COVID-19 infections and vaccines, as well as certain cancer treatments, can play roles in myocarditis – whose incidence has increased about tenfold in recent years. This update from cardiologist Clifton Watt, MD, clarifies that selecting appropriate diagnostic and therapeutic tools depends on many factors, from the case’s severity to the patient's health status and history. Illustrating his talk with tissue biopsy and cardiac MRI images, he discusses the range of inflammation called myocarditis, how and when to use imaging, options for critically ill patients, and how to counsel young athletes with post-vaccine chest pain. Bonus: Hear about novel treatments to consider in the ICU setting.
Myocarditis, um, now we're in 2024, and we've, uh, been through, um, a lot fairly recently, uh, with regards to myocarditis, um, and some of it's invaded sort of the, the, the, the non-medical news space too. So, so, um, uh, you know, lots of us have heard about, um, uh, about myocarditis, myocarditis even more recently. Um, so I'll, I'll talk, uh, hopefully about some of these kind of new, new and, and, uh, and fresh, uh, things that we know about and, uh, myocarditis and I've heard about. All right. All right, so, so, so a brief outline. Again, I'll talk a little bit about um updates on our understanding of what myocarditis is, and what I was referring to was, of course, COVID, and, and how COVID and the COVID-19 vaccines, uh, have changed, um, our understanding, um, and, um, how we see myocarditis as a disease and how it's really affected. Uh, the prevalence and incidence of, of this disease. Um, something also that, um, has been, um, more recent is certain cancer treatments and its impact on myocarditis, which I'll, which I'll bring up, and, and finally, um, you know, novel treatments for Myocarditis, um, I'll, I'll spend a, spend a little bit of time on. All right. So, just, just to set the table, um, in terms of definitions and diagnosis, um, so, as we probably know, myocarditis is an inflammatory disease of the heart muscle or the myocardium. Um, and that's a very broad, as you might expect, that's a very broad, uh, definition, and it's probably because, uh, it's a very broad, uh, Uh, uh, broad spectrum of disorders, um. And we'll get into that, um, and, you know, there's probably some, some immuno, um, um, immunologic basis to it, infectious nature to it, um, and, you know, it's very much a very broad spectrum of, of disease state, um, and that's part of why, you know, it can be challenging to make a diagnosis of myocarditis. Um, the, the current state, the diagnosis typically is made, um, with multiple different methods. There's no one test that we can use to diagnose myocarditis. We certainly use the, the clinical situation, um, we use histologic or, um, immunologic, histologic sort of tissue, um, um, diagnose diagnostic methods. Um, and imaging too. So, you know, imaging the heart from outside the body is, is, is now, um, a, a very commonly used. So, you know, even though the gold standard of diagnosing myocarditis is using histologic, you know, looking at the tissue under a microscope and using staining with immunologic uh methods, these are still considered the gold standard. Um, now we're doing bio, you know, quite frequently using biomarkers like, uh, blood testing, troponins. Um, and imaging using echocardiography and MRI of the heart. Um, so, you know, going way back historically, you know, uh, there was, uh, a set of criteria called the Dallas criteria that was, uh, going back to the 80s, um, proposed by a a cardiac, uh, a, a, a, a group of cardiac pathologists, and this group of, uh, of, uh, providers, um, really looked at, um, classifying myocarditis. Um, based on, you know, one biopsy, um, so tissue, as well as, you know, subsequent biopsies. So not just one biopsy, but, you know, multiple, um, and so that can, that could help, they proposed that that could help categorize, categorize myocarditis as not just, you know, a single disease process in at one time point, but also sort of moving forward. Um, you know, myocarditis is not just, you know, a, a, a, a process that is acute, but can be, you know, acute and healed, or acute and healing, um, or persistent or chronic, um, and so this group, um, proposed, uh, you know, a classification system. And I won't go into too much detail, but included one table in their, um, landmark paper here on the, on the lower right, um, basically, based on tissue biopsy. Um, so, again, you know, using multiple biopsies, um, not just one, but the first biopsy could tell us whether there's definite myocarditis, borderline, or not at all. Um, and then, you know, using subsequent biopsies to tell us if, you know, the myocarditis was an ongoing process. Um, and what we, what we see, what we could see with biopsies, um, are, are multiple different possibilities. What obviously we could see is, you know, cardiac myocyte damage. So you could see, you know, you know, uh, necrotic cells, um, you could see, instead of the The, the cardiac myocytes, replacement of those cardiac myocytes with, um, you know, vacuoles, empty sort of, um, hollow cells, if