Untargeted metabolomic network analysis identified 3 modules significantly correlated with right ventricular function, including an odd-chain fatty acid module linked to diastolic function.
Observational (n=89)
No
Circulating odd-chain fatty acids and anti-inflammatory lipid mediators are associated with preserved right ventricular diastolic function in patients with suspected pulmonary hypertension.
Abstract Rationale Right ventricular (RV) function is the primary determinant of mortality in pulmonary hypertension (PH), but the factors that influence RV resilience versus vulnerability to altered loading conditions remain poorly defined. We have previously shown that metabolite combinations selected from a narrowly targeted metabolomics panel are robustly associated with intrinsic measures of RV function measured by gold-standard pressure-volume loops; however, selection of metabolites on the basis of their predictive capacity overlooks metabolic interrelationships and limits pathway-level inference. Here, we build on our prior work by applying weighted gene co-expression network analysis (WGCNA) to high-dimensional untargeted metabolomic data to uncover biologically coherent metabolic modules. We hypothesized this approach would reveal biologically-based associations with RV functional measures to provide mechanistic insights and potential therapeutic targets. Methods 89 subjects were prospectively enrolled at Johns Hopkins Hospital after referral for suspected PH. All subjects underwent right heart catheterization and RV-PV loop analysis, with gold-standard measurement of load-independent measures of RV function. Global untargeted metabolomics (Metabolon HD4 panel) were performed on fasting pulmonary arterial samples using LC-MS. Metabolites were grouped into co-expression modules using WGCNA and correlated with hemodynamic and PV-loop-derived indices of RV function. Results We constructed a WCGNA with a soft-thresholding power of 3, which achieved a strong scale-free topology fit (R² = 0.85). The analysis identified 14 modules that were robust to tuning parameters and adjustment for age and sex. Modules demonstrated low inter-module correlation and explained a high percentage of variance in metabolite abundance, indicating distinct, biologically coherent metabolic programs. When modules were correlated with RHC and RV-PV loop data, 3 modules demonstrated robust, directionally consistent correlations that survived false discovery rate correction. The magenta module was associated with both hemodynamic and RV-intrinsic measures of diastolic function, including Tau, a measure of diastolic relaxation derived from PV-loop data. The magenta module was enriched with odd-chain fatty acids and included fatty acids with lipokine properties (palmitoleate 16: 1n7) and precursors to the Resolvin pathway (EPA 10:5n3 and n3 DPA 22:5n3). Conclusions We identified a biologically coherent and novel signature of RV resilience in PH defined by circulating odd-chain fatty acids and anti-inflammatory lipid mediators. These findings suggest activation of anti-inflammatory pathways and a shift toward odd-chain fatty acid fuel substrates may be protective of RV diastolic function. Further mechanistic studies to define whether and how these pathways may be therapeutically modulated are warranted. This abstract is funded by: R03HL176624 (CES), R01HL17501 (CES), NIH/NHLBI R01 HL114910
Clinton et al. (2026) conducted an observational in Pulmonary hypertension (n=89). Untargeted metabolomic network analysis identified 3 modules significantly correlated with right ventricular function, including an odd-chain fatty acid module linked to diastolic function.