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Circulation on the Run

Each monthly episode will discuss recent publications in the fields of genomics and precision medicine of cardiovascular disease.
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Now displaying: June, 2017
Jun 26, 2017

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.

Jun 19, 2017

Dr. Carolyn Lam:               Welcome to Circulation on the Run your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

                                                Is it time to end our debates on short versus long duration of dual anti-platelet therapy? Well I will be discussing this with two very special guests in just a moment. But first here is your summary of this week's journal.

                                                The first paper tells us that HDL particle number may serve as a biomarker of residual risk when assessed on statin therapy. First author Dr. Khera, corresponding author Dr. Mora from Brigham and Women's Hospital and colleagues of the JUPITER trial assessed HDL cholesterol levels, apolipoprotein A-1, cholesterol efflux capacity and HDL particle number at baseline and 12 month in a nested case control study of the JUPITER trial. That was a randomized primary prevention trial that compared rosuvastatin to placebo in individuals with normal LDL but increased CRP levels.

                                                In the current study the authors found that cholesterol efflux capacity was moderately correlated with HDL cholesterol, apoA-I, and HDL particle number. Baseline HDL particle number was inversely associated with incident cardiovascular disease, while there was no significant association for baseline cholesterol efflux capacity, HDL or apoA-I levels. On-statin cholesterol efflux capacity was inversely associated with incident cardiovascular disease but HDL particle number again emerged as the strongest predictor.

                                                Thus for both baseline and on-statin analyses, HDL particle number was the strongest of four HDL-related biomarkers as an inverse predictor of incident events and biomarker of residual risk.  Whether therapies designed to enhance cholesterol efflux capacity or an increased HDL particle number can also reduce cardiovascular risk however remains uncertain.

                                                The next study sheds light on mechanisms underlying the de-differentiation and lineage conversion of adult human fibroblast into functional endothelial cells. First author Dr. Zhang, corresponding authors Dr. Rehman and Malik from University of Illinois College of Medicine first generated CD34+ progenitors by de-differentiating adult human skin fibroblasts and showed that these intermediate progenitors could give rise to endothelial cells as well as erythrocytes. They then showed that lineage conversion of fibroblasts via partial de-differentiation recapitulated in part the embryonic development of the vasculature as evidenced by up regulation of anti-aging enzyme telomerase and the bi-lineage potential of the generated progenitors.

                                                Importantly they showed that transcription factor SOX17 functioned as a switch which regulated the cell fate of CD34+ progenitors towards an endothelial versus erythroid lineage. Finally implanted fibroblast derived CD34+ progenitors stably engrafted to form functional human blood cells in mice that improved cardiac function after myocardial infarction. Thus the molecular switch SOX17 provides a means to optimize the generation of endothelial cells for vascular tissue regeneration or disease modeling.

                                                What do drones have to do with out of hospital cardiac arrest? Well in this next study by first author Dr. Boutilier corresponding author Dr. Chan and colleagues from University of Toronto, the authors hypothesized that a drone network designed with the aid of a mathematical model combining both optimization and queuing could reduce the time to AED arrival.

                                                Using data from over 50,000 historical out of hospital cardiac arrests covering over 26,000 square kilometers in Ontario, Canada, they found that a drone network designed to reduce the median AED arrival time by three minutes relative to the historical 911 response could also reduce the 90th percentile of the AED arrival time by between 6 minutes and 43 seconds in most urban regions and 10 minutes and 34 seconds in most rural regions.

                                                Thus this study tells us that drone delivered AEDs have the potential to be a transformative innovation in the provision of emergency care to cardiac arrest patients especially those who arrest in a private or rural setting.

                                                The next study provides thresholds for ambulatory blood pressure among African Americans. Dr. Ravenall and colleagues from New York University School of Medicine analyzed data from the Jackson Heart Study, a population-based cohort comprised exclusively of African-American adults and of whom more than 1000 participants completed ambulatory blood pressure monitoring at baseline.

