ARTICLE IN PRESS

Medical Treatment Strategies for Hypertrophic

Cardiomyopathy
Erika Hutt, MD, MSc, and Milind Y. Desai, MD, MBA*

Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic heart disease inherited in

an autosomal dominant pattern with an estimated prevalence of 0.6% in the general popu-
lation. Clinical manifestations of HCM vary considerably, with symptoms ranging from
none or mild exercise intolerance to severe lifestyle-limiting symptoms, advanced heart
failure, and sudden cardiac death. Current management options for HCM include lifestyle
modifications, familial screening with genetic counseling, pharmacotherapy for symptom
control, sudden cardiac death risk stratification with or without defibrillator implantation,
septal reduction therapy, and, in some cases, heart transplantation. Only recently have
strongly targeted medical therapies for HCM, such as myosin inhibitors, been studied in
multicenter randomized controlled trials. In this report, we review the currently available
medical treatments for HCM and the future directions of HCM pharmacotherapy, and we
highlight important unmet needs in this population. © 2023 The Author(s). Published by
Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/) (Am J Cardiol 2023;00:e1−e9)
Keywords: hypertrophic cardiomyopathy, medical therapies, cardiac myosin inhibitor

Pathophysiology and Implications for Management the mitral valve leaflets. This is often associated with ana-
tomic abnormalities of the mitral valve such as long leaflets
Hypertrophic cardiomyopathy (HCM) is a genetic heart
and abnormalities of the subvalvular apparatus such as pres-
disease inherited in an autosomal dominant pattern and is the
ence of multiheaded, hypertrophied, and anteriorly displaced
leading cause of sudden cardiac death (SCD) in young ath-
papillary muscles, all of which cause a narrow LVOT.5
letes. Early epidemiologic studies reported a prevalence of
Patients with HCM without LVOT obstruction or non-oHCM
0.2%1 in the general population, but it is now recognized that
(nHCM) comprise 1/3 of cases and pose a diagnostic and ther-
this is underestimated and that up to 0.6% of the population
apeutic challenge. Symptoms such as dyspnea and chest dis-
may carry HCM-causing sarcomere mutations.2 Currently,
comfort are common and are a result of increased LV filling
variants in 1 of 8 genes that encode cardiac sarcomere proteins
pressures due to diastolic dysfunction, increased myocardial
have been implicated in the development of HCM, but the 2
oxygen demand, and microvascular dysfunction.6 Recent
most common pathogenic gene variants are ꞵ myosin heavy
studies have recognized that patients with nHCM may have a
chain 7 (MYH7) and myosin-binding protein C3.3
larger scar burden and higher rates of microvascular ischemia
HCM is characterized by left ventricular (LV) hypertrophy
than do those with oHCM, and that long-term mortality risk is
in the absence of other cardiac, systemic, or metabolic dis-
not low as previously believed.7,8 Until recently, this patient
eases capable of explaining the degree of LV hypertrophy.
population had no proved medical treatment options, and
Clinical manifestations of HCM vary considerably, with
heart transplantation was the only definitive therapy, which in
symptoms ranging from none or mild exercise intolerance to
many cases is a challenge owing to unfavorable organ alloca-
severe lifestyle-limiting symptoms such as chest pain second-
tion for this condition.
ary to microvascular ischemia, syncope, or dyspnea on exer-
Current management options for HCM include lifestyle
tion secondary to LV outflow tract (LVOT) obstruction, atrial
modification, familial screening with genetic counseling,
and/or ventricular arrhythmias, diastolic dysfunction,
pharmacotherapy for symptom control, SCD risk stratifica-
advanced heart failure, and SCD.4 Obstructive HCM (oHCM)
tion with or without defibrillator implantation, septal reduc-
is characterized by LVOT obstruction and is present in
tion therapy (SRT), and, in some cases, heart
approximately 75% of patients with HCM.3 LVOT obstruc-
transplantation.4 Until recently, pharmacotherapy in HCM
tion is due to a combination of septal hypertrophy and abnor-
was limited to b blockers, calcium channel blockers, and
mal blood flow kinetics causing systolic anterior motion of
disopyramide and diuretics in refractory cases, but cardiac
myosin inhibitors (CMIs) are rapidly becoming the pre-
The Hypertrophic Cardiomyopathy Center, Department of Cardiovas-
ferred medical therapy in HCM, with mavacamten being
cular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio. Manuscript the first-in-class Food and Drug Administration-approved
received October 20, 2023; revised manuscript received and accepted October agent to specifically target symptomatic oHCM.
26, 2023.
This article is published as part of a supplement supported by an indepen- Medical Management of oHCM
dent educational grant from Bristol Myers Squibb to AcademicCME.
Funding: none. Beta blockers
See page e7 for Declaration of Competing Interest.
*Corresponding author: Tel: 216-445-5250. Medical management of HCM was first studied in 1967
E-mail address: [email protected] (M.Y. Desai). by Dr. Eugene Braunwald, who described amelioration of

