[SCD-FORUM] 53E: Dr. Pérez Riera to Dr. Ruth Kam

星期一十月 23 18:07:42 ART 2006

53E:  Dr. Pérez Riera  to Dr. Ruth Kam

尊敬的来自新加坡的Ruth Kam博士，以下是巴西圣保罗 
Andrés RIcardo Pérez RIera的答复。

动作电位（AP）1期虽时程短暂，但可观察到数种重要 
的离子流：Ito1、Ito2、IKATP、ICl.swell以及通过Na+/Ca2+交 
换体逆向Na+-Ca2+交换形成的Na+外流。

Ito1通道，亦称ItoA、对4-氨基吡啶(4-AP)敏感的非钙依 
赖性瞬时外向性电流、复极化初始阶段电流、不依于 
Ca2+、电压门控、电压依赖性非Ca2+依赖性瞬时外向性 
电流、Itof或Ito-fast，它是一种电压和时间依赖性电 
流，除决定复极化初始阶段AP形态外，还是动作电位 
时程(APD)及心室心肌复极异质性的物质基础。有证据 
表明，克隆的Kv4.3亚基与人类Ito1通道相似。Ito离子流 
密度由以下因素决定：年龄（新生儿缺如）、性别、 
心率（心动过缓时更显著）、细胞类型、局部心室壁 
厚度、心肌形态、病理环境。

Brugada综合征(BRS)作为一种无明显器质性改变的心脏 
病，是以快速Na+流为遗传基础的离子通道病；在该疾 
病病理状态下，复极2相期的早期外向钾电流（Ito1） 
和慢钙内向电流形成体表心电图的J点和ST段抬高改 
变，可触发2相折返(RF2)并引发多形室速(PVT) 、特发性 
室颤(IVF)。一些药物，如奎尼丁、丙吡胺、氟卡尼、 
阿义马林、普鲁卡因酰胺、吡西卡尼等，可通过影响 
Ito1而改变Brugada综合征患者V1-V3导联的J点和ST段水平。

极少情况下（8％），早期复极综合征(ERS) 表现为 
Brugada综合征的特征性心电图波形，易与Brugada综合征 
发生混淆，对此，结合临床有助于进行鉴别。

动作电位1期，即快速复极初期，体表心电图表现为J 
点（QRS终点、ST段起点），为快速Na+内流关闭和外向 K 
+流瞬时开放形成。

在动作电位的短暂1期，以下离子通道开放：

1) Ito1通道，亦称ItoA、对4-氨基吡啶敏感的非钙依赖 
性瞬时外向性电流、电压门控通道、电压依赖性非Ca2 
+依赖性瞬时外向性电流，因快速激活并快速失活， 
故又可称作Itof 或Ito-fast。该通道失活也具有时间依 
赖性。在人类， 已发现克隆的Kv4.3亚基是最主要的 
Ito1通道相似亚基(1)。

2) Ito2通道, 又称Itob、Ca2+激活电流、ICl.Ca、Ca2+激活氯 
电流、钙激活的瞬时外向氯电流、瞬时外向性电流成 
分、对4-氨基吡啶不敏感的瞬时外向电流、慢速激活 
电流、Ito-s或Ito-slow、4-氨基吡啶不敏感成分。

3) IKATP通道、ICl cAMP通道：细胞内ATP水平下降至一定 
程度时，IKATP会发生不同程度的激活；ICl cAMP即cAMP/腺 
苷酸环化酶激活的非时间依赖性氯电流。ATP敏感性钾 
电流（IKATP）的激活，可导致急性心肌缺血时的ST段 
抬高。

4)肿胀激活氯通道(ICl,swell):心脏肿胀激活氯通道的特 
征和功能与生理或病理条件相关。I(Cl,swell)广泛分布 
于心脏，可因静水压、渗透压改变引起的细胞容积增 
大而激活，也可被改变细胞膜压力的物质或直接的机 
械牵张激活。I(Cl,swell)具有外向整流特性，于平台期 
和静息电位相期逆转，在生理电压范围内表现为非时 
间依赖性；可导致动作电位时程缩短、去极化、细胞 
容积降低。激活I(Cl,swell)的刺激原同时可激活牵张激 
活阳离子通道，所以推断I(Cl,swell)是机械电反馈 
(mechanoelectric feedback)的潜在效应器。缺血或非缺血性 
扩张型心肌病的I(Cl,swell)激活可能发生在缺血和再灌 
注过程中。I(Cl,swell)在心律失常、心肌损伤、预激、 
心肌细胞凋亡中发挥作用，因此，该通道可能成为一 
个新的治疗靶点（2）。

5)通过Na+/Ca2+交换体反向Na+-Ca2+交换形成的Na+外流:肌膜 
Na+/Ca2+交换体受胞内Ca2+调节,位于Ca2+转运位点之外与Ca2 
+亲和力很高。 Ca2+调节位点位于Na+/Ca2+交换体蛋白的 
一个大的胞内环上。次级Ca2+ 调节通过正向Na+/Ca2+交 
换体或Ca2+流出方式进行。 Ca2+ 调节可以改变交换体 
的转运特征，而不仅仅是控制活性状态下交换体的结 
构。

影响动作电位1期各离子通道的特征

Ⅰ)Ito1通道，也可称作ItoA、对4-氨基吡啶敏感的非钙 
依赖性瞬时外向性电流、Itof 或Ito-fast，在动作电位 
快速复极初期（1期）激活。1期与体表心电图的J点相 
对应。Ito1通道是电压门控通道，当电压于0mV左右  
( +30mV 至-10mV)范围内变化时开放。Ito通道的激活与失 
活决定于瞬时电压，在-30Mv至+10mV范围内激活；该通 
道的失活也是时间依赖性的。

在新生儿没有发现Ito1，在犬类3-5月后才出现该电 
流，这与新生儿心外膜和M细胞上notch蛋白缺失现象相 
一致（年龄异质性）。

Brugada综合征在男性居多，这是由于男性Ito 较女性更 
为显著的缘故（3-4）。

猝死综合征（SUDS）在男性居多，但一个欧洲大家系 
表现与此相异，该家系存在一个错义突变——R367H， 
以往认为此突变与SUDS相关，这表明导致性别差异的 
原因非此突变而是其他因素（5）。据AntzelevItch等研 
究，心室肌Ito1 通道分布的不均衡的后果是（6）：

