Circulation April 19, 2022 Issue

This week, please join author Andrew Chapman and Guest
Editor Harvey White as they discuss the article "Coronary Artery
and Cardiac Disease in Patients With Type 2 Myocardial
Infarction: A Prospective 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, Associate Editor and Director of the
Pauley Heart Center at VCU Health in Richmond, Virginia.


Dr. Greg Hundley:


Well, Carolyn, this week's feature on April 19th refers to
coronary artery and cardiac disease in patients with type two
myocardial infarction. And we will have more to learn about that,
but how about we grab a cup of coffee and get started with some
of the other articles in the issues.


Dr. Carolyn Lam:


Please? You first.


Dr. Greg Hundley:


Thanks Carolyn. So Carolyn, this team investigated the
observational and causal associations of 90 cardiovascular
proteins, which were measured using affinity based proteomic
assays to estimate their association with incident heart failure.
And so to accomplish this, the team, led by Dr. Thomas Lumbers
from University College of London, utilized a fixed effect
meta-analysis of four population-based studies comprising a total
of 3,000 plus participants with 732 heart failure events. Now,
the causal effects of heart failure associated proteins were then
investigated by Mendelian randomization using CIS protein,
quantitative loci, genetic instruments identified from
genome-wide association studies or GWAS and over 30,000
individuals.


Dr. Carolyn Lam:


Wow! Big study, important stuff. So what did they find?


Dr. Greg Hundley:


Right Carolyn, several things. So 44 of 90 proteins were
positively associated with the risk of incident heart failure.
Now, among these eight proteins had evidence of a causal
association with heart failure that was robust to multiverse
sensitivity analysis. Higher CSF1, Galectin-3 and KIM-1 or kidney
injury molecule one were positively associated with the risk of
heart failure, whereas higher adrenomedullin chitinase-3
like-protein-1, cathepsin L1, and fibroblast growth factor 23,
and matrix metalloproteinase 12 were protective. And so Carolyn
in summary, the team identified 44 circulating proteins that were
associated with incident heart failure of which eight showed
evidence of a causal relationship, and seven were identified as
being drugable, including adrenomedullin, which represents a
particularly promising drug target.


Dr. Greg Hundley:


Additionally, Carolyn, this is a really interesting study as the
teams approach demonstrates a tractable roadmap for the
triangulation of population genomic and proteomic data for the
prioritization of therapeutic targets for complex human diseases.


Dr Carolyn Lam:


Wow! Super cool. Yeah, indeed the methodology is significant
there too. Thanks Greg. Well, this next paper deals with
hypertrophic cardiomyopathy and we know that familial
hypertrophic cardiomyopathy is the most common inherited cardiac
disease and is typically caused by mutations in genes encoding
sarcomeric proteins that regulate cardiac contractility. But how
exactly is the dysregulated sarcomeric force production sensed
and how does that lead to pathological remodeling?


Dr. Carolyn Lam:


Well, today's authors and they are Dr. Qyang from Yale University
School of Medicine and colleagues gained insights from a severe
phenotype of an individual with hypertrophic cardiomyopathy and a
second genetic alteration in a sarcomeric mechanosensing protein.
They derived cardiomyocytes from patient specific induced
pluripotent stem cells and developed robust, engineered heart
tissues to study human cardiac mechanobiology at both cellular
and tissue levels. They further used computational modeling for
muscle contraction and rescue of disease phenotype via gene
editing and pharmacological interventions to identify a new
mechanotransduction pathway in hypertrophic cardiomyopathy.


Dr. Greg Hundley:


Wow, Carolyn! Tell us more about this new pathway.


Dr. Carolyn Lam:


The study presents a novel biomechanical mechanism by which
enhanced myofilament contractile force generation due to
sarcomeric mutations, destabilize the muscle limb protein Z-disc
mechanosensory complex, and this leads to disinhibition of
calcineurin nuclear factor of activated T-cells or NFAT signaling
and consequently leads to hypertrophy. Normalization of
hypercontractile force in proband cardiomyocytes either with gene
editing approaches or with ectomyosin crossbridge inhibitor
mavacamten, resulted in an increase in Muscle Lim Protein levels,
a decrease in that calcineurin and fat activity and a rescue from
the hypertrophic cardiomyopathy defects.


Dr. Carolyn Lam:


The authors provided evidence that the common Muscle Lim Protein
W4R variant is an important modifier that worsens the disease
severity of hypertrophic cardiomyopathy, but alone does not
appear sufficient to cause disease. All in all, these data
established a foundation for developing innovative
mechanism-based treatments for hypertrophic cardiomyopathy that
stabilize the Z-disc Muscle Lim Protein mechanosensory complex.


