Ventricular Arrhythmias in Inherited Channelopathies

31  Ventricular Arrhythmias in Inherited Channelopathies OUTLINE Long QT Syndrome, 976 Genetics of the Long QT Syndrome, 977 Pathophysiology of the Long QT Syndrome, 980 Epidemiology, 983 Clinical Presentation and Natural Course, 983 Electrocardiographic Features, 985 Diagnosis of the Long QT Syndrome, 989 Differential Diagnosis: Acquired Long QT Syndrome, 992 Risk Stratification, 994 Principles of Management, 996 Brugada Syndrome, 1000 Genetics of the Brugada Syndrome, 1000 Pathophysiology of the Brugada Syndrome, 1002 Epidemiology, 1004 Clinical Presentation, 1004 Electrocardiographic Features, 1005 Diagnosis of the Brugada Syndrome, 1008 Differential Diagnosis, 1009 Risk Stratification, 1011 Principles of Management, 1013 Short QT Syndrome, 1017 Genetics of the Short QT Syndrome, 1017 Pathophysiology of Short QT Syndrome, 1018 Epidemiology, 1018 Clinical Presentation, 1018 Electrocardiographic Features, 1018 Diagnosis of the Short QT Syndrome, 1019 Differential Diagnosis, 1019 Risk Stratification, 1019 Principles of Management, 1019

Catecholaminergic Polymorphic Ventricular Tachycardia, 1020 Genetics of Catecholaminergic Polymorphic Ventricular Tachycardia, 1020 Pathophysiology of Catecholaminergic Polymorphic Ventricular Tachycardia, 1020 Epidemiology, 1022 Clinical Presentation, 1022 Electrocardiographic Features, 1022 Diagnosis of Catecholaminergic Polymorphic Ventricular Tachycardia, 1022 Differential Diagnosis, 1024 Risk Stratification, 1024 Principles of Management, 1024 Idiopathic Ventricular Fibrillation, 1025 Genetics of Idiopathic Ventricular Fibrillation, 1025 Pathophysiology of Idiopathic Ventricular Fibrillation, 1026 Epidemiology, 1026 Clinical Presentation, 1026 Electrocardiographic Features, 1026 Diagnosis of Idiopathic Ventricular Fibrillation, 1026 Principles of Management, 1028 Early Repolarization Syndromes, 1029 Genetics of Early Repolarization Syndrome, 1029 Pathophysiology of Early Repolarization Syndromes, 1030 Epidemiology, 1031 Clinical Presentation, 1031 Electrocardiographic Features, 1031 Diagnosis of Early Repolarization Syndrome, 1034 Differential Diagnosis, 1034 Risk Stratification, 1034 Principles of Management, 1037

Sudden cardiac death (SCD) is a major contributor to population mortality, with an overall incidence in the United States estimated to be between 0.1% and 0.2%, resulting in approximately 300,000 to 350,000 deaths annually. Ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) is the initial rhythm recorded in 25% to 36% of witnessed cardiac arrests occurring at home, but in a much higher proportion (38% to 79%) of witnessed cardiac arrests occurring in a public setting. The majority of SCD events are associated with structural heart disease, with coronary artery disease and its complications being involved in up to 60% to 80% of cases, followed by other cardiomyopathies. However, in 10% to 20% of SCDs, no cardiac structural abnormalities are detectable. The lack of an apparent cause in many of those cases initially led to the classification as “sudden unexplained death syndrome” (SUDS) or “sudden infant death syndrome” (SIDS). Many of these are caused by primary electrical disorders, including long QT syndrome

(LQTS), catecholaminergic polymorphic VT (CPVT), Brugada syndrome, and short QT syndrome (SQTS), as well as cases identified as “idiopathic VF” when the underlying cause often remains unknown.1

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LONG QT SYNDROME The LQTS is an uncommon inherited cardiac channelopathy that is associated with an abnormally prolonged QT interval and an increased propensity for life-threatening ventricular arrhythmias in the presence of a structurally normal heart. In 1957, Anton Jervell and Fred Lange-Nielsen published the first report on a familial (autosomal recessive) disorder (“Jervell and LangeNielsen syndrome”) characterized by the presence of a striking prolongation of the QT interval, congenital deafness, and a high incidence of SCD at a young age. Subsequently, Romano and Ward independently

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies identified an almost identical, but autosomal dominant, disorder that is not associated with deafness (“Romano-Ward syndrome”). A genetic relationship between the two was then proposed and the two syndromes were considered variants of one disease under the unifying name of “LQTS.” In the contemporary literature, Romano-Ward syndrome is used interchangeably with LQTS, but is now less commonly used in favor of the LQT1 to LQT17 scheme according to the underlying genetic mutation (see later). The initial molecular studies suggested that all genes linked to the LQTS phenotype encode for various subunits of cardiac ion channels. Subsequent findings, however, revealed that LQTS could also be caused by mutations of gene coding for channel-associated cellular structural proteins as well. Nonetheless, the concept that LQTS genes ultimately affect cardiac ion currents, either directly (ion channel mutations) or indirectly (modulators), still holds true.

Genetics of the Long QT Syndrome To date, more than 600 mutations of 17 different genes responsible for a hereditary form of LQTS have been identified (LQT1-17) (Table 31.1; Fig. 31.1), with the majority (more than 90%) of the known mutations located in the first three genes: LQT1 (KCNQ1) mutations account for 40% to 55% of genetically positive LQTS, LQT2 (KCNH2) for 30% to 45%, and LQT3 (SCN5A) for 5% to 10%. Overall, nine of these genes encode ion channel subunits that are specifically involved in cardiac action potential generation. LQT4, LQT9, LQT11, LQT12, and LQT14-LQT17 are caused by mutations in a family of versatile membrane adapters other than ion channel subunits. The majority of LQTS cases are inherited in an autosomal dominant fashion. Conversely, Jervell and Lange-Nielsen syndrome, which is inherited in an autosomal recessive fashion, is very rare, affecting less than 1% of LQTS cases. Genetic analysis reveals two or more mutations in 8% to 11% of LQTS patients with clinical phenotypes of autosomal dominant RomanoWard syndrome. These compound mutations (so-called “double hits”)

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appear to be associated with a more severe phenotype than that associated with a single hit. Most reported LQTS genetic mutations occur in coding regions, although noncoding mutations (resulting in the loss of allele expression) have also been described. Most LQTS families have their own mutations, which are often termed “private” mutations. Several genetic mechanisms have been implicated in the development of LQTS including abnormalities in protein synthesis (transcription, translation), posttranslational protein processing resulting in abnormal transport to the cell surface membrane (protein trafficking, folding, assembly of subunits, glycosylation), ion channel gating (biophysical and kinetic properties), or permeation (ion selectivity, unitary conductance). The majority of LQTS cases are caused by heterozygous disease; thus mutations causing abnormalities in channel coassembly or trafficking result in up to 50% maximal reduction in the number of functional channels (haplotype insufficiency), because the gene product from the healthy allele remains intact. On the other hand, mutations that abolish channel function while preserving subunit assembly can result in dominant-negative suppression of the healthy allele as well, causing a more severe reduction (up to 94%) of the total amount of functional protein (dominant-negative effect) and favoring a more severe clinical course and a higher frequency of arrhythmia-related cardiac events.

