Alright, good morning, everyone. Thanks again for joining us. It's a great pleasure to introduce one of my trusted colleagues at Northwestern, Dr. Alex Kikosz. Dr. Kikosz is associate professor of medicine at Northwestern and serves as the director of our EP lab. He also has carved out a clinical interest as well as research niche within the field of cardiac sarcoidosis and actually runs the sarcoid registry at Northwestern. So he is going to speak to us this morning about arrhythmias in cardiac sarcoidosis. Thanks so much, Alex. I'm going to turn it over to you. Thanks, Nishant. Okay, so I have a lot of slides, so I'll start. I'll be talking about arrhythmias in cardiac sarcoidosis from an EP perspective. So as you know, sarcoidosis is an inflammatory disease and we have different stages of inflammation. We have an early stage of lymphocytic myocarditis. We have a granulomatous phase, which is an intermediate stage of inflammation. These granulomas are non-necrotizing or non-caseating as opposed to tuberculosis. And then we have a late stage where the myocytes and other tissue that has been destroyed by inflammation is replaced by a scar. So let's talk a little bit about the pathophysiology of cardiac sarcoidosis. First, as we talked, you have inflammation which can be acute, chronic, can be low-grade, or high-grade. The active inflammation leads to myocyte loss and repair fibrosis, and then you have scar. So the substrate for arrhythmia in cardiac sarcoidosis is complex. It's dynamic because it changes. It waxes and wanes, flares up, and reactivations frequently go undetected. They're silent clinically until they cause arrhythmias or congestive heart failure or other cardiac symptoms. Their location, it's a patchy substrate. It's not like you see in a ischemic cardiomyopathy with well-defined myocardial infarction. It can be mesocardial, epicardial, or endocardial. The border zone is an irregular zone, and it's heterogeneous. To further complicate the substrate, you have rekinja fibers that may be entrapped at the edge of scar or in inflammation. It can be an arrhythmia, of course, themselves. Many studies we have about arrhythmias in cardiac sarcoidosis are somewhat old, and I think we are making the diagnosis earlier these days, and the substrate is likely changing and the patient population is changing. So we have less patients with end-stage scar and more patients with acute sarcoidosis and actively inflamed substrate. This is a pathology picture to show you what sarcoidosis can look like. In figure A, you see dense infiltrate scar, probably with granulomas at the borders. In figure B, you see a diffuse pattern where you see strands here. In figure C enlarged, you see strands of fibrosis interspersed with some probably viable myocytes. And in this picture at the right, you see that it can be very patchy. You have anteroceptal infiltrates, which are quite characteristic and oftentimes associated with AV conduction problems. And you have patchy infiltrates in the septum, epicardial, mesocardial, and so forth. This is a figure that I designed for a patient lecture. Why is heart involvement dangerous in sarcoidosis and what can happen? Well, you can have sarcoidosis infiltrates in the myocardium, in the ventricular myocardium, leading to damage to heart muscle and weak hearts. Then you can have interruption of the conduction system leading to heart block and loss of the heart rhythm. And then you can have a focal infiltrate that represents a substrate for re-entry leading to ventricular tachycardia and cardiac arrest. And that only shows the ventricles, in fact, because obviously you can have infiltration in the atria as well. Most important first step is to make the diagnosis. And who makes the diagnosis? Well, I'm going to show you how we can make the diagnosis from a general cardiology perspective, from an electrophysiologist perspective. And then remember, this is a multidisciplinary disease. Sarcoidosis is a systemic disease. So you have a lot of cases that are diagnosed by pulmonologists, traumatologists, ophthalmologists, ENT, GI, liver, dermatology, etc. So this is an example of a case, 34-year-old athletic male with new exertional dyspnea. I don't know if anyone wants to activate the microphone and say what they see. I'm going to give you five seconds to look at it. Well, it's okay. There is prolongation of the PR interval and it's 370 milliseconds. And this patient presents to a general cardiologist. Everyone will notice that the PR interval is this prolonged and it's markedly abnormal for a 34-year-old. So there is no doubt that further investigations are indicated. Because he has exertional dyspnea, he was sent for a stress test, treadmill stress test. And this is what happens during his treadmill. You see he's exercising, heart rate here is about 110. And then all of a sudden it drops to, I'll help you, it's about half. And you see a P-wave before each QRS, but if you look carefully, there are P-waves. There is 2 to 1 block. There are P-waves on the T-waves here, which is markedly abnormal. And this patient on cardiac MRI had delayed enhancement in the septum, in the infrared septum, but also in the anterior septum, which explained his AV conduction