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: October, 2017
Oct 30, 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.

                                                This week's journal is really special. It is the 2017 cardiovascular surgery-themed issue of "Circulation." To summarize this issue, I am so privileged to have the editors, Dr. Marc Ruel from University of Ottawa Heart Institute, as well as Dr. Timothy Gardner from Christiana Care Health System. Welcome gentleman.

Dr. Timothy Gardner:     Hello.

Dr. Marc Ruel:                   Hi, Carolyn. Glad to be here.

Dr. Carolyn Lam:               Thank you for another beautiful themed issue, Marc. I see that there are four general themes within this theme, if I may. The first of which are a collection of papers on coronary disease and coronary surgery. Could you maybe start by giving us an overview of that?

Dr. Marc Ruel:                   One of the main topics that have been looked at in the surgical-themed issue this year is coronary surgery. We all know well that 2016, 2017, the academic year was quite fertile in providing new information around coronary surgery, especially with the release of the ART trial had actually scientific sessions of the American Heart Association the last November with simultaneous publication.

                                                Interestingly, the cardiovascular surgical-themed issue has several coronary papers and one that deals with essentially with graft failure, if you will. There's an in-depth review written by Mario Gaudino, who is well known and does fantastic work at Cornell, who essentially put a team together looking at several aspects of coronary graft failure. I guess we can say that these are looked in quite great depth, and they deal with several aspects of what would lead to a coronary bypass graft to fail.

                                                First and foremost, Mario and the team look at the blood components. Then the artery and the native bed itself. Then they focus a lot on the conduit, not only the nature of the conduit being a venous versus arterial conduit, but also the way of storing the conduit prior to performing the bypass. Also, the technique that's used around the use of that conduit.

                                                Finally, I'd say that the review culminates with the patient bioreactor, for lack of a better term, aspect. Endothelial dysfunction in the patient with diabetes, age, gender, hypertension, dyslipidemia, etc., all these things that do act as a significant substrate for the fate of the conduit vessel.

                                                A very unique, I think, first-time, in-depth review that, certainly, the "Circulation" editorial team and reviewers were very excited about. I think this will be quite impactful and provide very, very detailed information for future research and future improvement and fate of the coronary graft conduits.

Dr. Carolyn Lam:               And, Dude, I agree. It's the new look at perhaps a classic, old, central surgery, the cardiovascular surgery. Very nice, indeed.

Dr. Marc Ruel:                   Precisely, thank you. We also have a couple of important, seminal original papers within the realm of coronary surgery. In fact, these also deal, to some extent, with the fate of conduits and certainly how they work in the patient population in long ago bypass surgery.

                                                One is a randomized control trial, a single center randomized control trial that was performed in South Manchester. It's called the VICO trial, a study comparing vein integrity and clinical outcomes. Essentially, the study looked at open vein harvesting versus two types of endoscopic vein harvesting for coronary artery bypass grafting.

                                                The study was performed at a single center in England with three sound methods, having three groups of 100 patients who were compared with regards to the vein harvest technique. The primary outcome was with regards to actual vein integrity, looking at muscular damage and endothelial function and integrity on microscopy.

                                                Surprisingly and actually quite reassuredly that there were very few differences between endoscopic vein harvest and open vein harvest. Certainly the investigators also looked, as one of their secondary outcomes, at quality of life. It was quality of life that was gained in patients who had endoscopic vein harvest versus those who had open vein harvest.

                                                Overall, there was no difference in major adverse cardiac events. Therefore, showing at least in an internally valid fashion that these investigators at their center could do endoscopic vein harvesting as well as open vein harvesting.

Dr. Carolyn Lam:               I know that there are other original research papers, perhaps. Would you like to highlight any of them?

Dr. Marc Ruel:                   Yes, for sure. Carolyn, there's also one more coronary surgery paper, which I wanted to highlight and that is the paper entitled, "Does Use of Bilateral Internal Mammary Artery Grafting Reduce Long-Term Risk of Repeat Coronary Revascularization?"

                                                This is a multi-center analysis with first author is Iribarne from Northern New England. Essentially, seven medical centers got together and took about 20 years of consecutive CABGs with a total number of 50,000 operations, or just shy of 50,000 operations.

                                                The median duration of follow-up was 13 years, and these patients were well matched together using a propensity matching scheme. I think this paper and this research is unique and of high impact. Even though it does have shortcomings of not being a randomized control trial, it is very welcome information, especially in light of the recent ART trial, which, as you know, did not show any difference at five years analysis between single and bilateral internal thoracic artery use.

                                                The particularity of the Iribarne paper is that it is a very large data set up with close to 50,000 patients. It is multi-centered, therefore, it is real life. It is a consecutive series. The patients are extremely well matched, and it is remarkable to hear that the patients, in fact, had no difference in mortality until about five years after the operation.

                                                As opposed to many previous series where single versus bilateral internal mammary grafting shows a mortality difference very early on, which always raises the suspicion of poor matching or confounding by indication, if you will, this paper did not have that.

                                                Finally, the follow-up was quite long and at about six years, there was really a mechanistic signal with regards to repeat revascularization events, which seemed to match the difference in late mortality. There was no difference in early and five-year mortality, but afterwards as repeat revascularization events started to occur more frequently in the single mammary group, this was matched by a difference in mortality, as well.

                                                I think a very useful, large, long follow-up mechanistically-based information that I think adds very significantly to the current information we have about bilateral versus single mammary use.

Dr. Carolyn Lam:               Thank you, Marc. Two original papers, highlighted, dealing with really very important modern controversies in this area. Open vein versus endoscopic vein harvesting, single versus bilateral mammary artery bypass. Excellent.

                                                Let's move on now to the next sub-theme, if you will. And that is the collection of papers on "Adult Congenital Heart Conditions," really, really an increasingly important and growing population that we're seeing. Tim, would you like to summarize maybe some of the highlights of the papers there?

Dr. Timothy Gardner:     The first paper, as you point out, is focused on adult patients with repaired tetralogy of Fallot. This series came from the UK and it examines the course of almost 60 patients, at a mean age of 35 years following a repair of tetralogy as infants or young children, developed right heart failure and required pulmonary valve replacement.

                                                This is a common scenario that we're seeing, successfully repaired children who appear to do well but as they get into their late 20s and 30s, their pulmonary valve function, which is often inadequate or not even present valve, require an intervention.

                                                The important learning here is that pulmonary valve replacement, either surgically or by catheter technique, was shown to be highly effective in salvaging right ventricular function. That is based on imaging studies as well as hemodynamic studies of right ventricular function. There was an almost, in this group of patients, almost an immediate reverse remodeling of the right ventricle after placement of the valve, that continued to improve over time.

                                                This was, I think, quite reassuring. There, historically, was a bit of a reluctance to operate on these patients as their right heart was failing, despite the fact that without some intervention to take the volume load off of the RV, the patients didn't do well. This is good news for an important group of patients who we are all seeing, who oftentimes present to the adult cardiologist because of this right ventricular failure problem. A nice, reassuring study.

                                                Actually, the other two congenital papers are, again, focused on the infant. They both deal with the infant with hypoplastic left heart syndrome or single ventricle pathology. The first paper seems sort of specialized in terms of its focus, "The Optimal Timing of Stage-2-Palliation for Hypoplastic Left Heart Syndrome." This was a report from the NIH Pediatric Heart Network. They had a single ventricle reconstruction trial.

                                                This network is comprised of about 10 North American centers, both in the U.S. and Canada and has provided excellent data about the management of pediatric heart disease but, in particular, the single ventricle trial has been excellent.

                                                In this particular paper, they look at the optimal timing for stage-2 repair. Just to remind ourselves, the first part of the three-stage treatment for hypoplastic left heart syndrome is the Norwood procedure, which has to be done shortly after birth, as the patent ductus arteriosus closes and converts, essentially, the single right ventricle into the systemic ventricle.

                                                The stage-2 comes along, usually done with a Glenn-type of shunt, increases pulmonary blood flow and stabilizes these infants until they can reach the age for, and the heart function for definitive repair. This has been a particularly difficult problem for the congenital heart surgeons. What is the optimal timing?

                                                This study, which involved over 400 patients, identified optimal timing for the second stage between three and six months after the Norwood. I think this was very reassuring, is reassuring or supportive for the congenital heart community in terms of both patients and also good evidence base that a delay of three to six months does, in fact, produce the best transplant-free survival.

                                                In fact, the other aspect of this observation was that infants who developed the need for another second stage operation sooner than that did not do well, and the reasons for the required earlier surgery could be failure of the initial operation or additional anatomic risk factors. But this, I think, was an important, large series, multi-center study that will prove to be very helpful in sorting out this complex timing of a three-stage repair.

