Circulation July 3, 2018 Issue

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 features Circulation Global Rounds, a brand-new series of papers from all across the world that you are going to want to hear about, coming right up after these summaries. The first original paper this week tells us that community trends and acute decompensated heart failure may differ by race and sex. Dr Patricia Chang from University of North Carolina in Chapel Hill and colleagues examine the 10-year rates and trends of hospitalized acute decompensated heart failure in the Atherosclerosis Risk in Communities or ARIC study, which sampled heart failure–related hospitalizations in four US communities from 2005 to 2014, using ICD-9 codes. They found that acute heart failure with reduced ejection fraction was more common in black men and white men, whereas acute heart failure with preserved ejection fraction was most common in white women. Rates of hospitalized acute decompensated heart failure increased over time, with higher rates in blacks, and rising cases of preserved ejection fraction heart failure. Mortality rates were 30% at one year with a more pronounced decrease over time in blacks but generally did not differ by heart failure types. Whether racial differences may be related to age of onset comorbidities, or other community level and social economic factors, deserve further study. The next paper is a population-based study identifying long-term outcomes and risk factors and children with hypertrophic cardiomyopathy. Dr Alexander from Boston Children's Hospital and colleagues examine the National Australian Childhood Cardiomyopathy Study, a long-term national cohort study with a median follow-up duration of 15 years. They found that the greatest risk of death or transplantation for children with hypertrophic cardiomyopathy was in the first year after diagnosis, with 14% of patients achieving this combined end point compared to 0.4% per year thereafter. Risk factors for death or transplantation included symmetric left ventricular hypertrophy at diagnosis, Noonan syndrome, increasing left ventricular free wall thickness, and lower fractional shortening during follow up. The majority of surviving patients had no symptoms. Thus, children with hypertrophic cardiomyopathy who are alive one year after diagnosis have a low long-term rate of death or transplantation. Deaths from heart failure usually occur soon after diagnosis, whereas the risk of sudden cardiac death is ongoing. The next paper is the first demonstration of a peripheral clock in the perivascular adipose tissue that could contribute to the homeostatic regulation of circadian blood pressure variation. Co-corresponding authors Dr Chang and Chen from University of Michigan and their colleagues used a novel brown adipose specific aryl hydrocarbon receptor, nuclear translocator-like protein 1 or Bmal1 and angiotensinogen knockout mouse model to demonstrate that local Bmal1 in perivascular adipose tissue regulated angiotensinogen expression and the ensuing increase in angiotensin II, which acted on smooth muscle cells in the vessel walls to regulate basal activity and blood pressure in a circadian fashion during the resting phase. In fact, deletion of Bmal1 or angiotensinogen in the perivascular adipose tissue resulted in a superdipper phenotype with exacerbated hypotension during the resting phase. These findings imply that it is possible that obesity could alter the perivascular adipose tissue peripheral clock, thus promoting abnormal dipper phenotypes and increasing cardiovascular risk. The results therefore inform the design of novel therapeutic approaches for hypertension by targeting the perivascular adipose tissue peripheral clock. What is the net clinical benefit of oral anticoagulation for very elderly patients with atrial fibrillation? Well, the next paper by first author Dr Chao, cocorresponding authors, Dr Chen from Taipei Veterans General Hospital and Dr Lip from University of Birmingham, addresses this question. These authors use a nationwide cohorts study in Taiwan to compare the risks of ischemic stroke and intercerebral hemorrhage between patients with and without atrial fibrillation, all aged 90 years and above, from 1996 to 2011, and they also compared patients treated with warfarin and non-vitamin K antagonists oral anticoagulants, or NOX from 2012 to 2015 when NOX were available in Taiwan. They found that even among these very elderly patients aged 90 years and above, atrial fibrillation was associated with an increased risk of ischemic stroke compared to patients without atrial fibrillation. Warfarin use was associated with a lower risk of ischemic stroke, with no difference in intercerebral hemorrhage risk compared to nonwarfarin treatment. The use of warfarin was associated with a positive net clinical benefit compared to being untreated or to antiplatelet therapy. Compared to warfarin, NOX were associated with a lower risk of intracerebral