Circulation April 6, 2021 Issue

For this week's Feature Discussion, please join authors Igor
Klem, Pasquale Santangeli, Mark N.A. Estes III, and Associate
Editor Victoria Delgado as they discuss, in a panel forum, the
articles: " The Relationship of LVEF and Myocardial Scar to
Long-Term Mortality Risk and Mode of Death in Patients with
Non-Ischemic Cardiomyopathy," "Prognostic Value of Non-Ischemic
Ring-Like Left Ventricular Scar in Patients with Apparently
Idiopathic Non-Sustained Ventricular Arrhythmias," and "Cardiac
Magnetic Resonance Imaging in Nonischemic Cardiomyopathy:
Prediction Without Prevention of Sudden Death."


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 in Richmond, Virginia. Well Carolyn, this
week we've got another sort of double feature with a forum and
our focus is going to be on myocardial scar that's observed with
late gadolinium enhancement during cardiovascular magnetic
resonance and the two author groups we'll be discussing the
impact of that scar on the development of ventricular
arrhythmias. But before we get to that, how about we grab a cup
of coffee and jump into the other articles in the issue? Would
you like to go first?


Dr. Carolyn Lam:


I certainly would. Although I have to say, can't wait for the
double feature. I love those, and this is right up your alley
too. All right. But first, the first paper I want to talk about
provides new randomized trial information regarding the benefits
of catheter ablation in atrial fibrillation in patients who also
have heart failure. Now, this is a sub-study of the CABANA trial.


Dr. Greg Hundley:


So Carolyn, remind us a little bit about the CABANA trial first.


Dr. Carolyn Lam:


I thought you might ask. Well, CABANA randomized 2,204 patients
with atrial fibrillation who were 65 years or older or less than
65 with one or more risk factors for stroke at, it was huge at
126 sites, and they were randomized to ablation with pulmonary
vein isolation or drug therapy. Now of these, 35% of 778 patients
had New York Heart Association Class II or higher at baseline,
and really formed the subject of the current paper. Although this
sub-study was not specifically designed to evaluate patients with
heart failure with preserved ejection fraction, about 91% of the
patients with a clinical diagnosis of heart failure participating
in CABANA for whom such data on injection fraction were
available, really had an ejection fraction of above 40% and fully
79% had an ejection fraction above 50%. So excitingly, this is
really majority talking about, have HFpEF. Now, what did they
find well in patients with New York heart Association Class II or
III heart failure at trial entry, most of whom did not have a
reduced ejection fraction.


Dr. Carolyn Lam:


There was substantial clinical outcome benefits with the ablation
over drug therapy with a 36% relative reduction in the primary
composite endpoint of death, disabling stroke, serious bleeding
or cardiac arrest. Benefits were evident for both all-cause
mortality and atrial fibrillation reduction. However, the effects
on heart failure hospitalization were small and not significant.
Authors also caution that these results should not be viewed as
practice changing until they are reproduced in a confirmatory
trial of ablation in the same population. And this is beautifully
discussed in an editorial by Lynda Rosenfeld and Alan Enriquez
from Yale University School of Medicine.


Dr. Greg Hundley:


Oh, wow. Thanks Carolyn. Well, my first paper comes from the
world of basic science and it's from Professor Thomas Braun, from
the Max Planck Institute for Heart and Lung Research. So Carolyn,
vascular smooth muscle cells show a remarkable phenotypic
plasticity allowing acquisition of contractile or synthetic
states, but critical information is missing about the
physiological signals that promote formation and maintenance of
contractile vascular smooth muscle cells in vivo. So BMP-9 and
BMP-10 are known to regulate endothelial quiescence after
secretion from the liver and right atrium. And these
investigators are studied the role of BMP-9 and 10 for
controlling formation of contract, all vascular smooth muscle
cells.


Dr. Carolyn Lam:


Greg, talking about vascular smooth muscle cells always reminds
me of their role in pulmonary hypertension, am I right?


Dr. Greg Hundley:


Yes, Carolyn. So these investigators found that in mouse models,
BMP-9 and BMP-10 act directly on vascular smooth muscle cells for
induction and maintenance of their contractile state, and
surprisingly the effects of BMP-9 and 10 in vascular smooth
muscle cells are mediated by different combinations of BMP type 1
receptors in a vessel bed specific manner. And therefore, just as
you suggest, Carolyn, these results may offer new opportunities
to manipulate blood pressure in the pulmonary circulation.


