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.


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.
Ahmed
S Hinan
SH
Department of Medicine, Medical University of South Carolina, RHJ Department of Veterans Affairs Medical Center, Charleston, SC, USA.
Clark
Leslie L
LL
Pennington
Weems R
WR
Webb
Carson S
CS
Bonnema
D Dirk
DD
Leonardi
Amy H
AH
McClure
Catherine D
CD
Spinale
Francis G
FG
Zile
Michael R
MR
D000368:Aged; D017364:Collagenases / Q000097:blood; D005260:Female; D006333:Heart Failure / Q000201:enzymology* / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000150:complications*; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D020782:Matrix Metalloproteinases / Q000097:blood*; D008875:Middle Aged; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000097:blood*; D020257:Ventricular Remodeling
D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9