伊布利特对人体心房与心室电生理特性的影响

探讨伊布利特对人体右房、左房及右室有效不应期(RA-ERP、LA-ERP及RV-ERP)与房间、室间传导时间的影响。测定25例射频消融术后患者于静脉推注伊布利特(0.0167mg/kg)前后在基础起搏周长为600ms时的RA-ERP、LA-ERP及RV-ERP,同时测量起搏与窦性心律时的心房、心室传导时间。其中通过起搏冠状静脉窦远端间接起搏左房。结果:①伊布利特明显延长RA-ERP、LA-ERP及RV-ERP(P均<0.001)。②使用伊布利特后,对窦性心律时的P波宽度、PR间期、QRS时限、AH及HV均无明显影响(P>0.05),对房间及室间传导时间无明显影响(P>0.05),亦对急性期的起搏阈值无明显影响(P>0.05)。③使用伊布利特后2例出现右束支阻滞。结论:伊布利特可明显延长RA-ERP、LA-ERP及RV-ERP,但不影响房间、室间传导时间。     

阵发性心房颤动患者心房颤动发作前后、发作时体表心电图QT间期的变化

目的探讨阵发性心房颤动（简称房颤）患者房颤发作前后、发作时体表心电图QT间期的变化。方法收集35例阵发性房颤患者的24h动态心电图。测量房颤发作前窦性心律（SRbaseline）、房颤发作、房颤自行转为窦性心律即刻（SRpostAF）时的QT间期。测量连续3个心动周期QT间期。测量每阵房颤的持续时间。分别采用Bazetts、Ffidencia和Framingham公式校正QT间期（QTc）,分析房颤发作时间与SRpostAF的QTc之间的关系。结果sRpo札AF的QTc显著短于SRbaseline的QTc[（407±38）msvs（435±34）m2;（397±31）msv8（423±31）ms;（393±35）msVs（422±30）ms,P均〈0．001],而房颤发作时QTc较SRbaseline、SRpostAF的QTc显著性延长[采用三种QT校正公式的QTc分别是（503±69）,（454±53）,（449±44）ms]。SRpostAF的QTc缩短与房颤短阵发作持续时间无显著相关,与房颤发作前的QT间期相关（相关系数分别是：0．500,0．547,0．507;P均〈0．01）。结论房颤发作时QTc显著延长,而房颤发作自行转复窦性心律后QTc显著缩短。     

心脏再同步治疗对心肌复极离散度的影响

目的观察心室不同位点起搏时心电图上心肌复极标志的变化,了解以双心室起搏技术为核心的心脏再同步治疗（CRT）对心肌复极离散的影响。方法 入选接受CRT植入的患者在起搏器植入后1周内记录12导联心电图,分别将起搏器程控为无起搏、右心室内膜下起搏（RV—EndoP）、左心室外膜起搏（LV—EpiP）及双心室同步起搏（BivP）四种不同状态并记录心电图。阅读不同起搏位点时的QRS时限、QT问期及TP-E时限。QTc用Bazett公式[QTc=实测QT／（RR）1／2]进行矫正。结果基线QYc为（489．2±51．2）ms,而RV—EndoP、LV—EpiP起搏导致QR明显延长[RV-EndoP（537．3±45．7）ms,P〈0．05;LV—EpiP（592．4±60．2）ms,P〈0．001],而BivP起搏为（491．3±52．7）ms,P〉0．05;基线TP．F（113．8±15．7）ms,RV-EndoP、LV—EpiP均导致TP-E明显延长[RV．EndoP（124．8±24．7）ms,P〈0．05;LV．EpiP（133．3±37．8）ms,P〈0．005],BivP时TP-E时限为（109．9±17．1）ms,有轻度缩短,但差异没有统计学意义（P〉0．05）。结论左心室外膜起搏可明显延长心肌复极离散指标;双心室同步起搏可减少由单纯左心室外膜起搏引起的复极离散度的增大。     

