Nassal Michelle M J, Wan Xiaoping, Dale Zack, Deschênes Isabelle, Wilson Lance D, Piktel Joseph S
The Heart and Vascular Research Center and Department of Physiology, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio; and.
The Heart and Vascular Research Center and Department of Emergency Medicine, MetroHealth Campus, Case Western Reserve University School of Medicine, Cleveland, Ohio.
Am J Physiol Heart Circ Physiol. 2017 May 1;312(5):H886-H895. doi: 10.1152/ajpheart.00298.2016. Epub 2017 Mar 10.
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 (d/d) 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 d/d and 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. Therapeutic 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.
急性心肌缺血会导致传导速度（CV）减慢和传导阻滞，进而引发折返性心律失常，最终导致心脏骤停。此前，我们发现轻度低温（MH；32°C）可减轻早期全心缺血犬模型中缺血诱导的传导阻滞和CV减慢。急性缺血会损害细胞兴奋性和缝隙连接（GJ）蛋白连接蛋白（Cx）43。我们推测，MH通过保留GJ表达和定位来预防缺血诱导的传导阻滞和CV减慢。将处于对照温度（36°C）或MH温度（32°C）的犬左心室标本进行无血流长时间（30分钟）缺血处理。从左心室透壁记录光学动作电位，并在整个缺血过程中测量CV。使用共聚焦免疫荧光（IF）和/或蛋白质印迹分析评估Cx43和钠通道（NaCh）重塑。通过微电极记录动作电位上升速度（d/d）和静息膜电位（RMP）来确定细胞兴奋性。在36°C和32°C下测量分离的犬心肌细胞中的NaCh电流。正如预期的那样，MH在30分钟的缺血过程中预防了传导阻滞，并减轻了缺血诱导的CV减慢。通过IF和蛋白质印迹分析，MH维持了Cx43在闰盘（ID）处的表达，并减轻了缺血诱导的Cx43降解。MH还保留了d/d和NaCh功能，而不影响RMP。通过IF或蛋白质印迹分析在ID处未观察到NaCh表达的差异。总之，MH通过维持ID处的Cx43表达和维持NaCh功能来在长时间缺血期间保留心肌传导。低温保存GJ偶联和NaCh可能是复苏期间新的抗心律失常策略。治疗性低温现在是心脏骤停复苏的I类推荐。这项研究确定，低温在急性心肌缺血期间保留缝隙连接偶联以及Na通道功能，减轻传导减慢并预防传导阻滞，这表明诱导低温可能是复苏中一种新的抗心律失常策略。
