Activation of the Homeostatic Intracellular Repair Response During Cardiac Surgery

BACKGROUND: The homeostatic intracellular repair response (HIR2) is an endogenous beneficial pathway that eliminates damaged mitochondria and dysfunctional proteins in response to stress. The underlying mechanism is adaptive autophagy. The purpose of this study was to determine whether the HIR2 response is activated in the heart in patients undergoing cardiac surgery and to assess whether it is associated with the duration of ischemic arrest and predicted surgical outcomes. STUDY DESIGN: Autophagy was assessed in 19 patients undergoing coronary artery bypass or valve surgery requiring cardiopulmonary bypass. Biopsies of the right atrial appendage obtained before initiation of cardiopulmonary bypass and after weaning from cardiopulmonary bypass were analyzed for autophagy by immunoblotting for LC3, Beclin-1, autophagy 5-12, and p62. Changes in p62, a marker of autophagic flux, were correlated with duration of ischemia and with the mortality/morbidity risk scores obtained from the Society of Thoracic Surgeons Adult Cardiac Surgery Database (version 2.73). RESULTS: Heart surgery was associated with a robust increase in autophagic flux indicated by depletion of LC3-I, LC3-II, Beclin-1, and autophagy 5-12; the magnitude of change for each of these factors correlated significantly with changes in the flux marker p62. In addition, changes in p62 correlated directly with cross-clamp time and inversely with the mortality and morbidity risk scores. CONCLUSIONS: These findings are consistent with preclinical studies indicating that HIR2 is cardioprotective and reveal that it is activated in patients in response to myocardial ischemic stress. Strategies designed to amplify HIR2 during conditions of cardiac stress might have a therapeutic use and represent an entirely new approach to myocardial protection in patients undergoing heart surgery. (J Am Coll Surg 2013; 216: 719-729. (C) 2013 by the American College of Surgeons)