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 Ͼ38% at day 90 after MI (PϽ0.05). MMP-9 increased by Ͼ150% from control at day 1 after MI (PϽ0.05) and remained elevated. MMP-8 rose to Ͼ120% at day 3 after MI (PϽ0.05) and fell to control values by day 5. TIMP-1 increased by Ͼ60% from control at day 1 after MI (PϽ0.05), 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 (PϽ0.05). 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.

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 (HTNϩLVH) but no CHF, and (4) hypertensive subjects with controlled blood pressure, LVH, and CHF (HTNϩLVHϩCHF). Compared with CTL, patients with HTN had no significant changes in any MMP or TIMP. Patients with HTNϩLVH had decreased MMP-2 and MMP-13 values and increased MMP-9 values. Only patients with HTNϩLVHϩCHF had increased TIMP-1 values. A TIMP-1 level Ͼ1200 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.

Bradshaw AD, Baicu CF, Rentz TJ, Van Laer AO, Bonnema DD, Zile MR. Age-dependent alterations in fibrillar collagen content and myocardial diastolic function: role of SPARC in post-synthetic procollagen processing. Am J Physiol Heart Circ Physiol 298: H614 -H622, 2010. First published December 11, 2009; doi:10.1152/ajpheart.00474.2009.-Advanced age, independent of concurrent cardiovascular disease, can be associated with increased extracellular matrix (ECM) fibrillar collagen content and abnormal diastolic function. However, the mechanisms causing this left ventricular (LV) remodeling remain incompletely defined. We hypothesized that one determinant of age-dependent remodeling is a change in the extent to which newly synthesized procollagen is processed into mature collagen fibrils. We further hypothesized that secreted protein acidic and rich in cysteine (SPARC) plays a key role in the changes in post-synthetic procollagen processing that occur in the aged myocardium. Young (3 mo old) and old (18 -24 mo old) wild-type (WT) and SPARC-null mice were studied. LV collagen content was measured histologically by collagen volume fraction, collagen composition was measured by hydroxyproline assay as soluble collagen (1 M NaCl extractable) versus insoluble collagen (mature cross-linked), and collagen morphological structure was examined by scanning electron microscopy. SPARC expression was measured by immunoblot analysis. LV and myocardial structure and function were assessed using echocardiographic and papillary muscle experiments. In WT mice, advanced age increased SPARC expression, myocardial diastolic stiffness, fibrillar collagen content, and insoluble collagen. In SPARC-null mice, advanced age also increased myocardial diastolic stiffness, fibrillar collagen content, and insoluble collagen but significantly less than those seen in WT old mice. As a result, insoluble collagen and myocardial diastolic stiffness were lower in old SPARC-null mice (1.36 Ϯ 0.08 mg hydroxyproline/g dry wt and 0.04 Ϯ 0.005) than in old WT mice (1.70 Ϯ 0.10 mg hydroxyproline/g dry wt and 0.07 Ϯ 0.005, P Ͻ 0.05). In conclusion, the absence of SPARC reduced age-dependent alterations in ECM fibrillar collagen and diastolic function. These data support the hypothesis that SPARC plays a key role in post-synthetic procollagen processing and contributes to the increase in collagen content found in the aged myocardium.secreted protein acidic and rich in cysteine; aging LEFT VENTRICULAR (LV) structural remodeling, such as changes in LV mass, volume, and geometry, are important predictors of functional and clinical outcomes (21,22,27,45). Advancing age, independent of any concurrent cardiovascular disease, can itself be associated with significant LV structural remodeling (16, 24). These age-dependent changes in LV structure may play an important role in the functional limitations that occur in advancing age (16,24). Previous studies have shown that with increasing age, the LV develops concentric remodeling (characterized by an increased LV mass-to-...

Background-The mechanisms causing age-dependent changes in left ventricular (LV) structure and function are not completely understood. Matrix metalloproteinase (MMPs) and tissue inhibitors (TIMPs) constitute one important proteolytic pathway affecting LV remodeling. However, whether these determinants of ECM composition change as a function of age has not been examined in an aging population free of clinically significant cardiovascular disease.