Podcasts about new york heart association

Circulation 68, No. 5, 939-950, 1983Background  Coronary artery bypass surgery (CABG) had grown in popularity through the 1970s and 1980s. By 1981, approximately 159,000 bypass surgeries had been done.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.The goal of the CASS trial was to rigorously evaluate the effect of surgical vs medical therapy on total mortality in well-defined subsets of patients with coronary artery disease.Patients Eligible patients had to be 65 years of age or below and have angina that was Canadian Cardiovascular Society class I or II with or without a history of myocardial infarction, or had to have a well-documented MI more than 3 weeks before randomization. Clinical criteria for exclusion were prior CABG, unstable or progressive angina, angina more severe than class II (angina occurring after climbing one flight of stairs or walking two blocks is class III), congestive heart failure (New York Heart Association class III or IV), a coexisting illness that would increase the likelihood of death within 5 years, and a variety of practical exclusions that might limit active participation during follow-up.Angiographic requirements for participation in the trial included the presence of significant operable coronary artery disease, defined as either 70% or greater reduction in the diameter of the right, left anterior descending, or left circumflex coronary artery, or 50% or greater reduction in the diameter of the left main coronary artery. Patients with 70% or greater luminal diameter reduction of the left main were excluded. Also excluded were patients with LVEF (measured by left ventriculography) of less than 35% or those patients who required valve surgery or LV aneurysm repair.Baseline Characteristics There were 390 patients randomized in both the surgical and medical arm. The mean age was 51 years; 90% were males and 98% were White. Approximately 60% had previous MI, 30% had hypertension and only 3% had congestive heart failure. About 40% were smokers.Angiographic criteria were well matched—27% had one-vessel disease, 38% had two-vessel disease, and about a third had three-vessel disease. Nearly a third of patients in both groups had proximal LAD disease. The LVEF was more than 50% in 73-74% of patients in both groups. The LVEF was less than 50% in a fifth of patients in both arms.Procedures CASS authors were quite clear in the screening and randomization process. Slightly more than 16,600 patients were screened for participation in the trial at 11 centers. Figure 1 in the manuscript shows the reasons for exclusion, which included normal or minimal coronary disease (28%), Class 3 or 4 angina (36%), and left main disease more than 70%n (1.5%). Other exclusions totaled 16%.Ultimately there were 2099 patients eligible to be randomized, however, 1319 patients were not included in the trial due to physician preference.Randomization was stratified by clinical site, number of diseased vessels, and ejection fraction within three different clinical subgroups. Patients with angina and ejection fractions of at least 0.50 were randomized within group A (n =514), those with angina and EF less than 0.50 were randomized within group B (n=106) and those free of angina after well-documented MI were randomized within group C (n=160).A total of 954 distal anastomoses were constructed in 357 patients in the surgical group, an average of 2.7 per patient. A total of 334 distal anastomoses were evaluated in the 129 patients; 90% of the grafts were open, 97% of patients had at least one open graft, and in 81% of patients all grafts were patent. Medical therapy consisted mostly of nitrates, and beta-blockers. Statin drugs were not available during the trial. Endpoint The primary endpoint was all-cause mortality. It was assessed with the intention-to-treat method. Results There were no significant differences in mortality.At 5 years, the average annual mortality rate in patients assigned to surgical treatment was 1.1%. The annual mortality rate in those receiving medical therapy was 1.6%. Expressed differently, the rate of death at 5 years was 9.2% in the medical group versus 7.4% in the surgical group. Annual mortality rates in patients with single-, double-, and triple-vessel disease who were in the surgical group were 0.7%, 1.0%, and 1.5%; the corresponding rates in patients in the medical group were 1.4%, 1.2%, and 2.1%.There were also no significant differences in survival when patients were grouped according to degree of coronary artery disease (number of vessels) or EF or by a combination of diseased vessels and EF.Crossovers did occur. Approximately 23% of the 390 patients assigned to the medical group had surgery during the follow-up period (4.7% per year). Of the patients assigned to surgery, 31 of 390 patients (8%) did not have surgery.Conclusions The CASS authors write in the abstract of the manuscript that they observed excellent long-term survival in both groups and that for patients similar to those in the trial, surgery could be deferred until symptoms worsen.The CASS trial had caveats. First was that the 780 patients enrolled in the trial were highly selected from a total of more than 16,000 patients in the registry. The CASS registry revealed widely disparate annual mortality in patients managed medically, ranging from 1.3% for those with single-vessel disease and normal EF to 12.5% in those with three-vessel disease and impaired EF. Another caveat was the lower-than-expected annual mortality in the medical arm of only 1.6%. This was lower than previous surgery trials (3.3% noted in the European Collaborative Study and 4.3% reported in the Veterans Administration Study). CASS authors estimated a 2-4% annual mortality. This reduces the power to find differences in the two groups.It is interesting however, that for the 1319 patients in whom their physician declined randomization, the outcome in those treated medically was similar to that reported in the randomly assigned patients who received medical therapy.In conclusion, as early as the 1980s, the CASS study showed that stable coronary artery disease was quite stable, and that revascularization in selected patients did not improve survival over medical therapy. Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

Kontrast ilişkili akut böbrek hasarı ilk olarak 1950'lerin başında tanımlanmıştır.​1​ O zamandan beri, bu advers olay ve uzun süreli sekellerine ilişkin endişeler, uzamış hastanede kalış süresi ve buna bağlı maliyetler dahil olmak üzere, özellikle kontrast riski yüksek olduğu düşünülen hastalarda radyokontrast madde ile yapılan prosedürlerde önemli sınırlamalarla karşılaşıldı. Aslında amaç; kullanılan kontrast madde (KM) aracılığıyla dokular arasındaki yoğunluk farkını arttırıp organları daha belirgin hale getirmektir. Bu durum tanı koymayı kolaylaştırırken, hastanın böbrekleri için zorlu bir serüvenin başlangıcına neden olabilir.   KM'nin uygulamasından sonraki 48-72 saat içinde kreatinin seviyesinin başlangıca göre %25 artışı veya mutlak kreatinin değerinde 0.5 mg/dL'lik artış olmasına kontrasta bağlı nefropati (KBN) denir. Kontrastla ilişkili akut böbrek hasarı riski yaşa, önceden var olan komorbiditelere (örn. diyabet veya kronik böbrek hastalığı) ve prosedürün türüne göre önemli ölçüde değişir. Özetle, temel mekanizma kontrast maddenin kan viskositesini arttırarak kan akışına karşı direç gelişmesine sebep olur. Yavaş akan kan intravasküler çamurlanmaya bağlı lokal iskemiye ve hücresel düzeyde tübüler hasara neden olan reaktif oksijen radikallerinin aktive olmasına sebep olur. Kliniklerimizde hem tanı hem tedavi sürecinde sıklıkla kullandığımız bu maddelerin neden olduğu akut böbrek hasarını önceden tahmin edebilecek skorlar ile ilgili çalışmalar hala devam etmektedir. Bugün sizlere Lancet dergisinde yayınlamış, sekiz yıllık veriler sonucunda anjio yapılan hastalarda kontrastın neden olduğu akut böbrek hasarı riskini tahmin etmede gayet başarılı bulunan bir skordan bahsetmek istiyorum​2​. Acil serviste kullanımı için elimizde henüz net bir veri yok; ama kreatinin sonucuna bakıp arada kaldığımız hastalar için bence fikir verebilir. Kontrast madde nefropatisi ile ilgili daha detaylı bilgi almak için sitemizde bulunan yazılarımızı okumayı unutmayın. Kontrast Madde Nefropatisinden Gerçekten Korkmalı Mıyız?, Kontrast Nefropati: Nedir? Ne yapılmalıdır?, Sepsiste Kontrast Madde Nefropatisi, https://acilci.net/acil-konusalim-4-kontrast-nefropatisi/ Mehran Score for Post-PCI Contrast Nephropathy Mehran Skoru​3​ ParametrelerPuanHipotansiyon SKB< 80mmHg*5Aortik içi balon pompası kullanımı5KKY†5Yaş ≥754Anemi‡3Diabetes mellitus3Kontrast madde miktarı (her 100 mL başına)1Serum Kreatinin > 1,5 mg/dLveyaGlomerüler filtrasyon hızıGFR 40-60GFR 20-40GFR

This week, please join author Xuerong Wen, Associate Editor Sandeep Das, and Guest Host Mercedes Carnethon as they discuss the article "Comparative Effectiveness and Safety of Direct Oral Anticoagulants and Warfarin in Patients With Atrial Fibrillation and Chronic Liver Disease: A Nationwide Cohort Study." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass of the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, I'm so excited about today's feature paper. It deals with the important condition where atrial fibrillation exists in patients with chronic liver disease and what do we do for anticoagulation in these patients. It's a comparative effectiveness and safety study of direct oral anticoagulants compared with warfarin in these patients. A huge, wonderful, important study that we're going to discuss. But before we get there, I'd like to tell you about some papers in this issue and I'd like you to tell me about some too. You got your coffee? Dr. Greg Hundley: Absolutely. Dr. Carolyn Lam: All right. I'll go first In this paper that describes a quantitative prognostic tool for the mitral valve prolapse spectrum and it's derived from the new mitral regurgitation international database quantitative or MIDA-Q registry, which enrolled more than 8,000 consecutive patients from North America, Europe, Middle East. And these were patients all diagnosed with isolated mitral valve prolapse or MVP in routine clinical practice of academic centers, all of which also did prospective degenerative mitral regurgitation quantification. The MIDA-Q score was calculated based on characteristics collected in routine practice combining the established MIDA score, which integrated guideline based markers of outcomes like age, New York Heart Association status, atrial fibrillation, LA size, pulmonary artery pressure left ventricular and systolic, I mentioned, and ejection fraction. Integrating that with scoring points based on the degenerative mitral regurgitation quantitation that is measuring effective regurgitant orifice and volume. Dr. Greg Hundley: Very interesting Carolyn. So a scoring system that combines clinical information with what we might assess with echocardiography like regurgitant volume or regurgitant orifice area. So how well did this mortality risk score perform? Dr. Carolyn Lam: So the new score was associated with an extreme range of predicted survival under medical management and that ranged from 97% to 5% at five years for the extreme score ranges. And it was strongly, independently and incrementally associated with long-term survival over all the markers of outcomes. So the authors concluded, and these by the way were authors led by Dr. Maurice Serrano from Mayo Clinic, Rochester, Minnesota. These authors concluded that the score should allow integrated risk assessment of patients with mitral valve prolapse to refine clinical decision making in routine practice and ultimately reduce degenerative mitral regurgitation under treatment. Dr. Greg Hundley: Wonderful description Carolyn. Well I'm going to switch to the world of electrophysiology, Carolyn. And so as you know, the Brugada syndrome is an inherited arrhythmia syndrome caused by loss of function variants in the cardiac sodium channel gene SCN5A and that occurs in about 20% of subjects. And these authors led by Dr. Dan Roden at Vanderbilt University School of Medicine identified a family with four individuals diagnosed with Brugada syndrome, harboring a rare missense variant in the cardiac transcription factor, TBX5, but no SCN5A variant. And upon identifying these individuals, their objective was to establish TBX5 as a causative gene in Brugada syndrome and to define the underlying mechanisms by which it would be operative. Dr. Carolyn Lam: Oh wow. So a new gene variant. So what was the relationship? Dr. Greg Hundley: Right Carolyn? So using induced pluripotent stem cell derived cardiomyocytes from members of the affected family, multiple electrophysiologic abnormalities were detected in these cardiomyocytes including decreased peak and enhanced late cardiac sodium current. In these cells these abnormalities were entirely corrected by CRISPR/Cas9 mediated editing of that TBX5 variant and transcriptional profiling and functional assays in unedited and edited pluripotent stem cell derived cardiomyocytes showed direct SCN5A down regulation caused decreased peak sodium current and that reduced PDGF receptor expression and blunted signal transduction to phosphoinositide-3-kinase. And interestingly, PDGF receptor blockade markedly prolonged normal induced pluripotent stem cell derived cardiomyocyte action potentials. And also Carolyn interestingly in this study they did a separate analysis. It reviewed plasma levels of PDGF in the Framingham Heart Study and they found that they were inversely correlated with the QT corrected interval. And so Carolyn, these results established decrease SCN5A transcription by the TBX5 variant as a cause of Brugada syndrome and also reveal a new general transcriptional mechanism of arrhythmogenesis of enhanced late sodium current caused by reduced PDGF receptor mediated phosphoinositide-3-kinase signaling. Dr. Carolyn Lam: Wow. Wow, that's significant. Thanks Greg. So this next paper is also really important and could change the practice in the field of cardiac resynchronization therapy or CRT. You see, it suggests that the practice of what we do now, which is combining right bundle branch block with intraventricular conduction delay patients into a single non-left bundle branch block category when we select patients for CRT, that this may not be the way to go. So let's go back a bit and remember that benefit from CRT varies with QRS characteristics and individual trials are actually underpowered to assess the benefit for relatively small subgroups. So the current authors led by Dr. Friedman from Duke University Hospital and colleagues, therefore performed a patient level meta-analysis of randomized trials of CRT to assess the relationship between QRS duration and morphology with outcomes. Dr. Greg Hundley: Very interesting Carolyn. So another wonderful paper from the world of electrophysiology in trying to understand optimal mechanisms to resynchronize the ventricle in patients with differing bundle branch blocks or intraventricular conduction delays. So what did they find? Dr. Carolyn Lam: They found that patients with intraventricular conduction delays and a QRS duration of 150 milliseconds or more, CRT was associated with lower rates of heart failure hospitalizations and all cause mortality. The magnitude of CRT benefit among these patients with the interventricular conduction delay of 150 milliseconds or more and those with the left bundle branch block of 150 milliseconds or more were similar. In contrast, there was no clear CRT benefit for patients with a right bundle branch block of any QRS duration, although the authors could not rule out the potential for benefit at a markedly prolonged QRS duration. So they concluded that the practice of combining right bundle branch block with intraventricular conduction delay patients into a single non-left bundle branch block category when we make patient selections for CRT is not supported by the current data. And in fact, patients with an intraventricular conduction delay of 150 milliseconds or more should be offered CRT as is done for patients with a left bundle branch block of 150 milliseconds or more. Dr. Greg Hundley: Wow, Carolyn, so really interesting point. No clear CRT benefit for patients with right bundle branch block regardless of the QRS duration. Well we've got some other articles in the issue. I'll describe a couple from the mail bag. There's a Research Letter from Professor Lassen entitled "Risk of Incident Thromboembolic and Ischemic Events Following COVID-19 Vaccination Compared with SARS-COV2 Infection." Also Bridget Kuhn has a wonderful Cardiology News piece entitled "Collaborative Care Model Helps Heart Failure Patients Meet End-of-Life Goals." Dr. Carolyn Lam: There's an exchange of letters between Doctors Donzelli and Hippisley-Cox regarding that risk of myocarditis after sequential doses of COVID-19 vaccine, there's an AHA Update by Dr. Churchwell on continuous Medicaid eligibility, the lessons from the pandemic. There's an On My Mind paper by Dr. Parkhomenko on Russia's war in Ukraine and cardiovascular healthcare. Wow, what an issue. Thanks so much, Greg. Shall we go on to the feature discussion? Dr. Greg Hundley: You bet. Dr. Mercedes Carnethon: Well welcome to this episode of Circulation on the Run podcast. I'm Mercedes Carnethon, associate editor of the journal Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine. I'm very excited to be here today with Xuerong Wen and Sandeep Das, my fellow associate editor here at Circulation to talk about a wonderful piece by Dr. Wen and colleagues from the University of Rhode Island. So welcome this morning Xuerong and thank you so much for sharing your important work with us. Dr. Xuerong Wen: Thank you Dr. Carnethon. It was great meeting you all and I'm the Associate Professor of Pharmacoepidemiology and Health Outcomes at the University of Rhode Island. I'm happy to introduce my study to everyone. Dr. Mercedes Carnethon: Well thank you so much and thank you as well Sandeep for identifying this fantastic article and bringing it forth. Dr. Sandeep Das: Thanks Mercedes. It's great to be with you. Dr. Mercedes Carnethon: Great. Well let's go ahead and get into it. There's so much here to talk about. So Dr. Wen and colleagues studied the comparative effectiveness and safety of direct oral anticoagulants or DOACs and warfarin in patients with atrial fibrillation and chronic liver disease. So this is such an important topic. Can you tell us a little bit about what your study found? Dr. Xuerong Wen: So our study is a comparative effectiveness and the safety analysis using a national health administrative data from private health plans. So we compared the risk of hospitalized ischemic stroke, systemic embolism and major bleeding between DOACs and warfarin in patients with atrial fibrillation and chronic liver disease. So we also had to had compare to these primary outcomes between apixaban and rivaroxaban in the study population. So our studies show that among patients with atrial fibrillation and chronic liver disease, DOACs as a class was associated with lower risk of hospitalization of ischemic stroke and systemic embolism and major bleeding, compared with warfarin. And when compared risk outcomes between individuals apixaban has lower risks as compared to rivaroxaban. So that's our study results. Dr. Mercedes Carnethon: Well thank you so much. This seems like such an important question. We hear a lot about DOACs and some of their risks as well as their considerable benefits. I think what leaves me the most curious is why did you choose to pursue this question and in particular in patients with both atrial fibrillation and liver disease. So why was the intersection of these two particular conditions of interest to your study team? Dr. Xuerong Wen: That's a great question. So the liver actually plays a central role in both the synthesis of coagulation factors and the metabolism of anticoagulant drugs. And the clearance of the anticoagulants in liver ranges from 20% to 100% for DOACs and warfarin. So in clinical practice anticoagulation abnormalities and elevated risk of spontaneous or unprovoked venous thrombotic complications have been reported in patients with liver disease. While these patients with cirrhosis were excluded from the clinical trials of DOACs and also population based, the real world experience is very limited. So that is why we initiated this retrospective cohort study and based on the real world data in this specific population. Dr. Mercedes Carnethon: Oh, thank you so much for explaining that. I definitely learned a lot and really enjoyed reading the piece. I think it was very well organized and well written and I know that our readership will appreciate it. It obviously stood out to you as well, Sandeep. Can you tell me a little bit about why you thought that this would be an excellent piece for circulation? Dr. Sandeep Das: Yeah, absolutely. Thanks for the question. So in the broad field of what we call observational comparative effectiveness research, so basically that's using large observational data sets to try to answer important clinical questions and it's a really challenging thing to do. I mean we're all very familiar with the idea of using randomized trials to assess important clinical questions because of the structure of that design allows you to mitigate some of the effects of confounding. Here, it has to be done analytically. So what's the important factor that really drives you towards a great observational comparative effectiveness piece? So first the clinical importance. I feel a little guilty because I'm old enough to remember when warfarin was the only option available, but really as a clinician, or every patient, I really prefer DOACs over warfarin just for ease of use and lifestyle. So there's a huge sort of importance to the question. Second, the patients with chronic liver disease were excluded from the larger RCTs and the DOAC trials. So really we don't have the answer to the question already. It's an important question. Obviously the bleeding risk is tied up with the liver, warfarin directly antagonizes vitamin K, so there's real questions about safety and so this is the perfect storm and then on top of it was a really well done and well executed study. So when this came across my desk, the very first thing I thought was not, "Is this something that we're interested?" But rather, "How do we make it better? How do we make it more useful to the reader?" This had me from hello. Dr. Mercedes Carnethon: Well thanks so much. We rarely have the opportunity when we read an article to be able to ask the authors questions. So Sandeep, I know that you had mentioned that you had some follow up questions as well. Dr. Sandeep Das: Yeah. So the real thought that I have then is would you argue based on this that we know enough that we should change our practice? And that do you feel comfortable advocating that people now prescribe DOACs to these patients? Dr. Xuerong Wen: I would say yes. Okay. Although this is not a clinical trial, but our study is actually systematically compare the effectiveness and safety between DOAC users and also the warfarin users. And if you look at our table one, we compare with so many variables between these two users and we use the propensity score adjustment and we after propensity score weighting and the two control group almost balanced. And I know right now FDA actually suggested that emulate the trial using the large real world data to do the emulated trial. So our study actually conducted is based on the large population using large data and we use the propensity score weighting to control all this potential compounding factors. Although there are still some limitations in this study. I think we mentioned that in the discussion section and we discussed all potential compounding factors that still may exist. And also there are some misclassifications and out of all this limitations and we still found the two drugs performed differently in this specific population. So we feel that comfortable to say that a DOAC drug performs better than warfarin. And also I think based on other studies that based on the clinical trial in the general population, DOAC drug is performs much better than warfarin and considering that the clearance in liver for DOAC is less than warfarin. So plus all this information together, I think DOAC may be safer than wafarin in the patients with AF and chronic liver disease. Dr. Sandeep Das: Yeah, I would say that I agree that these data, even if you're skeptical about observational CT generally, which I admit that I tend to be, these are really reassuring data that at least the DOACs are... There's absolutely nothing that suggests that they're any worse than warfarin and all of the sort of soft indications for ease of use and patient happiness really would seem to favor DOACs. So I think this is the sort of rare observational CT paper that may actually change my practice. Dr. Mercedes Carnethon: I have a follow-up question, Xuerong, related to the design and as well your strategy to address differences between the groups. So inverse probability weighting is certainly a standard in the field to be able to manage differences between groups when you have a situation where can't, where it's not a randomized trial. Do you as well, and educate me, I admit I'm an epidemiologist whose methodological skills are sometimes challenged. Do you have the opportunity using this design and with inverse probability weighting to evaluate subgroup effects? So my specific question is were you able to determine whether or not these associations were similar based on age and gender in particular? Dr. Xuerong Wen: That's a great question. We did conducted a lot of subgroup study but not by age or gender. We conducted I think this study in a lot of subgroups using the propensity score weighting, but the subgroup that I think we did a subgroup like a patient with a different chronic liver disease. So that's what we did. And we also tested different methods inverse probability score weighting. So we did trimming and we used a different percentage of trimming and to see how that affect the study results. So we have done a lot of subgroup studies. We did not check the age and the gender, but that's a very good point. Maybe later, well I'll ask my student to do that. Dr. Mercedes Carnethon: Well, you're a good mentor. So I think that is a really certainly an appropriate approach. Sandeep, did you have additional questions? Dr. Sandeep Das: No, I wish I had thought of yours before you did. I think exactly the older age, women, racial ethnic groups that are underrepresented historically in trials. I think that that's really, again, the sweet spot of this observational research. We definitely, and NH definitely working on trying to increase enrollment of all these groups in our CTs. However, while we wait for that, I think that's exactly what we should be doing. Dr. Mercedes Carnethon: Well that's great. And Xuerong, you really alluded to really, I think what is one of my final questions related to what do you think based on what you have observed in this study, what do you see as the next steps in the research field for your team, your students, or other people who are carrying out this type of work? Dr. Xuerong Wen: Well, that's a great question. We currently have a couple of more manuscripts ongoing in this field, and we will continue conducting the comparative effectiveness and analysis to compare drugs head to head as well as developing and implementing new methodologies to this field. And we hope our study provides real world evidence for clinical decision making, prescribing anticoagulants to patients with atrial fibrillation and chronic liver disease. We also expect the physicians and researchers more and more value the real world data studies, especially when clinical trials are not feasible or ethical. Dr. Mercedes Carnethon: Well, thank you so much. That was such an excellent vision that you provided us with and we're just very grateful that you submitted this fantastic work to the journal Circulation. I know that our readers will enjoy really digging in. The podcast is meant as a teaser to bring you to the journal so that you can read about this wonderful work by Dr. Wen and colleagues. So again, thank you. I'm Mercedes Carnethon, joined with my associate editor partner here, Dr. Sandeep Das. And thank you very much for spending your time with us today, Dr. Wen. Dr. Xuerong Wen: Thanks for this great opportunity to disseminate my study with us, thank you. Dr. Sandeep Das: Thanks Mercedes. Dr. Mercedes Carnethon: Thank you for joining us for this episode of Circulation on the Run. Dr. Greg Hundley: This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week's episode features special Guest Host Mercedes Carnethon, as she interviews author Miriam Cortese-Krott and Associate Editor Charles Lowenstein as they discuss the article "Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure." 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-host I'm Dr. Carolyn Lam, associate editor from The National Heart Center in Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, today's feature paper is one of those really, really landmark papers that really advance our understanding of Nitric oxide signaling. And it's about red blood cell and Endothelial eNOS, and how they independently regulate circulating nitric oxide, metabolites, and blood pressure. A real, real must, but let's go on and look at the other papers in this issue first. Greg, you want to go first? Dr. Greg Hundley: You bet, Carolyn. Better grab a cup of coffee. And my first paper is from professor Nathan Mewton from Hôpital Louis Pradel Hospices Civils de Lyon. Carolyn, these authors hypothesized that Colchicine a potent anti-inflammatory agent may reduce infarct size in left ventricular remodeling at the acute phase of STEMI. And so to address this hypothesis, they performed a double-blind multi-center trial and randomly assigned patients admitted for a first episode of STEMI referred for primary PTCA to receive oral Colchicine two-milligram loading dose followed by 0.5 milligrams twice a day, or matching placebo from admission to day five and the primary efficacy outcome was infarct size determined by cardiovascular magnetic resonance imaging at five days. And the relative left ventricular end-diastolic volume change at three months and infarct size at three months was also assessed by cardiac MRI. And these were secondary outcomes. Dr. Carolyn Lam: Nice. Okay. So what were the results? Dr. Greg Hundley: Right, Carolyn. So 192 patients were enrolled. 101 in the Colchicine group and 91 in the controls. And as a result of this trial, the oral administration of high dose Colchicine at the time of Reperfusion. And for five days thereafter did not reduce infarct size assessed by cardiac MRI. And so Carolyn, the clinical implications of these results suggest that other studies exploring the timing, pharma kinetics, and dose-response of Colchicine, as well as other anti-inflammatory agents are needed to identify an effective method to reduce infarct size and limit remodeling in this group of patients. Dr. Carolyn Lam: Wow, it's just such a rich field done with all this about Colchicine. Well, our next paper is a pre-specified sub-analysis of the randomized EAST-AFNET 4 Trial and the sub-analysis assess the effect of systematic early rhythm control therapy that is using Antiarrhythmic drugs or catheter ablation compared to usual care, which means allowing rhythm control therapy to improve symptoms in patients with heart failure. And this was defined in the sub-analysis as the presence of heart failure symptoms of New York Heart Association status two to three or a left ventricular ejection fraction of less than 50%. Dr. Carolyn Lam: Now, the authors led by Dr. Kirchhof at University Heart and Vascular Center UKE in Hamburg, Germany included 798 patients in this sub-analysis of whom 442 had HFpEF, 211 had heart failure with mid-range ejection fraction and 132 had HF-rEF over a median of 5.1 years of follow-up the composite primary outcome of cardiovascular death stroke or hospitalization for worsening heart failure, or for acute coronary syndrome occurred less often in patients randomized to early rhythm control therapy compared with patients randomized to usual care. And this was not altered by heart failure status with an interaction P-value of 0.6. Left ventricular function, symptoms, and quality of life improved equally in both treatment strategies. Dr. Greg Hundley: Wow, Carolyn, a lot of information here. So what can we take away from this? Dr. Carolyn Lam: Well, let's remember that this is a sub-analysis, albeit pre-specified of that randomized trial of the EAST-AFNET 4 Trial, but nonetheless, the data supports a treatment strategy of rhythm control therapy with Antiarrhythmic drugs or ablation within a year of diagnosing atrial fibrillation in patients with signs and symptoms of heart failure to reduce cardiovascular outcomes. Dr. Greg Hundley: Very nice, Carolyn. So, Carolyn, my next paper pertains to Alarmin Interleukin-1 Alpha, and it comes to us from Dr. Thimoteus Speer at Saarland University. So, Carolyn, Alarmin Interleukin-1 Alpha is expressed in a variety of cell types, promoting sterile systemic inflammation. And the aim of the present study was to examine the role of Alarmin Interleukin-1 Alpha in mediating inflammation in the setting of acute myocardial infarction and chronic kidney disease. Dr. Carolyn Lam: Wow, sterile inflammation. It's a really hot topic now. So what did these authors find? Dr. Greg Hundley: Right, Carolyn. So we're going to call Alarmin Interleukin-1 Alpha. Let's just call it IL-1 Alpha and so increased IL-1 Alpha surface expression on monocytes from patients with acute myocardial infarction in patients with chronic kidney disease was found to be associated with cardiovascular events. Next, IL-1 Alphas itself served as an adhesion molecule, mediating leukocyte-endothelial adhesion, and finally, abrogation of IL-1 alpha prevented inflammation after myocardial infarction and ameliorated chronic kidney disease in Vivo. Dr. Carolyn Lam: Wow. So what does this mean clinically? Dr. Greg Hundley: Right, Carolyn, so perhaps targeted therapeutic inhibition of IL-1 Alpha might represent a novel anti-inflammatory treatment strategy in patients with myocardial infarction and in patients with chronic kidney disease. Dr. Carolyn Lam: Amazing. Thanks, Greg. Well, in today's issue, there's also an exchange of letters between doctors Lother and Filippatos on Finerenone and risk of hyperkalemia in CKD and type two diabetes. There's an On My Mind paper by Dr. Sattler on the single-cell immunology and cardiovascular METs in, do we know yet what we don't know? Dr. Greg Hundley: And then Carolyn, from the mailbag, a Research Letter from Professor Wehrens entitled “Atrial Specific LK Beta One Knockdown Represents a Novel Mouse Model of Atrial Cardiomyopathy with Spontaneous Atrial Fibrillation.” Well, Carolyn, how about we turn our attention to those red blood cells and endothelial nitric oxide synthase. Dr. Carolyn Lam: Yeah. Can't wait. Dr. Mercedes Carnethon: Well, welcome to this episode of Circulation on the Run. Our podcasts, where we have an opportunity to speak with authors of important papers that are appearing in the journal of circulation. I'm pleased to introduce myself. My name is Mercedes Carnethon, professor and vice-chair of preventive medicine at the Northwestern University Feinberg School of Medicine. And I'm pleased today to invite our guest author, Miriam Cortese-Krott, who is the faculty of the University of Duesseldorf, and a guest professor at the Karolinska Institute in Stockholm. And we have with us as well the other associate editor who handled the piece for circulation, Dr. Charlie Lowenstein from Johns Hopkins University. So welcome to each of you this morning. Miriam Cortese-krott: Thank you. Dr. Charles Lowenstein : Thanks for having me. Dr. Mercedes Carnethon: Well, thank you. I'm really excited to jump right into this piece, Miriam, can you tell me a little bit about the rationale for carrying out the study, why you pursued it? Professor Miriam Cortese-Krott: The reason is because when I was working as a post-doc, I had to isolate an enzyme from red blood cells, which is a very, very difficult. And if you know, this enzyme is endothelial nitric oxide synthase, which produce nitric oxide, and actually, the red blood cell is full of the worst enemy of nitric oxide, which is hemoglobin. So actually, when I was talking about my project, everybody was asking, "Why are you doing that?" And I was actually able to isolate the enzyme and look at activity and be sure that the enzyme was fine, but the function of this enzyme was absolutely unknown. Professor Miriam Cortese-Krott: And the only way to study proteins in red blood cells is to make modification in the bone marrow of the mice. So in the Erythroid cells, because you can not, of course, if there are cells without nucleus you don't have any chance to modify them in culture, something like that. So the only way was to generate mice with modification specifically in the red blood cells. And I had the chance to create, to generate red cell-specific eNOS knockout mice. And of course, as a control endothelial-specific eNOS knockout mice by using the Cre-loxP technology. And with this technology, I could really understand what's happening to the physiology of the mouse if you remove this protein from the red blood cells. And so this was the whole idea. Dr. Mercedes Carnethon: Thank you so much. It was really exciting for me to read this piece. We are on opposite ends of the scientific inquiry spread as I'm an epidemiologist who does things at the population level, and you're identifying things at the basic science level. I thought the paper was extremely well-written and that encouraged people to dig in, even if you're unfamiliar, and in part that's because you provided such a great explanation of how your findings are used and how they're relevant to the process. Do you mind sharing a little bit about your findings and how you expect that they will be used by our scientific community? Professor Miriam Cortese-Krott: I think the main finding of this paper is that if you remove eNOS from the red blood cells if the mice are hypertensive, have hypertension, and this is completely something that you actually will not expect, as I told you that indeed red cells are full of the enemy of nitric oxide that remove it immediately. So you can ask yourself how it is possible. But I think the key finding here in this paper was that I also generated the opposite model. So I created the model a conditional eNOS Knockout model where you can decide in which tissue you want to have your enzyme. And of course, I applied for red blood cells. And what you see in this model is that you start from a global knockout mouse with hypertension, you reintroduce the eNOS just in the red blood cells, you have normal tension. So this means, this is the main finding. You have a switch in the red blood cells, which is the enzyme eNOS, which it's behaving in a completely different way clearly as compared to the vessel wall eNOS and still regulating blood pressure. Dr. Mercedes Carnethon: Well, thank you so much. I think this is the point at which I like to turn to the associate editor who handled the piece. Charlie, you and I don't get to talk as often given the diversity of work that we each pursue, but Charlie, tell me a little bit about what excited you about this piece? Dr. Charles Lowenstein: Thanks, Mercedes. So I love this piece. I thought Miriam, your article is so great. So a couple of thoughts. One is nitric oxide and nitric oxide synthase are so important in biology and medicine, nitric oxide regulates blood pressure. It regulates neurotransmission. It regulates inflammation. And this is true, not only in the lab, looking at cells in mice, but also in the human. So genetic variance in the endothelial nitric oxide synthase gene or NOS3 are associated with risks for diseases like coronary artery disease. So eNOS is just so important in biology and medicine. And now some ancient history. When I was a cardiology fellow, about a hundred years ago, I worked in the lab that first purified nitric oxide synthase proteins, and we cloned two of the nitric oxide synthase genes that was in the lab of Dr. Solomon Snyder at Johns Hopkins back in the 1700s. Dr. Charles Lowenstein: So when we cloned the nitric oxide synthase genes, when we and others did, we made a huge mistake. We chose the names for these isoforms from the tissue where they were first isolated. So we called the brain nitric oxide synthase nNOS, because it's a neurons, macrophages MCnos we called it MCnos and in endothelial cells, we called it the nitric oxide synthase eNOS or endothelial NOS. But in the last 20 years, lots of investigators have found these isoforms are in other cells, not just the original cells at discovery. And so Miriam's question is just so important, which cells make endothelial NOS also called NOS3. That's the history. Now what Miriam has discovered is just so important. I was so fascinated by her work because as she just said, she made two amazing discoveries. One, red blood cells make endothelial nitric oxide synthase. Dr. Charles Lowenstein: And that's been a controversy for a long time. Some people have said, "Yes." Some, "No." And Miriam made the definitive answer. Yes, red blood cells make eNOS, and secondly, she has discovered so much about the physiology of ENO coming from red blood cells, the nitric oxide that's made inside red blood cells regulates blood pressure. What a magical, interesting, and important finding. That's a little bit about the history. Nitric oxide and NOS are important in medicine. The people who originally cloned and purified the nitric oxide synthase isoforms named them after the tissue in which they discovered. And Miriam has made a major discovery that it's not only endothelial cells that make nitric oxide but also red blood cells. Dr. Mercedes Carnethon: Thank you so much for that summary. And I guess, I would have thought perhaps this was something of an Elixir of youth because if you've been working in this area for 200 plus years and Miriam, you started working on this as part of your dissertation work, you both have a lot of insight and background on where we've been and what the advances are. Miriam, can you tell me a little bit about how you'd like to see these findings used by the scientific community? Professor Miriam Cortese-Krott: I think I would like that the scientific community would use my mice first because I think, as Charles has said, it's not only red cells that express eNOS and it's not only endothelial cells. There are other cells producing eNOS and the function in the other cells is not known even in leukocytes, even when they have iNOS of course, but also have eNOS. So you can use my mice since it's a flux model. You can choose whatever you want, what cell you want, and then knock it in and knock it out. So this is one thing that I think the community could really do. I cannot do everything. So I'm happy to give my mice away. Professor Miriam Cortese-Krott: And the second thing is I would like too that in particular, the clinical community would see this link between Emathology and cardiovascular disease. This is something that was started, of course, there are studies looking at anemia and cardiovascular disease, but these studies have sometimes some issues I of course cannot speak as a basic scientist. I cannot speak about huge clinical trials, but I think this link exists and exists at the molecular level and it can be a target for pharmacological therapy. So I think this is what I would like to transport with this study to the clinical community and the basic science community. Dr. Mercedes Carnethon: Yeah. I think this is the point at which Charlie, I turn it to you because you really stand at the intersection of both of those communities. What questions do you have for Miriam going forward, as you think about spreading the word on this important work? Dr. Charles Lowenstein: So Miriam's discovery is just so important and she now has the tools to help answer really, really important questions. How is nitric oxide made in red blood cells? How is it stored in red blood cells? How is it transported throughout the body in red blood cells? What is the chemistry of nitric oxide, when it is stored, when it combines with oxygen when it forms nitrite and nitrate, how is it released from red blood cells? How is it targeted from a red blood cell to the vasculature? So there're these great basic science questions that Miriam and her colleagues are now poised to answer. So there's the science part of it. Then there's the medicine part of it because Miriam's mice and her great discovery have really huge implications for medicine. And so the question is, how can we use ENO? How can we deliver it? How can we target ENO to human tissues? Dr. Charles Lowenstein: How can we turn on erythrocyte, nitric oxide synthase? How can we turn it off? Because there are all these medical diseases where too much nitric oxide is bad, like in sepsis or inadequate amounts, don't protect the vasculature like atherosclerosis. Then there are all these other interesting questions. When we transfuse red blood cells, sometimes if you transfuse aged red blood cells, it's not good. You can harm people. Maybe we can load up or activate eNOS in stored red blood cells and then help deliver more ENO to patients who need red blood cells. So there are all these fascinating medical questions that we can look at based on Miriam's really important discovery. Dr. Mercedes Carnethon: Well, thank you so much. We're coming to the end of this wonderful and informative podcast. And I guess, I'd just ask Miriam, do you have anything else you'd like our listeners to know about your work and about the findings from this study? Professor Miriam Cortese-Krott: I would like people know that hard work help a lot, and that you have to believe in what you are doing and the quality of your science at the end would bring their true discoveries. So I think it's important specifically, for the young women in science that having this message too. So the science per se must be excellent and to proceed, you need a lot of work, but then the work goes to a good end. Dr. Mercedes Carnethon: Miriam, thank you so much for that inspirational note. The hard work that scientists need, the persistence across one's career and building from earlier discoveries, and bringing those forward through one's career are always critically important. And so I hope everyone has really enjoyed this episode and this opportunity to hear from Dr. Cortese-Krott. Miriam, you've done such wonderful work, and thank you as well, Charlie, for your insights about the intersection of this work with clinical care and basic science. Professor Miriam Cortese-Krott: Thank you. Dr. Charles Lowenstein: Thank you. Dr. Mercedes Carnethon: Thank you all very much for joining us today in this episode of 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.  

