Circulation June 14, 2022 Issue

This week, please join author Christan Mueller, editorialist
Christopher deFilippi, and Associate Editor Torbjørn Omland as
they discuss the research article "Skeletal Muscle Disorders: A
Non-cardiac Source of Cardiac Troponin T" and the editorial
"Skeletal Muscle Disorders: A Non-cardiac Source of Cardiac
Troponin T."


Dr. Greg Hundley:


Welcome, listeners, to this June 14, 2022, version of Circulation
on the Run. I am Dr. Greg Hundley, associate editor and director
of Poly Heart Center at VCU Health in Richmond, Virginia. This
week I don't have my good friend Carolyn with me, but we will
grab a cup of coffee and work through several of the articles in
the issue.


Dr. Greg Hundley:


Well, first, I want to tell you about the feature discussion
today, and we're going to interview with Christian Mueller and
talk about the utility of cardiac troponin T and its association
with an elevation in those individuals with skeletal muscle
disorders, but, before we get to that, let's go through some of
the other articles in this issue.


Dr. Greg Hundley:


Listeners, the first study comes to us from Professor Haidong Kan
from Fudan university. These investigators conducted a time
stratified, case crossover study among 1,292,000 acute coronary
syndrome patients from 2,239 hospitals across 318 Chinese cities
between January 1 of 2015 and September 30 of 2020 to determine
the associations between sub-daily or hourly levels of criteria
air pollutants with the onset of an acute coronary syndrome.


Dr. Greg Hundley:


Now, hourly concentrations of fine particulate matter, coarse
particular matter, nitrogen dioxide, sulfur dioxide, carbon
monoxide and ozone were collected, and the hourly onset data of
acute coronary syndrome and its subtypes including ST segment
elevation myocardial infarction, non-ST segment elevation
myocardial infarction and unstable angina were obtained.


Dr. Greg Hundley:


Listeners, what did the investigators find? Well, their results
indicated that transient exposure to the air pollutants of fine
particulate matter, nitrogen dioxide, sulfur dioxide, and carbon
monoxide, but not coarse particular matter or ozone may trigger
the onset of acute coronary syndrome even at concentrations below
the World Health Organization Air Quality Guidelines. Now,
greater magnitude of associations were observed among patients
that were older than 65 years in age or those without a history
of smoking or chronic cardiorespiratory diseases and those in the
cold seasons.


Dr. Greg Hundley:


Listeners, next, we're going to move from the study of air
pollution to the world of preclinical science. Listeners, this
study comes to us from Dr. Ming-Hui Zou from Georgia State
University. Indoleamine 2,3-dioxygenase 1 or IDO1 is the rate
limiting enzyme for tryptophan metabolism. IDO1 malfunction is
involved in the pathogenesis of atherosclerosis, and vascular
smooth muscle cells with an osteogenic phenotype promote
calcification and features of plaque instability, but it remains
unclear whether aberrant IDO1-regulated tryptophan metabolism
causes vascular smooth muscle cell osteogenic reprogramming and
arterial calcification.


Dr. Greg Hundley:


Listeners, what did this study find? Well, this investigative
team and their results revealed the previously unrecognized
protective role of IDO1 in arterial calcification in that
vascular smooth muscle cells defective of IDO1 result in enhanced
runt-related transcription factor 2 and ectopic calcium
deposition in plaques. In contrast, administration of kynurenine
via intraperitoneal injection markedly delayed the progression of
intimal calcification in parallel with decreased RUNX2
expression.


Dr. Greg Hundley:


Also, listeners, the authors found that patients with coronary
artery calcification have abnormal tryptophan metabolism, and
serum IDO1 activity was inversely associated with calcification
development in clinical settings, so, listeners, what are the
clinical implications here? Well, this work reveals a protective
role for IDO1 in mitigating arterial intimal calcification
through kynurenine production and then, secondly, developing
interventions toward the IDO1 kynurenine RUNX2 access may prevent
the pathogenesis of arteriosclerotic complications.


