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

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 meta lloproteinases (MMPs) attenuates left ventricular remodeling in experimenta l 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 sh ort-axis imaging at the midpapillary and apical levels. Infarction as defin ed 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 treatme nt 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 grou ps. At follow-up, infarcted mice allocated to MMP inhibitor had significant ly smaller increases in end-systolic and end-diastolic dimensions and areas at both midpapillary and apical levels compared with infarcted mice alloca ted to placebo (all P<0.05). In addition, infarcted animals that received M MP inhibitor had no change in fractional shortening (-3 +/- 13%), whereas a nimals 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 Ve ntricular dilatation (both P<0.05). Conclusions-Administration of an MMP inhibitor attenuates early left Ventri cular dilation after experimental MI in mice. Further studies in geneticall y altered mice and other models will improve understanding of the role of M MPs in left ventricular remodeling.