CRT_D介导室性心动过速的研究进展

心室再同步心脏转复除颤器(CRT_D)可有效改善心力衰竭(CHF)患者的运动耐量和生活质量,预防猝死,提高生存率,但CRT_D植入后由于心室激动顺序的改变,使QT间期延长、跨室壁复极离散度(TDR)增加,潜在致室性心律失常风险;且CHF患者通常存在心肌解剖改变,传导的不均一性,也为折返性心动过速的发生提供了维持的机制;而多次电击也可导致肌钙蛋白升高,引起心肌损伤,局部心肌复极离散度增加(DRVR)和QT间期延长,以及电除颤后心肌纤维化和急性细胞损伤,反复室速、室颤也会引起进行性左心功能不全、心肌细胞凋亡、恶化心律失常基质和增加心律失常易感性。CRT_D潜在致室性心律失常作用逐渐引起人们的重视,本文就近年来CRT_D致室性心律失常的电生理机制与临床防治对策等做一综述。     

心室不同部位起搏对正常犬和扩张型心肌病心力衰竭犬模型在体心肌跨室壁复极离散的影响

实验以正常犬和扩张型心肌病心力衰竭犬(dilated cardiomyopathy congestive heart failure,DCM-CHF)模型为对象、以心肌跨室壁复极离散的相关参数为指标,研究左心室心外膜起搏、双心室起搏(模拟临床上心室再同步治疗的方法)后的心肌电生理特性变化。实验以快速右心室起搏的方法制备DCM-CHF犬模型;正常犬和DCM-CHF犬均经射频消融希氏束制备三度房室传导阻滞模型;采用同步记录犬体表心电图和内膜下、中层、外膜下三层心肌单相动作电位(monophasic action potentials,MAP)的方法,测定不同部位起搏时的QT间期、Tpeak-Tend(Tp-Te)间期和三层心肌的单相动作电位时程(MAP duration,MAPD)、跨室壁复极离散度(transmural dispersion of repolaization,TDR)。结果显示:在正常犬,左室心外膜与双心室起搏后三层心肌的MAPD均延长,同时TDR增大(左室心外膜起搏47.16 ms、双心室起搏37.54 ms、右室心内膜起搏26.75 ms,P<0.001),体表心电图Tp-Te间期的变化与之平行;在DCM-CHF犬较正常犬已表现出中层心肌MAPD延长(276.30 ms vs 257.35 ms,P<0.0001)和TDR(33.8 ms vs 27.58 ms,P=0.002)增大的基础上,左室心外膜参与起搏后仍进一步使三层心肌的MAPD延长和TDR增大。研究结果提示,左室心外膜起搏和双心室起搏后使内膜下、中层     

表征心室复极不一致有效参数的仿真研究

建立了从心内膜到心外膜的一维心肌几何模型,采用心肌双域模型建立心电电位的仿真模型,通过改变缺血程度构造不同的心室复极不一致状态,利用有限差分法求解控制方程,模拟了心电兴奋在心室复极不一致状态下形成的心电电位,并从中提取QT离散度和兴奋恢复间期(activation-recovery interval,ARI)离散度。分析结果显示：缺血区与正常区电位的QT间期没有明显差异,QT离散度接近于零,不能有效地表征心室肌复极不一致;缺血区ARI明显区别于正常区,ARI离散度与缺血程度有很好的对应关系,可以用来表征心室复极不一致。     

