Circulation January 5, 2021 Issue

New in 2021, we will feature 2 Feature Discussions every other
week. For this week, we start with author Michael Gold and
editorialist Sana Al-Khatib as they discuss the article "Primary
Results from the Understanding Outcomes with the S-ICD in Primary
Prevention Patients with Low Ejection Fraction (UNTOUCHED)
Trial." Then, we switch to an important discussion about children
and COVID-19 as author Israel Valverde and Associate Editor
Gerald Greil discuss "Acute Cardiovascular Manifestations in 286
Children with Multisystem Inflammatory Syndrome Associated with
COVID-19 Infection in Europe."


TRANSCRIPT BELOW:


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.


Greg Hundley:


And I'm Greg Hundley, director of the Pauley Heart Center at VCU
Health in Richmond, Virginia. Well, Carolyn, we have two features
in this issue.


Dr. Carolyn Lam:


I know.


Greg Hundley:


Yeah. And I've got the first one. It's going to be evaluating the
acute cardiovascular manifestations in 286 children with
multi-system inflammatory syndrome.


Dr. Carolyn Lam:


Wow. That is so important in the current pandemic. Well, the
other is also so important. It's really, really critical results
from the subcutaneous ICD trial called UNTOUCHED. I think that
one might change clinical practice. So, do you want to tell us
about other papers first?


Greg Hundley:


Yes. Carolyn, I'm going to grab my cup of coffee and we'll get
started and my first paper comes from China. Professor Junbo Ge.
So Carolyn PCSK9, mainly secreted by the liver and released into
the blood elevates plasma load density lipoprotein cholesterol by
degrading LDL receptors. Pleiotropic effects of PCSK9 beyond
lipid metabolism have been shown. However, the direct effects of
PCSK9 on platelet activation and thrombosis, as well as the
underlying mechanisms still remain unclear.


Greg Hundley:


So this group detected the direct effects of PCSK9 on
agonist-induced platelet aggregation, dense granule ATP release,
integrin a2b beta-3 activation, alpha granule release, spreading
and clot retraction. They also investigated the underlying
mechanisms. Using myocardial infarct models, they explored the
effects of PCSK9 on microvascular obstruction and infarct
expansion, post myocardial infarction.


Dr. Carolyn Lam:


Oh, nice. And what did they find?


Greg Hundley:


Well, Carolyn, PCSK9 in plasma directly enhances platelet
activation and in vivo thrombosis, as well as myocardial infarct
expansion post MI by binding to platelet CD36 and thus activating
the downstream signaling pathways. PCSK9 inhibitors, or aspirin,
abolished the enhancing effects of PCSK9 supporting the use of
aspirin in patients with high plasma PCSK9 levels in addition to
PCSK9 inhibitors to prevent thrombotic complications.


Dr. Carolyn Lam:


Wow. Very interesting. Indeed, the pleiotropic effects. Well
guess what? My paper talks about the first non-LDL lowering
treatment that has been shown to reduce CABG in a blinded
randomized trial. Greg, can you guess what that treatment was?
Well, here's a hint, here's a hint. It's the REDUCE-IT trial.


Greg Hundley:


Well, Carolyn, thanks for the hint. It must be icosapent ethyl.


Dr. Carolyn Lam:


Indeed, indeed. As a reminder, REDUCE-IT was a multicenter
double-blind placebo controlled trial, which randomized statin
treated patients with elevated triglycerides, controlled LDL and
either established cardiovascular disease or diabetes plus other
risk factors to receive icosapent ethyl at four grams daily or
placebo. The primary and secondary composite end points were
significantly reduced. The current paper examined all coronary
revascularizations, recurrent revascularizations and
revascularization subtypes. First revascularizations were reduced
by icosapent ethyl versus placebo with a hazard ratio of 0.66,
which is a number needed to treat of only 24. Similar reductions
were observed in total revascularizations and across elective,
urgent and emergent revascularizations. Icosapent ethyl
significantly reduced PCI and CABG with a hazard ratio of 0.61.
So, icosapent ethyl reduce first and total coronary
revascularization, including PCI and CABG in patients with
elevated triglycerides and high cardiovascular risk despite well
controlled LDL. Isn't that cool?


Greg Hundley:


Very nice Carolyn. Well, my next paper comes from Professor Kari
Alitalo, from the University of Helsinki. So Carolyn recent
discoveries have indicated that in the developing heart, sinus
venosus and endocardium provide major sources of endothelium for
coronary vessel growth that supports the expanding myocardium.
The author set out to study the origin of the coronary vessels
that develop in response to vascular endothelial growth factor B
or VEGF-B in the heart and the effect of VEGF-B on recovery from
myocardial infarction.


