this program is brought to you by Emory University good morning everybody happy Friday morning welcome to another edition of Friday fellows conference our speaker this morning is Dr omed babani mad who uh first year fellow in the clinical track uh did medical school Northeast Ohio Medical University then did hisy here at Emory he going to talk to you about a very exciting topic today uh hypertrophic card opathy take it away Omen hey everyone Omid here uh thanks for coming today hypertropic cardiomyopathy been a h Hot Topic in the literature recently as you all know uh we'll start with some foundational stuff and try to talk about some recent trial data that's come out uh in the past few weeks actually so without further Ado let's get started so obviously no disclosures learning objectives today include the presentation pathophys phology and complications of HCM or hypertrophic cardiomyopathy we'll talk about Diagnostics and Therapeutics and uh obviously we'll talk about some of the trials definition it's uh you know actually it's a term coined by the World Health Organization hypertrophic cardiomyopathy um and the definition is hypertrophy um more than 15 mm or 1.5 CM without any other identifiable cause other causes include hypertension aortic stenosis some of these genetic diseases that you see there including infiltrative disease as well um other synonyms that HCM can be uh seen in the literature as include Hokum MSS and IHSS um Hokum is still interchangeably used with HCM as you may have seen but other ones are kind of like fading away prevalence wise most common you it's the most common genetic cardiovascular disease and it's also the most common cause of s and cardiac death um they've noticed that 70% of HCM patients also have lvot gradients uh greater than 30 millim of mercury at rest or with exercise or both so how do we classify HCM we can break it down into three kind of classifications here as you see on the figure on the right non-obstructive obstructive and latent obstructive non obstructive obviously we're not seeing gradients greater than 30 obstructive we're seeing resting gradients greater than 30 and then the latent obstruct we're seeing normal resting gradients but actually elevated exercise gradients or provocative uh gradients greater than 30 on exertion and then we have different phenotypes too um some of you uh may have seen apical hypertrophy uh HCM noted as Yamaguchi disease um but you can also see sigmo sepal disease reverse sepal Contour disease and neutral uh uh disease as well and you can see kind of the figure the differences in those phenotypes based on where the hypertrophy exactly is so in terms of pathophysiology uh you know buzzword is systolic anterior motion of the uh mital anterior leaflet uh this is pushed toward the ventricular septum ins cly can play a video here kind of visualize that uh this uh causes the LV to generate a higher pressure to compensate against this uh Dynamic obstruction and sometimes because of the difference in the pressure press gradient through that obstruction you decrease the pressure that's distal to the obstruction but proximal to the AV valve leading to a decreased pressure required to open the AV valve so you have premature closure of the AV valve um Dynamic obstruction is correlated directly to contractility and it's inversely correlated with your preload so it's really important to keep these variables in mind when we're thinking about Therapeutics and Diagnostics and so if you have less preload you'll have more obstruction due to less separation from the septum and the mital uh leaflet this decreases your lvot kind of outflow tract and then thus increases your gradient based on the ber equation and so this is notably different than fix obstructions I aortic stenosis or sub aortic stenosis this is a nice figure I really appreciated um it's talking about mechanisms in obstructive hypertrophy uh HCM sorry uh where you can have mitro regurgitation due to the Sam uh that can be caused by elongated mitro leaflets this can lead to subsequent cardiac hypertrophy papillary muscle abnormalities uh this can obviously lead to a consequence and and cascade of all these other effects as we can see lvot obstruction which can then lead to myocardial esia due to reduced coronary flow reserve and consequential pulmonary hypertension PBR is increased then over time you might develop some fibrosis and from fibrosis you might develop chronotropic incompetence and obviously you'll have diastolic dysfunction stiffness and left atrial enlargement and a lot of this is thought to be due to small vessel microvascular disease we'll talk about that a little bit later and here we have the histological breakdown of HCM and it's looking into the myocardial myocytes here you can see hypertrophy the cells are getting really bigger here they're getting really disorganized here we have the actual myosite right here and over here where the say this is all fibrosis that's over time building up which can lead to a lot of thick layer of endom cardiio fibrosis as you can see in this good slide here and so with all these bizarre Mite shapes and expanding collagen Matrix it was deduced that the scarring is from intramural coronary arterial dysplasia uh that uh has consequential effects over time leading to all this fibrosis symptoms the most common actually most common symptom is asymptomatic a lot of people have underlying disease and don't even realize they have it um but the actual most common symptom is dmia on exertion you can also have chest pain with exertion uh pre Syncopy or actual Syncopy palpitations obviously and most of these are all uh exacerbated by provocation so you can have worsening of that um notably if you eat you can increase you know the vasil dilation and your splint gut this will obviously decrease svr and that's kind of like a pseudo provocation of all these symptoms as well clinical course of HCM is important um 23% do have a normal life but you can develop heart failure and aib and these are increased um mortality risk factors for HCM um and this is important because you know over time the risk for sudden cardiac death does increase um annual mortality for HTM is 1% on physical exam uh we have a couple things we can actually look for uh obviously a systolic murmur in the left upper sternal border this can be due to lvot obstruction or Mr from the Sam that we're seeing in the Echo uh this obviously increases with provocation including Val Salva uh notably on the right you'll see a spike and Dome pulse here this is a bis fenis pulse where you can have a Brisk corate upstroke due to a lack of uh initial obstruction early syy and then the lvot obstruction comes into place and so you have a dampening of that waveform and then the syy progresses the obstruction is overcome uh from the ventu effect where it sucks in to cause the obstruction and the secondary rise and LV pressure overcomes this obstruction uh so you have kind of this Dome shape to as it overcomes this obstruction uh this is in contrast fixed aortic stenosis which is a fixed obstruction or parvis atart as you might see in this waveform where you have kind of like a delayed fix and delayed uh return back to U the downstroke in addition you can uh palpate the PMI and uh sometimes you can feel the the bifid waveform when you palpate the PMI obviously the PMI because of all the hypertrophy will be sustained and forceful so you can