                                                Just to comment, again, for readers who don't deal with infant congenital heart treatments very often, there's been a remarkable amount of success over the last two decades in salvaging and saving these very difficult infants with the hypoplastic left heart syndrome. In fact, an additional paper in this surgery-themed issue, comes from the UK and is, in fact, a report on the findings from the UK-wide audit of the treatment of infants with hypoplastic left heart syndrome.

                                                In fact, their findings, in this sort of real world, not in the Pediatric Heart Network trial group, is very similar. They found that infants who got to the second stage without additional refinement of the initial Norwood procedure and were able to be successfully treated with a Glenn shunt somewhere in the four-to-six-month age range, did well. They actually made the point that the anatomy was more of a determinant than anything else.

                                                I think that this particular review will reinforce what the congenital heart surgeons have learned about optimal timing for this three-stage treatment of what previously were unreconstructable children.

Dr. Carolyn Lam:               Thank you so much, Tim. Isn't it wonderful the way papers come in and they're actually complementary and consistent with one another. We're just so lucky to be publishing all of these great, high-quality, impactful papers in "Circulation."

                                                Moving on, the next paper actually reminds us why this is a cardiovascular surgery-themed issue and not just a cardiac surgery-themed issue. Didn't we just say that earlier, Marc? This one is on abdominal aortic aneurysm treatment. A population-based landscape of this. Could you tell us a little bit more about that one?

Dr. Marc Ruel:                   Absolutely. Carolyn, you're entirely right. We must remember that "Circulation" is also about peripheral vascular disease, saying this earlier, or cardiovascular surgery and anesthesia consult also when it encompasses vascular surgery. Precisely to that effect, one of the papers in our cardiovascular surgical-themed issue is a landscape population based analysis from Finland that looks at the incidence of abdominal aortic aneurysm between the years of 2000 and 2014.

                                                Finland has a population of about 5.5 million and remarkably has a very circumscribed healthcare system. They do not have an organized system of AAA care as some other countries have shown to have and potentially benefit from, but rather they have a treatment of this condition at several institutions, many of which may not be high volume.

                                                I think the paper is remarkable is that it is very well nested in terms of a population. It provides a comprehensive landscape of where this condition has evolved to over the last few years. Obviously, we see in the results from the authors that the mortality has decreased quite a bit, but also the incidence, probably as a result of better control of risk factors. And also the incidence of rupture outside the hospital.

                                                One thing that came out of this paper, as well, is a potential cohort of the benefits gained from developing an organized system of AAA care, from the reason that the mortality of AAA rupture in Finland was still quite high, despite this being a modern series. In fact, when you include ruptures, before arrival to hospital and at arrival to hospital, the overall mortality was almost 80% for ruptured AAA.

                                                Perhaps one message that comes out of this is that there may be a benefit in having specialized centers dealing with these conditions, especially as they are in the process of rupturing. One last observation was, obviously, the increasingly prevailing role of endoscopic vascular repair in the treatment of this condition, which, in fact, has now surpassed open repair as the dominant method of elective repair.

                                                I think, overall, a very comprehensive, well-nested, country-wide with good follow-up landscape of the AAA condition in a country that has essentially a similar socioeconomic status to much of the western world. Therefore, with external generalized ability to some extent.

Dr. Carolyn Lam:               Exactly, and contemporary data. I really enjoyed that you paired those with an excellent editorial, as well. Finally, before we wrap this up, I have to ask Tim to comment on this next paper, and it's on ventricular assist device malfunctions, I love the title, "It's More Than Just The Pump." Of course, as a heart failure physician, this one's very close to my heart. Forgive the pun. But, Tim, could you tell us about that?

Dr. Timothy Gardner:     This paper comes from the University of Pittsburgh and their artificial heart program. Robert Kormos is the first author and he's been one of the stalwart leaders in the use of LVADs and other pump devices. He reports on their experience with over 200 both HeartMate and HeartWare ventricular assist devices.

                                                It was interesting when we reviewed this paper by the editors, there was some thought that maybe this was a little too engineering focused and so on, but I think the point of the paper is that, as they say in the very first line in their report, reports of LVAD malfunction had focused on pump thrombosis.

                                                But they point out very appropriately that, in fact, controller failure, battery failure, cable failure and other causes of device failure, which can be critical and life threatening and so on, are engineering issues. It reminds us that when we're managing this difficult group of patients, and we're seeing many more patients today with getting LVADs than 10 or 20 years ago, we need to have the bioengineering abilities and resources available.

                                                Even the surgeon and the critical care physician who is dealing with these patients either has to acquire this kind of knowledge or capacity himself or herself, or needs to have a good bioengineer nearby.

                                                What's interesting, I think, that all of us define that these mechanical failures were more common in this pretty big experience than what we've more clinically worried about, which was thrombosis of the pump.

Dr. Carolyn Lam:               Exactly. That's so wonderful. And you know it just leads me to really thank you both, Marc and Tim, for this extraordinarily excellent selection of original research, state-of-the-art and perspective articles and editorials on congenital, coronary, vascular and heart failure surgery. This really appeals not just to the cardiovascular surgeons but really to the vast readership of "Circulation."

                                                Thank you for a wonderful themed issue and thank you for this great podcast.

Dr. Timothy Gardner:     Well, thank you.

Dr. Marc Ruel:                   Thank you very much, Carolyn.

Dr. Carolyn Lam:               Listeners, don't forget to tune in again next week.

Oct 23, 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. Today's feature discussion centers on the population burden of sudden death associated with hypertrophic cardiomyopathy. These are novel data from the ongoing Oregon sudden unexpected death study, results that may surprise you. Stay tuned and that's coming up right after these summaries.

                                             The first original paper in this week's journal tells us that risk reductions from air pollution control yields health benefits comparable to the control of systolic hypertension and smoking in a high risk segment of the urban Chinese population. First author Dr Huong, corresponding author Dr Gu and colleagues from Fu-Wai hospital in Beijing China projected the life years gained if urban China were to reach one of three air quality goals. First, Beijing Olympic games level. Second, China class 2 standard. Third, the WHO standard. They further compared projected air pollution reduction control benefits with the potential benefits of reaching WHO hypertension and tobacco control goals.

                                             Now to do this, the authors used the Cardiovascular Disease Policy Model: China, which is a computer simulation state transition mathematical model of coronary heart disease and stroke incidence, prevalence, mortality, non-cardiovascular deaths, and costs of health care in the Chinese population. They found that air quality improvement under the different scenarios could lead to a great health benefit, ranging from 241,000 life years gained to much greater benefits, benefits that were greater to or equal to the combined benefits of a 25% improvement in systolic hypertension control, and a 30% smoking reduction. Thus, the authors called for joint efforts of the whole society for air quality improvement in China.

                                             The next study describes six differences and similarities in atrial fibrillation epidemiology, risk factors, and mortality in the community. First author Dr [Magnusson 00:02:42], corresponding author Dr [Schnabel 00:02:44] and colleagues from University Heart Center Hamburg Eppendorf studied 79,793 individuals without atrial fibrillation diagnosis at baseline from 4 community-based European studies, namely, FINRISK, DanMONICA, Molisani, and Northern Sweden, all followed for a medium of 12.6 years. They found that cumulative incidence increased markedly after the age of 50 years in men and after the age of 60 years in women. The lifetime risk was similar in more than 30% for both sexes.

                                             Subjects with incident atrial fibrillation had a three and a half fold higher risk of death compared with those without atrial fibrillation. Among the classical risk factors, body mass index explained the largest proportion of atrial fibrillation risk. Six interactions were seen for the risk associations of body mass index and total cholesterol, wherein body mass index was associated with a greater risk increase in men than women, whereas total cholesterol was inversely associated with incident atrial fibrillation with a greater risk reduction in women than men.

                                             The next study describes a novel circular RNA as a potential target in diabetic proliferative retinopathy. Circular RNAs are a novel class of non-coding RNAs that regular gene expression and they're characterized by closed loop structures with neither five-prime, nor three-prime polarity nor a polyadenylated tail. In today's study, first author Dr [Shah 00:04:33], corresponding authors Drs. [Yen 00:04:33] and [Zhao 00:04:36] from Shanghai Medical College Fudan University in China characterized the expression and regulation of the circular RNA, circHIPK3 in retinal endothelial cells and diabetic retinal vascular dysfunction.

                                             CircHIPK3 expression was significantly up regulated upon high glucose stress in vivo and in vitro and regulated retinal endothelial cell function and vascular dysfunction by acting as an endogenous microRNA 30A-3P sponge that sequestered and inhibited its activity. In summary therefore, the circular RNA circHIPK3 plays a role in diabetic retinopathy by blocking microRNA 30A function, leading to increased endothelial proliferation and vascular dysfunction. These data suggest that the circular RNA may be a potential target for diabetic proliferative retinopathy.