0002-9149/© 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND www.ajconline.org
license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
https://doi.org/10.1016/j.amjcard.2023.10.074
 ARTICLE IN PRESS
e2 The American Journal of Cardiology (www.ajconline.org)

angina pectoris and improvement in exercise tolerance in significant difference between the results of the 2 drugs.
patients with “idiopathic hypertrophic subaortic stenosis” Thus, it showed effectiveness of verapamil for symptom
with the use of propranolol in a single-blind, placebo-con- management in HCM, comparable with propranolol. This
trolled study.9 This study included 7 patients with angina was followed by a double-blind crossover study that
and an established diagnosis of HCM, 5 of whom had revealed a comparable effect of oral diltiazem and verapa-
oHCM and 2 nHCM. Treatment with propranolol indicated mil for improving exercise tolerance in 32 patients with
improvement in exercise tolerance (12.5 minutes vs HCM.14
6.9 minutes, p <0.05) in 4 of 7 patients on the days of treat- Similarly to using b blockers, the aim of calcium chan-
ment compared with the days on placebo. nel blockers is to reduce symptoms by decreasing LV dia-
The mechanism by which b blockers are believed to stolic pressures and improving LV filling with a slower
improve symptoms and LVOT gradient in HCM is through heart rate. In addition, large concentrations of intracellular
a combination of decrease in heart rate, decreased wall ten- calcium have been identified in the myocardial tissue of
sion, and maximal contraction velocity causing increased patients with HCM who underwent surgery or transplanta-
preload, increased coronary perfusion, and decreased myo- tion, and have been associated with diastolic dysfunction
cardial oxygen requirement, all of which may decrease sys- due to incomplete myocyte relaxation.15 Thus, calcium
tolic anterior motion and LVOT obstruction, thereby blockade has been proposed to play an important role in the
improving LV function. In addition, sympathetic blockage treatment of diastolic dysfunction in this patient popula-
may inhibit supraventricular and ventricular arrhythmias.6 tion.16 This has been shown to be the case with intravenous
Since Braunwald’s first described use of b blockers in verapamil and diltiazem, but oral therapy has not consis-
HCM, ≥8 different b blockers have been studied in this tently showed improvement in diastolic function. Although
patient population (propranolol, praktolol, sotalol, acebutol, both b blockers and calcium channel blockers have indi-
nethalidol, bisoprolol, nadolol, and metipranolol). Beta cated symptom relief in patients with HCM, the combina-
blockers have been the first-line therapy for dynamic tion of these has not been studied but may have a role in the
LVOT obstruction in patients with oHCM on the basis of management of concomitant hypertension and atrial
observational cohort studies, small clinical trials, and clini- fibrillation.17
cal experience.6,10 It was not until recently that the first ran-
domized controlled trial evaluating b blockers in HCM was
Disopyramide
published.11,12 This was a double-blind, placebo-controlled,
randomized crossover trial in 29 patients with symptomatic Disopyramide is a sodium channel blocker that is a class
oHCM evaluating the hemodynamic and clinical effect of Ia antiarrhythmic drug. In contemporary practice, it is rarely
