Aldehyde Dehydrogenase 2 Activator Augments the Beneficial Effects of Empagliflozin in Diabetes Aassociated HFpEF

Abstract Objectives: To ameliorate diabetes mellitus associated heart failure with preserved ejection fraction (HFpEF), we plan to lower diabetes-mediated oxidative stress-induced 4-hydroxy-2-nonenal (4HNE) accumulation by pharmacological agents that either decrease 4HNE generation or increase its detoxification.Background: 4HNE, a cellular reactive carbonyl species (RCS), was significantly increased in diabetic hearts due to a diabetes-induced decrease in 4HNE detoxification by aldehyde dehydrogenase (ALDH)2, a cardiac mitochondrial enzyme that metabolizes 4HNE. Therefore, hyperglycemia-induced 4HNE is critical for diabetes-mediated cardiotoxicity and we hypothesize that lowering 4HNE ameliorates diabetes associated HFpEF. Methods: We fed high-fat diet to ALDH2*2 mice which have intrinsically low ALDH2 activity to induce type-2 diabetes. After 4 months of diabetes, the mice exhibited features of HFpEF and along with increased 4HNE adducts and we treated them with vehicle, empagliflozin (EMP) (3mg/kg/d) to reduce 4HNE and Alda-1 (10mg/kg/d), an ALDH2 activator to enhance ALDH2 activity as well as a combination of EMP + Alda-1 (E + A), via subcutaneous osmotic pumps. After 2 months of treatments, cardiac function was assessed by conscious echocardiography before and after exercise stress. Results: EMP + Alda-1 improved exercise tolerance, diastolic and systolic function, 4HNE detoxification and cardiac liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway in ALDH2*2 mice with diabetes associated HFpEF. This combination was even more effective than EMP alone. Conclusions: Our data indicate that ALDH2 activation along with the treatment of hypoglycemic agents may be a salient strategy to alleviate diabetes associated HFpEF.