Long QT syndromes

Opinion statement The clinical phenotype of the long QT syndrome (LQTS) is quite variable, with the frequency and type of life-threatening arrhythmias influenced by the specific genotype and a spectrum of genetic and environmental factors that are not well characterized. Patients with a history of recurrent syncope or aborted cardiac arrest are at increased risk of experiencing malignant ventricular arrhythmias, but such arrhythmias may also occur in affected individuals who previously have been asymptomatic. Beta-adrenergic drugs serve as the foundation for treatment of symptomatic patients with a history of syncope or aborted cardiac arrest and as primary prophylactic therapy in asymptomatic subjects with LQTS. Beta-blockers reduce the frequency of syncopal events, but they do not absolutely prevent the occurrence of sudden cardiac death, even in those who are compliant in taking full doses of beta-blockers. Pacemaker therapy is moderately effective in reducing the number of cardiac events in patients with inappropriate bradycardia. The implantable cardioverter-defibrillator (ICD) has functioned well as a fail-safe back-up therapy in high-risk patients, especially those with documented malignant arrhythmias or an aborted cardiac arrest. Left cervicothoracic sympathetic ganglionectomy should be reserved for patients with LQTS who are intolerant of beta-blockers or have recurrent syncope that is refractory to beta-blockers and who for one reason or another are not candidates for ICD therapy. Pharmacologically tailored gene-specific therapy for specific ion-channel disorders is in its infancy, and no specific recommendations can be made for the use of this therapy at this time.     

家族性电紊乱性心脏病未植入心律转复除颤器患者的长期随访研究

目的 研究家族性电紊乱性心脏病高危患者,未植入心律转复除颤器(ICD)的长期预后.方法 13例患者中11例长QT综合征(LQTS)、2例Brugada综合征,均有心脏性晕厥.男性4例,女性9例,平均年龄(44±19)岁.6例(46%)因心跳骤停住院治疗.4例LQTS植入起搏器,平均随访(7±4)年.结果 11例(85%)患者仍然发作晕厥,1例心脏骤停首次入院,5例(39%)心脏骤停再入院,2例LQTS死亡,其中1例(0.8%)猝死.结论 LQTS和Brugada综合征患者一旦出现晕厥,以后会反复发作,如果没有条件接受ICD治疗,其他的药物治疗、医生的密切监控随访、指导患者避免触发因素和针对家属的心肺复苏训练同样非常重要.     

Left cardiac sympathetic denervation in the therapy of congenital long QT syndrome. A worldwide report

BACKGROUND. Long QT syndrome (LQTS) is a congenital disorder accompanied by a high incidence of sudden cardiac death. beta-Adrenergic blockade is the therapy of choice, and it is successful in 75-80% of patients. For those in whom cardiac events (syncope or cardiac arrest) are not prevented by beta-blockade, experimental studies suggest that left cardiac sympathetic denervation (LCSD) may be useful. METHODS AND RESULTS. We identified 85 LQTS patients worldwide who underwent LCSD, and we provide here the first large-scale evaluation of its efficacy. The time interval between the first cardiac event and LCSD and the follow-up period after LCSD were similar (5.6 +/- 6.1 versus 5.9 +/- 5.7 years). The mean age of the patients at surgery was 20 +/- 13 years. LCSD was followed by highly significant (p less than 0.0001) decreases in the number of patients with cardiac events (from 99% to 45%), in the number of cardiac events per patient (from 22 +/- 32 to 1 +/- 3), and in the number of patients with five or more cardiac events (from 71% to 10%). There were seven sudden deaths (8%), and the 5-year survival rate was 94%. The marked reduction in the incidence of tachyarrhythmic syncope suggests that LCSD has also reduced the risk for sudden death in this high-risk population. CONCLUSIONS. The present findings demonstrate that for LQTS patients who continue with syncope or cardiac arrest despite the use of beta-blockers, LCSD is a very effective therapy.     

The congenital long QT syndromes from genotype to phenotype: clinical implications

The long QT syndrome (LQTS) is a genetic disorder responsible for many sudden deaths before age 20. The identification of several LQTS genes, all encoding cardiac ion channels, has had a major impact on the management strategy for both patients and family members. Genotype-guided therapy allows more effective individually tailored therapy. Therapeutic options, including beta-blockers, left cardiac sympathetic denervation, and implantable defibrillators are discussed for patients of known and of unknown genotype. The recent identification of modifier genes which amplify the effect of an LQTS mutation may change the approach to risk stratification.     