                                             The next study identified important new principles of endogenous chromatin structure that have key implications for epigenetic therapy. In this study from first author Dr Rosa-Garrido, corresponding author Dr Vondriska, and colleagues of David Geffen School of Medicine in UCLA, the authors examined changes in chromatin configuration in cardiomyocytes isolated from mouse hearts subjected to transverse aortic constriction or hearts subjected to Tamoxifen inducible cardiac specific excision of CTCF, which is a ubiquitous chromatin structural protein.

                                             There was several important findings from this work. Firstly, the authors found that depletion of CTTF was sufficient to induce heart failure in mice and human heart failure patients receiving LVADs also showed increase CTCF abundance. Pressure overload or CTCF depletion selectively altered the boundary strength between topologically associated domains, which are regions of DNA in which physical interactions occur frequently. The authors showed that there were changes in the compartmentalization of active chromatin and inactive chromatin segments, which is a measure of genomic accessability.

                                             Heart failure involved decreased stability of chromatin interactions around disease causing genes. In summary, these finding provide a high resolution chromatin architectural resource for cardiac epigenomic investigations and also demonstrate that global structural remodeling of chromatin underpins heart failure.

                                             The final study is the first to provide insights into the fluid mechanics of transcatheter valve thrombosis. First author Dr Midha, corresponding author Dr Yoganathan and colleagues from Georgia Institute of Technology and Emory University in Atlanta analyzed post-procedural four dimensional volume rendered CT data of transcatheter aortic valve replacement, or TAVR patients, enrolled in the Resolve trial, excluding patients on anticoagulation. Patients were classified as having transcatheter heart valve thrombosis if there was any evidence of hypoattenuated leaf thickening. The authors studied the flow characteristics within the neo sinus which is formed followed deployment of a transcatheter valve into a native aortic valve.

                                             The authors found that post deployment valve geometry and final implant position affected the flow within the neo sinus, which in turn, may affect the predisposition to thrombus formation. The impact of geometry and position varied according to the different valve types. A supra-annular transcatheter heart valve deployment resulted in a nearly seven fold decrease in stagnation zone size when compared to an intro-annular deployment. In addition, the in vitro model indicated that the size of the stagnation zone increased as cardiac output decreased. In summary, deployed transcatheter heart valve geometry may have implication on the occurrence of thrombosis and a supra-annular neo sinus may reduce thrombosis risk due to reduced flow stasis. While additional prospective studies are clearly needed, these results may help identify patients at higher thrombosis risk and aid in the development of the next generation of devices with reduced thrombosis risk.

                                             Well, that wraps it up for our summaries. Now for our feature discussion.

                                             Sudden death in hypertrophic cardiomyopathy has been and still is a very hot topic in cardiology. Of course it's understandable given all the high profile deaths that have occurred in young athletes ascribed to hypertrophic cardiomyopathy and the fact that these deaths may potentially be preventable with implanted defibrillators. However, we're so proud to have in this week's journal, some of the first data on the population-based burden of sudden death associated with hypertrophic cardiomyopathy. I'm so happy to have with us the corresponding author of this research letter, Dr Sumeet Chugh from Cedar Sinai Medical Center, as well as Dr Mark Link, associate editor from UT Southwestern. Welcome, gentlemen.

Dr Sumeet Chugh:            Thank you.

Dr Mark Link:                    Thank you.

Dr Carolyn Lam:               Sumeet, you know as I said in the introduction, sudden death in hypertrophic cardiomyopathy, we've talked about it a lot. There's been lots published. What makes your data so novel?

Dr Sumeet Chugh:            There is indeed a large body of work related to hypertrophic cardiomyopathy but most of it came from registries. Probably what's a bit unique about our work is that it was done in one large, US community over a number of years.

Dr Carolyn Lam:               Indeed. So population-based statistics, not just of hypertrophic cardiomyopathy, but of sudden death related to it, isn't it?

Dr Sumeet Chugh:            That's correct, Carolyn.

Dr Carolyn Lam:               I think the other thing that we were just actually chatting about is the fact that it's contemporary. Could you tell us maybe the period you're looking at and then give us your findings?

Dr Chugh:                           Yes. The study was initiated in 2002 and is now in it's 16th year, so this particular analysis was conducted between the time period 2002 and 2015. What we do in the process of this community-based work is that we track prospectively every cardiac arrest that happens in the community centered around Portland, Oregon in the USA. The work in performed in the process of doing a multiple-source ascertainment where we take the help of the first responders or the ambulance personnel, the hospital emergency rooms, as well as the police, and the coroner network. It's a fairly comprehensive way of ascertaining sudden cardiac arrest.

Dr Carolyn Lam:               That is a very unique and valuable data set. Could you summarize the top line results, because they were rather surprising?

Dr Sumeet Chugh:            We are already learning that over time, with more awareness, education, and modern management of hypertrophic cardiomyopathy, the risk of sudden cardiac arrest and the overall morbidity from hypertrophic cardiomyopathy may be on its way down. What this study is showing is, that actually the risk of sudden cardiac arrest and the burden of sudden cardiac arrest from hypertrophic cardiomyopathy in the community may be quite low. Those are the main findings.

Dr Carolyn Lam:               Yeah. In fact, I was just so impressed because first of all, you excluded the individuals in this population and found that hypertrophic cardiomyopathy was responsible for 1 in 30 of the cardiac deaths, but that the incidence of the sudden deaths were 0.2 to 0.3% among these hypertrophic cardiomyopathy patients, perhaps less than others may have expected.

                                             Mark could I bring you in on this for a moment? What do you think are the take home messages for something like this, because in a young and middle age population, is any rate really too low?

Dr Mark Link:                    I think this is great data because it encompasses an entire population, so it gets us good data on the true incidence of sudden cardiac death. In the study, if you look at the total number of patients that either had an ECHO or had an autopsy, about 5%, a little over 5% of them, had hypertrophic cardiomyopathy. Roughly 5% of the individuals dying suddenly, under age 60 are dying secondary to hypertrophic cardiomyopathy. That's the sort of data that we really didn't have before because we didn't have such a nice population-based study.

                                             It was interesting also, they tended to be younger, 10 years younger than the others dying suddenly, so it was a younger cohort. They more often had ventricular fibrillation or ventricular tachycardia than the others dying suddenly. It really does give us some nice data on the true incidence of sudden death due to HCM in the community.

Dr Carolyn Lam:               What I thought was also valuable was the fact that the diagnosis of hypertrophic cardiomyopathy was quite often missed prior to the cardiac arrest and I'm trying to wrap my head around about what that implies.

Dr Sumeet Chugh:            That's a very important point, Carolyn. These findings also give us the message that our risk classification methodology continues to need more work. The fact remains that a significant proportion of patients with hypertrophic cardiomyopathy are also going to be asymptomatic. Sometimes they just don't come to our attention.

                                             Another important point, however, that's related to this work is that there may have been during the course of this time period, at least a few patients in this community who would have received an implantable defibrillator and their sudden cardiac arrest would have been averted, so we're not able to count those individuals who were already found and managed.

Dr Mark Link:                    That's a very important point because if a person is found with HCM and has risk factors, they would get a implantable defibrillator. Those individuals would not show up in this database because they wouldn't die.

Dr Carolyn Lam:               Mm-hmm (affirmative)-

                                             That's a very, very important point. Thank you for highlighting that. I think it goes back to why these data are so important, because they are contemporary as well and we really need such estimates, so congratulations Sumeet and thank you for giving us these valuable data.

                                             I'd like to switch tracks a little bit though, and point out this was a research letter, a big data set, important findings, but published as a research letter. Should I even say but? Mark could you comment a little bit about research letters in circulation versus original articles?

Dr Mark Link:                    We increasingly are using research letters in circulation for original research that drives home a basic single point. If that basic single point can be made in 1,200 words, we actually like the research letter format. It's a quick read, people remember it, it's cited. It is something that authors that we ask to turn a full length manuscript into a research letter, should be taking that as a positive sign, because that means that we're interested in the topic and would like to see it in print.

Dr Carolyn Lam:               I completely agree and in fact, Sumeet, if I could ask you to weigh in. Sometimes it's harder, isn't it, to write a research letter than to write a full length manuscript? How was your experience?

Dr Sumeet Chugh:            I have to admit that the first responses as you said, where you feel, "Oh, I've spent a lot of effort in writing this large paper, and now I have to squeeze it into 1,200 words," but the second thought for me was, "The fact is that this is a one bullet message and why not make it shorter and snappier as it is?" I think I've come around in the appropriate situation to appreciating this opportunity of writing a research letter.

Dr Mark Link:                    when you read the research letters, they're very succinct. I actually like them. They get the message across quickly and I think it's a great way to produce science and to show what you've done.

Dr Carolyn Lam:               Yeah. The thing is that we also restrict to a single figure, or a single table and I cannot tell you how many times I've referred to that single figure because it usually tells the full story and it's beautiful summary.