sometimes palpate that as well in terms of Diagnostics we have a lot of uh multimodality Imaging we can use uh we always start with serum markers BNP is is a you know hot biomarker to use in all these clal trials we're about to review in terms of EKG you obviously see LBH due to all that hypertrophy from the meiocytes you can see pseudo infar pattern from the repolarization abnormalities in addition to Chronic findings of left atrial enlargement and aips second great to that on Echo obviously you want a thickness of greater than 15 millimeters you might see hyper dnamic uh EF Sam as we mentioned before Mr secondary to that Sam and that premature closure of the normal uh normal structure of the AV valve which we mentioned before previously they used to use provocative testing with Amo nitrate but apparently that's died off we usually just do exercise Echoes um and another interesting fact on Echo if you have this e e Prime greater than 15 it is a predictive indicator for studying cardiac death on cardiac MRI it's useful because we can evaluate for apical hypertrophy U papillary muscle involvement and ruling out infiltrative disease genetic diseases as well with cath um they actually don't have much coronary disease often but you can see thicken vessels from all that collagen that position we reviewed earlier and if you do a vram you might see cavity obliteration and hypodynamic uh left ventricle you can actually measure the gradients obviously on cath as well and the way they do it you put the catheter and LV and catheter um in the aorta is probably the most accurate way to do it so that you're not transposing the AV valve and causing sort of like a open defect as you measure the two gradients um but sometimes you can just go into the LV and then just pull back and get that gradient as well is probably the easier way to do it um and then the famous brocken bro bronald Moro sign where as you can see on this image on the right if you stimulate a PBC by you know irritating the muscle you'll have a decrease in your stroke volume which leads to an increase of your gradient here and we'll talk about this afterwards excuse me genetics Wise It's autosomal dominant with variable penetrants um 27 plus genes and that's a little bit older data I'm sure there's more genes now have been identified in HCM and most of these code for myosin actin and troponin components uh these are the most common genes and this is the myosin head this is the myosin binding protein this is the troponin n and this is the Tron and I and so uh people who are negative permutations are usually age greater than 50 in the setting of hcn so how do we screen for these people um you know obviously we use a basic EKG and Echo we'll look for first-degree relatives of HCM uh it can start as early as h12 uh people can have early onset of HCM and people who do have early ons we like to screen them very much more frequently and then once they reach early adult kind of space it out in terms of medical management this is where all the money is uh beta blockers are usually considered first line you can alternatively use calcium channel blockers non dihydro purine calcium channel blockers um in addition disopyramide is kind of like second or third line here um not as frequently used but it is reached for often and then if you have someone in the ICU who's you know now responding to uh you know for whatever reason they're hypotensive you actually want to reach for Ivy phenol afrine uh so that you don't have the inotropic effect of other oppressors um on the on heart in terms of septo my or sorry this should say myomectomy um this is for people who are uh symptomatic and refractory to to all those medicines and here you'll see they'll go through the trans aortic surgical approach and they'll uh look for the proximal symptom right here and they'll make a Nick here and here as you'll see and slowly resect that away and it's considered definitive treatment because you're obviously removing this obstruction um as we mentioned these are uh symptomatic and Pat uh sorry symptomatic patients who are refractory to medical management or you're asymptomatic in a younger age population and your gradient is severely High greater than or equal to 75 millimeters of mercury there's a high success rate with uh septo myomectomy uh you reduce these lv2 gradients that's what's the whole point of this and in addition it reduces any pre-existing Mr it's durable longterm and has a low operative mortality survival is pretty good um but they haven't actually uh it there's one study that says it's better than doing U treating obstructive hypertropic cardiopathy without myomectomy but this was only one study in mayo and other studies haven't been able to demonstrate that pretty well um what's interesting is you'll get a left bundle 93% of the time and it was one statistic recorded So if you have a right bundle as well you have to be thinking about a pacemaker as well so uh most of these people uh might have to come out with an additional uh procedure percutaneous alcohol sepal oblation is another procedure for people who aren't surgical candidates uh as we mentioned they have to be symptomatic and refractory to medical management uh it's considered you know it's debated that it's less effective than uh myomectomy um but it is deemed beneficial if the lvot obstruction is due to combination of the thick and septum and the mitro leafl touching the septum um ideally some places look for a septum that's between 1.8 to 2.5 cm if it's greater than it's not very successful if it's less than that it's thought to be only due to a mitro leaflet issue and that way the alcohol sepal oblation is actually a contra indication uh it's steamed durable and also has a low operative mortality but it has a lot more side effects you have to be mindful of and so the PPM rate is a little bit higher as well um this was a nice chart that actually compar the two this is in the HDM guidelines from 2020 you can see similar mortality both have complications but this one has a higher rate of heart block heart block um but the rest are uh relatively the same um they do mention that myomectomy does lead to more lb gradient reduction and less complications it's preferred if you have other concominant surgeries this is a nice figure that shows the alcohol oblation you want get the catheter into the sepal artery and then you inject ethanol and it's usually 1.5 to 2.5 milliliters um as the mentioned here there's a lot more uh complications but they have comparable mortality rates another debate was whether PPM therapy can help HCM physiology and the theory behind that was if you initiate the RV Apex and the distal septum contraction first you can probably get a stronger uh uh Force generated to overcome that obstruction before it becomes an issue due to the vent ventu effect so uh the thought was this would decrease the gradient and improve symptoms but it's actually failed in randomized control trials so it's not really pursued that often as a primary intervention endocarditis prophylaxis uh was an older top uh older topic that people would actually give routine antibioprophylaxis for uh hypertrophic cardiomyopathy um but there was recently A reversal by the ACC and aha um that was a little bit controversial because they had said that we don't need to do that anymore without presenting any new clinical data that was convincing to uh make that switch and so some uh