May 2023 Discover CircRes

This month on Episode 48 of Discover CircRes, host Cynthia St. Hilaire highlights three original research articles featured in the April 28th issue of Circulation Research. This Episode also includes a discussion between Dr Mina Chung, Dr DeLisa Fairweather and Dr Milka Koupenova, who all contributed to manuscripts to the May 12th Compendium on Covid-19 and the Cardiovascular System.     Article highlights:   Heijman, et al. Mechanisms of Enhanced SK-Channel Current in AF   Chen, et al. IL-37 Attenuates Platelet Activation   Enzan, et al. ZBP1 Protects Against Myocardial Inflammation   Compendium on Covid-19 and the Cardiovascular System.   Cindy St. Hilaire: Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire, from the Vascular Medicine Institute at the University of Pittsburgh. Today, I'm going to be highlighting articles from our April 28th and May 12th issues of Circulation Research. I'm also going to have a chat with Dr Mina Chung, Dr DeLisa Fairweather and Dr Milka Koupenova, who all contributed to articles in the May 12th COVID Compendium. But before we have that interview, let's first talk about some highlights.   The first article I want to present is titled Enhanced Calcium-Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation. This article is coming from the University of Essen by Heijman and Zhou, et al. Atrial fibrillation is one of the most common forms of heart arrhythmia in humans and is characterized by irregular, often rapid heartbeats that can cause palpitations, dizziness and extreme fatigue. Atrial fibrillation can increase a person's risk of heart failure, and though treatments exist such as beta blockers, blood thinners and antiarrhythmia medications, they can have limited efficacy and side effects. A new family of drugs in development are those blocking small-conductance calcium-activated potassium channels called SK channels, which exhibit increased activity in animal models of AF and suppression of which attenuates the arrhythmia. In humans however, the relationship between SK channels and atrial fibrillation is less clear, at least in terms of SK channel mRNA levels. Because mRNA might not reflect actual channel activity, this group looked at just that and they found indeed that channel activity was increased in cardiomyocytes from atrial fibrillation patients compared to those from controls even though the mRNA and protein levels themselves were similar. The altered currents were instead due to changes in SK channel trafficking and membrane targeting. By confirming that SK channels play a role in human atrial fibrillation, this work supports the pursuit of SK channel inhibitors as possible new atrial fibrillation treatments.   The next article I want to present is titled IL-37 Attenuates Platelet Activation and Thrombosis Through IL-1R8 Pathway. This article comes from Fudan University by Chen and Hong, et al. Thrombus formation followed by the rupture of a coronary plaque is a major pathophysiological step in the development of a myocardial infarction. Understanding the endogenous antithrombotic factors at play could provide insights and opportunities for developing treatments. With this in mind, Chen and Hong, et al. investigated the role of interleukin-1 receptor 8, or IL-1R8, which suppresses platelet aggregation in mice, and of IL-37, a newly discovered human interleukin that forms a complex with IL-1R8 and is found at increased levels in the blood of patients with myocardial infarction. Indeed, the amount of IL-37 in myocardial infarction patients negatively correlates with platelet aggregation. They also show that treatment of human platelets in vitro with IL-37 suppresses the cell's aggregation and does so in a concentration-dependent manner. Moreover, injection of the protein into the veins of mice inhibits thrombus development and better preserves heart function even after myocardial infarction. Such effects were not seen in mice lacking IL-1R8. This suggests IL-37's antithrombotic action depends on its interaction with the receptor. Together, the results suggest IL-37 could be developed as a antithrombotic agent for use in MI patients or indeed perhaps other thrombotic conditions.   The last article I want to present before our interview is titled ZBP1 Protects Against Mitochondrial DNA-Induced Myocardial Inflammation in Failing Hearts. This article is coming from Kyushu University and is by Enzan, et al. Myocardial inflammation is a key factor in the pathological progression of heart failure and occurs when damaged mitochondria within the stricken cardiomyocyte release their DNA, triggering an innate inflammatory reaction. In a variety of cells, DNA sensors such as Z-DNA-binding protein 1 or ZBP1 are responsible for such mitochondrial DNA-induced inflammation. In theory then, it's conceivable that therapeutic suppression of ZBP1 might reduce myocardial inflammation in heart failure and preserve function. But as Enzan and colleagues have now discovered to their surprise, mice lacking ZBP1 exhibited worse, not better heart inflammation and more failure after induced myocardial infarction. Indeed, the test animals' hearts had increased infiltration of immune cells, production of inflammatory cytokines and fibrosis together with decreased function compared with the hearts of mice with normal ZBP1 levels. Experiments in rodent cardiomyocytes further confirmed that loss of ZBP1 exacerbated mitochondrial DNA-induced inflammatory cytokine production while overexpression of ZBP1 had the opposite effect. While the reason behind ZBP1's opposing roles in different cells is not yet clear, the finding suggests that boosting ZBP1 activity in the heart might be a strategy for mitigating heart inflammation after infarction.   