Deep phenotyping of the right ventricular–pulmonary circulation reveals biological overlap between pulmonary arterial hypertension and combined post-capillary pulmonary hypertension

Background The distinction between pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with left heart disease (PH-LHD) remains clinically relevant but biologically uncertain, particularly in combined post- and precapillary PH (CpcPH) and PAH associated with cardiovascular comorbidities (coPAH). Purpose To characterize clinical, hemodynamic and right ventricular (RV) phenotypes across PAH, coPAH, CpcPH and isolated post-capillary PH (ipcPH), and to explore biological overlap between groups. Methods We conducted a prospective study including 68 patients (classical PAH n=11; coPAH n=11; CpcPH n=32; ipcPH n=14) undergoing right heart catheterization and cardiac magnetic resonance imaging. Untargeted multi-omics profiling was performed, including proteomics (Olink platform), metabolomics (high-resolution HPLC-MS and CE-MS), and genome-wide DNA genotyping using the Illumina Infinium Global Screening Array v3.0. Time-to-event analyses were performed for a prespecified composite endpoint of death, urgent transplantation, or hospitalization for heart failure. Results Age and comorbidity burden increased progressively from classical PAH to coPAH, CpcPH and ipcPH (all P<0.01, Table). Mean pulmonary artery pressure and pulmonary vascular resistance were highest in classical PAH and lowest in ipcPH (P<0.001), while pulmonary artery wedge pressure was elevated in CpcPH and ipcPH by definition. Right atrial pressure was significantly higher in CpcPH and ipcPH, indicating greater RV congestion. Cardiac magnetic resonance showed lower RV ejection fraction in classical PAH and coPAH compared with CpcPH and ipcPH (P=0.022), whereas left atrial area and markers of LV diastolic burden (E/E’) were markedly increased in CpcPH and ipcPH (P<0.001). Six-minute walk distance tended to be higher in classical PAH and lower in coPAH and CpcPH (P=0.060). During follow-up, classical PAH exhibited the most favorable prognosis, whereas coPAH, CpcPH and ipcPH showed overlapping and worse trajectories for the composite clinical event (Figure). Principal component analysis of omics data did not reveal clear clustering across clinically defined groups, suggesting substantial biological overlap, particularly between coPAH and PH-LHD phenotypes. Conclusion Despite distinct hemodynamic profiles, coPAH and CpcPH share adverse clinical trajectories and overlapping biological signatures with PH-LHD. These findings support a continuum model of pulmonary hypertension beyond conventional classification.