Objective The goal of this study was to determine if biomarkers of collagen metabolism in pulmonary arterial hypertension (PAH) identify patients with worse disease and higher risk of death. Background The relationship between markers of collagen metabolism, degree of disease, and outcome in PAH is unknown. Methods Stable idiopathic, anorexigen-associated and hereditary PAH patients were prospectively enrolled. Collagen biomarkers levels were measured: N-terminal propeptide of type III procollagen (PIIINP), C-terminal telopeptide of collagen type I (CITP), matrix metalloproteinsase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1). Patients were divided into mild, moderate, and severe PAH groups. Data was compared between tertiles of each biomarker. Pearson correlation and Spearman rank coefficient analyses were performed. Data on time to death or transplantation was examined by Kaplan-Meier survival curves. Results Circulating levels of PIIINP, CITP, MMP9 and TIMP1 were higher in the PAH group (N=68) as compared to age- and gender-matched healthy controls (N=37) (p<0.001 for each). PIIINP levels increased with the severity of disease (p=0.004). PIIINP tertile data indicated that with increasing levels, six-minute walk distance (6MWD) and cardiac index (CI) decreased and WHO FC worsened, and resting heart rate increased. A significant correlation existed between PIIINP with worsening WHO FC (rs=0.319, p=0.008) and a negative correlation with CI and 6MWD (r=-0.304 and -0.361 respectively; p<0.05). PIIINP tertiles showed a trend towards worse outcome in patients with higher tertile (lung transplant or death) (p=0.07, log rank test). Conclusions Markers of collagen metabolism were associated with worse disease in PAH patients.

Objectives The goal of this study was to investigate the association between collagen metabolism biomarkers and health related quality of life (HRQoL) in PAH patients. Methods We prospectively enrolled 68 stable idiopathic, anorexigen-associated, and hereditary PAH subjects and 37 healthy controls. Serum samples were analyzed for N-terminal propeptide of type III procollagen (PIIINP), c-terminal telopeptide of collagen type I (CITP), matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1). The Minnesota Living with Heart Failure (MLWHF), Euro QoL-5D (EQ-5D), Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) and Short Form (SF-36) general health survey were administered at the time of blood draw. General linear models, as well as logistic regression models were used to assess associations between variables. Results CITP, PIIINP, MMP9, and TIMP1 levels, and all HRQoL domains were significantly different between controls and PAH patients (p<0.001 for each). Interestingly, PIIINP levels were significantly associated with MLWHF physical (coef=1.63, and p=0.02), SF-36 physical (coef=−2.93, p=0.004), and EQ-5D aggregate (coef=0.34, p=0.001) scores. Several of the CAMPHOR scores strongly linearly associated with PIIINP. The odds of obtaining a walk distance ≥330 meters decrease by 38% per unit increase in PIIINP (OR=0.62; 95% CI=0.43, 0.90) and a PIIINP cutoff of 5.53 μg/L provided 81% sensitivity and 82% specificity. Conclusions PIIINP is a good predictor of disease severity, and is strongly related to HRQoL scores in PAH patients. These relationships suggest PIIINP as a promising tool for PAH clinicians to determine or confirm the level of disease severity.

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