Dr. Carolyn Lam:


So what were their results?


Greg Hundley:


Well Carolyn, the myocardial VEGF-B trans-gene promotes the
formation of endocardium-derived coronary vessels during
development, endothelial proliferation in sub-endocardial
myocardium in adult mice and structural and functional rescue of
cardiac tissue after myocardial infarction. So VEGF-B could
provide a new therapeutic strategy for cardiac neovascularization
after coronary occlusion to rescue the most vulnerable myocardial
tissue. Well, Carolyn that's all of the main articles. How about
we turn to some of the other articles and letters in the issue?


Dr. Carolyn Lam:


Yeah. Why not? And Greg, let me start by talking about an
exchange of letters between Dr. Wei and Dr. Fox on interpreting
the net clinical benefit from rivaroxaban plus aspirin versus
aspirin for chronic vascular disease. There's also an ECG
challenge by Dr. Patel elusively entitled, A Rainy Day. Here's a
hint, it's about hypothermia. In cardiology news by Bridget Kuhn.
She talks about how the pandemic throws cardiovascular trials off
course, there is an On My Mind paper by Dr. Most entitled, The
Striking Similarities of Multi-system Inflammatory Syndrome in
Children and a Myocarditis-like Syndrome in Adults: The
overlapping manifestations of COVID-19. As a couple of Research
Letters, one by Dr. Malhotra on Defining the Normal Spectrum of
Electrocardiographic and Left Ventricular Adaptations in Mixed
Race, Male, Adolescent Soccer Players, as well as by Dr. Qi on
adherence to a healthy sleep pattern and incident heart failure,
a prospective study of more than 400,000 UK Biobank participants.


Dr. Greg Hundley:


Very nice Carolyn. Well, I've got a primmer review of Cardiac
Involvement in Multi-system Inflammatory Syndrome in Children
with the corresponding author being Dr. Kevin Freedman. Well, how
about we get off quickly to those next two feature discussions?


Dr. Carolyn Lam:


Yay! Let's go, Greg.


Dr. Greg Hundley:


Well, listeners, we are to the first of our double feature for
the new year 2021. And with me is Israel Valverde from King's
College in London and our own associate editor, Dr. Gerald Greil
from UT Southwestern in Dallas. Welcome gentlemen. And as we get
started Israel, could you tell us a little bit about the
background that framed this study and the hypothesis that you
wanted to address?


Dr. Israel Valverde:


Thank you. I mean, the main problem we had in Europe around April
2020, was that both the Center for Disease Control and Prevention
in the U.S. simulated a clinical ALIT about a newly described
immune disease and inflammatory syndrome in children associated
with a COVID infection. And there were similarities with all the
well-known syndromes, such as viral myocarditis, Kawasaki
disease, Kawasaki shock syndrome, and toxic shock syndrome, that
we were a bit of confused, because of the overlap in clinical
presentation, because it was a true diagnostics challenge. So the
hypothesis in this study is we wanted to describe the
cardiovascular implications in this newly described sinus
syndrome.


Dr. Greg Hundley:


Very nice. So tell us a little bit about your study design and
what study population did you assemble to address this question?


Dr. Israel Valverde:


I think that was the most difficult thing in the study, because
thanks to the Association For European Pediatric Cardiology, the
APC, we coordinated a multicenter study involving all they would
appear on centers that we were 55 centers from 17 countries all
over Europe. And we were able to recruit 286 children with this
new newly described syndrome and cardiovascular manifestations.


Dr. Greg Hundley:


And tell us, what did you find?


Dr. Israel Valverde:


I think we can summarize that in three main findings. First is
that cardiac involvement is very common in children with
multi-system inflammatory syndrome associated with coronavirus
disease, 2019 infection. Second, that inflammatory markers were
significantly raised in most children, particularly their
C-reactive protein, ferritin, pro-calcitonin, N-terminal pro BNP
natriuretic peptide, interleukin 6, and D-dimer level. And
finally, that 65% of patient with MIS-C had evidence of previous
infection with severe acute respiratory syndrome coronavirus too,
either by PCR, immunoglobulin M or immunoglobulin G.


Dr. Greg Hundley:


Were there any particular aspects of your results that may have
segregated to the boys versus the girls?


