Circulation July 11, 2017 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
Youth National University of Singapore. Coming right up, we will
be discussing fascinating new data on the prevalence of
subclinical coronary artery disease in masters endurance athletes
but first, here's your summary of this week's journal. The first
paper provides insight into ischemic cellular post conditioning.
Now, we know that cardiosphere derived cell therapy has been
utilized as a strategy to treat ischemic heart disease and reduce
chronic scar burden when administered months after myocardial
infarction. In the current study, by first author Dr. de Couto,
corresponding authors Dr. Marban and Berman from Cedars-Sinai
Heart Institute in Los Angeles, California, the authors used rat
and pig models of myocardial infarction to show that exosomes,
which are nanosize lipid bi-layer vesicles, actually mediate the
cardio protective effects of cardiosphere derived cells when
administered after reperfusion of myocardial infarction.


                                               
They further show that treatment with either cardiosphere-derived
cells or their secreted exosomes reduce infarct size and improved
functional recovery. Using RNA sequencing to determine exosome
content and alterations in gene expression profiles on
macrophages from cardiac tissue or bone marrow, they found that a
specific micro RNA species miR 181-B within the exosomes, acted
on macrophages and was implicated as a key mediator of the
cardio-protective benefits. Thus, this study gives new reason to
test the idea that allogeneic cardiosphere-derived cells may be
efficacious in preventing scar formation and improving cardiac
function, when given in the earlier reperfusion period. The data
further support that exosomal transfer of miR 181-B from these
cardiospheric-derived cells into macrophages underlie the
cardio-protective effects after reperfusion.


                                               
The next study describes a potential new therapeutic strategy for
vasoproliferative retinopathy which can underlie age-related
macular degeneration, the leading cause of blindness in
industrialized nations. First author, Dr. Bucher, corresponding
authors Dr. Yea and Friedlander, from the Scripps Research
Institute in La Jolla, California used rodent models of retinal
neo-vascular disease to show that Tspan-12, beta-catenin
signaling plays an important role in the development of
vasoproliferative retinopathy. As background, Tspan-12 belongs to
the Tetraspanin family, which mainly includes cell surface
proteins characterized by four transmembrane domains and two
extra cellular domains.


                                               
Members of the Tspan family participate in a diverse cellular
processes and act as signaling platforms by forming
Tspan-enriched micro domains in plasma membranes. The authors
went further to use a novel phage display combinatorial antibody
library to specifically design a Tspan-12 blocking antibody which
is capable of interacting with human and mouse Tspan-12 antigen.
They then provided strong evidence that the Tspan-12 blocking
antibody prevents developmental pathological neovascularization
in  murine models of vasoproliferative retinopathy.
Combination therapy with a known anti-VEGF agent demonstrated
significant synergy supporting the potential clinical use of the
anti-Tspan-12 antibody as a novel angiomodulatory agent.


                                               
The next study addresses the paradox that blacks have higher
coronary heart disease mortality compared with whites, but
non-fatal coronary heart disease risks may be lower for black
versus white men. To address this paradox, first author Dr.
Colantonio, corresponding author, Dr. Safford and colleagues from
Weill Cornell Medical College in New York, compared fatal and
non-fatal coronary heart disease incidents and case fatality
among blacks and whites in three studies. The Atherosclerosis
Risk in Communities or ARIC study, cardiovascular health study,
and reasons for geographic and racial differences in stroke or
regards study, all stratified by gender.


                                               
They found that the incidents of non-fatal coronary heart disease
was consistently lower among black versus white men, although
black men have a higher burden of unfavorable social determinants
of health and cardiovascular risk factors and a higher fatal
coronary heart disease incidents. Following adjustment for social
determinants of health and cardiovascular risk factors, black men
and women had a similar risk of fatal coronary heart disease, but
a lower risk of non-fatal coronary heart disease compared with
white men and women respectively. Finally, blacks with incident
coronary heart disease had a higher case fatality compared with
whites and the difference remained similar after adjustment for
social determinants of health and risk factors. Thus, there is an
apparent lower risk for non-fatal coronary heart disease among
black versus white men and women, which needs to be further
studied. Blacks have a higher risk of their initial coronary
heart disease event being fatal compared with whites,
highlighting the need for reinforcing primary prevention in this
population.


                                               
The next study provides important information on the burden of
re-admissions after hospitalization for critical limb ischemia.
First author, Dr. Kolte, corresponding Dr. Aronow and colleagues
from Brown University in Providence, Rhode Island, used the
2013/2014 nationwide re-admissions databases to identify almost
61,0000 hospitalizations for primary diagnosis of critical limb
ischemia during which patients underwent endovascular or surgical
therapy. They found a 30-day re-admission rate of 20.4%.
Independent predictors of 30-day re-admission included
presentation with an ulcer or gangrene, age above 65 years,
females, large hospital size teaching hospital status, known
coronary artery disease, heart failure, chronic kidney disease,
anemia, coagulopathy, obesity, major bleeding, acute myocardial
infarction, vascular complications, and sepsis. Interestingly,
mode of revascularization was not independently associated with
re-admissions.


