Circulation November 30, 2021 Issue

Please join first author Cecilia Bahit and Associate
Editor Graeme Hankey as they discuss the article "Predictors of
Development of Atrial Fibrillation in Patients With Embolic
Stroke Of Undetermined Source: An Analysis of the RE-SPECT ESUS
Trial."


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 and Director of the
Pauley Heart Center at VCU Health in Richmond, Virginia. Well,
Carolyn, this week's feature, we're going to analyze the RE-SPECT
ESUS trial. What does that pertain to? Well, you're going to have
to wait and find out, but it relates to atrial fibrillation and
embolic stroke. But before we get to that, how about we grab a
cup of coffee and go through some of the other articles in the
issue? Would you like to go first?


Dr. Carolyn Lam:


I sure would. Greg, we know that Chronic kidney disease is
associated with adverse outcomes among patients with established
cardiovascular disease or diabetes. The question is: What are the
effects of Icosapent Ethyl across the range of kidney function in
patients with established cardiovascular disease or diabetes from
the REDUCE-IT trial?


Dr. Greg Hundley:


Ah, Carolyn, can you remind us what was the REDUCE-IT trial? What
did it encompass there?


Dr. Carolyn Lam:


The REDUCE-IT trial was a multicenter double-blind,
placebo-controlled trial that randomized statin treated patients
with elevated triglycerides, who had cardiovascular disease or
diabetes, and one additional risk factor, two treatment with
icosapent ethyl at 4g daily versus placebo. After a median follow
up period of 4.9 years, the study drug demonstrated a 25%
relative risk reduction in the primary composite endpoint of
cardiovascular death, myocardial infarction, stroke, coronary
revascularization, or unstable angina.


Dr. Greg Hundley:


Ah, great summary of the original paper, but now this is sort of
a follow-up paper. What did this paper research?


Dr. Carolyn Lam:


Well first, remember they focused on renal function and the
median baseline GFR was 75 ml/min with a range of 17 to 123
mL/min/1.73 m2. Treatment with Icosapent Ethyl led to consistent
reduction in both primary and secondary composite endpoints
across the baseline GFR categories. Patients with the GFR >60
treated with Icosapent Ethyl had the largest absolute, but
similar relative risk reduction for the primary composite
endpoint. And while patients with GFR >60 treated with
Icosapent Ethyl had the highest numerical rates of atrial
fibrillation of flutter and serious bleeding. The hazard ratios
for atrial fibrillation flutter and serious bleeding were similar
across GFR categories. In summary Icosapent Ethyl reduced
cardiovascular events among patients with elevated triglycerides
in a well-controlled LDL on statin therapy across a wide range of
baseline renal function.


Dr. Greg Hundley:


Oh, Carolyn. Beautiful presentation. That presentation was so
good that I know you are ready for a quiz. We haven't had
Carolyn's quiz in a week, so we've got to get right back to that.


Dr. Carolyn Lam:


No, we don't (laughs).


Dr. Greg Hundley:


Can you describe the primary sequelae of Hutchinson-Gilford
progeria syndrome?


Dr. Carolyn Lam:


Oh wow. Okay. So this is the syndrome where there's premature
aging, there's a lot of vascular stiffening, calcification. I'm
going to guess some sort of atherosclerotic consequence (laughs).


Dr. Greg Hundley:


Very nicely done Carolyn. Oh my goodness. I need to get you to
take my ABIM recertification-


Dr. Carolyn Lam:


(laughing)


Dr. Greg Hundley:


Beautifully done. So Carolyn, this paper comes to us from Dr.
Vicente Andrés from Centro Nacional De Investigaciones
Cardiovasculares Carlos III, and Hutchinson-Gilford progeria
syndrome is a rare disorder characterized, just like you said,
Carolyn by premature aging and death, mainly due to myocardial
infarction, stroke or heart failure. The disease is provoked by
progerin, a variant of lamin A expressed in most differentiated
cells. Carolyn, these patients look healthy at birth and symptoms
typically emerge in the first or second year of life. In
assessing the reversibility of progerin induced damage, and the
relative contribution of specific cell types is critical to
determining the potential benefits of late treatment and to
developing new therapies.


Dr. Carolyn Lam:


Wow, you've really, really piqued my interest. So what did these
investigators do and what did they find?


