Long QT Syndrome

Clinical Description

LQTS is an inherited or acquired disorder of repolarization identified by the electrocardiographic abnormalities of prolongation of the Q-T interval corrected for heart rate (QTc), usually above 460 to 480 ms; relative bradycardia; T-wave abnormalities (Figure 54-1); and episodic ventricular tachyarrhythmias, particularly torsades de pointes (Figure 54-2).⁷ The inherited form of LQTS is transmitted as an autosomal dominant or autosomal recessive trait. Acquired LQTS may be seen as a complication of various drug therapies or electrolyte abnormalities. Whether the abnormality is genetic or acquired, the clinical presentation is similar.^1,7 The initial presentation of LQTS is heterogeneous and most commonly includes syncope, which, in many instances, is triggered by emotional stress, exercise, or auditory phenomena. Other presenting features include seizures or palpitations. SCD is the first symptom in some individuals, but some other cases are diagnosed by surface electrocardiogram (ECG) as a family screening evaluation necessitated by family history of LQTS or SCD.

FIGURE 54-1 Electrocardiogram leads II and V5 demonstrating prolonged Q-T intervals and T-wave alternans. Bazett’s formula, used to calculate the Q-T interval corrected for heart rate (QTc), is noted.

FIGURE 54-2 Polymorphic ventricular tachycardia in a patient with long QT syndrome.

Gene Identification in Romano-Ward Syndrome

KVLQT1 or KCNQ1: The LQT1 Gene

The first of the genes mapped for LQTS, termed LQT1, required 5 years from the time that mapping to chromosome 11p15.5 was first reported to gene cloning.²³ This gene, originally named KVLQT1, but more recently called KCNQ1 (Table 54-1), is a novel potassium channel gene that consists of 16 exons, spans approximately 400 kb, and is widely expressed in human tissues, including the heart, inner ear, kidney, lung, placenta, and pancreas but not in the skeletal muscle, liver, or brain.²⁴ Although most of the mutations are “private” (i.e., only seen in one family), at least one frequently mutated region (called a “hot spot”) of KVLQT1 exists.^25–27 This gene is the most commonly mutated gene in LQTS.

Table 54-1 Common Arrhythmia Syndromes and Their Genetic Basis

Analysis of the predicted amino acid sequence of KVLQT1 suggests that it encodes a potassium channel α-subunit with a conserved potassium-selective pore-signature sequence flanked by six membrane-spanning segments similar to shaker-type channels (Figure 54-3).^24,27–29 A putative voltage sensor is found in the fourth membrane-spanning domain (S4), and the selective pore loop is located between the fifth and sixth membrane-spanning domains (S5,S6). Biophysical characterization of the KVLQT1 protein confirmed that KVLQT1 is a voltage-gated potassium channel protein subunit, which requires coassembly with a β-subunit called minK to function properly.^28,29 Expression of either KVLQT1 or minK alone results in either inefficient or no current development. When minK and KVLQT1 are co-expressed in either mammalian cell lines or Xenopus oocytes, however, the slowly activating potassium current (I_Ks) is developed in cardiac myocytes.^28,29 The combination of normal and mutant KVLQT1 subunits forms abnormal I_Ks channels, and these mutations are believed to act through a dominant-negative mechanism (the mutant form of KVLQT1 interferes with the function of the normal wild-type form through a “poison pill” type mechanism) or a loss-of-function mechanism (only the mutant form loses activity).³⁰

FIGURE 54-3 Genetics of ventricular arrhythmias. The genetic loci and known genes identified for long QT syndrome are shown along with the ion channel protein structure. Note that the potassium channel α-subunits KvLQT1 and HERG require association with β-subunits (minK and KVLQT1=IKs; MiRP1 and HERG=IKr for normal function).

Because KVLQT1 and minK form a unit, mutations in minK could also be expected to cause LQTS. This fact was subsequently demonstrated (discussed below).³¹

HERG or KCNH2: The LQT2 Gene

The LQT2 gene was initially mapped to chromosome 7q35-36 by Jiang et al, and subsequently, candidate gene screening identified the disease-causing gene HERG (human ether-a-go-go-related gene), a cardiac potassium channel gene to be the LQT2 gene (see Table 54-1).^27,32 HERG was originally cloned from a brain cDNA library and found to be expressed in neural crest–derived neurons, microglia, a wide variety of tumor cell lines, and the heart.^33–37 LQTS-associated mutations were identified in HERG throughout the gene, including missense mutations, intragenic deletions, stop codons, and splicing mutations.^27,37,38 Currently, this gene is thought to be the second most common gene mutated in LQTS (second to KVLQT1). As with KVLQT1, “private” mutations that are scattered throughout the entire gene without clustering preferentially are seen.

HERG consists of 16 exons and spans 55 kb of genomic sequence.³⁷ The predicted topology of HERG (see Figure 54-3) is similar to that of KVLQT1. Unlike KVLQT1, HERG has extensive intracellular amino-and-carboxyl termini, with a region in the carboxyl-terminal domain having sequence similarity to nucleotide binding domains (NBDs).