                                                Based on the outcome derived approach for systolic blood pressure and a regression derived approach for diastolic blood pressure, the following definitions corresponded to clinic blood pressure of 140/90 and were proposed as ambulatory blood pressure definitions for African Americans. Daytime blood pressure above 140/85, 24 hour blood pressure above 135/80 and nighttime blood pressure above 130/75 mmHg. Note that these ambulatory blood pressure thresholds identified for African Americans were higher than those from published recommendations mainly derived in European, Asian and South American populations. The use of these ambulatory blood pressure thresholds for African Americans will lead to a lower prevalence of daytime, 24 hour and nighttime hypertension compared with the current published recommendations.

                                                The next paper provides pre-clinical evidence of a novel target in plaque information in atherosclerosis. Dr. Stachon and colleagues from Heart Center Friburg University in Germany hypothesized a functional role of the signal axis ATP binding to purinogenic receptor P2X7 in inflammasone activation and chronic inflammation driving atherosclerosis.

                                                In an elegant series of experiments they showed that P2X7 receptor activation was crucial for inflammasone assembly and interleukin-1-beta secretion. The lack of P2X7 in mice abolished inflammasone activation in atherosclerotic lesions. P2X7 was expressed in murine and human atherosclerotic lesions. LDL receptor deficient mice lacking P2X7 receptor had reduced plaque inflammation and were less prone to develop atherosclerosis.

                                                Thus this study shows that P2X7 inhibition could be a treatment strategy against plaque inflammation in atherosclerosis.

                                                The next paper describes the first prospective clinical study of adenosine use in pediatric and young adult patients after heart transplantation. Now prior to this study adenosine was relatively contraindicated post-transplant due to a presumed risk of prolonged atrioventricular block in denervated hearts.

                                                In the current study first author Dr. Flyer corresponding author Dr. Silver and colleagues from Columbia University performed a single center prospective clinical study testing whether adenosine caused prolonged asystole after transplant and if it was effective in blocking AV nodal conduction in healthy heart transplant recipients aged 6 months to 25 years presenting for routine cardiac catheterization. Following catheterization, a transvenous pacing catheter was placed and adenosine was given following a dose escalation protocol until AV block was achieved.

                                                Eighty patients completed adenosine testing. And no patient required rescue ventricular pacing. AV block was observed in 77 patients with the median longest AV block of 1.9 seconds and the mean duration of adenosine effect of 4.3 seconds.

                                                Thus, this study suggests that adenosine may be safe and effective in patients post transplantation and establishes both a safe and effective starting dose of 25mcg/kg or 1.5mg for patients weighing 60kg and more. It also establishes a stepwise therapy escalation plan to avoid prolonged bradycardia. Although patients after heart transplantation may require less adenosine to achieve AV block it appears to be safe and effective as therapy for evaluation and or treatment of tachycardia in this population.

                                                Well those were your summaries, now for our feature discussion.

                                                Today for our feature discussion we are talking about a very familiar situation, dual anti-platelet therapy following coronary intervention and the decision of long versus short duration of therapy. A debate we've heard many times but according to the perspective piece in today's journal, maybe a debate we should end. And I am so pleased to have the author, Dr. Glenn Levine from Baylor College of Medicine as well Dr. Laura Mauri associate editor from Brigham and Women's Hospital.

                                                Welcome both.

Dr. Laura Mauri:               Thank you Carolyn.

Dr. Glenn Levine:             Thank you.

Dr. Carolyn Lam:               Glenn would you like to start by presenting your case. It's time to end a dualistic short versus long duration of DAPT debate. I really like that title, tell us more.

Dr. Glenn Levine:             Thank you Carolyn.

                                                The point we make in our editorial is that over the last five or six years there have been studies comparing what I term standard, which is usually about 12 months DAPT versus shorter duration DAPT and there are other studies comparing standard DAPT versus longer duration DAPT. Those generated important information in different people interpret them in different ways. What though has happened over the last several years is certainly for both educational and entertainment value at meetings as well in editorials, the idea of how long people should be treated with DAPT has been oversimplified to whether all patients should be treated with short duration or long duration. And Laura herself knows that as she has been in many of these debates.

                                                While I think that initially that was educational and entertaining, I think these days people understand those points and a greater issue is in that we should treat some people with short duration, some with what I call standard and some with long duration. And rather than debating whether everyone should treated with short or everyone should be treated with long, I think what we need to focus on now is which patients should be treated with short duration, which are probably best treated with a standard duration and which are best treated with prolonged or extended duration DAPT.

