Chapters Transcript Video Update in Medical Management in HCM Um you know, I would be focusing more uh on the medical management of patients with uh hypertrophic cardiomyopathy. There have been a lot of changes. Uh and we also go over, you know, some of the basics while uh you know, diagnosing these uh patients. So, um these are my disclosures, uh you know, by definition, hypertrophic cardio myopathy should be uh you know, presence of increased left ventricular wall thickness, which is not explained by any other loading conditions, meaning somebody having aortic stenosis or someone is having just uncontrolled hypertension there on 10 different blood pressure medicines, you know, so that's really not that secondary, right? So you should not have any systemic evidence. Why there is hypertrophy in the heart, right? Um And you know, and the presentation of these patients can be varied, right? Um Just like this guy, which doctor, yeah, he had presented, you know, he was like 23 year old, but having chest pains right and had a murmur and if nobody would have perceived uh the excellent work of that, our team did, we, he would have, you know, ignored this. And the worst scenario is some patients can present with sudden cardiac death, you know. Um so the presentation can be varied and uh it's a great masquerader. I mean, we have seen hypertrophic cardiomyopathy patients and they have been mislabeled as asthmatic, you know, we have seen patients for years. Someone has diagnosed them with murmur, they get sent for an echocardiogram and you don't find any valvular disease like what's going on, where is this murmur coming from? Right. Um But as the echo shows nothing, we just stop there, right? Uh some of these patients as again, uh we saw in the case they had systolic anterior motion of the mitral valve leading to mitral regurgitation. And you know, people become more focused on the mitral valve than the actual physiology. Why the mitral valve is kind of misbehaving. Many of these patients have arrhythmias and they are again mislabeled as anxiety disorder or having panic attack. We see this so many times. Um and another psychological condition like depression, right? Um It's very important when you're treating or evaluating a patient with hypertrophic my uh cardiomyopathy uh to rule out these mimics because it could be a disaster, uh ignoring their underlying um you know, pathophysiology. If you don't know if you miss a diagnosis of Amyloid or Fabris disease or uh you know, certain drug induced cardiomyopathies or just, you know, common conditions like thyroid disorders can cause left ventricular hypertrophy, right? And then there are storage disorders which can be uh treated and also uh not too mistaken, um you know, athletes, heart with hypertrophic cardeal apathy. So, uh as I said, sudden cardiac death can be uh one of the first manifestation of hypertrophic cardiomyopathy. And that's the importance of uh disease. And, you know, the major, you know, reliance we have is EKG and echo. I didn't see any show any EKG um they all get uh some sort of uh you know, testing and EKG and echo is the first step we do, right? Um What's important uh on the echo assessment is provocative testing, right? If you don't uh do provocative testing, you can miss hypertrophic ay and uh these, you know, echo findings you can see on the image on the right that if just you go by the resting images, the gradients were almost normal or non-existent. But as soon as the patient uh was made to do valsalva and all our echos do a great job kudos to them uh being more uh you know, focused on getting the diagnosis done for us, right? And you know, eyes won't see what mine doesn't know. So why uh to know the obstructive uh pathologies as you can see on the graph there years after gradient measurement, if you have no obstruction versus obstruction, uh there is an implication, right? There is a survival, right? Uh issue there, right? Um If you have hired the gradient verse is your survival and that's why we have to do everything to provoke these gradients. Right. Well, have a good 1015 2nd breath holding uh if that's not possible treadmill testing, you can do bike exercise or amyl nitrate, right. Um So, you know, at rest, around 25% of the patients would have uh lvot obstruction or gradient. And with all these provocative manures, you can see at least 70%. So you can miss so many patients if you don't do provocative manures. So that's important, right? So falsely, these patients may then get designated as non obstructive and they're not offered the treatment which we are gonna see. So if you won't find it, you're not gonna treat it right. So, very important to know that. And then also we have to consider alternative sites of uh obstruction. Right? Commonly we talk about left ventricle outflow tract obstruction, but many of these patients have a mid cavity obstruction, right. So, um it's very important to know that other uh you know, nuances are patient with uh atypical variants. There are patients who may not have LVH on echo, but they would just have a very bizarre looking papillary muscle or BFIT papillary muscle or a very displaced papillary muscle. And