Circulation July 27, 2021 Issue

This week's episode features author Aaron Baggish and Associate
Editor & Editorialist Satyam "Tom" Sarma as they discuss the
article "SARS-CoV-2 Cardiac Involvement in Young Competitive
Athletes."


Dr. Carolyn Lam:


Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the Journal and its editors. We're your
co-hosts ... I'm Dr. Carolyn Lam Associate Editor from the
National Heart Center and Duke National University of Singapore.


Dr. Greg Hundley:


And I'm Dr. Greg Hundley, Associate Editor, Director of the
Pauley Heart Center from VCU health in Richmond, Virginia.


Dr. Carolyn Lam:


Greg, this feature discussion is just so relevant to our current
times. It talks about SARS-CoV-2 cardiac involvement in young
competitive athletes. Oh, one that I'm sure we're all dying to
get to. Very important. But first, let's tell you what's in this
week's issue. Greg, you want to go first?


Dr. Greg Hundley:


You bet, Carolyn. I'm going to grab a cup of coffee, and we're
going to dive into the world of preclinical science. Our first
paper comes to us from Professor Naftali Kaminski from Yale
University. Carolyn, these investigators reprocessed human
control single-cell RNA-sequencing, or scRNA sequence data from
six datasets to provide a reference atlas of human lung
endothelial cells to facilitate a better understanding of the
phenotypic diversity and composition of cells comprising the lung
endothelium. Also, the signaling network between different lung
cell types was studied.


Dr. Carolyn Lam:


Wow. Okay. So what did they find, Greg?


Dr. Greg Hundley:


Six lung single-cell RNA-sequencing datasets were reanalyzed and
annotated to identify over 15,000 vascular endothelial cells from
73 individuals. Beyond the broad cellular categories of
lymphatic, capillary, arterial and venous endothelial cells, the
co-authors found two previously indistinguishable populations.
Pulmonary venous endothelial cells, called COL15A1neg localized
to the lung parenchyma and systemic venous endothelial cells,
COL1581positive localized to the airways and visceral pleura.


Dr. Greg Hundley:


Now, among capillary endothelium cells, the authors confirmed
their subclassification into recently discovered aerocytes
characterized by EDNRB, SOSTDC1, and TBXX2 and general capillary
endothelial cells. The authors confirmed that all six endothelial
cell types, including the systemic venous endothelial cells and
aerocytes, are present in mice and identified endothelial marker
genes conserved in both humans and mice.


Dr. Greg Hundley:


So Carolyn, I'm going to take a question I bet you're getting
ready to ask. What are the clinical implications of this
research? Well, mainly that understanding the lung endothelial
diversity is crucially important to identify new therapeutic
approaches for vascular diseases such as pulmonary hypertension.


Dr. Carolyn Lam:


Wow. That was interesting, Greg. Thank you. I've got another one
from basic science world as well, and this one talks about the
initial functional characterization of an exercise-induced
cardiac physiological hypertrophy associated novel long
non-coding RNA or LncRNA.


Dr. Greg Hundley:


Okay, Carolyn. Quick quiz. Can you remind us what these
long-coding RNAs are?


Dr. Carolyn Lam:


Ha. Sure. So long non-coding RNAs or LncRNA refers to RNAs that
are longer than 200 nucleotides and lack the potential to encode
proteins, but have still been closely related to the occurrence
and development of many diseases.


Dr. Carolyn Lam:


The current paper comes from co-corresponding authors, Dr. Li
from the First Affiliated Hospital of Nanjing Medical University
and Dr. Xiao from Shanghai University. They identified a LncRNA
in the heart named cardiac physiological hypertrophy associated
regulator, or CPhar. This was increased following exercise
training and was necessary for exercise-induced cardiac growth.
In neonatal mouse cardiomyocytes, over expression of this LncRNA
induced an increase in these cardiomyocytes' size and expression
of proliferation markers while inhibition of the LncRNA reduced
these neonatal mouse cardiomyocytes' size and the expression of
proliferative markers. Over expression of the LncRNA led to a
reduction in oxygen glucose deprivation reperfusion-induced
cardiomyocyte apoptosis, while LncRNA knockdown aggravated the
apoptosis.


Dr. Carolyn Lam:


In vivo over expression of that LncRNA prevented myocardial
ischemia reperfusion injury and improved cardiac function. So
mechanistically though, the transcription factor, ATF7, acted as
the functional downstream effector of this cardiac physiological
hypertrophy associated regulator, the LncRNA.


