LESLIE T. COOPER, JR.: 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-COV-2, there's a whole lot of discussion on myocarditis. Interestingly, the traffic on the myocarditis foundation website increased about 30%, starting in the summer when the major sports teams, the Big Ten and the Pac-12, canceled their seasons, before they reopened their seasons. And so there is 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, SARS-COV-2, 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 of myocarditis. And I put a spin on it because this is a heart failure group.
I'm not going to talk about arrhythmias and sudden death very much. We can do that if you want. I talk a little bit about chest pain because it's really, really common. And I'm not going to talk about chronic heart failure and that whole controversy over whether myocarditis can cause meaningful inflammation in the context of a chronic cardiomyopathy. That's really interesting. It's debatable, and we can talk about it later if you want. But we're going to focus on acute cardiomyopathy and management.
So as you know, once SARS-COV-2 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. There was the Chinese experience, the 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 from hospitalization and acute SARS-COV-2, you could have these MRI findings. So this was a paper from Valentina Puntmann, her husband [INAUDIBLE], and the group 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, some on ventilators, and so fairly sick group. But nonetheless, at a time point when you think they were clinically better and feeling great, they had persistent or a surprisingly large rate of MRI abnormalities. So this is one of the studies that led to the cancellation of a lot of sports 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 should what's the recommendation based on this?
So let's take a step back. So we know SARS-COV-2 can infect the heart. This is a cardiac myocyte, invisible pluripotent stem cell from Jay Schneider's lab in Rochester, showing innumerable viruses and groups of viruses budding off of an infected cardiac myocyte, and lots of other studies, which I'll show a little bit of, that 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 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-2 virus is different than enteroviruses, coxsackievirus. And that viral shedding here-- and I'm not sure which screen you're seeing. Do you see my cursor right now moving? You do, OK, so it's the right screen.
So see, viral shedding starts, as we know, before you're symptomatic [INAUDIBLE], and then continues all the way through your illness and then into the late phases as well. That's different than a typical enterovirus, coxsackievirus, where you would typically clear it in this range, and then you'd have a post-infectious inflammatory response giving you your lymphocytic myocarditis. Actually, the cardiac involvement in the typical hospitalized older sick patient is quite late, with the vasculitis coagulopathy, maybe some myocarditis systemic cytokine storm. All of us who have been on the hospital service for the last six months have seen these older people, very sick, late in the course getting their troponin rise, 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, with 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 in 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. And there were reports, and we'll look at some of them some of our data on that. And it is a part of some SARS-COV-2 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 thrombotic 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 the young athletes are, obviously, 19, 20 years old. They have no pre-existing heart disease, and they're generally pretty healthy. They don't have any hospitalization, they're not on ventilators. And then 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, a few get STEMIs, not a lot, but some. Most of the ST segment elevation is more 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 vasoplegic shock. Occasionally, some pericardial disease and a fairly high rate of thrombotic complications, which we're hearing more and more about. So that's the big picture.
What about the heart? So we know from the original SARS experience, this paper from Peter Liu and colleagues, that in people who die of SARS-COV-2, 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 histologically, not typical of a fulminant myocarditis at all.
And so the question becomes, what is the mechanism? Is the heart damage causing the death? Is it incidental and not clinically important or what? And so Jay 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 myocytes as well as inside of these inflammatory cells in the heart and that the virus actually creates syncytia and moves between cardiac myocytes. It doesn't kill them and make them explode right, like an enterovirus or lytic 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, some of the other figures about that. But the mechanism of viral infection and damage and propagation is very different in this disease than it is in any other model that we know of, of myocarditis. And that's why what you see on the MRI is not lymphocytic myocarditis. It's something that's histologically different, the prognosis and the clinical significance of which we just don't know.
