Dr. Amit Badiye discusses how Fabry disease can mimic hypertrophic cardiomyopathy as both are inherited disorders that can cause left ventricular hypertrophy (LVH).
So, uh as Doctor Hay said, you know, hypertrophic cardiomyopathy is like now in lime light, you know, limelight, we were so much focused on dilated cardiomyopathy and you know, L VA transplant. And then suddenly, now we are seeing a pandemic of uh not only he pe but also hypertrophic cardiomyopathy. You know, we all see LVH so commonly left ventricular hypertrophy seen almost 15 to 20% of the population, predominantly we diagnose it on echo and EKG, right. But then uh many of these patients, they don't just have LVH, but they do have hypertrophic cardio myopathy and which could be genetic, it could be from sarcomere mutations, it could be from infiltrative diseases. And as uh you know, again, Doctor Hari alluded that uh you know, with onset of an availability of myosin inhibitors is so important to diagnose these patients um correctly so that they can get the appropriate treatment because if you miss the diagnosis, it can be a disaster, right? And, and that's why I decided that, you know, to follow with my prior talk, which I gave in May about um hypertrophic cardiomyopathy. I just wanted to share some uh you know, insight on uh hypertrophic cardiomyopathy mimics conditions which may uh you know, mimic uh hypertrophic cardio myopathy, but may have some other etiologies. These are my disclosures. Nothing relevant here. I would like to start with the case. So this was a very nice uh uh 44 year old woman who presented to the cardiology clinic for further evaluation of chest pain. So she recently had an er visit with chest pain. It, it was crushing substernal pain, there was an exertional component to it. Um And you know, as soon as you come to the emergency room with chest pain, the first thing you get is troponin, right? So she got uh two sets of troponins. Her EKG was uh grossly abnormal. So the er attending was not very happy uh what to do with her and really got her schedule immediately with the cardiology clinic. Um There was no significant family history or past medical history mentioned which had any cardiac relevance. As you can see, this was her EKG uh pretty bizarre looking EKG deep uh symmetrical T wave inversions, predominantly in inferior and lateral leads, secondary S TT changes and you know, maybe a short pr interval. So uh you know, of course, he came to the, you know, uh clinic appointment and uh after further history, physical exam looking at the EKG, further evaluation was ordered with an echo. And as I see a lot of our echocardiography text here. Thank you for joining and as you can clearly see that there is no significant valvular disease, but there seems to be uh left vicar hypertrophy and it's predominantly located to the apex of the heart. So, um you know, with this, uh she was not advised any treatment, her blood pressure was normal. Uh she was told that maybe she can take some sublingual nitroglycerin. And uh you know, as she had persistent chest pain, she was sent for um you know, coronary angiogram. So who in the room here think that this coronary angiogram is normal? Do you see any blockages? So, yeah, I would not quiz you guys, but you know, Doctor Summers is here, he can clearly tell you that there is something in the left main uh in the proximal or ostium of the left main. Now, we don't know if this is catheter induced spasm or something else. Uh You can see the right coronary artery is normal, even the led uh as you can see, has relatively slow flow and really narrows down distally. So, uh she also had some palpitations when she came for her cat. And by finding these results that there was some something abnormal, her palpitations got even worse and for which an event monitor was ordered and it was negative for any significant arrhythmias. Further. This uh angiogram was also evaluated with Ivers and that left me in a him was not significant. Um So meanwhile, uh the cardiologist was very astute that's how we are at S CS. You know, we really uh want to thoroughly investigate our patients to wanna go to the root of it. So LVH on echo abnormal EKG what's going on to further evaluate this card of myopathy? The next appropriate step was to uh get an MRI on her as well. Um I'm not an imaging guy. If doctor soy is listening to this and all our new uh you know, imaging cardiologist, they can definitely tell from this MRI that there is no uh late gadolinium enhancement, but it's definitely a disproportionate hypertrophy of the papillary muscle as you can see in the first image. And again, you see uh some apical uh hypertrophy and some right vicar involvement as well. Well, all the investigations are done. She's been given nitrate, she didn't tolerate that. She got hypertensive, she was given ranolazine, um she got very dizzy with it. Uh Still not feeling well. So what do you do next? She keeps going to the er with chest pains. So in boards, the answer referred to a specialist is not the right answer, but here she was referred to the best team in center of