Let's go ahead and start then. Welcome, everybody. I'm really looking forward to this exciting seminar. We have a group of Education Committee planning members who have chosen this topic that we give on an every monthly basis for our Heart Failure Society members and non-members interested in heart failure. I'm very excited about this particular topic that we're going to be talking about on a focus on novel and emerging myocarditis recognition and management. Excited because it's a very interesting topic that's evolving and as well as having a wonderful world-renowned speakers to update us on the particular matter. When we talk about... These are the three speakers, which I'll get back to in a little while, but just in terms of what the learning objectives are. There's the saying, this isn't your father's blank blank. Well, I don't think myocarditis at all is your father's disease anymore. I think over the last two decades, it has really evolved with different etiologies. It's very important, I felt, for the Heart Failure Society members to learn what's new in the last two decades, even though it says the past century in the first objective to see what changes have occurred in the epidemiology, who gets it. We didn't have immune checkpoint inhibitors two decades ago. HIV, of course, was present, but a lot with COVID going on. It was very important for our Heart Failure Society members to be updated on myocarditis. Then, of course, we have a lot of changes in terms of diagnosing clinical imaging as we move forward with it. One of the important things as providers and clinicians that we need to know is how to treat common diseases well and how to recognize rare diseases so we don't miss them, especially when there's the opportunity of changing the outcome. Those are the two main things that we look for in these webinar topics. I think recognizing sometimes it can be subtle in terms of myocarditis will be the second objective. Then we'll be talking the third presentation will be on the treatment, which also has evolved over the last two decades. Our speakers, we are very fortunate to have outstanding speakers. Let me start off with Dr. Leslie Cooper, who is the chair of this seminar, a world-renowned entity. He would probably even call him Mr. Myocarditis in the U.S., founder of the Myocarditis Foundation. He was such a sought-after speaker. We changed our date. We changed our day that we give this seminar to make sure that we had Dr. Leslie Cooper talk to us. He is the chair of medicine and cardiovascular disease at the Mayo Clinic in Florida and, of course, well-known in and contributed to a lot of guidelines, epidemiology, and a lot of research that's going on. Thank you very much, Dr. Cooper, for volunteering for this particular seminar. We're so proud and lucky to have you. We also have Dr. Wilson Tang, who will be giving the second presentation on diagnosis and imaging, biomarkers, recognition of this entity. Dr. Tang, of course, is a household word in the heart failure society, large contributions, many years of it, well, highly regarded in the world of heart failure. I have to give you a personal way of saying how much he's looked up to. I was recently offered a research trial. When I saw that Wilson Tang was on the subcommittee running it, I said, well, I have to be on this particular trial. That's how highly regarded he is. Dr. Wilson Tang is a professor at Case Western and also works at Cleveland Clinic, where he is a very key member of the heart failure transplantation and heart failure section. Then last but not the least, we are so fortunate to have Dr. Craig Beavers from the University of Kentucky. He did most of his training and is currently at the University of Kentucky, was at University of Tennessee for a short time, very critical member in terms of heart failure and pharmacy. It takes a village to take care of heart failure patients. Certainly, pharmacists and nurse practitioners are major contributors to the house and village that takes care of heart failure. Dr. Beavers is certainly one who has lent a lot of his expertise in terms of leadership for the pharmacy component to it. I'd also like to thank the program planners, two of which I've already introduced, Dr. Cooper and Dr. Beavers. Dr. Proffitt is the nurse practitioner who is part of the planning committee, a member of the HFSA, worked before, absolute sheer delight to work with. Thank you very much to the planning committee for all that's gone into it. Let's see, do we have anything more to talk? Here we already talked about the agenda and what we'll be talking about. Just a little housekeeping remarks for continuing education information to claim credit. You have to complete the course evaluation that comes at the end. Of course, when you've joined the course, we will give you the code to get into our learning system, HFSA's learning environment to get into, to look at their slides, et cetera. Thank you very much for joining. We have a really full house today of approximately 100 speakers. We look forward and why don't we start with you, Dr. Cooper, with the first presentation. Franny, thank you so much. It's great to be with you. I really am honored by the chance to be in front of this audience. I'm going to start by sharing my slides. My task in the next 20 minutes is to describe the epidemiology, the latest epidemiology of emerging myocarditis, not only on a global scale, but the more specific ones, those related to immune checkpoint inhibitors, such as the epilimumab or nivolumab, and the latest on long COVID, both the role of inflammation in long COVID, but more importantly, the role of and the latest on long COVID, both the role of inflammation in long COVID, but more importantly, the relative risks of third booster vaccines, which since most of the population has had the primary series. I have really no disclosures that are relevant to this particular talk. These are my potential conflicts. We have two questions to begin. We're not seeing your slides. You're not seeing the slides. Okay, let's hit escape. Let's go back to Zoom. Do you see? You have to go to the share slide. Okay. There you go. Okay. Do you see now? How about now? Franny, do you see them? I see. I see your slides. Yes. Great. You can go on to the polling question. Yes, go ahead. So with that introduction, we're going to start with the first polling question. In 2021, the global number of cases of myocarditis was approximately one or two per 100,000, 10 to 20 per 100,000, or 100, 200 per 100,000. Will now please take a moment to vote. Okay, Freddie, do we, oh, there we go. So you can see the majority 56% voted for 10 to 20 per 100,000, but quite a few thought the myocarditis was even rarer at one to two per 100,000. Our second question is illustrated here. Myocarditis affects what fractions of patients treated with immune checkpoint inhibitors? One in a thousand, about one in a hundred, or one in 10? We will come back to these at the end. And even split between 1 in 1,000 and 1 in 100. So we're going to keep going. Can you close the polling? Thank you. So we're going to start with the 2021 Global Burden of Disease study, which was published this past April. And in that study, there were about 1.2 million incident cases, or 16 per 100,000 cases in the population globally. In the US, it varies by state considerably, with the lowest rates in the upper Midwest and the Western Montana and Seattle areas, with the highest rates in Louisiana, parts of Louisiana, parts of Alabama, and the panhandle of Florida. There are only about 500,000 prevalent cases, consistent with what we know today, that most myocarditis is self-limited. It's a disease that is generally not fatal and does recover fully. However, there were 31,000 deaths. And these are the patients, the young people who die suddenly, or the older patients who go on to chronic heart failure and sometimes heart transplant, that we're going to try and focus on throughout this hour to understand how you can differentiate the really serious myocarditis that's going to progress and requires specific management from those cases that are more benign. Males, as always, have a numerically higher incidence and prevalence in the current GBD study. When you look at it by age and sex, this figure illustrates the findings from a large multi-center study from Berlin and the US inpatient sample published this year. And you can see in prepubescent males and females, boys and girls, there's a very low rate of myocarditis and that it is equal between the sexes. As you get to puberty in group two, there are more males. And that difference between males and females in group three, which is between ages 18 and 35, is most traumatic. When you get out beyond the mid-50s, the sex difference disappears, but the rate of myocarditis remains high, about equal in men and women, but much higher than at a young age. These data, which were published recently from the United Kingdom, show a very similar pattern. In this case, men are in blue. And you can see the number of cases admitted to all NHS hospitals over a three-year period was much higher in teenage and young adult males than in females, illustrated here in red. But by about 55, right about here, the numbers equalize. And so what about severity? You can see that although there are very few cases in young children, that those infants and young children who have immature immune systems have a high rate of in-hospital mortality. The disease tends to be more severe, and with about a 6% in-hospital death rate. That compares to less than a 2% rate in 18 to 35-year-olds. But again, as you get older, in group five, over age 54, there's less resilience. There's also the development of age-related coronary disease and vascular disease, which contributes to a higher and in-hospital mortality rate. Everything we've talked about is stage C or symptomatic myocarditis. And that means you have symptoms of chest pain, maybe syncope, palpitations, or classic heart failure symptoms. In patients acutely, within the first two to four weeks of symptoms, there's a clear indication for endomyocardial biopsy, which Dr. Tang will discuss, or cardiac MRI imaging. These are not mutually exclusive, and they have specific