Abstract 14390: The Cardiac Myosin Inhibitor, Ck-3772271, Attenuates Cardiac Fibrosis and Diastolic Dysfunction in the Dahl/salt Sensitive Rat Model of Heart Failure With Preserved Ejection Fraction

Abstract

Introduction: Heart failure with preserved ejection fraction (HFpEF) is characterized by underlying contractile dysfunction and progressive myocardial fibrosis and stiffness. CK-3772271 (CK-271) is a novel small molecule cardiac myosin inhibitor that reduces cardiac myosin ATPase activity and reduces cardiac contractility in unloaded isolated cardiomyocytes in vitro and in healthy rats and dogs in vivo . The effect of chronic CK-271 treatment on cardiac function and morphology was evaluated in the Dahl/Salt Sensitive (DSS) rat hypertension model of HFpEF. Methods: DSS male rats were fed either a control low salt (LS, 0.3% NaCl) or high salt (HS, 4% NaCl) diet to induce a hypertension-driven HFpEF disease phenotype. 6 weeks after HS diet treatment, DSS rats were randomized into two sub-groups: continued HS diet or a HS diet formulated with CK-271 (100 ppm) for an additional 6 weeks. Body mass, systolic blood pressure, and cardiac function were measured longitudinally. After 12 weeks of HS treatment, hearts were collected to assess cardiac fibrosis. Results: HS diet treatment increased systolic blood pressure (LS:132.2 ± 4.7 mm Hg vs. HS: 163.5 ± 4.0 mm Hg, mean ± SEM, p< 0.001) and caused cardiac hypercontractility as evidenced by an increase in the end-systolic pressure-volume relationship (LS: 0.8 ± 0.17 vs. HS: 2.1 ± 0.46 mm Hg/ml). HS diet also increased isovolumic relaxation time (IVRT) (LS: 16.8 ± 0.6 vs. HS: 22.8 ± 0.6 ms, p<0.0001), left atrial area (LS: 30.3 ± 0.8 vs. HS: 42.5 ± 2.2 mm 2 , p<0.0001) and cardiac fibrosis (LS: 3.4 ± 0.4 vs. HS: 5.0 ± 0.6 %). 6 weeks of CK-271 treatment reduced fractional shortening (HS: 53.8 ± 1.4 vs. HS+CK-271: 42.7 ± 1.0 %, p<0.0001) and reduced HS diet-induced diastolic dysfunction, including IVRT (HS: 22.8 ± 0.6 vs. HS+CK-271: 19.5 ± 0.5 ms, p<0.0001) and left atrial area (HS: 42.5 ± 2.2 vs. HS+CK-271: 35.4 ± 0.8 mm 2 , p<0.0001). Furthermore CK-271 reduced the development of cardiac fibrosis (HS: 5.0 ± 0.6 vs. HS+CK-271: 3.5 ± 0.3 %, p<0.05) induced by HS diet. Conclusion: The small molecule cardiac myosin inhibitor, CK-3772271, attenuated the development of cardiac hypercontractility, diastolic dysfunction and fibrosis in the DSS rat model of HFpEF. Cardiac myosin inhibition may be a novel approach to mitigate the development of HFpEF.