Sudden cardiac death without structural heart disease: Update on the long QT and brugada syndromes

The long QT syndrome (LQTS) and the Brugada syndrome (BrS) are the most common genetic causes of malignant ventricular arrhythmias and sudden cardiac death in young patients with normal cardiac morphology. To date, more than 250 different mutations in seven genes have been identified as causing LQTS, whereas the only gene identified to be linked to BrS is SCN5A. In both syndromes, genespecific mutations have been shown to be associated with specific phenotypic expressions. Risk stratification in LQTS and BrS is based mainly upon a constellation of electrocardiographic findings and a history of prior symptoms. In patients identified as high risk for arrhythmic mortality, the implantable cardioverter defibrillator is the most effective treatment and has been shown to provide near-complete protection during long-term follow-up.     

Diagnosis, sudden death risk stratification, and treatment of main long QT syndrome molecular-genetic variants

Inherited long QT syndrome (LQTS) refers to the primary electrical diseases of the heart. It is characterized by QT prolongation on resting ECG and syncope due to life-threatening ventricular arrhythmias. This review focuses on diagnosis, differential diagnosis, risk stratification of sudden cardiac death, and treatment strategy of patients with most prevalent genetic fOrms of LQTS - LQT1, LQT2 and LQT3, which accounted for about 90% of all genetically confirmed cases. Recent advances in understanding of relationship between clinical, electrocardiographic features (on ECG, body surface mapping, stress test) and genetic variants of LQT presented. Characteristics of syncopal events and ECG features of LQTl, LQT2 and LQT3 in the majority of cases are helpful to make an appropriate choice for therapy, even before positive result of molecular genetic testing. Management has focused on the use of beta blockers as first-line treatment and exclusion of triggers of life-threatening arrhythmia which are specific for each molecular-genetic variant. Implantation of cardioverter defibrillator for secondary prevention of sudden death in the high-risk patients or patients with insufficient effect of antiarrhythmic therapy is required.     

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.     

Electrocardiogram in Andersen-Tawil Syndrome. New Electrocardiographic Criteria for Diagnosis of Type-1 Andersen-Tawil Syndrome

Andersen - Tawil syndrome (ATS) is an autosomal - dominant or sporadic disorder characterized by ventricular arrhythmias, periodic paralysis, and distinctive facial and skeletal dysmorphism. Mutations in KCNJ2, which encodes the α-subunit of the potassium channel Kir2.1, were identified in patients with ATS. This genotype has been designated as type-1 ATS (ATS1). KCNJ2 mutations are detectable in up to 60 % of patients with ATS. Cardiac manifestations of ATS include frequent premature ventricular contractions (PVC), Q-U interval prolongation, prominent U-waves, and a special type of polymorphic ventricular tachycardia (PMVT) called bidirectional ventricular tachycardia (BiVT). The presence of frequent PVCs at rest are helpful in distinguishing ATS from typical catecholaminergic polymorphic ventricular tachycardia (CPVT). In typical CPVT, rapid PMVT and BiVT usually manifest during or after exercising. Additionally, CPVT or torsade de pointes in LQTS are faster, very symptomatic causing syncope or often deteriorate into VF resulting in sudden cardiac death. PVCs at rest are quite frequent in ATS1 patients, however, in LQTS patients, PVCs and asymptomatic VT are uncommon which also contributes to differentiating them. The article describes the new electrocardiographic criteria proposed for diagnosis of type-1 Andersen-Tawil syndrome. A differential diagnosis between Andersen-Tawil syndrome, the catecholamine polymorphic ventiruclar tachycardia and long QT syndrome is depicted. Special attention is paid on the repolarization abnormalities, QT interval and the pathologic U wave. In this article, we aim to provide five new electrocardiographic clues for the diagnosis of ATS1.     

