Plasma Proteins Differ by Etiology and Six Minute Walk Distance in Patients With Pulmonary Arterial Hypertension

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Abstract RATIONALE: Pulmonary arterial hypertension (PAH) leads to significant morbidity and mortality despite advanced treatments. Plasma protein levels may vary with PAH etiology and six-minute walk distance (6MWD) and could enlighten disease pathophysiology. We sought to characterize the expression of 369 cardiometabolic proteins by etiology and 6MWD in a population of clinical trial participants with PAH. METHODS: PHANTOM was a phase II, randomized, double-blind, placebo-controlled clinical trial of 1 year of anastrozole (an aromatase inhibitor) versus placebo. Plasma was collected from 84 participants at 0,3,6 and 12 months and analyzed using the Olink Cardiometabolic panel including 369 proteins. 6MWD was obtained at each time-point. We analyzed the normalized protein expression (NPX) of each assay in predicting baseline 6MWD, change in 6MWD and PAH etiology (idiopathic/heritable PAH (I/HPAH), connective tissue disease-associated PAH (CTD-PAH) and other PAH). We used multivariable regression and longitudinal mixed effects models adjusted by age and sex. P-values were adjusted using the Benjamini-Hochberg procedure to account for multiple testing. RESULTS: The sample size included 84 adults, 51 (60.7%) of whom were female, with a mean age of 59.4 years. 48% of subjects had I/HPAH, 23% CTD-PAH and 30% other PAH. Mean 6MWD was 434.9m at baseline with a change of +9.8m at 12 months. There were no statistically significant differences in biomarkers by treatment arm. Patients with CTD-PAH had had significantly lower CA4 expression (β= -0.66, p = 0.001) and higher CCN3 ( β= 0.77, p = 0.035) and TNFSF13B expression compared to I/HPAH (β= 0.61, p = 0.035) (Figure 1A). 15 proteins were associated with 6MWD at baseline(Figure 1B). Higher COL18A1 (β=164.5 p = 0.021), GDF15 (β=58.4, p = 0.021) and NT-proBNP (β=18.69, p = 0.021) were associated with lower 6MWD. NT-proBNP (β=12.61, p = 0.001), NPPB (β=9.46, p = 0.01), IL1RL1 (β=30.52, p = 0.045) and IGFBP7 (β=62.46, p = 0.045) were significantly associated with change in 6MWD when analyzed across all timepoints. CONCLUSIONS: This study identifies 15 plasma proteins associated with baseline 6MWD, 4 associated with change in 6MWD and 3 with PAH etiology. Several of these have demonstrated significance in PAH, including COL18A1, an angiostatic peptide previously shown to improve mortality risk prediction in PAH. Our work differentiates subsets of proteins associated with baseline 6MWD from those whose change over time corresponds to resulting change in 6MWD. We further identify proteins differentiating I/PAH from CTD-PAH. Additional efforts are necessary toward validating these proteins as clinically useful biomarkers.

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