Mavacamten vs. alcohol septal ablation in obstructive hypertrophic cardiomyopathy: an echocardiography-derived pressure-volume analysis

Background Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by left ventricular outflow tract (LVOT) obstruction, which increases afterload and chronically activates the Anrep effect, a compensatory (afterload-driven) state of hyperdynamic systole, prolonged systolic ejection time (SET), 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 (ASA). Methods Thirty-six symptomatic oHCM patients were treated with mavacamten. Of these, 29 who achieved a resting LVOT gradient <50 mmHg at 3 months (responders) underwent echocardiography-derived pressure–volume (PV) analysis before and after therapy. For direct comparison, a separate cohort of 13 oHCM patients underwent identical PV analysis before and 3 months post-ASA. Key Anrep-related indices were quantified: afterload (LV end-systolic pressure [LVESP], effective arterial elastance [Ea]), contractility (end-systolic elastance [Ees], end-systolic volume at 150 mmHg [ESV150]), and systolic duration (SET). Myocardial workload (stroke work [SW], potential energy [PE], pressure–volume area [PVA]) and diastolic function (LV end-diastolic pressure [LVEDP], end-diastolic volume [EDV], and volume at 15 mmHg LVEDP [V15]) were also assessed. Results At baseline, patients exhibited a hemodynamic signature of chronic Anrep activation: elevated afterload (high LVESP, Ea), hypercontractility (high Ees, low ESV150), and prolonged SET, accompanied by increased mechanical workload (elevated SW, PE, PVA). After 3 months, both mavacamten responders and ASA responders showed comparable ventricular unloading: reductions in afterload and contractility, shortened SET, and decreased myocardial workload, all while preserving stroke volume and mechanical efficiency. Diastolic indices showed modest improvements, with increased EDV and V15, and decreased LVEDP. Conversely, in the 6 mavacamten non-responders (LVOT gradient >50 mmHg at 3 months), Anrep-related indices and myocardial workload were unaltered, although a slight reduction in myocardial wall stress was observed. Conclusion In oHCM, chronic Anrep activation maintains cardiac output against elevated afterload at high energetic cost. Our finding that mavacamten (molecular myosin inhibition) and ASA (anatomic relief) produce highly comparable hemodynamic corrections establishes the reversal of this afterload-driven state as a central mechanistic target of therapy in oHCM.