Dr. Carolyn Lam:


Now Greg, following your example, I'm going to ask what are the
clinical implications and tell you. So these results provide new
insights into the regulation of exercise-induced cardiac
physiological growth, demonstrating the cardioprotective role of
this LncRNA known as cardiac physiological hypertrophy associated
regulator in the heart. It also expanded our knowledge and
understanding of the functions and fundamental mechanisms of
LncRNAs in general.


Dr. Greg Hundley:


Wow, Carolyn. Beautifully described. Well, my next paper comes to
us from the world of clinical science and really it's kind of
something that's going to get into spending. It comes to us from
Dr. Brandon Bellows from Columbia University.


Dr. Greg Hundley:


So Carolyn, spending on cardiovascular disease and cardiovascular
risk factors, in total cardiovascular spending, accounts for a
significant portion of overall US healthcare spending. The
author's objective was to describe US adult cardiovascular
spending patterns in 2016 and changes from 1996 to 2016, and look
at the factors associated with these changes over time.


Dr. Carolyn Lam:


Wow. Okay. So were the authors are viewing time-dependent changes
in cardiovascular spending. Is that it? What did they find?


Dr. Greg Hundley:


Absolutely Carolyn. So a bunch of data. Just kind of some
interesting facts here. So let's work through them. Adult
cardiovascular spending increased from 212 billion in 1996 to 320
billion in 2016, a period when the US population increased by
over 52 million people and the median age increased from 33 to
36.9 years.


Dr. Greg Hundley:


Next, over this period, public insurance was responsible for the
majority of cardiovascular spending at 54% followed by private
insurance at 37% and out-of-pocket spending at 9%.


Dr. Greg Hundley:


Next, health services for ischemic heart disease at about 80
billion and hypertension, 71 billion, led to the most spending in
2016.


Dr. Greg Hundley:


Next, increased spending between 1996 and 2016 was primarily
driven by treatment of hypertension, hyperlipidemia, and atrial
fibrillation flutter on which spending rose by $42 billion, $18
billion and $16 billion respectively. Increasing service price
and intensity alone were associated with 51% or 88 billion, and
cardiovascular spending increased from 1996 through 2016.
Whereas, changes in disease prevalence was associated with a 37%
or $36 billion spending reduction over the same period after
taking into account population growth and population aging.


Dr. Greg Hundley:


So in summary, Carolyn, US adult cardiovascular spending
increased by about $100 billion from 1996 to 2016. Maybe policies
tailored to control service price and intensity and
preferentially reimburse higher quality care, perhaps that could
help counteract future spending increases due to population aging
and growth.


Dr. Carolyn Lam:


Oh, wow. Those are staggering numbers. Thanks Greg. Now let's go
through what else is in this week's issue. There's an exchange of
letters between doctors Mehmood and Houser regarding the article,
Cardiac Remodeling During Pregnancy with Metabolic Syndrome: A
Prologue of Pathological Remodeling. There's an ECG challenge by
Dr. Real on an unusual call from the urology ward. There's also a
Research Letter from Dr. Molkentin on cardiac cell therapy
failing to rejuvenate the chronically scarred rodent heart. And
finally a Special Report by Dr. Althouse on Recommendations for
Statistical Reporting in Cardiovascular Medicine: A Special
Report from the American Heart Association.


Dr. Greg Hundley:


Great, Carolyn, and I've got a Perspective piece entitled,
Intravenous Iron Therapy in Heart Failure with Reduced Ejection
Fraction: Tackling the Deficiency. It's from Professor Ardehali.


Dr. Greg Hundley:


Well, Carolyn, how about we get on to that feature discussion and
learn more about SARS-CoV-2 in young competitive athletes.


Dr. Carolyn Lam:


Ooh, let's go. In our current COVID-19 pandemic a huge question
is, does cardiac involvement in athletes with COVID-19 preclude
their further participation in sports? What is their involvement
after they've recovered from COVID-19? Guess what? Today's
feature discussion is really hitting the spot with this question.
So pleased to have with us the corresponding author of the
feature paper, Dr. Aaron Baggish from Massachusetts General
Hospital, as well as Dr. Satyam Sarma also known as Tom Sarma,
our dear Associate Editor from UT Southwestern, who is also an
editorialist for today's paper. So welcome Aaron and Tom. Aaron,
could you start us off by describing your study and what you
found?


