Drug-Induced Long QT Syndrome in Women

Congenital long QT syndromes (LQTS) are inherited heart diseases that can present as palpitations, syncope (fainting), seizures, cardiac arrest, and sudden death. Acquired LQTS mostly occurs as a result of exposure to an environmental stressor that is responsible for the excessive prolongation of the QT interval. The most common environmental stressor is adverse drug reactions, which can lead to drug-induced LQTS (di-LQTS). Female gender has been increasingly recognized as an independent risk factor for di-LQTS, which in females is influenced by other factors, including age, menstrual cycle, and hormone replacement therapy. The estrogen-mediated reduced repolarization reserve in women is believed to be responsible for their higher susceptibility to di-LQTS. More studies, especially randomized trials, should be carried out to confirm these findings, and elucidate the clinical impact of gender disparity in modifying the risk of di-LQTS in women, with the ultimate goal of promoting the clinical safety of medication. In this article, we review current knowledge about di-LQTS, specifically in women, and discuss methods for the prevention of di-LQTS in females.     

Depressive symptoms in the congenital long QT syndrome

Background. A proportion of patients with congenital long QT syndrome (LQTS) experience potentially life-threatening cardiac arrhythmias.

Aim. To examine whether depressive symptoms are related to arrhythmic events among symptomatic and asymptomatic LQTS patients, and syncope events among their relatives not carrying the family's LQTS-causing mutation.

Methods. The participants were 569 molecularly defined LQTS mutation carriers and 622 non-carrier relatives from the Finnish LQTS registry. Depressive symptoms were self-rated with a revised version of the Beck Depression Inventory.

Results. LQTS patients with arrhythmic events scored higher on depressive symptoms than those without (P=0.011) or the control group (P=0.005). In addition, in the binary logistic regression analysis including symptomatic and asymptomatic LQTS mutation carriers, depressive symptoms showed an age- and sex-adjusted association of odds ratio (OR) 1.40 (95% confidence interval (CI) 1.12–1.74) with symptomatic status of LQTS. In similar analysis including non-carriers of the LQTS mutation, there was no association between depressive symptoms and history of syncope events OR 1.23 (95% CI 0.99–1.53).

Conclusion. Our results from this relatively large genotyped LQTS patient cohort indicate that depressive symptoms are associated with arrhythmic events in LQTS patients. Whether depressive symptoms are causally related to arrhythmias in LQTS remains uncertain.     

Sex differences in ventricular repolarization: from cardiac electrophysiology to Torsades de Pointes

A number of non-cardiovascular drugs have been withdrawn from clinical use due to unacceptable adverse cardiac side-effects involving drug-induced Torsades de Pointes (TdP)--a rare, life-threatening polymorphic ventricular tachycardia associated with prolongation of the action potential duration of ventricular myocytes and, hence, prolongation of the QT interval, of the electrocardiogram (ECG), which measures the total time for activation of the ventricles and their recovery to the resting state. Research has suggested that women are more prone to develop TdP than men during administration of medicines that share the potential to prolong the QT interval, with 65-75% of drug-induced TdP occurring in women. Clinical and experimental studies show that female sex demonstrate differences in the electrocardiographic pattern of ventricular repolarization in human and other animal species and is associated with a longer rate-corrected QT (QTc) interval at baseline than males. Reports of a similar propensity towards drug-induced TdP in both premenopausal and postmenopausal women support factors in addition to those of female sex hormones eliciting sex-based differences in ventricular repolarization. However, conflicting evidence suggests sex hormones may have a role in increasing the susceptibility of women or ultimately reducing the susceptibility of men to TdP. Cyclical variations in hormone levels during the menstrual cycle have been associated with an increased and reduced risk of TdP. In contradiction to this finding, the male sex hormone is thought to be beneficial. Modulation of the ventricular repolarization by testosterone may explain why the QTc interval shortens at puberty, and might account for the tendency towards an age-dependent reduction in the incidence of drug-induced TdP in men. Mechanisms underlying these differences are not fully understood but a case for the involvement of gonadal steroids is obviously strong. Therefore, further non-clinical/clinical investigations ought to be a necessary step to elucidate any sex differences in cardiac repolarization characteristics, QT interval prolongation and susceptibility to cardiac arrhythmias. This may have implications for the development of the safest medicinal products and for the clinical management of cardiac arrhythmias.     

Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome

Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K+ channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of IKs and IKr currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (>50% at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary IKr and IKs without affecting the steady state levels of the native polypeptides. Thus, the elimination of 1 repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type alpha subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death.     

Torsades de pointes in congenital long QT syndrome following low-dose orphenadrine

We report the case of a woman, affected by congenital long QT syndrome (LQTS), who experienced three syncopal episodes shortly after the assumption of a low dose of orphenadrine. The ECG revealed a QT interval of 600 ms, and the corrected QT interval (QTc) was 537 ms. No structural cardiac disease was demonstrated by echocardiography. Orphenadrine treatment was discontinued. During the first 12 h of monitoring, three short-lasting, asymptomatic episodes of torsades de pointes occurred. No other sustained ventricular arrhythmia was revealed at Holter monitoring in the following days. During the ensuing 6 months, the patient remained asymptomatic, and the QTc did not change. Orphenadrine is an analogue of diphenhydramine, an antihistaminic drug that produces sodium channel blockade similar to that caused by quinidine and other Class Ia antiarrhythmic drugs. Our case rises the suspicion that orphenadrine could cause life-threatening arrhythmias in LQTS even at a low dose, and independently from concomitant assumption of potentially QT-prolonging drugs.     

The genetic basis for cardiac dysrhythmias and the long QT syndrome.

Cardiac muscle excitation is the result of ion fluxes through cellular membrane channels. Any alterations in channel proteins that produce abnormal ionic fluxes will change the cardiac action potential and the pattern of electrical firing within the heart. The idiopathic long QT syndrome (LQTS) is an inherited cardiac pathology localized to mutated genes encoding for myocardial, voltage-activated sodium and potassium ion channels. The expression of abnormal sodium and potassium channels results in aberrant ionic fluxes that produce a prolonged ventricular repolarization. This prolonged time to repolarization is the electrophysiologic basis for prolongation of the QT interval. Individuals with LQTS are at significant risk for developing lethal ventricular dysrhythmias due to an abnormal pattern of cardiac excitation. Identification of a genetic basis for LQTS has had significant implications for genetic counseling, the development of effective antidysrhythmic drug therapies, and nursing interventions.     

Molecular characterization of two founder mutations causing long QT syndrome and identification of compound heterozygous patients

BACKGROUND: Mutations of at least six different genes have been found to cause long QT syndrome (LQTS), an inherited arrhythmic disorder characterized by a prolonged QT interval on the electrocardiogram (ECG), ventricular arrhythmias and risk of sudden death. AIM: The aims were to define the yet undetermined phenotypic characteristics of two founder mutations and to study clinical features in compound heterozygotes identified during the course of the study. METHODS: To maximize identification of the compound heterozygotes, we used an extended group of LQTS patients comprising 700 documented or suspected cases. Functional studies were carried out upon transient expression in COS-7 or HEK293 cells. RESULTS: The KCNQ1 IVS7-2A>G (KCNQ1-FinB) mutation associated with a mean QTc interval of 464 ms and a complete loss-of-channel function. The HERG R176W (HERG-FinB) mutation caused a reduction in current density as well as slight acceleration of the deactivation kinetics in vitro, and its carriers had a mean QTc of 448 ms. The HERG R176W mutation was also present in 3 (0.9%) out of 317 blood donors. A total of six compound heterozygotes were identified who had the HERG R176W mutation in combination with a previously reported LQTS mutation (KCNQ1 G589D or IVS7-2A>G). When present simultaneously with an apparent LQTS-causing mutation, the HERG R176W mutation may exert an additional in vivo phenotypic effect. CONCLUSIONS: The HERG R176W mutation represents a population-prevalent mutation predisposing to LQTS. Compound heterozygosity for mutant LQTS genes may modify the clinical picture in LQTS.     