心房颤动患者心房肌组织醛固酮水平和CYP11B2基因与心房结构重构研究

目的探讨心房颤动（房颤）患者心房肌组织醛固酮水平和醛固酮合成酶基因CYP11B2mRNA表达与房颤时心房结构重构的关系。方法入选进行人工心脏瓣膜置换术的风湿性心脏瓣膜病患者25例，其中窦性心律者12例，慢性房颤（≥6个月）者13例。上述患者均于术前行经胸超声心动图检查并留取相关资料，于手术时同时取左右心房侧壁组织。用放射免疫法测定心房组织醛固酮水平；用VG染色法对胶原容量分数（CVF）半定量分析；实时荧光定量PCR测定CYP11B2mRNA在心房肌组织中的表达情况。结果与窦性心律组比较，房颤组左心房内径显著扩大（P〈0．01）；心房肌组织醛固酮水平和CVF均明显增加（P均〈0．001）；心房肌组织CYP11B2mRNA表达也明显增加（P〈0．001）；上述指标无论是在窦性心律时还是在房颤时其在左右心房之间差异无统计学意义（P均〉0．05）。CVF和左心房内径显著正相关（r=0．845，P〈0．001）；心房组织醛固酮水平与左心房内径（r=0．814，P〈0．001）和CVF（r=0．885，P〈0．001）均呈明显正相关；CYP11B2mRNA表达量和CVF亦呈明显正相关（r=0．757，P〈0．001）。结论心房颤动时心房结构重构与其组织醛固酮水平增加和CYPI1B2mRNA表达增加有关，醛固酮受体拮抗剂可能在阻止房颤的心房结构重构进程上发挥治疗作用。     

ⅤⅥ起搏器更换者心功能和心房颤动发生情况的临床观察

目的评估长期VVI起搏对患者心功能和心房颤动（房颤）发生的影响。方法对植入VVI起搏器的103例患者分别于VVI起搏器首次植入时和因脉冲发生器电池耗竭行更换术前进行临床、心电图、24h动态心电图、超声心动图检查，并评价心功能（NYHA分级）和房颤发生情况。结果VVI起搏器平均更换时间为8．4年。首次VVI起搏器植入时左心房内径平均36．27mm，左心室舒张末内径49．62mm，患者在更换VVI起搏器时左心房内径、左心室舒张末内径分别增加到40．39mm（P〈0．001）和53．27mm（P=0．007）。左心室射血分数由首次植入时的0．65下降到更换时的0．61（P=0．0485）。同时发现患者心力衰竭加重（P=0．0284），持续性房颤发生率增加（P=0．0283）。结论长期VVI起搏引起患者心功能恶化，持续性房颤发生率增加。     

房间隔起搏在心脏再同步治疗中的应用

目的通过简单的超声多普勒方法评价房间隔起搏在心脏再同步治疗（CRT）中的效果。方法在23例行CRT治疗的患者中进行了超声多普勒测量，9例患者存在房间阻滞，心房起搏导线固定在房间隔，其余14例常规固定在右心耳。结果右心耳起搏组中心房间传导延迟时间（IAD）延长[（46±20）ms vs（53±23）ms，P〈0．05]，IAD和心室间传导延迟时间（IVD）的差异增大[（53±23）ms VS（40±17）ms，P〈0．05]，左机械房室延迟时间（LMAVD）和右机械房室延迟时间（RMAVD）的差异明显增加[（172±25）ms vs（210±32）ms，P〈0．001]。房间隔起搏后IAD明显减小[（34±12）ms VS（12±11）ms，P〈0．001]，IAD和IVD的差别减少[（12±11）ms VS（18±16）ms，P〉0．05]，LMAVD和RMAVD差异无统计学意义[（187±43）ms vs（182±50）ms，P〉0．05]。二尖瓣A峰速度时间积分在房间隔起搏后明显增加[（8．9±4．9）cm vs（13．0±4．0）cm，P〈0．001]。结论房间阻滞可以导致左心和右心房室收缩顺序的差异，房间隔起搏能纠正这种差异，增加二尖瓣舒张期充盈进一步改善心脏再同步治疗。     

