited about this Fit featured podcast. Dr. Carolyn Lam:               We have a very special episode today. First of all, because we don't have a print issue that follows this week and so, there's no usual summaries, but we do have special guests and these are the Fellows-in-Training.                                                 Now, we sent out a call online to all the fellows to tell us a bit about themselves as well as which articles in Circulation stood out to them, and we had an overwhelming response from all over the world, of which these two fellows really stood out.                                                 So, join me in welcoming Dr. Punag Divanji from United States and Dr. Mayooran Namasivayam from Australia. Welcome. Dr. Punag Divanji:            Hi, thank you so much for having us. Dr. Mayooran Namasivayam:      Thank you very much. Dr. Carolyn Lam:               So, Punag, could you start us off by telling us a little bit about yourself, your training, your dreams, and why you chose that particular paper from this month's Circulation that spoke to you? Dr. Punag Divanji:            I'm currently a second year Cardiology Fellow, completing my General Fellowship and beginning a research year at the University of California in San Francisco. I will be pursuing research in women's health and subsequently pursuing an Interventional Cardiology Fellowship. Subsequently, this, hopefully, will lead to a career in academic Interventional Cardiology. Dr. Carolyn Lam:               Now, we asked you to pick an article from Circulation. I really wonder which was your pick? Dr. Punag Divanji:            I think one of the most important ones that spoke to me recently was the CVD-REAL Study, the comparative effectiveness of cardiovascular outcomes in new users of SGLT2 inhibitors. The CVD-REAL Study from Dr. Kosiborod of the Saint Luke's Mid America Heart Institute and an international group of colleagues was the first multinational retrospective observational study to compare CVD outcomes in patients with type 2 diabetes, who were prescribed sodium-glucose co-transporter 2 inhibitors or SGLT2 inhibitors. The primary objective of this study was to compare the risk of hospitalization for heart failure in patients with established type 2 diabetes that were newly initiated on SGLT2 inhibitors.                                                 Patients who were newly initiated on an SGLT2 inhibitor had a 39% lower risk of hospitalization for heart failure compared with those newly initiated on other glucose lowering drugs. There was significant geographic variation in the use of SGLT2 inhibitors, with the predominance of canagliflozin in the United States, dapagliflozin in European countries, and no more than 7% penetration of empagliflozin in any of these six countries.                                                 Despite this, there was no signs of significant heterogeneity across the countries, suggesting the cardiovascular benefits observed may be class related. In addition, the reduced risk of hospitalization for heart failure was stable across sensitivity analyses, including sequential occlusion of other glucose-lowering drugs like insulin, metformin, or even the GLP-1 receptor agonists, the only other class of drug with benefits in CVOTs. Dr. Carolyn Lam:               Punag, give us an idea why this paper stand out to you. I mean, we had the EMPA-REG Outcome Trial, and I'd love to know how much you use this medication in your practice, and did it change after this? Dr. Punag Divanji:            This is, I think, a profoundly important study for a number of reasons. Type 2 diabetes carries a significant burden of cardiovascular risk. It's associated with complications like heart failure, myocardial infarction, and all caused death, of course. We have for many years been treating cardiovascular disease in diabetes with an aim towards reduction in hemoglobin A1c. However, we know that reduction in hemoglobin A1c has not necessarily resulted in improvement in cardiovascular outcomes. The EMPA-REG Outcome Study and the recent CANVAS Study seem to suggest that these medications may have a benefit, these SGLT2 inhibitors may have a benefit in cardiovascular outcomes.                                                 In practicing clinical cardiology, we often refer our patients with diabetes to endocrinologists or to their Primary Care physicians to initiate diabetes medications, and aren't directly involved in that decision making. The result of trials like these though, seems to indicate that medications that can have a cardiovascular outcome in this high-risk patient population, may indeed benefit from the input of cardiologists.                                                 With the high penetrance of medications like insulin and metformin in this population, there may indeed be room for initiation of SGLT2 inhibitors, and if it is indeed a class effect, as this seems to indicate, there is considerable room for addition of this medication into our  [inaudible 00:05:13]. And potentially a pretty significant benefit, in terms of cardiovascular outcomes. Dr. Carolyn Lam:               I agree. I took that with me as well, especially because, you know, it's as the name says, CVD-REAL was supposed to be a real world setting, and it included diabetic patients, like you nicely emphasized that didn't have established cardiovascular disease, so maybe addressing a wider population than that was seen in EMPA-REG Outcomes. Thank you so much, Punag.                                                 