14 days of metoprolol treatment. Metoprolol treatment used to control arrhythmias owing to its proarrhythmic
caused lower resting LVOT gradient (25 mm Hg vs 72 mm potential and negative inotropic properties. However, it is
Hg, p = 0.007) than did placebo, lower exercise LVOT gra- because of this negative inotropic effect with no vasodilator
dient (28 mm Hg vs 62 mm Hg, p <0.001), and lower post- effect that disopyramide can be effective in reducing the
exercise LVOT gradient (45 mm Hg vs 115 mm Hg, p LVOT gradient of patients with oHCM.18 Its use, however,
<0.0001). In addition, patients’ New York Heart Associa- is limited by anticholinergic side effects that include dry
tion (NYHA) functional class, quality of life measured by mouth, dizziness, fatigue, and nausea, and by QT prolonga-
the Kansas City Cardiomyopathy Questionnaire (KCCQ- tion with the risk for torsades de pointes.
OSS), and LV global longitudinal strain were better during Disopyramide was first evaluated in oHCM in 1982 by
metoprolol treatment than with placebo, but exercise capac- Pollick et al,19 who reported efficacy of disopyramide in
ity, peak oxygen consumption, and N-terminal pro−B-type decreasing basal and provoked LVOT gradient in the cathe-
natriuretic peptide (NT-proBNP) did not differ between terization laboratory. The drug was subsequently evaluated
the study groups.11,12 This study did not show long-term in a multicenter registry of patients with symptomatic
effects of metoprolol, but it provides a guide on what to oHCM, showing amelioration of symptoms and a 50%
expect concerning LVOT gradient reduction with b block- reduction in LVOT gradient without major safety concerns.
ers and confirms its low side-effect profile in this patient This study also found that 66% of patients were managed
population. without the need for SRT and that all-cause mortality was
slightly less in patients treated with disopyramide, although
this finding did not reach statistical significance.20 Although
Calcium channel blockers
many of these patients were not on either b blocker or
Soon after Dr. Braunwald’s description of beta-blockade calcium channel-blocker therapy, disopyramide became
use in HCM, Rosing et al13 described the use of oral verapa- the third-line pharmacotherapy in oHCM. Given dis-
mil therapy for improvement in exercise capacity and opyramide’s antiarrhythmic properties, its use in patients
symptom relief in 19 patients with HCM (17 with oHCM with HCM may also be advantageous for preventing atrial
and 2 with nHCM) in a randomized double-blind study. fibrillation.
This study compared exercise duration of patients while on Current guidelines recommend using disopyramide or
placebo, while on small and large doses of propranolol, and SRT when nonvasodilating b blockers and/or nondihydro-
while on small and large doses of verapamil. It showed pyridine calcium channel blockers (verapamil or diltiazem)
improvement of exercise duration by 26% while on verapa- have been ineffective or not tolerated in patients with
mil compared with placebo (p <0.005) and by 21% on pro- HCM. Thus, this agent is a third-line option for patients
pranolol compared with placebo (p <0.025), without with oHCM who have persistent severe symptoms
 ARTICLE IN PRESS
XXX/Medical Treatment of Hypertrophic Cardiomyopathy e3

