Genetics of Arrhythmias
Aadhavi Sridharan
Jason S. Bradfield
James N. Weiss
INTRODUCTION
Cardiac arrhythmias comprise a wide spectrum of abnormalities of the heart rhythm; these can be benign, can increase the risk of stroke or embolism, or can even be life-threatening, resulting in sudden cardiac death (SCD). Because of the significant advances in the area of cardiovascular genetics over the past three decades, several arrhythmia syndromes previously considered idiopathic are now known to be caused by mutations in genes primarily encoding ion channels.1 This has facilitated an improved understanding of the pathophysiology of these disorders and recognition of important genotype-phenotype associations, which has in turn resulted in significant diagnostic, prognostic, and therapeutic implications. This chapter includes a brief discussion of the cardiac action potential and associated ion channels, followed by the genetic basis and genotype-phenotype correlations of common hereditary arrhythmia syndromes.
CARDIAC ACTION POTENTIAL AND ION CHANNELS
A fundamental knowledge of the cardiac action potential is necessary to understand the genetics of cardiac arrhythmias. The cardiac action potential is a brief change in voltage across the cell membrane of myocytes, achieved through a complex, orchestrated change in permeability of sodium (Na+), potassium (K+), calcium (Ca2+), and chloride (Cl–) ions through different types of ion channels.
The action potential in a typical ventricular myocyte is divided into five phases, named phase 0 through phase 4 (Figure 51.1). During phase 4, also termed the resting phase, there is a higher concentration of Na+ and Ca2+ outside the cell and a higher concentration of K+ inside the cells. During this phase, an abundance of open K+ channels allowing slow leakage of K+ out of the cell maintain the membrane potential at approximately -90 mV, near the equilibrium potential of K+. When these resting myocytes reach a threshold voltage of approximately -70 mV, they enter phase 0. During phase 0, also known as rapid depolarization, a transient increase in Na+ conductance and decrease in inward rectifier K+ current results in a positive membrane potential closer to the equilibrium potential of Na+. Phase 1 represents an initial, rapid repolarization phase that is caused by a transient outward K+ current. During phase 2, also termed the plateau phase, there is inward Ca2+ current through the L-type calcium channels that are activated when the membrane potential depolarizes to -40 mV. Inward Ca2+ currents and outward K+ currents are relatively balanced during this plateau phase. Phase 3 is the repolarization phase during which there is inactivation of Ca2+ current and an increase in outward K+ current caused by activation of several different time-dependent potassium channels.2,3
Maintenance of normal sinus rhythm is thus dependent on the coordinated movement of ions mediating the cardiac action potential. Ion channel dysfunction can have significant consequences that present as arrhythmias, some potentially lethal.
Recent progress in the area of cardiovascular genetics has led to a better understanding of the pathogenesis of inherited arrhythmia syndromes, also referred to as channelopathies. Mutations in genes encoding for specific ion channels have been shown to cause specific forms of heritable arrhythmia disorders occurring in the structurally normal heart. Figure 51.2 and Table 51.1 summarize the common genes and proteins associated with common inherited arrhythmia syndromes. Current guidelines recommend genetic counseling or mutation-specific genetic screening of first-degree relatives of patients with inherited arrhythmia syndromes to identify affected family members, caused by increased risk of adverse cardiac events in genotype-positive patients.4
Recent progress in the area of cardiovascular genetics has led to a better understanding of the pathogenesis of inherited arrhythmia syndromes, also referred to as channelopathies. Mutations in genes encoding for specific ion channels have been shown to cause specific forms of heritable arrhythmia disorders occurring in the structurally normal heart. Figure 51.2 and Table 51.1 summarize the common genes and proteins associated with common inherited arrhythmia syndromes. Current guidelines recommend genetic counseling or mutation-specific genetic screening of first-degree relatives of patients with inherited arrhythmia syndromes to identify affected family members, caused by increased risk of adverse cardiac events in genotype-positive patients.4
 FIGURE 51.1 Cardiac action potential and respective ion currents during various phases. IK1, inward rectifier K current; INa, Na current; Ito, transient outward K current; IKur, ultrarapid component of the delayed rectifier K current; IKr, rapid component of the delayed rectifier K current; IKs, slow component of the delayed rectifier K current; NCX, Na-Ca exchanger; If, hyperpolarization-activated nonselective pacemaker “funny” current; IKACh, Acetylcholine-activated K current. (Reprinted by permission from Nature: Nattel S, Carlsson L. Innovative approaches to anti-arrhythmic drug therapy. Nat Rev Drug Discov. 2006;5(12):1034-1049. Copyright © 2006 Springer Nature.) |
 FIGURE 51.2 Genes and proteins involved in the pathogenesis of hereditary cardiac arrhythmias. The genes that encode ion channels and proteins in the sarcoplasmic reticulum are color-coded according to the inherited arrhythmia disorder in which they are implicated. BrS, Brugada syndrome; CPVT, catecholaminergic polymorphic ventricular tachycardia; LQTS, long QT syndrome; SQTS, short QT syndrome. Reprinted with permission from Schwartz PJ, Ackerman MJ, Antzelevitch C, et al. Inherited cardiac arrhythmias. Nat Rev Dis Primers. 2020;6:58. |
COMMON HEREDITARY ARRHYTHMIA SYNDROMES
Long QT Syndrome
