Ever-smoking in PAH was associated with higher right atrial pressure (β=0.54, p=0.019), lower pulmonary artery pulsatility index (β=-1.12, p=0.003), and altered pro-resolving lipid pathways.
Observational (n=2,367)
Yes
Does smoking alter circulating specialized pro-resolving mediators and right ventricular function in patients with pulmonary arterial hypertension?
Smoking in PAH is associated with adverse right ventricular hemodynamics, a relationship that may be partially mediated by the depletion of specific pro-resolving lipid mediators such as Maresin 1.
Effect estimate: β = 0.54 (RAP); β = -1.12 (PAPi)
p-value: p=0.019 (RAP); 0.003 (PAPi)
Abstract Rationale Smoking contributes to vascular remodeling and endothelial dysfunction. Specialized pro-resolving mediators (SPMs) regulate inflammation and vascular repair and have shown protective effects in experimental models of smoke-induced injury. However, the relationship between smoking, circulating SPMs, and right ventricular (RV) function in pulmonary arterial hypertension (PAH) remains unclear. We aimed to determine whether low circulating SPM levels mediate the association between smoking and RV maladaptation in PAH. Methods We evaluated 2,367 participants with PAH from the National Biological Sample and Data Repository for PAH (PAH Biobank) with available plasma samples. SPMs were quantified using targeted liquid chromatography-mass spectrometry (LC-MS). Group differences by ever-smoking status were assessed using parametric or non-parametric tests as appropriate. Associations between SPMs and smoking status, as well as with right atrial pressure (RAP) and pulmonary artery pulsatility index (PAPi), were evaluated using linear regression models adjusted for age, sex, and body mass index (BMI). Mediation analyses using g-computation, adjusted for the same covariates, were then performed to test whether SPMs mediated the relationship between smoking and RV maladaptation, defined by elevated RAP and/or reduced PAPi. Results Among 2,367 patients with PAH, 961 (41%) were ever-smokers. Ever-smokers demonstrated higher right atrial pressure (RAP; β = 0.54, p = 0.019) and lower pulmonary artery pulsatility index (PAPi; β = -1.12, p = 0.003). Smoking was associated with lower circulating levels of several SPMs, including Maresin 1, Maresin 2, 12-HEPE and related lipid metabolites. In mediation analysis, Maresin 1 partially mediated the association between smoking and RV hemodynamics, suggesting that SPM depletion may represent a biological link between smoking exposure and RV dysfunction in PAH. Interestingly, one SPM (Resolvin E1) was elevated in smokers and demonstrated a significant negative mediation effect on RAP (p = 2.9 × 10-4), indicating a potential compensatory metabolic response that partially offset the adverse hemodynamic effects of smoking. Conclusion Smoking in PAH is associated with right ventricular maladaptation and alterations in pro-resolving lipid pathways. While lower Maresin 1 levels linked smoking to adverse RV remodeling, higher levels of Resolvin E1 were associated with a favorable hemodynamic profile, suggesting a divergent, potentially adaptive resolution response among smokers. This abstract is funded by: NIH
Yuguchi et al. (2026) conducted an observational in Pulmonary arterial hypertension (n=2,367). Smoking vs. Never-smokers was evaluated on Right atrial pressure (RAP) and pulmonary artery pulsatility index (PAPi) (β = 0.54 (RAP); β = -1.12 (PAPi), p=0.019 (RAP); 0.003 (PAPi)). Ever-smoking in PAH was associated with higher right atrial pressure (β=0.54, p=0.019), lower pulmonary artery pulsatility index (β=-1.12, p=0.003), and altered pro-resolving lipid pathways.