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Tex Heart Inst J. 2007; 34(1): 67–75.
PMCID: PMC1847921

Inherited Arrhythmic Disorders

Long QT and Brugada Syndromes
Amirali Nader, MD, Ali Massumi, MD, Jie Cheng, MD, PhD, and Mehdi Razavi, MD

Abstract

Inherited arrhythmic disorders comprise a group of syndromes with unique genetic abnormalities and presentations but with very similar clinical outcomes and complications, the most terrifying of which are life-threatening arrhythmias and sudden cardiac death. Advances in molecular biology have enabled us to define and pinpoint many such disorders, which were previously labeled as idiopathic, to specific genes on various chromosomes. The current trend in the management of these potentially deadly disorders is to use pharmacotherapy (antiarrhythmic agents) and defibrillators for the prevention of sudden death; however, targeted therapy at a molecular level appears to be the path of the future. Herein, we review long QT and Brugada syndromes and focus on the genetics, pathophysiology, and clinical manifestations of these inherited arrhythmogenic disorders that affect patients with structurally normal hearts.

Key words: Action potentials/genetics, arrhythmia/etiology/genetics/pathophysiology, Brugada syndrome/complications/genetics/pathophysiology, death, sudden, cardiac/etiology, electrocardiography, ion transport, long QT syndrome/complications/genetics/pathophysiology, potassium channels, sodium channels, ST-segment elevation, syncope

Long QT syndrome and Brugada syndrome are inherited arrhythmic disorders—part of a larger group of syndromes with unique genetic abnormalities and presentations but with very similar clinical outcomes and complications, including life-threatening arrhythmias and sudden cardiac death (SCD). Advances in molecular biology have enabled us to define and pinpoint many such disorders, which were previously labeled as idiopathic, to specific genes on various chromosomes. Beyond today's pharmacologic and defibrillator therapies, treatments of the future may be targeted at the molecular level. Herein, we review long QT and Brugada syndromes, both of which affect patients with structurally normal hearts. We discuss the genetics, pathophysiology, and clinical manifestations of these inherited arrhythmogenic disorders.

Long QT Syndrome

Long QT syndrome (LQTS) is an inherited disorder characterized by a predisposition to the development of life-threatening ventricular tachyarrhythmias and prolongation of the QT interval on the electrocardiogram (ECG). The QT interval on the surface ECG is measured from the beginning of the QRS complex to the end of the T wave and represents the duration of activation and recovery of the ventricular myocardium. The corrected QT interval for heart rate (QTc) is considered to be less than 0.44 sec. Intervals longer than this increase the risk of ventricular arrhythmias exponentially (Fig. 1).

figure 14FF1
Fig. 1 QT interval.

It is currently estimated that one in every 7,000 to 10,000 people in the United States is affected by LQTS.1 It is worth noting, however, that at least 10% to 15% of those who carry the LQTS gene have a normal QTc duration and remain asymptomatic.

Pathophysiology

To understand the pathogenesis of LQTS, a review of the basic cardiac physiology is warranted. In the heart, electrical signals originate in the sinoatrial node and travel through a network of fibers before triggering action potentials (APs) in the cardiac myocytes. The QRS complex observed on the surface ECG is a representation of the sum of the APs generated in individual myocardial cells (atrial and ventricular tissue, excluding the sinoatrial and atrioventricular nodes).2

The cardiac AP, illustrated in Figure 2, is the AP of a ventricular myocyte. Phase 4 is referred to as the resting membrane potential and describes the membrane potential when the myocyte is not being stimulated. This resting potential is determined by the selective permeability of the membrane to various ions: in particular, potassium ions. Phase 0 (the rapid depolarization phase) of the AP is due to the opening of the fast sodium channels, which causes the rapid influx of positively charged sodium ions into the myocytes. Phase 1 occurs as a result of the closure of the fast sodium channels. Phases 0 and 1 together correspond to the R and S waves on the surface ECG. Phase 2, otherwise known as the plateau phase, corresponds to the ST segment of the ECG and is a result of a balance between inward movement of calcium ions (ICa) and outward movement of potassium ions. Phase 3, the repolarization phase, is determined by the efflux of positively charged potassium ions from the cells and corresponds to the T wave on the ECG. This order of ion channel activation gives rise to the overall electrical current generated in the heart.2

figure 14FF2
Fig. 2 Normal phases of the cardiac action potential and the contributions of the sodium (Na+) and potassium (K+) ion transfers in the action potential.