other institutions might actually recommend giving antibiotic prophylaxis uh whenever you think of HCM you think of sudden cardiac death as well should be mindful of that and younger patients it's usually during exerion when this happens their incidence is less than 1% per year risk factors uh they've Den noted that obviously you have to have these HCM characteristics as we mentioned before nsvt is a risk factor people who have decrease or similarity in their blood pressures with exercise as a risk factor uh same could be obviously you know a red flag family history as well on CTIC MRI you might see Lake galium enhancements indicating fibrosis that's also a risk factor indic apical aneurysm is usually a secondary consequence of long-term HCM that's also a risk factor as well if you have HCM with with he ref your uh risk of the mortality goes up as well terms of primary prevention of how it can screen for sudden cardiac death uh halters are usually reached for um 88% of people with HCM uh who have a halter have PVCs so it's a very high rate and those uh with PVCs have non-sustained VT with 30 or 31% so having nsvt has a very high negative predictive value for uh sudden cardiac death um but a very low positive predictive value so absence is reassuring and the presence is non-specific they've done EP studies to try to you know delineate how much burden someone has and it's not predictive in s for certain cardiac death um and there's uh you know whole algorithms on whether to consider icds for prevention of serent cardiac death uh as primary prophylaxis and secondary prophylaxis and over here you can see as secondary prophylaxis obviously if you survive it's a class one indication and people do have an 11% fire rate after that incident but in terms of primary prophylaxis you know it's a class 2B recommendation um but people do have fire rates even though that's very low they've also built an ICD registry of uh hypertrophic cardiomyopathy and they looked at how many shocks people are having per year and 3 3.6% of that population of 56 patients um in terms of icds that were placed for primary prophylaxis and people had placed icds uh for primary prophylaxis when they had one of these risk factors over here and so some argue that if you have one of these risk factors uh that could warrant ICD placement if you go look in the guidelines it's very niii on how you should consider ICD uh placement as Prof as Primary profilaxis in terms of Athletics obviously this is a concern you're putting uh potential HCM patients in a situation where they're provocating their um lb gradients to the threshold that becomes dangerous and so it's deemed that lowlevel exercise is generally okay but with strenuous exercise such as competitive Sports you have to be a little bit more mindful but obviously you need uh you know a case-by casee basis this needs shared decision- making between the heart team and the patient um obviously people want to succeed with their careers if they're in competitive Sports so they have to be mindful of their health as well as their career so it's it's a tough decision to make uh notably some of you may know H Gathers he was uh very famous in the80s uh when he was in college he transferred from USC to lyola and uh he was going up for an alley dunk against the Portland Pilots when he you know succeeded the dunk of course but then he collapsed and uh this was in the setting of you know cardiologists repeatedly telling him you need to take your medicine and he was giving off the impression that he was taking it but there was some concern about non-compliance um and as you can see he was a very successful person and leading and the NCA scoring and rebounding and he unfortunately passed away right one yard away from this guy if you don't know him that's the Miami Heat coach Eric spola so you can tell he's very concerned when that happened um but you know obviously it's a serious matter and and sudden cardiac death you try to optimize people but um compliance is always a question mark and so it's important during the shared decision-making you stress the importance of uh medication adherence and the severity of the situation even though they feel like they might be okay and their career is more important um Asal fibrillation is a a significant risk factor for HCM it's thought to be um the most prevalent rhythm in HCM with a very high incidence uh it's important because uh if you remember you're preload dependent uh with HCM so losing that H kick is is not helpful in that situation and so you do have lower survival rates when you do have aib uh coinciding with HCM when compared a sinus rhythm um they've also looked uh when you think of aib they you think of stroke and they've looked at people with HCM who did have stroke it was only a 6% incident but most of those 6% had aib so needs to be mindful of apib and and the elevated risk in these patients and so if what to do about it you want to cardiovert these people you want to attain Rhythm control um it's it's very makes a significant difference um additionally in in up destructive hyper uh HCM you want to avoid dejin due to the positive inotropic effect but it's actually okay in um non-obstructive hypertrophic cardiomyopathy so always be mindful that when you're us reaching for toxin what sort of physiology the patient has um additionally if you can achieve uh you know uh Rhythm control with anti rhythmics you can reach for ablation or surgical procedures as well HCM and pregnancy is always a question mark and people wonder if the physiology you know is is compatible with fetal life and and usually people do fine can deliver vaginal even um with low morbidity mortality so it's it's uh obviously is a concern with complications uh you know with maternity and and Fetal complications but you know overall they do pretty they do pretty good um uh overall the course of the pregnancy um what you want to do is encourage po hydration because of the preload and then you have more increased demand for the uh fetus so uh you want to make sure those intravascular volumes are plump uh in addition if you're using medical therapy you want to be mindful at feet of braa cardia when you're putting them on beta blockers um or Rhythm control at the same time um and then there's a debate uh initially years ago with sympathetic blockade when you give spinal anesthesia that this would cause a loss of Venus return from the lower extremities and and and have issues with your physiology and and unfortunately that would didn't panic out there have been multiple success stories obviously people have done fine and and it's continuing to be administered without issue so we talked a lot about obstructive hypertrophy uh sorry I keep saying hypertrophy it's HCM hypertrophic cardiomyopathy uh some of these acronyms are used interchangeably here and the criteria is you want to have the LV thickness of course and the absence of other ideologies but your gradient is less than 30 30% of HCM have uh they don't have this gradient of greater than 30 so uh it's it's pretty significant uh proportion of these patients with hypertropic cardiopathy that don't have obstruction uh what you want to do is exercise Echo to evaluate for Laten obstruction where you have a normal gradient at rest but it might be provocated with exertion um exercise Echo is preferred over like dobutamine Echoes just because you you want to look at the patient's functional status