Mutations Related to the Potassium Current Mutations related to the slowly activating delayed rectifier potassium current.  Slowly activating delayed rectifier potassium current (IKs) contributes to human atrial and ventricular repolarization, particularly during action potentials of long duration, and plays an important role in determining the rate-dependent shortening of the cardiac action potential. Mutations in LQT1, LQT5, and LQT11 result in attenuation of IKs and, as a consequence, prolongation of repolarization, action potential duration and QT interval. LQT1 is caused by loss-of-function mutations of

TABLE 31.1  Molecular Basis of the Congenital Long QT Syndrome Disease

Gene

Protein

Functional Effect

Frequency

LQT1 LQT2 LQT3 LQT4 (Ankyrin-B syndrome) LQT5 LQT6 LQT7 (Andersen-Tawil syndrome) LQT8 (Timothy syndrome) LQT9 LQT10 LQT11 LQT12 LQT13 LQT14 LQT15 LQT16 LQT17 (Triadin knockout syndrome) JLN1 JLN2

KCNQ1 (KvLQT1) KCNH2 (HERG) SCN5A ANKB KCNE1 KCNE2 KCNJ2 CACNA1C CAV3 SCN4B AKAP9 SNTA1 KCNJ5 CALM1 CALM2 CALM3 TRDN KCNQ1 (KvLQT1) KCNE1

Kv7.1 Kv11.1 Nav1.5 Ankyrin-B MinK MiRP1 Kir2.1 Cav1.2 Caveolin 3 Navβ4 Yotiao Syntrophin-α1 Kir3.4 (GIRK4) Calmodulin 1 Calmodulin 2 Calmodulin 3 Triadin Kv7.1 MinK

↓IKs ↓IKr ↑INa Aberrant ion channel/transporter localization ↓IKs ↓IKr ↓IK1 ↑ICaL ↑ INa ↑INa ↓IKs ↑INa ↓IKACh ↑ICaL ↑ICaL ↑ICaL ↑ICaL ↓IKs ↓IKs

40%–55% 30%–45% 5%–10% <1% <1% <1% <1% <1% <1% <1% <1% <1% <1% 1%–2% <1% <1% 2% Very rare Very rare

ICaL, L-type Ca2+ current; IK1, inward rectifier K+ current; IKACh, acetylcholine-activated inward rectifier K+ current; IKr, rapidly activating delayed rectifier K+ current; IKs, slowly activating delayed rectifier K+ current; INa, Na+ current; JLN1 and JLN2, Jervell and Lange-Nielsen syndrome types 1 and 2, respectively; LQT1 to LTQ17, long QT syndrome types 1 to 17, respectively.

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

Fig. 31.1  Current-Centric Classification of Long QT Syndrome (LQTS) Genotypes. The clinical phenotypes resulting from the abnormal ventricular cardiac action potential depolarization (purple) or repolarization (orange) are grouped according to the specific current perturbed by an underlying genetic defect. Blue circles represent mutations that confer a loss of function to the specified current, whereas green circles confer a gain of function. Solid lines indicate those disorders that are autosomal dominant, whereas dashed lines indicate those disorders that are autosomal recessive. Solid black outlines indicate nonsyndromic genotypes and solid orange outlines represent multisystem genotypes. ABS, Ankyrin-B syndrome; COTS, cardiac-only Timothy syndrome; JLNS, Jervell and Lange-Nielson syndrome; ICa,L, L-type calcium current; IK1, inwardly rectifying potassium current; IKAch, G-protein–coupled inwardly rectifying potassium current; IKr, rapid component of the delayed rectifier potassium current; IKs, slow-component of the delayed rectifier potassium current; INa, cardiac sodium current; TKO, triadin knockout syndrome. (From Giudicessi JR, Ackerman MJ. Calcium revisited. Circ Arrhythmia Electrophysiol. 2016;9:e002480.)

the KCNQ1 (KvLQT1) gene, which encodes the α subunit (Kv7.1) of the inward IKs. More than 170 mutations of this gene have been reported, comprising many Romano-Ward (autosomal dominant) syndromes and accounting for approximately 40% to 55% of all genotyped LQT families. Of note, mutations involving the transmembrane domain of KCNQ1 result in more severe disease compared with C-terminal mutations. LQT5 is caused by loss-of-function mutations of the KCNE1 gene, which encodes the β- subunit (MinK) that modulates IKs. Homozygous or compound heterozygous loss-of-function mutations of either the KCNQ1 or KCNE1 genes cause the autosomal recessive form of LQTS (the Jervell and Lange-Nielsen syndrome). Patients with KCNQ1 mutations (type 1 Jervell and Lange-Nielsen syndrome) have an almost sixfold greater risk of arrhythmic events, whereas patients with KCNE1 mutations (type 2 Jervell and Lange-Nielsen syndrome)

appear to be at lower risk. Although the Jervell and Lange-Nielsen syndrome is the most severe among the major variants of LQTS, the parents of Jervell and Lange-Nielsen syndrome patients are generally less symptomatic than other LQT1 patients, despite the fact that they all are heterozygous for the same gene. This is likely related to the observation that most of the LQT1 genetic variants are missense mutations exerting a dominant-negative effect, whereas most (74%) Jervell and Lange-Nielsen mutations of KCNQ1 are frame-shift/truncating mutations that are unable to cause dominant-negative suppression but are likely to interfere with subunit assembly. Jervell and Lange-Nielsen syndrome accompanies complete loss of IKs in hair cells and endolymph of the inner ear, which results in congenital deafness. LQT11 is caused by loss-of-function mutations of the AKAP9 gene, which encodes an A-kinase anchoring protein (Yotiao), shown to be

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies an integral part of the IKs macromolecular complex. The presence of Yotiao is necessary for the physiological response of the IKs to betaadrenergic stimulation. LQT11 mutations reduce the interaction between Yotiao and the IKs channel (Kv7.1), preventing the functional response of IKs to cyclic adenosine monophosphate (cAMP) and adrenergic stimulation and causing an attenuation of IKs.

