研究背景： 心脏性猝死(SCD)的直接原因是致命性心律失常(FA)，其中最主要的FA是室性心动过速(VT)和心室颤动(VF)。致命性室性心律失常发生的可能机制包括自律性增高、触发机制和折返机制，但最常见和最有价值的是折返机制。研究证实，跨心室壁复极离散度(TDR)增加是2位相折返最基本的条件和基础，但其只有在冠脉灌注的心肌组织块的细胞电生理研究中才能获得。1994年严干新创立了冠脉灌注的组织块生理模型，证明M细胞占左室心肌的70%左右，动作电位时程(APD)最长，复极结束最晚，与T波的终点(end of T)对应；而心外膜APD最短，复极结束最早，与T波的顶点(Peak of T)对应。因此，Tp-e是目前唯一可从心电图间接反映TDR的指标，其增大与长QT间期综合征(LQTS)患者发生尖端扭转型室性心动过速(Tdp)或SCD的危险性增高二者具有显著的相关性，可作为室性快速心律失常发生的一个重要预测指标。 研究目的： 健康成人Tp-e及Tp-e/QT比值的正常范围，并与ST段抬高型急性心肌梗死(AMI)患者相比较，探讨Tp-e/QT比值与恶性室性心律失常发生的细胞电生理机制及其临床意义。同时，建立冠状动脉灌注兔左室心肌楔形组织块模型，探讨LQT2模型早期后除极(EAD)、跨壁折返以及Tdp的发生机制。 材料和方法： 1)选择健康体检和ST段抬高型AMI病人为研究对象，测量QT、QTd、QTc、Tp-e并计算Tp-e/QT比值，分析其与恶性室性心律失常发生的关系。 2)建立冠状动脉灌注兔左室心肌楔形组织块模型，应用浮置玻璃微电极和心电图同步记录技术，以I〓且断剂d-sotalol作为工具药模拟LQT2型，并与延迟整流钾电流I〓阻滞剂azimilide对比，观察两者对兔心内膜和外膜层心肌细胞APD、TDR、EAD、 R-on-T早搏和Tdp的作用。 结果： 1)入选健康体检者67例。其中，男52例，女15例，平均年龄为(59.5±10.8) 岁。入选ST段抬高型AMI患者68例。其中，男55例，女13例，平均年龄为(62.5±12.6)岁；前壁心肌梗死52例，下壁心肌梗死11例，下壁及右室心肌梗死5例。健康成人Tp-e范围为：50-120ms，Tp-e的中位数是80ms，平均数是 89.55±12.61ms；Tp-e/QT 比值的范围为：0.16-0.24，中位数是0.18，平均数是0.21±0.03。 2)68例STEMI患者中，室性心律失常的发生率为47.1%。其中，发生室早二联律的有3人；室早连发的有2人；频发室早的有8人；多源性室早的有0人；短阵室速的有18人；持续室速的有0人；室颤的有1人。最常见的室性心律失常是短阵室速(56.3%)，其次是频发室早(25.0%)和室早二联律(9.4%)。 3)与健康成人相比较，STEMI患者心电图上QTd、Tp-e及QTc均明显延长((33.66±16.76)ms vs (55.29±31.12)ms，(89.55±12.61)ms vs (142.65±39.33)ms 和(426.57±65.03)ms vs (482.26±48.03)ms； P<0.001)，且 Tp-e/QT 比值显著增加(0.21±0.03 0.29±0.07；P<0.001)。 4)68例STEMI患者中，发生恶性室性心律失常的有19人(27.9%)，心电图上QTd，Tp-e及QTc均较无恶性室性心律失常者延长，但只有Tp-e及Tp-e/QT比值显著增加((157.66±40.52)ms vs (127.65±32.18)ms，0.32±0.07 vs 0.26±0.05；P<0.001)。 5)d-sotalol(100 μmol/L)延长QT间期和APD的同时，显著增加 TDR((43.3±14.2)ms vs (134.8±9.6)ms；P<0.05)；而azimilide(10μmol/L)则明显延长了外膜的 APD，缩短了TDR((32.3±8.7)ms vs (21.3±7.1)ms；P<0.05)。 6)d-sotalol (100 μmol/L)和 azimilide(10μmol/L)容易诱发 EAD，其发生率为7/7和5/7，而对照组无EAD，R-on-T早搏和自发性Tdp发生；d-sotalol (100 μmol/L)诱发的EAD能至心外膜，触发R-on-T早搏，并产生跨壁折返，而azimilide诱发的EAD虽然也能形成R-on-T早搏，但EAD和R-on-T早搏不能形成跨壁折返。说明TDR是EAD和R-on-T早搏形成跨壁折返的基础。 结论： 1)Tp-e/QT比值与恶性室性心律失常的发生有显著的相关性，是SCD最重要的预警指标之一。 2)TDR的增加不仅是EAD产生的基础，更是发生折返和维持Tdp的重要机制。 关键词：心脏性猝死；Tp-e/QT比值；跨壁复极离散度；早期后除极；尖端扭转型室性心动过速 论文类型：应用基础

 Backgroud: The immediate cause of sudden cardiac death(SCD) is fatal arrhythmia(FA), of which the ventricular tachycardia(VT) and ventricular fibrillation(VF) overriding. Both autorhythmicity increasing, trigger mechanism and reentry mechanism may be the mechanism of fatal ventricular arrhythmia, but of which reentry mechanism be the most common and valuable. The amplification of transmural dispersion of repolarization(TDR) has been confirmed to provide the functional substrate for phase 2 reentry. However, it can only be obtained in cellular electrophysiologic study of coronary arterially perfused cardiac musculature. In 1994, Yan Ganxin established an electrophysiological model in coronary arterially perfused left ventricular wedge, with which they are demonstrated that the M cells, accounting for 70% left ventricular, have the longest action potential duration(APD) and epicardial cells the shortest APD; meanwhile, the end of repolarization of M cells coincides with the end of the T wave and the end of repolarization of epicardial cells coincides with the peak of the T wave in wedge-ECG. Therefore, it is the only one index in 12-lead ECG reflecting TDR indirectly and correlates significantly with chanciness being heightened in both torsades de pointes(Tdp) of long QT syndrome(LQTS) and SCD, which may serve as the important predictive index of ventricular tachyarrhythmia. Objectives: To summarize the normal range of Tp-e interval and Tp-e/QT ratio in healthy individuals, which will be compared with them of the patients with acute ST-segment elevation myocardial infarction(STEMI). Thus the relation of Tp-e/QT ratio and malignant ventricular arrhythmia will be studied. Simultaneously, to investigate the generation and transmural propagation of early after depolarization(EAD), reentry and the initiating and maintaining mechanisms of Tdp in LQT2 model under the establishment of the coronary arterially perfused rabbit left ventricular wedge preparation. Methods: 1)Using the healthy individuals and patients with acute STEMI according the criterion as study object, both the interval of QT, QTd, QTc and Tp-e were measured and the Tp-e/QT ratio calculated. The relation between the Tp-Te/QT ratio and malignant ventricular arrhythmia was analyzed. 