Kolb, Todd M.

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.

Background Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood. Methods We performed global untargeted metabolomics on plasma from 55 patients who underwent gold‐standard RV‐PA coupling measurements using multibeat pressure volume loop assessment in a single‐center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex‐adjusted linear regression was performed to identify associations between metabolites and coupling metrics. Additionally, we performed a metabolic flux analysis using gene expression data from RV tissue in an independent cohort of 32 patients. Partial least squares–discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. Results RV‐PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α‐ketoglutarate and fumarate were significantly associated with all coupling metrics in both cohorts. Metabolic flux analysis indicated that decompensated RVs exhibited aberrant TCA cycle activity, including reduced acetyl coenzyme A entry and increased lactate elimination, suggesting a shift from the TCA cycle toward glycolysis at the RV tissue level. Conclusions We identify an association between circulating TCA cycle intermediate levels and RV‐PA uncoupling in 2 independent cohorts, and dysregulated TCA cycle metabolism in decompensated PA hypertension RVs, suggesting that aberrant TCA cycle metabolism could represent a hallmark of RV maladaptation in PA hypertension. Further study of this pathway is warranted to develop novel biomarkers of RV function or RV‐targeted therapies.

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.

Background: Patients with combined post- and precapillary pulmonary hypertension due to left heart disease have a worse prognosis compared with isolated postcapillary. However, it remains unclear whether increased mortality in combined post- and precapillary pulmonary hypertension is simply a result of higher total right ventricular load. Pulmonary effective arterial elastance (Ea) is a measure of total right ventricular afterload, reflecting both resistive and pulsatile components. We aimed to test whether pulmonary Ea discriminates survivors from nonsurvivors in patients with pulmonary hypertension due to left heart disease and if it does so better than other hemodynamic parameters associated with combined post- and precapillary pulmonary hypertension. Methods and Results: We combined 3 large heart failure patient cohorts (n=1036) from academic hospitals, including patients with pulmonary hypertension due to heart failure with preserved ejection fraction (n=232), reduced ejection fraction (n=335), and a mixed population (n=469). In unadjusted and 2 adjusted models, pulmonary Ea more robustly predicted mortality than pulmonary vascular resistance and the transpulmonary gradient. Along with pulmonary arterial compliance, pulmonary Ea remained predictive of survival in patients with normal pulmonary vascular resistance. The diastolic pulmonary gradient did not predict mortality. In addition, in a subset of patients with echocardiographic data, Ea and pulmonary arterial compliance were better discriminators of right ventricular dysfunction than the other parameters. Conclusions: Pulmonary Ea and pulmonary arterial compliance more consistently predicted mortality than pulmonary vascular resistance or transpulmonary gradient across a spectrum of left heart disease with pulmonary hypertension, including patients with heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, and pulmonary hypertension with a normal pulmonary vascular resistance.