局部给药跨室壁氯化钾单相动作电位记录电极的研制

目的研制局部给药跨室壁氯化钾单相动作电位(MAP)记录电极(KC lMAP电极),探讨模拟在体犬交感神经不均一的致心律失常机制。方法由5F动脉鞘管和0.2 mm的绝缘银丝,组构成3对MAP记录电极,鞘芯腔内注入含30%氯化钾琼脂糖凝胶即制成KC lMAP电极。用自制的电极记录犬左室前壁跨室壁MAP,观察局部异丙肾上腺素对三层心肌细胞动作电位时程(APD)及跨室壁复极离散度(TDR)的影响和心律失常的诱发情况。结果KC lMAP电极能稳定记录三层心肌MAP 120 m in以上,随时间的延长动作电位振幅逐渐降低但不影响复极特性的分析;局部给予异丙肾上腺素(10-5mg/m l)能显著降低中层心肌细胞的APD90(236.9±3.8 m s vs 226.3±3.0 m s)和TDR(35.7±4.8 m s vs 24.9±3.9 m s),中层心肌细胞易于诱发早期后除极及触发活动并引起室性心律失常。结论KC lMAP电极可理想地用于跨室壁心肌复极特性的研究;异丙肾上腺素降低正常犬的TDR,其诱发室性心律失常的机制与后除极和触发活动有关。     

犬短QT综合征发生心室颤动的电生理机制研究

目的：研究犬短QT综合征模型易发致命性心室颤动的电生理机制.方法：应用吡那地尔建立比格犬短QT综合征模型,利用篮状电极标测左室心内膜心肌电位.比较静脉推注吡那地尔（负荷剂量0.5 mg/kg,维持剂量每小时0.5 mg/kg）前后,QT间期、T波峰末间期（Tp-Te）、心肌细胞复极90％的动作电位（APD90）及激动恢复时间（ARI）、心室颤动周长（VF-CL）等参数的变化. 结果：与基础状态相比,吡那地尔显著缩短窦性心律和300 ms起搏时的QT间期,分别为（264±17） ms对（240±15） ms,P＜0.01;（247±7）ms对（229±10） ms,P＜0.01.应用吡那地尔后,APD90、ARI和VF-CL均较基础值显著降低,分别为（175±11） ms对（164±11） ms,P＜0.01;（156±11） ms对（147±10） ms,P＜0.01;（104±9） ms对（95±7）ms,P＜0.01.同时,Tp-Te间距较基础状态延长19％,即（35.8±3.4） ms对（44.1±1.4） ms,P＜0.01. 结论：不应期缩短和不应期心室跨壁离散度增加可能是吡那地尔诱导短QT综合征并发致命性室性心律失常的电生理基础.     

β受体激动剂对LQT1模型的电生理影响

目的探讨LQT1患者在交感神经兴奋时发生室性心律失常的机制。方法实验切取犬楔形心室肌组织块,用30μmol/L chromanol 293B(I_(Ks)阻断剂)灌流该标本模拟LQT1,采用玻璃微电极和特制的金属电极,同步记录造模前后的中层和外层心室肌细胞的跨膜动作电位(TAP)和跨壁心电图(TECG),并观察异丙肾上腺素(Iso,100 nmol/L)对造模后的TAP和TECG的影响。结果chro- manol 293B使中层和外层心室肌细胞动作电位时限(APD_(90))均匀延长[中层：(287±12)ms vs(362±18)ms,P＜0．05；外层：(229±13)ms vs(303±20)ms,P＜0．05],跨壁复极离散度(TDR)增加不明显[(46±5)ms v8(49±7)ms,P＞0．05],TECG示QT间期延长[(314±13)ms vs(389±16)ms,P＜0．05]。加入Iso后,中层心室肌细胞APD_(90)延长[(362±18)ms vs(388±14)ms,P＜0．05],并出现早期后除极(EAD),外层心室肌细胞APD_(90)缩短[(303±20)ms vs(285±12)ms,P＜0．05],TDR明显增加[(49±7)ms vs(87±11)ms,P＜0．05],TECG示QT间期延长[(389±16)ms vs(405±15) ms,P＜0．05],并能自发产生室性早搏和室性心动过速。结论在LQT1模型中,Iso对中层和外层心室肌细胞TAP的影响不一致,引起TDR增加,这可能是交感神经兴奋使LQT1患者发生室性心律失常的机制。     