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gene, which encodes the α subunit (Kir3.4, GIRK4) of the inward acetylcholine-activated potassium current (IKACh). Kir3.4 mutations exert dominant-negative effects on Kir3.1/Kir3.4 channel complexes by disrupting membrane targeting and stability of Kir3.4.

channel that is responsible for the sodium content (INa). LQT3 accounts for approximately 5% to 10% of genotype-positive LQTS cases. More than 200 mutations have been identified in the SCN5A gene, with the majority being missense mutations mainly clustered in Nav1.5 regions that are involved in fast inactivation, or in regions that stabilize fast inactivation. Several mechanisms have been identified to underlie ionic effects of SCN5A mutations in LQT3. Most of the SCN5A mutations cause a gain of function through disruption of fast inactivation of the Na+ channel, allowing repeated reopening during sustained depolarization and resulting in an abnormal, small but functionally important sustained (or persistent) noninactivating Na+ current (Isus) during the action potential plateau that acts to slow repolarization and prolong the action potential duration (eFig. 31.1). Other, less common mechanisms (eFig. 31.2) include increased window current, which results from delayed inactivation of mutant Na+ channels, occurring at more positive potentials and widening the voltage range during which the Na+ channel may reactivate without inactivation. In addition, some mutations cause slower inactivation, which allows longer channel openings, and causes a slowly inactivating Na+ current (the late Na+ current, INaL). Regardless of the mechanism, increased Na+ current (Isus, window current, INaL, or peak INa) upsets the balance between depolarizing and repolarizing currents in favor of depolarization. Gain-of-function LQT3 mutations often increase INaL two- to fourfold. Because the general membrane conductance is small during the action potential plateau, the presence of a persistent inward Na+ current, even of small amplitude, can potentially have a major impact on the plateau duration and can be sufficient to prolong repolarization and QT interval. The resulting delay in the repolarization process triggers EADs (i.e., reactivation of the L-type Ca2+ channel during phase 2 or 3 of the action potential), especially in Purkinje fiber myocytes where action potential durations are intrinsically longer. Also, increased influx of Na+ (via the enhanced INaL) can stimulate the Na+-Ca2+ exchanger in the reverse mode (3 Na+ ions out, one Ca2+ ion in), with consequent intracellular Ca2+ overload and DADs. QT prolongation and the risk of developing arrhythmia is more pronounced at slow heart rates, when the action potential duration is longer, allowing more Na+ current to enter the cell.2 LQT9 is caused by gain-of-function mutations of the CAV3 gene, which encodes caveolin-3, a plasma membrane scaffolding protein that interacts with Nav1.5 and plays a role in compartmentalization and regulation of channel function. Mutations in caveolin-3 induce kinetic alterations of the Na+ channel that result in persistent late Na+ current (Isus) and have been reported in cases of SIDS. LQT10 is caused by gain-of-function mutations of the SCN4B gene, which encodes the β-subunit (Navβ4) of the Nav1.5 ion channel. To date, only a single mutation in one patient has been described, which resulted in a shift in the inactivation of the Na+ current toward more positive potentials, but did not change the activation. This resulted in increased window currents at membrane potentials corresponding to phase 3 of the action potential. LQT12 is caused by mutations of the SNTA1 gene, which encodes α1-syntrophin, a cytoplasmic adaptor protein that enables the interaction between Nav1.5, nitric oxide synthase, and sarcolemmal Ca2+ adenosine triphosphatase (ATPase) complex that appears to regulate ion channel function. By disrupting the interaction between Nav1.5 and sarcolemmal calcium ATPase complex, SNTA1 mutations cause increased Nav1.5 nitrosylation with consequent reduction of channel inactivation and increased Isus densities.

Mutations Related to the Sodium Current

Mutations Related to the Calcium Current

LQT3 is caused by gain-of-function mutations of the SCN5A gene, which encodes the α subunit (Nav1.5) of the cardiac voltage-gated Na+

Mutations related to the L-type calcium current.  Timothy syndrome (LQT8) is caused by gain-of-function mutations of the CACNA1C

Mutations related to the rapidly activating delayed rectifier potassium current. Rapidly activating delayed rectifier potassium

current (IKr) presents the principal repolarizing current at the end of the plateau phase in most cardiac cells and plays an important role in governing the cardiac action potential duration and refractoriness. Mutations in LQT2 and LQT6 result in attenuation of IKr and cause a decrease in the K+ outward current and prolongation of repolarization, action potential duration, and QT interval. LQT2 is caused by loss-of-function mutations of the KCNH2 (HERG) gene, which encodes the α-subunit (Kv11.1) of the inward IKr. LQT2 syndrome accounts for almost 30% to 45% of all genotyped congenital LQTS cases. Approximately 200 mutations in this gene have been identified, which result in rapid closure of the hERG channels and decrease the normal rise in IKr, leading to delayed ventricular repolarization and QT prolongation. Mutations involving the pore region of the hERG channel are associated with a significantly more severe clinical course than nonpore mutations; most pore mutations are missense mutations with a dominant-negative effect. LQT6 is caused by loss-of-function mutations of the KCNE2 gene, which encodes the accessory β-subunit (MiRP1) of the hERG channel. LQT6 displays clinical resemblance to LQT2. Mutations related to the inward rectifier potassium current.  Inward rectifier potassium current (IK1) contributes to the terminal portion of phase 3 repolarization. Andersen-Tawil syndrome (LQT7) is caused by loss-of-function mutations of the KCNJ2 gene, which encodes the voltage-dependent K+ channel (Kir2.1) that contributes to the inward IK1. Kir2.1 channels are expressed primarily in skeletal muscle, heart, and brain. The majority of mutations exert a dominant-negative effect on channel current. Disruption of the IK1 function can potentially lead to prolongation of the terminal repolarization phase and QT interval, which can predispose to the generation of early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs) causing ventricular arrhythmias. However, unlike other types of LQTS, where the afterdepolarizations arise from reactivation of L-type Ca2+ channels, the EADs/DADs generated in LQT7 are likely secondary to Na+-Ca2+ exchanger-driven depolarization. It is believed that the differential origin of the triggering beat is responsible for the observed discrepancy in arrhythmogenesis and the clinical features compared with other types of LQTS. In addition, it is likely that prolongation of the action potential duration in LQT7 is somewhat homogeneous across the ventricular wall (i.e., transmural dispersion of repolarization is less prominent than in other types of LQTS), which can potentially explain the low frequency of torsades de pointes. Flaccid paralysis results from failure to propagate action potentials in the skeletal muscle membrane as a result of sustained membrane depolarization.

Mutations related to the acetylcholine-activated potassium current.  LQT13 is caused by loss-of-function mutations of the KCNJ5

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies Ventricular myocyte action potential

1 Fraction of channels activated

Membrane potential (mV)

0 –30 –60 –90

0.8

0.8

0.6

0.6

0.4

0.4

0.2

0.2

0

A

–120

–100

–80

–60

–40

–20

0

Window current

Sustained sodium current

Peak sodium current

B

A

1

1

0.8

0.8

0.6

0.6

0.4

0.4

0.2

0.2

0 –120

Fraction of channels inactivated

Fraction of channels inactivated

0

0 nA

0 nA

C

Fraction of channels inactivated

30

1

0 nA

Late sodium current

B

0 –100

–80

–60

–40

–20

0

0 nA

Membrane potential (mV)

eFig. 31.1  Mechanism of Long QT Syndrome Type 3 (LQT3). (A) QT interval prolongation results from delayed repolarization of ventricular action potentials. (B) Delayed repolarization in LQT3 is often due to the presence of abnormal sustained non-inactivating sodium current (green area). (C) Sustained current results from incomplete inactivation of the sodium channels (green circles). (From Amin AS, Asghari-Roodsari A, Tan HL. Cardiac sodium channelopathies. Pflugers Arch Eur J Physiol. 2010;460:223–237.)

