Circulation July 26, 2016, Issue

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.