                                             So, listeners, you've heard about the research letters in circulation. Please have a look at them. I'm pretty sure that you will fall in love with the format just like we all have.

                                             Thank you so much, Sumeet and Mark for joining me today. I'm afraid our time is up, but I've so enjoyed talking to you. Thank you, listeners, for following us today. Don't forget to tune in again next week.


Oct 16, 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 feature discussion this week centers on the temporal changes in natriuretic peptides preceding heart failure hospitalizations and patients at high risk. Data that are really novel and have implications for the way we perhaps monitor and categorize these high risk patients. Well, more soon right after these summaries.

                                                The first original paper this week provides the first epigenome-wide association study in patients with heart failure. Now, epigenetics refers to biochemical DNA modification such as methylation of gene bodies, and post-translational modification of histones, which is increasingly recognized to play a crucial, regulatory interface between genes, environment, and the transcriptome.

                                                The lack of availability of myocardial specimens from patients has been a major roadblock for elucidating the impact of such epigenetic changes on complex cardiovascular traits. However, in today's paper from first author, Dr. Meder, corresponding author, Dr. Katiz and colleagues from University of Heidelberg, Germany. The authors performed the first multi-omic study in myocardial tissue and blood of patients with dilated cardiomyopathy compared to controls.

                                                They detected 59 epigenetic loci that are significantly associated with dilated cardiomyopathy, with three of them reaching epigenome-wide significance. 29 of these loci could be replicated in independent cohorts and authors further linked a subset of 517 epigenetic loci with dilated cardiomyopathy and cardiac gene expression.

                                                Finally, they identified distinct epigenetic methylation patterns that are conserved across tissues. Thus representing novel, epigenetic biomarkers for heart failure.

                                                The next study is the first to assess a diagnostic and prognostic value of cardiac myosin binding protein-C in patients presented with possible acute myocardial infarction or AMI. Cardiac myosin binding protein-C is a cardiac restricted protein that is more abundant than the cardiac troponins and is released more rapidly following AMI.

                                                In today's paper, first author, Dr. Kaya, corresponding author, Dr. Marber and colleagues from the Rayne Institute In St. Thomas's hospital in London evaluated cardiac myosin binding protein-C as an adjunct or alternative to cardiac troponins in the early diagnosis of AMI in 1,954 unselected patients presenting to the emergency department with symptoms suggestive of AMI.

                                                The final diagnosis of AMI was independently adjudicated in 340 patients. The authors found that concentrations of cardiac myosin binding protein-C at presentation were significantly higher in those with versus without an AMI. The discriminatory power for AMI quantified by the area under receiver operating curve was comparable for cardiac myosin binding protein-C to high sensitivity cardiac troponins T and I, and even superior to standard sensitivity cardiac troponin I. The use of cardiac myosin binding protein-C more accurately classified patients with a single blood test and to rule out or rule in categories in early presenters, meaning those with chest pain of less than three hours.

                                                The improvement in rule in or rule out classification with cardiac myosin binding protein-C was larger compared with higher sensitivity cardiac troponins T and I. Finally, cardiac myosin binding protein-C was superior to high sensitivity and standard troponin I and similar to high sensitivity cardiac troponin T at predicting death at three years. Thus in summary, this paper shows that cardiac myosin binding protein-C at presentation provides discriminatory power comparable to high sensitivity troponins T and I in the diagnosis of AMI and may perform favorably in patients presenting early after symptom onset.

                                                The next paper describes the discovery of a novel candidate cardiomyopathy or arrhythmia gene. First author, Dr. Barryfield, corresponding author Dr. McNally from Center of Genetic Medicine in Chicago and colleagues studied a family with dilated cardiomyopathy and associated conducted system disease in whom prior clinical cardiac gene panel testing was unrevealing. Whole genome sequencing however, identified a premature stop codon in the gene encoding a novel myo filament component, the myosin binding protein-H-like.

                                                Having identified this gene, they turned to experimental approaches. The myosin binding protein-H-like gene was found to have high atrial expression with low ventricular expression. The truncated protein failed to incorporate into the myo filament. Human cell modeling demonstrated reduced expression of the mutant allele. Heterozygotes and nullumites exhibited a reduction in fractional shortening and increased diastolic ventricular chamber size, aberrant atrio-ventricular conduction and an increased rate of arrhythmia associated with the expression of the myosin binding protein-H-like in the atria, as well as in discrete puncta throughout the right ventricular wall and septum.

                                                These findings therefore support that myosin binding protein-H-like truncations may increase the risk for human arrhythmias and cardiomyopathy.

                                                Transplantation of cells into the infarctant heart has significant potential to improve myocardial recovery. However, low efficacy of cell engraftments still limits the therapeutic benefit. In today's paper, authors describe a method for the unbiased, in-vivo selection of cytokines that may improve Mesenchymal stromal cell engraftment into the heart. In this paper from first author, Dr. Bortolotti, corresponding author Dr. Giacca, and colleagues from University of Trieste in Italy, an arrayed library of 80 secreted factors were individually cloned into adeno-associated viral vectors.

                                                Pools from this library were then used for the batch transduction of bone marrow derived Mesenchymal stromal cells ex-vivo, followed by intra myocardial cell administration in normal and infarctant mice. Three weeks after injection, the vector genomes were recovered from the few persisting cells, and identified by sequencing DNA barcodes that were uniquely labeled for each of the tested cytokines.

                                                Using this novel, competitive, engraftment screening methodology, the authors identified that the most effective molecule was cardiotrophin-1 a member of the IL-6 family. Intra cardiac injection of Mesenchymal stromal cells preconditioned with cardiotrophin-1 preserved cardiac function and reduced infarct size parallel to the persistence of the transplanted cells in the healing hearts for at least two months after injection. Thus, preconditioning with cardiotrophin-1 might represent an efficient manner to improve the currently poor cell retention in patients treated with Mesenchymal stromal cell therapy.

                                                The final paper presents results of the early myo trial, a non-inferiority trial comparing a pharmacoinvasive strategy with half-dose alteplase versus primary PCI in patients with STEMI, presenting six hours or less after symptom onset but with an unexpected PCI related delay.

                                                First author, Dr. Poole, corresponding author, Dr. Hua and colleagues from Shanghai Jiao Tong University in China randomized a total of 344 patients from seven centers to a pharmacoinvasive arm or a primary PCI arm. They found that pharmacoinvasive strategy was non-inferior to primary PCI for the primary endpoint of complete epicardial and myocardial reperfusion after PCI defined as TIMI flow grade 3, TIMI myocardial profusion grade 3, and ST-segment resolution of more than 70%.

                                                There was no significant differences in the frequency of the individual components of the combined endpoint. Infarct size and left ventricular ejection fraction were similar in both groups and there was no significant differences in 30-day rates of total death, re-infarction, heart failure, major bleeding events, or intracranial hemorrhage. However, minor bleeding was observed more often in the pharmacoinvasive group.

                                                Thus the authors concluded that a pharmacoinvasive approach with reduced dose alteplase seems to offer effective and safe reperfusion in low-risk patients with STEMI with an unexpected PCI related delay. Further large, randomized control trials powered for clinical endpoints are needed.

                                                Well, that wraps it up for your summaries. Now for our feature discussion.

                                                The measurement of natriuretic peptides BNP, NT-proNP have certainly become the cornerstone of heart failure management. We measure these levels by guidelines in patients who are presenting with symptoms and suspected heart failure, in patients who are hospitalized. We measure them for prognostication purposes at discharge. However, what we don't really know is how the preceding changes in natriuretic peptides may precede heart failure hospitalization in patients who are at high risk of developing heart failure.

                                                For example, patients with a recent coronary event or type-2 diabetes. And this is the very subject of our feature paper today, and I am so pleased to have the corresponding author of today's paper which is really a research letter. Dr. Brian Claggett from Brigham and Women's Hospital as well as Dr. Biykem Bozkurt who's our senior editor from Baylor College of Medicine.

                                                Welcome both, and maybe I could start, Biykem could you let us know, what are the unanswered questions in heart failure relating to natriuretic peptides and how do you see this paper falling in, clinically?

Dr. Biykem Bozkurt:        Carolyn, this is a wonderful I think prelude to perhaps preventing heart failure events. And as you are aware, we in the recent year changed our guidelines at the ACC, AHA, and the HFSA incorporating screening high risk patients for development of incident heart failure. And the study that resulted in this consideration was a STOP-HF trial which was utilizing natriuretic peptides in high risk patients to determine whether their closer follow up in a multidisciplinary fashion would result in earlier detection and prevention of heart failure, and which it did.

                                                And this study I think is straddling the concept of high risk or stage A or B patients because they are individuals who have had heart attacks, coronary events, and they have type-2 diabetes so they are definitely high risk. And doing natriuretic peptides as an outpatient, whether that would predict the heart failure hospitalizations.