QT Interval Variability and Adaptation to Heart Rate Changes in Patients with Long QT Syndrome

Background: Increased QT variability (QTV) has been reported in conditions associated with ventricular arrhythmias. Data on QTV in patients with congenital long QT syndrome (LQTS) are limited.
Methods: Ambulatory electrocardiogram recordings were analyzed in 23 genotyped LQTS patients and in 16 healthy subjects (C). Short-term QTV was compared between C and LQTS. The dependence of QT duration on heart rate was evaluated with three different linear models, based either on the RR interval preceding the QT interval (RR₀), the RR interval preceding RR₀ (RR_-1), or the average RR interval in the 60-second period before QT interval (mRR).
Results: Short-term QTV was significantly higher in LQTS than in C subjects (14.94 ± 9.33 vs 7.31 ± 1.29 ms; P < 0.001). It was also higher in the non-LQT1 than in LQT1 patients (23.00 ± 9.05 vs 8.74 ± 1.56 ms; P < 0.001) and correlated positively with QTc in LQTS (r = 0.623, P < 0.002). In the C subjects, the linear model based on mRR predicted QT duration significantly better than models based on RR₀ and RR_-1. It also provided better fit than any nonlinear model based on RR₀. This was also true for LQT1 patients. For non-LQT1 patients, all models provided poor prediction of QT interval.
Conclusions: QTV is elevated in LQTS patients and is correlated with QTc in LQTS. Significant differences with respect to QTV exist among different genotypes. QT interval duration is strongly affected by noninstantaneous heart rate in both C and LQT1 subjects. These findings could improve formulas for QT interval correction and provide insight on cellular mechanisms of QT adaptation.     

Drugs for men and women - how important is gender as a risk factor for TdP?

The cardiac arrhythmia known as torsade de pointes (TdP), which is a very rare but potentially lethal side effect of a variety of drugs, occurs approximately twice as often in women as it does in men. Most drugs that have this adverse effect prolong the repolarization phase of the cardiac action potential which can be detected by a lengthening of the QT interval on the ECG. The gender difference in susceptibility to TdP only appears after puberty suggesting that sex hormones are contributory factors. Studies in patients indicate that testosterone-induced shortening of action potential duration may account for the shorter rate-corrected QT interval in men rather than any effect of estradiol in women, whereas drug-induced QT prolongation can be potentiated by estradiol. Experimental investigations suggest that sex hormones may alter either Ca(2+) currents, K(+) currents, or both and that actions on these ionic currents may account for the gender differences in cardiac repolarization. Although estradiol exacerbated drug-induced TdP in an in vivo model, no similar information is available for progesterone or testosterone. Further studies are required to clarify the influence of these sex hormones and to investigate the importance of the balance between sex hormones in both genders. Such information would assist in risk:benefit analysis and may allow the development of "drugs for men" and "drugs for women".     

Pharmacological and non-pharmacological management of the congenital long QT syndrome: the rationale

The congenital long QT syndrome (LQTS) is a familial disorder characterized by a prolongation of the QT interval on the ECG and occurrence of life-threatening cardiac arrhythmias especially, but not only, under conditions of increased sympathetic activity. Symptomatic untreated patients are at high risk for sudden cardiac death. Twelve LQTS genes have been identified and most of them encode cardiac ion channels. Very effective therapies are available and in carefully treated patients mortality is around 0.5-1% over 20 years.The initial treatment should always involve β-blockers, with propranolol and nadolol being the two most effective ones. With few exceptions all mutation carriers should be treated because of the risk of sudden death during the first cardiac event. Approximately 20% of patients continue to have syncope despite the β-blockers and the most rationale next level of therapy is represented by Left Cardiac Sympathetic Denervation (LCSD), which is highly effective and can complement any other therapy. One important limitation of LCSD is that, without valid reasons, it is available only in a few selected centers. Whenever syncope recurs despite LCSD, or whenever an aborted cardiac arrest has occurred, it becomes logical to resort to the implantation of a cardioverter defibrillator (ICD). The latter, however, is burdened by a high rate (31%) of adverse events including severe ones such as endocarditis, inappropriate shocks, and by the need of frequent battery replacements. A scoring system, based on simple clinical variables, can identify the patients more and less likely to benefit from ICD implantation.     

