LAUSR

Rationale: Approximately 50% of heart failure patients are diagnosed with Heart Failure with preserved Ejection Fraction (HFpEF), but there are currently no effective treatments. Hypothesis: Treatment of a feline HFpEF animal model with a pan HDAC inhibitor, SAHA, will improve the cardiopulmonary phenotype and mediate changes in the metabolome and skeletal muscle composition. Methods and results: Male domestic short hair cats (n=21, age 2mo) underwent either a sham procedure (n=5) or aortic constriction (n=16) using a customized pre-shaped band causing slow progressive pressure overload during maturation. At 2-months post-banding, banded animals received either daily treatment with 10mg/kg SAHA (b+SAHA) (n=8) or vehicle (b+veh) (n=8) for 2 months. At 4 months post-banding, b+ SAHA animals had significantly reduced LV wall thickness, LA size (LA/Ao), and improved LA function (LA EF) vs. b+ veh animals (fig). Invasive hemodynamics and lung mechanics were performed after 2 months of treatment. Banded animals had significantly increased filling pressures (LVEDP), increased pulmonary arterial pressures (mPAP), decreased lung compliance and arterial oxygenation (A-aDO 2 ). SAHA significantly reduced LVEDP, mPAP, and A-aDO 2 and increased lung compliance (fig). b+SAHA animals had an increase in the percentage of type 1 muscle fibers (increased oxidative capacity) compared to type 2 (fig). Blood-based metabolomics revealed SAHA-induced a metabolic shift towards increased lipolysis and mitochondrial oxidation. Conclusion: Treatment with SAHA improved cardiopulmonary structure and function in banded animals and caused changes in the metabolome and skeletal muscle.