Circulation March 28, 2023 Issue

This week, please join author Vincent Aengevaeren and
Associate Editor Jarett Berry as they discuss the article
"Exercise Volume Versus Intensity and the Progression of Coronary
Atherosclerosis in Middle-Aged and Older Athletes: Findings From
the MARC-2 Study."


Dr. Gregory Hundley:


Welcome listeners to this March 28th issue, and I am one of your
co-hosts, Dr. Gregory Hundley, Associate Editor and Director of
the Pauley Heart Center at VCU Health in Richmond, Virginia.


Dr. Peder Myhre:


And I'm Dr. Peder Myhre, Social Media Editor from Akershus
University Hospital and University of Oslo in Norway. And today,
Greg, we have such an interesting feature paper. It comes to us
from Professor Aengevaeren and it discusses the progression of
coronary atherosclerosis in middle-aged and older athletes.
They're looking at exercise volume versus intensity in the MARC-2
study. So Greg, this is really something us master athletes are
interested in, and I'm really excited to hear this discussion.


Dr. Gregory Hundley:


Very nice. Well, how about we jump into some of the other
articles first, Peder? And I could go first. So Peder, my first
article involves pregnancy related complications. And as you
know, these pregnancy complications are associated with increased
risk of developing cardiometabolic diseases and an earlier
mortality. However, much of the prior research has been limited
to individuals of White race. So these investigators led by
Professor Cuilin Zhang from the National Institutes of Health
aimed to investigate pregnancy complications in association with
total and cause specific mortality in a racially diverse cohort,
and then evaluate whether associations differ between Black and
White individuals. And they performed their work using the
Collaborative Perinatal Project, which was a prospective cohort
study of 48,197 pregnant women across 12 US clinical centers from
the period of time of 1959 through 1966.


Dr. Peder Myhre:


Oh wow, Greg. Almost 50,000 pregnant women. Very huge initiative.
So what did they find?


Dr. Gregory Hundley:


Right, Peder. So overall, 15% of participants had preterm
delivery, 5% had hypertensive disorders of pregnancy, and 1% had
gestational diabetes or impaired fasting glucose. Now, the
preterm delivery was higher in individuals of Black race at 20%
relative to those of White race, which were 10%. Now, in relation
to all-cause mortality, the following were associated with
increase adjusted hazard ratios. One, spontaneous labor; two,
induced labor; three, pre-labor cesarean delivery. And all of
those, those adjusted hazard ratios in comparison with a full
term delivery.


Next, in the world of blood pressure, preeclampsia and eclampsia
as well as superimposed preeclampsia and eclampsia were all
associated with adjusted hazard ratios that were elevated
compared to individuals with normal blood pressure. And then
finally, in those individuals with gestational diabetes or
impaired fasting glucose, their adjusted hazard ratio, again for
all-cause mortality, was elevated relative to those with normal
glycemia. Now interestingly, in comparing the two racial groups,
preterm induced labor was associated with greater mortality risk
among those of Black race relative to those of White race.
However, or while, preterm pre-labor cesarean delivery
interestingly and conversely was associated with a higher
adjusted hazard ratio for those of White race as compared to
individuals of Black race.


So Peder, in summary, within this large diverse US cohort,
pregnancy complications were associated with higher mortality
almost 50 years later. And the higher incidents of some
complications occurred in individuals of Black race. And
differential associations with mortality risk indicate that
because of these racial differences, there could really be
disparities in pregnancy related health. And finally, that these
disparities and their relationship with overall health really
could have long life implications for earlier mortality in these
patients.


Dr. Peder Myhre:


Well, that is really interesting, Greg. Are you ready for the
next paper?


Dr. Gregory Hundley:


Absolutely.


Dr. Peder Myhre:


So this paper is about the glucagon-like peptide-1 receptor
agonist and large CV outcome trials clearly show that several
GLP-1 agonists reduce CV outcomes in patients with Type 2
diabetes. Whether their cardioprotective effects are related to
drug dose or potency remains uncertain however, but important due
to recent introduction of high dose and high potency agents for
diabetes and for weight loss indications. And therefore, Greg, in
this paper, the investigators from the AMPLITUDE-O trial led by
corresponding author Hertzel Gerstein from McMaster University
Hamilton Health Sciences analyzed the effect of the different
doses of the GLP-1 agonist efpeglenatide that is four milligram,
six milligram compared to placebo. And the effect was assessed on
major adverse cardiovascular events.


