Circulation November 16, 2021 Issue

Please join authors Babken Asatryan and
Anwar Chahal, and Associate Editor
Ntobeko Ntusi as they discuss the Primer article "Inflammation
and Immune Response in Arrhythmogenic Cardiomyopathy:
State-of-the-Art Review."


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.


Dr. Greg Hundley:


And I'm Dr. Greg Hundley, associate editor, director of the
Pauley Heart Center at VCU Health at Richmond, Virginia. Well,
Carolyn this week, our feature discussion, we're not going to go
with one of our original articles, but we are going to feature a
primer and a primer is a state of the art review article. The
topic is going to be on arrhythmogenic cardiomyopathy and we'll
be looking at the role of inflammation and the immune response in
arrhythmogenic cardiomyopathy. But before we get to that feature,
how about we grab a cup of coffee and talk about some of the
other articles in the issue? Would you like to go first?


Dr. Carolyn Lam:


I would, because guess what? I'm going to be talking about
prescription opioids. We know these are a major contributor to
the ongoing epidemic of persistent opioid use. What do you think
is the incidence after cardiac implantable electronic device
procedures? Greg, let's start with a Greg Hundley quiz. I'll give
you multiple choice, how about that? Do you think it is 1%, 10%,
25%. 50%?


Dr. Greg Hundley:


All right, Carolyn, I'm going to guess here. I'm going to go 10%.


Dr. Carolyn Lam:


Smart. Well, guess what? Today's paper actually gives us insight
into that question, it's from Dr. Frankel from the hospital of
the university of Pennsylvania and his colleagues, and these
authors performed a retrospective cohort study using data from a
national Administrative Claims Database from 2004 to 2018 of
patients undergoing cardiac implantable electronic device
procedures. Adult patients were included if they were opioid
naive during the 180 day period before the procedure and did not
undergo another procedure with anesthesia in the following 180
days.


Dr. Carolyn Lam:


Persistent opioid use, which is what we're interested in, was
defined by filling an additional opioid prescription more than 30
days following the procedure. So, here's your answer. Of the more
than 143,000 patients meeting these inclusion criteria, 11%, so
you were right Greg, 11% filled an opioid prescription within 14
days of surgery. Among these patients, persistent opioid use
occurred in 12.4% of patients, 30 to 180 days after surgery. The
likelihood for developing persistent opioid use was increased for
patients who had a history of drug abuse, pre-operative muscle
relaxant or benzodiazepine use or opioid use in the prior five
years. Also, patients who have prescribed more than 135
milligrams of oral morphine equivalence had a significantly
increased risk of persistent opioid use.


Dr. Carolyn Lam:


Now, this is important because all physicians who perform cardiac
implantable electronic device procedures and care for these
patients should be aware of the risk of persistent opioid use.
This is discussing in editorial by Dr. Kandil from UT
Southwestern.


Dr. Greg Hundley:


Very interesting Carolyn, so connecting sometimes the
prescription use of opioids after cardiac implantable electronic
devices. Great presentation. Well, my first paper comes to us
from the world of preclinical science and it's from our prior
editor in chief Dr. Joseph Loscalzo from Brigham and Women's
Hospital and the Harvard Medical School. So Carolyn, interferon
gamma, producing CD4 positive and CD8 positive T-lymphocytes,
have been identified as the predominant pathological cell subsets
in human atherosclerotic plaques.


Dr. Greg Hundley:


While the immunological consequences of these cells have been
extensively evaluated, their interferon gamma mediated metabolic
effects on endothelial cells remains unknown. So Carolyn, the
purpose of this study was to determine the metabolic consequences
of the T-lymphocyte cytokine interferon gamma on human coronary
artery endothelial cells.


Dr. Carolyn Lam:


Interesting. So what did Dr. Loscalzo and colleagues find?


Dr. Greg Hundley:


Right, Carolyn. So, the authors found that interferon gamma
impairs endothelial glucose metabolism via altered tryptophan
metabolism while depleting NAD plus, which results in a metabolic
shift toward increased fatty acid oxidation, and therefore,
Carolyn, this work suggests a novel mechanistic basis for
pathologic T-lymphocyte endothelial interactions in
atherosclerosis, mediated by interferon gamma, linking
endothelial glucose, tryptophan, and fatty acid metabolism with
NADH and ATP generation and their adverse endothelial functional
consequences.