cardiology and that's the A HF team. So, so, so she was like, I don't know what's going on with this lady. I mean, I have 20 patients in the clinic. I I can't, you know, uh here even monitor is normal. Her MRI just shows hypertrophic cardiomyopathy. Take care of her. Fine, great. So now she comes to um our office. Um So first thing we do whenever we see a patient with hypertrophic cardiomyopathy is like a really detailed family history, right? I cannot overemphasize how important it is to get a three generation family history. And then we kind of got bumped because she was like, oh, well, my grandfather was adopted, so we kind of stopped it, right. Um uh We still like, you know, trying to get some red flags here. Now, you know, if something else going on, you know, what are we missing there? Some vasculopathy. Uh the cat was, you know, not really normal, normal. Uh We can't ignore what we saw on that angiogram. Uh She was seen by two international cardiologists as well for that left knee stenosis. Uh and she was like, you know, I have a bilateral carpal tunnel uh syndrome. I have a lot of pain. I'm gonna see uh an orthopedic surgeon. She also had some tingling in the, you know, her toes and her fingers just you have some neuropathy. And also she was, she would uh and um you know, I always, any patient who comes to me with dizziness, uh no matter what vitals are given to me by my nurse, I always measure and check the blood pressure myself, make them stand and do my orthostatics myself. So she did have postal hypertension and then, you know, uh we were so engrossed with, you know, missing amyloid patient and we have an avalanche of amyloid. I was worried about um you know, infiltrated cardiomyopathy like amyloid and uh you know, as part of the work, uh we ordered a PYP scan on her and uh genetic testing for Amyloid and her P IP scan was positive, you know, uh as you can see her visual uptake score was too where uh the heart kinda looks similar um in intensity to the ribs. And um you know, it's a pretty sensitive test. So we started working on treating her for amyloid. Um and you know, it's a very expensive medicine. So uh we requested all the insurance authorization and all that and I would just like to show you a quick video here coming. My diagnosis is that he is suffering from the prostate trouble. Well, in my opinion, he's got uh hemorrhoids. Well, why don't we ask him? Yeah, I say, excuse me, we're both doctors and we've just been trying to ascertain your problem. Tell me, is it prostate? Which my colleague uh diagnosed or is it hemorrhoids, which I diagnosed? Which what I was right? You said prostate, you said you're wrong and you're wrong and I'm wrong cos I thought it was a fart sorry about the stink F so, so you know, it, it, it, it, it looks funny but you know, we are mocked around when we see this LVH patients. And you know, after seeing 8, 10 doctors, you know, finally someone diagnoses them either here or some other center or in some other doctor's office, something completely different, right? And they are like, hey, you know, by the way, this patient, you referred to me as XYZ. So to our surprise, you know, the genetic testing came back and she had mutation in the pathogenic mutation in GL a suggestive of Fabris disease. So, you know, looking back, you know, I mean, I, I just, you know, wanted to tell everybody that, you know, hypertrophic cardio, it is really a great masquerader clinically. These patients are uh you know, diagnosed with uh you know, exercise into asthma. Uh some of these patients, they have a murmur, uh those with obstructive disease, they uh you know, are diagnosed with mitral valve prolapse, you know, um many of these women, they go with palpitations and then they are just given a v uh basket diagnosis of like, you know, anxiety disorder, panic attack and, and they are sent home with some uh you know, an anti anxiety drugs and some of them have depression. Unfortunately, some patients, subgroup of patients, they come to us in extremist with cardiac arrest. So, you know, um it, it, it doesn't remain as funny anymore, right? Uh and, and that's why we have to know these HCM mimics like, you know, infiltrative cardiomyopathies like Amyloid fabrice disease. Just uh the case I uh uh you know, just showed you plaque P related cardiomyopathy also can present with uh you know, significant left ventricular hypertrophy, thyroid. And on, you know, on transplant side, we see extensive amount of patient with Prograf related hypertrophic cardiomyopathy. Predominantly, these patients have diffused at cm and again, uh sarcoidosis, other glycogen storage uh disorders than disease, hemochromatosis. Athlete's heart are one of the differentials with uh you know, hypertrophic cardy um just to quickly recap in athlete's heart and hypertrophic aom myopathy. The majority difference is, you know, the LV cavity will always be small in hypertrophic cardiomyopathy unless you're dealing with a burnt out hypertrophic cardio, right? And there's difference in the wall thickness. Um also uh you know, generally the athletic heart is concentric