Relations of biomarkers of extracellular matrix remodeling to incident cardiovascular events and mortality

Abstract

Objective: To evaluate if biomarkers reflecting left ventricular/vascular extracellular matrix remodeling are associated with cardiovascular disease (CVD) and death in the community.

Methods and results: In 922 Framingham Study participants (mean age, 58 years; 56% women), we related circulating concentrations of matrix metalloproteinase-9 (binary variable: detectable versus undetectable), log of tissue inhibitor of matrix metalloproteinase-1, and log of procollagen type III aminoterminal peptide (PIIINP) to incident CVD and death. On follow-up (mean, 9.9 years), 51 deaths and 81 CVD events occurred. Each SD increment of log of tissue inhibitor of matrix metalloproteinase-1 and log-PIIINP was associated with multivariable-adjusted hazards ratios of 1.72 (95% CI, 1.30 to 2.27) and 1.47 (95% CI, 1.11 to 1.96), respectively, for mortality risk. Log-PIIINP concentrations were also associated with CVD risk (hazard ratio [95% CI] per SD, 1.35 [1.05 to 1.74]). Death and CVD incidence rates were 2-fold higher in participants with both biomarkers higher than the median (corresponding hazard ratio [95% CI], 2.78 [1.43 to 5.40] and 1.77 [1.04 to 3.03], respectively) compared with those with either or both less than the median. The inclusion of both biomarkers improved the C-statistic (for predicting mortality) from 0.78 to 0.82 (P=0.03). Matrix metalloproteinase-9 was unrelated to either outcome.

Conclusions: Higher circulating tissue inhibitor of matrix metalloproteinase-1 and PIIINP concentrations are associated with mortality, and higher PIIINP is associated with incident CVD, in the community.

Figure 1

A: Cumulative incidence of all-cause mortality in participants with PIIINP above median and at or below median. B: Cumulative incidence of all-cause mortality in participants with TIMP-1 above median and at or below median.

Figure 1

A: Cumulative incidence of all-cause mortality in participants with PIIINP above median and at or below median. B: Cumulative incidence of all-cause mortality in participants with TIMP-1 above median and at or below median.

Figure 2

Cumulative incidence of all-cause mortality in participants with both TIMP-1 and PIIINP above median and either or both biomarkers at or below median.