Targeting mitochondrial bioenergetics as a therapeutic strategy for cardiopulmonary complications related to COVID-19

Cardiovascular complications are common in COVID-19, manifested as right ventricular (RV) and left ventricular (LV) dysfunction in a significant number of hospitalized patients. Alterations in ventricular function are usually induced by the changes in bioenergetics of cardiac mitochondria. This study was conducted to assess the effects of cardiometabolic drug meldonium on the development of ventricular dysfunction and mitochondrial bioenergetics in experimental models of RV and LV dysfunction. RV failure in Sprague-Dawley rats and LV systolic dysfunction in C57Bl6/N mice was induced by a single administration of monocrotaline (MCT) at a dose of 60 mg/kg and lipopolysaccharide (LPS) at a dose of 10 mg/kg, respectively. Meldonium at a dose of 200 mg/kg was administered to rats for 4 weeks after MCT injection. Mice received meldonium at a dose of 100 mg/kg for three weeks before the administration of LPS. Dimensions and function of heart ventricles were assessed by echocardiography. Mitochondrial function was tested in the permeabilized cardiac fibers by respirometry measurements. Administration of MCT increased Fulton index and decreased RV fractional area change (RVFAC). Treatment with meldonium attenuated increase of Fulton index for 20% and decline of RVFAC for 50%. LV ejection fraction (LVEF) in LPS-treated mice decreased for 30%. Treatment with meldonium significantly prevented the decrease of LVEF. Administration of MCT or LPS resulted in a significant decrease in the FAO‐dependent OXPHOS coupling efficiency with concomitant increase in pyruvate metabolism. Treatment with meldonium in both models restored FAO‐dependent OXPHOS coupling efficiency and decreased pyruvate metabolism to the level of healthy control. Obtained results show that meldonium treatment prevents development of RV and LV systolic dysfunction and improves mitochondrial function in experimental models of cardiovascular diseases which resemble cardiovascular complications of COVID-19.