Electrophysiological and biophysical characterization of expressed HERG in Xenopus oocytes established that HERG encodes the rapidly activating delayed rectifier potassium current I_Kr.^39–41 Electrophysiological studies of LQTS-associated mutations showed that they act through either a loss of function or a dominant negative mechanism.^41,42 In addition, protein trafficking abnormalities have been shown to occur.^43,44 This channel has been shown to coassemble with β-subunits for normal function, similar to that seen in I_Ks. McDonald et al initially suggested that the complexing of HERG with minK is needed to regulate the I_Kr potassium current.⁴⁵ Bianchi et al provided confirmatory evidence that minK is involved in the regulation of both I_Ks and I_Kr.⁴⁶ Abbott et al identified MiRP1 as a β-subunit for HERG (discussed below).⁴⁷

SCN5A: The LQT3 Gene

The positional candidate gene approach was also used to establish that the gene responsible for chromosome 3–linked LQTS (LQT3) is the cardiac sodium channel gene SCN5A (see Table 54-1).^48,49 SCN5A is highly expressed in the human myocardium and brain but not in the skeletal muscle, liver, or uterus.^50–52 It consists of 28 exons that span 80 kb and encodes a protein of 2016 amino acids with a putative structure that consists of four homologous domains (DI to DIV), each of which contains six membrane-spanning segments (S1 to S6) similar to the structure of the potassium channel α-subunits (see Figure 54-3).^27,39 Linkage studies with LQT3 families and SCN5A initially demonstrated linkage to the LQT3 locus on chromosome 3p21-24, and multiple mutations were subsequently identified.^50,51 Biophysical analysis of the initial three mutations were expressed in Xenopus oocytes, and it was found that all mutations generated a late phase of inactivation-resistant, mexiletine- and tetrodotoxin-sensitive whole-cell currents through multiple mechanisms.^53,54 Two of the three mutations showed dispersed reopening after the initial transient current, but the other mutation showed both dispersed reopening and long-lasting bursts.⁵⁴ These results suggested that SCN5A mutations act through a gain of function mechanism (the mutant channel functions normally, but with altered properties such as delayed inactivation) and that the mechanism of chromosome 3–linked LQTS is persistent non-inactivated sodium current in the plateau phase of the action potential. Later, An et al showed that not all mutations in SCN5A are associated with persistent current and demonstrated that SCN5A interacted with β-subunits.⁵⁵

minK or KCNE1: The LQT5 Gene

minK (IsK or KCNE1) was initially localized to chromosome 21 (21q22.1) and found to consist of three exons that span approximately 40 kb (see Table 54-1). It encodes a short protein consisting of 130 amino acids and has only one transmembrane-spanning segment with small extracellular and intercellular regions (see Figure 54-3).^30,31,56 When expressed in Xenopus oocytes, it produces potassium current that closely resembles the slowly activating delayed-rectifier potassium current I_Ks in cardiac cells.^56,57 The fact that the minK clone was only expressed in Xenopus oocytes and not in mammalian cell lines raised the question whether minK is a human channel protein. With the cloning of KVLQT1 and the coexpression of KVLQT1 and minK in both mammalian cell lines and Xenopus oocytes, it became clear that KVLQT1 interacts with minK to form the cardiac slowly activating delayed rectifier I_Ks current.^28,29 minK alone cannot form a functional channel but induces the I_Ks current by interacting with endogenous KVLQT1 protein in Xenopus oocytes and mammalian cells. Bianchi et al showed that mutant minK results in abnormalities of I_Ks, I_Kr as well as protein trafficking abnormalities.⁴⁶ McDonald et al showed that minK also complexes with HERG to regulate the I_Kr potassium current.⁴⁵ Splawski et al demonstrated that minK mutations cause LQT5 when they identified mutations in two families with LQTS.³¹ In both cases, missense mutations (S74L, D76N) were identified; they reduced I_Ks by shifting the voltage dependence of activation and accelerating channel deactivation. This was supported by the fact that a murine model of minK-defective LQTS was also created.⁵⁸ The functional consequences of these mutations include delayed cardiac repolarization and, hence, an increased risk of arrhythmias.

MiRP1 or KCNE2: The LQT6 Gene

MiRP1, the minK-related peptide 1, or KCNE2 (see Table 54-1), is a novel potassium channel gene recently cloned and characterized by Abbott and colleagues.⁴⁷ This small integral membrane subunit protein assembles with HERG (LQT2) to alter its function, enabling full development of the I_Kr current (see Figure 54-3). MiRP1 is a 123–amino acid channel protein with a single predicted transmembrane segment similar to that described for minK.⁵⁶ Chromosomal localization studies mapped this KCNE2 gene to chromosome 21q22.1, within 79kb of KCNE1 (minK) and arrayed in opposite orientation.⁴⁷ The open reading frames of these two genes share 34% identity, and both are contained in a single exon, suggesting that they are related through gene duplication and divergent evolution.