you will, um, in place of the myocytes. Um, you know, inflammation is a, as you'll see, is a huge part of, of, uh, what we think is myocarditis. So, inflammation could include lymphocytes, polymorph, uh, polymorphonuclear, uh, leukocytes, um, typically T cells is, is what we see in the inflammatory, um, milieu, uh, on biopsy. Um, you can see fibrosis, so scar tissue, um, um, on biopsy. Um, in certain types of myocarditis, you can see granulomas, um, um, for example, in cardiac sarcoid, um, and the giant cell myocarditis is one of the, the more, uh, you know, sort of the more dangerous, uh, um, you know, uh, life-threatening, um, uh, forms of myocarditis. Um. Um, and then you can see an eosinophilic or neutrophilic, um, yeah, um, predominance, um, on biopsy. So, um, I will, uh, one more slide on sort of, you know, biopsies, um, because this is the gold standard, um, still, um, uh, for diagnosing myocarditis. Um, Even though endomyocardial biopsy is the gold standard, uh, actually recommendations or in, in real life, uh, biopsies to assess for myocarditis are actually not, um, as commonly done as, as we might think. Um, um, and there are multiple reasons for that, but, you know, one of the main reasons is, you know, if you're You know, putting a catheter inside the heart to take a tissue sample, you know, there can be complications, um, and obviously these complications can be very, you know, um, they, they can be fatal. I mean, they, you know, there, there, there can be significant risk to the, to the procedure. Um, so, you know, it, it, it, you know, major complication rates could be around 1 or 2% and include perforation of the, of the ventricle, either the left ventricle or the right ventricle, um. Particularly with the right ventricle, as the right ventricle wall tends to be a little thinner, um, Minor complications can, you know, I've seen go up to, you know, an incidence of 5%. So, it's not a, not a completely benign procedure. So, that may be one reason why biopsies for myocarditis are not, uh, not always done. Um, in addition, myocarditis, uh, from a, on a tissue level can be focal, meaning, you know, it, it's, it's, it's, when you biopsy a tissue, um, The myocardial tissue in, in a patient with myocarditis, um, you know, that, that tissue, uh, involvement doesn't have to spread throughout the entire heart muscle. It can, it can be patchy, um, and so, biopsies, um, you might expect can miss the diagnosis, uh, for that reason. Um, And, and, you know, based on, and, and probably because of some of these elements, uh, biopsies are oftentimes used, uh, or done, um, mainly in higher risk patients, uh, more ill patients, patients who are hospitalized, um, in the ICU or CCU, um, you know, where, you know, you may have indication to, you know, do invasive procedures anyways, uh, for standard of care. Um, so that's where biopsies are more often done. Um, whereas in lower-risk patients, um, and we'll get into this, uh, you know, biopsies are less often done, and we're often, more often resorting to, you know, doing blood work and looking at the clinical situation and doing EKGs and doing non-invasive testing like echocardiography and, and, uh, cardiac MRI. Um, so, so that's sort of an, an, an sort of an initial, um, um, sort of primer on, on how we approach, uh, diagnosis, um. Yeah, uh, so, so, uh, you know, as you can see, sort of in this lower right corner, you know, there are, there are situations where biopsy, um, proven myocarditis is quite clear, you know, you can see, you know, in this, you know, the bottom panel, um, um, you know, you can see a lot of inflammatory infiltrate here, you know, in, in, in the midst of the, the cardiac myocyte, uh, tissue versus a normal sample on the top. Um, and this is, this is another, uh, sample from a paper, um, in a, in a 29, uh, representing a 29-year-old, um, female patient with acute myocarditis. And so, um, on the left, this is a This is a path sample, pathology sample, um, showing if you can see, you know, these patches of, of sort of purplish stained um cells here amidst the normal myocardium. So the normal myocardium appears pink. Here and, and, uh, this is an H&E stain for the pathologists out there, um, um, uh, showing, you know, these patches of, of, of dense aggregates of mononuclear, um, leukocytes, um, um, suggesting the diagnosis of myocarditis. Um, and then on the right, this is an MRI, a sample MRI of this patient, um, showing, um, what we call late gadolinium enhancement, um, which essentially tells us about, um, scar or fibrosis in a very typical pattern, um, consistent with myocarditis, um, in the red arrows, uh, shown by the red arrows here in the, in the anterior septum, um. In the midwall, the, the midwall of the anterior septum here, as well as the inferolateral wall of the left ventricle, um, what we call subendocardial left, uh, late gadolinium enhancement. So these, these are patterns that are quite classic for myocarditis on, on cardiac MRI. All right. So, so, enough about, uh, you know, the, the, some of the path, uh, pathology and imaging, although we'll get back to it. So, epidemiology, um, so, I think, you