Dr. Carolyn Lam:


Oh, very nice, Greg. Thank you. The next paper describes a
comprehensive characterization of cardiomyopathy caused by
filament C truncating variance.


Dr. Greg Hundley:


Whoa. Okay, Carolyn. Now what is filamin-C?


Dr. Carolyn Lam:


I thought you may ask and I wasn't going to quiz you, see Greg?
The filamin-C gene can cause a striated muscle protein that
crosslinks actin and anchors cell membrane proteins to the
cytoskeleton, sarcolemmal and sarcomere Z-disc. So, the
co-corresponding authors of today's paper Drs. Mestroni and
Taylor from University of Colorado, Denver Anschutz Medical
Campus, analyzed longitudinal clinical data from an international
multicenter cohort of 85 carriers of this filamin-C truncating
variants. And this is what they found.


Dr. Carolyn Lam:


First, the cardiomyopathy associated with filimin-C truncating
variants appeared to be a disease with heterogeneous phenotypic
presentation, ranging from typical dilated cardiomyopathy to
arrhythmogenic, right ventricular cardiomyopathy, and with
frequently overlapping forms.


Dr. Carolyn Lam:


Number two, left ventricular ejection fraction was associated
with the risk of death, either all cause or non-arrhythmic, heart
transplantation, or LVAD, but not with the risk of sudden cardiac
death or major ventricular arrhythmias, highlighting the need for
alternative strategies of stratification of the arrhythmic risk
in these patients with the filimin-C truncating variant
cardiomyopathy.


Dr. Carolyn Lam:


And number three, this cardiomyopathy was associated with a high
risk of ventricular arrhythmias with frequencies of
life-threatening ventricular arrhythmias, not significantly
different from things like Lamin and desmoplakin cardiomyopathy.


Dr. Greg Hundley:


Well, Carolyn, just fantastic. My next paper comes to us from
Professor Lena Claesson-Welsh from Uppsala University and
Carolyn, palmdelphin belongs to the family of paralemmin proteins
implicated in cytoskeletal regulation and single nuclide
polymorphisms in the palmdelphin locus that result in reduced
expression are strong risk factors for development of calcific
aortic valve stenosis, and predict the severity of the disease.


Dr. Carolyn Lam:


Wow, interesting. Palmdelphin, great. So tell us, what did they
find and what are the clinical implications please?


Dr. Greg Hundley:


Right, Carolyn, great question. So first, calcific aortic valves
stenosis patients with the single nucleotide polymorphism RS754
3130 express reduce palmdelphin levels in valve endothelial
cells, which shows hallmarks of palmdelphin deficiency, such as
loss of cytoplasmic RanGAP1, altered nuclear morphology and
nuclear rest of P53 of P21. Carolyn, second, gene-regulatory
changes affecting actin reorganization, are detected in seemingly
healthy regions of calcifying bowels, in agreement with disturbed
actin-dependent processes, being an early event, instigating the
calcific process. And so Carolyn, the take home message is that
palmdelphin is prominently expressed in endothelial cells and the
presence of the palmdelphin single nucleotide polymorphism
correlated both with a Barrett endothelium and calcific aortic
valve stenosis suggesting that endothelial cell dysfunction is
essential in development of calcific aortic valve disease.


Dr. Carolyn Lam:


Oh, wow, wow. Thank you for translating that into the clinical
implication. Thanks Greg. Let's maybe discuss what else is in
today's issue. There's a prospective piece by Dr. Kirchof
entitled “In Patients With Recently Diagnosed Atrial
Fibrillation, Think Anticoagulation And Rhythm Control.” There's
an exchange of letters between Drs. Liao and Hakala regarding the
article Cardiovascular Risk Factor Trajectory Since Childhood And
Cognitive Performance In Midlife, The Cardiovascular Risk In
Young Finns, study.