Theoretically, if we were to block potassium ions from moving out of the myocytes, the AP would be prolonged (Fig. 3A). Conversely, if we could block the entrance of sodium ions into the myocytes, we would decrease the velocity of the AP conduction, in addition to prolonging the QRS duration (Fig. 3B).2

figure 14FF3
Fig. 3 Changes in the slope and duration of the cardiac action potential caused by sodium and potassium channelopathies.

In essence, the QT prolongation described above is caused by an overload of myocardial cells with positively charged ions during ventricular repolarization. If the AP is sufficiently prolonged, calcium channels that normally close toward the end of the AP now have time to reopen again and generate a 2nd excitation wave before the AP is complete. The correlation seen with AP and QT prolongation is shown in Figure 4.2

figure 14FF4
Fig. 4 Action potential (AP) prolongation and its correlation with the surface electrocardiogram (ECG).

A 2nd excitation phase (called early after-depolarization) is generated by individual cells in the myocardium that have automaticity potential. This new wave of excitation does not follow the sequence normally initiated in the sinoatrial node. The overall result is a loss of synchronization and the development of arrhythmias such as torsades de pointes.3

The mechanisms underlying the formation of arrhythmias are slightly different in the various subtypes of LQTS. However, almost all of these mechanisms are the result of an imbalance between the repolarization currents and the reactivation of the depolarization currents (Fig. 5).

figure 14FF5
Fig. 5 Ionic shifts in a ventricular cell.

Genetic studies conducted in families with LQTS have linked this disorder to gene mutations affecting cardiac ion channels—specifically the sodium and potassium channels. Because of this finding, LQTS was once referred to as a channelopathy. Thus far, 6 chromosomal loci and 5 specific genes have been identified on chromosomes 11, 3, 4, 7, and 21.4 Depending on the type of ion channel involved, the LQTS can be categorized into separate types: Types LQT1 through LQT3 and LQT5 to LQT6 encode cardiac ion channel subunits. According to the pattern of inheritance and certain clinical characteristics, the LQTS types have been further sub-typed as the Romano-Ward, the Brugada, and the Jervell and Lang-Nielsen (JLN) syndromes.4 The JLN syndrome has been associated with congenital deafness, in addition to QT prolongation andventricular arrhythmias.4 Details regarding these inherited arrhythmic disorders are presented in Table I.5

Table thumbnail
TABLE I. Inherited Arrhythmic Disorders5

By convention, the 1st letter of the gene's name denotes the ion species involved (K for potassium, S for sodium, Ca for calcium, and CN for channel).

Disorders Involving the Potassium Ion Channel

Types LQT1 and LQT2, caused by potassium channel gene mutations KCNQ1 and KCNE2, respectively, account for the most prevalent genetic forms of LQTS.4 Approximately 87% of these genotyped patients have a mutation on 1 of these 2 genes.4,6 The KCNQ1 gene normally codes for the α-subunit of the “slow” component of the delayed rectifier potassium channel, IKs, which contributes to the repolarization of the cardiac AP (phase 3). Therefore, we can say that a “loss of function” mutation in the KCNQ1 gene results in a decreased potassium efflux through IKs channels and causes a de-lay in the repolarization of the overall AP.7,8 Similarly, mutations in KCNE2, which normally encode the α-subunit of the rapid component of the delayed rectifier potassium channel, IKr, lead to the LQT2 syndrome. Like IKs, IKr contributes to the repolarization phase of the AP, which results in less potassium efflux during the repolarization phase and causes prolongation of the QT interval.4,8 The LQT5 type is caused by mutations in KCNE1 (the β-subunit of IKs), and LQT6 is caused by mutations in KCNE2 (the β-subunit of IKr). Type LQT5 is an uncommon variant of LQTS and accounts for approximately 2% to 3% of all genotyped patients; LQT6 appears to be the rarest form of the disease.4