know, some of us, uh, remember prior to the pandemic, um, you know, it feels like ages ago, but, but, uh, before then, we, you know, there, uh, myocarditis was a well-known entity. It was not a very common disorder, um, Um, uh, you know, maybe 1 to, uh, 1 to 10 cases per 100,000 people per year. Um, and, uh, incidentally, the, the, the, the most common, uh, presentation was in younger, younger males, uh, between 20 to 40, uh, years of age, and this was prior to the pandemic. Um, and then, you know, as we may remember during the pandemic, uh, you know, we started to, you know, see cases of myocarditis, both acute and chronic, in the hospital and, um, outside of the hospital. Um, and, uh, so, you know, you know, there's been a good amount of research looking at, you know, the, the numbers. Um, and how, you know, how the incidence of myocarditis did go up, um, during the pandemic. So, you know, quite, uh, multiple fold here, you know, 2.4, um, 22 to 4 or 2 to 5, um, patients, uh, cases per 1000, um, um, uh, people, um, in, uh, with, with COVID. Um, and so we, you know, this made sense to us, uh, you know, COVID being a viral illness, you know, we knew that, uh, you know, there are, in the past, we knew that there were other viruses, um, you know, coronaviruses, rhinoviruses, um, adenoviruses that, that could precipitate COVID, uh, sorry, precipitate myocarditis, and so, You know, it, it, it, it made sense to us, um, that COVID-19 SARS-COVID-2, um, could do something similar. Um, And, uh, and then, you know, when, when the COVID-19 vaccines came along, um, you know, I, and I remember this, uh, uh, very clearly, um, not too long ago, but, uh, you know, we, we started to see cases of, of myocarditis that we thought were associated with the vaccination, um, and particularly with, uh, mRNA vaccines, um, um, uh, Pfizer, um, and Moderna. Um, and so, you know, again, we saw these cases, you know, not too commonly, um, that, and that's important to note, 1 case in 100,000 people vaccinated. Um, we still saw the same pattern, more commonly, um, you know, in younger males, um. So, um, I, overall, you know, there's been documentation that, you know, at least, um, the, the, the, the, the incidence of myocarditis and pericarditis, um, has gone up at least 10 times, um, you know, compared with pre-COVID, pre-pandemic levels. So, it's definitely something that we see and, um, and deal with. Um, I think. Um, luckily, uh, uh, most of the cases, um, of either COVID-19 myocarditis and certainly COVID-19 vaccine related, um, myocarditis tend to be mild and, um, And resolve, uh, with supportive treatment. Although, you know, at, at the hospital, I have seen, you know, patients with COVID, um, uh, myocarditis that were very sick and, and did require a transplant. Um, so, um, the, the spectrum of disease does, uh, is, is quite wide. Right. Um, so, um, and I know, I know many of us know how these patients often present. Um, they, they often present with chest pain, um, clinically, so, and it's oftentimes acute. Um, you know, along with that, people can also present with shortness of breath, um, you know, dizziness, you know, multiple non, more non-specific symptoms. Um, and that's oftentimes what we see in clinic, um, in the outpatient setting is, you know, people come in with chest pain, uh, you know, after getting, uh, after contracting COVID, um, or after getting a vaccine. Um, you know, obviously, this is a, this has been a, maybe a more difficult situation for us in, in cardiology where, you know, we You know, I remember during, you know, right after the, the COVID-19 vaccines, uh, came out, you know, I had a flood of patients coming in with, uh, chest pain, and, and they, they thought that this was all vaccine related. Um, and, uh, again, to emphasize that the, the data have shown that truly the incidence of myocarditis, like more definite probable myocarditis related to the vaccine is very low, um, but, you know. The media perhaps played a role in, in, in, in this, in, in, in the sense of, well, you know, it was kind of presented in the, the, the, the lay non-medical media and patients, you know, when they had symptoms after a vaccine, they were worried that, you know, oh, do I have myocarditis or pericarditis related to the vaccine, you know, these were, you know, not, these were new vaccines to the population, so, uh, there, there understandably was a lot of, um, worry, um. Um, but, but again, to, to re-emphasize that, you know, the, the not only the, the numbers were of vaccine related. Um, myocarditis are still quite low, and the prognosis was quite good. Or is quite good. Um, but in some cases, you know, patients can present with very severe illness. Um, as I mentioned before, they can have, they can be in shock, they can be critically ill, um, you know, with heart failure, and, uh, and, uh, you know, they can require mechanical support, um, heart transplant, um, so, you know, this, this, when I read this figure, it was quite staggering to me, you know, these Um, you know, registry data showing, you know, almost a 30% rate of either death or transplantation, um, in, at 60 days in patients