hypertrophy and it regresses as you stop exercising, right? And the diastology is normal. So whenever um you are, you guys are scanning all these hearts, make sure you focus on diastology, right? And if you're still, you know, not sure what's going on, take a few extra minutes and do uh specter tracking and strain imaging in these patients where it's normal in athletic heart, you know. So just kind of moving towards more towards Fabris disease. So, Fabri is a rare ex link inherited lysosomal storage disorder, which is caused by a deficiency of alpha galactose a activity. Ok. And as this enzyme is absent or activity is uh reduced. This accumulation of glory Ayam also known as GB three in the affected tissues, including heart and this infiltration is what you see on echo as left ventricular hypertrophy. So, 60% of this patient they present with either, you know, have puff or shortness of breath on exertion present with arrhythmias because of the infiltration or chest pain. Just like our patient presented, right. Generally happens or you know, expressed in men, more than 30 years of age, females are a little bit late onset after 40 around less than one person, males and 0.9 0.90% females with HCM have a GL a pathologic variant. So, you know, if you look at all the, you know, HCM patient, maybe one person would have something like this. And um I'll tell you why it's important. And, and in addition to this accumulation of um glycosphingolipid, you know, an inflammatory pathway is generated. And that's also uh has been kind of um involved in the path of physiology of this disease. And LVH is seen in almost 53% of males and more than 33% females after their third decade. Um Any race can be affected. So, just like Amyloid, it's not affected to certain um uh ethnicity with certain mutations. Um And we already said that it's an excellent and it leads to accumulation of this lysosomal uh GB three heart pods of the kidneys, vasculature, peripheral nervous system are predominantly involved including skin. Uh and there are now more than 1000 variants which have been uh you know, diagnosed and the incidence is, it looks rare, you know, one in 40,000 to 1 in 117,000. But if when the newborns are screened, uh the prevalence is like almost one in 9000, right? So that means by the time these women come to adulthood, we're missing them, we are missing their diagnosis. So it's important to have um you know, uh a keen focus, uh a high index of suspicion. Uh There are different variants which are prevalent in different parts of the world, especially in females. I wanted to highlight that, you know, as it's an excellent disease in um females have two X chromosomes. So one of the chromosome may get inactivated and that's why you may see heterogeneous presentation with different organs. If there are more pathogenic cells in the kidneys, these females will present with more proteinuria, more renal dysfunction. If there is more expression of these cells in the heart, they'll present with more cardiac symptoms. So that's why it's so important in uh females with fabric disease in med school learning about fabric. They're like, ah don't diagnose Fabri in female patients. You know, that's not true because there is moses is and they can have late onset Fabre and then if you ignore it right, you're not treating it, uh then they can have progression of the disease and, and organ dysfunction. Um So, you know, the pathophysiology is really uh as I alluded, you know, there is accumulation of this uh GB three, it goes into the myocyte, right. Um And then the it leads to the left ventricular hypertrophy uh leads to progressive diastolic dysfunction and he p uh uh kind of symptoms, right. If there is cell uh death from either from myocardial ischemia or just overwhelming the hypertrophic process, then you get into the phase of systolic dysfunction with progressive myocardial fibrosis. If the conduction tissue is involved, of course, patients will present with arrhythmias and conduction disturbances. They may end up needing pacemaker or IC DS or EP studies with ablation if they have any accessory pathway um at the cellular level, uh you know, uh the genetic defect leads to this, you know, abnormal accumulation of GB three in the lysosome. There is dysfunction of the gauge apparatus. The mitochondrial channelopathy occurs. This impaired energy production into the cell leads to cy comic dysfunction, dysfunction of the myocyte. Uh over all these proteins, this products, they are not able to be recycled and there is impaired autophagy. And then with, you know, a cellular infiltrate with natural killer cells leads to inflammation. So they are both physical and inflammatory pathway which leads to the pathophysiology. So what are the red flags we should be looking for, you know, trying to figure out whether our patient would have fabric or not. So um there could be a family history, very important, right? They are often present in young patient with cryptogenic stroke. Ok. In addition to heart failure and kidney failure, uh they may have G I symptoms, constipation or diarrhea, um neuropathic