Dr. Greg Hundley:


Well, listeners, a really interesting article, and now let's turn
our attention to some of the other articles in the issue. Well,
first, there's a Research Letter from Professor Modarai entitled
“A Higher Incidence of Chromosomal Aberrations in Operators
Performing a Large Volume of Endovascular Procedures,” and then,
also, there is an AHA Update from our exiting AHA president who
addresses “What Does the American Heart Association Do (and How
Can You Help)?” Well, now, listeners, let's turn now to our
feature related to a discussion of the utility of troponin T as
well as troponin I in those with skeletal muscle disorders that
may also present with acute coronary syndromes.


Dr. Greg Hundley:


Welcome, listeners, to this June 14 issue, and we're very excited
today. We have with us Dr. Christian Mueller from the University
Heart Center at Basel, Switzerland, Dr. Torbjorn Omland from the
University of Oslo in Oslo, Norway, and Dr. Chris deFilippi from
Inova Heart and Vascular Institute in Falls Church, Virginia.


Dr. Greg Hundley:


Welcome, gentlemen, and, Christian, we'll start with you. Could
you describe for us some of the background information that went
into your study, and what was the hypothesis that you wanted to
address?


Dr. Christian Mueller:


Thank you very much for giving me the opportunity in this podcast
to discuss our study with you and together with Torbjorn and
Chris, who both contributed so enormously to the field with their
own research. It's about cardiac troponin, cardiac troponin, an
essential pillar in our early diagnosis of myocardial infarction.
In this specific study, we tried to address possible non-cardiac
causes of cardiac troponin T. In our clinical practice, we use
and guidelines recommend both cardiac troponin T and I more or
less as equivalent in providing identical information and, when
going back from the clinical practice to biology, we have learned
that, the troponin complex, that it is composed of three
isoforms, T, I, and C.


Dr. Christian Mueller:


While they are very similar in their function, they are distinct
regarding amino acid sequence in configuration in cardiac and
skeletal muscle. As the cardiac form, of course, is the one that
we are interested in, cardiac-specific assays have been developed
both for cardiac troponin T and cardiac troponin I. As with any
other tests in medicine, they are very good, but they may have
limitations, and the specific questions that we had set for this
study is whether skeletal muscle disease might be non-cardiac
source for cardiac troponin T as measured in blood, therefore,
with the possible harm of having false positive increases that
could lead to a misdiagnosis of acute myocardial infarction.


Dr. Greg Hundley:


Very nice. We're trying to understand the utility of cardiac
troponin T measures in those individuals that may have
concomitant skeletal muscle disorders. Christian, what was your
study population, and describe for us your study design?


Dr. Christian Mueller:


Our study had two components, a clinical component and a
translational component. The clinical component included 211
consecutive patients that presented with active and chronic
muscle symptoms to a workup either with a rheumatologist or a
neurologist or internal medicine specialist, so more or less
elective workup for muscle, skeletal muscle symptoms, to have a
population that is broad and reflects all possible skeletal
muscle disorders, their possible impact on cardiac troponin T
concentration.


Dr. Christian Mueller:


In this population, we quantified cardiac involvement as this is
common in some of these musculoskeletal disorders to be either
major, minor or are not. They're according to patient history,
according to … ECG and cardiac imaging, and we did the
measurement of high sensitivity cardiac troponin using the high
sensitivity cardiac troponin T assays used all over the world and
three high sensitivity cardiac troponin I assays to look for
mismatches, the percentage of patients that might have elevated T
concentration, but not I as a possible sign that the T might be
from the muscle, not the heart, particularly in those patients
that didn't have any imaging evidence of cardiac involvement, and
then we correlated the amount of high sensitivity cardiac
troponin T with the amount of muscle injury as quantified by CK.


Dr. Christian Mueller:


In the translational part, those patients who have received a
skeletal muscle biopsy with quantified by differential gene
expression, the MRNA of the cardiac isoform of cardiac troponin T
as well as of I in those patients who had the biopsy and matched
it and compared it to controls to see whether the cardiac isoform
would be upregulated in those with the cases of skeletal muscle
disease.


