Leslie T. Cooper Jr., M.D., a cardiologist and chair of Cardiovascular Medicine at Mayo Clinic in Florida, presents in the Advanced Heart Failure Grand Rounds series giving a clinical update on myocarditis.
it's great to be virtually with everyone this morning and to spend a little time going over an update on myocarditis of course, with SARS Kobe to there's a whole lot of discussion on myocarditis, interesting, the traffic on the Myocarditis Foundation website increased about 30% once uh starting in the summer when they major sports teams, the big 10 in the PAC 12 cancelled their their seasons before they reopen their seasons. Um and so there's unexpectedly a lot of interest in myocarditis for that reason, but there are other things that are happening, checkpoint inhibitor myocarditis and a lot of mechanistic studies go over two things first. Uh sorry, it's gonna be too, I was going to spend just 10 minutes because it's timely. It's kind of interesting. It's different and then do the standard overview of epidemiology, diagnosis and management, management of micro notice and I put a spin on it because this is a heart failure group. I didn't I'm not going to talk about arrhythmias in sudden death very much we can do that if you want. Or I talk a little bit about chest pain because it's really, really common but I'm not going to talk about chronic heart failure uh and that whole controversy over whether myocarditis can cause meaningful inflammation in the context of a chronic cardiomyopathy. That's really interesting and it's debatable but well and we can talk about it later if you want, but we're going to focus on acute cardiomyopathy and and management. So as you know, um one star is Kobe to hit all of our practices, our lives were turned upside down. And then there were lots of papers that came out on acute cardiac illness right? There was a chinese experience in new york experience Seattle italy all these papers came out about acute illness. And then beginning in about May. The first paper was in May, but the second paper, which was much bigger was this one in july, which said that in recovery in recovery from hospitalization and acute SARS-cov-2, you could have these MRI findings. So this was a paper from Valentina Pointman, her husband, Ike Nagle and the group in in Frankfurt. I think most people have heard, if not seen this paper that 78% of patients had MRI abnormalities 71 days after illness. This was an older ish group, 49 years old, with a third of them were in the hospital, someone ventilators and so a fairly sick group. But nonetheless, at a time point when you think they were clinically better and feeling great, they had persistent or or surprisingly large rate of MRI abnormalities. So this is one of the studies that led to the cancellation of a lot of sports uh this past summer. But the question was really, what's the clinical implication of this? Because we really didn't know if this puts you at a higher risk of arrhythmias or cardiomyopathy. And should you stop playing sports? What what's the recommendation based on this? So um let's take a step back. So we know SARS-cov-2 can affect the heart. This is a cardiac minus site uh invisible pluripotent stem cell from J Schneider's lab in Rochester showing innumerable virus viruses and groups of viruses budding off of an infected cardiac maya site. And lots of other studies which I'll show a little bit of suggest that macrophages and lymphocytes can be infected. And so there's enough data that you can get injury. A variety of injuries from SARS-Cov-2 in the heart and theoretically that you could have enduring injury. And so uh there are questions about mechanisms and clinical significance. This paper again focusing on mechanisms from Peter liu and colleagues out of Ottawa shows how the SARS cov virus is different than enteroviruses coxsackie virus in that viral shedding here. And I'm not sure which screen you're seeing. Do you see my cursor right now moving? You do? Okay, so it's the right screen. So see viral shedding starts as we know before you're symptomatic. Um and then it can add like hope hicks and then continues all the way through your illness and then into the late phases as well. That's different than a typical enterovirus coxsackie virus, where you would typically clear it in this range and then you have a post inflammatory, post infectious inflammatory response giving you your lymphocytic myocarditis. Actually, the cardiac involvement in the typical hospitalist older sick patient is quite late uh with the vasculitis, globular apathy, maybe some myocarditis systemic side. Again from all of us have been on the hospital service the last six months have seen these older people very sick um late in the course getting the troponin arise and then they may or may not recover. But having said this, myocarditis is not necessarily the mechanism in this setting. And you can see here, this is one of the earlier studies from Wuhan that in the course of a