pain, um skin lesions like angiokeratoma, uh cornea vertica is finding you see in the eyes, many of these women, they don't sweat, you know. So there's failure uh to um uh of sweating and, and they are very exercise. Intolerant patients can have sudden hearing loss, you know, and of course, if they have proteinuria can have renal failure. And there is abnormal findings in the brain with SIA of the basilar artery. Uh on EKG, we have already seen LV eight signs of, you know, conduction disturbances A V blocks on echo. We already elucidated it on the, you know, abnormous uh uh longitudinal strain predominantly in the basal and inferolateral wall. Um They can have aortic si and dilatation and secondary aortic stenosis and thickening. Um And I also showed in our patient, uh hypertrophy of papillary muscle, you know. So you see these findings and you should start thinking as a clinician. Are we missing something? Uh is there a uh you know, infiltrative disease? And of course, MRI is very important in this patient can show late gin enhancement and low T scores. And this one also can have lymphoedema, right. So, just like in Amyloid, we classically tell bilateral carpal tunnel syndrome, you know, lumbar canal stenosis is this kind of symptoms are important in Amy uh in fab and this is just on youtube where, you know, early classic, you know, male, you know, they would have reduced sweating. They may, this childhood, early childhood would be um, you know, with significant, you know, limb pain, uh neuropathy like symptoms, they would have this rash, uh predominantly in the torso. They may have G I tracts and, you know, this may get diagnosed with anxiety and what not in school. They're, you know, uh uh quickly diagnosed and learning disability and all that, but they are really suffering with Fabre, you know, um and if you don't treat them, they of course have an organ damage and then the non classic or late on say they may not have the G I things, they may not have the burning and uh and HED, but they may have other symptoms related to the end organ damage they're already having, you know. Um So this is like um kind of a bull's eye picture where all this constellation of findings you act together. Uh You can establish a diagnosis of Fabri. Uh This is the slide eyes, you know, God uh from the web about cornea. Uh Vertica, also known as V Katy. This is the first eye finding. Uh you can get in patients with the fabric uh if you look carefully, um it's predominantly in the uh inferior body of the top image. If you see this whirling or swirling of, you know, um deposits in the cornea, you can see that in the slit uh image slit lamp exam, um they don't interfere with the vision. And that's why it can get unnoticed because they are predominantly inferior quadrant of the eye. As the cornea is developing from periphery to central, as you can see in the bottom image, it's like a linear shadow first. And then as the cornea develops, it becomes more curve uh curvilinear and gets like a word like pattern. So this is the first I sign if someone is giving boots, uh they may ask you this uh you know, question other conditions where this can happen is uh a round induced carnal deposits. Um The skin angiokeratoma, I wanted to show these pictures so that, you know, um you can see this and say like, oh is this patient with LVH has something else? These are just abnormal capillaries in the superficial part of the skin. Um And the dolichoectasia of the basilar artery. Uh There is the basilar artery seen as a dotted line. This patient presented with stroke, the MRI had very subtle um uh findings uh with white hyperintensities. But then when they did diffusion scan, the whole temporal lobe is gone. And that's the finding in this patient with, you know, uh Fabri in the brain where there was such a slowing of the blood flow in that abnormal basilar artery was patent, but it was like slow flow state, right. Um So these are some of the um you know, findings, you should kind of keep in mind dealing with this fabric patient. So how do you uh what's the flow chart for diagnosing this patient? So if you see a patient where this unexplained uh LVH have a high index of suspicion, right? Um males, they can just get screened with uh enzymatic uh you know, analysis, especially in kids. They do this dried blood spot test that gives you the diagnosis immediately. Um If they have extra cardiac red flags, um we already discussed males, you can quickly diagnose with the enzymatic activity in females. The as there is Cheer or Moses is you may, may not have a lower enzymatic activity. And that's why it's very important to do genetic analysis just like my patient, right? She had gotten blood test, someone was thinking about it, but the enzyme activity was normal. So it was like, oh you don't have fabric. That's a mistake in females. You have to do genetic analysis. Um And most importantly, MRI, in our patient, the MRI did not show a classic low T one score. Um but that's something which uh helps many centers now uh have MRI as one of the key uh tests to be done uh for finding uh you know, fabric