Circulation August 17, 2021 Issue

This week's episode features author Philippe Gabriel Steg
and editorialist Gregg Stone as they discuss the article
"International Observational Analysis of Evolution and Outcomes
of Chronic Stable Angina: The Multinational Observational CLARIFY
Study."


TRANSCRIPT BELOW


Dr. Carolyn Lam:


Welcome to Circulation 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 here with
my other co-host, a little bird that you can hear I think in the
background and then my real co-host, Greg.


Dr. Greg Hundley:


Thanks so much, Carolyn. Yes, I'm Dr. Greg Hundley. I'm not the
bird this week. Associate editor, director of the Pauley Heart
Center in Richmond, Virginia. Carolyn, so this week, our feature
discussion is really going to be on the importance of stable
angina and what that means prognostically. But before we get to
that, how about we grab a cup of coffee, talk to our other bird
friends and then we jump in and talk about the other papers in
the issue. Would you like to go first?


Dr. Carolyn Lam:


Love it, Greg. Thank you so much. This first paper, very
important question. We know that while the 99th percentile is the
recommended diagnostic threshold for myocardial infarction, some
guidelines also advocate the use of higher troponin thresholds to
rule in myocardial infarction at presentation. It's still unclear
whether the magnitude or change in troponin concentration can
differentiate causes of myocardial injury and infarction in
practice. And so today's paper is really important from Dr. Mills
from the University Center for Cardiovascular Science Royal
Infirmary of Edinburgh in the University of Edinburgh and
colleagues.


Dr. Carolyn Lam:


What they did was a secondary analysis of the high stakes trial
of more than 46,000 consecutive patients with suspected acute
coronary syndrome. They evaluated the performance of the 99th
percentile rule in threshold and thresholds of 64 ng/L and five
times the upper reference limit for the diagnosis of type 1
myocardial infarction. They found that troponin concentrations at
presentation have a low, positive predictive value for type 1
myocardial infarction and a threshold of 50 times the upper
reference limit is required to achieve a positive predictive
value of more than 70%. A change in troponin on serial testing
only marginally improved positive predictive value for type 1
myocardial infarction over the presenting troponin alone.


Dr. Greg Hundley:


Interesting, Carolyn. Very important data. What's our take home
message here.


Dr. Carolyn Lam:


Well, troponin concentrations at presentation are insufficient to
distinguish type 1 myocardial infarction from other causes of
myocardial injury or infarction and should not be used in
isolation to guide management decisions in patients with
suspected ACS. Consideration of other important clinical factors
may be more helpful than any particular rule in threshold to
guide initial triage and management.


Dr. Greg Hundley:


Wow, Carolyn, so really great new data and more data on the
utility of these troponin concentrations.


Dr. Greg Hundley:


Well, my next paper comes from the world of preclinical science
and it's from Professor Vladimir Kalinichenko from Cincinnati
Children's Hospital Medical Center. Carolyn, as we know,
pulmonary hypertension is a common complication in patients with
alveolar capillary dysplasia with misalignment of pulmonary
veins, a severe congenital disorder associated with mutations in
the Foxf1 gene. Now, while the loss of alveolar microvasculature
causes pulmonary hypertension in, and we're going to abbreviate
this ACDMPV patients, it is unknown whether increasing neonatal
lung angiogenesis could prevent pulmonary hypertension and right
ventricular hypertrophy in these subjects.


Dr. Carolyn Lam:


Wow. Wow. Okay. Let's repeat that. ACDMPV stands for alveolar
capillary dysplasia and misalignment of pulmonary veins. Really
cool stuff. What did they find, Greg? This sounds like a first of
its kind study.


Dr. Greg Hundley:


Right, Carolyn. Thanks. The Foxf1 wild type, S52 mice developed
pulmonary hypertension and RV hypertrophy after birth. The
severity of pulmonary hypertension in these mice directly
correlated with mortality, low body weight, pulmonary artery
muscularization and increased collagen deposition in the lung
tissue. Second, increased fibrotic remodeling was found in the
human ACDMPV lungs. Third, the mouse endothelial cells carrying
the S52F Fox1 mutation were used to produce chimeras via
blastocyst complementation and to demonstrate that the Foxf1 wild
type S52F endothelial cells have a propensity to differentiate
into pulmonary myofibroblasts. And then finally, intravascular
delivery of nanoparticles carrying Stat3 copy DNA protected the
Foxf1 wild type S52F mice from RV hypertrophy and pulmonary
hypertension, improved their survival and decreased that fibrotic
lung remodeling. Carolyn, nanoparticle therapies increasing
neonatal pulmonary angiogenesis may be considered to prevent
pulmonary hypertension in alveolar capillary dysplasia with
misalignment of pulmonary veins.


