Interleukin-6 Regulation In The Canine Myocardium After Cardiopulmonary Bypass ♦ 104

Abstract

A systemic inflammatory reaction occurs in response to cardiopulmonary bypass (CPB). Recent evidence suggests myocardial involvement in this response. Interleukin-6 (IL-6) is a pleiotrophic cytokine with pro-inflammatory properties, known to induce cardiac myocyte intercellular adhesion molecule-1 (ICAM-1) production in vitro (thus supporting neutrophil-myocyte adhesion) and also known to have negative inotropic properties as well. Although plasma IL-6 levels have been shown to increase after CPB, the details of IL-6 induction and regulation after CPB are unknown. Also, tissue IL-6 levels may be physiologically more important than those in the circulation. Thus, to examine myocardial IL-6 regulation, dogs underwent 90 mins of hypothermic CPB (26-28°C) with 60 mins of cardioplegic arrest. After rewarming, dogs were reperfused open chest for either 3 hrs (n=4) or 6 hrs (n=4) at the end of which myocardial biopsies were obtained. An additional 4 dogs underwent open midline sternotomy without CPB and served as time-matched controls. Northern blot analysis of myocardial mRNA showed a marked increase in IL-6 in 3/4 dogs at 3 hrs and 3/4 dogs at 6 hrs of reperfusion when compared to sham bypass controls. Northern blots of mRNA extracted from isolated neutrophils and mononuclear leukocytes obtained from blood samples prior to CPB, at the end of CPB, and at 3 hrs of reperfusion failed to demonstrate IL-6 induction. In situ hybridization studies of the biopsied myocardium confirmed cardiac myocytes as a source of IL-6 production 3 hrs after CPB, with both sequestered monocytes and neutrophils also producing IL-6 by 6 hrs after CPB. Results of northern blots for ICAM-1 performed on the same myocardial tissue as the IL-6 studies showed ICAM-1 induction which was highly concordant with the IL-6 results. Thus, ischemia/reperfusion during CPB, despite myocardial protection with cold cardioplegic arrest, appears to be a sufficient stimulus to induce myocardial IL-6 synthesis. Myocardial IL-6 production may play a pivotal role in the development of depressed myocardial function postoperatively.