多态T 波区间检测技术的研究

目的:利用小波变换进行T波区间的检测。方法:在23尺度上通过模极大值法定位R波。在24尺度上首先根据R峰以及T波起点和终点的经验值确定起始T波区间。然后对每个心拍在此区间上找到T波的模极大值,根据模极值的个数和正负顺序确定T波波形的形态。由于不同形态的T波对应不同的T波起点和终点的检测方法,实现T波区间的分类检测,提高T波检测的精确度。由于本文算法是作为T波交替检测的前期工作,为了验证算法的准确率,采用了QT数据库中的部分记录进行了仿真,评价实验结果。结果:仿真实验证明了本文算法能正确地分辨出每个T波的形态,并在此基础上得到较为准确的T波区间。结论:本文采用模极大值算法根据T波的不同形态进行T波区间的分类检测,检测结果比较理想,且计算简单,较易实现。     

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.     

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.     

Risk factors for drug-induced long-QT syndrome

Congenital long-QT syndrome (cLQTS) is a ventricular arrhythmia that is characterised by a prolonged QT interval on the surface electro-cardiogram (ECG). Clinical symptoms include sudden loss of consciousness (syncopes), seizures, cardiac arrest and sudden death. The prevalence of this inherited disease is approximately one in 10,000 in Caucasians. Over the last decade, more than 200 different diseases causing mutations have been identified in five genes that encode ion channels involved in the delicate balance of inward and outward K/Ca currents during the cardiac action potential. A prolonged QT interval accompanied by very similar clinical symptoms as in cLQTS can also occur in otherwise healthy individuals after the intake of specific drug(s). This phenomenon is known as ''acquired'' or ''drug-induced'' long-QT syndrome. Because the clinical symptoms of the two forms are very similar, the question arises whether a common underlying genetic basis also exists. Several studies indicate that only a minority (approximately 10%) of the drug-induced LQTS cases can be explained by a mutation or polymorphism in one of the known LQTS genes. Even though the disease can often at least partially be explained by environmental factors, mutations or polymorphisms in other genes are also expected to be involved, including genes encoding drug-metabolising enzymes, adrenergic receptors, hormone-related genes and mitochondrial genes. This article reviews the current knowledge on risk factors for drug-induced LQTS, with a special emphasis on the role of genetic determinants.     

Dependence of the vulnerability index on the heart cycle length

Index of vulnerability is a parameter based on ventricular gradient evaluating the risk of arrhythmia development. The index is derived from isointegral maps of the QT interval. Individual characteristics of isointegral maps are influenced by different factors, which contribute to the relatively high variability among measured parameters of maps in measured subjects. While several electrocardiographic indexes have been introduced, there are only few studies of their dependence on heart rate. In this study we set out to establish the dependence of vulnerability index on the RR interval or heart rate in healthy population. A positive linear correlation between RR intervals and mean and minimum values of vulnerability indexes was found.     

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.     

Pharmacometabolomic Approach to Predict QT Prolongation in Guinea Pigs

Drug-induced torsades de pointes (TdP), a life-threatening arrhythmia associated with prolongation of the QT interval, has been a significant reason for withdrawal of several medicines from the market. Prolongation of the QT interval is considered as the best biomarker for predicting the torsadogenic risk of a new chemical entity. Because of the difficulty assessing the risk for TdP during drug development, we evaluated the metabolic phenotype for predicting QT prolongation induced by sparfloxacin, and elucidated the metabolic pathway related to the QT prolongation. We performed electrocardiography analysis and liquid chromatography–mass spectroscopy-based metabolic profiling of plasma samples obtained from 15 guinea pigs after administration of sparfloxacin at doses of 33.3, 100, and 300 mg/kg. Principal component analysis and partial least squares modelling were conducted to select the metabolites that substantially contributed to the prediction of QT prolongation. QTc increased significantly with increasing dose (r = 0.93). From the PLS analysis, the key metabolites that showed the highest variable importance in the projection values (>1.5) were selected, identified, and used to determine the metabolic network. In particular, cytidine-5′-diphosphate (CDP), deoxycorticosterone, L-aspartic acid and stearic acid were found to be final metabolomic phenotypes for the prediction of QT prolongation. Metabolomic phenotypes for predicting drug-induced QT prolongation of sparfloxacin were developed and can be applied to cardiac toxicity screening of other drugs. In addition, this integrative pharmacometabolomic approach would serve as a good tool for predicting pharmacodynamic or toxicological effects caused by changes in dose.     