Dr. Carolyn Lam:


Wow, thank you, Greg. Such incredibly hopeful papers here. The
next paper identified a key role of a particular amino acid in
cardiac aging.


Dr. Greg Hundley:


Ah, Carolyn, so you didn't ask me the quiz but I guess it's
implied here. Okay, I give up. Which amino acid is it?


Dr. Carolyn Lam:


Spot on, Greg. Well, the answer is phenylalanine. This is an
essential amino acid whose levels are regulated by the
tetrahydrobiopterin or BH4 dependent rate limiting enzyme,
phenylalanine hydroxylase and whose expression is physiologically
restricted to the liver and the kidney. Well, co-corresponding
authors Dr. Czibik and Derumeaux from Paris, France, hypothesized
that phenylalanine plays a causal role in promoting cardiac
senescence and dysfunction based on prior evidence from human
metabolomics that shed light on a link between amino acids, aging
and heart failure, as well as data showing that plasma levels of
phenylalanine increase with age and inversely correlate with
leukocyte telomere length. In addition, increased serum
phenylalanine levels are associated with heart failure. Here, the
authors tested their hypothesis in a series of elegant mouse
experiments and showed for the first time that a decline in
hepatic phenylalanine catabolism was a causal contributor to a
rise in systemic levels, leading to cardiac ectopic phenylalanine
hydroxylase activity and resultant cardiac aging.


Dr. Carolyn Lam:


They demonstrated that phenylalanine administration induced a
remarkable premature cardiac deterioration in young mice, closely
mimicking that of aged mice and leading to cellular senescence in
vitro. They identified hepatic phenylalanine catabolism to
decline with age in a p21 dependent manner, while demonstrating
that p21 deficiency prevented age related cardiac dysfunction.
Administration of phenylalanine hydroxylase cofactor BH4 or
dietary phenylalanine restriction, both abrogated the age related
rise in the plasma levels and reversed age associated cardiac
alterations. This study really identifies phenylalanine and its
hydroxylase modulation as a potential therapeutic strategy to
promote cardiac health and prevent age related cardiac
impairment. Amazing, isn't it?


Dr. Greg Hundley:


Yeah, Carolyn. Really interesting about phenylalanine and while
it may impact cardiovascular health and the aging process.


Dr. Greg Hundley:


Well, I know we've got some other articles in this issue, so how
about I'll go and dip into the mailbag first? The first is from
Professors Wong and Finn and they're exchanging letters regarding
the prior publication entitled, Microthrombi as a Major Cause of
Cardiac Injury in COVID-19 and it's a pathologic study. There's a
nice Research Letter from Dr. Zhu entitled, “Catheter Based
Adrenal Ablation Remits Primary Aldosteronism: A Randomized
Medication Control Trial.” There's a Perspective piece from Dr.
Stehlik entitled, “The Long and Winding Road to an Effective Left
Ventricular Assist Device: The Demise of Medtronic's HVAD.” And
then finally a report from Dr. Mehta and colleagues, really
Carolyn, thinking about clinicians' wellbeing and addressing
global needs for improvements in the healthcare field. And it's a
Joint Opinion representing the American College of Cardiology,
the American Heart Association, the European Society of
Cardiology and the World Heart Federation. Really a nice report
on really addressing physician stress in the workplace.


Dr. Carolyn Lam:


Nice. Well, there's also an ECG Challenge by Dr. Shi entitled,
“An Acutely Breathless Patient with Inferior St-Segment
Elevation: A Diagnostic Trap.” In Cardiology News, Bridget Kuehn
describe studies detailing heart risks for firefighters. Wow,
what an interesting issue, but let's go on now to the feature
discussion shall we, Greg?


Dr. Greg Hundley:


You bet.


