Sodium–glucose co‐transporter 2 inhibition with empagliflozin improves cardiac function in non‐diabetic rats with left ventricular dysfunction after myocardial infarction

Abstract

AimsSodium-glucose co-transporter 2 (SGLT2) inhibition reduces heart failure hospitalizations in patients with diabetes, irrespective of glycaemic control. We examined the effect of SGLT2 inhibition with empagliflozin (EMPA) on cardiac function in non-diabetic rats with left ventricular (LV) dysfunction after myocardial infarction (MI).Non-diabetic male Sprague-Dawley rats underwent permanent coronary artery ligation to induce MI, or sham surgery. Rats received chow containing EMPA that resulted in an average daily intake of 30 mg/kg/day or control chow, starting before surgery (EMPA-early) or 2 weeks after surgery (EMPA-late). Cardiac function was assessed using echocardiography and histological and molecular markers of cardiac remodelling and metabolism were assessed in the left ventricle. Renal function was assessed in metabolic cages. EMPA increased urine production by two-fold without affecting creatinine clearance and serum electrolytes. EMPA did not influence MI size, but LV ejection fraction (LVEF) was significantly higher in the EMPA-early and EMPA-late treated MI groups compared to the MI group treated with vehicle (LVEF 54%, 52% and 43%, respectively, all P < 0.05). EMPA also attenuated cardiomyocyte hypertrophy, diminished interstitial fibrosis and reduced myocardial oxidative stress. EMPA treatment reduced mitochondrial DNA damage and stimulated mitochondrial biogenesis, which was associated with the normalization of myocardial uptake and oxidation of glucose and fatty acids. EMPA increased circulating ketone levels as well as myocardial expression of the ketone body transporter and two critical ketogenic enzymes, indicating that myocardial utilization of ketone bodies was increased. Together these metabolic changes were associated with an increase in cardiac ATP production.

Evaluation of the effect of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR‐Reduced trial

“…It is expected that the diabetic and non‐diabetic subgroups will each be large enough to explore the presence of a treatment‐by‐diabetic status interaction if one exists. However, since the benefits of SGLT2 inhibitors in heart failure are not related to glucose‐lowering and have been observed in non‐diabetic models of HFrEF, such an interaction is not anticipated.…”

Dapagliflozin in heart failure: new frontiers

“…In rats (pre‐)treated with empagliflozin, diuresis was increased without affecting renal function. Empagliflozin also improved cardiac function post‐myocardial infarction, increased ATP availability, and attenuated pathological cardiomyocyte hypertrophy and cardiac fibrosis in both rats treated with empagliflozin before the infarct as well as in rats receiving empagliflozin 2 weeks after surgery …”

“…13 A recent experimental study in non-diabetic rats undergoing permanent coronary artery ligation to induce myocardial infarction compared to sham surgery supports the hypothesis of a unique cardiac effect of SGLT2 inhibitors. 15,16 Rats were given empagliflozin saturated chow vs. control either before or 2 weeks after surgery. In rats (pre-)treated with empagliflozin, diuresis was increased without affecting renal function.…”

“…Empagliflozin also improved cardiac function post-myocardial infarction, increased ATP availability, and attenuated pathological cardiomyocyte hypertrophy and cardiac fibrosis in both rats treated with empagliflozin before the infarct as well as in rats receiving empagliflozin 2 weeks after surgery. 15 Clearly, with the great expectations for SGLT2 inhibitors in the treatment of prevalent HF, DAPA-HF provides important . .…”

Myocardial adiposity in heart failure with preserved ejection fraction: the plot thickens

“…Third, studies investigating novel lipid‐lowering therapies are of interest in the context of treating HFpEF. Drug therapies, such as sodium–glucose co‐transporter 2 (SGLT2) inhibitors, are promising in the treatment of HF, as they appear to improve myocardial metabolism and reduce the secretion of pro‐inflammatory adipokines . However, if SGLT2 inhibitors also influence myocardial triglyceride content remains to be demonstrated.…”