with, um, myocarditis and cardiogenic shock, um, versus 2% without cardiogenic shock. Um, Patients with myocarditis can present with ventricular arrhythmias, as well as atrial arrhythmias, um, atrial fibrillation, atrial flutter. Um, but ventricular tachycardia, um, is, is, um, is a more dangerous rhythm that, that can be associated with myocarditis. Um, AV block, um, you know, sometimes require a pacemaker, um, and sudden cardiac death, um, you know, potentially due to a ventricular arrhythmia. Um, you know, uh, to remind us, you know, some, you know, sometimes these patients with myocarditis, um, um, in, in the non-severe case, um, they, they can have a normal EKG and a normal troponin. So these, these, these are not, um, tests that we can hang our hat on in terms of diagnosing myocarditis. So, other things that we can use to um help diagnose uh myocarditis is imaging. Um, so, the kind of the, the idea behind cardiac, non-invasive cardiac imaging is to look for, um, you know, ventricular wall motion abnormalities or left or right ventricular dysfunction. Um, while, of course, excluding, uh, coronary disease. So if, of course, if we're, if we, if we have patients coming in with chest pain and then they have an abnormal EKG and an abnormal troponin, then our first thought is thinking, well, are they having an acute MI? Are they having a heart attack, uh, myocardial infarction, and we, we, we probably have to look at their coronary arteries, um. Um, but if we've excluded coronary artery disease as the, the etiology of their, their situation, then, then myocarditis is certainly on the differential. Um, and, uh, echo, echocardiograph, echocardiography is the, you know, the first line test that we, that we use. Um, it's a test that, you know, I mean, can give us an idea of, of, of, uh, of ventricular dysfunction, wall motion abnormalities. It's, it's, you know, easy to do, quick, um, non-invasive, and, uh, can happen very quickly in the outpatient and inpatient setting. Um, cardiac MRI is, uh, uh, a modality that's been around for a long time, but, you know, I think in general, the, the its use is increasing, and myocarditis is one of the, the key, uh, use cases for cardiac MRI. Um, so, we've already talked a little bit about how we can see, um, you know, abnormalities like late gadolinium enhancement. Um, um, which, which, uh, I won't get too much into, cause it's not a radiology talk, but, but, uh, you know, that's a finding on cardiac MRI with gadolinium contrast that is, um, that is consistent with scar or fibrosis. Uh, but certain patterns of, of, um, late gadolinium enhancement. Um, edema, myocardial edema, we can actually measure, um, edema from, um, certain cardiac MRI, um, techniques, and, and this can help us with, help us with the diagnosis of cardiac, uh, myocarditis. Um, keep in mind that, uh, that the, the diagnostic sensitivity for, for myocarditis using cardiac MRI is, is highest, um, um, within, you know, 2 to 4 weeks, uh, of symptom onset. Um, so, in another, said another way, you know, in a patient who had resolved or had acute myocarditis and, um, and it completely resolved, um, an MRI done, you know, you know, a few months afterwards could be completely normal. Um, and so, um, this is something to keep in mind when we're thinking about the timing of Of ordering tests and, and the test results impacting our, our, our, our diagnosis. Um, and part of what plays into this perhaps is, is sometimes cardiac MRI is not as accessible, um, you know, we don't, you know, cardiac MRI is not done at every site. Um, you want to have a site, a center that does cardiac MRI and is very facile at interpreting results, um, and looking for things like cardiac, uh, for looking at things like myocarditis and, and, and, uh, And, and, uh, and cardiomyopathy in general. And so, you know, I, and I've seen this before too, where, you know, patients um may not be May, may be in a place where they don't have um good access to cardiac MRI and they, they get an echocardiogram that shows LV dysfunction, um, and maybe they're given the diagnosis of non-ischemic cardiomyopathy. They have a cath and, and, uh, and, uh, they have no coronary artery disease, um, um, um. But they don't, don't, they do not end up getting a cardiac MRI in, in timely fashion, perhaps because they don't have access to it. There's, there's not a, a cardiac, um, MRI locally, and, um, yeah, I mean, that's something that could potentially lead to, um, under diagnosis of, of something like myocarditis. Um, this is, these are some other MRI images. Um, um, we've already shown some images, but some other images of, uh, of a patient with, uh, acute myocarditis, again, showing if you can see this sort of brightness. Um, this is the left ventricle, this is the MRI cross-sectional short axis view with the left ventricle here, the right ventricle here, and this is the intraventricular septum. And, um, you can see sort of this, this band, um, here, um, this, this darker area here, um, at this interventricular septum that is late gadolinium enhancement, um, uh, that is suggestive of scar fibrosis in a, in a myocarditis type