Abstract Background Pulmonary hypertension (PH) is a high-mortality disease lacking effective biomarkers for risk assessment and outcome prediction. The microbiota-dependent carnitine-trimethylamine N-oxide (TMAO) pathway has been implicated in the progression and poor prognosis of PH. This study aimed to evaluate the potential of γ-butyrobetaine (γ-BB), a metabolic intermediate in the carnitine-TMAO pathway, as a novel biomarker for mortality prediction and disease management in PH patients. Methods This cohort study included 480 consecutive patients diagnosed with pulmonary atrial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) between June 2019 and November 2022, with all-cause mortality as the primary endpoint. The association between γ-BB and mortality was assessed in overall patients using restricted cubic spline (RCS) analysis, Spearman's rank correlation, and multivariable Cox regression. Kaplan-Meier survival analysis identified the prognostic value of γ-BB in PAH patients, while Harrell's C-index evaluated its contribution to COMPARE 2.0 risk models. The mediating role of IL-6 in the γ-BB-mortality relationship was also investigated. Results γ-BB was significantly associated with the severity of PH and remained a strong predictor of mortality after bias adjustment (hazard ratio HR 1.47, 95% confidence interval CI: 1.20, 1.80 per standard deviation, P 0.001), particularly in PAH patients. The distribution of γ-BB levels varied across different risk stratification in PAH patients, suggesting a positive correlation between metabolite levels and risk categorization. Incorporating γ-BB into the COMPARE 2.0 risk model enhanced its predictive power, as evidenced by improvements in the Harrell C-index, the net reclassification improvement and integrated discrimination improvement. Mediation analysis revealed that IL-6 accounted for 6.97% of the association between γ-BB and mortality. Conclusions γ-BB is a promising novel biomarker for predicting all-cause death and improving risk stratification accuracy in PAH patients, offering potential for more effective patient management.K-M analysis Multivariate Cox analysis
Yan et al. (Sat,) studied this question.