PHIHDL: A Novel HDL Index Predicting Baseline Pulmonary Hemodynamics and Long-Term Survival in PAH

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Abstract Rationale Pulmonary hypertension is defined by pulmonary hemodynamics, but diagnostic and prognostic biomarkers remain limited. Nuclear magnetic resonance (NMR) spectroscopy provides detailed insights, particularly in the lipid metabolism. Objectives To explore circulating NMR-derived metabolites and lipoprotein-related parameters for their association with pulmonary hemodynamics and to analyse their prognostic properties in pulmonary arterial hypertension (PAH). Methods Retrospective analysis of a PAH cohort with complete diagnostic workup including right heart catheterization and baseline serum samples, from the prospective GRaz Pulmonary Hypertension-Metabolism (GRAPH-M) registry. Measurements NMR-derived metabolites and lipoprotein-related parameters were analyzed for their association with clinically relevant parameters of PAH. We defined PHIHDL, a score derived from high-density lipoprotein (HDL) related measures based on their strong association with pulmonary hemodynamics, and evaluated its prognostic value. Results We included 100 patients with PAH treated at the PH clinic of LKH University Hospital, Medical University of Graz, between 2011 and 2021. Age was 61±15 years, female/male ratio 2.5, BMI 26±7 kg/m 2 , mPAP 41±16 mmHg, PAWP 8.8±3.2 mmHg, PVR 8.0±4.9 WU, and median survival was 8.0 years. During follow-up, 46 patients died. We identified a cluster of 12 HDL-related measures that showed significant inverse association to pulmonary hemodynamics and derived PHIHDL from the reversed scaled average of these particles. PHIHDL was associated with all-cause mortality after adjustment for age and sex (HR 2.96, 95% CI 1.52-5.70), independent of the clinical risk scores COMPERA 2.0 and REVEAL Lite 2. Conclusion PHIHDL, a pulmonary hemodynamics-based metabolomic score, provides independent prognostic information beyond established risk scores in PAH.

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