Circulation February 1, 2022 Issue

Please join senior author Louise Olde Nordkamp,
Editorialist Sana Al-Khatib, and Associate Editor Mark Link as
they discuss the original research article Efficacy and Safety of
Appropriate Shocks and Antitachycardia Pacing in "Transvenous and
Subcutaneous Implantable Defibrillators: An Analysis of All
Appropriate Therapy in the PRAETORIAN trial" and the editorial
"Just When We Thought the Debate About the Value of
Anti-Tachycardia Pacing Was Over Perplexing Results from the
PRAETORIAN Trial Emerged."


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, your host and Associate Editor from the National
Heart Center and Duke National University of Singapore. And as
you can tell, I am sorely missing my co-host, Dr. Greg Hundley,
who cannot make it today, but yet I am so excited to tell you
about the wonderful papers in today's issue. Now, right after
these summaries, we will be discussing appropriate shocks and
anti-tachycardia pacing in transvenous and subcutaneous
implantable defibrillators. A really interesting analysis from
the PRAETORIAN trials. The results may surprise you as they did
for me. I really highly recommend you listen to the discussion,
important clinical take home messages there. Now, though, let me
tell you about some original papers in today's issue. We know
that symptomatic children with catecholaminergic polymorphic
ventricular tachycardia and that's a mouthful.


Dr. Carolyn Lam:


So, I'll abbreviate it as CPVT. They are at risk for recurrent
arrhythmic events, beta blockers decreases risk, but are some
types of beta blockers better than others in this regard? That's
what coauthors and corresponding authors, Dr. Peltonberg and van
de Werf from University Medical Center, Amsterdam and colleagues
looked at. Studying 329 patients with RYR2 variant carrying
symptomatic children from two international registries of
patients with CPVT, these authors found that beta-1 selective
beta blockers were associated with a higher risk for arrhythmic
events, defined as syncope, appropriate ICD shock, sudden cardiac
arrest, or sudden cardiac death. And this was compared with
non-selective beta blockers. The difference in non-selective
versus beta-1 selective beta blockers was driven by a
significantly lower risk for arrhythmic events in patients
treated with nadolol compared with metoprolol, bisoprolol, and
atenolol. So, what are the clinical implications? Well,
symptomatic children with catecholaminergic polymorphic
ventricular tachycardia should preferably be treated with nadolol
or another non-selective beta blocker such as propranolol should
nadolol be unavailable.


Dr. Carolyn Lam:


The next paper deals with the super hot topic of
myocarditis-related COVID-19 vaccination in adolescents and young
adults. Now, suspected myocarditis temporarily related to
COVID-19 vaccination has been reported in adolescents above 12
years old and young adults since the emergency use authorization
of the Pfizer COVID-19 vaccine. And this is particularly in male
adolescents and young adults. Understanding the clinical course
and short-term outcomes of suspected myocarditis following
COVID-19 vaccine, of course, has important public health
implications in the decision to vaccinate youth. So, these
authors led by corresponding author, Dr. Truong from University
of Utah and Primary Children's Hospital from Salt Lake City in
Utah, retrospectively collected data on patients younger than 21
years old presenting before July 2021 with suspected myocarditis
within 30 days of COVID-19 vaccination. And they found that in
139 adolescents and young adults with 140 episodes of suspected
myocarditis, 49 of which were confirmed and 91 were probable.


Dr. Carolyn Lam:


And these were at 26 centers. Most patients were male and white
with a median age of 15.8 years. Suspected myocarditis occurred
in 98% following mRNA vaccine with 94% following the Pfizer
vaccine, 91% occurring after the second dose. Symptoms started a
median of two days after vaccination. The most common symptom was
chest pain. 26 patients or 19% were in the ICU. Two were treated
with inotropic vasoactive support and none required ECMO or died.
The median hospital stay was two days. So, while the majority of
patients with suspected vaccine associate myocarditis had normal
ventricular systolic function on echocardiogram, many had
abnormal findings suggestive of myocarditis on cardiac MRI in the
setting of elevated troponin and electrocardiographic changes.
The take home message is that despite lab and cardiac MRI
evidence of cardiac injury, the majority of adolescents and young
adults with suspected myocarditis following COVID-19 vaccination
have rapid recovery of symptoms and a mild clinical course.
Further studies are needed to better understand the timing of
resolution of myocardial injury, mechanisms of myocardial injury,
and the long term outcomes.