This was a recent autopsy study of patients who died of SARS-COV-2, and you can see they had lymphocytic myocarditis here, signs of epicarditis, but it was not huge. It was a epicardial, 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-- there's a case report. But it shows the epicondyle pattern that we just saw in the autopsy series at autopsy showing on MRI. This guy comes in with chest pain, high troponin, typical myocarditis, negative for all the other viruses, positive for SARS-COV-2, and he actually recovered pretty nicely in that case report. But the idea being that you do get myocarditis, but is it the kind of microdata that kills you and what should you do about it?
I would say it's a bit different in children. They tend to do very well 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 pre-existing heart disease compared to a young population of super healthy people, who may infrequently get a significant involvement.
So this is the current recommendations from 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 OK.
The second is, if you're symptomatic and you've got a mild illness, you may get an EKG 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 troponin, and then you recover, then they have cautionary words here that says, consider stress test, Holter, cardiac MRI, and definitely have a cardiac eval. It depends on how sick you were on what the evaluation should be.
I do think that in the Big Ten, looking at the Ohio State report, medically, and the other reports that have come out that that are a lot more conservative, everybody that I've seen in the reports who 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-2.
This is just a quick slide from Heart Failure or JACC Heart Failure, now about a month, two issues ago, suggesting in a different way how has the COVID pandemic affected heart failure care, not directly related to myocarditis per se. But I like 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 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 to-- that's not it. My slide started advancing. Did that just advance for you? It did? Good. The keyboard is not advancing for me.
Now we're going to make a transition. That was the first 15 minutes. And again, if you guys are interested in it, we can dive deep into the cellular mechanisms at the end. But instead, let's go on. And I do think, by the way, there are going to be a lot more papers on the MRI story coming out in the very near future, better papers that suggest a minority do have myocarditis.
But let's move now onto the regular myocarditis talk. And I have a couple of slides here on epi. And as you know, on a global scale, not everybody has a cath lab with a bioptome, 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 GBD project in 2007, we reported myocarditis and cardiomyopathy together, because I felt it, and I think our group of writers felt that 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 paper on the GBD project, we had 3.1 million cases of myocarditis and cardiomyopathy together. In the 2015 paper, we had 343,000 deaths, about 200,000 men and about 143,000 women, and a death rate of about 5 and 1/2 per 100,000 in men, and about 4 and 1/2 per 100,000 in women.
Now, I should say that just yesterday we returned the proofs for the JACC paper for the 2019 study, and those proofs, I'll tell you, separate out myocarditis clearly for the first time. And myocarditis is about a third. There 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 ICD-9 and ICD-10 codes, there was no proof of myocarditis, so they fell into a bucket of other. That went way up. The bucket went up, like, 50%.
So I think that actually myocarditis is conservatively a third of this total in the 2019 study. But this gives you an idea, men over women, always death rates of about 5 per 100,000. The prevalence is 22 per 100,000. So the death rate is less than-- it is about a 5% death rate overall in the first year.
In the US, it's super interesting. There's a huge variability. Overall, the US 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 areas up here in Idaho, the rate's about two per 100,000. The lowest city is actually Seattle, for reasons that are of-- 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 30, which is pushing like Eastern Europe levels. And so I think it has to do with global health, that there is just a lot more unhealthy lifestyle maybe down here than there is up here. But nobody really knows the reason. But I think that's interesting in the US for myocarditis and cardiomyopathy.
There are four ways that myocarditis presents. The most common is chest pain. Come into the ER, myopericarditis, or chest pain syndrome resembling acute MI or ST segment MI. 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 a young person devastating, and we always remember that. And so we'll come back to-- we're not going to talk about sudden death today, but we can talk about it at the end if you want.
We're going to spend most of our time on acute dilated cardiomyopathy and fulminant myocarditis. And again, we're not going to talk about chronics 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 epicardial myocarditis and pericarditis. And this is a coxsackievirus B model of mixed autoimmune myocarditis with the CVB infection. And this is an MRI, a typical MRI, I've been using for 16 years. I should probably get a new slide. It's a good MRI, and it's typical of that inferior, posterior, lateral epicardial 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 ST 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's areas and in Germany, the Q restorations 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 cardiomyopathies, but it's certainly true in every case series that's looked at it that I'm aware of from myocarditis, as well as a high-degree heart block.