Congenital long QT syndrome (LQTS), the most prevalent of the inherited arrhythmias occurring in about 1 in 2000 people,5 is characterized by delayed myocardial repolarization and prolongation of the QT interval (corrected QT [QTc] >470 msec), resulting in an increased risk of syncope owing to torsades de pointes, seizures, and SCD in otherwise healthy children and adolescents with structurally normal hearts.1,6 It is most commonly inherited in an autosomal dominant manner (and was previously known as Romano-Ward syndrome), and rarely as a recessive disorder (known as Jervell and Lange-Nielsen syndrome,7 characterized by a severe cardiac phenotype and sensorineural hearing loss). At the genetic and molecular levels, LQTS is a heterogeneous disorder consisting of several distinct cardiac channelopathies. Approximately 90% of patients with a clinical diagnosis of LQTS have mutations in one of the three major LQTS-susceptibility genes that encode ion channels essential in coordinating the duration of the cardiac action potential: KCNQ1-encoded IKs (Kv7.1) potassium channel, KCNH2-encoded IKr (Kv11.1) potassium channel, or SCN5A-encoded INa (Nav1.5) sodium channel. Loss-of-function mutations in KCNQ1 underlie about 30% to 35% of LQTS type 1 (LQT1). Loss-of-function KCNH2 mutations cause approximately 25% to 40% of LQTS type 2 (LQT2). These loss-of-function mutations can directly impair channel function or indirectly reduce their trafficking to the cell membrane, resulting in prolongation of the action potential at the cellular level and hence QT prolongation. Gain-of-function SCN5A mutations account for roughly 5% to 10% of LQTS type 3 (LQT3). Gain-of-function mutations in the Na+ channel prolong the action potential duration by impairing channel inactivation and increasing late Na+ currents, which results in increased vulnerability to early afterdepolarizations and triggered activity initiating torsades de pointes, polymorphic ventricular tachycardia, and ventricular fibrillation. About 15% to 20% of patients with a definite clinical diagnosis of LQTS remain genotype-negative even after extensive genetic testing.1,6
Mutations in genes encoding ion channel subunits (KCNE1, KCNE2, KCNJ5, and SCN4B) or proteins that regulate ion channel function (CALM1, CALM2, CALM3, AKAP9, CAV3, ANK2, SNTA1, and TRDN) have also been implicated in LQTS pathogenesis and account for about 5% of cases.1,6
TABLE 51.1 Genes Implicated in Inherited Cardiac Arrhythmia Syndromes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Genotype-Phenotype Correlations
Relatively specific genotype-phenotype correlations have been described in LQTS. Swimming- and exertion-induced cardiac events are strongly associated with LQT1, auditory-triggered events and those occurring in the postpartum period are associated with LQT2, and events occurring during periods of sleep or rest are associated with LQT3. On electrocardiogram (ECG), LQT1 is typically characterized by a broad-based T wave (Figure 51.3A), LQT2 by a low-amplitude notched or biphasic T wave (Figure 51.3B), and LQT3 by a long isoelectric segment followed by a narrow-based T wave (Figure 51.3C). Efficacy of β-blocker therapy is greater among LQT1 patients compared to LQT2 and LQT3 patients.6,8 Although a vast majority of mutations are single nucleotide substitutions or small insertion/deletions, approximately 5% to 10% of LQTS patients have multiple mutations in these genes. These patients typically present at a younger age with a more severe phenotype than patients with a single mutation.
Diagnosis and Treatment
Although the diagnosis of LQTS is clear in a young patient presenting with an episode of syncope in the setting of physical or emotional stress and prolonged QTc interval on ECG, it may be more challenging in asymptomatic individuals with
only modestly prolonged QTc intervals, with such cases being detected during mandatory screening prior to participation in sports. Secondary causes of QT prolongation (such as medications, disease states, or electrolyte disturbances) must be excluded. Exercise testing should be performed to assess for exercise-induced arrhythmias (although rare in LQTS), changes in T wave morphology, and presence of a maladaptive QT response during the recovery phase. Ambulatory rhythm monitoring can provide supportive information, including intermittent QT prolongation and underlying dynamic T wave changes, especially at night. The LQTS diagnostic score, also known as the Schwartz Score,9 first developed in 1985 and most recently updated in 2011, should be calculated (Table 51.2). A high probability Schwartz score (≥3.5 points) carries ˜80% likelihood of a positive LQTS genetic test. Genetic testing should not be pursued in patients with a low Schwartz score (<1 point). The likelihood of LQTS is ˜5% to 20% for an intermediate probability Schwartz score, and negative genetic testing in this situation would not warrant a diagnosis of LQTS. Genetic testing not only aids in the diagnosis of LQTS in the presenting patient but also helps identify asymptomatic but at-risk family members who may not have been otherwise diagnosed and received life-saving therapy.1
only modestly prolonged QTc intervals, with such cases being detected during mandatory screening prior to participation in sports. Secondary causes of QT prolongation (such as medications, disease states, or electrolyte disturbances) must be excluded. Exercise testing should be performed to assess for exercise-induced arrhythmias (although rare in LQTS), changes in T wave morphology, and presence of a maladaptive QT response during the recovery phase. Ambulatory rhythm monitoring can provide supportive information, including intermittent QT prolongation and underlying dynamic T wave changes, especially at night. The LQTS diagnostic score, also known as the Schwartz Score,9 first developed in 1985 and most recently updated in 2011, should be calculated (Table 51.2). A high probability Schwartz score (≥3.5 points) carries ˜80% likelihood of a positive LQTS genetic test. Genetic testing should not be pursued in patients with a low Schwartz score (<1 point). The likelihood of LQTS is ˜5% to 20% for an intermediate probability Schwartz score, and negative genetic testing in this situation would not warrant a diagnosis of LQTS. Genetic testing not only aids in the diagnosis of LQTS in the presenting patient but also helps identify asymptomatic but at-risk family members who may not have been otherwise diagnosed and received life-saving therapy.1
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