A Small Molecule Inhibitor of Sarcomere Contractility Acutely Relieves Left Ventricular Outflow Tract Obstruction in Feline Hypertrophic Cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is an inherited disease of the heart muscle characterized by otherwise unexplained thickening of the left ventricle. Left ventricular outflow tract (LVOT) obstruction is present in approximately two-thirds of patients and substantially increases the risk of disease complications. Invasive treatment with septal myectomy or alcohol septal ablation can improve symptoms and functional status, but currently available drugs for reducing obstruction have pleiotropic effects and variable therapeutic responses. New medical treatments with more targeted pharmacology are needed, but the lack of preclinical animal models for HCM with LVOT obstruction has limited their development. HCM is a common cause of heart failure in cats, and a subset exhibit systolic anterior motion of the mitral valve leading to LVOT obstruction. MYK-461 is a recently-described, mechanistically novel small molecule that acts at the sarcomere to specifically inhibit contractility that has been proposed as a treatment for HCM. Here, we use MYK-461 to test whether direct reduction in contractility is sufficient to relieve LVOT obstruction in feline HCM. We evaluated mixed-breed cats in a research colony derived from a Maine Coon/mixed-breed founder with naturally-occurring HCM. By echocardiography, we identified five cats that developed systolic anterior motion of the mitral valve and LVOT obstruction both at rest and under anesthesia when provoked with an adrenergic agonist. An IV MYK-461 infusion and echocardiography protocol was developed to serially assess contractility and LVOT gradient at multiple MYK-461 concentrations. Treatment with MYK-461 reduced contractility, eliminated systolic anterior motion of the mitral valve and relieved LVOT pressure gradients in an exposure-dependent manner. Our findings provide proof of principle that acute reduction in contractility with MYK-461 is sufficient to relieve LVOT obstruction. Further, these studies suggest that feline HCM will be a valuable translational model for the study of disease pathology, particularly LVOT obstruction.

Fig 1. Isoproterenol increases heart rate and contractility and induces dynamic LVOT obstruction in cats with HCM.

Treatment with isoproterenol 0.04 μg/kg/min IV (A) augments heart rate, fractional shortening (FS) and LVOT gradient (n = 5, mean ± SD), (B) provokes mitral valve SAM and mitral/septal contact (LV = left ventricle cavity, MV = anterior leaflet mitral valve), (C) induces an LVOT pressure gradient (scale bar 0.5 m/s) and (D) mitral regurgitation.

Fig 2. MYK-461 reduces contractility in feline HCM in an exposure-dependent manner.

(A) Study scheme depicting timing of echocardiograms (numbered) and administration of isoproterenol (iso) at constant dose and MYK-461 or vehicle as a ramp infusion. Timepoints with asterisks correspond to blood draws to measure plasma concentration of MYK-461. Timepoint 1: baseline following anesthesia; timepoint 2: stable isoproterenol; timepoints 3–6: stable isoproterenol with increasing MYK-461 dose; timepoint 7: stable MYK-461 dose without isoproterenol. (B) Decrease in contractility with MYK-461 treatment by M-mode echocardiography. (C) Before and after plot of FS in response to treatment with MYK-461 (n = 5) or vehicle (n = 3) in the absence of isoproterenol (*, p = 0.03 vs vehicle by unpaired t-test; **, p = 0.01 vs. pre-dose by paired t-test). (D) Linear correlation of FS with MYK-461 plasma concentration for timepoints 2–6 in the presence of isoproterenol (n = 3 cats, p<0.0001).

Fig 3. Treatment with MYK-461 abolishes mitral valve SAM and reduces LVOT gradients in cats with HCM.

Treatment with MYK-461 abolishes (A) SAM and (B) LVOT obstruction induced by isoproterenol treatment. (C) Before and after plot of LVOT pressure gradient for cats treated with isoproterenol 0.04 μg/kg/min IV and either MYK-461 (n = 5) or vehicle (n = 3) (*, p = 0.038 vs. vehicle by unpaired t-test; **, p = 0.0007 vs. pre-dose by paired t-test). (D) Linear correlation of relative LVOT pressure gradient (normalized to values prior to MYK-461 treatment) with the plasma concentration of MYK-461 at timepoints 2–6 (n = 3 cats, p<0.0001).