Could I turn to you now, Mayooran? So, all the way from Australia, could you tell us a little bit about yourself and your training? Dr. Mayooran Namasivayam:      I'm in my third year of Cardiology Fellowship at St. Vincent's Hospital in Sydney, Australia. I'm also involved with post-graduate research doing my PhD through the University of New South Wales and the Victor Chang Cardiac Research Institute doing clinical work here at St. Vincent's. And my particular areas of interest are cardiac imaging and heart failure, and I'll be looking to do an advance Fellowship in imaging and/or heart failure in the near future. Dr. Carolyn Lam:               Brilliant! So, which paper did you pick over the last month? Which spoke to you? Dr. Mayooran Namasivayam:      I picked two papers. But the first one I was going to discuss was the paper by Nickenig and colleagues, which looked at trans-catheter treatment of severe tricuspid regurgitation using edge-to-edge MitraClip technique, which I found very interesting. So this was an observational feasibility study, which primarily looked at safety outcomes at 30 days, but also the technical feasibility of performing this procedure for tricuspid regurgitation therapy. Essentially the authors demonstrated that there was a reduction in tricuspid regurgitation severity or TR grade in 91% of their cohort. There are also improvement in soft surrogate endpoints such as New York Heart Association class and six-minute walk test distance, and importantly there were no intraprocedural major adverse events; however, there were three in-hospital deaths.                                                 I found the study particularly interesting because it's a very emerging technology using the MitraClip in the tricuspid position and to date, this is the largest study on this subject. It recruited patients from 10 centers. I think, interestingly, the 22 patients in that cohort, had both mitral and tricuspid valve disease treated with the MitraClip technique. I think it really bodes well for the future of transcatheter valve interventions and I think shows that this is A, technically possible, but in the early stages at least safe and possibly efficacious, but certainly we would need longer term data to confirm that this is making a difference for people and that it is safer in the long term. I think it raised a lot of important issues going forward using transcatheter interventions in the tricuspid position. Dr. Carolyn Lam:               You said that you're interested in heart failure and training in heart failure. Do you see that a lot, because I certainly do? Dr. Mayooran Namasivayam:      Yes, we see it quite a lot at our center. Our center is a [inaudible 00:08:10] transplant center and so a lot of our patients with cardiomyopathy have quite bad tricuspid regurgitation. Many of them in the setting of left heart failure, some in the setting of pulmonary hypertension, and then some in our post transplant population we see some tricuspid regurgitation as well.                                                 I think we're following on from the surgical literature, which shows that if you have some degree of mitral regurgitation that requires surgical intervention and there's at least moderate tricuspid regurgitation, then correction of that may be of some benefit. If we follow that on using transcatheter methodology, then certainly this may be an option going forward for patients that have transcatheter mitral valve repairs or replacements. One of the benefits of using a transcatheter method is you're not limited to the one opportunity you have with cardiopulmonary bypass where a decision's made to seek either both mitral and tricuspid together or potentially do it as staged procedure if we were to use the transcatheter approach.                                                 So, yeah, we certainly see severe tricuspid regurgitation a lot and I think options such as this really do give us therapeutic opportunities for our patients who may not have the surgical robustness to have a general anesthetic and a big tricuspid valve replacement or repair surgically. I think the other key population where this may be relevant is tricuspid valve intervention in the post transplant setting where re-operation in the setting of immunosuppression may be problematic and fraught with adverse events. I think it's quite promising going forward and I'd love to see more data on this in the near future. Dr. Carolyn Lam:               Indeed, and it's just so nice to hear about how the articles in our journal have, well, if I may say, inspired both of you.                                                 Amit, I know that we want to get our fellows talking a little bit more about Circulation On The Run. Can I hand it over to you now? Dr. Amit Khera:                 Sure, absolutely, and thank you Carolyn for handing the baton.                                                 I first want to give my full disclosure. I'm a Fellowship Program Director and of all the hats I wear, I find that to be one of the most important ones. You know, at Circulation, we certainly appreciate that Fellows-in-Training are the future of cardiovascular medicine and cardiovascular science. We are actively looking for ways to better engage the Fellows-in-Training and to make sure we're meeting their needs and enhancing their career trajectory. So, I appreciate both of you being on the call today and for this inaugural Fit podcast series, and this will not be the last of this series. So, we look forward to doing more.                                                 Maybe I will ask each of you individually, and I'll start with you Mayooran, can you tell me a little bit about how you consume the medical literature. I appreciate that it's generational and back in the day, everybody would get their print copy in the mail and now there's many different ways to consume it. Tell me a little bit about how you go through the medical literature and your way around that. Dr. Mayooran Namasivayam:      I tend to do a regular periodic browsing of the online journals. I tend to have a few journals, one of which is Circulation that I read sort of on a weekly or at most, fortnightly basis. Just to dig out the key articles of interest and the major updates. At our hospital the fellows have a weekly journal club meeting, which I actually chair. It's quite refreshing to get everyone's different opinions in their own areas of interest from the fellows to discuss topics of interest from various journals.                                                 