跨壁复极离散在多形性折返性室性心动过速发生中的作用

目的探讨跨壁复极离散与室性心律失常发生的关系。方法以冠状动脉灌注兔左室楔形组织块为研究对象,对标本施加刺激基础周长分别为500,1000,2000ms的S1刺激,记录内、外膜侧心肌细胞动作电位和跨壁心电图,测量QT间期、时间易损窗及Tp-e/QT值。每10个S1刺激后施加期前S2刺激,S1S2耦联间期以1ms递增,以测量引起单向传导阻滞的时间易损窗。结果时间易损窗与QT间期呈正相关;Tp-e/QT比值在0.10～0.14之间无多形性室性心动过速(PVT)发生,当Tp-e/QT比值大于0.15,可引起PVT发生,而该比值在0.18～0.21时,无论S2刺激施加于内膜侧还是外膜侧,均可引起PVT。结论随着QT间期的延长时间易损窗增大;Tp-e/QT比值越大,室性心律失常越易发生。     

电紧张扩布在折返性室性心律失常发生中的作用

目的探讨电紧张扩布在折返性心律失常发生中的作用。方法以冠状动脉灌注兔左室楔形组织块标本为研究对象,同步记录内、外膜侧心肌细胞动作电位和跨壁心电图。以1 000 ms的刺激周长(BCL)对标本施加基础刺激S1。根据期前刺激(S2)发放的位置,分为期前刺激内膜侧组和外膜侧组,每10次S1后施加S2。S1S2间期以1 ms的步长递增,诱发单向传导阻滞和室性心律失常,观察了S2刺激位置的改变对所诱发早搏QRS波极性的影响。同时用计算机仿真方法观察了动作电位过程中Na通道门控因子的特点。结果无论期前刺激S2在内膜侧,还是外膜侧,所诱发的第一个室性早搏的QRS波均为倒置的,提示不同位置S2刺激引发的室性早搏的兴奋均来自于外膜侧。由于内膜侧心肌细胞动作电位时程明显长于外膜侧,激活和失活门控因子逐步恢复至初始状态延迟。结论在此过程中缓慢的电紧张扩布起了重要作用,并参与了折返激动的产生。     

跨壁复极离散在多形性折返性室性心动过速发生中的作用

目的探讨跨壁复极离散与室性心律失常发生的关系。方法以冠状动脉灌注兔左室楔形组织块为研究对象，对标本施加刺激基础周长分别为500，1000，2000ms的S1刺激，记录内、外膜侧心肌细胞动作电位和跨壁心电图，测量QT间期、时间易损窗及Tp-e／QT值。每10个S1刺激后施加期前S2刺激，S1S2耦联间期以1ms递增，以测量引起单向传导阻滞的时间易损窗。结果时间易损窗与QT间期呈正相关；Tp-e／QT比值在0．10～0．14之间无多形性室性心动过速（PVT）发生，当Tp-e／QT比值大于0．15，可引起PVT发生，而该比值在0．18～0．21时，无论S2刺激施加于内膜侧还是外膜侧，均可引起PVT。结论随着QT间期的延长时间易损窗增大；Tp-e／QT比值越大，室性心律失常越易发生。     

Brugada综合征的分子遗传和细胞致病机制

目前发现的Brugada综合征（BS）的致病基因有SCN5A和GPD1L，或许还有多个基因位点存在，此有待发现。目前认为BS产生心律失常的基质是由于1相复极未期内外离子流所达平衡点的进一步偏移，此导致了外膜而非内膜动作电位平台期消失，从而引起动作电位时程不一致，造成复极和不应期离散度增加，从而产生易损窗。外膜离散度增加导致2相折返形成，室性早搏落在易损窗通过折返机制促发室性心动过速／心室颤动。     

Brugada综合征的分子遗传和细胞致病机制

目前发现的Brugada综合征(BS)的致病基因有SCN5A和GPD1L,或许还有多个基因位点存在,此有待发现。目前认为BS产生心律失常的基质是由于1相复极未期内外离子流所达平衡点的进一步偏移,此导致了外膜而非内膜动作电位平台期消失,从而引起动作电位时程不一致,造成复极和不应期离散度增加,从而产生易损窗。外膜离散度增加导致2相折返形成,室性早搏落在易损窗通过折返机制促发室性心动过速/心室颤动。     