This week, please join author Uwe Tietge and Associate Editor Anand Rohatgi as they discuss the article "High-Density Lipoprotein Anti-Inflammatory Capacity and Incident Cardiovascular Events" (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.050808) Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke-National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, we've got a very interesting feature this week. It involves another paper in the line of the story of HDL, and looking at HDL and future cardiovascular events. But before we get to that, how about we grab a cup of coffee and jump in and review the other articles and the issue? And Carolyn, this week, maybe I'll go first. Dr. Carolyn Lam: Go, I've got my coffee. Dr. Greg Hundley: Very good. So Carolyn, this paper comes to us from Dr. Huso Hakala, from the University of Turku at Turku University Hospital, and the study pertains to cognition and cardiovascular disease. So Carolyn, as you know, cardiovascular risk factors such as high blood pressure, adverse serum lipids, and elevated body mass index, and midlife may harm cognitive performance. So importantly, perhaps the presence of cardiovascular risk factors since childhood, Carolyn, may impact cognition later in life. So these authors studied the associations of the cardiovascular risk factors from childhood to midlife, their accumulation and midlife cognitive performance. They gathered their data beginning in 1980 from a population-based cohort of 3,596 children who are aged three to 18 years that were repeatedly followed up for 31 years, and they assess blood pressure, serum lipids, body mass index, all in the follow-ups. Dr. Carolyn Lam: Wow. So accumulating risk, I suppose, Greg. So what did they find? Dr. Greg Hundley: Great. Carolyn, glad you asked. So consistently high systolic blood pressure or serum total cholesterol associated with worse midlife episodic memory and associated learning, compared to situations when blood pressure or cholesterol values were low. Obesity since childhood associated with worse visual processing and sustained attention compared to individuals or children that had normal weight. And an inverse trend association was observed for the cardiovascular risk factor accumulation with episodic memory and associated learning with visual processing and sustained attention and with reaction and movement time. So the take home Carolyn, is that, maybe we should be launching preventative strategies against some of these cardiovascular risk factors beginning in childhood, because perhaps they could benefit primordial promotion of cognitive health for those later in adulthood, maybe like you and me. Dr. Carolyn Lam: Oh, wow. Thinking back on my blood pressure, cholesterol and weight, I suppose, since childhood, yikes. Well, the next paper Greg is an important analysis from DAPA-HF. Now as a reminder in the DAPA-HF trial, the sodium glucose co-transporter two inhibitor dapagliflozin was shown to reduce the risk of cardiovascular death and a first episode of worsening heart failure, in patients with heart failure with reduced ejection fraction or HFpEF. In the current paper from Drs. Jhund and colleagues from University of Glasgow, they described the efficacy of dapagliflozin on the predefined secondary end point of total heart failure hospitalizations. That's the first and recurrent heart failure hospitalization and cardiovascular death. And this is so important because we know that patients with HFrEF are known to experience multiple episodes of heart failure during the course of the disease. Dr. Greg Hundley: So Carolyn, what did they find? Dr. Carolyn Lam: Well, they did this analysis by two methods in the first, which was the Lin, Wei, Ying and Yang or LWYY model the rate ratio for the effect dapagliflozin on recurrent heart failure, hospitalizations or cardiovascular death was 0.75. Dr. Carolyn Lam: And the second method, a joint frailty model, the rate ratio for total heart failure hospitalizations was 0.71 while for cardiovascular death, the hazard ratio was 0.81. The factors associated with more hospitalizations were, being a men, having a higher heart rate, NT-proBNP, New York Heart Association class type 2 diabetes, and a longer duration of heart failure with less hospitalization in those with higher systolic blood pressure and higher ejection fraction. So in summary, dapagliflozin in reduced the risk of total heart failure, hospitalizations and cardiovascular death. In fact, if you compare it to the time to first analysis, you can see that, that actually underestimated the benefit of dapagliflozin in HFpEF. Dr. Greg Hundley: Very nice Carolyn, well, my next paper comes to us from the world of basic science. And so Carolyn, neonatal mouse cardiomyocytes undergo a metabolic switch from glycolysis to oxidative phosphorylation, which results in a significant increase in reactive oxygen species production that induces DNA damage. These cellular changes contribute to cardiomyocytes cell cycle exit and loss of the capacity for cardiac regeneration. Now the mechanisms that regulate this metabolic switch and the increase in reactive oxygen species production have been relatively unexplored. Dr. Carolyn Lam: Okay, Greg. So what did this current paper find? Dr. Greg Hundley: Right, Carolyn, so Dr. Ahmed Mahmoud from University of Wisconsin-Madison, they found that malonate, a competitive inhibitor of succinate dehydrogenase, promotes adult cardiomyocyte proliferation, revascularization of the infarct zone and myocardial regeneration following infarction. They also found that SDH inhibition by malonate is consistent with a metabolic shift from oxidative phosphorylation to glucose metabolism in the adult heart. So Carolyn, the clinical implications include the observation that transient inhibition of SDH may represent an important metabolic target to promote adult heart regeneration, following myocardial infarction. Dr. Carolyn Lam: Cool. Thanks Greg. Well, I've got another basic science paper. Let me try to tell you about la ribonucleoprotein domain family member seven. And I'm going to call that LARP7. Again, it's la ribonucleoprotein domain family members seven. Now LARP7 is a master regulator that governs the DNA damage response. The authors today, Dr. Zhang, from Xin Hua Hospital and Shanghai Jiao Tong University and colleagues aim to study its role in heart failure, pathogenesis by assessing LARP7 expression in human heart failure and in non-human primate and mouse heart failure models. Dr. Greg Hundley: Great, Carolyn. So what did they find? Dr. Carolyn Lam: LARP7 was essential for mitochondrial biogenesis energy production and cardiac function by modulating silent mating type information regulation to homolog-1, which is cert one, cert one homeostasis and activity. Now, reduction in LARP7 and diseased hearts due to activation of ataxia-telangiectasia mutated protein pathway contributed to the heart failure pathogenesis and conversely restoring LARP7 in the injured heart conferred myocardial protection. So in some, these results identified that this LARP pathway is a target or rather is a potential target for therapeutic intervention in heart failure. Dr. Greg Hundley: Great, Carolyn. One of the things I love about our journal is really the translational basic science that really could have future implications for how we manage patients with cardiovascular disease. So I, to follow, have another basic science article, and it comes to us from Dr. Florian Weinberger from the University Medical Center in Hamburg-Eppendorf. So Carolyn, human engineered heart tissue transplantation represents a potential regenerative strategy for our heart failure patients and has been successful in preclinical models. Clinical application requires upscaling, adaptation to good manufacturing practices and determination of the effective dose. So these authors performed studies in which cardiomyocytes were differentiated from three different human induced pluripotent STEM cell lines, including one reprogrammed under these GMP conditions. Protocols for human induced pluripotent STEM cell expansion, cardiomyocyte differentiation and engineered heart tissue generation were adapted to substances available in good manufacturing process quality. Engineered heart tissue geometry was modified and repair efficacy was evaluated at three doses in a cryo-injury Guinea pig model, human scale patches were epicardialy transplanted onto healthy hearts in pigs to assess the technical feasibility of this entire process. Dr. Carolyn Lam: Wow. And what did they find? Dr. Greg Hundley: Right, Carolyn? I mean, this is just so exciting, the practicality of how you implement some of these new strategies that we work on in the lab. So Carolyn, they found that human engineered heart tissue patch transplantation resulted in a partial re-muscularization of the injured heart and improved left ventricular function in a dose dependent manner in a Guinea pig injury model and human scale patches were successfully transplanted in pigs in a proof of principle study. So an exciting new front for engineered cardiac tissue transplantation. I mean, this is a really exciting article. Dr. Carolyn Lam: Wow, well, indeed. Thanks, Greg. Well, other than those wonderful papers in today's issue, we have an exchange of letters between Drs. Morgan and Lopes regarding initial invasive versus conservative management of stable ischemic heart disease patients with a history of heart failure of left ventricular dysfunction and that's insights from the ischemia trial. Tracy Hampton does her wonderful review from the literature and it covers new research published in nature medicine, which indicates the impact of a Mediterranean diet on cardio-metabolic disease risks, which may be affected by an individual's gut microbes and goes all the way to network correcting therapeutic candidate for heart valve disease, which was published in science and even a newly discovered genetic arrhythmia syndrome, which was described in science translational medicine. That's a perspective piece by Dr. Kuwabara on the Japanese national plan for promotion of measures against cerebral vascular and cardiovascular disease. Dr. Greg Hundley: Great, Carolyn. Well, you've heard of mission accomplished. Well, Dr. Brooke has an On My Mind piece entitled mission unaccomplished, the optimal hyper, any hypertensive therapy. And then finally, Dr. Glembotski has a Research Letter entitled optimizing AAV9 for studies of cardiac chamber specific gene regulation. Well, Carolyn, what a great issue and integrating all the wonderful world of basic science in a translational fashion. Now, how about we get on and move toward our feature discussion? Dr. Carolyn Lam: Yep. HDL, here we come. Dr. Greg Hundley: Well, listeners, we are onto our feature discussion today and we're very excited to have with us today, professor Uwe Tietge from Stockholm, Sweden, and our own associate editor Anand Rohatgi from UT Southwestern. Welcome gentlemen. And Uwe, could you describe for us the hypothesis that you wanted to test and tell us a little bit about your study design? Dr. Uwe Tietge Okay. So thank you very much for inviting me and for having the opportunity to discuss this article with you today. So we've been for a long time interested in HDL function, and we have developed an HDL anti-inflammatory see, and we have tested it in some cross-sectional studies. And we have seen in this cross-sectional work, for example, in the acute mi or diabetes, are associated with significant reductions in HDL anti-inflammatory function. So we felt that the next important step would be to study this prospectively in the general population. So this is why we made use of the prevent cohort, which is a prospective general population study with white participants from Groningen, which is a city in the North of the Netherlands. Prevent stands for prevention of menial and stage disease, and prevent has a total number of participants of 8,592. Dr. Uwe Tietge So we first excluded all that had already experienced mi intrusion. And then we took all subjects, was the first cardiovascular disease events during follow up and matched controls for sex, age, smoking, and importantly also for HDL cholesterol levels. And we felt that such a design would allow us to truly identify changes in HDL function, independent of HDL cholesterol levels. So then finally we ended up with 340 match case control pairs. Dr. Greg Hundley: Uwe, sounds like a very interesting hypothesis. So what was your methodology and how did you perform your analysis? And then also describe for us, what did you find? Dr. Uwe Tietge The key method that we used was our essay determining the atrial anti-inflammatory capacity and the main outcome measured was incident cardiovascular disease. And in our case, that was deaths from cardiovascular disease, hospitalization from mi, PDCA, ischemic heart disease, or CABG. We did not have stroke in our study. So with respect to HDL function, we isolate HDL by means of PEG precipitation. And this is an established method that is widely used in larger cohort studies. We then take a primary industry that cells, humans, and we pre incubate them for 30 minutes with the individual engineer preparations. Then the agents removed and TNF alpha is added for another five hours. And after these five hours, we isolate RNA and determine BK1 and mRNA levels by quantitative real time PCR. Then we calculate the results relative to the [inaudible 00:16:09] or without the edit HDL. So when the empties data, we use statistical analysis to determine the perspective association in, based on HDL anti-inflammatory function and the outcome measure incident CVD. Dr. Uwe Tietge So to summarize the main findings of the study. So first of all, the anti inflammatory activity of HDL baselines intrusion in this study was significantly higher in controls than in cases. Next, the HDL anti-inflammatory activity was not correlated with any other CBD related biomarkers. Importantly also know it was HDL cholesterol at 8.1, but also not, for example, with triglycerides, or isolated CRP, and also not with [inaudible 00:16:58] capacity, which is another function metric of HDL. Dr. Uwe Tietge The further finding was that in conditional logistic regression analysis, we found that baseline HDL anti-inflammatory activity was significantly associated with future CV events, even in a fully adjusted model. Then finally, when we were adding this function of HDL to the premium, this form, or when we were replacing anti-inflammatory capacity in the score that improved risk prediction and interestingly adding cholesterol reflux and other HDL function, as said before, resulted in a further improvement. Dr. Uwe Tietge So the general conclusion was that of the HDL functional measures in the case of our actual study, this is the HDL anti-inflammatory activity has the potential to provide clinic information independent of conventional use biomark. Dr. Greg Hundley: Very nice who made. So we always think of HDL is the good cholesterol. And sounds like you're describing a whole nother process by which HDL could be beneficial. Well, Anand turning to you now. I know you see many papers come across your desk. What drew your attention to this particular manuscript and how does this new HDL anti-inflammatory capacity or activity impact the remaining science that we have that focuses on other beneficial effects of HDL? Dr. Anand Rohatgi: Thank you, Greg. And I would like to first start by thanking Dr. Tika to submitting his article to circulation and thinking about us for his studies. I will say when this came across my desk, I became extremely excited as HDL function is an area that is near and dear to my heart as well. And Dr. Tika is an international expert in this area. So we are quite excited. The reason why this really picked our attention at circulation is that this was really the first and large demonstration that this novel marker on anti-inflammatory capacity was linked to the incidents of cardiovascular events, so that it wasn't just the range and people who already had disease, but at baseline, in people who are otherwise healthy, it could predict those who would go on to be at higher risk of atherosclerotic events. So in this case, what we saw was a truly unique and novel cardiovascular marker. Dr. Anand Rohatgi: It was a significant translational study working in effort on the part of Dr. Tika and his research team to be able to do this, and so many participants, this is not an easy undertaking. So to be able to do this and show the results that they were able to show is really remarkable, which is really why it elevated to our interest at circulation. A couple of things in terms of the implications in science are that when they recorded this study, they intriguinly we found that there were really no other stablished risk factors, cholesterol levels, or other markers that are associated with this novel anti-inflammatory capacity, it really wasn't associated with high sensitivity CRP, a global marker of inflammation. And it wasn't associated with the only other HDL function that had been shown to be linked to cardiovascular events, cholesterol influx. Dr. Anand Rohatgi: So really what we have here is a truly novel marker that stands on its own. And it's not confounded by the usual things of obesity or other cardiovascular risk factors, and is clearly imparting different information than a global marker, like CRP. I'll extend that these observations to one or two concepts, when it comes to inflammation, there are a couple of things to think about. One is the timing of the inflammatory cascade. A lot of markers are studied at the time where people are in an acute disease state and pro-inflammatory already, and so that can actually have an effect itself on the markers. In this case, by self-report, the participants did not have any acute illness. And so the relationship we see here between anti-inflammatory capacity and cardiovascular events is presumably in the context of a healthy, low inflammatory state. So I think that's important. The other thing that's important, I think for our audience to know is that the inflammation can have tissue specific effects. Dr. Anand Rohatgi: So when you think of global markers like CRP or interleukin 6, those are flagged systemic levels of inflammation in your body, and they are also predictive. But when it comes to atherosclerosis, we think about specific tissue types, the endothelium, macrophages, dipocytes. And in this case, what this marker represents is specific activity at the level of the endothelium, which is a key player in the atherosclerotic process. So it really gives us new and novel insights into that process. And it highlights the potential to find maybe therapeutic targets that can be more precise in targeting the atherosclerotic process and improving outcomes. So those were some of the main things that we saw that were exciting. Dr. Greg Hundley: Very nice. Uwe, as an international expert. What do you see as the next study that needs to be performed that will perhaps use this new market? Dr. Uwe Tietge I think what we need here first would be validation in another cohort and ideally a cohort that involves different ethnicities because our participants were predominantly white. So in terms of generalization, I think this is the next step that we would need. In terms of making this essay applicable to clinical settings in the daily routine, so to speak, we need to simplify it. And this is another issue that we are currently working on, trying to have an easier essay that gives us quicker readouts and ideally, maybe not using primary industry, but something that is better standardizable. And I mean, when you think about next steps, then also identification of a certain biomarker, comes to mind. So something that would reflect the dimension, the activity component of the age that reflects its functioning. And can be used in daily routine and is applicable. It lies to take all the types of essays. Dr. Greg Hundley: Very good. Anand, do you have anything to add to that? Dr. Anand Rohatgi: Well, I agree completely. I think when you always see a novel marker, you want replication and validation, and I think extending this to other nonwhite cohorts is important. The prevent cohort with 70% men, and also add average out there were probably higher than contemporary populations, at least in the United States. So it'd be nice to see an extension of these observations and cohorts that reflect that diversity. Interestingly, cholesterol wheat blocks the other HDL functions that's been associated with events is not linked through vascular events, it's mostly linked to coronary events. So it would be really interesting to find out how the anti-inflammatory capacity relates to events related to other vascular beds outside of the coronary tree. And then I guess a question that I had for professor Tika is, do you think there might be certain groups of people either by disease or demographic that this might be more powerful formative? Or do you think you would have the same kind of information across the board? Dr. Uwe Tietge Yeah, that's a relevant question of course. When we divided our population by participant level characteristics, we saw that there are sex differences. So the predictive capacity seems to be a bit better in females are significantly better than females, which is in male. And also in participants with lower BMI, with ahigher BMI. And the third parameter was in participants with was lower for this one was higher this month. So yes, I expect that some parameters can play a role here and it would be very wise to explore these connections. Dr. Greg Hundley: Very good. Well listeners, what an excellent discussion. And we want to thank Dr. Uwe Tika and his team from Stockholm, Sweden, and also our associate editor, Dr. Anand Rohatgi for bringing to us this new research regarding this marker of anti-inflammatory capacity involving HDL, that demonstrates an inverse association with cardiovascular events. Dr. Greg Hundley: On behalf of both Carolyn and myself. We want to wish you a great week and we will catch you next week on the run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. 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.  

For this week's Feature Discussion, please join authors Erik Näslund, Mehran Anvari, Editorialist Philip Schauer, and Associate Editor Ian Neeland as they discuss, in a panel forum, the articles: "Association of Metabolic Surgery With Major Adverse Cardiovascular Outcomes in Patients With Previous Myocardial Infarction and Severe Obesity: A Nationwide Cohort Study," "Bariatric Surgery and Cardiovascular Outcomes in Patients With Obesity and Cardiovascular Disease: A Population-Based Retrospective Cohort Study," and accompanying editorial "After 70 Years, Metabolic Surgery has Earned a Cardiovascular Outcome Trial." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary, and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Director of the Pauley Heart Center in Richmond, Virginia with VCU Health. Well, Carolyn, another double feature this week and investigating the world of metabolic, or as we also know, bariatric surgery and the impact of bariatric surgery on cardiovascular outcomes. Dr. Greg Hundley: But before we get to that double feature discussion today, how about we grab a cup of coffee and we jump into some of the other articles in the issue. I'll go first this week, Carolyn. The first article comes from Professor Andreas Schuster from University Medical Center in Göttingen. Carolyn, as you know, right heart catheterization using exercise stress represents a key method for the diagnosis of heart failure with preserved ejection fraction but carries the risk of that invasive procedure. These authors hypothesized that real time cardiovascular magnetic resonance exercise imaging with pathophysiologic data at excellent temporal and spatial resolution may represent a contemporary non-invasive alternative for diagnosing HFpEF. Dr. Carolyn Lam: Wow, Greg, you know how I love talking about HFpEF? I actually managed this paper. Could you just describe what they found? It's so exciting. Dr. Greg Hundley: Yeah, Carolyn. Even the methods are interesting here, where these authors created a situation where you're riding a bicycle and obtaining an MRI scan at the same time. Let's get to the results. The HFpEF stress trial, prospectively recruited 75 patients with echocardiographic signs of diastolic dysfunction and dyspnea on exertion with E to E primes greater than eight, New York Heart Association class greater than or equal to two. To then, undergo echocardiography, right heart catheterization and then this real time pedaling a bicycle CMR exam at rest and during exercise stress. And so what they found Carolyn, the real time CMR allowed a highly accurate identification of HFpEF during physiological exercise and qualifies, perhaps, as a suitable non-invasive diagnostic alternative to the invasive procedures. So Carolyn, I think these results will need to be confirmed in a multicenter prospective approach, but really interesting innovation here, in this particular study. Dr. Carolyn Lam: So Greg, the paper I want to talk about, actually, is the first indicative critical role of cardiac macrophages in pressure overload-induced cardiac fibrosis and dysfunction and reveal macrophage micro RNA-21 as a key molecule for the pro-fibrotic role of cardiac macrophages. Now, this comes from Dr. Engelhardt from Munich, Germany, and colleagues who show that within the myocardium, micro RNA-21 has the strongest expression in cardiac macrophages. Where it is also the single strongest express micro RNA among all micro RNAs. Targeted genetic deletion of micro RNA-21 in macrophages of mice prevented their pro-inflammatory polarization and subsequent pressure overload-induced cardiac fibrosis and dysfunction. Analysis of intercellular communication using cell sequencing identified the cardiac fibroblasts as the primary recipient cell of intercellular signals that emanate from activated cardiac macrophages and that are controlled by micro RNA-21. Dr. Greg Hundley: Oh, Carolyn, really interesting findings. What are the clinical implications? Dr. Carolyn Lam: Ah, glad you asked? What this implies is that interference with the activation of cardiac macrophages represents a promising therapeutic strategy in myocardial remodeling and dysfunction. In fact, synthetic oligonucleotide inhibitors against micro RNA-21 are currently undergoing clinical testing against fibrotic disease. This is really, really fascinating. Dr. Greg Hundley: Well, Carolyn, my next paper also comes from the world of basic science and it's from Dr. Anke Tijsen from Amsterdam University Medical Center, University of Amsterdam. Carolyn, as you know, titin, the largest protein in human, forms the molecular spring that spans half of the sarcomere to provide passive elasticity to cardiomyocytes. Mutations that disrupt the titin transcript are the most frequent cause of hereditary heart failure. These investigators evaluated the role of titin and specifically a class of circular RNAs for regulating splicing of key muscle genes in the heart. Dr. Carolyn Lam: Fascinating. Tell us what do they find. Dr. Greg Hundley: Yeah, Carolyn. In this study, the authors found that the back splice junction formed by circular RNAs creates a unique motif, which binds SRSF10, to enable it to regulate splicing. And furthermore, they show that one of these circular RNAs, cTTN1, distorts both localization of, and splicing of, RBM20. Carolyn, the authors demonstrate with this work that circular RNAs formed from the titin transcript are essential for normal splicing of key muscle genes by enabling splice regulators, RBM20 and SRSF10. This shows that the titin transcript also has regulatory roles besides its well-known signaling and structural function. So, really interesting new work involving titin. Dr. Greg Hundley: Well, Carolyn, as we transitioned to the other articles in the issue, I want to tell you about Dr. Maskoun. He has a cardiovascular case series entitled, A Plumbing and Electrical Problem: An Unusual Cause of Syncope. Dr. Carolyn Lam: I like that title. Well, there's also a perspective fees by Dr. Lindman on unloading the stenotic path to identifying medical therapy for calcific aortic valve disease, talking about its barriers and opportunities. Dr. Carolyn Lam: Tracy Hampton reviews the literature and fascinatingly highlights papers like how DNA base editing treats Hutchinson-Gilford progeria syndrome in mice, how some researchers have identified the protein involved in cardiac repair, which is the ZEB2 protein and more information on mapping early heart formation in the embryonic mouse heart. Dr. Carolyn Lam: We've got a research letter by Dr. Levine. This one is so fascinating. It's about the cardiac effects of repeated weightlessness during extreme duration swimming and how that compares with spaceflight. Is that cool? Dr. Greg Hundley: Yeah. Dr. Carolyn Lam: Anyways, this was just such a power-packed issue. Now, let's just go to our feature discussion. Shall we? I can't wait, Greg. Dr. Greg Hundley: You bet. Dr. Greg Hundley: Well listeners, we have got another exciting feature discussion today on this April 13th issue. We have with us Erik Naslünd from Karolinska Institute in Stockholm, Ari Doumouras from McMaster Institution in Ontario, Canada, Ian Neeland our own associate editor from Cleveland, Ohio, and Phil Schauer from Pennington Biomedical Research Center-LSU. Welcome gentlemen. Let's start with you today, Erik. Could you describe for us, what was the hypothesis that your study wanted to address and what were your study population and design? Dr. Erik Naslünd: Well, what we want to study was if metabolic surgery affects the outcome in patients with previous myocardial infarction. And in Sweden, we are lucky that every Swede has their personal identification number, which is connected to essentially anything that we do, including all healthcare and we then have several registries. One is in a metabolic surgery registry, and then we also have one for cardiovascular disease called SWEDEHEART. What we did was, we went into these registries and we found patients who had undergone metabolic surgery. And then, we went to the SWEDEHEART registry and we looked at those patients who'd had a previous myocardial infarction. And then, we were able to get a match cohort, the same BMI and so on, in the SWEDEHEART registry. We were able to compare these two. We got a cohort then of roughly 500 patients who'd had metabolic surgery without a prior myocardial infarction and 500 who'd had a myocardial infarction. We then, assessed to see what the outcome was. Dr. Greg Hundley: Very nice. And can you describe for us your results? Dr. Erik Naslünd: Yeah, what we found was... Our main outcome measure was in the major adverse cardiovascular event and we found that, that was lower in the group that underwent metabolic surgery. We also then looked at death, which was also lower. We also looked at the risk for new onset of heart failure, which was also reduced. We also then assessed the risk for a major complication of the surgery in the group that had undergone metabolic surgery. We compare that to our surgical registry and we found that that was essentially the same. There was not really difference in terms of outcomes in terms of severe complications after the surgery. Dr. Greg Hundley: Excellent. Now, Ari, you also have a study that is involving bariatric surgery or metabolic surgery. Could you describe for us your hypothesis and your study population and design? Dr. Aristithes Doumouras: Yes. Thanks, Greg. Our hypothesis, first and foremost, was very similar to Erik's that patients who underwent metabolic surgery, who already had a history of heart disease when compared to a group that didn't receive bariatrics or metabolic surgery would decrease the future cardiovascular risk through a MACE outcome. Our secondary hypothesis we had, that was that those with heart failure would actually have a greater effect of metabolic surgery because of the decrease in obesity compared to those without heart failure or patients with ischemic, just ischemic heart disease with no heart failure. Dr. Aristithes Doumouras: The setting of the study was Ontario, Canada, where we have a centralized bariatric surgery network called the Ontario Bariatric Network. Like Erik, in Ontario, we're able to have multiple databases that are connected. They have one unique identifier for each patient. And so we looked at all patients who underwent bariatric surgery in Ontario during a timeframe. To note, we have a very large private system. Most bariatric surgeries, more than 95%, happen in the public system so we're able to track a lot of our bariatric surgery patients and don't lose a lot. We tracked all of our bariatric patients and matched them, on a one-to-one ratio, with very similar patients who also had heart disease and access to cardiology care, access to family physician care and followed them over 10 years. And so the design was a retrospective matched cohort in this way, comparing these two groups. Dr. Greg Hundley: Thank you, Ari. And Ari, what did you find? Dr. Aristithes Doumouras: Once again, like Erik, we found that there was a lower rate of MACE outcomes in the patients who underwent metabolic surgery and the absolute values were actually quite high. The absolute risk difference between the two groups was 8% and actually that went up to almost 19% in patients with heart failure. There was no action causing interaction between ischemic heart disease and heart failure, so they were the same. And the risk was about 40% lower for future MACE events in the surgery group. Dr. Greg Hundley: Wow, a large difference. Ian, as an editorialist for Circulation, the American Heart Association, you see a lot of papers come across your desk, what attracted you to these two manuscripts?   Dr. Ian Neeland: When I first read these excellent papers, I thought that first of all, it was globally diverse. One study was in Europe, the other one in North America. And nevertheless, they showed strikingly similar relative risk reductions in MACE. One of them showed between 40 to 50% and so did the other. That was one really striking thing, was the consistency of a risk reduction despite being globally diverse with different systems in each country. Second of all, the absolute risk reduction was astounding. Assuming you could translate the absolute risk reduction to a clinical trial, to real-world experience, you're looking at a number needed treat between five to 12 for MACE, which is astounding and much greater than many of the evidence-based therapies we have today. The magnitude of the findings were striking and the ability to generalize globally were really interesting. Dr. Greg Hundley: Thank you, Ian. Well listeners, we also have an editorialist that can help us put all of this in context of what we known previously about bariatric surgery or what we are calling metabolic surgery. So we're going to turn to Phil. Phil help us put the results of these two studies in the context of cardiovascular medicine specialists or even family practitioners, internists that are managing patients with cardiovascular disease that happened to be morbidly obese. Dr. Phillip Schauer: Yeah, Greg. Well, these are both outstanding observational studies. And congrats to Erik and Ari and their teams for putting these studies together. Now, what's unique about these studies, is that I think these are the first to actually look at metabolic surgery for secondary prevention. Now, there are nearly 30 studies looking at metabolic surgery as primary prevention. These are all observational. They're not prospective randomized trials, but they all show, nearly all of them, show mortality reduction and MACE event reductions. These two studies are the first to show that metabolic surgery is good for secondary prevention. This is really important because I think, up till now, cardiologists have been very reluctant to refer patients to metabolic surgery. Patients who've already had a heart attack because of the least perceived operative risk and surgeons have been reluctant to operate on these patients. And both Erik and Ari have showed that the perioperative risks were remarkably low for this population, operative mortality way below 1%. Dr. Phillip Schauer: And so within a very short period, within a year or two, the mortality reduction, by far, supersedes any perioperative risk. I think this is really very good news. We now have quite a large amount of observational data in the primary prevention side. These two studies, nearly identical, showing mortality, MACE event reductions, as Ian pointed out, 40 to 50%. That's a lot. That rivals almost anything else out there in terms of mortality reduction, whether it's an SGLT2 inhibitor, a GLP-1, or a statin, I mean, people dance in the street when you see a five and 10% reduction. With surgery, it looks like we're seeing 40 to 50%. So, this is remarkable news but we do have a little more work to do. Perhaps we can talk about that, your next question. Dr. Greg Hundley: What a great lead-in Phil. So listeners, striking results with this surgical intervention for patients with cardiovascular disease that have morbid obesity. Erik, let's start with you, but we'll go through all of our expert panelists here. Erik, what do you think is the next study that needs to be performed in this sort of area of research? Dr. Erik Naslünd: Well, I mean, the obvious answer to that is that we need to do a randomized control trial to verify these results. That's the number one. Number two, I think, we also need to tease out, if we can, which are the most suitable patients. And is there a difference between the most commonly performed metabolic surgery procedures. That's where I would suggest that you need to do next. Dr. Greg Hundley: Ari, how about you? Dr. Aristithes Doumouras: I agree with Erik. I think everyone's going to say the same thing. That I think a randomized trial is the next step when looking at bariatric surgery and the role of secondary prevention-based patients, as these are all observational studies. And they just need to be confirmed. We're starting on a pilot study for this exact randomized trial at our institution and obviously looking for more partners later on, but yeah, that's definitely the next step in the process for sure. Dr. Greg Hundley: Ian, what would you like to add? Dr. Ian Neeland: No, I definitely agree an RCT is needed. I think one that combines both primary and secondary prevention patients is important to try to understand that the difference. One could imagine that secondary patients may actually derive much greater benefit than prime prevention patients given their baseline risk. And if one can show that the operative morbidity, mortality is low in both populations, as both papers showed observationally, then I think there's a lot of benefit there. I also think it's important to try to randomize people to different procedures, to really try to understand is it the gastric sleeve? Is it the bypass? And which one has greater benefit in the setting of a RCT as well as how do the risks and safety outcomes differ between those two in the real-world RCT setting. Dr. Greg Hundley: Very nice. Well, Phil we've heard randomized trials, maybe also, do we need longer follow-up? Dr. Phillip Schauer: Yeah, Greg. In the title of my editorial, and I hope that the listeners actually do read it, is after 70 years, metabolic surgery has earned a prospective randomized trial, and it's true. This field is 70 years old, there's not a single prospective large randomized controlled trial. There are quite a few small studies that were powered for biomarkers, but not hard clinical end points. We need this and it is doable. For example, for coronary artery bypass surgery, there's over a hundred prospective randomized controlled trials. So we definitely need this type of study. It needs to be long follow-up, probably five years or more. As Erik and Ari pointed out, it should have a mixture of primary and secondary prevention. Dr. Phillip Schauer: I'll share with you right now, I'm working with a group in the US. Along with Steve Nissen, a very noted cardiologist, Bob Eckel, who's currently the president of the American Diabetes Association and a number of other experts. David Aterburn, Sonia Thomas, who are working together to try to develop a study. The question is who will fund this? And frankly, we've been talking to various funding organizations. And frankly, we need the help of the cardiology community to help us support this. This information is very important. Dr. Phillip Schauer: If I may say one more thing, it's interesting the entire field of obesity treatment, everybody who has obesity gets treatment to cause weight loss. Yet in 2021, we do not have data that shows that weight loss actually reduces morbidity and mortality. The closest thing we have is a look ahead trial, and it looked at weight loss via a lifestyle intervention. After 10 years, they got 6% weight loss, 6% weight loss is not enough. With metabolic surgery, we can get 25 to 30% weight loss. So we need to do this study, not just to show that metabolic surgery is effective, but to show that weight loss itself could actually reduce morbidity and mortality. And frankly, it's not just cardiovascular. The second most common cause of death in these studies is cancer. And that's the other interesting thing that should be looked at. Hopefully, we can get organizations like NCI to come in and support this initiative. Dr. Greg Hundley: Thank you. Well, listeners, what a wonderful discussion today, really a feature symposium. And we want to thank Erik Naslünd, Dr. Aristithes Doumouras, Ian Neeland and Phil Schauer for their time and expertise and sharing that with us today. Especially on this topic of bariatric, but now maybe more commonly called metabolic surgery, where these two studies have been demonstrating efficacy of these procedures now in patients with cardiovascular disease and even those post myocardial infarction. Dr. Greg Hundley: On behalf of Carolyn and myself, I want to wish you another great week ahead and we will catch you in that next week, on the run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021.  

