Podcast appearances and mentions of scot heart

Join our scientific team in the discussion of the 3 most clinically impactful papers of the month, the crème de la crème of our weekly top picks.This month we're discussing:Coronary CT angiography-guided management of patients with stable chest pain: 10-year outcomes from the SCOT-HEART randomised controlled trial in ScotlandDOI: 10.1016/S0140-6736(24)02679-5Subcutaneous weekly semaglutide with automated insulin delivery in type 1 diabetes: a double-blind, randomized, crossover trialDOI: https://doi.org/10.1038/s41591-024-03463-zEvidence-Based Application of Natriuretic Peptides in the Evaluation of Chronic Heart Failure With Preserved Ejection Fraction in the Ambulatory Outpatient SettingDOI: https://doi.org/10.1161/CIRCULATIONAHA.124.072156Scientific team:Ricardo Ladeiras Lopes, Mário Santos and João Sérgio NevesDiscover Medical Portfolio App weekly top picks - the latest and most relevant papers, curated by our team of experts! ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://linktr.ee/medicalportfolioapp⁠

Mit einer neuen SCOT-HEART-Publikation liegen jetzt 10-Jahres-Daten vor. Im neuen EvidenzUpdate-Podcast schauen wir, was sie für die CCTA bei V.a. KHK bedeuten. Wir reden über die Zukunft der NVL. Und jetzt neu: Scherers Soundmaschine.

Coronary CT angiography-guided management of patients with stable chest pain: 10-year outcomes from the SCOT- HEART randomised controlled trial in Scotland Michelle C Williams, Ryan Wereski, Christopher Tuck, Philip D Adamson, Anoop S V Shah, Edwin J R van Beek, Giles Roditi, Colin Berry,Nicholas Boon, Marcus Flather, Steff Lewis, John Norrie, Adam D Timmis, Nicholas L Mills, Marc R Dweck, David E Newby, on behalf of theSCOT-HEART Investigators* Summary Background The Scottish Computed Tomography of the Heart (SCOT-HEART) trial demonstrated that management guided by coronary CT angiography (CCTA) improved the diagnosis, management, and outcome of patients with stable chest pain. We aimed to assess whether CCTA-guided care results in sustained long-term improvements in management and outcomes. Methods SCOT-HEART was an open-label, multicentre, parallel group trial for which patients were recruited from 12 outpatient cardiology chest pain clinics across Scotland. Eligible patients were aged 18–75 years with symptoms of suspected stable angina due to coronary heart disease. Patients were randomly assigned (1:1) to standard of care plus CCTA or standard of care alone. In this prespecified 10-year analysis, prescribing data, coronary procedural interventions, and clinical outcomes were obtained through record linkage from national registries. The primary outcome was coronary heart disease death or non-fatal myocardial infarction on an intention-to-treat basis. This trial is registered at ClinicalTrials.gov (NCT01149590) and is complete. Findings Between Nov 18, 2010, and Sept 24, 2014, 4146 patients were recruited (mean age 57 years [SD 10], 2325 [56·1%] male, 1821 [43·9%] female), with 2073 randomly assigned to standard care and CCTA and 2073 to standard care alone. After a median of 10·0 years (IQR 9·3–11·0), coronary heart disease death or non-fatal myocardial infarction was less frequent in the CCTA group compared with the standard care group (137 [6·6%] vs 171 [8·2%]; hazard ratio [HR] 0·79 [95% CI 0·63–0·99], p=0·044). Rates of all-cause, cardiovascular, and coronary heart disease death, and non-fatal stroke, were similar between the groups (p>0·05 for all), but non-fatal myocardial infarctions (90 [4·3%] vs 124 [6·0%]; HR 0·72 [0·55–0·94], p=0·017) and major adverse cardiovascular events (172 [8·3%] vs 214 [10·3%]; HR 0·80 [0·65–0·97], p=0·026) were less frequent in the CCTA group. Rates of coronary revascularisation procedures were similar (315 [15·2%] vs 318 [15·3%]; HR 1·00 [0·86–1·17], p=0·99) but preventive therapy prescribing remained more frequent in the CCTA group (831 [55·9%] of 1486 vs 728 [49·0%] of 1485 patients with available data; odds ratio 1·17 [95% CI 1·01–1·36], p=0·034). Interpretation After 10 years, CCTA-guided management of patients with stable chest pain was associated with a sustained reduction in coronary heart disease death or non-fatal myocardial infarction. Identification of coronary atherosclerosis by CCTA improves long-term cardiovascular disease prevention in patients with stable chest pain.

Join Dr. Joel Kahn as he invites you to register for the Reversing Heart Disease Naturally Summit 3.0: drtalks.com/summit/reversing-heart-disease. This week, Dr. Kahn dives into fascinating new studies on topics such as forest bathing, glyphosate (RoundUp) and its connection to heart disease, the risks of carnivore and ketogenic diets, fat accumulation in muscles, and the health benefits of legumes like lentils in managing pre-diabetes. The main focus of the episode is an in-depth look at the latest research on heart calcium and CT imaging. Dr. Kahn discusses the predictive power of calcium scores, particularly when results exceed the 90th percentile. He also reviews findings from the SCOT-HEART study, which compared CT angiography to standard care, demonstrating improved outcomes when clinicians have CT data. Additional topics include the role of CT imaging in detecting heart disease in athletes and the significance of breast artery calcium as a marker of cardiovascular health.

