Abstract 214: Therapeutic Hypothermia Promotes Arrhythmogenic Calcium-Mediated Delayed Afterdepolarizations During Sympathetic Stimulation

Abstract

Introduction: Most patients who undergo therapeutic hypothermia (TH) suffer cardiac arrest due to ischemia-induced ventricular fibrillation (VF). Ischemia and hypothermia both cause cellular calcium (Ca) overload, a substrate for Ca-mediated triggered arrhythmias. Previously, we showed that under non-ischemic conditions, TH suppresses Ca-mediated arrhythmias. However, the mechanistic relationship between hypothermia-induced Ca dysregulation and arrhythmias during ischemia, the most common clinical scenario, is unknown. We hypothesized that TH and ischemia would synergistically promote spontaneous Ca release and subsequent arrhythmogenic delayed afterdepolarizations (DADs). We examined this relationship during sympathetic stimulation, as occurs when epinephrine is given during resuscitation from VF. Methods and Results: Dual optical mapping of Ca transients and action potentials was performed in canine left ventricular wedge preparations during 10 minutes of no flow ischemia during normothermia (NT, 36°C, n=5) and TH (32°C, n=7) with and without beta-sympathetic stimulation (isoproterenol, 0.2uM, each n=5). Multicellular spontaneous Ca release events (mSCRs) and resultant DADs were induced by rapid pacing. During ischemia, TH increased mSCR amplitude (44±3%) vs. NT (26±4%, p<0.04). In contrast, the slope (amplitude/rise time) of mSCRs, an important determinant of triggered activity (TA), and DAD amplitudes were similar in TH and NT (24±6 and 21%±2% respectively, both p=NS). Importantly, when sympathetic stimulation was present during ischemia, TH increased the amplitude mSCRs compared to NT (61±5 vs. 31±7%, respectively p<.01) and the slope of mSCRs was 2-fold greater (p<.01), resulting in greater amplitude of DADs (50±9 vs. 28±7%, p=.08) and TA was observed. Conclusions: During ischemia, TH is not arrhythmogenic unless sympathetic stimulation is introduced, where it promotes spontaneous Ca release and DADs. Moreover, these data suggest that when TH is initiated during ischemia, as in intra-arrest cooling, sympathetic stimulation during cardiac arrest may be proarrhythmic by increasing susceptibility to Ca-mediated triggered arrhythmias.