Interview with Gregg C. Fonarow, MD, and Stephen J. Greene, MD, authors of Comparison of New York Heart Association Class and Patient-Reported Outcomes for Heart Failure With Reduced Ejection Fraction, and Paul A. Heidenreich, MD, MS, author of The Growing Case for Routine Collection of Patient-Reported Outcomes

Interview with Gregg C. Fonarow, MD, and Stephen J. Greene, MD, authors of Comparison of New York Heart Association Class and Patient-Reported Outcomes for Heart Failure With Reduced Ejection Fraction, and Paul A. Heidenreich, MD, MS, author of The Growing Case for Routine Collection of Patient-Reported Outcomes

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Dr Greg Hundley, associate editor for Circulation, from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article, this issue reminds us of the importance of the physical exam in patients with heart failure and reduced ejection fraction involving those that were enrolled in the PARADIGM-HF. Remember a trial of sacubitril/valsartan versus ACE inhibition in those with a reduced ejection fraction? Can't wait to hear more of the discussion of the importance of that physical exam. Carolyn, how about you talk about your first article? Dr Carolyn Lam:                I will because this first paper reports a novel ventricular tachycardia or VT ablation strategy guided by a voltage independent mapping display during sinus rhythm. Dr Greg Hundley:             Well, Carolyn, since many of us don't do VT ablations every day, how about a little background on this one first? Dr Carolyn Lam:                Substrate modification during sinus rhythm is actually the mainstay ablation strategy for scar related VT. With the recent trend being more extensive ablation, aimed to homogenize the entire scar region. These authors are led by Dr Tung from the University of Chicago Medicine Center for Arrhythmia Care, and colleagues. They had hypothesized that a greater understanding of the nature and characteristics of the scar would be most prone to reentry, may actually improve the precision and yield of ablation. Now, they had previously demonstrated that sites critical for reentrant VT localized to regions of activation slowing during sinus rhythm or so-called deceleration zones rather than regions with latest activation. In the current study, they aim to prospectively assess the outcomes of VT ablation guided primarily by targeting these deceleration zones identified by propagational analysis of ventricular activation during sinus rhythm. Dr Greg Hundley:             Interesting. What did they find, Carolyn? Dr Carolyn Lam:                They studied 120 patients with scar related VT who are prospectively enrolled in the U Chicago VT ablation registry between 2016 and 2018, who underwent 144 ablation procedures for scar related VT. They performed high density mapping during baseline rhythm and identified the deceleration zones which all localized to successful termination sites in 95% of cases. The median total radio frequency application duration was 29 minutes to target the deceleration zone, representing ablation of 18% of the low voltage area. At a mean of 12 months, 70% freedom from VT recurrence was achieved with an overall survival rate of 87%. A novel voltage independent high-density mapping display may further identify the functional substrate for VT during sinus rhythm and guide targeted ablation thus obviating the need for extensive radio frequency delivery. Dr Greg Hundley:             Fantastic, Carolyn.                                                 Well, my first paper is from Professor Mark Nicolls from Stanford University. It's entitled Phenotypically Silent Bone Morphogenic Protein Receptor 2 or Bmpr2 mutations, that predispose rats to inflammation induced pulmonary arterial hypertension by enhancing the risk for neointimal transformation. While being the most common inherited risk factor for pulmonary arterial hypertension, Bmpr2 germ line mutations only result in disease in 20% of mutation carriers. A finding that suggest a second hit is required to elicit vascular pathology. Transgenic mouse models of Bmpr2 mutations were developed in this study to better understand the relationship between these phenotypically silent gene mutations and the predisposition to pulmonary arterial hypertension. Dr Carolyn Lam:                Huh. What did they find Greg? Dr Greg Hundley:             In this new two hit model of disease, Bmpr2 mutant rats subjected to pulmonary inflammation, developed severe pulmonary arterial hypertension with vascular remodeling and the pulmonary arterial endothelial cell transformation that occurred did so in three phases. An initial apoptosis phase induced by exogenous LTB4. Second, a proliferative phase relying on P38 mediated noncanonical TGF-beta signaling. And then finally a terminal inflammatory phase in which pulmonary arterial endothelial cells utilized the canonical TGF-beta pathway, expressed mesenchymal markers and produced LTB4, IL6 and NF-kappa beta signaling molecules. The clinical implications include that in phenotypically silent Bmpr2, haploinsufficient individuals, a second hit of pulmonary inflammation may put them at risk for subsequently developing pulmonary arterial hypertension. And this lung inflammation while usually self-limited may cause durable and inflammatory vascular lesions in these genetically susceptible patients. Dr Carolyn Lam:                Wow, that is super interesting. Thanks Greg for that great summary.                                                 Well, my next paper really looks at the temporal trends in survival after pediatric in hospital cardiac arrest in the United States. This is from Dr Holmberg from Beth Israel Deaconess Medical Center and colleagues who performed an observational study of hospitalized pediatric patients who received CPR from January 2000 to December 2018 and were included in the Get With the Guidelines resuscitation registry. Dr Greg Hundley:             Carolyn, what did they find? Dr Carolyn Lam:                They found that survival has improved for pediatric events requiring CPR in the US with a 19% absolute increase in survival for in hospital pulseless cardiac arrests and a 9% absolute increase in survival for non-pulseless events between 2000 and 2018. However, survival from pulseless cardiac arrest appeared to have reached a plateau following 2010. The increase in survival over time is reassuring and perhaps provides some evidence for the progress of quality improvement efforts. However, given the plateau and survival following 2010, there is a continued need for clinical focus and new interventions to improve outcomes of pediatric in hospital cardiac arrests. And Greg, are you now going to tell us what's in the mailbag? Dr Greg Hundley:             Absolutely Carolyn. Professor Wei, from Harvard, provides a new perspective on using the restricted mean survival time difference as an alternative to the proportional hazards model and hazard ratios for analyzing risk in clinical cardiovascular studies. In another article, Eric Peterson from Duke provides a white paper discussing randomized clinical trials versus EMR extracted data to inform new therapies in cardiovascular disease. And he really reviews what are the issues we need to overcome using these EMR strategies? And on my mind piece from Dr Glenn Levine from Baylor, discusses the role of psychological wellbeing as it relates to cardiovascular disease. And then we have a large series of letters in this issue.                                                 First, Otmar Pfister and Kari Nytrøen, each have letters regarding high intensity interval training. Dong-Vu Nguyen, asked for several points of clarification regarding the utility of BNP assessments in syncope and whether other metrics incorporating clinical information could be useful. There's a corresponding response from Christian Müller from the PRICIPLE study with great discourse. And then finally an important research letter from Dr Rodés-Cabau in Quebec, evaluates the left atrial occlude or thrombus occurrence among eight centers in Canada and in this letter provides data that suggests thrombi can occur in those that have implanted left atrial occluders and raises considerations for anticoagulation of these patients. Great set of letters in this issue of the journal. Dr Carolyn Lam:                Absolutely Greg and thanks for sharing that. Let's go onto our feature discussion. Dr Greg Hundley:             You bet.                                                 Welcome everyone to discussion of our featured article and today we have Senthil Selvaraj from University of Pennsylvania and our own Mark Drazner, associate editor at Circulation from the University of Texas Southwestern and we're going to be discussing some very interesting results regarding the physical exam as they've been generated from the PARADIGM heart failure trial. And remember that's a prospective comparison of an Angiotensin Receptor-Neprilysin inhibitor with an angiotensin converting enzyme inhibitor to determine the impact of those two therapies on all-cause mortality and also morbidity in heart failure. Senthil, welcome to this discussion. We're very excited to have the opportunity to discuss your article and I wonder before we get started, could you tell us a little bit about the background and the hypothesis for why you wanted to perform the study and then afterwards tell us a little bit about the study population and the methods. Dr Senthil Selvaraj:          I think the impetus for this study torn out of the fact that we do the clinical exam so often, and I think like many cardiology clinicians in the community, we perform this so often, but we don't know what the actual impact is of performing the clinical exam. What I wanted to understand and the primary motivation was to really understand what the change in the physical exam meant in terms of subsequent prognosis. Does decreasing congestion actually relate to improved cardiovascular outcomes? I think this is an area that is hard to study by randomized controlled trials. In my opinion I think there is not so much equipoise in performing a trial of decongestion versus no decongestion. I think this is sort of one way that we can understand epidemiologic methods, whether lowering congestion improve outcomes.                                                 I had a number of other interesting analysis. I think the first is we've had a number of studies that have evaluated the physical exam, but I think that an updated analysis in a population receiving contemporary management was particularly important, particularly given the fact that the risk rad versus insignificantly in the past couple of decades essentially related to improvements in therapy. The second is we formed the physical exam in conjunction with a number of other additional forensic markers in the use of validated risk scores that to understand those and have utility above and beyond this. For instance, can I just check a natural aside and will that be doing a physical exam. And I think while that's easier, I don't know that that necessarily is the right thing to do. And that was another motivation. Dr Greg Hundley:             What was your overall study design and your study population? Dr Senthil Selvaraj:          The overall study design was to use the PARADIGM-HF cohort. And in our analysis, we did a time updated analysis, which is different than many other analyses previously done. That means that every single point that a patient goes into a clinical trial visit, we updated their physical exam, possible because the study investigators did perform an exam at each of these visits. And so what we did was we used the physical exam and number of signs of congestion as the time bearing covariate and looked at its relationship to outcomes, but also just as importantly why might think decreasing congestion or changing congestion has really stuck out as very important about to want to feel better. And I anything quantifying that relationship while it's intuitive I think is also very important. Dr Greg Hundley:             And just remind us who's in PARADIGM heart failure? Well what was the study population? And just very quickly the randomization arms? Dr Senthil Selvaraj:          PARADIGM-HF was a randomized controlled international multicenter trial of patients with heart failure ejection fraction which has been defined in this study as less than or equal to 40%, near two, three or four symptoms, elevated natriuretic peptides, depending on the trial compared an angiotensin converting enzyme inhibitor and Angiotensin Neprilysin inhibitor to control valsartan. Dr Greg Hundley:             Tell us what were your study results? And how did they pertain to the outcomes that were gathered in PARADIGM-HF? Dr Senthil Selvaraj:          We first divided our cohort based upon the total number of signs and as might imagine increasing congestion was associated with a number of adverse clinical features. We then looked at the association between the number of signs and the efficacy outcomes, which included a primary composite outcome of time to heart failure, hospitalization as well as cardiovascular mortality and then we individually looked at those as well as all-cause mortality. And as we show in our paper, there was really a striking relationship between time updated times of congestion as well as all of the efficacy adjusted for baseline natriuretic peptides which are available in all of our participants in PARADIGM-HF as well as MAGGIC risk score and New York Heart Association class to get at the question of whether improving congestion, where the relationship congestion above and beyond symptoms is still valid.                                                 The other thing that we did is because we only looked at natriuretic peptides at baseline is that we've formed a sub study where we evaluated, since you had natriuretic peptides during follow-up as well at the one month visit and eight month visit and compare the utility of signs of congestion and outcomes and you can still see that there was a significant relationship in this sub analysis. The participants would complete NP data. We further looked at relationship and congestion and quality of life and there is a significant relationship such that for every sign of congestion that you decrease, there is a five-point increase in KCCQ, the quality of life score which some have considered to be a clinically significant increase in times of congestion.                                                 We also looked at the relationship between the treatment arm and reduction of congestion as sacubitril/valsartan was associated with significant reduction in clinical congestion, which has mirrored its impact on natriuretic peptides as well. And finally to understand whether reducing congestion was actually associated with improved outcomes, we entered both the baseline congestion and change of congestion into models that looked at the relationship with outcomes and found that change of congestion was a very strong predictor of outcomes even after baseline congestion, which we interpreted to mean that reduction in congestion was a mutable factor, and that reducing congestion is actually associated with improved outcomes. Dr Greg Hundley:             Signs of congestion on the physical exam, you had JVD, peripheral edema, rales, and then an S3 and so you're adding those up and making a score. And so when one of those particular findings dropped off in terms of score, that's what you're indicating by change in congestion, is that correct? Dr Senthil Selvaraj:          That's really correct. We analyzed this in two methods. The first is a dichotomous presence of a physical exam science. As you said, the presence or absence of JVD, the presence or absence of a DMO rales and an aspirate. The investigators also graded two of those signs of congestion, which included a DMN rale that we formed a complimentary analysis where we created a sign score where we gave partial credits to gradations of the physical exam and we saw very similar outcomes as well. Dr Greg Hundley:             Mark Drazner at UT Southwestern has done a lot looking at the importance of our physical exam and assessing patients with heart failure. Mark, how do you feel the results of this study compare with previously published works? Dr Mark Drazner:             Thanks Greg. First, always a pleasure to join you on this and I do want to congratulate Dr Selvaraj and his team on this outstanding paper to generate considerable enthusiasm among the editorial team and reviewers I'd say. It's a really interesting study for several fold and you've heard a lot of the important methods by Dr Selvaraj already. I would just highlight there've been a number of previous studies that have looked at markers of congestion from physical exam and showed that they had prognostic utility, but a major question that has been addressed to me personally and I think in the field, does that add any independent information beyond just sending BMPR natriuretic peptide level measurement?                                                 And this analysis here as you've heard, one of the big advances was that they were able to adjust for natriuretic peptide levels and showed that the exam or the markers of congestion did add independent prognostic information. I think that's an important step forward, as is bringing the relevance again about the markers of congestion and prognostic utility to patients being receiving the most modern-day therapy including ARNI therapy, which is unparalleled opportunity because of the PARADIGM trial to look at that question. I think those two are really set this paper. I think this is going to be a standard, this is the standard for assessing prognostic utility congestion in heart failure by far in the literature in my opinion. Dr Greg Hundley:             What we're saying is that our following the patients and identifying these physical exam changes during an initiation of ARNI therapy can be really helpful in determining that particular patient's long-term prognosis. Coming back to both of you, maybe first Mark and then we'll come back to Senthil, what do you see is the next study in this field? Both in terms of new therapies in heart failure and the relationship of physical exam and then also perhaps just briefly some thoughts on ARNI therapy. Dr Mark Drazner:             I think this paper highlights the incredible importance of congestion in modern day therapy. And there are a number of other studies that looked at this recently, including there's an analysis of TOPCAT preserved heart failure showing again congestion being linked to adverse outcomes. I think that question is resolved that even in modern day therapy. The next step in my opinion is to understand why clinical congestion, the pathway from clinical congestion to adverse outcomes. What are the links? Can we target those links to try to interrupt that cycle? And what is the most effective way to achieve decongestion? We heard that now ARNI appears to be a mediator of decongestion and we need more work on that I think. I would say looking at the pathway from congestion to adverse outcomes and then what is the optimal way to decongest our patients. Dr Greg Hundley:             Very good. Senthil, do you have anything to add to that? Dr Senthil Selvaraj:          I think that's great. I completely agree with Dr Drazner on this. I think one question would be to understand truly as Dr Drazner said, the optimal way to decongest patients and so for instance, the way that we have traditionally done this is by increasing diuretic. There are a number of experimental and novel ways that we can decongest patients. I think one unanswered question actually is does increasing a diuretic potentially at the expense of activating the renin angiotensin aldosterone access, actually afford benefit if you decongest patients. It's an analysis that I think is ripe and timely and not been adequately addressed. I think that that would be one potential way to go. And the second is, I think as you mentioned in clinical trials, I think clinical congestion may not be an outcome, a pre-specified outcome of course. But I do think that it is an important outcome aside from just looking at decreases in other surrogate markers such as natriuretic peptides. It's easy to perform. It's collected on many investigator visits during these trials and therefore these are ripe analyses. Dr Greg Hundley:             Listeners, we look forward to speaking with you next week and have a great week. Dr Carolyn Lam:                This program is copyright American Heart Association 2019.  

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, associate editor at Circulation and director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, have you ever wondered about instead of coding a stent, coding balloons with paclitaxel? Well, the feature article day is going to look at mortality assessments of paclitaxel-coated balloons in a meta-analysis from the ILLUMENATE clinical program, the three-year outcomes. Do you have a paper you want to start us off? Dr Carolyn Lam:                I sure do. First of all, we know that diabetes impairs atherosclerosis regression following cholesterol lowering in both humans and mice. Now in this process of plaque regression, what's the role of functional high density lipoprotein or HDL, which is typically low in patients with diabetes?                                                 Well, this first paper that I chose looks just at that and it's from Dr Fischer from New York University School of Medicine and colleagues, who aimed to test if raising functional HDL levels in diabetic mice prevents monocytosis, reduces the quantity and inflammation of plaque macrophages and enhances atherosclerosis regression following cholesterol lowering. So to do this, the authors used aortic arches containing plaques, which were developed in LDL receptor null mice, and these were transplanted into either wild type or diabetic wild type or diabetic mice transgenic for human APL lipid protein A1, which have elevated functional HDL. Dr Greg Hundley:             So Carolyn, what did they find in this interesting study? Dr Carolyn Lam:                Well, diabetic wild type mice had impaired atherosclerosis regression, which was normalized by raising HDL levels. The benefit was linked to suppressed hyperglycemia-driven myelopoiesis, monocytosis and neutrophilia. Increased HDL improved cholesterol efflux from bone marrow progenitors, suppressing their proliferation and monocyte neutrophil production capacity. ACL also suppressed the general recruitability monocytes to inflammatory sites and promoted plaque macrophage polarization to the M2 phenotype, which is an atherosclerosis resolving state. There was also a decrease in plaque neutrophil extracellular traps or nets, which are atherogenic and increased by diabetes. So raising apolipoprotein AI and functional levels of HDL promoted multiple favorable changes in the production of monocytes and neutrophils and in the inflammatory environment of atherosclerotic plaques in diabetic mice after cholesterol lowering. And this may represent a novel approach to reduce cardiovascular risk in patients with diabetes. Dr Greg Hundley:             Really interesting, Carolyn. Well, I'm going to talk to you a little bit about a large study in patients with valvular heart disease and it's a contemporary presentation and management study and it's from the Euro Observational Research Program Valvular Heart Disease II, Roman numeral two, survey. And the corresponding author is Professor Bernard Iung from Bichat Hospital. So the VHDII survey was designed by the Euro Observational Research Program of the European Society of Cardiology to analyze actual management of valvular heart disease and compare practice with guidelines.                                                 Now in short, patients with severe and native valvular heart disease or previous valvular intervention were enrolled prospectively across 28 countries over a three-month period in 2017. Indications for intervention were considered concordant if the intervention was performed or scheduled in symptomatic patients corresponding to class one recommendation specified in the 2012 ESC and in the 2014 American Heart Association American College of Cardiology valvular heart disease guidelines. Dr Carolyn Lam:                Wow. So what did they find, Greg? Dr Greg Hundley:             Okay, so there's 7,247 patients. 4,483 were hospitalized, and 2,764 were outpatients, and they were included across 222 centers. The median age was 71 years and 1,917 patients were over the age of 80, and 3,400 were women. Now, aortic stenosis was present in 2,000 plus patients, aortic regurgitation in 279, mitral stenosis and 234, mitral regurgitation in 1,114. And multiple left-sided valvular heart disease was present in 1,297, right-sided valvular heart disease in 143, and 2,028 patients had prior vascular intervention.                                                 So the decision for intervention was concordant with class one recommendations in symptomatic patients with severe single left-sided valvular heart disease in 79.4% of those with AS, 77% with aortic regurgitation, 68.5% for mitral stenosis, and 71% for primary MR. Valvular interventions were performed in 2,150 patients during the survey. Of them, 47.8% of the patients with single left-sided native valvular heart disease were in New York Heart Association class three or four, and transcatheter procedures were performed in 38.7% of the patients with AS and 16.7% of those with MR. Dr Carolyn Lam:                Wow, Greg. So what are the take home messages? That was a lot of numbers. Dr Greg Hundley:             Yep. Lots of data there. And so couple things. First, recommendations for interventions in symptomatic patients with severe valve disease are better applied today in this paper than in the previous European survey conducted in 2001, particularly for those individuals with aortic valve disease. Second, multi-modality imaging is now more frequently used, but stress testing remains underused in asymptomatic patients. And finally, transcatheter therapies are now widely used in patients with stenotic valve disease, and we would expect that, particularly for the use in the elderly. Dr Carolyn Lam:                Great, Greg. So what are the clinical implications? Dr Greg Hundley:             Okay, so Carolyn, first, late referral for intervention shows the need for increasing awareness of valvular heart disease by general practitioners and cardiologists. Second, the high burden of elderly patients highlights the need for multidisciplinary heart team approaches to assess the risk benefit ratios of the different modalities of valvular interventions. And finally, number three, echocardiographic quantification of regurgitation should be more accurate and pay more attention to quantitative measurements. Those are the main take homes from this large registry analysis. Dr Carolyn Lam:                Nice. Thanks, Greg. My next paper is the characterization of the first transgenic mouse model of ARVC 5. Now, that is the most aggressive form of arrhythmogenic right ventricular cardiomyopathy caused by a specific mutation in transmembrane protein 43. So this paper's from co-corresponding authors, Dr Lara-Pezzi from CNIC in Madrid and Dr Garcia-Pavia from Hospital Universitario Porto de Hero in Madrid, and with their colleagues, they generated transgenic mice over expressing transmembrane protein 43 in either it's wild type or that specific mutant form in postnatal cardiomyocytes under the control of alpha-myosin heavy chain promoter.                                                 And they found that these transgenic mice expressing the specific mutant in transmembrane protein 43 showed fibro fatty replacement of the myocardium and died at a young age. The model confirmed that transmembrane protein 43 is mostly localized at the nuclear membrane and provides new information regarding the pathophysiological mechanisms underlying ARVC five. One of them is that the GSK3 beta signaling pathway plays an important role in this disease. Dr Greg Hundley:             So that's great, Carolyn. Sounds like we have a new model that's been created by this group and certainly this disease has spread. It's something we definitely worry about. Do you see any therapeutic implications for their work? Dr Carolyn Lam:                Great question, and indeed the authors tested two new therapeutic approaches for ARVC five. In the first they found that targeting fibrosis really had no beneficial effect. But in the second, they found that inhibition of GSK3 beta improved cardiac function and survival, thus opening the way to a new therapeutic approach focused on GSK3 beta inhibition in patients with ARVC five. Dr Greg Hundley:             Very good. So we look forward to seeing what the results of that study will be. How about now we talk about some of the other articles in this issue? Dr Carolyn Lam:                I love that. I think it's a great idea to tell everybody about this amazing issue. So we start with an article from our Global Rounds, and this time from Argentina, so a great status update and future strategies for cardiovascular disease in Argentina. We also have a perspective paper and that's on the new World Symposium on Pulmonary Hypertension guidelines, really questioning some of the cutoffs that we've taken for granted and asking, "Should 21 be the new 25?" Intrigued? Well, you really need to pick this one up and read it.                                                 And then there's a white paper, and this is a report from the 2018 NHLBI workshop that really talks about unlocking the secrets of mitochondria in the cardiovascular system and asking if this may be a path to cure in heart failure. We also have a research letter, and I love these. They're so succinct and really contain an important message. And this one talks about the evolution of Medicare formulary coverage changes for antithrombotic therapy after the guideline update. So very topical subject. Dr Greg Hundley:             Very good, Carolyn. So I've got a couple. There's a Paths to Discovery article that John Rutherford did discussing with Paul Zimmet regarding reflections of the evolving global diabetes epidemic. Second, there is a very nice On My Mind piece from Samuel Tretheway from Birmingham, England who discusses medical misinformation, kind of like medical fake news. And he discusses how this occurs and it depends on the motivation of both authors and publishers, and he reviews responsibilities of all of us, how to avoid generating this type of material. And then finally, a really interesting Cardiology News piece by Bridget Kuehn, who discusses diet and microbes in heart failure, and with that there's a very nice piece of artistry work that would be great for your office. So that's all included in the journal. Dr Carolyn Lam:                Oh, you got us all curious. Finally, I just want to highlight, we have a section called Highlights from Major Meetings, and this time from my part of the world with Dr Aijun Sun and Dr Junbo Ge summarizing the 13th Oriental Congress of Cardiology takeaways. Cool issue, isn't it? Dr Greg Hundley:             Absolutely. So how about onto our feature discussion? Dr Carolyn Lam:                You bet, Greg. Dr Greg Hundley:             Welcome everyone to our feature discussion. And this afternoon or this morning, wherever you may be, we are going to have an opportunity to discuss the utility of paclitaxel-coated balloons in terms of management of patients with peripheral arterial disease. And our article today comes to us from Bill Gray and colleagues from Mainline Health in Philadelphia, Pennsylvania. And we have our own Josh Beckman, associate editor from Vanderbilt, who will be joining us in the discussion. Bill, welcome to Circulation. We really appreciate you sending us this article. Can you tell us a little bit about the background of why you wanted to perform your study and also, what was your study design, study population? Dr William Gray:               The study was really prompted by a prior report by Katsanos et al in JAHA about nine months ago. When we started this study, it was much more fresh. And what we did was we realized we had data from multiple studies using the Stellarex drug-coated balloon that we could use to address some of the issues raised with the Katsanos paper. Just to review that briefly, the Katsanos paper suggested that there was a significant mortality signal in patients who were randomized to drug-coated balloons using paclitaxel versus PTA or patients randomized to drug eluting stent versus PTA or other stents. That signal was seen late at two years and at five years, and so we sought a given the data, the tightly controlled and well-reported data and this experience to see if we could see a signal as well.                                                 The study design really involved taking all the data from the randomized trials, and there were two, which comprised an aggregate of about 600 patients, unequally randomized, about 400 in the drug-coated balloon arm and about 170 or 200 patients in the PTA arm. And then we also looked at all the poolable data, which was controlled data, so we had two randomized control studies I mentioned just a minute ago, as well as three single arm studies in one registry. Now, these had quality oversight and data reporting. And then those data were adjudicated for adverse events, including death, by a blinded third party CEC, and then those data reported out by Kaplan–Meier estimates as well, and then we do a multi-variable analysis looking at predictors of death, and then I can talk about that in a moment. Importantly, the data here has followed out to three years. As I mentioned before, the original paper which incited the concern had reported unequal deaths at two and five years, so we're somewhere splitting that difference. That's the genesis of the study and the study design. Dr Greg Hundley:             So Bill, tell us now about the results. Dr William Gray:               It turns out the baseline characteristics were largely similar between these trials and the patient arms, even though they weren't strictly speaking the same trials, except that the drug-coated balloon arm was a bit younger and smoked more frequently, so they were at a little bit more risk. In the randomized control analysis, which was done first, there was no difference in all-cause mortality between the PTA patients and the patients who received paclitaxel drug-coated balloons. That was true at one year, two years and three years. When we looked at the pooled analysis, which included not only the drug-coated balloon randomized trial patients, but also all the single arm studies and registries, we also found that there was no differences between those treated with drug-coated balloons in those additional studies and the control group of 170 patients in the randomized trial arm of PTA alone.                                                 Interestingly, when we started to look at the multi-variable analyses, we did something that we ordinarily would not do, but because of the pressing issue around paclitaxel mortality, we actually did a standard covariate analysis looking at predictors and then we forced drug and drug dose into the model to see if they would come up positive as a predictor of outcome. As you might expect, not surprisingly, we found that age, congestive heart failure, diabetes and renal insufficiency were the four major predictors of mortality in a group of patients who were largely claudicates with significant peripheral vascular disease. No surprise there. We all know the patients don't die of claudication, they die of cardiovascular disease, and this I think bears that out.                                                 When we force drug into the model, in point of fact, not a dose nor the presence of drug had any impact on death rates in the model, so there was no predictive value there whatsoever. Those are the results. Again, they're out to three years, and I think one of the important things that we have to recognize is that the numbers are relatively small and the follow-up is relatively limited and by itself, although it doesn't show any signal, it probably doesn't stand on its own to refute a larger meta-analysis, but does I think contribute to the dataset that is becoming more evident that the individual analysis do not appear to show mortality effects. Dr Greg Hundley:             Very good. So this is Dr Josh Beckman at Vanderbilt University. Josh, could you talk to us a little bit and put this paper in perspective relative to the prior published literature in terms of how you manage patients with peripheral arterial disease? Dr Joshua Beckman:        I have to say first, I'm really glad that we're able to publish this paper from Bill Gray and his group. We are, and I'm going to put this in really muted terms, in extraordinary times. I have never seen what is going on now happen with any other technology or really even medical therapy in the 20 plus years I've been a practicing physician. I think for the audience, it's really important to understand what is going on right now because if you don't pay attention to this space, you may not realize what's really been happening. Bill did a nice job at telling you why he did the study, which was this Katsanos aggregate level meta-analysis that was published in JAHA back in December.                                                 On the basis of this paper, there has been a rapid development of worry and concern that these devices may be associated with late mortality. This concern has spread to the Food and Drug Administration, which has now put out three letters to healthcare professionals, each of them basically suggesting that you should choose non drug-coated either balloons or stents first, and if you want to use these, you have to have an extended conversation with the patients discussing the risks. And so in response to this aggregate level meta-analysis, which had an extensive number of lost to follow-up patients and didn't account for crossovers and the usual problems with this kind of information, I have been really impressed by the community of people who are interested in this topic and work with these kinds of devices.                                                 And by that, I mean, the response has not just been a series of editorials. The response has really been, "Let's find every single piece of data that we can find to see whether or not this signal holds up," because as evidence-based physicians, we take one piece of data and say that it is one piece of data, and then we have to put it into the context of all of the other pieces of data that were published. And so I know that Dr Gray is old enough to remember 10 years ago when these devices were being used in the coronary arteries with drug eluting stents. And as far as anybody can tell with studies that were two to three times larger or meta analyses two to three times larger than the study published in December, there was no mortality signal.                                                 It should be made clear that in doses that dwarf the doses from these devices, when these medications are given to pregnant women who have breast cancer, not only is the mother fine but the fetus is fine. And so I think paper that we are discussing this morning in particular, but the group of investigators in the space has really stepped forward to publish as much data as possible to fill out our understanding and place the original study in the correct context. And so when you understand what's happening in the community, and there's been a significant reduction in the use of these devices on the basis of that one publication at the expense of patients for whom these devices are really much better at limb outcomes, then you can understand why we were so interested in the paper by Dr Gray.                                                 This is another brick in creating the foundation to really have a fuller and better understanding of any possible relationship between the use of these devices and a nonspecific increase in mortality two to five years later, which as far as I can tell, I've never seen something that may end up being a poison that doesn't have a specific mechanism of causing morbidity or mortality. And so when we got this paper, I was really happy to be able to work with Bill and bring it to the level that it is now so that when it's published in October, it's going to be another really important contribution and I just want to congratulate the authors for doing that work. I will say, and I'd like to get Bill's perspective on how he thinks the information that's now being published is going to help us understand what to do with these devices. Dr William Gray:               Yeah, that's a great question, and I want to emphasize something you brought up, which I did not, which is at the aggregate level data that Katsanos used to publish his analysis was really all he had access to, which means that he had some numerical data from prior published publications but did not have patient level data. And so what Josh is referring to appropriately is the concept that each individual holder of those data, those patient level data, are now coming forward with their own analysis of those data at a patient level, which allows us to look more granularly and more clearly at the causes of death. For example, in this study, the causes of death did not cluster around cancer. They were largely cardiovascular, and they were not dis-equally distributed or unequally distributed between the two groups.                                                 So I think that patient level data, to get back to your original question, Josh, the patient level data will be incredibly important from each of the experiences with the various drug-coated balloons and drug eluting stents on the market because it does allow us to look more closely at the mechanism of death and whether there's any putative cause that might be assigned to paclitaxel. As you mentioned, the pharmacology of this is not understandable. The only type of pharmacology that would work like this was if paclitaxel was radioactive and accumulated a hazard along the way, but we know that's not true.                                                 I think extend your question, it's important to say that both the FDA and other independent groups like VIVA have looked closely at the meta analytic data both from a patient level and aggregate level data set, and they have seen a signal at five years. The problem with that is that data starts to winnow down very quickly at five years. There's not a lot of numbers, so that's the first problem, and the meta-analysis that have followed the publication by Katsanos. The second problem is, as Josh alluded to, there's a lot of missing data. Either patients withdrew or got lost to follow-up, and that didn't happen at an equal distribution between the control and the active arms, so there's some ascertainment bias there.                                                 And lastly, there's a crossover, that is patients who are in the control arm crossed over near as we can tell at a rate of about one in five or one in four to an active arm in the first year alone, which means they need to be reassigned to a risk pool that includes the original assignment of paclitaxel randomization. My sense is that those data will not get any better in the near-term future because the problems I just listed are not going to go away anytime soon. And so we are left with these individual patient level data and other big data, like Medicare analyses of tens of thousands of patients or Optum insurance analyses of again, tens of thousands of patients, which actually show no difference between the treatment with paclitaxel in the real world and patients treated with non-paclitaxel devices. So while we are comfortable and happy to publish these data and we think that are meaningful in terms of contributing to the larger dataset, we recognize the flaws and the limitations in the meta-analysis, which will not be solved soon or quickly. Dr Joshua Beckman:        So, I totally agree with what you just said. I will also say that every time data like this is published, it adds to the picture to make our understanding clearer. And you are responding directly to the Food and Drug Administration, who basically said they are not settled on this question either. It is noted, they are worried about it, and what they've really asked for is for more data to be published. And so when people analyze data like these, I think it is really helpful to the rest of us to create a fuller and more granular picture of the overall state of the field. Dr Greg Hundley:             We want to thank again both Josh for his time and Bill for his time. Hope you have a great week, and both Carolyn and I look forward to sharing with you again next week. Take care everyone. Dr Carolyn Lam:                This program is copyright American Heart Association 2019.  