1）  ST段改变，可以表现为J波、房室交界波、预激 
波、Osborn波、驼峰征、峰样偏移（hump-like deflection） 
等严重低温时的特征性表现。J波并非严重低温心脏 
所特有，也可见于其他与低温无关的临床状态，如急 
性脑损伤（蛛网膜下腔出血）(7)、可卡因过量(8)、心 
脏骤停、颈部交感神经系统紊乱、高钙血症（9）及 
Brugada综合征。

2）  药物敏感性不同：乙酰胆碱、异丙肾上腺素、Ca2 
+拮抗剂、Na+通道阻滞剂、钾通道开放剂、胺碘酮。

3）  心外膜心肌细胞动作电位时程的心率依赖性更 
强。较之心内膜心肌细胞动作电位，心外膜心肌细胞 
动作电位的0期振幅较小、1期复极更显著、2期振幅比 
0期大。与心内膜动作电位不同，心外膜动作电位表 
现为"尖峰一穹窿"(spike-and-dome)形态,随心率减慢而逐 
步增强（10）。

4）  心外膜细胞的动作电位在T波对K+改变更加敏感。 
缓慢激活延迟整流钾电流(IKs) 的异质性造成的电压梯 
度形成体表心电图的T波，T波的极性和宽度受通过缝 
隙连接形成的细胞间耦联较大。K+通过影响快速激活 
延迟整流钾电流(IKr)而影响T波形态。长QT综合征的IKs ,  
IKr和I(Na) (快钠电流)（分别对应LQT1, LQT2、LQT3）表现 
出特征性QT间期和T波改变；LQT1的QT间期延长，T波无 
变宽（？译者注：LQT1的典型特征是基底部宽大）； 
在较强心外膜Ito 背景下的I(Na)加速失活导致严重程度 
不一的ST段抬高（Brugada样表型）。IKATP的激活引起急 
性缺血期的ST段抬高。

5）  超常期只在心外膜细胞出现，心内膜则无。

6）  在"M"细胞，Ito1通道只存在于接近心外膜的细 
胞，接近心室心内膜的细胞则无。

心室复极化初期的跨壁电压梯度是心外膜Ito介导的AP 
切迹造成的（心内膜上无），在体表心电图上表现为 
J波。J波与早复极综合征（ERS）、 Brugada综合征等疾 
病相关。发生在Brugada综合征和急性心肌缺血的ST段抬 
高，不能完全以经典的“损伤电流”由损伤心肌向非 
损伤心肌流动的假说来解释，由心外膜动作电位的穹 
隆缺失导致的可能性更大。

T波是跨室壁复极离散度存在的标志。

“R-on-T”现象（室性早搏落在T波上）可能是由于复 
极化后较早阶段跨室壁产生RF2造成的，可引起PVT或VF  
(11)。

Ito,IK,IKATP,IK-Ach和延迟整流钾电流(IKS,IKr和IKur)可被奎 
尼丁阻断。此IA类药物通过影响钠离子流的摄取和释 
放（4-8秒）降低电位变化的最大速率，同时通过阻滞 
1期－3期各种外向钾电流而延长动作电位时程，从而 
延长有效不应期，增加JTc和QTc间期，形成早期后除极 
(EADs)；同时可形成触发活动，易于发生TdP。对奎尼丁 
和丙吡胺阻滞Ito1的机制的理解非常重要，其他抗心 
律失常药物如普鲁卡因酰胺、阿义马林没有这种功 
能。这些差异在Brugada综合征的PVT、VF形成过程中非常 
重要。由于非特异性阻滞钾通道，奎尼丁可以减少心 
律失常的复发，此外，抗迷走神经（M2受体阻滞）和 
兴奋交感神经作用可以促进复极化进程。口服奎尼丁 
可用来治疗Brugada综合征的“电风暴”(electrical storm) 
(12-13)。

心率较慢时Ito1更为显著，形成更大的心电图切迹； 
Ito1在动作电位早期起重要作用，影响2期、平台或圆 
顶，从而影响动作电位时程。在遗传性或盐诱导高血 
压、肺动脉阻塞性肥厚、急性心肌梗死后21天、心衰 
（病理生理异质性）情况下Ito1电流密度降低，使动 
作电位时程延长(14)。后者导致明显的Ito1电流密度降 
低及动作电位时程延长，但具体机制不清。果蝇Shal 
基因的异构体——K+通道α亚基，极有可能参与Ito或 
其中部分成分的形成 (15)。

Ⅱ) Ito2,又称ItoB、Ca2+激活电流、ICl.Ca,Ca2+激活氯电 
流、钙通道激活氯电流、对4-氨基吡啶不敏感的氯离 
子形成的瞬时外向电流、慢速激活电流、Ito-s 或Ito- 
slow。Ito2存在证据部分建立在几种氯离子阻滞剂药物 
效应基础上。ICl.Ca2+在生理条件下引起心肌动作电位 
的复极化，主要由肌质网(sarcoplasmic reticulum)释放的Ca2 
+激活。心脏主要通过L型钙通道释放Ca2+，但近来证据 
表明，电压和/或钠电流激活的通过Na+/Ca2+ 交换体的 
反向Na+-Ca2+交换也起到一定作用(16)。Ito2可以被以下 
因素激活：

1)   细胞内Ca2+浓度的升高，继而释放出更多的肌浆网 
阳离子(17)；

2)   乙酰胆碱使细胞膜超极化、动作电位时程缩短， 
后者见于窦房结、房室结和心房心肌；

3)   花生烯酸及其代谢物。

Ito2可以被4-乙酰胺基-4-异硫氐-2,2-二磺酸(SITS)、4， 
4′-二硫氰-2，2′二磺基芪(DIDS)阻滞(18)。

Ⅲ) IKATP通道、ICl cAMP通道：细胞内ATP水平下降至一定 
程度时，IKATP会发生不同程度的激活；ICl cAMP即cAMP/腺 
苷酸环化酶激活的非时间依赖性氯电流。ATP敏感性钾 
电流（IKATP）的激活，可导致急性心肌缺血时的ST段 
抬高。