The FLOW trial of semaglutide, the DANCAVAS CV screening trial, non-invasive tests for chest pain, and conflicts of interest on social media are the topics John Mandrola, MD, discusses this week. This podcast is intended for healthcare professionals only. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I. Semaglutide for CKD Semaglutide Significantly Improves Chronic Kidney Disease https://www.medscape.com/viewarticle/semaglutide-significantly-improves-chronic-kidney-disease-2024a10009w9 FLOW Trial II. CV Screening Judicious CVD Screening May Work in Men: DANCAVAS https://www.medscape.com/viewarticle/980153 DANCAVAS 6-Year Outcomes https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004403 DANCAVAS Main Trial NEJM https://www.nejm.org/doi/full/10.1056/NEJMoa2208681 III. Non-invasive Cardiac Testing in Chest Pain Circulation Outcomes Paper https://www.ahajournals.org/doi/abs/10.1161/CIRCOUTCOMES.123.010457 Scot Heart https://www.nejm.org/doi/full/10.1056/NEJMoa1805971 IV. COI and Social Media JAMA letter https://jamanetwork.com/journals/jama/fullarticle/2816900 You may also like: The Bob Harrington Show with the Stephen and Suzanne Weiss Dean of Weill Cornell Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

This week's episode features a panel discussion. Please join author Harmony Reynolds, editorialist David Newby, and Associate Editors Nicholas Mills and Sandeep Das as they discuss the articles "Natural History of Patients with Ischemia and No Obstructive Coronary Artery Disease: The CIAO-ISCHEMIA Study, "Outcomes in the ISCHEMIA Trial Based on Coronary Artery Disease and Ischemia Severity," and editorial "Forget ischemia, it's all about the plaque." Dr. Greg Hundley: Welcome listeners to this week's, September 28th, issue of Circulation on the Run. And I'm Dr. Greg Hundley, Director of the Poly Heart Center at VCU Health in Richmond, Virginia, and associate editor at Circulation. And this week, listeners, we have an outstanding feature discussion. It's actually forum where we're going to discuss from Dr. Reynolds two papers pertaining to the ischemia trial. One looking really at the functional importance of stress testing, the other looking at the anatomical importance of cardiac CT scanning. We're going to have two of the associate editors along with Dr. Reynolds, each that handled the two papers and also a guest editorialist that will help put the entire paper together. Well, before we get to that, we're going to start and review some of the other papers in this issue. And let's grab a cup of coffee and get started. Dr. Greg Hundley: The first comes to us from Dr. Maliheh Nazari-Jahantigh from Ludwig Maximilian University in Munich, Germany, and it pertains to atherosclerotic plaque rupture. So the necrotic core of an atherosclerotic plaque is partly formed by ineffective efferocytosis, which increases the risk of an atherosclerotic plaque rupture. And in cell biology, efferocytosis comes from the Latin word effero, which means to take to the grave or to bury. And it's really the process by which apoptotic cells are removed by phagocytic cells. And so therefore, it can be regarded as the burying of "dead cells." Now MicroRNAs contribute to necrotic core formation by regulating efferocytosis as well as macrophage apoptosis. We also know that atherosclerotic plaque rupture occurs at an increased frequency in the early morning, indicating that diurnal changes occur in plaque vulnerability. Now all those circadian rhythms play a role in atherosclerosis, the molecular clock output pathways that control plaque composition and rupture susceptibility are unclear. Dr. Greg Hundley: And so these authors investigated this phenomenon. And what they found, interestingly, their results suggest that the molecular clock in atherosclerotic lesions induces a diurnal rhythm of apoptosis regulated by circadian Mer 21 expression in macrophages that is not matched by efferocytosis, and thereby increasing the size of the necrotic core of these plaques. So clinically, the implications are that a macrophage death clock controlled by mer 21 may enhance lesion growth and susceptibility to plaque rupture indicating that the molecular clock can have detrimental effects under pathologic conditions. And additionally, the molecular clock in lesional macrophages may contribute to the circadian pattern of myocardial infarction, which could be a target for preventive measures to limit the mismatch between apoptosis and efferocytosis and thus reduce plaque vulnerability in the early morning. Dr. Greg Hundley: Well, our second paper comes to us also from the world of preclinical science, and it's from Professor Thomas Braun from the Max Planck Institute for heart and lung research. And this particular paper pertains to pulmonary hypertension. And as we know, pulmonary hypertension and chronic obstructive pulmonary disease, or COPD, originate from a complex interplay of environmental factors in genetic predispositions and little is known about developmental abnormalities or epigenetic dysregulation that might predisposed individuals to develop pulmonary hypertension or COPD in adults. So these authors screen a cohort of human pulmonary hypertension in COPD patients for changes of histone modifications by immunofluorescent staining. And also, they developed knockout mouse lines targeting cardiopulmonary progenitor cells and different heart and lung cell types. Dr. Greg Hundley: Now molecular, cellular and biochemical techniques were applied to analyze the function of SUV420H1-dependent epigenetic processes in cardiopulmonary progenitor cells and their derivatives. Well, what did they find? So the investigators found that loss of SUV420H1 in cardiopulmonary progenitor cells caused a COPD-like pulmonary hypertension phenotype in mice, including formation of perivascular tertiary lymphoid tissue, and goblet cell hyperplasia, hyperproliferation of smooth muscle cells and myofibroblast, impaired alveolarization and maturation of defects of the microvasculature leading to massive ripe ventricular dilation and premature death. Dr. Greg Hundley: Now mechanistically SUV420H1 bound directly to the five prime upstream in regulatory element of Superoxide Dismutase 3 gene to repress its expression and increased levels of the extracellular Superoxide Dismutase 3 enzyme in SUV420H1 mutants increased hydrogen peroxide concentration causing vascular defects and impairing alveolarization. So what can we take away, listeners, from this clinically? Well, the author's findings reveal a pivotal role of histone modifier SUV420H1 in cardiopulmonary co-development and uncover developmental origins of cardiopulmonary diseases. And now these results suggest that this study will facilitate the understanding of pathogenic events causing pulmonary hypertension in COPD and aid the development of epigenetic drugs for treatment of other cardiopulmonary diseases. Dr. Greg Hundley: Well, listeners, what else is in, we call it, the mail bag, but some of the other articles in the issue? Well, doctors Varricchi and Wang exchanged letters regarding the prior article, the role of IgE FcεRI in pathological cardiac remodeling and dysfunction. And our own Sara O'Brien highlights articles from our circulation family of journals. Professor Ross has a Research Letter regarding the effects of walnut consumption for two years on lipoprotein subclasses among healthy elders findings from the WAHA randomized controlled trial. And then finally, Dr. Maurer has a really nice On My Mind piece that raises concerns pertaining to the use of cardiac scintigraphy and screening for transthyretin cardiac amyloidosis. And now listeners, we're going to turn to that forum discussion where we have an author, our associate editors and an editorialist discussing two really important papers from the ischemia trial. Dr. Greg Hundley: Well, listeners, we are very excited today to discuss in sort of the