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Mechanism of Complement Activation After Coronary Artery Occlusion: Evidence That Myocardial Ischemia in Dogs Causes Release of Constituents of Myocardial Subcellular Origin That Complex With Human C1q In Vivo

To evaluate whether ischemic myocardium releases molecules that react with the first component of complement, we studied cardiac lymph from eight dogs before and at intervals after coronary artery occlusion and reperfusion. Before occlusion, the dogs were injected intravenously with radiolabeled human C1q. Labeled C1q could be detected in the cardiac lymph within minutes following injection. Rabbit antisera, prepared against substances precipitated from postreprefusion cardiac lymph by anti-human C1q, also reacted with specific constituents of isolated cardiac sarcoplasmic reticulum and mitochondria. To evaluate whether mitochondria are the source of these C1q-bindlng proteins, we isolated intramyofibrillar and subsarcolemmal mitochondria from canine heart and incubated sonicates of these with purified C1q, immobilized on nitrocellulose. Molecules bound to the immobilized C1q were removed with 0.1% sodium dodecyl sulfate, fractionated under reducing conditions by polyacrylamide gel electrophoresis, and transferred electrophoretically to nitrocellulose paper. Antisera prepared against postreperfusion lymph reacted with a 31,000–32,000-dalton protein in these nitrocellulose paper replicas. Since this protein originates from mitochondria, binds to C1q, and is recognized by antibodies made against postreperfusion lymph, this protein is likely to be one of the subcellular constituents that, upon release from ischemic cells, activates the complement cascade. To evaluate the clinical relevance of these observations, we tested sera from 53 patients obtained 48–72 hours after hospitalization for suspected myocardial infarction. Sera from 12 of 15 patients (80%) with documented myocardial infarctions contained abnormally large quantities of substances that formed macromolecular complexes with C1q; C1q-binding substances were found in sera from only 5 of 38 patients (13%) who did not fulfill the criteria for myocardial infarction (p<0.001). Serial tests of sera from 19 patients showed that high levels of C1q-binding activity were temporally associated with significantly depressed C4 and/or C3 levels in 4 of 6 patients with and only 1 of 13 patients without myocardial infarctions. These observations are consistent with the hypothesis that myocardial ischemia results in the release of subcellular constituents of cardiac muscle that bind C1q. These C1q-binding substances may activate the complement cascade, trigger release of leukotactic anaphylatoxins, and stimulate infiltration of inflammatory cells that may extend the myocardial tissue injury associated with ischemia.