title: Mild hypothermia preserves myocardial conduction during ischemia by maintaining gap junction intracellular communication and Na+channel function.
abstract: Acute cardiac ischemia induces conduction velocity (CV) slowing and conduction block, promoting reentrant arrhythmias leading to sudden cardiac arrest. Previously, we found that mild hypothermia (MH; 32°C) attenuates ischemia-induced conduction block and CV slowing in a canine model of early global ischemia. Acute ischemia impairs cellular excitability and the gap junction (GJ) protein connexin (Cx)43. We hypothesized that MH prevented ischemia-induced conduction block and CV slowing by preserving GJ expression and localization. Canine left ventricular preparations at control (36°C) or MH (32°C) were subjected to no-flow prolonged (30 min) ischemia. Optical action potentials were recorded from the transmural left ventricular wall, and CV was measured throughout ischemia. Cx43 and Na+channel (NaCh) remodeling was assessed using both confocal immunofluorescence (IF) and/or Western blot analysis. Cellular excitability was determined by microelectrode recordings of action potential upstroke velocity (dV/dtmax) and resting membrane potential (RMP). NaCh current was measured in isolated canine myocytes at 36 and 32°C. As expected, MH prevented conduction block and mitigated ischemia-induced CV slowing during 30 min of ischemia. MH maintained Cx43 at the intercalated disk (ID) and attenuated ischemia-induced Cx43 degradation by both IF and Western blot analysis. MH also preserved dV/dtmaxand NaCh function without affecting RMP. No difference in NaCh expression was seen at the ID by IF or Western blot analysis. In conclusion, MH preserves myocardial conduction during prolonged ischemia by maintaining Cx43 expression at the ID and maintaining NaCh function. Hypothermic preservation of GJ coupling and NaCh may be novel antiarrhythmic strategies during resuscitation.NEW & NOTEWORTHYTherapeutic hypothermia is now a class I recommendation for resuscitation from cardiac arrest. This study determined that hypothermia preserves gap junction coupling as well as Na+channel function during acute cardiac ischemia, attenuating conduction slowing and preventing conduction block, suggesting that induced hypothermia may be a novel antiarrhythmic strategy in resuscitation.
authors.affiliation: The Heart and Vascular Research Center and Department of Physiology, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio; and.
authors.forename: Michelle M J
authors.initials: MMJ
authors.lastname: Nassal
authors.affiliation: The Heart and Vascular Research Center and Department of Physiology, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio; and.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wan
authors.affiliation: The Heart and Vascular Research Center and Department of Emergency Medicine, MetroHealth Campus, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Zack
authors.initials: Z
authors.lastname: Dale
authors.affiliation: The Heart and Vascular Research Center and Department of Physiology, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio; and.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Deschênes
authors.affiliation: The Heart and Vascular Research Center and Department of Emergency Medicine, MetroHealth Campus, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Lance D
authors.initials: LD
authors.lastname: Wilson
authors.affiliation: The Heart and Vascular Research Center and Department of Emergency Medicine, MetroHealth Campus, Case Western Reserve University School of Medicine, Cleveland, Ohio jpiktel@metrohealth.org.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Piktel
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002450:Cell Communication; D017630:Connexins / Q000378:metabolism; D004285:Dogs; D017629:Gap Junctions; D006329:Heart Conduction System; D007036:Hypothermia, Induced / Q000379:methods*; D008297:Male; D008839:Microelectrodes; D018613:Microscopy, Confocal; D032342:Muscle Cells / Q000378:metabolism; D017202:Myocardial Ischemia / Q000628:therapy*; D015222:Sodium Channels; D016277:Ventricular Function, Left
chemical_list: D017630:Connexins; D015222:Sodium Channels
keywords: arrhythmias; connexin43; hypothermia; ischemia; ventricular fibrillation