forum feature, two papers pertaining to the ischemia trial. And with us this day, we have Dr. Harmony Reynolds from New York University Grossman School of Medicine in New York city; two of our associate editors, Dr. Nick Mills from university of Edinburgh in Scotland; and Dr. Sandeep Das from UT Southwestern; and then also an editorialist, Dr. David Newby, who's also University of Edinburgh in Scotland. Welcome to everyone. Dr. Greg Hundley: Harmony, we're going to start with you. And in the first paper, the natural history of ischemia and no obstructive coronary artery disease, can you describe for us a little bit of the context of what shaped this question for you, what hypothesis did you want to test? And then describe for us a little bit your study population and your study design. Dr. Harmony Reynolds: Sure. Thanks so much for having me here to discuss these papers. I'm really appreciative of the attention from circulation, and I'm excited for this discussion today. So in this first natural history paper, we were looking at ischemia with non-obstructive corona arteries, INOCA, the kind of thing that used to be called cardiac syndrome X. And we know this is an extremely common problem. It's defined by having signs or symptoms of ischemia and no 50% or greater lesion on coronary imaging. And we also know from prior invasive studies that the mechanisms of this are overwhelmingly microvascular coronary disease and provokable coronary spasm. Some patients prove to be normal and invasive testing, but most will have some objective abnormality. Dr. Harmony Reynolds: We know this problem is associated with a higher risk of cardiovascular events and with high costs, but what we didn't know was whether the symptoms and ischemia on stress testing are tracking together in these patients. So if we're trying to treat these patients, should we be doing serial stress testing and targeting the medical therapy to ischemia abrogation or should we just be making their symptoms go away? And would this provide any long range insights for us into when we can figure out the symptom are truly ischemic in nature? Dr. Harmony Reynolds: So we decided to use the ischemia trial, and we had a fantastic platform for that in ischemia because, as you know, patients were screened in part for randomization using coronary CT angiography. And even though these patients had moderate or severe ischemia, some had no obstructive coronary disease on that CT coronary angiogram. And those are the patients that we enrolled in CIAO-ISCHEMIA. They had an assessment of angina at baseline, and they had to be symptomatic at some point. They didn't have to be symptomatic at the moment. They were enrolled in CIAO, but they had their stress test generally to evaluate ischemic symptoms. And they had their stress echocardiogram read by a core lab. Importantly, that core lab did not know the result of that CT scan. So they read them like all the other ischemia stress echoes. And then these patients had an angina and ischemia assessment with a repeat stress echo at one year. Dr. Greg Hundley: And what did you find? Dr. Harmony Reynolds: There were a number of interesting findings from this study. The first thing was that the severity of ischemia in the CIAO patients with INOCA was very similar to the ischemia patients who had obstructive coronary disease. So that tells us that the INOCA problem can happen with quite a lot of ischemia, and that had not been as well delineated before. Another finding expected, but we did find that is that there were many more women in the INOCA group, two thirds of our child population was female. And in ischemia, overall, it was closer to a quarter. We found that the symptoms and the ischemia were quite changeable. So at one year, the stress echocardiogram was normal in half of the child participant and only 23% still had moderate or severe ischemia. Angina had improved in 43%, and it worsened in 14%. There was an awful lot of change over one year, but the change in angina and the change in ischemia did not track together. And that was a bit of a surprise to me. Dr. Greg Hundley: Very nice. Well, Nick, I know serving it as an associate editor, you see many papers come across your desk. What attracted you to pushing this paper forward for publication? Dr. Nicholas Mills: Thanks, Greg, and congratulations. Harmony, we love the papers you've been sending from ischemia trial, which genuinely is changing clinical practice all over the world. And it's been great to see the secondary analysis and follow-up papers. So this paper attracted me because it addresses an area where I still don't fully understand in clinical practice, what recommendations to make for my patients and what tests to arrange. As you say, INOCA is more common in women. I think these patients have largely been understudied over many decades, and there remains a lot of uncertainty. I liked it because you had a core lab, blinded core lab analysis with systematic follow up and it was a really well-done study. It reassured me in many ways because it told me that actually a lot of these patients, their symptoms get better, sort of irrespective of what we do. The treatments didn't seem to track within improvements of symptom, nor did the severity of ischemia, and that I think provides a lot of reassurance to our patients who are in this situation. Dr. Nicholas Mills: Of course, there is a group there who continue to have moderate to severe ischemia a year later. And I think this trial helps us understand maybe how we should study this group more, understand the heterogeneity that you've observed in this population in order to really try and resolve that and resolve their ongoing symptoms. But for the majority, four in five patients, they're going to do well and they're going to get better over time. And I think that's an important message from this study. Dr. Greg Hundley: Thank you so much, Nick. Well, Harmony, we're going to come back to you. You have a second paper, the outcomes in the ischemia trial really based on coronary artery disease and ischemia severity. Can you describe for us, again, working us back through, what were some of the constructs that you really wanted to address here? What was your hypothesis? And again, how did this study population maybe differ a little bit in this second paper? Dr. Harmony Reynolds: Thanks so much. So this paper tracked outcomes based on the severity of ischemia and the severity of coronary artery disease on the CT coronary angiogram now in randomized patients in the ischemia trial. So all of these had obstructive coronary disease and they were selected for randomization. And the premise of the ischemia trial was partly that we would be able to select patients who might benefit from revascularization and from an invasive strategy really based on how much ischemia they had on the stress test. Moderate or severe ischemia was required for randomization and for entry into the trial, but a core lab read those stress tests independently and independently assessed ischemia. And in some cases, when the site thought there was moderate or severe ischemia, the core lab did not agree. And the core lab independently decided whether it was moderate or severe. So we wanted to understand whether the ischemia severity at the time of trial entry influenced outcomes and influenced the outcomes by randomization treatment assignment. Dr. Harmony Reynolds: Similarly, about half of the patient had a CT that was interpretable for the number of vessels disease. And we wanted to understand in the context of all those prior stable ischemic heart disease trials, showing a lot of heterogeneity by the amount of coronary disease, whether in ischemia as well, there would be heterogeneity of the treatment effect based on how much coronary disease you started with. So the ischemia population, and this is almost the entire randomized cohort, but it's important to