Methods of assessment and clinical relevance of QT dynamics

The dependence on heart rate of the QT interval has been investigated for many years and several mathematical formulae have been proposed to describe the QT interval/heart rate (or QT interval/RR interval) relationship. While the most popular is Bazett's formula, it overcorrects the QT interval at high heart rates and under-corrects it at slow heart rates. This formulae and many others similar ones, do not accurately describe the natural behaviour of the QT interval. The QT interval/RR interval relationship is generally described as QT dynamics. In recent years, several methods of its assessment have been proposed, the most popular of which is linear regression. An increased steepness of the linear QT/RR slope correlates with the risk of arrhythmic death following myocardial infarction. It has also been demonstrated that the QT interval adapts to heart rate changes with a delay (QT hysteresis) and that QT dynamics parameters vary over time. New methods of QT dynamics assessment that take into account these phenomena have been proposed. Using these methods, changes in QT dynamics have been observed in patients with advanced heart failure, and during morning hours in patients with ischemic heart disease and history of cardiac arrest. The assessment of QT dynamics is a new and promising tool for identifying patients at increased risk of arrhythmic events and for studying the effect of drugs on ventricular repolarisation.     

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.     

Pharmacogenetic issues in thorough QT trials

Drug-induced QT prolongation (DI-LQT), through its associated arrhythmias, is a leading cause of drugs being withdrawn from the market. As a consequence, the US FDA and other regulatory agencies are mandating that all new drugs go through a so-called 'Thorough QT' (TQT) study to evaluate the potential for 'QT liability', specifically the potential for a drug to cause a discernible increase in the QT interval. Several genetic factors that modulate the risk of DI-LQT have been discovered. These are genes responsible for the congenital long QT syndrome, drug metabolism genes (mainly CYP2D6 and CYP3A4), and genes in other regulatory pathways. Here, we briefly review the links between genetic variants and drug-induced QT risk, and propose approaches to consider for using pharmacogenetics in planning and analyzing TQT studies.     

Repolarisation and vulnerability to re-entry in the human heart with short QT syndrome arising from KCNQ1 mutation--a simulation study

Idiopathic short QT syndrome (SQTS) is a recently identified, genetically heterogeneous condition characterised by abbreviated QT intervals and an increased susceptibility to arrhythmia and sudden death. This simulation study identifies mechanisms by which cellular electrophysiological changes in the SQT2 (slow delayed rectifier, I_Ks, -linked) SQTS variant increases arrhythmia risk. The channel kinetics of the V307L mutation of the KCNQ1 subunit of the I_Ks channel were incorporated into human ventricular action potential (AP) models and into 1D and 2D transmural tissue simulations. Incorporating the V307L mutation into simulations reproduced defining features of the SQTS: abbreviation of the QT interval, and increases in T wave amplitude and T_peak–T_end duration. In the single-cell model, the V307L mutation abbreviated ventricular cell AP duration at 90% repolarisation (APD₉₀) and increased the maximal transmural voltage heterogeneity (δV) during APs; this resulted in augmented transmural heterogeneity of APD₉₀ and of the effective refractory period (ERP). In the intact tissue model, the vulnerable window for unidirectional conduction block was also increased. In 2D tissue the V307L mutation facilitated and maintained reentrant excitation. Thus, in SQT2 increases in transmural heterogeneity of APD, δV, ERP and an increased vulnerable window for unidirectional conduction block generate an electrical substrate favourable to reentrant arrhythmia.     