Dr. Carolyn Lam:


Thank you, Greg. Well, my next paper provides the first proof of
principle of gene therapy for complete correction of Type 1 Long
QT syndrome.


Dr. Greg Hundley:


Ah, so tell us a little bit about Type 1 Long QT syndrome,
Carolyn.


Dr. Carolyn Lam:


Okay. Well Type 1 long QT syndrome is caused by loss of function
variants in the KCNQ1 and coded potassium channel alpha sub-unit.
And that is essential for cardiac repolarization providing the
slow delayed rectifier current. Now no current therapies target
the molecular cause of this Type 1 long QT syndrome. Well, this
study from Dr. Michael Ackerman colleagues from Mayo Clinic
Rochester really established a novel dual component suppression
and replacement KCNQ1 gene therapy approach for Type 1 long QT
syndrome. And it's the type that contains the KCNQ1 short hairpin
RNA to suppress endogenous expression and a codeine altered short
hairpin RNA immune copy of this KCNQ1 for gene replacement.


Dr. Carolyn Lam:


So this very novel approach rescued the prolonged action
potential duration in inducible pluripotent STEM cell
cardiomyocytes derived from four patients with unique Type 1 Long
QT syndrome, causative, KCNQ1 variants. So it's super cool. Just
go have a look.


Dr. Greg Hundley:


Well, thanks Carolyn.


Dr. Carolyn Lam:


I want to also tell you about other things in the mail bag. We
have ECG Challenge by Dr. Dai on “Severe Arrhythmia Caused by a
Chinese Herbal Liqueur. What's the Diagnosis?” I'm not going to
tell you. You have to go see. We have Dr. Karen Sliwa writing a
beautiful Joint Opinion paper from the World Heart Federation and
American College of Cardiology, American Heart Association, and
European Society of Cardiology on "Taking a Stand Against Air
Pollution, the Impact on Cardiovascular Disease."


Dr. Greg Hundley:


Well, thanks Carolyn. So I've got a couple other articles. First
Professor Yacoub has a global rounds describing and working
towards meeting the challenges of improving cardiovascular health
in Egypt. Those are really interesting features to learn about
cardiovascular care worldwide. Next there's an In Depth article
by Professor Thum entitled, "Therapeutic and Diagnostic
Translation of Extracellular Vesicles in Cardiovascular Diseases,
Roadmap to the Clinic." And then finally, a Research Letter from
Dr. Bottá entitled, "Risk of Coronary Artery Disease Conferred by
Low Density Lipoprotein Cholesterol Depends on Apologetic
Background." Well, Carolyn, what a great issue and how about now
we proceed on to that double feature?


Dr. Carolyn Lam:


Oh, I can't wait. Thanks Greg.


Dr. Greg Hundley:


Well, listeners, we are here for a really exciting feature
discussion today that's going to focus on imaging, in particular
magnetic, resonance imaging, and some new findings in that era
and how those findings may pertain to ventricular dysrhythmias.
With us today, we have Dr. Igor Klem from Duke University who
will be discussing a paper, Dr. Pasquale Santangeli from
University of Pennsylvania, our own associate editor, Dr.
Victoria Delgado from Leiden and an editorialist, Dr. Mark Estes
from UPMC in Pittsburgh. Welcome to all of you. Well, Igor, we're
going to start with you. Could you tell us what was the
hypothesis for your study and what was your study population in
study design?


Dr. Igor Klem:


Yes. Good morning, Greg and thanks for the invitation. We wanted
to know if you have a patient who you diagnosed with non ischemic
cardiomyopathy based on clinical grounds and you refer him for a
cardiac MRI study with contrast, what is the additional
information that you get from the MRI study? And so we wanted to
compare, and that's primarily related to the findings on scar
imaging with late gadolinium enhancement. And we wanted to
compare that to one of the most robust clinical parameters in
cardiology, which is left ventricular ejection fraction, and in
particular using a cutoff of 35%, which somehow in our clinical
management has sort of as established as a break point for many
clinical decisions.


