3072-LB: Selective HDAC6 Inhibition Improves Cardiometabolic and Diastolic Dysfunction in a Two-Hit Mouse Model of Heart Failure with Preserved Ejection Fraction

Introduction and Objective: Heart failure with preserved ejection fraction (HFpEF) is recognized as a cardiometabolic disorder arising from obesity-associated insulin resistance, endothelial nitric oxide pathway impairment, and chronic low-grade inflammation. Mechanistically, HFpEF involves impaired cytoskeletal dynamics, increased microtubule stiffness, mitochondrial dysfunction, and increased inflammatory signaling. Histone deacetylase 6 (HDAC6), a predominantly cytoplasmic deacetylase regulating α-tubulin and other non-histone substrates, controls cytoskeletal organization, protein quality control, intracellular trafficking, and cellular stress responses. HDAC6 inhibition therefore represents a targeted strategy to improve cardiomyocyte compliance and metabolic homeostasis. We evaluated AGT-010, a selective, non-hydroxamic, non-oxadiazole HDAC6 inhibitor, which is currently progressing through IND-enabling development, in a high-fat diet (HFD)/L-NAME model of HFpEF. Methods: C57BL/6N mice were exposed to HFD/L-NAME for 12 weeks and then treated with AGT-010 (3, 10, or 30 mg/kg) for 6 weeks. Assessments included echocardiography, LV pressure recordings, oral glucose tolerance tests, blood pressure monitoring, and treadmill exercise testing. Results: HFD/L-NAME induced metabolically driven HFpEF with grade II diastolic dysfunction, LV hypertrophy, elevated filling pressures, preserved systolic function, and insulin-resistant glucose intolerance. AGT-010 improved diastolic mechanics (increased E′/A′, reduced E/E′), decreased LV pressures, and attenuated hypertrophy—effects consistent with enhanced α-tubulin acetylation and reduced cytoskeletal stiffness. AGT-010 also improved glucose tolerance, β-cell responsiveness, and insulin sensitivity. Conclusion: AGT-010 improves cardiometabolic and diastolic abnormalities in HFpEF, supporting HDAC6 inhibition as a therapeutic strategy for treatment of HFpEF Disclosure T. Cornelissen: None. T. Tezil: None. L. Van Robbroeck: None. T. Vanwelden: None. J. Bruyland: None. L. Vanderwegen: None. B. Rugeri: None. F. Rombouts: None. R.S. Hansen: None.