Dr. Greg Hundley:


Oh, wow Carolyn! What a really nice mechanistic study and
important new information too. Well, Carolyn, my next paper comes
to us from Dr. Anthony Rosenzweig, Massachusetts General Hospital
at the Harvard Medical School and Carolyn the LV myocardium
increases in mass in response to pathological as well as
physiological stimuli. The former or pathologic hypertrophy,
often proceeds cardiomyocyte loss and heart failure. The latter
or physiologic, paradoxically protects the heart enhances
cardiomyogenesis. The mechanisms underlying these differences
remain incompletely understood. Now, while long non-encoding RNAs
are important in cardiac development and disease associated with
pathologic hypertrophy, less is known about their roles in
physiologic hypertrophy or cardiomyogenesis.


Dr Carolyn Lam:


Oh, interesting! So what did these authors find about link RNAs
and physiologic hypertrophy?


Dr Greg Hundley:


Right, Carolyn. So in this study of mice, the authors identified
exercise regulated cardiac link RNAs termed lncExACT and
lncExACT1 was evolutionarily conserved and decreased in exercised
hearts, but increased in experimental heart failure. Cardiac
lncExACT1 over expression caused pathological hypertrophy and
heart failure while lncExACT1 inhibition induced physiologic
hypertrophy and cardiomyogenesis protecting against cardiac
fibrosis and dysfunction.


Dr. Greg Hundley:


Now, lncExACT1 functioned by regulating microRNA 222 calcineurine
signaling, and Hippo/Yap1 signaling through DCHS2. Cardiomyocyte
DCH2 over expression in zebra fish induced pathological
hypertrophy and impaired cardiac regeneration promoting scarring
after this injury. In contrast mirroring DCH2 deletion, induced
physiological hypertrophy and promoted cardiomyogenesis.


Dr. Carolyn Lam:


Oh, wow, Greg! Okay. Could you wrap it up for us? What's the take
home message?


Dr. Greg Hundley:


You bet, Carolyn. These studies identify that lncExACT1 DCHS2 is
a novel pathway regulating cardiac hypertrophy and
cardiomyogenesis. lncExACT1 DCHS2 acts as a master switch,
toggling the heart between physiological and pathological growth
to determine functional outcomes, providing a potentially
tractable therapeutic target for harnessing the benefits of
exercise.


Dr Carolyn Lam:


Oh, thank you, Greg. Well, also in this issue is an In-Depth
paper by Dr. Luesebrink on “Percutaneous Transvalvular Micro
Exhale Flow Pump Support in Cardiology.” There's a Research
Letter by Dr. Shekhar on “Age and Racial or Ethnic Disparities in
Pediatric Out-of-Hospital Cardiac Arrest.”


Dr. Greg Hundley:


Right, Carolyn. Well, Carolyn from the mailbag, we have a Letter
to the Editor from Dr. Gronda entitled “The Failing Heart and
SGLT2 inhibitor Renal Effects: Are They Mutually Engaged in
Business?” We also have from Dr. Viskin, an ECG challenge
entitled “Sinus Node Dysfunction with a Nice Twist.” And finally,
Carolyn, there's a Perspective piece from Dr. Schulman entitled
“The Price and Quality of the Generic Pharmaceutical Market.”
Well, how about at Carolyn we get on our feature discussion
involving type two myocardial infarction.


Dr. Carolyn Lam:


Yay! Let's go.


Dr. Greg Hundley:


Well, listeners, welcome to our feature discussion on this April
19th and we have with us today, Dr. Andrew Chapman from Edinburg,
Scotland and Dr. Harvey White from Auckland, New Zealand. Welcome
gentlemen. And we'll start with you, Andrew. First, could you
describe for us some of the background information that went into
the preparation of your study?


Dr Andrew Chapman:


Good morning and good evening and thank you very much for the
invitation. So type two myocardial infarction is an interesting
diagnosis. It was first introduced in around 2007 in recognition
that patients could have heart injury when they were in hospital
with other problems that led to an imbalance in myocardial oxygen
supply, or an unmet need in myocardial oxygen demand, without the
presence of atherothrombotic coronary artery disease. We don't
know a great deal about these patients.


Dr. Andrew Chapman:


There have been a number of observational cohort studies,
including from ourselves in Scotland, which have demonstrated the
outcomes for this patient group are poor. We know only around
one-third of patients with type two MI, survive to five years
after diagnosis. And we also know, and previously demonstrated
from patients in Scotland that those with underlying coronary
artery disease actually had the worst outcomes and were at
increased risk of future myocardial infarction events due to
plaque rupture. So we hypothesized that patients with type two
myocardial infarction may have failed a physiological stress test
due to another illness and we wanted to investigate what the
prevalence of underlying coronary artery disease and/or
structural heart disease was, using a panel of different imaging
modalities.


