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(light acoustic music) - Welcome to this episode titled, "Hypertrophic Cardiomyopathy: Managing Symptoms." I'm Carolyn Ho.

I'm the Medical Director of the Cardiovascular Genetic Center at Brigham and Women's Hospital in Boston, Massachusetts.

In this episode, we'll discuss the best approaches for managing symptoms in patients with HCM including newly available options that provide our patients with more choices to find the right treatment that might be best for them.

When we're thinking about starting therapy for patients with hypertrophic cardiomyopathy, it really hinges on whether or not they have symptoms referable to HCM, meaning do they have functional limitations, effort intolerance that is impeding on their quality of life?

If patients do not have symptoms, then really no medical therapy is indicated.

Disease modifying therapies have not yet been fully established, although this is an active area of investigation.

And I'll point you to the VANISH trial, which look at Valsartan to potentially attenuate disease progression in early sarcomeric HCM.

And so if they do have symptoms and the most common symptoms related to HCM are effort intolerance, typically shortness of breath, light headedness or chest discomfort with exercise, that's important to establish the mechanism and that really needs to determine whether they have obstructive physiology or not.

So the question commonly comes up about how much obstruction is enough.

So obstructive HCM is identified or defined by having a peak gradient greater than 30 millimeters of mercury.

And so that peak gradient can be either at rest or with Valsalva maneuver or with exercise.

But when we think about a gradient or a degree of obstruction that is sufficient to result in symptoms, we really want that peak gradient to be at least 50 millimeters of mercury.

And remember, obstruction is a dynamic process.

Sometimes it's not present at rest, but it can be provoked or magnified or worsened if there's more vigorous contraction, decreased vascular resistance, decreased intracavitary or total volume as with volume depletion, and an increased heart rate.

So you really need to look hard for obstruction to see if it's present.

And that relies on performing provocative maneuvers either in the echo lab, in the exercise lab, and in the office to see if you can provoke obstruction when it's not present at rest.

So in the echo lab, we'll typically have the patients do a Valsalva maneuvers.

So first identify the resting gradient and then have them do Valsalva maneuvers and carefully interrogate the outflow tract to see if more obstruction is provoked.

In the office, I find that the most reliable maneuver to do is to have people stand up from a squatting position and then also exercise can be extremely helpful.

But because not only do you get the usual very valuable prognostic and functional information from exercise testing, but you can also see if you can provoke obstruction with the most physiological stressor of upright exercise.

And so you want to make sure that you're doing true exercise, not pharmacologic stress.

So you don't wanna do vasodilator stress testing or dobutamine stress because dobutamine can provoke obstruction even relatively normal heart so that can you have a high false positive rate from that.

So you really wanna do physiologic exercise either on a bike or on a treadmill.

And so it's important to look hard for obstruction because that really will color how you manage your patients.

So there's no obstruction and patients have symptoms, then we think about medical therapy, that would include beta blockers or calcium channel blockers as well as diuretics if congestion is present.

So this is really along the lines of what you would use for a patient with heart failure with preserved ejection fraction, trying to slow the heart rate, allow more time for diastolic filling to occur.

If patients have refractory symptoms then we really have to move into the realm of advanced heart failure management.

Oftentimes it's can be very helpful to do right heart catheterization to define hemodynamics.

We unfortunately have limited options if severe restrictive physiology is present.

In these types of the patients, we might have to consider cardiac transplantation.

Left ventricular cyst device is really not very helpful.

If there's a small hyper contractile heart, the unloading is not necessarily going to be beneficial in that population so they can be very challenging to treat.

And indeed one of our most challenging patients manage are those individuals with restrictive physiology and refractory symptoms.

But if you are more able to identify obstruction either at rest or with any type of provocation and you're confident that the obstruction is the cause of symptoms, again, you want that obstruction to be fairly substantial, greater than 50 millimeters of mercury at least.

Again, you want to first think about correcting exacerbating factors.

So the most common factors that we'll run into that can worsen obstruction are volume depletion and the common use of vasodilators.

So you want to make sure that patients know to be well hydrated.

I usually counsel them to make sure that they're drinking all the time and not wait to feel thirsty before drinking.

And you wanna make sure that you aggressively hydrate with exercise and in the hot summer months.