pattern. Um, and, um, you, you also see a similar area here. Um, again, left ventricle, right ventricle, this is a short axis view. This is the inferolateral wall, um, uh, late gallinium enhancement at the inferolateral wall. These locations and the, the, the locations of, uh, late gadolinium enhancement are fairly classic for myocarditis. All right. So now, we'll move on to um uh myocarditis in the setting of COVID-19. So, Um As, as we sort of talked about, there, you know, it's not surprising to a lot of us that COVID-19 can trigger myocarditis, and we don't, we're still trying to understand why or how that, uh, the, the mechanism is, but there are multiple different, um, hypotheses, um, you know, oxygen supply demand mismatch and ischemia. Um, you know, microvascular thrombosis, um, could be, you know, a culprit. Certainly, inflammation, um, is a, is part of our understanding of, of myocarditis, and so, um, as illustrated in this lower right panel is, is when you have, um, you know, a SARS-COVID-2 viral particle that, you know, binds to the cardiac myocyte. Um, you know, that can trigger, you know, a cascade of events, uh, much of which are, uh, inflammatory in nature. Um, I remember during the pandemic, we, we saw or and heard, um, about patients in the ICU with what we call cytokine storm, where, you know, they, their inflammatory markers were up, you know, they were febrile, um, um, they, they, you know, they had, um, you know, evidence of inflammation with, with elevated white blood cell counts, um, for example, um, and we, we, we think that Um, you know, this, uh, this, uh, uh, the, the, the binding of SARS-COVID-2 to the heart can set off, um, um, a cascade of events, not just directly affecting or infecting the cardiac myocyte, but also, you know, contributing to, you know, this inflammation, which is part of the disease process itself. So, so again, not just an Uh, and it's not just an infection problem, but it's also that, you know, subsequent inflammatory response that that can be part of the disease. Um, And so, you know, in, in, in, uh, patients with COVID-19, we saw, uh, you know, a, a significant percentage of patients with myocarditis, COVID-19 myocarditis, that had a fulminant presentation, i.e., you know, you know, cardiogenic shock, heart failure, severe LV dysfunction, um, and they ended up having very poor outcomes or, or needing transplant. Um, the, you know, these, these, these diagnoses of myocarditis may have been underestimated given that they, they would have, um, you know, multi-organ involvement including the lungs and, and so this could have, uh, affected our ability to diagnose myocarditis in these, um, in these very, very ill patients. Um. You know, another important thing to remember is that, you know, troponins in these patients with acute myocarditis correlate really with prognosis. Um, you can have a patient with mild disease with a normal troponin. Um, and so the absence of an elevated troponin does not rule this out. Now, in, in hospitalized patients with fulmin and myocarditis, you know, inevitably, you know, they're all gonna have elevated troponins. Um, um, but, uh, in the outpatient setting, for example, um, the troponin may not be, you know, don't, don't hang your hat on that troponin. Um, in the outpatient setting in, in patients with mild, mild disease. Um, this is another cartoon from, from, uh, uh, that same paper, um, and I won't go into this in too much detail, but just wanted to kind of illustrate the, the, uh, you know, the complexity of, of, you know, cellular mechanisms and how they may Affect the clinical presentation of myocarditis. Um, and so this is a cartoon of a mast cell, which is a, which is a, a, a, a white blood cell of myeloid lineage, and, and, uh, this, the, the, the effect of SARS-COVID-2 on the mast cell is Thought to be an important part of, of the pathophysiology of myocarditis. Um, so, you know, here when, you know, you see this on the lower left here, you see this SARS-COVID-2, uh, viral particle, um, you know, we've heard of the, the spike protein, um, and how, and, and that's, and that's on the outside of the viral particle. And how it binds to the ACE2 receptor on the um on, on this particular cell, and that triggers a cascade of, of events, uh, um, including clotting factor release, inflammatory factors release, IL-6, IL-1, histamines, um, uh, which, which can, can again be part of the, the, the disease process and cause hemodynamic instability. Um, and, and so this is thought to be a, a key part of the, uh, of the, of the disease process, not just the virus entering the cell. The virus does, we think, still directly infect the cell and, and, uh, uh, you know, cause cell death that way, um, but it's probably more complicated. Uh, the disease process is probably more complicated than that. All right. So, moving on to, from COVID-19 to the COVID-19 vaccines and, and it's their relationship to myocarditis. So, um, as we know, um, you know, the mRNA, the messenger RNA vaccines have been most clearly correlated with, um, cases of myocarditis. So, the mRNA vaccines, they contain modified mRNA. That encodes