A common variant in SLC8A1 is associated with the duration of the electrocardiographic QT interval

Prolongation of the electrocardiographic QT interval, a measure of cardiac repolarization, predisposes one to ventricular arrhythmias and sudden cardiac death. Since NOS1AP, a regulator of neuronal nitric oxide synthase, was discovered in a genome-wide association study (GWAS) as a novel target that modulates cardiac repolarization, several loci have been linked to the QT interval in studies (QTGEN and QTSCD) of European descendents. However, there has been no GWAS of the QT interval in Asian populations. We conducted a GWAS with regard to the QT interval in Korea Association Resource (KARE [n = 6,805]) cohorts. Replication studies in independent populations of Korean (n = 4,686) and Japanese (n = 2,687) groups validated the association between a SNP, rs13017846, which maps to near SLC8A1 (sodium/calcium exchanger 1 precursor, overall p = 8.0 × 10(-14)), and the QT interval. The minor allele frequency (MAF) of rs13017846 varies widely between ethnicities-0.053 in Europeans (HapMap CEU [Utah residents with ancestry from northern and western Europe from the Centre d'étude du Polymorphisme Humain collection] samples) versus 0.080 in Africans (HapMap YRI [Yoruba in Ibadan, Nigeria] samples)-whereas a MAF of 0.500 has been reported in Asians (HapMap HCB [Han Chinese in Beijing, China] and JPT [Japanese in Tokyo, Japan] samples). This might explain why this locus has not been identified in Europeans in previous studies.     

The electrocardiogram of the Beagle dog: reference values and effect of sex, genetic strain, body position and heart rate

The aim of the study was to establish a database for electrocardiographic parameters of Beagle dogs used for toxicological studies and to evaluate the influence of supplier, sex, heart rate (HR) and body position for electrocardiogram (ECG) recording on ECG parameters. Peripheral ECG leads were recorded from 934 female and 946 male dogs from Marshall Farms and 27 females and 30 males from Harlan, either standing on a table or restrained in a hammock. HR, RR, PQ and QT intervals, P and QRS duration and P-wave amplitude were measured. There were no major differences between sexes for ECG parameters. The axis of the heart was shifted to the left when the animals were restrained in a hammock compared to when they were standing on a table. The PQ interval was higher (about 9%) in Harlan than in Marshall dogs. HR was negatively correlated with QT (coefficient of linear correlation: r=-0.61 to -0.74), which emphasizes the need for a formula correcting QT interval for HR when interpreting changes in QT interval. HR was also negatively correlated with PQ intervals (r=-0.26 to -0.11), whereas a positive correlation was found between HR and the amplitude of the P wave (r=0.21-0.34). The level of the respiratory sinus arrhythmia (SA) was quantified by calculating the ratio of maximum to minimum RR interval measured over a 10 s period. This ratio was negatively correlated with HR (r =-0.49 to -0.33). Therefore, at high HRs, SA was less marked than at low HRs, but it did not completely disappear. Analysis of beat-to-beat variation indicated that QT and PQ intervals and the amplitude of P wave fluctuated over time and the degree of this variability was positively correlated with the level of SA. In conclusion, we have established reference values for the duration and/or amplitude of some ECG parameters both in terms of means and variability over the recording period, and we have evaluated the influence of body position, genetic strain and HR on the ECG parameters. These data can be used as baseline for the interpretation of the ECG of Beagle dogs.     

Computational prediction of drug response in short QT syndrome type 1 based on measurements of compound effect in stem cell-derived cardiomyocytes

Short QT (SQT) syndrome is a genetic cardiac disorder characterized by an abbreviated QT interval of the patient’s electrocardiogram. The syndrome is associated with increased risk of arrhythmia and sudden cardiac death and can arise from a number of ion channel mutations. Cardiomyocytes derived from induced pluripotent stem cells generated from SQT patients (SQT hiPSC-CMs) provide promising platforms for testing pharmacological treatments directly in human cardiac cells exhibiting mutations specific for the syndrome. However, a difficulty is posed by the relative immaturity of hiPSC-CMs, with the possibility that drug effects observed in SQT hiPSC-CMs could be very different from the corresponding drug effect in vivo. In this paper, we apply a multistep computational procedure for translating measured drug effects from these cells to human QT response. This process first detects drug effects on individual ion channels based on measurements of SQT hiPSC-CMs and then uses these results to estimate the drug effects on ventricular action potentials and QT intervals of adult SQT patients. We find that the procedure is able to identify IC₅₀ values in line with measured values for the four drugs quinidine, ivabradine, ajmaline and mexiletine. In addition, the predicted effect of quinidine on the adult QT interval is in good agreement with measured effects of quinidine for adult patients. Consequently, the computational procedure appears to be a useful tool for helping predicting adult drug responses from pure in vitro measurements of patient derived cell lines.     

