Congenital Long QT Syndrome

Congenital long QT syndrome (LQTS) is an inherited condition of abnormal myocardial repolarization. It is characterized clinically by increased risk of potentially fatal ventricular arrhythmias, especially torsades de pointes, manifesting as syncope, cardiac arrest, and sudden unexplained death in otherwise healthy young adults and children. The disease is typically recognized in late childhood or early adolescence, but extreme cases may present during early infancy or in the perinatal period.¹³ The syndrome most often transmitted is in families as an autosomal dominant trait (Romano-Ward syndrome; see also Chapter 93).

Approximately 10% of autosomal dominant LQTS cases are explained by SCN5A mutations,¹⁴ and this form of the disease is referred to as LQT-3. The proportion of sodium channel mutations in LQTS cases presenting during the perinatal and neonatal time periods may be higher.¹⁵ The first SCN5A mutation described was an in-frame deletion of three highly conserved amino acid residues (delKPQ 1505-1507) located within the cytoplasmic loop connecting domains 3 and 4 of Na_V1.5¹⁶—a structural domain required for fast inactivation of the channel.

Since the discovery of the first SCN5A mutation, more than 75 mostly missense SCN5A mutations have been associated with LQT-3 (Figure 50-1, B). Although mutations are found throughout the channel sequence, multiple mutations are clustered in a small number of structural regions. One of these regions is the S4 segment of domain 4 (D4), a critical structural determinant of voltage sensing. Another mutation cluster can be found in the aforementioned cytoplasmic inactivation gate. Finally, several mutations are found in the proximal carboxy terminus, which includes binding sites for several interacting proteins that can modulate sodium channel function.¹¹

Persons with SCN5A mutations associated with LQTS often present with distinct clinical features, including sinus bradycardia, and a tendency for cardiac events to occur during sleep or rest.¹⁷ In addition to bradycardia, certain features of the surface electrocardiogram (ECG), such as narrow and late-onset peaked or biphasic T waves, may offer additional clues to the presence of an SCN5A mutation in the setting of LQTS.¹⁸ Cardiac events are less frequent in the settings of SCN5A mutations as compared with the two major forms of LQTS caused by potassium channel mutations (LQT-1, LQT-2).^19,20 However, in children and adults, the risk of dying after a cardiac event is greater for LQT-3 than for either LQT-1 or LQT-2.

In LQT-3, most SCN5A mutations exhibit a dominant gain-of-function phenotype at the molecular level characterized by defective inactivation leading to increased persistent sodium current (Figure 50-2).²¹ Some mutant channels may also exhibit accelerated recovery from inactivation—a phenomenon consistent with an unstable inactivated state. At the level of single sodium channels, increased persistent sodium current has been correlated with an increased tendency for channel reopening, which may occur in bursts.²¹ More severe slowing of inactivation may be noted in mutations associated with clinically severe LQTS,^13,22 while a small number of mutations may alter voltage dependence of activation and/or inactivation with less dramatic effects on the level of persistent current.^23,24

Increased persistent sodium current has also been observed when wild type Na_V1.5 channels were coexpressed with LQTS-associated mutations in certain auxiliary subunits and interacting proteins. Specifically, mutations in SCN4B encoding the β₄ auxiliary subunit,²⁵ CAV3 encoding the vesicular trafficking protein caveolin-3,²⁶ and SNTA1 encoding the adapter protein α₁-syntrophin,^27,28 exert their pathologic effects by disturbing sodium channel inactivation, leading to increased persistent current. The mechanism responsible for increased persistent current associated with SNTA1 mutations involves activation of neuronal nitric oxide synthase (nNOS) complexed with Na_V1.5, leading to increased cell levels of nitric oxide and nitrosylation of the sodium channel. Activation of nNOS is the result of disrupted scaffolding of a plasma membrane Ca²⁺-ATPase (PMCA4b) that normally inhibits the enzyme in a multi-protein complex with Na_V1.5 and α₁-syntrophin.²⁸

Increased persistent sodium current provides an explanation for delayed repolarization in LQTS.²⁹ Cardiac action potentials last several hundred milliseconds because of a prolonged depolarization phase (plateau), the result of opposing inward (mainly Na⁺ and Ca²⁺) and outward (K⁺) ionic currents. Repolarization occurs when net outward current exceeds net inward current. Increased persistent sodium current will shift this balance toward inward current and will delay onset of repolarization, thus lengthening the action potential duration and the corresponding QT interval. Delayed repolarization predisposes to ventricular arrhythmias mainly by increasing the probability of early afterdepolarization (EAD) and by increasing the dispersion of the action potential duration.³⁰ These phenomena promote conditions that allow electrical signals from depolarized regions of the heart to prematurely reexcite adjacent myocardium that has already repolarized—the basis for a reentrant arrhythmia.