Dr. Greg Hundley:


Welcome listeners to our feature discussion. And today we have
with us Dr. Gabriel Steg from Paris, France, Universite de Paris.
And also Dr. Gregg Stone, an editorialist from Mount Sinai in New
York. Welcome gentlemen. And Gabriel, we'll start with you first.
Could you describe for us some of the background related to your
study and what was the hypothesis that you wanted to test?


Dr. Gabriel Steg:


Thank you, Greg. As you know, there have been tremendous changes
in cardiology over the past 25 years with the advent of effective
anti-anginal therapy, with the advent of myocardial
revascularization and the dramatic changes produced by widespread
availability of percutaneous coronary intervention and finally
the availability of evidence based secondary prevention
therapies. And there has been really a sea change in the
presentation and treatment, management and outcomes of patients
with coronary artery disease. And when we started off, we asked
ourselves, is angina pectoris really prognostic in patients with
stable coronary artery disease? Is the symptom of angina really
prognostic? That was the question we tried to address.


Dr. Greg Hundley:


And Gabriel, what was your study population and your study
design?


Dr. Gabriel Steg:


It was a very simple descriptive design. We use a large
international registry of patients with stable coronary artery
disease called the CLARIFY registry, which enrolled almost 35,000
patients with stable coronary artery disease and followed them up
for five years. Now, how was stable coronary artery disease
defined? It was defined as any of the following conditions, a
prior MI, more than three months before enrollment, a prior PCI
or a CBG, angina pectoris was a demonstration of myocardial
ischemia on noninvasive stress testing or finally the presence of
a fixed stenosis of the coronary arteries on an angiogram. And
you could get any of these criteria. Of course you could have
more than one at the same time. And the design was to describe
the anginal status at baseline and every year based on
investigator reports, not a formal angina questionnaire, as there
are several, including the Seattle angina questionnaire. We had a
very simple assessment of angina and angina severity based on
presence or absence and then Canadian class of angina.


Dr. Greg Hundley:


Did you follow these individuals too? Did they experience
specific events?


Dr. Gabriel Steg:


Yes. We collected all the cardiovascular hospitalizations events,
revascularizations. We followed the medications and we collected
the biological results, although there was no core lab but we
collected the results of the tests that were done. We essentially
aimed was that registry to describe the population, their
management and their outcomes over five years. And this is over
40 plus countries. And fortunately does not include any patient
from the United States but has a substantial contribution from
Canada and Mexico.


Dr. Greg Hundley:


Very nice. And so what did you find, Gabriel?


Dr. Gabriel Steg:


Well, the first observation is the prevalence of angina at
baseline and it's 22%. We found that in a patient population
selected for having stable coronary artery disease, approximately
a fifth to a quarter will have anginal symptoms. I don't think
that's a major surprise but what was a big surprise to us is that
angina resolved very, very substantially, 40% of the patients who
had angina at baseline had no longer angina by one year. And what
was even more surprising is what caused the resolution of angina.
And it was rarely changes in anginal medications, rarely
revascularization. It was largely spontaneous. Almost 80% of the
patients had spontaneous resolution of angina. And so, yes, it's
been known that angina can regress but we did not expect that it
would regress that often and that much spontaneously without
intervention or need for increasing medications.


Dr. Gabriel Steg:


And the other aspect is then we looked at what happened for those
patients who had angina resolution at one year and what were the
subsequent outcomes? And we found they were indistinguishable
from those who had no angina at baseline. And then we looked at
those patients who had persistent angina at one year or
occurrence of angina at one year, despite not having angina at
baseline. And again, we found that having angina at one year was
detrimental to the longterm prognosis. It's really good that you
either not have angina or that your angina resolve. That's really
important.


Dr. Greg Hundley:


Did you find any differences, Gabriel, between men and women?


Dr. Gabriel Steg:


No. We looked at a variety of subgroups. We looked by criteria
for enrollment. We looked across geographic locales. We looked
according to the presence or absence of diabetes and sex and
other variables and there were really no major differences. The
results were remarkably consistent.


Dr. Greg Hundley:


Very nice. Well listeners, one of the advantages of some of the
publications that we pursue at Circulation is the ability to
bring in an editorialist. And with us today, we have Dr. Gregg
Stone from Mount Sinai in New York. And Gregg, we want to turn to
you. How do we put the results of this study in perspective with
other studies that have been involved in this sphere of research?