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）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_DCHFCRTD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CRTD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。     

Ventricular repolarization: An overview of (patho)physiology,sympathetic effects and genetic aspects

Most textbook knowledge on ventricular repolarization is based on animal data rather than on data from the in vivo human heart. Yet, these data have been extrapolated to the human heart, often without an appropriate caveat. Here, we review multiple aspects of repolarization, from basic membrane currents to cellular aspects including extrinsic factors such as the effects of the sympathetic nervous system. We critically discuss some mechanistic aspects of the genesis of the T-wave of the ECG in the human heart.Obviously, the T-wave results from the summation of repolarization all over the heart. The T-wave in a local electrogram ideally reflects local repolarization. The repolarization moment is composed of the moment of local activation plus local action potential duration (APD) at 90% repolarization (APD₉₀). The duration of the latter largely depends on the balance between L-type Ca²⁺ current and the delayed rectifier currents. Generally speaking, there is an inverse relationship between local activation time and local APD₉₀, leading to less dispersion in repolarization moments than in activation moments or in APD₉₀. In transmural direction, the time needed for activation from endocardium toward epicardium has been considered to be overcompensated by shorter APD₉₀ at the epicardium, leading to the earliest repolarization at the subepicardium. In addition, mid-myocardial cells would display the latest repolarization moments. The sparse human data available, however, do not show any transmural dispersion in repolarization moment. Also, the effect of adrenergic stimulation on APD₉₀ has been studied mainly in animals. Again, sparse human data suggest that the effect of adrenergic stimulation is different in the human heart compared to many other mammalian hearts. Finally, aspects of the long QT syndrome are discussed, because this intrinsic genetic disease results from repolarization disorders with extrinsic aspects.     

Ventricular repolarization: an overview of (patho)physiology, sympathetic effects and genetic aspects

Most textbook knowledge on ventricular repolarization is based on animal data rather than on data from the in vivo human heart. Yet, these data have been extrapolated to the human heart, often without an appropriate caveat. Here, we review multiple aspects of repolarization, from basic membrane currents to cellular aspects including extrinsic factors such as the effects of the sympathetic nervous system. We critically discuss some mechanistic aspects of the genesis of the T-wave of the ECG in the human heart.

Obviously, the T-wave results from the summation of repolarization all over the heart. The T-wave in a local electrogram ideally reflects local repolarization. The repolarization moment is composed of the moment of local activation plus local action potential duration (APD) at 90% repolarization (APD₉₀). The duration of the latter largely depends on the balance between L-type Ca²⁺ current and the delayed rectifier currents. Generally speaking, there is an inverse relationship between local activation time and local APD₉₀, leading to less dispersion in repolarization moments than in activation moments or in APD₉₀. In transmural direction, the time needed for activation from endocardium toward epicardium has been considered to be overcompensated by shorter APD₉₀ at the epicardium, leading to the earliest repolarization at the subepicardium. In addition, mid-myocardial cells would display the latest repolarization moments. The sparse human data available, however, do not show any transmural dispersion in repolarization moment. Also, the effect of adrenergic stimulation on APD₉₀ has been studied mainly in animals. Again, sparse human data suggest that the effect of adrenergic stimulation is different in the human heart compared to many other mammalian hearts. Finally, aspects of the long QT syndrome are discussed, because this intrinsic genetic disease results from repolarization disorders with extrinsic aspects.     