冠心病患者平板运动负荷试验中的QT间期滞后现象

目的观察冠心病患者在平板运动负荷试验中的QT问期滞后现象。方法收集21例经冠状动脉造影确诊的冠心病患者（冠心病组）和20例健康志愿者（对照组）。分析两组的平板运动负荷试验心电图,每份心电图测量50个点的RR间期、QTp间期（Q波起始到T波顶峰的时间）和QTe间期（Q波起始到T波终末的时间）,采用Bazett公式[QTc=QT／（RR）”。]计算QTpc间期及QTec间期。以RR间期为横坐标,QTp问期、QTe问期、QTpc问期或QTec问期为纵坐标,作散点图及曲线。比较RR问期为600、550、500、450、400ms时,运动期QTp间期、QTe问期、QTpc间期或QTec间期与恢复期的差异。结果对照组运动期和恢复期的QT／RR曲线几乎重叠;冠心病组运动期和恢复期的QT／RR曲线在RR间期500～600ms段明显分离,恢复期低于运动期。对照组在各RR问期下,运动期QT间期和QTc问期与恢复期的差异无统计学意义（P〉0．05）。冠心病组在RR问期为550、500、450ms时,运动期QTp问期和QTpc间期显著高于恢复期（P〈0．05）;在RR问期为550、500ms时,运动期QTe间期和QTec间期显著高于恢复期（P〈0．05）。结论冠心病患在平板运动负荷试验中有明显的QT滞后现象,后者可能在冠心病的早期无创检测中发挥一定作用。     

三氧化二砷诱导豚鼠心脏QT间期延长及其分子机制研究

目的 观察三氧化二砷（As2O3）对豚鼠心脏QT间期的影响，并探讨其对延迟整流钾通道蛋白mRNA表达的影响。方法 按静脉给予的As2O3剂量，将豚鼠随机分为4组：0（对照组）、0．4、0．8、1．6mg／kg组。测量不同时间点的心电图，观察校正QT间期（QTc）的变化。用反转录聚合酶链式反应（RT—PCR）方法观察As2O3对心肌延迟整流钾通道蛋白mRNA表达的影响。结果 在120min时，As2O3 0．8、1．6mg／kg组QTc分别为（368±29）、（388±31）ms，与对照组[（324±20）ms]比较，明显延长（t值分别为9．26、16．37，P〈0．01）。RT-PCR结果显示，与对照组比较，As2O3,1．6mg／kg可以使豚鼠心肌缓慢型延迟整流钾通道蛋白（KvLQT1）mRNA表达降低（t=12．83，P〈0．01），而对快速型延迟整流钾通道蛋白（ERG）mRNA表达则无明显影响。结论 As2O3可引起豚鼠心脏QT间期延长，其机制可能与抑制KvLQT1 mRNA表达有关。     

维拉帕米抑制犬在体心脏早期后除极及室性心动过速的研究

用心外膜接触电极记录犬左室外膜单相动作电位（MAP），观察维拉帕米（异搏定）对氯化铯（CsCl）诱发的早期后除极（EADs）、QT间期延长及室性心动过速（VT）的影响。11只大，CsCl按0．5mg·kg-1次（首剂加倍），每15分钟一次静脉注射，直至诱发出VT。然后在给下一剂CsCl前，先给予维拉帕米0．1～0．2mg／kg静脉注射，后再给予此剂CsCl，以后仍每15分钟静脉注射CsCl一次直至VT再被诱发。结果维拉帕米给药前及给药后的15～60分钟CsCl诱发的EAD振幅占相应MAP振幅的29．2±7．0％和24．8±8．1％、QTc间期分别从对照组386±33ms延长至443±66ms（P＜0．01）和从441±107ms延长至516±93ms（P＜0．01），但给予维拉帕米后即刻，CsCl诱发的EADs仅为16．7±7．6％（与前述二值比较P均＜0．01）、QTc间期仅从对照的418±56ms延长至425±49ms（P＞0．05）。给维拉帕米前CsCl分别在7只和4只诱发出持续性和非持续性室速，给予维拉帕米后即刻仅在4只诱发出非持续性室速。结果示维拉帕米可以抑制CsCl诱发的EADS、QT间期延长及VT。     