and symptoms uh so it's it's important to look for late and obstruction in that manner treatment is a little bit more difficult and and you know we reach for beta blockers because this decreases heart rate decreases contractility calcium channs improve diastolic dysfunction and so um you know it it's mindful to be thinking about these variables uh when treatment is difficult to see how you can modify uh patients physiology when they're non-obstructive ideologies and 5% of patients with non-obstructive hypertrophic cardiomyopathy um the LV may burn out over time and least heart failure as we mentioned that is a risk factor when you have both heart failure and HCM for sudden cardiac death and so uh you know beta blockers have been very popular they're they're you know uh deemed first line for hypertropic cardiomyopathy uh the most recent trial I could find on data blocker therapy in obstructive hypertrophic cardiomyopathy was 2021 the tempo trial where they compared uh Placebo with two weeks of mopol treatment and their goals were to uh obtain these objectives here um and over and you know let's go through the inclusion criteria first before each jump J to it there's uh HCM patients basically who meet all all our criteria including all symptomatic classes of nyha and they're all adults um exclusion criteria included people who basically had very severe uh Advanced HDM physiology requiring interventions or had arhythmia issues and limitations from the study include like a small sample size it was a crossover study and a long-ter ethicacy because it was 14 days is unclear but you can see here the lvot gradients at rest exercise post exercise all went from you know 60 or 75 plus to less than 50 some even going to the 25 range um Val Sala notably did not go down with uh below the threshold here so it's interesting to know but you know this is the patient's functional status and this is what we want to be reducing so they did a good job demonstrating that they also demonstrated you know the subjectivity of these symptomatic classes does improve your class 3es came became more class 2os your class 2os became class ones so that's important you the whole point is to improve the patient's quality of life and their Canadian CCS scores also incre uh improve the same manner and they also use this uh subjective um uh score UHA Kansas City uh questionnaire to show that there is a significant difference between Placebo andoral and improving symptoms over here is there uh all their outcomes data in one table um interestingly you know the biomarkers here we'll see uh most these studies uh will measure these two biomarkers in this study we did see a lowering of uh you know chronically elevated tronent we didn't see any decrease in the B&P so it's important to be mindful of that as we go through the rest of the studies in addition the EF was not really affected that much unless you using an alpha of 10% for your significance value um as you can see here not much difference so and this is important as well as we go through the rest of those studies next study we'll talk about uh is going to be surrounding mavic Campton and the brand name is chos or chos however you want to pronounce it and the mechanism of action for mavi Campton it it's allosteric inhibitor of the myosin atpa and preventing ATP hydrolysis but also has some other um um you know effects on the rest of the uh mil and aced cross bridging uh uh cycle um that are also uh noted in the literature um and so over here this is a gray picture showing that um the the thought is that mavi Campton by inhibiting that you're decreasing the number of myin actin bound Bridges and so if you're decreasing that you're theoretically decreasing your hypercontractility leading to improved compliance and energetics um and in HCM which is uh what we're aiming to do as a direct modulating uh therapeutic and this has been a big deal recently because uh a lot of money has being put behind it due to a lot of reassuring data that this this seems like a a therapeutic that can have a tremendous effect on HCM patients um and they they paid 13 billion do to buy out the smaller company that initially uh found this strug they think it's a significant growth driver in the medium to long term and that they can expand the use of mavic Hampton Beyond obstructive HCM and so they they're so convinced that they had two other candidates they're investing in those too so there's a lot of new drugs that they're they're putting money into that they think will uh change this whole field of HCM um um Therapeutics this is kind of like the mavic campon pharmaceutical card I thought it was interesting uh it's uh important to note that it's extensively metabolized in the liver and that you have all these sip interactions and a very long halflife to be mindful of um after it's metabolized it gets excreted in the urine and one of the biggest side effects we want to be mindful of with MAV Campton is this decrease in lvef um to less than 50% uh we'll see later that it is reversible but it's it's something to be mindful of when you're selecting patients to consider for mavic campon you want to make sure they have at least a normal EF otherwise you could be causing exacerbations uh by initiating M campon this is a road map that uh Dr billan and I worked on together it kind of denotes that you know you have genotypes that can predispose you to primary physiological changes where you're asymptomatic uh and these genotypes can you know uh hopefully in the future be modified with genetic therapies but over time you'll have secondary remodeling of this primary physiological changes that lead to all these things we discussed earlier in this lecture and so these myin modulators namely mavic Hampton and and more more recently afy Campton um you know thought to inhibit the mein act in Cross bridging cycle is is becoming kind of like this movement to get it initiated really early in this primary physiological change uh phase um uh while also also considering these other therapies and in our Arsenal and so one of the landmark studies behind mavic Hampton was this phase three trial in 2020 Explorer HCM and so the inclusion criteria included obstructive hypertrophic card cardiomyopathy with people with ef of greater than or equal to 55% and notably nyha Class 2 and three but not four um patients and they excluded people again with more advanced disease they're hoping to get people in the reversible phas of HCM and their methods basically split people into two groups uh one with Placebo one with mavic Hampton I started at 5 milligrams and they went higher and the way they did that is they measured the plasma concentration of mavic Campton they wanted to get the actual absorb the rate to be between 350 to 700 micrograms don't know exactly how they chose that number but that's what their target was and they did serial checkups with all the cardiographic and the plasma concentrations to make sure they're at therapeutic levels limitations of the study uh excluded the use of patients on diamide patients were notably mostly on beta blockers and or calcium channel blockers and as I mentioned before didn't include class four patients uh probably trying to stay in this um reversible phase of HCM another limitation was mostly uh White and older patients so they felt like they didn't get really good external validity in representing uh a divers local landscape uh this was their