And then you want to take a good look at their medication list and try to avoid angiotensin receptor blockers, ACE inhibitors, nitrates, dihydropyridine, calcium channel blockers like amlodipine, and also PDE5 inhibitors can exacerbate and worsen obstructive tendencies.

So medical therapy aimed at trying to ameliorate symptomatic obstruction includes beta blockers and calcium blockers as first line therapies, again helping to slow the heart rate to allow more time for diastolic filling and increase intracavitary volume as much as possible.

And also because of their mildly negative inotropic effects to help decrease contractility and decrease the drive to obstruction.

If those first line therapies of beta blockers and calcium channel blockers are not adequately successful, then you can think about disopyramide as a more powerful negative inotropic agent.

You wanna be very cautious with using diuretics in this crowd.

If they have front congestion also contributing to symptoms, then you can very cautiously apply some diuretics and watch carefully because again, if diuretics are used too aggressively then that can result in volume depletion which can worsen obstruction.

And then if symptoms are refractory to these first and second line medical therapies, then we typically think about moving on to invasive septal reduction therapy, and that would include either surgical myectomy or alcohol septal ablation.

So there are few things to consider when thinking about invasive septal reduction therapy.

Again, the usual indications are when symptoms are refractory to our usual medications.

That can be they are truly refractory and you have titrated the doses up to the maximum tolerated or the maximum effective doses, or it could be that the medications result in side effects that are not well tolerated.

And typically with disopyramide, we can run into problems with anticholinergic side effects.

And then you also wanna make sure that you're quite confident that the obstruction is the cause of the symptoms.

Again, you want to make sure that the gradient is at least 50 millimeters of mercury, that again can be their resting gradient or provoked gradient.

And then there are some factors that might lead you to favor myectomy.

This has been the standard approach to symptomatic obstruction that's medically refractory.

It's been around since the 1970s and it's good for individuals that have really extensive left ventricular hypertrophy where the surgical resection can result in a more complete gradient reduction.

If there's intrinsic mitral valve disease that would benefit from some surgical intervention, if there's surgical amounts of coronary artery disease, then also a key feature is available expertise.

Do you have an experienced myectomy surgeon at your institution or will you have or the patient have access to travel to a site that has myectomy expertise?

And of course patient preference in terms of their interest in going through cardiac surgery is a key feature.

And then factors favoring ablation are here.

Ablation has been around since about the mid nineties and it's ideal for patients that have comorbidities or other factors that might increase their surgical risk.

So neither you nor the patient is enthusiastic about going through a surgical septal myectomy, ablation can be a great alternative.

And then the patients that are just really quite not enthusiastic in themselves about going through a big cardiac surgery procedure, ablation could be a great alternative for them.

But patients have to have suitable coronary anatomy.

They have to have septal perforator branches that supply exactly the right portion of the septum that's contributing to the CM septal contact and is a target for ablation.

If those septal perforators aren't available then unfortunately ablation would not be an option.

And again, you wanna make sure that you have the appropriate expertise either at your center or within reach of the patient to travel to.

And so HCM is a very complex disease and one size really does not fit all for management.

Our current medical therapy may not provide adequate symptom relief, and the invasive septal reduction therapy is effective but may not be for everyone.

Their access to expertise may be an issue.

You have to have favorable anatomy both for ablation and myectomy.

You have patients may have comorbidities which increase their risk either for surgery or even for catheter-based procedures.

The improvement can be somewhat variable, particularly with ablation where the control over the amount of tissue that's impacted and the reduction of obstruction may not be as reliable or as complete as what we can get with surgical myectomy.

Patients may have strong ideas about whether they wish to have invasive therapies.

And of course there's also the inherent morbidity and mortality related to invasive therapies.

So there's a clear unmet clinical need to provide more effective medical therapy that can improve symptom burden and avoid the risk of invasive therapy.

And so this is where there's been a lot of progress over the last few years and it's really been an exciting time for those of us who have been interested in HCM, because disease specific therapies have been developed for the first time based on better understanding of the molecular underpinnings of HCM.

So just to quickly review that, the physiology, you'll recall that normally there's very carefully regulated actin myosin interaction through the chemo mechanical cycle that leads to normal contractility and effective relaxation.

So one simplified model of HCM pathophysiology is that the sarcomere mutations result in having too many myosin heads engaged with the actin thin filament.

So this results in hyper contractility, impaired relaxation, and altered myocardial energetic where energetics are inefficient.

