Hypertrophic cardiomyopathy is defined as increased left ventricular wall thickness or mass exceeding 15 millimetres that cannot be explained by loading conditions such as hypertension. In children, the wall thickness must exceed two standard deviations above the predicted mean for body surface area. The disease is typically inherited in an autosomal dominant fashion, driven by variants in sarcomere protein genes, with MYH7, MYBPC3, TNNT2 and TPM1 together accounting for roughly 30 to 40 percent of cases. Historically estimated to affect about one in 500 people, newer estimates suggest prevalence could be as high as one in 300 or one in 200, making it the most common identifiable cause of sudden cardiac death in young people under 35. Yet overall survival for most patients is comparable to an age- and sex-matched population without heart disease, and many carriers never develop clinically detectable disease, with reported penetrance of 57 percent.

At the molecular level, the disease disrupts the energetic economy of the heart muscle. In a healthy heart, 40 to 50 percent of myosin heads sit in an energy-sparing off state; in hypertrophic cardiomyopathy, this proportion is cut by more than half, leaving only 15 to 20 percent switched off. The surplus active myosin heads consume extra adenosine triphosphate and bind actin more readily, generating excessive cross-bridges during both contraction and relaxation. The result is inefficient, overly forceful contraction and impaired filling, which over time triggers pro-hypertrophic, pro-inflammatory and pro-fibrotic pathways, producing fibrosis, myocyte disarray and increased mechanical stress. When this hypertrophy narrows the outflow tract — through thickening of the interventricular septum and its interaction with the mitral valve’s systolic anterior motion — the condition is classified as the obstructive form, which is associated with dangerous ventricular arrhythmias.

Traditional drug therapy remains the first step. Non-vasodilating beta blockers, titrated to the maximum tolerated dose, have been recommended since the mid twentieth century; they reduce the outflow tract gradient by slowing heart rate and contractility, improving diastolic filling. Evidence comparing individual agents is sparse, but one of the few randomised trials showed metoprolol significantly reduced outflow gradients before, during and after exercise by 47, 34 and 70 millimetres of mercury respectively, with improved symptoms and quality of life. In the BASIC study, bisoprolol produced a mean gradient reduction of 28 millimetres of mercury, with 36 percent of patients falling below 30 millimetres and 33 percent improving by at least one New York Heart Association class. The non-dihydropyridine calcium channel blockers verapamil and diltiazem offer alternatives, though verapamil is contraindicated with beta blockers because of the risk of severe bradycardia, hypotension and conduction block, and should not be used in severe obstruction or raised pulmonary pressure because of the risk of pulmonary oedema.

For patients who remain symptomatic, disopyramide — a class IA antiarrhythmic with strong negative inotropic effects — is added on top of an atrioventricular nodal blocking agent rather than used alone. It is particularly effective at lowering outflow gradients in adults, but carries anticholinergic side effects including constipation, urinary retention, blurred vision and dry mouth, requires routine QTc monitoring with dose reduction above 500 milliseconds, and is contraindicated with other QT-prolonging drugs, glaucoma and prostatism. A cautionary note comes from a 2023 study of 51 children with the condition, the largest to date in childhood use, in which early symptomatic improvement exceeding 80 percent was not maintained in 33 percent of patients — a tachyphylaxis phenomenon that may limit the drug’s long-term value as a way of deferring escalation. Supply chain problems in the United Kingdom have further complicated its use.

When drugs fail, invasive septal reduction therapy takes over. Surgical ventricular septal myectomy, the primary surgical option, is an open-heart procedure performed under general anaesthesia with cardiopulmonary bypass, in which hypertrophied basal septal tissue is excised through an aortotomy under transoesophageal echocardiographic guidance. It reduces outflow tract gradients in more than 90 percent of patients, and concomitant procedures — mitral valve repair in about 9 percent of cases, coronary bypass grafting in roughly 5 percent, and Cox-Maze IV ablation for atrial fibrillation — address associated anomalies in around 30 percent. A 2005 study of 289 patients reported survival of 98, 96 and 83 percent at one, five and ten years, comparable to the general population, while a study following 1,999 children over more than 45 years found operative mortality of just 1 percent, with redo myectomy needed in 5.8 percent at five years and 8.3 percent at ten years.