attributable to LVOT obstruction despite first- and second- More recently, VALOR-HCM (A Study to Evaluate
line therapy, particularly those who are not candidates for Mavacamten in Adults With Symptomatic Obstructive
SRT or have no access to an expert center capable of per- HCM Who Are Eligible for Septal Reduction Therapy), a
forming optimal SRT.6 Because disopyramide can enhance multicenter, randomized, double-blind, placebo-controlled,
conduction through the atrioventricular node, it should only phase 3 trial in 112 patients with oHCM (on maximally tol-
be used in combination with either b blocker, verapamil, or erated background medical therapy, including combination
diltiazem to prevent rapid conduction of atrial fibrillation.6 therapy § disopyramide), conducted at 19 sites in the
Although all 3 therapies described above are consid- United States, studied whether patients who were recom-
ered class 1 recommendations by the current societal mended for SRT were still eligible for SRT after taking
guidelines, the level of evidence is B-nonrandomized, mavacamten for 16 weeks. In addition, there was a planned
meaning there is moderate-quality evidence from ≥1 second phase with placebo to mavacamten crossover at
nonrandomized or observational studies. This historical 32 weeks and a longer-term planned extension up to
background indicates the great unmet need that patients 128 weeks. At 16 weeks, only 18% of patients in the mava-
with HCM faced until recently regarding available effec- camten group met the primary end point of SRT eligibility
tive pharmacotherapy. versus 77% in the placebo group (p <0.0001). Secondary
end points were also met, including decrease in postexer-
cise peak LVOT gradient 37.2 mm Hg (95% CI 48.1 to
CMIs
26.2 mm Hg) and reduction by ≥1 NYHA functional class
Mavacamten is a first-in-class, cardiac-specific molecule in 41.1% (95% CI 24.5% to 57.7%).27 At 32 weeks, 89%
that reversibly inhibits the binding of ꞵ-cardiac myosin to patients in the mavacamten group no longer remained SRT
actin through allosteric modulation.21 It was first studied in eligible, with significant improvements in NYHA class,
a feline model of oHCM and showed reduction in contrac- biomarkers, LVOT gradient, and KCCQ score.28 In addi-
tility and decrease in LVOT obstruction in an exposure- tion, both EXPLORER-HCM and VALOR-HCM have
dependent manner.22 Subsequently, a phase 1 clinical study shown a significant improvement in LV mass, left atrial
in 86 healthy subjects and 15 patients with HCM showed a volume index, markers of diastolic function, and myocar-
favorable safety profile, which led to the design of PIO- dial fibrosis.29,30
NEER-HCM (Pilot Study Evaluating MYK-461 in Subjects Although SRT has been shown to significantly reduce
with Symptomatic Hypertrophic Cardiomyopathy and Left symptoms and improve long-term survival of patients with
Ventricular Outflow Tract Obstruction), a prospective, oHCM to an equivalent rate to that of the general popula-
phase 2, multicenter, open-label study in 21 patients with tion,31−33 only a few experienced centers are able to pro-
oHCM.21 This study showed that mavacamten, used for vide optimal results and less postoperative morbidity and
