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Circulation on the Run

Aug 3, 2020

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: And I'm Dr Greg Hundley from VCU Health, the Pauley Heart Center in Richmond, Virginia.

Dr Carolyn Lam: Our feature paper today is very important and pertinent to the times, talking about the multi-system inflammatory syndrome in children in our current global SARS coronavirus 2 pandemic. Really, really important stuff, but you have to hold on, listen with us to this summary which is full of really exciting papers. You know what, Greg? I'm going to start. So what do you know about the rostral medial prefrontal cortex of our brains?

Dr Greg Hundley: Well, let's see. I wonder if it has anything to do with emotion or stress maybe?

Dr Carolyn Lam: Oh, you're too smart. Either that or that coffee is loaded. Very good answer. The rostral medial prefrontal cortex is an important brain region that processes stress and regulates immune and autonomic functions. Now, since psychological stress is a risk factor for major adverse cardiovascular events in individuals with coronary artery disease, our authors today, Dr Shah and colleagues from Rollins School of Public Health, Emory University, hypothesize that changes in the rostral medial prefrontal cortex activity with emotional stress may be informative for future risk of MACE or major adverse cardiovascular events. They examined 148 participants with stable coronary artery disease who underwent acute mental stress testing using a series of standardized speech or arithmetic stressors and simultaneous brain imaging with high resolution positron emission tomography brain imaging. They defined high rostral medial prefrontal cortex activation as a difference between stress and control scans greater than the median value for the entire cohort. They also measured interleukin-6 levels 90 minutes post stress and high frequency heart rate variability during stress.

Dr Greg Hundley: Wow, Carolyn, what an intriguing article correlating the imaging findings with stress and systemic inflammation. What did they find?

Dr Carolyn Lam: So they found that higher roster medial prefrontal cortex activity with mental stress was independently associated with higher risk of major adverse cardiovascular events. Immune and autonomic responses to mental stress contributed to the increased of adverse events among those with the higher stress reactivity. Stress-induced activation may therefore represent a new method of risk stratification of individuals with coronary artery disease.

Dr Greg Hundley: Very nice. That really ties a lot together. Makes a lot of sense, Carolyn. Well, my first paper is from Dr Patrick Ellinor from Massachusetts General Hospital and the Harvard Medical School, but first Carolyn a quiz. So here's the background to the quiz. I'm going to talk about the heart myocytes versus the fibroblast versus the microcirculatory cells. So within each of those groups, Carolyn, this is a way or no way, are all the cell types the same?

Dr Carolyn Lam: Well, at embryonic stage maybe? All right, I'll be superficial about it. No way, they're different.

Dr Greg Hundley: Very good, Carolyn. These authors applied recent advances in low input RNA sequencing that allowed definitions of cellular transcriptome to assess the cellular and transcriptional diversity of the non-failing human heart.

Dr Carolyn Lam: Wow. What did they find?

Dr Greg Hundley: Carolyn, the author sequences the transcriptomes of 287,269 single cardiac nuclei, revealing a total of nine major cell types and 20 subclusters of cell types within the human heart. Cellular subclasses included two distinct groups of resident macrophages, four endothelial subtypes, and two fibroblast subsets. Comparisons of cellular transcriptomes by cardiac chamber or sex reveal diversity not only in cardiomyocyte transcriptional programs, but also in subtypes involved in the extracellular matrix remodeling and vascularization. Using genetic association data, the authors identified strong enrichment for the role of cell subtypes in cardiac traits and diseases. Therefore, Carolyn, the authors' identification of discrete cell subtypes and differentially expressed genes within the heart will ultimately facilitate the development of new therapeutics for cardiovascular diseases.

Dr Carolyn Lam: Okay, I have to admit that's a lot more diversity than I anticipated. Very cool, Greg. Ha, I got a question for you. What do you think of abdominal aortic aneurysms and Niemann-Pick disease have in common?

Dr Greg Hundley: I definitely need phone a friend.

Dr Carolyn Lam: Here, let me tell you about it. The link is in transcription factor EB. Now what is transcription factor EB? It's a master regulator of lysosome biogenesis that has beneficial effects on lysosomal storage diseases. Now, Dr Fan from University of Cincinnati College of Medicine and Dr Chen from University of Michigan Medical Center are co-corresponding authors of this paper and they and their coauthors found that transcription factor EB expression was reduced in human aneurysms. Vascular smooth muscle cells selective knockout promoted abdominal aortic aneurysm development via induction of vascular smooth muscle cell apoptosis in mice. In addition, they found that 2-hydroxypropyl beta cyclodextrin, which is an FDA approved cyclodextrin derivative currently used to increase the solubility of drugs and under phase two clinical trial to treat Niemann-Pick disease type C1. So they found that this compound activates transcription factor EB and inhibits abdominal aortic aneurysm in multiple mouse models. So these findings intriguingly demonstrate the potential use of transcription factor EB activators to treat abdominal aortic aneurysms.

