Matrix metalloproteinase-1 and its inhibitor, TIMP-1, in systolic heart failure:: relation to functional data and prognosis

Jordan A, Roldan V, Garcia M, Monmeneu J, de Burgos FG, Lip GYH, Marin F (University General Hospital of Elche, Elche, Spain; Hospital Morales Meseguer, Murcia, Spain; Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK; and University General Hospital of Alicante, Alicante, Spain). Matrix metalloproteinase-1 and its inhibitor, TIMP-1, in systolic heart failure: relation to functional data and prognosis. J Intern Med 2007; 262: 385-392. Background. Structural remodelling of left ventricle is a common feature in the progression of congestive heart failure (CHF). Matrix metalloproteinases (MMPs) have been directly implicated as they degrade extracellular proteins. To test the hypothesis that MMP-and its inhibitor, tissue type inhibitor of matrix metalloproteinases (TIMP-1), could be related to functional status and prognosis in CHF, we examined the relationship of MMP-1 and TIMP-1 to peak oxygen consumption (VO2) and peak minute ventilation/carbon dioxide production relationship (VE/VCO2), and assessed their prognostic value. Methods. We studied 50 patients with CHF, who were compared with 53 controls echocardiogram and ergoespirometry were performed, and serum levels of MMP-1 and TIMP-1 were assayed by ELISA. Patients were followed up for 17.5 +/- 8.9 months, and total mortality, readmissions for heart failure and cardiac transplantation were recorded. Results. Patients with CHF had lower levels of MMP-1 (P = 0.027), and higher levels of TIMP-1 and TIMP-1/MMP-1 ratio (both P < 0.01) than controls. TIMP-1 levels and the TIMP-1/MMP-1 ratio correlated negatively with peak VO2 (Spearman, r: -0.51; P = 0.001 and r: -0.42; P = 0.030, respectively). During the follow-up period, 23 patients (47.9%) suffered endpoints - these patients had higher baseline peak VE/VCO2 (P = 0.001), TIMP-1 (P = 0.004), and TIMP-1/MMP-1 ratio values (P = 0.002), whereas MMP-1 levels were lower (P = 0.027). On multivariate analysis, VE/VCO2, MMP-1 levels and age were the only variables independently related to prognosis (all P < 0.05). Conclusion. Poor functional capacity in CHF can be related to abnormal extracellular matrix turnover. Patients who suffered endpoints had more abnormal indices of matrix turnover, where MMP-1 levels showed independent prognostic value.