胺碘酮对家兔急性心肌缺血左室跨壁复极离散度的影响

目的:探讨胺碘酮对家兔急性缺血左室心肌楔形组织块电生理特性和跨壁复极离散度（TDR）的影响及其抗缺血心律失常的机制。方法: 建立冠状小动脉灌注家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,观察急性无灌流心肌缺血时,胺碘酮对内外层心肌细胞的动作电位时程（APD）、TDR和心律失常的影响。结果: ①左心室楔形组织块停止灌注后,胺碘酮组内、外膜心肌细胞的APD较对照组明显延长[(228±19) ms vs.(212±6) ms,P<0.05］,且外膜APD的延长更明显[(203±15) ms vs.(180±5) ms,P<0.05］。②急性缺血各时间段,APD较缺血前均缩短,以外膜APD缩短更明显,导致TDR增大。用药后TDR明显短于对照组。结论: 胺碘酮可延长内、外膜心肌细胞的APD,且外膜APD的延长明显,并可减小急性缺血心肌的TDR,这可能是其抗心律失常机制的细胞电生理基础。     

奎尼丁对吡那地尔诱导的犬右心室跨壁复极离散的影响

目的　由吡那地尔诱导犬右心室肌细胞产生“全或无”复极,观察奎尼丁对这种跨壁复极离散的影响。方法　应用标准玻璃微电极技术在1000ms刺激周长下,记录犬右心室肌细胞不同部位(外膜下、M区、内膜下)在不同情况[正常对照、吡那地尔(2 5μmol/L)、吡那地尔( 2 5μmol/L) +奎尼丁(5μmol/L) ]的动作电位。结果　吡那地尔( 2 5μmol/L)在3层细胞产生“全或无”复极,使跨壁复极离散增大,动作电位时程跨壁复极离散由(48 .5±9 .2)ms升为(128. 7±13. 5)ms(P<0. 01),进一步灌注奎尼丁(5μmol/L)后,减为(54 .3±10 .8)ms(P<0. 01)。奎尼丁部分恢复动作电位2相平台,延长了被吡那地尔缩短的动作电位时程。结论　在犬右心室肌组织,奎尼丁(5μmol/L)减小了由吡那地尔造成的跨壁复极离散,维持了跨壁电稳定性。     

短QT间期综合征发生室性心律失常机制探讨

目的:探讨吡那地尔(pinacidil)建立的短QT间期综合征模型致室性心律失常的机制,并观察缝隙连接激动剂抗心律失常肽(AAP10)对该模型电生理参数的影响.方法:利用pinacidil灌注家兔楔形心肌块建立短QT间期综合征模型. 将20只新西兰长耳白兔随机分成pinacidil组和AAP10组,每组10只.pinacidil组灌流10 μmol/L的pinacidil,AAP10组灌流AAP10 500 nmol/l和pinacidil 10 μmol/L的混合液,同步记录灌流前后内外膜动作电位和容积心电图,观察灌流前后QT间期,跨室壁离散度(TDR),程序性刺激观察心肌组织不应期和室性心律失常的诱发情况.结果:灌流pinacidil后,QT间期从(291±19)ms缩到(232±19) ms (P<0.05),TDR从(44±12)ms减少到(22±7)ms(P<0.05),而不应期从(164±8)ms减少到(112±14)ms(P<0.05),室性心律失常发生率从0/10增加至8/10(P<0.05).AAP10 组和pinacidil组的TDR、QT间期、不应期及室性心律失常的诱发率无显著差别.结论:TDR减小和不应期的缩短可能是pinacidil建立的短QT间期模型致室性心律失常的基础,AAP10对pinacidil诱导的短QT间期综合征模型电不稳定性无明显影响.     

四氢巴马汀对在体犬跨室壁复极离散度的影响

从跨室壁复极离散度(TDR)的角度研究左旋四氢巴马汀(L-THP)的电生理作用。采用自制电极同步记录在体犬左室三层心肌细胞的单向动作电位(MAP),观察静脉注射L-THP前后动作电位时程(APD)、振幅(APA)、TDR及各层心肌有效不应期(ERP)的变化。结果:应用L-THP后三层心肌的动作电位复极90%的时程均延长(内、中、外层心肌分别为189.67±23.29msvs182.83±23.70ms、194.67±24.12msvs192.17±24.49ms和185.08±24.53msvs173.42±22.06ms,P均<0.01),内、外层心肌ERP显著增加(分别为164.54±20.53msvs159.08±20.08ms、161.60±21.28msvs150.99±18.93ms,P<0.01)、TDR降低(9.58±2.94msvs18.75±3.77ms,P<0.01),对APA无明显影响。结论:L-THP降低心室肌的TDR,延长心室内、外膜心肌细胞的ERP。     