So, for me personally, it's a combination of browsing online journals with combining a more formal setting as our journal club. But from a research perspective, I use things like the RSS feeds and Journal Alerts, so journal articles that come up in key topics of research interest for myself. With regards to clinical practice, I tend to browse. Speaking to colleagues of mine, they use various things like social media or apps which will highlight major developments or summarize key articles. I think increasingly, that will be the way forward. But that's the way I go about it. Dr. Amit Khera:                 What I really like what you said were a few things. Obviously there's an overwhelming amount of literature and by using tools like RSS feeds and table of contents, you can sort of keep up. I like that you're complementing that at your institution with this deep dive of journal club; this thing that many institutions including ours do, where you're really vetting articles in detail and hearing different perspectives. So, a nice blend of ways to consume it.                                                 Punag, I'm going to ask you a little bit about social media. When I looked, turns out CVD REAL, the one that you chose, had an altmetric score of 487, so we think of impact factor, but altmetric's a whole other way to look at impact of our articles.                                                 I'm curious about your thoughts on social media and the place of social media with disseminating scientific literature. I know many fellows are actively involved on Facebook and Twitter and other pathways. Tell us a little bit about your thoughts on that. Dr. Punag Divanji:            You know, very similar to the practice described in Australia, it's very similar to what we do here. We have weekly journal clubs, we discuss these articles with the faculty and really try to integrate it into our practice. A big part of that at, I think, many institutions across the country is the use of social media.                                                 It is particularly robust, I think, in the cardiovascular field, especially at national or international meetings wherein late breaking clinical data is rapidly disseminated. The outcomes and a few important trials that will impact clinical practice are rapidly disseminated, such that we are able to, I think, quite quickly access information, but beyond that, learn for example, the description is such that medical literature is doubling every two to three years. It's difficult to keep pace with that, but when thought leaders in the field present data that they find most interesting, most useful, or most relevant to patient care on a platform like social media, it's, I think, a wonderful way for Fellows-in-Training to quickly aggregate high quality data. It's something that I rely on heavily. Dr. Amit Khera:                 I think that's a great point, and where things have changed now is not only can you get information quickly through social media, but as you pointed out, the ability to interact with luminaries in the field to get their opinion on it and even engage in a conversation. That certainly wasn't available several years back and I think it's a great advance for Fellows-in-Training.                                                 I'm going to stick with you for a second and hear your thoughts a little bit on how Circulation may better engage Fellows-in-Training or meet their needs.                                                 How can Circulation or other journals for that matter help in the pathway for Fellows-in-Training? Dr. Punag Divanji:            I think the concerns of Fellows-in-Training are unique in comparison to those already in practice. We are at a point in our careers where we're trying to learn the basic important groundwork of cardiology, but at the same time, given the rapid evolution of data, it's imperative that we have the ability to learn new things on top of that foundation.                                                 Engaging fellows in that way, I think, involves a strategy that looks at a couple of different things. One is obviously social media, which is, let's be honest one of the core ways that trainees interact, and let's be honest, one of the most common things you see a trainee doing is looking at their phone. Dr. Amit Khera:                 And faculty. Dr. Punag Divanji:            And faculty for that matter, fair enough. But if you're able to provide information via Twitter or via this Circulation app and be able to alert someone of a new update in the field or a new guideline document or a way to better risk stratify patients that come in with myocardial infarction, this type of rapidly accessible data I think plays well to the [ethos 00:15:32] of the fellow wherein we like to be able to do things quickly and effectively, but also expand our knowledge in the most efficient way possible. Dr. Amit Khera:                 That's very insightful. So, if I hear you correctly, it's sort of continuing to make sure that we disseminate information quickly and rapidly to Fellows-in-Training in a way that is easy for them to consume.                                                 This brings to the point about when we look at our metrics, the podcast and other digital media strategies we have really hit broadly in an international audience, which we're very excited about.                                                 