LQT2模型尖端扭转型室性心动过速的发生机制

目的探讨LQT2模型早期后除极(EAD)、跨壁折返以及尖端扭转型室性心动过速(Tdp)的发生机制。方法采用冠状小动脉灌注兔左室心肌楔形组织块标本,应用浮置玻璃微电极动作电位及ECG同步记录技术,以IKr阻断剂d-sotalol作为工具药模拟LQT2,并与延迟整流钾电流IK阻滞剂azimilide对比,观察两者对兔心内膜和外膜层心肌细胞动作电位时程(APD)、跨壁复极离散度(TDR)、EAD、R-on-T早搏和Tdp的作用。结果d-sotalol和azimilide均显著延长心内膜和外膜层心肌细胞APD和QT间期;d-sotalol显著增加TDR,诱发EAD、R-on-T早搏和自发性Tdp的发生率分别为7/7,7/7和3/7;azimilide不增加TDR和不形成跨壁折返,但可诱发EAD和R-on-T早搏。结论通过冠状小动脉灌注兔左室心肌组织块LQT2模型,发现整体心室肌组织在QT延长的条件下,2相EAD是触发并引起Tdp的机制;TDR增加是产生EAD和形成折返的基础。     

兔肥厚左心室跨壁复极离散度和室性心律失常发生机制

目的 探讨肥厚左心室跨壁复极离散度变化及室性心律失常发生机制.方法 制作压力超负荷兔模型,分别记录对照组、肥厚组心室肌内、外膜动作电位并同步记录跨室壁心电图,比较两组动作电位时限（APD90）、跨心室壁复极离散度（TDR）和室性心律失常发生率、尖端扭转性室性心动过速（Tdp）危险度评分.结果 （1）与对照组相比,肥厚组内、外膜APD90显著延长,以内膜层心肌更为明显;TDR显著增大（P＜0.01）;上述变化呈现显著慢频率依赖性;（2）肥厚组室性心律失常发生率、Tdp危险度评分明显高于对照组.结论 动作电位时限延长、跨心室壁复极离散度增大基础上的早期后除极和跨室壁折返激动是肥厚心室心律失常的主要机制.     

低钾对长QT综合征心室肌组织易损窗的影响——计算机仿真研究

目的探讨细胞外低钾时长QT综合征(LQTS)室性心律失常发生率增高的原因。方法采用计算机仿真方法,分别观察了不同程度低钾对LR91一维非均质心室肌模型的时间、空间及电压易损窗的影响。实验分为正常组和LQTS组。以500,1000和2000ms的刺激周长对一维模型施加基础刺激S1(-70μA/μF、1.5ms)10次后,测量动作电位时程及传导速度。每10次S1后施加期前刺激S2,S1S2间期以1ms的步长递减测量易损窗。结果在不同刺激频率条件下,随[K+]O的减低,正常组和LQTS模型组的时间、电压、空间易损窗逐渐增大,且LQTS模型组易损窗均大于正常组。易损窗变化表现有频率依赖性。结论低钾增加了单向传导阻滞的发生机率,是导致室性心律失常发生率增高的重要原因。     

左右心室间复极异质性的研究进展

左右心室间存在复极异质性 ,主要表现为左右心室的动作电位时程 (APD)不同、早期后除极 (EADs)的振幅及发生率不同 ,而且病理生理因素和某些药物可增加或减小这种异质性。心室间复极异质性的产生机制与不同部位心肌细胞离子流性质不同有关。心室间复极异质性在某些室性心律失常如 :尖端扭转型室性心动过速和多形性室性心动过速的发生中具有重要作用。     