12 weeks, can reduce LVOT obstruction and improve exer- mortality.34 Thus, a noninvasive option for the management
cise capacity and symptoms in patients with oHCM. After of oHCM such as mavacamten meets an important need,
this, the phase 3 EXPLORER-HCM study (Clinical Study but the durability of its effect is still unclear.
to Evaluate Mavacamten (MYK-461) in Adults with Symp- Data on extended use of mavacamten, however, are gradu-
tomatic Obstructive Hypertrophic Cardiomyopathy), a mul- ally accumulating. At European Society of Cardiology 2023,
ticenter, randomized, double-blind, placebo-controlled trial updated results of the open-label extension of VALOR-HCM
in 251 patients with oHCM (on background standard mono- were released. Patients in the original study who had been
therapy), showed that mavacamten met its primary end treated with mavacamten for 16 weeks were retained on drug;
point with an improvement in PVO2 ≥1.5 ml/kg/min with patients who had been randomized to placebo were switched
≥1 NYHA class improvement or PVO2 by 3.0 ml/kg/min to open-label mavacamten. Of the 112 patients with highly
without worsening of baseline NYHA class at 30 weeks in symptomatic oHCM originally enrolled, 108 were consid-
37% of the mavacamten group, compared with 17% in the ered eligible for the 56-week evaluation. At that time, 8.9%
placebo arm (difference +19.4%, 95% confidence interval of patients in the original mavacamten group and 19.2% of
[CI] 8.7 to 30.1, p = 0.0005). In addition, secondary analy- patients in the placebo crossover group met the composite
ses have indicated an improvement in postexercise LVOT end point. In the original mavacamten group, 3 underwent
gradient and in various cardiopulmonary exercise parame- SRT; 1 was SRT eligible, and 1 was not SRT evaluable. In the
ters, and significantly improved KCCQ scores with mava- placebo crossover group, 3 underwent SRT; 4 were SRT eli-
camten.23−25 gible, and 3 were not SRT evaluable. Overall, 96 of 108
The long-term extension of this study (MAVA-LTE) patients continued mavacamten long term.35 The authors
is an ongoing 5-year study with 231 patients from concluded that for patients with symptomatic oHCM, there is
EXPLORER-HCM. Preliminary data at a median of sufficient and sustained improvement with mavacamten,
62 weeks show persistent change in resting LVOT gradient thereby reducing the need for SRT and representing a useful
of (mean § SD) 32.8 § 30.8 mm Hg, decrease in Val- therapeutic option for patients.
salva LVOT gradient 46.4 § 35.8 mm Hg and decrease Although mavacamten is the first disease-specific ther-
in NT-proBNP peptide of 488 ng/L (interquartile range apy, other CMIs are undergoing clinical trials. This includes
1,098 to 166) whereas reduction in LV ejection fraction aficamten, which has completed the phase 2 trial (RED-
(LVEF) was 9 § 8.1%. There was also a notable decrease WOOD-HCM) and is expected to complete phase 3 trial
in NYHA class, with 68% decreasing ≥1 NYHA class and soon (SEQUIOA-HCM).36 Aficamten is a selective inhibi-
the percentage of patients in NYHA class III decreasing tor of cardiac myosin that acts by binding directly to cardiac
from 29% to 4.9%.26 myosin at a distinct allosteric binding site.37 The phase 1
 ARTICLE IN PRESS
e4 The American Journal of Cardiology (www.ajconline.org)