Implantable cardioverter-defibrillator therapy in patients with congenital long-QT syndrome: a long-term follow-up.

OBJECTIVES: The purpose of this study was to evaluate retrospectively a single-center experience with the use of ICDs in patients with long QT syndrome (LQTS) concerning outcome, complications, and optimal programming. BACKGROUND: Use of implantable cardioverter-defibrillator (ICD) in patients with congenital LQTS is controversial but is generally accepted in high-risk patients. METHODS: We enrolled 27 symptomatic patients with LQTS undergoing ICD therapy (QTc 540 +/- 64 ms(1/2); 85% female, 63% cardiac arrest; 33% syncope despite beta-blockers; 4% with severe phenotype) and 81 genotyped patients with LQTS undergoing conventional drug therapy (28 LQT1, 39 LQT2, 1 LQT3, 13 LQT5). During a mean follow-up of 65 +/- 34 months, one death occurred in the ICD group that was not LQTS related. A total of 178 appropriate shocks were observed in 10/27 patients (37%), mostly in survivors of cardiac arrest (in 58% of cardiac arrest patients vs. in 20% of non-cardiac arrest patients). RESULTS: In a logistic regression analysis, only QTc interval (121/178 shocks (68%) for QTc > 500 ms(1/2)) and "survived cardiac arrest" were prognostic for ICD shocks. In 30% of patients in the ICD group, multiple shocks occurred and could be reduced after increase of antibradycardia pacing rate, adding beta-blocker therapy, or starting the rate-smoothing algorithm (average 7.1 shocks before to 0.75 shocks after additional intervention annually). CONCLUSION: ICD therapy is a safe and useful tool in high-risk patients with LQTS. QTc interval and cardiac arrest survivors were prognostic factors for appropriate ICD shocks. The results of this large single-center experience suggest that beta-blockers should always be added to ICD therapy. In addition, some patients might benefit from additional antibradycardia pacing, prolonged detection time, and a rate-smoothing algorithm to prevent recurrent episodes.     

The Long QT Syndrome

The long QT syndrome (LQTS) is a genetically transmitted cardiac arrhythmia due to ion channel protein abnormalities, which affects the transport of potassium and sodium ions across the cell membrane. Patients with LQTS may present with syncope, seizures or aborted cardiac arrest. LQTS is also an important cause of unexplained sudden cardiac death in the young. The diagnosis of LQTS is generally made on an ECG showing the prolonged QT interval. The establishment of LQTS registry and the discovery of genetic mutations causing LQTS have contributed greatly to the understanding of this condition and have also provided an impetus in understanding of other inherited cardiac arrhythmias. Genotype-phenotype correlation studies have allowed risk stratification of LQTS patients. Life style modification to avoid triggers for malignant cardiac arrhythmias, and the use of beta-blockers, pacemakers and implantable defibrillators, help to treat symptoms and reduce mortality in these patients.     

Long QT syndrome

The hereditary long QT syndrome (LQTS) is a genetic channelopathy with variable penetrance that is associated with increased propensity to syncope, polymorphous ventricular tachycardia (torsades de pointes), and sudden arrhythmic death. This inherited cardiac disorder constitutes an important cause of malignant ventricular arrhythmias and sudden cardiac death in young individuals with normal cardiac morphology. Risk assessment in affected LQTS patients relies upon a constellation of electrocardiographic, clinical, and genetic factors. Administration of beta-blockers is the mainstay therapy in affected patients, and primary prevention with an implantable cardioverter defibrillator or left cervicothoracic sympathetic denervation are therapeutic options in patients who remain symptomatic despite beta-blocker therapy. Accumulating data from the International LQTS Registry have recently facilitated a comprehensive analysis of risk factors for aborted cardiac arrest or sudden cardiac death in pre-specified age groups, including the childhood, adolescence, adulthood, and post-40 periods. These analyses have consistently indicated that the phenotypic expression of LQTS is time dependent and age specific, warranting continuous risk assessment in affected patients. Furthermore, the biophysical function, type, and location of the ion-channel mutation are currently emerging as important determinants of outcome in genotyped patients. These new data may be used to improve risk stratification and for the development of gene-specific therapies that may reduce the risk of life-threatening cardiac events in patients with this inherited cardiac disorder.     