Cindy St. Hilaire:         The May 12th issue of Circulation Research is our COVID compendium, which consists of a series of 10 reviews on all angles of COVID-19 as it relates to cardiovascular health and disease. Today, three of the authors of the articles in this series are here with me. Dr Mina Chung is a professor of medicine at the Cleveland Clinic. She and Dr Tamanna Singh and their colleagues wrote the article, A Post Pandemic Enigma: The Cardiovascular Impact of Post-Acute Sequelae of SARS-CoV-2. Dr DeLisa Fairweather, professor of medicine, immunology and clinical and translational science at the Mayo Clinic, and she and her colleagues penned the article, COVID-19 Myocarditis and Pericarditis. Dr Milka Koupenova is an assistant professor of medicine at the UMass Chan School of Medical and she led the group writing the article, Platelets and SARS-CoV-2 During COVID-19: Immunity, Thrombosis, and Beyond. Thank you all for joining me today.   DeLisa Fairweather:    Thank you so much for having us.   Mina Chung:   Thank you.   Milka Koupenova:       Thank you for having us, Cindy.   Cindy St. Hilaire:         In addition to these three articles, we have another seven that are on all different aspects of COVID. Dr Messinger's group wrote the article, Interaction of COVID-19 With Common Cardiovascular Disorders. Emily Tsai covered cell-specific mechanisms in the heart of COVID-19 patients. Mark Chappell and colleagues wrote about the renin-angiotensin system and sex differences in COVID-19. Michael Bristow covered vaccination-associated myocarditis and myocardial injury. Jow Loacalzo and colleagues covered repurposing drugs for the treatment of COVID-19 and its cardiovascular manifestations. Dr Stephen Holby covered multimodality cardiac imaging in COVID, and Arun Sharma covered microfluidic organ chips in stem cell models in the fight against COVID-19.   Cindy St. Hilaire          As of today, worldwide, there have been over six hundred million individuals infected with the virus and more than six and a half million have died from COVID-19. In the US, we are about a sixth of all of those deaths. Obviously now we're in 2023, the numbers of individuals getting infected and dying are much, much lower. As my husband read to me this morning, one doctor in Boston was quoted saying, "People are still getting wicked sick." In 75% of deaths, people have had underlying conditions and cardiovascular disease is found in about 60% of all those deaths. In the introduction to the compendium, you mentioned that the remarkable COVID-19 rapid response initiative released by the AHA, which again is the parent organization of Circ Research and this podcast, if I were to guess when that rapid response initiative started, I would've guessed well into the pandemic, but it was actually March 26th, 2020. I know in Pittsburgh, our labs have barely shut down. So how soon after we knew of SARS-CoV-2 and COVID, how soon after that did we know that there were cardiovascular complications?   Mina Chung:               I think we saw cardiovascular complications happening pretty early. We saw troponin increases very early. It was really amazing what AHA did in terms of this rapid response grant mechanism. You mentioned that the RFA was announced, first of all, putting it together by March 26th when we were just shutting down in March was pretty incredible to get even the RFA out. Then the grants were supposed to be submitted by April 6th and there were 750 grants that were put together and submitted. They were all reviewed within 10 days from 150 volunteer reviewers. The notices were distributed April 23rd, less than a month out.   Cindy St. Hilaire:         Amazing.   Mina Chung:               So this is an amazing, you're right, paradigm for grant requests and submissions and reviews.   DeLisa Fairweather:    For myocarditis, reports of that occurred almost immediately coming out of China, so it was incredibly rapid.   Cindy St. Hilaire:         Yeah, and that was a perfect lead up to my next question. Was myocarditis, I guess, the first link or the first clue that this was not just going to be a respiratory infection?   DeLisa Fairweather:    I think myocarditis appearing very early, especially it has a history both of being induced by viruses, but being strongly an autoimmune disease, the combination of both of those, I think, started to hint that something different was going to happen, although a lot of people probably didn't realize the significance of that right away.   Cindy St. Hilaire:         What other disease states, I guess I'm thinking viruses, but anything, what causes myocarditis and pericarditis normally and how unique is it that we are seeing this as a sequelae of COVID?   DeLisa Fairweather:    I think it's not surprising that we find it. Viruses around the world are the primary cause of myocarditis, although in South America, it's the parasite Trypanosoma cruzi. Really, many viruses that also we think target mitochondria, including SARS-CoV-2, have an important role in driving myocarditis. Also, we know that SARS-CoV-1 and MERS also reported myocarditis in those previous infections. We knew about it beforehand that they could cause myocarditis.   