Alcohol septal ablation offers a minimally invasive alternative: one to three millilitres of 96 to 100 percent ethanol is injected into a targeted septal branch of the left anterior descending coronary artery, inducing a controlled localised infarction that thins the septum and widens the outflow tract over weeks to months. It works best in patients with septal thickness of at least 17 millimetres and favourable coronary anatomy, and about 90 percent of patients improve to New York Heart Association class I or II. But it carries a pacemaker requirement in 5 to 15 percent of cases, ventricular arrhythmias in 1 to 2 percent, and a risk of coronary damage. Generally, myectomy is preferred for younger, lower-risk patients with marked hypertrophy above 30 millimetres or complex mitral and subvalvular anatomy, while ablation suits older or higher-risk patients unsuitable for surgery. A 2023 study of 19,007 patients treated between 2010 and 2019 found surgical outcomes depended strongly on hospital volume, whereas ablation outcomes did not — though low-volume operators were associated with increased 30-day mortality for both procedures.

Into this landscape come the myosin inhibitors, which directly address the disease’s core mechanism by stabilising myosin heads in their inactive, ATP-bound state, limiting cross-bridge cycling and reducing contractility. Mavacamten, approved by the FDA in 2022 and by the MHRA and NICE in 2023, was the first in class. In the pivotal EXPLORER-HCM trial — a phase 3, randomised, double-blind, placebo-controlled study of 251 adults with New York Heart Association class II or III symptoms and outflow gradients of at least 50 millimetres of mercury despite background therapy — 37 percent of mavacamten patients met the primary composite functional endpoint versus 17 percent on placebo, with significant gradient reduction, symptom improvement and generally good tolerability, though a small number experienced reversible ejection fraction reductions requiring monitoring. Benefits have been sustained through 180 weeks of extension follow-up, with up to 80 percent of patients achieving elimination of obstruction after six months in subsequent studies.

Aficamten, a second-in-class agent approved by the FDA and NICE, is building its own evidence base rapidly. The SEQUOIA-HCM phase 3 trial of 282 participants showed improved exercise capacity, symptoms, outflow gradients and mitral regurgitation, with serious adverse events in only 5.6 percent; among patients eligible for septal reduction at baseline, 88 percent were no longer eligible after 24 weeks. The MAPLE-HCM study demonstrated aficamten’s superiority over metoprolol in obstructive disease, raising the possibility that myosin inhibitors could challenge beta blockers as default first-line therapy in selected patients. Similarly, the VALOR-HCM trial found that only 17.9 percent of mavacamten-treated patients referred for septal reduction remained eligible at 16 weeks, compared with 76.8 percent on placebo. These findings suggest many patients once destined for surgery may be managed pharmacologically instead.

Important limits remain. The drugs act slowly, typically needing four to eight weeks for significant gradient reduction, and achieve reductions of 30 to 50 millimetres of mercury — substantial, but less consistently complete than myectomy’s near-universal reductions below 10 to 20 millimetres. Discontinuation leads to recurrence of obstruction, and lifelong echocardiographic surveillance of ejection fraction is required to avoid excessive systolic suppression. In non-obstructive disease the picture is mixed: mavacamten failed to improve exercise capacity or health status over placebo in the 580-person ODYSSEY-HCM trial, while aficamten met its primary endpoint in ACACIA-HCM, though its effect on peak oxygen uptake (0.64 millilitres per kilogram per minute) was far smaller than in the obstructive SEQUOIA trial (1.8). Longer-term durability data, cost-effectiveness analyses, access and monitoring burden remain unresolved, and the authors note that treatment choice — including gene therapy, which has so far shown promise only in mouse models — should be individualised through a multidisciplinary team balancing anatomy, comorbidities and patient preference.

Subject of Research: Treatment options for hypertrophic obstructive cardiomyopathy, including traditional drug therapies, septal reduction procedures and the emerging role of cardiac myosin inhibitors

Article Title: Treatment options for hypertrophic obstructive cardiomyopathy in the era of myosin inhibitors

Article References: Nwuba, C., & Dungu, J. N. (2026). Treatment options for hypertrophic obstructive cardiomyopathy in the era of myosin inhibitors. Frontiers in Cardiovascular Medicine, 13, 1814860. https://doi.org/10.3389/fcvm.2026.1814860

Image Credits: AI Generated

DOI: 10.3389/fcvm.2026.1814860

Keywords: hypertrophic obstructive cardiomyopathy, mavacamten, aficamten, myosin inhibitors, septal myectomy, alcohol septal ablation, left ventricular outflow tract obstruction, beta blockers, disopyramide, EXPLORER-HCM, SEQUOIA-HCM, sudden cardiac death