Dr. Igor Klem:


And so we created a registry among three centers of patients who
undergo a cardiac MRI study, where we found an LVEF of less than
50% and we followed them for a number of outcomes. One is all
caused death. And then we wanted to separate a little bit the
events into those who have cardiac mortality to look at a little
epidemiology because in those patients, we have two major adverse
events: one as heart failure related mortality. One is arrhythmia
related mortality.


Dr. Greg Hundley:


And how many subjects did you include?


Dr. Igor Klem:


We included about a thousand patients from three centers and
coming to the major findings of our study, we found that both
left ventricular ejection fraction, as we know, is a robust
marker of all cause mortality and cardiac death. And so it was
the presence of myocardial scar on cardiac MRI. But the major
difference was in relation to the arrhythmic events. We founded
left ventricular ejection fraction in particular, when we use the
35% cutoff actually had very little predictive power to inform us
who is at risk of arrhythmic events. In contrast, there was a
very strong and robust relationship or multiple statistical
methods to stratify patients who are at risk for sudden cardiac
death, appropriate ICD shock, as well as arrhythmic cardiac
death.


Dr. Greg Hundley:


Very good. Well, Pasquale understand you also performed a
research study utilizing cardiovascular magnetic resonance. Could
you describe for us your hypothesis as well as what was your
population and your study design?


Dr. Pasquale Santangeli:


Thank you, Greg. And of course, thanks to the editor for the
interest in our paper. I need to thank also the first call
authors Daniele Muser and Gaetano Nucifora for putting together a
registry of 70 institutions throughout the U.S., Europe, and
Japan and the our hypothesis came from a clinical need. We do
know that patients with idiopathic ventricular re we ask, which
includes not sustain a weakness like PVCs or non-sustained VT.
Very few of them, but there is a group of them that have a higher
risk of ending malignant and up comes in terms of your ethnic
events over follow-up. And prior studies have shown that by doing
an MRI and showings and the detecting scar related announcement,
there is an increase with how we make events of a follow-up.
However, if you do look at those studies late, an answer's been
reported in up to 70% of these patients, which you never view is
a highly practical way of re-stratifying these patients, because
you have a risk factor that is present 70% of those, then it's
hard to use it for clinical decision-making.


Dr. Pasquale Santangeli:


So in this registry, which you put it again at 686 patients with
panel data idiopathic, not sustained ventricular arrhythmias,
which were defined by a normal WBC gene status, a normal
echocardiogram and a normal stress test. We looked at whether
there is a specific pattern of late announcement. So how
basically I believe lands, and it looks on the MRI, they may
predict better or outcomes over follow-up. And again, we use a
composite and Pauline the full cost mortality, but associated
cardiac arrest due to ventricular fibrillation or a
hemodynamically unstable BP, or in a subgroup of patients that
underwent ICD therapy. We also looked at, I approve SED shocks.


Dr. Pasquale Santangeli:


The groups were divided in three different categories. The first
one, which is a larger group of 85% of patients and no late
announcement. The second group, the one with late announcement,
which represents the remaining 50% of 15% of patients, we divided
it into a ring light pattern, which was defined as that word
says, as a ring like distribution of the lead announcement in the
mid-market segments, which involves a three consecutive
continuous segments in a short axis view. It looks like really at
least half the ring or three-quarters of the ring.


Dr. Pasquale Santangeli:


And the other group is the one that had the leader announcement
without a ring light pattern. And it's interesting that the third
and the latest announcement was not that similar between the ring
light and the one without ring light late announcement. What we
did find though for our follow-up the patient with a ring light
pattern, a significantly higher rate of the primary composite
endpoint, which happened in the median follow-up about 61 months
so it was quite long. And the composite outcome occurred in 50%
of patients in the ring light group versus 19% in the no ring
light a positive announcement group and a 0.3%. So really, really
rare in patients. So then concluded that of course, late
announcement does provide some information in general,
particularly the type of announcement that increases the risk
significantly. Probably although this has to be confirmed
prospective fashion patient with a ring light pattern may benefit
from other forms of interventions, including potentially
defibrillator therapy in a prophylactic fashion.


Dr. Greg Hundley:


Very nice. So now listeners, we're going to turn to our associate
editor. One of the imaging experts here at Circulation, Dr.
Victoria Delgado. Victoria, you see a lot of papers come across
your desk and as an imaging expert, what attracted you to these
two papers? And what do you think are their significance?