typical illness of non survivors on the bottom after you get your fever and cough in the first week and then your respiratory insufficiency in the second week. The cardiac injury comes in late toward the end of the illness. And so the question there is, is this a demand ischemia? Is this part of the cytokine storm stress cardiomyopathy? What's actually causing this clinically late in the game? And these older people with risk factors. So we wrote this paper now in april about six months ago suggesting that viral myocarditis was one part of it. But there were reports and we'll look at some of them and some of our data on that and it is a part of some star is gonna be the infection. But in the big picture of the typical older patient in the hospital, I don't think it's a big picture. I think cytokines, stress, cardiomyopathy, this microvascular thrombosis, tick injury that we see at autopsy are probably playing a bigger role along with just regular old demand ischemia down here. But it's different in the young people so that the young athletes are obviously 1920 years old. They have no preexisting heart disease and they're generally pretty healthy, right? They don't have any hospitalization, they're not on ventilators. And then uh it's what's surprising is that they're getting MRI abnormalities as well. So when you go through the older patients in our paper from april um a few get the stem ease. Not a lot but some most of the S. T. Segment elevation is more non ischemic. I mean non obstructive with myocarditis and the other factors we talked about. And then these together with the demand ischemia can lead to the clinical syndromes of arrhythmia, heart failure, cardiogenic shock evolving from basically GIC shock. Occasionally some of pericardial disease and you know a fairly high rate of thrombin arctic complications which we're hearing more and more about. So that's the big picture. Um What about the heart? So we know from the original Stars experience this paper from Peter Liu and colleagues that um in people who die of SARS COv two you can find virus in the heart about a third of the time and that it tends to be in the context of macrophages. So unlike a typical lymphocytic myocarditis, this looks very different, histological e not typical of a full minute myocarditis at all. And so the question becomes, what is the mechanism is there, is the heart damage causing the death? Is it incidental and not clinically important or what? And so we uh j Schneider and colleagues looked at this. This is a paper that's currently about to be submitted to nature actually showing the viruses inside of cardiac maya sites as well as inside of these uh inflammatory cells in the heart. And that the virus actually creates since ISHA and moves between cardiac mine sites. It doesn't kill them and make them explode right? Like a like an enterovirus politic virus. This is a virus that gets inside the cell and then travels between cells through cell cell junctions. It's kind of interesting and I can show you at the end if you're interested in some of the other figures about that. But the mechanism of viral infection and damage and and and propagation is very different in this disease than it is in um any other model that we know of myocarditis and that's why what you see on the MRI is not lymphocytic myocarditis. It's something that's histological different the prognosis and the clinical significance of which we just don't know. This was a recent autopsy study of patients with who died of SARS. Cov two and you can see they had lymphocytic myocarditis here signs of card itis but it was not huge. Right? It was an epic are ideal. Not so impressive kind of lesion questionable whether it had anything to do with the death of these patients. And similarly here's a young man from paris. It is a case report, but it shows the epic cardinal pattern that we just saw in the autopsy series. Um at autopsy showing on M. R. I. This guy comes in with chest pain, high troponin typical microsd itis negative for all the other viruses positive for SARS-CoV-2. And he actually recovered pretty nicely in that case report. But the idea of being that you do get myocarditis but is it the kind of micro titus that kills you? And what should you do about it? Um I would say it's a bit different in Children. They tend to do very well on overall. But if you do get this Kawasaki's inflammatory syndrome you can get myocarditis with it. And 14% had actually coronary aneurysms in one report. So I do think that the disease is very different in an old population with preexisting heart disease compared to a young population of super healthy people who may infrequently get a significant involvement. So this is the this is the current recommendations from this. These two groups, the American Medical Society of Sports Medicine and the High School equivalent. And basically I'll summarize the busy slide with three points number one. If you're asymptomatic and you're SARS-COv-2 positive, Don't