Circulation July 26, 2016, Issue

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Carolyn: 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 Centre and Duke National University of Singapore. I am so excited to be joined in just a moment by Dr. Andrea [inaudible 00:00:21] and Dr. Wendy Post to discuss the feature paper this week about leisure-time physical activity and the risk of coronary heart disease in young women. First, here's the summary of this week's issue.

The first paper, by Dr. Bohula and colleagues at the TIMI Study Group at Brigham and Women's Hospital in Boston, Massachusetts, aim to test the hypothesis that an atherothrombotic risk stratification tool may be useful to identify high-risk patients who have the greatest potential for benefit from more intensive secondary preventive therapy such as treatment with Vorapaxar following a myocardial infarction. As a reminder, Vorapaxar is a first-in-class anti-platelet agent that inhibits thrombin-mediated activation of platelets via the protease activator receptor 1. The authors studied almost 8,600 stable patients with a prior myocardial infarction followed for a median of two and a half years.

In the thrombin receptor antagonist and secondary prevention of athrothrombotic ischemic events, TIMI 50 trial. They identified nine independent risk predictors which were age, diabetes, hypertension, smoking, peripheral artery disease, prior stroke, prior coronary bypass grafting, heart failure and renal dysfunction. A simple integer-based scheme using these predictors showed a strong graded relationship with the rates of cardiovascular death, myocardial infarction or ischemic stroke. Moreover, the net clinical outcome was increasingly favorable with Vorapaxar across the risk groups.

In summary, this paper provides a practical strategy that could be used by clinicians to assist with risk stratification and therapeutic decision-making regarding Veropaxar use for secondary prevention after myocardial infarction.

The next paper is by first author Dr. [inaudible 00:02:40] and corresponding authors, Dr. [Gerstein 00:02:43] from the Beth Israel Deaconess Medical Center and Dr. [Carr 00:02:47] from the Broad Institute of Harvard and MIT, who look at aptamer-based proteomic profiling. Now DNA aptamers are [alu 00:02:57] nucleotides of approximately 50 base pairs in length selected for their ability to bind proteins with high specificity and affinity. They therefore holds considerable promise for biomarker and pathway discovery in cardiovascular diseases.

These authors applied a novel technology that uses single-stranded DNA aptamers to measure over 1,100 proteins in a single blood sample. They applied this to a model of planned myocardial injury and that is patients undergoing septal ablation for hypertrophic cardiomyopathy, and they found that 217 proteins were significantly changed in the peripheral vein blood after planned myocardial injury in this derivation cohort. They validated 79 of these proteins in an independent cohort. Furthermore, among 40 validated proteins that increase within one hour after myocardial injury, 23 were also elevated in patients with spontaneous myocardial infarction.

Finally, the authors applied this to archive samples from the Framingham heart study and showed 156 significant protein associations with the Framingham risk score. This study is so exciting because it highlights any merging proteomics tool that captures a large number of low abundance analytes with high sensitivity and precision, thus providing important proof of principle for future clinical applications and this is discussed in an excellent editorial that accompanies this paper by doctors Graham [Malini 00:04:37], [Lau Enleui 00:04:39] from the University of Ottawa Heart Institute.

The next paper is by Dr. [Anter 00:04:51] and colleagues from the Beth Israel Deaconess Medical Center in Boston, Massachusetts, who looked at post infarction, reentrant ventricular tachycardia and addressed the problem that in vivo descriptions of ventricular tachycardia circuits are currently limited by insufficient spatiotemporal resolution. The authors therefore utilize a novel, high resolution mapping technology to characterize the electrophysiological properties of these reentrant circuits in 15 swine.

The main finding was that the zones of slow conduction within the reentrant circuits with the inward and outward curvatures while conduction velocity in the comment channel isthmus itself was nearly normal. The authors further demonstrated that entrainment mapping over estimated the true size of the isthmus. Thus, the conclusion was that high resolution activation mapping of ventricular tachycardia may better guide ablation therapy and ablation at zones of high curvature may be an attractive target for ablation.

The final papers from first author, Dr. [Tang 00:06:08] and corresponding author Dr. [Fitzgerald 00:06:10] from the University of Pennsylvania Perlman School of Medicine in Philadelphia. These authors studied the cardiovascular consequences of prostanoid I-receptor deletion in microsomal prostaglandin E synthase-1 deficient hyperlipidemic mice. The clinical background to this research question is that inhibitors of cyclooxygenase-2 or Cox-2 are well-known to relieve pain, fever and inflammation by suppressing biosynthesis of prostacyclin and prostaglandin E2.