中层心肌细胞分布与长QT综合征中折返激动发生机制的计算机仿真研究

中层心肌 (M)细胞的分布是决定心室不应期空间分布的重要参数。特定离子通道的基因突变是产生遗传性长QT综合征的基础。但在离子通道水平上对M细胞分布状态与长QT综合征中尖端扭转型室性心动过速 (Tdp)折返机制关系的理论研究甚少。用Luo Rudy心室肌细胞动作电位模型LRd0 0进行二维心室肌组织仿真研究。采用特定M细胞岛形分布观察心室激动的跨壁传播特点。通过设置快速延迟整流钾电流 (IKr)通道的电导为零 ,模拟动物实验中灌注d sotalol阻断IKr形成LQT2模型 ,并在四种仿真条件下观察复极跨壁异质性的特征。在LQT2模型中 ,动作电位的时程延长 ,复极跨壁分布的最大值从对照条件下的 1 5ms/mm延长至 2 5ms/mm ,提示动作电位跨壁复极离散度增大。在LQT2模型中 ,M细胞岛形分布形状对不应期的空间分布起着重要的决定性作用。传导阻滞、Tdp形成、以及壁内折返环的维持均与M细胞的分布形状有关。结论 :M细胞的特征分布是产生不应期在空间上异质性的基础。不应期的局部延长是产生功能性折返的基础。在长QT综合征中 ,M细胞的特征分布对Tdp的折返形成起着重要的作用     

Reentrant ventricular arrhythmias in the late myocardial infarction period in the dog. 13. Correlation of activation and refractory maps

Isochronal maps of ventricular activation were analyzed in dogs 3-5 days after ligation of the left anterior descending coronary artery utilizing a 64-channel multiplexer. Isochronal maps of the effective refractory period were determined from 62 epicardial sites and correlated with the activation maps. The ischemia occurring in the surviving epicardial layer prolonged refractoriness in a spatially nonuniform manner. The resulting pattern of refractoriness on the epicardial surface resembled concentric rings of isorefractoriness which increased in duration from the normal zone to the center of the ischemic zone. The formation of an arc of functional unidirectional conduction block occurred along the gradient of refractoriness and the exact location of the arc depended on the S1-S2 interval. When a short S1-S2 failed to induce reentry, fewer adjacent sites with sufficiently disparate refractoriness formed a smaller arc of block. A subsequent S3 encountered further nonuniformly shortened refractoriness (normal areas had shortened refractoriness greater than ischemic areas) and the arc of block was lengthened. This required a longer time for the wavefront to circulate around the arc. When it then reached the distal side of the arc, refractoriness had expired proximal to the arc and reentry occurred. Similarly, nonuniform shortening of refractoriness explained why one reentrant beat may or may not produce successive reentrant beats. Therefore, the spatial pattern of refractoriness forms the substrate for the arc of unidirectional conduction block that is fundamental to the development of ventricular reentry in this experimental model.     

兔左室跨壁电活动短期记忆的异质性特征

目的观察兔左室内、外膜侧心肌电活动动态恢复曲线、局部S1S2恢复曲线,以及短期记忆特性随刺激频率的变化。方法采用8只冠状动脉灌注兔左室楔形组织块标本,同步记录跨壁心电图和内、外膜侧心肌细胞动作电位,测量每一次搏动的动作电位时程。对标本经心内膜侧心尖部施加干扰向下扫描刺激方式刺激。首先给予基础刺激周长(BCL0)为2 000 ms 10次刺激后,改变BCL1刺激(自600～300 ms),观察恢复曲线整体图及其跨壁异质性。结果随刺激加快两种恢复曲线斜率均逐渐增大。但内膜侧斜率增大更为明显,随刺激加快内、外膜间差异具显著性(P<0.05)。动态恢复曲线斜率的改变较局部S1S2恢复曲线斜率更为明显。动态恢复曲线与S1S2恢复曲线斜率的夹角α值反映瞬时短期记忆现象,随BCL减小α值逐渐增大,且内膜侧增大更为明显(P<0.05)。结论兔左心室壁内膜侧的动态恢复曲线和局部S1S2恢复曲线斜率均较外膜侧大,内膜侧心肌的短期记忆现象更为明显,可能为起源于心内膜侧期前刺激所引起单向传导阻滞易损窗大于外膜侧的机制之一。     

Reentrant ventricular arrhythmias in the late myocardial infarction period. II. Burst pacing versus multiple premature stimulation in the induction of reentry