遗传性长 QT 综合征的药物及器械治疗

遗传性长 QT 综合征（long-QT syndrome,LQTS）以心电图上 QT 间期延长及其相关的尖端扭转型室性心动过速（torsade de pointes,TdP）为特征,易导致心脏性猝死。它的危险因素有 QTc 长度、基因型、晕厥史等。LQTS 的治疗手段包括β受体阻滞剂治疗、外科心脏左侧交感神经节切除术（LCSD）、心脏起搏治疗以及植入式心律转复除颤器（ICD）治疗。β受体阻滞剂治疗是 LQTS 治疗的基石;心脏起搏治疗适用于伴有心动过缓的 LQTS,可明显降低心脏事件的复发率,但不降低死亡率。对高危的 LQTS 应植入 ICD,皮下 ICD 并发症较少,值得推广。LCSD 技术实用性较差,更适用于 ICD 植入后频繁电击治疗的患者。     

Congenital long QT syndrome: Diagnosis and management in pediatric patients

Opinion statement The long QT syndrome (LQTS) is characterized by electrocardiographic abnormalities and a high incidence of syncope and sudden cardiac death (SCD). The diagnosis is suggested when ventricular repolarization abnormalities result in prolongation of the corrected QT interval. When LQTS is suspected, genetic screening may identify a specific long QT subtype and provide guidance for appropriate therapy. Treatment depends on the relative risk of SCD, which is increased with longer QT durations, prior cardiac events, and a family history of SCD. β Blockers are considered the initial treatment of choice, with implantable cardioverter-defibrillator (ICD) therapy warranted in high-risk patients. In patients with frequent ICD shocks or in those at high risk for SCD where ICD placement cannot be performed, cardiac pacing and/or left cardiac sympathetic denervation may be indicated.     

Genotype‐Specific Risk Stratification and Management of Patients with Long QT Syndrome

Long QT syndrome (LQTS) is an inherited disorder associated with life‐threatening ventricular arrhythmias. An understanding of the relationship between the genotype and phenotype characteristics of LQTS can lead to improved risk stratification and management of this hereditary arrhythmogenic disorder. Risk stratification in LQTS relies on combined assessment of clinical, electrocardiographic, and mutations‐specific factors. Studies have shown that there are genotype‐specific risk factors for arrhythmic events including age, gender, resting heart rate, QT corrected for heart rate, prior syncope, the postpartum period, menopause, mutation location, type of mutation, the biophysical function of the mutation, and response to beta‐blockers. Importantly, genotype‐specific therapeutic options have been suggested. Lifestyle changes are recommended according to the prevalent trigger for cardiac events. Beta‐blockers confer greater benefit among patients with LQT1 with the greatest benefit among those with cytoplasmic loops mutations; specific beta‐blocker agents may provide greater protection than other agents in specific LQTS genotypes. Potassium supplementation and sex hormone–based therapy may protect patients with LQT2. Sodium channel blockers such as mexiletine, flecainide, and ranolazine could be treatment options in LQT3.     

Clinical and genetic characteristics of long QT syndrome

Long QT syndrome (LQTS) is an arrhythmogenic ion channel disorder characterized by severely abnormal ventricular repolarization, which results in prolongation of the electrocardiographic QT interval. The condition is associated with sudden cardiac death due to malignant ventricular arrhythmias similar in form to the hallmark torsade de pointes. Eleven years after the identification of the principle cardiac channels involved in the condition, hundreds of mutations in, to date, 10 genes have been associated with the syndrome. Genetic investigations carried out up until the present have shown that, although the severe form of the disease is sporadic, there are a number of common polymorphisms in genes associated with the condition that may confer susceptibility to the development of torsade de pointes in some individuals, particularly when specific drugs are being administered. Moreover, some polymorphisms have been shown to have regulatory properties that either enhance or counteract a particular mutation's impact. Understanding of the molecular processes underlying the syndrome has enabled treatment to be optimized and has led to better survival among sufferers, thereby demonstrating a key correspondence between genotype, phenotype and therapy. Despite these developments, a quarter of patients do not have mutations in the genes identified to date. Consequently, LQTS continues to be an area of active research. This article contains a summary of the main clinical and genetic developments concerning the syndrome that have taken place during the last decade.     

Assessment of Microvolt T‐Wave Alternans in High‐Risk Patients with the Congenital Long‐QT Syndrome