abnormality. So it's important to think about how to screen patients, who to screen for sarcoidosis. When should we think about sarcoidosis in a patient that doesn't have any history of sarcoidosis anywhere else? Say you have patients that are relatively young and the age cut off, it's obviously unclear. I would say younger than 65. That present with unexplained high degree block, Mobitz type 2 or 3 degree. Say you have patients that present with unexplained ventricular tachycardia, unless it's a clear benign variety of ventricular tachycardia, such as outflow tract VT, fascicular VT, or known ischemic heart disease. If you have a patient presented with concomitant cardiomyopathy and heart block, now there are the other genetic cardiomyopathies that can present like this, but sarcoidosis definitely is something we should think about. If a patient presents with ventricular arrhythmia and heart block, we should also think about why does the patient have both of these manifestations? A patient presenting with cardiomyopathy, ventricular arrhythmia, or heart block, in the presence of high, low, or mediastinal lymphadenopathy, obviously any other organ system involvement, but I think high, low lymphadenopathy is something that we easily look for. Patients have chest x-rays, many patients have CAT scans. I oftentimes just open up their CAT scans or chest x-rays and see, oh, there's high, low lymphadenopathy. We should really look into this further. Patients with unexplained myocardial infiltrate from cardiac MRI obtain for other reasons. We should always think of sarcoidosis as a possibility. Let me give you another example here. This is a 36-year-old male with exertional palpitations. We see that during the treadmill test exercise, page three, he has PVCs. These PVCs look pretty narrow. They're right bundle superior axis. Because they're right bundle superior axis, we think, well, they're coming from the left ventricle, post-inferior wall. This could be fascicular PVCs. It could be a variety of benign PVC. Here, he has a brief run of ventricular tachycardia also during the exercise. This is a 36-year-old, highly active. We could discount this as a benign fascicular VT. This pattern that he has of monomorphic ventricular tachycardia coming in bursts, you could call it repetitive monomorphic ventricular tachycardia. However, it doesn't match what we categorize as the benign variety of repetitive monomorphic VT because those are actual tract ventricular tachycardia. This behavior is somewhat different. It's somewhat not expected necessarily for this type of morphology. Now, in addition to that, just wanted to show you that, in fact, he also has Q waves inferiorly, which are narrow but quite big. There is some suspicion there. Here, I'm pointing out the PVCs, the Q waves. And he does have on cardiac MRI delayed enhancement in the inferior wall, in the left ventricle, right ventricle, and he was diagnosed with sarcoidosis. Another example, and again, this is from an electrophysiologist point of view, 57-year-old female with syncope, presents with syncope. I'll give you a few seconds to review this EKG. But you can see that there is right bundle branch block. There is left axis deviation consistent with left anterior fascicular block, so she has bi-fascicular block. You can see that PR interval is prolonged, so there is possible tri-fascicular block. So, she was also noted to have transient complete heart block, and she received a permanent pacemaker. Just to go further in her history, a year and a half later, she had complete heart block. She was 100% placed in the right ventricle, and her left ventricular ejection fraction was now down to 21%. She underwent coronary angiogram, which was normal. So, she was referred for upgrade to a biventricular device. The thought was that maybe her cardiomyopathy is related to RV pacing. And six months later, she had two ICV shocks, four ventricular fibrillation, and at this time, ejection fraction was 15%. Her FDG PET showed extensive uptake and mediastinal and hyaluronic adenopathy, and extensive patchy left ventricular and right ventricular uptake. So, she underwent biopsy of the lymph nodes in the mediastinum, and she had cardiac sarcoidosis. I mean, she had sarcoidosis diagnosed and a highly probable cardiac sarcoidosis. She was treated with supressants and optimal medical therapy for her cardiomyopathy. And now, eight years later, her ejection fraction has improved to 29%, and she has been stable and without ventricular arrhythmias. So, the other aspect of diagnosis is finding cardiac involvement in patients who have extra cardiac sarcoidosis that is known. So, any patient with sarcoidosis anywhere should be screened for symptoms every visit, and we should ask about palpitations, syncope, and dyspnea that's not explained by their lung involvement or out of proportion. Electrocardiogram, yearly at least, it's an easy thing to do, looking for any abnormality. And I say any abnormality, even though initially, I was thinking, well, is it heart block or bundle branch block? I'll show you an example. T-wave inversions, any abnormality should prompt some, you know, suspicion. A halter, I recommend once a year, once every couple of years, particularly