Dr. Carolyn Lam:


The next paper is the first study to look at examining the
genetic architecture of the plasma protein using whole-genome
sequencing in persons of African ancestry and really provides a
chance to look at rare ancestry specific variation. Authors led
by corresponding author, Dr. Gerszten from Beth Israel Deaconess
Medical Center in Boston, Massachusetts performed proteomic
profiling of 1,301 proteins in 1,852 black adults from the
Jackson Heart Study using aptamer-based proteomics or the
SOMAscan. Whole-genome sequencing association analysis was
ascertained for all variants with minor allele count of five or
greater. Results were validated using an alternative
antibody-based proteomic platform, the Olink platform as well as
replicated in the multiethnic study of atherosclerosis or MESA,
and the HERITAGE family study. A huge amount of work. So, this
large study added 114 novel genomic [inaudible 00:07:00]
associated with protein levels and an additional 217 novel
sentinel variant protein relationships. Novel cardiovascular
findings included genetic variant associated with amyloidosis in
persons with African ancestry shown to be associated with retinol
binding protein four levels, even in those without cardiomyopathy
implicating it as a potential biomarker.


Dr. Carolyn Lam:


Taken together, these results provide evidence of the functional
importance of variants in non-European populations and suggest
new biological mechanisms for ancestry specific determinants of
lipids, coagulation, and myocardial function. And this is
discussed in an excellent editorial by Professor Dr. Schunkert
from German Heart Center, Munich. And the final original paper
deals with high-salt intake, which we know to be the leading
dietary risk factor for cardiovascular disease. We also know that
clinical evidence suggests that high-salt intake is associated
with non-alcoholic fatty liver disease. Now, could the two be
linked, in other words, could hepatic steatosis induced by
high-salt diet mediate cardiovascular damage and how? This is
exactly what these authors did. Corresponding author, Dr. Zhu
from Army Medical University in Chongqing, Institute of
Hypertension in China and their colleagues in an elegant series
of mouse experiments demonstrated that reduced SERT three
expression in the liver is an important mediator of salt-induced
hepatic inflammation and steatosis.


Dr. Carolyn Lam:


High-salt diet inhibits the transcription of SERT three through
epigenetic modification mechanisms resulting in the persistence
of hepatic inflammation in the liver. Notably, the over
expression of SERT three in the liver using an adeno-associated
virus eight vector or activation of SERT three by metformin
effectively relieved the progression of persistent hepatic damage
in mice and thus counteracted salt-induced cardiovascular damage.
Taken together, these findings suggest that the MK SERT three
pathway may be a promising interventional target for treatment of
persistent cardiovascular damage in populations exposed to
high-salt diet, and finally rounding up the other papers in
today's issue, there's an AHA Update by Dr. Lloyd-Jones on the
power of patient stories to inspire us to prevent cardiovascular
disease and death, personal reflections on AHAs scientific
sessions 2021. There is an On My Mind paper by Dr. Dashwood on 30
years of no-touch saphenous vein harvesting, a timely jubilee
gift.


Dr. Carolyn Lam:


There's a Frontiers paper by Dr. Rivard on a tremendous
contribution on atrial fibrillation and dementia, a report from
the AF Screen Interventional Collaboration. And finally a
research letter from Dr. Joe on genetic proliferation tracing
revealing a rapid cell cycle withdrawal in pre-adolescents
cardiomyocytes. Well, that wraps it up for the summaries. Now,
let's go on to our feature discussion.


Dr. Greg Hundley:


Welcome listeners to our feature discussion today on this
February one. And we're very excited because we have three
individuals that will be discussing this paper, Dr. Louise Olde
Nordkamp from Amsterdam, Netherlands, the primary author. Dr.
Sana Al-Khatib, who is our editorialist for this paper. And
finally, Dr. Mark Link, who is our associate editor. Welcome to
you all. Louise, we're going to start with you. Can you describe
for us some of the background pertaining to why you formulated
this study and then what was the hypothesis that you wanted to
address?


