Circulation August 4, 2020 Issue

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.