recognize for the CT analysis that only about three quarters of the patients had CT. They didn't get a CT, if your GFR was too low or if you had known coronary anatomy. And among those Cts, not every CT is perfectly interpretable for the number of vessels disease. These are sicker patients. These are not the super stable patients who have a low prevalence of disease. These were pretty sick, multi-vessel coronary disease patients, and they couldn't always hold their breast all that well. There was a lot of calcification in these. Dr. Harmony Reynolds: So for example, if there was motion artifact in the right coronary artery, we wouldn't be able to quantify the number of vessels disease. And that left us with a cohort of about half of our ischemia population, but that's still a giant cohort of several thousand patients. So that's how our study. Dr. Greg Hundley: Very good. And what did you find here? Dr. Harmony Reynolds: Here, we found that more severe ischemia was not associated with outcomes. Now that does go along with the COURAGE study in which after you adjust for clinical characteristics, ischemia was not associated with outcomes. But still it came as something of a surprise that even severe ischemia was not associated with a higher risk of outcomes than moderate or mild ischemia. We also found that in the coronary disease group, no matter how you measure the severity of coronary disease, the Duke prognostic index, the number of vessels disease, the segment involvement score, the segment stenosis score, all of these measures were very strongly associated with our outcomes, whether it was all cause mortality MI or our composite. Dr. Harmony Reynolds: When it came to treatment effect, we found that the ischemia severity were no relationship to treatment effect. There was no ischemia subgroup in which there appeared to be an advantage with an invasive strategy. But in the coronary disease group, and again taking into account the caveats of not everybody had a CT interpretable for the number of vessels disease, in those with the most severe coronary disease, that's the Duke 6 subgroup. And they had multi-vessel severe disease, either two vessel including the proximal LAD at 70% or three vessels with 70% stenosis. There was no benefit on mortality. But if we looked at the composite endpoint of cardiovascular death or MI, there appeared to be some advantage to the invasive strategy. Dr. Greg Hundley: Very good. Well, Sandeep, similar to Nick, working as an associate editor and meeting weekly, what attracted you to this particular paper? And why did you want to really see it come forward to be published? Dr. Sandeep Das: So first of all, I want to echo Nick's comments that these are great papers, and thanks very much for sending those our way and letting us have sort of first crack at them before they're released to the world. And I also want to comment on the side that Harmony and her team were just absolutely fantastic to work with in this process. From having been on the other side when you get 300 different comments from the editors and reviewers and you respond to them thoroughly and with grace, that's a feat in and of itself. So I want to shout out Harmony and her team for just being fantastic partners, because really we see ourselves as sort of the author's partners in kind of making the paper as good as it can be as the best it can be. Dr. Sandeep Das: So I'll admit upfront, I think it's kind of fashionable for people to say, well, I knew that this was going to show this, I knew this all from COURAGE, and this is not surprising to me. But I'll admit that I was surprised. And so this has been practice-changing for me, so this whole evolution post ischemia. And I really feel like a little bit of an existential crisis because I'm not sure I understand what ischemia means anymore. You ask me five years ago, I would've been very confident that I knew the answer to that. So you know what, really, as soon as this paper crossed our desk, I thought, wow, this is something we want to keep, this is something that's going to be really important to practice of cardiology. It's going to be really important to our readers. It's a great paper from a great group. This is something we want. So really it was never a question of, well, am I interested or am I not? I was interested from reading the abstract. Dr. Sandeep Das: So the question then became what are the real important questions that we need to sort of tease out and help elucidate for the clinician for the reader? And really for me, the question has always been, is there a subset of people where... So in my heart of hearts, I always kind of thought that burden of ischemia, if there was enough burden of ischemia, that it probably did help to revascularize that, right? I definitely practiced that way, right? There was some sort of number where I would start to say, that's a lot of ischemic myocardium and maybe we need to do something about that. Even though I know my intellectual brain says, no, there's no data that supports this, I really kind of thought it was true. And so Harmony and her team put another nail in that coffin here because it doesn't seem to be true, which to me was interesting and different and practice-changing. Dr. Sandeep Das: So the real questions here were sort of to tease out the interaction between anatomic severity, and we've all known that sort of anatomic burden of disease is proportional to adverse outcomes. That's not surprising. But the question then is, can we tease out a group where there may be benefit to revascularization? So there's a real interesting sort of interplay here between degree of ischemia and anatomic burden of disease. And is there a subset with enough of an anatomic burden of disease where you really may be interested in going after that to improve heart outcomes? So that's what I thought this was really fascinating paper. Dr. Greg Hundley: Very good. Well, David, we're going to turn to you next as the editorialist and asking you to sort of put the results of each of these two studies together. One, kind of highlighting for us how functional imaging might be useful to identify whether ischemia is present or not. And then the second study, really defining for us an association between anatomy and outcomes. So putting these all together, could you share your thoughts with us regarding these two papers? Dr. David Newby: Yes. Thank you. So I think that the CIAO-ISCHEMIA is very interesting, isn't it? And those clinicians were often challenged with symptoms versus our objective tests and trying to work out exactly what's going on, and it is. And such an important group as Harmony says, I can't agree more. We have a lot of morbidity here. As Nick said, I think the short term, a lot of the patients do seem to get better with just conservative management is good, but there's a core group that clearly are a problem. And as Harmony highlighted, you've got people with terrible regional wall-motion abnormalities on stress echo and yet no angina, others with no angina with no apparent difficulty on repeat testing. And then you've got a core group that has both, and it is fascinating to try and unpick that. And clearly, the symptoms are not correlating with our tests, and that's not the patient's fault. Dr. David Newby: And very often, no, no, you're wrong, can we say that to the patient? No, no, the patient is right and our tests are wrong, and we've got to work out how best to manage them. And I have a bit of analogy with Takotsubo cardiomyopathy as well, I think is at play here. I mean, here, you've got people with stable pain. We're not coming in as an acute emergency, but they're having regional wall motion abnormalities at times. They're getting a lot of symptoms. And we see similar things with Takotsubo, which is, I suppose, a much more flurry thing. I know that's something close to Harmony's his heart too. Excuse the pun. But this