do competitive sports for two weeks and then go back if you feel okay. The second is if you're symptomatic and you've got a mild illness you may get an E cage or a clinical evaluation. But the recommendation at least as of july was not to go with mris and fancy testing. On the other hand, if you had myocarditis, if you were hospitalized, if you had a chest pain syndrome, elevated proponent and then you recover, then they have cautionary words here that says consider stress test, hold her cardiac MRI and definitely have a cardiac a bell. So it depends on how sick you were, you know, on what the evaluation should be. I do think that in the big 10 looking at the Ohio State report medically and the other reports that have come out that there are a lot more conservative. Everybody who got that I've seen in the reports you've got clinical myocarditis which seems to be getting an MRI. Although we don't know what the clinical significance is. So that's really the end of SARS COV two. This is just a quick slide from heart failure. Jack heart failure now, about a month to two issues ago. Um suggesting in a different way. How is the covid pandemic affecting heart failure care? Um Not directly related to myocarditis per se, but I liked the article and I don't know if you guys looked at it, but it was kind of a thoughtful article about stuff that we're already doing with telemedicine, virtual visits trying to minimize contact, and then some of the regulatory changes that have allowed us to do virtual visits and bill for them. And then they went on to talk about home monitoring for heart failure, and then um a few specific things about increased nursing and sometimes palliative care at home. But I just wanted to give you the reference. So let's move on here, too. That's not my slides aren't advancing. Did that just advance for you? It did good. Yeah. Their keyboards not advancing for me. Um now we're going to make a transition. That was the 1st 15 minutes. Uh and again, if you guys are interested in it, we can dive deep into the into the cellular mechanisms at the end. But instead let's go on. And I do think, by the way, they're gonna be a lot more papers on the MRI story coming out in the very near future. Better papers that suggests a minority do have myocarditis. Let's move now onto the regular myocarditis talk and have a couple of slides here on epi. And as you know, on a global scale, not everybody has a cath lab with a biopic film and not everybody has access to cardiac pathologists and very few places in sub Saharan africa and Parts of Asia have mris. And that's why for years since I started working with the GPD project in 2007, we reported myocarditis and cardiomyopathy together because we felt, I felt, and I think our group of writers felt that the it was more honest to lump them together because you really couldn't distinguish myocarditis from other forms of cardiomyopathy on a global scale. So, as of 2018 which was the last uh paper on the DVD project, We had 3.1 million cases of market eyes and cardiomyopathy. Together In the 2015 paper we had 343,000 deaths, about 200,000 men and about 143,000 women and of the death rate of about 5.5 per 100 400,000 women. Now I should say that just yesterday we returned the proofs for the Jack Paper for the 2019 study. And those proofs, I'll tell you separate out myocarditis clearly for the first time. And if you add myocarditis is about a third. There are about a million cases of myocarditis worldwide. But the methodology changed between 17 and 19 so that the group of cardiomyopathy ascribed to other, which is just this grab bag called other. It means that on I. C. D. Nine and I see 10 codes there was no proof of myocarditis so they fell into a bucket of other um that went way up But the bucket went up 50%. So I think that actually myocarditis is conservatively a third of this Total in the 2019 study. But this gives you an ideal male over women. Men over women always death rates of about 500,000. The prevalence is 20-400,000. So the death rate is less than, It's about a 5% death rate overall in the first year um In the U. S. It's super interesting. You know there's a huge variability overall. The U. S. Is higher than average with about 9.6 per 100,000 deaths from cardiomyopathy. Myocarditis that's about double the average for the whole world. But if you look at Montana and you look at You know areas up here in Idaho the rates about 2,000,000. The lowest city is actually. Seattle For reasons that are maybe they drink good coffee up there, I'm not sure. But the worst areas down here in Louisiana and the Southeast region where it gets up to like 30 which is pushing like Eastern Europe levels. And so um I think it has to do with global health. You know that there's just a lot more unhealthy lifestyle maybe down here then there is up here but nobody really knows the reason. But I think that's interesting in the U. S. From myocarditis and cardiomyopathy. Um You know there are four ways