Dr. Greg Hundley:


Oh Carolyn, very clever design. So the authors use CRISPR-Cas9
technology to generate mice engineers to ubiquitously express
progerin while lacking lain A and allowing progestin suppression
in lain A restoration in a time and cell type specific manner
upon CRE recombinase activation. They characterize the phenotype
of these engineered mice and cross them with CRE transgenic lines
to assess the effects of suppressing progestin and restoring lain
A ubiquitously at different disease stages, as well as
specifically in vascular smooth muscle cells and cardiomyocytes.
So Carolyn, what did they find? Well, number one, like
Hutchinson-Milford progenia syndrome patients, their engineered
mice appeared healthy at birth, and progressively developed
Hutchinson-Milford progenia syndrome symptoms, including failure
to thrive, Lipodystrophy, vascular smooth muscle cell loss,
vascular fibrosis, electric cardiographic anomalies and early
death. Their median lifespan was 15 months versus 26 months in
the wild types.


Dr. Greg Hundley:


Second, ubiquitous progestin suppression in lain A restoration
significantly extended lifespan, when induced in six month old,
mildly symptomatic mice, and even in severely ill animals aged 13
months, although the benefit was much more pronounced upon the
early intervention. And then finally, Carolyn remarkably major
vascular alterations were prevented and lifespan normalized in
engineered Hutchinson-Milford progenia syndrome mice when
progestin suppression and lain A restoration were restricted to:
just Vascular smooth muscle cells and Cardiomyocytes.


Dr. Carolyn Lam:


Wow, just fascinating, but, okay. What is the clinical take home
message?


Dr. Greg Hundley:


Right, Carolyn. So these authors findings suggest that it is
never too late to treat Hutchinson-Milford progenia syndrome,
although the benefit is much more pronounced when progestin is
targeted early in mice with mild symptoms. Also, restricting its
suppression to Vascular smooth muscle cells in Cardiomyocytes is
sufficient to prevent Vascular disease and normalize lifespan in
mice, and therefore these data suggest that strategies to treat
Hutchinson-Milford progenia syndrome through gene therapy or RNA
therapy should consider targeting Vascular smooth muscle cells
and Cardiomyocytes.


Dr. Carolyn Lam:


Oh wow. Very, very cool. Well, my next paper is a basic science
paper that's significant for both its methods and its results.


Dr. Greg Hundley:


Oh wow, Carolyn, I can't wait. So tell us about this novel
methodology.


Dr. Carolyn Lam:


Well, this paper is from Dr. Chang from Westlake University in
Hangzhou, China, and colleagues who use a gene editing approach
to efficiently institute Exon Skipping without introducing DNA
double-strand breaks. So harnessing a fusion of a nuclease
defective Case protein, and a cytidine deaminase, which is, we're
going to abbreviate it as Targeted AID-induced mutagenesis (TAM)
or base editor three (BE3), their approach precisely edited
conserved guanines at splice sites, thus abrogating Exon
recognition resulting in a programmable skipping of the targeted
Exons. Isn't that neat?


Dr. Greg Hundley:


Yeah, it really is sophisticated Carolyn, wow. So what did they
do using these methods?


Dr. Carolyn Lam:


A novel mirroring model of Duchenne muscular dystrophy was
generated, which recapitulated many cardiac defects observed in
the human form of the disease, including dilated cardiomyopathy,
reduced left ventricular function and extensive cardiac fibrosis.
Using this model, they examined the feasibility of using a
cytidine base editor to install Exon Skipping and rescue the
dystrophic cardiomyopathy in vivo. A single dose administration
of an Adenovirus 9EtAm, instituted over 50% targeted Exon
Skipping in the Chengdu muscular dystrophy transcripts and
restored up to 90% dystrophin in the heart. And as a result,
early ventricular remodeling was prevented and cardiac and
skeletal muscle function were improved, leading to an increased
lifespan of the mice. Despite gradual decline of the Adenovirus
vector and base editor expression, the dystrophin restoration and
pathophysiological rescue of muscular dystrophy lasted for at
least a year. And so this technique really has the potential to
be applied to monogenic human diseases, to modulate Exon Skipping
or inclusion. Isn't that cool?


Dr. Greg Hundley:


Absolutely, Carolyn. Beautifully explained.


Dr. Carolyn Lam:


Well, let me end by sharing what else is in today's issue.
There's a Perspective piece by Dr. Alexander on “Chest Pain
Redux: Updated and Patient Centered.” There is an In Depth paper
by Dr. Kroemer on NAD plus metabolism in cardiac health, aging
and disease. And there's a Research Letter by Dr. Shepherd on
sudden death in female athletes, with insights from a large
regional registry in the United Kingdom.