Dr. Aaron Baggish:


Sure. So just very briefly, some historical context. As everyone
is quite aware, when we first started seeing COVID-19 in the
hospital, there was a lot of concern about what the virus did to
the hearts in people that were sick enough to be hospitalized.
Those of us in the sports cardiology community were quite
concerned that when young athletes that developed COVID-19
infection got sick and then returned to sport, that we'd be
seeing the adverse events associated with cardiac involvement. So
that was the impetus to start the ORCCA Registry, which was
really an opportunity to try to capture the large-scale
experience with collegiate athletes returning to sport after
COVID-19 infection. Indeed, with roughly 19,000 student athletes
across 42 universities, there were approximately 3,000 that
developed COVID-19 infection and then went through some form of
cardiac screening prior to return to play. The registry was
really about telling that story of what we found and what we
think the implications are.


Dr. Carolyn Lam:


Aaron, I mean, first of all, more than 19,000 athletes recruited
in just ... What was it? September 1st to December 31, 2020? How
did you accomplish this amazing registry so quickly? That's
amazing.


Dr. Aaron Baggish:


I need to acknowledge the fact that this was an incredible team
effort. I was joined and continue to be joined in this by my
co-PIs, Dr. Jon Drezner and Kim Harmon, who are sports medicine
physicians out of the Seattle area, and the combination of
cardiology, expertise and sports medicine expertise really able
to pull in many of the large universities and colleges around the
country, including most of the Power Five schools to participate
in this registry.


Dr. Aaron Baggish:


In short order, team physicians from all these schools understood
the importance of this work and agreed to partner with us to work
very hard to enroll their student athletes and to provide us with
the information we needed.


Dr. Carolyn Lam:


Incredible. But with the foresight, congratulations, this in and
of itself is amazing. Now, could you please tell us what you
found?


Dr. Aaron Baggish:


Sure. So we found that indeed, as we expected, that these student
athletes were undergoing a fair bit of cardiac testing prior to
being allowed to return to sport, and that there was variability
in terms of what type of testing they were getting. The majority
of schools were following what at that point were the
recommendations, which were do, what we call the cardiac triad
testing, which includes an echocardiogram, a high-sensitivity
troponin, and an ECG and to use that information to either clear
athletes or send them through further clinically indicated tests.
A small number of early adopters had decided to do mandatory
cardiac MRIs. So within that, we were able to understand what the
prevalence, if you will, of cardiac involvement in these COVID-19
student athletes looked like, and it varied as a function of what
type of tests people were doing.


Dr. Carolyn Lam:


And? Give us a sneak peek.


Dr. Aaron Baggish:


As people would expect, the more sensitive tests you do, the more
abnormalities you detect. So among the schools that were using a
mandatory cardiac MRI approach, there was a 3% prevalence, if you
will, of either definitive, probable or possible COVID-19 cardiac
involvement. When schools were following the triad testing first
followed by clinically indicated CMR that prevalence was much
less. It was approximately 0.5 or 0.6%. So I would emphasize that
on the whole, regardless of which test was being used, that the
involvement was at a much lower rate than we expected based on
what we saw early in the hospitalized patient experience. So I
think it's a very good news story.


Dr. Carolyn Lam:


Indeed. That's exactly, I think the title almost of Tom's
editorial. Tom, could I bring you in here, please? Could you give
us the context of this and then tell us what as editors we
thought of the paper when it kind of reached out doors at
Circulation?


Dr. Satyam “Tom” Sarma:


Sure. No, this was, I actually remember almost exactly when I was
asked to handle this paper from an editorial standpoint. Joe
texted me, Joe, our editor-in-chief texted me ... I think, the
night, actually it was a Friday night I think ... That we had a
really important paper, would you be able to take care of it on
an expedited basis? I said, "Of course." So took a look at it
over the weekend, and it's one of those papers when you're
reading it, you almost wish you had a time machine because you
realize if we had known this information eight, nine, 10, 11
months ago, it would have totally changed how we handle the
pandemic from an athlete and young person standpoint. So from
that aspect, I thought this is obviously a very high impact
paper.


Dr. Satyam “Tom” Sarma:


Which then led me to the second challenge is finding the right
reviewers for this paper because obviously this is a very
controversial topic. We wanted to make sure we had the best
reviewers we can get. The challenge, unfortunately, was that a
lot of my usual go-to reviewers were actually members of the
ORCCA Registry. So there were some issues with conflict of
interest there, and so from a reviewer standpoint, I looked to
sort of leaders in the field who had done something similar. The
first thing that came to mind was really how the field has
handled ECG screenings for our young athletes. I think there's,
again, a perspective there that I think is very similar to how do
you handle patients or young athletes with COVID and then how do
you emphasize shared decision making? So from that standpoint, I
had a narrow list of experts in shared decision making in sports
cardiology, and really leaned on them to help guide us through
the process because this is a complex paper.


