Abstract 3468: Beneficial Effects of Trimetazidine on Right Ventricular Function and Myocardial Metabolism in Right Ventricular Hypertrophy Induced by Pulmonary Artery Banding
Introduction: Right ventricular hypertrophy (RVH) and right ventricular failure are major determinants of prognosis and functional state of patients with congenital heart disease or pulmonary artery hypertension (PAH). We previously reported that a metabolic shift to glycolysis occurs in RVH associated with experimental PAH. Moreover, dichloroacetate, an inhibitor of mitochondrial pyruvate dehydrogenase kinase enhances glucose oxidation and improves RV function in experimental PAH. We hypothesize that another metabolic modulator, trimetazidine, a blocker of fatty acid oxidation, will also restore RV function by blocking fatty acid oxidation and improving glucose oxidation in RVH caused by pulmonary artery banding (PAB).
Methods and Results: RVH was induced in Sprague-Dawley rats by PAB (using a 1.3 mm constrictor placed by partial median sternotomy). Trimetazidine (0.7g/L) was added to drinking water after the surgery. 8 weeks later, the RV/LV+Septum weight ratio was increased from 0.25±0.01 to 0.60±0.03 with PAB and reduced to 0.50±0.03 by trimetazidine (P<0.05). Cardiac output measured using thermodilution decreased from 165±15 to 91±4 ml/min with PAB and increased to 118 ml/min by trimetazidine (P<0.005). O2-consumption of 140 mg samples of RV was measured using high-resolution respirometry. PAB reduced RV O2-consumption from 296±23 to 258±9 pM/(sec*ml) (P<0.005) and was improved by trimetazidine to 386±26 pM/(sec*ml) (P<0.05). Immunostaining showed a 2-fold increase of Glut1 expression in RV myocytes in PAB. Trimetazidine normalized glut1 expression in RV myocytes. In the RV Langendorff model, the monophasic action potential at 20% repolarization was prolonged from 12.66±1.41 to 24.25±0.75 ms in PAB group and reduced to 12.71±0.39 ms by trimetazidine (P<0.01). The QTc on the surface EKG (lead II) increased from 0.12±0.01 to 0.22±0.01 s and reduced to 0.19±0.01 s by trimetazidine (P<0.05). Consistently, the downregulation of Kv1.5 observed in PAB-induced RVH was restored by trimetazidine.
Conclusions: Trimetazidine, an inhibitor if fatty acid oxidation, partially reverses electrical remodeling and enhances RV function in the PAB model. Trimetazidine is a potential therapy for RVH.