                                               
The most common reasons for re-admissions included infections,
persistent or recurrent manifestations of peripheral artery
disease, cardiac conditions, procedural complications, and
endocrine issues. Finally, the costs of 30-day re-admissions for
critical limb ischemia during the study period were 624 million
U.S. dollars. Thus, this study provide knowledge of independent
predictors and reasons for re-admissions that will help
clinicians and hospitals to identify, develop, and implement
strategies to reduce re-hospitalizations and healthcare costs
associated with critical limb ischemia.


The final study tells us that there may be a direct relationship
between life-long exercise volume, and coronary atherosclerosis
in athletes. Dr. Aengevaeren and colleagues from Radboud
University Medical Center in the Netherlands, studied 284
middle-aged men engaged in competitive or recreational leisure
supports, using contrast enhanced CT to assess coronary artery
calcification and plaque characteristics.


                                               
Participants also reported life-long exercise history patterns
and exercise volumes were quantified as metabolic equivalent of
task or met minutes per week. They found that participants in the
more than 2,000 met minutes per week group had a higher
prevalence of coronary artery calcification and atherosclerotic
plaques. The most active group did, however, have a more benign
composition of plaques with fewer mixed plaques and more often,
only calcified plaques. These observations may explain the
increased longevity typical of endurance athletes, despite the
presence of more coronary atherosclerotic plaques in the most
active participants. Well, that wraps it up for your summaries.
Now for our featured discussion.


                                               
Our current physical activity guidelines recommend 150 minutes of
moderate exercise and that's supposed to protect against
cardiovascular disease and increase longevity. However, what do
we really know about the dose response relationships and the
effects of exercises doses that exceed current recommendations.
Well, recent data, including a paper in this week's issue,
suggests that long-term, high volume endurance exercise may
actually accelerate, rather than reduce coronary atherosclerosis.
To discuss this exciting paper, we have the corresponding author,
Dr. Sanjay Sharma, from Saint George's University of London, as
well as editor of digital strategies and associate editor at UT
Southwestern who handled this paper, Dr. Amit Khera. Welcome,
gentleman.


Dr. Amit
Khera:                
Good morning.


Dr. Sanjay
Sharma:         
Thanks for having us.


Dr. Carolyn
Lam:              
First, Sanjay, oh yikes! As a runner and as a person who strongly
advocates regular exercise, please, please, put us out of our
misery. Tell us what you've found and what you think are the
possible explanations.


Dr. Sanjay
Sharma:          I'm
a runner too, and I don't think anyone would argue that the
benefits of exercise on the cardiovascular system are unrivaled.
People who exercise regularly do reduce their risk of an adverse
event from a heart attack by 50% when they're in their 5th and
6th decade and they live around three years longer than people
who don't exercise at all. Now as you rightly point out, the
current recommendation suggests 2 1/2 hours of moderate physical
activity per week and by that I would mean, at maximum, a
15-minute mile pace. Clearly, our endurance athletes exercise
much, much more than that. They exercise 10 to 20 times greater
than that volume and in parallel with this has been the emergence
of a large number of people participating in marathon runs. For
example, in Europe, there were two million marathon runs per
annum and that figure's going up by about 5%.


                                               
Coinciding with this burgeoning increase in endurance exercise,
is the development of several reports that show that exercise may
cause release of biomarkers of cardiac damage. Animal experiments
have shown that exercise may cause scaring in the heart and human
studies have shown that some marathon runners have more calcium
in their coronary arteries compared to relatively sedentary
individuals. One of the problems with these studies is firstly,
the biomarker release is very transient, it goes away after about
two days. Animal experiments cannot really reflect what goes on
in human beings because they're artificial and animals are forced
to exercise with electrical shocks, et cetera. The studies in
human beings have been conducted in runners who have been former
smokers.


                                               
In fact, the most commonly reported study or cited study,
contained individuals of whom 50% had risk factors for coronary
artery disease. What we decided to do was to do a clean study,
where we took 150 individuals who had none of the risk factors
for coronary artery disease and 92 relatively sedentary controls
who exercise within the normal limits. We have to exclude a lot
of people because we have to exclude anyone that had ever smoked,
anyone that had high blood pressure, high cholesterol, or a
family history of permanent cardiac disease. We actually
subjected them to all sorts of investigations and we found that a
small number of male runners had more calcium in their arteries
compared to sedentary individuals.


Dr. Carolyn
Lam:              
Wow! Please tell us that there's something good that you can say
about that. First of all, I really want to congratulate you on
this most elegant study and Amit, I'm sure you put in what the
editor's thought but we're just so proud to be publishing such a
high quality study here. Amit, is there anything you might want
to add of what the editors thought?


