P5996HDAC inhibition improves myofibrillar relaxation and metabolism in a feline model of HFpEF

Abstract

Abstract Background Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for about 50% of all cases of HF and there are currently no effective therapies. Purpose To assess the effects of histone deacetylase (HDAC) inhibition on cardiac and mitochondrial function and the plasma metabolome in a large mammalian model of slow-progressive pressure overload with features of HFpEF. Methods Male domestic short hair cats (n=26, aged 2mo), underwent either sham (S) procedures (n=5) or aortic constriction with a customized pre-shaped band (n=21), resulting in slow progressive pressure overload during growth. 2 months post-banding, animals 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. Serial in-vivo cardiopulmonary phenotyping was performed monthly, and invasive hemodynamic and gas exchange parameters were evaluated 4 months post-banding. Ex-vivo myofibril mechanical studies and blood-based metabolomic profiling were performed. Data is presented as mean±SEM. Results Echocardiography at 4-months post-banding revealed that b+SAHA animals had a significant reduction in left ventricular hypertrophy (LVH) and LA size vs. b+veh animals. Left ventricular end-diastolic pressure (LVEDP) and mean pulmonary arterial pressure (mPAP) were significantly lower in b+SAHA vs. b+veh. SAHA treatment also improved ex-vivo myofibril relaxation independent of LVH and this effect correlated with in-vivo improvements of LV relaxation. Furthermore, SAHA treatment preserved lung structure, and improved lung compliance and oxygenation, reflected by a decrease in alveolar-capillary wall thickness and intrapulmonary shunt. SAHA treatment also reduced perivascular fluid cuffs around extra-alveolar vessels, suggesting attenuated alveolar-capillary stress failure. Treatment with SAHA caused an increase in both oxygen consumption in-vivo and the percentage of type 1 skeletal muscle fibers (higher oxidative capacity). SAHA also increased mRNA levels of coactivators that regulate mitochondrial function and induced metabolic reprogramming towards mitochondrial oxidation preferentially utilizing fatty acids. SAHA treated HeLa cells showed a significant increase in oxidative phosphorylation and ATP production. Effects of SAHA Conclusion These results show that slow-progressive pressure overload mimics critical features of HFpEF. SAHA can improve cardiac, pulmonary, and metabolic derangements caused by chronic pressure overload. Therefore, HDAC inhibition may be an interesting therapeutic strategy to treat the ever growing HFpEF population. Acknowledgement/Funding NIH [HL33921 to S.R.H, HL116848, HL127240 to T.A.M]; AHA [16SFRN31400013 to T.A.M.]; Medical University of Graz [M.W.], Stadt Graz [M.W.]