抑制晚钠电流对短QT间期心脏心电生理指标的影响及抗室性心律失常的机制

目的探讨抑制晚钠电流的药物对短QT间期心脏可能的电生理作用及其机制。方法采用Langendorff灌流装置制备兔离体心脏电生理研究模型。选择新西兰大耳白兔80只, 首先任意选取34只, 未用药时为对照A组(n=34)、给予IKATP开放剂吡那地尔后为吡那地尔A组(n=34), 再从吡那地尔A组中选取27只, 联用钠通道抑制剂或传统的用于治疗短QT综合征的药物奎尼丁后分为雷诺嗪联用组(n=9)、美西律联用组(n=9)、奎尼丁联用组(n=9)。在剩余的46只新西兰兔中选取19只, 未用药时为对照B组(n=19), 给予吡那地尔后为吡那地尔B组(n=19)。其余27只分为雷诺嗪单用组(n=9)、美西律单用组(n=9)、奎尼丁单用组(n=9)。采集对照A组、吡那地尔A组的心电生理参数, 在对照B组、吡那地尔B组中采用程序电刺激诱发室性心律失常并采集心电图。采集吡那地尔联用组和单用药物组的心电生理参数, 同时诱发室性心律失常并采集心电图。吡那地尔、雷诺嗪、美西律、奎尼丁药物浓度分别为30、10、30、1 μmol/L。结果与对照A组相比, 吡那地尔A组的QT间期、心外膜和心内膜动作电位复极化完成...     

氯化铯诱发在体心脏触发性心律失常的实验研究

心内膜单相动作电位研究表明,单相动作电位的复极进程能够正确反映心肌细胞动作电位复极时程。狗静脉注射氯化铯后早期后除极电位(EAD)的发生率为100％,单相动作电位90％复极时程明显延长(224.4±50.6ms VS 368.4±34ms),与QT间期延长相一致。氯化铯诱发的室性心律失常发生于EAD顶峰,触发心律联律间期与EAD联律间期密切相关。硫酸镁使EAD和室性心律失常同时消失。提示该心律失常为EAD触发活性所致。     

兔LQT2模型时空复极异质性变化与室性心律失常发生的关系

为探讨心室跨壁复极离散度(TDR)和动作电位时程(APD)恢复性质的变化在LQT2室性心律失常发生中的作用,笔者采用冠状动脉灌注的兔左室肌楔形组织块制备LQT2模型。标本随机分四组:对照组(标准台氏液灌注);LQT2模型(简称模型)组(100μmol/Ld,l-sotalol灌流);模型+低钾(3mmol/L)组和模型+低钾+维拉帕米(2μmol/L)组。观察不同基础周长(BCL)刺激(500,1000和2000ms)条件下,四组标本APD90、TDR和APD恢复性质的变化与室性心律失常发生的关系。结果:①在不同BCL条件下,与对照组相比,模型组、模型+低钾组及模型+低钾+维拉帕米组的内外膜心肌细胞的APD90均增大,以内膜心肌细胞的APD90增大显著,导致TDR增加。②BCL为500和1000ms时,与对照组相比,模型组、模型+低钾组的APD恢复曲线斜率显著增加,而模型+低钾+维拉帕米组,差异无显著性。③在BCL为1000和2000ms时,给予S1S2程序刺激,模型+低钾组尖端扭转性室性心动过速发生率为5/7。结论:TDR增大和APD恢复性质的变化在室性心律失常的发生中均起着重要的作用。     

Transseptal Dispersion of Repolarization and Its Role in the Development of Torsade de Pointes Arrhythmias