牛磺酸镁抗豚鼠尖端扭转型室速的作用研究

目的：研究牛磺酸镁配位化合物（TMCC）抗豚鼠心脏尖端扭转型室速（TdP）的作用。方法：取健康、体重250~300 g的成年雄性豚鼠,随机分为4组：① TdP模型组（n=7）：离体心脏以K-H灌流液灌流20 min,然后使用IKs阻滞剂10μmol/L Chromanol 293B合并低钾（钾离子浓度为1.8 mmol/L）进行灌流,建立TdP模型。②~④ TdP模型+TMCC低中高浓度组（n=6）：正常灌流稳定20 min后,在建立TdP模型的同时分别给予1、2、4 mmol/L TMCC。采用Langendorff逆行主动脉灌流法灌流豚鼠离体心脏,利用Biopac电生理记录仪采集并记录豚鼠离体心脏表面心电图。从心电图第Ⅱ导联图形获取各组豚鼠离体心脏TdP发生率、跨室壁复极离散度、QT间期不稳定性,以观察TMCC对TdP的影响。观测指标量取时间分别为：豚鼠离体心脏正常灌流20 min时、TdP发生前及给药60 min时。结果：TdP模型组的TdP发生率为6/7。1、2、4mmol/L TMCC可降低TdP发生率,三组TdP发生率分别为5/6、1/6、0/6。与给药前相比,TdP模型组中Chromanol 293 B合并低钾可使豚鼠离体心脏校正后的跨室壁复极离散度显著增大（P<0.01）;与TdP模型组相比,TdP模型+1、2、4mmol/L TMCC组可明显减弱Chromanol 293B合并低钾导致的豚鼠离体心脏校正后的跨室壁复极离散度增大（P>0.05）。与模型组相比,2、4mmol/L TMCC明显降低Chromanol 293B合并低钾导致的QT间期不稳定增大（P<0.05）。在TdP模型建立过程中,从心电图中可观察到连续多个心动周期的P波消失,而在TdP模型+TMCC组中,心电图始终拥有独立P波。结论：TMCC可通过降低离体心脏跨室壁复极离散度和QT间期不稳定性以及抑制早后除极的发生而发挥抗TdP作用,降低TdP发生率。     

晚钠电流在获得性心血管病合并心律失常发生中的作用及其意义

心肌细胞的晚钠电流出现于动作电位的复极期,正常心肌细胞存在内源性晚钠电流,幅度小;晚钠电流幅度增大可见于长QT综合征3、4、9、10和12型,也见于多种病理及药物作用下,导致动作电位时程延长,诱发恶性室性心律失常,如尖端扭转型室性心动过速等;同时由于平台期延长,钙离子内流时间延长,改变心肌收缩力并参与钙相关心律失常的发生。近年来,随着对心血管疾病及其合并心律失常发病机制的深入认识,发现越来越多的获得性心血管疾病患者心律失常的发生与晚钠电流异常增大相关,极大地扩大了晚钠电流相关心律失常的范畴,选择性晚钠电流抑制剂已成为抗心律失常药物新的亚类。     

酸中毒后室性心律失常仿真研究

本文旨在分析酸中毒对心脏电生理活动的影响,探讨其诱发室性心律失常的机制.首先建立了具有pH和钙/钙调素依赖蛋白激酶Ⅱ(calcium/calmodulin dependent protein kinaseⅡ,Ca MKⅡ)调控作用的人体心室酸中毒计算模型,然后模拟了酸中毒过程中细胞和组织电活动的变化,并定量分析了心电图的改变情况.实验结果表明:在酸中毒期间,细胞动作电位时程的缩短和复极离散度的降低导致心电图QT间期缩短、T波幅值和宽度减小.同时,细胞静息电位的抬高和最大去极化速率的降低也促进了组织电兴奋的缓慢传导和传导阻滞.另外,酸中毒后的初期,肌浆网钙超载促进钙释放增多,导致细胞产生延迟后除极(delayed afterdepolarization,DADs),使心电图上表现为室性早搏.而缓慢传导、传导阻滞和室性早搏有利于折返波的产生,进而发展为室速.因此,酸中毒后细胞的触发活动是诱发室性心律失常的主要原因之一.     

氧自由基的损伤程度决定制动应激对损伤心脏心室电稳定性的影响

本文比较了在制动应激过程中正常及阿霉素心肌损伤大鼠心室电稳定性（ＶＥＳ）的变化间的差异。应激各时程,ｉｖｇｔｔ乌头碱（０．８μｇ／ｍｉｎ）,心肌损伤大鼠出现心律失常的潜伏期均较正常鼠明显缩短,说明其较正常大鼠更易发生心律失常。正常大鼠随应激时程的延长,ＶＥＳ变化表现为先降后升,而阿霉素大鼠制动２ｈ,室速、室颤潜伏期及其持续时间虽也显著缩短,但制动８ｈ心律失常发生却无明显改变,提示持续制动应激对正常     

