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(Circulation. 2004;110:II-180 – II-186.)
© 2004 American Heart Association, Inc.

Cardiac Transplantation and Surgery for Congestive Heart Failure

Inhibition of Matrix Metalloproteinase Activity by TIMP-1 Gene Transfer Effectively Treats Ischemic Cardiomyopathy

Vasant Jayasankar, MD; Y. Joseph Woo, MD; Lawrence T. Bish, BA; Timothy J. Pirolli; Mark F. Berry, MD; Jeffrey Burdick, BS; Ramesh C. Bhalla, PhD; Ram V. Sharma, PhD; Timothy J. Gardner, MD; H. Lee Sweeney, PhD

From Department of Surgery (V.J., Y.J.W., M.F.B., J.B., T.J.G.) and Department of Physiology (L.T.B., H.L.S.), University of Pennsylvania School of Medicine, Philadelphia, Pa; Department of Anatomy and Cell Biology (R.C.B., R.V.S.), University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa.

Correspondence to Y. Joseph Woo, MD, Division of Cardiothoracic Surgery, University of Pennsylvania School of Medicine, 6 Silverstein Pavilion, 3400 Spruce Street, Philadelphia, PA 19104-4283. E-mail wooy{at}uphs.upenn.edu

Background— Enhanced activity of matrix metalloproteinases (MMPs) has been associated with extracellular matrix degradation and ischemic heart failure in animal models and human patients. This study evaluated the effects of MMP inhibition by gene transfer of TIMP-1 in a rat model of ischemic cardiomyopathy.

Methods and Results— Rats underwent ligation of the left anterior descending coronary artery with direct intramyocardial injection of replication-deficient adenovirus encoding TIMP-1 (n=8) or null virus as control vector (n=8), and animals were analyzed after 6 weeks. Both systolic and diastolic cardiac function was significantly preserved in the TIMP-1 group compared with control animals (maximum left ventricular [LV] pressure: TIMP-1 70±10 versus control 56±12 mmHg, P<0.05; maximum dP/dt 2697±842 versus 1622±527 mmHg/sec, P<0.01; minimum dP/dt –2900±917 versus –1195±593, P<0.001). Ventricular geometry was significantly preserved in the TIMP-1 group (LV diameter 13.0±0.7 versus control 14.4±0.4 mm, P<0.001; border-zone wall thickness 1.59±0.11 versus control 1.28±0.19 mm, P<0.05), and this was associated with a reduction in myocardial fibrosis (2.36±0.87 versus control 3.89±1.79 µg hydroxyproline/mg tissue, P<0.05). MMP activity was reduced in the TIMP-1 animals (1.5±0.9 versus control 43.1±14.9 ng of MMP-1 activity, P<0.05).

Conclusions— TIMP-1 gene transfer inhibits MMP activity and preserves cardiac function and geometry in ischemic cardiomyopathy. The reduction in myocardial fibrosis may be primarily responsible for the improved diastolic function in treated animals. TIMP-1 overexpression is a promising therapeutic target for continued investigation.

Key Words: gene therapy • heart failure • metalloproteinases • remodeling