primary endpoint uh data you see a significant difference between mavic Campton and Placebo in achieving um cardiopulmonary testing uh Improvement and in the P VO2 uh with greater than or equal to NY class Improvement so they either had this parameter increase in their pb2 with symptomatic Improvement or they didn't have symptomatic Improvement in terms of their classification but they did have a more significant cardiopulmonary testing uh Improvement in their outcomes and you can see that U 37 patients 37% of patients in the MAV campon group compared to 17% of patients did have this Improvement um at their primary endpoint some of the secondary uh biomarkers that they look for BNP uh significantly decrease you can see almost uh 500 uh unit decrease in the BNP anti Pro BNP which is thought to be a better Market than BNP and they also saw chronically elevated tronent kind of diverge here at at six to 18 weeks um where the tronent is decreasing this was also statistically significant um the resting lvot gradient is something we really care about obviously you have a significant decrease there's our threshold 30 and they all made it down within four weeks is below that threshold Val Salva same thing this threshold was 50 and we bring it down within four weeks below that threshold and then post exercise which is more representative of the patient's functional status below 50 within 30 uh weeks uh this is a nice table I thought was important to see that uh 27 patients of the mavic Campton group had complete response meaning they had complete resolution of uh elevated resting gradients elevated Val Salva gradients elevated exercise gradients and post exercise gradients and of that 27% um patient 57% had less than 30 um millimet of mercury resolution and then 74% had less than 50 so uh whether you have extensive resolution or some resolution a significant amount of those did get resolution um one of the most important things as we mentioned before is the decrease in lvef and you can actually see a diverging slowly between four to six weeks you start to see roughly a five unit decrease in your EF um and so if you're enrolling patients who are at the 50% level you want to be mindful of that 5% and other studies will see 5 to 10% so it's important to be mindful of that when you're picking patients for mic Campton uh subset of the Explorer HTM trial was an Explorer MRI they basically took patients and uh who who succeeded uh in reaching the end of the explor HCM uh phase three trial and looked at their MRI studies and so you you saw a statistically difference significant difference in the mass index the wall thickness the volume index late galum enhancement in terms of fibrosis and uh all of these were stally significant and uh being improved relatively uh to Placebo with ef you see of five to 10% uh inching towards 15% so uh again being mindful of that here we see indias and syy and the MRI studies mavic Campton versus placebo and they're showing uh that at Baseline you have this hypertrophy of the papillary muscles with week 30 you kind of gets obliterated you can kind of see here it gets attenuated here and cyly whereas Placebo you kind of uh it's it it looks kind of the same here actually but it's a little bit more prominent here and over here obviously um a little bit more prominent so uh you can see the the relative changes are a little bit more significant here than here um but obviously um it's important to have a placebo control group to see how much of this is actually Placebo versus Therapeutics mava LTE is an extension study of the Explorer HCM trial that was the phase three Landmark trial and so they're trying to basically extend the data long term uh and at 84 weeks these these results were released I think one or two weeks ago they're showing consistent uh decrease and maintenance of that decrease in the resting lvot gradients over time so uh the it it's thought that with mavi Campton therapy uh the reversibility um while on therapy is is not a concern um and so that's important to not you see that with the Val Salva GR Radiance as well uh the BNP biomarkers as well this is all very good data and then the EF they use two different centers to show uh there is no reader variability uh or to rule out reader variability I should say and you can see that actually uh you know patients started out Baseline 74% within four weeks um you know facilities are measuring somewhere between 65 and 70% so that's if you take the you know lower average of this one it's almost 10 units U so that's pretty significant to be wondering this is they're showing maintenance of this reduced EF with continued mavic Hampton therapy um an important uh you know table I thought they included in their um article of the mava LTE internal results uh they took all the patients that had reduced EF less than 50% they showed you know at the event and at their latest assessment the dose that were they were on the dose at the last assessment whether they had any intercurrent illnesses like h control arhythmia or hypertensive emergency or emergency and how they decided to uh you know continue forward with the mavic Campton treatment you can see those with arhythmia kind of got terminated from the study and those without p uh continued forward forward so uh it'll be interesting to see um how these patients turn out over time um again these patients are on the background beta blocker um calcium channel blocker uh monotherapy in addition to mavic Campton so have to take that into account when we're looking at these decreases in EF uh wondering if there's some interaction or uh synergistic effect uh the next study is another important study that's been in the literature cited a lot is the Valor HCM study released in 2022 this took patients that were obviously HCM patients obstructive physiology who were eligible for sepal reduction therapies including myomectomy or uh alcohol seal oblation therapy and they randomized these eligible patients to mavic Hampton versus placebo to see if they would remain eligible or get better and so over time it's actually interesting uh only 10 10 out of 56 or 177% of those patients that were eligible remained eligible uh versus placebo where 76% remained eligible of course without any therapy so this was very significant obviously uh two uh two of those patients out of the 10 decide to proceed with sepal reduction therapy while they on mavic Canton and eight did not uh so it'll be interesting how these patients get compared with each other in the future if they decide to continue the study um they have some secondary end points here as well some objective endpoints as well um and here we can see with Valor study with mavi Campton obviously we're having decrease in the BMP over time statistically significant and then as well as of subjective uh symptomatic scores and the tronent elevations that are chronic uh the gradients again in the Valor study were demonstrated to reduce with mavic Campton therapy as we saw before in the Explorer uh study and this was with B Salva this is with breast um and then patients who underwent septal reduction therapy or remain guideline eligible for SRT this was a nice graphic that kind of demonstrated you know 77% uh versus 18% in the mavic Hampton um and then over here you can see kind of the differences uh in changes in the NY symptomatic scores or sorry subjective classifications were um Mo most shifted towards uh none or one