2型糖尿病对冠心病患者复极离散度和稳定性的影响

目的研究2型糖尿病对冠心病患者复极离散度和稳定性的影响。方法对冠心病合并2型糖尿病组（试验组,65例）、冠心病组（78例）,进行标准12导联的体表心电图检查,比较两组患者的复极离散度和稳定性：QT、QT间期（QTc）、TpTe、TpTe/QT、QT变异指数（QTVI）和QT短时变异性（STVT）。结果与冠心病组相比,试验组患者QT时程（387.7ms±25.2ms vs 384.2ms±23.6ms,P=0.12）和STV30（2.40±0.55vs 2.37±0.51,P=0.70）差异无统计学意义;而心率较快（71.9次/min±13.1次/min vs 66.5次/min±7.3次/min,P=0.02）,QTc（396.9ms±21.3ms vs 387.3ms±23.2ms,P=0.01）、TpTe（83.2ms±1 2.7ms vs 76.7ms±9.4ms,P〈0.01）、TpTe/QT（0.23±0.04vs0.19±0.03,P〈0.01）和QTVI（-0.32±0.05vs-0.52±0.08,P〈0.01）显著延长,差异均有统计学意义。结论 2型糖尿病增加冠心病患者的复极离散度和不稳定性,可能是患者室性心律失常和心脏性猝死风险增加的重要原因。     

Frequency-Dependent Electrophysiological Effect of Ibutilide on Human Atrium and Ventricle

Most of the class III antiarrhythmic agents developed in recent years blocks the rapid component of delayed rectifier potassium current (IKr). IKr blocker shows reverse use-dependency and also may cause torsades de pointes at slower heart rate. Ibutilide fumarate, a novel class III antiarrhythmic agent, increases window Na(+) current at the action potential plateau phase. We studied the rate-dependent effect of ibutilide on the electrophysiological parameters of human atrium and ventricle. Franz catheter and a pacing catheter were placed closely in the high right atrium and right ventricular apex to record monophasic action potentials (MAP) during pacing at cycle length (PCL) of 600 ms and 350 ms in eight patients who underwent electrophysiological study. MAP duration of right atrium (RA-MAPD) and right ventricle (RV-MAPD), effective refractory period of RA and RV (RA-ERP and RV-ERP), intra-atrial conduction time (IACT) and intra-ventricular conduction time (IVCT) were measured before and after intravenous administration of ibutilide (0.01 mg/kg up to 1mg). A conduction time from RA pacing spike to distal coronary sinus potential was used to measure IACT, while QRS duration of surface ECG during RV pacing was used to measure IVCT. Ibutilide prolonged RA-MAPD by 60 ms at PCL 600 ms and by 53 ms at PCL 350 ms; RV-MAPD by 48 ms at PCL 600 ms and by 55 ms at PCL 350 ms. Ibutilide did not affected RA and RV-ERP/MAPD ratio, IACT, and IVCT. Ibutilide prolongs MAPD and ERP of human atrium and ventricle without reverse use-dependency.     

Alterations in atrial electrophysiology associated with chronic atrial fibrillation in man.

BACKGROUND: The purpose of this study was to determine the changes in atrial electrophysiology associated with chronic persistent atrial fibrillation in man. METHODS AND RESULTS: Atrial monophasic action potential duration at 90% repolarization and the effective refractory period were measured in 13 patients with chronic persistent atrial fibrillation after low-energy endocardial cardioversion, and compared to eight controls without a history of atrial fibrillation. Measurements were made at the right atrial appendage and midlateral right atrial wall at basic, 600 ms and 400 ms drive cycle lengths. In control patients, the effective refractory periods were significantly longer at the atrial appendage than the lateral wall at 600 ms (right atrial appendage 265 ms, midlateral right atrial wall 228 ms, P<0.05), and 400 ms cycle lengths (right atrial appendage 270 ms, midlateral right atrial wall 218 ms, P<0.05), but this was not evident in patients with atrial fibrillation. The monophasic action potentials and effective refractory periods at both atrial sites were shorter in the atrial fibrillation patients compared to controls; however, only the effective refractory periods at atrial appendage at 600 ms (atrial fibrillation 210 ms, controls 265 ms, P<0.001), and 400 ms cycle lengths (atrial fibrillation 200 ms, controls 270 ms, P>0.001) reached statistical significance. Effective refractory period dispersion was significantly greater in controls than in patients with atrial fibrillation (cycle length 600 ms: controls 36, atrial fibrillation 13, P=0.01; cycle length 400 ms: controls 54, atrial fibrillation 18, P<0.01). CONCLUSIONS: In patients without a history of atrial fibrillation, the refractory period at the right atrial appendage is significantly longer than at the midlateral right atrial wall. This 'normal' pattern of atrial refractory dispersion is lost in patients with chronic persistent atrial fibrillation, with marked shortening of the effective refractory period at the right atrial appendage. This may explain the high risk of recurrence of atrial fibrillation following successful electrical cardioversion.     