So what about MRI? So we're going to spend a little bit of time on MRIs. It's been about 22 years since the first papers came out, in children actually, on T2 weighted imaging for the diagnosis of acute myocarditis, and then the T1 delayed gadolinium imaging shortly thereafter. And over the years, in 2009, we had the Lake Louise 1 criteria, and we revised it with mapping sequences in 2018, in December 2018, here.
And this is a subsequent comparison of the different techniques [INAUDIBLE] the accuracy, which is a combination of the sensitivity and the specificity analysis for the revised Lake Louise 2 criteria on the right. They do come out marginally better than individual sequences, a lot better than extracellular volume. And I think that they're still probably in the good centers the way to go, when you do have mapping sequences available in normal values.
This revision, to remind you, is one T2 weighted image has to be positive. That could be a T2 map, native T2 map, or an image, or T1 weighted map, which is-- and one T1 weighted map, which is, again, the map or a post-gadolinium delayed enhancement, or an early T1 hyperemia sequence. And you need one from each group to be positive.
And they're only positive in the beginning. So this is a slide showing the time course of recovery in days. So there is 7 days, one month, three months, and this is T1 and T2 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, too. Biopsies tend to get back to normal within a month or two.
So I like to say, two to four weeks is best. If you can get your MRI in the two- to four-week window, I think the T2 and the T1 sequences are probably accurate. But when you get out here it's 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 in the most recent papers from Italy, about 16% of patients with abnormal T1 delayed enhancement completely normalize at six months. About 13% get worse, and about 70% stay the same.
So in addition to diagnosis, what's the prognostic value of MRI? And there are a couple of slides I just want to show you. There are a bunch of papers, but I'm going to 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, they were very, very few events, 26 out of 374 people over 4 and 1/2 years, so very low event rate. But the pattern of delayed enhancement, 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 anteroseptal, the rate was higher. And there's other data from Germany that suggests that anteroseptal delayed enhancement has a different mechanism perhaps. Interestingly, in this population, the CRP or sed rate was higher in the typical and lower, statistically lower, in the anteroseptal, suggesting again maybe more of a non-inflammatory mechanism.
This series, which was from northern Italy, there's a high rate of desmosomal 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's 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 experience, 20% with PVCs or heart rhythm problems, bit older, 13% with a wide QRS. They were followed again for a little under five years and, like many other series, have shown the presence of delayed enhancement at all is associated with the worst outcome, in terms of transplant or death, with a 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 of prognostic difference. Once you've got an EF of 30, that trumps delayed enhancement, in my opinion. Your low EF is the big driver of events, a lot more events in the low the EF group compared to the normal EF group, or 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.
In the acute cardiomyopathy setting, if you do not have mechanical circulatory supported inotropes require, which would be the definition of fulminant, or high-grade heart block or symptomatic or sustained VT, then consider the MRI, is the way we wrote it. And I think with the newer papers, this might be 2A. We might move from 2A to 2, and we might move to B, I think, because some of these are prospective. 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 1% of heart biopsies in the Brigham series-- Gayle Winters' series a number of years ago had giant cell 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 I level of evidence B recommendation in that setting. So we'll come back to that.
This recommendation was repeated in the fulminant myocarditis scientific statement from January, which we published. HFSA and AHA endorsed this.
And everybody, I'm sure, on the call knows fulminant myocarditis clinically. But if you get cardiogenic shock or early shock and your low voltage QRS with suggesting edema, it wouldn't obviously be amyloid, it would be more edema. In the absence of a pericardial effusion, you may have pericarditis, high troponin, and the normal heart size with the thickened walls. That's your phenotype of the fulminant myocarditis, most typically.