class uh and very few had two class in terms of the EF they did show a slight Divergence here you can't really see the breakdown in the tick marks and and on the graph here but there is a slight Divergence and and they called it 4% in this study U so we're seeing somewhere in average you know 5% in between all these studies and decreasing the EF um another study that came out more recently in 2023 was Phase 2 Redwood HCM trial they had um two cohorts in varying doses of afy campon um afy Campton is is gaining a lot of momentum because it's thought to be slightly more better than mavi Campton because of the shorter halflife and wider therapeutic V window as a consequence of that and also less um drug to drug interactions which we saw with the mavic Campton you have a lot of sip interactions in the liver and so this is gaining a lot of momentum because of all those uh very um uh preferred um pharmacokinetic profile um here with ay Campton you can actually see I really appreciate this figure over you know within two to four weeks you see a decrease in your resting and Val Salva gradients and as soon as you uh let go of the therapy and wash out there's reversibility demonstrated and so it was mentioned in the other studies U that there was reversibility but this was a nice graph that we saw for the first time that showed the wash out period uh leading to reversibility of the gradient so um if there's any issue you know well we can rest assur that if we withhold therapy we can re go back to Baseline status over here is a nice patient that or sorry nice graph that shows the uh two different cohorts and the difference in the percentage of uh patients who had improved gradients compared to this study shows the EF differences uh we're seeing actually a little bit more significant uh decreases in EF here 75 to you know perhaps 65 so maybe almost 10% if you want to eyeball test that these were all statistically significant but with wash out period these all return back to not statistically different so that's uh interesting to note and here we can see the BNP markers over time the AY campon cohort 1 and cohort 2 based on the different doses that that they were on compared to Placebo we're seeing Improvement in bnps so over time uh we're seeing all these biomarkers and and consistent results from different trials which is very good for uh a validity P purposes and and redemonstration this this medicine's effect in terms of biomarkers and Physiology and symptomatic scores all these are consistently uh improving with this direct therapy uh here are the gradients uh they compared cohort 1 and cohort 2 over time all these are statistically significant compared to Placebo um the Val Salva for some reason a little bit more of a delay effect but the resting and the exercise ones are repeatedly showing that they're improving the forest HCM trial is ongoing it's uh it's it's a much more it's basically the extension study of the afy Campton uh trial and so they're doing a similar study uh with Force HCM where they're also measuring CMR uh characteristics of HCM and they're showing that there is uh improvements in cardiac structure and function based on those objective measures we' saw the explore MRI trial and also uh stabilization of any my cardiio fibrosis which also was uh alluded to in the Explorer MRI trial earlier uh phase three trial that's going on now uh seoa HCM this is also with afy Campton and you can see over time they're measuring between uh Placebo and Affy Campton kind of the same setup as the Explorer HCM trial except with instead of mavic Campton we're doing AIC Campton because of the better Farm cinetic profile um they're using almost the same exact primary and secondary end points as we saw earlier and uh similarly they're looking at you know EF and other safety measures we want to be mindful of whenever we're giving someone medicine especially when it's new to the market um and these are some of their exploratory uh endpoints as well uh kind of similar to the other tables we saw earlier in the Explorer HCM trial they're being very thorough in their workup of course uh trials that are uh you know on the horizon where uh we don't have much insight into uh the data I thought this was a very uh this is going to be a huge study actually in the near future estimated completion date of 2025 where they compare ay campon directly with moper LA and so uh you know in previous trials especially with the Explorer trial we had background monotherapy in addition to mavi Campton uh so you know we have this confounding factor and there's question whether these uh Mosin Inhibitors uh should be first line or second line behind beta blockers and so this this trial I think will will be a landmark study uh when it comes out in the future and obviously they're testing different doses so that's good we're seeing uh different variations so we'll look at all that data and see um you know which one uh might be U preferred as a primary uh modality for treatment of HCM another study that's uh actually done more uh recently completed in 2020 was a Maverick HCM this is for non-obstructive HCM specifically whereas previous ones were obstructive HCM and they kind of use the same inclusion criteria um exclusion criteria was mostly just making sure it's not obstructive and you didn't have elevated QTC uh limitations of the study again limited um uh racial minorities the length of the study and the exploratory was Finding nature of it and this was basically their main table uh you have group one mavic Campton at 200 group two mavic Campton at 500 you have a pooled mavic Campton uh uh stratification here and your placeo group over there of course same kind of objective markers and so um when you look at this study as well they also had background HCM therapy and over 63% of patients uh consistently across these map campon groups and compared to placebo um but notably the BNP kind of had a decrease only in this group two mavic hampon group compared to Placebo whereas the group one and the pool did not have much of a difference uh with the placebo group and then lvef uh notably not much difference here as you can see in this Maverick non-obstructive hyperopic cardiomyopathy so this is good from an EF perspective but in terms of a BMP perspective maybe a little bit more subtle with lower doses we do see a dose dependent response and so we can kind of visualize that here as well in addition to uh you know the reversibility where the end of treatment is here and then week 24 all that has reversed and the same thing with the troponin usually these goes hand in hand and then this one is uh another mavic campon study specifically nonobstructive hypertropic cardiomyopathy uh this one uh you know they kind of want to model it similar to the mavic Campton study phase three instead larger study with 4 20 enrollment so we'll see what that one has to say for nonobstructive given that this is a little bit more difficult to treat we want to make sure mavi Campton can help these this subset of patients as well and as we said the company is really trying to expand this for multiple physiologies um another study for um he is mavic campon for hepf now uh we all feel differently about hepf and and it'll be interesting how they classify patients with hepf and how mavic Campton will affect that subass of fpf patients so this will be something else we'll be looking on the horizon this will be a phase two