if they have symptoms, but even if they don't, looking for ventricular tachycardia, any AV block, PDCs, say if they have more frequent than expected, or if there are morphologies that are really not expected. Now, it's tough with the ZioPatch that we have now, which is just single lead, it's tough to really tell what morphology the PVC has, but we used to have the three lead, and you could tell, well, is outflow tract PVC likely, or this is kind of, this PVC is not likely to be outflow tract. And echocardiograms, it's an easy, non-invasive, cheap test without radiation. So I think it should be done initially, and then it's unclear how often, but maybe once every two, three years, every year in the beginning, then spaced out every two, three years, and maybe less often later. Any abnormality should prompt the further evaluation, including probably MRI or FDG PET. I'll give you an example. After we had multidisciplinary conference, I had this patient referred by an ophthalmologist, the patient, he was treating a patient, a young, healthy patient, asymptomatic, with stable sarcoid uveitis, and did a screening ECG, which was read as abnormal. When I first saw the preliminary report of the ECG, the computer report, the nonspecific T wave changes, I said, oh my god, this is going to be low yield. But then when I saw the electrocardiogram, yeah, the patient has some T wave inversions inferiorly. Her echocardiogram showed normal ejection fraction, but there was severe hypokinesis of the inferolateral wall. And then cardiac MRI confirmed wall thinning and severe hypokinesis in the mid and apical inferolateral wall. And on the MRI, her ejection fraction was read as 42%. A monitor showed that she did have 5,000 PVCs in 48 hours, so 2.5% burden or so. And these PVCs are right bundle, superior axis, corresponding to the T wave inversions and abnormalities seen on MRI and echocardiogram. And let's move on to another example. 42-year-old male sees his doctor for screening because his mother has congestive heart failure, and his ejection fraction turns out to be mildly increased, 40 to 45% on echocardiogram. And the MRI does show patchy delayed enhancement in the septum and anterolateral wall. An FDG PET scan shows increased uptake. And this is his increased uptake, where he has increased uptake in the basal and midseptum, and also in the lateral wall. And you might think he has cardiac sarcoidosis, right? But keep in mind that this is an isolated cardiac uptake, so isolated cardiac involvement. So it's tough, because we can't make diagnosis with biopsy. Oftentimes, biopsies are negative, even if you target low voltage, because the substrate, the inflammation is not endocardial. And it turns out that he has pathogenic dysmorphic mutation, seen, diagnosed by our colleagues in cardiology. And he actually has familial arrhythmogenic ventricular cardiomyopathy. And so there is this paper published in 2019. They looked at 16 patients with definite ARVC. Seven of them had positive FDG PET scans. Two turned out to have cardiac sarcoidosis on endocardial biopsy. So there is clearly a two-way street of confusion between ARVC and cardiac sarcoidosis. But of the remaining five, two carried pathogenic dysmorphic mutations. So not all positive PET scans represent cardiac sarcoidosis. You can have genetic cardiomyopathies, where areas of necrosis are triggering local inflammation and turn a PET scan positive. You can have other myocarditis, such as viral lymphocytic giant cell. And of note, recent ablation, and even not so recent ablation, can cause a positive PET scan. Let me show you some interesting examples here. This is a patient who underwent radiofrequency ablation in the right atrium. He had a lot of scar in the right atrium and arrhythmias. He underwent extensive ablation in the right atrium on November 29, 2019. This is the PET scan on March 5th. He still has intense patchy uptake in multiple areas in the right atrium. This was called by the radiologist initially possibly cardiac sarcoidosis. Of course, we knew that he had extensive ablation there, so we said hold off treatment, obviously, and repeat the PET scan later. And we repeated the PET scan nine months after his ablation. There is still some patchy mild increase in uptake, but it was read as almost completely resolved. But it's remarkable that nine months after ablation, you can still see some increased uptake. I think that's very important. So how long do PET abnormalities persist after ablation? This is another example. This patient had ventricular tachycardia and a mild cardiomyopathy in normal coronary arteries. He had some VT ablation in the basal septum on August 24, 2018. He had 44 RF lesions, and this is his PET scan a week later or 10 days later. Of course, the floor people, when they got the results, they said, oh, he has cardiac sarcoidosis. No, wait a minute. We just ablated right there. And we said, well, let's repeat several months later because we really didn't know for sure what the patient had at this stage, and we wanted to show that things improved. He did have a cardiac MRI as well that showed that endocardium demonstrated multiple areas of focal signal loss, which is what you expect after a recent ablation. And