Isochronal maps of ventricular activation were analyzed in dogs 1 to 5 days after infarction utilizing a 64 channel multiplexer. Only dogs in which circus movement reentry could not be induced by a single premature stimulus were analyzed. Reentrant rhythms could be successfully induced equally by multiple (double or triple) premature stimuli and by burst pacing. Successive premature stimuli as well as successive beats during burst pacing resulted in progressively longer arcs of functional conduction block or slower circulating wave fronts, or both, that succeeded in reexciting myocardial zones on the proximal side of the arc of block to initiate reentry. However, for manifest reentry to be induced by burst pacing, the paced run had to be terminated after the beat that resulted in a critical degree of conduction delay. Otherwise, reentrant activation could be confined (concealed) by the subsequent paced wave front, which could also arrive earlier to the reentrant circuit zone of slow conduction resulting in block and interruption of reentry. Termination of a paced run after this beat would not result in reentry. If the paced run was extended past this beat, a new sequence of ventricular activation patterns characterized by progressively longer arcs of block or slower conduction, or both, developed again. The number of beats in a paced run that could initiate reentry varied with the cycle length of pacing, as well as in different experiments, and was difficult to standardize. It is therefore concluded that random burst pacing as a technique for induction of reentrant rhythms should probably be abandoned in favor of multiple premature stimulation.     

Concealed extrasystoles due to Wenckebach conduction delay within the reentry loop.

Long electrocardiographic strips were analyzed from an aged patient whose heart rhythm had periods of unifocal ventricular extrasystoles with fixed coupling intervals. Periods of gradual prolongation of the coupling interval finally led to omission of a ventricular premature beat. This sequence was repetitive and is considered to be the results of reentrant extrasystoles with a 3:2 Wenckebach type of conduction delay within the reentry loop. The mechanism of concealed conduction due to overlong propagation within the reentry loop is discussed.     

Concept of reentry versus automaticity

Arrhythmias can result from abnormal impulse initiation or conduction. Abnormal initiation results from either automatlcity or triggered activity. Enhanced automaticity may be due to a normal automatic mechanism (a normal property of the sinus node and specialized conducting fibers) or to an abnormal mechanism such as automaticity in depolarized fibers. Triggered activity is caused by afterdepolarizations that occur either during repolarization (early afterdepolarization) or after repolarization is complete (delayed afterdepolarization). Triggered activity due to delayed afterdepolarizations is dependent on critical heart rates. Overdrive pacing may distinguish between normal and abnormal automaticity. Antiarrhythmic drugs can alter arrhythmias that result from abnormal impulse initiation. To suppress an arrhythmia resulting from abnormal impulse generation, a drug may (1) suppress the abnormal automatic mechanism, i.e., specific effect on ionic current; (2) suppress afterdepolarizations; (3) depress conduction in tissue surrounding automatic focus; or (4) modify refractory period of tissue in and around automatic focus.Abnormal impulse conduction results in reentrant excitation. Conditions necessary for reentry include a combination of unidirectional block and slowed conduction. A reentrant mechanism can be determined by an anatomically defined circuit or solely by the functional properties of the tissue (leading circle mechanism). Circus movement reentry around an anatomic obstacle may respond to antiarrhythmic drugs differently from reentry caused by a leading circle mechanism. Initiation and perpetuation of a reentry mechanism depends on a delicate interplay between conduction velocity and duration of the functional refractory period in the reentry circuit. Drugs can prevent a reentry mechanism by (1) eliminating premature beats that initiate the mechanism; (2) reducing the disparity in effective refractory periods; (3) improving conduction, thereby preventing unidirectional block; (4) further depressing conduction in a part of the circuit producing a bidirectional block; and (5) lengthening the functional refractory period in the tachycardia circuit more than the total circuit time. The effectiveness of drugs on reentry depends on the electrophysiologic substrate contributing to the reentrant mechanism.All of these mechanisms cause arrhythmias in the in situ canine heart and probably occur in humans. However, clinical pacing techniques are not sufficiently discriminating to distinguish between arrhythmic mechanisms. Ability to inltiate ventricular tachycardia with 1 or more premature beats is suggestive of reentry but does not rule out triggered automaticity. Demonstration of continuous fragmented electrical activity before the first beat of tachycardia and perpetuation of such activity during tachycardia provides more definitive evidence for a reentry mechanism.     

