Abstract Rationale In pulmonary arterial hypertension (PAH), the right ventricle (RV) exhibits variable responses to increased afterload, ranging from preserved (adaptive) to impaired (maladaptive) function. The molecular determinants of this heterogeneity remain poorly defined. Specialized pro-resolving mediators (SPMs) are bioactive lipids derived from omega-3 polyunsaturated fatty acids that promote resolution of inflammation and vascular repair. Given their established role in cardiovascular homeostasis but limited data in PAH, this study aimed to investigate associations between circulating SPMs and hemodynamic measures of RV adaptation in patients with PAH. Methods Plasma samples from patients with all World Health Organization (WHO) Group 1 PAH subtypes enrolled in the National Biological Sample and Data Repository for Pulmonary Arterial Hypertension (PAH Biobank) were analyzed. Right atrial pressure (RAP) and pulmonary artery pulsatility index (PAPi), obtained from right heart catheterization (RHC), were used as hemodynamic surrogates of RV adaptation. SPMs were assayed using targeted liquid chromatography-mass spectrometry (LC-MS). Linear regression models adjusted for age, sex, and baseline pulmonary vascular resistance (PVR) were used to assess associations between SPMs (and related metabolites) and RAP or PAPi. Statistical significance was defined as p 0.05 with false discovery rate (FDR) correction at q 0.10. Results A total of 2,373 patients (78% female; mean age 52.3 ± 17.8 years) were included. Among 23 pre-specified SPMs and related metabolites, higher plasma levels of Resolvin E1 (RvE1) were significantly associated with lower right atrial pressure (RAP) per 1 SD increase in analyte concentration (β = -0.49, 95% CI -0.69 to -0.28; p 0.001). Consistent with this, several RvE1 precursors, including eicosapentaenoic acid (EPA) and 18-HEPE, were also associated with lower RAP (β = -0.25, 95% CI -0.47 to -0.04; p = 0.02 and β = -0.26, 95% CI -0.49 to -0.02; p = 0.04, respectively). These metabolites, along with Maresin 2 (MaR2), demonstrated trends toward higher pulmonary artery pulsatility index (PAPi), suggesting a relationship with more favorable RV adaptation. In contrast, higher levels of Resolvin D3 (RvD3) were associated with higher RAP (β = 0.50, 95% CI 0.29 to 0.72; p 0.001) and lower PAPi (β = -0.58, 95% CI -0.94 to -0.22; p = 0.002), indicative of a maladaptive RV profile. Conclusion Distinct SPM profiles are associated with differential RV adaptation in PAH. These findings suggest that dysregulation of endogenous resolution pathways may contribute to RV maladaptation and could inform future strategies aimed at improving RV function in PAH. This abstract is funded by: This work was supported in part by NIH grants K08HL166950
Robertson et al. (Fri,) studied this question.