The Jervell and Lange-Nielsen syndrome. Natural history, molecular basis and clinical outcome

Data on the Jervell and Lange-Nielsen syndrome (JLN), the long QT syndrome (LQTS) variant associated with deafness and caused by homozygous or compound heterozygous mutations on the KCNQ1 or on the KCNE1 genes encoding the IKs current, are still largely based on case reports. We analyzed data from 186 JLN patients obtained from the literature (31%) and from individual physicians (69%). Most patients (86%) had cardiac events and 50% were symptomatic already by age 3. Their QTc was markedly prolonged (557 +/- 65 ms). Most of the arrhythmic events (95%) were triggered by emotions or exercise. Females are at lower risk for cardiac arrest and sudden death (CA/SD). A QTc>550 ms and history of syncope during the first year of life are independent predictors of subsequent CA/SD. Most mutations (90.5%) are on the KCNQ1 gene; mutations on the KCNE1 gene are associated with a more benign course. beta-blockers have only partial efficacy as 51% of the patients had events despite therapy and 29% had CA/SD. Conclusions: JLN syndrome is a most severe variant of LQTS, with a very early onset, major QTc prolongation, and is not well responsive to beta-blockers. Subgroups at relatively lower risk for CA/SD are identifiable and include females, patients with a QTc pound550 ms, without events in the first year of life, and with mutations on KCNE1. Early therapy with ICDs has to be considered.     

Inherited long QT syndrome

Inherited long QT syndrome (LQTS) is characterized by a prolonged ventricular repolarization (QTc interval) and symptoms (syncope, sudden cardiac arrest) due to polymorphic ventricular arrhythmias. As of today, 13 different cardiac ion channel genes have been associated with congenital LQTS. The most common ones are due to KCNQ1 (LQT-1), KCNH2 (LQT-2), and SCN5A (LQT-3) gene mutations and account for up to 75?% of cases. Typical clinical findings are an increased QT interval on the surface electrocardiogram, specifically altered T wave morphologies, polymorphic ventricular arrhythmias, or an indicative family history. Recently, in the HRS/EHRA expert consensus statement, comprehensive genetic testing of major LQTS genes was recommended for index patients for whom there is a strong clinical suspicion of LQTS. Overall, antiadrenergic therapy, in particular ??-receptor blockers, has been the mainstay of therapy and has significantly reduced cardiac events. For high-risk patients, an implantable cardioverter defibrillator (ICD) is recommended. Importantly, lifestyle modification and avoidance of arrhythmia triggers are additional important approaches.     

Long QT syndromes and torsade de pointes

In the long QT syndromes (LQTS), malfunction of ion channels impairs ventricular repolarisation and triggers a characteristic ventricular tachyarrhythmia: torsade de pointes. Symptoms in the LQTS (syncope or cardiac arrest) are caused by this arrhythmia. In congenital LQTS, mutations in the genes encoding for ion channels cause this channel malfunction. Six genotypes (LQT1 to LQT6) have been identified, and attempts are being made to correlate different mutations with clinical signs and specific therapy. In acquired LQTS, channel malfunction is caused by metabolic abnormalities or drugs. The list of drugs that may impair ion-channel function expands continuously. Moreover, attributes that increase the risk for drug-induced torsade (eg, female sex, recent heart-rate slowing, or hypokalaemia) and electrocardiographic "warning signs" are recognised. Recent data suggest that patients with an acquired LQTS have some underlying predisposition to proarrhythmia. Mutations causing "silent" forms of congenital LQTS, in which the patient remains free of arrhythmias until exposed to drugs that further impair repolarisation, are now recognised.     

Inherited long QT syndromes: a paradigm for understanding arrhythmogenesis

The inherited long QT syndrome (LQTS) is a familial disease characterized by QT interval changes that often are labile, syncope, and sudden death due to arrhythmias, predominantly in young people. Multiple mutations in five genes encoding structural subunits of cardiac ion channels now have been identified in families with LQTS. Correlations are being described between genotype and specific clinical features in LQTS. However, increasing screening of affected families and sporadic cases has identified incomplete penetrance with highly variable clinical manifestations, even among individuals carrying the same mutations. The identification of LQTS disease genes represents a crucial first step in developing an understanding of the molecular basis for normal cardiac repolarization. This information will be important not only for identifying new therapies in LQTS, but also in further understanding arrhythmias, and their potential therapies, in situations such as heart failure, cardiac hypertrophy, myocardial infarction, or sudden infant death syndrome, where abnormal repolarization has been linked to sudden death. LQTS thus presents a new paradigm to cardiac electrophysiology, in which new molecular information is being brought to bear both on clinical management of patients and on development of a new framework to study the fundamental causes of arrhythmias and new approaches to therapy.     