Spontaneous termination of reentry after one cycle or short nonsustained runs. Role of oscillations and excess dispersion of refractoriness

This study describes factors that contribute to spontaneous termination of reentry lasting one to 10 cycles after induction by a single premature stimulus. Reentry was studied in vitro in rings of canine atrial tissue from around the tricuspid valve orifice. Activation was recorded from a circular array of 10 extracellular bipolar electrodes equally spaced around the ring. In some experiments, transmembrane or monophasic action potential recordings were made near critical sites. Termination of reentry within one cycle after induction was recorded 110 times in 11 of 35 experiments. Important factors contributing to termination were 1) an obligatory reversal of the activation sequence that resulted in a long coupling interval in the critical region beyond the site of unidirectional block after the premature stimulus and 2) much longer refractory periods limited to this critical region, which facilitated unidirectional block but contributed to termination when this region was first activated with a short coupling interval at the end of the first reentrant cycle. Termination of nonsustained reentry lasting longer than one cycle resulted from oscillations of conduction and refractoriness initiated by the abrupt shortening of cycle length after initiation of reentry. Oscillations of conduction resulted from interval-dependent conduction of reentrant impulses that encountered partially refractory tissue. For reentry to become sustained, the oscillations after induction of reentry must dampen. Thus, damped cycle length oscillations after induction may identify clinical tachycardias caused by reentry with a partially excitable gap.     

Electrocardiographic antecedents of primary ventricular fibrillation. Value of the R-on-T phenomenon in myocardial infarction.

Primary ventricular fibrillation was seen in 20 of 450 consecutive patients (4-4%) admitted within 24 hours after the onset of acute myocardial infarction. Compared with patients without primary ventricular fibrillation they showed a lower mean age group and a higher incidence of anterior infarction. Warning ventricular arrhythmias preceded primary ventricular fibrillation in 58% of cases. However, warning arrhythmias were also present in 55% of patients without primary ventricular fibrillation. The following mechanisms of initiation of primary ventricular fibrillation were seen. 1) In one patient, it was initiated by supraventricular premature beats showing aberrant intraventricular conduction. 2) In 2 patients, ventricular tachycardia degenerated into primary ventricular fibrillation. 3) In 17 patients, it was initiated by a ventricular premature beat; in 10 of these, the premature beat showed early coupling (RR/QT less than 1--the R-on-T phenomenon). However, ventricular premature beats showing the R-on-T phenomenon were also observed in 49% of patients without primary ventricular fibrillation. In 7, primary ventricular fibrillation was initiated by a late-coupled ventricular premature beat (RR/QT greater than 1); in 2, the very late coupling resulted in a ventricular fusion beat. The study suggests that warning arrhythmias and the R-on-T phenomenon are poor predictors of primary ventricular fibrillation in acute myocardial infarction. The observation that 41% of primary ventricular fibrillation was initiated by a late-coupled ventricular premature beat suggests that ventricular vulnerability during acute myocardial infarction may extend throughout most of the cardiac cycle and is not necessarily confined to the QT interval.     

Interdependence of modulated dispersion and tissue structure in the mechanism of unidirectional block

We previously showed that a premature stimulus can significantly alter vulnerability to arrhythmias by modulating spatial gradients of ventricular repolarization (ie, modulated dispersion). However, it is not clear if such changes in arrhythmia vulnerability can be attributed to the formation of an electrophysiological substrate for unidirectional block and what the potential role is of tissue structure in this process. Therefore, the main objective of the present study was to examine the concomitant effect repolarization gradients and tissue structure have on unidirectional block. Optical action potentials were recorded from 128 ventricular sites (1 cm(2)) in 8 Langendorff-perfused guinea pig hearts. Propagation was confined to the epicardial surface using an endocardial cryoablation procedure, and a 12-mm barrier with a 1.5-mm isthmus was etched with a laser onto the epicardium. A premature stimulus (S2) was delivered over a range of S1S2 coupling intervals to modulate repolarization gradients in a predictable fashion. When a second premature stimulus (S3) was delivered from the center of the isthmus, the occurrence and orientation of unidirectional block were highly dependent on repolarization gradients created by the S2 beat. In this model, a local repolarization gradient of 3.2 ms/mm was required for unidirectional block at this isthmus. In addition, the formation of unidirectional block was critically dependent on the presence of the source-sink mismatch imposed by the isthmus. These results may explain how the interplay between spatial heterogeneities of repolarization and tissue structure form a substrate for unidirectional block and reentry.