Increased peak sodium current

C eFig. 31.2  Alternative Mechanisms of Sodium Channel Gain-ofFunction in Long QT Syndrome Type 3. (A) Increased window current due to delayed inactivation of cardiac sodium channels (green circles). Increased windows current is carried at potentials corresponding to phases 2 and 3 of the ventricular action potential (green area), remote from the peak sodium current during phase 0 (blue area). (B) Slower inactivation creates a late sodium current (green area). (C) Increased peak sodium current. (From Amin AS, Asghari-Roodsari A, Tan HL. Cardiac sodium channelopathies. Pflugers Arch Eur J Physiol. 2010;460:223–237.)

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

gene, which encodes the α subunit (Cav1.2) of the voltage-dependent L-type Ca2+ channel that contributes to L-type calcium current (ICaL). Recently, multiple nonsyndromic LQTS-causative mutations in CACNA1C were described in LQTS patients with isolated QT prolongation and propensity to ventricular arrhythmias in the absence of congenital heart defects and extracardiac manifestations that define Timothy syndrome clinically (nonsyndromic LQT8).3 Other CACNA1C mutations were found to cause cardiac-only Timothy syndrome (COTS), characterized by the concomitant but variably expressed phenotypes of LQTS (QT prolongation), hypertrophic cardiomyopathy, congenital heart defects, and SCD in the absence of any extracardiac symptoms.3,4 The inward ICaL sustains depolarization and gives rise to the plateau phase essential for excitation-contraction coupling. Gain-of-function mutations of CACNA1C result in near complete elimination of voltagedependent inactivation of Cav1.2 channels, leading to inappropriate continuation of the depolarizing ICaL and lengthening of the plateau phase, predisposing to the generation of EADs. In addition, augmentation of ICaL leads to intracellular Ca2+ overload, which promotes spontaneous ectopic Ca2+ release from sarcoplasmic reticulum and the generation of potentially arrhythmogenic DADs.3 The exact pathophysiology of hypertrophic cardiomyopathy, congenital heart defects, and extracardiac manifestations of Timothy syndrome and their relation to CACNA1C mutations remain unclear. Mutations related to calmodulin (calmodulinopathy).  Calmodulin is a small cytoplasmic Ca2+-binding protein with ubiquitous expression. Calmodulin is involved, directly and indirectly, in modulation of several ion channels, including Na+, K+, L-type Ca2+, and RYR2 channels. The main binding partner of calmodulin in cardiac cells is RyR2, which regulates Ca2+ release from the sarcoplasmic reticulum. Acting as an intracellular Ca2+ sensor, Ca2+-saturated calmodulin binds RYR2 to inhibit Ca2+ release by stabilizing the RyR2 channel closed state. Three different genes (CALM1–3) in the human genome encode exactly the same calmodulin protein. Recent genetic studies have identified several calmodulin mutations associated with CPVT, LQTS, and idiopathic VF. Defective calmodulin–RyR2 binding results in impaired calmodulin inhibition of RyR2 function with consequent dysregulation of sarcoplasmic reticulum Ca2+ release. Further, de novo mutations in CALM1, CALM2, or CALM3 genes were found to disrupt Ca2+-dependent inactivation of the cardiac L-type Ca2+channel (Cav1.2), which leads in augmentation of ICaL, prolongation of the plateau phase of action potential, and LQTS phenotype (LQT14–16).5,6 Mutations related to triadin: triadin knockout syndrome.  TRDN encodes triadin, a sarcoplasmic reticulum protein functionally and physically related to the RYR2. Homozygous or compound heterozygous loss-of-function mutations in TRDN likely reduce triadin-mediated negative feedback on the L-type Ca2+ channel, resulting in augmentation of ICaL, prolonged action potential duration, and the recessively inherited LQTS phenotype (LQT17). Intracellular Ca2+overload and increases in spontaneous sarcoplasmic reticulum Ca2+ release, particularly in the setting of beta-adrenergic stimulation, result in ventricular arrhythmias. LQT17 is characterized by extensive T wave inversions in the precordial leads V1 through V4, with either persistent or transient QT prolongation, exercise-induced cardiac arrest in early childhood (2 to 6 years of age), and mild-to-moderate proximal skeletal muscle weakness. Because all TRDN-null patients display a strikingly similar phenotype, it has been proposed that either triadin knockout syndrome or TRDN-mediated autosomal-recessive LQTS should be used rather than LQT17.3,7

Mutations in the Ankyrin-B Gene: Ankyrin-B Syndrome LQT4 is caused by loss-of-function mutations of the ANK2 gene, which encodes ankyrin-B, a structural membrane adapter protein that anchors

ion channels to specific domains in the plasma membrane. Functionally, ankyrins bind to several ion channel proteins, targeting these proteins to specialized membrane domains, such as the anion exchanger (chloridebicarbonate exchanger), Na+-K+ ATPase, INa, the Na+-Ca2+ exchanger (INa-Ca), and Ca2+ release channels (including those mediated by the receptors for inositol triphosphate [IP3] or RyR2). Hence, ANK2 mutations can potentially result in improper localization and activity of ion-conducting proteins. Mutations of the ANK2 gene have been reported to lead to increased intracellular concentration of Ca2+ and, sometimes, fatal arrhythmia. However, QT interval prolongation is not a consistent feature in patients with ankyrin-B dysfunction, and the clinical phenotypes often extend beyond the typical LQTS, including sinus node dysfunction (SND), atrioventricular (AV) block, and atrial fibrillation (AF), in addition to idiopathic VF, exercise-induced, polymorphic VT, and SCD. Therefore ankyrin-B dysfunction is now regarded as a clinical entity distinct from classic LQTS (referred to as the “ankyrin-B syndrome”).

Pathophysiology of the Long QT Syndrome Mechanism of QT Interval Prolongation

Any factor that evokes lengthening of the action potential duration holds the potential of causing an LQTS phenotype, especially if it does it heterogeneously. Electrophysiologically, prolongation of the action potential duration and QT interval can arise from either a decrease in the outward repolarizing current (K+ currents: IKr, IKs, IK1, IKACh) or an increase in inward depolarizing membrane current (INa, ICaL) during phases 2 and 3 of the action potentials (Fig. 31.2). Most commonly, QTc prolongation is produced by delayed repolarization due to attenuation of IKs (LQT1, LQT5, LQT11), IKr (LQT2, LQT6), IK1 (LQT7), or IKACh (LQT13). Less commonly, QT prolongation results from prolonged depolarization due to an increase in INa (LQT3, LQT4, LQT9, LQT10, LQT12) or ICaL (LQT8, LQT14–17).

