EXERCISE-INDUCED ORGAN PROTECTION IN A MURINE MODEL OF CARDIAC ARREST AND RESUSCITATION

Abstract

Cardiac arrest causes whole-body ischemic injury and cell death. Successful cardiopulmonary resuscitation paradoxically confounds recovery by increasing the rate of cellular death and tissue damage through global reperfusion injury. Despite decades of basic and clinical research, the prognosis after a resuscitated cardiac arrest continues to be poor. The substantial effects of cardiac arrest on neurologic function are a major contributor to the high incidence of mortality following resuscitation. Engaging in moderate-intensity aerobic exercise 24 to 72 hours prior to prolonged ischemic exposure can create a prophylactic, conditioned response that minimizes tissue damage. This exercise-induced effect resembles protection conferred by surgical induction of a series of brief, sub-lethal ischemic episodes, known as ischemic preconditioning. The unpredictability of cardiac arrest renders ischemic preconditioning impractical and useless as a neuroprotective defense mechanism. In light of this impracticality, aerobic exercise could provide the only reasonable preventative measure for inducing sustainable organ protection from ischemic injury. Furthermore, characterization of the murine electrocardiogram during and immediately following resuscitated cardiac arrest is exceedingly limited in the current literature. Thus, a clear knowledge gap exists in the methodology of murine models of arrest which we attempted to fill. We hypothesized that exercise preconditioning can confer neuroprotection against prolonged, global ischemia associated with cardiac arrest. Additionally, we proposed that real-time electrocardiographic pattern recognition in the first 30 seconds post-arrest can be used to predict survival in a murine model of cardiac arrest and resuscitation. We tested these hypotheses using male C57Bl/6J mice 10-12 weeks of age in a potassium-induced model of arrest. The mice were trained in a forced treadmill exercise training protocol pre-arrest and neurologic function was serially tested. In the post-arrest period, neurologic testing was repeated to detect changes in cognitive function and emotionality. Our results showed that real-time ECG pattern recognition is a reliable tool for determining the success of resuscitation efforts. Key characteristics of survival emerged in the visual appearance of the RR interval, PR interval, QRS complex, heart rate, and the relation of the J-point to the isoelectric line. These characteristics were substantiated on post-hoc quantitative analysis. Furthermore, as predicted, exercise preconditioning confers neuroprotection during cardiac arrest. This was evidenced by a lower fraction of hippocampal neuronal apoptosis compared with non-exercised animals and a concomitant preservation of retrograde memory.