2)An electrophysiological model in arterially perfused rabbit left ventricular wedge was made to simulate LQT2 model by using d-sotalol. The transmembrane action potentials of epicardium( Epi), endocardium(Endo) cells and transmural ECG in arterially perfused rabbit left ventricular wedge preparation were recorded by floating glass microelectrode. The role of d-sotalol and azimilide on APD of different layers, TDR, EAD, and R-on-T premature beat and Tdp were observed. Results: 1)In the present study, 67 cases of the healthy individuals were selected, including 52 men and 15 women, whose mean age was (59.5±10.8) years. Meanwhile, 68 cases of ST-elevation AMI were selected, including 55 men and 13 women, whose mean age was (62.5±12.6) years. There were 52 cases of anterior myocardial infarction, 11 cases of inferior myocardial infarction and 5 cases of inferior and right ventricular myocardial infarction. The rang of Tp-e interval in the healthy individuals was from 50 to 120 milliseconds (ms),median value of 80 ms ,and the mean of 89.55±12.61ms. The rang of Tp-e /QT ratio in the healthy individuals was from 0.16 to 0.24, median value of 0.18 ,and the mean of 0.21±0.03 . 2)The incidence of ventricular arrhythmia was 47.1% in 68 cases of ST-elevation AMI, among which 3 cases of ventricular premature beat with bigeminal rhythm, 2 cases of coupled ventricular premature beat, 8 cases of frequent ventricular premature beat, 0 cases of multi-source ventricular premature beat, 18 cases of paroxysmal VT, 0 cases of persistent VT and 1 case of VF were included. The most comman ventricular arrhythmia included both paroxysmal VT(56.3%), frequent ventricular premature beat(25.0%) and ventricular premature beat with bigeminal rhythm(9.4%). 3)Compared with the healthy individuals, the interval of QTd, Tp-e and QTc were significantly lengthened((33.66±16.76)ms vs (55.29±31.12)ms, (89.55±12.61)ms vs (142.65±39.33)ms and (426.57±65.03)ms vs (482.26±48.03)ms; P＜0.001). Moreover, the Tp-e/QT ratio was notably increased (0.21±0.03 vs 0.29±0.07; P＜0.001). 4) There were 19 cases of malignant ventricular arrhythmia in 68 cases of ST-elevation AMI, whose interval of QTd, Tp-e and QTc were prolonged than those without malignant ventricular arrhythmia. However, only the interval of Tp-e and Tp-e/QT ratio were significantly increased((157.66±40.52)ms vs (127.65±32.18)ms, 0.32±0.07 vs 0.26±0.05, respectively; P＜0.001). 5)D-sotalol(100 μmol/L) increased TDR significantly while it prolonged the interval of QT and APD((43.3±14.2)ms vs (134.8±9.6)ms; P＜0.05). However, azimilide(10μmol/L) prolonged APD of Epi and shortened TDR notably ((32.3±8.7)ms vs (21.3±7.1)ms; .P＜0.05). 6)The incidence of EAD was easily induced by d-sotalol(100 pmol/L) and azimilide(10 μmol/L) (7/7 vs 5/7, respectively), but no EAD, R-on-T premature beat and automatic Tdp were observed in control. EAD, induced by d-sotalol(100 μmol/L), could spread to Epi and initiate R-on-T premature and transmural reentry. Although azimilide could induce EAD and R-on-T premature beat, but which could not generate transmural reentry. It is suggested that TDR is the functional substrate for transmural propagation of EAD, reentry and R-on-T premature. Conclusion: 1)The Tp-e ratio associates notably with malignant ventricular arrhythmia, and may be one of the most important predictive index of SCD. 2)An amplified TDR can not only provide the substrate for EAD being generated, but also be the important mechanisms of facilitating the reentry and maintenance of Tdp. KEYWORDS: Sudden cardiac death; Tp-e/QT ratio; Transmural dispersion of repolarization; Early after depolarization; Torsades de pointes TYPE OF DISSERTATION: Application Fundamentals