Mavacamten Versus Alcohol Septal Ablation in Obstructive Hypertrophic Cardiomyopathy: An Echocardiography-Derived Pressure-Volume Analysis

Background: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by left ventricular (LV) outflow tract obstruction, which increases afterload and chronically activates the Anrep response, a compensatory (afterload-driven) state of hyperdynamic systole, prolonged systolic ejection time, and increased myocardial workload. We investigated whether the myosin inhibitor mavacamten reverses this state, comparing its effects to the anatomic relief achieved by alcohol septal ablation. Methods: Thirty-six patients with symptomatic oHCM were treated with mavacamten. Of these, 29 who achieved a resting LV outflow tract gradient <50 mm Hg at 3 months (responders) underwent echocardiography-derived pressure-volume analysis before and after therapy. For comparison, a separate cohort of 13 patients with oHCM underwent identical pressure-volume analysis before and 3 months post-alcohol septal ablation. Anrep-related indices were quantified: afterload (LV end-systolic pressure and effective arterial elastance), contractility (end-systolic elastance and end-systolic volume at 150 mm Hg), and systolic ejection time. Myocardial workload (stroke work, potential energy, and pressure-volume area) and diastolic function (LV end-diastolic pressure, end-diastolic volume, and volume at 15 mm Hg LV end-diastolic pressure) were also assessed. Results: At baseline, all patients showed chronic activation of the Anrep response: elevated afterload (high LV end-systolic pressure and effective arterial elastance), hypercontractility (high end-systolic elastance and low end-systolic volume at 150 mm Hg), and prolonged systolic ejection time, accompanied by increased mechanical workload (elevated stroke work, potential energy, and pressure-volume area). After 3 months, both mavacamten responders and alcohol septal ablation responders showed comparable ventricular unloading: reductions in afterload and contractility, shortened systolic ejection time, and decreased myocardial workload, all while preserving stroke volume. Diastolic indices improved (increased end-diastolic volume and volume at 15 mm Hg LV end-diastolic pressure, and decreased LV end-diastolic pressure). Conversely, in mavacamten nonresponders (persistent LV outflow tract gradient ≥50 mm Hg at 3 months), Anrep-related indices and myocardial workload did not change. Conclusions: In oHCM, chronic Anrep activation maintains cardiac output against elevated afterload at high energetic cost. Our finding that mavacamten and alcohol septal ablation produce comparable hemodynamic corrections establishes the reversal of this afterload-driven state as a central mechanistic target of therapy in oHCM.