Dr. Greg Hundley:


Very nice, and so, Christian, was this one single measurement at
one point in time or did you have a series of measures over time?


Dr. Christian Mueller:


In fact, this is a large, ongoing project where patients will
receive followup appointments. The current study reports the
first phase versus single measurement at a single time point was
performed.


Dr. Greg Hundley:


Very good. Christian, what did you find?


Dr. Christian Mueller:


We first found that even in those patients with active skeletal
muscle disease, cardiac troponin T still reflected the presence
of cardiac disease. Those patients with severe cardiac disease
did have significantly higher concentration than those patients
with mild or with no cardiac disease. That was the good thing.
However, the more challenging one for this biomarker in this
setting is that high sensitivity cardiac troponin T was
significantly higher in these patients as compared to controls.
We had the chance to have a couple of thousand controls from
another study that presented with non-cardiac chest and no
skeletal muscle disease and, while high sensitivity troponin I
concentrations were similar, cardiac troponin T was elevated,
resulting in a much higher prevalence of elevated T concentration
versus elevated I concentration and corresponding mismatches in
these patients.


Dr. Christian Mueller:


In the second part, we were able to show that there was a
significant correlation between high sensitively cardiac troponin
T with CK quantifying somehow muscle damage while this was not
seen in the correlation with high sensitivity I, and that
signaled that some of the systemic cardiac troponin T
concentration seems to be derived from the muscle. It was
confirmed in the translational part of the study in which the
differential gene expression showed an eightfold over-expression
of cardiac troponin T in skeletal muscle biopsies of those
patients with disease, so with active skeletal muscle disease.
This … expression correlated with disease activity, a
pathological score that quantifies the extent of damage in the
skeletal muscle history and correlated with the high sensitivity
cardiac troponin T plasma concentration measured with the
immunoassay.


Dr. Greg Hundley:


Very nice. Listeners, it sounds as if, in patients with skeletal
muscle disorders, Christian's team observed an elevation in
cardiac troponin T, but not necessarily cardiac troponin I, and
you've got mechanistic understanding from the biopsies where you
see this cardiac troponin T expression in the damaged skeletal
muscles. Well, Torbjorn, you have many papers come across your
desk. What attracted you to this particular paper?


Torbjorn Omland:


Thank you, Greg. I think, in general, when I receive papers from
circulation, there are three main criteria I consider. The first
is whether this is an interesting research question and then,
second, whether the study is well-designed and the third is
whether they're in themselves are novel, robust and interesting
with potential clinical implications.


Torbjorn Omland:


For this specific papers, I must say it seemed to me to fulfill
all these criteria and that it would be able to bring this field
forward. The study of re-expression of troponin T in skeletal
muscle is not entirely novel because it has been done in small
samples, but mainly with rare and neuromuscular diseases
previously, but this study broadened that or generalized that to
a much more clinically relevant population. The clinical
implications also seemed to be much greater than what has been
reported by previous papers.


Dr. Greg Hundley:


Very nice. Listeners, we have in addition to Dr. Omland, we have
another expert with us today, Dr. Chris deFilippi, really in the
area of biomarkers particularly as they pertain to cardiac
injury.


Dr. Greg Hundley:


Chris, now turning to you, how do we put the context of the
results today really with the broader scope of what we have
learned about cardiac troponin I and cardiac troponin T and then
their use in diagnosing acute ischemic syndromes or even
forecasting future cardiovascular events down the road?


Dr. Christopher deFilippi:


Thank you, Greg, and thank you Circulation for inviting me to
participate in this podcast and to write this editorial. First,
Christian, this was a terrific paper and one that was probably
great to review during the pandemic because, as I spent a good
Sunday peeling back layers of the onion and reiterating what
Torbjorn said, this paper makes a tremendous contribution where
there already was some knowledge to maybe the expression of the
cardiac specific troponin T and skeletal muscle, but there's
something there for everyone just to get the takeaway message,
but for those who really want to delve in, there are supplemental
tables that contribute a huge amount of nuance and detail that I
think will help guide researchers in the future in maybe how to
optimally use cardiac troponin T and troponin I both in the
evaluation for acute myocardial infarction and then in a variety
of chronic conditions, so first putting this in context of how
you would evaluate patients with acute myocardial infarction, and
that's the predominant indication for measuring a high
sensitivity troponin T or troponin I.


