Abstract 5364: Vitamin B1 Analogue Benfotiamine Supplementation Prevents Diabetic Cardiomyopathy through Activation of eNOS/Akt Signaling Pathway

Abstract

Cardiomyopathy (DCM) is increasingly recognized as contributing to mortality and morbidity of diabetic patients. Importantly, initial signs of cardiac dysfunction are detected in 75% of young patients with well controlled diabetes, suggesting the necessity for early prevention. Vitamin B1 is defective in diabetics and supplementation with vitamin B1 analogue Benfotiamine (BFT) has been demonstrated to be protective against experimental diabetic limb microangiopathy, nephropathy and retinopathy. Here, we tested whether supplementation of BFT could exhibit its protective effects against DCM. Streptozocin-induced CD1 diabetic (DM) mice were fed with BFT (70mg/kg/day) or vehicle starting from 2wks after glycosuria documentation. Cardiac function was monitored every month using Vevo high resolution echocardiography. 12wks after DM induction, the animals given vehicle started developing the signs of diastolic and systolic dysfunction which was more significant at 20wks of DM. However, BFT (without insulin supplement) markedly suppressed the DM induced left ventricular cavity dilatation (LV end-diastolic volume; 61±4 vs 74±5μl, p<0.001), improved fractional shortening (40±4 vs 26±4%, P<0.001) and ejection fraction (72±5 vs 54±4%, p<0.001) and shifted pressure volume loop leftward compared with the vehicle treated animals. BFT also improved indexes of systolic and diastolic function (dp/dt max 5886±400 vs 4730±356mmHg/s and dp/dt min 3963±282 vs 3145±284mmHg/s, P<0.05 for both comparison). Further, BFT benefited cardiac perfusion (4.5±0.4 vs 3.8±0.1ml/min/gm of tissue, P<0.01, using fluorescent microspheres), which was supported by increased microvasculature (4332±321 vs 3654±263 capillaries/mm 2 ). Moreover, BFT (150μM) reduced the high glucose (30mM) induced apoptosis of cultured adult cardiomyocytes by 21±4% (P<0.05) through activation of the cell survival Akt and eNOS pathway, suggesting its direct effect on cardiomyocytes. Altogether, these results demonstrate that BFT supplementation protects the heart from DM induced cardiac dilatation and dysfunction through activation of prosurvival mechanisms and preservation of myocardial perfusion. Thus, BFT merits attention for potential application in clinical practice.