study, in healthy participants, showed that aficamten gradients (resting, 35.3 [33.0] mm Hg; Valsalva, 47.0
reduced myocardial contractility in a dose-dependent fash- [37.3] mm Hg), left atrial volume index ( 8.5 [10.3] ml/
ion and was well tolerated. Its pharmacokinetic profile sug- m2) and E/e’ average ( 3.9 [5.0]). At week 120, 83.5% of
gests a half-life that allows dose-titration every 2 weeks, a the patients had a Valsalva LVOT gradient ≥30 mm Hg,
shallow exposure-response relation, reversibility of drug further showing durability of benefit in nHCM.41 The phase
effect within 24 hours of discontinuation, and lack of signif- 3 trial evaluating the clinical efficacy of this drug in nHCM
icant drug-drug interactions.38 The phase 2 REDWOOD- is under way (ODYSSEY-HCM, NCT05582395) and
HCM trial showed that aficamten reduced resting and Val- expected to show results in 2025.
salva LVOT gradients compared with placebo and caused a
significant decrease in NT-proBNP levels.37 There was also Incorporation of CMI into clinical practice
improvement in NYHA functional class. Interim results of
The role of CMIs in the medical management of patients
the open-label extension of REDWOOD-HCM show that
with HCM is very promising.
aficamten significantly improved NYHA functional class in
At ESC 2023, the European Society of Cardiology
78% of the participants and was also associated with
updated their cardiomyopathy management guidelines to
improvement in quality of life.
recommend the following42:
Although CMIs appear safe, the most important safety
concern with their use is a reduction in LVEF to <50%; this
has been reported to occur with mavacamten in 2% to 3%  Cardiac myosin adenosine triphosphatase inhibitor
of patients with oHCM.24,27,28 Regarding aficamten, the (mavacamten), titrated to maximum tolerated dose with
REDWOOD-HCM trial showed a modest reduction in echocardiographic surveillance of LVEF, should be con-
LVEF of 6% to 12%. At the time of this review, mava- sidered in addition to a b blocker to improve symptoms
camten is prescribed only through the Risk Evaluation and in adults with resting or provoked LVOT (class IIa,
Mitigation Strategy program, to ensure safe and monitored level A).
administration of the drug.39  Cardiac myosin adenosine triphosphatase inhibitor
(mavacamten), titrated to maximum tolerated dose with
echocardiographic surveillance of LVEF, should be con-
Medical Management of nHCM sidered as monotherapy in adults with symptomatic rest-
Symptom management of nHCM poses a therapeutic ing or provoked LVOT obstruction who are intolerant
challenge, given the limited effectiveness of currently avail- or have contraindications to b blockers, verapamil/
able therapies. Although the use of b blockers and calcium diltiazem, or disopyramide (class IIa, level B).
channel blockers has a class 1 recommendation in current
HCM guidelines, this has been based on the small historical On the basis of the available evidence, mavacamten
trials described earlier, which did not specifically evaluate should be recommended for patients with oHCM who have
patients without LVOT obstruction. In fact, patients with ongoing symptoms and LVOT obstruction despite trial of b
nHCM have large symptom burden mostly driven by dia- blockers or calcium channel blocker (or be intolerant to
stolic dysfunction, and current therapies are focused on these drugs). In addition, they will likely be indicated in
managing arrhythmias and decreasing LV filling pressures patients who have an indication for SRT but wish to avoid
with b blockers, verapamil, and diuretics.21 The first trial or delay surgery or have no access to an expert HCM center
evaluating safety of mavacamten in nHCM was MAVER- able to provide optimal SRT. Whether CMIs become first-
ICK-HCM (A Randomized, Double-blind, Placebo-con- line therapies in oHCM is still to be determined. We expect
trolled, Concentration-guided, Exploratory Study of disopyramide will likely fall from favor and become a
Mavacameten in Patients With Symptomatic Non-Obstruc- fourth to fifth line of therapy, only indicated for patients
tive Hypertrophic Cardiomyopathy (nHCM) and Preserved with contraindications or intolerance to CMIs.
Left Ventricular Ejection Fraction), a phase 2, multicenter, Concerning the use of CMI in nHCM, data are limited
double-blind, randomized, placebo-controlled study. It to include its use in this patient population in guidelines,
included 59 adults with symptomatic nHCM and indicated but this will likely change in the next 5 years. Figure 1 and
that treatment was associated with a significant reduction in Table 1 summarize the level of evidence, study findings,
NT-proBNP and cardiac troponin I, suggesting improve- and pharmacologic effect of the available medical treatment
ment in myocardial wall stress.40 for patients with HCM.
In an extension study, MAVERICK-LTE, longer-term
mavacamten was well tolerated and showed sustained
Future Directions in Medical Management
reduction in NT-proBNP in patients with nHCM.41 A fur-
ther extension of open-label mavacamten use in these Despite limited advances in the medical treatment of
patients was reported at European Society of Cardiology HCM since its initial description and early trials in the
2023, with follow-up now available to 120 weeks. Mava- 1960s, over the past decade, a major development occurred
camten dosing of the 80 patients who reached week 120 with the introduction of mavacamten to the market
was 2.5 mg (27.5%); 5 mg (31.3%); 10 mg (26.3%); and (Figure 2). It is too early to know the extent of the impact
15 mg (12.5%). From weeks 48 to 120, 14.7% of patients CMIs will have on current practice because long-term
underwent dose adjustments. Results indicated mavacamten effects on outcomes remain to be determined. However, the
treatment was associated with sustained improvements in short- and medium-term effects on symptoms and quality
mean [SD] change from baseline to week 120 in LVOT of life are very positive. Future head-to-head comparison of
 ARTICLE IN PRESS
XXX/Medical Treatment of Hypertrophic Cardiomyopathy e5