Mechanism of Dispersion of Repolarization LQTS is caused by an excessive and heterogeneous prolongation of the repolarization phase of the ventricular action potential. In the normal ventricle, there are heterogeneous cell types with different action potential morphologies and durations, mainly attributed to cell-specific and regional variability in the functional expression of different populations of ion channels (transient outward K+ channels [Ito], IKs) and the Na+ window current (INa), and their accessory proteins. Some experimental studies proposed the presence of three irregular cell layers in the ventricular wall with distinct electrical properties: endocardial, midmyocardial (putative M cells), and epicardial cells. Overall, the midmyocardial cells (which have a smaller IKs, a larger late INa, and a larger Na+-Ca2+ exchange current [INa-Ca]) appear to generate longer action potential durations that are more susceptible to modification compared with the endocardium and epicardium. The epicardial cells have the shortest action potential durations because of a prominent Ito. Repolarization of endocardial cells usually occurs between repolarization of the epicardial and midmyocardial cells. Notably, factors that prolong the action potential appear to elicit a disproportionate prolongation of the action potential duration in midmyocardial cells. As a result, dispersion of the action potential duration becomes irregularly exaggerated across the ventricular wall, yielding an increase in the action potential duration heterogeneity. Conditions leading to a reduction in IKr (e.g., LQT2) or augmentation of late INa (e.g., LQT3) produce a preferential prolongation of the midmyocardial cell action potential. Consequently, QT interval prolongation is accompanied by a dramatic increase in transmural dispersion of repolarization. In contrast, conditions leading to a reduction in IKs alone (e.g., LQT1) result in a homogeneous prolongation of action

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies IKs Block Control

IKr Block

Chromanol 293 B (30 µM)

Control

Increased late INa

D-Sotalol (100 µM)

Control

ATX-II (20 nM)

Endo

50 mV

M cell

50 mV

Epi

50 mV

ECG

0.5 mV 42

A

85

200 msec

59

B

200 msec

80

53

C

156

200 msec

Fig. 31.2  Pathophysiology of Long QT Syndrome. Transmembrane action potentials and transmural electrocardiogram (ECG) traces in control and after IKs block (A), IKr block (B), and increase in late INa (C), in arterially perfused canine left ventricular wedge preparations. (A) to (C) depict action potentials simultaneously recorded from endocardial (Endo), M cell, and epicardial (Epi) sites, together with a transmural ECG trace. Basic cycle length, 2000 milliseconds. In all cases, the peak of the T wave in the ECG is coincident with the repolarization of the epicardial action potential, whereas the end of the T wave is coincident with the repolarization of the M cell action potential. Repolarization of the endocardial cell is intermediate between that of the M cell and epicardial cell. Transmural dispersion of repolarization across the ventricular wall, defined as the difference in the repolarization time between M and epicardial cells, is denoted below the ECG traces. ATX-II, Sea anemone toxin; INa, sodium current; IKr, rapidly activating delayed rectifier K+ current; IKs, slowly activating delayed rectifier potassium current. (From Antzelevitch C. Drug-induced channelopathies. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 5th ed. Philadelphia: WB Saunders; 2009:195–203.)

potential duration across the ventricular wall with little increase in transmural dispersion of repolarization. However, concurrent betaadrenergic stimulation (e.g., exercise, isoproterenol) results in abbreviation of epicardial and endocardial action potential duration with little or no change in the midmyocardial cell action potential, resulting in marked augmentation of transmural dispersion of repolarization and arrhythmogenesis (see Fig. 31.2).

Mechanism of Torsades de Pointes The excessive increase in the spatial and/or temporal heterogeneity of the duration of the action potential favors the generation of EADs caused by reactivation of L-type Ca2+ channels, and on some occasions the late INa or Na+-Ca2+ exchanger. EADs can cause premature ventricular complexes (PVCs) (predominantly arising from the Purkinje network) that can potentially infringe on the underlying substrate of heterogeneous repolarization to initiate polymorphic reentrant VT. Excessive transmural heterogeneity of the action potential duration provides the substrate for unidirectional block and functional reentry circuits to perpetuate torsades de pointes. Although controversy still exists, it is likely that the propagation of torsades de pointes is facilitated by intramural reentrant mechanisms giving rise to one or more intramural rotors that impose a rapid ectopic ventricular rhythm (typically 150 to 300 beats/min) while migrating inside the ventricular wall. Hence, with each new cycle the principal depolarization focus migrates accordingly, resulting in a progressive change of the electrical axis, typically rotating 180 degrees in approximately 10 to 12 cycles. This results in a polymorphic VT with the characteristic sinusoidal “twisting of the points” pattern on the 12-lead electrocardiogram (ECG).8 Notably, although the atrium seems to be resistant to generating EADs in response to agents that prolong repolarization, atrial EADs

and “atrial torsades de pointes” have been reported in some LQTS patients as well as cesium-treated dogs.

Mechanism of Exercise-Induced QT Interval Changes Arrhythmic events in LQTS are strongly associated with triggers linked to inappropriate QT adaptation to changes in heart rate. Patients with LQT1 and LQT2 genotypes have differing patterns of QT adaptation during beta-adrenergic stimulation (e.g., during stress, exercise, or epinephrine infusion). LQT1 patients appear to have less repolarization reserve during exercise as evidenced by a progressive or persistent pattern of QTc prolongation at faster heart rates, compared with patients with LQT2, in whom maximal QTc prolongation occurs at submaximal heart rates in the early phase of sympathetic stimulation with subsequent fall toward baseline values at faster heart rates. IKs is an important determinant of rate-dependent shortening of the cardiac action potential and QT interval. As heart rate increases, IKs increases because channel deactivation is slow and incomplete during the shortened diastole. This allows IKs channels to accumulate in the open state during rapid heart rates and contribute to the faster rate of repolarization. Furthermore, IKs is markedly enhanced by beta-adrenergic stimulation through G-protein/cAMP-mediated channel phosphorylation by protein kinase A (PKA) (requiring AKAP9 [Yotiao]) and PKC (requiring MinK). Importantly, IKs is functionally upregulated when other repolarizing currents (such as IKr) are reduced, potentially serving as a “repolarization reserve” and a safeguard against loss of repolarizing power, especially when beta-adrenergic stimulation is present. LQT1 subjects have compromised IKs channels that are not as responsive to sympathetic stimulation, and phase 3 repolarization in these individuals is retarded. Consequently, during beta-adrenergic stimulation, there are relatively more unopposed depolarizing forces via the L-type Ca2+

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channel and the Na+-Ca2+ exchanger that prolong the action potential duration and the QT interval. In contrast, subjects with LQT2 have dysfunctional IKr channels, which represent a smaller fraction of the K+ channels responsible for phase 3 repolarization and are not as sympathetically responsive as IKs channels. Therefore, in LQT2 patients, the QT fails to shorten at the intermediate heart rates in the early phase of exercise or epinephrine infusion because of attenuation of IKr. This is followed by recruitment of IKs (“repolarization reserve”) at faster heart rates during continuing exercise or epinephrine infusion, with concomitant appropriate abbreviation of the action potential duration and QT shortening, which persists into the recovery phase. This consequently leads to an exaggerated QT difference between the exercise and recovery QT/R-R curves that is manifested as increased QT hysteresis, which appears to be a characteristic feature of the LQT2 phenotype. The LQT3 phenotype is characterized by a constant reduction of the action potential duration with epinephrine because of stimulation of the intact IKs channel and augmentation of the late inward INa. In fact, LQT3 patients may have supernormal QT adaptation in response to exercise compared with control subjects. SCN5A mutations in LQT3 cause a gain of function through disruption of fast channel inactivation, allowing repeated reopening during sustained depolarization and resulting in a small but functionally important enhancement of the INa during action potential plateau. As a consequence, the risk of developing arrhythmia will be expected to be particularly high at slow heart rates, when the action potential duration is longer, allowing more Na+ current to enter the cell. The differences in the dynamic response of ventricular repolarization to sympathetic stimulation may explain the epidemiological observation that patients with LQT1 are more likely to have life-threatening events during sympathetic activation compared with patients with other genotypes and also may underlie the responsiveness of LQT1 patients to beta-blocker therapy.9

