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Background:

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder, affecting 1 in 500 individuals worldwide, with obstructive physiology in ~70% of patients. Untreated HCM carries significant risks: sudden cardiac death, progressive heart failure, atrial fibrillation, and thromboembolic stroke. HCM pathophysiology involves excessive actin-myosin cross-bridge formation, causing myocardial hypercontractility, left ventricular outflow tract (LVOT) obstruction, impaired diastolic relaxation, and increased myocardial energy demands. Traditional therapies (beta-blockers, calcium channel blockers, disopyramide), offer symptomatic relief but fail to address the underlying sarcomeric dysfunction. Cardiac myosin inhibitors represent a substantial breakthrough, directly targeting sarcomeric hypercontractility through allosteric inhibition of myosin ATPase, reducing cross-bridge formation and allowing for a relaxed, energy-sparing state. Mavacamten (FDA approved  2022) and aficamten (approved 2025) have demonstrated substantial improvements in patient outcomes, both physiologically and symptomatically. However, real-world data on clinical response patterns, hemodynamic correlates, and genetic influences on treatment outcomes remain limited, compelling a real-world multicenter analysis to optimize and personalize HCM management.

Objective: 

To explore whether there are clinical, hemodynamic, and cardiogenetic associations of mavacamten use outcomes in a real-world multicenter cohort of patients with obstructive hypertrophic cardiomyopathy, with a focus on symptom improvement, LVOT gradient reduction, dose modification, and adverse outcomes. 

Methods: 

We performed a retrospective multicenter observational study of patients with obstructive HCM treated with mavacamten across 5 centers. Clinical, echocardiographic, laboratory, and cardiogenetic data were collected. Analysis focused on patients with completed follow-up. Treatment response was assessed by changes in New York Heart Association (NYHA) class and LVOT gradients after mavacamten initiation, including follow-up at 3, 6, 9, and 12 months. Outcomes of interest included dose modification, treatment discontinuation, and adverse clinical events. Group comparisons were performed using descriptive statistics and unadjusted exploratory analyses. 

Results:

286 of 336 patients treated with mavacamten across 5 centers, had completed follow-up. Mavacamten was associated with significant symptomatic and hemodynamic improvement, with NYHA class improving at 3, 6, 9, and 12 months. In patients with paired echocardiographic data, median resting LVOT gradient decreased from 39.0 to 9.5 mmHg (n=242, p<0.0001) and median Valsalva LVOT gradient decreased from 77.0 to 19.0 mmHg (n=240, p<0.0001). Dynamic LVOT obstruction improved in substantially more patients than it worsened (136 yes-to-no versus 5 no-to-yes, n=262 paired), although 52/110 baseline-obstructive patients with 12-month data remained obstructive. Down-titration and/or discontinuation occurred in 75 and 43 patients, respectively and one or more recorded adverse outcomes/interventions occurred in 118/286 patients. Exploratory preliminary analyses suggested that adverse outcomes were associated with higher baseline BMI, obesity, and obstructive sleep apnea, whereas no consistent cardiogenetic associations with treatment response or adverse outcomes were identified.

Conclusions:

In a real-world multicenter cohort of patients with obstructive hypertrophic cardiomyopathy, mavacamten was associated with significant improvement in symptoms and LVOT gradients. Dose modification and treatment discontinuation were not uncommon, and exploratory analyses suggested that patients with a higher baseline comorbidity burden, particularly higher BMI, obesity, and obstructive sleep apnea, were more likely to experience adverse outcomes, whereas no clear cardiogenetic associations were identified.