title: Selective matrix metalloproteinase inhibition with developing heart failure: effects on left ventricular function and structure.
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/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.
authors.affiliation: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Mary K
authors.initials: MK
authors.lastname: King
authors.forename: Mytsi L
authors.initials: ML
authors.lastname: Coker
authors.forename: Aaron
authors.initials: A
authors.lastname: Goldberg
authors.forename: James H
authors.initials: JH
authors.lastname: McElmurray
authors.forename: Himali R
authors.initials: HR
authors.lastname: Gunasinghe
authors.forename: Rupak
authors.initials: R
authors.lastname: Mukherjee
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
authors.forename: Timothy P
authors.initials: TP
authors.lastname: O'Neill
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
mesh_terms: D000818:Animals; D002304:Cardiac Pacing, Artificial; D003971:Diastole; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology*; D006333:Heart Failure / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D018377:Neurotransmitter Agents / Q000097:blood; D013552:Swine; D013599:Systole; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D018377:Neurotransmitter Agents; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2