Dr. Gregory Hundley:


Interesting, Peder. So what did they find?


Dr. Peder Myhre:


So Greg, during a median follow-up of 1.8 years, MACE occurred in
9.2 participants assigned to placebo, 7.7 in participants
assigned to efpeglenatide four milligrams, and 6.2% in
participants assigned to efpeglenatide six milligrams. And
participants receiving high dose of this GLP-1 agonist also
experienced fewer secondary outcomes, including the composite of
MACE coronary revascularizations or hospitalizations for unstable
angina, a kidney composite outcome comprising sustained new
microalbuminuria, decline in eGFR more than 40%, or renal
failure. And there was also a clear dose response relationship
noted for all primary and secondary outcomes with a P4 trend that
was significant. So Greg, the authors conclude that the graded
relationship between efpeglenatide dose and CV outcomes suggests
that titrating this drug and potentially other GLP-1 agonists to
high doses may maximize their cardiovascular and kidney benefits.


Dr. Gregory Hundley:


Very nice, Peder. Well, my next paper comes to us and involves
the world of bleeding associated with Factor Xa inhibitors. So
Peder, andexanet alfa is a modified recombinant inactive Factor
Xa designed to reverse Factor Xa inhibitors. ANNEXA-4 is a
multicenter prospective phase 3B single group cohort study that
evaluated andexanet alfa in patients with acute major bleeding.
And the study is led by Dr. Truman Milling of Seton Dell Medical
School Stroke Institute and colleagues, and they present the
results of their final analyses.


Dr. Peder Myhre:


Oh, this is really interesting, Greg. So what did they find?


Dr. Gregory Hundley:


Right, Peder. So first, 479 patients were enrolled. And their
average age was 78 years. 54% were men, 86% were White. 81% of
the individuals enrolled were anticoagulated for atrial
fibrillation. And they had received this drug 11 hours median
time since the last dose. 51% of the individuals were on a
apixaban, 37% were on rivaroxaban, and 8% were on edoxaban, and
then finally 5% were on enoxaparin. Now bleeding, Peder, was
predominantly intracranial in 69%, it was GI in 23%. In evaluable
apixaban patients, median anti Factor Xa activity decreased from
146.9 to 10 nanograms per milliliter. That's a 93% reduction. In
rivaroxaban patients, it decreased from 214 to 10.8 nanograms per
milliliter. That's a 94% reduction. In edoxaban patients, it
decreased from 121 to 24 nanograms per milliliter; a 71%
reduction. And in enoxaparin, it decreased from 0.48 to 0.11
international units per milliliter or a 75% reduction.


So Peder, excellent or good hemostasis occurred in 274 of the 342
evaluable patients. So in 80%. In the safety population,
thrombotic events occurred in about 10% of patients. And in 16
patients, this occurred during treatment with prophylactic
anticoagulation that began after the bleeding event. So no
thrombotic episodes occurred after oral anticoagulation restart.
So Peder, in conclusion, in patients with major bleeding
associated with the use of Factor Xa inhibitors, treatment with
enoxaparin and andexanet alfa reduced anti Factor Xa activity and
was associated with good or excellent hemostatic efficacy in 80%
of patients.


Dr. Peder Myhre:


Oh wow. That was really impressive.


Dr. Gregory Hundley:


Yeah, what a very practical study. Well, Peder, we have some
other articles in the issue. How about I go first? So first,
there's a Research Letter from Professor Eleanor entitled “A
Mouse Model of Atrial Fibrillation in Sepsis.” And then from
Tracy Hampton we have some Cardiology News. First from Professor
Shane et al, a paper on the impact of coffee subtypes on incident
cardiovascular disease, arrhythmias, and mortality, long-term
outcomes from the UK Biobank study, which is published in the
European Journal of Preventive Cardiology. Next from Professor
Morashige, there is a paper entitled “Extra Cardiac BCAA
Metabolism Lowers Blood Pressure and Protects From Heart
Failure.” And that's published in Cell Metabolism. And then
finally from Professor Kessler and associates, the paper is
entitled “Common and Rare Variant Associations with Colonial
Haematopoiesis Phenotypes.” And that particular paper is
published in Nature.