Mechanism of Genotype-Phenotype Variability The LQTS is a complex and multifactorial disorder characterized by significant phenotypic heterogeneity. The clinical phenotype (QTc values, arrhythmia-related symptoms, and outcomes) is highly variable, with a broad continuous spectrum of clinical or subclinical phenotypes, not only between families carrying different pathogenic mutations, but also among family members carrying an identical mutation. One end of this spectrum is concealed LQTS (silent carriers of disease-causing mutations), whereby no QT prolongation or related symptoms are observed. At the other end of the spectrum are the severe symptomatic LQTS patients, who often represent the index cases easily identified in families. In between are patients with different degrees of QT prolongation and different levels of severity of arrhythmias. A multitude of genetic and acquired interacting factors (some defined but many still unknown) influence the pathophysiology and clinical course of each LQTS subject and ultimately determine a spectrum of phenotypes. Among these factors is the fact that action potential generation is a polygenic process; different LQTS genes affect different ion current mechanisms. Even mutations in the same gene can affect gene expression levels and ionic current activity to different extents and via different mechanisms. As noted above, mutations located in the transmembrane segment (for LQT1) or pore region (for LQT2) of the ion channel generally result in more malignant disease compared with mutations in other locations. Similarly, mutations causing a dominantnegative effect (e.g., missense mutations involving the pore region of the channel) result in more profound channel dysfunction and more severe clinical disease than those associated with haplotype insufficiency (e.g., mutations causing coassembly or trafficking abnormalities).

The “repolarization reserve” concept can underlie, at least in part, the phenotypic heterogeneity in LQTS. Cardiac muscle repolarization has built-in redundancy, or reserve, such that perturbation of one ion current does not necessarily result in excessive repolarization changes because other currents can compensate. Hence, there exists an inherent variability of arrhythmic response to QT interval prolongation with the relationship between perturbations of one ion channel in relation to the sum total of repolarizing currents. This concept implies that often multiple “hits” to repolarization are required to compromise repolarization and surpass the threshold for developing clinical QT prolongation and torsades de pointes. In this setting, a mutation in one of the LQT-linked genes causing an attenuation of a cardiac ionic current may result in only a limited disruption of the repolarization process, which can be clinically concealed and become unmasked (manifesting as QT prolongation and arrhythmias) only when accompanied by another insult to the same or a different ionic current (e.g., drugs or electrolyte abnormalities). In fact, it has been suggested that some cases of acquired LQTS represent inadvertent “unmasking” of subclinical congenital LQTS.10,11 Adding to the complexity is the “double-hit” phenomenon, secondary to either two mutations in the same gene (compound heterozygosity) or mutations in two different LQT genes (digenic heterozygosity). Double hits occur in 5% to 10% of LQTS patients and the resulting phenotype is more severe than with a single hit. Genetic factors are also involved in the control of cardiac repolarization at the population level. The heritability of the QTc interval has been estimated as being between 25% and 52%. Ventricular action potential is under the joint control of multiple ionic currents, and the activity and expression levels of the channels underlying each of these currents establish a subtle equilibrium between depolarizing and repolarizing currents determining the action potential duration in each individual. Common genetic variants differing from the ancestor sequence by one nucleotide (i.e., single nucleotide polymorphism) in genes coding for proteins that are known or suggested to affect ion channel function appear to influence this equilibrium even via weak effects on activity and/or expression level of channel subunits and can potentially play a role in determining cardiac repolarization duration and QTc length in healthy individuals. Therefore apart from the known LQT-linked genetic mutations, allelic variation elsewhere in the genome, most often single nucleotide polymorphisms, in the same disease-causing gene or in other genes, can amplify otherwise subclinical disturbances of the repolarization into overt LQTS and potentially contribute to the variable penetrance and clinical phenotype heterogeneity. Furthermore, the resultant intrinsic risk for arrhythmias can be modulated by a variety of intrinsic or extrinsic environmental factors, including age, gender, heart rate, sympathetic tone, electrolyte balance, presence of QT-prolonging drugs, as well as inherited and acquired pathological conditions such as LV hypertrophy, and heart failure. In summary, the interaction of the underlying LQTS genetic mutation with other genetic factors in the same gene or elsewhere in the host genome (“modifier genes”), as well as with multiple superimposed acquired risk determinants (“disease modifiers”), has a substantial impact on the expressivity of the phenotype of the LQT genotype.12

Mechanism of Gender Effects In the healthy population, QTc intervals are longer in women than in men, a difference that becomes apparent only after puberty. This is associated with a higher susceptibility to drug-induced LQTS and torsades de pointes; women account for 70% of cases of drug-induced QT prolongation and torsades de pointes. In healthy volunteers, druginduced QT interval prolongation is greatest during the menses and ovulation phases and least during the luteal phase. Age-dependent

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies gender-related differences also exist among patients with congenital LQTS. Although the risk of cardiac events is higher in boys with LQTS as compared with girls during childhood and early adolescence, a gender risk reversal occurs after the onset of puberty. LQT1 and LQT2 women of childbearing age have longer QT intervals and higher risk for polymorphic VT and SCD than men. The extent of QT prolongation and the risk of cardiac events appear to be more pronounced during periods with high estradiol and low progesterone levels (e.g., during the follicular phase of the menstrual cycle) and mildly reduced during periods with higher progesterone/estradiol ratio (e.g., during the luteal phase of the menstrual cycle, and during pregnancy). The arrhythmogenic risk markedly increases immediately postpartum (especially among women with the LQT2 genotype), when serum progesterone concentrations abruptly decline.13–15 The mechanisms underlying these gender-related differences are poorly understood. Environmental (increased physical activity), hormonal, and genetic factors (modifier genes not shared by boys and girls) have been proposed. Current evidence supports the role of sex hormones as a significant contributor to the action potential duration. Recent studies suggest that the duration of ventricular repolarization and QTc interval are influenced by complex interactions between sex steroid hormones and gonadotropins depending on gender, rather than on one single hormone. In general, testosterone in men and an increased progesterone/estradiol ratio in women shorten repolarization, whereas follicle-stimulating hormone prolongs repolarization in both genders.15,16 The effect of sex hormones on the QT interval and arrhythmogenesis in LQTS can partly be explained by direct and indirect interaction with the ion channel. Experimental studies suggest that estrogen suppresses IKr, and increases ICaL, Na+-Ca2+ exchanger activity, RyR2 leakiness, and alpha1- and beta2-adrenoceptor responsiveness. Estradiol also enhances the sensitivity of IKr channels to their specific antagonist and predisposes to greater drug-induced QT prolongation. Conversely, testosterone enhances the outward currents (IKr, IKs, IK1) and reduces the inward current (ICaL). Progesterone, a testosterone precursor, enhances IKs and reduces ICaL. Thus estradiol can potentially exert a proarrhythmic effect

