The Cardiac Myosin Inhibitor, CK-3773274, Reduces Contractility in the R403q Mouse Model of Hypertrophic Cardiomyopathy

Cardiac sarcomere hypercontractility appears to underlie pathological hypertrophy and fibrosis in select genetic hypertrophic cardiomyopathies. The small molecule, CK-3773274, is a novel cardiac myosin inhibitor that decreases contractility in vitro and in healthy animals in vivo . The objective of this study was to evaluate the effect of CK-3773274 in the genetic R403Q mouse model of hypertrophic cardiomyopathy. At approximately 40 weeks of age, left ventricular wall dimensions were determined by echocardiography in male wild type (WT) and heterozygous R403Q mice. As an indicator of cardiac hypertrophy, R403Q mice had significantly greater septal and posterior wall thickness than WT mice (septal wall WT: 0.93 ± 0.03 mm vs. R403Q: 1.22 ± 0.08 mm; posterior wall WT: 0.84 ± 0.04 mm vs. R403Q: 1.09 ± 0.04 mm; mean ± SEM, p< 0.05). R403Q mice were treated with single oral doses of CK-3773274 ranging from 0.25 to 1.5 mg/kg and fractional shortening (FS) and heart rate were assessed at select time points over a 24-hour period. One hour after dose administration, CK-3773274 significantly reduced FS in a dose-related fashion relative to pre-dose baseline values (FS % R403Q baseline: 55.5 ± 2%; 0.25 mg/kg: 43.9 ± 2%; 1 mg/kg: : 27.3 ± 2%; 1.5 mg/kg: 13.7 ± 1%; mean ±SEM, p<0.05 vs. baseline at all doses) without any changes to heart rate. At all dose levels, fractional shortening returned to baseline values by 24 hours. The plasma concentration at 10% and 50% reduction of FS relative to baseline (IC 10 and IC 50 ) was 0.11 and 0.78 μM, respectively. In summary, single oral dose administration of CK-3773274 reduced fractional shortening in a dose and concentration-dependent manner in the genetic R403Q mouse model of hypertrophic cardiomyopathy. Cardiac myosin inhibition may be a viable approach to reduce underlying hypercontractility of the cardiac sarcomere in hypertrophic cardiomyopathies.