Ding Chao, Fu Xiang-hua, He Zhen-shan, Chen Hui-xiao, Xue Ling, Li Jun-xia
Department of Cardiology, Second Hospital of Hebei Medical University, Institute of Cardiocerebrovascular Disease of Hebei Province, Shijiazhuang, Hebei 050000, China.
Chin Med J (Engl). 2008 Mar 20;121(6):551-6.
Recent studies have revealed that pretreatment with statin is effective in preventing arrhythmia, but its electrophysiological mechanism is unclear. This study was conducted to investigate the cardioprotective effects of simvastatin on reversing electrical remodeling in left ventricular myocytes of rabbit heart undergoing ischemia-reperfusion, so as to explore the ionic mechanism responsible for the anti-arrhythmic effect of statin.
Forty-five rabbits were randomly divided into three groups: ischemic-reperfusion group (I-R), simvastatin intervention group (Statin) and sham-operated control group (CON). Anesthetized rabbits were subjected to 30-minute ischemia by ligation of the left anterior descending coronary artery and a 60-minute reperfusion after a 3-day administration of oral simvastatin of 5 mg x kg(-1) x d(-1) in the Statin group or a placebo in the I-R group. Single ventricular myocytes were isolated enzymatically from the epicardial zone of the infracted region derived from the hearts in the I-R and Statin group and the same anatomical region in the CON animals. The whole cell patch-clamp technique was used to record membrane ionic currents, including sodium current (I(Na)), L-type calcium current (I(Ca-L)) and transient outward potassium current (I(to)). Simultaneously, the level of serum cholesterol was examined.
There was no significant difference in the serum cholesterol concentration among the three groups. The peak I(Na) current density (at -30 mV) was significantly decreased in I-R ((-22.46+/-5.32) pA/pF, n=12) compared with CON ((-42.78+/-5.48) pA/pF, n=16, P<0.01) and Statin ((-40.66+/-5.89) pA/pF, n=15, P<0.01), while the peak I(Na) current density in the Statin group was not different from CON (P>0.05). The peak I(Ca-L) current density (at 0 mV) was significantly increased in I-R ((-4.34+/-0.92) pA/pF, n=15) compared with CON ((-3.13+/-1.22) pA/pF, n=13, P<0.05) and Statin ((-3.46+/-0.85) pA/pF, n=16, P<0.05), while the Peak I(Ca-L) current density in Statin was not different from CON (P>0.05). The I(to) current density (at +60 mV) was significantly decreased in I-R ((9.49+/-1.91) pA/pF, n=11) compared with CON ((17.41+/-3.13) pA/pF, n=15, P<0.01) and Statin ((14.54+/-2.41) pA/pF, n=11, P<0.01), although there was a slight reduction in the Statin group compared with CON (P<0.05).
It is implied that ischemia-reperfusion induces significant down-regulation of I(Na) and I(to) and up-regulation of I(Ca-L), which may underlie the altered electrical activity and long abnormal transmembrane action potential duration of the surviving ventricular myocytes, thus contributing to ventricular arrhythmias during acute ischemia-reperfusion period. Pretreatment with simvastatin could attenuate these changes and reverse this electrical remodeling without lowering the serum cholesterol level, contributing to the ionic mechanism of statin in treatment of arrhythmia independent of a decrease in cholesterol.
近期研究表明，他汀类药物预处理对预防心律失常有效，但其电生理机制尚不清楚。本研究旨在探讨辛伐他汀对兔心脏缺血再灌注左心室心肌细胞电重构的心脏保护作用，以探索他汀类药物抗心律失常作用的离子机制。
45只兔随机分为三组：缺血再灌注组（I-R）、辛伐他汀干预组（Statin）和假手术对照组（CON）。对麻醉后的兔进行如下处理：Statin组口服5 mg·kg⁻¹·d⁻¹辛伐他汀3天，I-R组口服安慰剂，之后通过结扎左冠状动脉前降支使兔经历30分钟缺血，再进行60分钟再灌注。酶法分离I-R组和Statin组心脏梗死区域心外膜区以及CON组动物相同解剖区域的单个心室肌细胞。采用全细胞膜片钳技术记录膜离子电流，包括钠电流（I(Na)）、L型钙电流（I(Ca-L)）和瞬时外向钾电流（I(to)）。同时检测血清胆固醇水平。
三组血清胆固醇浓度无显著差异。与CON组（(-42.78±5.48)pA/pF，n = 16，P<0.01）和Statin组（(-40.66±5.89)pA/pF，n = 15，P<0.01）相比，I-R组（(-22.46±5.32)pA/pF，n = 12）在-30 mV时的I(Na)电流峰值密度显著降低，而Statin组的I(Na)电流峰值密度与CON组无差异（P>0.05）。与CON组（(-3.13±1.22)pA/pF，n = 13，P<0.05）和Statin组（(-3.46±0.85)pA/pF，n = 16，P<0.05）相比，I-R组（(-4.34±0.92)pA/pF，n = 15）在0 mV时的I(Ca-L)电流峰值密度显著增加，而Statin组的I(Ca-L)电流峰值密度与CON组无差异（P>0.05）。与CON组（(17.41±3.13)pA/pF，n = 15，P<0.01）和Statin组（(14.54±2.41)pA/pF，n = 11，P<0.01）相比，I-R组（(9.49±1.91)pA/pF，n = 11）在+60 mV时的I(to)电流密度显著降低，尽管Statin组与CON组相比略有降低（P<0.05）。
这表明缺血再灌注可导致I(Na)和I(to)显著下调以及I(Ca-L)上调，这可能是存活心室肌细胞电活动改变和异常跨膜动作电位时程延长的基础，从而导致急性缺血再灌注期室性心律失常。辛伐他汀预处理可减轻这些变化并逆转这种电重构，且不降低血清胆固醇水平，这为他汀类药物治疗心律失常的离子机制提供了依据，且该机制独立于胆固醇降低作用。
