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(Circulation. 2005;112:1136-1144.)
© 2005 American Heart Association, Inc.

Heart Failure

Increased Cardiac Expression of Tissue Inhibitor of Metalloproteinase-1 and Tissue Inhibitor of Metalloproteinase-2 Is Related to Cardiac Fibrosis and Dysfunction in the Chronic Pressure-Overloaded Human Heart

Stephane Heymans, MD, PhD; Blanche Schroen, MS; Pieter Vermeersch, MD; Hendrik Milting, MD, PhD; Fangye Gao, PhD; Astrid Kassner, PhD; Hilde Gillijns, MS; Paul Herijgers, MD, PhD; Willem Flameng, MD, PhD; Peter Carmeliet, MD, PhD; Frans Van de Werf, MD, PhD; Yigal M. Pinto, MD, PhD; Stefan Janssens, MD, PhD

From Experimental and Molecular Cardiology/CARIM, University of Maastricht, the Netherlands (S.H., B.S., Y.M.P.); Molecular and Vascular Biology and Center for Transgene Technology and Gene Therapy, University of Leuven (S.H., P.V., F.G., H.G., P.C., S.J.), and the Departments of Cardiovascular Surgery (P.H., W.F.) and Cardiology (F.V.d.W., S.J.), University Hospital of Leuven, Belgium; and the Herz-und Diabeteszentrum NRW, Universitätsklinik der Ruhr-Universität Bochum, Erich und Hanna Klessmann-Institut für Kardiovaskuläre Forschung und Entwicklung, Bad Oeynhausen, Germany (H.M., A.K.).

Correspondence to Stephane Heymans, MD, PhD, Experimental and Molecular Cardiology Laboratory/CARIM, Department of Cardiology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. E-mail s.heymans{at}cardio.unimaas.nl

Received October 27, 2004; revision received April 22, 2005; accepted May 16, 2005.

Background— Alterations in the balance of matrix metalloproteinases (MMPs) and their specific tissue inhibitors (TIMPs) are involved in left ventricular (LV) remodeling. Whether their expression is related to interstitial fibrosis or LV dysfunction in patients with chronic pressure overload–induced LV hypertrophy, however, is unknown.

Methods and Results— Therefore, cardiac biopsies were taken in 36 patients with isolated aortic stenosis (AS) and in 29 control patients without LV hypertrophy. Microarray analysis revealed significantly increased mRNA expression of collagen types I, III, and IV and transcripts involved in collagen synthesis, including procollagen endopeptidase and lysine and proline hydroxylases, in AS compared with control patients. Collagen deposition was greater in AS than in control patients and was most pronounced in AS patients with severe diastolic dysfunction. Cardiac mRNA expression of TIMP-1 and TIMP-2 was significantly increased in AS compared with control patients (mRNA transcript levels normalized to GAPDH: TIMP-1, 0.67±0.1 in AS versus 0.37±0.08 in control patients; TIMP-2, 9.5±2.6 in AS versus 1.6±0.4 in control patients; P<0.05 for both) but did not differ significantly for MMP-1, -2, or -9. Cardiac TIMP-1 and -2 transcripts were significantly related to the degree of interstitial fibrosis and proportional to diastolic dysfunction in AS patients.

Conclusions— Cardiac expression of TIMP-1 and TIMP-2 is significantly increased in chronic pressure-overloaded human hearts compared with controls and is related to the degree of interstitial fibrosis.

Key Words: metalloproteinases • remodeling • hypertrophy • hypertension • collagen

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