                                                And that in a nutshell is the main point that we make in this perspective editorial.

Dr. Carolyn Lam:               Laura, so do you agree?

Dr. Laura Mauri:               I couldn't agree more. I think clinicians really are looking for guidance and what happens at these debates is you see these polarizing opinions that debaters are asked to defend when in actuality there's such a wide spectrum of what individual patients need. And the real question I think going forward is how to end these debates and how to provide really more tailored information so clinicians and patients can make better decisions together. And I think that's really where the piece that Glenn has written really helps direct us.

Dr. Carolyn Lam:               Yeah, Glenn, I mean are we talking about the usual risk versus benefits and precision metsan or individualized risk assessment here?

Dr. Glenn Levine:             Yeah, what we're talking about is looking at the ischemic risks which are primarily leg stent thrombosis or spontaneous MI versus the bleeding risks which is obviously bleeding and balancing them. And there clearly are decision tools available to clinicians. Laura has pioneered the DAPT score which is an incredibly user friendly and easy tool to use to assess which patients should be continued with prolonged DAPT or not. And there are also some other tools out there including the Paris registry score perhaps a little more complex and then there's also now the precise DAPT score which one can at least assess bleeding risk and indirectly assess the ischemic and bleeding risk.

                                                But really I think that is the focus now on balancing bleeding and ischemic risks and having pools to allow clinicians to easily do that.

Dr. Carolyn Lam:               That's true. Now do you think guidelines have to catch up or have they caught up?

Dr. Glenn Levine:             Our DAPT duration guideline was coming out just as Laura's DAPT score was about to be published, several months after it had been presented. And we did mention the DAPT score in our paper, it was too early to formally incorporate it into the guidelines. Nevertheless, the way our guidelines are written, they clearly give practitioners the option for individualizing therapy based on ischemic and bleeding risk and Laura's DAPT score fits perfectly into what we aim to do, namely to encourage practitioners to assess patients on an individual level and assess what duration of DAPT is best.

Dr. Carolyn Lam:               I do have a question for Laura here though. I see Asian patients, I'm talking to you here from Singapore. And sometimes you wonder the trial situations and what you derive there. How does it differ from real world and how is it impacting your practice for example Laura?

Dr. Laura Mauri:               That's a great question. I think you have a number of points there. One is the generalized ability or results from one trial across the world where you might have many different patient populations. And while the DAPT score was an international trial it would be interesting to see more data coming out from other different countries. And as you know there are trials in Asia that have looked at randomized DAPT duration as well.

                                                I think now that we have better access to information especially in cardiology globally, we can get that information and better tailor therapy. When we look at any one randomized trial the results might seem kind of black and white and to certain extent so do guideline recommendations but we are getting better at using the results from randomized trials to really identify risk factors. I think that with time we'll be able to either validate the DAPT score in other patient populations or develop tailored scores from unique data sets. I think the challenge really is making sure that we still get good randomized evidence for our treatment decisions but then when we have treatments that have both benefit and risk that we identify which sub-populations of patients really do achieve most of the benefit. And then the other populations that might be harmed. And that's really what we try to do with this score.

                                                And I think what you'll see, you asked about precision medicine which usually we think about using genetics but I think there's so much just really basic information that we have about patient lesion characteristics and other specific factors that we record routinely in their medical records that we can use and you'll see this, I think more and more frequently across different areas of investigation and in cardiovascular medicine.

                                                One really interesting example recently was this French trial. Data was used to be able to predict, very similar to what we did, but to predict which patients would benefit from lower blood pressure without the risk of more aggressive treatment.

Dr. Carolyn Lam:               Yeah, I love the way you put that. Those are really words of wisdom, I do think that that is the way cardiovascular medicine is gonna move. Glenn, how do you put all this into practice for yourself?

Dr. Glenn Levine:             I think whether or not I formally calculate a DAPT score or Paris registry score, I think clearly we integrate the factors in those scores into our everyday practice. And clearly there are patients who are at high bleeding and low ischemic risk and vice versa. I would also encourage listeners to in addition to all the scores, one has to think about the consequences of a recurrent MI or stent thrombosis. Obviously someone who has stent thrombosis of a proximal LED lesion, if they already have a depressed EF or occluded RCA, those consequences are likely much more dire then someone who occludes say at a distal OM3 stent who has the normal ejection fraction. It also encourages them to think about the consequences of stent thrombosis as well as the consequences of a recurring MI.