伊布利特在持续性心房颤动射频消融术中转律的疗效特点

目的 评价伊布利特在持续性心房颤动(房颤)射频消融术中应用的有效性及影响因素.方法 入选接受射频消融手术的持续性房颤患者18例,男性16例,女性2例,平均年龄(56.3±14.0)岁,体质量(81.22±8.93) kg,合并原发性高血压3例、肥厚型心肌病2例.所有患者术中经环肺静脉电隔离、线性消融、碎裂电位消融后房颤未终止,或者转为心房扑动,给予伊布利特l mg、10min内静脉注射,观察开始给药后30 min内的转复率及4h内的不良反应.根据用药后是否成功转律分为转律组与非转律组.结果 (1)18例患者用药后30 min内成功转律11例,转复律为61.11％,平均转律时间为(13.80 +7.64) min,转复剂量为(0.94±0.13)mg.1例患者用药后15 min时出现窦性停搏16 s,后恢复稳定窦性心律,术后观察4h无不良反应,另1例患者用药后出现窦性心动过缓,持续约lh后恢复正常心率,期间无低血压等血流动力学改变.余16例患者术中及术后4h内无室性心动过速及低血压等不良反应.(2)使用伊布利特后30 min的AA间期(0.51±0.08)s,明显长于用药前的AA间期(0.39±0.21)s,P＜0.01;用药后30 min的QTc(0.51±0.08)s,明显长于用药前QTc(0.39±0.21)s,P＜0.01.(3)两组临床资料差异无统计学意义.转律组患者左房瘢痕区比例(5.12±3.83)％,明显小于非转律组左房瘢痕区比例(12.40±11.03)％,P＜0.01.(4)左心房内径＜40mm患者的转复率(75.00％)与内径≥40 mm患者的转复率(50.00％)差异无统计学意义(P＞0.05).结论 静脉注射伊布利特在持续性房颤射频消融术中应用疗效迅速,对消融后心房扑动转复率更高.转律的成功率与术中标测瘢痕区面积所占比例相关.     

Usefulness of handgrip to improve ibutilide efficacy in organizing atrial electrical activity during atrial fibrillation

We analyzed the effect of handgrip on atrial electrical activity during atrial fibrillation (AF) by recording right and left atrial activity in 15 patients with persistent AF under baseline conditions and after saline and ibutilide infusions. The handgrip test for 15 seconds, which was always associated with a significant increase in mean atrial cycle length, was recorded in both atria (right atrium: saline vs saline + handgrip 141 +/- 29 vs 171 +/- 24 ms, p <0.001; ibutilide vs ibutilide + handgrip: 197 +/- 43 vs 221 +/- 39 ms, p <0.005). Handgrip favorably modifies atrial electrophysiologic properties during AF.     

Effects of verapamil and procainamide on acute atrial electrical remodeling induced by short-term rapid atrial pacing in humans

Atrial electrical remodeling (ER) after spontaneous or pacing-induced atrial fibrillation has been previously described in humans. We investigated atrial ER induced by a 5-minute period of rapid atrial pacing and the pharmacologic effects of verapamil and procainamide on this atrial ER phenomenon. The atrial effective refractory periods (ERPs) at drive cycle lengths of 400 (ERP 400 ) and 600 (ERP 600 ) ms, at five representative atrial sites (high right atrium [HRA]; proximal, middle and distal coronary sinus; interatrial septum), were determined in 20 patients at baseline and immediately after cessation of a 5-minute period of rapid pacing from the HRA at a rate of 150 bpm. The degrees of atrial ERP 400 and ERP 600 shortening after pacing were calculated as acute atrial ER. The same protocol was repeated in another 15 patients after intravenous administration of verapamil (0.15 mg/kg) and in another 15 patients after intravenous administration of procainamide (15 mg/kg). The results demonstrated that, in the control state acute atrial ER can be significantly demonstrated at each atrial representative site ( p < 0.001). The mean ERP 400 and ERP 600 shortenings were 9 +/- 4% and 8 +/- 4%, respectively. After procainamide infusion, but not after verapamil, baseline ERP 400 and ERP 600 values were significantly prolonged at the five representative atrial sites ( p < 0.01). Acute atrial ER could still be demonstrated at each atrial site after procainamide or verapamil infusion ( p < 0.001). In conclusion, acute atrial ER can be demonstrated after only a 5-minute period of rapid atrial pacing in humans. Intravenous verapamil or procainamide does not abolish this ER process.     