Three missense mutations associated with LQTS and ventricular fibrillation (VF) were identified in KCNE2 by Abbott et al, and biophysical analysis demonstrated that these mutants form channels that open slowly and close rapidly, thus diminishing potassium currents.⁴⁷ In one case, the missense mutation, a C-to-G transversion at nucleotide 25, which produced a glutamine (Q) to glutamic acid (E) substitution at codon 9 (Q9E) in the putative extracellular domain of MiRP1, led to the development of torsades de pointes and VF after intravenous clarithromycin infusion (i.e., drug induced).

Therefore, like minK, this channel protein acts as a β-subunit but, by itself, leads to ventricular arrhythmia risk when mutated. These similar channel proteins (i.e., minK and MiRP1) suggest that a family of channels that regulates ion channel α-subunits exists. The specific role of this subunit and its stoichiometry remain unclear and are currently being hotly debated.

Genotype-Phenotype Correlations in Long QT Syndrome

Therapeutic Options in Long QT Syndrome

Currently, the standard therapeutic approach in LQTS is the initiation of β-blockers at the time of diagnosis.⁷ Recently, Moss et al demonstrated significant reduction in cardiac events using β-blockers.⁷⁷ However, syncope, aborted cardiac arrest, and SCD do continue to occur. When β-blockers cannot be used, such as in patients with asthma, other medications such as mexiletine have been tried.⁷⁸ When medical therapy has failed, left sympathectomy or therapy with an implantable cardioverter-defibrillator (ICD) has been used.⁷

Genetics-based therapy has also been described. Schwartz et al showed that sodium channel blocking agents (i.e., mexiletine) shorten the QTc in patients with LQT3, whereas exogenous potassium supplementation or potassium channel openers have been shown to be potentially useful in patients with potassium channel defects.^78–80 However, long-term potassium therapy with associated potassium-sparing agents has been unable to keep the serum potassium above 4 mmol/L because of renal potassium homeostasis. This suggests that long-term potassium therapy may not be useful. In addition, no definitive evidence that these approaches (i.e., sodium channel blockers, exogenous potassium, or potassium channel openers) improve survival has been published.

Andersen Syndrome (LQT7)

Brugada Syndrome

Clinical Aspects of Brugada Syndrome

The first identification of the electrocardiographic pattern of RBBB with ST elevation in leads V1 to V3 was reported by Osher and Wolff.⁸⁵ Shortly thereafter, Edeiken identified persistent ST elevation without RBBB in 10 asymptomatic males, and Levine et al described ST elevation in the right chest leads and conduction block in the right ventricle in patients with severe hyperkalemia.^86,87 The first association of this ECG pattern with SCD was described by Martini et al and later by Aihara et al.^88,89 This association was further confirmed in 1991 by Pedro and Josep Brugada, who described four patients with SCD and aborted SCD, with ECGs demonstrating RBBB and persistent ST elevation in leads V1 to V3 (Figure 54-4).⁹⁰ In 1992 these authors characterized what they believed to be a distinct clinical and electrocardiographic syndrome.³

FIGURE 54-4 Electrocardiographic features of Brugada syndrome. Note the ST-segment elevation (cove type) in leads V1 and V2.

The finding of ST elevation in the right chest leads has been observed in various clinical and experimental settings and is not unique to or diagnostic of Brugada syndrome by itself.⁹¹ Situations in which these ECG findings occur include electrolyte or metabolic disorders, pulmonary or inflammatory diseases, and abnormalities of the central or peripheral nervous system. In the absence of these abnormalities, the term idiopathic ST elevation is often used and may identify patients with Brugada syndrome.

The ECG findings and associated sudden and unexpected death have been reported as common problems in Japan and Southeast Asia, where it most commonly affects men during sleep.⁹² This disorder, known as sudden and unexpected death syndrome (SUDS) or sudden unexpected nocturnal death syndrome (SUNDS), has many other names in Southeast Asia: bangungut (to rise and moan in sleep) in the Philippines; non-laitai (sleep-death) in Laos; lai-tai (died during sleep) in Thailand; and pokkuri (sudden and unexpectedly ceased phenomena) in Japan. General characteristics of SUNDS include young, healthy males in whom sudden death, preceded by a groan, occurs usually during sleep late at night. No precipitating factors are identified, and autopsy findings show no structural heart disease.⁹³ Life-threatening ventricular tachyarrhythmias as a primary cause of SUNDS have been demonstrated, with VF occurring in most cases.⁹⁴

The risk of SCD associated with Brugada syndrome and SUNDS in European and Southeast Asian individuals has been reported to be extremely high; approximately 75% of patients, as reported by Brugada et al, survived cardiac arrest.^3,90,95 In addition, symptomatic and asymptomatic patients have been considered to be at equal risk. Priori et al have, however, disputed this claim.⁹⁶ In a study of 60 patients with Brugada syndrome, asymptomatic patients had no episodes or events. The importance of this difference is its impact on therapeutic decision making, as currently all patients receive ICD therapy. Should the data of Priori et al hold up, selective use of ICDs would be appropriate.⁹⁶ If selective use of ICDs were to be considered, other diagnostic tests for risk stratification would be necessary.