Dr. Christopher deFilippi:


As Christian in an earlier study has shown and others have shown,
actually, the correlation between a high sensitive troponin I by
a variety of commercial assays. Troponin T is really pretty good.
I think in one study from Christian's group, it was measured at
0.89. Now, the issue that's relevant is more around the edges.
People who come in with just a low elevation and, as Christian
pointed out and colleagues pointed out in the paper, using the
ESC algorithm, a number of those patients would have qualified
for myocardial infarction with the skeletal myopathies
particularly the myositis or the non-inflammatory myopathy. If
there is an index of suspicion for these disorders I think
particularly around the cutoff for troponin T, one has to be
cautious. Whether one can actually look at serial changes and try
to differentiate that way I think is an open question. It may be.


Dr. Christopher deFilippi:


I think the other thing that gets quite interesting for me in an
area that we've delved in over the past decade is the use of high
sensitive troponin T or troponin I as a measure of chronic injury
that's been codified in the fourth universal definition of MI
published four years ago to identify individuals at risk. These
can be individuals who are living in the community without known
cardiovascular disease or actually without, perhaps, a lot of
other comorbidities other than advanced age, for example, who an
elevated troponin I or troponin I can be indicative of an
increased risk for incident heart failure over the next five to
10 years. It can be patients with other chronic comorbidities.


Dr. Christopher deFilippi:


Actually, what drew me to this paper and thinking along these
lines was a paper that Torbjorn had published back in 2013 where,
using the key study which are individuals who have chronic
ischemic heart disease without heart failure, he measured both
troponin I and troponin T and found there was quite a
discordance. There, we're looking at … value of about 0.4 and
found that troponin I was a great predictor for the risk of
coronary heart disease event and an acute myocardial infarction
in the future, but T was not, but both T and I were good
predictors of incident heart failure in the future.


Dr. Christopher deFilippi:


Other investigators, the … investigators, investigators from
Scotland have also found this discordance between I and T in
chronic ambulatory populations with or without comorbidities, and
so it opens an interesting question in individuals with maybe
conditions of pre-frailty or frailty or some element of
sarcopenia, subclinical skeletal muscle disease. Does this cause
this discordance? Ultimately, we know particularly with heart
failure, with preserved ejection fraction, it is a systemic
disorder, and measures of skeletal muscle disease may be relevant
in ultimately determining who's going to have symptomatic heart
failure.


Dr. Christopher deFilippi:


I think it really opens things wide open potentially to further
investigation. Is this modifiable? Is it through intervention
simply like physical activity? Could you see changes in cardiac
troponin T that may be reflecting cardiovascular changes and
skeletal muscle changes, but maybe not so much with I, and does
this have relevant prognostic implications? I think I was really
excited about it based on the defined pragmatic findings with
respect to evaluating patients for myocardial infarction who have
these underlying skeletal muscle diseases, but also implications,
what this might mean in chronic disease populations as well.


Dr. Greg Hundley:


Very nice. Well, Chris, you've led us really to our next series
of questions, and maybe we'll circle back with each of you,
first, Christian. What do you see, Christian, as the next study
to be performed in this space?


Dr. Christian Mueller:


I think the next study should address two aspects. The first one
is I think we already, with the current population have found
that skeletal muscle disease includes various pathologies, and as
indicated by Torbjorn, the cardiac troponin T re-expression seems
to be at least of our current understanding limited to the two
groups of myositis and the muscular dystrophies, whereas the
other skeletal muscular disorders at least in those that we have
currently investigated did not seem affected. However, we were
limited by the number of patients in this subgroup, and so for
sure need a larger population to cover all aspects or all
classifications of skeletal muscle disease in more detail.


