Brugada and Long QT‐3 Syndromes: Two Phenotypes of the Sodium Channel Disease

Brugada and long QT‐3 syndromes are two allelic diseases caused by different mutations in SCN5A gene inherited by an autosomal dominant pattern with variable penetrance. Both of these syndromes are ion channel diseases of the heart manifest on surface electrocardiogram by ST‐segment elevation in the right precordial leads and prolonged QT_c interval, respectively, with predilection for polymorphic ventricular tachycardia and sudden death, which may be the first manifestation of the disease. Brugada syndrome usually manifests during adulthood with male preponderance, whereas long QT3 syndrome usually manifests in teenage years, although it can also manifest in adulthood. Class IA and IC antiarrhythmic drugs increase ST‐segment elevation and predilection for polymorphic ventricular tachycardia and ventricular fibrillation in Brugada syndrome, whereas these agents shorten the repolarization and QT_c interval, and thus may be beneficial in long QT‐3 syndrome. Beta‐blockade also increases the ST‐segment elevation in Brugada syndrome but decreases the dispersion of repolarization in long QT‐3 syndrome. Mexiletine, a class IB sodium channel blocker decreases QT_c interval as well as dispersion of repolarization in long QT‐3 syndrome but has no effect on Brugada syndrome. The only effective treatment available at this time for Brugada syndrome is implantable cardioverter defibrillator, although repeated episodes of polymorphic ventricular tachycardia can be treated with isoproterenol. In symptomatic patients of long QT‐3 syndrome in whom the torsade de pointes is bradycardia‐dependent or pause‐dependent, a pacemaker could be used to avoid bradycardia and pauses and an implantable cardioverter defibrillator is indicated where arrhythmia is not controlled with pacemaker and beta‐blockade. However, the combination of new devices with pacemaker and cardioverter‐defibrillator capabilities appear promising in these patients warranting further study.     

Near Fatal Ventricular Fibrillation in Brugada Syndrome Despite Presence of an Implanted Implantable Cardioverter Defibrillator

A 38-year-old man with Brugada syndrome and aborted cardiac arrest was treated with quinidine only, based on the results of electrophysiologic drug testing. Six months later, after suffering a vaso-vagal syncope, he opted to receive an implantable cardioverter defibrillator and decided to discontinue quinidine against our recommendation. Sixty-seven months later, he had recurrent ventricular fibrillation that was terminated only by the sixth maximal energy shock delivered by the device (which has the capability to deliver a maximum of 8 shocks). This case suggests the possible risk in only relying on an implantable cardioverter defibrillator in the management of cardiac arrest survivors with Brugada syndrome.     

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.     

Brugada syndrome--an under-recognized electrical disease in patients with sudden cardiac death

In 1992, Brugada and Brugada described 8 patients with a history of aborted sudden death and a distinct ECG pattern of right bundle-branch block with ST segment elevation in leads V1-V3 and normal QT interval in the absence of any structural heart disease. It is called Brugada syndrome now and is believed to be responsible for 4-12% of all sudden deaths and around 20% of deaths in patients with structurally normal hearts. Although this syndrome is observed worldwide and the exact prevalence is unknown, it is more common in the Southeast Asian countries. Repeated syncope, ventricular fibrillation, and sudden cardiac death have been reported in patients with Brugada syndrome. The clinical presentation of Brugada syndrome is distinguished by a male predominance and the appearance of arrhythmic events at an average age of 40 years. The Brugada syndrome is inherited in an autosomal dominant manner with incomplete penetrance and an incidence ranging between 5 and 66 per 10,000. The surface ECG manifestations of the syndrome can transiently disappear, but can be unmasked by potent sodium channel blockers in some cases. Mutations of the cardiac sodium channel SCN5A have been detectable in <20% of patients with Brugada syndrome. Recent genetic studies have confirmed the genetic heterogeneity of the disorder. Antiarrhythmic drugs appear to be of little use in prolonging survival and in preventing recurrences of ventricular arrhythmias. To date, implantable cardioverter defibrillator remains the best therapy to prevent sudden death in these patients.     

Brugada syndrome associated with supraventricular tachycardia

We report the case of a patient with Brugada syndrome and a history of palpitations who presented with an episode of syncope and developed supraventricular tachycardia in the electrophysiological study. The patient was treated with radiofrequency ablation for the supraventricular tachycardia and an implantable cardioverter defibrillator for the Brugada syndrome. At 18?months following implantation of the defibrillator an electrical storm with ventricular fibrillation episodes occurred followed by appropriate discharges of the defibrillator.     