Dr Greg Hundley: I don't think I would've gotten that quiz right for sure. My next paper is from Professor Marco Valgimigli from the University of Bern. It's entitled "Cangrelor Tirofiban and Chewed or Standard Prasugrel Regimens in Patients with ST Segment Elevation Myocardial Infarction". These are the primary results of the Fabulous Faster trial. Since the standard administration of newer oral P2Y12 inhibitors, including Prasugrel or Ticagrelor provides suboptimal early inhibition of platelet aggregation in ST segment elevation myocardial infarction patients undergoing primary PCI. These authors sought to investigate the effects of Cangrelor, Tirofiban, and Prasugrel administered as chewed or integral loading dose on inhibition of platelet aggregation in patients undergoing primary PCI.

Dr Carolyn Lam: Ah. So what was the design of this study and who did they enroll, Greg?

Dr Greg Hundley: Carolyn, a total of 122 P2Y12 naive ST elevation myocardial infarction patients were randomly allocated one to one to one to Cangrelor, 40 subjects, Tirofiban, 40 subjects, both administered as bolus and two hour infusion followed by 60 milligrams of Prasugrel or 60 milligram loading dose of Prasugrel, 42. The latter group underwent an immediate one-to-one some randomization to chewed, so 21 subjects there, or integral, 21 subjects there, tablets administration. The trial was powered to test three hypotheses: non-inferiority of Cangrelor compared with Tirofiban using a noninferiority margin of 9%. Second, superiority of both Tirofiban and Cangrelor compared with chewed Prasugrel. And finally, superiority of chewed Prasugrel as compared with integral Prasugrel, each with an alpha of 0.016 for the primary end point that was 30 minute inhibition of platelet aggregation at light transmittance aggregometry in response to 20 micromoles per liter of adenosine diphosphate.

Dr Carolyn Lam: Wow. A comprehensive study. Okay, so what did they find?

Dr Greg Hundley: Well, Carolyn. Cangrelor proved inferior on inhibition of platelet aggregation compared with Tirofiban. Next, both treatments yielded greater on inhibition of platelet aggregation compared with chewed Prasugrel which led to higher active metabolite concentration, but not greater inhibition of platelet aggregation compared with integral Prasugrel. Therefore, Carolyn, Tirofiban by exerting more potent and consistent innovation of platelet aggregation may be more effective than Cangrelor in reducing the risk of acute ischemic complications. Now, all of these results need to be further ascertain in the context of studies powered for clinical end points.

Dr Carolyn Lam: Thanks, Greg. All right, well, let's sum up what else is in this issue. I've got few papers really related to COVID-19. First as a perspective by Dr Oudit on ACE2: A Double-Edged Sword. Then we have an On My Mind paper by Dr Kevin Shah titled Tissue is the Issue, Even During a Pandemic. We have a research letter by Dr Adusumalli on Telemedicine Outpatient Cardiovascular Care During the COVID-19 Pandemic, is this bridging or opening the digital divide? And finally, another research letter by Dr Priori on the association of hydroxychloroquine with QT interval in patients with COVID-19.

Dr Greg Hundley: Very good, Carolyn. Well, I've got a couple extra papers as well. The first is an exchange of letters between Dr Ji-jin Zhu and our own Dr James de Lemos regarding the article Racial Differences in Malignant Left Ventricular Hypertrophy and Incidence of Heart Failure: A Multicohort Study. Also, Dr Daniel Schimmel has a case series entitled Not for the Faint of Heart: A Rapidly Evolving Case of Syncope During Pregnancy. And then finally, Dr Michael Sayre has a research letter focusing on the prevalence of COVID-19 in out of hospital cardiac arrest, implications for bystander CPR.

Dr Carolyn Lam: Nice Greg. Well, let's hop on to the feature discussion, shall we?

Dr Greg Hundley: You bet.

Dr Carolyn Lam: We've been hearing a lot about the COVID-19 pandemic and its effects in adults, but today's feature paper deals with the so important and topical issue of the multi-system inflammatory syndrome in children in the context of this COVID-19 pandemic. I am so pleased to have with us the corresponding author of today's feature paper, Dr Damien Bonnet from the Necker Sick Children's, University of Paris, as well as our associate editor, Dr Gerald Greil from UT Southwestern. Damien, thank you so much for this very, very important study. Everyone's been looking for data, and I truly think yours are just the definitive ones that we have now, but please tell us a bit about the study and what you found.

Dr Damien Bonnet: In Paris, we have been alerted by an increase of admission of children with acute heart failure in context of long-lasting fever with different organ involvement. So we started in mid-April to signal to our health authorities that there was an emerging entity. Since then we have seen these rare entity about 100 of times in various areas. So it's so rare entity because there are 3 million children living in my area. And this syndrome is composed of different signs. The first one is a high fever lasting for more than three days, gastrointestinal or digestive symptoms, sometimes skin anomalies, heart arrhythmia, and of course heart failure with sometimes shock.

