Circulation July 6, 2021 Issue

This week's show features a panel discussion between authors
Adrian Wells and Hyeon Chang Kim as they discuss their articles
"Improving the Effectiveness of Psychological Interventions for
Depression and Anxiety in Cardiac Rehabilitation PATHWAY—A
Single-Blind, Parallel, Randomized, Controlled Trial of Group
Metacognitive Therapy" and "Associations of Ideal Cardiovascular
Health and Its Change During Young Adulthood With Premature
Cardiovascular Events: A Nationwide Cohort Study."


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, also your co-host. And Associate
Editor, Director of the Pauley Heart Center, VCU Health in
Richmond, Virginia.


Dr. Carolyn Lam:


Greg, we're starting off the month with double features, and
these are just so interesting. The first paper talks about
psychological interventions for depression and anxiety in cardiac
rehabilitation. And the next talks about ideal cardiovascular
health and its change during young adulthood and how that relates
to premature cardiovascular events. Cool, huh?


Dr. Greg Hundley:


Absolutely. Well, Carolyn. How about we grab a cup of coffee and
start discussing some of the other articles in the issue? And I
could go first. Carolyn, the first article that I've got is from
Mrs. Elizabeth Jordan from Ohio State University Wexner Medical
Center. And it really pertains to cardiomyopathies. And remember,
Carolyn, classically, we categorize hypertrophic, dilated, and
arrhythmogenic right ventricular cardiomyopathy. And each has a
signature genetic theme. Hypertrophic cardiomyopathy and ARVC are
largely understood as genetic diseases of sarcomere or desmosome
proteins. But in contrast, there are over 250 genes spanning more
than 10 gene ontologies that have been implicated in dilated
cardiomyopathy. And therefore, it really represents a very
complex and diverse genetic architecture. So to clarify this, a
systematic curation of evidence to establish the relationship of
genes with dilated cardiomyopathy was conducted by an
international panel with clinical and scientific expertise in
dilated cardiomyopathy genetics. And they evaluated evidence
supporting monogenic relationships of genes with idiopathic
dilated cardiomyopathy.


Dr. Carolyn Lam:


Oh, wow. That sounds like a lot of work. And what did they find,
Greg?


Dr. Greg Hundley:


Right, Carolyn. So in the curation of 51 genes, 19 had high
evidence. 12 are definitive strong, and seven moderate. And
notably, these 19 genes only explain the minority of cases,
leaving the remainder of dilated cardiomyopathy genetic
architecture really incompletely addressed. And clinical genetic
testing panels include most high evidence genes. However also,
the panel noted that genes lacking robust evidence are very
commonly observed clinically.


Dr. Greg Hundley:


So Carolyn, the take home message from this international panel
is that while dilated cardiomyopathy genetic testing panels
include an average of about 60 genes, when curating published
evidence for dilated cardiomyopathy, only 19 have really emerged
as high levels of evidence. And then in this study, 51 genes were
evaluated. And the 19 genes appraised as high evidence were
recommended to be routinely used in the genetic evaluation of
dilated cardiomyopathy. And one more point. Rare variants from
genes without moderate, strong, or definitive evidence should not
be used in clinical practice to predict dilated cardiomyopathy
risk most importantly when also you're screening at risk family
members.


Dr. Carolyn Lam:


Wow. Very nice. Stunning numbers. Well, my paper is identifying a
novel therapeutic target in pulmonary arterial hypertension. Do
you want to know what that is?


Dr. Greg Hundley:


Ah, yes, Carolyn. Very interesting. So what is it?


Dr. Carolyn Lam:


It's switch-independent 3A. Which is an epigenetic modifier,
which is drastically down-regulated in pulmonary arterial
hypertension patients and rodent models of pulmonary arterial
hypertension. And strongly associated with decreased bone
morphogenic protein receptor type two, or BMPR2 expression. So
this switch-independent 3A overexpression up-regulated BMPR2
expression by modulating critical epigenetic pathways and
decreasing a specific transcription factor binding to the BMPR2
promoter in pulmonary vascular smooth muscle cells. Furthermore,
aerosolized lung-targeted gene transfer of adeno-associated virus
zero type one and containing switch-independent 3A reversed and
prevented pulmonary arterial hypertension phenotype in
preclinical animal models. So this beautiful study, from Dr.
Hadri from Icahn School of Medicine at Mount Sinai in New York
and colleagues, really suggests that switch-independent 3A can be
a clinically relevant molecule for the treatment of pulmonary
arterial hypertension.


