Effects of age on plasma matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs).

BACKGROUND: The mechanisms causing age-dependent changes in left ventricular (LV) structure and function are not completely understood. Matrix metalloproteinase (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) constitute one important proteolytic pathway affecting LV remodeling. However, whether these determinants of extracellular matrix (ECM) composition change as a function of age has not been examined in an aging population free of clinically significant cardiovascular disease. METHODS AND RESULTS: Subjects (n = 77, age 20-90 years) with no evidence of cardiovascular disease underwent echocardiography and measurement of plasma MMP-2, 7, 8, and 9 and TIMP-1, 2, and 4 (enzyme-linked immunosorbent assay). As subject age increased, volume/mass ratio decreased and mitral E/A ratio decreased. As subject age increased, MMP-2 increased (from 1188 +/- 99 ng/mL to 1507 +/- 76 ng/mL), MMP-7 increased (from 1.2 +/- 0.1 ng/mL to 3.1 +/- 0.6 ng/mL), MMP-9 decreased (from 29 +/- 7 ng/mL to 8 +/- 2 ng/mL), and TIMP-1, 2, and 4 increased (from 728 +/- 46 ng/mL to 1093 +/- 73 ng/mL, from 34 +/- 5 ng/mL to 53 +/- 6 ng/mL, and from 1.26 +/- 0.22 ng/mL to 2.34 +/- 0.30 ng/mL, respectively) (all P < .05). There were significant correlations between decreased LV volume/mass and E/A ratio and increased MMP-7 and TIMP-1 and 4. CONCLUSIONS: MMPs and TIMPs changed as a function of age in the absence of clinically significant cardiovascular disease. These age-dependent alterations in MMP and TIMP profiles favor ECM accumulation and were associated with concentric remodeling and decreased LV diastolic function. Because of these age-dependent changes in this proteolytic system, the superimposition of disease processes such as myocardial infarction or hypertensive heart disease in the older subject may result in different myocardial ECM remodeling than that seen in a younger subject.

Specific temporal profile of matrix metalloproteinase release occurs in patients after myocardial infarction: relation to left ventricular remodeling.

BACKGROUND: Changes in matrix metalloproteinase (MMP) and tissue inhibitors of MMPs (TIMPs) contribute to left ventricular (LV) remodeling after myocardial infarction (MI). We tested the hypothesis that a specific plasma MMP/TIMP profile would emerge after MI and be associated with the degree of LV dilation. METHODS AND RESULTS: LV end-diastolic volume and MMP/TIMP plasma profiles were determined in 53 age-matched control subjects and 32 post-MI patients from day 1 through 180 after MI. LV end-diastolic volume increased by > 38% at day 90 after MI (P < 0.05). MMP-9 increased by > 150% from control at day 1 after MI (P < 0.05) and remained elevated. MMP-8 rose to > 120% at day 3 after MI (P < 0.05) and fell to control values by day 5. TIMP-1 increased by > 60% from control at day 1 after MI (P < 0.05), whereas TIMP-2 increased only at later time points. Cardiac-specific TIMP-4 fell by 40% at day 5 after MI and remained reduced. A persistent or elevated MMP-9 at day 5 was accompanied by a 3-fold end-diastolic volume increase at day 28 (P < 0.05). CONCLUSIONS: A specific temporal pattern of MMP/TIMPs occurred in post-MI patients that included an early and robust rise in MMP-9 and MMP-8 and a uniform fall in TIMP-4. These findings suggest that a specific MMP/TIMP plasma profile occurs after MI and holds both prognostic and diagnostic significance.

Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease.

BACKGROUND: Chronic hypertension may cause left ventricular (LV) remodeling, alterations in cardiac function, and the development of chronic heart failure (CHF). Changes in the composition of the extracellular matrix (ECM) known to occur in hypertension are believed to be causally related to these structural, functional, and clinical outcomes. However, whether the determinants of ECM composition, such as the balance between ECM proteases (matrix metalloproteinases [MMPs]) and their tissue inhibitors [TIMPs]), are altered in hypertensive heart disease is unknown. METHODS AND RESULTS: Plasma MMP-2, -9, and -13 values, TIMP-1 and -2 values, and Doppler echocardiography images were obtained for 103 subjects divided into 4 groups: (1) reference subjects (CTL) with no evidence of cardiovascular disease, (2) hypertensive (HTN) subjects with controlled blood pressure and no LV hypertrophy, (3) hypertensive subjects with controlled blood pressure and with LV hypertrophy (HTN+LVH) but no CHF, and (4) hypertensive subjects with controlled blood pressure, LVH, and CHF (HTN+LVH+CHF). Compared with CTL, patients with HTN had no significant changes in any MMP or TIMP. Patients with HTN+LVH had decreased MMP-2 and MMP-13 values and increased MMP-9 values. Only patients with HTN+LVH+CHF had increased TIMP-1 values. A TIMP-1 level >1200 ng/mL was predictive of CHF. CONCLUSIONS: Patients with hypertension but normal LV structure and function had normal MMP/TIMP profiles. Changes in MMP profiles that favor decreased ECM degradation were associated with LVH and diastolic dysfunction. An increased TIMP-1 level predicted the presence of CHF. Although these findings should be confirmed in a larger prospective study, these data do suggest that changes in the MMP/TIMP balance may play an important role in the structural, functional, and clinical manifestations of hypertensive heart disease.