Dr. Greg Hundley:


And so Andrew tell us the hypothesis that you wanted to address?


Dr. Andrew Chapman:


So we believed that observational evidence suggested that
coronary artery disease was important in patients with type two
myocardial infarction and we felt that this was increasing their
susceptibility to these events. Our primary hypothesis was that
the majority of patients with type two myocardial infarction
would have underlying coronary artery disease, which was
previously quiescent undetected.


Dr. Greg Hundley:


Tell us a little bit about the study design and the study
population that you use to answer this question.


Dr. Andrew Chapman:


Demand MI is to our knowledge, the first prospective
observational cohort study in which patients who were in hospital
with evidence of myocardial injury, so a raised cardiac troponin,
were screened for the presence of supplier demand imbalance and
the clinical diagnosis of type two MI. Now, in those patients
that we were able to recruit, we did obviously have important
exclusion criteria, but we designed a series of different
investigations depending on individual patient risk factors and
the appropriateness of such, but the primary goal was to
undertake coronary angiography, ideally using an invasive
coronary angiogram, which would allow us to undertake additional
testing, such as plaque imaging and pressure wire study, to look
for the functional consequences of stenosis. In those not fit for
an invasive angiogram, we undertook CT coronary angiography. And
in all patients we undertook structural imaging and we aimed to
do cardiac MRI in all. Due to the coronavirus pandemic and for
other reasons, we used echocardiography where MRI was not
available.


Dr. Greg Hundley:


And so the total number of subjects here was how many?


Dr. Andrew Chapman:


We recruited 100 patients with a clinical diagnosis of type two
myocardial infarction.


Dr. Greg Hundley:


Very good. And so now, Andrew, what were your results?


Dr. Andrew Chapman:


It's a really fascinating study, obviously, in my opinion. So we
recruited 100 patients with a clinical diagnosis of type two
myocardial infarction who had evidence of supplier demand and
balance, a raised cardiac troponin concentration and evidence of
symptoms and/or signs of myocardial ischemia. So in line with the
universal definition criteria. Of 100 patients after undertaking
coronary imaging, we reclassified the diagnosis in seven.


Dr. Andrew Chapman:


In five patients, we found that there was evidence of either
plaque rupture or a stent thrombosis. And in two patients, we
found evidence of myocarditis and stress cardiomyopathy
respectively. The first principle finding is that actually
despite careful characterization and really detailed screening,
we were correct in 93 of 100 patients and we got the diagnosis
wrong in seven. The principle hypothesis related to the
prevalence of coronary artery disease and this was, as alluded
to, undertaking with invasive and noninvasive imaging. But
overall, the prevalence of coronary artery disease was 68% of
those with type two myocardial infarction and this was
obstructive in 30%.


Dr. Andrew Chapman:


We also undertook structural imaging as mentioned. We observed
evidence of left ventricular systolic dysfunction in 34% of
patients, of around a third, and perhaps most surprisingly,
although we had a clear diagnosis of myocardial infarction in
these patients, we only found imaging evidence of in part pattern
late gadolinium enhancement, which is considered the gold
standard for its diagnosis of myocardial infarction. We only
observed that in 42%, which raises some interesting questions.


Dr. Andrew Chapman:


One of the principle clinical findings of the study is that these
underlying conditions of coronary artery disease and left
ventricular impairment, both of which are readily treatable with
secondary prevention. These conditions were previously
unrecognized in 60% of patients and only one-third were on
appropriate evidence-based treatment, which gives me some cause
for optimism, that there may be a role here for targeted
treatment, which could plausibly, plausibly impact on outcomes.


Dr. Greg Hundley:


And Andrew, just a clarification point, maybe a subgroup
analysis, any differences in your findings in regarding men
versus women?


Dr. Andrew Chapman:


Excellent question. And in most studies of type two myocardial
infarction, it's thought that this condition is more prevalent in
women than men, but undoubtedly in all observational cohorts,
there is selection bias as you will only diagnose a type two
myocardial infarction if a clinician requests to test troponin in
the first place. In our study, interestingly, we recruited more
men than women. We had 56% men and we did not find any
differences by sex in our analysis.


Dr. Greg Hundley:


Well listeners, what an excellent description from Dr. Chapman. A
very interesting study. And we now want to turn to one of our
editors, guest editors, Dr. Harvey White, and Harvey, we want to
thank you for your work here with us at the American Heart
Association and Circulation, and you receive many articles to
review. What attracted you to this particular article and how do
we put in context, these results with others that have been
published pertaining to type two myocardial infarction?


