Published Online
on April 24, 2006

A more recent version of this article appeared on May 2, 2006

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Submitted on July 7, 2005
Revised on January 30, 2006
Accepted on February 17, 2006

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

S. Hinan Ahmed MD, Leslie L. Clark MS, Weems R. Pennington MD, Carson S. Webb MD, D. Dirk Bonnema MD, Amy H. Leonardi BS, Catherine D. McClure RDCS, Francis G. Spinale MD, PhD, and Michael R. Zile MD^*

From the Departments of Medicine (S.H.A., W.R.P., C.S.W., D.D.B., C.D.M., M.R.Z.); Biostatistics, Bioinformatics, and Epidemiology (L.L.C.); and Surgery (L.L.C., A.H.L., F.G.S.), Medical University of South Carolina and RHJ Department of Veterans Affairs Medical Center, Charleston, SC.

^* To whom correspondence should be addressed. E-mail: zilem{at}musc.edu.

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.

Key words: heart failure • hypertension • hypertrophy • matrix metalloproteinases

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