Other diseases involving potassium channel mutations include the JLN syndromes 1 and 2, which account for less than 1% of the overall cases of LQTS.4 Of note, the risk of cardiac events (syncope, cardiac arrest, and SCD) is higher in patients who have JLN1 and JLN2 than in those who have LQT1 through LQT6. In addition, patients with LQT1 and LQT2 tend to have a higher risk of cardiac events than do those with LQT3. Furthermore, among patients treated with β-blockers, there is a higher rate of cardiac events observed with the LQT2 and LQT3 genotypes.9

Disorders Involving the Sodium Ion Channel

The LQT3 and Brugada syndomes are both caused by the SCN5A gene mutation, which encodes the α-subunit of the cardiac sodium channel.10 It is believed that sodium channel mutations lead to LQTS by inducing an increase in the sodium inward current (INa), which causes prolongation of the AP and hence of the QT interval. The prevalence of LQT3 is estimated to be 10% to 15% of the overall LQTS genotypes.11 Whereas patients who have LQT3 experience most of their cardiac events at rest or during sleep, those with LQT1 and LQT2 have cardiac events during physical or emotion-al stress.12 Furthermore, death during a cardiac event is substantially more frequent in patients with LQT3 than in those with LQT1 and LQT2. It has been suggested that the inconsistency observed in the LQT3 phenotype may be a result of variable cell surface expression of proteins.13 The SCN5A mutations are “gain of function” mutations, which means that they prevent channels from switching off during the plateau phase of the AP, resulting in an increased influx of sodium ions and a prolongation of the plateau and the QT interval.14

Clinical Features of Patients with Long QT Syndrome

Patients who have LQTS are usually diagnosed after a cardiac event has already taken place. Syncope and seizures are the most typical clinical manifestations; car-diac arrest and SCD have also been frequently reported. The severity of these manifestations ranges from mild to severe and appears to be highly variable, mostly depending on the degree of QT prolongation.15 A family history of sudden cardiac arrest at a young age or unexplained death suggests the presence of this syndrome.4 Neuronal hearing deficit may provide a clue in the diagnosis of JLN. In addition, syndactyly has been described in some patients who have idiopathic LQT1.16,17 Physical examination may be an aid in excluding other causes of syncope, such as hypertrophic cardiomyopathy, valvular heart disease, and neurological disorders. Electrocardiographic findings other than prolonged repolarization (long QT interval) include abnormal T-wave morphologies and torsades de pointes. The sex of the individual does not appear to affect the severity of clinical manifestations associated with LQT1, but a higher risk of complications has been described for females who have LQT2 and LQT3 and for males who have the Brugada syndrome.18,19 There seems to be an association between the LQT genotypes and the triggers of arrhythmia. Patients with LQT1 primarily have exercise-related arrhythmic events. Events related to swimming may be specific to LQT1 (those that occur either immediately after diving into water or during recreational or competitive swimming activities).20,21 Events triggered by auditory stimuli, such as an alarm clock or telephone ringing, are most typically seen in individuals with LQT2.21 Acute arousal events (such as exercise, emotion, or noise) are much more likely to be triggers in patients with LQT1 and LQT2 than LQT3.4,20,22 Those with LQT3 are at highest risk of events when at rest or asleep (see the section on Brugada syndrome); the risk is low during sleep for those with LQT1 and accounts for only 3% of events.22