this is a repeat PET scan at the end of February, five months after his ablation. And there is still some increased uptake, which is nearly completely resolved, but still there. So many months later, you still see increased PET uptake. And this patient turned out to have Lamin mutation and numerous VT morphologies, and endocardial ablation was not going to ever succeed. So there's a possible over-diagnosis of cardiac sarcoidosis. If the patient is misdiagnosed, he's going to end up on immunosuppression, which is quite a severe treatment when the patient doesn't need immunosuppression. So for example, I saw a patient who had papillary PVCs and a mild cardiomyopathy, and he had a PET scan and MRI soon after an ablation, and they were all positive. And he was treated with methotrexate, prednisone initially, and methotrexate for nearly a year before he presented for second opinion. And because we knew that his PET scan was spotted soon after ablation, we said, well, let's repeat. And then we took him off methotrexate for several months, and we repeated a PET scan. There was no activity anywhere. And so we ruled out sarcoidosis, and he's just being treated for his disease. And just wanted to point out that there was a study published in 2015 in the Heart Freedom Journal, where at UCLA, I believe, or Cedars-Sinai, they did 103 PET scans in patients with unexplained non-ischemic cardiomyopathy referred for ventricular arrhythmias, including ventricular tachycardia and PVCs. And half of those PET scans were positive for increased FDG uptake, and that was quite surprising for everyone. And out of those patients, so 50 patients or so were positive, 18 patients were diagnosed with sarcoidosis. But systemic inflammation and lymph node uptake was observed in 17 patients, but isolated cardiac involvement was seen in 33 patients that have positive PET scans. And that raises questions. I mean, is it truly sarcoidosis? Could be other inflammatory cardiomyopathies. Could be genetic cardiomyopathies, as we discussed. Because usually with sarcoidosis, you don't see isolated cardiac involvement. And just wanted to point out that we do not, in this paper, we do not have a history of how many patients had ablation within the previous three, six, nine, 12 months. So I suspect a lot of those, in fact, had positive PET scans because they had been ablated. And looking further at the paper, I find that five patients have catheter ablation performed at an outside hospital, which is a common scenario. We see patients come here referred for ventricular VT ablation. The local electrophysiologist attempted VT ablation as well. So if you do a PET scan, of course, it's going to turn out positive. And one patient had ablation at the institution where the study was reported prior to the abnormal PET scan. So yeah, a lot of these patients might have had either other cardiomyopathies, not sarcoidosis, or just spuriously positive PET scans because of prior ablation. We're part of the cardiac sarcoidosis registry. And an abstract in 2015 from that registry, we found that 12% of patients had isolated cardiac sarcoidosis. And these are patients that have met other criteria for sarcoidosis, including biopsy. But I wonder if some of these actually do not have cardiac sarcoidosis. They could have, as we discussed, other cardiomyopathies or just spuriously positive PET scans. So 12% may be an overestimate. End of note, even if a PET scan only lights up in the heart, if they have some lymphadenopathy, or even if you don't see lymphadenopathy on a CAT scan in the hyla and mediastinum, transbronchial biopsy and lavage is oftentimes positive. So it's worth doing. Next, after you make the diagnosis, then you wonder, what do you do for these patients? So the question that first comes up and comes up often is, which patients could benefit from a defibrillator? Well, clearly, if they have cardiac arrest or sustained ventricular arrhythmia, it's in all the guidelines. If they have inducible sustained ventricular cardiac arrhythmia or ventricular fibrillation. If they have unexplained syncope, that's felt to be arrhythmic, so you don't hear that they have vagal symptoms or other situational trigger. Looking at the ventricular ejection contraption, that might help us. We'll talk about that a little more. Extent of ventricular involvement on MRI, and there are some papers suggesting that. Some people say if you have any evidence of delayed enhancement on MRI or uptake on PET scan, you may consider a defibrillator. If you want to be more nuanced, if you have MRI involvement of more than 6% of myocardium, those patients may benefit more from a defibrillator. Presence of heart block, because these patients need pacemakers. So once you decide they need a device anyway, we should probably have a low threshold for a defibrillator. Let's talk a little bit about that. The role of programmed electrical stimulation in risk stratification. This is based mainly on this one study published in 2011 from Mount Sinai, New York. 76 patients with biopsy-proven sarcoidosis, but without cardiac symptoms. They had no symptoms, and they had evidence of cardiac sarcoidosis. Patients with prior defibrillator or ventricular arrhythmia were excluded. So