Dr. Satyam “Tom” Sarma:


I think their feedback was instrumental in really helping to kind
of distill the message, to kind of phrase things in a way that
allowed the message to be easily digested by both the lay media,
but more importantly, by sports trainers and athletic directors
around the country. From that standpoint we really work hard and
again, really thank you to Aaron and Jonathan on this manuscript
because they worked so hard with our reviewers. They were
incredibly responsive to almost every review comment. From that
standpoint, I think the end result was amazing to really see it
in final format.


Dr. Carolyn Lam:


I love that behind-the-scenes look. Thank you so much, Tom. What
is the strong clinical implication of this? If you have questions
for Aaron, please go ahead.


Dr. Satyam “Tom” Sarma:


Sure. No, I think the biggest thing for us as editors and sort of
from the public health impact was, as Aaron mentioned, some
schools have unlimited resources to really throw as much money as
they can at the problem or what they think is the best approach
to the problem. Again, when you have unlimited resources, you can
get the "best tests." I think, unfortunately not every school in
this country, both from a collegiate or high school level, has a
capacity and more importantly, around the world. That's a really
important limiting factor.


Dr. Satyam “Tom” Sarma:


Is there a way to distill the algorithm in a way that's both safe
for the athletes, but more importantly is feasible for most
schools? For us, that was the most important public health
message was really to get that out there. The second of course,
was that thinking back to last summer, just how many COVID
myocarditis papers we handled in Circulation. Looking back with
the again, in the heat of the battle, things are always
challenging, but just to sort of see how the pendulum shifted in
such a 180 degree sort of manner. So that also I think was
important to get out there as well.


Dr. Carolyn Lam:


Yeah. And exactly why this paper is so important. So thank you
once again for publishing it with Circulation. Tom though ...
Okay. I mean, not to underestimate the MRI findings and so on. I
think you had a question for Aaron in relation to that?


Dr. Satyam “Tom” Sarma:


I do. One of the challenges, again, being on the myocardial side
is that we're not always experts in the papers we're assigned,
and it's obviously been an incredible learning process. For me, I
was hoping to pick your brain a little bit about the MRIs and
sort of how you think the field will evolve from a sports
cardiology standpoint. Especially as scanners get more powerful,
as scanners get more sensitive, the challenges I think the
field's going to have is really detecting the tiniest fleck of an
abnormality.


Dr. Satyam “Tom” Sarma:


I think the context here is really the recent paper out of the
Big 10 where they MRI'd, I believe, everyone in that registry ...
I want to say it was over 2,000 athletes. Just out of curiosity,
how was that handled, again, amongst your co-authors in deciding
how best to present the MRI data? I like how you use the
probabilistic language of it's either definite, probable or
possible. How do you see that sort of progressing in terms of is
that something practical that can be used by sports trainers and
sports medicine staff to help restratify your athletes or
athletes?


Dr. Aaron Baggish:


Tom, there's so much packed into that question. Let me try to
unpack it piece by piece. So first off in our registry, there
were a few schools that were early adopters in mandatory CMR
screening, and so we wanted to very much responsibly report that.
Again, there was about a 3% prevalence of something being
abnormal with the myocardium based on the scans. We also realized
that not all abnormalities were created equal, and that's why we
did come up with that definitive, possible, probable nomenclature
to really capture the fact that there were a few people that
looked like they had overt myocarditis. But the vast majority had
non-specific findings that those of us as clinicians pre-COVID
would not have considered myocarditis.


Dr. Aaron Baggish:


The issue with MRI is a complicated one. The way I like to think
about this as, as you mentioned earlier, is to go back to the
historical experience we had with ECG screening in which doing
that before we understood how to use it as a screening tool
caused more problems than it solved.


Dr. Aaron Baggish:


It was really back in the mid-2000s when the Italians published
their first ECG screening paper that the Americans got interested
in it. What we learned is that if you used ECG, and this applies
to MR too, without having good normative data, without
understanding the cost implications, without having the experts
prepared to interpret the test and deal with the downstream
findings, that you're just not ready for prime time.


Dr. Aaron Baggish:


While I think the use of MRI as a screening technique during
COVID was done with the best of intentions, I think the Big 10
paper, which is a very important dataset in this discussion,
highlighted why MRI is just simply not a useful screening tool
right now. If you look across their schools, they had
tremendously variable rates of cardiac involvement, which is not
a function of pathobiology. This virus is not different in
Virginia than it is in Tennessee than it is in Wisconsin. It's
just simply that people are using the tool in different ways and
coming up with different findings. What we're now seeing
clinically is that all these MRIs are finding a lot of stuff that
either we don't want to care about or we don't want to know, and
we're stuck dealing with it. So a challenge ahead of us, for
sure.