Dr. Laura Mauri:               Just to make it clear, we know that clinicians have always tried to balance these different risks of ischemia and bleeding when faced with this decisions. I think the challenge really has been the limited amount of information that we've had to be able to do that. And so we've really just used kind of our gut until recently when we've had several large randomized data sets to be able to look to. And what that's done is it's given us the ability to construct these new tools to be able to make practice more data driven. Now still individualized but based on data that's tailored to our patients.

                                                And so I think we can use that to be able to improve outcomes. That being said, we don't want to rely on a statistic or a score alone and things like the DAPT score are based on patients like the ones that were enrolled into the randomized trial. Those were patients who could take longer anti-platelet therapy. It helps to identify who can take it for longer. But there are patients who get anti-coagulation or have other serious bleeding risks who really are going to benefit from new technologies to be able to shorten anti-platelet therapy.

Dr. Carolyn Lam:               Well thank you Glenn once again for a wonderful perspective piece that has really got us thinking about situations even beyond dual anti-platelet therapy. Thank you Laura for your insights and thank you listeners for joining us today. Join us again next week.

Jun 12, 2017

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:              

Jun 5, 2017

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 today provides important trial evidence that will guide interventional management of symptomatic femoral artery disease, but first, here's your summary of this week's journal.

                                                The first paper sheds light on the interaction between left ventricular dysfunction and mesenchymal stromal cell activation. First author, Dr. Naftali-Shani. Corresponding author, Dr. Leor and colleagues from Neufeld Cardiac Research Institute in Israel isolated mesenchymal stromal cells from cardiac and subcutaneous fat tissues of mice with left ventricular dysfunction, 28 days after myocardial infarction or sham operation. They further injected mesenchymal stromal cells or saline into the infracted myocardium of mice and evaluated left ventricular remodeling 28 days after myocardial infarction. They found that left ventricular dysfunction switched cardiac mesenchymal stromal cells towards an inflammatory phenotype and that these pro-inflammatory mesenchymal stromal cells contributed to adverse left ventricular remodeling and dysfunction. The inflammatory polarization of cardiac mesenchymal stromal cells by left ventricular dysfunction was mediated by toll-like receptor four. Finally, toll-like receptor four deficiency in mesenchymal stromal cells attenuated their pro-inflammatory activation, improved their reparative properties, graft survival, infarct repair and left ventricular remodeling.

                                                In summary, the environment of the failing and infarcted myocardium drove resident and transplanted mesenchymal stromal cells towards a pro-inflammatory phenotype that restricted their survival and reparative effects in a mechanism mediated by toll-like receptor four. Targeting toll-like receptor four in mesenchymal stromal cells could improve the safety and efficacy of cell therapy in heart failure.

                                                The next study provides evidence that fractional flow reserve or FFR is a useful index for decision-making in real life daily cath lab practice. First author, Dr. Ahn, corresponding author, Dr. Park and colleagues from Heart Institute Asan Medical Center in South Korea, evaluated the prognosis of deferred and revascularized coronary stenosis after FFR measurement in the IRIS-FFR registry of 5,848 prospectively enrolled patients. This large prospective registry showed that the FFR was linearly associated with the risk of cardiac events in deferred lesions. In addition, revascularization for coronary artery stenosis with a low FFR of less than 0.75 was associated with better outcomes than deferral, while for a stenosis with a high FFR of greater than 0.76, medical treatment would be a reasonable and safe strategy. Thus, the authors concluded that FFR may be considered a clinical prognostic index in addition to a physiological quantification for flow-limiting stenosis. These and other issues are discussed in an accompanying editorial by Doctors De Bruyne, Fournier and Barbato.