Kakishita et al studied a high-risk group of patients, 37% of whom had experienced spontaneous episodes of VF.⁹⁷ As the majority of patients had ICDs, the authors were able to show that 65% of episodes were preceded by premature ventricular complexes (PVCs), which were essentially identical to the initiating PVCs of VF in morphology. In fact, the PVCs initiating all VF episodes arose from the terminal portions of the T wave, and pause-dependent arrhythmias were rare. This suggests that vigilant evaluation by Holter monitoring could identify at-risk patients. In addition, the authors suggested that the use of radiofrequency (RF) ablation targeting the initiating PVCs could be helpful in reducing risk and reducing the need for ICD placement.

Molecular Genetics of Brugada Syndrome

In 1998, our laboratory reported the findings on six families and several sporadic cases of Brugada syndrome.¹⁰⁰ The families were initially studied by linkage analysis by using markers to the known ARVD loci and LQT loci, and linkage was excluded. Candidate gene screening using the mutation analysis approach of single-strand conformation polymorphism (SSCP) analysis and deoxyribonucleic acid (DNA) sequencing was performed, and SCN5A was chosen for study on the basis of the suggestions of Antzelevitch.^{91,99,101–103} In three families, mutations in SCN5A were identified (see Table 54-1): (1) a missense mutation (C-to-T base substitution) causing a substitution of a highly conserved threonine by methionine at codon 1620 (T1620M) in the extracellular loop between transmembrane segments S3 and S4 of domain IV (DIVS3-DIVS4), an area important for coupling of channel activation to fast inactivation; (2) a two-nucleotide insertion (AA), which disrupts the splice-donor sequence of intron 7 of SCN5A; and (3) a single nucleotide deletion (A) at codon 1397, which results in an in-frame stop codon that eliminates DIIIS6, DIVS1-DIVS6, and the carboxy-terminus of SCN5A (Figure 54-5).¹⁰⁰ Since the initial report, multiple confirming mutations have been identified. SCN5A mutations have also been found in the case of SCD in children.¹⁰⁴

FIGURE 54-5 The molecular architecture of the cardiac I_Na sodium channel encoded by SCN5A and the mutations causing LQT3 (purple) and Brugada syndrome (white).

Biophysical analysis of the mutants in Xenopus oocytes demonstrated a reduction in the number of functional sodium channels in both the splicing mutation and the one-nucleotide deletion mutation, which should promote development of re-entrant arrhythmias. In the missense mutation, sodium channels recover from inactivation more rapidly than normal. Subsequent experiments conducted in modified HEK cells revealed that at physiological temperatures (37° C), reactivation of the T1620M mutant channel was actually slower, whereas inactivation of the channel was significantly accelerated. These alterations leave the transient outward current unopposed and thus able to effect an all-or-none repolarization of the action potential at the end of phase 1.¹⁰⁵ Failure of the sodium channel to express, as with the insertion and deletion mutations, results in similar electrophysiological changes. Reduction of the sodium channel I_Na current causes heterogeneous loss of the action potential dome in the right ventricular epicardium, leading to a marked dispersion of depolarization and refractoriness, an ideal substrate for development of re-entrant arrhythmias. Phase 2 re-entry produced by the same substrate is believed to provide the premature beat necessary for the initiation of the VT and VF responsible for symptoms in these patients. Interestingly, however, Kambouris et al identified a mutation in essentially the same region of SCN5A as the T1620M mutation (R1623H), but the clinical and biophysical features of this mutation were found to be consistent with LQT3 and not Brugada syndrome.¹⁰⁶ More recently, mutations in SCN5A, in which both Brugada syndrome and LQT3 features were seen in the same patient, has been described.¹⁰⁷ Hence, there clearly remains a gap in our understanding of these entities.

Risk Stratification in Brugada Syndrome

Most symptomatic or at-risk patients with Brugada syndrome manifest an ECG with a coved-type ST-segment elevation with or without provocation with sodium channel blocking agents such as ajmaline or flecainide (Figure 54-6).¹⁰⁸ The other form of ST-segment elevation, the so-called saddle type, is not associated with definitive Brugada syndrome unless it transitions into a coved type by provocation or independently. Brugada et al have suggested, however, that the risk of SCD is not different between symptomatic patients and asymptomatic patients, including those with concealed forms of disease.^90,95,108

FIGURE 54-6 Ajmaline provocation in Brugada syndrome. A, Normal electrocardiographic findings in leads V1 and V2 in an individual with asymptomatic concealed Brugada syndrome and an SCN5A mutation. B, The response to ajmaline, identifying ST-segment elevation in leads V1 and V2.

