Low output syndrome after cardiac surgery is mediated through extra corporal circulation induced RAGE activation

Abstract

Objective Coronary artery bypass grafting (CABG) is a surgical procedure routinely performed using extracorporeal circulation (ECC). This on‐pump CABG is known to be associated with severe postoperative organ failure including cardiac dysfunction and low cardiac output syndrome. Mechanisms inducing cardiac dysfunction are complex but may include on‐pump CABG induced inflammation due to exposure of the blood to the bypass circuit, potentially increasing serum concentrations of inflammatory mediators. High‐mobility group box 1 (HMGB1) functions as an inflammatory mediator and has been shown to induce cardiovascular dysfunction in sepsis and impair cardiomyocyte contractility in experimental models. However, the impact of HMGB1 on on‐pump CABG induced myocardial dysfunction is not known. Therefore, we tested the hypothesis that on‐pump CABG associated increases in serum concentrations of inflammatory mediators induce cardiomyocyte dysfunction in vitro and investigated potential mechanism including the role of the HMGB1‐RAGE (receptor for advanced glycation end products) axis. Approach After institutional revenue board approval, informed consent, and IACUC approval, serum samples (n = 18) were collected from CABG patients pre, 1, 6, and 24 h after aortic de‐clamping. TNFa, IL‐1b, IL‐6, HMGB1, and sRAGE serum concentrations were analyzed by ELISA. Primary murine cardiomyocytes were incubated with patient serum and single cell contractility was assessed at frequencies between 0.5 and 10Hz using an optical contractility system (IonOptics LLC, Westwood, MA). Results IL‐6, HMGB1, and sRAGE serum levels were increased after CABG (Figure 1). In preliminary studies we incubated murine cardiomyocytes with human serum collected from healthy volunteers and determined the highest serum concentrations that did not affect cardiomyocyte contractility. Cardiomyocytes were incubate with human serum and serum collected pre‐surgery had no effects on murine cardiomyocyte contractility. However, primary murine cardiomyocytes incubated with serum collected 1h and 6h after aortic de‐clamping showed a significant decrease in % peak shortening. Pre‐incubation with the RAGE antibody FPS‐ZM1 (Cayman, Hamburg, Germany) prevented the serum induced cardiomyocyte dysfunction (Figure 2). Conclusion on‐pump CABG increased protein serum concentrations of inflammatory cytokines including HMGB1. HMGB1 has been shown to cleave and activate RAGE. sRAGE serum levels have been increased after on‐pump CABG. Deactivating RAGE with the high‐affinity inhibitor FPS‐ZM1 prevented serum induced cardiomyocyte dysfunction, suggesting that the HMGB1‐RAGE axis is mediating on‐pump CABG associated low‐cardiac‐output syndrome.