Dr Carolyn Lam:                Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your cohosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, associate editor from the Poly Heart Center at VCU health in Richmond, Virginia. Carolyn, oh, this is going to be an exciting featured article today, and we're going to discuss the combination of agents or their administration et al that are best suited for managing both anticoagulation and antiplatelet therapy and those with coronary disease, peripheral arterial disease and heart failure. And, we'll speak with Dr Kelley Branch from the University of Washington. Dr Carolyn Lam:                And me! Dr Greg Hundley:             Yes. How am I going to interview you? And, we'll discuss the utility of Rivaroxaban with or without aspirin in patients with heart failure or peripheral arterial disease from the compass trial. Dr Carolyn Lam:                Well, I'm not going to let you get there until I tell you about this first basic paper I've chosen because it focuses on the unfolded protein response. Dr Greg Hundley:             What's that? Dr Carolyn Lam:                Well, Greg, I was really hoping you'd ask. The unfolded protein response is a cellular adaptive process to cope with protein folding stress. Now, approximately 40% of human proteins are predicted to be either transmembrane or secretory. The synthesis, the folding, the cellular transportation and location of these proteins rely on proper functioning of this secretory pathway. Numerous studies have established that the unfolded protein response plays versatile roles during development and under physiologic and pathophysiologic conditions. However, the role of this unfolded protein response in the regulation of cardiomyocyte growth is unclear. Dr Greg Hundley:             That's fantastic, Carolyn. I've already learned something here. So, what did this paper show? Dr Carolyn Lam:                This is from Dr Wang and colleagues from UT Southwestern, and basically, they use both gain and loss of function approaches to genetically manipulate spliced X-box binding protein one or XBP1, which is the most conserved signaling branch of the unfolded protein response in the heart. In addition, primary cardiomyocyte cultures were employed to address the role of XBP1S in cell growth in a cell autonomous manner. They found that XBP1S expression was reduced in both human and Rhode and cardiac tissues with heart failure deficiency of XBP1S lead to decompensation and exacerbation of heart failure progression under pressure overload. On the other hand, cardiac restricted over expression of XBP1S prevented the development of cardiac dysfunction. Mechanistically, they found that XBP1S stimulated adaptive cardiac growth, your activation of mechanistic target of rapamycin or MTOR signaling which is mediated via the FK-506 binding protein 11, which is a novel transcriptional target of XBP1S. So in conclusion, this study really showed a critical role of the XBP1S FKB or FK-506 binding protein 11 and MTOR axis in coupling the unfolded protein response and cardiac cell growth regulation. Dr Greg Hundley:             Boy Carolyn, you explained that so well, and I learned a lot from that. I hope I can do as well with this next article from Professor Johann Backs from the University of Heidelberg. Now paradoxically, some glucose lowering drugs have been shown to worsen heart failure, raising the question of how glucose mediates protective versus detrimental cardiac signaling, and this study from his group focused on one of the class two histone deacetylases or HDAC's namely HDAC-4, which functions as an important epigenetic regulator by responding to upstream stress signals, and linking them to downstream gene regulatory programs involved in among other things, metabolic regulation. Dr Carolyn Lam:                Very interesting. So what did they find? Dr Greg Hundley:             What they found is that HDAC4 acts as an important maintenance factor of cardiac function in diabetes and O-glycine-N0acetylglucosamine of HDAC4 at searing 642 induces the production of cardio-protective HDAC F-end terminal fragment and attenuates cardio detrimental Cam kinase two mediated phosphorylation of HDAC4 at searing 632. Vice versa, Cam kinase two mediated phosphorylation of HDAC4 at searing 632 attenuates HDAC-4 n terminal production. Thus, these findings lay the ground for the development of novel therapeutic strategies for diabetic patients with heart failure by inhibiting Cam kinase phosphorylation at CIHR 632 or enhancing o-glycine and escalation at searing 642. Dr Carolyn Lam:                Fascinating, Greg. Well, my next paper is a subgroup analysis of EUCLID and is the first to assess acute limb ischemia in the context of a large-scale clinical trial studying a primary peripheral artery disease population. Dr Greg Hundley:             So Carolyn, reminded us what was the EUCLID trial. Dr Carolyn Lam:                Okay, so EUCLID stands for Examining Use of Ticagrelor in Peripheral Artery Disease, and this was a randomized clinical trial that included acute limb ischemia as an adjudicated outcome in a primary peripheral artery disease population randomized to ticagrelor versus clopidogrel. Now in EUCLID ticagrelor was not superior to Clopidogrel for the prevention of cardiovascular events in patients with stable peripheral artery disease. However, a EUCLID subgroup analysis of patients with and without prior limb revascularization demonstrated significantly higher risk for acute limb ischemia hospitalization in patients with prior low extremity revascularization. Dr Greg Hundley:             So Carolyn, that's interesting. So, what did they find related in this study that focused on the acute limb ischemia? Dr Carolyn Lam:                Right. So, today's paper is from Dr Hess and colleagues at University of Colorado School of Medicine and CPC, clinical research in Aurora, Colorado. And, they found that acute limb ischemia occurred in 1.7% of almost 13,900 randomized patients with a median time to hospitalization for acute limb Ischemia of 320 days after randomization. In this population, prior lower extremity revascularization, atrial fibrillation and lower ankle brachial index identified patients at higher risk for acute limb ischemia. Hospitalization for acute limb ischemia was associated with subsequent cardiovascular and limb ischemic events. So, the take home message is providers should monitor for signs and symptoms of acute limb ischemia in patients with stable symptomatic peripheral artery disease, particularly those with prior lower extremity revascularization, atrial fibrillation, and lower ankle brachial index. Dr Greg Hundley:             That's very instructive, Carolyn. Fantastic message. So, I'm going to ask you if you could select one lipid biomarker to forecast future adverse cardiovascular events, which would you select? Total cholesterol, HTLC, non-HTLC, direct and calculated LDLC, APO-A1, or APO-B? Dr Carolyn Lam:                Well, I'm traditional. I would have chosen LDL. Dr Greg Hundley:             Okay. Well, the authors of this study led by Dr Paul Welsh at the University of Glasgow attempted to answer this question by studying participants from the UK Biobank without baseline cardiovascular disease and not taking statins with relevant lipid measurements. They had 346,686 participants. An incident fatal or nonfatal cardiovascular event occurred in 6,200 participants of which 1,656 were fatal, and they occurred over a median time of 8.9 years. So, the associations of non-fasting lipid measurements, total cholesterol, HDLC, non HDLC, direct and calculated LDLC, APO-a1, and APO-B with cardiovascular disease were compared using Cox models, adjusting for classical risk factors and predictive utility was determined by the C-index and net reclassification index. Also, prediction was tested in 68,649 participants taking a statin with or without baseline cardiovascular disease, and that group experienced 3,515 cardiovascular events. Dr Carolyn Lam:                Okay, so drum roll. What did they find? Dr Greg Hundley:             So, measurement of total cholesterol and HDLC in the non-fasted state is sufficient or was sufficient to capture the lipid associated risk in the cardiovascular disease prediction with no meaningful improvement from addition of APO lipoproteins, direct or calculated LDLC. And, similar findings were reproduced in those taking a statin at baseline.                                                 As such, the authors feel like calls for widespread use of APO lipoproteins are not warranted given the negligible difference in risk prediction beyond total cholesterol in HDLC. And, direct LDLC is also not required for risk prediction. Non HDLC is a cheaper or equivalent predictor of risk on and off statins without the requirement of one of us being fasting. This is an excellent article for our listeners to review or download. Dr Carolyn Lam:                Wow, that is so cool. So, from one excellent paper to another excellent paper in our feature discussion. Let's go, shall we? Dr Greg Hundley:             Welcome everyone to discussion of our featured article. We have Dr Kelley Branch from the University of Washington and our own Carolyn Lam, and they're going to be discussing the compass trial. So Kelley, could you tell us a little bit about the rationale for compass as opposed to the previously published commander study? Dr Kelley Branch:              So, in order to understand compass and compare it to commanders, we're going to have to go back a little bit in time here. And recall, you know well over 20 years ago that when we used anticoagulants in coronary artery disease, that was actually shown to be more beneficial than aspirin alone, but because of the excess bleeding risk, warfarin or vitamin K antagonists not used, and aspirin won. Fast forward a number of years, and now we have the non-vitamin K anticoagulants, and the was potentially that we could find the goldilocks, if you will, the good balance of benefit as well as less bleeding maybe used to these new agents. So, the compass trial was really born from an atlas ACS one and Atlas ACS two, which found that a low dose of, in this case, Rivaroxaban 2.5 milligrams VAB as well as five milligrams VAB were shown to be beneficial in patients after acute coronary syndrome.                                                 And then, it was thought what happens if we treat these patients with now chronic coronary disease as well as arterial disease? And from this 27,000 patients, 47,395 patients were tested, and our study very specifically looked at patients with a baseline or a history of heart failure when they answered compass. Compass were shown to be beneficial with specifically the use of aspirin plus Rivaroxaban, 2.5 milligrams BAD. And, our idea was to test this in patients with this baseline or history of heart failure. Now, this is in real contradistinction to what the commander tried to do. And the reason why encompass, we actually excluded patients with severe heart failure. This was defined as a New York Heart Association class three or four or an ejection fraction less than 30%. Now if you looked at patients with commander, these patients had ejection fraction less than 40%. That was a criteria to get in. And of course, these patients had to have a recent hospitalization for heart failure. So, these are very different patient populations. Well, both of them, yes, they did have coronary artery disease, but really very different patient populations. Dr Greg Hundley:             Very good. So Kelley, tell us specifically, what were your treatment group assignments and the doses and the outcomes that you were going to follow, and then lead us into what did you find? What were the outcomes of your study? Dr Kelley Branch:              Sure, so compass was actually developed as a partial three by two factorial. The arm that we're going to be talking about is the rivaroxaban arm. There was also another arm that tested the use of Proton pump inhibitors, and that actually was shown to not be as beneficial as we thought to decreased bleeding. But specifically for rivaroxaban, the baseline was aspirin, and this was on top of guideline based medical therapy. And then patients were randomized to either aspirin alone plus placebo or Rivaroxaban, five milligrams BAD, plus placebo. So, no aspirin at all or aspirin, a hundred milligrams daily, plus Rivaroxaban, 2.5 milligrams BAD. Those were really the three treatments. Patients were going to be followed for about three to four years. That's what we expected to get our 2200 events , an event-driven trial. But, because of the overwhelming benefits at 23 months median follow up, this trial was actually stopped early, so we only had a little over 1300 events at that time.                                                 And with that we saw substantial reduction in major adverse cardiovascular events, about 24% mortality was reduced 18%, and there was a bleeding risk along with this, major bleeding, little different way of actually measuring major bleeding, but that was increased by about 70%, and that was the overall trial results. So, looking at the patients with heart failure, though, there was actually a relatively large proportion of patients, so 5,902 patients, about 22% of patients, actually had either baseline heart failure or had a history of heart failure coming in. Now, this was defined specifically by the PI's. These were not rigorously defined as compared to say commander, but these were patients where the PI said this patient has history or has chronic heart failure. So, with these 5,902 patients, we looked specifically at the outcomes of major adverse cardiovascular events similar to what we saw with compass and that is cardiovascular death, myocardial infarction, or any stroke, that combination. And then, looked at some others exploratory analysis like mortality.                                                 And, what we found is that in patients with heart failure, the baseline rate was substantially higher for a mate's. Not too surprising because this tends to be a higher risk patient population. But, what we found is that the hazard ratio was about 0.68, so pretty similar to what we've seen the 24% relative risk. In this case, this was a 32% relative risk reduction in those patients with heart failure. Now, if we looked at a patients without heart failure, the hazard ratio is 0.79, so fairly similar and the [conference intervals 00:16:33] overlap. No statistical heterogeneity or no difference between those, but what we did see if we looked at the absolute risk reduction, was an absolute risk reduction in heart failure of 2.4% reduction. That means a number needed to treat of about 42. If you look at the absolute risk reduction for those patients without heart failure, that was 0.9 to 1.0 depending on what the rounding was. We took 1.0 so that means the number needed to treat of 103. So, these were slightly different relative risks, but overall, what we saw is that the hazard ratio is very consistent with the overall effect of compass in the same direction.                                                 Interestingly, and actually I think even for me it was surprisingly, we actually looked at the hazard ratios for bleeding, and when we looked at the hazard ratios for bleeding, we fully expected that because it's the higher risk patient population, we actually expected that to go up. What we saw is that the bleeding actually was no difference at all, and if anything in the heart failure population was slightly lower. And, this was fairly surprising to us because we thought that the patients with heart failure, the bleeding would actually trend up because this was a higher risk patient population. So it looks like it's something can be used and really no substantial increase in bleeding. Dr Greg Hundley:             Very good. Well Carolyn, as someone that's managing patients with heart failure, what do you see are the clinical implications of this study? Dr Carolyn Lam:                That is a beautifully simple, direct question but is not as easy to answer as I may have thought. And, that's because the commander trial that Kelley did describe a bit earlier was neutral on its primary outcome. And, the commander trial is what we would traditionally think of as a heart failure trial. And why? Because those were patients that we rigorously define heart failure, including a naturally acid peptide inclusion criteria. And, because we really wanted these to be severe heart failure patients, we recruited them very close to their hospitalization or decompensation event. So, I just want to reiterate what Kelley has already so beautifully described that commander was neutral, whereas this heart failure subset of compass showed very impressive results that were consistent with the very impressive positive results of the overall compass trial.                                                 So, how do we reconcile all of it? Well, first of all, I have to humbly remind myself that this heart failure subset of compass, the entire subset was actually bigger in numbers than the entire of the commander trials. So, this is not a small little subgroup analysis. This is a huge subgroup analysis. And that's why a paper like this, we're so proud to be publishing in circulation.                                                 So, how do I apply it? Well, when I have a compass like patient, which means it's a stable coronary artery disease or peripheral artery disease patient who happens to have some mild heart failure. I think of this patient as a compass patient and I think that the combination of aspirin and low dose Rivaroxaban has been shown to be effective in these patients. So, in such a patient, I continue the aspirin rivaroxaban combination. However, if I have a new patient coming in with decompensated heart failure, a very low ejection fraction and has some coronary artery disease, by the way, I see that as a commander patient, and I just want to make sure that in such a patient I'm not trying to reduce their overall mortality by treating them with a combination of aspirin Rivaroxaban because commander has shown that I don't impact their overall survival with this combination, even though we may still have beneficial effects on their thromboembolic thrombotic events.                                                 Kelley, would you agree? Dr Kelley Branch:              I would completely agree. That was actually born out very, very well by Barry Greenberg who had a really a wonderful sub analysis which he looked at the thrombotic events published in Jama cardiology and really showing that yes, you can affect the thrombotic events, but I mean really what it comes down to is we want to save lives. We want people to be better. There's just an overwhelming risk for these patients with heart failure that is really non thrombotic, primarily. And so, you're really not going to move the needle very much. You may prevent a stroke here, you may prevent some cardiovascular death from a thrombotic problem, but overwhelmingly pump failure, arrhythmia, et cetera. Those are really going to be the drivers for the commander like population. Dr Carolyn Lam:                But Kelley, this comes up a lot when we've chatted, but if you have a compass patient who has heart failure and then gets admitted with heart failure, what would you do then? Dr Kelley Branch:              That's a really interesting question, right? It depends on what the overall goal is. So, if the patient gets admitted for heart failure, now has it decreased ejection fraction sick. So has an MI, now decreased the ejection fraction. What's the end game? Right? Well you know, you may not be affecting mortality in this case because there's now competing events. However, if the goal was to decrease stroke, we've seen that. Still this goal is to decrease MI to some extent than we see that also. So, it would be reasonable to continue in order to prevent those events. But, just knowing full well that there's many other medications which actually do much better for the patients with decreased ejection fraction. And, those would probably be considered first line, but it's reasonable to continue. But, I would never start it. Dr Carolyn Lam:                Kelley, I couldn't agree more. And here I think the, your data showing that the bleeding risk is not significantly increased in this patient matters a lot. So, if I had a patient, a compass patient who was already on the combination and then gets admitted with heart failure, I too, if there's no additional bleeding risk, I would continue the combination as well. Dr Kelley Branch:              Couldn't agree more. Dr Greg Hundley:             Well listeners, this was a fantastic discussion, and we look forward to seeing you next week. Have a great week. Dr Carolyn Lam:                This program is copyright American Heart Association 2019.  

Paul Wang:         Welcome to the monthly podcast On The Beat, for Circulation: Arrhythmia and Electrophysiology. I'm Dr. Paul Wang, editor in chief, with some of the key highlights from this month's issue. In our first paper, Moo-Nyun Jin, Tae-Hoon Kim, and associates examined the 1-year serial changes in cognitive function, with or without atrial fibrillation catheter ablation. They used the Montreal cognitive assessment score in 308 patients undergoing atrial fibrillation ablation, the ablation group and 50 atrial fibrillation patients on medical therapy who met the same indication for atrial fibrillation ablation, the control group at baseline three months and 12 months. Cognitive impairment was defined as a published cutoff score of less than 23 points. Pre-ablation cognitive impairment was a detected in 18.5%. The Montreal cognitive assessment score significantly improved one year after radio frequency ablation. In both the overall ablation group, 24.9 to 26.4 p less than 0.001, and the propensity matched ablation group 25.4 to 26.5, but not in the control group. 25.4 to 24.8 p equals 0.012. Pre-ablation cognitive pyramid odds ratio 13.7, was independently associated with an improvement in one-year post ablation cognitive function. In our next paper, Zian Tseng, James Salazar and associates studied World Health Organization defined sudden cardiac deaths autopsied in the POstmortem Systemic InvesTigation of sudden cardiac death, the POST SCD study to determine whether premortem characteristics could identify autopsy defined sudden arrhythmic death among presumed sudden cardiac deaths. They prospectively identified 615 World Health Organization defined sudden cardiac deaths, of which 144 were witnessed. Autopsy defined sudden arrhythmic death had no extra cardiac or acute heart failure cause of death. Of the 615 presumed sudden critic deaths, 348 or 57% were autopsy defined, sudden arrhythmic deaths. For witness cases, using an emergency medical system model area under the receiver operator curve 0.75, included presenting rhythm of ventricular tech or cardiac fibrillation, pulseless electrical activity, while the comprehensive model, adding medical record data and depression, area under the curve 0.78. If only VTVF witness cases, 48 of those were classified as sudden arrhythmic death. The sensitivity was 0.46, and specificity 0.90. For unwitnessed cases, the emergency medical system model, area under the curve 0.68, included black race, male sex, age, time since last seen normal, while the comprehensive, area into the curve 0.75, added the use of beta blockers, antidepressants, QT prolonging drugs, opiates, illicit drugs and dyslipidemia. If only unwitnessed cases, less than one hour, n equals 59, were classified as sudden arrhythmic deaths, the sensitivities were 0.18, and specificity was 0.95. The authors concluded that models could identify pre-mortem characteristics to better specify autopsy defined sudden arrhythmic deaths, among presumed sudden cardiac arrests. The authors suggest that the World Health Organization definition can be improved by restricting witnessed sudden cardiac deaths to ventricular tachycardia fibrillation or non-pulseless electrical activity rhythms in unwitnessed cases to less than one hour since last normal, at a cost of sensitivity. In our next paper, Rafael Jaimes III and associates performed optical mapping of trends, membrane, voltage and pacing studies on isolated Langendorff-perfused rat hearts to assess the cardiac electrophysiology after mono-2-ethylhexyl phthalate, a phthalate with documented exposure in intensive care patients. The authors found that a 30-minute exposure to mono-2-ethylhexyl phthalate increased the atrioventricular node effector in period 147 milliseconds compared to 170 milliseconds in controls and increased the ventricular effective refractory periods of 117 milliseconds compared to 77.5 milliseconds in controls. Optical mapping revealed prolonged action potential duration at slower pacing cycle lengths. Mono-2-ethylhexyl phthalate exposure also slowed epicardial conduction velocity, 25 centimeters per second compared to 60 centimeters per second in controls. The authors concluded that acute mono-2-ethylhexyl phthalate exposure, at clinically relevant doses, has a significant effect on cardiac electrophysiology in the intact heart. Heightened clinical exposure to plasticized medical products may have cardiac safety implications and lead to cardiac arrhythmias. In our next paper, Stephan Willems and associates report the use of a novel, non-contact imaging and mapping system that uses ultrasound to reconstruct atrial chamber anatomy and measure timing and density of dipolar, ionic activation or charge density across the myocardium to guide ablation of atrial arrhythmias. They conducted a prospective non-randomized study, the UNCOVER AF trial which was conducted at 13 centers across Europe and Canada. In 127 patients with persistent atrial fibrillation who underwent mapping and catheter ablation, acute procedural efficacy of 98% was seen. At 12 months, the single procedure freedom from atrial fibrillation, on or off antiarrhythmic drugs, was 72.5%, with 23% undergoing retreatments following one or two procedures. Freedom from atrial fibrillation was 93.2%. The primary safety outcome was 98% was no device related major adverse events reported. In our next paper, Anne-Floor Quast, Niek Beurskens, and associates describe a novel, completely extracardiac pacing system, with a lead in the anterior mediastinum, outside the pericardium and circulatory system. A total of 166 or 95% out of 174 patients had a viable lead access path through the fourth, fifth, or sixth intercostal space. Access to the targeted implant location using delivery tool was successful in all five cadavers and three humans, without use of fluoroscopy, with an average lead delivery time of 121 seconds. No damage to the lung, pericardium, heart or internal thoracic vessels occurred. Pacing performance in six human subjects showed a voltage threshold of 4.7 volts in a threshold pulse width of 1.8 milliseconds. In our next paper, Yasuhiro Shirai and associates compare the ability to identify ventricular tachycardia isthmuses in ischemic and nonischemic cardiomyopathies. Of 445 patients, 228 with ischemic cardiomyopathy and 217 with nonischemic cardiomyopathy, undergoing VT ablation. Detailed entrainment mapping of at least one tolerated VT was performed in 111 patients, 71 with ischemic cardiomyopathy and 40 with nonischemic cardiomyopathy. Of 89 nonischemic cardiomyopathy VTs, the isthmus could be identified by endocardial entrainment in 55 or 62%, compared to only eight out of 47 or 17% nonischemic cardiomyopathy VTs, p less than 0.01. With combined endocardial and epicardial mapping, the isthmus could be identified in 56 or 63% ischemic cardiomyopathy VTs, and 12 or 26% of nonischemic cardiomyopathy VTs, p less than 0.01, while a similar proportion of patients any critical component, defined as entrance, isthmus or exit, could be identified in 85% of ischemic cardiomyopathy VTs and 79% of nonischemic cardiomyopathy VTs, p equals 0.3. Complete success, no inducible VT at the end of the procedure was 82% versus 65%, p equals 0.04 and a one-year single procedure VT survival, 82% versus 55%, p less than 0.01. Both higher in patients with ischemic cardiomyopathy. The authors concluded that among mappable ischemic cardiomyopathy VTs, critical circuit components can be usually identified on the endocardium. In contrast, among mappable nonischemic cardiomyopathy VTs, although some critical components can be typically identified with the addition of epicardial mapping, the isthmus is less commonly identified, possibly due to midmyocardial location. In our next paper, Miki Yokokawa and associates targeted documented but non-inducible clinical VTs, based on stored, implantable cardioverter defibrillator electrograms. Radio frequency ablation was performed in a consecutive group of 66 postinfarction VTs, in whom clinical VTs were non-inducible during an ablation procedure. In the first 33 patients, the control group, only inducible VTs were targeted. In the second 33 patients, non-inducible clinical VTs were targeted by pace mapping based on stored ICD-electrograms, the ICD electrogram guided ablation group. VT recurred in five patients or 15% in the ICD-electrogram guided approach, and in 13% or 39% in the control group. Freedom from recurrent VT was higher, p equals 0.04, in the ICD-electrogram-guided group, but there was no difference in ventricular fibrillation or total mortality between groups. In our next paper, Albert Feeny and associates examined whether machine learning could predict cardiac resynchronization therapy or CRT response. A training cohort was created from all Johns Hopkins patients and an equal number of randomly sampled Cleveland Clinic patients. All remaining patients comprise the testing cohort. Response was defined as greater than or equal to 10% increase in left ventricular ejection fraction. Machine learning models were developed to predict CRT response using different combinations of classification algorithms in clinical variable sets on the training cohort. 925 patients were included. On the training cohort, the best machine learning model was a naive Bayes classifier using nine variables, QRS morphology, QRS duration, New York Heart Association classification, left ventricular ejection fraction and end-diastolic diameter, sex, ischemic cardiomyopathy, atrial fibrillation, and epicardial LV lead. On the testing cohort, machine learning demonstrated better response prediction than guidelines, area under the curves 0.7 versus 0.65, p equals 0.012, and greater discrimination of event-free survival, concordance index 0.61 versus 0.56, p less than 0.001. The fourth quartile of machine learning model had greatest risk of reaching the composite endpoint, while the first quartile had the least, hazard ratio of 0.34, p less than 0.001. The authors found that machine learning with nine variables incrementally improved prediction of CRT response and survival beyond guidelines, but its performance with not improved by incorporating more variables. In our next paper, Bernhard Kaess, Charlotte Andersson and associates examine the familial clustering of cardiac conduction defects in the Framingham heart study, using multivariable-adjusted logistic regression models to investigate the association of parental AV block, complete bundle branch block, or a pacemaker insertion with occurrence of cardiac conduction abnormalities on offspring. Individuals with at least one effected parent with a conduction defect had at 1.65-fold odds for manifesting AV block, and 1.62-fold odds for developing complete bundle branch block. If at least one parent had any electrocardiographic conduction defect or pacemaker insertion, the offspring had 1.62-fold odds for experiencing any of these conditions. The Danish and nationwide administrative registries of nearly 3 million individuals and about five thousand incident pacemaker implantations, individuals with at least one first degree relative with a history of pacemaker insertion, had a multivariable-adjusted 1.68-fold incident rate ratio of undergoing pacemaker insertion. If the affected relative was less than or equal to 45 years of age, the incident rate ratio was markedly increased to 51.0. In our final paper, a review article, Venkat Nagarajan, Siew Ho Yen, and Sabine Ernst provide a detailed discussion of anatomic landmarks and considerations that will aid in his bundle pacing lead implantation. That's it for this month. We hope that you'll find the journal to be the go to place for everyone interested in the field. See you next time. This program is copyright American Heart Association 2019.  

