Abstract 849: Rho Kinase Inhibition Produces Dose-Dependent Improvements in Diastolic Dysfunction, Independent of Changes in Afterload, in a Rat Pressure Overload Model
Diastolic dysfunction is characterized by prolonged myocardial relaxation and abnormal tissue stiffness contributed by increased myocardial fibrosis. The Rho-Rho kinase (Rho-ROCK) signaling pathway may be of relevance in this setting, as shown by early ROCK effector activation in pressure overload cardiac hypertrophy (POH), a model of diastolic dysfunction and ultimately heart failure. However, as yet, there has been no data on the effect of ROCK inhibition on POH-induced diastolic dysfunction.
Objective: To determine the effect of ROCK inhibition on diastolic function in POH
Methods: POH was induced by suprarenal abdominal aortic constriction in rats. In sham animals, the aorta was not constricted. The POH rats were divided into 3 groups, with highly selective ROCK inhibitor (GSK 576371 1 or 3 mg/kg bid) or vehicle treatment. Echocardiogram was performed at baseline and at the end of treatment (4 weeks). At the end of the study, hemodynamic data was obtained and tissues harvested.
Results: There were no differences in baseline characteristics. GSK did not affect BP, heart and lung weight but improved Doppler indices of LV filling: E-wave deceleration time (DT), isovolumic relaxation time (IVRT) and MV annular velocity (MV E′/A′), as well as LV end diastolic pressure (LVEDP), in a dose-dependent manner. GSK also restored relative wall thickness (RWT) toward sham values. Collagen deposition was significantly attenuated with treatment.
Conclusion: ROCK inhibition dose-dependently improved diastolic dysfunction, independent of changes in afterload. Attenuation of pathological collagen deposition may be an important mechanism contributing to these beneficial effects.