Prognostic value of plasma IgG N-glycome traits in patients with pulmonary arterial hypertension: an observational cohort study

Abstract

BackgroundBNP (brain natriuretic peptide) or NT-proBNP (N-terminal proBNP) is the only blood biomarker in the established risk calculators for pulmonary arterial hypertension (PAH). New plasma biomarkers of systemic origin may improve the risk assessment in PAH.MethodsWe utilized a robust mass spectrometry-based method to identify prognostic plasma IgG N-glycome traits in PAH patients from two national referral centers in China (Beijing [discovery] cohort, n = 273; Shanghai cohort [validation], n = 349). Then the candidate IgG N-glycan traits were evaluated in combined cohorts adjusted for potential confounders and subgroup analyses. At last, the candidate IgG N-glycan traits were further evaluated against the established prognostic risk equation (three-strata model from the SPAHR and COMPERA analyses) for PAH. The primary endpoint was all-cause mortality.ResultsIgG Fucosylation was found to predict survival independent of age and sex in the discovery cohort (HR: 0.377, 95% CI: 0.168-0.845,P= 0.018) with confirmation in the validation cohort (HR: 0.264, 95% CI: 0.445-0.751,P= 0.005). IgG Fucosylation remained a robust predictor of mortality in PAH patients in the combined cohorts adjusting for potential confounders and in subgroup analyses based on sex and treatment strategies. Moreover, the addition of the IgG Fucosylation to the established three-strata model significantly improved the predictive accuracy from AUC of 0.67 to AUC of 0.70 (P= 0.043) and IgG Fucosylation was useful in further stratifying the intermediate risk PAH patients classified by the three-strata model into intermediate-low and intermediate-high risk subgroups.ConclusionsThe plasma IgG Fucosylation informs prognosis independent of the existing clinical assessments in PAH and may be useful in the clinical management of patients with PAH.Clinical Perspective What is new?The plasma IgG Fucosylation, which is in different pathophysiological pathways from other established risk factors of pulmonary arterial hypertension (PAH), can inform prognosis independent of the existing clinical assessments in patients with PAH.The addition of the IgG Fucosylation to the established three-strata model for PAH prognosis significantly improved the predictive accuracy.IgG Fucosylation was useful in further stratifying the intermediate risk PAH patients classified by the three-strata model into intermediate-high and intermediate-low risk subgroups.What are the clinical implications?Plasma IgG N-glycan biomarkers may provide a refined risk stratification in PAH used in combination with the established risk factors.IgG Fucosylation involved in inflammatory pathways may not only be a promising prognostic biomarker but also a potential novel therapeutic target, distinct from existing targets, for patients with PAH.