many of these patients, they can then have surgical restoration um of the papillary muscle or mitral valve and still can be treated. So, it's very important to recognize and keep these atypical variants in mind. So, just an historical perspective, you know, the condition was first diagnosed, uh, with Ron Wall, he had a 20 year old Canadian young kid with a murmur and at that time, there was no echo. You know, the EKG S were rudimentary, right? And this guy was very symptomatic. He kept passing out and Doctor Brown could hear a murmur and he sent him to the, or, um, and Doctor Morrow was the surgeon at that time and he opened the chest and he, uh you know, called Doctor Brown V immediately to the or, and uh he said you messed up and Doctor Brown was like, what's going on? What did I do? Like, you've told me to open the chest of 20 year old young kid. And at that time, the diagnosis was sub aortic membrane, right? Um And because they didn't know what this entity is and he was like, look, he the surgeon put his finger through the aortic valve, put another finger through the mitral valve and there is no obstruction. He said, you know, you messed up. And then five days later, you know, when doctor um Brown wall was like, still recovering from this mishap, uh there was another patient, same 25 year old with Synco B, same findings. And then that led to uh you know, they realized that these patients have very significant asymmetric hypertrophy. Uh And then that's kind of was the birth of septal myectomy. And um that's how the treatment uh of uh you know, HCM. Started and now we have latest guidelines, 2024 A H AC C guidelines uh recently uh come up in actually may of this year updating all the therapies. So uh you know what we have to know in LVOT obstruction and hypertrophic cardio myopathy is increased by preload. Uh uh sorry, it's decreased by pre uh the gradients are increased by decreased preload. So don't let this patient dry, right. Um You know, the gradients, they also, you know, when you have reduced afterload, the gradients increase and hyper conduct activity. So, tachyarrhythmias are bad, they cannot be dehydrated, right? And you cannot give medicines which uh you know, reduce their afterload and these gradients again, on opposite thing you do, the gradients are decreased, right? So that's why important to know if you have an obstructive uh patient with an obstructive physiology, avoid diuretics, avoid nitrates, right. Avoid ace inhibitors. A RBS hydrALAZINE cloNIDine processing, right? And not recently, yesterday, we had a cardiogenic shock alert from one of our sister hospitals where they called for patient to be put on ECMO. And when the team evaluated the patient, the hearts ejection fraction was normal. And then we looked at the echo patient had obstructive physiology and they were treated with exactly the wrong medicine. So, you know, these patients are not just seen as an outpatient, but they may come with an obstructive shock. Ok. Um So overall the landscape of hypertrophic ay, but it has been, you know, as we know, there is a Saric variant which leads to, you know, hypercontractility of the ventricle. There is diastole dysfunction, this progressive fibrosis of the muscle and then there are secondary effects from all that. So when you have LVOT obstruction, you, the recommendation is to start with beta blockers or nondihydropyridine calcium channel blockers like verapamil or dilTIAZem and then di isopro which is a class one, a antiarrhythmic agent. And if these things fail, you go for invasive septal reduction therapies, which are going to be covered by doctor summers and then all the arrhythmias are going to be covered by Dr Patel. And we have to just one thing I want to emphasize is these patients, if they have a FB, they need to be anticoagulated regardless of their chat vasco. So these are all the drug targets in the sarcoma for uh inpatient with hypertrophic ay. At the end, you can see all these agents at different, you know, sites uh of the sarcoma working. So this is the treatment algorithm, right? Patient who are symptomatic and they have obstructive physiology. You go with either beta blockers or verapamil beta blockers are the first choice treat uh you know, agents. Um The funny story is when Doctor Brown War was treated these patients, they're trying to figure out what to do. At the same time, Professor James Black, he got the Nobel Prize for invention of beta blockers. So it was the propranolol was the first beta blocker, which was invented and he gives few vials of propranolol to Dr Brown. And he used propranolol at that time in this, you know, so called sub obstructive uh aortic stenosis patient. And he realized that their gradients got better and he invasively studied those and that was the birth of beta blockers uh in these patients. And we are still using um selective beta blockers as the first agent. You know, um if these veins are intolerant to beta blockers, then you move to verapamil, right? If uh they are not uh tolerating verapamil or they still have gradients and are symptomatic, right? Um then you go to Isoyama and then if they still have refractory symptoms, then