Influence of empaglifozin on the heart of rats with myocardial infarction-induced cardiac remodeling

Abstract

Despite advance on cardiac remodeling prevention and treatment, mortality after myocardial infarction (MI) is still elevated. The sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce renal glucose reabsorption improving diabetes control. In the EMPA-REG OUTCOME Study, empaglifozin addition to the standard therapy of patients with type 2 diabetes and high risk for cardiovascular disease reduced mortality and the risk for heart failure (HF) hospitalization. Beneficial effects were observed in both HF and non-HF patients, started three months after initiating treatment, and lasted longer than three years. Several effects of SGLT2 inhibitors were described, such as reduction in hyperglycemia, visceral adiposity, serum concentration of insulin, blood pressure, albuminuria, and oxidative stress; attenuation of endothelial dysfunction, and decrease in progression rate of renal disease. However, it seemed unlikely that a slight improvement in glycemia, lipids levels, and blood pressure was responsible for the better outcomes. Therefore, it was suggested that empaglifozin may have direct influence on the cardiovascular system and three hypotheses have been launched to explain the results: 1) a diuretic effect associated with the SGLT2 inhibition and a subsequent reduction in left ventricular (LV) hemodynamic load; 2) changes in cardiac metabolism; and 3) restoration of myocyte sodium and calcium homeostasis. Great interest has emerged on the role of empaglifozin on cardiac metabolism. Furthermore, the results of studies using SGLT2 inhibitors in diabetic patients allowed to raise the hypothesis that this drug class and, particularly, empaglifozin, have protective effects on the cardiovascular system in patients without diabetes. Currently, there are no published studies on renal or cardiovascular effects in non-diabetes patients. Only a few investigators evaluated the effects of SGLT2 inhibitors in experimental cardiac remodeling. We have not found research on the effects of SGLT2 inhibitors on ventricular function after a chronic process of cardiac remodeling. Therefore, to better interpreting clinical trials, it is necessary to evaluate mechanisms involved on SGLT2-induced changes in chronic cardiac remodeling. The purpose of this study is to evaluate the effects of empaglifozin on the heart of normal rats and rats with MI-induced cardiac remodeling. Specifically, we will analyze cardiac structure and function, myocardial metabolism, oxidative stress, and expression of proteins involved in intracellular calcium and sodium transient and in myocyte hypertrophy signaling. MI will be induced by anterior descending coronary artery ligation. Ten days after surgery, transthoracic echocardiogram will be performed to evaluate MI size. Rats with MI lower than 30% of LV size will be excluded. Rats will then be assigned to four groups: Sham (n=15), Sham + empagliflozin (n=15), MI (n=25), and MI + empagliflozin (n=25). Empaglifozin will be added to rat chow (5 mg/kg/day) for 12 weeks. Echocardiogram will be repeated at the final of the experimental period. Myocyte diameters and collagen interstitial fraction will be assessed in LV. Expression of proteins involved in intracellular calcium transient (phospholamban and SERCA2a) and in myocyte hypertrophy (MAPK) will be assessed by Western blot. Oxidative stress and metabolism will be analyzed in LV myocardium. Statistical analyzes will be performed using ANOVA. Comparison between MI size will be evaluated by the Student's t test. Association between variables will be assessed by Pearson or Spearman's correlation. (AU)