Figure 1. Summary of treatment effect of medical management of HCM.

CMIs with SRT may allow us to better understand whether operator.33 In addition, future head-to-head comparisons of
medical management of HCM will ever be comparable to different CMIs will help us better understand optimal medi-
surgical management, which is very effective and close to cal management in patients with HCM. As mentioned ear-
curative in patients with oHCM, with low associated surgi- lier, ongoing studies will determine the benefit of CMIs in
cal mortality (<0.5%) and low stroke risk (as low as 0.7%) patients with nHCM. Furthermore, the effect of CMIs
but carries a risk of complete heart block requiring perma- in suppressing ventricular arrhythmias and SCD remains
nent pacemaker implantation (7%), postoperative atrial not known, but early introduction of CMIs, before the
fibrillation (20%), and suboptimal LVOT obstruction relief development of fibrosis, may decrease the incidence of
requiring redo cardiac surgery (3.4%) despite experienced SCD, need for defibrillator therapy, and ventricular

Table 1
Available medical treatment for patients with HCM with study findings and level of evidence
Medication Study findings Level of evidence
Beta-blockers -Propranolol improves angina and exercise tolerance compared to placebo -Single-blind placebo controlled study
-Metoprolol lowers resting and exercise-induced LVOT obstruction and -Observational cohorts
improves quality of life compared to placebo -Double-blind, placebo-controlled, randomized
crossover trial
Calcium channel -Verapamil improves exercise capacity compared to placebo at a compara- -Randomized double-blind study
blockers ble effect with propranolol -Double-blind crossover study
-Diltiazem improves exercise tolerance similar to verapamil
Disopyramide -Disopyramide improves symptoms and lowers LVOT gradient by 50% -Multicenter observational registry
Cardiac myosin -Mavacamten (Phase 1, 2 and 3 trials) improves exercise capacity, LVOT -Randomized placebo controlled trials
inhibitors obstruction, NYHA functional class,
and health status in oHCM compared to placebo
-Mavacamten significantly reduces the fraction of patients meeting guide-
line criteria for SRT
-Mavacamten reduces NT-proBNP and troponin in nHCM
-Aficamten improves exercise capacity, LVOT gradient, NYHA class
(PHASE 2)
LVOT = left ventricular outflow tract; nHCM = non-obstructive hypertrophic cardiomyopathy; NYHA = New York Heart Association;
oHCM = obstructive hypertrophic cardiomyopathy; SRT = septal reduction therapy.
 ARTICLE IN PRESS
e6 The American Journal of Cardiology (www.ajconline.org)

Figure 2. Major landmark studies evaluating available medical therapies for patients with oHCM.

arrhythmias. Future studies should be designed to answer editing, and gene replacement.43,44 In recent years, gene
these questions. Based on what is known, we propose editing using adenoviral and adeno-associated viral vectors
Figure 3 as an algorithm to guide management of symptom- has been increasingly studied in HCM. Clustered regularly
atic patients with HCM. interspaced short palindromic repeats (CRISPR) gene edit-
An important and developing approach in the manage- ing has been evaluated in vitro and in vivo using mouse
ment of HCM is the development of gene therapies that models with pathogenic myosin-binding protein C3 or
include allele-specific ribonucleic acid silencing, gene MYH7 variants, using adenine base editing with adenoviral

Figure 3. Suggested treatment algorithm for managing patients with HCM.

EDV = end diastolic volume; MR = mitral regurgitation; QoL = quality of life; RCT = randomized controlled trial.
*Mavacamten is approved in patients with oHCM and NYHA class II to III who are not on disopyramide monotherapy or dual therapy with blocker or cal-
cium channel blocker. On the basis of trials, it is expected to receive a class I indication, likely after a trial of blockers.
 ARTICLE IN PRESS
XXX/Medical Treatment of Hypertrophic Cardiomyopathy e7

or adeno-associated viral vectors to deliver on-target 1. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE.
editing.45,46 Those studies have shown correction of patho- Prevalence of hypertrophic cardiomyopathy in a general population of
genic variant in up to 70% of ventricular cardiomyocytes young adults. Echocardiographic analysis of 4111 subjects in the
CARDIA study. Coronary Artery Risk Development in (Young)
with reduction in hypertrophy and fibrosis but have been Adults. Circulation 1995;92:785–789.
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2018;138:1387–1398.
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