Management of Patients with Long QT Syndrome

As noted previously, there appears to be a close link be-tween the onset of cardiac events and increased sym-pathetic activity in patients with LQTS. As a result, the initial pharmacological approach to the treatment of congenital LQTS is the use of β-blockers to interrupt this sympathetic input to the myocardium.23 β-Blockers are used in both symptomatic and asymptomatic patients with LQTS.24 It is thought that these medications can shorten the QT interval by decreasing activation from the left stellate ganglion and decreasing the incidence of torsades de pointes.25 Furthermore, studies have shown that β-blockers can decrease the incidence of syncope and SCD in patients with LQTS.24,25 A hypothetical concern, however, is that by decreasing the sinus rate, β-blockers could prolong repolarization and possibly predispose patients to torsades de pointes. In 1 animal study, β-blockade prevented the induction of torsades de pointes in dogs with LQT1 and LQT2, but facilitated its induction in those with LQT3.26 For patients with LQT3, the calcium channel blocker verapamil may be effective in preventing torsades de pointes by shortening the endocardial mean APs and by suppressing the early after-depolarization phase.27 Left cardiac sympathetic denervation may be considered if a patient is unresponsive or intolerant to β-blockers.23 Placement of a permanent pacemaker may be indicated in patients with LQTS who have bradycardia-dependent tachyarrhythmias or atrioventricular block. Prophylactic placement of an implantable cardioverter defibrillator (ICD) is recommended for patients with LQTS who have survived an episode of cardiac arrest. Of note, early intervention with an ICD has been shown to be cost-effective in young patients with inherited cardiac arrhythmias.28

The Brugada Syndrome

As an inherited abnormality of the cardiac sodium channel, Brugada syndrome has been of clinical interest since it was first described in 1992.29 During the 1980s, the Centers for Disease Control and Prevention had reported cases of sudden death in young immigrants from Southeast Asia, described as Sudden Unexplained Death Syndrome (SUDS).30,31 Research has now shown that Brugada syndrome and SUDS are phenotypically, genetically, and functionally the same disorder. The occurrence of SCD in normal hearts, without ischemia or obvious electrolyte imbalances, is rare.32 Aside from the SCD that occurs in patients with Brugada syndrome, most SCD is attributable to LQTS, pre-excitation syndrome, or commotio cordis. Of patients diagnosed clinically with Brugada syndrome, only 18% to 30% have the SCN5A gene mutation.33–35 As previously noted, this gene encodes the α-subunit of the sodium ion channel and is the only gene that has been linked to Brugada syndrome to date. When SCN5A is present, the resultant nonfunctional protein leads to altered protein trafficking and eventually to the development of cardiac arrhythmias.36 Brugada syndrome is transmitted within families in an autosomal dominant fashion with variable penetrance, which means that such patients usually have a parent with this condition. Given the nature of this syndrome, there has been extensive debate on the advantages and disadvantages of implementing a mass screening protocol for newborns and infants in order to prevent SCD at a later age.37

Pathogenesis, Diagnosis, and Clinical Manifestations

At a molecular level, the SCN5A gene mutation seen in Brugada syndrome leads to the failure of expression of the sodium channel, its increased inactivation, and a prolonged recovery time before its reactivation.34 It is believed that, through various mechanisms, the end result of this gene mutation is the development of the life-threatening arrhythmias encountered in Brugada syndrome. It is important to note that Brugada syndrome is essentially an “electrical” disease that causes abnormal electrophysiologic activity in the right ventricular epicardium.38,39

The ventricular myocardial tissue is composed of 3 layers—the epicardium, the endocardium, and the mid-myocardium (M cells)—each with unique electrophysiologic properties.40 In general, the epicardium has the shortest AP duration (Fig. 6) and the highest concentration of transient outward (Ito) current.41 The M cells have the longest AP duration and the lowest concentration of Ito current.41 The endocardium, on the other hand, has intermediate AP duration and Ito concentration. A decrease in the AP duration is observed when the ICa currents are overwhelmed by Ito currents, which leads to a significant shortening of phase 2 of the AP. This phenomenon occurs in some myocytes in the epicardial tissue; the others maintain normal AP durations.41,42 This difference in electrical properties, observed in myocytes within the same epicardial tissue, creates a heterogenous population of cells with different AP durations and, subsequently, different refractory periods. Cells with shorter refractory periods have the potential to be re-excited by cells in the surrounding tissue that have normal AP duration.41,42 This phenomenon, referred to as phase-2 re-entry, is believed to be the cause of the ventricular arrhythmias in patients who have Brugada syndrome.41,42 These mechanisms have been elegantly described by Antzelevitch and coworkers,41,42 and recent optical mapping studies have further supported them.43

figure 14FF6
Fig. 6 Cellular mechanism behind Brugada.