Dr. Victoria Delgado:


Thank you, Greg. I think that these two papers are important
because right now, if we follow the clinical guidelines, we
decide implantation. For example, of an ICD based on the ejection
fraction, and we see that in many patients based on ejection
fraction, they may not benefit ever from an ICD because they
don't have arrhythmias. What other patients who do not meet the
criteria often injection fraction below 35%. They may have still
arrhythmias. So the article by Igor highlights the relevance of
the amount of burden of late government Huntsman with CMR, in
patients with non ischemic cardiomyopathy, which are sometimes
very challenging patients on how to decide when we implant an ICD
or not. We need sometimes to base the decision on genetics.


Dr. Victoria Delgado:


If we have an on the other hand, the paper of Pasquale, these
were patients with normal echocardiogram. So what patient, having
arrhythmias where we don't see on echocardiogram, that is the
first imaging technique that we usually use to evaluate these
patients. We don't see anything, but CMR can give us more
information in terms of structural abnormalities and particularly
not only the burden of scar, but also the pattern of the scar.
And we have seen in other studies that for example, not only for
ICD implantation, but for ventricular tachycardia ablation. The
characteristics of that scar and some areas where these are short
of panel that can be targeted for that ventricular tachycardia
ablation can lead to much more precise treatment if you want of
these patients.


Dr. Greg Hundley:


Thank you, Victoria. So it sounds like listeners we're hearing
late gadolinium enhancement, regardless of EF could be
forecasting, future arrhythmic events. And then also the pattern
of late gadolinium enhancement, where contiguous segments in a
ring-like fashion may also offer additional prognostic
information. Well, now we're going to turn to our editorialists
and as you know, listeners at Circulation, we'll bring in an
editorialist to really help put things together and uniquely here
today, we have Dr. Mark Estes, who is really not an imager per
se, but like many of us uses the information from imaging to make
clinical decisions. Mark, how do you see this late gadolinium
enhancement as perhaps a new consideration for placement of
devices?


Dr. N.A. Mark Estes:


Greg, that's one of the key questions. There's no doubt, not only
based on these two studies, which extend our prior information
about LGE and patients with valid and non ischemic
cardiomyopathies that scar burden is important in predicting not
only total mortality, but arrhythmic events. All of the criteria
that were used in the original ICD studies, which include the
definite, the Skuid half Danish and made it our it trials use
only ejection fraction and functional status, no imaging. These
are legacy trials. Now, many of them, a decade or more older. And
the treatment of advanced heart failure has progressed to the
point that the total mortality is dramatically lower than it was
at the time of these studies. In some instances down to 4 or 5%
per year. The studies are important in that they identify a
subgroup of patients with low ejection fractions, less than 35%,
who might qualify for ICDs, who are unlikely to benefit.


Dr. N.A. Mark Estes:


They also identify a group of patients with preserved ejection
fraction greater than 35%, less than 50 in whom the risk of
sudden death may be substantial. And it extends prior
observations about patchy, mid Meyer, cardio wall fibrosis,
subendocardial, subepicardial and important ways. But the key
issue here, and it was alluded to with Pasquale's comments about
prospective validation, is that when one has a risk stratifier
and identifies a high risk population that has to be linked to an
unequivocal therapy, it improves survival. And we don't have that
link quite yet.


Dr. N.A. Mark Estes:


Prospective randomized trials are unlikely to be done in the low
ejection fraction because they would probably be considered
unethical. Given the trials that have shown the benefit you can't
randomize to defibrillator versus an implantable loop recorders.
I think the future really lies in risk stratification for people
with preserved ejection fractions greater than 35%, less than 50
using LG in that patient population. Currently, I think the best
information we can give to clinicians is to stick with the AHA
guidelines, which is PF less than 35% with dilated, nonischemic
class II symptoms who have had optimal medical therapy for at
least three months using perhaps in that patient population LGE
for shared decision-making in patients about the magnitude of the
risk. And I think that's as far as we can go pending future
studies, and there is one which we can discuss later on the CMR
study at just that preserved ejection fraction LGE randomizing to
defibrillator versus ILR.


Dr. Greg Hundley:


Thank you, Mark. So listeners just really quickly, let's go back
to each of our experts and ask them, you know, in 20 seconds,
Igor, Pasquale, Victoria, and Mark, what's the next study that
needs to be performed in this space? Igor, we'll start with you.