Dr. Louise Olde Nordkamp:


Yes. Thank you very much for joining this podcast on our study.
Our study was designed because in ICD therapy, antitachycardia
pacing, ATP has been developed as a painless method to terminate
ventricular arrhythmias, and it might decrease the number of
appropriate shocks. But on the other hand, ATP might also be
given unnecessarily for VTs that would've been ended
spontaneously and might even accelerate VTs. The reported
efficacy ranges from 52 to 81%, and some studies have observed
even higher mortality in patients treated with ATP. The
subcutaneous ICD has been developed 10 years ago approximately,
and it's completely extra thoracic. And due to this extra
thoracic design, it is incapable of providing pacing therapy
including ATP. And this was a pre-specified analysis from the
PRAETORIAN trial, which was a randomized trial comparing the
transvenous and the subcutaneous ICD. And in this pre-specified
secondary analysis, we're aimed to determine the efficacy of ATP,
the safety of ATP and shocks by comparing appropriate therapies
in both arms. So, both the SICD and transvenous ICD, and
specifically, we investigated whether ATP reduced the number of
appropriate ICD shocks.


Dr. Greg Hundley:


Very nice. And so describe for us a little bit more the study
population and the design particularly of the PRAETORIAN trial.


Dr. Louise Olde Nordkamp:


Yeah. So, we published at PRAETORIAN trial in August 2020, in The
New England Journal of Medicine and it was the first randomized
trial to compare the subcutaneous ICD with the transvenous ICD in
patients with a regular ICD indication, but without a pacing
requirement. And in 39 census throughout Europe and US of 849
patients were randomized to either the subcutaneous and
transvenous ICD in a one-to-one ratio. And during a median follow
up of 49 months, the rate of the primary endpoint composite of
device related complications and inappropriate shocks were
similar between the subcutaneous ICD and the transvenous ICD arm.
But here we looked at the appropriate therapy in the study. So,
it was defined as both ATP or shock therapy and appropriate
therapy was also defined as therapy for ventricular arrhythmias.
The PRAETORIAN trial population in overall was, as I said before,
regular ICD population with a median age of 63 years, 20% were
female. Two-third of patients had an ischemic cardiomyopathy and
20% of patients had a secondary prevention indication.


Dr. Greg Hundley:


Very nice. And so tell us your study results.


Dr. Louise Olde Nordkamp:


Our findings were that in this trial, there was no significant
difference in number of patients with appropriate therapy, so
shocks and ATP. There were 86 patients in the SICD group and 78
patients in the transvenous ICD group. But patients in the
subcutaneous ICD group were one and a half times more likely to
be treated with at least one shock. So, if we look at shocks
only, and that has a hazard ratio of 1.52 and that was
statistically different of significance between the groups. The
first shock efficacy was similar in the SICD and in the
transvenous ICD. And the first ATP attempt successfully
terminated 46% of all monomorphic VTs, but it accelerated through
arrhythmia in 9.4%. And although, ATP successfully terminated 46%
of all monomorphic VTs, the total of number of shocks, as I said
before, was not statistically different between the two groups.


Dr. Louise Olde Nordkamp:


So, we looked at discrete episodes where ATP does reduce the
number of appropriate shocks. But when we looked at storm
episodes, which was defined as more than three shocks within 24
hours, we saw that there was a higher number of shocks in the
transvenous ICD arm, despite a randomized design of the trial and
the distribution of shocks between the discrete and the storm
episode was there for opposites in the SICD, in the transvenous
ICD. So, there was a high number of shocks in storm episodes in
the transvenous ICD group, which can partly explain by the number
of patients and electrical storms in this group, because there
was 10 patients with an SICD who had an electrical storm and
there were 18 patients with a transvenous ICD who had an
electrical storm. So, patients with appropriate therapy had
therefore almost twofold increased risk of an electrical storm in
the transvenous ICD arm.


Dr. Greg Hundley:


Very nice. Listeners, next, we're going to turn to the associate
editor for this paper, Dr. Mark Link, and Mark, you have many
papers come across your desk. What attracted you to this
particular manuscript?


Dr. Mark Link:


Thanks, Greg. And thanks, Louise for contributing this papers. We
were really very happy to have it. And the reason that we were
happy to have it is that this is a very important question in our
clinical practice. That is, should we give a patient a subcu ICD
or a transvenous ICD? Then, there are risk and benefits of both.
It's a discussion that I have multiple times a week with
patients. And so getting data on the efficacy of shocks and the
efficacy of ATP is very, very important for us as we will discuss
this with our patients. So that's why we really like this paper,
because we thought it was very clinically relevant to our
readership and to the practicing EP community.