criteria, which other speakers will discuss. It's important that this really applies to the paradigm of just symptomatic myocarditis. What I would challenge you with is that we should be thinking about myocarditis at an earlier stage. There are certainly people, for example, those who are taking immune checkpoint inhibitors who have up to a 1% or so risk of developing myocarditis, generally in the first 27 to 35 days after starting treatment. And this group is at high risk when they become symptomatic. So this is a group to be mindful of. These are examples of checkpoint inhibitors. The mRNA vaccines affect males generally between 12 and 39 years, particularly after the second dose, at a rate on average of about 1 in 10,000, higher in the 18 to 21-year-old range. But again, it's an at-risk group to be mindful that they could have a specific, although generally self-limited, myocarditis. Other systemic disorders, such as sarcoidosis, when it is diagnosed in the lungs, can certainly trigger a screening, EKG, physical exam, and in some cases, an echocardiogram. Perhaps the same should be true with more severe forms of lupus. And now, as we are learning more about genetics in myocarditis, those patients who themselves have a previous history of myocarditis in a second episode, or a desmosomal gene mutation, such as desmoplakin, can be at higher risk of recurrent myocarditis. These would be the stage A patients. But there is also those patients in stage A who were found to have abnormal imaging. If you did the cardiac MRI or the PET scan in the suspected sarcoid, they would have no symptoms, but they would have imaging features suggestive of inflammation. And this is an area where there is a lack of data. In those patients with immune checkpoint inhibitor therapy, we often recommend holding therapy or switching to a different checkpoint inhibitor. Or in systemic sarcoid, there is, again, a divergence of expert opinion on the best management strategy. But it is something that we need to confront, even in the absence of symptoms. This is an example of myocarditis under the microscope, showing a diffuse and severe lymphocytic infiltration. These are generally CD8 positive T lymphocytes. In a patient of mine who had a particularly severe checkpoint inhibitor myocarditis, it's quite real, fortunately, relatively uncommon. So the risk factors and clinical characteristics to remember are 1 in 300 to 1 in 100 treated patients, generally after the second or third dose, three to four or five weeks after initiation of therapy. Double therapy with two checkpoint inhibitors or more, female sex and thymoma have been described as risk factors, possibly older age. And the co-occurrence with myositis and myasthenia gravis occurs in up to 15%. The mortality, once symptomatic, can be quite high. But there are many patients who have minor elevations in troponin who do not have such risk. So we're going to switch now to the second part of the talk, which is about COVID-19-associated myocarditis. I'm not going to spend much time on the acute disease because that was really a story from 2020, 2021, and into 2022. I will share one relatively recent paper. This came from Enrico Amoretti from 57,000 hospitalized patients with COVID-19. And this was in Italy. And of those with chart review, only 112 had strongly suspected acute myocarditis. After detailed chart review, only 54 met a definite or probable characteristic reduced 2.4 per 1,000. That's still a high number, higher than the general population, but not an enormous number. Most of the cardiac injury in acute COVID in the initial and delta waves was from preexistent coronary disease, sepsis, and multifactorial shock. But of these patients who had myocarditis, about 20% died or required temporary mechanical support. And again, the cause of death was not always myocarditis. In some cases, it was pneumonia. This is a paper looking at vaccine-associated myocarditis. There are many outstanding papers, but in the interest of time, I chose only the most recent one from 2024. And this is a report from Australia of all the adverse events reported to the Australian Medicines Agency from the year 2021. There were 271 reports per 100,000, which is a high number. Most were simply vaccine site-associated reactions. But there were 4,000 cases in the whole country of Australia of myocarditis or pericarditis. And there were 13 deaths out of all the vaccinated people linked to vaccination. But they were mainly by thrombosis in older individuals. And none of them were related to myocarditis. When you break it down by vaccine, Moderna, which is spike vax, had the highest rate in yellow in the middle-aged people who would have the young males who would have the highest risk. The Pfizer vaccine, in this case on the left, had a significant but lower than Moderna risk. And finally, the non-mRNA vaccine had a very low risk in all age groups. There are many other very good papers. I wanted to just share this as an example that was relatively recent. Relevant to today in the United States in particular is the booster vaccines. As you know, on June 27, the FDA recommended that all people over the age of six months have a booster vaccine. And that's going to be rolling out, I believe, in September. Excuse me. And so what is the risk of getting myocarditis after a booster? So in this study of 8.8 million individuals from the Scandinavian countries, they focused on 12 to 39-year-old individuals, males and females. The results are illustrated in the bottom here. After Moderna, which had the higher risk, there was a 1 in 50,000 rate after third dose in males. After Pfizer, it was 1 in 100,000. And in females in the same age group, the rate was approximately 1 in a million. A relatively low rate, and most other studies which we're not going to cite, showed this is, in most cases, a relatively benign, self-limited kind of myocarditis. So to summarize with one figure what we've just covered, the risk of myocarditis after SARS-CoV-2 might be as high as 2 per 1,000. The risk after a second dose of mRNA vaccine using a standard interval is as high as 1 in 10,000. But the risk after an mRNA vaccine dose, even in the highest risk group, young males, is 1 in 50,000 using the highest dose vaccine. What can you do about this? If they're getting a primary series, increase interval time to more than six weeks between vaccine doses. Choose a lower dose vaccine, such as Pfizer over Moderna. And you can choose non-mRNA vaccines. So what about long COVID? This is what many of us are struggling with today in the clinic. And you can see here what we recently published three months ago from the Mayo Clinic. These were 363 patients with long COVID symptoms. And if you also see these types of patients, you may have had a similar experience. About 2 third, 67%, after a thorough evaluation, did not have an identifiable cardiac cause. About another quarter had pre-existing coronary disease that was unmasked or which became symptomatic. And about 9% had POTS. And the remaining 10.7% actually had a new cardiac diagnosis that could be attributed to long COVID. And they were myocarditis, rhythm disorders, the most common at 3%, and pericarditis. So there is a real disease after long COVID. But the majority, it's hard to define what the mechanism is. The last two slides are illustrated here. Inflammatory heart disease, you can see as the third row, had a 2.2 relative to predicted risk or baseline risk. But the absolute number of cases for long COVID, this is long COVID after the actual infection, not vaccines, was quite small because these are rare cases. Compare that to dysrhythmias where the hazard ratio was less than that for myocarditis and pericarditis, but the absolute number of patients was 24 per 1,000, a very high number. Dysrhythmia being much more common than myocarditis after COVID-19. And this is really my final slide. And that is about what does vaccination in the Omicron era help you to decrease long COVID? And the answer is yes. If you look at the pre-Delta era before vaccines, the rate of long COVID was about 10 per 100, 10%, 10 per 100. It went down a little bit in the Delta era, and it went down to about 8% with the Omicron variant, which is less severe. But even in non-hospitalized patients, there is a high rate of long COVID, although lower than in the sicker patients. And vaccine, even in the Omicron era, decreases your risk approximately 50%, down from 8% to 4%. So to summarize, that's a high level of the most recent data that I think is relevant to our clinical practices today as we talk about patients getting vaccines and getting COVID in the Omicron era. So let's re-answer those two questions. 2021 GBD study, what was the incident cases of myocarditis? And again, the majority, absolutely right. It was 16 per 100,000 on a global scale, a little bit lower than that in the US, but not much. And our second question, in patients who receive checkpoint inhibitors, what is the approximate rate of developing myocarditis? And we will have extensive time for questions and answers after the three presenters are finished. again, and even split, the answer is about one in 100. It's a bit under 1%. If you have low risk factor groups with a single ICI, it's probably one in 300. On average, maybe one in 200. And in the highest risk and people getting multiple checkpoint inhibitors, probably one in 100. Thank you. And now I would like to introduce our second topic. Wilson Tang is going to be presenting the biomarkers and imaging section of this webinar. Thank you. Stop share. Okay. Thank you, Leslie. That was awesome. Great. Great. Well, good afternoon, everybody. Can you see my slides? Yes, we can. Great. Well, thank you, Leslie. It's a hard act to follow. Always wonderful to learn something new, particularly with the new reports. The assignment on my topic is on recognition and diagnosis, and with some discussion on novel biomarkers and imaging. And so these are my disclosures. I do, I'm in the steering committee of cardiotherapeutics and also a volunteer member for Myocarditis Foundation under Dr. Leslie Cooper. So two polling questions. This is a very standard 35-year-old otherwise healthy man, recent viral illness seen at the ED, non-exertional