                                                And in essence I think it's a good concept. Perhaps the challenging concepts are how often should we screen our patients, and what will be the threshold of the rise that would potentially make us act in either earlier diagnostic strategies, or management strategies. I think those are the two unanswered questions that remains.

                                                How are we gonna screen our patients? Our high risk patients to determine when they are developing heart failure before they become symptomatic? So, what threshold are we going to use?

Dr. Carolyn Lam:               That is a perfect set up. I just wanted to add as well in addition to STOP-HF there was the PONTIAC study in diabetics which is very relevant to today's paper that also sort of used NT-proBNP to risk stratify patients for prevention of heart failure. But neither of these studies talked about the temporal changes in natriuretic peptides. And I think a lot of the reason for that is, is that the methods, I mean the statistical methods to do that sort of thing are mind-blowing.

                                                And so Brian, could you now please share with us what you did, the methodology and basically what you found before we discuss the two questions that Biykem brought up?

Dr. Brian Claggett:           What was really interesting is the method that we came up with to look at these questions. It's something that we like to believe will be generalizable and can be used in other scenarios and for other biomarkers. But the idea that we have is that we are always used to thinking about the design of a clinical trial as being very regimented. So, you see a patient once at baseline, and then maybe six months later, and then maybe six months after that, and so on. And so it's hard to know what's going on, on a day to day or week to week basis.

                                                But if you think backwards, and you think backwards from the time of any sort of event, because those events whether they're hospitalizations or MIs or death, they happen not on that same schedule. And so odds are at the end of a trial, you had a patient who came to a scheduled visit and then had an event the next day. And you probably had a patient who came in for a visit two days before an event, and another patient who came in a week before an event. So if you start thinking on that time scale, you can piece together all these different time frames when you do have data collected and try to reconstruct something that looks like an actual continuous natural history of what that biomarker would have looked like over say a two year period, if it had been measured continuously.

Dr. Carolyn Lam:               So, tell us what you found. First of all, let's just make sure that everyone knows you were looking at the ELIXA cohort, right?

Dr. Brian Claggett:           Yes, the data that we had available for this analysis comes from the ELIXA trials, it was 6,068 patients all with type-2 diabetes and a recent ACS event. Recent meaning within the last 180 days. And they were randomized placebo versus a diabetes drug, lixisenatide. And they were followed up for cardiac outcomes.

                                                Beyond that, the natriuretic peptides were measure systematically at baseline, month 6, month 18, and month 24 in all patients who were participating in the trial. So this was the richest collection of a large number of patients being measured multiple times, systematically and not in just a sub-sample of the population. So, we felt like this was a great opportunity to learn something about what happens. What can you learn when you measure these natriuretic peptides over and over again.

                                                And even more interesting than that, the fact that this wasn't a heart failure trial meant that some of the patients already had heart failure at baseline. Other patients didn't have heart failure, but as the trial went on, they developed or were hospitalized for heart failure for the first time. And so we were able to also look at differences between patients experiencing their first heart failure, versus those with more long standing disease.

Dr. Carolyn Lam:               And that was very, very unique methodology that you spoke about. And I fully agree that it's going to be used more. I am staring at your beautiful figure one right now. That really, really says it all. Could you walk us through the results?

Dr. Brian Claggett:           Sure, I think our key finding is that, I guess no matter when you measure patients. Patients with a higher level of NT-proBNP, or a higher level of BNP at any given time are going to be at higher risk of developing heart failure in the future.

                                                But as we start looking at this as a temporal process, what we see is that there seem to be a noticeable acceleration in these increases, specifically in the last six months before development of heart failure. Or, before a hospitalization for heart failure. And that increase in the final six months seems to occur both in patients who had no prior history of heart failure and also in patients with a history of heart failure. So that six month window I think is something that we learned that we didn't necessarily know before.

Dr. Carolyn Lam:               But, going back to Biykem's questions, do you think we have answers to how often we need to survey natriuretic peptides in these high risk patients and what threshold we need to act on?

Dr. Brian Claggett:           I think both are very important. I think maybe the timing and the thresholds are somewhat separate questions. I think we're better able to answer the timing question. At the very least we can say that if dramatic changes are happening over a six month window that measuring patients only once every six months probably isn't enough. Whether that means it needs to be every three months, or two months, or one month, or something more than that, I think it's hard to know exactly what the right answer is. But I think we are confident in saying that things happen relatively quickly and we need to be measuring these things more frequently.

                                                As far as the question of thresholds, I think that's maybe even a more difficult question. Or even the idea of a threshold means that we think that there's some magic number and I am not sure that we know for sure what's more important, the absolute number or is it the ... if someone starts relatively low and that relatively low number doubles over the course of six months. That might still be prognostically just as important as someone who's been consistently edging just below or just about that threshold level.

                                                I'm not sure that we're confident enough to say that the changes, the speed of the changes, or the relative changes, or some absolute threshold is the most important thing to be paying attention to. But, I think where these two are related is the more ... that we can start to collect this data more frequently and be able to analyze it. I think that gives us a lot better chance of being able to successfully answer that question about thresholds.

Dr. Carolyn Lam:               Indeed. Stuff for future work, huh? Biykem, what do you think?

Dr. Biykem Bozkurt:        I wanted to point out two things from Brian's study which was quite interesting. One is the trajectory of the rise, or the delta changes in the natriuretic peptides was quite different in the patients with no history of heart failure compared to those with a history of heart failure. The trajectory, or the linear rise, or the delta changes were more prominent in the individuals with no history of heart failure. Probably intuitively expected so because their baseline levels are not as high as the individuals with history of heart failure.

                                                So, it almost gives the impression that maybe in low low risk, the screening or the frequency may need to be lower, and if low, then probably the likelihood of the rise may be less. But those individuals who, as you said, are edging upward, then maybe the frequency may need to be higher and there may be perhaps a linear rise or a more prominent rise about six months before the incident event.

                                                So, it's an interesting concept just to look at people's trajectories. But, as you said, probably individualization and monitoring or targeting may need to be individualized according to personal risk and other features. And one then wonders futuristically if this would be a concept that would be point of care testing maybe done by the patients similar to glucose monitoring. And in the event that we were to be able to carry the platform to self-test.

Dr. Brian Claggett:           You're talking to a statistician, so I am always going to be in favor of collecting more data all the time. So I agree with that.

Dr. Carolyn Lam:               Wow, what an insightful discussion. Thank you both for joining us on this podcast today.

                                                Ladies and gentlemen out there, you heard it right here in Circulation on the Run. Tune in again next week.

Oct 10, 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.

                                                We know that excessive sedentary time is bad in terms of health outcomes, but does it matter how that sedentary time is accrued, whether in short or long bouts? Today's feature paper gives us some answers. More soon, right after the summary of this week's journal.

                                                The first original paper in this week's journal provides insights into the mechanisms underlying neointima formation in arterial restenosis. Co-first authors, Dr. Cheng and Shi, corresponding author Dr. Li from Wuhan University in China, and their colleagues, performed an elegant series of experiments in which they demonstrated that interferon regulatory factor 4, or IRF4, which is a member of a family of key, innate, immune regulators known to play a role in cardiometabolic disease, actually protects arteries against neointima formation.

                                                They further probed the mechanism underlying this protective effect and found that IRF4 promoted the expression of Krüppel-like factor 4 by directly binding to its promoter. Genetic over-expression of Krüppel-like factor 4 in smooth muscle cells reversed the neointima promoting effect of IRF4 ablation. Whereas, ablation of Krüppel-like factor 4 abolished the protective function of IRF4, thus indicating that the protective effects of IRF4 against neointima formation were Krüppel-like factor 4 dependent.

                                                These findings suggest that the previously undiscovered IRF4 Krüppel-like factor 4 axis plays an important role in vascular proliferative pathology and thus may be a promising therapeutic target for the treatment of arterial restenosis.

                                                The next paper highlights that high-spacial resolution in gene expression signatures can reveal new regulators, genetic pathways, and transcription factors that are active in well-defined regions of the heart.

                                                Now we know that traditional genome-wide transcriptome analysis has been disadvantaged by the fact that the signals are derived from tissue homogenates. Thus, the authors of this current paper, including Co-First authors Dr. Lacraz and Junker, corresponding author Dr. Van Rooij from University Medical Center Utrecht in the Netherlands used tomo-seq to obtain genome-wide gene expression signature with a high spacial resolution, spanning from the infarcted area to the remote areas to identify new regulators of cardiac remodeling.

                                                Using this technique, they identified SOX9 as a potent regulator of cardiac fibrosis. In vivo loss of SOX9 reduced the expression of many extracellular matrix genes, which coincided with a blended cardiac fibrotic response upon ischemic injury.

                                                These data therefore were able to unveil currently unknown relevance of SOX9 as a key regulator of cardiac fibrosis, thus underscoring that tomo-seq can be used to increase our mechanistic insights into cardiac remodeling, and to help guide the identification of novel therapeutic candidates.

