Selective Matrix Metalloproteinase Inhibition With Developing Heart Failure

Abstract

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/cm 2 ; P <0.05) and was reduced with selective MMPi (208±9 g/cm 2 ; 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.