ischemia relationship, these regional wall motion abnormalities with chest pain, particularly in women, is something we really need to get our heads around and understand what's going on. It just reflects our ignorance, I think, of knowing exactly how to manage these patients. Dr. David Newby: And so for me, ischemia testing is about symptoms. It's about working out what's going on with the patient. It doesn't always give us the answer, but I certainly think that the role of ischemia testing is more about the symptoms. Dr. David Newby: And then when it comes to the second paper and outcomes with the ischemia trial, I absolutely was delighted to see those findings. I have to say place to what my prejudice is, I suppose, as someone that's been working with CT. And I suppose the slightly obvious thing is that the more disease you have, the more you will benefit from an intervention. And plaque and the burden of plaque is critical to that because how do you have a heart attack? Well, you have to have plaque, right? And it has to rupture. So the more plaque you have, the more likely you are. And I think that the analysis is again reinforcing what we've learned from some of the imaging trials with PROMIS and SCOT-HEART. Actually, the more plaque you have, the worse you are. Dr. David Newby: And yes, ischemia predicts risk, but ischemia predicts risk through its association with plaque burden, not through ischemia itself. And what I think we're seeing very nicely being played out in ischemia trial is the risk is definitely much stronger for CT than it is for imaging. And that's very clear, and that's exactly what PROMIS found exactly what SCOT-HEART found as well, and it's a rise robust finding. The interaction with the treatment effect that I find also fascinating and again plays to some of the bypass surgery trials that we've seen, bypass surgery tends to prevent spontaneous MIs and, even in some cases, mortality. And we're seeing trends in ischemia for mortality, can't over call them. I'd love to see what happens in 10 years. But I think in terms of the prevention of MIs, I'm putting all my money in one basket, which is the bypass surgery, 25% of course of patients revascularized that way. I don't believe that PCI is going to prevent the myocardial infarction. So I think all my money is in that box. Dr. David Newby: But it's absolutely fascinating data. It is all about the plaque if you're talking about prevention of clinical events downstream. And I think that's where the dichotomy is, scheme is about symptoms and understanding the patient's problems in terms of symptomatic improvement. If you want to improve their long term outcome, it's all about the plaque, understanding the burden of plaque and what you can do to hopefully prevent downstream event. Dr. Greg Hundley: Great. Thank you so much. And so listeners, we're going to ask each of our speakers today in really 20 or 30 seconds to go through and identify what do they think is the next study really to be performed in this space? So Harmony, we're going to start with you and then Nick, Sandeep and then finish up with David. Harmony? Dr. Harmony Reynolds: Thanks. Well, when it comes to INOCA, I would like to see more studies in the vein of CorMicA. So I'd like to see routine invasive testing to define the underlying pathophysiology problem and then targeted medical therapy interventions, and I'd like to see outcome trials. There's one outcome trial going on. It's a challenge because the event rate, though very important and higher than in the general population for sure, is low enough that these trials have to be quite large, and we look at ischemia with a relatively high event rate. And even so it's a stable population and that had to be large, this would have to be even larger. So we're going to need more mechanistic studies in order to lead to the treatment trials that will really influence practice. Dr. Harmony Reynolds: And in terms of the severity of coronary disease, this is a tough one. We felt like ischemia was a lift, and I'm not sure that there will be another huge stable ischemic heart disease trial. But sure, I'd love to see in people selected by CT for their advanced severity of coronary disease, whether an invasive management strategy makes a difference compared to medical therapy. I don't know that we'll see that one come to pass, but you never know. Dr. Greg Hundley: Nick? Dr. Nicholas Mills: Yeah. I agree. We need more mechanistic research, but I'd like to see more non-invasive methods to understand the mechanistic basis of this condition because CorMicA has caught an invasive protocol for a condition, which we know is benign and who most patients get better without any treatment. I would also like to see randomized blinded studies of treatment effects and because there are too many observational on blinded studies here. And I think the outcome has to be patient-focused and symptoms. Dr. Greg Hundley: Sandeep? Dr. Sandeep Das: Yeah. So everything that's been raised so far are fantastic comments and really on point. For me, I think if we can tease out the population that may benefit to get back to Dave's earlier comment that there's possibly not going to be a little humble here, there's possibly a population that has extensive, extensive CVD that could benefit from bypass surgery. And I think that that hasn't really been firmly demonstrated yet, although it's been suggested strongly. So that I think is an interesting study, and I hope that that gets done as a trial, but I can understand that it'd be a giant undertaking. And then the other thing I think is just algorithmic approaches that are driven by anatomical studies like SCOT-HEART and things like that, where we really try to make decisions based on the anatomical approach and pretend like the last 15 years never happened and that we kind are starting fresh with our best approach to how to treat these patients. Dr. Greg Hundley: And finally, David. Dr. David Newby: Yeah. I'm actually going to agree with everybody there, and I'm rooting for this trial actually because that's the one I want to do is look at advanced coronary disease on noninvasive imaging, irrespective of symptoms. And that's the big call actually if you've got no symptoms to put yourself through a bypass, because it's bypass, it's not standing. Bypass, we need. I'd also love to see some substudy coming out of ischemia. I think you're doing them. I hope you are looking at plaque burden and plaque characteristics because I think that's another level of complexity. We're so obsessed with stenosis, actually. And again, even anatomical and ischemia testing plays to that, it's not just about stenosis, stenotic arteries have big plaque burdens, et cetera. And it's not bypassing them, it's bypassing all the nonobstructive plaque and the obstructive plaque that has given you the benefit of revascularization with surgery. So I think you need to think about a really nice cool trial where we can do that trial even in the presence of nonobstructive disease, but big plaque burden, adverse plaque characteristics, and think about bypass. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Harmony Reynolds for bringing us these two really informative studies from the ischemia trial, and also our associate editors, Dr. Nick Mills and Dr. Sandeep Das for providing their perspective and our editorialist, Dr. David Newby, who really helped us organize our thoughts and put both of these two studies into great perspective highlighting in the first that functional testing can really help us identify the presence or absence of ischemia. And then our second study highlighting the association between CT coronary angiography and the identification of the anatomic severity of disease with cardiac outcomes. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2021. The opinions expressed by speaker in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.