Various other risk stratifiers have also been identified.^109–112 Assessment of noninvasive markers by Ikeda et al demonstrated that late potentials noted using signal-averaged ECGs were present in 24 (73%) of 33 patients with a history of syncope or aborted SCD.¹¹⁰ Using multivariate logistic regression, the authors showed that the presence of late potentials were significantly correlated with the occurrence of life-threatening events in patients with Brugada syndrome. The evaluation of these same patients with microvolt T-wave alternans and corrected Q-T interval dispersion failed to correlate with outcome. These findings were supported by others as well.¹¹²

Finally, spontaneous episodes of VF in patients with Brugada syndrome were shown to be triggered by PVCs with specific morphologies. Kakishita et al suggested that the use of ICD therapy not only could be lifesaving but also could record the specific triggering events.⁹⁷ They suggested that this knowledge could define risk and potentially lead to either ablative therapy or the ability to stratify the risk of SCD.

Hence, the identification of coved-type ST-segment elevation on surface ECG, the identification of late potentials on signal-averaged ECG, and the finding of triggering PVCs could provide insight into those patients with Brugada syndrome at high risk. Addition of family history could allow for further improvements of risk stratification.

Cardiac Conduction Disease

Syncope and SCD may also be caused by bradycardia. The most common form of life-threatening bradycardias include disorders in which complete atrioventricular (AV) block occurs.¹¹³ These disorders require pacemaker implantation for continued well-being. Two major forms of conduction system disease in which no congenital heart disease is associated include isolated forms of conduction disease associated with dilated cardiomyopathy.^113–115

Progressive cardiac conduction defect, also known as Lev-Lenègre disease, is one of the most common cardiac conduction disorders.^113–116 This disorder is characterized by progressive alteration of conduction through the His-Purkinje system with development of RBBB or left bundle branch block (LBBB) with widening of the QRS complexes. Ultimately, complete AV block occurs, resulting in syncope and SCD. Lev-Lenègre disease represents the most common reason for pacemaker implantation worldwide, accounting for 0.15 implants per 1000 population yearly in developed countries. This disorder has been considered a primary degenerative disease, an exaggerated aging process with sclerosis of the conduction system, or an acquired disease. The first gene identified for Lev-Lenègre disease was reported in 1999 by Schott et al.¹¹⁶ They identified a missense mutation and deletion mutation, respectively, in SCN5A (see Table 54-1), the cardiac sodium channel gene, in two families with autosomal-dominant inheritance (Figure 54-7). Although the authors suggested that the biophysical abnormality was channel loss of function, no electrophysiological analysis was provided. As SCN5A also causes LQT3, Brugada syndrome, and SIDS (see Figure 54-7), all diseases in which ventricular tachyarrhythmias result in syncope and SCD, the association of conduction disturbance with SCN5A mutations was initially surprising.^{107,114,117,118} However, it is now known that conduction disturbance occurs in these disorders as well.

FIGURE 54-7 Cardiac sodium channel (SCN5A) gene mutations associated with cardiac arrhythmias and conduction system diseases. Cardiac arrhythmias: sudden infant death syndrome (yellow), Brugada syndrome (black), Lev syndrome (green), and isolated conduction disease (red). Note that mutations for all the disorders are scattered throughout the channel protein domains. They are found within the transmembrane portions and pore regions of the channel as well as within intracellular and extracellular regions of the protein.

A similar disorder, known as isolated cardiac conduction disease, also results in complete AV block, syncope, and SCD. This disorder has been considered to be genetically inherited (autosomal dominant trait) and not acquired. Brink et al and de Meeus et al independently mapped a gene to chromosome 19q13.3 in families with isolated conduction disturbance in 1995, but the gene has remained elusive (see Table 54-1).^119,120 Recently, however, Tan and colleagues identified a mutation in SCN5A in this disorder (see Figure 54-7) and also presented biophysical analysis (see Table 54-1).¹¹⁴ This mutation, a G-to-T transversion in exon 12 of SCN5A, resulted in a change from glycine to cysteine at position 514 (G514C) encoding an amino acid within the DI-DII intercellular linker of the cardiac sodium channel. Biophysical characterization of the mutant channel demonstrated abnormalities in voltage-dependent gating behavior. The sodium current (I_Na) was found to decay more rapidly than the wild-type channel. In the mutant, open-state inactivation was hastened, but closed state inactivation was reduced and destabilized. Computational analysis predicted that the gating defects selectively slowed myocardial conduction without provoking the rapid cardiac arrhythmias seen in LQTS and Brugada syndrome. When comparing Brugada syndrome, LQT3, and conduction disease biophysics, the following findings are notable. In Brugada syndrome, SCN5A mutations cause reduction in I_Na, hastening epicardial repolarization and causing the development of VT and VF. In contradistinction, LQT3 mutations in SCN5A result in excessive I_Na, delaying repolarization and torsades de pointes VT. Importantly, the G514C mutation evokes gating shifts reminiscent of both LQT3 and Brugada syndrome, including an activation gating shift responsible for reducing I_Na and destabilization of inactivation that causes an increase in I_Na. Tan et al showed that these voltage-dependent gating abnormalities may be partially corrected by dexamethasone, consistent with the known salutary effects of glucocorticoids on the clinical phenotype.¹¹⁴ It is also worth noting that some patients with LQT3 and Brugada syndrome have been reported to have conduction disturbances.