And so cardiac myosin inhibitors have been developed to counteract some of these fundamental biochemical abnormalities, and the first to market is mavacamten.

And so these are first in class targeted allosteric inhibitors of cardiac myosin which can increase the proportion of heads in a very super relaxed state that's improving relaxation and most fundamentally, they act by interfering with the initial rate limiting ATPAs that initiates the power stroke.

And so this reduces ATP hydrolysis and therefore decreases the number of actin myosin crossbridges that are in play.

And so with myosin inhibitors, you can see decreased hyper contractility and potentially improved energetics and diastolic function.

And so the clinical trial testing mavacamten was the Explorer-HCM trial.

This was published in the Lancet in 2020 and it had a primary endpoint that looked at improvements of either peak VO2 by cardiopulmonary exercise testing and New York Heart Association class.

And compared to placebo, you can see that mavacamten met its primary endpoint and had a significantly higher rate of either increasing both peak VO2 and NYHA class or having a more substantial increase in peak VO2 and no worsening of NYHA functional class.

And then in secondary findings and ancillary studies, mavacamten was also shown to have favorable effects of decreasing NT-proBNP, improving the Kansas City Cardiomyopathy Questionnaire score, So improving health related quality of life, increasing E prime velocity, so the suggestion of improving diastolic function.

There was also some important remodeling that was seen with a decrease in LV mass, and a decrease in left atrial volume.

And so most recently the VALOR HCM trial was formed which looked at the role of mavacamten in patients with obstructive HCM that had severe symptoms and were actually being considered for invasive septal reduction therapy.

And this study showed that mavacamten provided adequate clinical improvement for patients to choose to defer invasive septal reduction therapy and instead stay on a long-term extension study of mavacamten.

And because of its mechanism of action as a myosin inhibitor, cardiac contractility is decreased and you can see a fall in left ventricular ejection fraction.

And so typically this trials have shown that there's usually just a modest change in left ventricular ejection fraction so EF will fall by about 4 EF percent.

So if you start with an LVEF is 70%, on mavacamten, then that will typically fall to about 66%.

And with this modest change in LVEF, there can be a very dramatic reduction in left ventricular outflow tract gradient.

So over about a 40 millimeter of mercury reduction in gradient was seen both at rest with post Valsalva and with stress.

So this a substantial reduction in LVOT gradient, much more dramatic than has been seen with any other medical therapy and almost on par with what is seen with invasive septal reduction therapy.

But one thing to keep in mind is that some patients, about 7% in the trials, have had a more dramatic but reversible decrease in left ventricular ejection fraction where it fell below the predefined cutoff of 50%, resulting in temporary cessation of study drug and/or dose reduction.

And there is also an additional myosin inhibitor that is making its way through clinical trials, this is aficamten.

It is completing its phase two trials, a Redwood trial which showed that aficamten, like mavacamten, can result in the substantial decrease in left ventricular outflow tract gradient and NT-proBNP with a relatively modest reduction in left ventricular ejection fraction.

100

And the phase three Sequoia HCM trial in a symptomatic obstructive HCM is nearing a completion of enrollment.

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And so we'll be eagerly awaiting those results in the near future.

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And so where do myosin inhibitors fit into our current clinical practice?

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We can think about using them in a somewhat exploratory way, testing the impact of improving obstruction on your patients with symptoms.

104

And this might be most helpful in patients that have multiple comorbidities, be it primary pulmonary disease, obesity, deconditioning, other medical conditions that might impact effort tolerance and functional capacity.

105

Then you can try a myosin inhibitors and see what gradient reduction does in terms of improving the symptoms.

106

And if symptomatic improvement is successful, then this can be continued as long-term therapy or it can be potentially as an interim step prior to invasive septal reduction therapy if patients wish to have a more definitive mechanical solution to symptomatic obstruction rather than continuing on long-term medical therapy.

107

And other patients may be very happy to avoid any type of invasive procedure.

108

And cardiac myosin inhibitors can be tried in patients who have refractory symptoms after first-line therapy with either beta blocker or calcium channel blocker to hopefully achieve more successful symptomatic benefit in the long-term.

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Because of the potential effect of mavacamten reducing left ventricular ejection fraction in a more substantial manner, it was approved by the FDA in April, 2022 but with a risk evaluation mitigation strategy requirement, or REMS requirement.

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And so this is a program that was required by the FDA and providers, pharmacists, and patients all have to be familiar with and enroll in the REMS program.