disease. And again, I want to emphasize here that don't ignore the females with fabric disease, right? They are just not carriers, right? They have a very high occurrence of serious complication, right? Uh than females in general population. They have a 11% risk of having end stage renal disease, four times higher risk of having stroke, seven times, uh you know, brain vessel damage and two times um damage to the heart, you know, chamber or LVX, right. Um And 70% of the females are symptomatic, right? They have diarrhea, nerve pain, proteinuria or abdominal pain. So, uh don't ignore that. And these are really the proposed stages of cardiac involvement in February because we need to catch them early, right? If you wait too long, then you would be dealing with advanced cardiomyopathy where they have heart failure. The EF is down, you know, uh the MRI shows uh extensive scarring and gio line enhancement with myocardial thinning an extremely high. Um you know, ant pro B and B level, if we can catch them in the middle stage, you know, early diagnosis. Uh you may see myocardial dysfunction with spec tracking, right. Um You will see LVH have findings, there will be low T one score on the MRI and the troponin T will be uh high and the BNP will be elevated but not as significantly that you see in the late stages. Uh and then it all starts with, you know, uh cell dysfunction and cell damage before you start seeing these uh you know, findings and the reason to know this is, you know, patients who get started on enzyme replacement, you can really slow down the progress of the disease. So there is treatment available just like amyloid, right? They would say like, oh, forget about amyloid. You will see one patient in your lifetime and forget about it. Now we are seeing 2 to 7 patients of amyloid every week because now we are looking for them, right? There's treatment available when Tai started, right? Uh uh Tower started. We were like, oh my God, you guys are crazy. You are putting valves in 90 year olds look how to feel as advanced. Now we see a tower patient and we're like, oh it's routine five years ago, 10 years ago, Mitra clip, oh my God, who is going to do this? I mean, you still have residual Mr we were not even looking at Mr now every time even the hospitalist in his mi regurgitation, the goes to the structural heart disease, right? The awareness is more because now we know that there is hope for this patient. There is a treatment and now saying giving the same example Truss clips, right? Every patient we see now has tr for regurgitation, right? Doctor Summer's team is doing a great job clipping this patient giving them hope because this patient would end up with, you know, um cardio hepatic syndrome, cirrhosis and you know end up dying with multiple para and test that same emphasis I want to give here on this kind of infiltrated cardiomyopathies there treatment available. You have to make sure that they will lead to the diagnosis. So MRI is the cornerstone in the diagnosis. Why? Because in early stages, you know, on T one mapping there is a low score. Uh this may, may not have LVH, they generally don't have late galina enhancement. As the disease progresses, the T one score remains low and now you will start seeing LVH on MRI, you will see subtle inferolateral, uh you know, late casual enhancement and then in later stages, you know, and the T one score actually starts rising because now you have more fibrosis and whatnot and you continue to have inferolateral clinic. So the extracellular volume in this patient is normal, right, as opposed to uh you know, patient with amyloid. So that's the way you differentiate amyloid from fabric, uh you know, on MRI. And these are just the images of uh MRI where you can see that green circle is that low T one scoring. Um And as the stages progress, you can see classic scarring on the lateral wall of this ventricle. Um And you can see that the LVH is more common in men than in women, right? So, um and this is just a schematic, just wanted to show how the team relaxation times are calculated so that you can an MRI figure out like, oh my God, it's close to 800 it's probably fibres uh around 1000 it's hypertrophic and then a high score is probably a dose. Um And maybe our imaging guys can give a lecture. This is a patient 54 year old with chest pain and no red flags. She has the N 21 5 S variant and you can see pretty diffuse uh symmetric T wave inversion. Our echo had uh apical hypertrophy and you can see on tissue Doppler velocities are uh are reduced and the TV scoring is in the 5850 range rather than normal around 900. Um You know, there is another uh patient with classic disease where you can see disease progression. Uh First EKG there a re some T wave inversion. There is LVH follow up after several years, the T wave inversions, a re deepening baseline MRI. You know, we there is no late gasoline enhancement and now you will start seeing gasoline enhancement and scarring on the subsequent MRI in the bottom slides. Um So where do we go with the treatment of uh Fabris disease? You know. So the treatment right