Ⅳ) 肿胀激活氯通道(ICl,swell):心脏肿胀激活氯通道的 
特征和功能与生理或病理条件相关。I(Cl,swell)广泛分 
布于心脏，可因静水压、渗透压改变引起的细胞容积 
增大而激活，也可被改变细胞膜压力的物质或直接的 
机械牵张激活。I(Cl,swell)具有外向整流特性，于平台 
期和静息电位期逆转，在生理电压范围内表现为非时 
间依赖性；可导致动作电位时程缩短、去极化、细胞 
容积降低。激活I(Cl,swell)的刺激原同时可激活牵张激 
活阳离子通道，所以推断I(Cl,swell)是机电反馈 
(mechanoelectric feedback)的潜在效应器。缺血或非缺血性 
扩张型心肌病的I(Cl,swell)激活可能发生在缺血和再灌 
注过程中。I(Cl,swell)在心律失常、心肌损伤、预激、 
心肌细胞凋亡中发挥作用，因此，该通道可能成为一 
个新的治疗靶点（2）；该通道可以被9-蒽甲酸（9- 
anthracene carboxylic acid）阻滞，I(Cl,swell)可以缩短动作 
电位时程。

Ⅴ)通过Na+/Ca2+交换体反向Na+-Ca2+交换形成的Na+外流。3 
个Na+交换1个Ca2+。Na+移动方向依赖于膜电位和细胞内外 
Na+ 和Ca2+浓度。Na+/Ca2+ 交换体介导的这种离子流可以 
触发肌浆网的Ca2+释放。

Ito1电流特征及在心室复极中的作用

不是所有的心肌细胞都具备Ito1电流,其浓度或密度取 
决于所研究的区域。

心肌细胞出现在AP第一相期的突出切迹是此电流密度 
高的特征，表现为尖峰-穹隆构形态。所以在心室肌 
细胞中，仅在快浦肯野氏纤维、中层心肌细胞的M细 
胞，还有那些外膜下细胞才出现明显的切迹（区域异 
质性）。

当我们考虑肌层厚度时,心室肌细胞AP和收缩细胞的第 
1至3相期有显著差异。所以，除了存在于心脏传导系 
统的浦肯野氏细胞，我们要区分三个区域。Ito1电流 
在心室肌细胞层的不均匀分布会造成：

1）特发性J波，融合波，损伤电位，迟发电位，Osborn 
波，驼峰信号或峰样转折，这些可能在体温过低 
(19)、脑病变(20)、昏迷、高钙血症(21)、大量摄取可卡 
因(22)和其他一些体表ECG的J点区发现。如在无结构性 
心脏疾病患者的右胸导联V1-V2或从V1至V3出现，可作为 
Brugada的标志。有很少（8%的病例）的报道在运动员出 
现，可作为良性早期复极综合征（ERS）（23）；

2）对不同药物的不同敏感度：乙酰胆碱，异丙肾上 
腺素，Ca2+拮抗剂，Na+通道阻断剂，K+电流的启开剂和 
胺碘酮；
    3) 与心率变化相关心外膜细胞APD的较高依赖；
    4) 心外膜细胞AP对K+更敏感从而对T波极性外观的影 
响；
    5) 仅在心外膜而不在心内膜出现的超常相；
    6)  与左室相比，Ito1所依赖的第一相期的深度在右 
室更显著。这也解释了急性缺血条件下触发的心律失 
常对右室损伤更强 (24)。

在心房细胞中，迷走神经释放乙酰胆碱开通Ito通道。 
这些通道与肌纤维膜摄取乙酰胆碱是偶联的。
    BrS是一种离子通道病种或是通道病(25)。
    在BrS中主要受累通道是快Na+通道，其次是早期外 
流的K+电流，L型慢或长效钙通道ICa-L型 ICa2+-L。其他 
受影响较小的通道是Ito2, IK-ATP和IKr。
    在RVOT的心外膜而不是在心内膜出现的AP深切迹或 
穹峰形态是决定2相期持续时间的主要原因，能占到 
大约70%左右，导致外膜APD较心内膜的显著缩短。这一 
现象起源于心室透壁梯度，是因为J点和右胸前导联V1- 
V2或房室隔V1 至 V3(Brugada 信号)ST段的的弓形抬高（弓 
形至顶点），偶伴随T波倒置(26)，从而在ECG的QRS波群 
后出现的J波穹隆状转折。心室复极化初期的透壁电 
压梯度起源于心外膜，而不是心内膜的瞬时钾电流外 
流介导的AP切迹，这对形成ECG的J波很重要。

另外J点和ST段抬高的多样性在BrS中也可能观察到，这 
是很少见的特征，即鞍马型，也恰恰是RV心外膜中的 
尖峰-穹隆、平台或第2相期的部分缺失所形成。 这种 
情况下的离散度是最小的，出现PVT/Vf的可能性很小 
(27)。在无结构性心脏疾病的患者，如果没有低体 
温、缺血或电解质紊乱，在下壁导联很少见到弓形J 
点和ST段抬高， 这就是所谓的不典型Brugada或隐匿型 
(27-28-29-30-31)。某些快Na+通道的阻滞剂，例如IA 和 IC 
类抗心律失常药物：阿义马灵, 普鲁卡因胺，普罗帕 
酮，氟卡胺，吡西卡尼和乙酰胆碱（迷走神经刺激） 
(32)，增强RV心外膜细胞中第1时相的切迹，随后缩短 
穹顶或第2时相间期。这些情况会造成心室肌细胞不 
均匀和更大的复极离散度。在心内膜下和心外膜下细 
胞之间， 2相折返产生的基质，有助于确定BrS中IPVT/ 
IVF的机制。外向电流移动显著时，在心外膜心肌层出 
现提早复极，造成的电压梯度 促进2相折返的发生。

氟卡胺缩短先天长QT综合征变异3型（(LQT3)的QT间期， 
因此建议给予口服治疗此型。另外，在这些患者中能 
引起“Brugada样”J点和ST段抬高(33)。

