Limitation of reperfusion injury by a monoclonal antibody to C5a during myocardial infarction in pigs

Abstract

The complement system has been implicated in reperfusion injury during acute myocardial infarction. We therefore attempted to reduce reperfusion injury with a monoclonal antibody (MAb) to the complement component, C5a. In 13 control pigs and 9 pigs pretreated with this MAb, ischemia was induced by a 50-min occlusion of the left anterior descending coronary artery, followed by 3 h of reperfusion. Infarct area (as percent of risk area) was reduced from 58 +/- 5% in controls to 38 +/- 7% (P < 0.05) in MAb-treated animals. Heart rate-systolic blood pressure product, left ventricular (LV) first derivative of pressure, LV end-diastolic pressure, and coronary blood flow were similar (P > 0.05) in the two groups. At 15 min of reperfusion, immunoreactive factor Bb began to increase significantly (P < 0.05) in regional coronary venous plasma, consistent with activation of the alternative complement pathway. The anti-C5a MAb did not attenuate formation of the membrane attack complex (C5b-9) as assessed by a hemolytic complement assay. Myocardial myeloperoxidase activity, a marker of tissue neutrophil concentration, was similar in the risk regions of the two groups, suggesting that neutrophil infiltration was unaltered by the MAb. However, in vitro the MAb (15 and 30 micrograms/ml) reduced C5a-stimulated neutrophil aggregation (67.4 and 70.9%), chemotaxis (52.5 and 81.4%), degranulation (66.7 and 75.8%), and superoxide generation (26.7 and 100%). In conclusion, myocardial infarction-reperfusion is associated with activation of the alternative complement pathway. Furthermore, a MAb to C5a that inhibits neutrophil cytotoxic activity, but neither the membrane attack complex nor myocardial neutrophil accumulation, decreases infarct size in pigs. These data suggest an important role of the alternative complement pathway and C5a in the propagation of ischemia cardiac damage during reperfusion.

C4d Deposition Reveals Myocardial Infarction After Cardiac Arrest -Experimental Study

“…In contrast to some [1,5,6, 19], we did not observe increased C4d deposition in hearts with IRI per se. Reperfusion alone has not been demonstrated convincingly in humans to induce C4d deposition [1].…”

“…It has previously been shown that complement activation occurs in the infarction area in otherwise healthy hearts [1,5,6,17]. In our study, C4d was found in the myocardium remote to the infarction after IRI, and C4d was not only encompassed in the infarction area.…”

“…Few postmortem evidence [1] and experimental studies [5,6] suggest that complements are activated after MI. Complement activation is an early marker of tissue destruction [7][8][9][10][11][12][13].…”

Reversal of Reflex-Induced Myocardial Ischemia by Median Nerve Stimulation

“…The procedure for measurement of risk and infarct areas has been described previously. 17 Briefly, patent blue violet dye (0.5%) was injected into the left atrium and the heart was fibrillated by application of direct current to the epicardium. The heart was excised, rinsed in cold saline and sliced in breadloaf fashion into four to six rings from apex to base.…”

Isolation, Characterization, and Cloning of Porcine Complement Component C7

“…Inhibition of the terminal complement complex through C5 attenuates myocardial ischemia/reperfusion injury (15). Protection to the ischemia/reperfused myocardium by inhibition of C5a and C5b-9 provided more protection than inhibition of C5a alone (15,34). Furthermore, C5b-9 and not C5a appears to be the major mediator of renal ischemia/reperfusion injury (16).…”