Racanelli, Alexandra C.

BACKGROUND: The metabolic mechanisms underlying right ventricular (RV) dysfunction are poorly understood, particularly outside of group 1 pulmonary hypertension (PH). We aimed to identify metabolites and pathways associated with RV systolic function and explored whether associations differed by pulmonary vascular resistance, PH group 1 status, and sex. METHODS: We analyzed data from the multicenter PVDOMICS (Pulmonary Vascular Disease Phenomics) cohort. RV systolic function metrics included fractional area change (echo), global longitudinal strain (echo), and ejection fraction (cardiac magnetic resonance). We used linear regression adjusted for age, sex, body mass index, and PH group to assess associations between metabolites and RV function. Pathway enrichment analyses were used to identify pathways significantly associated with RV function. Interaction terms were assessed to determine whether metabolite associations were modified by pulmonary vascular resistance, group 1 PH status, or sex. Least absolute shrinkage and selection operator regression was used to develop metabolite-based scores for RV function, and prognostic performance was assessed. RESULTS: There were 979 participants with plasma metabolomics and RV function data. Linear regression identified 170 metabolites that were significantly associated with all 3 RV metrics. Androgenic steroid, gamma-glutamyl amino acid, polyamine, vitamin A, fatty acid, and sterol pathways are most strongly associated with RV systolic function. Two metabolites interacted with group 1 PH status, and 6 interacted with pulmonary vascular resistance. Four androgenic steroids are associated more strongly with RV systolic function in women compared with men. Metabolite-based scores were prognostically equivalent to RV systolic function metrics and less accurate than REVEAL Lite 2 scores. CONCLUSIONS: We provide a blueprint of metabolites and metabolic pathways associated with RV systolic function across the spectrum of PH. Novel links to vitamin A and glutathione metabolites were observed. We detected few metabolites that associated with RV systolic function differentially by group 1 PH status or degree of pulmonary vascular resistance elevation. Androgenic steroids may associate more strongly with RV systolic function in women compared with men.

Introduction: PH increases RV afterload, often leading to RV systolic and diastolic failure. The metabolic mechanisms underlying RV dysfunction remain poorly understood and are largely unexplored across non-PAH forms of PH. Aims: We aimed to identify which metabolites and metabolic pathways associated with imaging measures of RV systolic function. Methods: We analyzed data from the multi-center PVDOMICS cohort, which includes echo, CMR, invasive hemodynamics, clinical phenotyping, and untargeted plasma metabolomics (via Metabolon). RV systolic function metrics selected as the outcome measures for this study were fractional area change (echo), global longitudinal strain (echo), and RVEF (CMR). Associations between non-xenobiotic, named metabolites and RV function measures were assessed using linear regression adjusted for age, sex, BMI, and PH group, with significance defined by FDR <0.05. Metabolite set enrichment analysis (MSEA) was performed to identify significantly enriched pathways (FDR <0.20). To complement MSEA, we conducted mean-aggregation analysis: we averaged metabolite concentrations within each pathway and tested associations with RV function using the same covariate adjustments (FDR <0.05). Results: We identified 979 participants with plasma metabolomics and at least one available outcome measure (317 Group 1 PH; 106 Group 2 PH; 140 Group 3 PH; 51 Group 4 PH; 26 Group 5 PH; 81 Healthy Controls; 258 Disease Comparators). Linear regression identified 170 metabolites from the 647 named metabolites significantly associated with all 3 RV metrics (Top 10 by average ranked p-value displayed in Image 1 ). MSEA revealed seven enriched pathways across all RV metrics: Androgenic Steroids, Pregnenolone Steroids, Progestin Steroids, Fatty Acid Metabolism (Acyl Choline), Histidine metabolism, Vitamin A metabolism, Gamma-glutamyl Amino Acid ( Image 2) . Mean aggregation analysis showed that higher concentrations of Androgenic/Pregnenolone Steroids and Vitamin A metabolites strongly associated with improved RV function, while higher levels of Fatty Acid Metabolism (Acyl Carnitine) and Acetylated Peptides associated with worse function ( Image 3 ). Conclusions: Using data from the multi-institutional PVDOMICS cohort, we provide a blueprint of metabolites and metabolic pathways associated with RV systolic function across the spectrum of PH. Steroid hormones as well as Vitamin A and fatty acid metabolites emerged as central to RV systolic 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.