                                                The next paper reports the primary results of the effect of ferric carboxymaltose on exercise capacity in patients with iron deficiency and chronic heart failure, or EFFECT-HF study, which is a randomized control trial of intravenous ferric carboxymaltose, compared to standard of care on the primary end point of change in peak Vo2 from baseline, to 24 weeks in patients with symptomatic, chronic heart failure with reduced ejection fraction and iron deficiency.

                                                In this report from Dr. van Veldhuisen from University Medical Center Groningen and colleagues, intravenous ferric carboxymaltose was shown to significantly increase serum ferritin and transferrin saturation. At 24 weeks, peak Vo2 had decreased in the control group, but was maintained in the group receiving intravenous ferric carboxymaltose.

                                                Although a favorable effect on peak Vo2 was observed with ferric carboxymaltose, compared to standard of care in the primary analysis, this effect was highly sensitive to the imputation strategy for peak Vo2 among patients who died.

                                                They also reported that patient's global assessment and functional class, as assessed by New York Heart Association, improved on ferric carboxymaltose compared to standard of care.

                                                Whether ferric carboxymaltose is associated with an improved outcome in these high risk patients, deserves further study.

                                                The final study provides important long term clinical data to guide lead management decisions in patients with cardiac implantable electronic devices.

                                                Dr. Pokorney from Duke University Medical Center in Durham, North Carolina, and colleagues, analyzed over 6,000 Medicare patients and found that device extraction was associated with a lower adjusted five year infection rate, compared with a cap and abandon strategy. There was a lower absolute five year mortality with extraction, but after adjustment there was no association between extraction and a lower five year mortality.

                                                In summary, therefore, elective lead extraction for non-infectious indications in this Medicare cohort had similar long term survival, but lower risk of device infections at five years, compared to capping and abandoning leads.

                                                Patient and provider preferences are critical to decision making when considering extraction versus capping and abandonment of leads.

                                                Well, that wraps it up for your summaries. Now for our feature discussion.

                                                For today's feature discussion, we are talking about sedentary time and a metabolic risk of having too much of it. But, today's paper is so interesting because it tells us that it's not just the total amount of sedentary time that may matter, but how we accrue the sedentary time. Very, very novel concept in my point of view and I'm so pleased to have the first and corresponding author of this paper, Dr. Keith Diaz from Columbia University Medical Center with us, as well as Associate Editor from Johns Hopkins, Dr. Wendy Post.

                                                So pleased to have you both. Keith, could we just dive right into it? Tell us what population you were looking at, and what you found.

Dr. Keith Diaz:                    Sure, so we were studying a population of participants enrolled in the Hispanic Community Health Study, so it's a US populations of over 16,000 Hispanic adults. And essentially what we found was that sitting for prolonged bouts, so sitting for one, two hours at a time, was associated with poor glucose regulation.

Dr. Carolyn Lam:               Well, yikes. I've actually been sitting for a few hours in a row right now, actually. I think these results are phenomenal, but could you maybe expand a little bit on the details, like how long is too long? And, how often a break needs to happen for you to see differences in the metabolic risk?

Dr. Keith Diaz:                    It's a good question and, to be honest, we don't know. I think that's where the research needs to head, but right now it seems to be that taking a break every 30 to 60 minutes could be beneficial. I think that's what we've found thus far.

Dr. Wendy Post:               Keith, we were really excited to get your paper in. I think everyone on the Associate Editorial Board was especially interested in it because we can all relate. As Carolyn said, she's been sitting for a long time and when we have these meetings we have two hour meetings at a time and maybe we need to start saying that in the middle we should all stand up and take a break. So we can all relate to this.

                                                But I think one the biggest questions that we had related to data itself, was the association between the total sedentary time and the sedentary bout duration. Maybe you can tell us a little bit more about those correlations in the interaction and tell us also how you also measure sedentary bout duration and total sedentary time in this observational cohort.

Dr. Keith Diaz:                    Sure, so I'll start with that latter question. So, we measured sedentary time [inaudible 00:09:32] subjectively. So we actually used an activity monitor called an accelerometer to see how sedentary they are. And how we quantified sedentary bouts is we just looked at how long consecutively a person sat without moving. That was considered sedentary bout. In terms of correlation, what we found is that there are very closely linked. So, people who sit for long hours during the day for total volume, also sit in long bouts. And so what we wanted to do was try to figure out and piece apart, which one is more important? When we're trying to ... If we're thinking about guidelines and what we should be doing about our sedentary time, is it important to reduce our volume or interrupt our bouts? And so what we found is that they're not independent, and that they're in many ways synergistic. And that the association of prolonged sedentary bouts with glycemic biomarkers varied according to how much total volume you sit and vice-versa.

Dr. Wendy Post:               Can you expand a little bit more on that? So tell us about the interaction that you found between sedentary bout duration and total sedentary time.

Dr. Keith Diaz:                    Sure, so we did find that there was a specifically significant interaction between the two variables and so what we tried to do is actually categorize people as to whether they were high for both characteristics or high for just one of them. And so what we found was that those participants who are high for both, so they had high volume and sat in long bouts, they had the worst glucose regulation, and that those individuals that were high for just one of the characteristics had a little bit better glucose regulation. And so really what we thought the take home message was when thinking about how do we improve our sedentary behaviors is that it's targeting both. It's not sitting for large volumes during the day, but also making sure to take frequent breaks every 30 or 60 minutes.

Dr. Wendy Post:               And tell us about the glucose measures that you included in your study.

Dr. Keith Diaz:                    Yep, we had a couple glucose measures. One we had people do a two hour glucose tolerance test, so they took a glucose drink and then we measured their blood sugar levels two hours after having that drink. We also measured their H1Ac levels as well as their fasting glucose and fast to link insulin measures from which we can then derive measures of something called HOMA IR, which is a measure of insulin resistance.

Dr. Wendy Post:               And the associations that you saw were primarily with the HOMO IR and the two hour glucose levels but less with the hemoglobin A1c?

Dr. Keith Diaz:                    Correct.

Dr. Wendy Post:               So it really appears to be that insulin resistance that's most affected by the total sedentary time and sedentary bout duration. Tell us about potential confounders and how you factored that into your analysis.

Dr. Keith Diaz:                    Yeah, there was quite a number of potential confounders between this relationship of sedentary behavior and glycemic biomarkers. One of them in particular that we were concerned about most were things like body mass index or exercise or physical activity levels. And so we took a look at what we adjusted for those confounders how the relationship changed. And what we did find was that there was an attenuation and association between sedentary behavior and the glucose markers, but there was also ... were still statistically significant. So suggestive that maybe they're partly in the pathway of body mass index or exercise but they didn't make the relationship go away. I should add that we looked at a couple other confounders, we looked at things like inflammation, C-reactive protein, as well as whole bunch of other measures of cardiovascular risk factors. I'll stop there.

Dr. Wendy Post:               And what about the fact that study is cross-sectional, are there any caveats related to the study design that you'd like to point out to the audience?

Dr. Keith Diaz:                    Yeah, I think that's an important point, that this is cross-sectional, so by no means can we infer causality that sedentary behavior causes glucose dysregulation, it's just purely an association. So I think anyone listening to this podcast should keep that in mind when reading this paper or listening to this podcast.

Dr. Wendy Post:               So if you were writing the next set of guidelines what would you recommend in terms of how you implement these findings into guidelines? Not to imply that we think that these cross-sectional observational data mean that we're ready to change guidelines but, if these were replicated in randomized trial or some other more objective data study design, how do you think we should use these results to change our behaviors?

Dr. Keith Diaz:                    I think these guidelines point ... or, with the current guidelines are, sit less, move more, where the guidelines that came out from AHA in October of 2016. In part, they were not as specific because we don't have quite the quality of guidelines or data that we need for more qualitative guidelines, or quantitative guidelines. I think if we're able to replicate these data with [inaudible 00:14:10] or point us towards at least is, also, that we should be interrupting our sedentary bouts. And so what I'd like to see hopefully if we can replicate something I'd like guidelines that say every 30 minutes or every 60 minutes of sitting you should stand up and move. And hopefully with future studies that are coming out that we can make them even more specific and something along the lines of every 30, 60 minutes you stand up and walk for 5 minutes or you just stand up for 1 minute. That's where I'd like to see the science head and I think this study points us in the that direction of maybe we have to start thinking about breaking up our sedentary bouts.

Dr. Carolyn Lam:               All right you guys, I don't know about you, but I am literally standing up right now while I'm listening to you both. This is so interesting and I love the way, Wendy, you reflected the robust discussions we had as team when we were working through this paper. Congratulations again, Keith, for just this remarkable paper. Actually, maybe I could just ask, Wendy, what do you think? What do you think our next steps that may need to get these kinds of recommendations, perhaps into guidelines?