On this episode, Alastair and Praveen are joined by Dr. Michelle Williams to follow-up a previous episode on adverse plaque features from a subanaylsis of the SCOT-HEART trial. Dr. Williams is one of the SCOT-HEART trial principal investigators and the lead author of the trials' recent adverse plaque subanalysis. Dr. Williams provides her expert insight on the science and future of CT adverse plaque features. Tune in and enjoy!Link to publication: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.044720

Alastair and Praveen discuss the recently published subanalysis of the SCOT-HEART trial focused on low attenuation noncalcified plaque. What is really more important in the assessment of coronary artery disease: plaque or stenosis? Tune in and find out!https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.044720

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

With Stephan Achenbach, University of Erlangen - Germany & Victoria Delgado, Leiden University Medical Center - Netherlands.

Commentary by Dr. Valentin Fuster

In this episode of the Heart podcast, Digital Media Editor, Dr James Rudd is joined by Professor David Newby from Edinburgh University. They discuss the landmark SCOT-HEART trial, which demonstrated that a CT-guided investigation strategy for chest pain could reduce future myocardial infarction risk. How might this be the case? What does it mean for future guidelines? And should we ditch the treadmill test? If you enjoy the show, please subscribe to the podcast in your favourite podcast app to get episodes automatically downloaded to your phone or computer. Also, please consider leaving us a review if you enjoy the show. It really helps (https://itunes.apple.com/gb/podcast/heart-podcast/id445358212?mt=2). Links to published papers: Original study - https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60291-4/fulltext#seccestitle10 5 year outcome study - https://www.nejm.org/doi/full/10.1056/NEJMoa1805971

