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.