Dr. Israel Valverde:


Not really. We couldn't find any differences between boys and
girls, because our study population was quite similar, but we
couldn't find any differences between them. What we found is that
there is a huge difference between children and adults.


Dr. Greg Hundley:


And what was the age range of these children?


Dr. Israel Valverde:


From a couple of weeks, until 18 years old.


Dr. Greg Hundley:


And no differences in the scope of the syndrome that they
experienced in the younger children versus the-


Dr. Israel Valverde:


Initially we found two peaks. Similarly to the peaks of viral
myocarditises, which is affecting more of the children below two
years, and also adolescence.


Dr. Greg Hundley:


Well Gerald, multi-system inflammatory syndrome in children. How
to results from this study compare with perhaps other
inflammatory disease processes that have been observed in
children, such as Kawasaki disease, et cetera.


Dr. Gerald Greil:


So we and Circulation were very lucky to get a bunch of
submissions regarding a MIS-C and also have a radio article
regarding this and I would like to point our readers towards
that. I think the key issue is it's a new disease entity. The
community is pretty clear about it, that other diseases like
Kawasaki disease have similarities, but it's not the same thing.
And we wanted to be very clear about this. Obviously, more things
need to be investigated, but the key findings where Dr. Valverde
pointed out in other study groups within the U.S. and within
Europe, all point to the same direction, that is a new entity, we
need to further investigate.


Dr. Greg Hundley:


How about the cardiovascular aspects, what differences in
cardiovascular disease with this syndrome, again, relative to
other perhaps inflammatory diseases that might affect the heart
in children?


Dr. Gerald Greil:


As far as we know. And once again, when we're talking about a
very preliminary data, is that the outcome in children having
MIS-C usually good. Dr. Valverde pointed out in his study series
of more of 286 children, there was only one death and recovery
was pretty high rate. We have similar findings from U.S. groups,
other findings from a group in Paris and Europe. So, I would like
to point our readers to other summaries where it's pretty clear
that it's a new disease entity. Overall, it's actually rare in
children. So we want to make a pretty clear point that it's a
rare disease, which at this point in time seems to have a good
outcome.


Dr. Greg Hundley:


Well Israel, I'm going to come back to you. What do you see is
the next study that should be performed perhaps in this general
area of cardiovascular disease for children?


Dr. Israel Valverde:


So I think what we have learned is that the way to move forward
is the collaboration between centers. So now that we have a large
study multicenter group, our idea is continue describing the
long-term outcomes of the study population, because most of them
recovered, but a few of them keep, for example, coronary artery
dilatation. So do they recovering when you have time until you
have time, do they do the ejection fraction, the function of the
heart go back to normality soon? Or do we have to wait? So I
think that's the next step forward to probably the long-term
outcome of the study population.


Dr. Greg Hundley:


Longitudinal follow-up. And Gerald, do you have anything to add
to that?


Dr. Gerald Greil:


I would just like to reiterate what Israel said, that we need to
focus on multicenter studies. I hope Circulation can be a
platform to reunite different groups around the world. Because as
I mentioned before, I think we have a new disease entity in front
of us. We don't know the long-term outcomes. And in the interest
of our children confronted with new disease, we need to be very,
very careful to learn how we need to follow up these children and
how we potentially need to treat them in the long-term.


Dr. Greg Hundley:


Well, listeners, this has been a fantastic discussion with Dr.
Israel Valverde from King's College in London and our own Dr.
Gerald Greil from UT Southwestern, revealing some aspects of this
multi-system inflammatory syndrome that's associated with
COVID-19 in children. And so, on behalf of Carolyn and myself,
well, we've got to get to the next feature. So, I'm not going to
let you go just yet. Well, listeners, we are in the double
feature year 2021. In our second feature discussion today, we
have Dr. Michael Gold from Medical University of South Carolina
and our own associate editor, Dr. Sana Al-Khatib, who has written
an editorial on this paper. And she is from Duke University.
Welcome to you both. Michael, we'll start with you. Could you
describe for us a little bit about the background related to this
paper and what hypothesis did you want to address?


Dr. Michael Gold:


Well, thank you. And thank you for this opportunity. The
implantable defibrillator is a fundamental aspect of the
treatment and prevention of sudden cardiac death. It's been
around for almost 40 years now and is commonly used in the system
has evolved from being a surgical procedure, requiring a
thoracotomy to a transvenous procedure in which leads could be
placed into the heart. While it's very effective, the major
limitation of this in many people's minds were, major limitations
were both of complications associated with the transvenous lead.
Those include infections and lead failures, as well as
unnecessary or inappropriate shock to patients. And based on
that, the subcutaneous ICD was developed as the latest iteration
of this technology in which a lead is placed under the skin and
tunneled up along the sternum, so that one could sense and shock
the heart when necessary without being subjected to an
intravascular lead.