chest pain. I actually had a patient exactly like this yesterday. Proponent was slightly elevated at 16. The local upper limit of normal was 13, and the CRP was 10. The EKG showed non-ST changes, but QRS of 140. And the viral titers actually did come back quickly, and it shows Coxsackie B virus. ECHO actually showed normal EF and no obvious wall motion abnormalities. What's the next best test to confirm the diagnosis? Body catheterization, PET, cardiac MRI, or enamel cardiobiopsy? Okay, good. Well, next question. The diagnosis of acute myocarditis was confirmed. Which of the following biomarkers is indicative of poor prognosis? Elevated CRP, elevated troponin, QRS, or viral titers? Okay, that's a little bit more split here. So that's some discussion we could have. So the topics are recognition and diagnosis. Obviously, Dr. Cooper actually mentioned the stage A and stage B, which is really the importance of having the prepared mind to consider myocarditis as a differential diagnosis. This has become more and more relevant as we have broader accessibility of diagnostic testing, particularly in terms of cardiac troponin, rhythm evaluation, as well as cardiac MRI. So sometimes it's incidental, but sometimes actually we could see very important cases beyond classic clinical presentations, like chest pain, dyspnea. There are people who are otherwise young, otherwise healthy, who come to the hospital, doesn't have the clear, clear signs of acute coronary syndrome, but certainly concerning with myocarditis. It's almost like a wastebasket case when you don't see other obvious symptoms and signs or diagnostic testing. However, we are seeing more and more people with unexplained VTs and AV block, particularly when they're young, frequent PVCs, which I'm going to discuss a little bit more, that actually has underlying myocarditis when we do more advanced imaging. And clearly, with elevated troponin, it's really a differential diagnosis between minota and acute coronary syndrome, as well as myocarditis that needs further evaluation, and MRI is actually one of the most reliable way to actually look at. But there is also a wide range of non-ischemic and inherited chromopathy. Dr. Cooper mentioned about some inherited chromopathies now present with acute myocarditis. And so recognize this kind of unexplored kind of spectrum to actually go further to identify an underlying inflammatory phenotype is really what the evolving diagnostic characteristics of how we actually define myocarditis and recognizing its presence. The main reason is because there are some therapeutic kind of considerations if there's an inflammatory phenotype, and Dr. Beaver's going to talk about that later on. But clearly, one of the earliest things that we get is an EKG when somebody comes to the emergency room. Usually, it's not specific, as we all got learned in medical school and in residency and in training. Science tachycardia, not specific STT weight changes. There's some PR depression in some cases, there's elevation in APR. But most of the time, it's more diffuse ST elevation. There's no areas that we actually look at that potentially is a diagnostic of acute coronary syndrome. That's kind of a classic textbook kind of description. What is actually indicative of full prognosis, however, is something that we need to learn and recognize. And at least from kind of expert opinion as well as published data, we saw the Q waves, the QRS is elevated, showing kind of a conduction defect. There's some repolarization abnormalities with the QRST angle that we don't really routinely measure, but there's actually a repolarization defect and acute prolongation, and also malignant ventricular tachyarrhythmia. Now, the graph on the right side actually showed this dominant morphology usually is the right bundle branch superior axis. That's indicative of more of the inferior posterior LV wall involvement. Usually, the acute onset is a multifocal polymorphic nature, so pretty angry looking multifocal PVCs or multi-axis runs of ET. As the scarring does occur, there's a more defined kind of channel being developed. The historical myocarditis ended up being more regular and monomorphic. And so the temporal relationship of EKG abnormalities is not so recognizable, but the poor prognostic science really went there. It's actually true structural abnormalities that we can see. Of course, when you see inherited climatology, you also see low voltage T waves, low voltage leads. Chyotic troponin becomes more of a synoclonon of kind of a diagnosis of either minoca or acute coronary syndrome or acute myocarditis. Interestingly, the literature is not very well described in how the trend of the troponin is. Most of the time when we see in clinical practice, it can follow very similar to acute coronary syndrome. Although on the other hand, it could also be pre-undulating, kind of at the low level, close to the 99th percentile limit sometimes, and actually doesn't go up and down as much. It's more like a chronic persistent smoldering kind of myocarditis as well, which is not uncommon when people actually take some time to actually go to the emergency room. It is elevated actually only in 50 percent of the case with biopsy proven myocarditis, which shows us not all elevation is a direct demonstration of necrosis. So it's actually a very interesting observation that if you have the two and two side by side, you may or may not actually see it. Partly it's potentially because of the assays. Troponin T is actually a lot more sensitive for myocardial injury than troponin. Sorry, troponin I is much more high sensitive than troponin T. And troponin T also has a little bit interaction with the skeletal muscles as well. So sometimes you can have a high sensitive troponin I that goes quite high, and then when you check it later on with the troponin T, that's actually quite low. That is probably the reason. But interestingly, in both cases, the initial troponin, if it is in the lower range, is not as prognostic. There's also some people with false positive troponin assays that's on kind of the autoantibodies kind of clumping together called heterophil antibodies, but they are sometimes false positives. Oftenly, most of the time, the cardiac biomarkers, the anti-proBNP, unless it's chronic persistent myocarditis, is usually in the lower range, unless it's actually having an underlying myocardial dysfunction. The graph on the right actually talks about at least a paper that was published sometime a few years ago about troponin T positive, and it is prognostically significant, although that is whether or not they are on either influenza or COVID. And you see the death rate in influenza is a lot lower than COVID, despite both of them having an elevated troponin. So, you know, there's certainly other factors that drive the prognosis beyond the troponin elevation. Since this is an inflammatory disease, of course, we are worried about inflammatory biomarkers. The most common one is the high-sensitive CRP or just CRP itself. We see that as being elevated, sometimes actually quite a lot. So, this is actually one of the underutilized tests that we have that we have readily available. Most of it actually goes up to even 80 to 100 sometimes. You can see there are two actually risk scores that have been developed for the emergency room. And you can actually see the CRP is one of the highly recognized, you know, parameter of the diagnostic scores. Interestingly, however, how high the CRP is, it's not very prognostic either. So, the acute episode that actually causing the inflammation is indicative. It's very helpful to really, you know, hone down to the presence of an underlying, you know, inflammatory, you know, phenotype. But it's not necessarily, you know, show, you know, in terms of long-term outcome to be worsened. Clearly, you know, there are other sensitive biomarkers. This one actually is also FDA cleared. It's the soluble ST2. It is a decoy receptor with the IL-33 as a ligand. And interestingly, and Lisa Fairweather has actually described this increase in men, particularly younger men, which is presenting with myocarditis, is associated with worse NOIJ class. You can see the graph in the right side here. There's actually almost 60-something percent of men, less than 50 percent actually have an elevated level. Interestingly, in animals, we actually see testosterone is the main driver. In fact, it actually significantly elevated solubility to ST2 levels, suggesting that that is a mechanism. And they explain the observation that Dr. Kuperash talked about, about the sex difference, particularly in earlier and younger adult male. So, this is something that is quite interesting and provides a mechanistic biomarker. So, sometime later, we may end up utilizing this as a mechanism biomarker. But right now, this is still something that's accompanying the ability for diagnosis. So, talk about other things that we usually look at. Most of the time, the ultrasound is actually normal, unless there's underlying cardiomyopathy. The echo strain, however, particularly regional strain, can actually help us a little bit, particularly in the lateral wall, when actually there's a good amount of diminishing with edema that is associated when we look at MRI correlated, that the strain actually is diminished. So, regional wall strain, particularly looking at this, the global longitudinal strain, as well as the regional strain, can actually identify subtle wall motion abnormalities that is related to the amount of cardio edema. Now, the gold standard, at least right now, is still the histologic criteria that we learned from the Dallas criteria. This is something that is developed in the 70s, 80s, and that has been used traditionally in histopathology diagnosis. We actually, because of evolving imaging modalities, we have less and less biopsies, but then this is still an important way to confirm the presence of inflammatory infiltrates with particularly, more recently, the Warthog Foundation or the Marburg criteria that look at specific cell types. In the right, you can see sometimes when we stain the cell types, not only the presence of NHNE stains or the presence of CD3 cells, T cells, but also when we actually stain for macrophages, activated