Risk of cardiac events in patients with asthma and long-QT syndrome treated with beta(2) agonists

The clinical course and risk factors associated with beta(2)-agonist therapy for asthma have not been investigated previously in patients with the long-QT syndrome (LQTS). The risk of a first LQTS-related cardiac event due to beta(2)-agonist therapy was examined in 3,287 patients enrolled in the International LQTS Registry with QTc > or = 450 ms. The Cox proportional hazards model was used to assess the independent contribution of clinical factors for first cardiac events (syncope, aborted cardiac arrest, or sudden death) from birth through age 40. Time-dependent beta(2)-agonist therapy for asthma was associated with an increased risk for cardiac events (hazard ratio [HR] = 2.00, 95% confidence interval 1.26 to 3.15, p = 0.003) after adjustment for relevant covariates including time-dependent beta-blocker use, gender, QTc, and history of asthma. This risk was augmented within the first year after the initiation of beta(2)-agonist therapy (HR = 3.53, p = 0.006). The combined use of beta(2)-agonist therapy and anti-inflammatory steroids was associated with an elevated risk for cardiac events (HR = 3.66, p <0.01); beta-blocker therapy was associated with a reduction in cardiac events in those using beta(2) agonists (HR = 0.14, p = 0.05). In conclusion, beta(2)-agonist therapy was associated with an increased risk for cardiac events in patients with asthma with LQTS, and this risk was diminished in patients receiving beta blockers.     

Left cardiac sympathectomy prevents exercise-induced QTc prolongation in congenital long QT syndrome

Congenital long QT syndrome (LQTS) is a group of ion channel disorders of ventricular myocytes caused by mutations of genes that encode these ion channels. The main clinical features of LQTS are syncope, cardiac arrest and QT prolongation on body surface electrocardiogram. The present study reports on the case of a 42-year-old female patient with a 10-year history of LQTS and syncopal attacks resistant to beta-blocker therapy. Treadmill exercise testing in this patient increased the corrected QT interval (QTc) from 0.48 s to 0.54 s and reduced the amplitude of the T wave. Left cardiac sympathectomy did not affect the resting heart rate or QTc but it prevented exercise-induced T wave reduction and QTc prolongation. Therefore, sympathetic activation plays a key role in exerciseinduced QT prolongation and changes in T wave morphology in patients with congenital LQTS.     

Left Cardiac Sympathetic Denervation in Long QT Syndrome Patients

The idiopathic long QT syndrome (LQTS) is an unusual clinical disorder characterized by a prolongation of the QT interval and by syncopal episodes occurring among young subjects, most often during exercise, stress, or other conditions of increased sympathetic activity. Both an imbalance in sympathetic innervation and an intracar-diac defect in membrane currents have been proposed as pathogenetic. mechanisms. The latter appears substantiated by recent advances in molecular genetics showing a linkage on chromosomes 11,3,7, and 4, with identification of the genes for chromosomes 3 and 7. For symptomatic patients with the long QT syndrome, β-adrenergic blockade, with efficacy in approximately 80% of patients, currently remains the therapy of first choice. For the patients who continue to suffer syncope or cardiac arrest despite β blockade, evidence has been provided that left cardiac sympathetic denervation represents a very effective treatment. The improvement in the understanding of the molecular mechanisms involved may soon lead to gene specific therapy in most long QT patients.     