However, suppression of these prostaglandins particularly prostacyclin by Cox-2 inhibitors or deletion of the I-prostanoid receptor for prostacyclin is known to accelerate atherogenesis and enhance thrombogenesis in mice. In contrast, deletion of the microsomal prostaglandin E synthase1 has been shown to suppress PGE2 but increase biosynthesis of prostacyclin. It therefore confers analgesia while attenuating atherogenesis and does not predispose mice to thrombogenesis. Therefore, possibly contributing to cardiovascular efficacy.

In this particular study, therefore, the authors sought to determine the relative contribution of suppressing PGE2 versus augmenting prostacyclin to the impact of depletion of microsomal prostaglandin E synthase-1 in hyperlipidemic mice. The main findings were that augmentation of prostacyclin is the dominant contributor to the favorable thrombogenic profile of microsomal prostaglandin E synthase-1 depletion in these atherosclerotic mice while suppression of PGE2 accounted for the protective effects in atherosclerosis and the exciting clinical take-home message is that inhibitors of the microsomal prostaglandin E synthase-1 may be less likely to cause cardiovascular adverse effects than NSAIDS or specific inhibition of Cox-2. Those were the highlights of this week. Now for our feature paper.

Our feature paper today is entitled "The frequency, [type 00:08:41] and volume of leisure time physical activity and risk of coronary heart disease in young women" and I am so excited to be joined by two lovely ladies today to discuss this paper. First, the first and corresponding author Dr. Andrea [Comastick 00:08:58] from the School of Public Health of Indiana University Bloomington and Dr. Wendy Post, associate editor from the Johns Hopkins University. Welcome Andrea and Wendy.

Andrea: Hi. Thanks.

Wendy: Thank you so much for having us.

Carolyn: I am just so excited that we are talking about a paper about women being discussed by women. What more could you ask for? I have to say this is a first for Circulation on the Run, which is why I’m just so excited, so let’s get straight into it.

Andrea, maybe I could just ask you to start by sharing the story of how you and your team came up with some new questions and new data because I’m sure a lot of listeners are thinking there’s a lot of data on exercise and how good it is for cardiovascular health in women already.

Andrea: Yeah, that's a great question. When we started talking about conceptualizing this paper, the first thing was to focus on younger women. Most of the previous work on physical activity and heart disease has been in older adults and that's primarily because it's older adults that have heart attacks. It’s hard to get a large enough study of young women that has enough coronary heart disease events to be able to study this. We were fortunate where we had a large cohort in the nurses health study too of women and because it’s been followed for over 20 years, we had enough events to be able to examine this association.

We did want to think about, "Okay, what can we add?" because there’s a lot of information about just overall physical activity and health, so what can we do differently? I’m pretty familiar with the physical activity guidelines and really tried to look at what in the guidelines currently and then what could we add? What could be of interest when they start revising the guidelines which is actually going to happen very soon.

That was when we started focusing on, "Okay, instead of looking at just overall activity, look at intensity, comparing moderate and vigorous." We also wanted to look at frequency of physical activity and looking at frequency but also adjusted for a total time or total amount of physical activity that somebody does. Then we are also, the third thing was that we thought was important was looking at adolescent physical activity.

We know that kids, unfortunately as they get older and get into their teenage years, their activity declines quite a bit. Looking at how this physical activity during adolescence earlier life impact coronary heart disease risk in adulthood. Those were the three main things that we were focusing on when we first conceptualized the paper.

Carolyn: Nice. Tell us, what did you find?

Andrea: We did find that exercise is just as beneficial in younger woman as it is in older adults, which is great. We also found that moderate intensity exercise is just as beneficial as vigorous intensity exercise, which I think is a really important message to get out there. I think a lot of people, especially those that are really inactive to begin with are completely intimidated about the fact of trying to think about going to a gym or trying to jog or run a marathon or something like that.

I think really emphasizing that moderate intensity activity is beneficial and we found that walking was actually the most beneficial activity that we looked at in our study, that brisk walking was really really good for everybody and really lowered risk of coronary heart disease.

Carolyn: Hooray.

