Inflammation and Obesity Correlate in Pulmonary Hypertension but Are Associated with Diverging Outcomes

RATIONALE AND OBJECTIVES: Inflammation is associated with all types of pulmonary hypertension (PH), both as a known cause and as a putative confounder. The most common marker of inflammation, C-reactive protein (CRP), has not been widely studied in PH. This study set out to clarify if CRP informs clinical endotyping and outcomes. METHODS: Time-series clustering of longitudinal CRP concentrations was employed. Clinical differences between clusters were validated in three independent U.K./international cohorts using clinical cutoff values (n = 10,301; U.K. cohort, ASPIRE and FDA cohort). Associations were analyzed with functional and mortality outcomes by linear and Cox regression models including all causes of PH (groups 1-5). To add mechanistic insight, multiomics were interrogated from associated previously published arrays. MEASUREMENTS AND MAIN RESULTS: Patients were segregated into two stable CRP clusters (median CRP, 2 vs. 6.5 mg/L), with the high cluster exhibiting significantly higher body mass index (BMI) (difference between medians [DBM], 5.4 kg/m2), higher right atrial pressure (DBM, 2 mm Hg), and reduced 6-minute-walk distance (DBM, 55 m). Inflammation was associated with worse survival and comorbidities, higher pulmonary vascular resistance, and smoking status. CRP and BMI were associated with differing inflammatory profiles in proteomic and transcriptomic analyses. Despite the relationship with CRP, higher BMI was associated with improved survival and lower pulmonary vascular resistance and did not negatively affect 6-minute-walk distance treatment-related functional responses. CONCLUSIONS: We establish a relationship between CRP and BMI across all-cause PH, although CRP and BMI are associated with diverging clinical outcomes. Inflammation and obesity are relevant phenotypes for consideration in clinical trial design. Understanding their impacts on outcomes is important for clinical practice.