Metabolic Signature of Human Right Ventricular Heart Muscle in Pulmonary Arterial Hypertension and Comparison to Two Animal Models

Introduction: Molecular studies of the human right ventricle (RV) in pulmonary arterial hypertension (PAH) are lacking. Metabolic changes in the failing RV vary across different animal models and have not been directly compared with the human RV. We hypothesized that the BMPR2 murine model of PAH would closely recapitulate metabolic changes in the human PAH RV Methods: We performed metabolomic profiling of 596 compounds (Metabolon) on: RV specimens from patients with PAH and non-PAH controls (n=3 per group), BMPR2 mice (n=15), wild-type mice after pulmonary artery banding (PAB) (n=7), and wild-type control mice (WT) (n=7). Normalized metabolites per group were compared by Welch’s t-test between two groups, and two-way ANOVA for >2 groups, followed by adjustment for multiple comparison analysis Results: Principal component analysis (PCA) revealed markedly different metabolic profiles between PAH and controls ( Figure 1A ), with significant changes in 131 biochemicals in PAH. We observed an increase in glycolysis as evident by lactate accumulation and reduction in glycolytic intermediaries. We also observed a substantial reduction in fatty acid oxidation in the PAH RV, characterized by markedly reduced acylcarnitines and accumulation of long chain fatty acids, lysolipids, and glycerol compounds ( Figure 1B ). The BMPR2 model significantly reproduced the direction of difference in 43/131 metabolites and the PAB model 29/131. Both models were associated with an increase in glycolysis but only the BMPR2 model showed evidence of impaired fatty acid oxidation (accumulation of long-chain fatty acids, lysolipids, glycerol, and monoacylglycerols), as observed in the human PAH RV ( Figure 1C ) Conclusions: The failing RV of patients with PAH has a distinct metabolic signature characterized by increased glycolysis and impaired fatty acid oxidation. The BMPR2 model of PAH recapitulates more of the key metabolic changes observed in humans compared with a model of isolated pressure overload. The BMPR2 model may be preferable for metabolic studies of the failing RV