Selective matrix metalloproteinase inhibition with developing heart failure - Effects on left ventricular function and structure

被引:77
作者
King, MK
Coker, ML
Goldberg, A
McElmurray, JH
Gunasinghe, HR
Mukherjee, R
Zile, MR
O'Neill, TP
Spinale, FG
机构
[1] Med Univ S Carolina, Div Cardiothorac Surg, Charleston, SC 29425 USA
[2] Procter & Gamble Co, Div Pharmaceut Res, Mason, OH USA
关键词
left ventricular systolic function; myocardial stiffness; myocardial structure; matrix metalloproteinases; heart failure;
D O I
10.1161/01.RES.0000052312.41419.55
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:177 / 185
页数:9
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