Certainly, Mayooran, I'm going to ask you as well your views on how can Circulation or other journals for that matter help engage Fellows-in-Training or enhance their training and career trajectories? Dr. Mayooran Namasivayam:      I guess today is a wonderful opportunity for fellows to participate in Circulation's online activities and engage with fellows from around the world, so this is one such example. I think echoing some of the thoughts of Dr. Divanji, as a fellow, you're doing many things and you're wearing many hats. You're learning new procedures, you're learning core cardiology, you're involved in research, you're doing on-call activities and clinical duties, and sort of amassing the latest evidence and putting that together and working out how that's going to change your practice now and in the future is important, but is not always easy to do.                                                 I think features such as Circulation's podcast, which summarize key developments sort of state-of-the-art review articles, guideline summaries, which come out in Circulation, and even the simple things like the summaries that come out on the print journals which say what is new and what are the clinical implications, which allow us to read that in a minute or two, and then read on if we're so interested, but at least get a summary or a snapshot of a major article. I think those features are really key in sort of summarizing key developments in a short and accessible way. I think as been discussed already, engaging with the newer media, social media, online media in the way that other publishing modalities such as newspapers are sort of engaging with their audience I think, is certainly important in the future to an increasingly time-poor audience. Dr. Amit Khera:                 Well, glad to hear that these features are resonating well with you both and it's certainly helping you in terms of accessing and understanding the relevance of these articles in your daily practice.                                                 The final question, I'll finish with you and then come back to Punag, is, as Carolyn says every week, this is your backstage pass to the editorial process, so a way to look behind the curtain or Oz if you will on how journals work and we certainly strive for transparency at Circulation.                                                 So, I'm going to maybe ask you if you have any questions for us on how the journal works or any questions regarding the editorial process? Dr. Mayooran Namasivayam:      I guess one of the things that I was wondering was you must, particularly at Circulation, just be inundated with a huge array of papers, which I'm sure all are of excellent quality.                                                 When you're looking at a paper quickly to make a decision about whether it's something you'd pursue further or look into, what gives you that instinct that you know this is probably a good paper? Is it the abstract? Is it the cover letter? Is it the title? What gives you that first impression that we should really look into this a bit further? Dr. Amit Khera:                 Well that's a fantastic question. I'll answer and I'll see if Carolyn wants to add anything as an associate editor as well.                                                 First you have to realize that yes, there's enormous volume of papers, but the most important thing is to assemble an expert team. I think Dr. Hill, our editor-in-chief, Joe Hill has certainly done that. He's established an international group of associate editors that are well-accomplished across the breadth of cardiovascular spectrum, so your interest is in heart failure, you have a couple of imaging type articles, Punag has talked about women's cardiovascular health and also diabetes and cardiovascular disease. We have editors that really have expertise on each of these areas.                                                 The first level is our editorial, editor-in-chief, and deputy editors, et cetera who'll take the first pass at which articles seem to be well done and would meet priority for Circulation. Then distribute them to editors that are content experts, that really understand those areas well. I take that responsibility very seriously when I get a paper. I know I've been on the other end of that. It's a tremendous amount of work. All the authors have contributed, patients have contributed their data. So, we take that responsibility incredibly seriously.                                                 We try to be thoughtful, that if it's a paper that really will not meet priority, we should turn it around quickly and let the authors know that so that they can then move onto another journal and not waste time. The flip is, if something seems that in our field, in our expertise would meet priority to our readers and could advance the field, we send it out for expert review, then have a very thoughtful discussion, even in advance online, through a web portal and then as a group with all of our editors across the world, to really think critically about each paper, it's merits and ways to strengthen it. We always try to do that, which is to not only say yes or no on a paper, but what can we tell an author to make a paper better, because we want the very best products coming out on Circulation.                                                 I hope that gives you an idea of how we think about it. It's sort of a tiered approach, starting with our editor-in-chief and deputy editors and then down to associate editors. Again, we try to turn it around, how would we want our papers treated if we were submitting to a journal?                                                 Carolyn, do you have anything to add to that. Dr. Carolyn Lam:               Yeah.                                                 So, Mayooran, that's great question. I think I can guess where it's coming from, sort of if one were to submit a paper to Circulation, is there any particular part that you would want to focus on, because that's the part that immediately catches our attention, right? I think that's what you're asking.                                                 