                                                The next study sheds important insights into a potential disease modifier in pulmonary arterial hypertenstion, and that is vascular endothelial growth factor receptor three, or VEGF receptor three. First author, Dr. Hwangbo, Co-corresponding authors Dr. Chun and Dr. Jin from Yale Cardiovascular Research Center in Connecticut, used a combination of experimental animal models, human patient cells and detailed signaling studies to demonstrate the importance of a novel interaction between bone morphogenetic protein type two receptors, or BMPR2 and VEGF receptor three in regulating the robustness of endothelial bone morphogenic protein signaling response. They demonstrated that the interaction was critical for promoting BMPR2 internalization in response to bone morphogenic protein stimulation. They further showed that genetic deletion of endothelial VEGF receptor three in mice resulted in exacerbation of chronic hypoxia-induced pulmonary hypertension and impaired bone morphogenic protein signaling. Thus, these findings identify VEGF receptor three as a key regulator of endothelial BMPR2 signaling and a potential determinant of pulmonary arterial hypertension penetrance in humans.

                                                The next study tells us that a low-dose drug-coated balloon may be a promising treatment option in symptomatic superficial femoral or popliteal artery disease. Dr. Schroeder and colleagues of the Jewish Hospital in Berlin, Germany, reported results of the ILLUMENATE European Randomized Clinical Trial, which was a prospective randomized multi-center, single-blinded trial, where patients were randomized 3:1 to treatment with a low-dose drug-coated balloon or an uncoated percutaneous transluminal angioplasty balloon. The primary safety endpoint was a composite of freedom from device and procedure-related death through 30 days, and freedom from target limb major amputation and clinically-driven target lesion revascularization through 12 months. The primary effectiveness endpoint was primary patency at 12 months. The main results were that in symptomatic patients, with superficial femoral and/or proximal popliteal artery disease, low-dose, drug-coated balloon was safer and more effective than uncoated percutaneous transluminal angioplasty balloons through follow-up of 12 months. This is discussed as a novel strategy to reduce femoral popliteal restenosis in an accompanying editorial by Doctors Goldsweig and Aronow.

                                                The final study provides important genotype-phenotype correlations of SCN5A mutations in probands with Brugada syndrome. First author, Dr. Yamagata, corresponding author, Dr. Shimizu and colleagues of Nippon Medical School in Tokyo, Japan, studied 415 Japanese Brugada syndrome probands to assess the association between SCN5A mutations and clinical outcomes. During a mean follow-up period of 72 months, the overall cardiac event rate was 2.5% per year. Compared to probands without mutations, probands with SCN5A mutations experienced their first cardiac event at a younger age, had a higher positive rate of late potentials and exhibited longer P-wave, PQ and QRS durations, and had a higher rate of cardiac events, especially when the mutations were located in the pore region of the encoded protein. The conclusion was therefore, that genetic screening for SCN5A mutations among Brugada syndrome probands may be useful for stratifying such patients according to their risk of subsequent cardiac events. Well, that wraps it up for your summaries. Now for our feature discussion.

                                                Our feature paper today is the stuff that really could change guidelines. Now, we're talking about superficial femoral artery disease and its treatment. Unlike most other vascular beds, where stenting is the preferred modality of endovascular revascularization, the optimal therapy for superficial femoral artery disease remain controversial. However, today's paper really adds to our insight and I am so pleased to have the first and corresponding author Dr. Ilka Ott, from German Heart Center in Munich, as well as Dr. Manos Brilakis, Associate Editor, from UT Southwestern. Welcome both.

Dr. Ilka Ott:                         Welcome.

Dr. Manos Brilakis:           Morning.

Dr. Carolyn Lam:               Wonderful. So Ilka could you please share what you found?

Dr. Ilka Ott:                         We already know from previous studies there has been a lot of studies showing the drug-eluting balloon is superior to plain angioplasty in superficial artery disease. So then, in our study, we found that the treatment with the drug-eluting balloon plus stenting was very superior to the balloon angioplasty plus stenting and the directional atherectomy. The primary endpoint we used in the study was an angiographic endpoint. It was diameter of stenosis and this was significantly lower in the patients treated by drug-eluting balloon angioplasty, as compared to the balloon angioplasty and atherectomy group. Moreover, we had a clinical follow-up of 24 months and we found that also the target lesion revascularization was 70% in the group of drug-eluting balloon plus stent as compared to 37% in the balloon angioplasty and stent group, and 53% in the atherectomy group. We found a significant reduction also in the clinical endpoint of TLR at three years.