小鼠心肌肥厚发展过程中心电图动态变化

目的：探讨小鼠心肌肥厚发展过程中心电图的动态变化。方法：复制小鼠压力超负荷性心肌肥厚模型,连续动态监测小鼠从心肌肥厚早期至心力衰竭发展过程中的不同阶段体表心电图改变。结果：①对照组和模型组术后2周内小鼠未见自发性心律失常,而模型组术后5周、9周和13周小鼠出现自发性心律失常,主要表现为频发的室性早搏以及阵发性室性心动过速,心律失常发生率分别为15％、28％和63％。②与同期对照相比,术后2周、5周、9周和13周组动物伽间期以及帆间期明显延长,分别延长20．4％、32．7％、49．7％、61．0％和27．1％、32．1％、43．9％、59．1％（P〈0．01）。③心肌肥厚小鼠心电图的另一个特征为J波变化。所有对照组动物心电图均为正向J波,而模型组动物从2周开始J波正向值下降,5周逐渐变平,到13周时完全翻转。④与同期对照相比,模型组的PR间期没有改变,但术后2周RR问期轻微缩短。结论：心肌肥厚小鼠自发性心律失常发生率逐渐增加,QT间期进行性延长,J波幅值逐渐降低,表明随着疾病的进展心室复极化异常逐渐加重。     

面向短QT综合征的药物作用建模与仿真研究

短QT综合征(short QT syndrome,SQTS)是以心电图QT间期、心室和心房不应期明显缩短为主要显性特征,并伴有晕厥、高发心源性猝死(sudden cardiac death,SCD)和恶性心律失常风险的一类遗传性心肌离子通道病.据目前资料信息,关于SQTS致病机理的报道比较多,而对SQTS药物治疗的报道罕见.为了揭示在SQTS下的药物作用,本文通过计算机仿真构建人体心室细胞和组织的药物作用模型,利用该模型,从亚细胞、细胞、组织三个尺度,模拟SQT1、SQT2和SQT3下的普罗帕酮药物作用过程,并仿真心电图的变化情况.仿真结果表明:在SQT1下普罗帕酮延长了动作电位时程(action potential duration,APD)和心电图QT间期,并降低T波幅值;相反,在SQT2和SQT3下普罗帕酮缩短了APD和QT间期.计算使用药物前后细胞间膜电压和APD空间离散度的变化,定量分析了普罗帕酮降低T波振幅的原因.总之,对SQT1,普罗帕酮有效;对SQT2和SQT3,普罗帕酮没有改变其致心律失常的危险.仿真结果为普罗帕酮用于临床治疗SQTS提供理论参考.     

Tp-e间期、P波离散度对室性心律失常病情的预测价值

摘要 目的：探讨Tp-e间期、P波离散度(Pd)对室性心律失常病情的预测价值。方法：2016年6月到2018年6月选择在本院诊治的心绞痛患者110例,所有患者都给予动态心电图检查,记录Tp-e间期、Pd值与室性心律失常发生情况。随访患者的心绞痛复发情况,并判定预测价值。结果：在110例患者中,发生室性心律失常48例(失常组),发生率为43.6 %,其中偶发室早21例、频发室早19例、室早4例、心室颤动3例、室性心动过速1例。失常组的Tp-e间期、Pd值都显著高于非失常组(P<0.05)。随访至今,失常组的心绞痛复发率为45.8 %,显著低于对照组的8.1 %(P<0.05)。在失常组中,单因素与多因素logistics回归分析显示Tp-e间期、Pd都为影响患者心绞痛复发的重要因素(P<0.05)。ROC曲线分析显示Tp-e间期、Pd预测心绞痛复发的敏感性与特异性都在85.0 %以上。结论：心绞痛合并室性心律失常患者多伴随有Tp-e间期、Pd增加,也会增加患者的复发率,Tp-e间期、Pd对预测室性心律失常复发情况具有重要价值。     

Genetic determinants of QT interval variation and sudden cardiac death

Electrocardiographic QT interval prolongation or shortening is a risk factor for sudden cardiac death. The study of Mendelian syndromes in families with extreme long and short QT interval duration and ventricular arrhythmias has led to the identification of genes encoding ion channel proteins important in myocardial repolarization. Rare mutations in such ion channel genes do not individually contribute substantially to the population burden of ventricular arrhythmias and sudden cardiac death. Only now are studies systematically testing the relationship between common variants in these genes--or elsewhere in the genome--and QT interval variation and sudden cardiac death. Identification of genetic variation underlying myocardial repolarization could have important implications for the prevention of both sporadic and drug-induced arrhythmias.     