Dr. Peder Myhre:


That's great, Greg. And we also have an exchange of letters by
Dr. Ding and Dr. Kirshenbaum regarding the article “Proteasomal
Degradation of TRAF2 Mediates Mitochondrial Dysfunction in
Doxorubicin-Cardiomyopathy.” And finally we have On My Mind by
Bertram Pitt entitled “Early Implementation of aldosterone
Targeted Therapy in Patients with Hypertension.” Now Greg, let's
go to the feature paper to discuss the progression of coronary
atherosclerosis in middle-aged and older athletes.


Dr. Gregory Hundley:


Very good. Let's go.


Welcome listeners to this feature discussion on March 28th. And
we have with us today Dr. Vincent Aengevaeren from Radboud
University Medical Center in Nijmegen in the Netherlands. And
also with us one of our associated editors, Dr. Jarett Berry from
University of Texas Southwestern Medical Center in Dallas, Texas.
Welcome gentlemen. Well, Vince, we'll start with you. Can you
describe for us some of the background information that went into
the preparation of your study and what was the hypothesis that
you wanted to address?


Dr. Vincent Aengevaeren:


So this specific study is actually a follow-up study of a
previous study that we did on the relationship between exercise
and coronary atherosclerosis. The original study was published
also in circulation in 2017 and it really looked at the
association of relationship between exercise volume, lifelong
exercise volume and coronary atherosclerosis. And at that time we
found that there was actually a sort of paradoxical association
between lifelong exercise volume and coronary atherosclerosis
that with higher lifelong exercise volumes, there was a dose upon
dependent association with the prevalence of coronary
atherosclerosis.


And there was actually in the same issue, there was another paper
in 2017 from a London group shown similar findings. And actually,
yesterday on the ACC, there was another paper also showing
increased coronary atherosclerosis in athletes. And this study of
course there was also some critic like is this caused by
confounding, these were observational perceptional studies, could
there be other factors playing, but also none of the studies
looked at the differentiation between exercise volume and
exercise intensity. So the composition of the exercise. So that
was the main question actually for this study. We want to do a
follow-up study after at least five years do another CT scan,
again, get everyone back the questionnaire, exercise habits, and
then also specifically look at exercise volume versus exercise
and density.


Dr. Gregory Hundley:


Very nice. So it sounds like in this study you have a cohort that
you're following over time. So maybe describe for us a little bit
more the specific study design and who is included. Who is your
study population here?


Dr. Vincent Aengevaeren:


The study population is called the MARC study, Measuring Athletes
Risk of Cardiac events. And the study was originally designed
mainly based on the fact that healthy athletes, mainly male
athletes, sometimes suddenly die of coronary atherosclerosis,
which is not really recognized beforehand. So the main study idea
was to look at healthy male athletes who didn't experience any
symptoms and who underwent the screening, including an exercise
test with EKG with normal findings and who then subsequently
underwent a coronary CT scan. So blank CT scan for corona
calcification score, but also contrast enhanced CT scan to look
at the degree of coronary atherosclerosis to those of [inaudible
00:15:18] characteristics.


So that's how the original study was designed and it included 318
male individuals over the age of 45 with a very heterogeneous
exercise exposure. So they all had to do some type of sports, but
there was no minimal dose. So it really depended. So we have some
very high level athletes, but also some more of the regular
people who exercise a lot less. So very heterogeneous exposure.
And for this study, so in the follow-up study, we actually
included 291 of those 318 individuals after six years, which I
was pretty happy with. And for this specific analysis we excluded
two individuals due to their PCI in between. So that's pretty
much the cohort that we're looking at. And during this follow-up
period of six years, they did the equivalent of about 40 MET
hours per week, which equates to about five hours of the
exercise.


Dr. Gregory Hundley:


Very nice. And Vince, you said you had a very diverse group. I
mean, a lot of times I'll think about the extremes here. Folks
that do a lot of aerobic exercise, those that I think about the
power weightlifter. What kind of distribution of athlete, maybe
just some practical identifiers for our listeners here.


Dr. Vincent Aengevaeren:


So it's a very important point. So the main type of athletes in
this group who are endurance athletes, so mainly runners and
cyclists. Of course also some other type athletes and some
athletes do multiple type of sports, but mainly runners and
cyclists and definitely large proportion of [inaudible 00:16:53]
athletes.


Dr. Gregory Hundley:


Very nice. So Vince, describe for us your study results.


