Published online before print December 19, 2002, doi: 10.1161/01.RES.0000052312.41419.55
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Submitted on May 13, 2002
Revised on December 4, 2002
Accepted on December 4, 2002
Selective Matrix Metalloproteinase Inhibition With Developing Heart Failure. Effects on Left Ventricular Function and Structure
Mary K. King ;
From the Division of Cardiothoracic Surgery (M.K.K., M.L.C., A.G., J.H.M., H.R.G., R.M., M.R.Z., F.G.S.), Medical University of South Carolina, Charleston, SC; and Pharmaceutical Research Division (T.P.O'.N.), Procter and Gamble, Mason, Ohio.
The matrix metalloproteinases (MMPs) are an endogenous family of proteolytic enzymes implicated to contribute to LV remodeling. However, broad-spectrum MMP inhibition (MMPi), particularly inhibition of interstitial collagenase (MMP-1), may not be clinically applicable. This study examined the effects of selective MMPi (sparing MMP-1) in a model of developing congestive heart failure. Pigs were randomly assigned to 3 groups: (1) rapid pacing for 3 weeks (240 bpm, n=10); (2) selective MMPi (20 mg/kg per day-PO;PGE7113313) and rapid pacing (n=12); and (3) controls (n=10). LV peak wall stress increased from controls with rapid pacing (140±6 versus 319±18 g/cm2; P<0.05) and was reduced with selective MMPi (208±9 g/cm2; P<0.05. Preload recruitable stroke work was reduced with rapid pacing (4.3±0.4 versus 1.2±0.2 dyne · cm/mm Hg; P<0.05) and was increased with selective MMPi (2.6±0.3 dyne · cm/mm Hg; P<0.05). Plasma norepinephrine increased by 6-fold in the rapid pacing group (P<0.05) and was reduced from untreated values with selective MMPi (P<0.05). At the myocardial level, myocyte cross-sectional area was increased with selective MMPi but fibrillar collagen volume fraction remained unchanged relative to control values. These results suggest that targeting a selective portfolio of myocardial MMP species for inhibition may provide a more rational therapeutic strategy in the setting of congestive heart failure.
Key words: left ventricular systolic function • diastolic function • myocardial stiffness • myocardial structure • matrix metalloproteinases • heart failure
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