Dr. Carolyn Lam:               Wow Ilka, congratulations, but may I just ask, was there any reason to think that a drug-eluting balloon would not be similarly beneficial as in other vascular beds?

Dr. Ilka Ott:                         Well, I think is not a novelty of the study. We already know from previous studies that drug-eluting balloon is superior to plain balloon angioplasty so that's not a surprising result. However, in disease of the femoral superficial artery we often have the problems, in particular when we treat complex lesions like along occlusions or along calcified stenosis, that drug-eluting balloon is not sufficient, so you need to also stabilize the lesion to stabilize dissections. You also need to do a stent implantation. Our study now shows that the combination of drug-eluting balloon plus stent is superior than plain balloon angioplasty plus stent. The nice approach is most of the time if you need a stent, if you use drug-eluting balloon and the lesion is stable and you don't need a stent you are glad. This has shown previous studies, however, if you need further treatment and you need to place a stent, we now show that the pretreatment with a drug-eluting balloon is a superior option than just the plain balloon angioplasty.

Dr. Carolyn Lam:               Manos, what is your take on these results? Do you think it will impact guidelines?

Dr. Manos Brilakis:           First of all, I would like to congratulate Dr. Ott for an excellent study. I think what is particularly important here, is the comparative effectiveness component. We have several studies circulating already about drug-coated balloons, have studies on stents, but we don't have studies addressing the other modalities like atherectomy. Why I was particularly impressed, is I think the study will have a finally an assessment of atherectomy as a primary strategy for calcified lesions and it's interesting that that was not as good efficacy. It was actually tents for worse TLR as compared to plain old balloon angioplasty and stent. Would like to ask Dr. Ott what is your kind thoughts about the alone atherectomy give the results of the study? Are they still doing it or is it falling out of favor?

Dr. Ilka Ott:                         Yes, I think this is a very important point. I think atherectomy alone is not an appropriate treatment but there are some data that atherectomy in combination with drug-eluting balloon gives much better results, or you may even think about a combination of atherectomy and drug-eluting stent, so it often is the case. This study also raises a lot of questions and gives some thought into further studies. I think in the combination atherectomy might still have its place.

Dr. Carolyn Lam:               Could you tell us some of those plans for future studies?

Dr. Ilka Ott:                         Well, we are just in the initiation phase but I think one also very interesting concept is to compare drug-eluting balloon plus stent to the drug-eluting stents that have been on the market. However, as I said before, there's again the concept if you combine the drug-eluting balloon plus a stent it might be also, from the commercial aspect, better because sometimes you don't need the stent. And then moreover, the drug-eluting stents are much more expensive. It would be interested to see a study like that.

Dr. Carolyn Lam:               What about the concern that the superficial femoral artery is subject to a lot of stretching and external compression and it's long and ... Maybe I'm out of date here about the concern of stent fractures and so on. It looks like your study has disproven this, or do you think the follow-up's long enough?

Dr. Ilka Ott:                         I think the follow-up of two years is quite good, but you're right, it seems like in the superficial femoral artery the restenosis process is much longer and more prolonged. Of course, you would like not to place a stent in the SSA but from the interventional aspect, it's often not possible because if you have a dissection with a limiting the flow, you have to fix that by putting in a stent. Nitinol stents are pretty good these days. Moreover, we have another generation of the woven stents the Supera stents that might also be an interesting point to investigate in comparison to the strategy we now have shown to be superior.

Dr. Manos Brilakis:           I think what we need is more studies like this, that they take the other modalities like atherectomy, laser and combine them with what is currently the standard of care, which is drug-coated balloons or drug-coated balloons plus stent, as shared in the study. I just want to congratulate Dr. Ott on her study and encourage future studies from the group. I know the ISAR group is been a phenomenally productive group in coronary intervention and I'm delighted to see they're expanding on the peripheral world.

Dr. Carolyn Lam:               I couldn't agree more. Congratulations, once again, for a study that really will impact practice and that we're so proud to be publishing in Circulation.

                                                Listeners, I'm sure you learned as much as me, so please don't forget to tune in next week as well. Thanks.

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