【作者】 李剑；

【导师】 王建安；

【作者基本信息】 浙江大学 ， 内科学（心血管病）， 2001， 硕士

【摘要】 [研究背景] 近年来，药物治疗心律失常的观念发生了重大的变化，抗心律失常药物的选择已由广泛使用Ⅰ类转为Ⅲ类。目前β受体阻滞剂能显著降低心脏猝死及总的心源性死亡率已经得到了肯定。同时具有β受体阻滞作用和Ⅲ类抗心律失常作用的索他洛尔（STL）因此受到重视，正日益广泛地被研究和应用。临床研究表明STL对多种房性和室性心律失常均有较好的疗效，尤其对传统药物治疗无效的危及生命的严重室性心律失常，STL的疗效更为突出。虽然，长期应用STL在许多研究中被证明是有效和安全的，但STL仍然有值得关注的不良反应，其中包括严重威胁生命的尖端扭转型室速（torsades de pionts，Tdp）和持续性的室速。 国内对STL的研究较少，而且内容较局限。国外已从电生理、血流动力学、临床疗效及副作用观察等方面对STL进行了较多的研究，其中在电生理方面多为离体动物实验或静息状态下的在体动物实验以及起搏状态下的人体研究，有关运动这一重要生理状态下STL对心脏电生理的研究很少，对此状态下心室复极变化的研究仅有一篇，目前还未见到从用药安全性的角度详细阐述运动状态下STL对心血管功能影响的报道。 运动状态是人体重要的生理状态，运动状态下的一系列生理变化与许多疾 浙江大学硕士学位论文病状态时的生理变化相似，所以阐述运动状态下STL对心血管功能的影响，并探讨此状态下服药的安全性，对于器质性心脏病患者以及经常从事体育运动的服用者都有一定的指导意义。 l研究目的和内容］ ①察运动生理状态下，口服STL对心率、血压、心室复极、心室内传导、 心肌耗氧、心力储备、活动耐量等方面的影响。 ②基于对运动过程中上述心血管功能改变的观察，探讨运动状态对STL用 药安全性的影响。 【研究方法］本研究采用随机。双盲、安慰剂及心得安、自身交叉对照设计，以31例无明显器质性心脏病患者为研究对象，用活动平板运动试验进行研究。每例入选对象进行运动试验3次，每次随机口服单剂索他洛尔、心得安或安慰剂中的一种。 ［研究结果］ 1．与安慰剂对照，STL显著降低静息和运动高峰时的心率（STL分别为68．85 土9石6和 132．56土18刀0次／min，n＝30，P＜0刀of；安慰剂分别为 89刀0士9石1 和164．19土旧二6次加Zn，n＝3O，P＜0刀01），与心得安对照无显著差异。 2，与安慰剂对照，STL显著降低静息和运动高峰时的收缩压（STL分别为 105。33士13二5和 129三 士刀刀ommHg，n。30尸＜0．001：安慰剂分别为门石3 土15．74和141。50士14，59mmHg，n－30，P＜0刀of），与心得安对照无显著差 异。 3．STL显著延长静息时的 QTC和 JTC间期旧TC为 324．86土4．4QmS，JTC 为 245刀4士5刀oms）与安慰齐u旧TC为 314刀6士3．58Ins，JTc为 232石9士 4．04SS）对照分另uP＜0．of和 P＜0．00］；与心得安对照旧TC为 305，21土3．54SS， JTC为 224二士4．09＜S），分另0 P＜0．001和 P＜0，001。运动后月安慰齐时 QT＊ 和 JTC逐渐缩短，服 STL和心得安则先延长然后缩短。而且服 STL的 JTC 3 浙江大学硕士学位论文 缩短率（dJT。％）随运动级别的递增而增加，并与HR呈显著正相关（r—0．148； p＜0刀］），达运动高峰时盯L的订C间期仍显著长于安慰剂和心得安，但与 两者之间差异的显著性减小（与安慰剂和心得安对照，分别P＜O．01和0．05）， 显示运动过程中STL对心室复极具有逆频率依赖特性。 4静息状态时，口服安慰剂，女性的JT。为249．01士14．87ms，男性为223。09 士18刀gms，女性显著长于男性（p＜0刀01）；口服STL后，女性的JTC为271刀5 士18．09ms；男性为229厂5士15．59ms，女性也显著长于男性（p＜0．001），服 药前后厂c的变化率女性9．03士7．58o，男性3．33土7．43％，女性显著大于 男性（P＜0．01）。服 STL和安慰剂的最大肝c缩短率（max d JTC0）（运动 高峰比静息）女性均显著大于男性。而口服心得安时，女性的（max d JTc％） 也大于男性，但无统计学差异。 5．口服 STL，静息或运动备时段的 QRS fd期与口服心得安和安慰剂无显著 差异。 6．sTL显著降低静息和运动高峰时的心率－收缩压乘积（分别为7236．44土 12刀厂3和1N02．54士犯23．85次m＜＊旮Zn〕，与安慰剂对照均P＜0刀of 与心得安对照无显著差异。 7．口服STL者的运动时间为16＊ 土3．44min与服安慰剂和心得安对照（分 别为历．21士4．51和 16儿1士4刀3min）均无显著差异。 ［结论1一．STL降低静息、运动过程中和运动高峰时的心率、收缩压；此外，还降低 静息和运动各时段的心肌耗氧量，增加心力储备，这些作用主要是STL的 e受体阻滞作用所致。二．运动状态下，STL延缓心室复极的作?更多还原