that myocarditis presents. The most common is chest pain come into the Maya pericarditis or chest pain syndrome, resembling acute my RST segment am I? And those have a very good prognosis as we'll see when the EF is normal. On the other hand, sudden death is quite rare, but when it does happen it's generally it's a young person devastating and we always remember that. And so we'll come back to said, we're not going to talk about sudden death today, but we can talk about it in the end if you want. We're going to spend most of our time on acute dilated cardiomyopathy in full minute myocarditis. And again, we're not going to talk about chronic six in the interest of time, although that is a very high area of controversy. So this is what it looks like in a mouse with the red arrows here on the right, when you have epic are ideal myocarditis and pericarditis. And this is a coxsackie B model of mixed autoimmune myocarditis with the CVB infection. And this is an MRI. Typical MRI I've been using for 16 years. I should probably get a new slide. It's a good it's a good MRI. And it's typical of that in for a posterior lateral epic cardio pattern which is the most typical pattern you see and reflects that histology and so in this setting it's typical chest pain. You may have S. T segment elevation. You may not half the time the EKGs are pretty normal. But the thing to remember is that in both japan and the Brigham series and in Germany the cure restoration is greater than 120 milliseconds are always associated with the worst outcome. That by the way is not unique to myocarditis. It's true of other cardiomyopathy is but it's certainly true in every case series that's looked at it that I'm aware of from myocarditis as well as high degree heart block. So what about mris? We're going to spend a little bit of time on mris. You know, it's been about 22 years since the first papers came out in Children, actually on T. two weighted imaging for the diagnosis of acute myocarditis and then the T1 delayed gadolinium imaging shortly thereafter. And the over the years, uh in 2009 we had a liquid. We used one criteria. We revised it with mapping sequences in 2018 in December 2018 here. And this is a subsequent comparison of the different techniques that you could be accuracy, which is a combination of the sensitivity and specificity analysis for the revised Lake Louise. Two criteria on the right. They do come out marginally better than individual sequences, a lot better than extra cellular volume. Um And I think that there's still probably in the good center is the way to go when you do have mapping sequences available in normal values. These are this revision. If you to remind you is one T two weighted image has to be positive. That could be a T. To map native T. To map or an image or won T. One weighted map, which is and 1 to 1 made a map, which is uh again the map or a post gadolinium delayed enhancement or or an early T one hyperthermia sequence and you need one from each group to be positive. Um And there are only positive in the beginning. So this is a slide showing the time course of recovery in days. So there's seven days, one month, three months uh on and this is T. One and T. Two mapping in the dark and the light dotted lines. And you can see there's a fairly rapid by three months, they're back to normal, which is more or less the way the biopsies go to biopsies tend to get back to normal within a month or two. So I like to say uh 2 to 4 weeks as best. You know, if you can get your MRI in the 2 to 4 week window, I think the T. Two and the T. One sequences are probably accurate. But when you get out here at six months or a year, I think it's a crapshoot. Sometimes, whether you're going to be able to make a diagnosis of myocarditis or previous myocarditis, It's worth noting that, you know, in the most recent papers from Italy, about 16% of patients with abnormal T. One delayed enhancement completely normalized at six months, About 13% get worse and about 70% stay the same. So what is uh in addition to diagnosis, what's the prognostic value of MRI? And there are a couple slides, I just want to show you. They're a bunch of papers but I'm only gonna show two of them. The first is in the healthy population, these are the young guys with chest pain, normal ejection fraction of 62%. Pretty large series from Italy. And in this group there were very very few events 26 out of 374 people over 4.5 years. So very low event rate. But the pattern of the late enhancement, oh if it was typical or if it was absent, there was an extremely low rate of events 1% per year or less. But if the pattern was Andrea septal, the rate was higher. And there's other data from Germany that suggests that Andorra septal delayed enhancement has a different mechanism. Perhaps interestingly in this population, the crp or separate was higher in the typical and lower, statistically lower in the anterior septal, suggesting again maybe more of a non inflammatory mechanism. This series was from northern Italy. There's a high rate of desmond protein abnormalities probably in that population. And the question really is was this more of a genetic or environmental or inherited or other factors besides typical viral cardiomyopathy causing this myocarditis. And we don't know the answer to that yet. But from the Brigham series which is bigger. 