Prevention of sudden death in congenital long-QT syndrome]

Congenital long QT syndrome (LQTS) is associated to an increased risk of ventricular arrhythmia, syncope and sudden cardiac death (SD). Four disease genes have been identified and different mutations described in each gene. This locus heterogenicity appears to have important functional and prognostic implications. Sympathetic imbalance has been invoked to explain an arrhythmogenic substrate. Prolonged repolarization is associated to increased dispersion of repolarization enhancing the propensity to develop early afterdepolarizations that may initiate polymorphic ventricular tachycardia (torsade de pointes). Syncope or cardiac arrest usually occur in young patients during exercise, possibly in association with relative bradycardia. The annual incidence of recurrent syncope and SD is 5% and 1%, respectively. Diagnostic criteria include clinical and electrocardiographic variables, family history of early SD and propensity for recurrent syncope. Careful assessment of clinical manifestations and ECG characteristics of family members is justified. Female gender, QTc interval > 500 ms, history of syncope or cardiac arrest are independent risk factors that predict arrhythmic events. Pharmacological agents known to be able to cause QT prolongation or beta-adrenergic stimulation must be avoided. Clinical management of asymptomatic persons with the LQTS is still controversial. Initial treatment of choice for the large majority of patients is administration of propranolol. This treatment is effective in 75-80% of cases. Other therapeutic options include left cervicothoracic sympathectomy, pacemakers, and the implantable cardioverter defibrillator. Risk stratification and efficacy of the subsequent treatment has significantly changed the clinical outcome of patients with LQTS. Recent molecular biology studies and data analysis from the International LQTS Registry may contribute to the definition of the best strategy for the future.     

Asthma and the risk of cardiac events in the Long QT syndrome. Long QT Syndrome Investigative Group

While acquiring data for the International Long QT Syndrome Registry, we noticed that a number of patients referred for long QT syndrome (LQTS) were affected by asthma. The effect of asthma comorbidity on clinical course of LQTS has not been studied. This study aimed to evaluate the prevalence of asthma in patients with LQTS, determine the influence of asthma comorbidity on outcome of LQTS patients, and to investigate the confounding effects of beta mimetics and beta blockers on the occurrence of cardiac events in asthmatic patients. The influence of asthma on risk of cardiac events (syncope, aborted cardiac arrest, or LQTS death) was evaluated after accounting for age, gender, QTc, and RR interval duration, beta-blocker and beta-mimetic use. Asthma was identified in 226 (5.2%) of 4,310 studied LQTS family members. Longer QTc duration was associated with higher incidence of asthma (p <0.001). Asthma was independently associated with significantly increased risk of cardiac events in affected LQTS patients (hazard ratio 1.32; p = 0.048) and in borderline-affected family members (hazard ratio 2.08; p = 0.004) after adjustment for QTc, RR interval, and gender. An increased risk of cardiac events in asthmatic patients observed before beta-blocker therapy was reduced after initiation of treatment with beta blockers. In conclusion, the occurrence of asthma in LQTS patients increases with QTc duration. Asthma comorbidity in LQTS patients is associated with an increased risk of cardiac events. The asthma-associated increase in the risk of LQTS-related cardiac events is diminished after initiation of beta-blocker therapy, suggesting a possible role of beta-receptor modulation underlying asthma-LQTS association.     

Long QT Syndrome in Patients over 40 Years of Age: Increased Risk for LQTS‐Related Cardiac Events in Patients with Coronary Disease

Background: Previous studies of long QT syndrome (LQTS) have focused primarily on the clinical course of affected patients up to 40 years of age to avoid the confounding influence of acquired heart disease on LQTS‐related cardiac events in this genetic disorder. Methods: Patients were identified as having coronary disease if they had a history of hospitalization for myocardial infarction, coronary angioplasty, coronary artery bypass graft surgery, or were treated with medication for angina. LQTS‐related cardiac events included the first occurrence of syncope, aborted cardiac arrest, or sudden cardiac death without evidence suggestive of an acute coronary event. Cox proportional hazards regression modeling was used to analyze the independent contribution of coronary disease to LQTS‐related cardiac events. Results: Time‐dependent coronary disease was associated with an increased risk of LQTS‐related cardiac events (hazard ratio 2.24, 95% confidence interval 1.23–4.07, P = 0.008) after adjustment for syncopal history before age 40, QTc, and gender. Factors such as diabetes and hypertension that increase the risk for coronary disease were not associated with an increased risk for LQTS‐related cardiac events. Conclusions: This is the first study to demonstrate that coronary disease augments the risk for LQTS‐related cardiac events in LQTS. The findings highlight the need for more focused preventive therapy in LQTS patients above the age of 40.     