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 our feature discussion today, we will be talking about insights from the PROMISE Trial regarding the prognostic value of non-invasive cardiovascular testing in patients with stable chest pain. First, here's your summary of this week's journal.                                                 The first paper reports novel findings on gene smoking interactions in coronary heart disease. Co-corresponding authors Dr. Salahin from the University of Pennsylvania and Dr. Riley from Columbia University and colleagues used data on almost 61,000 coronary heart disease cases and more than 80,000 controls to investigate effect modification by smoking behavior at established coronary heart disease and smoking-related genetic loci.                                                 They found that the cardio-protective effects associated with allelic variation at the A-D-A-M-T-S seven, or ADAMTS7 locus, were attenuated by 60% in patients who smoked tobacco, compared to those who did not smoke. Allelic variation in ADAMTS7 associated with reduced coronary heart disease risk, was associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines.                                                 Furthermore, exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. These human genomic data therefore provide new insights into potential mechanisms of coronary heart disease in cigarette smokers and suggests that inhibition of ADAMTS7 may be a novel potential therapeutic strategy for coronary heart disease that may have particular benefits in individuals who smoke cigarettes. This is discussed in an editorial entitled Holy Smokes, an Interaction, by Dr. Braxton Mitchell.                                                 The next paper provides first evidence that genetic over-expression of CD39 may offer ischemic cerebral protection. CD39 is an ectoenzyme with a PYRase activity, which cleaves ATP and ADP. CD39 is expressed on the surface of myeloid and vascular endothelial cells where it dissipates the high local concentrations of ATP and ADP, which would otherwise serve as potent pro-inflammatory and pro-thrombotic signals.                                                 In the current study from first author Dr. Bick, corresponding author Dr. Pinsky from University of Michigan Medical Center and colleagues, authors used a model of permanent middle cerebral artery occlusion to show that CD39 expression reduced edema, infarct volume, and inflammation with corresponding improvements in neurological outcomes, compared to control mice. Over-expression of CD39 in only the myeloid cells also reduced cerebral infarct volume. Thus, amplification of endogenous CD39 expression, or even administration of exogenous circulating CD39, may be of future interest as a therapeutic target to minimize ischemic injury caused by cerebral ischemia.                                                 The next paper provides pre-clinical data to show that MicroRNA93 may have a therapeutic role in peripheral artery disease. First author Dr. Ganta, corresponding author Dr. Annicks and colleagues from University of Virginia, used MicroRNA-106b-93-25 cluster knockout mice and showed that MicroRNA93 over-expression alone was sufficient to enhance angiogenesis, arteriogenesis, and perfusion in ischemic muscle via increased M2-like macrophages.                                                 MicroRNA93 targeted interferon regulatory factor 9 to inhibit immune response gene 1, and itaconic acid generation in macrophages to induce M2-like macrophage polarization. Furthermore, MicroRNA93 over-expression produced a paracrine effect on macrophages that induced angiogenesis and skeletal muscle recovery under hypoxic conditions in vitro.                                                 Thus, these data demonstrate that MicroRNA93 induces beneficial effects in multiple cells that can enhance perfusion in ischemic limb and thus identifies MicroRNA93 as a putative therapeutic target in clinical peripheral artery disease.                                                 The next study is a large scale genetic analysis that represents the most comprehensive causal assessment of adiposity with cardiometabolic diseases to date. Co-corresponding authors Dr. Cassis and Dale from University College London used 97 snips for BMI, and 49 snips for waist-hip ratio adjusted for BMI, to conduct mendelian randomization analysis in 14 prospective studies supplemented with coronary heart disease data from CADRIoGRAM+C4D, stroke data from METASTROKE, Type II Diabetes data from DIAGRAM and lipids data from GLGC Consortium.                                                 They found that both waist-hip ratio adjusted for BMI, and BMI had causal effects on coronary heart disease and Type II Diabetes, and were associated with higher left ventricular hypertrophy, glycemic traits, interleukin 6 and circulating lipids. However, only waist-hip ratio adjusted for BMI increased the risk of ischemic stroke. Thus, both the amount of adiposity and its distribution play important roles in influencing multiple cardiometabolic traits and the development of cardiometabolic disease.                                                 Furthermore, the findings indicate that body fat distribution has multiple roles in disease that are independent of general adiposity. This suggests that physicians should pay attention to measures of adiposity beyond BMI.                                                 The next study addresses the conundrum that clinical trials show benefit of lowering systolic blood pressure in people aged 80 years and above, but yet, non-randomized epidemiologic studies suggest lower systolic blood pressure is associated with higher mortality. In the current study by Dr. Ravindrarajah and colleagues of King's College London, a population based cohort study was conducted using electronic health records of 144,403 participants aged 80 years and older, registered with family practices in the United Kingdom, and followed for five years.                                                 Mortality rates increased with frailty level, and were highest at a systolic blood pressure of less than 110 millimeters mercury. Furthermore, systolic blood pressure trajectories showed an accelerated decline in the last two years of life, without evidence of intensification of anti-hypertensive therapy.                                                 Thus, a terminal decline of systolic blood pressure in the final two years of life suggests that non-randomized epidemiological associations of systolic blood pressure with higher mortality may be accounted for by reverse causation. That is, participants with lower blood pressure values were closer on average to the end of life. This is discussed in an accompanying editorial by Dr. Naveed Sattar.                                                 Well, that wraps it up for our summaries. Now for our feature discussion.                                                 The evaluation of stable patients presenting with suspected coronary artery disease is by far one of the most common diagnostic evaluation strategies that we need to undertake in cardiovascular medicine. There's a whole host of evidence supporting prognostication based on various non-invasive tests, such as anatomic imaging with coronary computed tomography angiography, but also with stress testing, or functional testing, such as stress nuclear or echocardiography, or exercise electrocardiography.                                                 However, our paper today really sheds light on the comparison of these two strategies. And I'm just delighted to have starts with me. First, the primary author of the paper, from the PROMISE Trial, Dr. Udo Hoffmann, from Massachusetts General Hospital, Harvard Medical School, and the editorialist of a beautiful accompanying editorial, Dr. Leslee Shaw from Emory University School of Medicine, Atlanta, Georgia.                                                 Welcome both. Dr.  Udo Hoffmann:        Hi, Carolyn. Hi, Leslee. Dr. Leslee Shaw:               Hi, Udo, how are you? Dr. Carolyn Lam:               So, Udo, could you start by just sharing what you did in this PROMISE Trial? Dr. Udo Hoffmann:          The Promise Trial is a large comparative effectiveness trial that was done between 2009 and 2012, with follow-up ending 2013, at [inaudible 00:10:13] sites across the U.S. and Canada. And what it did was compare two strategies for testing patients with suspicion of coronary disease, symptomatic patients. These patients were randomized to either receive a functional test first, or an atomic test first, and the idea was to see whether providing the functional information or the anatomic information leads to differences in outcomes of these patients.                                                 