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, Associate Editor of Circulation from the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam:                Are NOACs, or non-vitamin K antagonist oral anticoagulants, safe and efficacious in patients with extremely high or very low body weight? Very interesting paper and discussion coming right up. Greg, I hear that you've got a couple of papers you'd like to highlight first. Dr Greg Hundley:             You bet, Carolyn. My two papers today both focus on ventricular dysrhythmia. The first one, from Yuki Komatsu from Tsukuba, Japan, researches the efficacy of catheter ablation of refractory ventricular fibrillation storm after myocardial infarction. VF storm attributed to focally triggered VF after MI is recognized as a distinctive, lethal, arrhythmogenic syndrome that differs from scar mediated monomorphic VT.                                                 This study investigated the acute and long-term outcomes of catheter ablation for the treatment of last resort in a large series of consecutive patients with post-MI VF storm refractory to medical therapies. In the study, investigators enrolled 110 patients averaging about sixty-five years in age. Ninety-two were men, and their average ejection fraction was approximately 31%. VF storm occurred in the acute phase of MI, about four and a half days after MI-onset, during the index hospitalization in about 39% of the patients. It was sub-acute (that is greater than 1 week later) in 44% of patients. It was remote (greater than 6 months later) in 17% of patients. And the focal triggers were found to originate from the scar border zone in 80% of the individuals. Dr Carolyn Lam:                And what did the study show? Dr Greg Hundley:             So Carolyn, during in hospital stay after ablation, VF storm subsided in 84% of patients and overall, 27% of in-hospital deaths occurred. The duration from the VF occurrence to the ablation procedure was associated with in-hospital mortality, with a P-value of 0.008. During follow-up after discharge from the hospital, only one patient developed recurrent VF storm. Of note though, 36% of the patients died, with a median survival of 2.2 years. And the long-term mortality was associated with a low EF (less than 30%), New York Heart Association class greater than 3 Heart Failure, a history of atrial fibrillation or chronic kidney disease.                                                 So in summary Carolyn, the results of this study show that in patients with MI presenting with focally-triggered VF storm, catheter ablation of the culprit triggers is life-saving and appears to be associated with short and long-term freedom from recurrent VF storm. The overall mortality for these patients is associated with the severity of their underlying cardiovascular disease, and those associated co-morbidities.                                                 Now my next paper is from one of our associate editors, Sami Viskin from Tel Aviv University. He's looking at a new form of polymorphic VT. Now as we think about polymorphic VT, I always think about the long QT interval syndromes associated with Torsades de Pointes. We have specific management strategies for those long QT syndromes, but Carolyn, there's a second category of polymorphic VT that's not related to QT prolongation. This second category involves patients without structural heart disease, who have genetic disorders like Brugada or patients that may have experienced hypothermia. There is also a third category of individuals with structural heart disease, during acute ST elevation MI.                                                 What Sami has discovered is there's now a fourth category of non-QT prolongation, which includes those with coronary artery disease but without evidence of ischemia. Dr Carolyn Lam:                So how did they show or find this fourth category? Dr Greg Hundley:             Well, this is a longitudinal cohort that he identified, and they basically followed forty-three individuals who developed polymorphic VT within days of an otherwise uncomplicated MI or coronary revascularization procedure. The in-hospital mortality was 17% with these patients with arrhythmic storm and the patients were treated with quinidine invariably survived to hospital discharge, just like the other categories of non-QT prolongation polymorphic VT.                                                 During long term follow-up of five and a half years, 16% of patients discharged without quinidine developed recurrent polymorphic VT and there were no recurrent arrhythmias in those individuals that were receiving quinidine therapy long term.                                                 So Carolyn, although quinidine therapy is usually considered contraindicated in patients with organic heart disease who develop ventricular arrhythmias, this therapy may be life-saving for patients with coronary disease developed arrhythmic storms due to polymorphic VT. Polymorphic VT storms may be a transient phenomenon. It's unclear for how long quinidine should be continued in these responsive patients. Dr Carolyn Lam:                Wow, neat! Well, for my two papers I'm going to start off with a basic paper and, in fact, a quiz for you this time, Greg! So, what do cilia have to do with the heart? All right, you get to ask me, do you remember what cilia are? Dr Greg Hundley:             Aren't cilia on prokaryotes? I mean, I think of bacteria. Dr Carolyn Lam:                All right, let me set us straight. The primary cilium is a cellular organelle and it's formed by a protrusion of the plasma membrane that functions as a signaling platform in eukaryotic cells and is found in many cells including neurons, pre-adipocytes and kidney tubular cells, where they have been reported to be involved in a variety of cellular functions such as proliferation, differentiation, cell cycle regulation as well as mechano-chemical sensing of diverse stimuli.                                                 Now, the importance of these cilia is highlighted by the role in several diseases, known as ciliopathies. Polycystic kidney disease is one such disorder with, by the way, numerous cardiovascular manifestations. Whereas ciliated cells have been described in the developing heart, a role for primary cilia in the adult heart has not been reported. It was therefore the aim of these authors and those co-corresponding authors Dr Hill from UT Southwestern and Dr Lavandero from University of Chile, who aimed to identify cells in the adult heart harboring a primary cilium and to determine whether these primary cilia play a role in disease-related remodeling. Dr Greg Hundley:             Carolyn, this is so interesting. I had no idea about these cilia. So what did they find? Dr Carolyn Lam:                So, in a series of elegant experiments, these authors identified for the first-time primary cilia in mouse, rats, and human hearts, specifically and exclusively in cardiac fibroblasts. Now these ciliated fibroblasts were enriched in areas of myocardial injury. Transforming Growth Factor beta-1 signaling and SMAD3 activation were impaired in fibroblasts that were depleted of the primary cilium. Extra cellular matrix protein levels and contractile function were also impaired. And in vivo depletion of PC1 inactivated fibroblasts after myocardial infarction impaired the remodeling response. Dr Greg Hundley:             So how do we use this clinically, and what does it mean for us? Dr Carolyn Lam:                These findings point to a pivotal role of cilia and PC1 in disease related pathological cardiac remodeling and suggest that some cardiovascular manifestations of autosomal dominant polycystic kidney disease, for example, derive directly from myocardium autonomous abnormalities. The findings also uncover novel fibrosis regulators and raise the prospect that this pathway may emerge as a target with therapeutic relevance. Dr Greg Hundley:             Wow, very interesting! Dr Carolyn Lam:                Thanks! And the next paper is also very interesting, in dilated cardiomyopathy and providing insights in how specific viral function may be involved in the development of dilated cardiomyopathy. Looking at the Group B enteroviruses, which are a common cause of acute myocarditis and can be a precursor of chronic myocarditis and therefore dilated cardiomyopathy leading to heart transplantation. In fact, enterovirus-induced dilated cardiomyopathy represents a third of idiopathic dilated cardiomyopathy cases.                                                 So these authors, led by corresponding author Dr Andreoletti from University of Reims, Champagne-Ardenne and Dr Semler from University of California, performed deep sequencing of viral RNA from cardiac tissue from patients with enterovirus related end stage dilated cardiomyopathy and then trans-factored viral RNA clones, mimicking the viral genomes found in patient tissues into primary human cardiac cells to assess their replication activities and impact on cardiomyocyte function.                                                 They found that the major persistent viral forms are composed of B-type enteroviruses harboring 5' terminal deletion in their genomic RNAs. These viruses alone, or associated with full length populations of helper RNAs, could impair cardiomyocyte function by viral enterovirus proteinase 2A activities in these enterovirus-related dilated cardiomyopathy cases. Dr Greg Hundley:             Very interesting, Carolyn. So what are the clinical implications of this viral infection of the heart? Dr Carolyn Lam:                Well, the findings seem to imply that it would be important for us to develop specific inhibitors of enterovirus proteinase 2A activity that might prevent viral replication and inhibit the shut-off of host cell translation as well as the disruption of dystrophin.                                                 Furthermore, in early diagnosed enterovirus induced dilated cardiomyopathy, the use of such protease inhibitors could potentially decrease and stop the chronic pathological process of dilated cardiomyopathy and therefore reduce the need for heart transplantation in this end-stage. Very interesting, but requires more work.                                                 So, that wraps up our summaries Greg. Shall we move to our feature discussion? Dr Greg Hundley:             Absolutely. Dr Greg Hundley:             Today we have Renato Lopes from Duke University in Durham, North Carolina and Brian Olshansky, Professor Emeritus from Iowa now in clinical practice in Waterloo and Mason City, Iowa. We're going to talk about our non-vitamin K oral antagonists, or NOACs, safe and efficacious in patients in extremely high (greater than 120 kg) or extremely low (less than 60kg) of body weight.                                                 Renato, welcome to our podcast in Circulation on the Run. Can you give us a little overview of your study, why you performed it and what results did you experience? Dr Renato Lopes:              The idea behind this study was to provide more data into the use of NOACs in these extreme body weight patients, where we don't have a lot of information. Some guidelines actually caution against the use of NOACs in patients with extreme body weight because of the lack of data.                                                 We had the opportunity to look at the Aristotle database, which was a large, randomized trial comparing apixaban versus warfarin for patients with atrial fibrillation, over 18 000 patients. We took advantage of this database to try to look at the extreme body weight and how those patients at weight more than 120 kg, more than 140 kg and less than 60 kg, performed in terms of the treatment effect of apixaban versus warfarin. This was the rational, to try to provide more data so people could gain additional confidence in using apixaban in clinical practice in those extreme body weight patients.                                                 What we showed was, in general the treatment effect of apixaban versus warfarin for the efficacy outcomes CHOKE, systemic embolism and all cause death and myocardial infarction was very consistent across the weight spectrum and preserved. Apixaban was superior to warfarin and this was consistent regardless of the weight category. For the low body weight patients less than 60 kg, we also found that apixaban results in terms if efficacy was preserved.                                                 So, going out to the bleeding and safety endpoints, apixaban was safer than warfarin across different spectrums of weight. Surprisingly, in patients less than 60 kg we saw an even greater relative risk reduction in bleeding, in patients treated with apixaban compared to warfarin. The main message was for efficacy, apixaban was better than warfarin - the same results as the Aristotle main trial. For bleeding and safety endpoints, we also saw the same results and consistent results with apixaban- in particular with patients below 60 kg, which is always a concern that people might have in clinical practice. It seems that apixaban was even safer with an even greater treatment effect. Dr Greg Hundley:             Very nice. Can you tell us a little bit about some of the sites where you enrolled patients and did you identify any variation in age, sex or region specific factors? Were there any differences in your findings related to race? Dr Renato Lopes:              That is a very interesting question because we know that these variables play an important role in body weight. We enrolled patients from thirty-nine countries in Aristotle, in over a thousand sites all over the world. Interestingly, I can tell you that the heaviest weight we had in our study was 205 kg, a patient from the United States. The lightest weight that we had was 39 kg, from the Philippines. You lose trading the variation that regions of the world can play out and how patients can perform. We haven't seen any major difference in these analogies. There were prior analogies that look at different BMIs, and we know that the treatment effect might be attenuated depending on race and sex. In this analogy, we did not find any significant difference according to race, region of the world or even sex. Dr Greg Hundley:             Just getting back to your body weight measurement, you mentioned percentage of individuals were above 120 kg and briefly mentioned some were above 140 kg. What percentage of your study cohort was that extra-large size, above 140 kg? Do you think more work needs to be done in that area or do you think the results were sufficient for that very heavy body weight? Dr Renato Lopes:              This is a very important question. If we look at the breakdown, we had about 11% of the entire trial in the low spectrum of weight, less than 60 kg in weight - almost 2000 patients. A good number of patients. In extreme weight more than 120, we have about 980 patients. That was 5.5% of the overall trial. When you look at greater than 140 kg, we had 258 patients, 1.4% of the overall trial population and about 25% of this category greater than 120.                                                 I think as we start getting greater than 140 kg, we had 258 patients. It is not a large number of patients. It is some information and it is good to have some data on these patients. Before that, we had no data on apixaban in this level of weight. What we are seeing is that above 140 kg, the death rate are very low. There is a trend to better bleeding endpoints and better bleeding profile with apixaban, similar to what we have seen in the entire spectrum of weight when we look at weight as a continuous variable. We also saw that trend in patients greater than 140 kg for bleeding. This is reassuring. I don't think we can say it is definitive, it is only 260 patients that we are talking about.                                                 It is reassuring that we now have data in patients more than 140 and up to 205 kg, and we didn't seem to see any major concern or any difference in the curves in terms of the direction of efficacy and safety of apixaban. For the majority of patients it is reassuring and gives us extra confidence that the dose we use in clinical practice five milligrams twice daily should also work in those heavy weight and the heaviest body weight patients. Dr Greg Hundley:             Very good. Brian you've done an excellent editorial and I wonder if you could help us put this study in perspective with what we know about NOACs and managing patients with atrial fibrillation? Dr Brian Olshansky:         It really is a fascinating study. Obesity is as growing problem for us here in the mid-west and probably throughout the world. It effects a variety of things including drug pharmakinetics, volume of distribution, drug clearance etc. So knowing how NOACs work at the extremes of body weight, either the massively obese or the vanishingly frail, it becomes important to understand the safety and efficacy of the use of NOACs in these individuals. There are guidelines that caution us against use of NOACs at extremes of body weight, particularly those patients who are over the 120 kg mark. The one point I would like to make is, at least here in the mid-west, 120 kg is becoming almost the norm. We are having people that are becomingly massively obese and this is really the question then in my mind, is what to do with those patients who are over 140 kg or even way more than that. This gets to points that I would like to make about some the issues we need to consider about this study and where we are with our understanding about the use of NOACs in the extremes of body weight.                                                 One thing to keep in mind is, in this analysis, this was a retrospective group analysis. That is one important point. We don't have prospective data that look at an entire large population, a very frail, a very low body weight population.                                                 Another issue is that weight is not a static measure. We only have assessment at the baseline. Variability in weight or body mass index may be important in terms of its relationship to the development of atrial fibrillation and sequelae. The other issue here to consider is that there are comorbidities that are associated with those who are at the extremes of body weight and there was a significant variation in this study in age composition, sex dominance, the region of enrollment, the presence of comorbidities between the different weight groups that could contribute to results we have seen. Those with low body weight had more comorbidities and a higher mean CHADSVASC score, and had the biggest difference between apixaban and warfarin.                                                 We have quite a bit to learn about how to understand these data, and when we consider the individuals who are over 140 kg, indeed there are concerns about the volume of distribution of a NOAC and its efficacy. We would like to rely on this data. The problem is that the number of individuals that are a part of this retrospective analysis at the very high body weight and very low body weights was a rather small number and so to project from that number, what we should do with all of our patients becomes somewhat of a concern.                                                 Although these are interesting and provocative data, what we really need is to have some well-designed large prospective randomized controlled trials that specifically address those individuals at the extremes of body weight because this is becoming more and more of a problem as time goes on. We are seeing more individuals that are at the extremes of body weight. While I have not specifically noticed a difference in my own clinical practice, what we need is a better understanding about the dosing of and potential risks and benefits of the NOACs for the extremes of body weight. Dr Greg Hundley:             On behalf of Carolyn and myself, we really appreciate you listening. Have a great week. We look forward to seeing you next week. Dr Carolyn Lam                  This program is Copyright American Heart Association 2019.  

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.                                                 Our featured paper this week reports the five-year clinical outcomes and valve durability in the largest available cohort to date of consecutive high-risk patients undergoing transcatheter aortic valve replacement. You must listen up for this discussion, coming right up after these summaries.                                                 The first original paper describes a personalized risk assessment platform that promotes the implementation of precision medicine by helping us with the evaluation of a genomic variant of uncertain significance. A genomic variant of uncertain significance is a rare or novel variant for which disease pathogenicity has not been conclusively demonstrated or excluded and thus cannot be definitively annotated. These variants therefore pose critical challenges to the clinical interpretation and risk assessment. New methods are therefore urgently needed to better characterize their pathogenicity.                                                 Co-first authors, Dr Ma, Zhang, and Itzhaki, corresponding author Dr Wu from Stanford University School of Medicine and colleagues recruited a healthy, asymptomatic individual lacking cardiac disease clinical history and carrying hypertrophic cardiomyopathy associated genetic variant in the sarcomeric gene, MYL3, which has been reported by ClinVar database to be likely pathogenic.                                                 Human-induced pluripotent stem cells or IPSCs were derived from the heterozygous carrier, and their genome was edited using CRISPR/Cas9 genome editing to generate karyo-specific IPSCs. Extensive essays, including measurements of gene expression, sarcomere structure, cell size, contractility, action potentials, and calcium handling were performed on the isogenic IPSC-derived cardiomyocytes, and together, the platform was shown to elucidate both benign and pathogenic hypertrophic cardiomyopathy-functional phenotypes.                                                 Thus, this paper demonstrates for the first time the unique potential of combining IPSC-based disease modeling and CRISPR/Cas9 genome editing technology as a personalized risk assessment platform for determining the pathogenicity of a variant of unknown significance for hypertrophic cardiomyopathy in a patient-specific manner.                                                 Transcatheter aortic valve replacement is increasingly being used for the treatment of severe aortic valve stenosis in patients at intermediate risk for surgical aortic valve replacement. The next paper provides real world data comparing indications and clinical outcomes of patients at intermediate surgical risk undergoing isolated transcatheter vs. surgical aortic valve replacement.                                                 Co-first and corresponding others, Dr Werner and Zahn from Clinical Ludwigshafen in Germany compared clinical characteristics and outcomes of more than 7,600 patients with intermediate surgical risk who underwent isolated transcatheter or conventional surgical aortic valve replacement within the prospective all-comers, German aortic valve registry between 2012 and 2014.                                                 Multi-variable analyses reveal that factors that were associated with performing transcatheter instead of surgical aortic valve replacement included advanced age, coronary artery disease, New York Heart Association class three or four, pulmonary hypertension, prior cardiac decompensation, and elective procedure, arterial occlusive disease, no diabetes mellitus, and a smaller aortic valve area.                                                 Unadjusted in-hospital mortality rates were equal for transcatheter and surgical aortic valve replacement, whereas unadjusted one-year mortality was significantly higher in patients with transcatheter aortic valve replacement. After propensity score matching, the difference in one-year mortality was no longer significant. Thus, this large registry analysis suggests that both transcatheter and surgical aortic valve replacement are reasonable treatment options in a real world population with aortic stenosis and intermediate surgical risk.                                                 The next paper demonstrates a key role of vascular endothelial growth factor receptor 1 in hemorrhagic telangiectasia type 2. Now, this is an inherited genetic disorder where haplo-insufficiency of the activin receptor-like kinase 1 gene, ACVRL1, results in blood vessels that are prone to respond to angiogenic stimuli, leading to the development of telangiectatic lesions that can bleed.                                                 First author, Dr Thalgott, corresponding author, Dr Lebrin from Leiden University Medical Center and colleagues used ACVRL mutant mice and found that vascular endothelial growth factor, or VEGF receptor 1 levels were reduced, causing increased VEGF receptor 2 signaling that promoted sprouting angiogenesis, correcting the abnormal VEGF gradient, by expressing membranal-soluble VEGF receptor 1 in embryonic stem cells or blocking VEGF receptor 2 with antibodies in mutant mice, normalized the phenotype both in vitro and in vivo.                                                 Importantly, VEGF receptor 1 was reduced in the blood and skin blood vessels of patients with hemorrhagic telangiectasia type 2 compared with H match controls, demonstrating an important role of VEGF receptor 1 in these patients and explaining why their blood vessels might respond abnormally to angiogenic signals. These findings support the use of anti-VEGF therapy in hemorrhagic telangiectasia type 2.                                                 The next study suggests that hydroxychloroquine could be repurposed to reduce the risk of rheumatic heart disease following acute rheumatic fever. First author, Dr Kim, corresponding author, Dr Wicks from Walter and Eliza Hall Institute of Medical Research and University of Melbourne and their colleagues analyzed the immune response to group A streptococcus in peripheral blood mononuclear cells from an Australian Aboriginal acute rheumatic fever cohort by a combination of multiplex cytokine array, flow cytometric analysis, and global gene expression analysis by RNA sequencing.                                                 They then tested the widely used immunomodulatory drug, hydroxychloroquine for its effects on this response. They found that group A streptococcus activated persistent IL-1 beta production and selective expansion of a specific group of T helper 1 cells that produce GMCSF. Furthermore, hydroxychloroquine limited the expansion of these group A streptococcus-activated, GMCSF-producing T helper cells in vitro.                                                 Gene transcriptional profiling of peripheral blood mononuclear cells from patients with acute rheumatic fever showed dynamic changes at different stages of disease. Given the safety profile of hydroxychloroquine and its clinical pedigree in treating autoimmune diseases such as rheumatoid arthritis where GMCSF plays a pivotal role, the authors therefore proposed that hydroxychloroquine could be repurposed to reduce the risk of rheumatic heart fever following acute rheumatic fever.                                                 The next paper identifies a new anchoring B genetic variant in unrelated Han Chinese probands with ventricular tachycardia. In this paper from co-first authors, Dr Zhu, Wang and Hu, co-corresponding authors, Dr Hong from Second Affiliated Hospital of Nanjing University, Dr Mohler from Ohio State University Wexner Medical Center and colleagues, the authors identified the first anchoring B variant, Q1283H, localized to the ZU5C region in a proband with recurrent ventricular tachycardia.                                                 Knocking mice with this variant showed an increased susceptibility to arrhythmias associated with abnormal calcium dynamics. The variant was associated with loss of protein phosphatase 2A activity, increased phosphorylation of ryanodine receptor, exaggerated delayed after depolarization-mediated trigger activity, and arrhythmogenesis. Furthermore, the administration of metoprolol or flecainide decreased the incidence of stress-induced ventricular arrhythmias, representing potential therapies for anchoring B variant-associated arrhythmias.                                                 Does variability in metabolic parameters affect health outcomes? First author, Dr Kim, corresponding author, Dr Lee from Seoul Saint Mary's Hospital College of Medicine and Catholic University of Korea and their colleagues used nationally representative data from the Korean National Health Insurance system, consisting of more than 6.7 million people who are free of diabetes, hypertension, or dyslipidemia and who underwent three or more health examinations from 2005 to 2012 and were followed to the end of 2015.                                                 Variability and fasting blood glucose and total cholesterol, systolic blood pressure and body mass index was measured using the coefficient of variation, standard of deviation, variability independent of the mean, and average real variability. They found that a high variability in fasting glucose and cholesterol, systolic blood pressure and body mass index was associated with a higher risk for all-cause mortality, myocardial infarction, and stroke. Variabilities in several metabolic parameters had additive associations with the risk of mortality and cardiovascular outcomes in the general population.                                                 These findings suggest that treatment strategies to reduce fluctuations in metabolic parameters may be considered another goal to prevent adverse health outcomes.                                                 How much exercise over a lifetime is necessary to preserve efficient ventricular arterial coupling? First author Dr Hieda, corresponding author Dr Levine from Texas Health Presbyterian Hospital Dallas and University of Texas Southwestern Medical Center and colleagues studied 102 seniors and grouped them based on their 25 years of exercise training history. The dynamic Starling mechanism was estimated by transfer function gain between beat-by-beat changes in diastolic pulmonary artery pressure and stroke volume index.                                                 They found that there was a graded dose-dependent improvement in ventricular arterial coupling with increasing amounts of lifelong regular exercise in healthy older individuals. Their data suggested that the optimal does of lifelong endurance exercise to preserve ventricular arterial coupling with age appeared to be at least four to five sessions per week. The sufficient lifelong endurance exercise was effective for maintaining the normal dynamic Starling mechanism, left ventricular compliance, and arterial compliance with aging, all of which may lead to favorable effect on cardiovascular stiffness or function.                                                 And that brings us to the end of our summaries this week. Now, for our feature discussion.                                                 Transcatheter aortic valve replacement is taking over the interventional world. It's really rapidly growing, and we're increasingly using it for the treatment of aortic stenosis. It was initially used for inoperable and high-risk patients but now is indicated even in the treatment of intermediate-risk patient, and even low-risk patients are being enrolled into current trials.                                                 So, with TAVR being used for low- and intermediate-risk patients, the longer-term results of this treatment involved your abilities becoming more and more important. Well, gratefully, we have today's feature paper, and it describes the five-year clinical outcomes and valve durability of the FRANCE-2 Registry.                                                 I'm so pleased to have with us the corresponding author, Dr Martine Gilard from University Hospital of Brest in France, we have our editorialist, Dr Anita Asgar from Montreal Heart Institute, and we have our associate editor, Dr Dharam Kumbhani from UT Southwestern.                                                 Martine, congratulations on this largest cohort of high-risk patients and long-term outcomes. Could you please tell us what you found? Dr Martine Gilard:            Yes, and I'll just quote, actually, to have a follow-up of five years. We have 1,200 patients arrive at five years after rotation of TAVI. Each patient was a high-risk patient because it was at the beginning of each treatment, and in this time, it's only the high-risk patient was implanted with TAVI, and actually, we can follow this 1,200 patients, 50% of these patients of these patients have an echography because when we analyze these patients, we have an echography at five years, and the patients who have not echography at five years, the only difference is the age.                                                 It's very old patient. It's very difficult to make this echography on this patient to come back in our center, so it's why there is not all the patient who have an echography at five years.                                                 But our patients who have an echography, we can see that it's a very, very good result at five years. There is always the same area, just after before, of the valve. There is the same gradient. There is not a sign of deterioration.                                                 As you know, we have some guidelines published last year about how we asked to define deterioration of the valve, surgical or TAVI, and if we apply this new recommendation, we saw that in this largest cohort, at five years, there is only 13% of patient who have some sign of deterioration, and of these patients, we never need to make another valve in valve because the deterioration was not so important, and patient leave with this valve like that. There is no necessity to make a new valve in valve, so at five years of this very high-risk patient treated by TAVI, there is no necessity to implant a second valve because the valve deterioration. It's a very, very important message. Dr Carolyn Lam:                Thank you, Martine. Indeed, an important message. And Anita, you wrote a beautiful editorial about it. First, could I ask you to frame the issue? I mean, is there any reason we would expect the durability to be any different from a surgical replacement? Dr Anita Asgar:                  I think that's a great question, Carolyn, and I congratulate again Martine and her team for doing a fantastic job to add some very important results to the clinical literature on TAVI. Five years is relatively early to see structural valve deterioration, so in a sense, it's not surprising, and we would consider this sort of medium-term follow-up rather than really long-term durability, but very reassuring that in a high-risk population of patients, that TAVR performs very well in this population of patients and as mentioned, is very low to the dynamic structural valve deterioration.                                                 One question I have for Martine is, as you mentioned, there was only about 12% that had some evidence of structural valve deterioration hemodynamically, but this didn't result in another procedure, and I wonder if you could explain a little bit about that, whether it's the hemodynamic dynamic value, and yet there's a clinical indication for re-intervention. How do you incorporate the two? Dr Martine Gilard:            It's actually hemodynamic deterioration, there is some form of regurgitation. However, there is no need or clinical indication to make another intervention. So, if you compare this research to the bioprostheses surgical paths, the only one who have, at five years, no need to make a re-intervention appearing rotated, which is a valve, a surgical valve we have a longer bioprostheses surgical path.                                                 So, if we compare this best bioprostheses surgical valve, we have sustained results at five years. At five years, we have no need to make a re-intervention because the deterioration was not so important or as needed for clinical evidence as a need to make a new intervention. Dr Anita Asgar:                  So, there were some increased rates of heart failure in those patients with structural valve deterioration in your paper, and I know that in the paper you did mention that this is not an adjudicated outcome, and there wasn't a VARC definition for heart failure, but what's your interpretation of increasing heart failure events in these patients with structural valve deterioration? Dr Martine Gilard:            We have no real definition about that. We know that there is another registry. We say that there is an increasing of heart failure, and during the follow-up, and the result of this heart failure increase in mortality. There is an increasing of heart failure, but the number of these patients, there is more. So I don't know if this due to because patient is a high-risk patient, or it's because of the TAVI, but it's very difficult actually to have a real explanation about that. Dr Carolyn Lam:                Thanks, Anita and Martin. Dharam, could you share some of the thoughts and the discussions that were going on behind the scenes with the editors when we saw this paper? Dr Dharam Kumbhani:   Professor Gilard, this was a really excellent paper. We really appreciated you sending it to us, and I think for us, the fact that this was a very large cohort, the largest published cohort that has gotten to five years in a TAVR population, in a multicenter study, and having very good follow-up up to five years, with these patients is always this competing hazard that you want to know what the valve is doing at five years from an echocardiographic and hemodynamic perspective, but there's such a high competing hazard of death, just given the population that you're enrolling, and still, you had one of the largest echo follow-ups on these patients, so we want to congratulate you on the study and really a monumental endeavor, and so really great, great work there.                                                 And I think this is, exactly some of the questions that I think we had and I'm sure that the audience would have as well, I guess the one other question I have, and it's not really a question about your paper. So the median Euro score is 21 in this study, approximately 21, so that's obviously gonna, consistent with the patients that are being enrolled at that time between 2007 and 2012, which were predominantly high-risk and inoperable patients. Can you talk to us a little bit about the landscape of, how is TAVR practice in France as a society or from the regulatory standpoint, what are the benchmarks that you have achieve as you move towards low-risk now? Because intermediate-risk, I'm assuming is a [inaudible 00:20:16], so could you talk to us a little bit about the landscape there? Dr Martine Gilard:            Yes. In France, it's difficult because we have the authority to follow, not immediately, the ESC recommendations, so actually in France, we are allowed to implant only patients with high risk, patients with complication of surgery, and actually just since one year, patients with automatic risk, but we have no authorization to implant patient with low risk.                                                 However, the most important fact is the heart team, and if they write. Because we need to have something written, and if they write, if they explain that it's necessary to implant a patient at low risk because of some point while not including the risk score or it's very difficult to explain, for example, frailty or something, we can implant a patient with low risk.                                                 But normally actually, it is only for complication or high risk and for intermediate risk like the recommendation of the ESC.                                                 So the rate of implantation in France increased because we implant only 2,000 people per year, but actually, in 2017, we have implanted 10,200 patient, and this year, we think that we implant 12,800 patients, so as the number of patients increase, the number of patients who have a very high risk decrease because there is a futile indication, and we have a lot of futile indication, so we doesn't implant patient while too high-risk, and we select the most majority of patient implanted in France was high-risk but also intermediate-risk. Dr Dharam Kumbhani:   So, you think you're implanting more intermediate, like that is a bigger population that is getting TAVIs right now in France? Dr Martine Gilard:            Yes, exactly. Dr Carolyn Lam:                How about perspectives from Montreal? What do you think the implications of this findings from today's paper in relation to the types of patients that you might perform this in now? Dr Anita Asgar:                  For us, this is exceptionally reassuring, and as Martine has said, I mean, we have transitioned as well away from that very inoperable cohort C type of patient to more your higher-risk patient or intermediate, and to be honest, everyone over the age of 80 in Canada essentially is getting a TAVR. Dr Carolyn Lam:                Oh, wow. Dr Anita Asgar:                  Because regardless of their risk, and we've been very aggressive with that because trying to get patients back to an appropriate quality of life is very important, and to seeing this very reassuring data is telling us that, as she has already mentioned, we have reached the standard, at least in midterm follow-up as the gold standard of surgical valve replacement, and so structural valve deterioration is not as big a concern.                                                 I think we still however need longer-term data when we're looking at lower-risk patients, and lower-risk patients, let's remember, are not 60-year-olds. They're the 75-year-old, perhaps. But we're still gonna need some more data, but it's very reassuring, and patients are asking for it and are really advocating on their behalf to have a less invasive approach, and I think we can say now with more certainty that we know after five years, your chance of structural valve deterioration is actually quite low, and so I think that's very helpful from our point of view. Dr Carolyn Lam:                I love that, Anita, and it's so consistent with the title of your editorial, "Closing in on the Finish Line". Love it, love it, and recommend all listeners pick it up and have a good read. Dharam, I want to leave the last words to you. What do you think are the implications of this paper? Dr Dharam Kumbhani:   Well, I think that, as Anita said, this is very encouraging results that, in this kind of extreme and high-risk patient cohort, that there appear to be no medium- to long-term signals of structural valve degeneration, that the biggest hazard from this procedure is all upfront, and after that, it's pretty much, it's as we have seen with surgery, that after that, the actuarial rates come back to what you would expect.                                                 If they didn't have aortic stenosis and then they would die from whatever causes they had. Now obviously, that wasn't tested, but it seems like looking at the curves, that that seems like what's going on, so I think they've done a great service to our TAVR community in terms of showing us these results in very large, multicenter cohorts from France. Dr Carolyn Lam:                Thank you so much for joining us today. Thank you, listeners. You've been listening to Circulation on the Run. Don't forget to tune in again next week.                                                 This program is copyright American Heart Association, 2018.  

Dr Paul Wang:                   Welcome to the monthly podcast On The Beat, where Circulation: Arrhythmia and Electrophysiology. I'm Doctor Paul Wang, editor in chief, with some of the key highlights from this month's issue.                                                 In our first paper, Parikshit Sharma and associates reported on the use of permanent his bundle pacing to improve hemodynamics in 39 patients with right bundle branch block. His bundle pacing was successfully performed in 37, or 95 percent of the patients, and resulted in narrowing of the QRS complex from 158 milliseconds to 127 milliseconds. P = 0.0001. An increase in left ventricular ejection fraction from 31 percent to 39 percent. P = 0.004, an improvement in the New York Heart Association functional class from 2.8 to 2.0 P = 0.0001. This work suggests that his bundle pacing maybe helpful in right bundle branch block patients with left ventricular dysfunction.                                                 In our next paper, Philippe Debruyne and associates added to our understanding of using catheter ablation to modulate the autonomic nervous system in patients with neurally mediated syncope, signs of no dysfunction and functional AV block. Prior reports of autonomic modulation using catheter ablation have required extensive ablation in both atria. In this article, the authors report a significant 95% reduction in syncope at six months as a result of targeted ablation in the right atrium alone, focusing on partial ablation of the interior right ganglionated plexus. Ablation is quite limited, taking a mean of seven minutes and creating a mean surface area of 11 millimeters squared. This technique has promise as a possible treatment for avoiding a need of pacemaker implantation in some patients.                                                 In our next paper, Shankar Baskar and associates examined the characteristics and outcomes of pediatric patients receiving implantable cardioverter defibrillators and compared them to their adult counterparts. They examined ICD recipients in the NCDRICD registry from 2010 to 2016. There were 562,209 total ICD implants, including 3461 pediatric patients. Of the pediatric patients, 60 percent of implants were for primary prevention with non-ischemic cardiomyopathy being present in 60 percent of the patients, the most common underlying disease. Over time, there is an increasing trend of both primary and secondary prevention ICD implantations, P less than 0.05. Compared to adults, pediatric patients were likely to have structural heart disease, hypertrophic cardiomyopathy, ion channelopathy, and to receive a single chamber device. All P less than 0.001. There is no difference in in-hospital complications between the adult and the pediatric cohorts, 2.4 percent versus 2.6 percent. However, among pediatric patients, lower weight, Ebstein's anomaly, worse New York Heart Association class dual chamber and resynchronization defibrillator were associated with greater risk of complications. Although, re-intervention for generator replacement or upgrade was more common in adults, the time to re-intervention was shorter in the pediatric cohort.                                                 In our next paper, Ahmed Hussein and associates examine the effect of using ablation index guiding ablation in 40 patients with persistent HO fibrillation on the rate of pulmonary vein reconnection. Pulmonary vein reconnection was seen as a mandatory repeat electro-physiologic study in 22 percent of patients, effecting seven percent of pulmonary veins. Ablation on the intravenous cryna was required in 44 percent of patients to achieve durable pulmonary vein isolation. Atrial tachyarrhythmia occurrence was documented in eight to 20 percent of patients, only one of whom had pulmonary vein reconnection at repeat study. At 12 months, 30 out of 40, or 95 percent of patients, were in sinus rhythm, with four or 10 percent of patients having starting antiarrhythmic drugs. Higher body mass index and excessive alcohol consumption were the only significant factors associated with atrial tachyarrhythmia occurrence.                                                 In our next paper, Atsushi Hirayama and associates examined whether acute exasperation of chronic obstructive pulmonary disease increases the risk of repeated atrial fibrillation related health care utilization. They examine 944 patients who are hospitalized for acute exasperation of chronic obstructive pulmonary disease and had emergency department visit or hospitalization for atrial fibrillation during a 450 day period. Compared to the reference period, the rate of atrial fibrillation related emergency department visits or hospitalizations significantly increased in the first 90 days after acute exasperation of chronic obstructive pulmonary disease. 7.3 versus 14.1 per one hundred person months, resulting in a risk ratio of 1.93.                                                 In our next paper, Namsik Yoon and associates examined the mechanisms underlying the electrocardiographic and arrhythmic manifestation of experimental models of early repolarization syndrome and the ameliorative effects of radio-frequency ablation. The authors recorded axis potentials, bi-polar electrograms, and transmural pseudo electrocardiograms for coronary perfused canine left ventricular wedge preparations in 11 animals.                                                 The ITO agonist, NS5806, the calcium channel blocker Verapamil and acetylcholine were used to pharmacologically mimic the effects of genetic defects associated with early repolarization syndrome. The provocative agents induce prominent j waves in the ECG secondary to the accentuation of the action potential notch in the epicardium but not the endocardium. Bipolar recordings displayed low voltage fractionated potential in the epicardium due to temporal and spatial variability and appearance of the action potential dome conceal the phase two reentry develop when the axon potential dome was lost at some epicardial sites but not others. Appearing in the bipolar electrogram, is discrete high frequency spikes. Successful propagation of the concealed phase two reentered beat precipitated ventricular tachycardia or ventricular fibrillation. Radiofrequency ablation of epicardium destroyed the cell displaying abnormal repolarization and thus suppressed the j waves and the development of ventricular tachycardia and ventricular fibrillation in six out of six preparations.                                                 Stavros Stavrakis and associates described ten patients out of 843 patients, or 1.2 percent with AV nodal reentry tachycardia who required ablation of the basal inferolateral left atria, during stable antegrade slow, retrograde fast, AV nodal reentry tachycardia, a single late atrial extra stimulus was delivered at the inferolateral left atria, near the mitral annulus. All patients had failed ablation in the inferior triangle of Koch, and or roof of the coronary sinus. In all ten patients, a late atrial extra stimulus advanced the his bundle potential by at least ten milliseconds and reset the tachycardia. Ablation at that site, eliminates slow pathway conduction and terminated the tachycardia. Ablation was successful at the site of the latest atrial extra stimulus delivered 49 milliseconds after the onset of this his bundle potential. In their series, no recurrent tachycardia was noted at one year follow up.                                                 In our final paper, Justine Bhar-Amato and Malcolm Finlay and associates examine the hypothesis that increased cholinergic tone exerts its pro-rhythmic effects in Brugada Syndrome through increasing dispersion of transmural repolarization in patients with spontaneous and drug induced Brugada Syndrome. Using a recording array in the right ventricular outflow tract and a micro-catheter in the great cardiac vein to record intracardial and epicardial signals, the authors constructed S1S2 restitution curves from the right ventricular apex at baseline and after edrophonium challenge.                                                 The authors studied eight Brugada Syndrome patients and compared them to eight control patients with super ventricular tachycardia. Electrophysiological studies in controls demonstrated shorter endocardial than epicardial right ventricular activation times, mean difference 26 milliseconds. In contrast, Brugada Syndrome patients showed longer endocardial than epicardial activation times, mean difference -15 milliseconds. Brugada Syndrome patients significantly larger transmural gradient in their activation recovery intervals, mean intervals 20.5 versus 3.5 milliseconds, with longer endocardial than epicardial activation recovery intervals. Edrophonium challenge increased the gradients in both controls to a mean of 16 milliseconds. In Brugada Syndrome, to 29.7 milliseconds. However, these changes were attributed to epicardial activation recovery, interval prolongation in control patients. In endocardial activation recovery interval prolongation in Brugada Syndrome patients. Dynamic changes in repolarization gradients were also observed across the right ventricular wall in Brugada Syndrome patients.                                                 That's it for this month. We hope that you'll find the journal to be the go to place for everyone interest in the field. See you next time.  