if they have non-sustained EP, they were excluded. So they underwent EP study for risk stratification, and they did the traditional protocol with singles, doubles, and triples from two sites at two basic life cycle lengths on and off isoprotermal. Eight patients had inducible sustained ventricular tachycardia, and they received defibrillators. This was the event-free survival. If the EP study was negative, the incidence of events was very, very low. If the EP study was positive, incidence of events was high. If you look at the left ventricular ejection fraction, it tended to be decreased in patients with a positive EP study and tended to be normal in patients with negative EP study. So this raises a question whether, well, is the EP study worth it or is knowing the ejection fraction is normal good enough? This is another study actually published in 2019, EP studies in 69 patients with probable cardiac sarcoidosis, meaning the biopsy was done elsewhere, not in the heart, but there is evidence of heart involvement. So they excluded the patients with any heart block, VTVF, or LD dysfunction. So these were patients with normal EF and no VTVF or LD block. If the EP study was negative, it was highly predictive of a good outcome. If the EP study was positive for inducible VT or VF, they had a high incidence of events. So it seems to be useful as a risk stratifier. So let me get back to the example of this 36-year-old male that I showed you earlier, who presented with palpitations that had PVCs and Q waves and inferior wall infiltrates and non-sustained VT. So we treated him. Let me skip over this. We did an EP study and it was negative for sustained VT, although he did have non-sustained VT, so we gave him a defibrillator. He was treated with prednisone. He underwent the initial high-dose prednisone of 40 or 60 milligrams, I can remember. And then he underwent a very slow taper all the way to October 2012, so 19 months, 20 months actually. He was asymptomatic. He was competing in triathlons and he returns in September 2013 after a lapsing follow-up of a year. He becomes tired more easily, although he is still training for triathlons. And his ICP interrogation shows that he has some events like this, 10 seconds of ventricular fibrillation with aborted ICD shot. And we also noted that R waves were decreasing amplitude. The R waves had been stable at 12 until February 2013. His ICD was placed in 2010. And so why would all of a sudden R waves decide to drop two or three years later? So this is one example. Events like this should prompt you to think maybe the sarcoidosis is reactivating. His repeat echocardiogram shows that EF is now 15%, unfortunately. So he's a young man who's competing in triathlons and just minimally tired. And FDG PET shows extensive ventricular myocardial uptake. And this is what his MRI looks like now and his PET scan. He has extensive infiltrates all over his left ventricle and right ventricle, all pertaining to core prognosis. So that leads me to an abstract that we sent to HRS in 2016. We looked at 60 patients we diagnosed here with cardiac sarcoidosis. And we saw that 37% presented as initial cardiac manifestation was symptomatic heart block. And their average EF was low normal, 49%. And after looking at these patients presenting with initial heart block and nearly normal EF, we followed them up for four years. Eight patients, 36%, developed subsequent tachycardia or ventricular fibrillation. And among these patients who developed ventricular arrhythmias, baseline of ventricular ejection fraction was on average 39%. And ultimately, initially, at baseline 30%, but they improved with treatment to over 50%. So a large percentage of patients with cardiac sarcoidosis that presented with heart block developed subsequent ventricular tachycardia or fibrillation despite a preserved ejection fraction. So we conclude that a lot of these patients that need a pacemaker, we should really think hard about getting a defibrillator initially. So cardiac sarcoidosis is dynamic and unpredictable. So I would keep a relatively lower threshold for recommending a defibrillator. And close surveillance for responsive therapy and monitoring for reactivation is necessary. So let me tell you about this paper about the efficacy and safety of implantable cardiac defibrillators for treatment of ventricular arrhythmias in cardiac sarcoidosis published in 2013. So they looked at 235 patients, followed up for about four years, and 36% received appropriate ICD therapies, and 30% of patients received an appropriate shot. The rest of them received anti-tachycardia pacing only. Anyway, just wanted to point out that patients who received appropriate therapies had slightly lower ejection fraction. However, notice that the confidence interval is quite broad. So normal ejection fraction doesn't mean you're spared. And so, these patients have a high incidence of appropriate shocks. Oh, I also wanted to point out that they're relatively young, 54 and 56 average age. So this is a set of relatively young patients with relatively preserved ejection fraction. Compare that in your mind with patients with non ischemic cardiomyopathy or ischemic cardiomyopathy, all those patients we give defibrillators when