And all of the badness, 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 fulminant disease and it was more of a chest pain or a relatively preserved EF presentation, the likelihood of death or transplant was just about 0 in the Ammirati series, 132 patients, as opposed to if you need inotropes 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 calcineurin-based anti-T lymphocyte therapy. 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 V-tach or high-grade heart block appeared 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 actually, that's how we got the 2007 recommendation, and then the Hopkins group and some other groups validated it.
This is a biopsy that looks like there is no myocardium left on the left, with one myocyte 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 myocyte, they come back, and you can heal.
And in the era of immunosuppression with giant self survival-- this is the [INAUDIBLE] series-- is about 80% overall at five years right here, and it's about 80% at five years. Ours was actually 90% at five years in our series, but that's including those who were transplanted.
So there's still a role for biopsy. Lymphocytic myocarditis actually has a good prognosis if you're getting on a VAD. If you look at the Penn series or the series that we published from the IMAC2 registry in 2012, the presence of myocarditis in a shorter duration of illness predicted bridge to recovery in VADs.
We do not use immunosuppression for lymphocytic myocarditis based upon-- routine lymphocytic based upon the myocarditis treatment trial and IMAC1, which was an IV IG trial for acute not necessarily inflammatory cardiomyopathy. 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 by a woman who was working, actually, with [INAUDIBLE] at the time-- she's now in San Diego-- showing that there was about a 50% rate of VAD death or transplant at four months if you had hypersensitivity myocarditis. A bad actor, we withdraw the offending agent and give steroids.
This is one example. Clozapine is one of the drugs, along with smallpox vaccination, where you can get myocarditis in a pretty high rate. If you guys know Bill Bobo-- he's the chair of psych here. I talked to Bill. 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. And 85% occur in the first two months, and a third-- a third-- do not have eosinophilia. So you can't count on the eosinophils.
So to close up here and to get ready for discussion, two final slides. What about arrhythmias? There is a guideline, AHA/ACC/HRS guideline on the management of arrhythmias that talks about myocarditis, and they're two board testable questions. They're both pretty intuitive.
The first is, if you have hemodynamic instability, go to a center that can handle it. That's level one. And the second is, if you have a giant cell and you expect to live more than a year, consider an ICD. And that's based on [INAUDIBLE] paper, and I think it's right.
There was a subgroup in our experience that did not have recurrent arrhythmias, people who never had arrhythmias in the beginning. It may be that there is a subgroup, but it's pretty small. And I think the downside of an ICD in this setting is pretty low.
And so let's sum the whole thing up. So this is to put it on the one slide. This is from a paper that is about to come out in Circ Heart Failure. I'm the co-senior author on it. And this figure was drawn by [INAUDIBLE], and he likes the emojis, like this one here.
And let's start at the bottom. So if you have normal heart rate and blood pressure and a normal-ish EF, and you're not having arrhythmias, you don't need to be transferred to Mayo. You don't need 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 immunosuppression. That's the common group.
Then what about, what if you have mild heart failure? You're not hemodynamically unstable, and you don't have-- and in this categorization, you may or may not have VT. If it looks like they're going down and it's progressive, you should transfer. You rarely need mechanical surgery to support in the hemodynamic setting.
Biopsy is controversial. I think if they're going down over a one to two week time course, but progressively, despite guideline-directed care, you could consider a biopsy. But an MRI would be more typical if they're hemodynamically stable.
And again, this is an international group with a lot of European authors on it, and some people would give immunosuppression in this setting. But it was variable. Some of us wouldn't unless we had the biopsy to show a giant cell or eosinophilic.
And finally, at the top, there's cardiogenic shock. Bad EF, VT may or may not be present. All of these people should go to hub centers, which is the way he phrased centers like us. 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 hemodynamically unstable requiring inotropes or MCS get biopsied, and 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 immunosuppression, 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 immunosuppression to active viral illness. And so you can't apply those data to this group. So it's quite possible that would help, but we don't have data.