Dr Carolyn Lam:                Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Our featured discussion today centers on the challenges of cardiovascular disease risk evaluation in people living with HIV infection, an important discussion coming right up after these summaries.                                                 The first original paper this week provides experimental evidence that nicotinamide riboside could be a useful metabolic therapy for heart failure. First author Dr. Diguet, corresponding author Dr. Mericskay, from University Paris-Sud investigated the nicotinamide adenine dinucleotide or NAD homeostasis pathways in the failing heart. They found that an expression shift occurs in both murine and human failing hearts in which the nicotinamide riboside kinase two enzyme, which uses the nucleoside nicotinamide riboside was strongly up-regulated for NAD synthesis.                                                 Nicotinamide riboside supplemented diet administered to murine models of dilated cardiomyopathy or pressure overloaded induced heart failure restored the myocardial NAD levels and preserved cardiac function. Nicotinamide riboside increased glycolysis as well as citrate and Acetyl-CoA's metabolism in these cardiomyocytes. Thus, nicotinamide riboside supplemented diet may be helpful in patients suffering from heart failure and may help them to cope with the limited myocardial ATP supply by restoring NAD coenzyme levels and its associated signaling.                                                 In the single ventricle reconstruction trial, one year transplant-free survival was better for the Norwood procedure with the right ventricle to pulmonary artery shunt compared with the modified Blalock‒Taussig shunt in patients with hypoplastic left heart and related syndromes. In the paper in this week's journal, authors compare transplant-free survival and other outcomes between these groups at six years. First and corresponding author Dr. Newburger from Children's Hospital Boston and her group showed that the right ventricular pulmonary artery shunt group had similar transplant-free survival at six years, but required more catheter interventions before the Fontan procedure.                                                 Right ventricular ejection fraction, New York Heart Association class and complications did not differ by shunt time. Cumulative incidences of morbidities by six years included 20% with a thrombotic event, 15% with a seizure, and 7.5% with a stroke. These data therefore emphasize the importance of continued follow-up of the cohort, and the need to find new strategies to improve the long-term outlook for those with single ventricle anomalies.                                                 The next paper presents results of the CREATIVE trial, which stands for Clopidogrel Response Evaluation and Anti-Platelet Intervention in High Thrombotic Risk PCI Patients). First and corresponding author Dr. Tang from Fuwai Hospital National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College conducted a head-to-head comparison of the safety and effectiveness of intensified anti-platelet therapies either a double dose clopidogrel or adjunctive cilostazol and conventional strategy in 1078 post-PCI patients at high thrombotic risk as identified thromboelastography, which is a platelet function test.                                                 The primary outcome was the incidence of major adverse cardiac and cerebral vascular events at 18 months post-PCI they find as a composite of all cause death, myocardial infarction, target vessel revascularization, or stroke. The authors found that the primary end point occurred in 14.4% of those in the conventional strategy. 10.6% in those given double dose clopidogrel alone. And 8.5% in those also given adjunctive cilostazol. Now, although both intensified anti-platelet strategies achieved increased platelet inhibition, only the triple strategy with adjunctive use of cilostazol significantly reduced adverse events in the long-term follow-up.                                                 No increased rates of major bleeding was found with the intensified anti-platelet therapy regimes. Thus, in patients with low responsiveness to clopidogrel as measured by thromboelastography, the intensified anti-platelet strategies with adjunctive use of cilostazol significantly improved the clinical outcomes without increasing the risk of major bleeding.                                                 The final original paper sheds light on the prevalence and predictors of cholesterol screening awareness and statin treatment among American adults with familial hypercholesterolemia or other forms of severe dyslipidemia. First and corresponding author Dr. Bucholz from Boston's Children's Hospital and their colleagues used data from the National Health and Nutritional Examination Survey, and showed a high prevalence of screening and awareness above 80%. However, there were relatively low rates of statin use among individuals with familial hypercholesterolemia at 52.3%.                                                 And even lower rates among those with severe dyslipidemia at 37.6%. The discrepancy between the prevalence of cholesterol screening and treatment was most pronounced in younger patients, uninsured patients, and patients without a usual source of healthcare. This study highlights an imperative to improve the frequency of cholesterol screening and statin prescription rates to better identify and treat this high risk population. Additional studies are needed to better understand how to close these gaps in screening and treatment.                                                 And that brings us to the end of our summaries. Now for our feature discussion. The natural history of infection with HIV has completely changed with the use of potent antiretroviral therapies. We now know that people living with HIV actually have morbidity and mortality patterns that really resemble the general population, especially with regards to cardiovascular disease, which is very prominent in this population. And I suppose it's this that has led to the assumption perhaps that risk prediction tools and intervention strategies that we apply in the general population may be used in patients living with HIV.                                                 Is this the case however? Well, this week's feature discussion is going to be so enlightening. And it's so important we are talking across the world here, from South Africa to the United States, and of course with me here in Singapore. I am so pleased to have the authors of this week's feature paper and they are none other than Dr. Virginia Triant from Massachusetts General Hospital, Dr. Ralph D'Agostino from Boston University. And our associate editor, Dr. Bongani Mayosi from University of Cape Town. Thank you so much for joining me for today's exciting discussion. Virginia, could I ask you to first describe your study? Dr Virginia Triant:             As you mentioned in the introduction, we have found that patients infected with HIV have an increased risk of cardiovascular disease. That includes both myocardial infarction and stroke compared to age-matched controls in the general population. And extensive data has suggested that the etiology of this increased risk is related both to traditional cardiovascular risk factors, as well as novel risk factors that are specific to HIV infection. And these include chronic inflammation in the immune activation. So consequently, it remains relatively unknown whether established cardiovascular risk prediction functions are accurate for patients with HIV because they include only risk factors that are traditional factors and they don't reflect the complete mechanism that we know is at play in cardiovascular disease associated with HIV.                                                 So in our study, we assess the performance of three established cardiovascular risk prediction functions, two Framingham functions, and then the ACC/AHA pooled cohort's equations and we applied this to a longitudinal HIV infected cohort that was comprised of men. And we investigated the performance of the risk scores in terms of comparing regression coefficients, discrimination and calibration, which are standard metrics in cardiovascular risk prediction. So I'll briefly summarize our overall results as a start. We found that overall, the risk prediction functions underestimated risk in our group of HIV-infected men.                                                 We found that discrimination was modest to poor, and this was indicated by low c-statistics for all of the equations. And we also found that the calibration or the agreement between observed or predicted risk was also poor across the board for all three risk prediction functions. So our results suggests that simply taking the risk prediction functions and transporting them to an HIV infected group may actually result in mis-classification in terms of patient risk. And in underestimation of cardiovascular risk. Dr Carolyn Lam:                Well, Virginia, beautifully summarized of a beautiful paper. But perhaps at this point, we should take a step back and ask ourselves how exactly were these risk prediction scores originally developed. And I can't imagine asking a better person than Ralph. Ralph, could you take us on a jaunt along history and tell us how were those Framingham risk scores developed in the first place? Who are they supposed to be applied to? And did these results surprise you? Dr Ralph D'Agostino:      After the second World War, what was becoming quite clear is things like cardiovascular disease were becoming very prominent. Things like infections and what have you, we were developing all sorts of ways of handling them with medicines and so forth. But with cardiovascular disease, it's a thing that progresses slowly over the years and it starts wiping out people. And back in those days, one out of three men between the ages of 30 and 60 had some kind of cardiovascular event. Women weren't that bad off, but they were pretty bad off also. And so what happened is the American government and the American Heart Institute set up this study in Framingham, where they took a third of the individuals between the ages of 30 and 60 and actually followed them. They took values of variables like blood pressure, cholesterol, things they thought might be useful.                                                 And took values on them. And they had to come back every two years and after as time went on, they took the data after six years, after 10 years they took the data, and started to look at how each individual's blood pressure related to cardiovascular disease. Does cholesterol, and the answer was yes. And then I started getting involved and we were developing these cardiovascular functions where you could actually take an individual, take their measurements now, and make a prediction that had a lot of validity, good discrimination, high predictability over what was going to happen in ten incidents and then the government, the US Government, started having guidelines and what we did is we ran a study where we took a number of different studies in the US, different cardiac studies, the ARIC studies, number of 'em, and we thought applying our functions how well would they do. And it turned out that for whites in the country, the Framingham functions did very well.                                                 But Japanese-Americans in the country, it over-predicted. Then we found out that you could make a calibration adjustment and what we've gone to, like in China, we have a big study where we had a function and Framingham function it over-predicted but calibration adjustment would make enough corrections and so now with Jeanne and the HIV, our hope was that you could take these functions and see how they work on the HIV population. When we did it we were quite well aware, because people have been looking at different things, there's something beyond the original cardiovascular risk. And what the paper shows, quite nicely, these cardiovascular risks do have some relationship but they don't explain enough. The HIV population have a much bigger burden and a simple calibration adjustment just isn't going to work. We need new variables, we need new insights on what to add to these functions. Dr Carolyn Lam:                Thank you so much for that. That's just such important part of history because I have to thank you for those equations. We apply those definitely in our Asian cohorts with that calibration factor. But I was just reflecting as you were telling that story of how we've come full circle now to actually talk about an infection again. It's the midst of an infection, like HIV infection, that we're now testing these equations once again. What better than to ask than Bongani, you're in the epicenter, if I may, of HIV infection. What do you think of the applicability of these findings to the patients you see? Dr Bongani Mayosi:         Yes. These findings are clearly of great interest to us here in the Sub-Saharan African region because it is really the epicenter HIV pandemic. We found population, in terms of risk factors for arteriosclerosis disease still remains low although there clearly derives, for example, in the incidence of myocardial infarction that's being detected in a number of the leading centers now. And with HIV we have observed cases of myocardial infarction while they tend to be younger men who almost always smoke and who get a lot more of a thrombotic episodes.                                                 When you catch them on a thrombotic load, you do not find arteriosclerosis disease. It's going to be important, I think, as we move forward to make sure that as we develop risk functions that will predict cardiovascular disease in patient HIV that the African epidemiological context is completed teaching that HIV affects younger people, affects large numbers of women, but that, quite clearly, is associated with decreased cardiovascular event and stroke and stroke is well demonstrated. But in terms of actually looking at the risk factor this population was still in the early day and certainly in future studies would have to have a major contribution of the African cohort. Dr Carolyn Lam:                That's true, Bongani, but may I ask how would you, perhaps, advise your African colleagues now to look at these data? Then I'd also like to turn that same question over to you, Virginia. What do we do? What's the clinical take home message of these findings? Dr Bongani Mayosi:         I think the message is true that HIV infection is associated with the increased risk of cardiovascular event, there's no doubt about that. That there are some risk factors that can carry through, such as the smoking population but it's important for all clinicians to be aware of that. The ordinary risk you find in using Framingham and other established risk functions is not going to give us all the information that we need. So that recommendation should come through we need to know that risk factors are unknown, that they're important and we need to learn more about these patients in order to give us a perfect prediction of what will happen in the future. Dr Virginia Triant:             I think the findings have a lot of clinical relevance. This suggests, I think, that there are a lot of clinical implications for any patient who has novel cardiovascular risk factors that may not be accounted for in heart functions. And what our findings suggest is that if functions don't reflect the actual composition of risk factors in the population, that can result in misclassification and thus we underestimate risk, we might miss high-risk individuals, high-risk patients who would benefit from aggressive risk reduction but are not currently receiving it. This is a real clinical challenge as sit in clinic and we pull up the scores and calculate them for our patients, whether that is a trustworthy number or whether we should, perhaps, thinking that it's higher, thinking that it's different than what we're seeing for predicted 10-year risk. I think what this suggests is that the functions may need to be further tailored to different populations and sub-populations to reflect the actual composition of risk factors in that population. Even within HIV patients and populations, the risk factors in South Africa might be different than those in Boston, with different relative contributions.                                                 One of the next stepped planned for our team is to actually look at developing, new risk functions which are tailored to HIV and incorporating both HIV itself as a risk factor, as well as HIV specific variables and to attempt to see if we can improve the performance of these functions for HIV populations. Perhaps HIV or HIV related factors might become sort of a new cardiovascular risk equivalent and we can serve patients in this population as higher cardiovascular risk baseline. I also just wanted to mention, briefly, that I think that there are important clinical implications beyond HIV that extend to other chronic inflammatory conditions. Inflammation is increasingly recognized as important in cardiovascular risk and this way HIV can serve as a prototype population. But these results are likely to extend to a lot of different populations who have chronic inflammation for different reasons. Dr Carolyn Lam:                That's a great point, Virginia. As I'm listening, I'm wondering is there no end to this because now we say HIV and then we put other inflammatory diseases, then we say, "Well, women may be different from men," and then different ethnicities may be different. I think gonna be going closer and closer to precision risk prediction, if I might say. Could I just pick your brain here? What do you think the future is? Where's the room for machine learning approaches for risk prediction, individual almost down to that level? What do you think? Dr Ralph D'Agostino:      I think you're right on target. In some sense, the functions we have there's a sort of massiveness about it, when you come to view this population, back in the 50s and 60s and so forth, cardiovascular disease was such a major ... it still is a major problem ... such a major problem you identify some of the real items like the blood pressure and cholesterol, and you attack and develop functions on that and you'd find that you're affecting positively a huge number of individuals, but now as, like Jeanne was saying, and others have been saying, you start focusing, you've got this massive group of individuals who should have their blood pressure controlled and what have you, but if you go into HIV, you go into a number of other populations and so forth, there are other things that are driving these disease and driving the manifestations of the disease. It isn't that blood pressure isn't important, it's that there's other things that are important. And so it's machine learning and so forth and deep learning that you're gonna have to be dealing with manifestations on very high levels and maybe even get into genetics.                                                 Look in the cancer field ... I do a lot of work with the FDA ... look at the cancer field now; how it's so genetically driven in terms of a lot of the drugs the so-called biomarkers, which are basically driven by uniqueness in populations. I think that's definitely going to be, or is the future of these cardiovascular functions. Dr Carolyn Lam:                Okay audience. You heard it, right here. These are exciting times. In the meantime, thank you so much for this precious, valuable piece of work. Virginia, Bongani, Ralph, it was great having you on the show.                                

