(Circulation. 1995;91:393-402.)
© 1995 American Heart Association, Inc.
Articles |
Cardioprotective Effects of a C1 Esterase Inhibitor in Myocardial Ischemia and Reperfusion
From the Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pa.
Correspondence to Dr Allan M. Lefer, Department of Physiology, Jefferson Medical College, 1020 Locust St, Philadelphia, PA 19107.
Background Myocardial injury after ischemia and reperfusion can be attributed largely to the effects of polymorphonuclear leukocytes (PMN). The complement system plays an important role as a chemotactic agent, affecting adhesion molecule expression and neutrophil accumulation.
Methods and Results In the present study, the cardioprotective effects of C1 esterase inhibitor (C1 INH) were examined in a feline model of myocardial ischemia and reperfusion (90 minutes of ischemia followed by 270 minutes of reperfusion). C1 INH (15 mg/kg) administered 10 minutes before reperfusion significantly attenuated myocardial necrosis compared with vehicle (10±2% and 29±2% necrosis as a proportion of area at risk, respectively; P<.01). Myocardial preservation was also related to reduced plasma accumulation of creatine kinase activity. C1 INH treatment resulted in improved recovery of cardiac contractility and preservation of coronary vascular endothelial function, as assessed by relaxation in response to acetylcholine, compared with contractility and preservation of endothelial function in vehicle-treated animals (69±6% and 20±4% relaxation, respectively; P<.01). In addition, cardiac myeloperoxidase activity (an index of PMN accumulation) in the ischemic area was significantly reduced after C1 INH treatment. Furthermore, immunohistochemical analysis of ischemic-reperfused myocardial tissue demonstrated deposition of the first component of the classic complement pathway, C1q, on cardiac myocytes and coronary vessels.
Conclusions Blocking of the classic complement pathway by C1 INH appears to be an effective means of preserving ischemic myocardium from reperfusion injury. The mechanism of this cardioprotective effect appears to be inhibition of PMN-endothelium interaction; this inhibition leads to preservation of normal endothelial function, which results in reduced cardiac necrosis.
Key Words: proteins • esterases • endothelium • leukocytes • reperfusion
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|
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|
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|
|
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|
|
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|
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|
|
|
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|
|
|
|
|
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|
|