Dr. Wendy Post:               I think as was alluded to before, these are observational data so they're important for hypothesis generation, but really to have evidence that would lead to changes in guidelines maybe having a randomized trial, where obviously you can't have very hard outcomes, but randomized trials of some duration that could potentially lead to changes and important outcomes, would then maybe lead to changes in guidelines. But there isn't anything that we would lose from trying to implement these kinds of behavior, changes into our lifestyle since the downside and the risk is pretty low. So even if they don't make the strongest level of evidence at this point, I think we can still all be mindful of this and so.

                                                One thing that we've been trying to do in our preventive cardiology group at Hopkins is trying to implement walking meetings. In fact, I just had an email discussion with one of my colleagues about meeting tomorrow and she said, "Well, where do you want to meet?" And I said, "Well, why don't we go for a walk? The weather should be nice." And so I think if we're all mindful of trying to, not only increase our amount of physical activity, but trying to limit the sedentary bout duration by being creative and trying to change, sort of, long standing traditions of having meetings sitting in an office, then that could be helpful.

                                                So, just something for our audience to think about as well.

Dr. Carolyn Lam:               That's brilliant. You know, the one thing that I was thinking, though, just thinking about the reception of these data in my country, in where I practice, in Asia. This was a purely Hispanic or Latino population. I suppose there is a perception that that population may be predisposed to cardiometabolic disease and so on, and so you know, what's the applicability to us in Asia? So, I'm really happy, particularly to hear how you've taken it on. I mean, it's a simple thing, why not, right? Just to be more active. There's surely can't be something wrong with that. What do you think of that?

Dr. Wendy Post:               Totally, I think it's important to emphasize the unique nature of these data and that they come from a Hispanic study, which is a really important addition to our literature in epidemiology and cardiovascular disease and certainly there are significant differences in lifestyle among different communities within the United States and across the globe, as you've experienced having lived in different countries. And so, I think we need obtain more data about how there might be differences based on various traditions and different lifestyles, and try to target those who are at greatest risk.

Dr. Carolyn Lam:               Keith, did you have anything to add to that?

Dr. Keith Diaz:                    Yeah, I think Wendy is right on and certainly I don't think we have any reason to suspect that sedentary behavior acting differently in Hispanics versus other populations, and so I still think going forth with this notion that we all should be reducing our sedentary behaviors is important to highlight.

Dr. Carolyn Lam:               Fantastic. Well, thank you both for a really wonderful discussion. This is really cool, I think a lot of people will be talking about this.

                                                Listeners, you've heard it first, though, in Circulation on the Run. Thank you for joining us today and don't forget to tune in next week.


Oct 2, 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.

                                                Today's issue features striking results from the ASSERT 2 trial of the prevalence of subclinical atrial fibrillation detected with implantable monitors in a group of high-risk older individuals. Much more soon, right after these summaries.

                                                The first original paper in this weeks' journal shows for the first time that myocardial edema, in the week after STEMI in humans, is a bimodal phenomenon. First off, there is Dr. Fernandez Jimenez and Barreiro-Perez, corresponding author Dr. Ibañez, and colleagues from CNIC in Madrid, Spain, evaluate that the time course of edema reaction in 16 patients with anterior STEMIs successfully treated by primary angioplasty compared to 16 matched controls using cardiac magnetic resonance and assessing its implications for myocardium at risk quantification. The STEMI patients were scanned serially within the first three hours after reperfusion and at, one, four, seven and 40 days, while controls were scanned once. Furthermore, they performed an experimental study of 20 pigs undergoing 40 minute ischemia reperfusion, followed by serial cardiac magnetic residence exams at 120 minutes, one, four and seven days after reperfusion.

                                                The authors found that am initial wave of edema appeared abruptly at reperfusion, but it was significantly attenuated by 24 hours. The initial wave of edema was followed by a second or differed healing related wave of edema several days after reperfusion, reaching a plateau around four to seven days after myocardial infarction. Of note, cardiac magnetic resonance myocardium at risk quantification at 24 hours post-reperfusion severely underestimated the infarct size.

                                                In summary, post-MI edema in patients follows a bimodal pattern, which affects cardiac magnetic resonance in estimates of myocardium at risk. The dynamic changes in post-STEMI edema, highlight the need for standardization of cardiac magnetic resonance timing to retrospectively delineate myocardium at risk and quantify myocardial salvage. According to the present clinical and experimental data, a time window between day four and seven, post-MI, seems a good compromise for standardization. However, further studies are needed to study the effect of other factors on these variables.

                                                The next paper sheds light on molecular mechanisms underline the progression of atherosclerosis, involving multiple inflammatory events, as well as the counteraction by inflammatory responses in cells such as the endothelium, circulating monocytes and resident macrophages in the arterial wall.

                                                Co-first authors, Dr. Li and Martin, corresponding author Dr. Shyy from Xi’an Jiaotong University Health Science Center and University Health Science Center and University of California, San Diego and colleagues, analyzed RNA seek data to identify cholesterol oxidation and e-flux genes regulated by Kruppel-like factor 4, which is a key anti-inflammatory transcription factor. They found that Kruppel-like factor 4 upregulates cholesterol 25 hydroxylase and liver X receptor in vascular endothelial cells and macrophages. In further in vitro and in vivo experiments, they show that access enhanced reverse cholesterol transport from the vascular wall, mitigated inflammation through suppression of sterile regulatory binding protein two and NOD-like receptor family hiring pyrin domain containing protein three inflammasome in endothelial cells and also promoted cholesterol e-flux in M1 to M2 transition in macrophages.

                                                In summary, Kruppel-like factor 4 trans-activates cholesterol 25 hydroxylase and liver X receptor, promoting the synergistic effects between individual cells and macrophages to protect against atherosclerosis susceptibility, and this may therefore be a therapeutic target for cardiovascular disease.

                                                The next study provides data on the safety and efficacy of a novel cobalt alloy-based coronary stent eluting the antiproliferative agent, ridaforolimus, for treatment of patients with coronary artery disease.

                                                Dr. Kandzari from Piedmont Heart Institute in Atlanta, Georgia and colleagues, reported the primary results of the bionics trial, which was a prospective international, one-to-one randomized trial conducted to evaluate in a noninferiority design, the relative safety and efficacy of ridaforolimus-eluting stents compared to slow release zotarolimus-eluting stents among 1,919 patients at 76 centers undergoing PCI. At 12 months, the primary endpoint of target lesion failure was 5.4% for both devices, thus meeting the prespecified criteria of noninferiority of ridaforolimus stent compared to the zotarolimus stent.

                                                Angiographic and intravascular ultrasound measures of restenosis, late lumen loss and nepintimal hyperplasia measured at 13 months, were similar in both devices. Treatment with the ridaforolimus-eluting stent resulted in low rates of myocardial infarction, repeat revascularization and stent thrombosis, and results were consistent in predefined patients and lesion groups. The authors therefore concluded that these results support the safety and efficacy of ridaforolimus-eluting stents in patients representative of every day clinical practice.

                                                Well, that wraps it up for your summaries. Now, for our future discussion.

                                                Today for our future discussion, we are going to talk about a true global public health problem. It's a condition that affects 33 million people worldwide, a number that is expected to double by 2050, and what we're talking about is atrial fibrillation. Those are the numbers of just what we know of detected atrial fibrillation, but today's paper deals with silent subclinical atrial fibrillation and the results of the ASSERT 2 trial. I'm so pleased I have the first and corresponding author with us today, Dr. Jeff Healey from Population Health Research Institute at McMaster University in Hamilton, Ontario. Welcome, Jeff.

Dr. Jeff Healey:                 Good morning.

Dr. Carolyn Lam:               Also on the show today is Dr. Sami Viskin, associate editor from Tel Aviv Medical Center. Hi, Sami.

Dr. Sami Viskin:                 Hi. Hello, everybody.

Dr. Carolyn Lam:               Jeff, from ASSERT to ASSERT 2, could you give us a bit of the picture of what made you do ASSERT 2 and what have we learned?

Dr. Jeff Healey:                 The ASSERT trial was a large 2,500 patient trial in patients in with pacemakers and also implantable defibrillators and it was really an easy first place to study this entity of sub-clinical atrial fibrillation because, of course all of these patient had implanted devices with electrodes in their atrial where they could report all of the internal activity continuously for many years at a time. This was done with really no incremental costs or inconvenience to the patient, the data were already being collected, so in ASSERT we asked the question, how common is atrial fibrillation as it is not detected clinically and is it associated with stroke? What we found was that over time, somewhere between 30% and 40% of patients with an implemented device developed atrial fibrillation, which we termed subclinical atrial fibrillation, because this was not detected by the usual clinical mean. Great results, very interesting, but begged the question, is this a unique entity that we see only in pacemaker patients or if you just took older individuals in the more general population, would you see subclinical atrial fibrillation as well? That was really the impetus for doing that ASSERT 2 trial in patients who are over the age of 65, had cardiovascular condition, placed them at increased risk or stroke in atrial fibrillation, but did not have implanted devices.