macrophages, CD68 plus. You can see the ones that actually had significant progressive and malignant disease, like sarcoidosis and jaw cell myocarditis is actually full of pretty angry macrophages that are trying to infiltrate. This is actually something quite helpful, particularly to identify those who develop complicated myocarditis that actually lead to adverse long-term outcomes. There has been a trilateral clinical position statement on endocardial myopsy, one of the earliest one that the three heart failure societies come together, which Dr. Cooper is actually a member of, and actually outlined all the different practices across the world, and particularly for clinically suspected myocarditis that's complicated. Fulminant myocarditis, people in cardiogenic shock, sudden death with severe symptoms, those are the ones that we actually think about myocarditis and we think about biopsies as to a histological diagnosis. Certainly those with refractory dilated chymopathy with progressive disease, we think about giant cells or sarcoidosis, those activated macrophages. So those are also important for tissue diagnosis. We do do some cancer therapy, cardiac toxicity, right now it's more in the immune checkpoint inhibitors. In the past, we used to do a lot more adriamycin-induced chymopathy, although that incidence also lower. But one of the underused areas, unexplained VT and heart block to actually rule out really malignant myocarditis. Even though sometimes autoimmune disease do have a cardiac involvement, we do rarely do that unless we are worried about eosinophil myocarditis without any obvious systemic effects. So we have to really need to identify that. Sometimes we do need to have a better accuracy and reliability for PET-guided biopsy, left-sided biopsy. The risks seem to be very similar and it's really on the skills and the hands of individual operators. But with the advent of MRI, we certainly have a lot more leverage to identify it in a broad population, although the subjectivity of this analysis remains a challenge. You can see the main criteria continue with a T2 and a T2-weighted images with non-ischemic etiologies, that's non-specific with abnormal T1, extracellular volume increase or regional late gadolinium enhancement as the main criteria, the supportive criteria of the presence of myocarditis, results of dysfunction, pericardial effusion or regional abnormalities. These are actually still somewhat non-specific finding and so this is actually have to be relevant to the clinical signs and symptoms and also to see the underlying manifestation. So the presence of a late Lewis-II criteria is sensitive to identify individuals, but sometimes it could be not as specific. So I think it's actually important to actually correlate with the clinical picture. But the trajectory of it is actually as it involves, it could actually develop into completely healed and completely resolving. There could be some regional late gadolinium enhancement showing some degree of scarring, although it could also progress with chronic myocarditis to dilated comalty. So that the natural history of that could be mapped out. And in fact, the original late Lewis criteria actually did discuss the fact that about four to six months out, we should actually repeat the MRI to actually see the resolution that distinguished from the minoca. We do see that the anterior septal pattern is actually the most prognostically important that actually showed the worst outcome compared to the other areas. And we do see that the two other areas of prognostication is elevated extracellular volume, the elevated ECV in the presence of LV dysfunction as well as the late gadolinium enhancement that's indicative of scar. So these are actually four prognosis in the patient with reduced left ventricular ejection fraction. PET scan obviously is the direct measurement of increased hypermetabolism. However, that sometimes can be false positive if there's not enough dietary suppression. So we see it a lot of time when people order a PET scan and show there's actually hypermetabolic and thought it was inflammation and started steroids and then it turns out it was actually something else. So it's actually be very, very careful right now. We use a lot of the PET scans to really indicate the presence of sarcoidosis-related inflammatory cardiopathy. The acute myocarditis diagnostic is less in all use, although there may be some specific use in the future. We also do see many times when people unexplained VT or rhythm problems that we use VT, although they have to be very careful about the diagnostics. It has been used to guide treatment and it's actually important to use it for that purpose. The frequent PVCs is something that we do see about 51% in a series that actually show increased uptake and then they actually get better when they receive therapy or immunotherapy. So that's like some early work that it seems like a guide therapy. So at least in summary, the diagnosis part, the biopsy and the MRI is certainly not, it's certainly complimentary to each other, depends on how sick the patient is. And clearly the indication that favors a much urgent treatment indicator for immunosuppression needs the tissue to confirm it. The cardiac MRI is quite sensitive and provide good prognostication. But again, it's sometimes not as specific. And the last three slides, I'm gonna talk about some novel stuff. There's certainly some novel biomarkers. We know that the specific immunologic pathway, particularly the L17 pathways and others are important. Certainly there are very specific biomarkers. In fact, a Spanish group has described one in the New England Journal that actually have multiple validation cohort showing that this mirror, like the microRNA marker that marks the L17 pathway, seem to be very specific, even compared to Minoka or Markata infarction. It seemed to raise in a week and then come back down very nicely. So kind of represent the actual inflammatory activation and subsequent diminution. Now, this has not been reported in subsequent studies. So we are still waiting for confirmation studies or clinical availability, but at least people are looking for more specific biomarkers. There are also novel techniques for myocarditis in terms of imaging techniques, advanced imaging, particularly in molecular imaging for PET scans. There's somatostatin receptors, as well as CCR2 positive. These are actually on the macrophages, the activated macrophages. So you can actually see them and identify them. And also processing kind of combination of processing for novel MRI processing analysis. So these are very, very promising to actually identify the specific areas. And most importantly, with the biopsies, we could actually also look at pathways or presence. We have a lot of data from Josh Hill's group in the past on transcriptomic biomarkers. We have more machine learning to look, to see these histologic specimens to actually define whether they are inflammation or not. We've been actually studying that in trans-lab world, but the spatial transcomic is most importantly to identify the pathway. So this study in the sarcoidosis described by Corey Levine's group, actually identify mTOR activation that may indicate potentially a therapeutic indication for sarcoidosis. So the take-home point is really recognize the broad spectrum of all things that lead to potential inflammatory phenotype of myopeditis, as well as the high-risk features. EKG and echo and cutting biomarkers are nonspecific, but can be helpful. Clearly, you know, to define the actual tissue, particularly in the presence of complicated myopeditis, it's important to do biopsy to guide treatment. MRI can diagnose and risk stratify, and we are getting more and more use, and most people actually recognize that in the poll questions. PET scan, you have to be very careful of the false positives, but then to detect active information. We hope that novel and more specific biomarkers emerging can be made better, identify myopeditis etiology and guide therapy. So thank you very much, and I'm going to go back to the polling question of our 35-year-old man with kind of signs and symptoms developing myopeditis, and I think, I hope we could get a 100% score here since I spent all this time talking about this. The answer is up 89. There's still something. Now, one can argue that, yes, we could talk about it in the discussion. There's still some concerns about, you know, hey, potentially there is, you know, some EKG changes and all that, but the patient is quite stable and doesn't seem to have a lot of very obvious. So this one for cardiac MRI probably is adequate. It's not a wrong thing to do a myocardial biopsy, but I think the next best test to confirm it probably is cardiac MRI. Next one, this is actually, we had a spread just now. What is the following biomarkers indicative of poor prognosis? An inflammatory biomarker, troponin, QRS, or viral titus. I think I explicitly described that. The answer is yes. So the majority picked the right one. The troponin is not entirely incorrect, but it's more troponin T than I, and the level of troponin T is quite low. So in a higher level for sure, yes. But in the lower level, the normal is like 13, and this is less than 30. It's actually not as prognostic. So this is actually something, but the QRS is very abnormal. So clearly something that need to further work on. So with that, I'm happy to introduce Dr. Rivas, who's going to talk about treatment. Very good, and I appreciate everyone for including me on today's webinar, and excited to be here, and kind of pull it all together to some extent to talk about treatment, or the management and treatment of myocarditis. I have no disclosures related to the content of this talk. I am on the editorial board for the Journal of Cardiac Failure, and I've done some advisory board work in the past for AstraZeneca. So I'm going to start out with a case. It's a 50-year-old male who's not received an updated COVID vaccination series, was admitted to the ED, to the hospital with fever and cough, and a complete respiratory pain was sent during the initial workup, which was positive for COVID-19 on PCR. And the patient presented with mild changes in oxygen