Cindy St. Hilaire:        Is it presenting differently in a COVID patient than say those South American patients with the... I forget the name of the organism you said, but does it come quickly or get worse quickly or is it all once you get it, it's the same progression?   DeLisa Fairweather:    Yeah. That's a good question. Basically, what we find is that no matter what the viral infection is, that myocarditis really appears for signs and symptoms and how we treat it identically and we see that with COVID-19. So that really isn't any different.   Cindy St. Hilaire:         Another huge observation that we noticed in COVID-19 patients, which was the increased risk of thrombic outcomes in the patients. Dr Koupenova, Milka, you are a world expert in platelets and viruses and so you and your team were leading the writing of that article. My guess is knowing what you know about platelets and viruses, this wasn't so surprising to you, but could you at least tell us the state of the field in terms of what we knew about viruses and platelets before COVID, before Feb 2020?   Milka Koupenova:       Before Feb 2020, we actually knew that influenza gets inside in platelets. It leads to not directly prothrombotic events, but it would lead to release of complement 3 from them. That complement 3 would actually increase the immunothrombosis by pushing neutrophils to release their DNA, forming aggregates. In cases when you have compromised endothelium and people with underlying conditions, you would expect certain thrombotic outcomes. That, we actually published 2019 and then 2020 hit. The difference between influenza and SARS-CoV-2, they're different viruses. They carry their genome in a different RNA strand. I remember thinking perhaps viruses are getting inside in platelets, but perhaps they do not. So we went through surprising discoveries that it seemed like it is another RNA virus. It also got into platelets. It was a bit hard to tweak things surrounding BSL-3 to tell you if the response was the same. It is still not very clear how much SARS or rather what receptor, particularly when it gets inside would induce an immune response. There are some literature showing the MDA5, but not for sure, may be responsible. But what we found is that once it gets in platelets, it just induces this profound activation of programmed cell death pathways and release of extracellular vesicles and all these prothrombotic, procoagulant form of content that can induce damage around, because platelets are everywhere. So that how it started in 2019 and surprisingly progressed to 2021 or 2020 without the plan of really studying this virus.   Cindy St. Hilaire:         How similar and how different is what you observe in platelets infected, obviously in the lab, so I know it's not exactly the same, but how similar and how different is it between the flu? Do you know all the differences yet?   Milka Koupenova:       No offense here, they don't get infected.   Cindy St. Hilaire:         Okay.   Milka Koupenova:       Done the proper research. The virus does not impact platelets, but induces the response.   Cindy St. Hilaire:         Okay.   Milka Koupenova:       That goes back to sensing mechanism. Thank goodness platelets don't get infected because we would be in a particularly bad situation, but they remove the infectious virus from the plasma from what we can see with function.   Cindy St. Hilaire:         Got it. So they're helping the cleanup process and in that cleaning up is where the virus within them activates. That is a really complicated mechanism.    Milka Koupenova:       Oh, they're sensing it in some form to alert the environment. It's hard to say how similar and how different they are unless you study them hint by hint next to each other. All I can tell is that particularly with SARS-C, you definitely see a lot more various kinds of extracellular vesicles coming out of them that you don't see the same way or rather through the same proportion with influenza. But what that means in how platelet activates the immune system with one versus the other, and that goes back to the prothrombotic mechanisms. That is exactly what needs to be studied and that was the call for this COVID compendium is to point out how much we have done as a team. As scientists who put heads together, as Mina said, superfast response, it's an amazing going back and looking at what happened to think of what we achieved. There is so much more, so much more that we do not understand how one contributes to all of these profound responses in the organs themselves, such as myocarditis. We see it's important and that will be the problem that we're dealing from here on trying to figure it out and then long COVID, right?   Cindy St. Hilaire:         Yeah. Related to what you just said about the mechanism, this cleanup by the platelets or the act of cleaning up helps trigger their activation, is that partly why the antiplatelet and anticoagulant therapies failed in patients? Can you speculate on that? I know the jury's still out and there's a lot of work to be done, but is that part of why those therapies weren't beneficial?   