Abstract 3363: Profound Cardioprotection With Chloramphenicol in the Swine Model of Myocardial Ischemia-Reperfusion Injury
Background: Evidence from our group suggests that the profound cardioprotection achieved with classic ischemic preconditioning (PC) may be due in part to up-regulation of autophagy: i.e., the cellular ‘housekeeping’ process responsible for the degradation and removal of damaged organelles and protein aggregates. If this premise is correct, we reasoned that a pharmacologic agent capable of inducing autophagy should act as a preconditioning-mimetic and render the heart resistant to a subsequent sustained ischemic challenge.
Methods: To test this hypothesis, we assessed whether chloramphenicol (CAP) - a bacteriostatic antimicrobial shown by our group to induce autophagy in HL-1 myocytes - would limit infarct size in a clinically relevant, large animal (swine) model of myocardial ischemia-reperfusion injury. Anesthetized open-chest pigs were randomly assigned to receive CAP (20 mg/kg slow bolus) or vehicle (saline), with drug or saline administered in a blinded manner via the left atrium (n=6 per group). Ten min after the onset of treatment, all pigs underwent 45 min of left anterior descending coronary artery occlusion followed by three hours of reperfusion. Primary endpoints were infarct size (delineated by tetrazolium staining and expressed as a percentage of the myocardium at risk), hemodynamics (including heart rate, arterial and left ventricular pressures) and the incidence of ventricular fibrillation (VF).
Results: CAP had no effect on hemodynamics, and did not alter the propensity for VF: 50% of pigs in both the CAP- and saline-treated groups developed VF during occlusion and/or immediately upon reflow, with all pigs successfully defibrillated and resuscitated. However, blinded analysis revealed a significant reduction of infarct size in CAP-treated pigs vs saline-controls (25±5% vs 56±6% of the risk region, respectively: p=0.002) - protection that is comparable in magnitude to the infarct-sparing effect achieved with PC in this swine model.
Conclusion: These data:
support the concept that a pharmacologic agent capable of inducing autophagy can initiate cardioprotection; and
identify chloramphenicol as an agent that may be of clinical benefit in patients at risk of ischemia-reperfusion injury.