Circulating Collagen Biomarkers as Indicators of Disease Severity in Pulmonary Arterial Hypertension
Can biomarkers of collagen metabolism in pulmonary arterial hypertension (PAH) identify patients with worse disease and higher risk of death?
Patients with stable idiopathic, anorexigen-associated, and hereditary PAH were prospectively enrolled. Levels of the following collagen biomarkers were measured: N-terminal pro-peptide of type III procollagen (PIIINP), C-terminal telopeptide of collagen type I (CITP), matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1. Patients were divided into mild, moderate, and severe PAH groups. Data were compared between tertiles of each biomarker. Pearson correlation and Spearman rank coefficient analyses were performed. Data on time to death or transplantation were examined by Kaplan-Meier survival curves.
Mean age was 45 (15) years, 91% were female, 53% were World Health Organization (WHO) functional class (FC) I-II, and 61/63 were being treated with PAH-specific therapy. Patients were followed for an average of 2.8 years, range 1.2-5.1 years. Circulating levels of PIIINP, CITP, MMP-9, and TIMP-1 were higher in the PAH group (n = 68) as compared with age- and sex-matched healthy controls (n = 37) (p < 0.001 for each). PIIINP levels increased with the severity of disease (p = 0.002). PIIINP tertile data indicated that with increasing levels, 6-minute walk distance and cardiac index decreased, WHO FC worsened, and resting heart rate increased. A significant correlation existed between PIIINP levels and worsening WHO FC (rs = 0.320; p < 0.01), and there was a negative correlation between cardiac index and 6-minute walk distance (r = -0.304 and r = -0.362, respectively; p < 0.05). PIIINP tertiles showed a trend toward worse outcome in patients with higher tertiles (lung transplant or death) (p = 0.07; log-rank test).
The authors concluded that markers of collagen metabolism were associated with worse disease in patients with PAH.
Among the many biomarkers of outcome studied in PAH (e.g., cardiac troponin T, uric acid, soluble ST2), only B-type natriuretic peptide (BNP) and N-terminal pro-BNP, which reflect left and right ventricular wall stress, have been established to be clinically useful.
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