the, that spike protein of the SARS-COVID-2 virus. And so, when you, you know, obviously when you give that vaccine, that, that, uh, that protein uh in the, sorry, the mRNA that encodes that protein leads to the antibody to the spike protein, um, and that, uh, that antibody, you know. Uh, prevents binding of the virus to the ACE2 inhibitor, uh, ACE2 receptors. So, so that's the way the mRNA vaccines work. Um, um, I, I'll, I'll talk about this, I think, in the next slide, but, uh, the, the, the, the, the reasons why the vaccine, the mRNA vaccines can cause or lead to myocarditis, still to be determined. We're still trying to figure that out. Um, but what we've seen is that the highest risk of myocarditis is with, uh, the second dose or after the 2nd dose of vaccine, and again in young, younger males. Um, so the, I think the, the significance of this happening typically after the 2nd vaccine is that, um, as you might expect, you know, after the 1st vaccine, um, you haven't developed the antibodies yet, uh. You know, after that first vaccine, the antibodies have now been formed, and then after the second vaccine dose, um, then you have sort of an immune response, um, uh, that's already built in. To lead to, uh, potentially lead to myocarditis, uh, sort of that, that, uh, that reaction. So, symptoms of, of myocarditis after the vaccine typically occur, we saw typically occurred, you know, within anywhere from 3 to 11 days after, again, after the second dose. And usually, you know, symptoms would be mild and transient. So, I, I remember seeing, you know, again, after the vaccines came out, I would, I, I saw a, a good number of patients in the clinic with, with, um, You know, who would complain of some chest pain and, you know, they, they would be worried that they had myocarditis, and, and, you know, I, I, I think at during those early times, you know, it was, it was, it was challenging to counsel them, you know, especially in, in, in the setting of, you know, these cases being, you know, these myocarditis cases after. Um, vaccines being reported and patients would be wondering, oh, I shouldn't have gotten the vaccine. Um, I, I, I would. I would, and I still point them to the literature, uh, showing that the The, the benefit of the vaccines. Um, would really outweigh the very low risk of the vaccines in terms of myocarditis risk. Um, and there's actually a very nice paper, and I think the in JAC or, or JAMA, um, actually doing that kind of risk-benefit comparison, if you're interested, you know, again, showing that, you know, Almost, you know, almost very clearly, you know, the benefit of the vaccines well outweigh, um, uh, the risk of developing myocarditis, even in, uh, the young, young male, uh, population. Um, so do keep that in mind. Um, so, I, I touched on this a little bit, uh, mechanism possible mechanisms behind, uh, uh, mRNA vaccine-induced myocarditis, pericarditis. Um, so, uh, you know, what we think potentially could be, uh, the culprit is the, you know, the spike protein of the virus, um, um, um. Kind of mimicking, um, the cardiac myosin or the cardiac cardiac uh myocyte, uh, uh, receptor molecule, and so, basically causing, um, you know, the attack on your own, on your own cells, and autoimmune reaction leading to, uh, myocarditis. Um, cytokine storm or sort of an inflammatory response, uh, from the vaccine itself. And it, it is, it is also a possible culprit. And then, um, the, the, the vehicle, the, the nanoparticle vehicle that, um, actually is the carrier for, if you will, for the mRNA vaccine could also be, uh, something that triggers an autoimmune response leading to myocarditis. Um, um, it is interesting that the, the myocarditis cases after vaccine, um, occur in a very similar, tend to occur in a very similar demographic, um, um, as the pre-COVID and the COVID myocarditis patients, i.e., you know, tend to happen more often in young, younger patients and in the male patients. Um, so there may be a commonality, uh, to that, uh, because of, because of that. All right. So, uh, uh, uh, uh, that's a little bit about COVID-19 myocarditis and COVID-19 vaccine myocarditis, and I'll now move on and touch a little bit about newer, um, fairly recent, uh, information that we have about certain cancer, um, treatments that can, um, trigger myocarditis. And so, There are specific, um, immune modulating, um, uh, treatments or medications called immune checkpoint inhibitors. Um, we, we, you know, easily said checkpoint inhibitors. And so these are actually monoclonal antibodies that are cancer treatments that target, um, um, host immune, um, uh, regulation receptors, and I'll, I'll show you a, a, a picture of this in the next slide, I think, or, or two slides later, which illustrates this. Um, basically, these antibodies, um, are designed to target the host immune, um, response to trigger the host immune system to, you know, kill the, the, the cancer cells, um, specifically. And so, um, these, uh, these, uh, treatments have been associated with development of myocarditis. And the mechanism behind this, again, very similar to maybe the vaccine, um, concept is a shared, a, a