Concurrent long QT and Brugada syndrome in a single patient]

We present a 61-year-old patient with previous cardiac arrest and frequent syncopal spells. ECG showed a typical Brugada pattern and a QTc interval of 425 ms. During programmed ventricular stimulation a self-limited syncopal polymorphic ventricular tachycardia was induced. On diagnosis of the Brugada syndrome an implantable cardioverter defibrillator was implanted. Two days later two episodes of polimorphic ventricular arrhythmia were converted by the device. The ECG at this time showed a prolonged QTc of 500 ms in addition to a typical Brugada pattern. Atenolol was started and after a 36-month follow-up the patient has remained asymptomatic without arrhythmic events. In conclusion, this patient has the Brugada syndrome and also fulfills the clinical and ECG characteristics of the Long QT syndrome. These findings suggest a genetic link between the two syndromes.     

Primär elektrische Herzerkrankungen im Erwachsenenalter—

Sudden cardiac death accounts for 100,000 victims in Germany per year. Predominantly, patients with structural heart disease such as coronary artery disease or dilated cardiomyopathy are affected. However, approximately 5-10% of sudden deaths hit patients without structural disease of the heart. The proportion of young patients (< 40 years of age) in this group is even higher (10-20%). In younger patients significantly more diseases like hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia and primary electrical diseases of the heart could be observed such as long QT syndrome, short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. The primary electrical diseases are different concerning their electrocardiographical pattern, clinical triggers of arrhythmias, results of invasive diagnostics and therapy. Meanwhile, molecular genetic screening can reveal specific mutations of ion channels and can identify consecutive functional defects. 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 implantable cardioverter defibrillator is the therapy of choice in most symptomatic patients. With increasing knowledge as a result of sophisticated molecular genetic screening, identification of underlying ion channel defects and new details of the mechanisms of arrhythmogenesis, a potential genotype-guided therapy will gain more importance in the future.     

Brief Review of the Recently Described Short QT Syndrome and Other Cardiac Channelopathies

There are many diseases related to ion‐channel disorders, so‐called “channelopathies.” Hereditary short QT syndrome is a clinical‐electrocardiographic entity with autosomal‐dominant mode of transmission and it is the most recently described channelopathy. The syndrome may affect infants, children, or young adults with strong positive family background of sudden cardiac death. Short QT syndrome is characterized by short QT and heart‐rate‐corrected QTc intervals. It is frequently associated with tall‐, peaked‐, and narrow‐based T waves that are reminiscent of the typical “desert tent” T waves of hyperkalemia. There is a high tendency for paroxysmal atrial fibrillation due to the heterogeneous abbreviation of action potential duration and refractoriness of atrial myocytes. The arrhythmia can also be induced by programmed electrical stimulation. The safest treatment suggested is an implantable cardioverter defibrillator, though the possibilities of inappropriate shocks have caused some concern, especially in teenagers. The ability of quinidine to prolong the QT interval has the potential to be an effective therapy for patients with short QT syndrome. This is particularly important in developing countries, where the implantable cardioverter‐defibrillator therapy is not always available. Since these patients are at risk of sudden cardiac death from birth, and implantable cardioverter‐defibrillator implantation has a lot of limitations in very young children, the utility of quinidine has to be evaluated further. Clinicians need to be aware of this deadly electrocardiographic (ECG) pattern as it portends a high risk of sudden cardiac death in otherwise healthy subjects with structurally normal hearts.     

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.     

Recommendations for participation in leisure-time physical activity and competitive sports of patients with arrhythmias and potentially arrhythmogenic conditions. Part II: ventricular arrhythmias, channelopathies and implantable defibrillators.

This consensus paper on behalf of the Study Group on Sports Cardiology of the European Society of Cardiology follows a previous one on guidelines for sports participation in competitive and recreational athletes with supraventricular arrhythmias and pacemakers. The question of imminent life-threatening arrhythmias is especially relevant when some form of ventricular rhythm disorder is documented, or when the patient is diagnosed to have inherited a pro-arrhythmogenic disorder. Frequent ventricular premature beats or nonsustained ventricular tachycardia may be a hallmark of underlying pathology and increased risk. Their finding should prompt a thorough cardiac evaluation, including both imaging modalities and electrophysiological techniques. This should allow distinguishing idiopathic rhythm disorders from underlying disease that carries a more ominous prognosis. Recommendations on sports participation in inherited arrhythmogenic conditions and asymptomatic gene carriers are also discussed: congenital and acquired long QT syndrome, short QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular cardiomyopathy and other familial electrical disease of unknown origin. If an implantable cardioverter defibrillator is indicated, it is no substitute for the guidelines relating to the underlying pathology. Moreover, some particular recommendations for patients/athletes with an implantable cardioverter defibrillator are to be observed.     