Dr. Harvey White:


Thanks, Greg, it's a pleasure to work for Circulation. This paper
is very close to my heart because I introduced the typing system
in 2007 and it had minimal support and people said, "Why do we
need a typing system? We've got killer class and Canadian class
and you've done a troponin release system as well". And people
stood up and then I laid out the type one plaque rupture. We know
the pathophysiology and we know the treatment. Type two, I'd
worked on beta blockers, supply and demand and I thought we
should define the pathophysiology and define the treatment.
That's 2007, which is 15, 16 years ago. And Andrew's paper is
really lovely. As I said, it's close to my heart and he inches
things forward. I've written an editorial, which I call "Zooming
in on the enigmas of type two MI" and enigma means mystery or
it's unclear, uncertain.


Dr. Harvey White:


And that's for sure we don't have full support for the diagnosis.
It's become very practical, used in clinical trials and
clinically, but we don't know how to manage it and we don't know
how to define the groups. Andrew and colleague study is very
nice. It's prospective and it has set out to define the coronary
artery disease. I've tried for about 10 years to subdivide type
two and to those without coronary disease and those with coronary
disease. And you could also have a type C, which hasn't been
investigated or unknown. And Andrew has answered one of the
enigmas and it's really interesting. Large proportion, normal
coronary arteries, diagnosis was changed a little bit based on
the finding of thrombus. We're challenged with that finding
because all MIs have thrombus at PM and really type one should be
ruptured plaque. But Andrew changed the diagnosis in a few where
one was an OTC, a marvelous case with marvelous pictures, changed
the diagnosis. So I like the study and I like the findings.
Thanks.


Dr. Greg Hundley:


Very nice. Well, Andrew, what a perspective and listeners getting
just to listen to Dr. White is really quite exciting for me.
Andrew, what do you see as the next study to be performed in this
sphere of research?


Dr. Andrew Chapman:


I think we've gone some way to provide some insights into the
underlying pathophysiology of this condition and these coexistent
conditions of coronary artery disease and left ventricular
impairment, which might increase an individual's susceptibility
to a type two myocardial infarction. The question is what can we
do about it and does targeted treatment with secondary prevention
therapies for coronary disease and treatment for heart failure
left ventricular impairment, does that improve outcomes?


Dr. Andrew Chapman:


The next study for me is clear. The next study for me, needs to
be a randomized controlled trial, whereby patients with type two
myocardial infarction are randomized to current best practice or
risk stratification by a cardiologist with an interest in this
condition, followed by targeted investigation for coronary
disease and LV impairment and thereafter treatment as
appropriate. This will be a trial of a complex intervention. I'm
very grateful that we've received funding in Scotland already for
this pilot phase of this trial, which we've called Targets Type
Two and we'll begin recruitment for that trial in August of this
year.


Dr. Andrew Chapman:


I must acknowledge colleagues in this area are looking at
coronary disease and type two myocardial infraction. Professor
Derek Chew is leading a study called Act Two, which is already
recruiting and that will also provide invaluable information as
to the prevalence of coronary disease and the potential benefits
of treatment of that coronary disease in patients with this
condition.


Dr. Greg Hundley:


And Harvey. How about your, what is your perspective in terms of
the next series of studies perhaps that need to be performed in
this space?


Dr. Harvey White:


There's a number and I like very much, Andrew's suggestion. The
study that we're doing is randomizing to angiography or not
angiography working with Derek Chew. I think all patients with MI
should have coronary angiography. It's simple, it takes about 10
minutes. There's obviously some contraindications, but the
information as Andrew has pointed out is really so useful. He
found dissection, he found an embolus. Normal coronary arteries
that in my view changes the management. Whether you should do an
angiogram is very important. Randomization to various treatments.
That's important. I would like to get more information about the
objective evidence of type two MI, the criteria for low
hemoglobin, shortness of breath, low blood pressure, high blood
pressure, and so forth. There's a lot to do. As Andrew pointed
out, the outcome may be worse than type one that's becoming more
common and I think these studies will be very, very important.


Dr. Greg Hundley:


Very nice well listeners. We want to thank Dr Andrew Chapman as
lead investigator and Dr Harvey White as guest editor for
bringing us this study using advanced imaging of patients with
type two myocardial infarction, which identified coronary artery
disease in two-thirds and left ventricular dysfunction in
one-third, and also highlighting that unrecognized and untreated
coronary or cardiac disease occurs in many patients with type two
MI and gives us pause for thought on a series of studies that may
be performed in the future.


Dr. Greg Hundley:


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


Dr. Greg Hundley:


This program is copyright of the American heart association,
2022. The 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, please visit
AHAjournals.org.