Dr. Christian Mueller:


The second point that I'd like to highlight is the followup and
to look for cardiac events and to look for cardiac changes,
functional or anatomical changes in cardiac imaging, because it
still may be that some of the T that is more commonly seen in
this patient, that the majority of this is derived from the
heart, so it's not a black and white, it's only from the muscle
or only from the heart. It's still possible that some of the
higher concentration of T found in these patients, as in many of
the skeletal muscle systemic disorders, they have cardiac
involvement which may not be identifiable by current imaging
techniques at the first visit. This may become apparent during
followup, and so these studies will help us to get a better
quantitative understanding, so ideally to understand is it just a
tiny amount, I don't know, 10, 20% of the systemic T
concentration that is derived from the muscle? Then it would have
a very different clinical implication as compared to if, I don't
know, more than 50% of the systemic concentration would be
derived from the skeletal muscle rather than the heart.


Dr. Greg Hundley:


Very nice. Torbjorn, I would like to turn to you. What do you see
as the next study to be performed in this space?


Torbjorn Omland:


Oh, I agree with Christian that the serial assessment of changes
of disease activity versus troponin changes would be very
interesting to study in more detail and also correlate that to
changes, for instance, by cardiac MRI if you can see whether
there are actually correlations there. Long-term prognostic
implications of skeletal muscle derived cardio troponin is
another subject, and then, finally, I think that we do need to
know even more accurately what is the impact of these alterations
on the diagnostic workup in the acute coronary syndrome setting.
Is it really a clinically important confounder? I think studies
that could address that will be important.


Dr. Greg Hundley:


Very nice, and then finally Chris, and, Chris, I want to add just
another question. Just from my listening to this, if I'm trying
to identify someone with an acute ischemic syndrome and then they
may also have an underlying skeletal muscle disorder, both
Christian was talking about inflammation, but you brought in
frailty and things of that nature. Should we really then turn
clinically to measuring cardiac troponin I in this setting when
we're trying to rule out, for example, acute myocardial
infarction?


Dr. Christopher deFilippi:


Yeah. I don't want to overstate that. I mean, Christian's work
and others have shown actually a high sensitive troponin T and a
variety of different high sensitive troponin Is in a very
heterogeneous chest pain population have been equivalent, looking
at receiver operator curves area under the curbs, and so they're
probably our people at the margins where this will make a
difference, but it should be. Listeners should be reassured at
this point because troponin T is a very common assay that it's
still quite efficacious and accurate for the diagnosis of acute
myocardial infarction from what we know, and a lot of Christian's
work has identified this.


Dr. Christopher deFilippi:


Again, moving into the more chronic disease population outside
the evaluation of acute myocardial infarction, maybe where we can
use it as a differentiator, it could be helpful in some instances
to look at interventions. Earlier work has shown in just small
numbers of patients have been published, but patients with
hypothyroidism, patients with statin-induced skeletal myopathies,
the treatment of these has actually led to a decrease in high
sensitive troponin I corresponding with decreases in CK, so there
may be opportunities for lifestyle interventions like physical
activity, and you could see that response and whether that has
prognostic implications. This could be of interest for future
research.


Dr. Greg Hundley:


Very nice. Well, listeners, what an incredible discussion today.
We want to thank Dr. Christian Mueller from University Heart
Center in Basel, Switzerland, Dr. Torbjorn Omland from the
University of Oslo in Oslo, Norway, and also Dr. Chris deFilippi
from the Inova Heart and Vascular Institute in Falls Church,
Virginia, for really helping us understand that in patients...
from this research, that in patients with active chronic skeletal
muscle disorders, elevations in cardiac troponin T are common and
may not be related to cardiac disease. These elevations were not
observed in those with assessment of cardiac troponin I and,
coming back to in the case of cardiac troponin T based on this
wonderful biopsy work, the elevations of the troponin T appear
related to re-expression of troponin T and skeletal muscle.


Dr. Greg Hundley:


Well, listeners, 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 aha journals.org.