So this syndrome has some similarities with a known other syndrome that is Kawasaki disease that we all know in pediatric cardiology. And we will discuss that later, I think. It's certainly a different entity. So we started to treat them as if they were Kawasaki-like disease with immune blood splints and the majority of them improved rapidly with this type of treatment. And while some of them were on ECMO at baseline or in severe condition, they all improved. And fortunately in my institution did not have any dead. So that's the summary of what we have submitted to circulation.

Dr Carolyn Lam: Thank you so much, Gerald, could you help frame for us once again how important this study is, and this condition is to recognize? And then I know you've got some questions for Damien too.

Dr Gerald Greil: Thank you so much, Damien, for submitting your work to circulation and the reason why we all thought it's particularly important because you guys in Europe got the first rife. In the United States, North America, South America, kind of getting confronted with all these patients. And we are all very keen to learn from you. And obviously one of the first things when we get confronted with these patients now is how are we going to treat them? You mentioned IVIG as a possibility, I'm sure you have other options or experiences. Can you explain what is your evidence and how did you choose current treatment strategies?

Dr Damien Bonnet: I think that at baseline, we used the IVIG because these patients resemble those with Kawasaki disease shock. Certainly today there has been different reports and the spectrum of clinical signs and biological anomalies in this syndrome differ from that of Kawasaki. But still the treatment with anti-inflammatory agents, IVIG, or other agents has the objective to accelerate recovery and potentially to prevent cardiac injury in Kawasaki disease.

We have not demonstrated that in the present entity. So there is today, I think no evidence to say that IVIG should be given to all patients with this disease. But certainly treating the severe inflammation as an impact in cardiac function.

Dr Gerald Greil: We were kind of reminded when you saw these patients of Kawasaki disease, which is probably every pediatrician, pediatric cardiologist has a similar idea when you see these patients. Is it Kawasaki disease? Is it not?

Dr Damien Bonnet: I think that we have to balance the answer. There are some clinical signs that are shared between the multisystem inflammatory syndrome and Kawasaki disease. The continuous signs, the lymphadenopathies with fever, but the inflammation is much more intense in this entity and the other aspect is Kawasaki disease mainly involves arteries, as in arthritis. And this syndrome is mainly affecting the mitochondria. That's what, at least what we see today. What we don't have is the late outcome.

But today, at least in the patient that we have seen in Paris, we have not seen a high prevalence of coronary artery involvement, both at initial phase and later on. I think that the mechanism, the exaggerated inflammation, and the deleterious effect on myocardium of this inflammatory storm, has similarities with that of Kawasaki disease.

Dr Gerald Greil: So since you've got a lot of experience, can you just summarize for us, how do you treat these patients once they come into your hospital? So we have a little bit of a guideline, but the current state of the arts.

Dr Damien Bonnet: The paper that we are discussing today does not include all categories of patients with this syndrome. We included in this paper only patients who were admitted for acute heart failure, but today we have seen children with less severe disease. So when we admit them in Paris, we systematically dose BNP or anticrobian B depending on the institution.

And if it is abnormal, we check the echo. And if the echo is abnormal, we will treat all of them with IVIG. That's the treatment that we do. If they are in shock, we associate IVIG and steroids. Today, I cannot say that it is a precise guideline two fold. It’s just our experience and we have not observed any fatalities. And the older patients recovered quite rapidly, let's say within a week for the majority of them.

Dr Gerald Greil: So what do you think are the next steps? I mean, we collected from different institutions around the world their experience with this kind of type of disease. It seems to become more prevalent. What do you think is the next step for us as physicians in the scientific community?

Dr Damien Bonnet: And that there are clinical issues. So the first one is to see or to look at potential cardiac residual anomalies, mitochondrial or coronary arteries aneurism, because today we have not precise information of that.

The second is probably observational because it will be difficult to randomize young children, is what is the optimal treatment at baseline or what is the optimal strategy? And is it possible to stratify the strategy as I just said, but I don't have evidence for that. And for the long term, I think that trying to identify why only some children have this disease and why the other don't have, if there is any genetic susceptibility, it will be something interesting. And potentially as we discussed already together, it might give us some keys to better understand Kawasaki disease as well.

Dr Gerald Greil: Thank you so much for summarizing that. I mean, we are all very much looking forward to working together with you and other groups around the world to get a little bit more and better insight in this kind of type of disease and how to treat them best and how to follow them up best.

Dr Carolyn Lam: Thank you so much, Damien and Gerald. I mean, I'm sure I speak behalf of the entire audience that I learned a lot just listening to your very open and honest conversation of what we've seen, what we've experienced, what we don't yet know. Listeners, you have to refer to a beautiful accompanying editorial that Gerald invited, and it is by Dr John Simpson and Dr Jane Newburger from Evalina London Children's Hospital and Harvard Medical School, respectively.

Thank you so much for joining us today. And please remember, you've been listening to Circulation on the Run. Tune in again next week.

Dr Greg Hundley: This program is copyright the American Heart Association, 2020.