Dr. Greg Hundley:


Very good, Carolyn. What a great issue. Now, how about we get to
that feature discussion?


Dr. Carolyn Lam:


Let's go, Greg.


Dr. Greg Hundley:


Welcome listeners to our feature discussion today on this
November 30th. And we have with us Dr. Cecilia Bahit from
Rosario, Argentina and our own associate editor, Dr. Graeme
Hankey from Perth, Australia to talk to us about a paper
pertaining to Atrial Fibrillation. Welcome to you both, and
Cecilia, we'll start with you. Could you describe for us a little
bit of the background information that went into formulating your
study, and then what hypothesis did you want to address?


Dr. Cecilia Bahit:


Thank you for the invitation. So we all know that embolic stroke
of undetermined source, which is called ESUS isn't just a subset
of cryptogenic stroke, and is associated with stroke recurrence
about 3-6% per year. And on the other hand, we know that
continuous cardiac monitoring in this patient population shows
that atrial fibrillation can be detected between 10% at six
months or 30% at three years. So the underlying atrial
fibrillation may be a mechanism for the recurrent thromboembolic
stroke in this patient population. So we know that prior studies
have identified some predictors of atrial fibrillation in these
patients. And if we are able to identify which patients could
benefit from cardiac monitoring and have a higher yield to detect
atrial fibrillation, we could do a better job at treating them.
So, that was our idea behind the paper. So using the RE-SPECT
ESUS trial, which was a trial that included patient with ESUS
stroke and were randomized to the bigger trend versus Aspirin, we
look at predictors of atrial fibrillation unassociated regarding
stroke.


Dr. Greg Hundley:


Very nice. And so, now was this a sub-study here and maybe define
for us a little bit, your study design and specific study
population.


Dr. Cecilia Bahit:


So this was a secondary analysis of a randomized clinical trial
that as mentioned it was not a sub-study, it was a secondary
analysis. We thought all along to do it because of the interest
of the clinical question. We look at the total patient population
was 5,390 patients. And we looked at those patients who developed
atrial fibrillation during the 19 months of follow-up. And it was
7.5%, 403 patients developed atrial fibrillation.


Dr. Greg Hundley:


Very good. And what were your results?


Dr. Cecilia Bahit:


So, as I mentioned, we saw that 7.5% of our patient population
developed atrial fibrillation during the follow-up. And we know
those patients were older, were like, have higher morbidities,
and we assessed, we did an one variable analysis and then a
multi-variable analysis, trying to identify predictors for atrial
fibrillation. And for our model, we identified different
predictors, older age, hypertension, lack of diabetes, and higher
body mass index, were independent predictors of atrial
fibrillation. So the patients who have atrial fibrillation have a
higher recurrence of stroke, it was 7.2 versus four, compared to
those that did not have atrial fibrillation.


Dr. Cecilia Bahit:


So I think there's an important part, that 20% of the patient
population of the overall trial, this is a little more than a
thousand patients, had NT-prob measure at baseline. And when we
included this biomarker into the model, only older age and
NT-prob were independent predictors of atrial fibrillation. In
addition, even though this was not the objective of this
analysis, we look at the treatment effect of the bigger trend.
And even though we saw that there was a statistical benefit of
the bigger trend versus Aspirin in the higher group of these in
our score, the overall treatment effect was not there. So we
couldn't assess the fact that the bigger trend was better
compared to Aspirin in patient with atrial fibrillation, but of
course the numbers were very small.


Dr. Greg Hundley:


Very good. Thank you so much for that wonderful description. And
Graeae, now we'll turn to you as associate editor for us at
Circulation, and also the editorialist on this particular paper.
What caught your attention about this particular study and the
results from the many papers that really come across your desk.


Dr. Graeme Hankey:


Thank you, Greg. And congratulations to Cecilia and her RE-SPECT
ESUS colleagues. I mean, this is a landmark study, the RE-SPECT
ESUS study, and just to go back, embolic stroke of undetermined
source is really common. About one in four ischemic strokes, we
don't know the cause of, and it's one of the major subtypes of
cryptogenic stroke is an embolic ischemic stroke in which the
source could have come from the heart or the aortic arch or the
carotids. And we're not really sure. And we think that some of
these patients have occult atrial fibrillation, but we can't pick
it up at the time. So one way is to try and monitor them with
prolonged ECG monitoring. And another way is to actually treat
them with anticoagulation because we know that, that's more
effective in people with cardio embolic stroke. And so RE-SPECT
ESUS and NAVIGATE ESUS used the latter strategy and said, let's
see if treating people with ESUS with anticoagulation is more
effective than antiplatelet therapy.