shared, um, antigen or, uh, yeah, a, a, a shared, um, um, uh, antigen between the tumor and the cardiac myocyte. Um, And, uh, this type of myocarditis is seen to be very quite uncommon, uh, uncommon, but, you know, the patients can have very high mortality. Um, I mean, even in some papers up to 50%. Um, these cases of myocarditis typically present within the 1st 1 to 2 months after initiating therapy. Um, and these therapies, you know, I see, I'm not a, I'm not an oncologist, but, uh, I see typically that these injection, these are injection, infusion medicines that are given once every few a few weeks or a couple of times a month. And so, you know, keep that in mind if you have, um, oncology patients, um, getting treatment with uh, a checkpoint inhibitor. Um, you know, this, the, you know, they can develop, um, symptoms of myocarditis. Look out for symptoms of myocarditis, um, um, you know, even one or two months after, after initiation of therapy. Um, and the treatment typically is stopping the, the therapy and, and using steroids. Um, prednisone or Solu-Medrol. Um, and so, so these are, this is a list of, um, I, I think a fairly current list of FDA approved, um, um, checkpoint inhibitors. And so, um, um, one of the, you know, and they're used for a variety of different cancers, including lung cancer, melanoma, skin cancers, um, etc. Um, the, the ones that I've seen most commonly used, pembrolizumab, uh, I hear it, uh, Pembro, uh, some of the oncologists say, so. So, Pembro and uh nivolumab um are also um um are, are some of the more commonly used um checkpoint inhibitors. So, so again, something to think about if you have patients on these medications and they have symptoms, um, kind of think about. Um, myocarditis. Um, yeah, so this is the cartoon that I was referring to. So, on the left, um, this is a cartoon, this is a tumor cell here on the top, and then on the bottom, this is a T cell, and this is a specific, um, um. Uh, situation where you have a checkpoint protein, um, you know, with PD1 binding to PDL1, and this binding of the checkpoint protein, um, promotes a negative regulation, sort of an off signal, so that the T cell does not attack that tumor cell. Um, so that's on the left panel. Um, on the right panel, this is the actual, um, uh, immune therapy, the checkpoint inhibitor, and it's here illustrated as this sort of red triangle here. So, this is a, this is a, this is a checkpoint inhibitor that binds to the PD1 of the T cell, and, um, this is, this is a, this is a, this binds on the tumor cell, and this turns off the off signal. So that now the T cell is um kind of activated to now cause and initiate tumor cell death and and lice the the the cancer cell. So that's a little bit about how the checkpoint inhibitors work, and, you know, potentially the, the, the, the, the The mechanism of myocarditis, um, in, in, in this treatment may be related to, again, you know, how this receptor may be very similar, um, to, you know, something on the normal, um, cardiomyocyte. Um, this is a, a sample EKG or ECG of a patient with immune checkpoint inhibitor myocarditis. So, so, the, you know, the top panel is the EKG of this patient before receiving the treatment. Um, and it's essentially normal PR interval, um, um. Pretty benign, fairly benign-looking ECG, you know, maybe, uh, incomplete right bundle branch block with a, with a, with an axis deviation. Um, but then on the bottom, I'll point out, it's nicely pointed out with the, with the, uh, with the circles and the, and the squares here. But, uh, this is a patient who is, this is the same patient who has received, um, immune checkpoint inhibitor treatment. Um, and has developed chest pain and evidence of myocarditis on imaging. And so, um, his EKG shows a prolongation in the PR interval, um, and PVCs. So, So, these are signs, well, I mean, the patient already had the diagnosis, but, but these are signs that this patient could have, you know, cardiac arrhythmia as part of their myocarditis presentation or has, has a cardiac arrhythmia that could progress to, say, uh, complete heart block, um, with their, with their myocarditis. Um, I, uh, I have two more slides and then we'll, we'll, we'll stop for questions. So, so, you know, myocardio, we talked a lot about, you know, the basics and of myocarditis and what we know, uh, more about myocarditis. Um, management, um, uh, this general management, uh, we've, we've, we continue to use, um, in patients who have left ventricular dysfunction and heart failure, we use standard heart failure treatment. Um, we support them hemodynamically, um, if they're in the hospital and need pressor support, you know, that's what, that's what they get. And, uh, eventually, you know, if they're sick enough, they, in cases of fulminant myocarditis, they may need, um, you know, um, uh, mechanical support, um, ventricular assist devices, um, um, and, you know, ECMO, um, and a heart transplant, um. Um, these are, these are, these are very, these can be very sick patients and, and, um, require very, very, um, specialized care in an ICU. Um, in terms of arrhythmia treatment, you know, the specific treatment