now, there are two FDA approved treatments which are available. One is the enzyme replacement therapy. Uh And uh the second is uh chaperone therapy. Uh Also uh the drug is known as megastar. All right. So how uh the enzyme therapy is very easy, you just replace the enzyme which is missing and it does what it's supposed to do in chaperon therapy. There are enzymes which are misfolded that are dysfunctional, these molecules. They actually attach to this misfolded enzyme make it fold correctly and then suddenly the enzyme becomes active and it starts doing what it's supposed to do. Um Other experimental therapies are also, you know, gene therapies and both in vivo and ex vivo. Um we are working on this. So focus on the enzyme therapy. There are two molecules which are available. Uh It's administered twice weekly. Ok. Biweekly. Um and it's intravenous, it's indicated in symptomatic patient, asymptomatic patient. There is no data. OK. Um And it's really has changed the natural history of this patient. It has improved their quality of life. You know, the neuropathy gets better, uh their exercise tolerance gets better, the G I symptoms, uh you know, improve and more importantly, uh you know, prevents their and delays cardiac disease progression. Um and also prevents LVH by early treatment. In some cases. There's also data that the LVH regresses on enzyme therapy. Of course, if you can catch them too late, they are poor responders with the chaperone therapy or migalastat. It's approved only in adults, not for the kids. Uh It's an oral formulation every other day. It's a very interesting dose 1 23 mg. Um but the cool thing about this is it's only for amenable GL A variants, meaning if there is an enzyme activity of less than 3% and if you can increase it by 20% in vitro outside the body in cultured lymphocytes, those patients are only, you know, eligible for this treatment. So if in vitro activity is not there, you cannot offer this oral therapy to the patient. So, so, um you know, it's, it's uh it, it gets really complicated um when it comes to that and I'll tell you why the, these are again, the agents, the uh ala said alpha and beta are the ones we just talked about. And the mega start, what are the advantages and limitations of the hormone or enzyme replacement therapy? A lot of evidence, you can really get the GB three levels down. Uh There is a long clinical experience since 2001. The problem is, you know, the revision uh or reversion of the pathology is not complete. You can get some regulation of LVH or maybe you can halt it but you can't normalize the heart rate. There is no cure for Fabri yet. Um there is limited tissue penetration. You know why you don't get complete regression in the heart? Probably because the enzyme gets denatured by the time it reaches the heart, right? And you cannot uh give a higher dose because there is anaphylactic uh reaction in around less than 5% of patients who get this um you know, um enzyme I va patient also form anti-drug antibodies. So within six months, you start developing antibodies to these immunoglobulins and progressively the drug can become ineffective. Um So, you know, it really needs a center of excellence to follow these patients. So that they can do all these expensive therapies and monitor these patients. You know, the first step is at least we can diagnose them correctly, right. And as you know, this is lifelong therapy and it has high cost with migalastat. Although they try to figure out which patients are gonna be responders in vitro, when they actually started giving the drug, they figured out that every patient had a different reaction, meaning some would respond, some would not respond. So what they have seen on the bench studies in the lymphocytes may not reflect clinically. So it can be a flip of coin with such an expensive medicine uh to give this uh oral therapy and it may not work. And again, there is a high cost. Um so that's why there are new therapies are under um you know, consideration, there are two other enzyme replacement therapies which are going through trials. They are both plant based. Um one is actually manufactured in tobacco plant cells and other one in moss, they are also substrate reducing therapies, wesat and lera stat and they are all going clinical trials including RN and gene therapies. So, you know, in conclusion, there is a lot to know about these LVH patients. They may not be just LVH, they could be right, genetic hypertrophic cardy, they may have infiltrative disease. So, having a systematic approach towards these patients with LVH or hypertrophic cardy is very important and it's very important to think about etc M mimics, you know, Fabris disease is a very important differential. I think we're missing a lot of these. And as there is treatment available, early diagnosis is very crucial. You know, it's very important to remember other mimics like athlete's heart amyloidosis, sarcoidosis, pla penny cardam and hemochromatosis. When you are dealing with an this patient with hypertrophic and I would stop here and uh wait for any questions you guys have. Thank you.