Milka Koupenova:       The answer to that in my personally biased opinion is yes. Clearly, the antiplatelet therapies couldn't really control the classical activation of a platelet. So what I think we need to do from here on is to look at things that we don't understand that non-classically contribute to the thrombotic response downstream. If we manage to control the immune response in some way or the inflammation of the infection or how a platelet responds to a virus, then perhaps we can ameliorate a little bit of the downstream prothrombotic effect. So it's a lot more for us to trickle down and to understand in my personal opinion.   DeLisa Fairweather:    There is one thing that was really remarkable to me in hearing your experience, Milka, is that I had developed an autoimmune viral model of myocarditis in mice during my postdoc. So I've been studying that for the last 20 years. What is unique about that model is rather than using an adjuvant, we use a mild viral infection so it doesn't take very much virus at all going to the heart to induce it. I also, more recently, started studying extracellular vesicles really as a therapy, and in doing that, inadvertently found out that actually, the model that I'd created where we passage the virus through the heart to induce this autoimmune model, we were actually injecting extracellular vesicles into the mice and that's what was really driving the disease. This is really brought out. So from early days, I did my postdoc with Dr Noel Rose. If you've heard of him, he came up with the idea of autoimmune disease in the '50s. We had always, in that environment, really believed that viruses were triggering autoimmune disease and yet it took COVID before we could really prove that because no one could identify them. Here we have an example and I think the incidence rates with COVID were so high for myocarditis because for the first time, we had distinguished symptoms of patients going to the doctor right at the beginning of their infection having an actual test to examine the virus, knowing whether it's present or not, whether PCR or antibody test, and then being able to see when myocarditis happened.   Cindy St. Hilaire:         Yeah. I think one thing we can all appreciate now is just some of the basic biology we've learned on the backend of this. Actually, those last comments really led well to the article that your team led, Dr Chung, about what we call long COVID, which I guess I didn't realize has an actual name, post-acute sequelae of SARS-CoV-2 or PASC is the now more formal name for long COVID. But what is it? We hinted at it that there's these bits about autoimmune and things like that. What counts as long COVID?   Mina Chung:   Yeah. Our article was led by Tamanna Singh. She did a fantastic job of putting this together. We've had, and others, theorized that the huge palette of symptoms that you can experience post-COVID, they can affect all these organ systems with brain fog, these atypical chest pains, postural orthostatic tachycardia, a lot of palpitations, atrial fibrillation, many weakness and fatigue. To us, really, you can get GI symptoms. We've been very interested in, is this an autoimmune phenomenon directed against nerves and all those things. It's also very interesting because many of the non-COVID syndromes that existed pre-COVID like POTS and chronic fatigue syndrome and a lot of other syndromes are associated with autoantibodies. So that is a very interesting area to explore. Is there a persistence of viral fragments. Is there autoimmunity? Is it also a component of persistence of the damage from the initial infection? So it's an area that still needs a lot of work and a lot of work is going into it, but this is like a post or inter pandemic of itself, so hopefully we'll get more insights into that.   Cindy St. Hilaire:         Yeah, it's really interesting. I have a friend who has very debilitating long COVID and one of her doctors had said, "If I didn't know any better, I would just describe this as a autoimmune type X." What do we know, I guess, about the current hypothesis of the pathogenesis of PASC? Are there any prevailing theories right now as to why it's occurring? Is the virus still active or is it these domino effects that are leading to multi-organ collapse of some sort?   Mina Chung:   Yeah. In some people, persistent viral particles can be identified for months, but whether or not that's what's triggering it, it's hard to know. We see more autoimmune disease that's been reported and various antibodies being reported. So those are clearly processes to be investigated. The microthrombosis is still up there in terms of potentially playing a role in long COVID.   Milka Koupenova:       Mina, you probably know better because you see patients, but to all I have been exposed to, long COVID does not really have a homogeneous symptom presentation and then a few theories as to what may be going on in these patients. Not everybody has a microthrombosis. Not everybody have a D-dimer elevated, but some people do. Some people have, as you pointed out, these spectacularly profound brain fog. People can't function. It's probably your friend, Cindy, right?   Cindy St. Hilaire:         Yeah.   