their ejection fraction is less than 35%. And despite being younger and having better ejection fraction, they get more appropriate shocks. This is a more arrhythmogenic condition than what we're used to. So again, who needs an ICD? Well, what I can tell you is an ICD is not indicated if all of these are true. Patient has no syncope, normal ventricle and right ventricle, no or minimal delayed enhancement on MRI and no or minimal activity on the PET scan. EP study is negative. There is no indication for pacing and you know the patient will be closely monitored for disease progression. Everyone else, you should really think about it. And so factors to consider, again, syncope without other explanation, that could be arrhythmic, presence of VP or VF, AV block, need for a pacemaker, left integral ejection fraction, if it's less than 35%, yes, everyone's in agreement. And this is mostly by extrapolation really from other cardiomyopathies. But I would really look into it if the EF is decreased at all 35% to 50%. If the ejection fraction is normal or mildly decreased, you may want to do an EP study. We look at the extent of the disease on MRI and the PET scan. We do EP study, which is helpful for recertification and their expected compliance with therapy and follow-up. So ICD is not enough. I think the job of the electrophysiologist is not done once you implant ICD. There are no clinical trials on how to treat sarcoidosis in general, by the way. It's all kind of grandfathered in with immunosuppression. So the mainstay of therapy of immunosuppression are corticosteroids. We use steroid sparing agents, methotrexate, and now more recently other agents, including infliximab, TNF inhibitors. Then we can use antiarrhythmic drugs to suppress arrhythmias, psoron, amiodarone, maybe naxxilatine, and ablation. So let's talk about those a little bit. So in terms of immunosuppression, we looked at outcomes in a cohort of our patients. And what we did, we did PET-guided immunosuppression. There are other papers, small papers published here and there in the past few years. So in our cohort, each patient had repeated PET scans, and we looked at their outcomes. We looked at the incidence of sustained ventricular arrhythmia, decreasing ventricular ejection fraction, heart transplant, or death. And this is an example how to treat these patients. This patient had intense uptake in the septum, lateral wall basal, maybe in the right ventricle, was put on prednisone, 60 milligrams daily. Some studies suggest 40 milligrams daily may be enough. Then he underwent a slow taper. Five months later, he had repeat PET scan. On this dose, it turned out that he still had persistent uptake. Methotrexate was increased. Five more months later, everything was suppressed. So he did well. So then he underwent slow taper of these. And 10 months later, he still has no FDG uptake, and he's on maintenance doses of prednisone and methotrexate. And with this approach, this is retrospective, obviously, but with this approach, we found that if complete PET suppression was achieved, outcomes were better in terms of death or heart transplant, in terms of the combined outcome of ventricular arrhythmia, death or heart transplant, and just the ventricular arrhythmias themselves. So everything was improved with this strategy of PET-guided immunosuppression. What's the role of antiarrhythmics? Well, in our cohort, arrhythmia-free course correlated with the ability to suppress inflammation. Now, PET-guided immunosuppression is not something without any cost or side effects. There is quite a bit of radiation. This is a very expensive study. How often do you repeat these PETs? How much radiation do you expose the patients to? Clearly, we have no prospective trial. And I just wanted to reiterate that this is a cohort of patients, a category of patients with highly arrhythmogenic substrate. So whenever we implant a defibrillator, we should also think of, if they have any ventricular arrhythmia, treat it with antiarrhythmics. But then what is the role of VT ablation? So what are the mechanisms of ventricular arrhythmias in cardiac sarcoidosis? So what are the mechanisms of ventricular arrhythmias in cardiac sarcoidosis? Well, you have acute myocardial inflammation, which may result in abnormal increased automaticity or triggered activity, like you see in acute myocarditis. So you have active stages of inflammation early on or during reactivation. So you can have a combination of scar and active inflammation. Corticosteroids have been shown in small cohorts that they reduce arrhythmia burden. Another substrate for ventricular arrhythmias is when you have scar-related reentry. And that's usually seen in more advanced stages. I guess it's possible to happen also if you have dense inflammation with active disease. I would say you can kind of form an idea of what type of arrhythmia you're dealing with, because if you see, with acute inflammation and increased automaticity, you may see irregular ventricular rhythms. You can see repetitive bursts, and you see pleomorphic or polymorphic ventricular arrhythmia. Whereas with fixed scar-based reentry, you see a regular sustained monomorphic ventricular arrhythmia. And that kind of guides your