Well, I would say without a doubt it's the science. So, you talked about the cover letter, you talked about abstract and things, the most important bar that the paper has to cross is validity. Then, right next to that would be novelty. So, for us, you know, once we can see that the science is well done and the results look robust, that has to be there before anything even happens beyond. Then, that's when the process kicks in like Amit said. Then we look at it from our specialty points of view and make sure that it's something novel and something that would be of interest to our Circulation audience.                                                 Does that answer your question? Dr. Mayooran Namasivayam:      It does. It does, thank you both very much. Thank you. Dr. Amit Khera:                 All right, I'm going to now pitch the same question to you, Punag.                                                 What are your thoughts? What sort of questions you have for us behind the curtain of Oz and the editorial process? Dr. Punag Divanji:            You know it's quite interesting, one of the most compelling components of the Circulation on the Run podcast is at the end when Dr. Lam has a wonderful discussion with the associate editor that was responsible for the article and the authors and gives us an idea not only of what drove their process of scientific discovery, but also what drove the editors to really believe in that article to warrant publication; to say that this is something that our readers need to see. I think that really quite remarkable to gain that point of view.                                                 My question is, you seemed to strike this balance between basic translation and clinical research when publishing each week. There are often a variety of topics that come from all three fields. Each week in the publication, there seems to be this balance between basic translational and clinical research wherein the readers really are able to gain perspective into the entire field of cardiology from articles that range from clinical outcomes from blood sugar management to the [pathophysiology 00:22:57] of takotsubo syndrome.                                                 How do you, as editors, strike that balance in each issue? How do you decide which articles are going to be published in concert with others? Dr. Amit Khera:                 That's a great question. Sort of looking at the spectrum of types of articles and types of science and how do you decide sort of what goes together. Kind of like a meal, you know, what components go together. Dr. Carolyn Lam:               I'd like to call it wine paring. Dr. Amit Khera:                 Wine pairing. I like that. So, if it's a roast, what sort of red wine and so forth. I think that's an excellent question.                                                 I think first, we do strive for balance and that, as you know, Dr. Hill has a ... his lab is a basic science lab, and Circulation has always been a journal which does the hightest quality science including both basic science and clinical and translational research. I also say we have other offerings as you know, which are thought pieces on my mind, and perspective pieces. So we really try to have the full spectrum. As we talk about, there are many people that enjoy their vegetables, the hard core original research articles, but a lot of people also like the deserts and the appetizers, these other types of articles that I mentioned.                                                 I think it's trying to find that right balance. We always like to have a balance of all of those together, because we appreciate there's a spectrum of readers and at the same time, we also appreciate that I'm more of a clinical researcher, I can gain insight and value from reading basic science research and similarly the basic scientist could gain value from the types of clinical articles we try to place in Circulation.                                                 So I think maybe as was mentioned, a little bit of a menu and a wine pairing we include this whole spectrum of different types of offerings, but I think the one bar is they all have to be articles that have some clinical implications, be it clinical, translational, or basic science, even the epidemiologic studies research that I do, they all have to, in the end, have some sort of clinical importance or relevance. I think that's the benchmark for all of the articles.                                                 Carolyn, do you want to add anything? Dr. Carolyn Lam:               No, I think you got it all. In fact, Amit, I'm going to turn it back to you for the last question.                                                 As Editor of Digital Strategies for Circulation, tell us, what's in store? Dr. Amit Khera:                 Well, you know, it's been a great first year and I think many would say one of the highlights has been the podcast for sure. I think we've developed a platform of social media engagement, of learning how to work though our digital strategies platforms and setting a high bar for our podcast.                                                 Now it's time to go to level two, or next level. How do we enhance what we're offering? How do we get creative about new types of podcasts, like this one we're doing today? How do we think about more interactive social media engagement? How do we further enhance the way we distribute science across the world? So, we have a big appetite and big ambition, but I think that is what we should be doing when we have such good science and making sure we disseminate it broadly.                                                 So, I think you'll see building on the platform we've already established, and apropos to today, I hope we really bring the Fits along with us on this ride to further expand our offering of our science. Dr. Carolyn Lam:               Thank you so much for joining us on this special episode. Don't forget to tune in next week.