Dapagliflozin Ameliorates Myocardial Remodeling in Heart Failure Induced Diabetic Rats

Abstract

Background: Diabetes mellitus is an independent risk factor for heart failure (HF). HF is the leading cause of hospitalization in type 2 diabetes (T2D) patients. Dapagliflozin is a highly selective sodium-glucose cotransporter-2 inhibitor that was recently developed to treat T2D. Dapagliflozin was found to reduce the incidence of cardiovascular mortality and HF hospitalisation. Dapagliflozin has been approved for the treatment of HF with reduced ejection fraction (HFrEF) patients by FDA in 2020. However, the mechanisms through which dapagliflozin mediate these benefits are not completely understood and its efficacy and clinical application are still controversial.

Objectives: to investigate the effect and possible underlying mechanism of action of dapagliflozin on HF induced diabetic rats.

Methods: HF was induced in diabetic rats by ligation of the left anterior descending coronary artery. Dapagliflozin (1 mg/kg/day) was administered for four weeks through gavage. Body weight (BW), heart weight (HW), heart rate (HR), blood pressure, fasting serum glucose, insulin, glycated hemoglobin A1C (HbA1c), cardiac specific enzymes [creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), cardiac troponin I (cTnI)], fibrotic markers [procollagen I C-terminal propeptide (PICP), procollagen III N-terminal peptide (PIIINT), transforming growth factor beta 1 (TGFβ 1), inflammatory mediators [tumor necrosis factor-alpha (TNF-α)], anti-oxidative markers [malondialdehyde (MDA) and super oxide dismutase (SOD)] and apoptotic mediators (BCL2 and caspase 3) were measured. Histopathological examination using hematoxylin and eosin for heart, lung and liver and masson trichrome for cardiac tissue was done. Vascular reactivity and direct effect of dapagliflozin on myocardial contractility was evaluated.

Results:  Dapagliflozin decreased blood glucose, HW, HW/BW, CK-MB, LDH, cTn1, PICP, PIIINP, TGF-β1, TNF-α, MDA and cardiac level of Caspase 3, while increased SOD and BCL2 levels. Dapagliflozin improved the histopathological picture of heart, liver and lung and improved the vascular reactivity of the aorta in HF induced diabetic rats.

Conclusion: Dapagliflozin alleviates myocardial remodeling and dysfunction in HF induced diabetic rats by attenuating hyperglycemia, fibrosis, inflammation, oxidative stress and apoptosis. Dapagliflozin improved histo-pathological changes in heart, lung and liver and improved vascular reactivity.