Milka Koupenova:       So one of the theories that I have been, from a viral perspective, very interested in is that a lot of the symptoms in certain individuals such as fatigue, brain fog, sensitivity to light and skin can very well be explained by a flare-up of Epstein-Barr virus that may be what SARS-CoV-2 somehow is inducing. I don't know, DeLisa, what your experience with long COVID is as a scientist. I hope only. But I would like to hear your perspective too because it's so heterogeneous and it is amazing what happens.   DeLisa Fairweather:    I have a very interesting perspective from a number of different directions. One, as I mentioned before, my long history with Dr Rose and I've written many articles theorizing how viruses could cause autoimmune disease. This has grown and really, I think this has been extremely revealing during COVID for many of those theories. One thing that I write about in the review for this article is that mast cells, from all the research I've done with myocarditis in our model, mast cells are central to what is driving everything. We show they're the first innate immune cell acting as an antigen-presenting cell, completely driving the response in a susceptible pattern. One of the things that's very important in autoimmune disease is both sex and race. I'd say one of the big weaknesses we have in myocarditis pre-COVID and post-COVID has been ignoring what's going on with race. In the United States, myocarditis is 90%, 95% white men that are under 50 years of age and most of the cases are under 40 or some of the ones really associated with sudden cardiac death are under 30. So it's very specific. I've been studying sex and race differences and we see those exact differences in our animal models. In animal models, whether you're susceptible or not depends on how many mast cells you have. Well, I've proposed from the beginning, looking, I've written a lot of different sex difference reviews looking at viruses and autoimmune disease with different autoimmune diseases and hypothesizing and really seeing that mast cells do a lot of the things we're talking about. They have all of the receptors, the whole group of them that have been related to SARS-CoV-2 so they can be activated or stimulated by the virus itself. They act as a antigen-presenting cell. They're critical in the complement pathway as well as macrophages. We see the dominant immune phenotype really being macrophages. Mast cells just are usually not counted anywhere. And of course, these receptors, a lot of them have to do with enzymes and things that are all related to mast cells pathways. Then how they activate the immune response and lead it towards the pathway that leads to chronic autoimmune disease with increased autoantibodies in females, mast cells are very different by sex. This has to do also when we talked in the Review about myocarditis and pericarditis. It's both those appearing. Although clinically, we have really boxed them as separate things, because there is some definite clinical pericarditis phenotypes that are different, myocarditis in animal models is always myopericarditis. It always then, in that outer pericardial areas where mast cells sit, they sit around the vascular area in most concentrated. So when they degranulate, we see inflammation coming in the vessel, but really concentrated with fibrosis there and along the pericardium. So that's very typical of what's going on. When we shift anything that shifts that, it changes whether you have more pericarditis or less pericarditis and the vascular inflammation by altering anything that affects the mast cells. I talk a little bit about in the review, I think there's only been a few recent things looking at it in COVID, but I think mast cells and certain susceptibility to autoimmune diseases that occur more often in women can really predispose.We need to pay more attention to mast cells and what they might indicate for all these pathways.   Milka Koupenova:       I think we should study the platelet mast cell access at this point.   DeLisa Fairweather:    Yes.   Milka Koupenova:       Because as you're talking about these sex differences, which is spectacular, these things to me are so mind-boggling how one, the infection itself would be more prevalent in men, but then long COVID is more prevalent in women. All of these things and why we understand so very little, what we found about a few years ago in the Framingham Heart Study in the platelets from those people is that all toll-like receptors are expressed at the higher level in women and they associate with different things between men and female. For instance, toll-like receptors in women will associate more with a prothrombotic response while in male with pro-inflammatory response. I think they grossly underestimate the amount of our sex differences from cell to cell.   DeLisa Fairweather:    It is, yeah.   Mina Chung:   One other thing that I learned about the sex differences from this compendium is Mark Chappell also notes, you mentioned TLR and TLR7 and ACE2 are X chromosome in an area that he says escapes X-linked inactivation. So it could very well be involved in further.   DeLisa Fairweather: Further, yeah. And ACE2 is expressed more highly in male cells for what's been researched because of the sex difference in COVID, both the COVID infection   Cindy St. Hilaire:         So a variety of organ systems are impacted in patients with PASC, also referred to as long COVID, the lungs, the heart, the pancreas, the GI system, pretty much any system, the brain, nervous system. We've just been talking about the mast cell impact. I was really thinking in my head, well, the one thing that connects all of it is the vasculature. I'm a vascular biologist, so I have certain biases, I'm sure, but how much of the sequelae that we see is a function of vascular phenotypes?       