Dr. Satyam “Tom” Sarma:


No, I think that's a really important point, Aaron. I think
looking back even from a clinical standpoint in those, didn't not
necessarily look at athletes, I think what you bring up is really
important. The cognitive bias. Find something abnormal. I do
wonder if you could talk a little bit about ... One of the other
concerns we had behind the scenes was if you know an athlete, if
you're an MRI reader and you know an athlete or the scan in front
of you says 19-year-old athlete with COVID, can you talk a little
bit about the cognitive biases that kind of go into sort of
assuming either the worst case scenario, especially with
athletes, because again, these are young, robust, healthy people
who may or may not be on TV or in a very public format. How do
you handle that as a sports cardiology in general, just kind of
overcoming the cognitive bias, both from a public policy
standpoint, but also from a lay public standpoint?


Dr. Aaron Baggish:


Yeah. So I think bias is such an interesting word to me because
bias has a negative connotation, but bias actually also has some
positive attributes associated with it. Bias really pushes people
to be, in this situation, to be conservative and to try to do
what they think is best.


Dr. Aaron Baggish:


But what I think it boils down to is going back to a very simple
tenet and that's understanding the pre-test probability of
disease. So when we interpret imaging data or exercise testing
data, it always goes back to the question of why did this person
get the test done in the first hand and what is our pre-test
probability of finding something wrong? I think what we've
learned through the COVID pandemic is that just simply having
COVID does not equate with a high pre-test probability of having
myocarditis in this young population. That it's really the kids
that present, and these are the rare few and far between, that
present with clinical findings that any doctor would think of as
being consistent with myocarditis, where the scan is really
helpful. The vast majority of time it's just simply not that
case.


Dr. Satyam “Tom” Sarma:


No, I agree. I think that's always the challenge as well, too
clinically as well too, with the diagnostic creep of you get one
test that's kind of abnormal and the next thing you know, you're
doing a cardiac biopsy and trying to figure out how you got to
where you got to.


Dr. Satyam “Tom” Sarma:


I wanted to circle back to Carolyn's comment. I guess obviously
COVID kind of really was the dominant health story over the last
12 to 14 months. Has there been a similar rash, in other words,
I'm thinking back to H5N1 or some other pandemics in the past,
was there a similar concern historically from the sports
cardiology community with those viral outbreaks?


Dr. Aaron Baggish:


No. Not to my knowledge, and that's simply because there wasn't
as much of an experience with hospitalized patients in the US in
those prior pandemics. Again, our concern in sports cardiology
world really stemmed from a very different population than the
one we deal with on a daily basis. I think we learned that,
although we thought that was a well-intending way to approach it,
that it turned out to be an overreaction.


Dr. Aaron Baggish:


Before we end, I want to return to Tom's comments about the
process and just share with the listeners what a satisfying
process this was as an author. Having been through the peer
review process, many hundreds of times with different journals, I
don't remember one that was as satisfying nor one that led to as
high quality of paper based on the feedback we got from the
reviewers. So very much appreciative.


Dr. Aaron Baggish:


I also want to acknowledge the American Heart Association that
has become a long-term partner in this effort. As we move out of
the pandemic, the ORCCA Registry will be pivoting to really
capture what happens to young athletes that are diagnosed with
genetic and congenital forms of heart disease. We're very
appreciative that the AHA has agreed to partner with us on this.


Dr. Carolyn Lam:


Aw, my goodness. Thank you so much, Aaron and Tom, for this
incredible discussion. I really want to end with, if I may Tom,
citing your editorial. I love the way you ended it by saying, "As
Nelson Mandela said, 'Sports has the power to change the world.
It has the power to inspire. It has the power to unite people in
a way that little else does.'" We got seriously scared with
COVID-19, but this paper is just so important in providing some
reassurance that there has not been a single case of cardiac
complication to date, documented to be clearly related to
COVID-19 in this population. It's a real testament to the hard
work that you've put in. So thank you. Thank you very much for
this paper. For all the effort. Thank you both for being here to
discuss this.


Dr. Carolyn Lam:


Well, audience, you've been listening to Circulation on the Run.
Thanks for joining us today, and don't forget to join us again
next week.


Dr. Greg Hundley:


This program is copyright of the American Heart Association,
2021. 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, visit ahajournals.org.