saturation, sharp and diffused chest pain, and low normal pressures. And the patient has a history of asthma. His ECG was positive, kind of building on some of the conversation we just had for widespread ST-segment elevations in V1 and V2 and AVR. His heart rate was 140 beats per minute. He had systolic blood pressures of 100 to 110 millimeters of mercury, and his chest x-ray was normal with normal pulmonary vascular no effusions or consolidation. Troponin was elevated, and the echo had mild left ventricular systolic dysfunction of 40 to 50%, and a moderate increase in left ventricular wall thickness with a pericardial effusion present. And then urgent cath had normal angiography, and labs were within normal limits. So the poll in question one is the working diagnosis of myocarditis. Beyond providing supportive care and managing the COVID infection, which would be the best to add to this treatment? Would it be to start aspirin 650 milligrams three times daily with colchazine 0.5 milligrams twice daily? Begin guideline-directed medical therapy with Secubitril, Valsartan, Metobroxol, L-inspirinolactone. Start intravenous methylprednisone 100 milligrams times three days to be followed by one milligram per kilogram, or start intravenous IVIG. And we'll go ahead and let people vote at this point. Right now we have about 73% that are looking at intravenous methylprednisone, and the second leading answer is the management with aspirin and colchazine. We'll talk a little bit more about this, and I think this will be good conversation as we get into the panel to see how folks would manage this, especially both after the repolling and after this point. So moving forward, just kind of the basics and overview of myocardial management is really to kind of target and think about what is going on with the patient as we begin the journey or understand that this isn't going to be what we're going to be dealing with or the particular diagnosis we're getting to, and of course, some of the basic concepts are if they have stable heart failure and you're at that point that you can optimize or manage on that, you do want to begin treating with guideline-directed medical therapy, and that includes our normal foundation diuretics, the ACE, ARB, and ARNI, beta blockers, aldosterone receptor antagonists, and sodium glucose transporter type 2 inhibitors, as well as if they are presenting with signs of arrhythmias at the point that you're seeing this in their journey, you want to most certainly manage whatever arrhythmic activity is occurring based on current management guidelines. Of course, as we alluded to and kind of talked about with the occurrence or noticing of sinus bradycardia and prolonged QRS duration being the most common. And then as you move on to this, you're going to think about when or at what point am I going to think about corticosteroids? And a lot of times you're thinking about this, is this going to be the initial upfront therapy that I'm going to use alone, or am I going to be using that in combination with immunosuppressants? And a lot of times these types of decisions and when to use them are really based or kind of directed towards the type of myocarditis we may be suspected that we're going to be managing. And of course, you have to kind of rule out other infective-related myocarditis at that point before you consider corticosteroids and look into this. And then of course, immunosuppressants can be a backbone depending on what type of subtype or type of myocarditis that we're dealing with. Usually it's azathioprine and or with cyclosporine with corticosteroids as we tie them in together. There is some limited literature or some data with tacrolimus in that process. But again, also ruling out that infection-related myocarditis is not to enhance or induce that. And then really if you get further along in the challenge or you're really seeing some resistance or issues in terms of seeing response, you can most certainly look at the use of intravenous immunoglobulin and may benefit really refractory viral autoimmune-related cases. And it's been shown in some instances to reduce mortality, improve left ventricular function in retrospective studies. And I do want to caveat this as we go through this. The data sources and the body of data that we're looking at is not numerous amounts of large randomized, large design-controlled trials. We're looking at a lot of retrospective and or registry-based data with some future optimism in terms of trials that are underway that may help better address and guide these questions. And some other foundational conversations that you want to talk that about or consider is you're really looking at if you have pericarditis, looking at colchazine with aspirin or NSAIDs for that concomitant management. I think that's the one time that we feel pretty confident about using NSAIDs and then adding the colchazine in that concomitant pericarditis in that stage C area. And of course, obviously the big risk with the NSAIDs, if they are having the heart failure symptoms is that the NSAIDs can contribute or enhance that heart failure picture. And that's where you kind of see the next bullet. You want to avoid NSAIDs specifically in symptomatic stage C or D with heart failure. And realistically, when we really look at NSAIDs as a whole, a lot of the data is mixed to not positive or negative in either one direction, especially in those lower risk categories of patients that necessarily, based on retrospective data, don't indicate that there is a huge amount of benefit, may alleviate some of the chest pain symptoms for that standpoint. But really as we progress in that stage C to D, we really do get concerned about that continual progression or negative effects towards the heart failure picture. Immunosuppression for select cases, we'll talk a little bit more about this as we go on, but really looking at those subtypes that are giant cell or ICR, the immune checkpoint inhibitor, myocarditis, the use of cofenacetalic and other autoimmune myocarditis. And this is kind of based on various expert consensus and statements. And really when you get into the progression of immunosuppression beyond even just using your traditional agents as you move into some of our newer based agents, you know, those are kind of used based on a foundation, mechanistic thought processes, not a lot of specific trials, maybe some case reports and things that are going to lead or promote the use of these agents in the context. And then of course you want to consider a viral genome assessment on endomyocardiobiopsy tissue where feasible to identify active viral infections. And another piece I didn't specifically point out on this slide is overall the other big kind of new topic in terms of management and looking at this is doing just a general genome assessment when able, especially on the onset of acute myocarditis to help identify other underlying causes and pathologies, and then maybe also identify other patients or family members that could be at risk for future myocarditis efforts and begin trying to be proactive in preventioning and managing the patient. I do like this particular overview because it does provide a high level kind of construct or framework really looking at patients that are low risk, intermediate risk, or high risk. And really what I draw your attention to, we've talked a little bit about, you know, when to do the imaging and endocardiomyocardiobiopsy, excuse me, but really looking at the far end is like, as you move up the risk, when you think about, you know, am I going to use steroids? What does that look like? And what are the specific cases? And as you get to the higher risk, it becomes more of a, we should consider this as a starting point and give that type of management. Whereas, you know, really when you're absent, you're not having symptoms of heart failure, you know, you don't really have the LVF picture and it's really low risk that you may not want to immediately jump to or add to the steroids from that particular perspective. But it really does take a risk and a staging and really going from the green, if you will, to no symptoms to the most severe symptoms in that process. And so if you look at maybe what our patient looks like and kind of tying it into an uncomplicated risk, you know, isolated chest pain, the EF is still somewhat normal. You know, you obviously start with the things we talked about monitoring ECG and troponins and so forth and ruling out your ACS. But then really get to the decision point, you know, do they have persistent chest pain? At that point, you consider doing some form of NSAIDs. You can consider that again, that's a kind of a mixed quality of evidence, but maybe if it's, you know, stage A and B heart failure, and you just want to kind of mitigate that risk. And then of course, if they have that pericardial effusion type situation, combining the two and then working to your diagnosis and confirming it through whatever means that you see appropriate, maybe through CMR as alluded in this particular algorithm, and then ruling out any other systemic or autoimmune or ICI-based myocarditis. And then if the chest pain resolves after a period of time and it's still lower risk, they haven't progressed to any other type of picture, then you can stop the NSAIDs. And then of course it discharged avoiding activity for three to six months and then following up and monitoring them from that standpoint. So as we continue our case, the patient has begun to become more hypotensive and he started to develop ventricular tachycardia. Point of care echo demonstrates a decline in EF to less than 40%. And the patient has developed an acute kidney injury of a serum creatinine of 2.1. And so in addition to managing acute heart failure and arrhythmias, which of the following would be the next best step? So you can add methylprednisone, 100 milligrams IV now, and then daily for the next three days, the intravenous antithiomyocyte gobulin, one milligram per kilogram times one, the oral cyclosporine twice daily with a target trough of 150 to 150 nanograms per ml, or the IV cyclophosphamide, 600 milligrams per meter squared now. Okay, about 92% of individuals in our current poll would reach for the