Apr 18, 2022
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.