The Brugada ECG pattern (described below) is seen much more frequently in men than in women,44 and studies suggest that most of the affected individuals are Asian.45 The most common triggers of death in Brugada syndrome are sleep, fever (malaria in endemic regions), and antiarrhythmic drugs for supraventricu-lar tachycardia or atrial fibrillation. Other triggers of arrhythmia and possibly SCD in Brugada patients are the use of β-blockers,24 the combination of glucose and insulin,46 the use of tricyclic antidepressants,47 alcohol and cocaine use, and electrolyte imbalances such as hypokalemia, hyperkalemia, and hypercalcemia.48 Unlike LQTS, exercise has not been shown to play a key role in triggering arrhythmias in Brugada patients.49 Sympathetic and parasympathetic states, as well as their imbalances, can alter ion channel activity in patients with LQT and Brugada syndromes and lead to the development of arrhythmias.50,51 Although SCD is often the initial clinical presentation of patients with Brugada syndrome (up to ~30%), several risk factors that place patients at a higher risk of SCD have been identified. These factors include frequent premature ventricular beats that morphologically resemble the beats that initiate ventricular fibrillation,52 a history of SCD, and unexplained syncope.53 Patients with a higher risk of SCD may benefit from elective electrophysiologic testing and often meet the criteria for ICD placement. Asymptomatic patients without the risk factors, on the other hand, have a much lower lifetime risk of severe arrhythmias and SCD.39 Although patients with Brugada syndrome tend to present with symptoms in the mid-dle or later decades of life (mean age at death, 45 years), several malignant forms have been described with much earlier (and deadly) manifestations.39

The Brugada Electrocardiogram

The main ECG findings in Brugada syndrome are ST-segment elevation in the right precordial leads (V1 through V3), right bundle branch block, and ventricular tachycardia. A few cases involving the inferior and the right precordial leads have also been described, and these patients are thought to have a unique missense mutation.54 Three patterns of ST-segment elevation have been described: the classic Brugada ECG (type 1), in which the elevated ST segment (≥2 mm) descends with an upward convexity to an inverted T wave. This pattern is referred to as the “coved-type” Brugada ECG (Fig. 7A). The type 2 and type 3 patterns have a “saddle-back” ST-T wave configuration: the elevated ST segment descends toward the baseline, and then rises again to an upright or biphasic T wave. The ST segment is elevated 1 mm or more in the type 2 pattern and less than 1 mm in the type 3 pattern (Fig. 7B).55,56 Of note, in patients with Brugada syndrome, a widened S wave characteristic of right bundle branch block (usually seen in the left lateral leads) is absent, suggesting the presence of a J wave that is mimicking right bundle branch block.45

figure 14FF7
Fig. 7 Brugada ECG patterns.

The sporadic and dynamic nature of the Brugada ECG makes the diagnosis somewhat challenging. Because of this, provocation testing with selected class IC antiarrhythmic drugs has been used. The flecainide provocation test has been shown to be highly sensitive and specific in unmasking the Brugada ECG pattern in affected subjects.57 Other agents that can be used to unmask the Brugada ECG are procainamide, ajmaline, β-blockers, and lithium.58–60 It is important to note that the diagnosis of Brugada syndrome depends on both ECG and clinical findings. A patient who presents with the Brugada ECG criteria but without the clinical characteristics is said to have the Brugada pattern but not the syndrome.55 The Brugada ECG pattern is seen up to 9 times more frequently in men than in women,44 most likely because of a more prominent Ito-mediated notch in the epicardium of males.61

Supraventricular tachycardias can develop in Brugada patients, and many of these arrhythmias are atrial fibrillation.62 One study reported up to a 20% incidence of spontaneous atrial fibrillation in patients with Brugada syndrome, compared with controls.62

It has been noted that, in Brugada syndrome, the epicardial layer (with a higher concentration of Ito) is more likely to have a “spike and dome” or even a premature termination (“dwarfing”) configuration of the AP (Fig. 8).41 A spike and dome or dwarfed epicardial AP, when combined with the more normal M-cell and endocardial APs, changes the gradients across the myocardial tissue (transmural voltage gradient) in such a manner that the ST segment develops an upward shift. This shift leads to the ST-segment elevation seen in the Brugada ECG (Fig. 9).41 The AP dome is lost in some areas of the myocardium and is normal in other areas, creating the conditions for a possible phase-2 re-entry as described previously, and leading to torsades de pointes or ventricular tachycardia and fibrillation.

figure 14FF8
Fig. 8 “Spike and dome” configuration seen in Brugada syndrome.
figure 14FF9
Fig. 9 ST segment elevation in Brugada.

