Dapagliflozin alleviates left ventricular hypertrophy and cardiac dysfunction in mice

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Ludwig Boltzmann Institute for Cardiovascular Research Introduction Sodium glucose cotransporter 2 inhibitors (SGLT2i) are a class of oral antidiabetic drugs. Recent clinical trials demonstrated and proved the cardiovascular benefit of SGLT2i in patients suffering from ischemic heart disease. In addition, left ventricular hypertrophy (LVH) is associated with cardiovascular events and using SGLT2i alleviated LVH in diabetic patients. However, only few studies investigated the effect of SGLT2i on regression of LVH in absence of diabetes. Aim of the study This study aimed to investigate whether the SGLT2i Dapagliflozin (DAPA) could attenuate LVH and cardiac dysfunction in a mouse model of pressure overload-induced LVH. Methods Male C57BL/6J mice (body weight 20-25g) were used. LVH was induced surgically by transverse aortic constriction (TAC). DAPA (1 mg/kg bodyweight/day) was administered through drinking water. The animals were divided in four groups: Group 1 underwent TAC for eight weeks (n=8). Group 2 concomitantly received DAPA for eight weeks after TAC (n=5). Group 3 received DAPA for only two weeks (in week 7 and 8 after TAC, n=5) to clarify if DAPA treatment could alleviate LVH at a later timepoint. Group 4 served as a sham control group (no LVH, n=8). Cardiac function was assessed using transthoracic echocardiography and invasive LV hemodynamic measurements. Results TAC resulted in a significant reduction in LV ejection fraction (LVEF) and significant increase in heart weight to body weight ratio (HW/BW) compared to sham (p<0.001). In addition, TAC mice showed a significant increase of LV systolic pressure and end-diastolic pressure compared to sham (p<0.01). Both the LVEF and LV functional parameters were markedly improved in mice treated with DAPA for eight weeks (p<0.05). LV mass decreased compared to the untreated group. More importantly, DAPA treatment for only two weeks also improved LVEF and alleviated LVH compared to untreated TAC mice (p<0.05). Furthermore, we also found that mice with only two weeks of DAPA treatment showed a tendency to improve LV hemodynamics. Conclusions DAPA was cardioprotective in a mouse model of pressure overload-induced LVH in absence of diabetes. It improved LV contractile function and LVH. DAPA also alleviated LVH and induced LV regression. Our findings uncovered that the SGLT2i DAPA contributed to the regression of LVH and cardiac fibrosis. Thus, administration of SLGT2i may be a novel adjunct therapy to boost reverse remodeling e.g. in patients with elective cardiac surgery and hypertrophic cardiomyopathy.