Circulation October 24, 2017 Issue

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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.

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