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And so this requires patients to have echocardiograms and clinical evaluation as relatively frequent points along the initiation and even the maintenance for mavacamten, the trained name being CAMZYOS.

112

So echoes are required at the time that treatment starts before initiating mavacamten, at four weeks after treatment is started, at eight weeks and then at 12 weeks after treatment is started.

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So every four weeks for the first 12 weeks after starting mavacamten and this is to assess LVEF, to make sure that it's not dropping lower than anticipated, and also to look at the effect on gradient and on symptoms.

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And during this initial 12 week period, dose can only be reduced.

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So if obstruction is completely resolved, there's a suggestion of trying to reduce dose.

116

If LVEF falls, then dose reduction is required.

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And then at 12 weeks, the patients will enter into a more of a maintenance phase where echo assessments will be done at every 12 week frequency.

118

And at that point the dose can be increased if there's still substantial residual gradient.

119

And so some of the take home points for managing patients for obstructive HCM are as follows.

120

So you want to accurately characterize on the pathophysiology that might be contributing to symptoms.

121

And this means to look hard to see if obstruction is present or not since that's gonna be such a big branch point for therapy, and because we have so many other options for treating obstruction than we do for treating patients with non-obstructive physiology.

122

The first line therapies for patients with symptomatic obstruction are beta blockers and calcium channel blockers.

123

And some patients may have adequate symptomatic relief with that, but if symptoms remain lifestyle limiting and impact quality of life, myosin inhibitors offer HCM patients an additional and effective medical option for improving symptoms.

124

Their impact on contractile function requires respect.

125

These are very potent medications, and there can be a more substantial reduction of LVEF than anticipated or than desired.

126

And in the United States, this is closely followed by the REMS program that FDA has required.

127

There's also limited cumulative experience with myosin inhibitors, they've only been available in trials for the past couple of years and so it's only been about 400 patient years of experience since 2018.

128

And so we need to get more experience with them to determine their long-term safety and efficacy and also potential additional applications such as a potential for disease modification and whether they may have benefit for non-obstructive HCMs.

129

Okay, so next on the horizon is non-obstructive HCM.

130

And as we talked about before, this is an extremely challenging area of managing patients with HCM.

131

We think that symptoms result because of diastolic abnormalities, restrictive filling, and inefficient myocardial energetics.

132

And these can all play into resulting in effort intolerance in our patients.

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And unfortunately, we really have no effective therapies for patients with severe symptoms related to non-obstructive HCM.

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There's great interest in whether myosin inhibitors may be able to improve symptoms in this cohort as well, owing to the potential of these agents to improve diastolic function and to improve myocardial energetics.

135

And the Maverick HCM trial was a phase two clinical trial that looked at the safety and efficacy of mavacamten in patients with symptomatic non-obstructive HCM.

136

So it wasn't power to look at real clinical benefit in terms of functional capacity or symptomatic relief, but there was intriguing and encouraging signal that NT-proBNP levels were substantially reduced in patients that were randomized to mavacamten versus placebo with a reduction in NT-proBNP levels by week four, which were sustained through the treatment period of 16 weeks.

137

And then once treatment was stopped, NT-proBNP values again increased to baseline.

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This suggests that there may be physiologic benefit from mavacamten or myosin inhibitors in non-obstructive HCM.

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And this is currently being tested in two phase three trials using cardiac myosin inhibitors for non-obstructive HCM.

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Currently, the ODYSSEY-HCM trial with mavacamten is enrolling and soon to be launched will be a phase three trial using aficamten and also for non-obstructive HCM.

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So there's a lot of excitement on the horizon.

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This is a great time to be involved in HCM.

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And I want to thank you all for participating in this activity with me today.

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There are a lot of important points about managing symptoms, about hypertrophic cardiomyopathy, and I hope this will be helpful for your practice.

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This activity is supported by an independent medical education grant by Bristol-Myers Squibb.

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The views and opinions in this activity are those of speakers and reflect the synthesis of science.

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The content should not be considered as the official policy of the AHA.

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And to get additional information, please visit AHA's hypertrophic cardiomyopathy website for more education.

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Thank you.