Dr. Greg Hundley:


Wow, Carolyn. Really nice. Very intricate science for the study
of pulmonary hypertension. Well, my next paper actually comes to
us from Dr. Joe Hill and colleagues at UT Southwestern Medical
Center. And Carolyn, as we know, cardiac hypertrophy is an
independent risk factor for heart failure. Of course, the leading
cause of morbidity and mortality globally. And the calcineurin
NFAT, or nuclear factor of activated T-cells pathway, and the MAP
kinase ERK, or extra cellular signal regulated kinase pathway,
contributes to the pathogenesis of cardiac hypertrophy as an
interdependent network of signaling cascades. However, Carolyn,
how these pathways interact really remains unclear. And so Dr.
Hill and colleagues engineered a cardiomyocyte-specific ETS2, a
member of the E26 transformation specific sequence or ETS domain
family knockout mouse, and investigated the role of ETS2 in
cardiac hypertrophy. Primary cardiomyocytes were also used to
evaluate ETS2 function in cell growth.


Dr. Carolyn Lam:


Wow. Okay. So what were the results, Greg?


Dr. Greg Hundley:


Right, Carolyn. Three main findings. First, ETS2 is activated by
ERK1/2, or extracellular signal-regulated kinase 1/2, in both
hypertrophied murine hearts and in human dilated cardiomyopathy.
Second, ETS2 is required for both pressure overload, and
calcineurin induced cardiac hypertrophy responses involving
signaling cascades distinct from, but interdependent with ERK1/2
signaling. And third, this group discovered that ETS2 synergizes
with NFAT to transactivate RCAN1-4, an established downstream
target of NFAT, or nuclear factor of activated T-cells. And they
identified an MIR-223 as a novel transcriptional target of NFAT
ETS2 in cardiomyocytes.


Dr. Carolyn Lam:


Wow. Wow. That sounds like a lot of detailed work. Could you tell
us what the clinical implications are, Greg?


Dr. Greg Hundley:


You bet, Carolyn. So in aggregate, these findings unveil a
previously unrecognized molecular interaction between two conical
hypertrophic signaling pathways, MAP kinase-driven hypertrophy,
and calcineurin driven hypertrophy. And therefore, as
pathological cardiac hypertrophy is an established risk factor
for heart failure development, this unveiling of novel signaling
mechanisms really is of potential clinical relevance.


Dr. Carolyn Lam:


Thanks, Greg. Well, let's round up with what else there is in
this week's issue. There's a Frontiers paper by Dr. Chris
Granger. And it's a big call to action to the cardiology
community, to incorporate SGLT2 inhibitors and GLP-1 receptor
agonists for cardiovascular and kidney disease risk reduction.
There's a Joint Opinion piece from the American Heart
Association, World Heart Federation, American College of
Cardiology, and European Society of Cardiology on, “The Tobacco
Endgame: Eradicating a Worsening Epidemic,” by Dr. Elkind.


Dr. Greg Hundley:


Oh great, Carolyn. Well, I've got an On My Mind piece from
Professor Bhatt. And it's entitled, “Does SGLT1 inhibition Add
Benefit to SGLT2 Inhibition in Type 2 Diabetes Mellitus?” And
next, Dr. Viskin has an ECG Challenge entitled, “Long QT Syndrome
and Torsade de Pointes Ultimately Treated With Quinidine, The
Concept of Pseudo Torsade de Pointes.” And then finally, there's
a Letter to the Editor by Dr. Lu regarding the article,
“Association of Body Mass Index and Age with Morbidity and
Mortality in Patients Hospitalized with COVID-19, Results from
the American Heart Association COVID-19 Cardiovascular Disease
Registry.” Well, Carolyn, I can't wait to get on to this double
feature.


Dr. Carolyn Lam:


Me too. Let's go.


Dr. Greg Hundley:


Welcome, listeners, to our feature discussion today. And again,
we're going to create today a forum, because we have two very
interesting papers to present during this timeframe. Our first is
going to come to us from Dr. Adrian Wells from University of
Manchester. And our second paper will come to us from Dr. Hyeon
Chang Kim from Yonsei University. I want to welcome you both,
gentlemen. And Adrian, I would like to start with you. Tell us a
little bit about the background related to your study. And then
what was the hypothesis that you wanted to address?


