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J Thorac Cardiovasc Surg 2003;125:602-610
© 2003 The American Association for Thoracic Surgery

Surgery for Acquired Cardiovascular Disease

Matrix metalloproteinase inhibition modifies left ventricular remodeling after myocardial infarction in pigs

From the Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC.

This study was supported by the National Heart, Lung, and Blood Institute grants HL-45024, HL-97012, and PO1-48788 and the National Institutes of Health postdoctoral training grant HL-07260.

Read at the Eighty-second Annual Meeting of The American Association for Thoracic Surgery, Washington, DC, May 5-8, 2002.

Received for publication June 10, 2002. Revisions requested Aug 1, 2002; revisions received Aug 12, 2002. Accepted for publication Aug 20, 2002. Address for reprints: Francis G. Spinale, MD, PhD, Cardiothoracic Surgery, Strom Thurmond Research Building, 770 MUSC Complex, Suite 625, Medical University of South Carolina, Charleston, SC 29425 (E-mail: wilburnm{at}musc.edu).

Background: Global and regional shape changes that occur within the left ventricular wall after myocardial infarction have been termed infarct expansion. A potential mechanism for this postinfarction remodeling is activation of the matrix metalloproteinases. Accordingly, the present study examined the effects of matrix metalloproteinase inhibition on left ventricular global geometry after myocardial infarction in pigs.
Methods: Myocardial infarction was created in pigs by means of occlusion of the first and second obtuse marginal branches of the circumflex coronary artery, resulting in a uniform left ventricular free wall infarct size of 21% ± 2%. At 5 days after infarction, the pigs were randomized to undergo broad-spectrum matrix metalloproteinase inhibition (n = 9; PD166793, 20 mg · kg^-1 · d^-1 by mouth) or myocardial infarction alone (n = 8). Ten pigs served as noninfarction control animals. Left ventricular end-diastolic area, determined by means of echocardiography, was measured 8 weeks after infarction.
Results: Left ventricular end-diastolic area increased in both the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition and myocardial infarction only groups compared to reference control animals (3.7 ± 0.2 cm²), but was reduced with broad-spectrum matrix metalloproteinase inhibition compared to myocardial infarction alone (4.5 ± 0.2 vs 4.9 ± 0.2 cm², respectively; P < .05). Regional radial stress within the infarct region increased in both infarction groups when compared to values obtained from reference control animals (599 ± 152 g/cm²), but was attenuated in the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition group compared to the myocardial infarction alone group (663 ± 108 vs 1242 ± 251 g/cm², respectively; P < .05). Similarly, regional myocardial stiffness increased in both the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition and the myocardial infarction only groups compared with that observed in reference control animals (14 ± 1 rkm, P < .05) but was lower with broad-spectrum matrix metalloproteinase inhibition than with myocardial infarction alone (42 ± 6 vs 68 ± 10 rkm, respectively; P < .05).
Conclusions: Matrix metalloproteinase inhibition reduced postinfarction left ventricular dilation, reduced regional myocardial wall stress, and modified myocardial material properties. These unique findings suggest that increased myocardial matrix metalloproteinase activation after infarction contributes directly to the left ventricular remodeling process.

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