Extracellular Matrix Turnover and Inflammatory Markers Independently Predict Functional Status and Outcome in Chronic Heart Failure

Background: Inflammatory pathways may promote extracellular matrix (ECM) remodeling and chronic heart failure (CHF) progression. The relationship between markers of inflammation and of ECM remodeling, and their influence on functional status and outcomes has not been examined in a large cohort of CHF patients. Methods and Results: We measured baseline blood serum collagen (amino-terminal propeptide of collagen III [PIIINP], metalloproteinase 1 [MMP-1], tissue inhibitor of metalloproteinase 1 [TIMP-1]), and inflammatory (high-sensitivity C-reactive protein [(hsCRP], interleukin [IL]-18, IL-10) markers in 1009 patients enrolled in the Research into Etanercept Cytokine Antagonism in Ventricular Dysfunction (RECOVER) trial. A positive correlation was detected between the 2 classes of markers (PIIINP to IL-18, MMP-1 and TIMP-1 to CRP, TIMP-1 to IL-18, MMP-1 to IL-10). In the adjusted multivariable model including all biomarkers, only PIIINP (P = .03) and MMP-1 (P = .048) were independent predictors of 6-minute walk test (6-MWT), whereas in another model including only inflammatory biomarkers, IL-18 was an independent predictor. PIIINP (P = .001) was the only biomarker independently associated with death and CHF hospitalization. Conclusions: The independent associations of PIIINP and MMP-1 with 6-MWT and PIIINP with CHF morbi-mortality suggest that excessive ECM turnover may be associated with functional capacity deterioration and poor outcome.