Dr. Michael Gold:


And the device has been around for 10 years or so. It's proven to
be effective, but primarily used in niche populations of younger
patients, patients with poor vascular access and those considered
at relatively low risk with few comorbidities, such as patients
with Brugada syndrome or long QT syndrome or possibly
hypertrophic cardiomyopathy. We felt it was important both to
establish the role of the subcutaneous ICD in a more typical
group of defibrillator patients, as well as with the multiple
evolutions now of programming, as well as technology within the
device of seeing if the more modern contemporary devices were as
effective in these sicker populations, and also could reduce some
of the issues seen earlier in terms of higher rates of
inappropriate shock therapy.


Dr. Greg Hundley:


So Michael we're working with subcutaneous ICDs. What was your
study population and how did you design this study to really test
the efficacy of the subcutaneous ICDs relative to the more
conventional transvenous lead systems in these high-risk
patients?


Dr. Michael Gold:


So what we did was to first identify a population and the most
common population price of the implantation in the United States
have for sure, in many of the countries is primary prevention
patients and low ejection fraction. So we restricted the study to
patients with an ejection fraction less than 35% and primary
prevention, meaning have never had an episode of sustained
ventricular tachycardia or cardiac arrest. So starting with that
population, this was a prospective large registry. The bandwidth
was out there to do a very large randomized trial, which was just
done, although not as in a sicker patient population that study
called PRAETORIAN was going on simultaneously. And what we
decided was to be aggressive if you will. And we defined our
endpoints for the study by looking at identified studies
previously with transvenous ICDs that have the most contemporary
programming and the lowest risk of inappropriate shock.


Dr. Michael Gold:


So we used the MADEIT-RIT study, which most people probably would
consider it to be the ultimate, if not one of the two
contemporary studies for that. And we wanted to essentially
compare head-to-head results with that, obviously without those
specific patients, but using that as in some ways a historical
control or benchmark. So, we set what we wanted to use as our
performance goal based on the MADEIT-RNT study for inappropriate
shocks, as well as looked at complication rates, using
performance goals that have been well-established by the FDA. And
we use an 18-month time window, because that's a time when most
inappropriate shocks as well as most complications will show up
with this device.


Dr. Greg Hundley:


So what did you find?


Dr. Michael Gold:


So, what we found was first that we accomplished the goal of
having patients who were had much more comorbidities or sicker,
if you will. A majority of patients of the over 1,000 patients in
the study had ischemic heart disease. I mean, ejection fraction,
it was down 26%. In perspective, the early studies of the S-ICD,
I mean, ejection fractions are 40% higher, almost 90% of patients
have heart failure rather than a third of patients in previous
studies and the incidents of diabetes, kidney disease,
hypertension and other things with two to three times higher than
what would have been done or shown in any early registries of the
S-ICD. So we're very pleased about that. Again, there were over
1,100 patients in this study. And what we showed was that at 18
months, the inappropriate shock rate for the whole population was
only 4%, hopefully 2.7% annually, which is quite low compared to
any other S-ICD study and was very favorably compared with the
MADEIT-RIT study easily met the performance goal for that.


Dr. Michael Gold:


And if we looked at that subgroup of patients who had generation
three of the most modern of the S-ICD devices that have a newer
discrimination algorithm, that number even became lower than
that. So again, very, very reassuring to see what we found there
and for the generation three device, it was only 2.9% of patients
in 18 months had any inappropriate shock for that. And if we then
looked at the other aspects of it, the all shock rate for
appropriate and inappropriate shock was only 10% of 18 months,
which meant the performance goal for that as well. And what's
important about the all shock rate is that it's nice to show that
the device can defibrillate a patient in the lab when you're
testing them. And this was successful in 98, 99% of the time,
which is typical for transvenous or subcutaneous devices. But
when we looked at spontaneous arrhythmic events, it was highly
effective, 100% of VT storms, and all but one case of a VTVF
episode was converted with defibrillator, that one case actually
spontaneously converted, but was officially listed as a failure,
because it didn't convert right away.


