Group, PVDOMICS Study

ABSTRACT Background Pulmonary arterial hypertension (PAH) is characterized by circulating metabolic alterations, but whether these reflect disease-specific metabolic programs or reorganization of normal metabolic architecture, and how they relate to right ventricular-pulmonary vascular function (RV-PV), remains unclear. We hypothesized that the PAH metabolome is organized into biologically coherent, co-regulated metabolic modules whose relationships to RV-PV function would provide insight into known and novel metabolic pathways. Methods We applied weighted gene co-expression network analysis (WGCNA) to untargeted metabolomic data from 412 PAH patients enrolled in the multicenter PVDOMICS study. Module preservation analysis was performed in 85 healthy controls, with external replication in an independent single-center pulmonary hypertension cohort of 89 patients. Results WGCNA identified 16 distinct metabolic modules organized around biologically coherent programs. A coherent fatty acid axis, spanning substrate pools, β-oxidation intermediates, and conjugated fatty acid disposal products, formed a central organizing structure, with downstream fatty acid oxidation modules strongly associated with adverse hemodynamics and worse RV-pulmonary artery (PA) coupling. Acylcholine-enriched and 5α-reduced androgen metabolite modules were associated with favorable hemodynamic indices. Module architecture was largely preserved in healthy controls, with subtle disease-associated modular reorganization, rather than emergence of novel modules, observed in PAH. Core modules were recovered in the replication cohort with conserved hub metabolites. Conclusions These findings establish a systems-level framework demonstrating that PAH involves structured intensification and reorganization of interconnected metabolic programs associated with favorable and adverse RV-PV phenotypes. This work provides new insight into the metabolic architecture underlying PAH and identifies coordinated metabolic pathways linked to pulmonary vascular and right ventricular function.

Abstract Rationale The pathophysiology and clinical impact of liver injury in pulmonary hypertension (PH) is poorly understood. Liver injury in PH is often attributed to hepatic congestion, but some studies have failed to find strong associations with hemodynamics, suggesting alternative mechanisms. We sought to define the prevalence of liver injury and patterns of liver injury across the spectrum of PH and to determine whether patterns of liver injury were associated with clinical characteristics, hemodynamics and outcomes. Methods We performed an analysis of the PVDOMICS study, a multicenter, prospective, longitudinal cohort study that enrolled incident and prevalent patients with PH and disease comparators. The prevalence of liver injury, defined as aspartate or alanine aminotransferase (AST or ALT) or total bilirubin above the upper limit of normal, and different patterns of liver injury [hepatocellular (elevated AST or ALT with normal bilirubin), cholestatic (elevated bilirubin) and no liver injury] was defined among participants with known or suspected PH. Associations between patterns of liver injury with demographics, hemodynamics, right ventricular function, exercise capacity and quality of life (QoL) were assessed. We used Cox proportional hazards models adjusted for age and sex to assess the association of liver injury patterns with transplant-free survival. Results Liver injury was present in 27.8% (288/1036) of participants (19.0% cholestatic and 8.8% hepatocellular). Patients with liver injury were less likely to be female and have prevalent disease with differences in PH classification (Table 1). Patients with hepatocellular liver injury had a higher body mass index. A cholestatic liver injury pattern was most consistently associated with worse functional class, biventricular filling pressures, pulmonary vascular resistance, right ventricular function, natriuretic peptide elevation, exercise capacity, and REVEAL risk scores. Total bilirubin levels and right atrial pressure as a marker of systemic congestion were weakly correlated (r2=0.02, p < 0.0001). Compared to no liver injury, cholestatic liver injury was associated with an increased risk of death in age and sex adjusted models (HR 1.6, 95% CI 1.3-2.1, p < 0.001) but hepatocellular liver injury was not (p > 0.05). Conclusions Liver injury is common among patients with known or suspected PH. In contrast to a hepatocellular injury pattern, a cholestatic liver injury pattern was most consistently associated with worse hemodynamics, exercise capacity, QoL and survival. However, the weak relationship between right atrial pressure and bilirubin suggests that systemic congestion alone is unlikely to completely explain cholestatic liver injury. Further study is needed to uncouple the pathophysiological basis of cholestasis in PH. This abstract is funded by: NHLBI

Abstract Rationale: The 7th World Symposium on Pulmonary Hypertension highlighted the importance of patient-reported outcomes in clinical assessment of pulmonary arterial hypertension (PAH). Patient-reported outcomes, such as health-related quality of life (HRQOL), have been associated with morbidity and mortality in PAH, but the added value of HRQOL measures to validated risk prediction models remains unknown. Methods: Adults with RHC-proven PAH from the Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics (PVDOMICS) Study, a multi-center observational study, were included in this study. The Pulmonary Hypertension Association Registry (PHAR) was used as a validation cohort. HRQOL was measured using the emPHasis-10 score, where higher scores reflect worse HRQOL. Noninvasive risk assessment was measured by REVEAL Lite 2 risk score, categorized into 3-strata. Cox proportional hazard models were used to model survival evaluating the interaction between risk strata and HRQOL scores, adjusting for age, sex, and incident diagnosis. Harrell's C-statistics were calculated to compare discriminative performance. Results: From the PVDOMICS and PHAR cohorts, 265 and 2671 individuals with PAH and complete emPHasis-10 and REVEAL Lite 2 scores were included. Both cohorts had similar demographics, with an average age of 52±13 and 56±16 years, 75% and 72% female, 81% and 75% White, in the PVDOMICS and PHAR cohorts respectively. Over 87% of PVDOMICS were prevalent cases of PAH, while in the PHAR half were incident. Most individuals (62%) in PVDOMICS were REVEAL Lite 2 low risk, with 16% intermediate and 22% high risk; by contrast, in PHAR 33% were low, 29% intermediate, and 38% high risk. REVEAL Lite 2 scores demonstrated weak to moderate correlation with emPHasis-10 scores in both cohorts (PVDOMICS r=0.48 p<0.001; PHAR r=0.33 p<0.001). Notably, the full range of emPHasis-10 scores were observed in the low-risk individuals across both cohorts. In the PVDOMICS adjusted Cox models, higher emPHasis-10 scores predicted poorer survival (p=0.047) particularly among low-risk individuals (interaction versus high-risk group p=0.08). Similar adjusted models in PHAR demonstrated emPHasis-10 to be a confounder (p=0.001) without significant interaction by risk strata (low vs high-risk interaction p=0.94), but the greatest change in median survival time was observed in the low-risk group (Figure 1). Addition of emPHasis-10 to REVEAL Lite 2 scores improved discrimination in predicting survival (PVDOMICS: C-statistic 0.71 vs 0.73; PHAR: C-statistic 0.67 vs 0.69). Conclusions: Across two multicenter cohorts of incident and prevalent PAH, HRQOL as measured by the emPHasis-10 score improved discrimination for survival, particularly among individuals with lower risk scores.