Abstract 227: Inhibition of Histone Deacetylase Catalytic Activity Improves Cardiac and Pulmonary Function in a Feline Model of Heart Failure with Preserved Ejection Fraction

Rationale: Heart Failure with preserved Ejection Fraction (HFpEF) accounts for about 50% of all heart failure cases but has no effective therapies. Hypothesis: Inhibition of histone deacetylase (HDAC) catalytic activity exerts beneficial effects on the cardiopulmonary system in a feline model of HFpEF. Methods and Results: Male domestic short hair cats (n=21, aged 2mo), underwent either a sham procedure (n=5) or aortic constriction (n=16) using a customized pre-shaped band, resulting in slow progressive pressure overload during growth. 2 months post-banding, banded cats were treated daily with either 10mg/kg suberoylanilide hydroxamic acid ( b+SAHA ) (n=8), a pan-HDAC inhibitor, or vehicle ( b+veh ) (n=8) for 2 months. At 4 months post-banding, b+SAHA cats showed significantly reduced LV wall thickness and LA size (LA/Ao) compared to b+veh cats (Fig). Invasively measured left ventricular end-diastolic pressure (Fig. LVEDP) at 4 months was significantly elevated in b+veh cats compared to b+SAHA and sham cats (Fig). After dobutamine infusion, the increase in dp/dt max was significantly attenuated in b+veh , but not in b+SAHA cats (Fig). In vivo measurements of pulmonary function at 4 months post-banding demonstrated marked improvement in b+SAHA cats, reflected by an increase in lung compliance and a decrease in alveolar-arterial oxygen gradient (A-aDO 2 ) and intrapulmonary shunt (Fig). Efficacy of SAHA in vivo correlated with enhanced ex vivo myofibril relaxation. Conclusion: HDAC inhibition rescues the established HFpEF phenotype by reducing LV hypertrophy, LVEDP, LA size, and enhancing myofibril relaxation, which ultimately results in improved pulmonary function.