Jul 26, 2021
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.