Background: Microvolt T‐wave alternans (MTWA) has been used for arrhythmogenic risk stratification in cardiac disease conditions associated with increased risk of sudden cardiac death. Macroscopic T‐wave alternans has been observed in patients with congenital long‐QT syndrome (LQTS). The role of MTWA testing in patients with LQTS has not been established. Objective: To determine the diagnostic value of MTWA testing in high‐risk patients with LQTS. Methods and results: We assessed MTWA in 10 consecutive LQTS index patients who survived cardiac arrest or had documented torsade de pointes tachycardia and 6 first‐degree family members with congenital LQTS which had been genotyped in 13 of 16 subjects (7 index patients, 6 family members). No LQTS‐causing mutation was identified in 3 index patients with overt QT prolongation. MTWA was assessed during standardized bicycle exercise testing using the spectral method and yielded negative (n = 8) or indeterminate (n = 2) results in index patients, respectively. Similarly, all first‐degree family members tested MTWA negative except for one indeterminate result. Two genotype positive family members could not be tested (two children—4 and 9 years of age). Conclusion: In patients with congenital LQTS, free from structural heart disease and with a history of life‐threatening cardiac arrhythmias, assessment of MTWA does not yield diagnostic value. Hence, determination of MTWA in lower risk LQTS patients without spontaneous arrhythmic events is likely not to be useful for arrhythmia risk stratification.     

Significance of noninvasive diagnostic techniques in patients with long QT syndrome.

The idiopathic long QT syndrome (LQTS) is an infrequently occurring disorder. Affected patients may have electrocardiographic alterations and are prone to syncope and sudden arrhythmogenic cardiac death. Adequate therapy may improve the prognosis of affected patients significantly. Therefore the early and precise diagnosis of LQTS has major prognostic impact. This study reports the diagnostic significance of standard electrocardiographic techniques and autonomic maneuvers in 14 patients with LQTS. The findings are compared with those of 14 healthy age-matched control persons. QTc duration was significantly longer in patients with LQTS during standard 12-lead electrocardiography (489 +/- 56 vs 412 +/- 30 ms, p < 0.005), exercise stress testing (490 +/- 38 vs 409 +/- 18 ms, p < 0.001), cold pressor testing (512 +/- 45 vs 407 +/- 19 ms, p < 0.001), Valsalva maneuver (497 +/- 49 vs 407 +/- 19 ms, p < 0.001), minimal heart rate during 24-hours of ambulatory electrocardiographic recording (482 +/- 69 vs 402 +/- 22 ms, p < 0.01) and maximal heart rate during Holter monitoring (460 +/- 47 vs 411 +/- 27 ms, p < 0.005). Four of 14 patients with LQTS had pathologic findings during ambulatory electrocardiographic monitoring (2 patients with short episodes of torsades de pointes tachyarrhythmia, 1 patient with intermittent sinoatrial block, and 1 patient with intermittent TU-wave alterations), whereas all control persons had normal ambulatory electrocardiographic recordings (p < 0.05). Thus, noninvasive standard electrocardiographic techniques in combination with autonomic maneuvers may contribute significant information for a precise diagnosis in patients with suspected LQTS.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long QT Syndrome

The hereditary Long QT syndrome (LQTS) is a genetic channelopathy with variable penetrance that is associated with increased propensity for polymorphic ventricular tachyarrhythmias and sudden cardiac death in young individuals with normal cardiac morphology. The diagnosis of this genetic disorder relies on a constellation of electrocardiographic, clinical, and genetic factors. Accumulating data from recent studies indicate that the clinical course of affected LQTS patients is time-dependent and age-specific, demonstrating important gender differences among age groups. Risk assessment should consider age-gender interactions, prior syncopal history, QT-interval duration, and genetic factors. Beta-blockers constitute the mainstay therapy for LQTS, while left cardiac sympathetic denervation and implantation of a cardioverter defibrillator should be considered in patients who remain symptomatic despite beta-blocker therapy. Current and ongoing studies are also evaluating genotype-specific therapies that may reduce the risk for life-threatening cardiac events in high-risk LQTS patients.     

Value of Holter monitoring in patients with the long QT syndrome.

The idiopathic long QT syndrome (LQTS) is an infrequently occurring disorder. It has major clinical impact as patients are prone to syncope, ventricular tachyarrhythmias and sudden arrhythmogenic cardiac death. This paper reports the value of ambulatory electrocardiogram (ECG) monitoring as a diagnostic tool to establish the diagnosis of LQTS. 14 patient with idiopathic LQTS were studied. The results were compared to those of 14 age- and sex-matched healthy control individuals. A 24-hour ambulatory ECG tracing was obtained in each individual. 5/14 patients with LQTS had pathological findings during ambulatory ECG monitoring (2 patients with episodes of torsade de pointes tachycardia, 2 patients with T-wave alternans and 1 patient with bradycardia due to an intermittent SA block), whereas all control persons had normal ambulatory ECG recordings (p < 0.03). Thus, ambulatory ECG recordings may contribute significant diagnostic information in patients with suspected LQTS.     