methylprednisone. We'll talk about that as we move forward in the next slide. And this, kind of going back to our framework of risk, and this goes into the yellow risk, and I just want to present this construct. This may not fully look at our patient at this particular time, but if you're thinking about it, and kind of going around the same trajectory, we saw this in the last kind of flow, monitoring the ECGs, ruling out the ACS, excuse me, and then realistically now we're at this reduced EF stage in a patient, and potentially, not in our particular patient's scenario, but maybe they have stable hemodynamics, looking to add their guideline-directed medical therapy to manage or optimize their heart failure picture. And then again, confirming our diagnosis, but here we're adding the CMR plus or minus the endocardiomyocardial biopsy, and then ruling out still that systemic autoimmune or ICI myocarditis. Of course, if it is ICI-related, or if there is some trigger that you can remove, or fix, or edit in terms of stopping therapy, as we alluded to earlier in the conversation, you know, kind of pulling that away and making that adjustment. And then if it is positive immune, or which we alluded to, positive autoimmune drug-induced, that's, you know, preventing or removing that agent, and then considering that we need to add some form of immunosuppression to manage the patient and stop that pathway from occurring. And then, of course, if you get beyond that, and you determine that is not the case, and you really dwelled down and figured out that it's giant cell, or is phenophilic, or cardiac pseudosis-related, continuing down, what are the next steps specifically for those disease states in terms of immunosuppression, and how you're going to tailor your therapy? And then again, the discharge follow-up is needed, in this case, adding an ICD. And then really, when you get a complicated presentation, I would borderline and say that, you know, as you develop the acute heart failure picture, that maybe we're starting to see with our patient in this scenario, maybe it's early signs of this, and could be developing arrhythmias. You're going to kind of do the same thing, but then determine what type of level of care they are going to need. Are they going to need ICU, mechanical circulatory support? You know, you still want to rule out ACS. And then at that point, you're really going to start treating if they have arrhythmias, you have to manage that piece, as we alluded to. Do they need isotropes or other mechanical circulatory support if they're starting to get in a fulminant-type situation, and really starting to consider immunosuppression. And this is where you would start maybe adding or considering the steroid or the pulse steroids up front in this particular scenario. And again, still working through our confirmation process and maybe really going through that endocardiomyobiopsy, I can't talk today, and then ruling out systemic autoimmune or ICI myocarditis, and then kind of the same pathway that we saw on the last particular slide. And looking at our subtypes by specific pharmacotherapy, you know, if you look at giant cell, we clearly have our pulses of steroids that we talk about in the taper, but then if we get into that hemodynamic instability, reaching down into our other agents, such as the anti-thiomyocyte goblin agents, and kind of moving down the chain of options. And then if it's hemodynamic stability, you're looking at cyclosporine specifically, and then looking at lymphocytic myocarditis, this is where you're talking about maybe it's acute HF, it's fulminant, maybe consider those initial pulses of methylprednisone for the first three days, and then one milligram per kilogram individualized followed by prednisone. We'll talk about this, but the MTT trials showed no benefit of prednisone in azathiropine or cyclosporine in this particular patient population. However, the MIST trial is underway looking specifically at methylprednisone in this particular patient population. And then cardiac sarcoidosis, again, starting out with the higher dose methylprednisone, kind of mg per kg, the 7 to 14 milligrams per kilogram, and pulse dosing for three days, and then tapering and switching over to prednisone. And then if you have to reach into that second line therapy, considering methotrexate for 5 to 25 milligrams per week, and then if it's persistent or refractory inflammation, you know, working your way down through our other immunosuppression agents that have been studied or used in this, including infliximab. And then eosophilic, you're looking at the corticosteroid as the first line use, whether it be prednisone or methylprednisone. Of course, you want to remove any offending agents that have led to this condition. And then, of course, if you're still seeing refractory efforts, you know, reaching down to IV cyclophosphamide and some of our other agents, including imatinib. And then, of course, we talked about ICI earlier, and that's for sure including removal of the ICI, but again, obviously continuing with the IV pulses of methylprednisone, and then continuing to look at IV abatilis up, and then, again, moving further down the line, if you're considering a refractory agent, looking at the options based on various case studies that are available from that standpoint. And then systemic autoimmune disorders, again, starting out that backbone of the IV pushes of methylprednisone, but then, again, moving to your next line of agents with IV cyclophosphamide, if you need a second line agent, and then maintenance with oral prednisone, plus MMF 500 to 1500 milligrams twice daily. And then, of course, Lyme disease, you know, depending on the severe cardiac presentation, then here you would start with your IV ceftraxone two milligrams once daily, and if it's mild, you can most certainly treat them orally from that standpoint with oral doxycycline for 100 milligrams twice daily. The ARMIS trial was done, and this looked at anaconera versus placebo, and it was a double-blind randomized placebo controlled trial looking at the treatment in acute myocarditis, and this looked at patients with a diagnosis within 72 hours with acute myocarditis looking at placebo versus treatment with anaconera for 100 milligrams sub-q listed there, plus ACE and beta blocker, and they looked at a follow-up of a number of days of lyes free of any myocarditis complications at 28 days after hospital discharge and followed them out. And essentially what they saw is there was really no difference in number of days freeze of complication between treatment or placebo at that particular juncture, and there was, you know, a total, when you looked at both patient populations, there's no increased risk of safety signal or harm, just did not show any differences in terms of their primary outcome in terms of number of complications or days free of complications at this particular juncture. There are future trials underway, as we alluded to, the MIF trials with myocarditis therapy and steroids, and they're looking at the beta CEP trial for treatment and immune checkpoint inhibitors specifically, looking at that in that particular trial, and then the impact of cannabidiol on myocardial recovery and acute myocarditis, and then specifically with the IMPROVE-MC study evaluating the efficacy of immunosuppressions in myocarditis and various other inflammatory cardiomyopathies, and we look forward to seeing the data and the outcomes of the study to add to this body of literature and further enhance our understanding of the treatment paradigm. The kind of take-home is to consider your risk profile, what your patient's looking at, are they high, medium, or low risk, and as you move along the risk, you want to add therapy or manage the risk appropriately, remove any offending agents, and of course, if you're having to reach for second line therapies, consider when you have to do that, and of course, tailor your therapy based on the specific type of myocarditis with the specific associated treatments. So polling question one in the repoll, you know, the working diagnosis that we talked about with our patient that had presented was viral myocarditis, and if you recall, they had a pericardial infusion that was presented on the echo, and beyond providing supportive care and managing the COVID infection, which they had presented with, which would be the best described, and if you recall, our patient was stable at the time, would you start aspirin, 650 milligrams three times daily with the Colchicine 0.5 milligrams twice daily, begin guideline-directed medical therapy, and remember at this particular juncture at the first case that EF was normal or above 40 percent, start intravenous IV methamphetanilazone, or start intravenous IVIG. We're about 50 to 40 percent, and I think in this instance, given the pericardial infusion, the answer I was trying to shoot for or get to people thinking about is starting the aspirin and the cultures needing to manage that infusion at this particular juncture. I don't think it's inappropriate to consider the IV methylprednisone, definitely something to be considered or talked about at that particular juncture, but maybe progressing to a later juncture or progression of the patient, and we most certainly can talk about this and see how our other team members would manage this in this particular scenario. Next slide. So question two. In addition, when our patient progressed, he started having a low EF, started having a lot more hemodynamic compromise. Maybe he was starting to develop some arrhythmia. What would be the next step for this patient? Starting the methylprednisone a hundred, excuse me, a thousand milligrams now, then daily for three times daily, the intravenous antithiomyocyte globulin one milligram per kilogram, and then oral cyclosporine twice daily with the target trough listed there or IV cyclophosphamide. Respond. And most people reach for still, we had a brief decline into starting out with steroids. And in this particular instance, I think it's, you know, as you look around the risk and they're starting to move into the higher risk category or starting to have some form of hemodynamic compromise, at this juncture it is worth considering or starting