Dr. Gregg Stone:


Well, thank you, Greg. First off, I'd like to congratulate
Gabriel and his colleagues for a tremendous study and thank you
and Circulation for offering David Waters and I, the chance to
provide our perspectives. I think this study raises a lot of
important issues. Angina is kind of like the common cold to
cardiologists. We're always dealing with it but it can be very
difficult to diagnose. There's typical angina, atypical angina,
anginal equivalent disease, non-anginal chest pain, et cetera.
And we've learned in the last several years or decade that the
etiology of angina can be very complex. It's not just epicardial
coronary disease. There can be microvascular disease, macro or
microvascular spasm and other causes. I think that we have to,
when we're thinking of angina, we have to try to understand the
mechanism and know whether or not it's really due to at least
epicardial coronary artery disease, which is the type of disease
that may respond to revascularization.


Dr. Gregg Stone:


In this regard, both David and I were struck with the fact that
the CLARIFY even though a very large population, is a very mature
population of patients with coronary disease, who I believe were
diagnosed at least approximately seven years ago, most had
undergone a prior revascularization therapy, about 50% ahead of
myocardial infarct and the minority interestingly had inducible
ischemia. We wondered is this real angina? Is this true angina
that these patients are having? Because they've been effectively
revascularized. In contrast, I was one of the co-principal
investigators of the ISCHEMIA trial, which was a very different
population because we took only with exercise induced moderate or
severe ischemia. And while we excluded most patients with class
three or four angina because we know those patients basically
don't tolerate medical therapy without frequent crossovers. We
found that in our trial, angina was more persistent and was
substantially reduced by revascularization, by an interventional
approach. Much more so than in the medical therapy arm. I think
that it really does depend on the patient population and the
likelihood of which the angina is due to true inducible ischemia
that may respond to a revascularization approach.


Dr. Greg Hundley:


Very nice. And so Gabriel, want to turn back to you, what do you
think is the next study that really needs to be performed in this
space?


Dr. Gabriel Steg:


Well, I think it's really in line with Dr. Stone's comments. I
think that what we need to do is to have a much more formal
prospective assessment of a broader population of patients with
angina using formalized questionnaire, such as the Seattle angina
questionnaire, which allow a much better and thorough
characterization of the presence, type and severity of symptoms
and to look across the whole spectrum of patients with and
without myocardial ischemia and look at the prognostic importance
of the symptoms. I think that teasing out the relationship
between the anginal symptoms, their severity, myocardial ischemia
and outcomes is really critical to our interpretation of the
series of recent trials, the last of which being ISCHEMIA, which
have revolutionized our thinking regarding management of coronary
artery disease. And we're still somewhat in the dark as to how to
incorporate that information relative to the symptoms and
outcomes of our patients. And I think we still have a lot of work
to do in that respect.


Dr. Greg Hundley:


Very Good. And Gregg, do you have anything to add to that?


Dr. Gregg Stone:


Yeah. I would certainly echo Gabriel's comments. In addition, I
think we have to think of angina as a collection of different
diseases. And we have to do a better job at trying to understand
the mechanisms underlying angina. First, we have to be able to
determine whether it's really cardiac in origin versus
non-cardiac. And then second, we have to understand again,
whether it's coming from epicardial coronary disease,
microvascular disease or other mechanisms. We've just been struck
in even many of our simple stent studies, how often patients
redevelop angina after treatment with no re-stenosis whatsoever,
suggesting that many of them may have other etiologies of angina.
I think these studies to me are very important because they
really highlight, yes how much we've learned but how much more
work there still is to do for us to be able to effectively
diagnose and treat these patients.


Dr. Greg Hundley:


Well listeners, we want to thank both Dr. Gabriel Steg, the
author of this paper and also Dr. Gregg Stone, who provided his
editorial expertise, in bringing us information from these 32,000
plus individuals from the CLARIFY registry, of patients with
stable coronary artery disease and helping us answer really two
questions regarding the presence of angina. One, both that angina
may resolve spontaneously and then second, persistent angina is
associated with future cardiovascular events.


Dr. Greg Hundley:


Well, on behalf of Carolyn and myself, I want to thank our
speakers and then also wish everyone 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. 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.