Andrea: Yeah, and the other thing we found which might be of interest for those that are also extremely busy, especially this target population where a lot of people are moms and working was that frequency didn't seem to matter, that as long as people were exercising for a couple hours a week that they should be that they could accumulate it in a couple times a week or they could do it more frequently, four or five times a week. It didn't seem to matter.

Carolyn: That’s cool. You know what? I think a lot of these things we'll also discuss at the Editorial Board when we're looking at this paper. Wendy, we promised that we would give a backstage pass to the Editorial Board and The Journal, so could you share a little bit about what we talked about there?

Wendy: Well, the Editorial Board was really excited about this paper. We loved the emphasis on young women and the important public health message about how we need to get out there and move and exercise to reduce our risk for cardiovascular disease. As was mentioned, there have been previous studies that also show the benefit of exercise but the Editorial Board especially liked the large sample size, the long duration of follow-up, the number of events that had been accrued that allowed for sophisticated analyses, adjustment for confounders and the very rigorous study design and excellent statistical methods that have been used in this study and so many other studies from the nurses health study, but I think we particularly just loved the message. The message was great.

We need to get out there and move. We need to tell our patients, especially young women, that now we have data that if you start exercising now, it will help in the future but also the study showed that if you hadn't exercised much in early life that’s starting to exercise more proximal to the event was also important as well.

Carolyn: Thank you Wendy. I also remember that we talked about the lack of interaction with body mass index, and I thought that was a great message. Andrea, could you maybe share a little bit about that?

Andrea: Yeah, this is something that previous investigators have looked at the interaction between body mass index and exercise. Unfortunately, we’ve all found the same thing so it doesn’t seem to matter whether women are normal weight or overweight or obese that they still get benefit when they exercise, and I think that’s really encouraging. I know a lot of people might start to exercise because they really want to drop some weight but just trying to emphasize even if the numbers on the scale aren't changing, that exercise still has all these really great benefits for heart disease and also for many other diseases.

Carolyn: Exactly. Can I just ask both of you and maybe I’ll start with Andrea, what will you do different now both as a woman and as a clinician seeing women now that you know what you do from your data?

Andrea: Well, I’m not a clinician. I’m an epidemiologist so unfortunately I don’t get to see patients and counsel them although I do try to talk to community members as a public health person and really get in the community on board with what we’re talking about. I just try to tell people, I actually talked to a group of people last week, and just trying to say, "Anything is better than nothing and just trying to even start with some short walks." Again, just emphasizing you don’t have to go to a gym or you don’t have to be doing anything that's super strenuous but just do stuff that feels good and just try to get your heart rate up a little bit like going out for a brisk walk. I think that's my main message that I try to tell everybody is at least start with something and get moving a little bit.

Carolyn: I love that. Wendy?

Wendy: I like to emphasize the data about brisk walking. I thought that was great because many of our patients don’t want to join a gym, don’t have the time to join a gym so just getting out and walking is fabulous exercise and now we have the data here that in young women that after 20 years of follow-up, brisk walking was associated with I think it was a 35% reduction in risk for cardiovascular disease during follow-up.

In addition, I liked the message about the total amount of time that you spend exercising in a week is what’s important. It doesn’t matter whether you divide that into seven days a week to get to that same amount of time or whether you do it in bursts of three days a week, and I think that’s particularly important for the many women who have so many different responsibilities and may not have time every day to go out and exercise. The days that you do have time, just exercise a little bit more those days, so lots of really important messages for our patients and for ourselves.

Carolyn: I really couldn’t agree more and just from my point of view, because I see a lot of patients in Asia and I do acknowledge just like you did, Andrea, in your paper that your data are predominantly in white populations. Still one of the messages I like to get out to the women I see is we have very skinny women and when I see younger women, and I really like emphasizing that, "Hey, just because you’re not struggling with an obesity issue or just because you’re young, it doesn’t mean you don’t need to exercise and that we all should just get moving." Thank you very, very much for that Andrea.

Andrea: Oh, no. It's my pleasure and thank you for having me come on today and talk about this.

Carolyn: Thank you too, Wendy. Do you have any other comments?

Wendy: No, but congratulations on your publication, Andrea.

Andrea: Oh, thank you so much, Wendy. I was really happy to get the message that guys were excited about it. Thank you so much.

Carolyn: You’ve been listening to Circulation on the Run. Thank you for joining us this week and please tune in next week.

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