Dr. Greg Hundley:


And Carolyn, I've got a research letter from Professor Ramin
entitled “Association Between Sarcomeric Variants In Hypertrophic
Cardiomyopathy In Myocardial Oxygenation, Insights From A Novel
Oxygen-Sensitive CMR Approach.” Well, how about now we get onto
that primer feature discussion relating to arrhythmogenic
cardiomyopathy?


Dr. Carolyn Lam:


Yay. All right, let's go, Greg.


Dr. Greg Hundley:


Well, listeners, we are now onto our feature discussion and this
week we've got a different aspect to the feature discussions.
We're going to work through a review article and what we call as
a primer. It's one of our state-of-the-art family of
publications, where we take a topic and perform a review on a new
evolutionary concept that might be occurring in a particular
field. This week, we are going to discuss arrhythmogenic
cardiomyopathy and we have with us two of the authors of this
primer, Dr. Babken Asatryan from Bern, Switzerland and also Dr.
Anwar Chahal from Lancaster, Pennsylvania. And of course, as
always, we invite one of our associate editors and we have with
us this week Ntobeko Ntusi from South Africa. Welcome gentlemen
and Babken, let's start with you. Can you give us just a little
bit of review regarding arrhythmogenic cardiomyopathy? We hear
that term as opposed to arrhythmogenic right ventricular
cardiomyopathy, and then maybe also, what are the underlying
fundamental histopathologic and pathophysiologic findings
associated with this disease?


Dr. Babken Asatryan:


Thank you, Greg. It's really an absolute pressure being here and
thank you for your invitation again. So arrhythmogenic
cardiomyopathic is genetically-determined heart disease and the
common cause of sudden cardiac death in individuals younger than
40 years of age, it's characterized pathologically by fibrosis
and/or fibro fatty infiltration of the myocardium. This
infiltration provides a substrate for electrical and stability
and leads to ventricular arrhythmias ranging from isolated
premature ventricular contractions to sustain ventricular
tachycardia and ventricular fibrillation. Live ventricular
arrhythmias are cardio manifestations of the orthogenic
cardiomyopathy, and they typically occur at early stages of the
disease, preceding pathological and functional abnormalities. We
call that a concealed stage of the disease.


Dr. Babken Asatryan:


The typical form for arrhythmogenic cardiomyopathy, which has
been previously termed as arrhythmogenic right ventricular
cardiomyopathy, primarily affects the right ventricle and has
been recognized for decades. Following implementation of
postmortem autopsy, increased use of contrast, enhanced cardiac
MRI, and improved understanding of the genotype phenotype
correlations, more recently cases with more pronounced left
ventricular involvement have been discovered as well as cases
with biventricular involvement of the disease.


Dr. Babken Asatryan:


Nowadays, we believe that around 60% of cases have also left
ventricular involvement, even if they're diagnosed based on the
2010 task force criteria for arrhythmogenic cardiomyopathy.
Causative variants in desmosomal genes are identified in about
60% of patients with typical arrhythmogenic right ventricular
cardiomyopathy.


Dr. Babken Asatryan:


Recently, there have been studies reporting non-desmosomal gene
variants in patients with arrhythmogenic right ventricular
cardiomyopathy, as well as in those left ventricular and
biventricular forms of the disease. But the left ventricular form
is quite new to us, so we are learning a lot every day about this
disease.


Dr. Babken Asatryan:


The pathogenesis of this condition appears to be quite complex.
We know that these pathogenic variant in desmosomal genes can
initiate several pathways and these could be gene dependent. What
we do know, that these eventually lead to fibrosis and fibro
fatty infiltration of the myocardium, which is the hallmark
feature of arrhythmogenic cardiomyopathy.


Dr. Greg Hundley:


And patients present generally when, in terms of lifespan?


Dr. Babken Asatryan:


So, patients present in between 30 to 40 years of age, there's a
typical presentation for arrhythmogenic cardiomyopathies but
young presentations are also common nowadays, particularly. So,
programs in families, they usually present 30 to 40 years of age.
But in families, we do discover patients who have typical
arrhythmogenic right ventricular cardiomyopathy or left and right
ventricular involvement were younger at age, but they still need
the criteria.