The pathogenic effects of increased persistent sodium current in LQTS have also been strongly supported by computer simulations of cardiac action potentials29,31 and by electrophysiological investigations of cardiac myocytes from genetically engineered mice. Mice engineered to carry the delKPQ mutation have spontaneous life-threatening ventricular arrhythmias.^32,33 At the cellular level, cardiomyocytes from these LQT-3 mice exhibit prolonged action potential duration and frequent EADs—findings that were exaggerated by slow pacing rates. These cells have increased persistent sodium current with faster recovery from inactivation—features that were predicted from studies performed in noncardiac cells.³² Further evidence from the delKPQ mouse suggests that delayed afterdepolarization (DAD) caused by a Ca²⁺-dependent diastolic transient inward current, possibly evoked by abnormal Na⁺ entry through mutant channels, also contributes to arrhythmia susceptibility and may account for the greater lethality of this LQTS subtype.³⁴

Knowledge of the basic mechanisms underlying LQT-3 has prompted new ideas regarding genotype-specific treatment. Mexiletine and other sodium channel blocking drugs can reduce persistent sodium current and shorten the QT interval in LQT-3 patients,35–38 although no data yet indicate that this therapeutic strategy will reduce mortality. In LQT-3 mouse models, mexiletine shortens the myocyte action potential and prevents arrhythmias,^30,39 mainly during slow pacing rates. Suppression of increased persistent current by the antianginal drug ranolazine has been demonstrated for LQT-3 mutations in vitro,⁴⁰ and ranolazine treatment of human with carrying the SCN5A-delKPQ mutation shortened the QTc interval significantly.⁴¹ Propranolol, but not the other β-adrenergic antagonists, may exhibit sodium channel blocking effects at high concentrations,^42–44 and certain SCN5A mutations have increased sensitivity to the drug.¹³ However, propranolol and other β-blockers did not suppress arrhythmias in the delKPQ mouse model.³³

Perinatal and Neonatal LQT-3

SCN5A mutations may cause life-threatening LQTS during gestation (fetal LQTS) and in neonates (neonatal LQTS). Clinical signs suggestive of fetal LQTS include ventricular tachycardia, second-degree atrioventricular (AV) block, and, most commonly, sinus bradycardia,⁴⁵ but such findings may go undetected because electrocardiographic testing of fetuses is not routine. Certain SCN5A mutations, many of which are de novo,^13,46–49 present with earlier onset and more severe congenital arrhythmia syndromes than is typical for LQT-3. The high rate of reported de novo SCN5A mutations in the perinatal period may reflect low heritability due to a survival disadvantage conferred by severe, life-threatening phenotypes. The functional effects of certain SCN5A mutations associated with fetal LQTS can also be potentiated by a developmentally regulated splice isoform involving alternative forms of exon 6.⁶

Evidence indicates that occult LQTS can clinically present as sudden infant death syndrome (SIDS) (see Chapter 98). Cardiac mechanisms including life-threatening arrhythmias have been suspected as risk factors for SIDS, and mutations in genes responsible for LQTS have been identified in approximately 10% of cases.^50,51 SCN5A mutations have accounted for approximately 50% of all LQTS mutations identified in SIDS. SCN5A mutations associated with SIDS promote increased persistent current overtly or under certain conditions such as intracellular acidosis or in the context of a common splice variant.^50,52–54

Arrhythmia Susceptibility With Common SCN5A Variants

Common variants within the SCN5A coding region have been identified in certain populations, and some of these may confer increased risk of cardiac arrhythmia. One variant common in subjects of African descent (S1103Y, also reported as S1102Y) has been associated with an eightfold increased risk for ventricular arrhythmia.⁵⁵ Functional consequences of S1103Y include increased transient and increased persistent current sufficient to evoke EADs in a computational model of cardiac action potentials. This variant may also increase arrhythmia risk in infants. One study suggested that African American SIDS victims are more often homozygous for SCN5A-S1103Y when compared with non-SIDS infants.⁵³ This study further demonstrated that SCN5A-S1103Y channels exhibit a greater level of persistent sodium current when exposed to intracellular acidosis. A subsequent study reported a significantly higher prevalence of heterozygous SCN5A-S1103Y carriers among 71 African American cases of SIDS as compared with African American controls.⁵⁶

Other common SCN5A variants may also be proarrhythmic because of altered sodium channel inactivation. The common variant R1193Q is common in Asians but is a rare variant (0.3%) in subjects of European ancestry.⁵⁷ This variant has been reported in subjects with both acquired and congenital LQTS^58,59 and in sudden unexplained death syndrome (SUDS).⁶⁰ This variant promotes an increased persistent sodium current⁵⁸ and faster inactivation.⁶⁰

Brugada Syndrome

Mutations in SCN5A have been associated with 20% to 30% of cases of Brugada syndrome (BrS), a heritable form of idiopathic ventricular fibrillation.61,62 Individuals with BrS have increased risk for potentially lethal ventricular arrhythmias (polymorphic ventricular tachycardia or fibrillation) typically during sleep, but in the absence of myocardial ischemia, electrolyte abnormalities, or structural heart disease. Increased risk for atrial fibrillation and intraventricular conduction abnormalities may also occur in BrS. Individuals with the disease may exhibit a characteristic baseline ECG pattern consisting of ST elevation in the right precordial leads but normal QT intervals.⁶³ Administration of sodium channel blocking agents (e.g., procainamide, flecainide, ajmaline) or fever may expose this ECG pattern in latent cases.^64,65 Inheritance is autosomal dominant with incomplete, often low, penetrance and a substantial male predominance. A family history of unexplained sudden death is typical. The sudden unexplained death syndrome (SUDS) is clinically similar to BrS and causes sudden death, typically during sleep, in young and middle-aged males in Southeast Asian countries.⁶⁶ Additional information about BrS may be found in Chapter 92.

Chen et al first identified three distinct SCN5A mutations in two unrelated BrS families and in a third sporadic case.⁶¹ One mutation was missense (T1620M), and the other alleles included a frameshift caused by a single nucleotide deletion and a putative splice-site defect. More than 375 mutations have been reported in BrS (Figure 50-1, C, D). SCN5A mutations have also been identified in subjects with SUDS.⁶⁰

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