Mechanism of IL-6-related spontaneous atrial fibrillation after coronary artery grafting surgery: IL-6 knockout mouse study and human observation.

Abstract

Clinical observation and ex vivo studies have established a strong association between inflammation and postoperative atrial fibrillation (POAF). However, it is unclear whether the inflammatory phenotype is causally linked to this event or is an epiphenomenon, and it is not known which inflammatory meditators may increase susceptibility to POAF. The limitations of available animal models of spontaneous POAF (sPOAF) makes it difficult to select an experimental system. Here, we provide experimental and clinical evidence for mechanistic involvement of interleukin-6 (IL-6) in sPOAF.\n\n\nPHASE I\nWe established a mouse model of cardiac surgery with non-paced sPOAF. IL-6 knockout mice were protected from sPOAF compared with wild-type mice.\n\n\nPHASE II\nAt 48 h after surgery, the heart was separated into six regions and cultured. IL-6 was expressed in all regions, with highest abundance in the left atrium (LA). In PHASE III, we demonstrated that IL-6 in the LA elicited early profibrotic properties in atria via the pSTAT3/STAT3 signaling pathway and contributed to sPOAF.\n\n\nPHASE IV\nIn a translational prospective clinical study, we demonstrated that humans with POAF had a higher IL-6 concentration in pericardial drainage (PD). This study provides preliminary evidence of a causal relationship between IL-6 and POAF in a novel non-paced sPOAF mouse model. IL-6 is a crucial prerequisite for eliciting profibrotic properties in cardiac myocytes via the pSTAT3 pathway during the early postoperative period, leading to an increased susceptibility to POAF. Measuring IL-6 in PD could be a new non-invasive biomarker for the clinical prediction of POAF.