Long QT syndrome

The long QT syndrome (LQTS) is characterized by prolongation of the QT interval, causing torsade de pointes and sudden cardiac death. This syndrome can be divided into idiopathic (congenital) and acquired forms. The idiopathic form is a familial disorder that can be associated with sensorineural deafness (Jervell and Lange--Nielsen syndrome, autosomal recessive) or normal hearing (Romano--Ward syndrome, autosomal dominant). The acquired form has a long QT interval caused by various drugs such as quinidine sotalol and dofetilide, also by noncardiovascular drugs such as antihistamine, antibiotics, antipsychotics and others. Also, the QT interval is prolonged by electrolyte abnormalities such as hypokalemia and hypomagnesemia, central nervous system lesions, significant bradyarrhythmias, cardiac ganglionitis, mitral valve prolapse and probucol. DNA variants appearing to predispose to drug-associated acquired long QT syndrome have been reported in congenital long QT.     

Molecular Biology of the Long QT Syndrome: Impact on Management

The long QT syndrome (LQTS) is a familial disease characterized by prolonged ventricular repolarization and high incidence of malignant ventricular tachyarrhythmias often occurring in conditions ofadrenergic activation. Recently, the genes for the LQTS linked to chromosomes 3 (LQT3), 7 (LQT2), and 11 (LQTl) were identified as SCN5A, the cardiac sodium channel gene and as HERG and KvLQTl potassium channel genes. These discoveries have paved the way for the development of gene-specific therapy for these three forms of LQTS. In order to test specific interventions potentially beneficial in the molecular variants of LQTS, we developed a cellular model to mimic the electrophysiological abnormalities of LQT3 and LQT2. Isolated guinea pig ventricular myocytes were exposed to anthopleurin and dofetilide in order to mimic LQT3 and LQT2, respectively. This model has been used to study the effect of sodium channel blockade and of rapid pacing showing a pronounced action potential shortening in response to Na⁺channel blockade with mexiletine and during rapid pacing only in anthopleurin-treated cells but not in dofetilide-treated cells. Based on these results we tested the hypothesis that QT interval would shorten more in LQT3 patients in response to mexiletine and to increases in heart rate. Mexiletine shortened significantly the QT interval among LQT3 patients but not among LQT2 patients. LQT3 patients shortened their QT interval in response to increases in heart rate much more than LQT2 patients and healthy controls. These findings suggest thatLQT3 patients are more likely to benefit from Na⁺ channel blockers and from cardiac pacing because they are at higher arrhythmic risk at slow heart rates. Conversely, LQT2 patients are at higher risk to develop syncope under stressful conditions, because of the combined arrhythmogenic effect of cate-cholamines with the insufficient adaptation of their QT interval. Along the same line of development of gene-specific therapy, recent data demonstrated that an increase in the extracellular concentration of potassium shortens the QT interval in LQT2 patients suggesting that intervention aimed at increasing potassium plasma levels may represent a specific treatment for LQT2. The molecular findings on LQTS suggest the possibility of developing therapeutic interventions targeted to specific genetic defects. Until definitive data become available, antiadrenergic therapy remains the mainstay in the management of LQTS patients, however it may be soon worth considering the addition of a Na + channel blocker such as mexiletine for LQT3 patients and of interventions such as K⁺ channel openers or increases in the extracellular concentration of potassium for LQTl and LQT2 patients.     

Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome

OBJECTIVE: To determine the spectrum, frequency, and ethnic-specificity of channel variants in the potassium channel genes implicated in congenital long QT syndrome (LQTS) among healthy subjects. SUBJECTS AND METHODS: Genomic DNA from 744 apparently healthy individuals-305 black, 187 white, 134 Asian, and 118 Hispanic--was subject to a comprehensive mutational analysis of the 4 LQTS-causing potassium channel genes: KCNQ1 (LQT1), KCNH2 (LQT2), KCNE1 (LQT5), and KCNE2 (LQT6). RESULTS: Overall, 49 distinct amino acid-altering variants (36 novel) were identified: KCNQ1 (n = 16), KCNH2 (n = 25),KCNE1 (n = 5), and KCNE2 (n = 3). More than half of these variants (26/49) were found exclusively in black subjects. The known K897T-HERG and the G38S-min K common polymorphisms were identified in all 4 ethnic groups. Excluding these 2 common polymorphisms, 25% of black subjects had at least 1 nonsynonymous potassium channel variant compared with 14% of white subjects (P < .01). CONCLUSIONS: To our knowledge, this study represents the first comprehensive determination of the frequency and spectrum of cardiac channel variants found among healthy subjects from 4 major ethnic groups. Defining the population burden of genetic variants in these critical cardiac ion channels is crucial for proper interpretation of genetic test results of individuals at risk for LQTS. This compendium provides a resource for epidemiological and functional investigation of variant effects on the repolarization properties of cardiac tissues, including susceptibility to lethal cardiac arrhythmias.     

Evidences of the gender-related differences in cardiac repolarization and the underlying mechanisms in different animal species and human

Clinical and experimental studies have shown that gender differences exist in cardiac repolarization in various animal species and human, as is evidenced by significantly longer QT, JT intervals and action potential duration in females than in males due to a reduced repolarization reserve in females. The latter is shown by the relatively greater increase in ventricular repolarization and higher incidence of torsades de pointes (TdP) in preparations from females by drugs blocking repolarizing K(+) currents. These results can be modulated by gonadectomy, suggesting that gonadal steroids are important determinants of gender difference in repolarization. In human subjects, QT and JT intervals are longer in women, whereas QT dispersion and Tp-e interval (the interval from the peak to the end of T wave) are longer in men. At slow heart rates greater prolongation in QT and increase in transmural repolarization heterogeneity (i.e. increase in Tp-e) may predispose to TdP tachycardias in women. In healthy postmenopausal women, hormone replacement therapy with estrogen alone usually produced a prolongation of QT interval, while estrogen plus progesterone had no significant effects on QT interval but reduced QT dispersion. Along with these, there are still conflicting data reported. Further work is needed before the elucidation of the basis of gender differences in ventricular repolarization.     

Family and population strategies for screening and counselling of inherited cardiac arrhythmias

Family screening in inherited cardiac arrhythmias has been performed in The Netherlands since 1996, when diagnostic DNA testing in long QT syndrome (LQTS) and hypertrophic cardiomyopathy (HCM) became technically possible. In multidisciplinary outpatient academic clinics, an adjusted protocol for genetic counselling, originally derived from predictive testing in Huntington's disease, is being used. 1110 individuals, including 842 relatives of index patients, were informed about their risks, and most were tested molecularly and/or clinically for carriership of the disease present in their family. Of 345 relatives who were referred for cardiologic follow-up, 189 are being treated, because of an increased risk of life-threatening arrhythmias. Evaluation of the psychological and social consequences of family screening for inherited arrhythmias can be performed by using the adapted criteria of Wilson and Jüngner, i.e., from a point of view of public health. Preliminary results of psychological research show that parents of children at risk for LQTS show high levels of distress. Many other aspects have to be evaluated yet, making final conclusions about the feasibility of family screening difficult, particularly in HCM. Clinical guidelines are urgently needed. Population screening by molecular testing, for instance in athletic preparticipation screening, will become possible in the future and has its own prerequisites for success.     

Catecholamine-induced T-wave lability in congenital long QT syndrome: a novel phenomenon associated with syncope and cardiac arrest

