Meldonium improves functioning of the right ventricle and mitochondrial bioenergetics in experimental model of pulmonary hypertension

Pulmonary hypertension (PH) is a progressive and debilitating vascular disease with limited treatment options to prevent the development of right ventricular failure and death. Meldonium is a cardioprotective drug which improves heart functioning in preclinical models of left-sided heart failure as well as induces clinical improvements in heart failure patients. The aim of our study was to assess effects of meldonium on monocrotaline (MCT)-induced PH and right ventricular (RV) failure in rats. Male Sprague-Dawley rats (n=34) were randomly divided into three groups. The control group (n=10) received saline injection. A single subcutaneous injection of MCT at a dose of 60 mg/kg was done in remaining 24 animals: MCT (n=12) and MCT+Meldonium (n=12) group rats. Animals from MCT+Meldonium group started to receive meldonium at a dose of 200 mg/kg together with drinking water for 4 weeks. After 4 weeks of treatment echocardiography and direct measurment of the RV systolic pressure were performed. After euthanasia, pulmonary and cardiac tissues were collected, weighted and prepared for histological analysis. Mitochondrial function was tested in the permeabilized cardiac fibers of the right ventricle by respirometry measurements. MCT administration increased RV systolic pressure, Fulton index, lung to body weight index and decreased RV fractional area change (RVFAC). Treatment with meldonium decreased lung to body weight index, right ventricle to body mass index along with Fulton index (p<0.05), reduced end systolic area (p<0.05) and increased RVFAC (p<0.05). Administration of MCT resulted in a decrease in the FAO‐dependent OXPHOS coupling efficiency with concomitant increase in pyruvate metabolism and complex I dysfunction. Treatment with meldonium restored FAO‐dependent OXPHOS coupling efficiency and complex I function as well as decreased pyruvate metabolism. Meldonium decreased dilation, improved function of RV and protected functionality of cardiac mitochondria in experimental model of PH and RV failure