Right Ventricular Remodeling and Circulating Metabolic Profiles of Patients with Chronic Thromboembolic Pulmonary Hypertension Before and After Pulmonary Endarterectomy

Background Right ventricular (RV) adaptation to chronic thromboembolic pulmonary hypertension (CTEPH) remains incompletely understood. Precise phenotyping of RV reverse remodeling after pulmonary endarterectomy (PEA) may help identify biomarkers and generate hypotheses for future mechanistic and therapeutic studies on RV. We aimed to assess longitudinal changes in RV imaging, histology, and circulating metabolites following PEA. Methods We conducted a prospective study including 10 patients with CTEPH who were referred for PEA and 10 controls with normal RV function who were referred for aortic surgery. All patients underwent preoperative echocardiography, cardiac magnetic resonance, 18-fluoro-deoxy-glucose positron emission tomography, perioperative RV myocardial biopsies, and mass-spectrometry-based untargeted metabolomic analyses of plasma samples. Imaging and metabolomic studies were repeated at 1 and 6 months after surgery in patients with CTEPH to assess their longitudinal evolution. Results Compared to controls, RV histology of patients with CTEPH demonstrated capillary rarefaction, cardiomyocyte hypertrophy, marked fibrosis, and macrophage infiltration, all of which were significantly associated with RV dysfunction, RV-pulmonary arterial (RV-PA) uncoupling, adverse remodeling, and increased myocardial glucose uptake. Circulating metabolic profiles of patients with CTEPH exhibited pronounced alterations in arginine, lysine, purine, and fatty acid metabolic pathways compared to controls, as assessed both cross-sectionally and longitudinally. These metabolic changes were correlated with both histological and imaging features. Conclusions Multimodality imaging, histology, and metabolomics highlighted longitudinal changes associated with RV reverse remodeling following PEA. Capillary rarefaction, cardiomyocyte hypertrophy, fibrosis, and inflammation were observed in CTEPH patients, consistent with previous experimental studies. Alterations in arginine, lysine, purine, and fatty acid metabolic pathways were associated with RV remodeling and recovery, generating hypotheses regarding potential metabolic biomarkers and mechanisms involved in RV adaptation in CTEPH.