Ventricular arrhythmias in the athlete

Life-threatening ventricular arrhythmias in the athlete nearly always occur in the presence of structural heart disease. In the last few years, 2 new causes of life-threatening arrhythmias have been described in patients with normal hearts-that of the Brugada syndrome and that of commotio cordis. Non-life-threatening premature ventricular beats and even nonsustained ventricular tachycardia are not rare, and although usually benign, can be secondary to cardiomyopathies. Athletes with symptoms of syncope, especially if exertional, warrant a complete evaluation. The treatment of athletes and other individuals with life-threatening ventricular arrhythmias has been revolutionized by the implantable cardioverter defibrillator, a device that affords excellent protection from sudden death. Defining those athletes who would benefit from the implantable defibrillator is not always clear. Furthermore, participation in competitive athletics for athletes with life-threatening arrhythmias or structural heart disease known to put the athlete at risk for life-threatening arrhythmias is usually prohibited.     

Long-term outcome of pharmacological and nonpharmacological treatment for ventricular arrhythmias

Recent advances of nonpharmacological therapy such as catheter ablation and implantable cardioverter defibrillator and lessons from the Cardiac Arrhythmia Suppression Trial(CAST) have changed the strategy for ventricular arrhythmias. The safety and efficacy of radiofrequency catheter ablation of symptomatic sustained monomorphic ventricular tachycardia without structural heart disease has made ablation the firstline curative therapy. In idiopathic ventricular fibrillation such as Brugada syndrome, an implantable cardioverter defibrillator is the most effective treatment to prevent sudden cardiac death. In patients with asymptomatic ventricular tachyarrhythmias in heart failure, class I antiarrhythmic drugs should be avoided due to proarrhythmic and negative inotropic effects that may be responsible for increased mortality in some trials. In such patients, amiodarone and beta-blocker may reduce sudden cardiac death. For patients with sustained ventricular tachycardia or ventricular fibrillation in heart failure, amiodarone or implantable cardioverter defibrillator should be considered. In comparison with amiodarone, implantable cardioverter defibrillator markedly reduced sudden death in ventricular tachycardia and ventricular fibrillation survivors in Antiarrhythmics Versus Implantable Defibriltors(AVID). Although better patient selection and clarification of mapping criteria improved the successful ablation rate in patients with structural heart disease, candidates of ablation are few. In patients with extensive structural heart disease, multiple ventricular tachycardias are often present. Catheter ablation of a single ventricular tachycardia may be only palliative. Therefore, implantable cardioverter defibrillator is the most effective treatment to prevent sudden cardiac death, with amiodarone and ablation as the adjunctive therapy to prevent frequent ventricular tachycardia. Furthermore, an implantable cardioverter defibrillator improved survival in selected patients with depressed ventricular function after myocardial infarction, who also have nonsustained and inducible sustained ventricular tachycardia in Multicenter Automatic Defibrillator Implantation Trial(MADIT) and Multicenter Unsustained Tachycardia Trial(MUSTT).     

Clinical and molecular genetics of the short QT syndrome

PURPOSE OF REVIEW: Sudden cardiac death in patients without structural heart disease remains a challenge in diagnostics and risk stratification. Genetically determined arrhythmias are a potential cause for a primary electrical disease. A recently discovered primary electrical disease is discussed. RECENT FINDINGS: The inherited short QT syndrome is a recently recognized genetic condition, which is associated with atrial fibrillation, syncope and/or sudden cardiac death. Attention has been focused on diagnostic ECG features, the identification of underlying mutations and mechanisms of arrhythmogenesis. SUMMARY: The short QT syndrome is clinically associated with atrial fibrillation, syncope and sudden cardiac death. A shortened QT interval (QTc <360 ms) and reduced ventricular refractory period together with an increased dispersion of repolarization constitute the potential substrate for reentry and life-threatening ventricular tachyarrhythmia. To date, gain-of-function mutations in KCNH2, KCNQ1, KCNJ2, encoding potassium channels and loss-of-function mutations in CACNA1C and CACNB2b, encoding L-type calcium channel subunits have been identified. The therapy of choice is the implantable cardioverter defibrillator in symptomatic patients. Quinidine has been shown to prolong the QT interval and to normalize the effective refractory periods of the atrium and ventricle in patients with short QT-1 syndrome.     

Manifestation of Brugada syndrome after pacemaker implantation in a patient with sick sinus syndrome

A 49-year-old woman experienced syncope 10 months after DDD pacemaker implantation for sick sinus syndrome. ECG revealed abnormal ST elevation in leads V1 to V3 during a paced rhythm. Multifocal premature ventricular contractions followed by ventricular fibrillation were documented. Saddleback-type ST elevation was confirmed after a mode change to AAI. The diagnosis of Brugada syndrome was made, and the DDD pacemaker was upgraded to an implantable cardioverter defibrillator. Brugada syndrome can be easily overlooked if the classic ECG findings are not initially noted but may be observed even during pacing therapy.     