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in LQTS patients, whereas testosterone and progesterone shorten QT duration and exert an antiarrhythmic effect with a reduced susceptibility to sympathetic stimuli.14,15,17 In fact, a recent study demonstrated potential benefit of oral progesterone for the prevention of drug-induced QT interval prolongation.18

Epidemiology There are no systematic studies on LQTS prevalence in the general population. A recent estimate of the prevalence of LQTS is 1 : 2000 live births, based on the results of genetic screening in families and the incidence of compound heterozygotes (i.e., persons with two mutations). However, the clinical disease is less common (approximately 1 in 5000) because most mutation carriers remain asymptomatic. The usual mode of inheritance is autosomal dominant, with the exception of the autosomal recessive Jervell and Lange-Nielsen type and triadin knockout syndrome (LQT17). LQT1, LQT2, and LQT3 comprise more than 90% of all genotyped LQTS cases. LQT1 is the most frequent genetic form of LQTS, accounting for 40% to 55% of genotyped LQTS cases. LQT2 and LQT3 account for 30% to 45% and 5% to 10% of genotyped LQTS cases, respectively (Table 31.2). The remaining 14 types (LQT4 to LQT17) make up less than 5% of the genotype-identified LQTS. Although LQT3 is infrequent among adolescents and adults with LQTS, it constitutes the most common genetic form associated with LQTS-related perinatal and early-infancy mortality. LQTS exhibits incomplete penetrance (i.e., not all carriers of the pathogenic mutation will develop a phenotypic expression) and variable expressivity (i.e., the level of phenotypic expression varies among affected patients).

Clinical Presentation and Natural Course Romano-Ward Syndrome

Most information regarding the clinical features of LQTS have been derived from analysis of data from large series of LQTS patients, the largest of which is the International LQTS Registry. LQTS probands

TABLE 31.2  Common Types of the Long QT Syndrome LQT1

LQT2

LQT3

Pathophysiology Gene Protein Ionic current

KCNQ1 (Kv LQT1) Kv7.1 Decreased IKs

KCNH2 (HERG) Kv11.1 Decreased IKr

SCN5A Nav1.5 Increased late INa

Clinical Presentation Incidence of cardiac events Incidence of SCD Arrhythmia triggers

63% 4% Emotional/physical stress (swimming, diving)

18% 4% Sleep/rest

Broad-based T wave Attenuated QTc shortening and an exaggerated QTc prolongation during early and peak exercise

46% 4% Emotional stress, arousal (alarm clock, telephone), rest Low-amplitude, bifid T wave Normal QT during exercise but with exaggerated QT hysteresis

+++ +++ + ++ +

++ +++ ++ ++ +

Electrocardiogram QT response to exercise Management Exercise restriction Response to beta-blockers Potassium supplement Left cervicothoracic sympathectomy Response to mexiletine

Long isoelectric ST segment Supernormal QT shortening

? ? + ++ ++

IKr, Rapidly activating delayed rectifier K+ current; IKs, slowly activating delayed rectifier potassium current; INa, sodium current; QTc, corrected QT interval; SCD, sudden cardiac death.

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are diagnosed at an average age of 21 years. The clinical course of patients with LQTS is variable, and is influenced by age, gender, genotype, environmental factors, therapy, and possibly other modifier genes. At least 37% of individuals with the LQT1 phenotype, 54% with the LQT2 phenotype, and 82% with the LQT3 phenotype remain asymptomatic and many are referred for evaluation because of the diagnosis of LQTS of a family member or the identification of a long QT interval on a surface ECG obtained for unrelated reasons. Symptomatic patients can present with palpitations, presyncope, syncope, or cardiac arrest. Syncope is the most frequent symptom, occurring in 50% of symptomatic probands by the age of 12 years, and in 90% by the age of 40 years. The incidence of syncope in LQTS patients is approximately 5% per year, but can vary depending on the LQTS genotype. Syncope in patients with LQTS is generally attributed to polymorphic VT (torsades de pointes), but can also be precipitated by severe bradycardia in some patients with LQT3. Cardiac arrest and SCD are usually due to VF. Recurrent syncope can mimic primary seizure disorders. The incidence of SCD is much lower, approximately 1.9% per year. Nonfatal events (syncope and aborted cardiac arrest) in LQTS patients remain the strongest predictors of subsequent LQTS-related fatal events. The overall risk of subsequent SCD in an LQTS patient who has experienced a previous episode of syncope is approximately 5% per year. Of individuals who die of complications of LQTS, SCD is the first sign of the disorder in an estimated 10% to 15%. The risk for SCD from birth to age 40 years has been reported as approximately 4% in each of the phenotypes. Risk and lethality of cardiac events among untreated individuals are strongly influenced by the genotype. The frequency of cardiac events is significantly higher among LQT1 (63%) and LQT2 (46%) patients than among patients with the LQT3 genotype (18%). However, the likelihood of dying during a cardiac event is significantly higher among LQT3 patients (20%) than among those with the LQT1 (4%) or the LQT2 (4%) genotype. Overall, LQT3 is to be considered a severe LQTS variant; the first cardiac event is more likely to be lethal and seems to occur later in childhood, during or after puberty.19 Cardiac events (syncope, cardiac arrest, SCD) in LQTS patients do not occur at random; the factors precipitating cardiac events seem to

be specific for each genetic variant. LQT1 patients present an increased risk during physical or emotional stress (90%), and only 3% of the arrhythmic episodes occur during rest or sleep. Swimming and diving appear as highly specific triggers in LQT1 patients. LQT2 patients are at higher risk for lethal events during arousal (44%), but are also at risk during sleep and at rest (43%). Only 13% of cardiac events occur during exercise. Cardiac events in LQT2 patients are characteristically associated with arousal and auditory stimulation. In fact, the triggering of events by startling, sudden awakening, or sudden loud noises (such as a telephone or alarm clock ring) is virtually diagnostic of LQT2. Notably, individual factors such as gender, location and type of mutation, and QTc prolongation appear to be associated with trigger-specific events; female adolescents with LQT2 appear to experience a greater than ninefold increase in the risk for arousal-triggered cardiac events compared with male adolescents in the same age group. In contrast, gender does not seem to be a significant risk factor for exercise-triggered events among carriers of the same genotype (Fig. 31.3). On the other hand, LQT3 patients experience cardiac events largely while asleep or at rest (65%) without emotional arousal, and only occasionally during exercise (4%). Notably, the majority of patients continue to experience their cardiac events under conditions similar to their first classified event.20 The effect of gender on outcome is age dependent, with boys being at higher risk than girls during childhood and early adolescence, but no significant difference in gender-related risk being observed between 13 and 20 years. The gender-related risk reverses afterward, and female patients maintain higher risk than male patients throughout adulthood. The genotype can potentially affect the clinical course of the LQTS and modulate the effects of age and gender on clinical manifestations. Although the three major LQTS genotypes (LQT1, LQT2, or LQT3) are associated with similar risks for life-threatening cardiac events in children and adolescents after adjustment for clinical risk factors (including gender, QTc duration, and time-dependent syncope), the risk for cardiac events is augmented in LQT2 women aged 21 to 40 years and in LQT3 patients greater than 40 years of age. The risk of syncope and SCD decreases during pregnancy but increases in the postpartum period, especially among LQT2 women.