Dr. Paul Wang:           Welcome to the monthly podcast On the Beat for Circulation Arrhythmia and Electrophysiology. I'm Dr Paul Wang, editor-in-chief, with some of the key highlights for this month's issue. We'll also hear from Dr. Suraj Kapa reporting on new research from the latest journal articles in the field.                                                 In our first article, Barry Maron associates report on the long term clinical course of hypertrophic cardiomyopathy patients following ICD therapy for ventricular arrhythmias. They studied a cohort of 486 high-risk hypertrophic cardiomyopathy patients with ICDs from eight international centers. Of these 486 patients over 6.4 years, 94 patients or 19% experienced appropriate ICD interventions, terminating VT or VF. Of the 94 patients receiving appropriate ICD therapy, 87 were asymptomatic or only mildly symptomatic at the time of appropriate ICD interventions. Of these 87 patients, 74 or 85% remained in classes one or two without significant change in clinical status of the subsequent 5.9 years up to 22 years. Among the 94 patients, there was one sudden death in three patients who died from non arrhythmic hypertrophic cardiomyopathy related processes. Post ICD intervention, freedom from hypertrophic cardiomyopathy, mortality was 100% at one year, 97% at five years, and 92% at 10 years, distinctly lower than the risk of ischemic or non ischemic cardiomyopathy in ICD trials.                                                 Hypertrophic cardiomyopathy patients with ICDs interventions reported the heightened anxiety and expectation of future shocks. However, they did not affect general psychological well-being or quality of life. The authors concluded that in hypertrophic cardiomyopathy, unlike ischemic heart disease, prevention of sudden death with ICD therapies unassociated with a significant increase in cardiovascular morbidity and mortality, nor transformation into heart failure deterioration, ICD therapy does not substantially impair overall psychological and physical well-being. In our next article, Abdulla Damluji and associates examined the cost of hospitalizations for cardiac arrest using the US nationwide inpatient sample from 2003 to 2012. Using the log transformation of inflation adjusted costs the authors examined 1,387,396 patients who were hospitalized after cardiac arrest. They had a mean age of 66 years. Inpatient procedures included coronary angiography in 15%, PCI in 7%, intra-aortic balloon pump in 4.4%, therapeutic hypothermia in 1.1%, and mechanical circulatory support in 0.1% of patients.                                                 Notably the rates of therapeutic hypothermia increased from 0 in 2003 to 2.7 in 2012, p less than 0.001. Both hospital charges inflation adjusted costs linear increased over time. In a multi-variant analysis predictors of inflation adjusted costs included large hospitals size, urban teaching hospital, and length of stay. Among co-morbidities, atrial fibrillation or fluid and electrolytes imbalance were the most common associated with cost. The authors found that during the period between 2003 and 2012 post cardiac arrest, hospitalizations had a steady rise and associated healthcare costs likely related to increase length of stay, medical procedures and systems of care.                                                 In our next paper, Peter Huntjens and associates examined intrinsic interventricular dyssynchrony as a predictor of human dynamic response to cardiac resynchronization. The authors use a cardiovascular computational model CircAdapt to characterize the isolated effect of intrinsic interventricular or intraventricular activation on resynchronization therapy response that is the change in LV dP/dt max. The simulated change in LV dP to dt max had a range of 1.3 to 26.5% increased considerably with increasing inter ventricular dyssynchrony. In contrast, the isolated effect of intra ventricular dyssynchrony was limited with the change in the LV dP/dt max range and the left ventricle from 12.3 to 18.3% in the right ventricle from 14 to 15.7%.                                                 Secondly, electrocardiographic imaging derived activation characteristics of 51 CRT candidates were used to create individual models of ventricular activation in CircAdapt. The model predicted change in LV dP/dt max was close to the actual value in left bundle branch block patients with 2.7% difference between measured and simulated when only intrinsic interventricular dyssynchrony was personalized. Among non left bundle branch block patients a change in LV dP/dt max was systematically over predicted by CircAdapt with a 9.2% difference between measured and simulated. Adding intra ventricular activation to the model did not improve the accuracy of response prediction. The authors found that computer revealed intrinsic interventricular dyssynchrony is the dominant component of the electrical substrate driving the response to CRT.                                                 In the next paper Kenji Kuroki and associates examined the use of voltage limit adjustment of substrate mapping and fast Fourier transform analysis of local ventricular bipolar electrograms during sinus rhythm to predict VT isthmuses. They performed these studies and nine post infarction patients who underwent catheter ablation for total of 13 monomorphic ventricular tachycardias. Relatively higher voltage areas on electroanatomical map or defined as high voltage channels, which were further classified as full or partial if the entire or more than 30% of the high voltage channel was detectable. 12 full high voltage channels were identified in seven of nine patients. Relatively higher fast Fourier transform areas were defined as high frequency channels, which were located on seven of 12 full high voltage channels. Five VT isthmuses or 71% were included in the seven full high voltage channels positive in high frequency channel positive sites.                                                 While no VT isthmuses were found in five full high voltage channel positive but high frequency channel negative sites, high frequency channels were identical to 9 out of 16 partial high voltage channels. Eight VT isthmuses or 89% were included in nine partial high voltage channel positive in high frequency channel positive sites, whereas no VTs isthmuses were found in the seven partial high voltage channel positive and high frequency channel negative sites.                                                 All high voltage channel positive in high-frequency channel positive sites predicted VT isthmus with a sensitivity of 100% and specificity of 80%. The authors concluded that based on this small series that combined use of voltage, limited adjustment and fast Fourier transform analysis may be useful method to detect VT isthmuses.                                                 In the next study, John Whitaker and associates examined the use of lesion index, LSI index, a proprietary algorithm combining contact force, radio-frequency application duration, and RF current. Cardiac CT was used to assess atrial tissue thickness. Ablation lines two to three per animal were created in the right atrium in seven mini pigs with point lesions using 25 watts of energy. Two weeks after the ablation, serial sections of targeted atrial tissue or examine histologically to identify gaps and transmural ablation. LSI guidelines had a lower incidence of histological gaps. Four gaps in the 69 catheter moved or 5.8% compared to ablation using LSI plus two millimeter lines in which there is seven gaps in 33 catheter moves or 21.2% and using LSI plus four millimeter lines in which there are 15 gaps in 23 moves or 65.2% p less than 0.0. The change in LSI was calculated retrospectively is a distance between two adjacent lesions above the mean LSI of the two lesions. Changing LSI values of 1.5 or less were associated with no gaps in transmural ablation.                                                 The authors concluded that in this mod of chronic atrial ablation delivery of uninterrupted transmural linear lesions may be facilitated using LSI to guide catheter movement. When change in LSI between adjacent legions is 1.5 millimeters or lower, no gaps in atrial linear lesions should be expected.                                                 In our next paper, Matthew Bennett and associate examined whether their response to antitachycardia pacing in patients with ICD could further discriminate ventricular from super ventricular arrhythmias in patients receiving ATP in the RAFT trial. The RAFT trial randomized 1,798 patients with New York Heart Association class two or three heart failure, left ventricular ejection fraction less than or equal to 30%, in QRS duration 120 millisecond or greater, to an ICD plus or a minus cardiac resynchronization. Beginning with 10,916 ATP attempts for 8,150 tachycardia episodes in 924 patients, the author's excluded tachycardias where ATP terminated the episode or were the specific etiology tachycardia was uncertain. In this study, they analyzed 3,676 ATP attempts delivered to 2,046 tachycardia episodes in 541 patients. The authors found that a shorter difference between the post pacing interval is PPI minus TCL, was more likely to be associated with VT than SVT, mean of 138.1 milliseconds for VT and 277.4 milliseconds for SVT p, less than 0.001. A PPI minus TCL value of less than or equal to 300 milliseconds had a sensitivity in 97.4% and a specificity of 28.3% for VT.                                                 The authors concluded that specifically the PPI minus TCL following antitachycardia pacing may help distinguish ventricular from supraventricular arrhythmias.                                                 In the next study, Shailee Shah and Amr Barakat and associates examined the outcomes after repeat AF ablation. The authors examined 137 patients out of a total of 10,378 patients undergoing Afib ablation who had had initial long-term success defined from recurrent arrhythmias for greater than 36 months off anti-arrhythmic drugs in subsequent underwent repeat ablation for recurrent atrial fibrillation. The median arrhythmia free period that define long-term success was 52 months. In redo-ablations reconnection of at least one of the pulmonary veins was found in 111 or 81% of patients. Additional non PV ablations were performed in 127 or 92.7% of patients. After a mean follow-up of 17 months, 103 patients or 75% were arrhythmia-free, 79 off anti-arrhythmics, and 24 on arrhythmics. The authors found that repeat ablations with re-isolation to the point of veins and modifying the atrial substrate had a good success rate.                                                 In the next article Qiongling Wang and associates hypothesized that genetic inhibition of CaMKII oxidation in a mouse model of Duchenne muscular dystrophy can alleviate abnormal calcium homeostasis thus preventing ventricular arrhythmias. The authors tested whether the selective loss of oxidation of the CaMKII effects ventricular arrhythmias in the mouse model of Duchenne muscular dystrophy. Genetic inhibition of ox-CaM kinase II by knocking replacement of the regulatory domain methionines with valines, which we'll call MMVV, prevented ventricular tachycardia in the mdx mice. Confocal calcium imaging of ventricular myocytes, isolated from the mdx MMVV mice revealed normalization of intra-calcium release events compared to myocytes from the mdx mice. Abnormal action potentials as assessed by optical mapping mdx were also alleviated by genetic inhibition of ox-CaMK II. Knockout of the NADPH oxidase regulatory sub-unit P 47 Fox normalized elevated ox-CaMK II, repaired intracellular calcium hemostasis and rescued inducible ventricular arrhythmias in the mdx mice. The authors concluded that inhibition of ROS or ox-CaMK II protects against pro-arrhythmic intracellular calcium handling, preventing ventricular arrhythmias in a mouse model of Duchenne muscular dystrophy.                                                 In the next article, Kyohei Marume and Teruo Noguchi and associates examined whether the combination of QRS duration of 120 milliseconds or greater in late gadolinium enhancement is a precise prognostic indicator for the primary endpoint of all cause death and a composite of sudden cardiac death or aborted sudden cardiac death in 531 patients with dilated cardiomyopathy. They also analyzed the association between the combination of late gadolinium enhancement and increased QRS duration in these end points among patients with a class one indication for implantable defibrillator. The author's divided study patients in three groups according to late gadolinium enhancement in QRS duration. Two negative indices that is late gadolinium enhancement negative and narrow QRS, one positive index with either late gadolinium enhancement positive or wide QRS or two positive indices late gadolinium positive and wide QRS and followed them for 3.8 years. Multiple variable Cox regression analysis identified to positive indices as significant predictors of all cause death. A hazard ratio of 4.29 p equals 0.026. Among the 317 patients with a class one indication for ICD, the five year event rate of sudden cardiac death or aborted sudden cardiac death was lowest in the two negative indices groups, 1.4%. With propensity score matching cohorts the two negative indices group had a significant lower event rate of sudden cardiac death or aborted sudden cardiac death than to two other groups hazard ratio 0.2, p equals 0.046.                                                 The authors concluded that the combination of late gadolinium enhancement in wide QRS provides additional prognostic stratification compared to late gadolinium enhancement status alone.                                                 In the next study, Matthew Sulkin and associates examined whether a novel local impedance measurement on an ablation catheter identifies catheter tissue coupling and is predictive of lesion formation. The author's first studied explanted hearts, 10 swine, and then in vivo 10 swine, using an investigational electro anatomical mapping system that measures impedance from an ablation catheter with mini electrodes incorporated into the distal electrode. Rhythmia and Intellanav, Boston Scientific.                                                 Explanted tissue was placed in a warmed 37 degree celsius saline bath mounted on a scale, and the local impedance was measured 15 millimeters away from the tissue to five millimeters of catheter tissue compression at multiple catheter angles. Lesions were created for 31 and 50 watts from 5 to 45 seconds for an N of 70. During in vivo valuation of the local impedance measurements of the myocardium 90 and blood pool 30 were guided by intracardiac ultrasound while operators were blinded to the local impedance data. Lesions were created with 31 and 50 watts for 45 seconds in the ventricle with an n of 72. The local impedance of myocardium, which was 119.7 ohms, was significantly greater than in blood pool 67.6 ohms the p of less than 0.01. Models that incorporate local impedance drop to predict lesion size had better performance that models incorporate force time integral r squared of 0.75 versus r squared of 0.54 and generator impedance drop r squared of 0.2 versus r squared of 0.58. Steam pops displayed a significantly higher starting local impedance and a larger change in local impedance compared to successful RF applications, p less than 0.01.                                                 The authors concluded that local impedance recorded for miniature electrodes provides a valuable measure of catheter tissue coupling and the change in local impedance is predictive of lesion formation during RF ablation.                                                 In the next paper, Boaz Avitall and associates found that the rising impedance recorded from a ring electrode placed two millimeters from the cryoballoon signifies ice formation covering the balloon surface and indicates ice expansion. The authors studied 12 canines in a total of 57 pulmonary veins, which were targeted for isolation. Two cryoapplications were delivered per vein with a minimum of 90 and a maximum 180 second duration. Cryoapplications was terminated upon reaching a 500 ohm change from baseline. Animals recovered 38 plus or minus six days post procedure, and the veins were assessed electrically for isolation. Heart tissue was histological examined. Extra cardiac structures were examined for damage. Pulmonary vein isolation was achieved in 100% of veins if the impedance reached 500 ohms in 90 to 180 seconds. When the final impedance was between 200 and 500 ohms within 180 seconds of freeze time, pulmonary vein isolation was achieved in 86.8%. For impedance of less than 200 ohms pulmonary vein isolation was achieved in 14%. No extra cardiac damage was recorded. The authors found that impedance rise of 500 ohms at less than 90 seconds with a freeze time of 90 seconds resulted in 100% pulmonary vein isolation.                                                 In our final papers Sally-Ann Clur and associates examined left ventricular isovolumetric relaxation time as the potential diagnostic marker for fetal Long QT Syndrome. Left ventricular isovolumetric contraction time, ejection time, left ventricular isovolumetric relaxation time, cycle length, and fetal heart rate were measured using pulse doppler wave forms in fetuses. Time intervals were expressed as percentage of cycle length, and the left ventricular myocardium performance index was calculated. Single measurements were stratified and compared between Long QT Syndrome fetuses and controls. Receiver operator curves were reformed for fetal heart rate in normalized left ventricular isovolumetric relaxation time. A linear mixed effect model including multiple measurements was used to analyze fetal heart rate, the left ventricular iso volume metric relaxation time, and the left ventricular myocardial performance index. There were 33 Long QT fetuses in 469 controls. In Long QT fetuses the left ventricular isovolumetric relaxation time was prolonged in all groups, p less than 0.001, as was the left ventricular isovolumetric relaxation time.                                                 The best cutoff to diagnose Long QT syndrome was the normalized left ventricular isovolumetric relaxation time greater than equal to 11.3 at less than or equal to 20 weeks, giving a sensitivity in 92% and a specificity of 70%. Simultaneous analysis of the normalized left ventricular isovolumetric relaxation time and fetal heart rate improved the sensitivity and specificity of Long QT Syndrome, AUC of 0.96. The normalized left ventricular isovolumetric relaxation time, the left ventricular myocardial performance index, and fetal heart rate trends differed significantly between Long QT Syndrome fetuses and controls throughout gestation.                                                 The authors concluded that left ventricular volumetric relaxation time is Prolonged QT fetuses. Findings of a prolonged normalize left ventricular isovolumetric relaxation time, and sinus bradycardia can improve the prenatal detection of fetal Long QT Syndrome.                                                 That's it for this month, but keep listening. Suraj Kapa will be surveying all journals for the latest topics of interest in our field. Remember to download the podcasts On the Beat. Take it away Suraj. Suraj Kapa:                          Thank you, Paul and welcome back to On the Beat were we will be summarizing hard-hitting articles across the entire electrophysiologic literature. Today we'll be starting within the realm of atrial fibrillation where we're review an article within the realm of anticoagulation and stroke prevention. Quon et al. published in last month's issue of JACC cardiac electrophysiology on anticoagulant use and risk of ischemic stroke and bleeding in patients with secondary atrial fibrillation. It is well known that use of anticoagulation in atrial fibrillation can reduce overall thromboembolic outcomes. However, its role in secondary atrial fibrillation is unclear. Thus, the authors sought to evaluate the effects anticoagulant use on stroke and bleeding risk. Amongst those where atrial fibrillation occurred in the setting of acute coronary syndrome, pulmonary disease, or sepsis. Amongst around 2300 patients evaluated retrospectively there was no evidence of a lower incidence of ischemic stroke among those treated with anticoagulants compared to those who are not.                                                 However, anticoagulation was associated with a higher risk of bleeding in those with new onset AF associated with acute pulmonary disease. The authors suggest as a result that there is unclear overall benefit for long-term anticoagulation in patients with presumed secondary atrial fibrillation. The difficulty in assessing this is how to define secondary atrial fibrillation. However, in many studies patients who developed in the setting of acute illness still had a high risk of developing quote unquote clinically significant AF in long-term follow-up. However, this was not necessarily absolute as many patients not necessarily develop AF that could be considered clinically significant. Thus, the clinical question that arises is: how long should we treat a patient with anticoagulation when they have presumed secondary atrial fibrillation. These data seem to suggest that there may be no net overall benefits. In other words, all-comers with secondary atrial fibrillation should not necessarily be forever treated with anti-coagulation. However, this slightly requires clinical trials to evaluate further.                                                 Next we delve into the realm of cardiac mapping and ablation where we view an article by Gaita et al. entitled 'Very long-term outcome following transcatheter ablation of atrial fibrillation. Are results maintained after 10 years of follow-up?', published in Europace last month. While pulmonary vein isolation is a widely accepted approach for treatment of atrial fibrillation, most reported studies review outcomes in terms of freedom of AF over a relatively short time period, generally two to five years. However longer term follow up is inconsistently reported. Gaita et al. sought to review 10 year outcomes amongst 255 patients undergoing ablation in a single center. They noted 52% remainder arrhythmia-free amongst a mixed cohort of both paroxysmal and persistent patients while 10% progressed to permanent atrial fiBrillation. They found that absence of increases in blood pressure, BMI, and fasting glucose was protective against an arrhythmia recurrence.                                                 These findings suggest that in a relatively small cohort of patients limited to a single center that even long-term outcomes after pulmonary vein isolation are generally quite good, exceeding 50%. However, future freedom from atrial fibrillation is heavily tied to control of other risk factors. In other words, if a patient is going to have poor control of diabetes, blood pressure, or gain weight, the benefit of their pulmonary vein isolation over long-term follow-up is likely less. These data thus highlight both the potential long-term benefit of PVI, but also the importance of counseling patients regarding the need for continued management and control of future and existing risk factors.                                                 Staying within the realm of atrial fibrillation we next review an article by Weng et al. entitled 'Genetic Predisposition, Clinical Risk Factor Burden, and Lifetime Risk of Atrial Fibrillation' published in last month's issue of circulation. The probability of detecting atrial fibrillation in patients based on clinical factors and genetic risk is unknown. Weng et al. sought to clarify whether a combination of clinical and polygenic risk scores could be used to predict risk of developing atrial fibrillation over long-term followup in the Framingham Heart Study. Amongst 4,600 individuals, 580 developed incident atrial fibrillation and had an overall lifetime risk of developing atrial fibrillation of 37%. Those are the lowest risk tertile based on clinical risk factor burden and genetic predisposition had a lifetime risk of 22% versus 48% in the highest. Furthermore, a lower clinical risk factor burden was associated with delayed atrial fibrillation onset. In order to identify patients with atrial fibrillation, before negative sequelae such as stroke occur, patient and physician understanding of risk and monitoring needs is necessary. The fact is that it will be great to identify every single patient who has atrial fibrillation before they have a negative sequela of that atrial fibrillation such as ischemic stroke.                                                 However, performing continuous monitoring of all patients with potential negative sequelae of atrial fibrillation is extraordinarily difficult. The reason is it's excessively costly. We cannot monitor the entire population irrespective of whatever the risk factors are. However, if we're able to identify the highest risk cohorts early on before the atrial fibrillation onsets, this may offer opportunities for use of newer cheaper monitors. The work by Weng et al. suggests one such possible approach combines clinical and polygenic risk scores. Actionability of these data, however, remains to be seen and further validation other cohorts is necessary to clarify generalized ability.                                                 The next article we review is published in last month's issue of the Journal of American College of Cardiology by Lopes at al. entitled 'Digoxin and Mortality in Patients With Atrial Fibrillation. Lopes et al. sought to evaluate the impact of the Digoxin on mortality in patients with atrial fibrillation and the association with the Digoxin serum concentration and heart failure status. They value this association in over 17,000 patients. At baseline 32% were receiving Digoxin. Baseline Digoxin use did not associate with risk of death, but even in these patients a serum concentration of greater than 1.2 nanograms per milliliter was associated with a 56% increase in mortality risk. For each .5 nanogram per milliliter increase in oxygen concentration the hazard ratio increased by 19% for overall mortality. This was irrespective of heart failure status. Furthermore, in patients who are newly started in Digoxin over the follow-up period, the risk and death and sudden death was higher. These data suggests a significant risk associated with Digoxin use for management of atrial fibrillation irrespective of heart failure status. Furthermore, serum valleys above 1.2 require close consideration of dose de-escalation. Whether there is any optimal dose, however, from the study is unclear. These data amongst a host of prior data strongly suggest again strategic use of Digoxin  principally for the management of atrial fibrillation.                                                 Moving on within the realm of atrial fibrillation, we review an article published in last month's issue of Circulation Research by Yan et al. entitled Stress Signaling JNK2 Crosstalk with CaMKII Underlies Enhanced Atrial Arrhythmogenesis. In this more acellular based study the mechanism underlying atrial arrhythmogenesis associated with aging was evaluated. Yan et al. sought to figure out whether the stress response JNK in calcium mediated arrhythmias might contribute to atrial arrhythmogenesis in aged transgenic mouse models. They demonstrated significant increased activity of JNK2 and aging atria, those furthermore associated with rhythmic remodeling. This association was mediated through CaMKII and ryanodine receptor channel function, with activation of the former leading to increased calcium leak mediated by the ladder. This in turn related to increase atrial fibrillation likelihood. Identifying novel targets for atrial fibrillation therapy is critical. Given atrial fibrillation is a complex disease process related to a multitude of risk factors it can be assumed that the contribution of any single factor may be mediated through distinct mechanisms.                                                 Aging in particular as well regarded, but considered to be non-modifiable risk factor for atrial fibrillation. Identifying genes or pathways, the immediate aging associated fibrillation, may take the risk of aging as no longer a non-modifiable thing. The finding of the significance of JNK2 and associate downstream effects with AF risks and aging hearts may hold potential in offering unique therapeutic targets.                                                 Finally, within the realm of atrial fibrillation, we're viewing article by Chen et al. in last month's issue of the Journal of the American Heart Association entitled Association of Atrial Fibrillation With Cognitive Decline and Dementia Over 20 Years: The ARIC-NCS Study. Multiple studies have suggested a significant association between atrial fibrillation risk of dementia. However, these studies have limited time follow-up and were often done and predominantly white patients. Thus, the authors sought to use the data from ARIC, the Atherosclerosis Risk in Communities Neurocognitive Study, to assess the risk of cognitive decline associated with atrial fibrillation. Amongst over 12,000 participants, a quarter of whom are black and half of whom are white, they noted 2100 patients developed atrial fibrillation and 1,150 develop dementia over a 20 year follow up period.                                                 There was a significantly greater risk of cognitive decline amongst those who developed atrial fibrillation. In turn incident atrial fibrillation for the follow-up period was associated with a higher risk of dementia even after adjusting for other clinical and cardiovascular risk factors such as incidents that ischemic stroke. These data further strengthened prior evidence of a direct link between atrial fibrillation and risk of cognitive decline and dementia. Understanding this long-term risk raises the need to additionally identify approaches to prevent this occurrence, which in turn is dependent on understanding the underlying mechanisms. The finding that the risk of cognitive decline dementias independent of ischemic stroke events raises concern that either subclinical micro-embolic events or other factors may be playing a role in this risk and in turn raises question as to how best to prevent them. Until better understood, however, the question of whether the association is causal remains to be seen.                                                 Changing gears yet again, we now delve into the realm of ICDs, pacemakers and CRT. Published in last month, issue of Heart Rhythm Tarakji et al. published a paper entitled 'Unrecognized venous injuries after cardiac implantable electronic device transvenous lead extraction.' Overall risk of transvenous lead extraction includes that of potentially fatal venous laceration. The authors sought to evaluate the incidence of venous injury that may be unrecognized based on microscopic study of extracted leads. Amongst 861 leads obtained from 461 patients they noted 80 leads or almost 9%. Amongst 15% of patients showed segments vein on the lead body, most of which were transmural including the tissue layer. However, in terms of clinical significance, only 1% had need for emergent surgical intervention for clinically significant venous laceration. Risk factors for having the entire vein on the lead included age of lead, ICD leads, and the use of the laser sheath.                                                 These findings suggest that there may be a high incidence of subclinical venous injury after lead extraction though rarely resulting clinically apparent sequelae. As would be expected, venous injury, including transmural removal of portions of the vein traversed by the lead, was more common amongst older leads, which generally more often require laser sheets and ICD leads. The question is however, whether this carries any direct clinical implications. One they may be considered is the potential additive risk of an advancing new lead through the same venous channel, particularly in the setting of potential transmural venous injury that already exists.                                                 Next in last month's issue of Heart Rhythm we review an article by Sharma at al. entitled 'Permanent His-bundle pacing as an alternative to biventricular pacing for cardiac resynchronization therapy: A multicenter experience.' The use of resynchronization therapy for treatment of patients with heart failure and wide QRS has been shown to offer morbidity and mortality benefits. However, many patients maybe non-responders, and recent studies on His bundle pacing of suggested potential clinical benefits. His bundle pacing essentially only requires one pacing catheter attached within the region of the His bundle Sharma et al. sought to evaluate the safety and success rates of His bundle pacing for patients who have either failed standard resynchronization therapy or in whom most tried as a primary intervention. They noted His bundle pacing was successful in 90% of patients with reasonable myocardial and His bundle capture thresholds. Patients in both groups exhibits significant narrowing of QRS morphology and improvement in left ventricular ejection fraction from a mean of 30 to 43%. However, a total of seven patients had lead related complications.                                                 These database on a retrospective analysis of two types of patients, those failing standard biventricular therapy, and those on whom his bundle pacing was attempted as a primary modality suggest overall safety and efficacy in a handful of experienced centers. The promise of His bundle pacing is that a may allow for more effective resynchronization than standard approaches. The high rate of success suggests that His bundle pacing maybe both safe and reasonable to pursue. However randomized trials across more centers are needed to fully prove its benefit, particularly as a primary modality of treatments.                                                 Next we review ICDs and chronic kidney disease. In last month's issue of JAMA cardiology by Bansal at al. entitled 'Long-term Outcomes Associated With Implantable Cardioverter Defibrillator in Adults With Chronic Kidney Disease.' While the benefit of ICDs in patients with low EF is widely recognized, modifying factors that may increase risk of death are not as well defined. These include things like advanced age and chronic kidney disease. Bansal et al. sought to evaluate long-term outcomes and ICD therapy in patients with chronic kidney disease. In retrospective study of almost 5,900 ambulatory patients amongst whom 1550 had an ICD, they found no difference in all cause mortality. However, ICD placement was associated with an increased risk of subsequent hospitalization due to heart failure or any cause hospitalization.                                                 In light of recent studies such as DANISH the robust sense of ICD benefit is being questioned. One of the thoughts for the absence of similar benefit to prior studies lies in the improving care of ambulatory heart failure patients. In patients with chronic kidney disease several questions rises to the risk with ICD, including infectious risk in dialysis patients and the concomitant mortality risk with renal dysfunction. The author suggested in retrospective study, no incremental benefit of ICDs in patients with chronic kidney disease and perhaps some element of added risk is related to hospitalization. However, this study has several limitations. It is retrospective and many patients received ICDs may have been perceived to be sicker in some way. Thus care must be taken in interpretation, but consideration of randomized studies to adjudicate benefit are likely necessary.                                                 Finally, within the realm of devices, we reviewed an article by Tayal et al. entitled "Cardiac Resynchronization Therapy in Patients With Heart Failure and Narrow QRS Complexes.' publishing the Journal of American College of Cardiology last month. Several parameters have been stressed to identify benefit of resynchronization therapy in patients with wide QRS include cross correlation analysis with tissue doppler imaging. However, many patients may have evidence in mechanical dyssynchrony even in the absence of an apparent wide QRS thus Tayal et al. sought to evaluate the benefit of resynchronization therapy amongst 807 patients with heart failure and a narrow QRS mean criteria in a randomized study. Of the 807 46% had delayed mechanical activation. Those without delay mechanical activation had underwent we standardization therapy and were associated with worse overall outcomes likely due to new delayed mechanical activation potentially related to CRT pacing. These data support the absence of a role for resynchronization therapy in patients with a narrow QRS. This is expected as resynchronization therapy likely offers the most benefit in patients with mechanical dyssynchrony that results from electrical dyssynchrony.                                                 Since by its very nature resynchronization therapy relies on non physiologic cardiac pacing thus compared to normal cardiac activation the nature of resynchronization pacing is desynchronization. These data support the absence of a role for resynchronization therapy in patients with heart failure and narrow QRS complexes.                                                 Moving on to cellular electrophysiology we review an article by Kozasa et al. published in last month's issue of Journal of Physiology entitled 'HCN4 pacemaker channels attenuate the parasympathetic response and stabilize the spontaneous firing of the sinoatrial node.' Heart rate is controlled by an interplay between sympathetic and parasympathetic components. In turn HCN4 abnormalities have been implicated in congenital sick sinus syndrome. The authors sought to clarify the contribution of HCN4 to sinus node autonomic regulation. They created a novel gain-of-function mouse where the HCN4 activity could be modulating from zero to three times normal. They then evaluated ambulatory heart-rate variability and responsive heart rate to vagus nerve stimulation. They found HCN4 over-expression did not increase heart rate, but attenuated heart-rate variability. It also attenuated bradycardic response to vagus nerve stimulation. Knockdown of HCN4 in turn lead to sinus arrhythmia and enhanced parasympathetic response. These data suggest HCN4 attenuates sinus node response to vagal stimuli thus stabilizing spontaneous firing of the node. The clinical application of this remain to be seen but are maybe important in that they highlight a mechanism for a heretofore poorly understood mechanism for how exactly HCN4 abnormalities may lead to sick sinus syndrome.                                                 Within the realm of ventricular arrhythmias we highlighted a number of articles published this past month. The first article we review was published in last month's issue of JACC clinical electrophysiology, entitled characterization of the electrode atomic substrate and cardiac sarcoidosis: correlation with imaging findings of scarring inflammation published by [inaudible 00:41:40] et al. In patients with cardiac sarcoidosis one of the questions is how to define the electronic atomic substrate, particularly before we entered the electrophysiology laboratory. Both active inflammation and replacement fibrosis maybe be seen in patients. The authors evaluated in 42 patients with cardiac sarcoidosis, the association between an abnormal electrograms and cardiac imaging findings including PET and Computed Tomography, as well as Cardiac MRI. They noted that amongst these 40 patients, a total of 21,000 electrograms were obtained, and a total of 19% of these were classified as abnormal. Most of the abnormalities occurred in the basal paravalvular segments and intraventricular septum. They further noted that many of these abnormalities in terms of electrograms were located outside the low voltage areas, particularly as it relates to fractionation. In about 90% of patients they notice late gadolinium enhancements and they noted abnormal FDG uptakes suggesting active inflammation in about 48%.                                                 However, it should be noted that only 29 of the 42 patients underwent cardiac imaging. Segments with abnormal electrograms tended to have more late gadolinium enhancement evidence scar transmurality, and also they noted that the association of abnormal PET scan did not necessarily occur with abnormal electrograms. Thus, they concluded that in patients with cardiac sarcoidosis and ventricular tachycardia pre-procedural imaging with cardiac MRI could be useful in detecting electroanatomic map abnormalities that may in turn be potential targets for substrate ablation. However, they were more likely associated with more scar transmurality and lower degrees of inflammation on PET scanning. These data are important in that they highlight potential non-invasive means by which to understand where substrate might occur in patients with the cardiac sarcoidosis. It is well recognized that cardiac sarcoidosis is associated with increased risk of ventricular arrhythmias. These risks have increased ventricular arrhythmias, might be targetable with ablation. Newer therapies might even offer non invasive means by which to perform ablation in patients best. Thus if we could identify non based on mechanisms of identifying the substrate, this will be even more critical.                                                 The critical findings of this particular paper lie in noting that most of the abnormalities still is in intra ventricular sePtum in basal segments, and also that it is MRI in late gadolinium enhancement and associates more with the abnormal electrograms. Interestingly, the absence of inflammation correlating with the presence of more abnormal electrograms suggests that it is not so much the act of inflammation as being reflected in the endocardial map, but the existence of scar.                                                 Next, again within JACC clinical electrophysiology we review an article by Porta-Sánchez et al. entitled 'Multicenter Study of Ischemic Ventricular Tachycardia Ablation With Decrement Evoked Potential Mapping With Extra Stimulus.' The authors sought to conduct a multicenter study of decrement evoked potential base functional tech ventricular tachycardia substrate modification to see if such mechanistic and physiologic strategies could result in reduction in VT burden. It is noted that really only a fraction of the myocardium in what we presume to be substrate based on the presence of low voltage areas are actually involved in the initiation and perpetuation of VT. Thus if we can identify the critical areas within the presumed substrate for ablation, this would be even a better way of potentially honing in on our targets. They included 20 consecutive patients with ischemic cardiomyopathy. During substrate mapping fractionated late potentials were targeted and an extra stimulus was provided to determine which display decrements. All patients underwent DEEP focus ablation with elimination being correlated with VT non-inducibility after radio-frequency ablation. Patients were predominantly male, and they noted that the specificity of these decrement evoked potentials to detect the cardiac isthmus for VT was better than that of using late potentials alone. They noted 15 of 20 patients were free of any VT after ablation of these targets over six months of follow-up, and there was a strong reduction in VT burden compared to six months pre ablation.                                                 They concluded that detriment evoked potential based strategies towards ablation for ventricular tachycardia might identify the functional substrate and those areas most critical to ablation. They in turn regarded that by its physiologic nature it offers greater access to folks to ablation therapies.                                                 This publication is important in that it highlights another means by which we can better hone in on the most critical regions for substrate evaluation in patients with ventricular tachycardia. The fact is more extensive ablation is not necessarily better and might result in increased risk of harm if we think about the potential effects of longer ablations or more ablation lesions. Thus if we could identify ways of only targeting those areas that are most critical to the VT circuits, we could perhaps short and ablation procedural time, allow for novel ways of approaching targeted ablation with limited amounts of ablation performed, or perhaps even improve overall VT outcomes by knowing the areas that are most critical to ensure adequate ablation therapy provided. However, we need to understand that this is still a limited number of patients evaluated in a non randomized manner. Thus whether or not more extensive ablation performed might have been better is as of yet unclear                                                 Staying within the realm of ventricular tachycardia we review an article published in last month's issue of Heart Rhythm by Winterfield et al. entitled the 'Impact of ventricular tachycardia ablation on healthcare utilization.' Catheter ablation of atrial tachycardia has been well accepted to reduce recurrent shocks in patients with ICDs. However, this is a potentially costly procedure, and thus effect on overall long-term health care utilization remains to be seen. The authors sought to evaluate in a large scale real world retrospective study the effect of VT ablation on overall medical expenditures in healthcare utilization. A total 523 patients met study inclusion criteria from the market scan database. After VT ablation median annual cardiac rhythm related medical expenditures actually decreased by over $5,000. Moreover the percentage of patients with at least one cardiac rhythm related hospitalization an ER visit decreased from 53 and 41% before ablation respectively, to 28 and 26% after ablation. Similar changes we're seeing in number of all cause hospitalizations and ER visits. During the year before VT ablation interestingly there was an increasing rate of healthcare resource utilization, but a drastic slowing after ablation.                                                 These data suggests that catheter ablation may lead to reduced hospitalization in overall healthcare utilization. The importance of these findings lies in understanding why we do the things we do. We can provide a number of therapies to patients, but we seek two different effects. One is the individual effect of improving their particular health. The second thing is trying to avoid increasing healthcare expenditures on a population level and making sure resources are utilized. If we can reduce recurrent hospitalizations and overall healthcare expenditure in patients by providing a therapy in addition to provide individual benefit, this is the optimal situation. These data suggests that VT ablation might provide such a benefits, that in fact it reduces overall healthcare utilization while improving overall outcomes.                                                 Next and finally within the realm of ventricular arrhythmias, we review more on the basic side the role of Titin cardiomyopathy leads to altered mitochondrial energetics, increased fibrosis and long-term life-threatening arrhythmias, published by Verdonschot et al. in last month's issue of European Heart Journal. It is known now that truncating Titin variants might be the most prevalent genetic cause of dilated cardiomyopathy. Thus, the authors sought to study clinical parameters and long term outcomes related to Titin abnormalities in dilated cardiomyopathy. They reviewed 303 consecutive and extensively phenotype dilated cardiomyopathy patients who underwent cardiac imaging, Holter monitoring, and endomyocardial biopsy and in turn also underwent DNA sequencing of 47 cardiomyopathy associated genes. 13% of these patients had Titin abnormalities. Over long-term followup they noted that these patients had increased ventricular arrhythmias compared to other types of dilated cardiomyopathy, but interestingly, they had similar survival rates. Arrhythmias in those Titin abnormal patients were most prominent in those who were subjected to an additional environmental trigger, including viral infection, cardiac inflammation, other systemic disease or toxic exposure. They also noted the cardiac mass was relatively reduced in titan admirable patients.                                                 They felt that all components of the mitochondrial electron transport chain we're simply up-regulated in Titin abnormal patients during RNA sequencing and interstitial fibrosis was also augmented. As a result, they concluded that Titin variant associated dilated cardiomyopathy was associated with an increased risk of ventricular arrhythmias, and also with more interstitial fibrosis. For a long time we have reviewed all non ischemic cardiomyopathy as essentially equal. However, more recent data has suggested that we can actually hone in on the cause. In turn, if we hone in on the cause, we might be able to understand the effects of specific therapies for ventricular arrhythmias based on that underlying cause. Patchy fibrosis might not be as amenable, for example, to ablation as discreet substrate that we might see in infarct related VT. Understanding the relative benefit in very specific types of myopathies might hold benefit in understanding how to, one, risk stratify these patients, and two, understand what type of therapy, whether pharmacologic or ablative, might result in greatest benefit to the patients.                                                 Changing gears entirely now to the role of genetics, we review multiple articles in various genetic syndromes published this past month. First, we reviewed an article by Providência et al. published in the last month's issue of heart entitled 'Impact of QTc formulae in the prevalence of short corrected QT interval and impact on probability and diagnosis of short QT syndrome.' The authors sought to assess the overall prevalence of short corrected QT intervals and the impact on diagnosis of short QT syndrome using different methods for correcting the QT interval. In this observational study they reviewed the sudden cardiac death screening of risk factors cohorts. They then applied multiple different correction formulae to the ECGs. They noted that the prevalence of individuals with the QTc less than 330 and 320 was extremely low, namely less than .07 and .02% respectively. They were also more frequently identified using the Framingham correction. The different QTc correction formulae could lead to a shift of anywhere from 5 to 10% of individuals in the cohort overall.                                                 They further noted, that based on consensus criteria, instead of 12 individuals diagnosed with short gut syndrome using the Bazett equation, a different number of individuals would have met diagnostic criteria with other formulae, 11 using Fridericia, 9 with Hodges, and 16 using the Framingham equation. Thus, they noted that overall the prevalence of short QT syndrome exceedingly low and an apparently healthy adult population. However, reclassification as meeting criteria might be heavily dependent on which QT correction formula is used. The importance of these findings is that not all QTs are created equal.                                                 Depending on how you compute the QT interval in which formula to use may affect how you actually risk characterize a patient. Unfortunately, these data do not necessarily tell us which is the right formula, but this highlights that it might be relevant to in the future evaluate the role of different formulae and identifying which is the most necessary to classify a patient.                                                 Moving on to an article published in last month's issue of the journal of clinical investigation by Chai et al. we review an article entitled 'Physiological genomics identifies genetic modifiers of Long QT Syndrome type 2 severity.' Congenital Long QT Syndrome is a very well recognized, inherited channelopathy associated life-threatening arrhythmias. LQTS type 2 is specifically caused by mutations in casein to encoding the potassium channel hERG. However, even with the mutation not all patients exhibit the same phenotype. Namely some patients are more at risk of life threatening arrhythmias in spite of having the same mutation as others who do not exhibit the same severity phenotype. The authors sought to evaluate whether specific modifiable factors within the remaining genetic code might be modifying the existing mutation. Thus, they sought to identify contributors to variable expressivity in an LQT 2 family by using induced pluripotent stem cell derived cardiomyocytes and whole exome sequencing in a synergistic manner.                                                 They found that patients with severely effected LQT 2 displayed prolonged action potentials compare to sales from mildly effected first-degree relatives. Furthermore, stem cells derived from patients were different in terms of how much L-type calcium current they exhibited. They noted that whole exome sequencing identified variants of KCNK17 and the GTP-binding protein REM2 in those patients with more severe phenotypes in whom greater L-type calcium current was seen. This suggests that abnormalities or even polymorphisms in other genes might be modifying the risk attributed to by mutations in the primary gene. This showcases the power of combining complimentary physiological and genomic analysis to identify genetic modifiers and potential therapeutic targets of a monogenic disorder. This is extraordinarily critical as we understand on one level that when we sequence a monogenic disorder that there might exist variants of uncertain significance, namely they have not been classified as disease causing, but could be. In turn, we also recognize that mutations in a family might effect different relatives differently. However, why this is has been relatively unclear.                                                 If we can understand and identify those patients who are most at risk of dangerous abnormal rhythms, this will be useful in how much to follow them, and what type of therapy to use in them. The fact that other genes might modify the risk even in the absence of specific mutations, suggests that novel approaches to characterizing the risk might help for the risk modified patients classification in general. Clinical use, however, remains to be seen.                                                 Moving on from long QT, we evaluate 'The Diagnostic Yield of Brugada Syndrome After Sudden Death With Normal Autopsy' noted in last month's issue of the Journal of American College of Cardiology and published by Papadakis et al. It is well known, the negative autopsies are not uncommon in patients, however, families might be wondering how at risk they are. Thus, the authors sought to assess the impact of systematic ajmaline provocation testing using high right precordial leads on the diagnostic yield Brugada syndrome in a large cohort of Sudden Arrhythmic Death syndrome families. Amongst 303 families affected by Sudden Arrhythmic Death Syndrome evaluation was done to determine whether or not there was a genetic inherited channelopathy cause. An inherited cardiac disease was diagnosed in 42% of the families and 22% of relatives Brugada syndrome was the most prevalent diagnosis overall amongst 28% of families. Ajmaline testing was required, however, to unmask the Brugada Syndrome in 97% of diagnosed individuals. Furthermore, they use of high right precordial leads showed a 16% incremental diagnostic yield of ajmaline testing for diagnosing Brugada syndrome.                                                 They further noted that a spontaneous type 1 regard or pattern or a clinically significant rhythmic event developed in 17% of these concealed regardless syndrome patients. The authors concluded the systematic use of ajmaline testing with high right precordial leads increases the yield of Brugada Syndrome testing in Sudden Arrhythmic Death Syndrome families. Furthermore, they noted that assessments should be performed in expert centers or patients could also be counseled appropriately. These findings are important and one of the big questions always becomes how aggressively to test family members of patients or of deceased individuals who experienced sudden arrhythmic death. Many of these patients have negative autopsies, and genetic autopsy might not be possible due to lack of tissue or blood products that can be adequately tested.                                                 The data here suggest that amongst a group of 303 sudden arrhythmic death, families that Brugada Syndrome is by far the most frequent diagnosis. If an inherited cardiac disease was identified. In turn, it is not ECG alone or echo alone that helps identify them, but requires drug provocation testing in addition to different electrode placements. Whether or not this will consistently offer benefit in patients in general or my result in overcalling remains to be seen next within the realm of genetic predisposition.                                                 We view an area where we don't know if there's a genetic predisposition in article published by Tester et al. entitled Cardiac Genetic Predisposition in Sudden Infant Death Syndrome in last month's issue of the journal of american college of cardiology. Sudden Infant Death Syndrome is the leading cause of post-neonatal mortality and genetic heart diseases might underlie some cases of SIDS. Thus the authors sought to determine the spectrum and prevalence of genetic heart disease associated mutations as a potential monogenic basis for Sudden Infant Death Syndrome. They study the largest cohort to date of unrelated SIDS cases, including a total of 419 individuals who underwent whole exome sequencing and targeted analysis for 90 genetic heart disease susceptibility genes. Overall, 12.6% of these cases had at least one potentially informative genetic heart disease associated variants. The yield was higher in those mixed European ancestry than those of European ancestry.                                                 Infants older than four months were more likely to host a potentially informative gene. Furthermore, they noted that only 18 of the 419 SIDS cases hold a [inaudible 01:01:26] or likely pathogenic variant. So in other words, only 4% of cases really had a variant that they could say was distinctly pathogenic or likely pathogenic. Thus, overall, the minority of SIDS cases have potentially informative variant in genetic heart disease susceptibility gene, and these individuals were mostly in the 4 to 12 month age group. Also, only 4% of cases had immediately clinically actionable variance, namely a variant, which is well recognized as pathogenic and where we could actually say that a specific therapy might have had some effect. These findings can have major implications for how best to investigate SIDS cases in families. It might suggest that SIDS cases where the individual was older, nearly 4 to 12 months of age might have a greater yield in terms of identifying variance.                                                 While this might not affect the deceased in fit, it might affect, families are planning on having another child in whom a variant can be identified.                                                 Finally, within the realm of genetics, we review an article published in last month's issue of Science Advances by Huang. et al. entitled 'Mechanisms of KCNQ1 Channel Dysfunction in Long QT Syndrome Involving Voltage Sensor Domain Mutations'. Mutations that induce loss of function of human KCNQ1 underlie the Long QT Syndrome type 1. While hundreds of mutations have been identified the molecular mechanism by which they result in impaired function are not as well understood. The authors sought to investigate impact of 51 specific variants located within the voltage sensor domain and emphasized effect on cell surface expression, protein folding, and structure. For each variant efficiency of trafficking of the plasma membrane, impact of proteasome inhibition, and protein stability were evaluated. They noted that more than half of the loss of function mutations were seen to destabilized structure of the voltage sensor domain, generally accompanied by mistrafficking and degradation by the proteasome.                                                 They also noted that five of the folding defective Long QT Syndrome mutant sites were located in the S0 helix, where they tend to interact with a number of other loss of function mutation sites in other segments of the voltage sensor domain. They suggested these observations reveal a critical role for the S0 helix as a central scaffold to help organize and stabilized KCNQ1 overall. They also note the importance of these findings is that mutation-induced destabilization of membrane proteins may be a more common cause of disease functioning in humans. The importance of these findings lies in better understanding why specific mutations lead to appa

Darryl is a 59-year-old male who presents the physical therapy with Class III Congestive Heart Failure. He has arrived from the inpatient unit after a severe exacerbation of his CHF but he is cleared by his M.D. for exercise. The physical therapist is challenged with understanding the pathophysiology related to congestive heart failure as well as the New York Heart Association stages. This knowledge is required in order to make sound and safe judgments regarding exercise prescription. Should we send this patient back to the physician for medical clearance or treat him? This is what we will uncover in this excellent episode based on treating Class III congestive heart failure. Are you in the free facebook group called, #smartnpteprep? Get access to test-taking strategies, live discussions, question & answers, and the most effective study tips. Come on in and join us! Click the link: Smart NPTE Prep Group [ Listen Here ]   