trial with estimated completion this year another phase three trial that's coming out is ACAA uh HCM this is going to compare ay Campton with Placebo and non-obstructive HCM so it's good that you're kind of putting their uh foot on the gas pedal and making sure they're being thorough with uh addressing all these uh HCM phenotypes um obviously with all the money being pushed behind it so um this one will be apy Campton versus placebo and nonobstructive hypertropic cardiopathy with an enrollment of 420 patients and an estimated completion of 2026 the Discover HCM registry is is an ongoing registry they're basically trying to see real world world treatment patterns and outcomes with symptomatic obstructive hypertropic cardiopathy and people who are being put on mavic Campton um and so excuse me um over here again they're looking at all the um primary objective markers that we saw previously and just seeing the long-term efficacy and the quality of life outcomes um with related with mavi Campton so this will be uh up to 1500 patients from 65 sites uh overall in the US and Puerto Rico over twoe span so this will be um a much more powerful study uh this is from Dr uh villan she uh had a patient uh Prem mavic campon and post mavic campon with severe lvot obstruction and severe Mr class 4 symptoms with heart failure unable to tolerate diuresis un maximally tolerated beta blocker and unfortunately there not even a septo reduction therapy candidate and so uh you know mavi Hampton was administered and you play this video here you can see a lot more hypertrophy here compared to here uh and and so it's pretty dramatic the differences you can see the lvt obstruction was deemed to be obliterated and there's only Trace Mr class ification of his nyha uh improved he diuresed much more successfully and even lost 20 pounds so you know this is a very dramatic uh case that Dr billan was able to demonstrate well with M studies as well uh another study that's um being spearheaded by the NIH is the Sesame study um they basically wanted to um see if they could develop a trans catheter uh myotomy procedure to offer patients who were not candidates for uh surgical myomectomy um and they started with pigs obviously I wanted test this in animals first naive pigs versus um LVH model pigs where they banded the aorta to develop LVH and so they use this uh what they call a Flying V kind of situation where they take guide wire here and guide catheter here and then kind of use electr surgery to kind of cut this uh uh hypertrophied septum out and so you can kind of see right here there's a little bit of uh fibrosis from the the electro surgery that cauterized the sepal myocardium here and where this was uh muscle is now a larger lvot outflow track um and so they said it increased by 101 millim Square uh there was thin fibrosis layer as you can clearly see there at the edge and this the thought is that this is different than a myomectomy where you're just spaying The myocardium versus resecting a large part of it uh as you saw in the search video we showed earlier this is more of kind of like a diagram showing the step-by-step U uh trans catheter methods of using Electro surgery to remove that hyperr septum so a going to b c pulling back retracting that snaring it and then boom you have this alil TR over here you have over here the the septum is here is this this hypertrophy and this is where they go in and create this Flying V and then retracted um and this is the CT kind of demonstration of how they get the catheter into that septum showing that it's in the right orientation when they use uh the CT guidance these are their parameters that they're measuring you can see um you know some of these parameters in terms of strain and uh uh olic volume indolic volume cardic output diastolic pressure and maps are all measured here strains were all significantly different uh EF here was not significantly different um and they're showing maintenance of U therapy and specifically um the this this uh enolic volume here and ejection fraction is unchanged over day 30 um notably The Strain is not significantly different at day 30 in these two graphs and in this graph as well here you can see the measurements post procedure in terms of the laceration length depth width uh this where the averages um that they measured the seple thickness went from 11 to the twos lvot area cine diely both improved and then the sepal distance also uh improved as well so these are all things you want to achieve when you're trying to create a larger outflow track these are all statistically significant when compared to Baseline and over here they kind of demonstrate that over time with um persistence at day 30 post procedure over here we're seeing kind of the the the Sesame post Sesame kind of picture in syy and diast we're seeing that in both uh phases of the cardiac cycle there this lvot uh outle tract is remaining patent um and over here you're not seeing uh too much fibrosis happening so there is a thin layer but it's not that significant ific this is what it looks like on surgery where they're kind of splaying The myocardium by creating that Flying V section of the septum and creating a more open alow tract this is what it looks like on histology you can see that there's this thin layer of myocardial fibrosis um kind of magnified that there and this is what it looks like when they reect the SE the septum they're measuring here you know one to two and so limitations of this procedure uh you know you can go too superficial or Too Deep of this myotomy which can if you go too deep can cause a vssd if it's too superficial you're not going to cause a significant effect uh in terms of producing a larger outflow tract so you really have to have skill operators doing this and and take your time making sure you're getting the right angles and reecting the right amount of uh uh muscle when you're using Electro surgery um so they actually tested the Sesame uh the Sesame procedure here at em uh Dr Green bomb and Dr B seem to be spearheading this initiative and so you know we have Baseline here we have the hypertrophy septum as noted here here's it is on Advanced Imaging and then after Sesame you see the resection here the septum is more sped here you can see that here on CT as well compared to Baseline and then this was done to help um you know permit placement of a trans cath mitro valve so they place that valve here and you can see that this outow tract is now much more open for blood to be moving between those two valves and so they did the the the BBM uh sign you can see before and after was U provocation was pretty significant difference in the gradient and then after the Sesame procedure uh there was a very similar uh gradients of resting and provocation phases uh this is three-dimensional representation where they're showing cavity uh obliteration with the obstruction that they do the Sesame were denoted in yellow and so this obliteration resolves because you have uh less strain than the LV and then they're able to show stability in sesame um after 30 days and I think this is six months as well based on the figure and here's another uh kind of picture where they wanted to demonstrate that this is where the Sesame occurred this was the original outflow tract and by now by reecting this uh uh sepal muscle you have this plus this going this this way these are all my references and thank you to Dr billan and Dr Williams for