Dr. Vincent Aengevaeren:


During this follow-up period, and it's important to state that
for this follow-up study we used the exercise characteristics
during the follow-up period, we found that exercise volume during
follow-up was not associated with progression of coronary
atherosclerosis, but exercise intensity was. So we defined
exercise intensity based on the MET score, the metabolic
equipment of task score, which is derived from previous studies.
And there's a compendium explaining MET scores for all the
different sports and we used that to categorize the different
sports. And we've found that vigorous intensity exercise, for
example cycling, was associated with less progression of coronary
calcification, but very vigorous intensity exercise, for example
running was associated with more progression or coronary
calcification. And if you then also look at plaque types, we also
saw that those who did the most very vigorous exercise also had a
bit more calcified plaque progression. So that was the main
findings.


Dr. Gregory Hundley:


And Vince, describe for our listeners, many whom are
cardiologists or others fellows, et cetera. Can you give me a
specific example of vigorous exercise versus very vigorous
exercise? Like, if I'm doing something during the week, describe
for me those two categories, examples.


Dr. Vincent Aengevaeren:


So typically, and of course this is a very typical vigorous
exercise was cycling and very vigorous exercise was running. But
of course as you do cycling at a higher intensity, for example
spinning on a spinning bike, it's traditionally at a higher
exercise intensity. So that was counted as a very vigorous
intensity exercise. And I have to say this was based on
questionnaire data, so I did not have six-year or lifelong heart
rate data. So it is based on questionnaire data, the
categorization of exercise intensity. That's a good example.
Other things of [inaudible 00:19:03] intensives, for example,
soccer, hockey, I don't know how popular those sports are in
America, but those are pretty popular in Netherlands as well.


Dr. Gregory Hundley:


When you mean very vigorous for some of our runners out there, I
mean for the casual runner that might run two or three miles a
day, is that very vigorous or are you talking about someone
that's training periodically for marathons and running three or
four marathons a year?


Dr. Vincent Aengevaeren:


That is really more, I guess, about volume. So if people do a lot
of marathons, that can actually be at a lower intensity. Like,
with intensity, we really, really mean the heart rate intensity
and not the intensity of the volume. So I have to specify that.
It's really exercise intensity such as for oxygen consumption or
heart rate and not the volume in the hours per week. So typically
the runners that we had were mostly very vigorous runners. So
couple hours per week traditionally they did like trainings of
one and a half hour, which is usually at a higher intensity.


Dr. Gregory Hundley:


Very nice. Well listeners, now we're going to turn to one of our
associate editors, Dr. Jarett Berry, who really has some
expertise in this area. And Jarett, you see many papers in
circulation. What do you find is unique about this particular
study and then how do you put its results really in the context
of other studies that have focused on exercise both in duration
as well as intensity?


Dr. Jarett Berry:


Yeah, thanks Greg. And Vince, a fantastic paper, such a privilege
to be able to visit with both of you today about this important
paper. I think if you take a step back here, challenges I think
we all have as physicians is dealing with these uncertain
questions that arise clinically where you encounter patients who
are exercising at these extreme levels. And although it's not
super common, we do encounter these scenarios clinically. And
what we need in context like this is we need some data and
understanding of what's happening clinically to be able to
provide guidance. And so we're really in a context like this in a
scenario where we have the common clinical problem of incomplete
information. And I think it's studies like this that really help
us move the needle to help us understand how to think about those
patients of ours that exercise at very high levels.


I do think it's important to put it into context, about 10% of
the participants in this study exercised below 1,000 minutes per
week. And so for those of you taking notes at home, that's the
guidelines in 500 and 1,000 minutes per week would be, I mean
you'd be hitting the guidelines. And two-thirds of these
individuals were exercising at 2,000 minutes per week. So I think
it's important to put it into context when we think about
applying and understanding the question about toxicity of
exercise, putting that into context that most of the patients
that we encounter are not exercising at these high levels.
However, as I mentioned, we do encounter this and we have to know
what to do with it.


The key here I think is... The other context is with a point
that's been raised already in some of the questions and
discussion is the heterogeneity that we see in individuals who
exercise at these high levels. When you're trying to think about
dose of exercise, we have to think about not just intensity but
volume. And I think what the study's done here has done a really
nice job of trying to parse that out because we can achieve the
dose of exercise that's recommended or the dose of exercise that
we want to achieve for personal reasons, but we can get there
through different ways. We can get there through more hours or we
can get there through a higher intensity. And then of course,
obviously combinations of the two.