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.     

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.     

Arrhythmogenic hereditary syndromes: Brugada Syndrome, long QT syndrome, short QT syndrome and CPVT

In approximately 10-20% of all sudden deaths no structural cardiac abnormalities can be identified. Important potential causes of sudden cardiac deaths in the absence of heart disease are primary electrical diseases such as Brugada syndrome, long QT syndrome (LQTS), short QT syndrome and catecholaminergic polymorphic ventricular tachyarrhythmias. Each of these cardiac channelopathies is charaterized by unique genetic and clinical features. The resting ECG and the ECG under exercise are pivotal for the diagnosis of ion channel diseases. Molecular genetic screening can reveal underlying mutations in a variable degree among the cardiac ion channel diseases in up to 70% (LQTS) and may identify individuals with incomplete penetration of the disease. In patients with primary electrical diseases specific clinical triggers for arrhythmic events such as syncope or sudden cardiac death have been identified including exercise, strenuous activity, auditory stimuli or increased vagal tone. The significance of programmed ventricular stimulation is at present unclear concerning risk stratification in patients with Brugada syndrome and short QT syndrome and of no significance in long QT syndrome and catecholaminergic polymorphic ventricular tachycardias. The success of medical therapy remains modest for prevention of sudden cardiac death and may necessitate the insertion of an implantable cardioverter. However, side effects with inappropriate therapies in this patient group with often young and active individuals have to be encountered. More insights into the arrhythmogenesis is critical for future development of effective medical treatment strategies.     

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.     

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.     

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.     

The long QT syndrome: therapeutic implications of a genetic diagnosis

The congenital long QT syndrome (LQTS) is a hereditary disorder characterized by a prolonged QT interval and a polymorphic ventricular tachycardia, known as torsade de pointes (TdP), leading to severe cardiac events such as syncope and/or sudden cardiac death. Molecular genetic studies have revealed a total of eight forms of congenital LQTS caused by mutations in genes of the potassium, sodium and calcium channels or membrane adapter located on chromosomes 3, 4, 7, 11, 12, 17 and 21. Genotype-phenotype correlation in clinical and experimental studies has been investigated in detail in the LQT1, LQT2 and LQT3 syndromes which constitute more than 90% of genotyped patients with LQTS, enabling us to stratify risk and to effectively treat genotyped patients.     

Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome

OBJECTIVES: The aim of this study was to test the hypothesis that epinephrine test may have diagnostic value for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome (LQTS). BACKGROUND: A differential response of dynamic QT interval to epinephrine infusion between LQT1, LQT2, and LQT3 syndromes has been reported, indicating the potential diagnostic value of the epinephrine test for genotyping the three forms. METHODS: The responses of 12-lead ECG parameters to epinephrine were retrospectively examined in 15 LQT1, 10 LQT2, 8 LQT3, and 10 healthy volunteers to select the best ECG criteria for separating the four groups. The epinephrine test then was prospectively conducted in 42 probands clinically affected with LQTS, their 67 family members, and 10 new volunteers. The best criteria were applied in a blinded fashion to prospectively separate a different group of 31 LQT1, 23 LQT2, 6 LQT3, and 30 Control patients (10 genotype-negative LQT1, 10 genotype-negative LQT2 family members, and 10 volunteers). RESULTS: The sensitivity (penetrance) by ECG diagnostic criteria was lower in LQT1 (68%) than in LQT2 (83%) or LQT3 (83%) before epinephrine and was improved with steady-state epinephrine in LQT1 (87%) and LQT2 (91%) but not in LQT3 (83%), without the expense of specificity (100%). The sensitivity and specificity to differentiate LQT1 from LQT2 were 97% and 96%, those from LQT3 were 97% and 100%, and those from Control were 97% and 100%, respectively, when Delta mean corrected Q-Tend >/=35 ms at steady state was used. The sensitivity and specificity to differentiate LQT2 from LQT3 or Control were 100% and 100%, respectively, when Delta mean corrected Q-Tend >/=80 ms at peak was used. CONCLUSIONS: Epinephrine infusion is a powerful test to predict the genotype of LQT1, LQT2, and LQT3 syndromes as well as to improve the clinical diagnosis of genotype-positive patients, especially those with LQT1 syndrome.