Implantable cardioverter defibrillator in high-risk long QT syndrome patients

INTRODUCTION: Implantable cardioverter defibrillators (ICDs) are increasingly being used in high-risk long QT syndrome (LQTS) patients, but there are limited data regarding clinical experience with this therapeutic modality. The aim of this study is to describe the clinical characteristics of 125 LQTS patients treated with ICDs compared with LQTS patients having similar risk indications who were not treated with ICDs. Among 125 LQTS patients with ICDs, there were 54 cardiac arrest survivors, 19 patients who had ICDs implanted due to recurrent syncope despite beta-blocker therapy, and 52 patients with ICDs implanted due to other reasons, including syncope and LQTS-related sudden death in a close family member. Patients with cardiac arrest and those with recurrent syncope despite beta-blocker therapy (n = 73) were compared to 161 LQTS patients who had similar indications (89 cardiac arrest and 72 recurrent syncope despite beta-blocker therapy) but did not receive ICDs. Total mortality was the endpoint of the analysis. There was 1 (1.3%) death in 73 ICD patients followed an average of 3 years, whereas there were 26 deaths (16%) in non-ICD patients during mean 8-year follow-up (P = 0.07 from log rank test from Kaplan-Meier curves). CONCLUSION: ICDs provide an important therapeutic option to prevent sudden arrhythmic death in high-risk LQTS patients. A long-term prospective study is needed to determine the benefit of this therapeutic modality in LQTS patients.     

Asthma and the risk of cardiac events in the long QT syndrome

While acquiring data for the International Long QT Syndrome Registry, we noticed that a number of patients referred for long QT syndrome (LQTS) were affected by asthma. The effect of asthma comorbidity on clinical course of LQTS has not been studied. This study aimed to evaluate the prevalence of asthma in patients with LQTS, determine the influence of asthma comorbidity on outcome of LQTS patients, and to investigate the confounding effects of β mimetics and β blockers on the occurrence of cardiac events in asthmatic patients. The influence of asthma on risk of cardiac events (syncope, aborted cardiac arrest, or LQTS death) was evaluated after accounting for age, gender, QTc, and RR interval duration, β-blocker and β-mimetic use. Asthma was identified in 226 (5.2%) of 4,310 studied LQTS family members. Longer QTc duration was associated with higher incidence of asthma (p <0.001). Asthma was independently associated with significantly increased risk of cardiac events in affected LQTS patients (hazard ratio 1.32; p = 0.048) and in borderline-affected family members (hazard ratio 2.08; p = 0.004) after adjustment for QTc, RR interval, and gender. An increased risk of cardiac events in asthmatic patients observed before β-blocker therapy was reduced after initiation of treatment with β blockers. In conclusion, the occurrence of asthma in LQTS patients increases with QTc duration. Asthma comorbidity in LQTS patients is associated with an increased risk of cardiac events. The asthma-associated increase in the risk of LQTS-related cardiac events is diminished after initiation of β-blocker therapy, suggesting a possible role of β-receptor modulation underlying asthma-LQTS association.     

Low incidence of cardiac events with beta-blocking therapy in children with long QT syndrome.

AIMS: To evaluate the effect of beta-blockers in children with long QT syndrome (LQTS) we reviewed the outcome of 122 patients (pts). METHODS: LQTS was diagnosed in 24 neonates and in 98 pts aged 0.5-15 years. Diagnosis was made because of syncope in 51 pts, bradycardia in 10 neonates and family history in 61 pts. The longest QTc ranged from 400 to 700 ms. Thirteen pts had 2:1 atrioventricular block and/or ventricular arrhythmias. Screening for mutations was performed in 118 pts. All children were treated with beta-blockers, annually checked by exercise testing and/or 24 h ECG monitoring. RESULTS: Four pts died. Survivors were followed-up for 1-18 years (7.5 +/- 5.3 years). Five neonates and 3 older pts received a prophylactic pacemaker (1 death) so that only 111/122 pts survived and were followed-up with beta-blockers alone. None of them died and five experienced a non-fatal cardiac event. There was no cardiac event among pts who were diagnosed because of familial history and among symptomatic KCNQ1 pts who were effectively treated with beta-blockers. CONCLUSION: The outcome of children with LQTS under effective beta-blockers is favourable. Persisting arrhythmia or symptoms despite beta-blockers should aim at identifying other genotypes than KCNQ1.