Abstract P503: Aldehyde Dehydrogenase 2 Activator 1 Potentiates The Effects Of Empagliflozin, A Sodium-glucose Cotransporter 2 Inhibitor, In Diabetes-mediated Heart Failure With Preserved Ejection Fraction

4-hydroxy-2-nonenal (4HNE), a cellular reactive aldehyde which is significantly increased in diabetic hearts due to decrease in the activity of its metabolizing enzyme, aldehyde dehydrogenase (ALDH)2, contributes to diabetes mellitus (DM)-mediated cardiotoxicity. Therefore, we hypothesize that lowering 4HNE ameliorates heart failure with preserved ejection fraction (HFpEF) in DM. To ameliorate DM mediated HFpEF, we will lower diabetes-mediated oxidative stress-induced 4HNE accumulation as well as augment 4HNE detoxification by activating ALDH2, via pharmacological agents. We induced type-2 DM by feeding high-fat diet (HFD) in ALDH2*2 mutant mice which have intrinsically low ALDH2 activity and thus having increased cardiac 4HNE levels. After 4 months of DM, the mice exhibited features of HFpEF and we treated the diabetic ALDH2*2 mice with vehicle (Veh), empagliflozin (EMP) (3mg/kg/d), a sodium-glucose cotransporter (SGLT) 2 inhibitor to reduce hyperglycemia and Alda-1 (10mg/kg/d), an ALDH2 activator to enhance ALDH2 activity as well as combination of EMP + Alda-1 (E + A), via subcutaneous osmatic pumps. After treating for 2 months, cardiac function was assessed by conscious echocardiography before and after exercise stress. EMP + Alda-1 improved running distance (RD, 231 ± 53 m), ejection fraction after running (EF, 69 ± 5 %), and decreased left atrial area (LA, 3.0 ± 0.2 mm ), cardiomyocyte cross-section area (CA, 251 ± 32 μm ) and myocardial fibrotic area (FA 1.0 ± 0.3 %) in ALDH2*2 mice with diabetic HFpEF compared to EMP (RD 142 ± 53 m; EF 62 ± 5 %; LA 3.5 ± 0.3 mm ; CA 303 ± 55 μm ; and FA 3.2 ± 1.8 %), Alda-1 (RD 183 ± 73 m; EF 68 ± 3 %; LA 3.2 ± 0.2 mm ; CA 288 ± 34 μm ; and FA 2.5 ± 1.2 %) and Veh (RD 52 ± 66 m; EF 55 ± 5.0 %; LA 4.7 ± 0.4 mm ; CA 448 ± 65 μm ; and FA 11 ± 3.5 %). This improvement was exerted by decreasing 4HNE levels as well as attenuating 4HNE-mediated decrease in cardiac liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. In conclusion, our data implicate that ALDH2 activation along with the treatment of hypoglycemic agents may be important strategy to alleviate diabetic HFpEF.

Duke Scholars

Author Bipradas Roy