Hypertrophic cardiomyopathy is a disorder in which the main pumping chamber of the heart thickens abnormally, and roughly two-thirds of affected individuals develop dynamic obstruction of the left ventricular outflow tract, the pathway through which blood exits the heart. Improved genetic testing has pushed estimated prevalence upward from about 0.16 to 0.23 percent toward 0.2 to 0.5 percent, with pathogenic gene variants identified in roughly 60 percent of cases. Traditional drug therapy relies on beta-blockers and non-dihydropyridine calcium channel blockers, which blunt symptoms but do not address the underlying hypercontractility that drives the obstruction. Mavacamten works differently: it selectively inhibits cardiac myosin, directly reducing the excessive contractile force at the root of the disease. China approved the drug on 24 April 2024 for patients in NYHA functional class II or III, marking a shift from purely symptomatic management toward mechanism-based treatment.

The new analysis drew on patients hospitalized at Fuwai Central China Cardiovascular Hospital between January 2024 and May 2025. Of 317 patients initially screened, 57 were excluded for reasons including age under 18, NYHA class I or IV status, severe renal or hepatic dysfunction, incomplete echocardiographic data, or refusal of follow-up. The remaining 260 eligible patients were assigned to groups according to mavacamten availability after its approval, standardized eligibility criteria, and physician judgment: 126 began mavacamten and 134 started conventional pharmacotherapy with beta-blockers, non-dihydropyridine calcium channel blockers, or both. After 30 weeks of follow-up, 38 patients had been lost, leaving 222 patients, 111 in each group, for the final analysis. To qualify, all patients had to meet diagnostic criteria from the 2023 Chinese guidelines, including a resting or Valsalva-provoked outflow tract gradient of at least 30 mmHg together with defined myocardial hypertrophy, and a baseline ejection fraction of at least 55 percent.

Mavacamten was dosed according to a hospital protocol adapted from the EXPLORER-HCM and EXPLORER-CN trials. Patients began at 2.5 mg once daily, with titration at weeks 6, 12 and 18 guided by serial echocardiography. Doses could be increased stepwise to 5, 10 and 15 mg if the resting gradient remained at or above 30 mmHg while the ejection fraction stayed at or above 55 percent. A dose reduction was mandatory if the ejection fraction fell to between 45 and 54 percent, and the drug was stopped immediately if it dropped below 45 percent. Electronic prescription records, outpatient follow-up notes and adverse event documentation were cross-checked to confirm adherence. The control group received conventional therapy prescribed at physician discretion under current American and Chinese guidelines, with dose adjustments at weeks 4 and 12 based on heart rate, blood pressure and symptoms.

The hemodynamic results were striking. By week 30, the resting outflow tract gradient in the mavacamten group had fallen to 23.76 plus or minus 4.09 mmHg against 78.49 plus or minus 13.21 mmHg in controls, a difference the authors report with a t-statistic of 24.074 and a p-value below 0.001. The Valsalva-provoked gradient fell to 48.95 plus or minus 11.10 mmHg versus 113.59 plus or minus 14.92 mmHg, with a t-statistic of 21.147. Longitudinal modeling with linear mixed-effects models confirmed significant group-by-time interactions for both gradients, showing that the mavacamten group improved continuously from baseline to week 30 while the control group initially worsened and then declined modestly, remaining far higher at every time point. Fully adjusted between-group differences at week 30 reached minus 50.96 mmHg for the resting gradient and minus 60.42 mmHg for the provoked gradient, with confidence intervals excluding zero.

Biomarkers of cardiac stress moved in the same direction. At week 30, high-sensitivity cardiac troponin I averaged 6.50 ng/L in the mavacamten group versus 13.19 ng/L in controls, and N-terminal pro-B-type natriuretic peptide was lower at a median of 1,082 pg/mL versus 2,361 pg/mL. However, the adjusted analysis complicates this picture: the troponin difference remained robustly significant after adjustment, but the NT-proBNP difference, initially significant in unadjusted comparisons at week 30, became marginally non-significant after full adjustment for baseline structural differences, age, sex and baseline values. The authors attribute this attenuation partly to baseline imbalances in left ventricular end-diastolic diameter, left atrial volume index and end-systolic volume between the groups, which reflect the non-randomized design. Tricuspid annular plane systolic excursion, a marker of right ventricular function, was higher in the mavacamten group at week 30, suggesting preserved right ventricular longitudinal function.

