Abstract 15341: Mild Hypothermia Preserves Myocardial Conduction During Ischemia by Both Maintaining Gap Junction Localization and Preserving Sodium Channel Function
Introduction: Acute cardiac ischemia induces arrhythmogenic conduction velocity (CV) slowing and conduction block. Previously, we found in a canine model of global ischemia that mild hypothermia (MH, 32°C) attenuates ischemia-induced CV slowing, reducing arrhythmia susceptibility. We sought to determine the mechanism by which MH preserved myocardial CV. CV is dependent upon both cellular excitability (via sodium channels) and electrical coupling (via gap junctions, GJ, at the intercalated disk, ICD). Ischemic remodeling of connexin 43 (Cx43), the primary ventricular GJ protein, causes CV slowing.
Hypothesis: MH prevents ischemia-induced CV slowing by preserving both GJ coupling and sodium channel (NaCh) excitability.
Methods: Canine left ventricle wedge preparations at control (C, 36°C) or MH were subjected to 15 minutes of no-flow ischemia. Cx43 localization was assessed by confocal IF and Cx43 remodeling by western blot. In additional preparations, analysis of the action potential upstroke rise time (RT), an index of NaCH function, was performed. As NaCH function is dependent on resting membrane potential and local potassium gradients, the IKATP blocker glibenclamide (Gli) was given to additional C wedges.
Results: MH significantly preserved Cx43 at the ICD, contributing to preserved CV (n=3 each, p<0.05). Interestingly, we did not observe differences in Cx43 phosphorylation at two sites previously implicated in ischemia induced uncoupling, serine 368 or 262 (n=3 each, p=NS). MH maintained action potential RT during ischemia (C t=22 ms, n=7 vs MH t=16 ms, n=6; p=0.01). Similarly to MH, Gli preserved RT and CV during ischemia (t=14ms, n=6; p=0.02), suggesting that by preventing IKATP activation during ischemia, MH may preserve localized potassium gradients, maintaining resting membrane potential and therefore NaCh function.
Conclusions: Mild hypothermia preserves myocardial conduction by both maintaining Cx43 at the intercalated disk and preserving sodium channel function, potentially through inhibiting IKATP. These data suggest that mild hypothermia may reduce arrhythmogenesis during ischemia through multiple mechanisms and may reveal novel antiarrhythmic targets during ischemia and resuscitation.
Author Disclosures: M.M. Jennings: None. L.D. Wilson: Other; Modest; Compound received from Zealand Pharma not for use with this project but potential future directions, no monies received. J.S. Piktel: Other; Modest; Compound received from Zealand Pharma not for use with this project but potential future directions, no monies received.
- © 2014 by American Heart Association, Inc.