on December 31, 2001
Published online before print December 31, 2001, doi: 10.1161/hc0602.103674
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Submitted on September 18, 2001
From the Leducq Center for Cardiovascular Research (M.L.L., J.G., M.A., P.L., R.T.L.), Cardiovascular Division, Department of Medicine, and the Department of Pathology (F.J.S., E.R.), Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; and Pfizer Central Research (L.L.-M., J.C., S.B., P.G.M.), Groton, Conn. * To whom correspondence should be addressed. E-mail: rlee{at}rics.bwh.harvard.edu.
Background—Broad
inhibition of matrix metalloproteinases (MMPs) attenuates left
ventricular remodeling after myocardial infarction (MI).
However, it is not clear if selective MMP inhibition strategies will be
effective or if MMP inhibition will impair angiogenesis after
MI. Methods and Results—We
used a selective MMP inhibitor (MMPi) that does not inhibit
MMP-1 in rabbits, which, like humans but unlike rodents, express MMP-1
as a major collagenase. On day 1 after MI, rabbits were
randomized to receive either inhibitor (n=10) or vehicle
(n=8). At 4 weeks after MI, there were no differences in infarct size
or collagen fractional area. However, MMPi reduced
ventricular dilation. The increase in
end-diastolic dimension from day 1 to week 4 was
3.1±0.5 mm for vehicle versus 1.3±0.3 mm for MMPi
(P<0.01). The increase in
end-systolic dimension was 2.8±0.5 mm for vehicle and
1.3±0.4 mm for MMPi
(P<0.05). Furthermore, MMPi
reduced infarct wall thinning; the minimal infarct thickness was
0.8±0.1 mm for vehicle and 1.6±0.3 mm for MMPi
(P<0.05). Interestingly, the
MMPi group had increased numbers of vessels in the subendocardial layer
of the infarct; the number of capillaries was increased in the
subendocardial layer (46±4 vessels/field versus 17±3 vessels/field
for vehicle; P<0.001), and the
number of arterioles was also increased (4.0±0.8 vessels/field versus
2.0±0.4 vessels/field for vehicle;
P<0.05).
Conclusions—MMP
inhibition attenuates left ventricular remodeling even when
the dominant collagenase MMP-1 is not inhibited;
furthermore, this selective MMP inhibition appears to increase rather
than decrease neovascularization in the
subendocardium.
Revised on November 29, 2001
Accepted on December 14, 2001
Selective Matrix Metalloproteinase Inhibition
Reduces Left Ventricular Remodeling but Does Not Inhibit
Angiogenesis After Myocardial Infarction
Key words: ventricles • myocardial infarction • metalloproteinases • remodeling
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