Dr. Greg Hundley:


And then when we diagnose this condition, do we also need to
think about, at least clinically, looking for other affected
individuals within a family?


Dr. Babken Asatryan:


Absolutely. So most of the arrhythmogenic biventricular
cardiomyopathy, arrhythmogenic left ventricular cardiomyopathy
cases are autosomal dominant diseases. So, this means if an
individual carries a pathogenic variant in one of the genes
responsible for the condition, the likelihood that the first
degree family members will carry the same variant is about 50%.
The disease however, presents with reduced penetrance and
variable expressivity. Some of the family members may have just
arrhythmias and others may develop arrhythmias and structural
heart disease. And some of the individuals who carry pathogen
occurrence in desmosomal are the genes responsible for the
condition may not show phenotype at all. So, that makes the
decision-making in families quite challenging.


Dr. Greg Hundley:


Very nice. Well, thank you so much Babken and now, we're going to
turn to one of your co-authors, Anwar and Anwar, in this primer,
you start to present a new sort of theme, that inflammation
actually may play a role in this disease, at least in terms of
adverse events. Can you describe a little bit what your team was
thinking here and what took you in this direction and what are
some of the research that you've revered here that supports this
new line of thinking?


 


Dr. Anwar Chahal:


Thanks, Greg and Ntobeko, for first, the kind invitation to come
on this podcast. I must add that I normally listen to the podcast
and very much enjoy it, so it's a great honor and privilege for
us.


Dr. Anwar Chahal:


Let me contextualize it, I think it's important to think about
what are problems are when we evaluate cases, whether that's the
program or the family members, and try to determine what's
actually going on. There's been a number of changes over the last
15 years that really evolve around a better understanding and the
availability of multimodality imaging, which has altered the way
we evaluate these cases. If you look at the 2010 taskforce
criteria, for example, they talk about volumetric changes and
injection fractions by echo or MRI, and even ventriculogram
synapse on fluoroscopy, which I don't think many people do
anymore, but they don't mention gadolinium enhancement, and there
is an updated version that will come out and talk about that, and
the advantages of MRI and even contrast-enhanced CT, and now
18F-FDG, CT PET imaging.


Dr. Anwar Chahal:


So, the patient journey and the problem that we face is that
actually some people present with very unusual features, chest
pain, troponin rise, undergo coronary angiography, normal
coronary arteries, or unobstructed coronary arteries. We put them
through MRI scanners and we see a little bit of gadolinium
enhancement. We follow them over the next five years or so, and
it develops into taskforce criteria, positive ARVC. So, that's
the sort of clinical angle where we've started to see this.


Dr. Anwar Chahal:


As we put people through scanners, we see the hearts lights up on
PET scanners, pretty reproducibly and reliably, that tells us
that there's some inflammation there. We look back into the
literature and actually very, very early work that was done,
autopsy-based, some of it endomyocardial biopsy-based describing
lymphocytic infiltrates. Usually that's dry, as you say, or
sterile, but there have been reports of even viral pathogens.


Dr. Anwar Chahal:


That's where it stirred this debate up for us about whether
there's this signal that we're seeing there, what is it? What's
actually going on? It raises a question, we recognize the other
mechanisms, the fiber fatty replacement, the apoptotic pathways,
that contribute to that. But there's such variable expressivity
with this disease. It's a difficult disease to pin down and it
raises a question. What are these other effect modifiers? Is
there something else that we do not recognize? And that's really
what's driven this.


Dr. Anwar Chahal:


Our group of co-authors are leaders in the field. Some of them
are colleagues in veterinary medicine, Dr. Anna Geltser, and we
work together on boxer dog patients. So, she is a practicing vet
and a scientist, and has lots of boxer dogs with arrhythmogenic
cardiomyopathy. We've been looking at how we could utilize that
as a model to test some of the findings that we have in humans
and pioneering work really by Bob Hamilton in Toronto, in this
paper where they described anti-DSG2 antibodies, which were found
not only in humans, whatever the underlying genotype, but also in
boxer dogs with arrhythmogenic cardiomyopathy. And that's been
followed up with work from Europe, describing anti-heart
antibodies, anti-intercalated disk antibodies.