Dr. Igor Klem:


Well, number one, following on Mark's comment on the less than
35% population, I think that it's unlikely that they're
randomized clinical trial is ethical in this population, but we
may consider a wealth of registry data by now that shows that
there is a subgroup of patients who have a lower risk or lower
benefit from an ICD. I think in the preserved ejection fraction
above 35%, maybe up to 45%, 50%. That's an interesting study
that's coming up. Maybe there's more trials that can provide us
that robust information that we need today in order to change the
guidelines to risk stratify, not based on the LVF, but on the
presence of scar or maybe subgroups of scar.


Dr. Greg Hundley:


Pasquale?


Dr. Pasquale Santangeli:


Yes. So I think of course, one of the major studies is the one
already alluded by this, which is a prospective study that links
as specific therapy like ICD or even additional risk factors like
we've been using program's stimulation some of these patients to
further risk for the five to see what they can benefit.


Dr. Pasquale Santangeli:


Based another one that I think is important for the study that we
did is a mechanistic more study to understand why the ring light
pattern was there, as opposed to other patterns. We do believe we
think that some of these patients may have an initial form of lb
dominant arrhythmogenic paramount. There wasn't really a
detective before and ran. Now, if we actually extending our study
and have a registry to try to screen also the family members or
patients with ring light pattern to understand whether there is a
familiar component to it, because really we do not see this type
of pattern that commonly and it'd been associated with lb
dominant. Magnetic kind of alpha in some others, small studies.


Dr. Pasquale Santangeli:


So that's the other part to dig in a little bit more into the
field type for these patients to understand why one pattern
versus another happens and whether that gets main to, to explain
why there's a higher risk in one population versus another.


Dr. Greg Hundley:


Victoria.


Dr. Victoria Delgado:


Yeah. Following what has been said. I think that from the imaging
point of view, we are always criticizing in a way that we
increase the burden or the cost of healthcare. But I think that
these studies or any randomized study where MRI or echo is used
in order to design a therapy and show the value of using that
imaging technique to optimize the health care costs is important.
So I will not add much on which sort of populations, but probably
patients within non ischemic cardiomyopathy with preserved
ejection fraction that do not fulfill the recent scores, for
example, in hypertrophic cardiomyopathy to be implanted with an
ICD. But probably if we see a lot of scar on a AGE where specific
patterns that can help to decide which are the patients that have
benefited from an ICD implantation, for example.


Dr. Greg Hundley:


Thank you. And finally Mark.


Dr. N.A. Mark Estes:


But I think all the major points have been hit here. And
unfortunately we have a bit of a dilemma. And that dilemma is
that these legacy trials for ICDs, which selected based on low
ejection fraction and functional class II were done at a time
when contemporary heart failure treatment was not as good as it
currently is pharmacologically. And it's been reflected with a
lower total mortality. When the mortality in this patient
population gets down to the 4 and 5% per year, it's unlikely that
any intervention for prevention of sudden death is going to
impact on that total mortality.


Dr. N.A. Mark Estes:


So I do think that the registries hold a lot of promise, giving
us insights into the subgroup of patients that previously would
have been selected for defibrillators who may not have as much
benefit or who may benefit the most. And I think that they will
play an important part in perhaps refining the risk
stratification with greater sensitivity and specificity in the
patient population, less than 35%. I think the CMR guide trial is
going to be a critical trial and looking at ICDs in the patient
population between 35 and 50%, but we need to be mindful of one
thing. And that in the Danish trial, they get a sub study looking
at about 240 patients using LGE. And they found that ICD in
patients with LGE that was positive, did not make a difference in
survival or total mortality. So again, we need to get the data. I
think the best clinical practice has come out of the best
clinical evidence. You'll clearly be limitations to what we can
do, but I think in the future, we'll have much better data to
make these judgment calls.


Dr. Greg Hundley:


Very good. Well listeners, we want to thank our panelists, Dr.
Igor Clem, Pasquale, Santangeli, Victoria Delgado, and Dr. Mark
Estes for this wonderful discussion related to magnetic resonance
imaging, late gadolinium enhancement, and how it may be useful in
identifying those at risk for future arrhythmic events. On behalf
of both Carolyn and myself, 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,
2021.