Effects of Meldonium on Right Ventricular Failure in a Preclinical Model and Patients. Doctoral Thesis

Abstract

Right ventricular failure (RVF) is associated with poor prognosis and currently has no known treatment. RVF is characterised by pathologically altered myocardial energy metabolism. In turn, modulation of myocardial energy metabolism pathways in heart muscle has been suggested as a promising therapeutic option. Meldonium is a cardiometabolic drug that improves cardiac function in preclinical models of the left-sided heart failure as well as improves the clinical status of heart failure patients. This study was conducted to analyse the incidence of two RVF-inducing diseases, pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), in the Latvian population and to evaluate the effects of meldonium in the preclinical RVF model and in RVF patients. The incidence of PAH and CTEPH was characterised by analysing data from the Latvian PH Registry. The effects of meldonium administration on the development of pulmonary hypertension-induced RVF was assessed in rats after monocrotaline administration. The safety and effects of meldonium treatment on functional capacity and dyspnoea were assessed in patients with PAH-induced RVF. The estimated incidence of PAH in 2021 was 9.5 per million inhabitants and 11.7 per million adult population. The incidence of CTEPH was 4.2 per million inhabitants and 5.0 per million adult population. In preclinical setup, in Sprague-Dawley rats, treatment with meldonium reduced lung-to-body weight index, right ventricle-to-body mass index along with Fulton index (p < 0.05), reduced RV end-systolic area (p < 0.05) and increased RV fractional area change (p < 0.05). In addition, meldonium treatment improved altered mitochondrial bioenergetics in the right ventricular cardiomyocytes. In RVF patients, meldonium treatment significantly improved WHO functional class and SF-36 scores (p < 0.05). Significant increase in walking distance in 6-minute walking test (p = 0.021) and decrease in Borg dyspnoea score after the 6MWT (p = 0.003) were also observed in patients with RVF. The overall incidence of PAH and CPTEH in Latvia has remained stable over the last five years and is in line with other European countries, but the majority of patients are still diagnosed at an advanced stage of the disease. In an experimental model of RVF, treatment with meldonium prevents the development of RVF by improving mitochondrial bioenergetics. In patients with chronic RVF, meldonium treatment is safe and well tolerated and increases functional capacity and decreases dyspnoea.