Dr. Amit
Khera:                
Sure, I first want to congratulate Dr. Sharma and his colleagues.
This was a carefully done study and we've talked a bit about the
coronary calcium but there was extensive investigation and I
really think this advanced the field. Sounds like all three of us
are runners, so this hit home to all of us and as he mentioned,
this has been a very hot area and one that's been very
controversial. I think here what we have is a manuscript that
really helped move the field forward, helped us better understand
the biology. The one thing I'll comment on that we found very
interesting was the observation that those that were the masters
athletes actually had more of a calcific phenotype, where as
those that were not looked like a soft plaque phenotype, if you
will. Actually, if you look, we have a companion article in
circulation looking at sort of dose dependent finding a similar
finding. My question, now turned back to Dr. Sharma is, what do
you counsel your patients now with these findings? Has it changed
now how you recommend exercise or your thoughts on how you
counsel them?


Dr. Sanjay
Sharma:         
Well, we examined 152 different athletes, or masters athletes in
92 controls. These athletes were aged 56 years old, who'd been
training for 36 years and had immediate marathon number of 13.
Now, what we've found in these individuals is that a small number
of males, that's 11%, had a coronary artery calcium score of more
than 300. Some men had more plaques than sedentary individuals
and these plaques were distributed throughout all three coronary
arteries. When we looked at the pathology of the plaques very
carefully, we found that the plaques in the athletes were
calcified. Indeed, 72% of athletes had very calcified plaques. We
know that such calcified plaques are stable, they're less likely
to fissure and are less likely to cause coronary thrombosis and
therefore, acute myocardial infarction.


                                               
This led us to propose that although exercise may be causing some
atherosclerosis through the sheering and stressful source during
exercise of the bending and kicking of vessels, we believe that
the repair mechanism here is different to that seen in people who
smoke or who have high cholesterol or high blood pressure. The
repair mechanism results in very calcified and stable plaques in
athletes and this may actually mitigate the risk of acute
myocardial infarction and may explain why the number of people
who actually suffer an acute myocardial infarction during a
marathon run is very small, around 1 in 50,000, and no different
to the number of people who suffer a sudden cardiac arrest
playing football or basketball, due to congenital or inherited
abnormalities of the heart. 


Dr. Carolyn
Lam:              
Sanjay, those are just such important points to keep in mind as
we read your paper. It did strike me as a significant minority,
actually, of these long term endurance athletes who develop
significant coronary artery calcification and it could
potentially be a clinically benign phenotype. At the end of the
day, this is a cross-sectional study, isn't it? We can't, I
suppose, extrapolate into the clinical events. What are your
postulations there and what could be future work that you're
planning?


Dr. Sanjay
Sharma:         
Well, you make a good point. This is a cross-sectional study and
the demonstration of an increased cardiopathy calcium does not
necessarily reflect future cardiac events. We have followed these
individuals up for the last 18 months. These masters athletes and
have not demonstrated a single one to develop an acute event that
would last 18 months. We really don't know what the meaning of
these plaques is. I think the only thing to do now, being we've
got the liberty of having so many people that do marathon runs
and so many people who've been exercising for three or four
decades, we can actually do a prolonged follow up study, so the
answers will be a while coming. To follow these people up with
high calcium, just to see whether they do go on to develop
adverse events in the future. All our study has shown is that
some male athletes who've exercised lifelong get an increasing
number of plaques. These plaques appear to be calcified and
stable and the long term effects of such  plaques is
unknown.


Dr. Carolyn
Lam:              
Sanjay, just circling back to Amit's question earlier and maybe
Amit, you could take it to after this. What do we recommend to
our athletes who come in and have a high coronary artery calcium
score? Do we tell them to stop?


Dr. Sanjay
Sharma:          I
certainly wouldn't and I'm much less worried about an increase
coronary calcium score in a lifelong runner or cyclist than I was
10 years ago. It appears that these plaques are there in some
individuals, they are calcified, they appear stable. Given the
fact that we know that coronary events during marathon running in
experienced runners are very, very low indeed. I don't think I
would be keen to do anything about it, not even consider stacking
therapy based on our findings at present. As I said before, we do
need longitudinal follow up to really identify all ascertain the
precise implications of these plaques in masters athletes.


Dr. Carolyn
Lam:              
Right, and this is again recognizing that your particular
population was free of traditional cardiovascular disease. Of
course, if we were to find these risk factors in our athletes, we
would most certainly treat the traditional risk factors. Amit,
anything to add there?


Dr. Amit
Khera:                
I think that was an excellent point about his approach to
counseling patients. I will mention on the editorial staff, we
felt like this was such an interesting area with emerging data
and fast moving, that it was warranting of an editorial. I
recommend people to look at the one by Aaron Baggish and Ben
Levine. I think they had a very similar conclusion and that was
that they don't necessarily proscribe exercise in patients with
high coronary calcium but rather, focus on risk mitigation
strategy, focusing on risk factors as we normally would do. I
think the conclusions are similar and the thoughts in that
editorial were insightful, pairing both of these papers and
helping us make sense out of this really evolving field.


Dr. Carolyn
Lam:              
Well, thank you Sanjay and Amit for this wonderful discussion. I
learned so much as I'm sure our listeners did. You've been
listening to Circulation On The Run. Tune in next week.