Abstract 17492: Chronic Treatment With a Mavacamten-Like Myosin-Modulator (MYK-581) Prevents Left-Atrial Remodeling, Decreases Cardiac Troponin Leakage, and Blunts Mortality in a Mini-Pig Model of Inherited Hypertrophic Cardiomyopathy

Abstract

Introduction: Hypertrophic cardiomyopathy (HCM) is a progressive disease characterized by cardiac remodeling, impaired relaxation, left-atrial enlargement, and exertional intolerance. Direct myosin-inhibition with mavacamten can normalize contractility and improve exercise capacity in patients with obstructive HCM (oHCM). However, mavacamten also limits residual cross-bridges during diastole, and therefore, may offer cardiac benefits beyond obstruction relief. This in vivo study evaluated the chronic effects of MYK-581, a mavacamten surrogate, in a genetic large-animal model of HCM. Methods: Young cloned Yucatan mini-pigs with a heterozygous MYH7 R403Q mutation were randomly assigned to one of two arms: untreated-controls (CTRL, n = 29) or daily MYK-581 (n = 22; PO); wild-type pigs (WT) untreated served as disease-controls. After 14 weeks of treatment, pigs underwent in vivo cMR imaging, including T1 mapping and extracellular volume (ECV) assessments. In a subset of pigs, biomechanical studies were performed in skinned left-ventricular (LV) and left-atrial (LV) fibers. *, #: P<0.05 vs. CTRL or WT. Results: In HCM pigs, MYK-581 treatment decreased mortality (9.0* vs. 37.9% in CTRL). MYK-581 blunted cTnT leakage, reducing both absolute values (21.2 ± 3.2* vs. 34.0 ± 4.3 ng/L in CTRL) and the incidence of cTnT > 20 ng/L (36* vs. 81% in CTRL). Treated pigs had smaller LA volumes (16 ± 1* vs. 29 ± 4mL in CTRL) with lower LV T1-times and ECV (27 ± 1* vs. 32 ± 2% in CTRL). LA fibers from untreated HCM pigs showed biomechanical remodeling characteristic of chronic overload: increased maximal force (21.8 ± 1.5# vs. 14.7 ± 1.4 mN/mm2 in WT) and slowed cross-bridge formation rates (Ktr: 4.9 ± 0.4 # vs. 6.6 ± 0.6 s-1 in WT) consistent with a switch towards slow-myosin isoforms. MYK-581 prevented this remodeling (e.g., Ktr: 8.1 ± 1.3 s-1*), preserving normal LA (fast) myosin content. Conclusions: Chronic direct myosin attenuation with a mavacamten surrogate prevented left-atrial remodeling, a known prognostic indicator in HCM. Chronic treatment also reduced cardiac troponin leakage characteristic HCM, and, more importantly, decreased mortality. Taken together, these pre-clinical observations show potential salutary effects beyond obstruction relief in HCM.