helping me put this uh presentation together all right thanks Omid U excellent summary um I I just put in a quick plug uh if you want to hear more about dror billins and I experience with hypertrophic um with mavi Campton in particular uh over this past year year and a half uh week from Monday we are presenting some of our experiences and talking sort of through some stuff at cardiovascular Grand rounds so week from Monday morning tune in for more exciting hypertrophic cardiy any questions uh from the group uh omed Stan Sherman uh it looked like a lot of patients were excluded or or should have been a lot of patients excluded because they had Paris way fibrillation uh and not you know some of them were permanent but but uh even paroxysmal atrial fibrillation was excl excluded from studies and is there an ongoing study in patients with atrial fib and and I'm not exactly sure why they were excluded to begin with except they're worried about decrease in LV function absolutely I think that's a a concern that needs to be addressed in the future I didn't see any clinical trials currently when I was looking through uh the system the database but I think that's a question that definitely needs to be answered uh you know prox ismal versus persistent a I think you know we need to see how MAV campon affects those population groups because we want to eventually expand uh any helpful Therapeutics for all patients not just a subset of them no matter how sick they are and especially for those sicker patients we want to see if we can help them out so in the future I assume uh you know once uh there's a lot of uh acceptance Behind These myosin Inhibitors um they'll start expanding the um population groups they're targeting for sure and this is this is Neil dickard I I um I'll I'll Channel Jonathan Kim uh for a minute which is uh which is difficult to do um but the the one thing I I would add is I think um just to contextualize a a little bit the discussion about um the role of activity in patients with hypertrophic card apathy I do think it's important to recognize that that's a real moving Target right now the the Liv HCM study that was that that came out last year um which was a pretty significant observational study of patients with hypertrophic cardiomyopathy did not demonstrate any association between vigorous exercise and risk of events the risk of events is present and increased in populations with hypertropic cardiopathy but the correlation with exercise is is not not what it or does not it's not obvious that it's what people have um uh uh thought that it should be so the importance of kind of engaging in real um shared decision- making is greater and the the certainty with which clinicians can make recommendations about um about activity restrictions I think is I I think really been called into question um so so I think um these decisions I think are are super interesting um but I do think that the kind of Dogma about about exercise in this patient population has been really substantially challenged um Robbie and and others who work in this space certainly have much more experience dealing with with patients in this conditions I'm interest in your thoughts on this but I think this is the Sands in this are really shifting you correct I mean this is a this is a a long and nuanced uh discussion but you're right I mean there's been a dramatic shift uh just in just in my time doing this over the past decade or so plus uh a much more you know the pendulum definitely swung sort of back the other way we're a lot more permissive and a lot more shared decision- making and you know just frankly there there are several uh highlevel competitive athletes out there participating with Hyper trophic cardiy I'm most with sort of disease on the milder end of the spectrum but right with proper precautions and everybody buying in including the team and organization slash uh School Etc uh there's there's it's it's something whereas you know 15 20 years ago this was just forbidden you know you know strictly forbidden and I think there's been a big shift not just in terms of competitive sports but like you said also with recreational exercise which I think we're very much encouraging all of our patients to engage in uh these days so yeah I think I think it's import a lot of the discussion tends to focus on you know kind of high level professional or or real other really high level organized people participating in organized sports but I think it's important for cardiologists to be aware when they have patients that might have particularly patients with milder phenotypes they don't need to reinforce the old recommendations that they can only bowl and play golf yeah no 100% And I've noticed to change too I can tell you years ago I would get patients and most of them would come in saying yep my doctor said I can't do any exercise at all you know and I'd have to sort of re relearn them on that and that that's definitely shifted you I'll ask them well what have you been advised by you know your other doctors and most of them like yeah yeah know they say I can do stuff you know maybe not go crazy and I'm like yeah all right you know and I'll even usually it's I you know we'll have sort of a more nuanced discussion about it but it's there's been a shift in the world where I think that message is has gotten out to the to the you know medical community at large good morning Rob I just wanted to make a comment this is awesome sitting right next to Dr Clemens um all congratulations fantastic work just wanted to make a comment on Dr Sherman's question Dr Sherman we are actually enrolling patients with stable atrial fibrillation and non obstructive ACM in Odyssey trial I think the reason that you know Atri filation was a concern in the earlier studies was because the patients have to get a cpath the primary outcome is Peak exercise tolerance at cpath and P oxygen saturation as well and the idea is if if during screening if they're in Atri prolation with rvr then that basically is going to obscure the results of the cpth um and also there's a concern that they might drop their EF transiently when they go into a rvr but I think moving forward we are going to enroll more patients with atrial tribulation in these trials all right well thank you can I make one comment it's Christina Taylor um so sorry I know it's getting late um from a diagnosis standpoint for kids coming out of Pediatrics they'll often be more severe phenotypes but the one thing to be aware of if they've had a septo myectomy is to make sure to get the original operative report because there's a lot of conal heart disease and different phenotypes that we also do SE septo myectomy for and so I have a handful of patients that have come out of Pediatrics and have landed in an adult cardiologist who have said oh they have H CM because of a sepa so getting the original op report is really important um in order to make sure that you're dealing with the same thing uh phenotype but if they have had a sept actom coming out of Pediatrics for HCM they do tend to be a more severe phenotype no agree right and you're not dealing with um pompies disease or fabes or something so all right well thank you everyone once again for tuning in um look forward to seeing everybody next week thanks again om for your for your talk so om pardon see you next week everyone thanks the proceeding program is 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