670 patients with suspected myocarditis, only half of whom had chest pain and a third of them had lv dysfunction. So very much a real world Cardiology experienced 20% with B. B. C. S. Or heart rhythm problems. Bit older, 13% with the wide QRS. They were followed again for a little under five years. And like many other series have shown that the presence of delayed enhancement at all is associated with worse outcome in terms of transplant or death With a pretty pretty significant difference out to notice this is 10 years. So it's a long follow up 10 year follow up and the curves don't separate here for one year. So long follow up for this one. But it's the people who had the preserved ejection fraction as opposed to the people who had the low ejection fraction where the MRI made a prognostic difference. Once you've got an EF of 30 that trump's delayed enhancing. In my opinion you're low E. F. Is the big driver of events. A lot more events in the low E. F. Group compared to the normal EF group relatively normal. So this is consistent with our current scientific statement that said that you should favor MRI in the people who are relatively healthy. Mhm. In the acute cardiomyopathy setting, if you do not have mechanical circulatory, the border I know tropes require which would be the definition of full imminent or high grade heart block or symptomatic or sustained Bt. Then consider the MRI is the way we wrote it. And I think with the newer papers this might be to a we might move from to A. To two and we might move to be I think because some of these are perspective. Um So this is getting stronger on the right on the left. If you've got these you have to worry about giant cell. And then there's a disease which although overall has a 11% of heart biopsies in the Brigham series. Gail winters series number of years ago had giant Cell uh in the native hearts. Overall it's a much higher rate. More like one in five or one in 10 if you biopsy just this group. And so this is a class one level of evidence. Be recommendation in that setting. So we'll come back to that. This was this recommendation was repeated in the full minute myocarditis. Scientific statement from january which which we published HFS A and H. A. Um endorse this and everybody, I'm sure I'm Nicole knows full minute myocarditis clinically. But if you get cardiogenic shock or early shock and your low voltage QRS with suggesting a Dema it wouldn't obviously be amyloid, it would be more oedema in the absence of a pericardial effusion. You may have pericarditis, height proponent and the normal hard size with the thickened walls. That's where your that's your final type of the full minute myocarditis most typically and all of the badness, right? All of the giant cell. All of the eosinophilic was down here in this italian series in the black line. If you did not have full minute disease and it was more of a chest pain or relatively preserved eF presentation, the likelihood of death or transplant was just about zero in the amaretti series, 132 patients as opposed to if you need Aina tropes or you have high grade heart block or VT. That's where you found all the giant cells down here. And so that a 35% rate of death or transplant with 28% of that occurring in the first few months right here. So why do you look for giant cell? Because there's a high rate of death or transplant, 90% rate of death or transplant much higher than lymphocytic myocarditis. And it responds to cal southern based anti T lymphocyte therapy. Um The reason we have the four criteria was in our retrospective new England Journal paper the rapidly progressive course failure to respond to usual care sustained or symptomatic the attack or high grade heart block a period to define that compared to lymphocytic myocarditis. And in the prospective study when we screened patients prospectively using at Mayo and in the trial eight of 28 or 29% actually had giant cell. So that actually that's how we got the 2007 recommendations and then the Hopkins group and some other groups validated. This is a biopsy that looks like there's no myocardial left on the left with one Maya site barely surviving. And this is the biopsy four weeks later in one of our trial patients, remarkably, even though it looks like you've killed every possible Maya site they come back and you can heal and in the era of immune suppression with giant cell survival. This is the Finland series Uh is about 80% overall at five is five years right here and it's about 80% at five years. Artist was actually 90 at five years in our series. But that's including those who are transplanted. So there's