aside from sort of hemodynamic support is Is, uh, you know, if they have ventricular tachycardia, sudden cardiac death, the question being, you know, do they need a defibrillator? And, uh, you know, this is obviously a, a, a decision that's, that's weighed, um, uh, with risks, with risks and benefits, and, you know, each specific case has, has its own details, but You know, in general, you know, you know, since myocarditis is a, a disease that can resolve, um, you know, we don't. Often jump to implanting a defibrillator, um, unless, you know, if, unless we know that there's some chronicity to the left ventricular dysfunction and, and, and, uh, or, or if the patient's continuing to have VT, um, um, um, throughout their hospital course, then, you know, these, these might be reasons to, to implant a defibrillator. Um, know that, uh, non-steroidal anti-inflammatory, uh, uh, agents are not beneficial for myocarditis. So, so, you know, different from pericarditis, um, NSAIDs are not beneficial for, for myocarditis patients. Um, and also, um, remember about, uh, patients with myocarditis and their need for physical activity restriction. There is data showing that, um, you know, patients who do not have restriction in their physical activity after a diagnosis of myocarditis, that can worsen their disease. And so, particularly, um, in patients who do athletics, um, you know, as we talked about young males. Um, being, you know, more some of the more, um, Um, more frequent, uh, um, populations to have myocarditis, you know, they, they might be, you know, athletes, um, but if they have myocarditis, the, the standard of care really is at least, um, 3 to 6 months of, of abstaining from, from significant athletics and certainly competitive athletics, um, uh, for, for their benefit. All right. Um, last slide. Oh, sorry, I think this is my 2nd to last slide. So, so, you know, I think I won't spend too much on this. There, there are lots of, you know, potential treatments, um, in addition to what, what I just mentioned about, um, you know, about, uh, general treatment for myocarditis. Um, some of these are quite new and there's no, you know, real strong randomized control trials to To, uh, show that these are, that these are the, the treatments to use, um, but, um, you know, oftentimes, um, if you have a a very critically ill patient in this, in the ICU and they're not responding to steroids, they're, they're not, uh, getting better, you know, you know, sometimes, you know, we try. Agents that, um, yeah, may not be proven, but, you know, we're, we're basically using a Hail Marys type of approach. So, so, um, even though not super data-driven, you know, IL-1 inhibitors or JAK-2 inhibitors, um, IVIG has been used, um, these are, these are again, You know, use on a case to case basis and only done really in the ICU with, with, uh, with, uh, with a team that is familiar with these, the use of these agents. Um, but definitely not, uh, uh, not a clear standard of care when it comes to, um, these types of treatments. So this is sort of a summary, uh, summary graph or pictorial that I got from a paper, um, again, sort of illustrating, um, you know, some of the workup that we do, um, and, um, uh, kind of stratifying it, um, uh, according to higher risk patients on the left and lowest risk patients on the right and the blue panel, and so. You know, if you're having, if you have a patient in your clinic who has chest pain and you're concerned about, um, uh, myocarditis, but this is a low, you know, you think, a low-risk patient, you know, they're not in heart failure, you know, they're in sinus rhythm, they're not having arrhythmias. You do an echo, their EF is normal, um, you know, you, you know, oftentimes what is done is, you know, Well, sending it to, sending this patient to a cardiologist would certainly be reasonable, um, and getting, eventually getting a a cardiac MRI, um, would, would be, uh, probably one of the next steps versus, you know, a higher, higher risk patient who you're probably not seeing in the office, um, but someone in the hospital who's in shock or in heart failure. These, the, you know, these patients definitely should be in a, you know, a, a specialized, um, center, uh, um, used to dealing with, you know, patients with critically ill, um, with critical illness, uh, and cardiac illness, and, you know, they, they, they oftentimes do get, um, biopsies to, um, for, for confirmation of diagnosis. And part of the reason why, why biopsy may be helpful in those situations is, you know, the, the treatment can be tailored based on the biopsy results. For example, if you have giant cell myocarditis on, on a biopsy sample, then, um, you know, they're treated differently than, say, a Patient with COVID, um, uh, COVID-19 myocarditis, which, you know, they would have, you know, they would, the COVID-19 myocarditis patient probably would, would, would be more of a supportive care type of situation. Whereas a giant cell myocarditis patient, you're using immunomodulators, steroids, um, um, to, for treatment. Um, those are my slides, and I'm, oh, it's one o'clock, so I'm happy to take questions.