Epilepsy Misdiagnosed as Long QT Syndrome: It Can Go Both Ways

Cardiogenic seizures are common and could be the sentinel event heralding the presence of congenital long QT syndrome (LQTS). Distinguishing a cardiogenic seizure from a neurogenic one is of the utmost importance. Herein, we present the case of a 12‐year‐old boy with recurrent episodes of syncope and seizures. Despite absence of QT prolongation on electrocardiogram, absence of documented arrhythmias, a negative LQTS genetic test, and recurrent episodes while on nadolol beta‐blocker therapy, he was diagnosed with LQTS and implanted with an implantable cardioverter defibrillator (ICD). When syncope and seizure occurred with normal sinus rhythm documented on the ICD, he was referred to neurology, and an electroencephalogram was positive for numerous bursts of bilaterally synchronous generalized discharges. He was started on antiepileptic treatment after which his seizures resolved. His LQTS diagnosis was removed, beta‐blocker therapy discontinued, and his ICD was explanted. He has been seizure‐free for over 2 years.     

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.     

Brugada syndrome with ventricular tachycardia and fibrillation related to hypokalemia.

A 60-year-old man with asymptomatic Brugada syndrome and neither a history of syncope nor family history of sudden death was admitted because of bronchial asthma. Serum potassium concentration was 3.8 mmol/L on admission, and decreased to 3.1 mmol/L on the 6th day, probably as a side effect of steroid therapy. The patient was found unconscious on the 7th day, and his serum potassium concentration was 3.4 mmol/L immediately after the episode. On the 8th day, the patient was again found unconscious, and polymorphic ventricular tachycardia and fibrillation (VT/VF) was documented on electrocardiographic (ECG) monitoring. The coved type of ST-segment elevation in leads V(1-3) was observed on the ECG after spontaneous recovery of sinus rhythm, and VT/VF associated with Brugada syndrome was diagnosed. The serum potassium concentration decreased to 2.9 mmol/L immediately after the episode, but QT prolongation was not observed during the clinical course. After the correcting the serum potassium concentration, there was no further recurrence of the malignant ventricular arrhythmia and syncope. An implantable cardioverter defibrillator was inserted to prevent sudden death. Hypokalemia that does not induce QT prolongation may contribute to the occurrence of VT/VF in Brugada syndrome.     

Asymptomatic right ventricular perforation by an implantable cardioverter defibrillator lead detected by home monitoring system

Right ventricular lead perforation is a rare but serious and potentially life-threatening complication of pacemaker or defibrillator lead implantation. This report describes a patient with Brugada syndrome in whom the diagnosis of asymptomatic right ventricular perforation by an implantable cardioverter defibrillator lead was detected 12 days after implantation, thanks to a report from home monitoring system. The patient was admitted to our institution, where the lead was explanted and replaced. This case illustrates the potential lifesaving benefit of the home monitoring system in patients with implantable cardioverter defibrillator.     

Is There a Role for Implantable Cardioverter Defibrillators in Long QT Syndrome?

ICDs in Long QT Syndrome. The congenital familial long QT syndrome (LQTS) is characterized by QT interval prolongation on ECG and potentially life‐threatening polymorphic ventricular arrhythmias. Antiadrenergic therapy, i.e., beta‐adrenoceptor blockade, left cardiac sympathetic denervation, and occasionally pacemaker therapy, sufficiently protects most LQTS patients. Implantable cardioverter defibrillator treatment, with some specific problems and setting requirements in LQTS patients, should at least be considered or implanted in patients with recurrent arrhythmias despite adequate antiadrenergic therapy. Some genetic subtypes, such as LQTS3, may not respond as well (or even adversely) to antiadrenergic therapy and, thus, benefit more from implantable cardioverter defibrillator therapy.     

Implantable cardiac arrhythmia devices--Part II: implantable cardioverter defibrillators and implantable loop recorders

Implantable cardiac devices have become firmly entrenched as important therapeutic tools for a variety of cardiac conditions. The second part of this two-part review discusses the contemporary use and follow-up of implantable cardioverter defibrillators (ICD) and the implantable loop recorder. The ICD has become the standard therapy for protecting patients against sudden cardiac death. Two recent trials, the Multicenter Automatic Defibrillator Trial II (MADIT II) and the Sudden Cardiac Death Heart Failure Trial (SCD-HEFT), demonstrated that the ICD is associated with a significant survival benefit for patients with reduced ejection fraction (< 0.30-0.35), particularly if heart failure symptoms are present. The ICD has an important role in the management of other conditions associated with a high risk for sudden death, such as hypertrophic cardiomyopathy, long QT syndrome, and Brugada syndrome. The implantable loop recorder has become an important diagnostic tool for the patient with unexplained syncope.