Dr. Michael Gold:


But no patients had a cardiac due to ventricular fibrillation
that could not be successfully treated or ended up requiring
external defibrillation. And finally, despite a much sicker
population, again, if you will, we showed that at 18 months, the
overall complication rate from the device was only about 7% in
total, which again is very low compared to what we'd expect to
see with other devices. And no patient developed a bloodborne
infection or a true lead failure, which is one of the major
complications that, and dreaded complications of transvenous
devices.


Dr. Greg Hundley:


Well, Sana as our editorialist, what stood out to you as being
really important findings in this study?


Dr. Sana Al-Khatib:


First of all, I want to start by congratulating Michael and his
team on the completion of this important study. And I agree that
this has been a really important addition to the armamentarium of
studies related to subQ-ICDs. We have had registries in the past.
In fact, Michael alluded to the publication of the PRAETORIAN
trial, which was really the first trial to compare the S-ICD with
the transvenous ICD in a randomized control trial design.
However, despite the important contributions of the PRAETORIAN
trial, there were several things that remain unaddressed or
unanswered in terms of the rate of the end points, especially in
appropriate shocks with the newer S-ICD models. So where we had
an abundance of those in the UNTOUCHED study, and then really the
important question of do the results of that trial, which was
largely not done in the United States, apply to the average
patient, seen in the United States.


Dr. Sana Al-Khatib:


And then could those results be extrapolated to sicker patients,
because as Michael very nicely highlighted that those patients
were not as sick as patients that we see in routine clinical
practice. So from my perspective, those are the findings of the
UNTOUCHED study are really important, because we now have
confirmation that the S-ICD is actually effective and safe in a
patient population representative of the average patient seen in
clinical practice in the U.S. with a primary prevention
indication for the ICD, no really sicker patients, good
representation of women, black patients. So overall, I think this
trial really gives me a reassurance that the subcutaneous ICD is
safe and effective, that the rate of inappropriate shocks with
the newer generation of ICDs is really low. That said, I just
wanted to highlight a couple of points that I'm hoping to see
more data on as we go forward.


Dr. Sana Al-Khatib:


The study was only 18 months long. It would be good really to
have a longer studies. Again, the average age of patients
enrolled in the trial was on the younger side in the 50s, and I
would love really to see more data on the S-ICD in older
patients. And also as Michael said that these results were
obtained in patients who had a primary prevention indication for
the ICD on the basis of systolic heart failure. Well, we have
other patient populations. And especially with, for example,
patients with hypertrophic cardiomyopathy, where the rate of
inappropriate shocks might be higher, and it would be great to
see even more data as we go forward on that patient population
and other subgroups of patients that were not included or not
well-represented in the trial, but overall a really important
trial.


Dr. Greg Hundley:


Very nice Sana. And Michael, just swinging back to you, what do
you think are some of the next studies that might be performed in
this space?


Dr. Michael Gold:


No, I think that Sana made some nice points. I should point out
that, in its, I think appropriate vision, the FDA require as
long-term evaluation of devices and studies. So the S-ICD
post-approval study, which I'm fortunate enough to be involved
with as well, is a five-year followup study. We've already
published a little bit on two and three-year data, but we will
have five-year data on this device in a patient that is closer to
the S-ICD than the early registries. It was not restricted to
just low EF patients, but it was a U.S.-only study of over 1,500
patients. So, a larger study that has the typical distribution of
patients that we see in a U.S. practice who would be eligible for
the S-ICD, those without pacing indications and both primary and
secondary prevention patients. So I think that will be very
important.


Dr. Michael Gold:


Where the technology is going is largely, there will still be
iterations of longer battery life, smaller devices and those
things, but there's been a real push to be able to also provide
pacing therapy without the need for intravenous leads. So there
are several models and systems approaches being used, including
adding a lead-less pacemaker that will communicate with a
subcutaneous ICD or placing a lead under the sternum, still extra
vascular with the capabilities of pacing. So I think the next
sort of group of trials will likely be seeing on this device
other than simply looking at other populations in a little more
depth will be further expansion of the technology to allow for a
greater use of a device for those patients who may require a
pacing.


Dr. Greg Hundley:


Well listeners, we want to thank Dr. Michael Gold from Medical
University of South Carolina and Dr. Sana Al-Khatib from Duke
University, our editorialists for describing this study. And in
regards to those, or in regards to subcutaneous ICDs, providing
confirmation that these devices are both effective and safe,
particularly in a U.S. population for primary prevention of
sudden death and really a high-risk patient population with low
ejection fraction. On behalf of Carolyn and myself, we want to
wish you a great week and we will catch you next week on the Run.
This program is copyright of the American Heart Association,
2021.