Finally, patients with conduction disease and dilated cardiomyopathy present a conundrum with regard to what comes first—conduction abnormalities leading to cardiomyopathy, or vice versa.¹¹⁵ Clinically, these patients tend to develop variable degrees of AV block in their teen years or 20s, with progression of this block over another 1 or 2 decades before developing the signs and symptoms of heart failure consistent with the cardiomyopathic phenotype. To date, only the gene lamin A/C located on chromosome 1q21 has been confirmed to cause this disease.^121,122 Lamins A and C are members of the intermediate filament multigene family, which are encoded by a single gene. Lamins A and C polymerize to form part of the nuclear lamina, a structural filamentous network on the nucleoplasmic side of the inner nuclear membrane. The specific causes of conduction disease and myocardial dysfunction are not currently known but could be attributed to the progressive degeneration of cardiac tissue analogous to that described in Lev-Lenègre disease.

Sudden Infant Death Syndrome

SIDS is defined as the sudden death of an infant younger than 1 year of age that remains unexplained after performance of a complete autopsy, review of clinical and family histories, and examination of the death scene. Although the incidence of SIDS has been dramatically reduced from 1.6 per 1000 live births to 0.64 per 1000 live births as reported in 1998 in the United States, it is still one of the most common causes of death among babies between 1 and 6 months of age. Death usually occurs during sleep.¹²³

The potential causes of sudden death in infants are many, including cardiac disorders, respiratory abnormalities, gastrointestinal diseases, metabolic disorders, traumatic injury, brain abnormality, or child abuse. One of the most referenced etiologic speculations was that described by Schwartz in 1976. He proposed that a developmental abnormality in cardiac sympathetic innervation predisposed some infants to lethal cardiac arrhythmias. Specifically, an imbalance in the sympathetic nervous system was speculated to result in prolongation of the Q-T interval on the ECG and in potentially lethal ventricular arrhythmias.^17,18 In 1998, Schwartz et al published data collected from 1976 to 1994, in which ECGs were recorded on the third or fourth day of life in 34,442 Italian newborns.⁴ These babies were followed up for 1 year; during that period, 34 babies died. Evaluation of these 34 babies demonstrated that 24 died of SIDS. These 24 SIDS victims were found to have longer QTc measurements compared with controls or other infants dying of other causes. In 12 of these 24 cases, the QTc was clearly prolonged, and the authors suggested that QTc prolongation during the first week of life is associated with SIDS.¹²⁵

Although this suggestion linking SIDS and LQTS was roundly criticized, the authors were subsequently able to identify a mutation in SCN5A (see Table 54-1) in one patient with aborted SIDS.^{118,126–132} In addition, Priori et al reported identification of an SCN5A mutation in an infant with Brugada syndrome.¹³³ More recently, Ackerman et al reported a molecular epidemiology study of 95 cases of SIDS, in which the myocardium obtained at autopsy was screened for ion channel gene mutations.¹³⁴ In 4 of 93 cases, mutations in SCN5A were identified in postmortem analysis, and the authors suggested that in 4.3% of this cohort SIDS was caused by mutations in this known arrhythmia-causing gene. Hence, it appears that ion channel mutations, particularly SCN5A, result in SIDS in some infants (see Figure 54-7). Biophysical analysis identified a sodium current characterized by slower delay, and a twofold to threefold increase in late sodium current similar to that seen in LQTS. The fact that these SIDS occurs during sleep is consistent with the features seen for this channel when mutations result in LQTS (LQT3). SCN5A mutations in SIDS have been further confirmed recently.¹³⁴ It is likely that other ion channel gene abnormalities will be found in infants with SIDS and that there is wide etiologic heterogeneity.

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by fatty infiltration of the right ventricle, fibrosis, and ultimately thinning of the wall with chamber dilatation (Figure 54-8).⁵ It is the most common cause of SCD in the young in Italy and is said to account for about 17% of SCD in the young in the Unites States.^135,136 Rampazzo et al mapped this disease in two families, one to 1q42-q43 and the other on chromosome 14q23-q24.^137,138 A third locus was mapped to 14q12.¹³⁹ A large Greek family with ARVD and Naxos disease was recently mapped to 17q21.¹⁴⁰ Two loci responsible for ARVD/C in North America were subsequently mapped at 3p23 and the other at 10p12.^141,142

FIGURE 54-8 Arrhythmogenic right ventricular dysplasia/cardiomyopathy. A, Gross anatomy with thinned right ventricle and fatty infiltration. B, Histology identifying fibro-fatty infiltration of right ventricle.