Ibutilide added to propafenone for the conversion of atrial fibrillation and atrial flutter

OBJECTIVES: We evaluated the safety and efficacy of ibutilide when added to propafenone in treating both paroxysmal and chronic atrial fibrillation (AF) and atrial flutter (AFL). BACKGROUND: The effects of ibutilide in patients with paroxysmal or chronic AF/AFL who were pre-treated with propafenone have not been previously evaluated. METHODS: Oral propafenone was initially given in 202 patients with AF/AFL without left ventricular dysfunction. Intravenous ibutilide was administered in 104 patients in whom propafenone failed to convert the arrhythmia. Two different propafenone dosage regimens were used according to the duration of the presenting arrhythmia: patients with paroxysmal arrhythmia (n = 48) received 600 mg loading dose, and patients with chronic arrhythmia (n = 56) were receiving 150 mg three times a day as stable-dose pre-treatment. RESULTS: Ibutilide offered an overall conversion efficacy of 66.3% (69 of 104 patients), 70.8% for patients with paroxysmal AF/AFL and 62.5% for patients with chronic AF/AFL. Ibutilide significantly decreased the heart rate (HR) and further prolonged the QTc interval (p < 0.0001). The degree of HR reduction after ibutilide administration emerged as the sole predictor of successful arrhythmia termination (p < 0.001). After ibutilide, one patient (1%) developed two asymptomatic episodes of non-sustained torsade de pointes, and 10 patients (9.6%) manifested transient bradyarrhythmic events; however, all bradyarrhythmic effects were predictable, occurring mostly at the time of arrhythmia termination. None of 82 patients who decided to continue propafenone after successful cardioversion had immediate arrhythmia recurrence. CONCLUSIONS: Our graded approach using propafenone and ibutilide appears to be a relatively safe and effective alternative for the treatment of paroxysmal and chronic AF/AFL to both rapidly restore sinus rhythm in nonresponders to monotherapy with propafenone and prevent immediate recurrences of the arrhythmia.     

伊布利特逆转犬48小时房颤心房肌电重构作用研究

目的探讨国产富马酸伊布利特逆转犬48h房颤心房肌电重构的作用。方法健康成年杂种犬20只,随机分为快速起搏组（Pacing组,10只）和假手术组（Sham组,10只）。Pacing组通过右侧股静脉置入起搏电极,600次／min频率起搏高右房（HRA）制备房颤模型。48h后终止起搏,在心电和血液动力学监测下,给予国产富马酸伊布利特0．001m·kg^-1·min^-1静脉推注,房颤转复或累计剂量达0．04mg／kg停止给药。观察给药前后HRA的有效不应期（ERP,BCL=300ms）、传导速度（CV）、折返波长（WL）、频率自适应性、房颤诱发率等心房肌电生理指标的变化。结果Pacing组在起搏停止后,8只犬恢复窦律,2只犬持续房颤,给予伊布利特后1min内房颤终止。起博48h后,Pacing组ERP、CV、WL较Sham组减少,频率自适应性较Sham组降低,房颤诱发率明显增加;而给药后均恢复到起博前及Sham组水平。结论国产富马酸伊布利特能够逆转犬高右房快速起搏48h的心房肌电重构,有预防阵发性房颤发生的作用。其电药理学作用机制为：延长房颤时的心房不应期、心房肌电传导的速度及折返波长,提高心房肌频率的自适应性。     

