Abstract 20593: In vivo Cardiac Effects of Mavacamten (MYK-461): Evidence for Negative Inotropy and Improved Compliance

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Abstract

Background: Hypertrophic cardiomyopathy (HCM) is a heritable cardiac disease characterized by hyper-contractility and impaired ventricular relaxation. Conventional negative inotropes can alleviate enhanced inotropy in HCM, but do not improve ventricular filling. Mavacamten (MYK-461) is a novel small molecule that reduces contractility by modulating cardiac myosin. This study assessed the acute and chronic cardiovascular responses to mavacamten in dogs.

Methods: For acute studies, dogs were chronically instrumented for arterial pressure and LV pressure-volume (LVPV) recordings. Data were obtained before and after oral treatment with either mavacamten (n = 8) or metoprolol (2 mg/kg, n = 6); systemic and LV hemodynamics, geometry, and load-independent function were examined by LVPV relationships. For chronic studies, non-instrumented dogs received either vehicle (VEH, n = 12) or mavacamten (n = 12) daily for 39 weeks; cardiac geometry and function were examined by echocardiography before and during treatment.

Results: Acutely, mavacamten decreased (P < 0.05) both load-dependent (dP/dtmax: -24 ± 5%, EF: -27 ± 5%) and independent (PRSW: -35 ± 2%) inotropic indices, while preserving systemic pressure (MBP: 107 ± 6 to 109 ± 5 mmHg). Mavacamten increased LV EDV (+13 ± 4%, P < 0.05), but preserved both EDP (6 ± 1 to 7 ± 1 mmHg) and estimated stiffness (2.0 ± 0.2 to 2.2 ± 0.3 mmHg/mL). In contrast, metoprolol at matched negative inotropy (PRSW: -31 ± 4%), increased (P < 0.05) both EDP (6 ± 0 to 10 ± 1 mmHg) and stiffness (1.8 ± 0.1 to 2.5 ± 0.1 mmHg/mL) with only modest changes in EDV (+3 ± 1%). Chronically, mavacamten decreased EF (-34 ± 3% vs. VEH) and increased EDV (+39 ± 6% vs. VEH), but preserved left-atrial dimensions (+2 ± 3%), IVRT (+6 ± 2%), E/e’ ratios (-12 ± 5%) and circulating NT-proBNP levels.

Conclusions: Direct myosin modulation with mavacamten has a unique in vivo cardiovascular profile characterized by reductions in systolic function with preserved systemic and ventricular filling pressures and improved LV compliance. This cardiovascular profile, supported by a right-/down-ward shift in LV pressure-volume relationships, could have salutary effects in patients with HCM and/or impaired ventricular filling.

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