treatment. In addition, you get an FDG PET scan, you see if there is active uptake, and that, again, guides your treatment. So what's the role of ablation in cardiac sarcoidosis for ventricular tachycardia? We only have a few series, small numbers of patients. Of these patients, a lot present with incessant VT storm. In those series that were published, most arrhythmias are scar-related monomorphic VT. But there are reports of Purkinje fiber-related bundle branch reentry, micro-reentry, and non-reentrant Purkinje focus. These are some of the small series that have been published in the last 15 years or so. But I'm just going to move on. There is a paper that's been submitted for publication from the Cardiac Sarcoidosis Consortium this month. And from this multi-center registry, international registry, we found 158 patients with immune age of 52 that underwent VT ablation. Median time from cardiac sarcoidosis diagnosis to the ventricular ablation was 827 days. So it tells you, these are, I think, selected patients that tend to be more late stage. They're not patients that have been just diagnosed with cardiac sarcoidosis. They're not patients that have just been diagnosed with cardiac sarcoidosis. So let's see what these patients are like. Well, they're relatively young. And they're relatively preserved ejection fraction. Average median ejection fraction was 45%. So half of them had an ejection fraction of less than 50%, meaning the other half had normal ejection fraction. Out of these patients, notice 15% presented with resuscitative cardiac arrest or had a history of. A third of them had syncope. Almost all of them had defibrillator. A quarter had complete heart block. 40% of these patients that underwent a VT ablation had history of VT, VF, storm, or incessant VT. And a tenth of them had polymorphic VT or VF. So it's a different presentation than you see in ischemic cardiomyopathy, for instance. And half of them, at least half of them, had failed treatment when antiarrhythmic immunosuppression. And a quarter of them had prior VT ablation. And half of them were in amyotrophic. And just wanted to point out that the median duration of their VT ablation was six hours. Tells you something about the degree of complexity. I thought the procedural complications were interesting. They're pretty 7% of the patients. Tamponade in five. Hematoma one. Coronary injury with stenting in one. Pneumothorax after epicardial access. Cardiogenic shock. And bacterial, one instance of bacterial pericarditis after epicardial access. So this was the, this was the, this was the bacterial pericarditis after epicardial access. So this was the incidence of VT recurrence. And you see there's a quite high rate of recurrence at two and a half years. Interestingly, if you count the ICD shocks the patients received in the month prior ablation and the month after ablation, there was a significant decrease. And if you look at what predicted recurrence of VT or heart transplant or death, EF less than 50%. Those patients had worse outcomes. And presence of inflammation on the PET scan. Those patients had clearly worse outcomes. But even those without any inflammation had recurrence of VT heart transplant and death or heart transplant. So in summary, VT storm was eliminated in these patients in 82%. But I would caution that all these patients, they'll also undergo escalation of their antiarrhythmic drug therapy as well as immunosuppression. But we can't eliminate VT storm in 82% of these patients with intensive treatment, including ablation. ICD shocks were significantly reduced. And during the medium to 0.5 years of follow-up, 50% of patients experienced recurrence of VT or heart transplantation or death. So this is a high risk, poor outcome group of patients. You've got to be really careful with these patients. Monitor them closely. LD dysfunction and inflammation in pre-procedural FDG PET were significantly associated with adverse prognosis. So there is a role for ablation, which has to be appropriately timed and in conjunction with medical therapy. So approach to ventricular arrhythmias in patients with cardiac sarcoidosis has to be stepwise and tailored to the patient. Implanting with a fibrillator, remember these patients have a high likelihood of shocks. 30% of them get shocks. So we need to do more, not just implant with a fibrillator. Think about antiarrhythmic drugs. Amiodarone probably is the mainstay of therapy in these patients. Sorol as well, especially because they're relatively young, you don't want to keep them on amiodarone long-term. However, oftentimes I start with amiodarone to get the best result and maybe a year down the road or whenever their arrhythmia is quiet, we think about transitioning to Sorol. I would watch closely for liver toxicity because a lot of these patients, they can get liver sarcoid involvement, they can get toxicity from methotrexate and the combination of all these and amiodarone, they're more likely to get liver problems. You need to assess for inflammation. If inflammation is present, immunosuppression is the mainstay of therapy and antiarrhythmic drug and go to ablation only if necessary. If inflammation is not present, antiarrhythmic drugs and ablation. So see, I