Dr. Adrian Wells:


Okay, well thank you for inviting me to take part in this
podcast. Following cardiac events, around one in three
individuals will develop significant anxiety and depression
symptoms. And we know that anxiety and depression can have an
impact on prognosis, quality of life, future outcomes.
Psychological treatment isn't routinely offered in cardiac
rehabilitation for anxiety and depression, despite the fact that
we identified that many of our patients felt that they would
benefit from a psychological intervention to address these
issues. And they felt that their needs were not really being met.
So our primary question was, can we improve psychological
outcomes in patients with cardiovascular disease?


Dr. Greg Hundley:


Very nice. And Adrian, what was your study population? And also,
what was your study design?


Dr. Adrian Wells:


So we selected patients who entered cardiac rehabilitation in the
UK. So these are patients with acute coronary syndrome,
revascularization, stable heart failure, heart transplantation,
and so on. And so, a wide group of individuals. We recruited 332
patients, all of whom had had anxiety and depression scores of
eight or more. So these were people showing mild to severe levels
of psychological distress. We conducted a two arm single blind
randomized controlled trial, with 332 patients who were randomly
allocated to one of these two conditions. And we assessed anxiety
and depression symptoms before treatment at four months and at 12
months.


Dr. Greg Hundley:


Describe a little bit some of the specifics of your intervention.
And then what did you find?


Dr. Adrian Wells:


We use relatively recent new treatment called metacognitive
therapy. And this was delivered in a group format over six
sessions. And we trained cardiac rehabilitation staff, nurse
consultants, physiotherapists, in the delivery of this
intervention. Metacognitive therapy works on helping patients
discover unhelpful patterns of thinking, such as worrying and
ruminating ,and excessive threat monitoring. And to reduce those
patterns of thinking that contribute to anxiety, depression, and
poor adaptation following stressful life experiences.


Dr. Greg Hundley:


And what did you find?


Dr. Adrian Wells:


Well, what we found was that the addition of metacognitive
therapy to treatment to usual cardiac rehabilitation,
significantly improved outcomes at four months and 12 months.
What was striking about this was that our effect sizes were
modest and moderate to large. They seem to be larger than those
obtained in other studies or psychological treatments. And of
note, the treatment seemed to impact well on both anxiety and
depression symptoms. Whereas other types of intervention
evaluated in the past have tended to treat the depression, but
not so much the anxiety.


Dr. Greg Hundley:


Very good. So it sounds like a group-based intervention. And I'm
assuming maybe participants interacted not only with your staff,
but with one another. How would you put your results really in
the context with other research that's going on in this space?


Dr. Adrian Wells:


Well, there have been a number of studies in the past that have
looked at individual and group-based treatments, and patient
preference for different types of intervention. I think this is
the first study to use a clear manualized intervention that's
based on the psychological theory of mechanisms that contribute
to the maintenance of psychological problems. Obviously, this
tended to use more prescriptive interventions like anxiety
management, stress management, taking techniques from a range of
different sources. So I think there's a difference of conceptual
basis to this kind of intervention. And it's something that is
highly manualized and structured, and in fact can be delivered by
a range of different healthcare professionals.


Dr. Greg Hundley:


Very nice. And also during cardiovascular rehab. Correct?


Dr. Adrian Wells:


Absolutely, yeah. During cardiac rehab. One interesting
finding... And we were a little concerned that this might
adversely affect attendance at cardiac rehab. But we found that
the treatment was well tolerated, and it didn't have any negative
impact on attendance at these other sessions.


Dr. Greg Hundley:


Excellent. Well, congratulations on this new finding. Well,
listeners, we're next going to turn to Dr. Hyeon Chang Kim from
Yonsei University in Korea. And Yong-Chan, could you describe for
us also the background related to your study, and the hypothesis
that your research wanted to test?


Dr. Hyeon Chang Kim:


Thank you for inviting me to this wonderful discussion. South
Korea is among the countries with the lowest cardiovascular
mortality in the world. And the rate is even decreasing. However,
cardiovascular risk factor is worsening. Especially in younger
generation in Korea. So these young people may not have a very
high cardiovascular risk, but I wanted to know the potential
impact of worsening cardiovascular risk profile in this younger
Korean generation. And furthermore, I wanted to know how much we
can lead youth cardiovascular risk by improving their
cardiovascular health profile.


Dr. Greg Hundley:


Very nice. And so tell us about your study design and what was
the study population, related to your study?


