The role of complement activation in myocardial injury.

Abstract

The mechanisms of the complement-mediated myocardial injury associated with ischemia and reperfusion have not been elucidated fully. Complement may directly mediate injury through actions of the anaphylatoxins (C3a, C5a), or generation of the membrane attack complex (C5b-9). An in vitro model was developed to examine the direct effects of complement activation on heart function, assess myocardial tissue damage, and determine which complement components mediate tissue injury. Rabbit isolated hearts were perfused with buffer containing human plasma as a source of complement. Rabbit tissue activates human complement. Perfusion with 6% normal plasma resulted in complement activation as assessed by generation of Bb, C3a, C5a, and SC5b-9. Complement activation caused a number of effects that were onset 7 to 15 minutes following plasma addition, and that developed fully over the next 20 to 30 minutes. The effects were dependent upon the complement titer, and included: (1) an increase in the end diastolic pressure; (2) a decrease in the developed pressure; (3) an increase in the coronary perfusion pressure; and (4) an increase in lymphatic fluid formation. These effects were not elicited when inhibitors of complement activation (FUT-175 or soluble complement receptor type 1) were present, or when heat-inactivated human plasma was used. The effects of complement activation on myocardial function could not be reproduced by treatment with recombinant C5a, zymosan-activated plasma, or plasma selectively depleted of C8. Myocardial tissue accumulated sodium and calcium, and lost potassium, as a result of complement activation. Activation caused the release of creatine kinase from myocytes. The data demonstrate that complement activation caused decrements in the studied physiologic parameters. The effects were not mediated by the anaphylatoxins, but were dependent upon the distal complement component C8, suggesting that the membrane attack complex (C5b-9) was responsible for the physiologic changes. Complement activation directly mediated tissue injury in a manner consistent with plasmalemmal disruption due to C5b-9 formation. Since it has been shown in other models that ischemically injured myocardial tissue can activate complement, the data are compatible with the view that the C5b-9 complex may mediate myocardial injury associated with ischemia and reperfusion.