Dr. Anwar Chahal:


It doesn't really matter what the genotype is, but we're seeing
these antibodies there and we're seeing these positive scans
indicating inflammation. So the big question is, is this
inflammation of primary insult or is it secondary? Is it that the
heart in somebody with a genetic cardiomyopathy is predisposed,
maybe the remodeling is affected. Bob Hamilton thinks this is
probably the best explanation to explain why, whatever the
genotype, that these antibodies were positive, that actually that
myocardium becomes exposed. The epitope of DSG is now exposed to
the immune system, which mounts an antibody response, and hence
you see the rise in these antibodies, but it's possible it could
it be primary as well. With COVID, and this is a bit of a
stretch, so just bear with me there, with COVID we've been
recognizing that there's myocardial injury.


Dr. Anwar Chahal:


There's not as much myocarditis as we expected, but there's been,
with virus SARS-CoV-2, we know regular human coronavirus is a
recognized cause of viral myocarditis. So, the question really
arose are we going to see a lot more of this myocarditis? In our
lab discussion, it was, "Well, do you think we're going to see
something similar in that we've seen with arrhythmogenic
cardiomyopathy, these genetically predisposed individuals are
more likely to get invaded? Now, we haven't really seen that with
COVID and I won't delve too much into it, but going back to the
classical viral infections that we see with myocarditis, here's a
really, really interesting biological link. Most of them invade
through the desmosome, so with SARS-CoV-2, we see the ACE2
receptors as the way the virus really invades. But with these
regular coxsackie virus, for example, parvovirus, a lot of them
invade through the desmosome, and that's where we thought, here's
a link.


Dr. Greg Hundley:


Very nice. Ntobeko, you see a lot of papers come across your
desk. What attracted you to this group of investigators and this
particular review article?


Dr. Ntobeko Ntusi:


Thank you very much, Greg. I want to start by congratulating
Babken, and Anwar for a really fantastic submission, which as an
associate editor, was an absolute pleasure to handle. There
really are six things that stood out for me about this article.
The first one really relates to the question that you ask Babken,
which relates to the nomenclature and people have traditionally
thought of this is a disease of the right ventricle. I think it's
now timely to consider a clear change in nomenclature, that
recognizes not only right ventricular involvement, but also left
ventricular involvement. And the common finding of biventricular
disease in patients with ACM.


Dr. Ntobeko Ntusi:


The second really important contribution for me from this primer
was that we've always thought of arrhythmogenic cardiomyopathies
as a genetic disorder with abnormalities in the genes, encoding
components of the desmosome. Many groups recently, including our
own group that described novel mutations for arrhythmogenic
cardiomyopathy in adhering to poultry and other genes outside of
the desmosome are showing that the genetic underpinnings are much
wider. But the key contribution here is really the consideration
of the centrality of inflammation to the pathogenesis of this
disease. Anwar has spoken to some length about that, so I won't
rehash those comments, but for me, what is key for future work in
this area is really to clarify whether the inflammation, as in
with many other forms of cardiovascular disease, is merely an
epiphenomenon, or whether it plays a critical role in the causal
pathway for the phenotypes that we see.


Dr. Ntobeko Ntusi:


The next important feature for me was the review of the
literature and evidence in the association with myocarditis. So,
we've seen lots of case reports and small case series showing
young people presenting with myocarditis and meeting either the
Dallas criteria histologically, or the Lake Louise criteria on
imaging, and then subsequent genetic testing confirming the
diagnosis of an arrhythmogenic cardiomyopathy. I thought for the
first time with quite a compelling review of the link between
these two.


Dr. Ntobeko Ntusi:


The fourth important contribution relates really to the
contribution of imaging modalities, both in diagnostics, but
critically in risk stratification for this clinical entity. And
for me, the importance of cardiovascular magnetic resonance,
either with planimetric mapping or late gadolinium enhancement to
really add to our ability to predict future events.