OBJECTIVE: To determine the effects of phenylephrine and dobutamine on repolarization lability in patients with genotyped long QT syndrome (LQTS). PATIENTS AND METHODS: Between December 1998 and August 2000, 23 patients with genotyped LQTS (13 LQT1, 7 LQT2, and 3 LQT3) and 16 controls underwent electrocardiographic stress testing at the Mayo Clinic in Rochester, Minn. Aperiodic repolarization lability was quantified from digitized electrocardiograms recorded during catecholamine stress testing with phenylephrine and dobutamine. T-wave lability was quantified as a root-mean-square of the differences between corresponding signal values of subsequent beats. The magnitude of aperiodic T-wave lability was quantified by using a newly derived T-wave lability index (TWLI). RESULTS: The TWLI was significantly greater in patients with LQTS than in controls (0.0945 +/- 0.0517 vs 0.0445 +/- 0.0123; P < .003). Marked T-wave lability (TWLI > or = 0.095) was detected in all 3 LQTS genotypes (10/23) but in no controls (P < .003). There was no correlation between the TWLI and the baseline corrected QT interval. All high-risk patients having either a history of out-of-hospital cardiac arrest or syncope had a TWLI of 0.095 or greater. CONCLUSIONS: Beat-to-beat nonalternating T-wave lability occurs in LQT1, LQT2, and LQT3 patients during catecholamine provocation and is associated with a history of prior cardiac events. The quantification of this novel phenomenon may assist in identifying LQTS patients with increased risk of sudden cardiac death.     

Prolonged QT syndrome in children: an uncommon but potentially fatal entity

Prolonged QT syndrome may be either congenital, as in Jervell and Lange-Nielsen or Romano-Ward syndromes, or acquired in nature. Affected children are at risk for syncope, seizures, dysrhythmias and sudden death. Physicians should consider long QT syndrome (LQTS) in all patients who present with syncope. A thorough personal and family history should be documented, with particular attention to prior syncopal episodes, congenital deafness, and unexplained sudden death. Syncope that is either recurrent or induced by exercise or stress is concerning and also should be noted. An electrocardiogram with manual calculation of the QT interval should be performed on all patients with a suggestive history. Furthermore, the diagnosis of LQTS warrants evaluation of all other family members. With recognition and appropriate treatment of affected patients, the potentially fatal consequences of LQTS may be prevented.     

A single strand conformation polymorphism/heteroduplex (SSCP/HD) method for detection of mutations in 15 exons of the KVLQT1 gene, associated with long QT syndrome

Congenital long QT syndrome (LQTS) is characterised by prolongation of the QT interval on ECG and cardiac arrhythmias, syncopes and sudden death. A rapid and reliable genetic diagnosis of the disease may be of great importance for diagnosis and treatment of LQTS. Mutations in the KVLQT1 gene, encoding a potassium-channel subunit of importance for the depolarisation of cardiac myocytes, is believed to be associated with 50% of all LQTS cases. Our data confirms that KvLQT1 isoform 1 is encoded by 16 exons, and not 15, as reported previously. We have used genomic DNA sequences to design intronic PCR primers for amplification of 15 exons of KVLQT1 and optimised a non-radioactive single stranded conformation polymorphism/heteroduplex (SSCP/HD) method for detection of mutations in KVLQT1. The sensitivity of the method was 100% when it was tested on 15 in vitro constructed mutants. By multiplexing the PCR amplification of KVLQT1, it is possible to cover all 15 exons in four PCR reactions.     

Clinical Value of Electrocardiographic Parameters in Genotyped Individuals with Familial Long QT Syndrome

MOENNIG, G., et al. : Clinical Value of Electrocardiographic Parameters in Genotyped Individuals with Familial Long QT Syndrome. Rate corrected QT interval (QTc) and QT dispersion (QTd) have been suggested as markers of an increased propensity to arrhythmic events and efficacy of therapy in patients with long QT syndrome (LQTS). To evaluate whether QTc and QTd correlate to genetic status and clinical symptoms in LQTS patients and their relatives, ECGs of 116 genotyped individuals were analyzed. JTc and QTc were longest in symptomatic patients (  n = 28  ). Both QTd and JTd were significantly higher in symptomatic patients than in asymptomatic (  n = 29  ) or unaffected family members (  n = 59  ). The product of QTd/JTd and QTc/JTc was significantly different among all three groups. Both dispersion and product put additional and independent power on identification of mutation carriers when adjusted for sex and age in a logistic regression analysis. Thus, symptomatic patients with LQTS show marked inhomogenity of repolarization in the surface ECG. QT dispersion and QT product might be helpful in finding LQTS mutation carriers and might serve as additional ECG tools to identify asymptomatic LQTS patients.