氟卡胺可以诱导LQT3患者ST段抬高，引发考虑氟卡胺治 
疗相关安全性的问题，证明LQT3 和BrS之间存在表型重叠 
(34)。低剂量口服氟卡胺能持续缩短QTc间期，并使伴随 
SCN5A:DeltaKPQ突变 的LQT3患者T波形态正常化(35)。
    IB类钠通道阻滞剂：慢心律明显缩短QTc，所以能预 
防TdP的出现。奇怪的是，在先天性LQTS中该药物的剂 
量不缩短长QT，而影响K+电流(HERG 的K+ 电流缺失)或LQTS 
变异2型。慢心律对LQT3的QT间期缩短是最有效的，也 
有效地减少复极的跨壁离散度(TDR)和预防Td P在所有 
LQT1, LQT2 和LQT3中的产生，显示它可作为LQT1 和 LQT2的 
潜在治疗(36)。

使用抑制Ito1电流的药物或刺激Ca2+内流能降低J点和ST 
段抬高的程度和改善复极化。所以，Ito1阻滞剂4-氨基 
吡啶(1-2mmol/L) 或奎尼丁(5micromol/L)增高第2相期或穹-峰 
持续间期并使ST段抬高正常化，从而预防TV/FV(37)。口 
服奎尼丁抑制BsS患者的电风暴和预防VF事件(38)。口服 
奎尼丁减少由Ito1介导的第1时相幅度，使ST段在右胸 
导联或从V1 至V3导联的抬高正常化。IA类药物阻滞Na 
+电流和增加Ito1，例如奎尼丁和吡二丙胺，改善BrS的 
ECG。同类药物例如普鲁卡因胺和阿吗灵专门阻滞Na+电 
流而不影响Ito1电流，从而使BrS患者的ST段抬高恶化并 
触发致命快速心律失常（39）。口服奎尼丁引起BrS患者 
ECG 正常化(40)。有文献报道使用该药物患者恶化  
(41)，也与肾上腺素beta1激动剂和副交感神经阻断剂的 
使用相关(42)。轻度缺血和迷走神经紧张可以对BrS产 
生电生理作用，抬高ST段和触发PVT/IVF突然发作。这些 
结果表明Brugada患者存在缺血时处于SCD的高危状态下 
(43)。
     相反，异丙肾上腺素恢复心外膜的第2相或穹峰， 
减少J点和ST段抬高。血管舒张剂西洛他唑通过相似机 
理作用：增高ICa+2-L和有效降低PVT/VF事件(44)。因此， 
异丙肾上腺素是BrS患者进行ES时的选择，与采用全身 
麻醉和心肺搭桥减少ST段在右胸导的抬高以及短配对 
间期早搏消失以消除VF的ES危象原理相同(45)。这些先 
兆事件包括不良事件再发和多重VF 或VT的增多：每天 
20次或更多，或4小时甚或每小时发作，最终在 BrS 中 
观察到。
     BrS 的ECG图形可能是间歇的，并成为由某些IA类 
（普鲁卡因胺和阿吗灵）和IC类（氟卡胺）抗心律不 
齐药和夜间迷走神经紧张引起隐匿病例的证明(46)。

这些事实支持J 点和 ST段抬高以及随后触发的PVT/VF是 
明显依赖Ito电流和RV心外膜的尖峰-穹隆形态(47)。

早期复极综合征(ERS),是正常的良性变异，在人群中发 
现占1%-2%，在急诊室胸痛患者中可发现13%-48%，J点和ST 
段抬高通常出现更深的凹度，在肢体导联中>/=1mm和在 
胸导>/=2，至少在两个邻近导联伴有切迹或QRS波群的R 
波末端顿挫，结果T波电压升高和V2 -V4中间导联的电 
极一致。ERS 最重要的鉴别诊断是心包炎、急性心梗 
和急性冠脉综合征，以免采取纤维蛋白溶解的错误治 
疗和不必要的血管造影术(49)。对可疑病例，除仔细 
追查既往病历外，必须采取以下检查：超声心动图， 
酶和肌钙蛋白 I 的检测(50)。
     Ito1电流在三种心脏细胞类型之间有明显的差异和 
梯度，尤其在Epi 和Endo 细胞中。这些差异在右心室电 
异质性有显著特征，可以是右室心律失常形成的重要 
离子基础和前提条件，包括BrS和其他疾病(51)。

ERS也可与心室壁瘤混淆。 ERS在运动员很常见，可以 
观察到80%的病例。很少（8%）的ECG构型使人联想到 
Brugada或类Brugada图。在这些病例中，下列元素是支持 
ERS的（Bianco修改）(23)。

1)  家族史：ERS阴性和BrS中经常发生SCD；

2)  心率：ERS中有心律过缓趋势。在BrS中，心率通常 
是正常的；

3)    SAQRS: ERS中趋向垂直，BrSe中9%出现末端偏左；

4)    PR 间期：ERS趋向短暂或正常和轻度降低。在BrS中 
是长的和50%的病例出现由HV增高引起的I度房室传导阻 
滞；

5)    QRS间期：BrS (110msec +/-2msec)比运动员和ERS携带者 
更大(90msec+/-1msec)；

6)  胸导临界区：ERS由于在纵轴逆钟向转位，通常出 
现急转。在BrS中观察不到；

7)  ST段抬高程度：BrS(4.4+/-0.7mm)比运动员(2.3+/-0.6mm)或 
非运动员(1.2+/-0.8mm) ERS携带者更大；

8)  种族：ERS通常黑种人，BrS通常黄种人；

9)  U波：ERS由于心动过缓在V3导明显可见。在BrS中不 
通常见。

下列在BrS 和良性ERS中共存：
1)  运动能使ST段抬高正常化；
2)  异丙肾上腺素能使ST段抬高正常化；

3)    在寄生虫性皮肤病中更常见；

4)  主要在年轻成人和50岁以下老人（54）；

5)  两者都能使ST段从凹面抬高到顶端，随后持续出现 
鞍马型。

Ito电流对早复极时相的外观有决定性作用。另外，它 
影响其他离子在下一时相（第2相）中的外流和内流 
以及AP不应期。

参考文献附后

车文良  江瑛 翻译   李翠兰校对

Dear Dr Ruth Kam from Singapore. Here Andrés Ricardo Pérez Riera from
Sao Paulo Brazil.

During phase 1 of AP, although brief, it is possible to observe
several categories of important ion channels for its profile
determination: Ito1, Ito2, IKATP, ICl.swell and Na+ outward movement
through the Na+/Ca2+ exchanger operating in reverse mode (Na+/Ca2+).

