Yarbrough William M, Mukherjee Rupak, Brinsa Theresa A, Dowdy Kathryn B, Scott Amelia A, Escobar G Patricia, Joffs Cassandra, Lucas David G, Crawford Fred A, Spinale Francis G
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29425, USA.
J Thorac Cardiovasc Surg. 2003 Mar;125(3):602-10. doi: 10.1067/mtc.2003.197.
Global and regional shape changes that occur within the left ventricular wall after myocardial infarction have been termed infarct expansion. A potential mechanism for this postinfarction remodeling is activation of the matrix metalloproteinases. Accordingly, the present study examined the effects of matrix metalloproteinase inhibition on left ventricular global geometry after myocardial infarction in pigs.
Myocardial infarction was created in pigs by means of occlusion of the first and second obtuse marginal branches of the circumflex coronary artery, resulting in a uniform left ventricular free wall infarct size of 21% +/- 2%. At 5 days after infarction, the pigs were randomized to undergo broad-spectrum matrix metalloproteinase inhibition (n = 9; PD166793, 20 mg. kg(-1). d(-1) by mouth) or myocardial infarction alone (n = 8). Ten pigs served as noninfarction control animals. Left ventricular end-diastolic area, determined by means of echocardiography, was measured 8 weeks after infarction.
Left ventricular end-diastolic area increased in both the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition and myocardial infarction only groups compared to reference control animals (3.7 +/- 0.2 cm(2)), but was reduced with broad-spectrum matrix metalloproteinase inhibition compared to myocardial infarction alone (4.5 +/- 0.2 vs 4.9 +/- 0.2 cm(2), respectively; P <.05). Regional radial stress within the infarct region increased in both infarction groups when compared to values obtained from reference control animals (599 +/- 152 g/cm(2)), but was attenuated in the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition group compared to the myocardial infarction alone group (663 +/- 108 vs 1242 +/- 251 g/cm(2), respectively; P <.05). Similarly, regional myocardial stiffness increased in both the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition and the myocardial infarction only groups compared with that observed in reference control animals (14 +/- 1 rkm, P <.05) but was lower with broad-spectrum matrix metalloproteinase inhibition than with myocardial infarction alone (42 +/- 6 vs 68 +/- 10 rkm, respectively; P <.05).
Matrix metalloproteinase inhibition reduced postinfarction left ventricular dilation, reduced regional myocardial wall stress, and modified myocardial material properties. These unique findings suggest that increased myocardial matrix metalloproteinase activation after infarction contributes directly to the left ventricular remodeling process.
心肌梗死后左心室内发生的整体和局部形态变化被称为梗死扩展。梗死后期重塑的一个潜在机制是基质金属蛋白酶的激活。因此，本研究检测了基质金属蛋白酶抑制对猪心肌梗死后左心室整体几何形态的影响。
通过闭塞冠状动脉左旋支的第一和第二钝缘支在猪身上制造心肌梗死，导致左心室游离壁梗死面积均匀为21%±2%。梗死后5天，将猪随机分为接受广谱基质金属蛋白酶抑制组（n = 9；口服PD166793，20 mg·kg⁻¹·d⁻¹）或单纯心肌梗死组（n = 8）。10头猪作为非梗死对照动物。梗死后8周通过超声心动图测量左心室舒张末期面积。
与正常对照动物相比（3.7±0.2 cm²），心肌梗死加广谱基质金属蛋白酶抑制组和单纯心肌梗死组的左心室舒张末期面积均增加，但与单纯心肌梗死组相比，广谱基质金属蛋白酶抑制使其减小（分别为4.5±0.2 vs 4.9±0.2 cm²；P<.05）。与正常对照动物测得的值相比（599±152 g/cm²），两个梗死组梗死区域内的局部径向应力均增加，但与单纯心肌梗死组相比，心肌梗死加广谱基质金属蛋白酶抑制组的局部径向应力减弱（分别为663±108 vs 1242±251 g/cm²；P<.05）。同样，与正常对照动物相比，心肌梗死加广谱基质金属蛋白酶抑制组和单纯心肌梗死组的局部心肌僵硬度均增加（14±1 rkm，P<.05），但广谱基质金属蛋白酶抑制组低于单纯心肌梗死组（分别为42±6 vs 68±10 rkm；P<.05）。
基质金属蛋白酶抑制可减少梗死后左心室扩张，降低局部心肌壁应力，并改变心肌材料特性。这些独特的发现表明，梗死后心肌基质金属蛋白酶激活增加直接导致左心室重塑过程。