Predicting the cardiac toxicity of drugs using a novel multiscale exposure–response simulator

A common but serious side effect of many drugs is torsades de pointes, a rhythm disorder that can have fatal consequences. Torsadogenic risk has traditionally been associated with blockage of a specific potassium channel and an increased recovery period in the electrocardiogram. However, the mechanisms that trigger torsades de pointes remain incompletely understood. Here we establish a computational model to explore how drug-induced effects propagate from the single channel, via the single cell, to the whole heart level. Our mechanistic exposure–response simulator translates block-concentration characteristics for arbitrary drugs into three-dimensional excitation profiles and electrocardiogram recordings to rapidly assess torsadogenic risk. For the drug of dofetilide, we show that this risk is highly dose-dependent: at a concentration of 1x, QT prolongation is 55% but the heart maintains its regular sinus rhythm; at 5.7x, QT prolongation is 102% and the heart spontaneously transitions into torsades de points; at 30x, QT prolongation is 132% and the heart adapts a quasi-depolarized state with numerous rapidly flickering local excitations. Our simulations suggest that neither potassium channel blockage nor QT interval prolongation alone trigger torsades de pointes. The underlying mechanism predicted by our model is early afterdepolarization, which translates into pronounced U waves in the electrocardiogram, a signature that is correctly predicted by our model. Beyond the risk assessment of existing drugs, our exposure–response simulator can become a powerful tool to optimize the co-administration of drugs and, ultimately, guide the design of new drugs toward reducing life threatening drug-induced rhythm disorders in the heart.     

A 24-HOUR AMBULATORY ECG MONITORING IN ASSESSMENT OF QT INTERVAL DURATION AND DISPERSION IN ROWERS WITH PHYSIOLOGICAL MYOCARDIAL HYPERTROPHY

Myocardial hypertrophy (MH) due to cardiac pathology is characterized by an increase in QT interval duration and dispersion, while the findings for exercise-induced myocardial hypertrophy are contradictory. The majority of published research findings have not explored this relationship, but there have only been a few conducted studies using 24-hour ECG monitoring. The aim of the study was to determine the QT interval duration and dispersion in short-term and 24-hour ECG in endurance athletes with myocardial hypertrophy and without it. Methods: A total of 26 well-trained rowers underwent a resting 12-lead ECG, 24-hour ECG monitoring and echocardiography. Results: Athletes with MH (n = 7) at rest did not show any increase in QTc interval duration and dispersion, or mean and maximal QTc duration in Holter monitoring compared to athletes without MH (n = 19). Left ventricular mass was not significantly correlated with any QTc characteristics. Furthermore, athletes with MH had significantly longer mean QT (P = 0.01) and maximal QT (P = 0.018) intervals in Holter monitoring and higher 24-hour heart rate variability indexes due to stronger vagal effects. Conclusions: The present study demonstrated that athlete''s heart syndrome with myocardial hypertrophy as a benign phenomenon does not lead to an increase in QT interval duration, or increases in maximal and mean duration in a 24-hour ECG. An increase in QT interval duration in athletes may have an autonomic nature.     

L-type Ca2+ channel mutations and T-wave alternans: a model study

A number of mutations have been linked to diseases for which the underlying mechanisms are poorly understood. An example is Timothy Syndrome (TS), a multisystem disorder that includes severe cardiac arrhythmias. Here we employ theoretical simulations to examine the effects of a TS mutation in the L-type Ca(2+) channel on cardiac dynamics over multiple scales, from a gene mutation to protein, cell, tissue, and finally the ECG, to connect a defective Ca(2+) channel to arrhythmia susceptibility. Our results indicate that 1) the TS mutation disrupts the rate-dependent dynamics in a single cardiac cell and promotes the development of alternans; 2) in coupled tissue, concordant alternans is observed at slower heart rates in mutant tissue than in normal tissue and, once initiated, rapidly degenerates into discordant alternans and conduction block; and 3) the ECG computed from mutant-simulated tissue exhibits prolonged QT intervals at physiological rates and with small increases in pacing rate, T-wave alternans, and alternating T-wave inversion. At the cellular level, enhanced Ca(2+) influx due to the TS mutation causes electrical instabilities. In tissue, the interplay between faulty Ca(2+) influx and steep action potential duration restitution causes arrhythmogenic discordant alternans. The prolongation of action potentials causes spatial dispersion of the Na(+) channel excitability, leading to inhomogeneous conduction velocity and large action potential spatial gradients. Our model simulations are consistent with the ECG patterns from TS patients, which suggest that the TS mutation is sufficient to cause the clinical phenotype and allows for the revelation of the complex interactions of currents underlying it.