Anne-Marie Koop

3 65 INTRODUCTION Right ventricular (RV) function is an important predictor for clinical outcome in a variety of cardiac diseases. 1-4 In patients with pulmonary hypertension (PH), RV failure is the main cause of death 2 . Development of RV failure due to sustained pressure load is characterized by progressive diastolic dysfunction, changes in fibrotic content and metabolic remodelling. 5-9 The healthy adult myocardium primarily uses long-chain fatty acids as substrates, in contrast to the fetal heart which uses primarily glucose and lactate. 10-13 Under stress, the heart switches to a so-called “fetal phenotype”, which includes a change in substrate utilization from oxidative metabolism towards glycolysis. 12 While these changes may have advantages, i.e. better ratio ATP production vs. oxygen use, they may also have disadvantages, e.g. increase of stimulation of inflammatory cascades via intermediaries. The right ventricle under pressure may be especially susceptible to changes in substrate utilization because of its unique physiological properties. 14 The RV is a thin- walled crescent shaped structure that under physiological conditions is coupled to low-resistance pulmonary circulation. Increased pressure load in the RV, prevalent in pulmonary hypertension, congenital heart disease, and also in LV failure, concerns a relatively high load for the RV. In addition, the RVmay be more susceptible compared to the left ventricle (LV) because of the relatively higher disadvantageous changes in coronary perfusion with increased afterload. Several studies have attempted to improve RV adaptation by metabolic modulation. Metabolic intervention tested whether direct or indirect stimulation of glucose oxidation by compounds as dichloroacetate (DCA), ranolazine (RAN), trimetazidine (TMZ) and 6-diazo-5-oxo-L-norleucine (DON), could be supportive in the pressure loaded RV. 15-21 Indeed, these modulation seems to affect cardiac performance positively, but due to the limited number of studies, different models, different compounds and different study parameters, consensus has not been reached, complicating translation to clinical practice. 22,23 To support the validated setup of clinical trials and to identify challenges and opportunities in evaluating metabolic findings in animal models for human disease, a comprehensive appreciation of all evidence collected in previous studies addressing metabolic adaptation of the RV to pressure load is necessary. The aim of this systematic review and meta-analysis is to provide an overview of the current knowledge about metabolic remodelling, focusing on carbohydrate and fatty acid metabolism in the pressure loaded RV. Both experimental and clinical studies