Dr. Ntobeko Ntusi:


Then there's been quite a number of publications in the last five
years that have clarified our understanding of the at risk
patient with arrhythmogenic cardiomyopathy who's likely to suffer
a sudden cardiac death event. This tends to be somebody who was
young, who was male, who has a history of documented
non-sustained ventricular tachycardia or a history of syncope and
on ECG, quite extensive T wave inversion. So again, this is
nicely reviewed, and we think about those as candidates who'll
benefit from implantation of an ICD.


Dr. Ntobeko Ntusi:


Then I thought for me, the last really nice contribution from
this piece was the review of advancing our understanding of the
hot phase. So in all forms of heart muscle disease, we speak of
the presentation of patients with the chest pain syndrome, with a
troponin leak, but unobstructed coronaries. On further
investigation, we don't really find any other evidence of an
inflammatory event. We call this a hot phase. And in some case
reports in small case series, endomyocardial biopsy has revealed
the association of these, whether in TCM, HCM, or arrhythmogenic
cardiomyopathy with lymphocytic infiltration. I thought this was
all very nicely reviewed.


Dr. Ntobeko Ntusi:


So, the question that really left me with having read this
review, was whether in the future, we may actually need to
consider targeting inflammatory pathways as a therapeutic target
in this heart muscle disorder. Thanks Greg.


Dr. Greg Hundley:


Yes. Thanks so much in Ntobeko. You've really led us to the next
question that I'm going to ask both Babken and Anwar, you've
discussed where do you feel this field is moving and what is the
next study or series of studies we need to perform. Babken, first
you, and then Anwar. Babken, what do you think is the next study
to be performed in this space?


Dr. Babken Asatryan:


I so much agree with Ntobeko, that perhaps understanding better
what can be targeted in these patients, in order to prevent
development of phenotype or least to prevent cardiac events, is
perhaps the most important next step. In our first figure, we
have summarized this potential mechanisms, involving inflammation
leading to with arrhythmogenic cardiomyopathy in these patients.
We have also highlighted the potential mechanisms that perhaps in
the future can be targeted. This could include both targeting the
inflammatory cytokines, as well as the primary agents that cause
the myocardial inflammation in patients, depending on the results
that we will receive over the next years and perhaps animal
models should be the next step to better understand how similar
arrhythmogenic cardiomyopathy phenotype, where inflammatory
contributors to the phenotype are important. And then we can
understand whether this can be the same in humans as well.


Dr. Greg Hundley:


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


Dr. Anwar Chahal:


Yes. So, agree with that. I guess I would add what are we doing
to try to help decipher this? So some of the work that we're
doing, I mentioned earlier with the boxer dog patients, who have
arrhythmogenic cardiomyopathy. So some of the aspects that we're
actually looking at is taking swab cells to see if we can
phenotype as a alternative tender myocardial biopsy. And one of
the co-authors, Angeliki Asimaki, really pioneered that as a
alternative tool because the desmosis are ubiquitous and this may
help us phenotype patients better. But also, we want to look at
using that as a tool in the pheno copies of arrhythmogenic
cardiomyopathy. So we would advocate, re-phenotyping people as
well as possible and trying to use some of these techniques.


Dr. Anwar Chahal:


The next thing we're really looking at is antibody based tools,
either working with collaborators, who've already described these
antibodies such as anti-DSG2, anti-heart antibody, and
anti-skeletal disc to see if we can develop those and perhaps
identify others in both human and ox models. And that will then
hopefully open the way for us to develop therapeutics that may be
able to target those and address that, and maybe use these
antibodies as markers to see disease progression, or halting of
disease.


Dr. Greg Hundley:


Very nice. Well listeners, we want to thank Dr. Babken Asatran
from Bern, Switzerland, Anwar Chalal from Lancaster,
Pennsylvania, and our own associate editor, Ntobeko Ntusi from
South Africa, really helping us see this new scientific
consideration regarding the potential role of inflammation in
causal pathways of adverse manifestations of arrhythmogenic
cardiomyopathy. 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.
This program is copyright of the American Heart Association,
2021. 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 visit ahajournals.org.