Safety findings deserve careful attention. Although the mean ejection fraction at week 30 did not differ significantly between groups, at 55.12 versus 56.78 percent, the change from baseline told a different story. The mavacamten group experienced progressive ejection fraction declines that peaked at minus 15.76 percent at week 18, compared with essentially stable values in controls, and the decline remained at minus 13.68 percent at week 30. Twelve mavacamten patients, 9.5 percent, saw their ejection fraction fall below 50 percent, versus 2.2 percent of controls, and four patients, 3.2 percent, discontinued the drug because their ejection fraction dropped below 45 percent. Overall adverse event rates were similar between groups, at 19.0 versus 20.9 percent, with serious events rare in both. The authors emphasize that these figures reinforce the necessity of routine echocardiographic surveillance and standardized dose-adjustment protocols, since delayed-onset systolic dysfunction is a recognized risk of myosin inhibition.

Functional and symptomatic outcomes were more nuanced. The six-minute walk distance improved steadily in the mavacamten group, reaching 456.83 meters at week 30 versus 385.47 meters in controls, a highly significant difference. On the Kansas City Cardiomyopathy Questionnaire, the symptom frequency and symptom burden subdomains favored mavacamten significantly, yet the overall clinical summary score did not differ between groups. The authors suggest several explanations: baseline scores in their cohort were higher than in the EXPLORER-HCM trial, leaving less room for improvement, the Chinese-language questionnaire may incompletely capture exertional breathlessness in these patients, and 30 weeks may be too short for symptomatic gains to catch up with hemodynamic improvement. Subgroup analyses found no significant heterogeneity by age, sex or clinical strata for the summary score.

Background medication use shifted in ways that may have influenced the comparison. In the mavacamten group, beta-blocker use fell from 70.6 percent at baseline to 55.6 percent at week 30, with some patients discontinuing background therapy entirely after their gradient dropped below 30 mmHg, likely reflecting physician caution about the combined negative inotropic effects. In the control group, beta-blocker use intensified from 76.1 to 86.6 percent, with higher equivalent metoprolol doses at week 30. The authors note that this dynamic, in which the intervention group de-escalates while the control group optimizes, introduces a form of performance bias that may underestimate mavacamten’s true incremental benefit. They also cite the PIONEER-HCM trial, where concomitant beta-blocker use attenuated the gradient reduction from 89.5 mmHg to 25 mmHg, and note that the absence of disopyramide at their institution means the control arm did not represent the full pharmacological arsenal available elsewhere.

The authors are careful about what the study can and cannot establish. As a retrospective, single-center observational study with physician-driven, non-randomized treatment allocation, the findings are associative rather than causal, and residual confounding from unmeasured factors such as myocardial fibrosis burden, specific sarcomere variants or prior treatment intensity cannot be excluded. No CYP2C19 metabolizer phenotyping or systematic genetic testing was performed. The 30-week follow-up also precludes conclusions about long-term durability, late-onset systolic dysfunction, or effects on septal reduction therapy, hospitalization and mortality. Within those limits, the study offers some of the first post-marketing Chinese real-world data on a drug that transforms the hemodynamics of obstructive hypertrophic cardiomyopathy, and it supports the growing case that mechanism-targeted myosin inhibition can deliver profound, sustained obstruction relief, provided that vigilant monitoring of cardiac function accompanies every step of dose titration.

Subject of Research: Real-world clinical effectiveness of mavacamten in obstructive hypertrophic cardiomyopathy

Article Title: Clinical effectiveness of mavacamten on cardiac function and disease-related indicators in patients with obstructive hypertrophic cardiomyopathy

Article References: Shi, Y.-N., Huang, J.-J., Liu, H.-Z., Xu, Y., & Yuan, F. (2026). Clinical effectiveness of mavacamten on cardiac function and disease-related indicators in patients with obstructive hypertrophic cardiomyopathy. Frontiers in Pharmacology, 17, Article 1861248. https://doi.org/10.3389/fphar.2026.1861248

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1861248

Keywords: mavacamten, obstructive hypertrophic cardiomyopathy, cardiac myosin inhibitor, left ventricular outflow tract gradient, LVEF, NT-proBNP, high-sensitivity troponin I, beta-blockers, echocardiography, retrospective study, drug safety, real-world evidence