The Ito1 channel, ItoA, transient outward current sensitive to
4-aminopyridine (4-AP), calcium-independent transient outward current,
initial repolarization, Ca2+ independent,  voltage-operated channel,
voltage-dependent Ca2+ independent transient outward current, Itof or
Io-fast . It is a  of voltage and time dependent, besides determining
the initial phase configuration of repolarization of the AP profile,
it is fundamental in its duration (APD) and in determining the
repolarization heterogeneity in the ventricular myocardium thickness.

Some evidence point that the cloned subunit Kv4.3 is similar to the  
human Ito1.

The Ito current density depends on a number of factors: age group
(absent in newborn babies), sex, heart rate (more noticeable in
bradycardia), cell type studied, localization in ventricular wall
thickness, topography of myocardium and pathologic circumstances with
or without organic substrate.

In BrS, an entity without apparently  structural heart disease, with
the fast Na+ current as genetic determinant of the channelopathy, the
initial outward K+ Ito1 current and the slow inward Ca2+ current in
phase 2 are essential regarding J point and ST segment level in
surface ECG, and consequently, in triggering reentry in phase 2(RF2),
and triggering bursts of PVT/IVF.

Several drugs, such as quinidine, disopyramide, flecainide, ajmaline,
procainamide, pilsicainide, etc., by modifying the functional state of
the Ito1 current, alter J point and ST segment level in right
precordial leads or from V1 to V3 in BrS.

Rarely (8% of cases), the early repolarization syndrome (ERS) may be
confused with BrS, for presenting a Brugada-like electrocardiographic
pattern. There are clinical-electrocardiographic elements that help in
making this important differentiation.
Phase 1 of  AP, of initial, early or fast repolarization, coincides
with J point in surface ECG (end of QRS complex and beginning of ST
segment), being essentially dependent on fast inward Na+ current
closure and transient opening of outward K+ currents.

During the short phase 1, several channels get started:

1)       Ito1, ItoA, transient outward current sensitive to
4-aminopyridine (4-AP), calcium-independent transient outward current,
voltage-operated channel, voltage-dependent Ca2+ independent transient
outward current, Itof or Ito-fast since it has fast activation and
inactivation kinetics. Inactivation is also time-dependent. The Kv4.3
current has been identified as the major and main cloned subunit
similar to the Ito1 current in humans(1);

2)       Ito2, Itob, Ca2+-activated current, ICl.Ca, Ca2+ activated
chloride (Cl-) current, calcium-activated transient outward chloride
current, current component of the transient outward current,
4-aminopyridine resistant transient outward current - carried by Cl-
ions, slow activation current, Ito-s or Ito-slow, 4-AP-resistant
component;

3)       Variant activated by the fall in intracellular supply of ATP
when it reaches a certain critical level (IKATP); CLcAMP or
time-independent chloride Cl- current regulated by the cAMP/adenylate
cyclase pathway. Activation of the ATP-sensitive potassium current,
IKATP, is sufficient to cause ST elevation during acute ischemia;

4)       Swelling-activated Cl- current (ICl(swell)): Characteristics
and functions of the cardiac swelling-activated Cl current  are
considered in physiologic and pathophysiologic settings. I(Cl,swell)
is broadly distributed throughout the heart and is stimulated not only
by osmotic and hydrostatic increases in cell volume, but also by
agents that alter membrane tension and direct mechanical stretch. The
current is outwardly rectifying, reverses between the plateau and
resting potentials, and is time-independent over the physiologic
voltage range. Consequently, I(Cl,swell) shortens APD, depolarizes,
and acts to decrease cell volume. Because it is activated by stimuli
that also activate cation stretch-activated channels, I(Cl,swell)
should be considered as a potential effector of mechanoelectrical
feedback. I(Cl,swell) is activated in ischemic and non-ischemic
dilated cardiomyopathies and perhaps during ischemia and reperfusion.
The current plays a role in arrhythmogenesis, myocardial injury,
preconditioning, and apoptosis of myocytes. As a result, I(Cl,swell)
potentially is a novel therapeutic target(2);

5)       The Na+ outward movement through the Na+/Ca2+ exchanger
operating in reverse mode: The sarcolemmal Na+/Ca2+ exchanger is
regulated by intracellular Ca2+ at a high affinity Ca2+ binding site
separate from the Ca2+ transport site. The Ca2+  regulatory site is
located on the large intracellular loop of the Na+/Ca2+ exchange
protein.  Secondary Ca2+ regulation with the exchanger in the forward
or Ca2+ efflux mode. The Ca2+ regulation modifies transport properties
and does not only control the fraction of exchangers in an active
state.

CHARACTERISTICS OF MODALITIES OF THE CHANNELS THAT AFFECT PHASE 1 OF AP

Ito1, IA, transient outward K+ current 1, 4-aminopyridine or
4-AP-sensitive current, the Ca2+ independent Ito1, activated during
phase 1, Itof or Ito-fast This channel activity occurs in phase 1 of
AP in early or fast repolarization. Phase 1 coincides with the J point
of surface ECG Ito1 channel is voltage-operated, and therefore, it is
opened by changes in voltage in a range around the 0mV (from +30mV to
-10mV). The Ito channel is activated or inactivated, depending on
instantaneous voltage. Thus, the activation is processed in the band
between - 30mV and +10mV. The inactivation process is time-dependent,
too.

The Ito1 current is not found in newborn babies, and it only becomes
manifest after three to five months in dogs, which explains the
absence of notch in epicardial and M cells in newborn babies (age
heterogeneity).

The predominance of the Brugada phenotype in males is a result of the
presence of a more prominent Ito in males versus females(3-4).

Male predominance of the phenotype observed in SUDS does not apply to
a large European family with a missense mutation, R367H, previously
associated with SUDS suggesting that factors other than the specific
mutation determine the gender distinction(5). According to
Antzelevitch et al, the consequences of this unequal distribution of
Ito1 channels in ventricular myocardial thickness are(6)

1) Alterations of the ST segment, variously referred to as J wave,
junctional wave, late delta wave, Osborn wave, camel-hump sign, and
hump-like deflection found characteristically in severe hypothermia. J
wave is not pathognomonic of sever hypothermia and also it has also
been described in other clinical entities not associated with
hypothermia, such as acute brain injury (subarachnoid hemorrhage)(7);,
accidental cocaine overdose(8),  cardiac arrest, dysfunction of
cervical sympathetic system, hypercalcemia(9) and BrS.