still a role for biopsy lymphocytic myocarditis actually has a good prognosis. If you're getting on a bad if you look at the pen series or the series that we published from the imac registry imac to registry in 2012. The presence of myocarditis and a shorter duration of illness predicted bridge to recovery and bads. We do not use immune suppression for lymphocytic myocarditis based upon routine lymphocytic based upon the myocarditis treatment trial. And I'm ac one which was an I. V. I. G. Trial for acute not necessarily inflammatory cardiomyopathy. Uh We do use predniSONE usually for eosinophilic disease, particularly if it's related to drug induced hypersensitivity myocarditis. This is a review of the world literature via uh Woman who was working actually with enrico at the time. She is now in San Diego showing that there was about a 50% rate of of bad death of transplant at four months if you have hypersensitivity myocarditis. Uh bad actor, we withdraw the offending agent and give steroids. This is one example, closet pain is one of the drugs along with smallpox vaccination where you can get myocarditis in a pretty high rate. Um If you guys know Bill bobo, he is the chair of the psych here. Bill I talked to Bill. He said he's had two cases of this in his experience. So it's not vanishingly rare but it's uncommon And it is about a 25% fatality rate. An 85% occur in the first two months and a third a third. Do not have you seen ophelia? So you can't count on the S. NFL's. So to close up here and get ready for discussion to final slides. What about arrhythmias? There is a guideline, a. J. C. C. H. R. S. Guideline on the management of arrhythmias. It talks about myocarditis And there are two board testable questions. They're both pretty intuitive. The first is if you have human dynamic instability go to a center that can handle it, that's level one. And the second is if you have a giant cell uh and you expect to live more than a year, consider an I. D. And that's based on rina candle in the paper. And I think it's right. We did not. There was a subgroup in our experience that did not have recurrent arrhythmias. People who never had arrhythmias in the beginning. Um It may be that there is a subgroup but it's pretty small and I think the downside of an I. C. D. In this setting is pretty low. Okay. And so let's sum the whole thing up. So what this is to put it all into one slide. This is from a paper that is about to come out and cirque heart failure. I'm the co senior author on it. Um And this figure was drawn by Enrico. Um And he likes the emojis. Yeah Like this one here. Um uh And let's start at the bottom. So if you have normal heart rate and blood pressure and a normal ish E. F. And you're not having arrhythmias, you don't need to be transferred to me. Oh you don't need a temporary mechanical support. You don't need a heart biopsy. But we do recommend an MRI based upon the literature I just showed you and we don't recommend immune suppression. That's the common group. Then. What about what if you have mild heart failure, you're not human dynamically unstable and you don't have a and in this categorization you may or may not have VT. If you're if it looks like they're going down and the progress is progressive, you should transfer. You rarely need mechanical circular to support in this human dynamic setting biopsy is controversial. Um We have if I think if they're if they're going down over 1 to 2 week time course progressively despite guideline directed care, you could consider a biopsy. Uh but an M. R. I would be more typical if they're human dynamically stable. And again, this is an international group with a lot of european authors on it and some people would give immuno suppression in this setting. Um but it was variable. Some of us wouldn't unless we had the biopsy to show giant cell or using a filler and finally at the top there's cardiogenic shock bad enough VT may or may not be present. All of these people should go to hub centres, which is the way he phrased people centers like us. Um This is the group to be ready for early mechanical support. We did recommend unloading of the ventricle when possible. Even with ECMO, we recommended that all of these people who are human dynamically unstable requiring Aina tropes or CS get biopsied and that that you delay MRI he put before discharge again coming from Milan, I don't know that you have to do it before discharge, but I think you should do it in the first month if you can, based upon time course of recovery and then for immune suppression. It's worth noting that these people were not included in the myocarditis treatment trial. In fact, the people who were within two weeks of symptom onset were almost systematically excluded from the myocarditis treatment trial cohort because they were afraid they'd give immune suppression to active viral illness. And so, um, you can't apply those data this group, so it's quite possible that would help. But we don't have data.