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.                                                 We know that excessive sedentary time is bad in terms of health outcomes, but does it matter how that sedentary time is accrued, whether in short or long bouts? Today's feature paper gives us some answers. More soon, right after the summary of this week's journal.                                                 The first original paper in this week's journal provides insights into the mechanisms underlying neointima formation in arterial restenosis. Co-first authors, Dr. Cheng and Shi, corresponding author Dr. Li from Wuhan University in China, and their colleagues, performed an elegant series of experiments in which they demonstrated that interferon regulatory factor 4, or IRF4, which is a member of a family of key, innate, immune regulators known to play a role in cardiometabolic disease, actually protects arteries against neointima formation.                                                 They further probed the mechanism underlying this protective effect and found that IRF4 promoted the expression of Krüppel-like factor 4 by directly binding to its promoter. Genetic over-expression of Krüppel-like factor 4 in smooth muscle cells reversed the neointima promoting effect of IRF4 ablation. Whereas, ablation of Krüppel-like factor 4 abolished the protective function of IRF4, thus indicating that the protective effects of IRF4 against neointima formation were Krüppel-like factor 4 dependent.                                                 These findings suggest that the previously undiscovered IRF4 Krüppel-like factor 4 axis plays an important role in vascular proliferative pathology and thus may be a promising therapeutic target for the treatment of arterial restenosis.                                                 The next paper highlights that high-spacial resolution in gene expression signatures can reveal new regulators, genetic pathways, and transcription factors that are active in well-defined regions of the heart.                                                 Now we know that traditional genome-wide transcriptome analysis has been disadvantaged by the fact that the signals are derived from tissue homogenates. Thus, the authors of this current paper, including Co-First authors Dr. Lacraz and Junker, corresponding author Dr. Van Rooij from University Medical Center Utrecht in the Netherlands used tomo-seq to obtain genome-wide gene expression signature with a high spacial resolution, spanning from the infarcted area to the remote areas to identify new regulators of cardiac remodeling.                                                 Using this technique, they identified SOX9 as a potent regulator of cardiac fibrosis. In vivo loss of SOX9 reduced the expression of many extracellular matrix genes, which coincided with a blended cardiac fibrotic response upon ischemic injury.                                                 These data therefore were able to unveil currently unknown relevance of SOX9 as a key regulator of cardiac fibrosis, thus underscoring that tomo-seq can be used to increase our mechanistic insights into cardiac remodeling, and to help guide the identification of novel therapeutic candidates.                                                 The next paper reports the primary results of the effect of ferric carboxymaltose on exercise capacity in patients with iron deficiency and chronic heart failure, or EFFECT-HF study, which is a randomized control trial of intravenous ferric carboxymaltose, compared to standard of care on the primary end point of change in peak Vo2 from baseline, to 24 weeks in patients with symptomatic, chronic heart failure with reduced ejection fraction and iron deficiency.                                                 In this report from Dr. van Veldhuisen from University Medical Center Groningen and colleagues, intravenous ferric carboxymaltose was shown to significantly increase serum ferritin and transferrin saturation. At 24 weeks, peak Vo2 had decreased in the control group, but was maintained in the group receiving intravenous ferric carboxymaltose.                                                 Although a favorable effect on peak Vo2 was observed with ferric carboxymaltose, compared to standard of care in the primary analysis, this effect was highly sensitive to the imputation strategy for peak Vo2 among patients who died.                                                 They also reported that patient's global assessment and functional class, as assessed by New York Heart Association, improved on ferric carboxymaltose compared to standard of care.                                                 Whether ferric carboxymaltose is associated with an improved outcome in these high risk patients, deserves further study.                                                 The final study provides important long term clinical data to guide lead management decisions in patients with cardiac implantable electronic devices.                                                 Dr. Pokorney from Duke University Medical Center in Durham, North Carolina, and colleagues, analyzed over 6,000 Medicare patients and found that device extraction was associated with a lower adjusted five year infection rate, compared with a cap and abandon strategy. There was a lower absolute five year mortality with extraction, but after adjustment there was no association between extraction and a lower five year mortality.                                                 In summary, therefore, elective lead extraction for non-infectious indications in this Medicare cohort had similar long term survival, but lower risk of device infections at five years, compared to capping and abandoning leads.                                                 Patient and provider preferences are critical to decision making when considering extraction versus capping and abandonment of leads.                                                 Well, that wraps it up for your summaries. Now for our feature discussion.                                                 For today's feature discussion, we are talking about sedentary time and a metabolic risk of having too much of it. But, today's paper is so interesting because it tells us that it's not just the total amount of sedentary time that may matter, but how we accrue the sedentary time. Very, very novel concept in my point of view and I'm so pleased to have the first and corresponding author of this paper, Dr. Keith Diaz from Columbia University Medical Center with us, as well as Associate Editor from Johns Hopkins, Dr. Wendy Post.                                                 So pleased to have you both. Keith, could we just dive right into it? Tell us what population you were looking at, and what you found. Dr. Keith Diaz:                    Sure, so we were studying a population of participants enrolled in the Hispanic Community Health Study, so it's a US populations of over 16,000 Hispanic adults. And essentially what we found was that sitting for prolonged bouts, so sitting for one, two hours at a time, was associated with poor glucose regulation. Dr. Carolyn Lam:               Well, yikes. I've actually been sitting for a few hours in a row right now, actually. I think these results are phenomenal, but could you maybe expand a little bit on the details, like how long is too long? And, how often a break needs to happen for you to see differences in the metabolic risk? Dr. Keith Diaz:                    It's a good question and, to be honest, we don't know. I think that's where the research needs to head, but right now it seems to be that taking a break every 30 to 60 minutes could be beneficial. I think that's what we've found thus far. Dr. Wendy Post:               Keith, we were really excited to get your paper in. I think everyone on the Associate Editorial Board was especially interested in it because we can all relate. As Carolyn said, she's been sitting for a long time and when we have these meetings we have two hour meetings at a time and maybe we need to start saying that in the middle we should all stand up and take a break. So we can all relate to this.                                                 But I think one the biggest questions that we had related to data itself, was the association between the total sedentary time and the sedentary bout duration. Maybe you can tell us a little bit more about those correlations in the interaction and tell us also how you also measure sedentary bout duration and total sedentary time in this observational cohort. Dr. Keith Diaz:                    Sure, so I'll start with that latter question. So, we measured sedentary time [inaudible 00:09:32] subjectively. So we actually used an activity monitor called an accelerometer to see how sedentary they are. And how we quantified sedentary bouts is we just looked at how long consecutively a person sat without moving. That was considered sedentary bout. In terms of correlation, what we found is that there are very closely linked. So, people who sit for long hours during the day for total volume, also sit in long bouts. And so what we wanted to do was try to figure out and piece apart, which one is more important? When we're trying to ... If we're thinking about guidelines and what we should be doing about our sedentary time, is it important to reduce our volume or interrupt our bouts? And so what we found is that they're not independent, and that they're in many ways synergistic. And that the association of prolonged sedentary bouts with glycemic biomarkers varied according to how much total volume you sit and vice-versa. Dr. Wendy Post:               Can you expand a little bit more on that? So tell us about the interaction that you found between sedentary bout duration and total sedentary time. Dr. Keith Diaz:                    Sure, so we did find that there was a specifically significant interaction between the two variables and so what we tried to do is actually categorize people as to whether they were high for both characteristics or high for just one of them. And so what we found was that those participants who are high for both, so they had high volume and sat in long bouts, they had the worst glucose regulation, and that those individuals that were high for just one of the characteristics had a little bit better glucose regulation. And so really what we thought the take home message was when thinking about how do we improve our sedentary behaviors is that it's targeting both. It's not sitting for large volumes during the day, but also making sure to take frequent breaks every 30 or 60 minutes. Dr. Wendy Post:               And tell us about the glucose measures that you included in your study. Dr. Keith Diaz:                    Yep, we had a couple glucose measures. One we had people do a two hour glucose tolerance test, so they took a glucose drink and then we measured their blood sugar levels two hours after having that drink. We also measured their H1Ac levels as well as their fasting glucose and fast to link insulin measures from which we can then derive measures of something called HOMA IR, which is a measure of insulin resistance. Dr. Wendy Post:               And the associations that you saw were primarily with the HOMO IR and the two hour glucose levels but less with the hemoglobin A1c? Dr. Keith Diaz:                    Correct. Dr. Wendy Post:               So it really appears to be that insulin resistance that's most affected by the total sedentary time and sedentary bout duration. Tell us about potential confounders and how you factored that into your analysis. Dr. Keith Diaz:                    Yeah, there was quite a number of potential confounders between this relationship of sedentary behavior and glycemic biomarkers. One of them in particular that we were concerned about most were things like body mass index or exercise or physical activity levels. And so we took a look at what we adjusted for those confounders how the relationship changed. And what we did find was that there was an attenuation and association between sedentary behavior and the glucose markers, but there was also ... were still statistically significant. So suggestive that maybe they're partly in the pathway of body mass index or exercise but they didn't make the relationship go away. I should add that we looked at a couple other confounders, we looked at things like inflammation, C-reactive protein, as well as whole bunch of other measures of cardiovascular risk factors. I'll stop there. Dr. Wendy Post:               And what about the fact that study is cross-sectional, are there any caveats related to the study design that you'd like to point out to the audience? Dr. Keith Diaz:                    Yeah, I think that's an important point, that this is cross-sectional, so by no means can we infer causality that sedentary behavior causes glucose dysregulation, it's just purely an association. So I think anyone listening to this podcast should keep that in mind when reading this paper or listening to this podcast. Dr. Wendy Post:               So if you were writing the next set of guidelines what would you recommend in terms of how you implement these findings into guidelines? Not to imply that we think that these cross-sectional observational data mean that we're ready to change guidelines but, if these were replicated in randomized trial or some other more objective data study design, how do you think we should use these results to change our behaviors? Dr. Keith Diaz:                    I think these guidelines point ... or, with the current guidelines are, sit less, move more, where the guidelines that came out from AHA in October of 2016. In part, they were not as specific because we don't have quite the quality of guidelines or data that we need for more qualitative guidelines, or quantitative guidelines. I think if we're able to replicate these data with [inaudible 00:14:10] or point us towards at least is, also, that we should be interrupting our sedentary bouts. And so what I'd like to see hopefully if we can replicate something I'd like guidelines that say every 30 minutes or every 60 minutes of sitting you should stand up and move. And hopefully with future studies that are coming out that we can make them even more specific and something along the lines of every 30, 60 minutes you stand up and walk for 5 minutes or you just stand up for 1 minute. That's where I'd like to see the science head and I think this study points us in the that direction of maybe we have to start thinking about breaking up our sedentary bouts. Dr. Carolyn Lam:               All right you guys, I don't know about you, but I am literally standing up right now while I'm listening to you both. This is so interesting and I love the way, Wendy, you reflected the robust discussions we had as team when we were working through this paper. Congratulations again, Keith, for just this remarkable paper. Actually, maybe I could just ask, Wendy, what do you think? What do you think our next steps that may need to get these kinds of recommendations, perhaps into guidelines? Dr. Wendy Post:               I think as was alluded to before, these are observational data so they're important for hypothesis generation, but really to have evidence that would lead to changes in guidelines maybe having a randomized trial, where obviously you can't have very hard outcomes, but randomized trials of some duration that could potentially lead to changes and important outcomes, would then maybe lead to changes in guidelines. But there isn't anything that we would lose from trying to implement these kinds of behavior, changes into our lifestyle since the downside and the risk is pretty low. So even if they don't make the strongest level of evidence at this point, I think we can still all be mindful of this and so.                                                 One thing that we've been trying to do in our preventive cardiology group at Hopkins is trying to implement walking meetings. In fact, I just had an email discussion with one of my colleagues about meeting tomorrow and she said, "Well, where do you want to meet?" And I said, "Well, why don't we go for a walk? The weather should be nice." And so I think if we're all mindful of trying to, not only increase our amount of physical activity, but trying to limit the sedentary bout duration by being creative and trying to change, sort of, long standing traditions of having meetings sitting in an office, then that could be helpful.                                                 So, just something for our audience to think about as well. Dr. Carolyn Lam:               That's brilliant. You know, the one thing that I was thinking, though, just thinking about the reception of these data in my country, in where I practice, in Asia. This was a purely Hispanic or Latino population. I suppose there is a perception that that population may be predisposed to cardiometabolic disease and so on, and so you know, what's the applicability to us in Asia? So, I'm really happy, particularly to hear how you've taken it on. I mean, it's a simple thing, why not, right? Just to be more active. There's surely can't be something wrong with that. What do you think of that? Dr. Wendy Post:               Totally, I think it's important to emphasize the unique nature of these data and that they come from a Hispanic study, which is a really important addition to our literature in epidemiology and cardiovascular disease and certainly there are significant differences in lifestyle among different communities within the United States and across the globe, as you've experienced having lived in different countries. And so, I think we need obtain more data about how there might be differences based on various traditions and different lifestyles, and try to target those who are at greatest risk. Dr. Carolyn Lam:               Keith, did you have anything to add to that? Dr. Keith Diaz:                    Yeah, I think Wendy is right on and certainly I don't think we have any reason to suspect that sedentary behavior acting differently in Hispanics versus other populations, and so I still think going forth with this notion that we all should be reducing our sedentary behaviors is important to highlight. Dr. Carolyn Lam:               Fantastic. Well, thank you both for a really wonderful discussion. This is really cool, I think a lot of people will be talking about this.                                                 Listeners, you've heard it first, though, in Circulation on the Run. Thank you for joining us today and don't forget to 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.

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. In just a moment, we will be discussing the sources of sodium in the US diet, results that may surprise you, and that carry profound public health importance. But first, here's your summary of this week's issue.                                                 The first original paper advances the field of cardiac tissue engineering by establishing a defined serum-free protocol to generate functional human myocardium from pluripotent stem cells. In this paper by first author, Dr. Tiburcy, corresponding author Dr. Zimmermann and colleagues from the University Medical Center Goettingen in Germany, the authors systematically investigated cell composition, matrix and media conditions to generate engineered human myocardium from embryonic and induced pluripotent stem cells and fiberglass, under serum-free conditions. The engineered human myocardium demonstrated important structural and functional properties of post-natal myocardium, including rod-shaped cardiomyocytes with M-bands, systolic twitch forces, a positive force-frequency response, inotropic responses to beta adrenergic stimulation, evidence of advanced molecular maturation by transcriptome profiling and the engineered human myocardium even responded to chronic cholinomimetic toxicity with contractile dysfunction, cardiomyocyte hypertrophy, cardiomyocyte death, and anti-pro BNP release, which are all classical hallmarks of heart failure.                                                 Finally, the authors demonstrated scalability of engineered human myocardium according to anticipated clinical demands for cardiac repair. In summary, this paper provides proof of concept for a universally applicable technology for maturation and scalable production of engineered human myocardium, something that is termed a stride forward in an accompanying editorial by Doctors Yang and Murray, from University of Washington in Seattle.                                                 The next paper describes a new frontier for interventional cardiology, the percutaneous therapy for tricuspid regurgitation. Here, Dr. Nickenig and colleagues, from University Hospital Bonn in Germany, recruited 64 consecutive patients deemed unsuitable for surgery who underwent mitroclip treatment for chronic, severe tricuspid regurgitation for compassionate use. Twenty-two patients were also concurrently treated with a mitroclip system for mitral regurgitation as a combined procedure. The degree of tricuspid regurgitation was severe or massive in 88% of patients before the procedure. The mitroclip device was successfully implanted in the tricuspid valve in 97% of cases.                                                 After the procedure, tricuspid regurgitation was reduced by at least one grade in 91% of patients. 13% of patients with tricuspid regurgitation remained severe after the procedure. There were significant reductions in effective regurgitant orifice area, vena contracta width, and regurgitant volume. There were no intra-procedural deaths, cardiac tamponade, emergency surgeries, stroke, myocardial infarction or major vascular complications.                                                 There were three in-hospital deaths. New York Heart Association class was significantly improved and six minute walk distance increased significantly. In summary, this study demonstrates that trans-catheter treatment of tricuspid regurgitation with the mitroclip system seems to be safe and feasible in this cohort of pre-selected patients.                                                 The next paper describes the pooled safety analysis of evolocumab, a fully human monoclonal antibody to PSK-9. Dr. Toth of Johns Hopkins University School of Medicine and the PROFICIO investigators perform this pooled analysis from the PROFICIO program, which included over 6,000 patients from 12 Phase 2 and 3 trials, and the corresponding open-label extension trials, and they showed that treatment with evolocumab, up to one year, was not associated with discernible differences in adverse events, serious adverse events, or key laboratory assessments, compared to control or standard of care.                                                 In addition, adverse events rates did not increase among patients attaining very low levels of LDL cholesterol, of less than 25 milligrams per deciliter, compared to patients attaining LDL cholesterol levels above 40 milligrams per deciliter. In summary, the present analysis confirms a favorable benefit risk profile for evolocumab treatment for up to one year.                                                 Does aggressive blood pressure lowering prevent recurrent atrial fibrillation after catheter ablation? Well, this question is addressed in a randomized, open-label clinical trial known as the Substrate Modification With Aggressive Blood Pressure Control or SMAC-AF Trial. In this trial, Dr. Parkash of Halifax, Canada and colleagues, randomly assigned 184 patients with atrial fibrillation and a blood pressure of greater than 130 over 80 to aggressive blood pressure lowering, with a target of less than 120 over 80, or to standard blood pressure treatment, to a target of less 140 over 90, prior to their scheduled atrial fibrillation catheter ablation.                                                 The primary outcome was symptomatic recurrence of atrial fibrillation, atrial tachycardia, or atrial flutter lasting greater than 30 seconds, determined 3 months beyond catheter ablation. The authors found no additional benefit to the addition of aggressive blood pressure lowering over a median of 3.5 months, over standard blood pressure therapy, in patients undergoing catheter ablation for atrial fibrillation to prevent recurring atrial arrhythmia.                                                 In subgroup analysis, a signal of benefit was observed in groups whose blood pressure were lower at the point of entry into the study, and in those patients who were older. The duration of blood pressure lowering in the study did not result in reduction of recurrent atrial fibrillation after catheter ablation, however there was a higher rate of hypotension requiring medication adjustment in the aggressive blood pressure group.                                                 Thus, this trial showed that neither aggressive blood pressure lowering compared to standard blood pressure lowering, nor the duration of aggressive blood pressure treatment reduced atrial arrhythmia occurrence after catheter ablation for atrial fibrillation, but resulted in more hypotension.                                                 Well, that wraps it up for our summaries! Now, for our feature discussion ...                                                 Our topic today is so universal and so important. It's about sodium intake and the sources of sodium, at least in the US, and I have with me two lovely ladies, the corresponding author of our paper, Dr. Lisa Harnack, from School of Public Health, University of Minnesota, and a regular on the show, shall I say, Dr. Wendy Post, Associate Editor from Johns Hopkins. Welcome, ladies! Dr. Wendy Post:               Thanks you, Carolyn! It's a pleasure to be here. Dr. Lisa Harnack:               Thanks, thanks. Dr. Carolyn Lam:               Lisa, let's dig right into your paper. Let's start by discussing that there was a prior paper that looked at sources of sodium in the US population. So please tell us, what inspired you to do your paper, and were you surprised by your findings? Dr. Lisa Harnack:               Right, well the previous study was over 25 years old, and it involved just 69 people from one geographic area, and, you know, it was informative, but it didn't tell us about America today, and how much sodium we're getting from different sources, and it didn't tell us much about a variety of ethnic groups ... we're a diverse country. So the CDC actually funded this study, and really they saw the need for it and laid out that this study needed to be done, as it was done, in three geographic areas, representing different ethnic groups. Dr. Carolyn Lam:               Tell us what you did. Dr. Lisa Harnack:               So, we recruited 450 people from 3 different areas, from Minneapolis/St. Paul metropolitan area ... Stanford was a partner in this study and they recruited people from that area of California, and then, finally, Birmingham, Alabama was a partner was a partner, and we got participants from there.                                                 So the racial groups we had represented were white Americans, African Americans, Asian Americans and Hispanics. Dr. Carolyn Lam:               Yeah, I was really struck ... you had almost equal representation of women as well, didn't you? Dr. Lisa Harnack:               Right, so we made sure we had half of the participants were women, so we could really see how things stood with a variety of groups. Dr. Carolyn Lam:               That's excellent. What I was really impressed, as I'm sure, Wendy, you were, too, was the detail of the methodology. Could you tell us a little bit about that? Dr. Wendy Post:               Right, so we wanted to know all the sources of sodium. Part studies have tended to not ask about salt added to food at the table, and in home food preparation, because it's really hard to actually know ... you know, if you ask somebody, "Oh, did you add salt at the table? How much did you add?" They don't know. They just say, "Oh, well, I shook some salt on." So, we had people collect duplicate samples of the salt they added to food at the table and home food preparation. We gave them little baggies ... collection bags ... you know, after they added salt at the table, shake some into the baggy. So, we knew exactly how much because people do add salt in the home, so they have some control over how much sodium is in their diet. But the question is in how much under people's control in their home versus what's coming from the food supply. Dr. Carolyn Lam:               Right. And what I loved about the results is ... I think that it would challenge a lot of what people expect. Because when we talk about sodium restriction, everyone thinks, "Oh, it's the additional salt we add." And your study actually had surprising results. So, could you tell us? Dr. Wendy Post:               Yes, so it really was clear that the salt that people add at the table is just 5% of their total sodium intake, on average, across people in our study, and the salt added in home food preparation, like maybe the salt you add to your pasta when you're boiling it or to your eggs ... that was just 6%. So, 11% of the sodium in our study participants' diets was sort of that under-your-control in-the-home, and the rest was from other sources. So, the other things we looked at was, "Will water contribute some sodium?" So, we wanted to see how much comes from your home tap water. There's sodium that's just naturally occurring in food, like milk just naturally contains some sodium. So we wanted to look and see how much came from just naturally occurring in the food, and then the other question was how much is added by food manufacturers as part of making the food product, and that included the salt that might be added in making potato chips, as well as in restaurants ... the salt that might be added in making French fries or a pasta dish at a restaurant. Dr. Carolyn Lam:               And the biggest culprit? Dr. Lisa Harnack:               Yes, the biggest culprit was that latter source ... food added in processing. Dr. Carolyn Lam:               I thought that was amazing. Wendy, what do you think the public health message is? I mean, 70% almost of the salt's coming from processed foods from outside. What do we do? Stop eating it? What do we do? Dr. Wendy Post:               Right, so, on the editorial board for Circulation, we really liked this paper because of its very high impact for a public health message. So, as was stated, the sodium that we're getting in our diet is largely coming from processed foods and from foods we eat in a restaurant. So there are a number of ways that that can be modified and one is for our patients to read food labels and to make smart choices when they are shopping for processed foods in the supermarket.                                                 But the other is for food manufacturers to decrease the amount of sodium in the products that they are making and there are voluntary suggestions by the FDA that food manufacturers reduce the sodium content of the food, and especially bread is incredibly high in sodium, and I suspect that most of our patients don't know that. So, if we were able to reduce the amount of sodium in the food supply by just a small fraction, it could have a large public health impact because we all eat.                                                 So, it would affect everybody, and then I think the other really important public health message is about eating in restaurants and, of course, some people eat out more than others, and some people eat out in fast food restaurants, which, of course, are very high in sodium, but even in some of the nice restaurants that we go to, even expensive restaurants, the food is very heavily salted and I, for one, when I go out to eat, and sometimes don't like the taste of the food because it has so much salt in it, when I'm used to eating a low sodium diet.                                                 So, there are a number of changes that occur on that level. One is for our patients to understand what foods tend to have a lot of sodium at a restaurant, but also for restaurants to notify their clientele of what foods are potentially lower in sodium and calories and generally provide the nutrient value so that we can make smart choices when we eat out. Dr. Carolyn Lam:               Yeah, indeed, congratulations, Lisa - what an important paper. Quick question, so that was the overall main message, but did you find any differences by different racial groups, by sex, by different socioeconomic status? Dr. Lisa Harnack:               We did find some differences. We found one difference was it looked like African Americans tend to add more salt at the table than some of the other groups, and, actually, Asians add less in our study. But still for all groups, that sodium added to food in processing was still the main source by a long shot, so, although there were some small differences by groups, it was clear that for all groups, the issue was the sodium added in processing. Dr. Carolyn Lam:               And for both Lisa and for Wendy, do you think these results are generalizable even beyond the US? Dr. Wendy Post:               I'd imagine that there would be quite a lot of variability, based on the habits of the various populations. So, here we're talking about eating outside the home, or food that's processed outside of the home, so there may be countries where most people are producing their own food and not necessarily buying processed foods or eating in restaurants, and then this would definitely be less applicable. And, of course, there are differences in foods that we eat based on our different ethnic groups. Dr. Lisa Harnack:               No, I would agree with what's just said. It really could be variable, but it does seem that a lot of countries are concerned about processed foods. Some countries implemented mandatory limits on the sodium in the foods in their food supply, so that would indicate to me that they know there's ... for some countries, there's serious concern about this source of sodium. Dr. Carolyn Lam:               Yeah, and I think this is really a wake-up message for us to examine where these sources of sodium ... I mean, even that simple message that it could be coming from bread, from drinking water, I think that would be surprising to a lot of us, even those of us practicing in medicine. Wendy, finally, you thought this was important enough to invite an editorial. I'd really like your thoughts there. Dr. Wendy Post:               You'll be able to read the editorial when it comes out in print, but the editorial also congratulates the authors on a really important paper, and the important public health messages, and, especially, compliments the authors on having a diverse group of participants, including ethnic minorities and men and women, and different geographic locations, so overall, it's a very important paper that I'm sure will have an important impact on the public health of our country and others. Dr. Carolyn Lam:               Listeners, you heard it right here. Remember, you're listening to Circulation on the Run. Please share this episode, and tune again next week!

Dr. Carolyn L.:                    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. On our podcast today we are discussing the role of diastolic stress testing and the evaluation of heart failure with preserved dejection fraction, a really hot topic indeed, but first here's your summary of this week's issue.                                                 The first study tackles the obesity paradox in cardiac surgery, where morbidity and mortality are lower in obese patients. This study sought to ask the question, "Is this due to reverse epidemiology, bias, or confounding?" To answer this question, Dr. Maris Kelko and colleagues from University Leicester in United Kingdom used two separate analysis. One, registry data from the National Adult Cardiac Surgery Registry and two, a systematic review in meta-analysis of studies. Of more than 400,000 patients in the cohort study and more than 550,000 patients in the systematic review, the authors found a U shape association between mortality and body mass index classes, where lower mortality was observed in overweight and obese class one and two patients, relative to normal weight patients, and mortality was increased in underweight individuals.                                                 Now, the obesity paradox has been attributed to reverse epidemiology where the survival benefit associated with obesity is thought to actually reflect worse outcomes in the underweight patients who also had frailty, cachexia, or severe chronic disease. However, in the current study, counter to the reverse epidemiology hypothesis, the protective effects of obesity were less in patients with chronic renal, lung, or cardiac disease and greater in older patients as well as in those with complications of obesity, such as metabolic syndrome and atherosclerosis. Furthermore, adjustments for important confounders did not alter the results. The authors therefore concluded that obesity is associated with lower risks after cardiac surgery with consistent effects noted in multiple analysis even after attempting to address residual confounding and reverse causation.                                                 The authors even went as far as to suggest that their findings do not support common practice where weight loss is recommended prior to surgery or where very obese patients are refused surgery in the morbidly obese. These provocative findings are discussed in an accompanying editorial by Doctor's Carnethon and Kahn from Northwestern University. While the editorialists agree that this well-designed study highlights an important knowledge gap, they pointed out that the obese class two patients had nearly five times greater risk for deep sternal wound infection and 25% higher likelihood of needing renal replacement therapy.                                                 In such patients additional intervention in the perioperative period may still be indicated and include weight loss recommendations and postoperative surveillance for complications. Thus, a more cautious final recommendation may be for future studies to prospectively assess weight loss interventions prior to elective surgery in the context of overall surgical risk as assessed by the EuroSCORE or STS models.                                                 The next paper describes mechanistic studies showing for the first time that nucleoside diphosphate kinase suppresses cyclic-AMP formation in human heart failure. In this paper by First Authors, Dr. Abu Taha and Hagemann, corresponding authors Dr.'s Tobref and Weilend from the Heidelberg University in Germany, the authors performed biochemical studies of nucleoside diphosphate kinase and G Protein signaling in human and rat tissue samples, assessed the functional impact of nucleoside diphosphate kinase C on cyclic-AMP levels and contractility and isolated red cardiomyocytes and determined that in vitro effects of these nucleoside diphosphate kinases on contractility in zebra, fish and mice.                                                 They identified nucleoside diphosphate kinase as the critical isoform for the regulation of G Protein function and cyclic-AMP levels in the heart with important consequences for cardiac contractility. The increased nucleoside diphosphate kinase membrane content in human heart failure could potentially counteract a fading beta adrenoceptor response in the early stages of heart failure by increasing the amount of G Alpha stimulatory proteins in the plasma membrane. However, by switching from stimulatory to G Alpha inhibitory to activation, nucleoside diphosphate kinase may play a role in heart failure progression by reducing cyclic-AMP levels, typical for end-stage human heart failure.                                                 The study, therefore contributes to a better understanding of the molecular processes, underlying alter G Protein signaling in heart failure, and may help to develop new heart failure therapies.                                                 The next study tested the hypothesis, that high intensity interval training is superior to moderate continuous training in reversing cardiac remodeling and increasing aerobic capacity in patients with heart failure and reduced ejection fraction.                                                 Doctor Ellingson and colleagues from the Norwegian University of Science and Technology, performed a multicenter trial, comparing twelve weeks of supervised interventions of high-intensity interval training at 90 to 95% maximal heart rate, moderate continuous training at 60 to 70% maximal heart rate, or a recommendation of regular exercise in 261 patients with heart failure and ejection fraction less than 35%, in New York Heart Association class II or III status.                                                 The primary end point of change in left ventricular end-diastolic diameter from baseline to twelve weeks was not different between the high-intensity and moderate continuous groups. There was also no difference between the high-intensity and moderate groups in peak oxygen uptake, although both were superior to the recommendation for regular exercise. None of these changes were maintained at follow up after 52 weeks. Serious adverse events were not statistically different. However, training records showed that 51% of patients exercised below the prescribed target, during supervised high-intensity interval training, and 80% above the recommended target in those with moderate continuous training. Given that high-intensity interval training was not superior to moderate continuous training, in reversing remodeling or improving secondary end points, and considering that adherence to the prescribed exercise intensity based on heart rate was difficult to achieve even in the supervised setting.                                                 The authors concluded that moderate continuous training remains the standard exercise modality for patients with chronic heart failure.                                                 The final paper tells us, that brain emboli after left ventricular endocardial ablation may be more common than we knew. First author Doctor Whitman, corresponding author Doctor Marcus and colleagues from University of California studied eighteen consecutive patients, scheduled for ventricular tachycardia or premature ventricular contraction ablation, over a nine month period. Twelve patients undergoing left ventricular ablation were compared to a control group of six patients, undergoing right ventricular ablation only. Heparin was administrated with a goal activated clotting time of 300 to 400 seconds for all left ventricular procedures. Pre impulse procedural brain magnetic resonance imaging was performed on each patient within a week of the ablation procedure. The authors found that seven of the twelve patients, or 58% undergoing left ventricular ablation, experienced a total of sixteen cerebral emboli, compared with none among patients undergoing right ventricular ablation. Seven of the eleven patients undergoing a retrograde approach to the left ventricle, developed at least one new brain lesion. Thus, more than half of patients undergoing routine left ventricular ablation procedures, experienced new brain emboli after the procedure, even in the absence of clinically apparent stroke.                                                 Future research is critical to understanding the long-term consequences of these lesions and to determine optimal strategies to avoid them. This is further discussed in an editorial entitled "The Sound of Silence". How much noise should we make about post ablation silence strokes? By Doctor Z and Vora from Stanford University. Well, those were your summaries, now for our featured discussion.                                                 I am so thrilled to have with me two special guests to discuss the topic of the diagnosis of heart failure preserved ejection fraction or HFpEF. As you all know, that's my favorite topic and I have favorite people with me today. First, the corresponding author of our feature paper, Doctor Barry Borlaug from Mayo Clinic, Rochester, Minnesota. And, for the first time on the podcast, Doctor Mark Drazner, Senior Associate Editor from UT Southwestern. So, welcome Barry and Mark. Barry Borlaug:                    Thank you Carolyn. Mark Drazner:                   Thank you, great to be here. Dr. Carolyn L.:                    So, Barry, you talked about the role of stress diastolic testing, shall I call it, in the  diagnosis of HFpEF in your paper. Could you tell us why you looked at it and what you found? Barry Borlaug:                    Sure, Carolyn. When you have dyspnea and fatigue and you got a low EF, it's pretty easy to make the diagnosis of heart failure reduced EF, but we've been struggling for years with making the diagnosis of dyspnea, whether it's HFpEF or not in people with normal ejection fraction. And that's because physical and laboratory and clinical signs of high filling pressures and congestion, are either difficult to see or only present during stress, like physical exercise, in patients. So that's really what motivated us to pursue this study.                                                 We took patients, that were referred to our cath lab for invasive hemodynamic exercise testing, so we directly measured filling pressures, PA pressures and cardiac output reserve, to get a gold standard assessment, whether people have heart failure or not. And then we performed simultaneous echocardiography and blood testing to measure NT-proBNP levels, and then we just looked at what we could figure out. Can you accurately discern HFpEF patients from patients without cardiac dyspnea, using these non invasive estimates.                                                 We saw that a lot of people, with, for example, NT-proBNP levels that are low enough to be where most would consider HFpEF excluded, actually had HFpEF. And we saw that there were modest correlations between non-invasive echocardiographic estimates of filling pressures, specifically the E to E Prime ratio, and directly measured left heart filling pressures. But when we applied the criteria that had been initially proposed, we saw poor sensitivity to make the diagnosis with exercise. And this was largely related to the difficulty with getting all of the different echocardiographic indices, that are currently examined as part of the diastolic stress testing non-invasively. Next, we looked at just adding the exercise E to E Prime, which is an estimate of filling pressures, and when we used the cut-point, that's already been proposed, according to contemporary data, we found that this substantially improved the sensitivity to identify HFpEF, but there was a bit of a trade-off in that specificity decrease. Dr. Carolyn L.:                    That's so cool. So let me summarize some of these take-home messages here. First of all, using just rest echo. I was really impressed to see that rest echo indices alone only identifies a third to maybe up to 60% of the patients you found with invasively proven HFpEF. So, we may be specific, but we're really missing quite a number of patients. And then if you exercise them, what your data is really showing is that it's better to exercise them and use this data for the negative predictive value, isn't that what you're saying? Barry Borlaug:                    You know, the exercise is really the gold standard, so it gives you both, the negative and positive. With the echocardiography, relying on the exercise E to E Prime ratio, that was really helping us, as you say, Carolyn, with the higher negative predictive value. So most people, that had HFpEF, in this series, where we could get adequate, highly controlled environments, adequate diagnostic echocardiographic data, most people that ended up having HFpEF fit those criteria, we could see an elevation in this E to E Prime on exercise, so it did provide good negative predictive value. Dr. Carolyn L.:                    These are just such important data, because I think we're all still struggling with how to make this diagnosis of HFpEF. Mark, could you just share some thoughts on whether you think this is going to really change practice, even change guidelines? Mark Drazner:                   I think, if you read this paper, you would recognize it, that it's certainly a critical question that we're all facing, how to make the diagnosis of HFpEF. And all of their guidelines that have been advocated, there really wasn't much data, and these really are the best data out there. So, certainly, it's [inaudible 00:15:41] me a direction of changing practices. Barry says, certainly, the approach will need to be validated, I think, before it reaches high level guidelines, but certainly I think it's a step in the right direction, and points the way towards the future in terms of improving our ability to diagnose HFpEF. And really, that's why both reviewers and [inaudible 00:15:59] this is such an important paper. Dr. Carolyn L.:                    Right. Barry, I have a quick question for you though. Doing exercise echo, not easy. E to E Primes are all over the place usually. How easy was it? How feasible was this test? Barry Borlaug:                    So, first I'd like to say that we have outstanding, very well-trained, very highly skilled research scenographers, here at Mayo doing this. In very controlled environment, we're providing plenty of time for them to obtain images and that's going to be a question moving forward, because not everybody in clinical practice has that capability. But with that said, in this very controlled environments, skilled scenographers, we were able to measure the exercise data during low level exercise about 85 to 90% of the time and at peak exercise about 75 to 80% of the time. So, it's fairly feasible, but even in this best case scenario, we can't get it on everybody. Mark Drazner:                   Even in the [inaudible 00:19:49] echo lab, the recommended approach by the ASE with the four measures. How many times they were not able to acquire all those images, are necessary for those four techniques and so, here you have a [inaudible 00:20:03] of AS echo lab not being able to do that, and being transparent about that, and [inaudible 00:20:08] to the community, saying that, although these are ideal measures, even the [inaudible 00:20:12] perhaps you can't acquire them. I think that was another important point that came out of this and then lead to the focus on the E to E Prime. Barry Borlaug:                    I couldn't agree more. You got one of the world renowned labs, very skilled scenographers doing imaging, and we're still not able to get it all in each patient, and that just points to the difficulty of getting really high quality diagnostic images, and a lot of time you need the next level test, when that happens. And invasive exercise testing is really that test, the gold standard. Mark Drazner:                   When you get echos from the outside and you look at the E to E Primes, are you confident that the data, that's generally acquired, is gonna be acceptable for this [inaudible 00:20:50]? Barry Borlaug:                    Yes and no, I mean I'm always a little bit concerned, but it's not just being a control freak, you know, wanting to see everything, but I think that if it's a still frame doppler, tissue doppler spectrum, you can see that the sample volume is in the right place, and it's really unequivocally normal or abnormal, I feel pretty good about that. Not as good as when they get a full dedicated study here. Mark Drazner:                   Of course, the gold standard is also difficult. The invasive measurement. Barry Borlaug:                    Yes it is, I didn't [inaudible 00:21:18] that, but we've been doing a lot of invasive exercise tests for the last ten years now. And we do like 250 a year here, so we're really quite [inaudible 00:21:28] but we have all hands on deck in the lab. We have a couple technicians running gas samples around, all over the place. Somebody is on the medgraphics card, measuring oxygen consumption. We've got a nurse in there, that's helping out, so it's complicated, and of course we're using the micromanometer catheters for the pressure assessments, because you get so much more artifacts from width and under damping and over damping with the pressure tracing, so that's also not easy to do if you say. Mark Drazner:                   So maybe for practicing cardiologists it's gonna be hard to duplicate that and perhaps spend the energy in terms of doing the exercise echo techniques off the speed, for example. Perhaps, it's another message. Barry Borlaug:                    I would agree completely. And I think that again, when you do that, if you do a really high quality exercise echo and it's still not quite definitive, then you can refer on to a center that does have that capability, because obviously it's just reality, not everybody is going to be able to do this. Not every place has the size and resources to be able to do these really advanced tasks.   Dr. Carolyn L.:                    And do you apply exercise echo now in making your diagnosis? How do you use this data, for yourself, clinically? Barry Borlaug:                    We started to think about this, and I think that the best case scenario where the  people, that really have an intermediate pretest probability, based on their clinical characteristics. Somebody has jugular distension and a very high NT-proBNP level, and edema, you really don't need further testing, you know that that's going to be HFpEF. And if somebody has no risk factors, and everything is stone cold normal, they don't.                                                 But in some of these people that have some signals, but they don't quite meet criteria, we are doing this, again, if they have adequate echocardiographic images at rest. And then we're looking really carefully at the exercise echocardiography data, one concern from this data, I want to make sure people are very circumspect and really critically looking at the quality of their data, because we shouldn't over-interpret equivocal findings. And as you said earlier, E to E Primes can be all over the map, they're very difficult to obtain during exercise. But I think that if everything looks very high quality and is definitely abnormal or definitely normal, that can be helpful. More so, if it's normal. We     did see more false positive, so if it is abnormal, we did suggest that you may want to perform further confirmatory testing, because of the higher false positive rate with exercise echo. Mark Drazner:                                                                   I would say for the listeners, they should take a look at his figure six, which really is a nice diagnostic algorithm, where Barry shows, or advocates, for taking patients with intermediate probability and then using this to restratify that, using [inaudible 00:19:40] approach. I know that, that figure resonated with the editors and the reviewers dramatically, so I'd encourage listeners to take a look at that. Dr. Carolyn L.:                    Listeners, you heard it right. [inaudible 00:22:36] Circulation on the Run. Don't forget to tell all your friends about this podcast and tune in next week.