hemorrhage, with no difference in the risk of ischemic stroke. Thus, oral anticoagulation may still be considered for thromboprophylaxis in very elderly patients with atrial fibrillation, with NOX being a favorable choice The final paper provides insights into the mechanisms linking obesity and cardiovascular diseases. Co-corresponding authors, Dr Kong and Wang from Peking University Health Science Center and colleagues use a combination of animal models and human adipose biopsies to characterize a new adipokine named family with sequence similarity 19, member A5 or FAM19A5. This novel adipokine was capable of inhibiting post injury neointoma information via sphingosine-1-phosphate receptor 2 and downstream G12/13-RhoA signaling. Thus, down regulation of FAM19A5 during obesity and loss of its vascular protective function may trigger cardiometabolic diseases. Well, that wraps it up for our summaries. Now for our feature discussion. I'm just so excited about today's feature discussion, because we're talking about Circulation going global. And I am just absolutely delighted to have with us, our Editor-in-Chief himself, Dr Joe Hill from UT Southwestern, as well as our Senior Advisory Editor, Dr Paul Armstrong from University of Alberta. So Joe, could you start by telling us a little bit more about your vision for the global outreach of Circulation? Dr Joe Hill: Thank you, Carolyn. As I hope our readers are aware, Circulation is a global journal with a global footprint. We have editors distributed around the world in 16 countries and 10 time zones. And importantly, those editors all have an equivalent role at the leadership table. Part of the reason for this is because cardiovascular disease is now, as we are all aware, a global scourge. There are no more final frontiers for cardiovascular disease. That said, the manifestations of cardiovascular disease differ in different parts of the world. In the developed world, and the developing world, for example, the way cardiovascular disease manifests itself can be very different. And at the same time, the way in which the disorders are tackled are different. The way we tackle heart disease in the West can be different than it is in the East, for example. And there are important initiatives that have emerged in different pockets of the world, best practices that we need to understand better. What can we all learn from the way in which cardiovascular disease manifests itself around the world and it's being addressed around the world? Dr Carolyn Lam: Joe, you had me at hello. I remember that when you first took over as Editor-in - Chief and I heard you say this, I was just floored, because coming from Singapore and all our listeners out there in Japan and China, we just really appreciate that global outlook. So thank you, on behalf of us all. Tell us a bit more about this new initiative then for the journal. Dr Joe Hill: I will tell you in broad strokes, that Paul Armstrong, a noted clinical trial is from Canada, who is a household name in the cardiovascular world, he and I cooked up a scheme that Paul will describe, where we will reach out on a regular basis for insights from various different countries, ultimately, circling the globe progressively over time. And I will defer to Paul to tell us more about the specifics. Dr Paul Armstrong: Carolyn, it's an exciting initiative and as someone a little long in the tooth, but still believing that you can teach an old dog new tricks, I would point out that Circulation is almost 70 years old, and it has staying power. And one of the reasons that it has staying power is because it is capable of reinventing itself, and so I was attracted to help out again, from the editorial process, given Joe's vision and leadership and the excitement around the reinvention that you've described, to get involved with this initiative. And I was inspired, of course, by the fact that those of us who do clinical trials appreciate that a lot of different ideas, a lot of different cultures and perspectives are brought to a collaborative table. And I'm thinking back now, Carolyn to three years ago, when you and I first met enjoying courses as part of a trial in heart failure, which involves 43 countries, 800 sites, it will be 5000 patients centers, we've traveled separately and together around the world, convincing people that there are unmet needs in heart failure and other parts of cardiovascular disease, we learned that the approach to standard of care, the rigor which is applied, the exquisite sensitivities around differences that are meaningful, and the tricks that some investigators and countries use that we can all I think, learn from has been very revealing. So I think in this initiative, we want to have thought leaders. And we've already I think, commenced and have two outstanding leaders from Japan and India to come forward in the first two quarters of this initiative. Tell us about the regional epidemiologic features, cardiovascular disease