Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice.

Abstract

BACKGROUND:

Extracellular matrix synthesis and degradation contribute to the morphological changes that occur after myocardial infarction (MI).

METHODS AND RESULTS:

We tested the hypothesis that inhibition of matrix metalloproteinases (MMPs) attenuates left ventricular remodeling in experimental MI. Seventy-one male FVB mice that survived ligation of the left anterior coronary artery were randomized to a broad-spectrum MMP inhibitor (CP-471,474) or placebo by gavage. Echocardiographic studies were performed before randomization (within 24 hours of surgery) and 4 days later and included short-axis imaging at the midpapillary and apical levels. Infarction as defined by wall motion abnormality was achieved in 79% of the procedures (n=56), and mortality rate during the 4-day protocol was 23% (9 of 36 on treatment vs 7 of 35 on placebo; P=NS). Baseline end-diastolic and end-systolic dimensions and areas were similar (P=NS) between treated and placebo groups. At follow-up, infarcted mice allocated to MMP inhibitor had significantly smaller increases in end-systolic and end-diastolic dimensions and areas at both midpapillary and apical levels compared with infarcted mice allocated to placebo (all P<0.05). In addition, infarcted animals that received MMP inhibitor had no change in fractional shortening (-3+/-13%), whereas animals that received placebo had a decrease in fractional shortening (-12+/-12%) (P<0.05). In an analysis stratified by baseline end-diastolic area, the effects of MMP inhibition on the changes in end-systolic area and end-diastolic area were most prominent in animals that had more initial left ventricular dilatation (both P<0.05).

CONCLUSIONS:

-Administration of an MMP inhibitor attenuates early left ventricular dilation after experimental MI in mice. Further studies in genetically altered mice and other models will improve understanding of the role of MMPs in left ventricular remodeling.

• Authors: L E Rohde, A Ducharme, L H Arroyo, M Aikawa, G H Sukhova, A Lopez-Anaya, K F McClure, P G Mitchell, P Libby, R T Lee
• Journal: Circulation (Circulation) Vol. 99 Issue 23 Pg. 3063-70 (Jun 15 1999) ISSN: 1524-4539 [Electronic] United States
• PMID: 10368126 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CP 471,474
• Halogenated Diphenyl Ethers
• Phenyl Ethers
• Protease Inhibitors
• Metalloendopeptidases

Topics

• Animals
• Echocardiography (drug effects)
• Halogenated Diphenyl Ethers
• Hypertrophy, Left Ventricular (diagnostic imaging, etiology, prevention & control)
• Male
• Metalloendopeptidases (antagonists & inhibitors)
• Mice
• Mice, Inbred Strains
• Myocardial Infarction (complications, diagnostic imaging, pathology)
• Myocardium (pathology)
• Papillary Muscles (pathology)
• Phenyl Ethers (pharmacology)
• Protease Inhibitors (therapeutic use)
• Time Factors