out with that backbone of the methylprednisone at least to do some pulse dosing to get started. And then, of course, if you get to a point there's appears to be some refractory and depending on what you get to in terms of diagnostic standpoint of what type of myocarditis you're dealing with. And of course, at this instance, we think it's viral or working through that. Then you can most certainly consider what are your other alternatives or second line agents to use to manage the patient. And again, definitely would love to hear everyone else's perspective on this. So I'll stop sharing my screen at this particular juncture. So. Franny, we move into the panel discussion at this particular time. Yes, thank you very much. It was excellent. All three presentations were very good. Leslie Can you see the questions. Yes. In the chat. I see. The one on the viral genome analysis and inflammatory markers and the second question on CMR. Right. So if you'd want to take some of those, or, you know, direct them to the appropriate speaker, or if you have some questions to start with. I think as the as the chair of the seminar they might be some that came out for you to present to the speakers first before we get to the audiences. I'll just tell the audience that you know Wilson I've been doing this for more than a couple decades together and every time I learned from his slides. Wilson I have to, you are so detailed and you know so many obscure references that are excellent that I learned from you. I have these notes right here in my hand of slides that I'm going to make from you so I put those in the audience I just want you to know that you got a world class talk from both of my co speakers for the questions I would just take briefly the first one to ask you guys to chime in and then maybe Wilson, since you were dealing with with MRI imaging you might do the second. The first question was about viral analysis, when would it be. I'll read it. It says, where do you begin with viral and inflammatory serologies. Let me start with viral analysis, more generally, that the European Society of cardiology scientific statement recommends doing viral genome analysis not serologies on heart tissue so you would when you did a heart biopsy you would get one or two either RNA later or or fresh frozen, and then send them for genome analysis so that means. So, if that's feasible, and you're at a place where that that can happen. There are data that would say that particularly in the more chronic setting that the presence of ongoing viral genomes could have a bad prognostic. Worse prognosis and in addition, the addition of steroids and as a fireprint over the course of a number of years five to eight years would improve possible transplant free survival. Those are not trials in the acute setting. It's a little bit different. I think that if you have a full minute patient who's going to the to get a heart biopsy, it's perfectly reasonable to check viral serologies, but that's not widely available, and my own feeling is that the value of that over and above the histology of giant cell, or as an affiliate or the clinical context is is not yet established. The second question what about inflammatory surgery is great question. So my personal approach. I'm sorry, Wilson, did you want that so this is a joke question between, you know, our European colleagues and in the States. There's actually a really interesting study published, not too long ago in Canada actually left us lights out thought it was a little too detailed. But they actually biopsy quite a lot of people across the board, you know, a scheming non ischemic, you know, and basically found a wide range of tissues have viral genome. So that is actually one of the bigger challenges guilty by association in terms of even the presence of genome doesn't necessarily mean it's actually pathologic so we actually have the evolution of malachitis now that is more so of the host. It's like the seed and the soil questions more so of the overarching response, the inflammatory immune response of the host, the range response that is actually destroying and you know damaging the heart that is actually driving the disease. And the culprit could be anything and that's actually one of the bigger challenges we have, particularly in the fact that we have not seen a lot of antivirals being, you know, very effective, nor even the attenuating the mediators that is that effective at this point. What Leslie talked about is actually in the presence of active virus infection. There is a worry that overtly immunosuppressed can be a harmful thing we actually heard this whole discussion in COVID and others too, you know, but at the end of the day we are still giving a lot of immunosuppression. That's actually helpful because actually tamed the over activation of the immune system. So short answer is we actually don't routinely do biopsies, because it's pretty nonspecific. Oh, you're muted. I'm talking about the viral DNA part. We're not routinely sent about at this point. And my only comment, very briefly about the autoimmune serology is like a and a rheumatoid factor, not unreasonable to get some mild screening but out the real coin of the realm there is clinical. When you see somebody who's got, you know, systemic sclerosis or telangie cases rheumatoid changes in their, their proximal joints. Those are things that are going to drive you to your clinical evaluation your rheumatoid factor your CCP and, or maybe it say they have and asthma maybe you'll get an anchor panel to look for a GPA. So, you want to always start with your clinical index of suspicion. Alita for you had a paper a couple years ago showing that high and a's had a adverse prognostic predictive value, but I think that was also. I think that it wouldn't be unreasonable to check, but you have to know what you're going to do with the data, a lot of nonspecific elevations in those a and a and low titer rheumatoid patients that then I'll. My question was more geared towards viral serologies, rather than genomes, and I guess the bottom line is you always have to put the clinical scenario first, because things like you know viral titers, etc are very common. Just like we have PFOs very common and if you have a stroke. You have to put in clinical context whether the PFO is the cause of the stroke because so many people have it. So I think it's probably the clinical context that is, I guess, Wilson and you are making the point right that you have to focus on. And again, you know, one of the challenges is that we are not therapeutically using and have hirals in the majority of cases. And so there's really a textbook teaching that you know viral titers are nonspecific and honestly I do find it sometimes helpful if you know exactly virus, then you can always tell the patient, hey, you know, there is a virus there but it's not really affecting the management. I think if you go back and you look at a build McKenna's paper from the late 90s and then from from London and then more recently. Enderman from Germany had looked at this question in different ways and I the results were very similar that that peripheral viral serologies were not incrementally useful over other variables. Right. Right. Okay, Janet, do you have any do we could go on to the next question but do you think there's anything in your practice that you see with myocarditis that becomes a challenge. In terms of diagnosing that were that comes up as a question frequently when they come in with chest pain and elevated troponin, which is every other day when people have ACS. And chest pain daily. So, yes, I usually get through the cardiac MRI and serial to opponents and at that point it's like, I think we're dealing with a myocarditis here and then I get my attending or the expert on myocarditis involved in the case to then start digging and drilling further. But as a nurse practitioner I will get through the cardiac MRI imaging, and then hand it off to the attending or the myocarditis expert. So just on that point, especially Wilson in relation to your first case you know where you said nation comes in the chest pain elevated troponin, you get a cardiac MRI right that was the answer. And I think that perhaps in the world of myocarditis that you live in. You probably would gravitate towards that and maybe you have more access to cardiac MRI. But what I see often happening. You know, is, and it happened with a patient. Oh dear, Franny. You froze. I could probably fill in the blanks I think actually have the access to cardiac MRI. And so the question is, so, you know, I think it can happen that you can be misled and fortunately for that patient. He started developing you know complete heart block. And so people started thinking that maybe he has something else is not just your typical type to you that you go through the paces. So what I wanted to ask you is, you know, you mentioned where you have the rise and fall of triple says proponent is like the workhorse right that's what most people in the ER are going to get, you're not going to go for the cardiac MRI in the ER thinking that that's part of the differential of chest pain and elevated troponin. Is that the same rise and fall I think people really don't use the kinetics of troponin, you know, to really make the diagnosis and maybe have picked up on this patient that that they misdiagnosed initially for the first two days and fortunately was a lung cancer patient on an ICI, because he started getting the complete heart block they started thinking of it. But, you know, you mentioned you see the rise and fall but it can't be the same rise and fall that you see with type two non STEMI and ACS right you see a 90% drop in troponin in the first 24 hours. Do you think maybe we should look a little bit more closely, maybe get a CRP and when we see that differential think more of my carditis and then lean towards cardiac MRI which is not as accessible. You know to the rest of America that may be to the people attending this Congress or I mean attending this seminar. What do you think about that. Well, I did mention that, unlike, unlike ACS we actually don't see a routine rise and fall we do see it every day. It's actually a highly variable in fact, when Leslie and I