in their regions, what the most important challenges are, what their best practices are, that you're alluded to, who provides cardiovascular care and what the impediments are to progressing because we think if we listen and learn as essentially knowledge brokers, because welcome to Circulation, we can facilitate raising the level of all of the boats in the water and potentially make new partnerships and do a better job. So I'm excited about this. I'm delighted that Joe was receptive and really look forward to working with him and some of these terrific people around the world, you included who brings such a unique and important perspective from which we can all learn. Dr Carolyn Lam: Oh, I love that so much Paul. Thanks for putting it that way. International knowledge brokers, that's what we hope to be. Isn't that fabulous, just an opportunity to learn from each other, everybody having stuff to bring to the table? Tell us a bit more though, what are you looking for in these papers? Dr Paul Armstrong: We have some guidelines. But as Joe insists we're not going to be formulaic. We're going to allow diversity of approaches. We're going to invite a thought leader and hope that that thought leader might invite one or two others, we want to limit it to three co-authors. We want obviously some insights into how cardiovascular health professionals are being trained, what research infrastructure exists, and how they access the literature, how do they read Circulation, how do they read other journals, and are there collaborative ideas that they've developed to their neighbors to the East and West that may be could be broadened? Are there unmet needs that they've indicated similar or different from those in Western Europe, South America? We've got about seven or eight points of light that we hope to illuminate in the course of this exercise. And the prospectus that's laid out in an editorial that Joe and I collaborated on that I believe, Joe, is going to come out in early July. Dr Joe Hill: That's exactly right, Paul. And I would just echo exactly what you said that just the opposite of a formulaic, cookie cutter approach. We want to leverage the beautiful diversity of our world. The different approaches that people take to attack this scourge that is keeping a humble approach to tackle instead of the visas that is humbling bar none. There is nothing that is more globally important than the continued growth and expansion of cardiovascular disease. And importantly, we can all learn from each other. There are exciting initiatives that I've learned about in South America and in pockets of Europe and in Asia, and in the Middle East that we can all benefit from, and we want to shine a bright light on that. These pieces will be relatively short. They will be in our Frame of Reference section, so 1200 words or so, so that they are accessible so that people, you know, feel that they can carve out, you know, four minutes in their busy day to read what cardiovascular disease looks like, as Paul said, our first ones will be from Japan and India, and we plan to reach out to South America and to the Middle East, and just continue on around until over the course of the next number of years, we've touched virtually every country in the world. Dr Carolyn Lam: And that's huge. And are there any specific types of cardiovascular disease that you might be looking to focus on? Dr Joe Hill: You know, I don't think so. One of the points that I have made and learned is that in the West, in the developed world, cardiovascular disease increasingly has become a chronic disorder where more and more people, over the course of the last six years are surviving their acute coronary syndrome, their tachyarrhythmia events, and they are developing chronic disorders like heart failure, whereas in the East, it is the atherothrombotic manifestations that have both MI and stroke that are expanding rapidly. So given that the face of cardiovascular disease is different in different parts of the world, different strategies have to be leveraged to address that, and we want to learn about that. Dr Carolyn Lam: I would love to have you both come talk again, when we receive some of these papers and just reflect on the things that we're learning. Paul, did you have anything else that you wanted to add? Dr Paul Armstrong: I think, Carolyn that hits the high spots. I suppose we should mention diabetes and obesity and the expanding epidemic that seems to effect some regions such as India, in the Middle East, even more than other areas, but I think this is going to be great. We're gonna have some fun and learn and exciting and hopefully it will catalyze better care and better thinking around this enemy that we all face. Dr Carolyn Lam: Listeners. You heard it right here, Circulation on the Run. I'm sure you're excited as I am about this. You have to read the editorial. It's a fantastic read. Thanks for joining us today. And don't forget to tune in again next week.