Role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes

This review examines the role of spatial electrical heterogeneity within the ventricular myocardium on the function of the heart in health and disease. The cellular basis for transmural dispersion of repolarization (TDR) is reviewed, and the hypothesis that amplification of spatial dispersion of repolarization underlies the development of life-threatening ventricular arrhythmias associated with inherited ion channelopathies is evaluated. The role of TDR in long QT, short QT, and Brugada syndromes, as well as catecholaminergic polymorphic ventricular tachycardia (VT), is critically examined. In long QT syndrome, amplification of TDR is often secondary to preferential prolongation of the action potential duration (APD) of M cells; in Brugada syndrome, however, it is thought to be due to selective abbreviation of the APD of the right ventricular epicardium. Preferential abbreviation of APD of the endocardium or epicardium appears to be responsible for the amplification of TDR in short QT syndrome. In catecholaminergic polymorphic VT, reversal of the direction of activation of the ventricular wall is responsible for the increase in TDR. In conclusion, long QT, short QT, Brugada, and catecholaminergic polymorphic VT syndromes are pathologies with very different phenotypes and etiologies, but they share a common final pathway in causing sudden cardiac death.     

Modeling of IK1 mutations in human left ventricular myocytes and tissue

Elucidation of the cellular basis of arrhythmias in ion channelopathy disorders is complicated by the inherent difficulties in studying human cardiac tissue. Thus we used a computer modeling approach to study the mechanisms of cellular dysfunction induced by mutations in inward rectifier potassium channel (K(ir))2.1 that cause Andersen-Tawil syndrome (ATS). ATS is an autosomal dominant disorder associated with ventricular arrhythmias that uncommonly degenerate into the lethal arrhythmia torsade de pointes. We simulated the cellular and tissue effects of a potent disease-causing mutation D71V K(ir)2.1 with mathematical models of human ventricular myocytes and a bidomain model of transmural conduction. The D71V K(ir)2.1 mutation caused significant action potential duration prolongation in subendocardial, midmyocardial, and subepicardial myocytes but did not significantly increase transmural dispersion of repolarization. Simulations of the D71V mutation at shorter cycle lengths induced stable action potential alternans in midmyocardial, but not subendocardial or subepicardial cells. The action potential alternans was manifested as an abbreviated QRS complex in the transmural ECG, the result of action potential propagation failure in the midmyocardial tissue. In addition, our simulations of D71V mutation recapitulate several key ECG features of ATS, including QT prolongation, T-wave flattening, and QRS widening. Thus our modeling approach faithfully recapitulates several features of ATS and provides a mechanistic explanation for the low frequency of torsade de pointes arrhythmia in ATS.     

Role of hERG potassium channel assays in drug development

Numerous structurally and functionally unrelated drugs block the hERG potassium channel. HERG channels are involved in cardiac action potential repolarization, and reduced function of hERG lengthens ventricular action potentials, prolongs the QT interval in an electrocardiogram, and increases the risk for potentially fatal ventricular arrhythmias. In order to reduce the risk of investing resources in a drug candidate that fails preclinical safety studies because of QT prolongation, it is important to screen compounds for activity on hERG channels early in the lead optimization process. A number of hERG assays are available, ranging from high throughput binding assays on stably expressed recombinant channels to very time consuming electrophysiological examinations in cardiac myocytes. Depending on the number of compounds to be tested, binding assays or functional assays measuring membrane potential or Rb+ flux, combined with electrophysiology on a few compounds, can be used to efficiently develop the structure-function relationship of hERG interactions.     

Role of hERG potassium channel assays in drug development

Numerous structurally and functionally unrelated drugs block the hERG potassium channel. HERG channels are involved in cardiac action potential repolarization, and reduced function of hERG lengthens ventricular action potentials, prolongs the QT interval in an electrocardiogram, and increases the risk for potentially fatal ventricular arrhythmias. In order to reduce the risk of investing resources in a drug candidate that fails preclinical safety studies because of QT prolongation, it is important to screen compounds for activity on hERG channels early in the lead optimization process. A number of hERG assays are available, ranging from high throughput binding assays on stably expressed recombinant channels to very time consuming electrophysiological examinations in cardiac myocytes. Depending on the number of compounds to be tested, binding assays or functional assays measuring membrane potential or Rb(+) flux, combined with electrophysiology on a few compounds, can be used to efficiently develop the structure-function relationship of hERG interactions.     