Dr. Greg Hundley:


Very nice. Next listeners, we're going to turn to our
editorialist, Dr. Sana Al-Khatib from Duke University and Sana,
help us put the results of this study in perspective with other
research in the field of both subcutaneous and transvenous
pacing.


Dr. Sana Al-Khatib:


Yeah, no, absolutely. I'd like to start by congratulating the
authors on this paper, I really enjoyed reading it and thank you
for sending it to circulation. I also enjoyed writing the
editorial. So, certainly this paper provided results that have
challenged some of the findings of prior studies, in the sense
that several prior studies had shown that antitachycardia pacing
reduces the risk of shocks, improves patients outcomes. And
that's not at the expense of them having syncope or having
adverse events. And this was the case in those trials even for
faster ventricular tachycardia. So in this particular study, they
excluded patients with slower ventricular tachycardia, but I
would also say that several of the prior studies had looked at
antitachycardia pacing for faster VT and showed better outcomes.


Dr. Sana Al-Khatib:


And so, this study certainly makes us question some of those
findings, but really I feel like it will be a great impetus for
different researchers to look at this question in relation to the
newer generation of transvenous ICDs as well as even potentially
looking at the combination of the subcutaneous ICD with perhaps
leadless pacemakers that could deliver antitachycardia pacing,
which is an area of research that we're going to hear more about.


Dr. Greg Hundley:


Very nice. And Sana, that really leads us into our next round of
questions with our panelists. We'll start with you first, Louise,
what do you see is the next focus of research that'll be
performed in this space?


Dr. Louise Olde Nordkamp:


So, I think the efficacy and also the potential harm of ATP
should be studied more thoroughly. So, I think a randomized trial
with ATP as a main focus, because this was a secondary analysis,
is the first step to do. And moreover as Dr. Al-Khatib already
mentioned is that new innovations are ongoing with a leadless
pacemaker in addition to a subcutaneous ICD and these clinical
results will be gathered in the coming months and years. And that
is really interesting to look at as well.


Dr. Greg Hundley:


And Mark, can you share your thoughts?


Dr. Mark Link:


Yeah. This study brings up many questions, tying in the leadless
pacemaker with the subcu ICD is certainly one that's being
explored by a number of manufacturers right now, ways to make
shocks less painful also would be very critical. I mean, I think
that the storms often are because of the catecholamine surges
that occur with shocks, if you could make shocks less painful,
that would be very keen. And that's been a focus of some
researchers for quite some time without good results at the time.
And then, increasing the efficacy of ATP because there was a
signal here that ATP could, what did generate faster VPs and VFs.
And so, the prevention of that I think is very crucial.


Dr. Greg Hundley:


Very nice. And Sana, do you have anything to add?


Dr. Sana Al-Khatib:


Yeah, no, absolutely. I completely agree with what was said. I
truly feel that this is an area where we're going to see a lot of
research being done. We have new algorithms of antitachycardia
pacing, Greg, that are being developed and incorporated into
devices that use machine learning, which is really exciting. So,
trying to look at hard outcomes related to those and comparing
them with, as I mentioned, the subcu ICD combination with a
leadless pacemaker would be really interesting. And then, this
whole question about the electrical storm, I commend the authors
for looking at that, but as they pointed out this was a secondary
analysis and the numbers that they had were pretty small. So,
trying to look at those findings in a larger population of
patients really designed to look at that question would be
important.


Dr. Greg Hundley:


Very nice. Listeners, we want to thank our electrophysiology
panelists today, Dr. Louise Olde Nordkamp, Dr. Sana Al-Khatib,
and Dr. Mark Link for bringing us the results from this trial
indicating that really there was no difference in observed shock
efficacy of the subcutaneous compared with the transvenous ICDs.
Well, on behalf of Carolyn and myself, we want to wish you a
great week and we will catch you next week on the run.


Dr. Greg Hundley:


This program is copyright of the American Heart Association 2022.
The opinion expressed by speakers in this podcast are their own
and not necessarily those of the editors or of the American Heart
Association. For more, please visit ahajournals.org.