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Лексика и советы по произношению к этому уроку

Этот урок разговорной практики построен на видео «Hypertrophic Cardiomyopathy (HCM): Managing Symptoms». Чаще всего повторяются слова: patient, symptom, Hcm, obstruction, therapy. В этом видео 149 предложений и 3461 слов для шедоуинга. Речь длится 23:59. Говорящий держит ровный темп — около 144 слов в минуту, удобный для шедоуинга. Только 74% слов входят в 3000 самых частых слов английского языка, поэтому лексика сложная.

Ключевая лексика этого видео

15 слов из видео, которые стоит выучить, с произношением и значением:

Слово	Произношение	Значение
symptom существительное	/ˈsɪm(p)təm/	симпто́м, при́знак
obstruction существительное	/əbˈstɹʌk.ʃən/	препя́тствие, обстру́кция
reduction существительное	/ɹɪˈdʌk.ʃən/	уменьше́ние, сниже́ние
decrease глагол	/dɪˈkɹiːs/	уменьша́ться, уме́ньшиться
cardiac прилагательное	/ˈkɑɹdiˌæk/	серде́чный, кардиа́льный
substantial прилагательное	/səbˈstænʃəl/	веще́ственный, материа́льный
dose существительное	/ˈdəʊ̯s/	до́за
surgical прилагательное	/ˈsɝd͡ʒɪkəl/	хирурги́ческий
fraction существительное	/ˈfɹæk.ʃən/	часть, части́ца
calcium существительное	/ˈkælsi.əm/	ка́льций
helpful прилагательное	/ˈhɛlp.fl̩/	поле́зный, любе́зный
functional прилагательное	/ˈfʌŋkt͡ʃənəl/	функциони́рующий, де́йствующий
beta существительное	/ˈbeɪtə/	бе́та
mercury существительное	/ˈmɜɹkjəɹi/	ртуть, гидра́ргирум
physiology существительное	/ˌfɪziˈɑ.lə.d͡ʒi/	физиоло́гия

Грамматика в этом видео

Конструкции, которые говорящий использует чаще всего, с точными словами из видео:

Конструкция	В видео
Present Perfect have/has + причастие прошедшего времени — прошлое действие, важное сейчас	have titrated · has been · It's been
Пассивный залог be + причастие прошедшего времени — важно, что происходит, а не кто это делает	is indicated · been fully established · is identified
Придаточные определительные who / which + предложение — уточнение о человеке или предмете	depletion which can · myosin which can · four, which were

Произношение, на которое стоит обратить внимание

Говорящий использует 24 сокращённых и редуцированных форм, например wanna, we'll, you're. Произносите их коротко, так, как слышите.

Звуки «th»: enthusiastic /ɪnˌθjuːzɪˈæstɪk/, thin /ˈθɪn/, synthesis /ˈsɪnθəsɪs/, thirsty /ˈθɝs.ti/
Звуки «sh» и «zh»: obstruction /əbˈstɹʌk.ʃən/, reduction /ɹɪˈdʌk.ʃən/, substantial /səbˈstænʃəl/, fraction /ˈfɹæk.ʃən/, medication /mɛdɪˈkeɪʃən/
Длинные слова — следите за ударением: physiology /ˌfɪziˈɑ.lə.d͡ʒi/, medication /mɛdɪˈkeɪʃən/, potentially /pəˈtɛnʃ(ə)li/, mechanical /məˈkænəkəl/, mechanism /ˈmɛk.ə.nɪ.zəm/

Звуки, трудные для русскоязычных:

/w/ — губы округлены, это не /v/: adequate /ˈæd.ə.kwɪt/, requirement /ɹɪˈkwaɪɹmənt/, frequency /ˈfɹiːkwənsi/, frequent /ˈfɹiː.kwənt/, await /əˈweɪt/
/h/ — лёгкий выдох, а не русское «х»: helpful /ˈhɛlp.fl̩/, horizon /həˈɹaɪ.zən/, inherent /ɪnˈhɪəɹənt/, inhibitor /ɪnˈhɪbɪtɚ/, hypertrophic /hʌɪpəˈtɹɒfɪk/
Звонкие согласные в конце слова — не оглушайте их: invasive /ɪnˈveɪsɪv/, expertise /ˌɛkspɜːˈtiːz/, restrictive /ɹɪˈstɹɪktɪv/, encourage /ɪnˈkʌɹ.ɪd͡ʒ/, preserve /pɹəˈzɝv/

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Запишите себя и сравните с оригиналом, обращая внимание на такие слова, как symptom, obstruction, reduction.

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