Department of Medicine-Cardiology, University of Bonn, Germany.
Basic Res Cardiol. 2012 Nov;107(6):299. doi: 10.1007/s00395-012-0299-8. Epub 2012 Sep 14.
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(-/-).
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，并导致心力衰竭。其对心脏电生理的影响尚不清楚。在成年雄性小鼠中进行了心脏特异性缺失 survivin（Surv（-/-）；n = 12）和野生型对照（Surv（+/+）；n = 12）的经静脉电生理研究。在 Langendorff 灌注的心脏中进行了心外膜激活映射（EAM）。在 16 只 surv（-/-）和 6 只 surv（+/+）小鼠中进行了表面心电图检查。体表心电图显示 surv（-/-）小鼠的心率较低（326 ± 66 bpm 与 440.6 ± 39 ms；P = 0.0001），同时 P 波显著延长（20.3 ± 5.8 与 14.6 ± 2.0 ms；P = 0.009），PQ-（47.4 ± 8.6 与 41.1 ± 3.7 ms；P = 0.043），QRS-（19.5 ± 4.8 与 14.0 ± 1.0 ms；P = 0.002）和 QT 间隔（41.6 ± 4.4 与 36.2 ± 3.4 ms；P = 0.003）。HV 间隔在 surv（-/-）小鼠中延长（12.1 ± 2.4 与 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 与 207.8 ± 68.6 ms；P = 0.003）和房室结传导受损（Wenckebach 周期：105.9 ± 15.9 与 79.6 ± 8.1 ms；P = 0.0002）。EAM 显示 surv（-/-）小鼠心肌的传导明显减慢和异质性。所有 surv（-/-）小鼠均出现自发性房性和室性异位搏动（P < 0.0001 与野生型相比）。连接蛋白 43（Cx43）的定量免疫荧光染色显示单个缝隙连接的心肌细胞内和细胞间的 Cx43 水平均降低。Surv（-/-）小鼠表现出心房和心室心肌以及特定的传导系统的严重整体传导衰减，同时 Cx43 水平降低。缺乏对 AF 和 VT 的易感性表明，减少的心肌细胞数量和增加的大小构成了心脏电稳定性的决定因素，并抵消了 surv（-/-）中潜在的致心律失常性 Cx43 丧失。