Transseptal Dispersion and TdP . Objective: This study was designed to quantitate transseptal dispersion of repolarization (DR) and delineate its role in arrhythmogenesis using the calcium agonist BayK 8644 to mimic the gain of function of calcium channel current responsible for Timothy syndrome. Background: Amplification of transmural dispersion of repolarization (TDR) has been shown to contribute to development of Torsade de Pointes (TdP) arrhythmias under long‐QT conditions. Methods: An arterially perfused septal wedge preparation was developed via cannulation of the septal artery. Action potentials (APs) were recorded using floating microelectrodes together with a transseptal electrocardiogram (ECG). These data were compared to those recorded from arterially perfused canine left ventricular (LV) wedge preparations. Results: Under control conditions, the shortest AP duration measured at 90% repolarization (APD₉₀) was observed in right ventricular (RV) endocardium (181.8 ± 15 ms), APD₉₀ peaked close to midseptum (278.0 ± 32 ms), and abbreviated again as LV endocardium was approached (207.3 ± 9 ms). Transseptal DR averaged 106 ± 24 ms and T_peak–T_end 84 ± 7 ms (n = 6). TDR and T_peak–T_end recorded from LV wedge were 36 ± 9 ms and 34 ± 19 ms, respectively (n = 30). BayK 8644 increased transseptal DR to 123.2 ± 35 ms (n = 5) and induced early and delayed afterdepolarizations (3/5), rate‐dependent ST‐T‐wave alternans (5/5), and TdP arrhythmias (3/5). Conclusions: Our data indicate that dispersion of repolarization across the interventricular septum is twice that of the LV free wall, predisposing to development of TdP under long‐QT conditions. Our findings suggest that the coronary‐perfused ventricular septal preparation may be a sensitive model in which to assess the potential arrhythmogenic effects of drugs and pathophysiological conditions. (J Cardiovasc Electrophysiol, Vol. 21, pp. 441–447, April 2010)     

Heterogeneity and cardiac arrhythmias: An overview

This lecture examines the hypothesis that amplification of spatial dispersion of repolarization in the form of transmural dispersion of repolarization (TDR) underlies the development of life-threatening ventricular arrhythmias associated with inherited ion channelopathies, including the long QT, short QT, and Brugada syndromes as well as catecholaminergic polymorphic ventricular tachycardia. In the long QT syndrome, amplification of TDR often is secondary to preferential prolongation of the action potential duration of M cells, whereas in Brugada syndrome, it is thought to be due to selective abbreviation of the action potential duration of right ventricular epicardium. In the short QT syndrome, preferential abbreviation of action potential duration of either endocardium or epicardium appears to be responsible for amplification of TDR. In catecholaminergic polymorphic ventricular tachycardia, reversal of the direction of activation of the ventricular wall is responsible for the increase in TDR. Thus, the long QT, short QT, Brugada, and catecholaminergic ventricular tachycardia syndromes are pathologies with very different phenotypes and etiologies. However, these syndromes share a common final pathway in their predisposition to sudden cardiac death.     

Amplification of spatial dispersion of repolarization underlies sudden cardiac death associated with catecholaminergic polymorphic VT, long QT, short QT and Brugada syndromes

This review examines the hypothesis that amplification of spatial dispersion of repolarization in the form of transmural dispersion of repolarization (TDR) underlies the development of life-threatening ventricular arrhythmias associated with inherited ion channelopathies including the long QT, short QT and Brugada syndromes as well as catecholaminergic polymorphic ventricular tachycardia. In the long QT syndrome, amplification of TDR is often secondary to preferential prolongation of the action potential duration (APD) of M cells, whereas in the Brugada syndrome, it is thought to be because of selective abbreviation of the APD of right ventricular epicardium. Preferential abbreviation of APD of either endocardium or epicardium appears to be responsible for amplification of TDR in the short QT syndrome. In catecholaminergic polymorphic VT, the reversal of the direction of activation of the ventricular wall is responsible for the increase in TDR. In conclusion, the long QT, short QT, Brugada and catecholaminergic VT syndromes are pathologies with very different phenotypes and aetiologies, but which share a common final pathway in causing sudden death.     

迷走神经刺激和乙酰胆碱灌注对心房肌电生理特性的影响

研究在体情况下迷走神经刺激(VNS)和乙酰胆碱(Ach)灌注对心房肌不同部位的电生理影响,并探讨其诱发心房颤动(AF)的机制。10只杂种犬自身随机对照,运用单相动作电位(MAP)记录技术,同步记录10只开胸犬的右心耳(RAA)、高位右房(HRA)、低位右房(LRA)、左心耳(LAA)、高位左房(HLA)、低位左房(LLA)的MAP,分别给予切断迷走神经、VNS、Ach灌注(分别做为对照组、VNS刺激组、Ach灌注组)后,观察诱发AF的情况和动作电位时程APD50、APD90和APD离散(dAPD)的变化。结果:10只犬在VNS刺激和Ach灌注同时,右心耳单一刺激分别有7只和6只犬诱发AF;VNS明显缩短APD50、APD90,其中RAA缩短最明显(APD50从72±5ms到19±4ms,APD90从136±7ms到43±5ms,P<0.001);Ach灌注也明显缩短APD50和APD90,与VNS相比,LLA的APD90缩短更明显(47±6msvs62±8ms,P<0.01);VNS明显升高心房肌APD50和APD90的离散(17±5msvs7±3ms,25±7msvs8±5ms,P<0.01)。结论:VNS和Ach灌注可引起APD缩短和离散升高,但影响的部位和程度稍有差异,都易诱发AF。     

