Filling Pressures and Collagen Metabolism in Hypertensive Patients With Heart Failure and Normal Ejection Fraction

This study was designed to evaluate the association between circulating biomarkers of collagen metabolism and elevated left-sided filling pressures (FPs), as assessed from elevated estimated pulmonary capillary wedge pressure (ePCWP), in hypertensive patients with heart failure with normal ejection fraction. Echocardiography was performed and ePCWP was calculated from the formula ePCWP=1.90+1.24(maximum early transmitral flow velocity in diastole:tissue Doppler early mitral annulus velocity). The biomarkers of collagen synthesis (carboxy-terminal propeptide of procollagen type I) and degradation (matrix metalloproteinase [MMP] 1 and tissue inhibitor of MMP-1 [TIMP-1]) were analyzed by ELISA methods. Seventy-eight patients with normal FPs (ePCWP < or =15 mm Hg) and 78 with elevated FPs (ePCWP >15 mm Hg) were included. Compared with controls, the levels of the 3 biomarkers were increased in the 2 groups of patients. The MMP-1:TIMP-1 ratio, an index of MMP-1 activity, was increased in patients with normal FPs and unchanged in patients with elevated FPs. Patients with elevated FPs exhibited higher TIMP-1 levels and a lower MMP-1:TIMP-1 ratio than patients with normal FPs. ePCWP was independently associated with TIMP-1 (r=0.349; P<0.001) and the MMP-1:TIMP-1 ratio (r=-0.240; P<0.01) in all of the patients. Receiver operating characteristic curves showed that a cutoff value of TIMP-1 of 1557 ng/mL provided 64% sensitivity and 67% specificity for predicting elevated FPs with a relative risk of 3.71 (95% CI: 1.91 to 7.22). These findings suggest that, in hypertensive patients with heart failure with normal ejection fraction and elevated FPs, collagen synthesis predominates over degradation because of a relative excess of TIMP-1. This imbalance can facilitate myocardial fibrosis, which, in turn, may contribute to the elevation of FPs in these patients.