And I think this study here does two things for us. Number one,
it gives us a delta question. We've seen this before with just
looking cross-sectionally and we have all the challenges that
come with that with regard to recall of exercise. Here we have a
prospective cohort that we're following or that events followed.
And secondly, the ability to parse out both volume and intensity
over time. And I think that for me, the finding that really
sticks out is that in addition to all the complexities that are
right here, we see that the story with regard the components of
the dose may not be uniform. That intensity or exercising at very
high intensity may be a different part of the equation beyond
just volume.


And I think that as we think about counseling our patients as
they are engaging in this type of high level of exercise, I think
it's one additional component of our way of interpreting this and
providing counsel to these patients about how to think about
volume and intensity. And maybe these data suggests the
hypothesis that the volume part of the dose equation may be safer
or maybe something that's more palatable for the heart perhaps
over time than the intensity. I think the big elephant in the
room, of course, is the fundamental question is that we're
dealing with an intermediate phenotype and we know lots of
observational data showing that more atheros bad. We all
recognize that, but you can get to athero through different
mechanisms here.


And I think that these data and others suggest that exercise is
one mechanism perhaps that though you can get athero, the
question is what is the true clinical significance from a
[inaudible 00:24:32] standpoint down the road as we try to
extrapolate the intermediate phenotype into the future. And I
think there's controversy, I think agreement about what the
intermediate phenotype means in these high volume exercisers. And
I think that question remains unknown, I think.


But in the interim, as I said in the beginning, that as we think
about putting all this into context, we don't have perfect
information and we do have to take the information that we do
have to provide the counsel that we need to provide if these
patients. And I think I take away from this that when providing
counsel, maybe I lean more towards volume and less towards this
really high volume, sorry, this really high intensity for those
individuals whose coronary calcium or their athero burden is
particularly high. But a fantastic study. Another step in the
road and it's really trying to understand an incredibly complex
story and one that will continue to unfold.


Dr. Gregory Hundley:


Very nice, Jarett. And listeners, we're going to turn back to
both Vince and Jarett here each in 30 seconds. Vince, what do you
see as the next study that your group or others might want to be
considering in this sphere of research?


Dr. Vincent Aengevaeren:


For me personally, the next big thing that we should do is really
cardiovascular risk. So what's the clinical relevance of this
finding? So coronary calcification is strongly associated with
cardiovascular risk, but how that is in these athletes in which
we see increased coronary calcification, that's still pretty much
the question. I mean, any plaque is worse than no plaque, but how
is this for the very vigorous exercisers who may show some more
calcification and whether that risk is different. I mean, that's
the question that all the athletes that email me after this type
of publication have the question. And also the mechanisms. Like,
what are the underlying mechanisms? That's also a next lead study
for me.


Dr. Gregory Hundley:


Very nice. And Jarett?


Dr. Jarett Berry:


Yeah, I think the ultimate question is, I completely agree, is
what is the clinical significance. I think that's going to be...
That's a challenging question to answer just because of the on
average these individuals are more rare. And so following these
individuals over time to really tease out the clinical
significance of this type of athero in these athletes, I think,
is a challenge. I think for me the next step would be more
studies like this where we can get more granular with regard to
measured exercise intensity. I think wearable devices, things
that Vince alluded to with regard to heart rate, really trying to
get more quantitative to try to parse out the contribution of
more objectively measured exercise intensities, I think would
probably, for me, represents kind of probably the next step, is
digging a little deeper into the phenotype and being a little bit
more precise perhaps with studies like this to help us begin to
understand the significance of these findings.


Dr. Gregory Hundley:


Very nice. Well, listeners, we want to thank Dr. Vincent
Aengevaeren from Radboud University Medical Center in Nijmegen in
the Netherlands, and our own associated editor, Dr. Jarett Berry
from University of Texas Southwestern Medical Center in Dallas,
Texas for bringing us this study highlighting that exercise
intensity but not volume was associated with progression of
coronary atherosclerosis during a six-year follow-up of this
cohort of really trained athletes and intriguingly the very
vigorous. So we want to distinguish that. The very vigorous
intensity exercise was associated with greater coronary artery
calcium calcified plaque progression, whereas simply just
vigorous intensity exercise, casual riding of the bike, casual
running, et cetera, was associated with less coronary artery
calcium progression.


Well, on behalf of Peder and Carolyn and myself, we want to wish
you a great week and we will catch you next week on the run. This
program is copyright of the American Heart Association 2023. The
opinions expressed by speakers in this podcast are their own and
not necessarily those of the editors or of the American Heart
Association. For more, please visit ahajournals.org.