【Abstract】 [Background] During recent years, the focus on antiarrhythmic drug therapy has shifted from the widespread use of Class I antiarrhythmic agents to an increasingly frequent administration of Class III compounds. Moreover the P blockder has been proved to be able to decrease the mortality in cardiovascular incidence. Sotalol as an antiarrhythmic agent with both Class III and P -block activities is increasingly widely used and studied. Clinical trial has confirmed the efficiency of sotalol in treating a lot of atrial and ventricular arrhythmia, special for some serious ventricular arrhythmias which are obstinate to traditional antiarrhythmics. Although long-term use of sotalol has been proved to be both efficient and safe by several trials. But sotalol still has certain extent proarrhythmia effect, including its resulting in torsade de pointes(Tdp) and ventricular tachyarrhythmias. Domestic study on stalol is not adeqate. Extensive researches have been made abroad on the electrophysiology, hemodynamics, the efficiency of antiarrhythmia and side effects of sotalol. Most of the studies on its electrophysiology are animal experiments or studies6on human under slow pacing. Research on the electrophysiology of sotalol during exercise in human is not enough. There is only one article demonstrates the rate dependence effect of sotalol on ventricular repolarization during exercise in human. There is no study so far reporting the effects of sotalol on cardiovascular physiology during exercise in human from the aspect of safety.Exercise is an important physiological state for human. Series of physiologic changes during exercise are similar to changes under the condition of disease. To demonstrate the effects of sotalol on cardiovascular physiology and to explore the safety of sotalol therapy during exercise may be helpful to patients with structive heart disease and to patients who often need to exercise.[Purpose]oTo observe the effects of single dose of sota]ol on heart rate, systolic blood pressure, ventricular repolarization and intraventricular conduct, the cardiac oxygen consumption and working power reservation, exercise tolerance and so on.?To explore the safety of sotalol therapy during exercise on the basis of the observations above.[Method] A design of randomization, double blind, auto-control with placebo and propranolo] is employed in the study. Thirty-one patients without overt heart disease are enrolled in the study. Each of them performed treadmill exercise tests for 3 times at an interval of seven days after being treated with single dose of sota]ol(lOOmg), placebo or propranolol(3Omg).[ResultloSotalol significantly decreases the heart rate by 24% at rest and by 20% at peak of the exercise. But in comparison with propranolol, there is no significant difference between them.7?Sotalol significantly decreases the systolic blood pressure by 10% at rest and by 7% at peak of the exercise. But in comparsion with propranolol, there is no significant difference between them.?Sotalol significant prolongs the QTc and JTc intervals at rest in comparison with placebo(324.86?.4Oms vs.314.06?.58 ms in QTc, p<O.Ol and 245.04?5.OOms vs. 232.69 ?4.O4ms in JTc, p<O.OOI )or propranolol (324.86 ?4.4Oms vs.305.21 ?.54 ms in QTc, p<O.OOl and 245.04?.OOms vs. 224.17?.O9ms in JTc, p<O.OO1 ). The QTc and JTc are reduced since the beginning of exercise after the admimistration of placebo. But the QTc and JTc were not shortened after either being treated either with sotalol or with propranolol at lower stage of exercise. The percent JTc reduction from rest to present stage( J iTc%) was increased with the grade up of exercise stage. There is a positive correlation between ~ JTc% with the heart rate(r0.148,p<O.Ol). To peak of the exercise, the JTc of sotalol therapyy remains longer than that of placebo and of propranolol.OThe JTc intervals is more significant in female than that in male after being treated with sotalol ,更多还原