put ablation here in parentheses. It's more of an add-on or if you need to. Initial series reported monomorphic VT, high success rate, but I think those were patients with end-stage sarcoidosis and we may see fewer of those these days. So the role of ablation, clearly if they present with VT storm, if they have multiple episodes of VT that's refractory to antiarrhythmic drugs, if they have multiple ICD shocks, if possible, try to buy some time, try to allow time for immunosuppression to work if inflammation is present. And then, of course, you look for potential targets. You can have a focal VT, you can have focal PVC triggers, and if you ablate the PVC, the patient then can respond to therapy and everything. They don't have recurrent VT or VF. You can address if they have a circuit, protect the dissonance exit site, obviously map the substrate. Always remember to check for bundle branch or vesicular reentry because a lot of these patients do have bundle branch blocks and they have the substrate for bundle branch reentry and they have the septal infiltrates inflammation. And if you do, map the substrate, get MRI, see where the scar is located, consider combined epicardial and endocardial approach. A lot of them have septal substrates, so consider bipolar RF or visceral radiational asymptotectomy. Thank you. Let me know if you have any questions. That was great, Alex. Thanks so much. Maybe I could just ask you a couple things. I think we see a lot of patients who might've been treated elsewhere and then maybe our index of suspicion is higher, so we end up diagnosing sarcoid that hasn't been diagnosed for a while. For the trainees, maybe you could reiterate or just tell them where their index of suspicion should be highest, what types of cases they should be thinking about this diagnosis in. I think that's a very good question. I think it's being diagnosed a lot more these days with the readily available MRI and that scanning. Let me go back to my slides. When should we think about it? Anytime a patient presents with complete heart block, I'm wondering why is this patient having heart block? Sure, patient, 82-year-old or you think maybe age. You don't think sarcoidosis obviously is low on the list. You don't need to do extensive investigation. The other day, I think we had a 64-year-old patient with chronic kidney disease came with complete heart block. Well, she had extensive calcification on the aortic annulus, so no wonder she had heart block. If you have patients younger than 65 years of age that just show up with heart block, always consider what's causing it and consider doing a cardiac MRI. A lot of them had CAT scans. Do they have lymphadenopathy? Do they have sinus or other organ system involvement? Minimal screening in your mind. If a patient shows with ventricular tachycardia, there are some tachycardias for which we don't bother doing a lot of investigation, say if it's clearly awful tract, but although even there, if you have a RBC that's not diagnosed with CAREFUL, getting a family history, looking at all the data. But unexplained PT, that's not a clearly benign version, so weird morphology of PBCs or PT, think about the possibility. Presence of cardiomyopathy and heart block. I mean, it's not normal or common for ischemic cardiomyopathy or non-ischemic cardiomyopathy to have both. Same as heart block and ventricular arrhythmia. If you have a patient receive a pacemaker and now all of a sudden they have non-sustained PT or brief runs of VF or polymorphic VT, that's just not, you don't expect that in a patient with just the isolated heart block. So those are the main instances. If you find infiltrates on the cardiac MRI done for another reason, say, then you have to start investigating and see where is there a delayed enhancement? Is it inflammatory? Is there mediastinal lymphadenopathy? Are other organs involved? Can we biopsy it? Cardiac biopsy, low yield in our experience. We even tried to go voltage-guided LZ biopsy, RV biopsy, low yield. But extracardiac biopsy, high yield, especially bronchoscopy. Yeah, I was going to ask you about endomyocardial biopsy, so I'm glad you addressed that. And then you've done a lot of work, as you mentioned, this is kind of a multidisciplinary disease. And you've done a lot of work with pulmonary and optho and all these other folks who are involved in care. Can you talk about a little bit of all the screening that our patients get once they get a diagnosis of cardiac sarcoid? Sure, yeah. So, yeah, give me a second here. Yeah, so we do screen, they screen for symptoms, cardiac symptoms every visit and they do EKG every visit or at least once a year and some of them do initial 48-hour Holter monitor and then an echocardiogram. I think every patient with any extracardiac sarcoidosis should get an initial baseline. Can you see this? Is this on your screen? Yep. Should have initial echocardiogram at baseline and then the question is how often do you repeat and maybe repeat in one year and then just space it out. I would say just do it based on symptoms. So that's what they do.

arrhythmias

cardiac sarcoidosis

inflammatory disease

heart

pathophysiology

ventricular tachycardia

diagnostic tests

management

disease progression