Dr. Hyeon Chang Kim:


My study is basically based on the national health checkup
program and national health insurance claim database. In Korea,
adults over the age of 20 and employed workers of all ages are
required to take general health checkup every two years. The
participation rate is between 70 and 80%. So we identified three
and a half million adults, age 20 to 39 years, who complete the
health checkup. And cardiovascular health scores was calculated
as the number of ideal cardiovascular health component, which
include non-smoking, moderate physical activity three times a
week, body mass index below 2030, normal blood pressure, normal
cholesterol and normal fasting glucose. So the score can range
from zero to six. And higher score meaning better cardiovascular
health. Our outcomes were myocardial infarction, stroke, heart
failure, and cardiovascular deaths in about 16 years. In
addition, we also evaluate the risk of cardiovascular disease.
According to two year change in how the vascular health score
using repeated health checkup data.


Dr. Greg Hundley:


Very nice. So evaluating a set of behavioral patterns and risk
factors in younger individuals, and then predicting what their
longer term adverse cardiovascular outcomes would be. So what did
you find?


Dr. Hyeon Chang Kim:


So even in this relatively low risk population, better
cardiovascular health score was associated with significantly
lower cardiovascular risk. About 20% reduction per one point
higher score. And more importantly, people with improving
cardiovascular score over two years showed leading toward
cardiovascular risk. Even if their baseline cardiovascular health
score was very low.


Dr. Greg Hundley:


Really unique findings. Tell us about the impact of your results
relative to other studies published in this space. And was this
also.... This was unique, because it's an Asian population,


Dr. Hyeon Chang Kim:


Asian population. And we are among the very low risk population.
And even in this low risk population, cardiovascular health score
was... Fear can be a good predictor of cardiovascular risk. And
compared to many Western countries, we have very low
cardiovascular risk. And our population was younger than most
other studies. So we can provide some evidence that even in the
higher risk population, they can do much better, based on our
study. Another important thing, we can check the impact of a
changing cardiovascular score, even in the younger generation.


Dr. Greg Hundley:


Very good. And just as a frame of reference for our listeners.
Give us some characteristics, if you wouldn't mind, on what
really constitutes practically a low risk score, versus what
would constitute a high risk score


Dr. Hyeon Chang Kim:


In this younger Korean population, their cigarette smoking, and
their obesity, and physical inactivity are the most common causes
of worsening cardiovascular profile. And the behavioral risk
factor also can attack the blood glucose and cholesterol blood
pressure. So in this younger generation, they're keeping the good
behavior. Past behavior is very important and it's beneficial in
the very long-term.


Dr. Greg Hundley:


Very nice, well listeners. We're going to turn to our experts
here. Two very interesting studies. And ask them both, what do
they think is the next study that needs to be performed in their
respective areas of research? So Yong-Chan, we'll start with you.
Since we just discussed your paper. What do you think is the next
study to be performed really in this sphere of research.


Dr. Hyeon Chang Kim:


Korea is a relatively low cardiovascular risk, has a very small
size, and no racial diversity. But even in this country,
disparity and inequality in cardiovascular health is becoming an
important issue. So I want to identify subcultural relatively
poor cardiovascular health among younger population. And also I
want to find ways to improve their cardiovascular score. The
conventional approaches, such as education and mass campaign, are
less effective oppose this younger adults have a poor
socioeconomic status. So, we may need to develop newer
target-specific strategies to improve their cardiovascular
health.


Dr. Greg Hundley:


Good. And Dr. Wells, our agent will turn next to you. What do you
see is the next area of investigation or research study that
needs to be performed in your sphere of interests?


Dr. Adrian Wells:


Well, I think the next step is to look at rollout of this
intervention. Is that feasible, and how acceptable is this to
cardiac services? In fact, the National Institute of Health
Research have just awarded us some funding to examine feasibility
and barriers to implementation in the healthcare system. In
addition to that, we're beginning to examine the effects of
metacognitive therapy with other health conditions, such as
cancer in children and adolescents.


Dr. Greg Hundley:


Nice. Well listeners, we have had just a wonderful discussion
today from both Dr. Adrian Wells from University of Manchester.
Who brought to us combining a group-mediated, psychological
stress-reducing, anxiety-reducing, intervention to the cardiac
rehab sphere. And how impactful that was in reducing both
anxiety, and overall depressive symptoms. And then also exciting
research from Dr. Hyeon Chang Kim from South Korea. Identifying
for us that in Asian population, as well as what we know in other
races, those individuals in their twenties to thirties with
favorable lifestyle habits, have reduced cardiovascular risk much
later in life.


Dr. Greg Hundley:


Well, on behalf of both Carolyn and myself, we want to wish you a
great week. And we'll catch you next week on the run.


Dr. Greg Hundley:


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.