Jun 13, 2022
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.