Trimetazidine-Induced Enhancement of Myocardial Recovery during Reperfusion: A Comparative Study in Diabetic and Non-diabetic Rat Hearts

Abstract

Background: Diabetes mellitus (DM) is a major predisposing factor for ischemic heart disease. Metabolic disturbances in diabetic heart including impaired myocardial glucose uptake and elevated plasma free fatty acids and increased rate of fatty acid ß-oxidation are probably important contributing factors to greater mortality. Trimetazidine (TMZ), a well-studied anti-ischemic agent, has been demonstrated to be beneficial in treatment of coronary artery disease as well as in treatment of diabetic patients. However, studies reporting the effects of the drug against global myocardial ischemia/reperfusion injury, particularly in diabetic hearts, are rare. This study was mainly aimed to investigate the cardioprotective action of TMZ against global ischemia in diabetic hearts and to compare its protective efficiency level with non-diabetics. Methods: Twenty streptozotocin-induced diabetic and 20 non-diabetic rats were divided into two groups each. Group I (diabetic, n = 10) and group III (non-diabetic, n = 10) rats were given saline in both pretreatment and acute treatment protocols and reserved as control groups. Group II (diabetic, n = 10) and group IV (non-diabetic, n = 10) rats were both pretreated orally with 3 mg/kg TMZ twice daily for 5 days and treated with TMZ infusion at a concentration of 10-6 M for 30 min during the experiment. Isolated hearts from each rat were submitted to Langendorff perfusion and a period of 60 min of global ischemia following 60 min of reperfusion. Myocardial post-ischemic recovery was compared in each group using hemodynamic data (peak systolic pressure, end diastolic pressure, +dP/dtmax), coronary flow, biochemical parameters (CK-MB, cTnT) from coronary effluent, and obtained data were statistically analyzed by both MANOVA and two-sample Hotelling's T2 tests. Results: Both hemodynamic and biochemical findings signaled a significantly enhanced myocardial recovery provided by TMZ treatment in diabetic and non-diabetic hearts as compared to non-treated hearts. Although efficiency level of TMZ on mechanical recovery was not different between diabetics and non-diabetics, the protective action of TMZ on myocardial damage measured by biochemical parameters was more evident in diabetic hearts than in non-diabetics. Conclusions: Shifting myocardial energy metabolism away from fatty acids toward glucose oxidation and regulating transmembrane ion disturbances by TMZ can be considered as an appropriate adjunctive treatment in diabetics, especially in patients undergoing open-heart surgery who will be exposed to global myocardial ischemia