Acute Effects of Sex Steroid Hormones on Susceptibility to Cardiac Arrhythmias: A Simulation Study

Acute effects of sex steroid hormones likely contribute to the observation that post-pubescent males have shorter QT intervals than females. However, the specific role for hormones in modulating cardiac electrophysiological parameters and arrhythmia vulnerability is unclear. Here we use a computational modeling approach to incorporate experimentally measured effects of physiological concentrations of testosterone, estrogen and progesterone on cardiac ion channel targets. We then study the hormone effects on ventricular cell and tissue dynamics comprised of Faber-Rudy computational models. The “female” model predicts changes in action potential duration (APD) at different stages of the menstrual cycle that are consistent with clinically observed QT interval fluctuations. The “male” model predicts shortening of APD and QT interval at physiological testosterone concentrations. The model suggests increased susceptibility to drug-induced arrhythmia when estradiol levels are high, while testosterone and progesterone are apparently protective. Simulations predict the effects of sex steroid hormones on clinically observed QT intervals and reveal mechanisms of estrogen-mediated susceptibility to prolongation of QT interval. The simulations also indicate that acute effects of estrogen are not alone sufficient to cause arrhythmia triggers and explain the increased risk of females to Torsades de Pointes. Our results suggest that acute effects of sex steroid hormones on cardiac ion channels are sufficient to account for some aspects of gender specific susceptibility to long-QT linked arrhythmias.     

On-chip constructive cell-network study (II): on-chip quasi-in vivo cardiac toxicity assay for ventricular tachycardia/fibrillation measurement using ring-shaped closed circuit microelectrode with lined-up cardiomyocyte cell network

Backgrounds

Conventional in vitro approach using human ether-a-go-go related gene (hERG) assay has been considered worldwide as the first screening assay for cardiac repolarization safety. However, it does not always oredict the potential QT prolongation risk or pro-arrhythmic risk correctly. For adaptable preclinical strategiesto evaluate global cardiac safety, an on-chip quasi-in vivo cardiac toxicity assay for lethal arrhythmia (ventricular tachyarrhythmia) measurement using ring-shaped closed circuit microelectrode chip has been developed.

Results

The ventricular electrocardiogram (ECG)-like field potential data, which includes both the repolarization and the conductance abnormality, was acquired from the self-convolutied extracellular field potentials (FPs) of a lined-up cardiomyocyte network on a circle-shaped microelectrode in an agarose microchamber. When Astemisol applied to the closed-loop cardiomyocyte network, self-convoluted FP profile of normal beating changed into an early afterdepolarization (EAD) like waveform, and then showed ventricular tachyarrhythmias and ventricular fibrilations (VT/Vf). QT-prolongation-like self-convoluted FP duration prolongation and its fluctuation increase was also observed according to the increase of Astemizole concentration.

Conclusions

The results indicate that the convoluted FPs of the quasi-in vivo cell network assay includes both of the repolarization data and the conductance abnormality of cardiomyocyte networks has the strong potential to prediction lethal arrhythmia.     

Preclinical cardio-safety assessment of torsadogenic risk and alternative methods to animal experimentation: The inseparable twins

The last decade has been marked by the withdrawal from the market of several medicines whose use in patients has been associated with the development of torsade de pointes (TdP), a potentially life-threatening polymorphic tachycardia. In a few cases, TdP can degenerate into ventricular fibrillation and lead to sudden death, thus constituting a real problem of public health. The recently finalized ICH S7B guideline defines the prolongation of the QT interval on the electrocardiogram as the best biomarker for predicting the torsadogenic risk of a given compound. However, a growing body of evidence suggests that drugs’ torsadogenic potential may not necessarily be proportional to their ability to prolong the QT interval. It is a dynamic combination of multiple predisposing factors and components rather than a single particular event that can trigger this particular tachycardia. Following recommendations of the guideline, pharmaceutical companies have intensively implemented methodologies to assess the possible risk of QT prolongation and TdP in humans. The main problem in cardiac safety pharmacology is how best to combine the capabilities of different methodologies with their strengths and limitations in order to detect the potential of one molecular entity to induce a lethal arrhythmia of very low clinical incidence. This publication will review the current methodologies, focusing on the alternative methods to animal experimentation, including an overview of cardiac modeling.     

The QT Interval and Selection of Alpha-Blockers for Benign Prostatic Hyperplasia

The QT interval is the electrocardiographic manifestation of ventricular depolarization and repolarization. Drug-induced long QT syndrome is characterized by acquired, corrected QT (QTc) interval prolongation that is associated with increased risk of torsade de pointes. Every physician must recognize if the drugs he or she prescribes prolongs the QTc interval, especially if the drug is prescribed for a chronic condition in older patients who are on polypharmacy. The evolution of alpha-blockers for the treatment of benign prostatic hyperplasia has allowed the development of drugs that are easier to administer and better tolerated. Because alpha-blockers generally have equivalent efficacy, this class of drugs is typically differentiated by safety and side effects. Studies suggest that alpha-blockers may vary in regard to their effect on the QT interval, and, therefore, on their predisposition to cause potentially life-threatening ventricular arrhythmias.