you move on to mechanical therapy. That's kind of the treatment algorithm we generally follow. And now we have direct myo inhibitor. That's meva, it's the first of its kind selective inhibitor of uh you know, cardiac myosin, it's an allosteric inhibitor and it reduces the uh hydrolysis of A TP. And as you know, in the relaxed state of myocardium is in diastole is the when heart uses the energy, right. So it improves myocardial energetics. The way I explained to you is, you know, in a normal heart, you have the acting and the myo filament, the acting filament is the red and the myo is the uh purple or violet. And you can see there are cross bridges between these two filaments um and you can see the rows there that's a very nicely arranged normal contractility and effective relaxation in a normal heart. In the middle of the cartoon. Here, you can see the acting and myo in filaments with um um you know, more increased cross bridging, right? So that's why there are these muscles are more thick and there is a mild fiber disarray and I compare it to these kayakers which are like there with their paddles facing all over the place and they're standing in a group there, right? So there's altered relaxation. There's impaired mechanics in hypertrophic cardam. What Mava Campton does is it reduces these acting myo in cross bridges. So the heart is more relaxed, right? And that's why you have less hypercontractility which you see uh in patients with hypertrophic cardio myopathy, very uh interesting that it stabilizes the myosin filaments in the resting state. It reduces the number of cross bridges and it spares energy, right? And it does not affect the myosin when it's bound to the acting. And that's why it has a lower potential to impact the diastole and it doesn't affect the contraction kinetics. And that's why there's a lower risk of systolic dysfunction. Although that's been um what we, you know, follow clinically, right? And it does not affect the calcium flux. So there's less risk of arrhythmias because every time we have a targeted agent, we always worry about arithmetic potential. Um and the trial which uh you know, led to the approval of this drug is the Explorer HCM study. It was the first of its kind uh study with this agent. It was placebo control, right. Um Patient had a screening phase, then they had a treatment phase and then um you know, post treatment phase follow right and baseline characters. If you can see these, all of these patients had their functional capacity, calculated they had some biomarkers and then majority of patients were nyh A class two. And these are their echo parameters showing significant uh gradients at rest and on exercise or on provocation. So the LVOT gradients and LVF over time, if you see in this patient, there is significant reduction of the LV gradients with mama. As you can see here, the reduction starts within 2 to 4 weeks and it's maintained. And you can also see that, you know, the ejection fraction is pretty much unchanged in these patients. Um So there is a FDA is closely monitoring this new drug, right. So there is a REMS program, uh risk evaluation and mitigation. So the provider has to be certified and enrolled in the REMS program. And uh once we provide education with the to the patient uh and share the information brochure you start uh therapy and then these patients are followed every four weeks with serial echoes biomarkers clinical evaluation. And then once they settle down with therapy, you titrate and there is a titration schema. As you can see in this figure, you start with 5 mg only if the ejection fraction is more than 55 per cent. And you see what happens at week four. If the gradients go down by less than 20 millimeters of mercury, you down titrate to 2.5 mg. And if the gradients remain about 20 you continue their 5 mg dose. Then at week eight, you do the same thing. If the gradients, they remain less than uh 20 you withhold the drug and return the therapy depending on their gradients. And during all these serial follow up echoes, you monitor their EFS. And that's why sometimes I see our echo text getting confused like oh what's going on? Patient is on treatment and suddenly the gradients are improving and now they're going up what's happening. Well, the protocol just for safety wants us to either reduce the dose or withhold the therapy. And that's why some of these patients you see that rebound increase in LD gradient, right? And the management continues according to the gradients and the ejection fraction. So they did another study known as valor SCM. And this uh study was actually was interesting because it allowed a combination therapy with different agents as opposed to explorer, which was only placebo control trial, right? And the interesting part about valor was the patient who were candidates for septal reduction therapy, right? So who can fail beta blocker or still symptomatic on beta blockers or calcium channel blockers. Those are the patients we go for septal reduction therapy, right? Those were the patients who were then randomized in valor at CM and their biomarkers were also followed. And again, this was the study design and what and the