慢性充血性心力衰竭时K_(ATP)通道与心室肌电生理特性变化的关系

探讨慢性充血性心力衰竭 (CHF)时三磷酸腺苷敏感性钾通道 (KATP通道 )在心室肌电生理特性改变和室性心律失常发生中的意义。采用阿霉素制作CHF兔模型。 2 9只兔分为健康对照组 (HC组 )和CHF实验组 ,后者包括CHF对照组 (CHFC组 )、CHF +KATP通道开放剂组 (P组 )、CHF +KATP通道阻断剂组 (G组 )、CHF +KATP通道开放剂和阻断剂组 (P +G组 )四个亚组。每组均予心房快速起搏 30min ,分别测定起搏前后 90 %单相动作电位时程(MAPD90 )、心室有效不应期 (VERP)及其离散度和兴奋时间 (AT)离散度 ,测定毕程序刺激诱发室性心动过速或心室颤动。结果 :快速起搏使MAPD90 、VERP延长 ,在CHFC组较HC组显著 (11.82± 10 .2 0vs 8.18± 6 .97ms,P <0 .0 5和14 .95± 12 .82vs 9.0 7± 8.79ms,P <0 .0 1) ,而G组和P +G组的MAPD90 、VERP延长更明显。各组快速起搏均未引起MAPD90 、VERP离散度变化 ,但CHFC组和P组都有AT离散度显著增大 (2 8.5 3± 8.6 3vs 36 .80± 6 .97ms ,P <0 .0 1和 2 6 .33± 5 .82vs 33.80± 9.5 0ms,P <0 .0 5 ) ,阻断剂可对抗AT离散度的增大。结论 :快速心房起搏可开放CHF心室肌KATP通道 ,一方面阻止MAPD90 、VERP的延长 ,另一方面又加大AT的非同步性 ,使室性心动过速易于诱发。     

Reduction of dispersion of repolarization and prolongation of postrepolarization refractoriness explain the antiarrhythmic effects of quinidine in a model of short QT syndrome

Background: Short QT syndrome (SQTS) is a newly described ion channelopathy, characterized by a short QT interval resulting from an accelerated cardiac repolarization, associated with syncope, atrial fibrillation, and sudden cardiac death due to ventricular fibrillation. As therapeutic options in SQTS are still controversial, we examined antiarrhythmic mechanisms in an experimental model of SQTS. Methods and Results: Pinacidil, an I_K‐ATP channel opener, was administered in increasing concentrations (50–100 μM) in 48 Langendorff‐perfused rabbit hearts and led to a significant reduction of action potential duration and QT interval, thereby mimicking SQTS. Eight simultaneously recorded monophasic action potentials demonstrated an increase in dispersion of repolarization, especially between the left and the right ventricle. During programmed ventricular stimulation with up to two extrastimuli, pinacidil significantly increased the inducibility of ventricular fibrillation (1 heart under baseline conditions, 29 hearts during pinacidil administration; P = 0.0001). Additional treatment with the I_Kr blocker sotalol (100 μM) and the class I antiarrhythmic drugs flecainide (2 μM) and quinidine (0.5 μM) randomly assigned to three groups of 16 hearts led to prolongation of repolarization as well as refractory period. Sotalol or flecainide did not reduce the rate of inducibility of ventricular fibrillation significantly (P = 0.63; P = 0.219). However, quinidine reduced the inducibility of ventricular fibrillation by 73% (P = 0.008). The antiarrhythmic potential of quinidine was associated with a significantly greater prolongation of MAP duration, refractoriness, and postrepolarization refractoriness (PRR) as compared with sotalol and flecainide. Moreover, quinidine, in contrast to sotalol and flecainide, reduced dispersion of repolarization. Conclusion: Pinacidil mimics SQTS via increasing potassium outward currents, thereby facilitating inducibility of ventricular fibrillation. Quinidine demonstrates superior antiarrhythmic properties in the treatment of ventricular fibrillation in this model as compared with sotalol and flecainide because of its effects on refractoriness, PRR, and by reducing dispersion of repolarization.