Cardiomyocyte-specific deletion of survivin causes global cardiac conduction defects
Cardiomyocyte-specific deletion of survivin causes global cardiac conduction defects
复制标题
DOI：
10.1007/s00395-012-0299-8
复制
发表时间：
2012-09
影响因子：
9.5
通讯作者：
J. Schrickel;L. Lickfett;T. Lewalter;K. Tiemann;G. Nickenig;H. Baba;G. Heusch;R. Schulz;B. Levkau
中科院分区：
文献类型：
--
作者：
J. Schrickel;L. Lickfett;T. Lewalter;K. Tiemann;G. Nickenig;H. Baba;G. Heusch;R. Schulz;B. Levkau
Survivin（Surv）属于凋亡抑制蛋白家族。其心脏特异性缺失导致心肌细胞数量减少、心肌细胞大小和倍性增加以及心力衰竭的发展。其对心脏电生理的影响尚不清楚。在心脏特异性缺失生存素的成年雄性小鼠（Surv-/-;n= 12）和野生型对照小鼠（Surv+/+;n= 12）中进行了体内经静脉电生理研究。在16只Surv−/−和6只Surv+/+小鼠的Langendorff灌注心脏中进行心外膜激活标测（EAM）。体表心电图显示Surv−/−小鼠的心率较低（326 ± 66 bpm vs. 440.6 ± 39 ms;P= 0.0001），伴有P波显著延长（20.3 ± 5.8 vs. 14.6± 2.0 ms; P= 0.009）、PQ-（47.4 ± 8.6 vs. 41.1 ± 3.7 ms;P= 0.043）、QRS-（19.5 ± 4.8 vs. 14.0 ± 1.0 ms;P= 0.002）和QT间期（41.6 ± 4.4 vs. 36.2 ± 3.4 ms;P= 0.003）。Surv−/−小鼠的HV间期延长（12.1 ± 2.4 vs 9.3 ± 1.4 ms;P= 0.0045）。我们发现窦房结功能受损（窦房结恢复时间：310.2 ± 76.6 vs. 207.8 ± 68.6 ms;P= 0.003）和房室结传导受损（文氏周期：105.9 ± 15.9 vs. 79.6 ± 8.1 ms;P= 0.0002）。EAM显示Surv−/−小鼠心肌传导显著减慢和异质性。所有Surv−/−小鼠均表现出自发性室上性和室性异位搏动（与野生型相比，P< 0.0001）。连接蛋白43（Cx43）的定量免疫荧光染色显示每个心肌细胞和单个缝隙连接均减少。Surv−/−小鼠在心房和心室心肌以及特定的传导系统中表现出严重的整体传导衰减，伴随着较低的连接蛋白43水平。房颤和室性心动过速的易感性缺乏表明，心肌细胞数量减少和体积增加构成了心脏电稳定性的决定因素，并抵消了Surv−/−中潜在的促心律失常性连接蛋白43丢失。
Survivin (Surv) belongs to the inhibitor of apoptosis protein family. Its cardiac-specific deletion results in reduced cardiomyocyte number, increased cardiomyocyte size and ploidy, and development of heart failure. Its impact on cardiac electrophysiology is unknown. In vivo transvenous electrophysiological studies were carried out in adult male mice with a cardiac-specific deletion of survivin (Surv−/−;n= 12) and wild-type controls (Surv+/+;n= 12). Epicardial activation mapping (EAM) was performed in Langendorff-perfused hearts of 16 Surv−/−and 6 Surv+/+mice. Surface-ECG showed lower heart rates in Surv−/−mice (326 ± 66 bpm vs. 440.6 ± 39 ms;P= 0.0001), accompanied by significantly prolonged P waves (20.3 ± 5.8 vs. 14.6 ± 2.0 ms;P= 0.009), PQ-(47.4 ± 8.6 vs. 41.1 ± 3.7 ms;P= 0.043), QRS- (19.5 ± 4.8 vs. 14.0 ± 1.0 ms;P= 0.002) and QT-intervals (41.6 ± 4.4 vs. 36.2 ± 3.4 ms;P= 0.003). The HV-interval was prolonged in Surv−/−mice (12.1 ± 2.4 vs. 9.3 ± 1.4 ms;P= 0.0045). We found impaired sinus-nodal function (sinus node recovery times: 310.2 ± 76.6 vs. 207.8 ± 68.6 ms;P= 0.003) and AV-nodal conduction (Wenckebach-periodicity: 105.9 ± 15.9 vs. 79.6 ± 8.1 ms;P= 0.0002). EAM showed significant slowing and heterogeneity of conduction in the myocardium of Surv−/−mice. All Surv−/−mice showed spontaneous supraventricular and ventricular ectopic beats (P< 0.0001 vs. wildtype). Quantitative immunofluorescence staining for connexin43 (Cx43) revealed a decrease in both per cardiomyocyte and single gap junction. Surv−/−mice exhibit severe global conduction attenuations in atrial and ventricular myocardium as well as the specific conduction system, accompanied by lower connexin43 levels. Lack of susceptibility to AF and VT suggests that reduced cardiomyocyte number and increased size constitute determinants of electrical stableness in the heart and counteract potentially proarrhythmogenic connexin43 loss in Surv−/−.