Dr. Graeme Hankey:


And both studies were not significant in terms of showing that
Dabigatran or Parovarian for NAVIGATE ESUS was more effective
than antiplatelet therapy. So we're left now with this default
that all patients with ESUS just get Aspirin, but we have a hunch
that some of them actually have cardiogenic embolism and are
being undertreated with Aspirin and need anticoagulation. So it's
a heterogeneous entity, but we're treating it homogeneously with
a sort of weak antiplatelet. So we want to try and find out who's
going to get AF or who's already got it that is occult. And this
study is a really great and prospective study with 5,000 patients
as Cecilia said, who of whom 7% did develop AF just through
annual ECG reporting and just with symptom reporting. And that's
probably an under report. You know, if they'd had monitoring,
they probably would've found about 20 or 30% would've developed
AF during that time of 19 months follow up.


Dr. Graeme Hankey:


And it's the first study to really then show that not just the AF
people had a higher stroke rate, but in that group who they
predicted to be at high risk of AF with older age and the
NT-prob, that the high risk group had a significant reduction
with Dabigatran versus Aspirin in that high risk group. It's
just, when you look for hetero homogeneity or heterogeneity
across the risk groups, it wasn't quite significant. And that
might be because it's not significant or it might be that study
was underpowered to look at those three, across those three risk
subgroups. And also it might be a bit confounded because of it,
the patients weren't randomized according to their risk status
for AF, they were just randomized, whether they had ESUS, so it's
further excited us that there might be a subgroup who needs
anticoagulation. And that's why the ARCADIA trial is ongoing now,
looking at where the people with ESUS who have high risk of AF
benefit from a apixaban versus aspirin.


Dr. Greg Hundley:


Very nice. And so, with these results that we have here, maybe
come back to Cecilia, what do you think would be the next series
of studies that needs to be performed in this area of research?


Dr. Cecilia Bahit:


Well, there's one side that's ongoing as Dr. Hankie mentioned,
but I think we should be able to identify which patients have a
higher risk of atrial fibrillation and those patients who use
cardiac monitoring for long term to identify atrial fibrillation
and to treat properly. So I think that would be key in this area.


Dr. Greg Hundley:


Very nice. And Graeae, what are your thoughts?


Dr. Graeme Hankey:


Yes. Well, one way is to have our ESUS patients have prolonged
ECG monitoring by implantable loop recorders, for example, and
then those who develop AF randomizing them to anticoagulation
versus antiplatelet therapy. Although if they declare themselves
with AF they're usually just go straight onto anticoagulation
therapy. So the burning question is, in these people with ESUS
who haven't declared themselves as AF, but have predictors of AF
like those shown in RESPECT ESUS, like older age, high blood
pressure, high BMI ,prob, and perhaps echo features, like left
atrial size or ECG features like lots of premature atrial
contractions or P wave of abnormalities.


Dr. Graeme Hankey:


Are these, the subgroups or even LV dysfunction, are these
subgroups who need to be more specifically targeted in a
randomized trial rather than the whole group of ESUS. And also
with longer follow up. NAVIGATE ESUS stopped after 11 months. The
bigger RESPECT ESUS stopped after a median follow up of 16 months
and the curves were diverging. Maybe with five years follow up, a
lot of these people would've developed AF and would've benefited
from longer term anticoagulation, but the trials were stopped
early, because there wasn't a signal of benefit and there was an
early risk of bleeding with anticoagulation.


Dr. Greg Hundley:


Very good. Well listeners, this has been a really interesting
study and we want to thank Cecilia and Graeme for sharing results
of the RESPECT ESUS study, highlighting that, in patients with
embolic stroke of undetermined source, atrial fibrillation occurs
and is a possible source of this stroke, and then also older age,
and elevation of NT-prob can be associated with development of
atrial fibrillation, subsequent to that stroke event.


Dr. Greg Hundley:


Well listeners, we want to wish you a great week. And on behalf
of Carolyn and myself, look forward to catching 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.