ARVD/C is a devastating disease because the first symptom is often SCD. Electrocardiographic abnormalities include inverted T waves in the right precordial leads, late potentials, and right ventricular arrhythmias with LBBB. In many cases, the ECG looks similar to that seen in Brugada syndrome, with ST elevation in V1 to V3.¹⁴³ The issue of SCD is compounded by the great difficulty in making the diagnosis of ARVD/C even when occurring in a family with a history of the disease. Since the disease affects only the right ventricle, it is difficult to detect it by using most diagnostic modalities. No diagnostic definitive standard is available at present. The right ventricular biopsy may be definitive when positive but often gives a false-negative result, since the disease initiates in the epicardium and spreads to the endocardium of the right ventricular free wall, making it inaccessible to biopsy. A consensus diagnostic criteria that includes right ventricular biopsy, magnetic resonance imaging (MRI), echocardiography, and electrocardiography was developed.¹⁴⁴

The genetic basis of ARVD/C has started to unravel recently. The first gene causing ARVD/C was identified by Tiso et al for the chromosome 1q42-1q43-linked ARVD2 locus in 2001 (Figure 54-9).¹⁴⁵ This gene (see Table 54-1), the cardiac ryanodine receptor gene (RYR2), a 105 exon gene that encodes the 565 kd monomer of a tetrameric structure interacting with four FK-506 binding proteins called FKBP12.6, is fundamental for intracellular calcium homeostasis and for excitation–contraction coupling. This large protein physically links to the dihydropyridine (DHP) receptor of the t-tubule, where the DHP receptor protein, a voltage-dependent calcium channel, is activated by plasma membrane depolarization and induces a calcium influx.^146,147 The RYR2 protein, activated by calcium, induces release of calcium from the sarcoplasmic reticulum into the cytosol. Hence, mutations in RYR2 would be expected to cause calcium homeostasis imbalance and result in abnormalities in rhythm as well as excitation-contraction coupling and myocardial dysfunction.¹⁴⁷ This causative gene is therefore, in many ways, similar to the mutant genes responsible for the ventricular arrhythmias of LQTS, Brugada syndrome, and SIDS, in which ion channel mutations cause the clinical phenotype. In those instances, potassium channel dysfunction and sodium channel dysfunction occur, whereas in ARVD2, intracellular calcium channel dysfunction plays a central role.

FIGURE 54-9 Chromosomal positions of ARVD1 (chromosome 14q23), ARVD2 (chromosome 1q42-q43), and ARVD3 (chromosome 14q12-q22) with identification of the ARVD2 gene, ryanodine receptor (RYR2).

Two other genes associated with arrhythmogenic cardiomyopathy have also been described. The first of these, plakoglobin, was shown to cause the chromosome 17q21-linked autosomal recessive disorder called Naxos disease (see Table 54-1).¹⁴⁸ This disorder is characterized by ARVD/C in association with abnormalities of skin (palmoplantar keratoderma) and hair (woolly hair) and, therefore, is not exactly the same as isolated ARVD/C, being a more complex phenotype.

Plakoglobin is a cell adhesion protein thought to be important in providing functional integrity to the cell. This protein is found in many tissues, including the cytoplasmic plaque of cardiac junctions and the dermal-epidermal junctions of the epidermis, and it has a potential signaling role in the formation of desmosomal junctions. It is believed that plakoglobin serves as a linker molecule between the inner and outer portions of the desmosomal plaque by binding tightly to the cytoplasmic domains of cadherins. The mutations identified, a homozygous 2 bp deletion, resulted in a frameshift and premature termination of the protein.¹⁴⁸ Support for this gene being causative of Naxos disease comes from a murine model with null mutations, which exhibit the heart and skin abnormalities seen in affected patients. The mutated protein is thought to cause disruption of myocyte integrity, leading to cell death and fibro-fatty replacement, with secondary arrhythmias being caused by the abnormal myocardial substrate.

The last gene identified, desmoplakin, is another desmosomal protein with similarities to plakoglobin (see Table 54-1).¹⁴⁹ Homozygous mutations in this gene resulted in a Naxos-like disorder, although the cardiac features occurred in the left ventricle instead of the right ventricle. The affected protein is an important protein in cell adhesion and appears to function similarly to that described for plakoglobin. Although it is easy to speculate that mutation in this gene and in plakoglobin causes the myocardial abnormalities, it remains unclear why differences in ventricular chamber specificity occurs and how the ventricular tachyarrhythmias develop.