Milka Koupenova:       I do think the vasculature is super important. It's clear that not all endothelial cells, for instance, will pick up the virus and respond to it. That's why you have this patchy breakage when you look at autopsies. Hence, platelets will respond according to what's local. That's why you find these micro thrombotic events at certain places. Why does it happen in each organ? How does the virus get to each organ to respond? Or is it just inflammation, but why is it in specific places? That's what we don't understand. That's where we need to go. Perhaps, as DeLisa points out, perhaps it's a lot more complicated than how we traditionally think of thrombosis. Actually, my personal bias, again 100% sure that it is a lot more complicated than the traditional mechanisms that we have understood, and that's where the immune system comes and autoimmunity perhaps stems from and they probably speak to each other, right? It's not just one thing.   DeLisa Fairweather:    Yeah. I think really, EVs are bringing lots of understanding. A lot of things we used to just think were maybe free-floating and the serum are inside EVs. I think that the immune response is perhaps even more specific than we ever thought and more regulated than we ever understood.   When an EV comes through a cardiomyocyte, whether it's from the mitochondria or through a lysosome, is part of what goes into its outer membrane, something that tells the immune system that that came from the heart, so it knows to go. This will solve a lot of our questions with autoimmune disease if it's very specific like that. It doesn't just have to be the release of free-floating cardiac myosin. We know cardiac myosin is the driver of the autoimmune response in myocarditis, but they're probably  much more fine-tuned.   Cindy St. Hilaire:         Yeah. I just would love to end with hearing from each of you. You each have your own domain of specialty. If I gave you a massive pot of money, what would be the question you would want to tackle? What's the gap you would love to answer?   Milka Koupenova:       We still don't understand specifically what kind of vesicles are coming out, what are their contents in addition to those vesicles. We don't understand. When it comes to platelets, what comes from their granules? We see these breakages of the membrane. Those are non-granule proteins, and non-granule proteins, they serve as dangerous associated molecular pattern signals and can be profoundly inflammatory to the surrounding environment, can be procoagulant. What are those? How are they affecting the surrounding environment? Ultimately, why is there a microthrombi? Why is there not a profound thrombosis everywhere? Thank goodness there isn't, but why isn't? That's what I would do with my money.   DeLisa Fairweather:    I think I would do something very similar. All of our research in our animal model, on the one side, we are looking in this viral myocarditis animal model and finding the EVs that come from that are driving myocarditis. On the other hand, we're using EVs that come from healthy human plasma or fat, and we're seeing a profound downregulation of everything if you give it early and we're trying to see how late you can give it and still get an effect. So looking at those and really understanding the components in the context of COVID and COVID vaccines to understand those components, I really think that's the future of where we're going to find what's causing disease and also how we can find therapies. They may be able to reverse this.   Mina Chung:   Yeah, I'm interested very much in the autoimmunity and the autoantibodies that are    and how they may react with those microthrombi. Perhaps there's autoantibodies within a lot of that material. We're looking at using human and pluripotent stem cell-derived cell models to study the effects of those. That is what I would use our money for.   Cindy St. Hilaire:        Well, Dr Mina Chung, Dr DeLisa Fairweather, Dr Milka Koupenova, thank you all so much for joining me today and talking about not only the articles that you wrote and with your colleagues, but also other articles in this amazing compendium. I do think this is one of the first all-encompassing compendiums or group of articles that focus specifically on COVID and cardiovascular disease. So thank you all so much.   Mina Chung:   Thank you.   DeLisa Fairweather:    Thank you.   Milka Koupenova:       You're welcome.   Cindy St. Hilaire:         That's it for highlights from the April 28th and May 12th issues of Circulation Research. Thank you for listening. Please check out the CircRes Facebook page and follow us on Twitter and Instagram with the handle @circres and #DiscoverCircRes. Thank you to our guests, Dr Mina Chung, Dr DeLisa Fairweather and Dr Milka Koupenova. This podcast is produced by Ishara Ratnayaka, edited by Melissa Stoner and supported by the editorial team of Circulation Research. Some of the copy text for the highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, your on-the-go source for the most exciting discoveries in basic cardiovascular research. 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 information, visit ahajournals.org.