2) Unequal sensitivity to drugs: acetylcholine, isoproterenol, Ca2+
antagonists, Na+ channel blockers, K+ channel openers, amiodarone;

3) Greater dependence of AP duration in epicardial cells regarding
heart rate. The epicardial AP when compared with that of endocardium
shows a smaller phase 0 amplitude, a much more prominent phase 1, and
a phase 2 amplitude that is greater than that of phase 0. Epicardial
APs, unlike those of endocardium, display a "spike and dome"
morphology that becomes progressively more accentuated at slower
stimulation rates (10);

4) AP of epicardial cells more sensitive to K+: changes in T wave.
Voltage gradients created by heterogeneities of the slow-delayed
rectifier potassium current( IKs) inscribe the T wave and  T-wave
polarity and width are strongly influenced by the degree of
intercellular coupling through gap-junctions. Changes in K+ modulate
the T wave through their effect on the rapid-delayed rectifier IKr.
Alterations of IKs , IKr, I and I(Na) (fast sodium current) in long-QT
syndrome (LQT1, LQT2, and LQT3, respectively) are reflected in
characteristic QT-interval and T-wave changes; LQT1 prolongs QT
without widening the T wave. Accelerated inactivation of I(Na) on the
background of large epicardial I(to) results in ST elevation (Brugada
phenotype) that reflects the degree of severity. Activation of the
ATP-sensitive potassium current, I(K(ATP)), is sufficient to cause ST
elevation during acute ischemia.;

5) Presence of supernormal phase just in the epicardium, and not in
the endocardium;

6) In the "M" cells, the Ito1 channel is found only in the epicardium,
and not in the ventricular endocardium.

A transmural voltage gradient during initial ventricular
repolarization, which results from the presence of a prominent Ito
mediated AP notch in the epicardium, but not endocardium, manifests as
a J-wave on the ECG. The J-wave is associated with the ERS, BrS and
others entities. ST-segment elevation, as seen in BrS and acute
myocardial ischemia, cannot be fully explained by using the classic
concept of an "injury current" that flows from injured to uninjured
myocardium. Rather, ST-segment elevation may be largely secondary to a
loss of the AP dome in the epicardium, but not endocardium.

The T-wave is a symbol of transmural dispersion of repolarization.

The R-on-T phenomenon (an extrasystole originating on the T-wave of a
preceding ventricular beat) is probably due to transmural propagation
of F2R early after depolarization that could potentially initiate
PVT/VF (11).

The Ito, inward rectifier IK, IKATP,  IK-Ach  and delayed rectifier
potassium channels ( IKS, IKr and IKur) are blocked by quinidine. This
drug of the IA class, with intermediate kinetics of uptake and release
with the Na+ current (4 to 8 seconds), moderately reduces maximal
velocity and it extends AP, and consequently, the effective refractory
period by block of the multiple outward K+ currents in phases 1 to 3,
increasing JTc and QTc intervals and fostering the appearance of EADs;
and these in turn, foster the triggered activity that will lead to a
higher tendency to TdP. It is very important understand that quinidine
and disopyramide block the Ito1 current, but other members of the
class don't, such as procainamide and ajmaline. This subtle difference
is very significant in PVT/VF genesis in BrS. By its nonspecific
potassium channel blocking action, quinidine may also reduce
arrhythmia recurrence. Additionally, it could improve repolarization
due to its vagolytic effect (M2 muscarinic receptor block) and to the
exacerbation of reflex sympathetic tone.

  Oral quinidine has a role in the treatment of electrical storm (ES)
in BrS(12-13).

The Ito1 current is more visible, causing a greater notch, during slow
cardiac rates, and it plays an important role in the early phase of AP
and it influences on phase 2, plateau or dome, and consequently, in AP
duration (APD).

Ito1 current density is very reduced and consequently, it extends AP
in genetically-conditioned and salt-induced high blood pressure, in
after-constriction hypertrophy of pulmonary artery, 21 days after
acute infarction by remodeling and in heart failure (pathologic
heterogeneity) (14).

The latter leads to a significant reduction of Ito1 density and a
marked prolongation in APD. The mechanism of this reduction is
unknown. The alpha subunit of the K+ current, a homologue of the
Drosophila Shal family, is very probably an encoder of all or a part
of the native Ito current (15).

II) Ito2, ItoB, Ca2+ activated channel, ICl.Ca, Ca2+ activated
chloride (Cl-) current, Ca2+ channel activated chloride (Cl-) current,
4-aminopyridine-resistant transient outward current carried by Cl-
ions, slow activation Ito-s or Ito-slow current. The evidence of the
Ito2 current existence is partially founded on the pharmacological
effect of several Cl- current blockers. The Ca2+-activated Cl(-)
current [I(Cl(Ca2+] contributes to the repolarization of the cardiac
AP under physiological conditions. I(Cl Ca2+) is known to be primarily
activated by Ca2+ release from the sarcoplasmic reticulum (SR). L-type
Ca2+ current represents the major trigger for Ca2+ release in the
heart. Recent evidence, however, suggests that Ca2+ entry via
reverse-mode Na+/Ca2+ exchange promoted by voltage and/or Na+ current
may also play a role (16). The Ito2 channel could be activated by:

1)       Increase in intracellular Ca2+ concentration, which in turn
releases the sarcoplasmic reticulum cation(17);

2)       Acetylcholine that hyperpolarizes potential and shortens AP.
The latter is found in the sinus node, AV node and atrial muscles;

3)       Arachidonic acid and its metabolites.