Brugada Syndrome and Arrhythmogenic Right Ventricular Dysplasia

Controversy exists concerning the possible association of Brugada syndrome and ARVD, with some investigators arguing that these are the same disorder or at least one is a forme fruste of the other.^{143,150–156} However, the classic echocardiographic, angiographic, and MRI findings of ARVD are not seen in patients with Brugada syndrome. In addition, patients with Brugada syndrome typically do not exhibit the histopathologic findings of ARVD. Further, the morphology of VT or VF differs.^91,143 Finally, the genes identified so far differ.^{61,144,145,149,152}

Polymorphic Ventricular Tachycardia

Familial polymorphic VT, an autosomal-dominant disorder characterized by episodes of bi-directional (Figure 54-10) and polymorphic VT, typically in relation to adrenergic stimulation or physical exercise, was first described by Coumel et al in 1978.¹⁵⁵ This disorder most commonly occurs in childhood and adolescence, presenting with syncope and SCD.^6,156 Mortality rates of 30% to 50% in patients aged 20 to 30 years have been reported, suggesting this is a highly malignant disorder. Autopsy data demonstrate this disorder to have no associated structural cardiac abnormalities.

FIGURE 54-10 Bi-directional ventricular tachycardia. The genetic cause, mutations within the ryanodine receptor gene (RYR2), is the same gene responsible for the chromosome 1–linked arrhythmogenic right ventricular dysplasia cardiomyopathy.

Mutations in the cardiac ryanodine receptor (RYR2), the same gene responsible for ARVD2 (see Figure 54-9), were recently independently identified by Laitinen et al and Priori et al in multiple families linked to chromosome 1q42 (see Table 54-1).^157–160 Interestingly, ARVD2 typically is considered to be the one form of ARVD/C in which catecholaminergic input is important in the development of symptoms. It is not clear at this time why patients with familial polymorphic VT have no associated structural cardiac abnormalities and patients with ARVD/C have classic fibro-fatty replacement in the right ventricle.

Mutations in another member of the ryanodine receptor gene family, RYR1, which is expressed in skeletal muscle, result in malignant hyperthermia and central core disease.¹⁶¹ The mutations in this gene appear to cluster in three regions of the gene, regions similar to the mutations found in RYR2 in the cases of VT reported, suggesting these to be functionally critical regions.

Wolff-Parkinson-White Syndrome

Wolff-Parkinson-White syndrome (WPW) is the second most common cause of paroxysmal supraventricular tachycardia (SVT), with a prevalence of 1.5 to 3.1 per 1000 individuals.² In some parts of the world such as China, WPW is even more common, being responsible for up to 70% of cases of SVT.¹⁶² Tachycardia presents typically in a bi-modal fashion, with onset common in infancy as well as during the teen years. Symptoms most commonly include syncope, presyncope, shortness of breath, palpitations, and SCD.¹¹³

WPW has long been described to be caused by accessory pathways derived from muscle fibers providing direct continuity between the atrial and ventricular myocardia.^2,163 These accessory pathways may be identified by the peculiar ECG findings seen in WPW, including short P-R interval, widened QRS complexes, and the classic δ wave in which an abnormal initial QRS vector is notable (Figure 54-11).^2,163–165 In a significant percentage of patients, conduction abnormalities including high-grade sinoatrial or AV block occur, necessitating pacemaker implantation. In most patients with WPW and SVT, RF ablation of the accessory pathways is curative.^166,167

FIGURE 54-11 Electrocardiogram showing the short P-R interval and δ wave associated with Wolff-Parkinson-White syndrome.

Some cases of WPW are associated with other primary disorders such as hypertrophic cardiomyopathy or left ventricular noncompaction cardiomyopathy, or the congenital cardiac disorder Ebstein’s anomaly.^166,168,169 Whether the underlying cause of WPW is similar in these cases compared with pure cases of WPW has been discussed for many years, but no definitive answers have been provided.

The first gene in patients with WPW was recently identified by Gollob et al and Blair et al independently in familial forms of WPW.^170,171 In both reports, autosomal-dominant inheritance was reported. Interestingly, this gene, which maps to chromosome 7q34-7q36, was found to cause WPW and hypertrophic cardiomyopathy in a significant percentage of patients in both reports (see Table 54-1).¹⁶⁸ The gene, the γ2 subunit of adenosine monophosphate–activated protein kinase, consists of 569 amino acids, is 63 kD in size, and functions as a metabolic sensor in cells, responding to cellular energy demands by regulating adenosine triphosphate (ATP) production and utilization.¹⁷² It is not clear whether this is a primary hypertrophic cardiomyopathy–causing gene or a WPW gene, particularly since the initial mapping of this locus was in patients with hypertrophic cardiomyopathy and associated WPW. Clearly, this is not the only gene responsible for WPW, and the functional and physiological abnormalities responsible for the resultant WPW are not yet obvious.

Summary

Ventricular arrhythmias appear to result from ion channel abnormalities. Whether this is necessarily a primary abnormality or a secondary one is becoming better understood. Therapeutic options including drug and device therapy are likely to be expanded once this knowledge has matured. These are detailed in Chapters 84, 94, and 95. Similarly, conduction system abnormalities have been shown to occur secondary to mutations in the ion channel gene and are widely but empirically treated with device therapy as discussed in Chapter 38. The individual disorders are now exhaustively discussed in Chapters 62 to 65.