As you know, the primary paper showed that the health outcomes of these two strategies were similar and not different. Now in this paper here, we took the slightly different approach and we really wanted to see how the results of the tests as they were seen by the [inside 00:11:02] so it was all based on the sight interpretations of these tests. How the results of these tests actually were associated, or were associated with the health outcomes. And so we directly compared categories of CT results, and categories of functional testing results, and how they are related to outcomes. The good news I think is that sight interpretations in real life do actually have prognostic value for both the anatomic or the CT, and also the functional testing, and so findings as significant disease [inaudible 00:11:36] ischemia have in fact similar prognostic value. And we also saw that on the lower end of the findings, so mildly abnormal findings for example, that the ability to see nonobstructive CAD, perhaps if you're a difference maker and identify from additional patients or group of patients that is at risk for [inaudible 00:12:01]. Dr. Leslee Shaw:               I think that often times we struggle with negative trial results, if I can put PROMISE in that negative trial results. And here we have a paper that I think really applies clinically. I think it's going to have far-reaching clinical implications. I think if you look at the CTA findings, this is a real world practice. I think there's a simplicity to CTA interpretations that really is amplified in the nice ability to risk stratify. Whereas the functional interpretation, as you both know, is complex. It integrates a lot of factors, wall motion, perfusion imaging, ST segment changes, exertional symptoms, all of that, and I think we see a lot of sight variability in that image interpretation on the ischemia-side of the functional testing arm.                                                 But there's and important finding from this paper, which I think we have seen in bits and pieces prior to this report, and that is that on the CTA side, you had about a third of the patients having pure normal coronaries. So you see that very low risk in that population. But what you see on the functional testing arm is that the event rate in patients with normal studies and in patients with a mildly abnormal study, the event rates were identical, which is fascinating.                                                 And importantly, two thirds of the population on the functional testing arm were in those normal and mildly abnormal subgroups, something like that. And that has important implications for what is in that one third on a CTA side with normal findings versus three quarters? Well I think from this randomized trial, I think we can infer that you're going to have some non-obstructive disease in that population, but you're also going to have non-ischemic obstructive disease.                                                 We know from FFR and all of the angiographic literature that not every obstructive lesion is ischemic. And so on the stress testing side, we have a lot of obstructive disease that potentially is missed. And I think this study really clearly illustrates that limitation of stress testing and it reflects sight variability in imaging and the interpretation. It reflects the patient populations and the struggles with doing stress testing, but also just flat out reflects the ischemic cascade, and what we can expect from an obstructive lesion, or a non-obstructive lesion, that may not elicit ischemia.                                                 So to that extent, I think Udo's paper is just, just far-reaching and really clearly one of the most advanced papers that we have seen in such a long time. From really providing an important message for those imagers and for folks doing stress testing in this country. Dr. Carolyn Lam:               should we then always do anatomic testing first before selective stress testing? Dr. Udo Hoffmann:          The choice of testing is very much I think tied to the population of the patient you're talking about. I think when you follow the literature, 30 years ago when all the classic studies out of [experienced centers 00:18:53] such as Cedar Sinai, were published, the ischemia burden was much higher in the tested population. Back then you had probably a third or 40% of patients who in fact had some abnormality or ischemia on stress testing. One of the findings here in this study, and that is true for both tests, is that the prevalence of severe findings, severe abnormalities, whether ischemia or obstructive disease, is what I found testing is pretty similar, so it's both around 12%, but it is relatively infrequent. And I think that has changed.                                                 And you cannot expect, as Leslee pointed out nicely, it is not expected from a stress test to detect non-obstructive disease that has prognostic value, but doesn't necessarily explain these symptoms that the patient is presenting. So we should not forget that these patients do not come for primarily for prognostic assessment, they come because they're symptomatic. And the primary question is do we find an equivalent that could explain the symptoms of the patient? And only once we are convinced that there's no such equivalent that would for example lead us to further assess the patient for potential reverse [inaudible 00:20:19] therapy, then the second question that can be answered is for the prognostic implication of the test. And I think in this relatively low risk population, this prognostic aspect gains more importance irrelative to the diagnostic aspect. Dr. Carolyn Lam:               I think Leslee made it very clear in her editorial as well, not to forget in essence at the extremes of disease, that both tests, both strategies conveyed similar prognostic information, and it was more for the fine grain teasing apart that perhaps we need to consider very, very carefully what your paper is saying. But at the end of the day, it's about treating the patients for their cardiovascular risk management, isn't it? Recognizing that even if you don't have ischemia, if you've got the risk factors, like you nicely showed, that we should be treating them for the risk factors.                                                 Leslee, want to share some of your thoughts there? You covered that so nicely in your editorial. Dr. Leslee Shaw:               Well I think that's one thing we've seen from PROMISE, SCOT-HEART, and many, many other recent trials as of late, over the last three or four years, is that the stress test is an opportunity not only to assess ischemic burden, or that CTA's not only a test to assess the extent and severity of coronary disease as well as plaque, but it's an opportunity to identify clear, preventive strategies for the patients.                                                 And this is really something that I don't think at least historically within the stress testing community, that we have taken upon ourselves in order to say, "Okay, here we have a symptomatic patient. We not only are going to assess ischemia, but we're going to look at what else they need to do in order for us to guide prevention." I think this is a clear reminder that this is a great opportunity for us to have a bit of a paradigm shift on the diagnostic testing, to take that whole picture if you will of the patient, and really to focus in on prevention because that is a great opportunity, as Udo talked about just a few minutes ago, it's a great opportunity for us to set the patient on the correct course.                                                 The guidelines, as both of you know, focus in on having that diagnostic evaluation and to implement guideline directed medical therapy as a front line examination. This is a great opportunity for us to just use that diagnostic evaluation ad the initiation of appropriate care for the patient, and then to look at symptom burden, recurrent symptoms, the need for additional interventions. But that first step is guideline directed medical therapy for the patient. Dr. Udo Hoffmann:          Continuing on Leslee's excellent point, I think the paper I think is hopefully a starting point to think about randomized trial, because we assume some maybe come to the conclusion, okay, if you have non-obstructive disease, you should be treated with [inaudible 00:23:13] and aspirin. But we don't know that. I think this is really a call for randomized trial. PROMISE was the one, and it was a good trial. It looked at the association of strategy with an outcome. I think one trial that is needed is to look what specific therapeutic decisions based on imaging or based on test diagnostic test findings, would be justified and would potentially lead to improved outcomes. And that is true for both the stress testing and the CT side. So I think this paper shows the opportunities, but I don't think we have the randomized data to exactly define what are the management options for each of these details of the information that these test results deliver us. Dr. Carolyn Lam:              

Commentary by Dr. Valentin Fuster

In this episode of the Heart Podcast, Heart Digital Media Editor Dr James Rudd is in conversation with Dr Chris Fordyce from the Duke Clinical Research Institute. His team has just published an Education in Heart paper on "Optimal non-invasive imaging test selection for the diagnosis of ischemic heart disease." In this podcast, they discuss the similarities and differences between the international guidelines on the investigation of chest pain. They also highlight the results of the landmark PROMISE and SCOT-HEART studies and discuss how the results of these trials might influence future guidelines. The paper contains many high-resolution multimedia elements, along with MCQs to test your knowledge in this area.