Empagliflozin improves left ventricular diastolic function of db/db mice

Area of Science:

• Cardiology
• Diabetology
• Pharmacology

Background:

• Sodium-glucose cotransporter 2 (SGLT2) inhibition is a novel therapeutic strategy for diabetes.
• Empagliflozin has demonstrated reductions in cardiovascular mortality and heart failure hospitalizations in patients with type 2 diabetes.
• The precise mechanisms underlying these cardioprotective effects remain largely unknown, with potential involvement of altered cardiac substrate utilization.

Purpose of the Study:

• To investigate the impact of empagliflozin-induced SGLT2 inhibition on left ventricular function in a preclinical model of diabetic cardiomyopathy.
• To elucidate the potential mechanisms mediating the observed cardiac benefits of empagliflozin.

Main Methods:

• Utilized db/db mice fed a high-fat western diet to model severe diabetes.
• Administered empagliflozin to assess its effects on cardiac function.
• Assessed left ventricular function using pressure catheterization, with and without dobutamine stress provocation.

Main Results:

• Empagliflozin treatment significantly increased glycosuria and improved glucose metabolism.
• Left ventricular diastolic function was ameliorated, and overall mortality was reduced in treated mice.
• These improvements correlated with reduced cardiac glucose levels and decreased activation of calcium/calmodulin-dependent protein kinase (CaMKII), leading to less ryanodine receptor (RyR) phosphorylation.

Conclusions:

• Empagliflozin-mediated SGLT2 inhibition improved diastolic function and reduced mortality in a murine model of severe diabetes.
• The beneficial effects on diastolic function were likely due to reduced spontaneous sarcoplasmic reticulum (SR) calcium release.
• These cardiac improvements were independent of alterations in cardiac ketone body or branched-chain amino acid (BCAA) metabolism.