Abstract 15701: Histone Deacetylase 6Inhibition Demonstrates Comparable Efficacy as Empagliflozin in a Mouse Model of Heart Failure With Preserved Ejection Fraction

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) is associated with high morbidity and mortality, yet there are few effective therapies for HFpEF. Previously, we have demonstrated that TN-301, a highly selective small molecule inhibitor of histone deacetylase 6 (HDAC6), works directly on the heart and on systemic metabolism and inflammation in mouse models of HFpEF. Recently, empagliflozin, a selective inhibitor of sodium-glucose transport protein (SGLT2) inhibitor, was approved in the U.S. for patients with HFpEF. Purpose: We aimed to compare the efficacy of HDAC6i and SGLT2i in a mouse model of established diastolic dysfunction with preserved ejection fraction. Methods and Results: To recapitulate systemic and cardiovascular features of HFpEF in humans, we induced diastolic dysfunction with a combination of high fat diet and inhibition of constitutive nitric oxide synthase using N ω -nitrol-arginine methyl ester (L-NAME). After the HFpEF phenotypes were established, mice received TYA-11018 (TN-301-like HDAC6i) or empagliflozin, or vehicle orally once daily for 9 weeks. We found that TYA-11018 reduced left ventricular hypertrophy and restored diastolic function with comparable efficacy to empagliflozin. In addition, TYA-11018 reduced fasting glucose and improved glucose tolerance in HFpEF mice, to levels similar to empagliflozin. Preliminary data suggested TYA-11018 corrects hyperglycemia independently of glucose urine excretion, which is distinct from SGLT2i. Using whole transriptome RNA-seq, TYA-11018 showed greater effects on correcting expression of gene sets associated with inflammation, fibrosis and mitochondrial energy production compared to empagliflozin in HFpEF hearts. Conclusion: Our results show that with its distinct HDAC6 inhibition mechanism, TYA-11018 reverses preexisting hypertrophy, diastolic dysfunction and glucose tolerance, demonstrated similar efficacy to that with a SGLT2 inhibitor in HFpEF model. The comparable efficacy seen in this HFpEF model with TYA-11018 and empagliflozin provides early but encouraging evidence of the potential translatability of these findings to clinical development. We are developing TN-301 for treating HFpEF patients.