actually started to write a pretty extensive review on the topic I think was published into like in Java about two, two, two years ago a year ago, we actually spent a lot of time looking at this and it turns out the description is always the diagnostic part, you know, just elevated proponent that's about it. The main reason is because there are some that are indulating with a chronic kind of, you know, the patients had it for a few days they come in, and they actually have an elevated level they don't see that rise and fall the same way they can behave that way particularly with proponent I some of the triple nice goes up to the hundreds. Okay. Yeah, yeah. And, and sometimes it just comes down very, very quickly that's the injury part, but the fascinating part is half of the patient don't even have any component. So just the fact that positive is not always the case. So I would argue that if there is a clinical suspicion, definitely, the CRP is the easiest thing to get. And I emphasize that in fact, the more I'm doing this, the more actually check the CRP. They go high, they go, not the two or three that you worry about risk fabrication, they go 50s. I had one patient that I saw in the outpatient last week the 67 as I you know there's this is something wrong something is burning there, you know, so that's something that actually raise a suspicion there's some immunologic response going to getting the MRI, which may not be as easy to get right. I just said, you know, there are two things one, we still have soluble st two, and at least in the young males soluble st two at least at Mayo you can order it by checking a box. So I think if you've got that on your lab list, and then the other is strain, most Phillips and GE, you know, systems for echo can do strain and strain is more sensitive for preserved EF myocarditis then, then, obviously the EF itself so I think doing strength is important, and if it's abnormal. In the, in the right clinical context, that could lead you either to the next step or to to to not write it off as being. Being ACS or core acute core some something with CD right. Actually what Craig talked about. And also I emphasize that too is really the suspicion of a higher risk complicated myocarditis. So I didn't, you know, I think, for example, I did mention about, you know, the QRS being elevated that's actually a high risk category so it's not entirely incorrect that you go and do a bio, but the problem is to identify somebody quickly. And if you have the MRI available that's actually within, you know, a few hours of, you know, being able to, you know, figure it out and trying to get somebody to actually do an MRI, and then you can actually raise the urgency of really identify make sure that this person is not getting worse. If it's obviously clinically unstable like patient and obviously the urgency of the biopsy will be a lot higher. So I think it's, it's really at the point of care. These diagnostic tests, give you an idea but the overarching part is to really have the mindset to think of myocarditis as a possible and then to identify the high features that would actually go down very fast. Because the majority of patients actually are quite stable, can actually wait, and even the MRI can be persistent for even for a week or so, when they actually have those features. Right. Three more questions. Should we, Franny, do you want us to do the three questions? Sure, sure. Maybe you could roll them up together too, because I think most of them are related to treatment. When do you have guidance on repeating the MRI is the first one, second is aisle one, six, aisle six, and the third is exercise and you guys, do you, I don't want to hog this, do you guys want to take any of it? Well, I could do the Lake Louise, I just did that. That's why, you know, literally yesterday I saw a patient almost similar to that and I struggle with that. Now, the issue, obviously, is if there's any features of high risk, you do want to actually make sure that that's resolved. And so, you know, there's no magic to, you know, justification. I think I definitely want to look at the tissue characterization and the presence of resolution. Usually for athletes, it's actually a very easy thing to do because there's a return of play question come along. You want a complete resolution before you actually approve them to do something. So that is actually always a good argument. Short of that is actually a little harder is really the finders keepers. And I think at some point we do want to emphasize, you know, there is a risk verification part, particularly if the early presentation have some high risk features. Go for it. I guess I can jump in on the IL-6 piece if anybody else, there is some underlying evidence and suggestion of correlation of IL-6 being elevated or several of these inflammatory markers in terms of this, obviously, given the state and the disease state and really understanding, you know, what that means or further understanding what that means in the context and then maybe considering designing trials or treatments to that. And what that looks for. But if you think about the backbone of therapy and what we're targeting, you're targeting a blanket broad, you know, process in terms of managing the reaction, you know, the anti-inflammatory reactions with steroids and then maybe getting more specific or targeted based on progression or what that disease state looks like. I don't know if you guys want to add anything to that. I'd say IL-6 is not specific for myocarditis in the heart. If you get a heart attack, if you get other types of pressure injury, the heart's not super smart. It's either TNF-alpha, IL-6 or IL-1, you know, Doug Mann likes to say that. And he knows a lot more than I do about this stuff. But honestly, it's really a, it's not specific to myocarditis, but it could be a marker of risk for sure. And it might be a therapeutic target as well in the right context. And it got popularized in the COVID era when IL-6 elevation is available. In my experience, actually, CRP came back much faster than IL-6. And it's basically look at the same thing. The active macrophages make the IL-6 too. So you wanted the indication. So we're coming to the top of the hour. We're actually a minute over. And I was just firstly, thank you everybody for your excellent presentations and the input. Let me just finish off with a quick question. Leslie, if you could answer one of the questions that our fellows had regarding exercise, you know, just day-to-day management beyond the very specifics of IL-6 versus TNK, etc. What do you recommend in terms of long-term follow-up exercise presentation? And one of the questions I had for Preg, if we have time to just answer quickly, as you mentioned, when we have an immune checkpoint inhibitor, that you would, the first step is to withdraw it. But, you know, we have situations where people have to have that. Yeah. So to your point, just to jump in on that question, and then we'll go back. I think you have to quantify, you know, clearly there's a risk-benefit balance. But I think if you have an ability to withdraw or manage the patient differently or look at alternatives, that's a part of that process. That's a part of the broader decision of the context of the patient. But I think if you're looking at the initial insult or injury, that if you're able to remove or stop the agent and come up with alternatives. But I think in oncology, there are cases of where they've reintroduced it and still, you know, oncologically, if there's no other options, right? Leslie, could you answer a little bit in terms of the long-term management for exercise, follow-up? So there are two things that I'd like to say. Number one, three months is what we've settled on as the minimum. And there is the science behind that is weak. But there is a lot of science in mouse models that show that if you have acute myocarditis and you exercise to a very high degree, 20 minutes on a treadmill for a mouse, then you will get a much worse outcome. So there's lots of data at a mechanistic level. There's also epi data, but we picked three months because it's the timeframe that most myocarditis would resolve. And it's a reasonable, it's something that people might be able to adhere to longer if you're sicker. The other thing is deconditioning. A lot of people have to struggle with that. It's layered on top of any organic disease. And then third thing is anxiety and depression. It complicates in young adults, athletes, for example, who have been used to being very healthy, they get a life-threatening disease, and then all of a sudden they have a stigma. It's very difficult. Not to forget the psychosocial impact. Can I just make a really quick input very fast? I know we're crunched for time, Frannie. For getting the EMR correct, in my progress notes, I have found that when you put in, according to study A, study B, re-imaging is recommended four to six months, therefore re-imaging will be ordered. If you quote the studies, a lot of times the insurance companies will go ahead and pay for the re-imaging and not fight you on that. So I state it right in my progress notes. As they are willing to read it, that's actually the problem. True, true. Okay, I know that was one of the concerns of the questions. All right, well, we're about five minutes over. Yeah, I do tell my patients to don't get alarmed when there's a rejection letter. So that's actually important to actually outline the plan with the patient too. Right, right. Okay. Well, on that note, thank you very much for all those practical suggestions and the very pointed treatments and diagnostics, risk stratification, really was an outstanding seminar. Thank you very much to the audience for your participation and thank you again to the speakers. Bye-bye. Take care. Bye, take care. Thanks very much.

myocarditis recognition

myocarditis management

evolving nature of myocarditis

advancements in epidemiology

diagnosis of myocarditis

treatment of myocarditis

immune checkpoint inhibitors

COVID-19 impact on myocarditis

diagnostic tools for myocarditis

novel biomarkers for myocarditis

immunosuppression intervention

risk stratification in myocarditis

personalized therapy for myocarditis