The Ito2 channel is blocked by disulphonic stilbenes derivatives
(SITS-DIDS) (18);

III) Variant activated by fall in ATP supply when it reaches a given
critical level (IK ATP), CLcAMP, or time-independent chloride Cl-
current regulated by the cAMP/adenylate cyclase pathway. Activation of
the ATP-sensitive potassium current, IKATP, is sufficient to cause ST
elevation during acute ischemia;

IV) Swelling-activated Cl- current or ICl-swell. Characteristics and
functions of the cardiac swelling-activated Cl current or ICl-swell
are considered in physiologic and pathophysiologic settings. ICl-swell
is broadly distributed throughout the heart and is stimulated not only
by osmotic and hydrostatic increases in cell volume, but also by
agents that alter membrane tension and direct mechanical stretch. The
current is outwardly rectifying, reverses between the plateau and
resting potentials and is time-independent over the physiologic
voltage range. Consequently, I Cl-swell shortens APD, depolarizes, and
acts to decrease cell volume. Because it is activated by stimuli that
also activate cation stretch-activated channels, ICl-swell should be
considered as a potential effector of mechanoelectrical feedback.
ICl-swell is activated in ischemic and non-ischemic dilated
cardiomyopathies and perhaps during ischemia and reperfusion.
ICl-swell  plays a role in arrhythmogenesis, myocardial injury,
preconditioning, and apoptosis of myocytes. As a result, ICl-swell
potentially is a novel therapeutic target.() This channel is inhibited
by 9-anthracene carboxylic acid. Its activation causes AP shortening;

V) Na+ outward movement through the Na+/Ca2+ exchanger operating in
reverse mode.

This mechanism exchanges 3 Na+ cations for 1 of Ca2+. The direction of
the Na+ movement depends on membrane potential and intra and
extracellular Na+ and Ca2+ concentration. The inflow mediated by this
current of Na+/Ca2+ exchange can trigger Ca2+ release in the
sarcoplasmic reticulum system.

CHARACTERISTICS AND ROLE OF THE Ito1 CURRENT  IN VENTRICULAR  
REPOLARIZATION

Not all of the myocardial cells have the Ito1 current and its
concentration or density depends on the area being studied.

The myocardial cells that have a high density of this channel are
characterized for presenting a prominent notch in phase 1 of AP,
showing a profile with a spike-and-dome configuration. Thus, in the
ventricular myocardium, only the fast Purkinje fibers, the M cells of
the middle myocardium, and those of the subepicardium have a
significant notch (regional heterogeneity).

There are marked differences in phases 1 to 3 in ventricular
myocardium cells AP and contractile cells when we consider thickness.
Thus, we distinguish three areas besides the Purkinje cells present in
the cardiac conduction system. This unequal distribution of the Ito1
current in ventricular myocardial thickness is responsible for:

1)       Idiopathic J wave, Junctional wave, injury potential, late d,
Osborn wave, camel-hump sign or hump-like deflection, which could
possibly be found in the J point region of surface ECG in
hypothermia(19),  brain lesion(20), over come coma, hypercalcemia(21),
massive ingestion of cocaine(22), and others. When present in right
precordial leads V1-V2 or from V1 to V3 in a patient without
structural heart disease, it is known as Brugada sign. Rarely (8% of
cases) it has been reported in the athlete as a benign Early
Repolarization Syndrome (ERS) (23);

2)       Unequal sensitivity to different drugs: acetylcholine,
isoproterenol, Ca2+ antagonists, Na+ current blockers, K+ current
openers and amiodarone;

3)       Higher dependency of APD of epicardial cells in relation to
heart rate changes;

4)       Epicardial cellular AP, more sensitive to K+, and
consequently, there are changes in the aspect of T wave polarity;

5)       Presence of supernormal phase only in the epicardium and not
in the endocardium;

6)       The depth of phase 1 Ito1 dependent is more marked in the
right ventricle (RV) when compared to the left one, which explains the
higher vulnerability of the RV in arrhythmias triggering in acute
ischemia conditions(24).

In atrial cells, there are Ito currents that are opened by vagal
acetylcholine release. These currents are coupled in the acetylcholine
uptake in the sarcolemma.

BrS is considered an ion channel entity or channelopathy (25).

The main affected channels in the BrS are primarily the fast Na+
current, and secondarily the initial outward K+ current, and the
L-type slow or long-lasting calcium channel ICa-L type ICa2+-L. Others
channels affected with minor importance are Ito2, IK-ATP and IKr.

The presence of a deeply notched AP or with spike-and-dome
configuration in the epicardium of the RVOT, but not in the
endocardium, is responsible for the duration of the dome or phase 2
lasting approximately a 70% less, causing a marked decrease in APD in
the epicardium in relation to the endocardium in ventricular wall
thickness of the RVOT. The phenomenon originates a ventricular
transmural gradient due to the coved type elevation( convex to the
top) of the J point and the ST segment in the right precordial leads
V1-V2 or on anteroseptal wall V1 to V3 (Brugada sign), sometimes
followed by  inverted T wave(26).. The J wave is a deflection with a
dome that appears on the ECG after the QRS complex. A transmural
voltage gradient during initial ventricular repolarization, which
results from the presence of a prominent AP notch mediated by the
transient outward potassium current or initial outward K+ current in
epicardium but not endocardium, is responsible for the registration of
the J wave on the ECG.

Another variety of J point and ST segment elevation that may be
observed in BrS is a less characteristic one, that of the saddleback
type, conditioned by just a partial loss of dome, plateau or phase 2
in the RV epicardium. In it, the degree of dispersion is minimal, with
a much lower tendency to appearance of PVT/VF (27). The coved-type J
point and ST segment elevation may rarely be observed in the inferior
wall leads in absence of hypothermia, ischemia or electrolytic
disorders in patients without structural heart disease, configuring
the so-called atypical Brugada pattern or latent type(27-28-29-30-31).
Certain blockers of the fast Na+ current, such as Class IA and IC
antiarrhythmic drugs  ajmaline,  procainamide, propafenone,
flecainide, pilsicadine.  and acetylcholine (vagal stimulation) (32),
enhance phase 1 notch in RV epicardial cells, with a subsequent
shortening in dome or phase 2 duration. This fact results in a
non-homogeneous and more heterogeneous repolarization dispersion in
the ventricular myocardial thickness, between the subendocardium and
the subepicardium, fostering the substrate for developing reentry in
phase 2, a mechanism responsible for IPVT/IVF in BrS. When the outward
current shift is marked, premature repolarization occur in epicardial
myocardium  and the resulting gradient may precipitate P2R.

Flecainide shortens the QT interval of variant 3 of congenital long QT
syndrome (LQT3), so its oral administration has been proposed to treat
this variant. Additionally, in these patients it can cause
"Brugada-like" J point and ST segment elevation(33).

Flecainide may induce ST segment elevation in LQT3 patients, raising
concerns about the safety of flecainide therapy and demonstrating the
existence of an intriguing overlap between LQT3 and BrS(34). Low-dose,
oral flecainide consistently shortened the QTc interval and normalized
the repolarization T-wave pattern in LQT3 patients with SCN5A:DeltaKPQ
mutation(35).