Atrial effects of the novel K(+)-channel-blocker AVE0118 in anesthetized pigs

OBJECTIVES: AVE0118 is a novel blocker of the K(+) channels K(v)1.5 and K(v)4.3 which are the molecular basis for the human cardiac ultrarapid delayed rectifier potassium current (I(Kur)) and the transient outward current (I(to)). The objective of this study was to investigate the effect of AVE0118 on atrial refractoriness (ERP), left atrial vulnerability (LAV) and on left atrial monophasic action potentials (MAP) in pentobarbital anesthetized pigs in comparison to the selective I(Kr) blocker dofetilide in order to assess the therapeutic potential of the novel K(+) channel blocker for atrial fibrillation. METHODS: Atrial ERP was determined with the S1-S2-stimulus method in the free walls of left and right atrium at 240, 300 and 400 ms basic cycle length (BCL). The inducibility of mostly nonsustained atrial tachyarrhythmias by the premature S2 extrastimulus, which is very high in the left pig atrium and referred to as LAV, was evaluated before and after drugs. Left atrial epicardial MAP was recorded to study the influence of the potassium channel blockers on the time course of repolarization. Left ventricular epicardial MAP, ERP and QT interval were measured to investigate a possible effect of AVE0118 on ventricular repolarization. RESULTS: ERPs determined at 240, 300 and 400 ms BCL were significantly shorter in the left vs. right atrium (99+/-3, 106+/-4 and 113+/-3 ms vs. 133+/-4 ms, 142+/-4 and 149+/-5, respectively; p<0.001; n=21). AVE0118 administered i.v. dose-dependently prolonged the atrial ERP independent from rate and inhibited LAV (100% at 0.5 and 1 mg/kg) while having no effect at all on the corrected QT (QTc) interval. At 1 mg/kg (n=5) AVE0118 prolonged left vs. right atrial ERP by 49.6+/-4.1 ms vs. 37.7+/-9.7 ms (means+/-SEM of changes at 240, 300, and 400 ms BCL), respectively, corresponding to a relative increase of 53.2+/-6.2% vs. 27.6+/-6.8% (p<0.05 for percent increase of left vs. right atrial ERP). In a separate group of pigs (n=5) AVE0118 had no effect on left ventricular ERP at 333, 400 and 500 ms BCL and no effect on MAP duration and QT at 600 ms BCL. After 1 mg/kg of AVE0118 the atrial MAP was significantly prolonged already at 10% repolarization (P<0.05; n=7) reaching the maximum at 40% repolarization. In contrast to AVE0118 the effect of dofetilide (10 microg/kg) on atrial MAP started to become significant only at 60% repolarization (n=6) with a maximum increase at 90%. Dofetilide, which prolonged the QTc interval by 16.9% (P<0.001), had a significantly stronger effect on right (34.7+/-5 ms) vs. left atrial ERP (23.5+/-7 ms) at 300 ms BCL, respectively, but did not significantly inhibit LAV (14%; n=6). CONCLUSION: The novel K(+) channel blocker AVE0118 prolonged atrial ERP and showed strong atrial antiarrhythmic efficacy with no apparent effect on ventricular repolarization in pigs in vivo.     

Effects of verapamil and ibutilide on atrial fibrillation and postfibrillation atrial refractoriness

INTRODUCTION: Early recurrence of atrial fibrillation (AF) after cardioversion may be related to shortening of the atrial effective refractory period (ERP). This study compared the effects of verapamil and ibutilide on AF cycle length (AFCL), atrial ERP, and susceptibility to recurrent AF. METHODS AND RESULTS: In 33 adults, the atrial ERP was measured at basic drive CLs of 350 and 500 msec before and after a brief episode of pacing-induced AF. During AF, verapamil, ibutilide, or saline was infused in 11 patients each. Shortening of the post-AF atrial ERP was attenuated by verapamil and prevented by ibutilide. AFCL shortened by 32+/-21 msec in the verapamil group (P < 0.01), prolonged by 44+/-14 msec in the ibutilide group (P < 0.001), and did not change in the control group. AF converted to sinus rhythm within 10 minutes less often after verapamil (0%) than after ibutilide (82%) or than in the control group (73%). Post-AF, AF lasting > 10 minutes was induced more often in the verapamil group than in the ibutilide group (26% vs 0%; P = 0.01). Another 10 patients received verapamil or ibutilide in the absence of AF. Atrial ERP was unchanged after verapamil and prolonged after ibutilide. CONCLUSION: Verapamil shortens AFCL and impedes the conversion of induced AF, whereas ibutilide prolongs AFCL and does not impede the early conversion of induced AF. Ibutilide is more effective than verapamil in preventing pos