Dr. Carolyn Lam:               Indeed, Jeff. That's a beautiful set up. The ASSERT was really quite a landmark study suggesting that what we know as clinical may be just the tip of the iceberg, isn't it? Now you've extended it, and I think it'd be really important for the audience to understand that ASSERT 2 was really a high risk cohort. Could you maybe tell us a little bit more of what you did and what more we learned?

Dr. Jeff Healey:                 Sure. These were typical patients who might be attending a cardiology clinic, an outpatient general medicine clinic who did not have pacemakers and did not have any history of atrial arrhythmias, but you're right, they were high-risk. These were patients over 65 who have had clinical risk factors, things like hypertension, or diabetes, but also some other marker of increased risk such as a BNP that was elevated or left atrial enlargement.

Dr. Carolyn Lam:               Yeah and your findings were so striking. Tell us.

Dr. Jeff Healey:                 What was quite was surprising was, indeed, we found that in the non-pacemaker, non-defibrillator population from ASSERT 2, we also found high prevalence of subclinical atrial fibrillation. This was really quite surprising. In fact, it was many times higher than we had predicted. We found that over time, the annual risk of developing atrial fibrillation in this cohort was 34.4% per year, which is truly astounding number of patients who developed atrial fibrillation.

Dr. Carolyn Lam:               That's like one in three of such patients experiencing at least one of these episodes lasting at least five minutes? That's really impressive.

Dr. Jeff Healey:                 It was high.  You could look into that study and find groups where the risk was even higher, so we chose to cut off left atrial volume of 58 millimeters and not correspondent with the median volume of the population series of Olmstead County for people over the age of 65 who came in for an echocardiogram, and that was the minimum left atrial size to get into the trial. If you then looked at within the ASSERT 2 trial and looked at the volumes within the trial, somewhere around 72 1/2 milliliters, if you looked at the patients who had the top of atrial size, that risk was as high 50% per year, so one in two.

Dr. Carolyn Lam:               Another thing I noticed though about your results is that the frequency of these episodes, it's not that frequent, and so what we would do typically in a 24-hour monitoring or even a seven-day monitoring would have captured only a small proportion of these. Isn't that the case, Jeff? Could you give us some numbers there?

Dr. Jeff Healey:                 Yes, of course. The episodes that qualified were at last five minutes in duration, we then do longer episodes in course, but these were much less frequent in the single digit percent risk, and what we found was there were, as you say, quite infrequent. So with the standard 24-hour halter monitor, for example, you would have had a very low pickup. It really goes to show that the longer you monitor, the more you will find. I think that's the key message out of this study and other studies like it.

                                                I think conversely, you also have to realize that the more you look, or the harder you look, you may be uncovering atrial fibrillation that behaves differently than atrial fibrillation you find, for example, in the single 12 lead ECG. We have found, and others have found, that the risk of stroke we find when we would have short episode picked up only with long term continuous monitoring is real but it's much lower than we see with atrial fibrillation that was picked up by ECB where patients are presenting in emergency rooms stroke with symptoms.

Dr. Carolyn Lam:               That's such relevant points, and it really brings up the unanswered questions perhaps, exactly what is the correlation with stroke risk? What should we do about it? Sami, I'm sure you have other questions when you handle this paper and we had so many discussions among the editor, would you like to just start the ball rolling in some of these considerations?

Dr. Sami Viskin:                 Well, actually, we understood from the beginning of the study was not powered to show any difference in outcome by intervention, by treating any of these patients that had discovered atrial fibrillation with anticoagulation, so we took this paper as what it is, a paper that shows the unexpectedly high privileges of atrial fibrillation in patients who have neither symptoms nor electrocardiographic documentation of atrial fibrillation when they undergo implantation of our recording device. So we took this paper for what it is, a very interesting finding that opens the door for new studies, testing perhaps the value of intervention with anticoagulation at an earlier stage.

Dr. Carolyn Lam:               Yeah, I agree. I'd love to hear Jeff’s thoughts on what those next steps may be, but just to point out to the audience, I mean, at the moment, our decisions on whether to anti-coagulate, like the CHADSVASC score and so on, doesn’t really take into account the type of atrial fibrillation or the duration of atrial fibrillation? Does it? What do we do now? What do we do in the context of the fact that results, like the COMPASS trial, that maybe just based on the presence of vascular disease, we should anti-coagulate, right? Jeff, how about your thoughts? What are the next steps?

Dr. Jeff Healey:                 You're right. I mean, is there a value for empirically anticoagulating individuals. That's really going to boil down to the individuals with an absolute risk of stroke and how well they do on anticoagulants. Good question.

                                                In the post-stroke world or post-cryptogenic stroke, which we now report to as [inaudible 00:16:48], these individuals are being evaluated with two large clinical trials, looking at this idea of just empiric anticoagulation with low dose, NOAC in comparison to aspirin.  These trials are ongoing, and they expect to report findings by the end of 2018.

                                                In the general population, no such large scale trial is ongoing at the present time. You mentioned COMPASS and the big COMPASS results were clearly a big result at the European Society meeting, but it must be clarified that the dose of NOAC or rivaroxaban used in COMPASS was not the typical dose that we would use in the treatment of patients with atrial fibrillation, so much lower. I think we have to be careful when we're talking about doses that may be different 5 to 10 fold and what is then coagulating a patient and what is not. I think, certainly, I would not consider the COMPASS tests right now to be an effective atrial fibrillation dose, but as we've discussed, subclinical atrial fibrillation is different and we may have further data in the future.

                                                Now, how do we get there? I think many people are aware of two ongoing trials, the ARTESIA trial, which is run by our group, the NOAH-AF Trial run by Kirchof and the group from Birmingham and the AF-NET organization, and these two ongoing trials have taken this question back again, so the pacemaker population that we are enrolling thousands of patients with pacemakers and defibrillators who have these short episodes, and they're being randomized treatment with a full dose new oral anticoagulant vs aspirin. These trials are ongoing, and I think these trials and the pacemaker population will actually give us the answer to what is the risk benefit for treating, so interesting course of event. We started in the pacemaker population to show there was risk for these short episodes, that this was hotly debated 10 - 15 years ago, and now we take ASSERT 2 and other trials into the non-pacemaker population to show that this is actually a problem for older individuals in general, and now the third step, go back into the pacemaker clinic again and to do trials to study the effectiveness in therapy.

Dr. Carolyn Lam:               Great point and great takeaways. How about, Sami? What do you think would be the take-home message for clinicians at this moment based on what we know now and based on this new data?

Dr. Sami Viskin:                 Well, the message is clear, the message is that atrial fibrillation is far more prevalent than what we think it is, the message is that for every event of atrial fibrillation that we feel we probably have many events that we don't feel we should be distrustful about judging the decision to anti-coagulate or not based on symptoms, and I'm referring now to patients who already have one event documented of atrial fibrillation and are waiting until they feel the next one, before they start taking anti-coagulations. This is another warning about how we should be careful about trusting symptoms when deciding to treat and when not to treat. I just said this opens a new door for a new line of studies, looking at how early to intervene with anticoagulation, what dosage should be used for these patients who probably have lower burden of atrial fibrillation. If you can see that the patients who have atrial fibrillation documented on the electric cardiogram, as patients who simply have a higher burden and therefore they are more likely to come up with documentation on a regular ACG, so perhaps those only have subclinical atrial fibrillation have a lower burden, perhaps they can benefit from lower doses of anticoagulation, but these are all fit, that need to be proven by trials.

Dr. Jeff Healey:                 It is not only an issue for implanted devices but with the implantable cardiac monitors, this is now relevant for many other patients who have these devices implanted for things like syncope, but also there's been a lot of progress in the last 5 to 10 years on surface-attached based monitors or other types of monitors that can be with patients for days, weeks and even months, and we're all grappling with this in clinical medicine, what to do with a person with 25 beats of an atrial tachycardia or 37 seconds on a 30-day monitor? It's all an issue of the density, the burden of arrhythmia, and we do believe there is some gradience in the risk of stroke ... You're right, the treatment is not obvious, but we should take our treatment for patients who are in atrial fibrillation a lot or all the time, and simply apply it upstream like, that we may have very different treatment or approaches that are more tailored to individual patient risk.

Dr. Carolyn Lam:               Thanks, Jeff, and thank you so much, Sami. Congratulations, Jeff. We discussed a lot of other questions that need to be answered, but you've really opened the door to look at some of these questions with your paper today and we're really very proud to be publishing your paper in this week's journal.

                                                Thank you very much, listeners for joining us this week. Don't forget to tune in again next week.