A class IB sodium channel blocker, mexiletine, significantly shortens
QTc, thus preventing the appearance of TdP. Strangely, the drug does
not shorten long QT in congenital LQTS, which affects the K+ current
(HERG defect of the K+ current) or variant 2 of LQTS. Mexiletine, is
most effective in abbreviating QT interval in LQT3, but effectively
reduces transmural dispersion of repolarization (TDR) and prevents the
development of Td P in all LQT1, LQT2 and LQT3 models, suggesting its
potential as an adjunctive therapy in LQT1 and LQT2(36).

The use of drugs that inhibit the Ito1 current or that stimulate Ca2+
inward movement can decrease the degree of J point and ST segment
elevation and improve repolarization in this entity . Thus, the Ito1
blocker with 4-aminopyridine (1 to 2mmol/L) or quinidine (5
micromol/L) increase phase 2 or dome duration and normalize ST segment
elevation preventing TV/FV(37). Oral quinidine suppress the electrical
storm and prevented VF episodes in BsS patients(38). Oral quinidine
reduces phase 1 extent mediated by Ito1, normalizing ST segment
elevation in right precordial leads or from V1 to V3. IA class drugs
that block Na+ current and additionally Ito1, such as quinidine and
disopyramide, improve ECG in BrS, while those of the same class, such
as procainamide and ajmaline, which block exclusively the Na+ current
without affecting the Ito1 current, worsen ST segment elevation and
may trigger fatal tachyarrhythmias in BrS(39). Oral quinidine induce
ECG normalization in patients with BrS(40). Publications report the
employment of the drug in malignant forms of the entity(41).
Associated with adrenergic beta1-agonist and the parasympathetic
antagonist was used (42).

The presence of mild ischemia and vagotony act sinergically with the
electrophysiologic substrate of BrS, elevating ST segment and
triggering PVT/IVF bursts. This observation suggests that the Brugada
Patients are under a higher risk of SCD in coexistence with
ischemia(43).

On the contrary, isoproterenol restores phase 2 or dome in the
epicardium, reducing J point and ST segment elevation. The vasodilator
cilostazol acts through a similar mechanism: increase ICa+2-L, and for
this reason may be effective in reducing episodes of PVT/VF(44).For
this reason, isoproterenol is the drug of choice in ES in BrS
associated with general anesthesia and cardiopulmonary "bypass"
diminishing the ST elevation in right precordial leads disappearance
of the short-coupled premature beats and in removing ES crisis of
VF(45). This ominous-sounding event consists of the incessant
appearing of recurring episodes and multiple VF or VT: 20 or more per
day or 4 or more per hour, eventually observed in BrS.

The ECG pattern in BrS can be intermittent and become manifest in
latent cases due to some IA class (procainamide and ajmaline) and IC
class (flecainide)  antiarrhythmic agents and by night vagotony(46)

These facts support the hypothesis that J point and ST segment
elevation and the subsequent triggering of PVT/VF are dependent of a
prominent Ito current and spike-and-dome morphology in the RV
epicardium(47).

In early repolarization syndrome (ERS), a normal benign variant, found
in 1% to 2% of the population, and 13% to 48%(48) in emergency rooms
in patients with precordial pain, J point and ST segment elevation
usually presents a concavity higher >/=1mm in limb leads and >/=2 in
precordial leads, in at least two adjacent leads and with notch or
slurring of the R terminal portion of the QRS complex, followed by T
waves of enhanced voltage and concordant polarity in the intermediate
leads from V2 to V4. The most important differential diagnosis of ERS
is pericarditis, acute infarction and acute coronary syndromes that
could be treated mistakenly with fibrinolysis or unnecessary
angiography(49).  In doubtful cases, besides a careful anamnesis, the
following must be conducted: echocardiogram, enzyme and troponin I
dosage(50).

There are evident differences and potent gradients in Ito1 between the
three cardiac cell types, especially between Epi and Endo cells. These
differences are among the prominent manifestations of right
ventricular electrical heterogeneity, and may form an important ionic
basis and prerequisite for some malignant arrhythmias in the right
ventricle, including those arising from BrS and other diseases(51).
ERS can be confused as well, with ventricular aneurysm.  ERS is very
frequent in athletes, in whom it is observed in more than 80% of the
cases. Rarely (8%), it can present a configuration that reminds the
Brugada sign or is Brugada-like. In such cases, the following are
elements in favor of ERS (modified from Bianco.) (23).

1)       Family history: negative in ERS and frequently positive for  
SCD in BrS;

2)       HR: tendency to bradycardia in ERS. In BrS, heart rate is
usually normal;

3)       SAQRS: in ERS it tends to be vertical, and in BrSe in a 9% of
cases it presents an extreme deviation to the left;

4)       PR interval: tendency to be short or normal and mildly
depressed in ERS. In BrS, it is long and in a 50% of cases
(first-degree AV block) by increase of HV;

5)       QRS duration: larger in BrS (110msec +/-2msec) than in
athletes carriers of ERS (90msec+/-1msec)

6)       Transition area in precordial leads: it is usually abrupt in
ERS by counterclockwise rotation in longitudinal axis. This is not
observed in BrS;

7)       Degree of ST segment elevation: much larger in BrS
(4.4+/-0.7mm) than in athletes (2.3+/-0.6mm) or non-athletes
(1.2+/-0.8mm) carriers of ERS;

8)       Race: it predominates in the black race in ERS. In BrS, in
the yellow race.

9)       U wave: it is usually very visible in V3 due to bradycardia
in ERS. It is not frequent in BrS.

Coincidences between BrS and benign ERS:

1)       Exercise can normalize ST segment elevation;

2)       Isoproterenol can normalize ST segment elevation;

3)       More frequent in males;

4)       Predominantly observed in young adults in productive age and
under 50 years old(54).

5)       Both can have ST segment elevation concave to the top,
saddleback type, and frequently persistent;

The Ito current has a decisive role in the aspect of the early
repolarization phase. Additionally, it influences on inward and
outward movement of other ions in the next phase (phase 2) and in AP
refractoriness.

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--
Dr. Sergio Dubner
President of Scientific Committee

Dr. Edgardo Schapachnik
President of Steering Committee