baseline characters was also the same. And what you can see is there was significant improvement um in uh in, in this patient's uh outcomes, right? Uh the NYH A class improved. Um the the uh the number of patients who were eligible for therapy for septal reduction at the end of the treatment, almost 75% of them that normalization of gradient, not needing septal reduction therapy. And even you go with the resting gradients uh with valsalva, you can see there was significant improvement and also favorable cardio mark. Um cardiac remodeling biomarkers like left atrial volume index um was also seen and biomarker reduction. So at the end of the trial completion, almost 95 per cent of patients, they continued uh you know, on the therapy and only five per cent of the patients of the 100 per cent who possibly were needing septal reduction benefited from the therapy. And that leads to inclusion of the drug in the guidelines where it was given designation. As you can see here. Class one where it says that for patients with obstructive HCM who are persistent symptoms from left vicar or obstruction despite beta blockers or non di hydrin calcium channel blocker, adding a Myosin inhibitor, you know, or Daisy in combination with a noodle blocking agents is indicated, right? Um So uh you know, so the therapy is changing right from beta blockers and calcium channel blocker, we are moving forward and these are the subtle differences between the European and our guidelines where we are really kept um septal reduction therapy mio in in meters at the same level as the isopro if they fail beta blockers and calcium channel blocker and now the new kid on the block. So as Meva Kampen was the first agent. Afic Campton is another allosteric inhibitor and works with similar uh pathway and uh not letting the uh hydrolysis of A TP. And the Redwood HCM trial was a trial which showed similar outcomes in these patients with LVOT gradients with biomarkers and you know, symptom improvement, right? And the Secure SDM trial also showed um improvement in patient derived uh functional uh symptoms, right? And all these studies have been published. So there are lot of new therapies uh available showing improvement in these patients. Um I'll just keep skipping through some of the slides for um you know, sake of time. But as you can see all these treatments are titrated. Afic Canton was also studied in non obstructive uh patients uh showing safety and feasibility uh and an improvement in NY A class and now gene therapy has been tried, right. So using Adenovirus vector, actually Cleveland Clinic did their first gene therapy for NY BC um uh mutation in hypertrophic cardio myopathy. So, the future is great. You know, we have two new drugs, we are working on gene editing gene therapy. Um And I cannot emphasize more on exercise in HTM patients. You know, diet and exercise is such an important part when we talk about cardiac care of these patients and they actually did a randomized trial where um they made patients to report their symptoms and let them exercise. And now we have data because traditionally we would tell these women like, oh, don't exercise, you know, and already these patients are symptomatic and we're making them couch potatoes, right? Uh, because you're worried about arrhythmias and whatnot. So, the live HCM study gave us that answer that it's safe, uh, to do exercise, whether it's vigorous or non vigorous. And the definition was like this, you know, um, at least one activity with Mets more than six for 60 hours per year. Right. And the moderate activity was between 4 to 6. Me. Right. That's how they categorize the activity. And, you know, that leads to a better recommendation for exercise in this, uh, patients in guidelines. So let's just do it, you know, let them do the exercise. Ok, don't stop them. And again, there are guidelines for what to do with athletes in this patient. It can be safe, but it just has to be monitored with the team. I know Dr Saris screens all the athletes in our area and it will be interesting to see his opinion on this. So overall, the current HCM trials are targeting what we call feel and function. Um We are not targeting trials with mortality uh yet. And you know, there's a lot of work ongoing. You know, the R DC trial is uh you know, evaluating Meva Campton in non obstructive at CM. The Cassia trial is using uh Afic Campton for non obstructive cases. Uh these long term effects of these medicines are being evaluated and as there were no head to head comparison between therapies, the Maple LCM trial is gonna try first time beta blockers and MYO inhibitors to see which therapy would be first line in this patient. So, um you know, overall, I think, um you know, HCM is very challenging and most common of the genetic disorders and we are having a lot of new therapies available now for our patients. So it's a great time uh to really for us to identify these patients and start them on appropriate therapy and I would stop here. Thank you. Published November 14, 2024 Created by Related Presenters Amit Badiye, M.D. Sentara Advanced Heart Failure Center View full profile
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