Diagnosis of Brugada Syndrome

Although characteristic ECG patterns are suggestive of Brugada syndrome, it is the presence of specific clinical features in addition to these ECG findings that leads to the diagnosis of Brugada syndrome.55 Brugada syndrome has been classified into 3 different categories. 1) The patients have an ECG with the coved-type ST-segment elevation (in >1 lead [in V1–V3]) and at least one of the following: unexplained syncope, self-terminating polymorphic ventricular tachycardia, documented ventricular fibrillation, family history of SCD at less than 45 years of age, type-1 ST elevation in a family member, nocturnal agonal respiration, and inducibility of ventricular tachycardia by electrophysiologic study.55 Category 2) and 3) patients must meet the type-2 and type-3 ECG patterns; have one of the clinical features noted above; and show saddle-back ST-segment elevation in more than 1 right precordial lead, with conversion to type 1 after a drug challenge with a sodium channel blocker.55 Despite all these diagnostic indicators, it is important to note that the definitive diagnosis of Brugada syndrome has yet to be determined.

Management of Patients with Brugada Syndrome

To date, no pharmacologic treatment has been shown to be completely effective in preventing SCD associated with Brugada syndrome. However, data suggest some benefit from quinidine and hydroquinidine.63,64 The effect of these medications may be mediated by blockade of Ito, which is the transient outward current that increases heterogeneity and promotes premature ventricular beats that act as triggers for ventricular tachycardia and ventricular fibrillation.42 Given the underlying mechanism of arrhythmogenesis in Brugada, Ito blockade could possibly improve the epicardial dwarfing of the AP and resolve the electrical imbalance responsible for the clinical manifestations of Brugada syndrome. Newer agents that may aid in the management of Brugada syndrome are cilostazol (a phosphodiesterase III inhibitor) and tedisamil (a cardioselective Ito blocker).65 Routine monitoring of serum potassium (and magnesium) levels in patients presenting with QT prolongation after arrhythmic events is warranted to eliminate secondary causes.48 Despite the encouraging results recently seen with pharmacotherapy alone, there are not yet sufficient data to recommend antiarrhythmic therapy as an alternative to an ICD. Interestingly, antiarrhythmic drugs may have a positive application in patients with an ICD who continue to have frequent discharges.25 Implantation of an ICD has shown a clear benefit in the prevention of SCD in patients with Brugada syndrome.34,56

The presence of a spontaneous Brugada type-1 ECG, along with ventricular fibrillation, syncope, or sudden death in a 1st-degree relative, warrants ICD placement. However, that benefit is less established in asymptomatic patients with inducible ventricular arrhythmias (class IIb), and there is no evidence of benefit in asymptomatic patients without inducible arrhythmias (class III).25 The SCN5A mutations in Brugada syndrome are also distinguished by profound bradyarrhythmias66; however, the concept that pacemakers might prevent SCD by preventing bradycardia is still investigational. The use of programmed electrical stimulation to identify individuals with Brugada who are at increased risk of cardiac arrest remains a subject of debate.67 Although some studies have shown that programmed electrical stimulation may be a good predictor of major cardiac events in Brugada patients, others have demonstrated conflicting results.32

In conclusion, long QT and Brugada syndromes have different phenotypes, but they share a common final pathway in causing sudden cardiac death. Brugada syndrome provides a model for understanding the pathogenesis of inherited arrhythmic syndromes. In the future, a more thorough knowledge of the disease processes of these syndromes may enable us to use targeted therapy alone and minimize the need for defibrillators.

Footnotes

Address for reprints: Mehdi Razavi, MD, Department of Cardiac Electrophysiology, Texas Heart Institute, 6624 Fannin Street, Suite 2480, Houston, TX 77030. E-mail: moc.liamg@1ivazaridhem

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