Trigger (frequency)

Risk factors

Beta-blocker efficacy

Arousal (44%)

Exercise (12%)

Nonexercise Nonarousal (44%)

Female >13 years +++ Pore-loop ++ Non–pore-loop TM +–

Non–pore-loop TM +++ Pore-loop + Gender –

Female >13 years +++ Pore-loop ++ Non–pore-loop TM + PAS + Missense ++

+–

+++

+–

Fig. 31.3  Trigger-Specific Risk Factors and Response to Therapy in Long QT Syndrome Type 2 (LQT2). Plus and minus signs are approximate representations of the risk/response based on the hazard ratios and associated P values from the multivariate models. PAS, Per-Arnt-Sim domain of the hERG channel; TM, transmembrane. (Reproduced with permission from Kim JA, Lopes CM, Moss AJ, et al. Trigger-specific risk factors and response to therapy in long QT syndrome type 2. Heart Rhythm. 2010;7:1797–1805.)

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

Jervell and Lange-Nielsen Syndrome The Jervell and Lange-Nielsen syndrome is the recessive variant of the LQTS, characterized by congenital deafness and cardiac phenotype (QT prolongation, ventricular arrhythmias, and SCD). The Jervell and LangeNielsen syndrome is caused by two homozygous or compound heterozygous mutations of one of the two genes (KCNQ1 and KCNE1) that encode components of the IKs channel. Patients with Jervell and Lange-Nielsen syndrome have a more severe cardiac phenotype than those with Romano-Ward syndrome. Patients begin to experience cardiac events very early in life; 15% suffer a cardiac event during the first year of life, 50% by age 3 years, and 90% by age 18 years. In untreated patients, approximately 50% die of ventricular arrhythmias by the age of 15 years. Furthermore, SCD occurs in more than 25% of patients despite medical therapy. In addition, complete loss of IKs in hair cells and endolymph of the inner ear results in congenital bilateral sensorineural deafness. The conditions that trigger the cardiac events are, overall, very similar to those described for LQT1. Up to 95% of events occur during sympathetic activation (exercise and emotions), and only 5% of the events occur at rest or during sleep.

Andersen-Tawil Syndrome Andersen-Tawil syndrome (LQT7) is a rare autosomal dominant disorder caused by mutations of the gene KCNJ2, which encodes the inward rectifier potassium channel, Kir2.1. This syndrome is characterized by a triad of a cardiac phenotype, a skeletal muscle phenotype (periodic paralysis caused by abnormal muscle relaxation), and distinctive craniofacial and skeletal dysmorphic features (low-set ears, ocular hypertelorism, small mandible, fifth-digit clinodactyly, syndactyly, short stature, scoliosis, and a broad forehead). Although Andersen-Tawil syndrome is classified as LQTS (LQT7), QT prolongation is more related to a prominent U wave (i.e., prolonged “QTUc interval”) rather than a QTc prolongation. Further, unlike other types of LQTS, cardiac arrhythmias in Andersen-Tawil syndrome are characterized by high burden of asymptomatic PVCs, ventricular bigeminy, or nonsustained VT, with a predominantly benign course and very rare degeneration into hemodynamically compromising rhythms like torsades de pointes. In addition, a specific type of polymorphic VT, bidirectional VT, is observed in Andersen-Tawil syndrome, similar to that observed in CPVT patients. Beta-blockers, Ca2+ channel blockers, and flecainide have been utilized for suppression of ventricular arrhythmias in these patients, but the efficacy of these drugs is yet to be proven.21 Patients with Andersen-Tawil syndrome present initially with periodic paralysis or cardiac symptoms (palpitations, syncope, or both) in the first or second decade of life. Intermittent weakness occurs spontaneously, or can be triggered by prolonged rest or rest following exertion; however, the frequency, duration, and severity of symptoms are variable between and within affected individuals, and are often linked to fluctuations in plasma K+ levels. Mild permanent weakness is common. There is a high degree of variability in penetrance and phenotypic expression. Approximately 60% of affected individuals manifest the complete triad and up to 80% express two of the three cardinal features.

Timothy Syndrome Timothy syndrome (LQT8) is an extremely rare multisystem disorder caused by mutations of the CACNA1C gene, which encodes the L-type Ca2+ channel (Cav1.2), and is characterized by syndactyly, QT prolongation, congenital heart disease, cognitive and behavioral problems, musculoskeletal diseases, immune dysfunction, and more sporadically, autism.

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Timothy syndrome is a severe form of LQTS, characterized by a remarkable prolongation of the QTc interval (QTc often exceeding 550 to 600 milliseconds), functional 2 : 1 AV block (observed in up to 85% of patients, and likely caused by the extremely prolonged ventricular repolarization and refractory periods), and macroscopic T wave alternans (positive and negative T waves alternating on a beat-to-beat basis). In addition, congenital heart defects are observed in approximately 60% of patients and include patent ductus arteriosus, patent foramen ovale, ventricular septal defect, tetralogy of Fallot, and hypertrophic cardiomyopathy. Timothy syndrome is highly malignant; the majority of patients seldom survive beyond 3 years of age. Polymorphic VT and VF occur in 80% of patients (commonly triggered by an increase in sympathetic tone) and are the leading cause of death, followed by infection and complications of intractable hypoglycemia.3 Extracardiac features include cutaneous syndactyly (variably involving the fingers and toes), which is observed in almost all patients. Facial findings (observed in approximately 85% of individuals) include low-set ears, flat nasal bridge, thin upper lip, small upper jaw, small, misplaced teeth, and round face. Neuropsychiatric involvement occurs in approximately 80% of individuals and includes global developmental delays and autism spectrum disorders. In general, the diagnosis of Timothy syndrome is made within the first few days of life based on the markedly prolonged QT interval and 2 : 1 AV block. Occasionally, the diagnosis is suspected prenatally because of fetal distress secondary to AV block or bradycardia. Although LQT8 (Timothy syndrome) is associated with gain-offunction in ICaL, reduction of ICaL influx by Ca2+ channel blockade (such as verapamil) failed to shorten QTc or prevent ventricular arrhythmias. A recent report suggested a potential antiarrhythmic benefit of ranolazine (an antianginal agent with inhibitory effects on multiple ion channels) in patients with Timothy syndrome.

Electrocardiographic Features Abnormal prolongation of the QT interval on the surface ECG, reflecting delayed ventricular repolarization, is the hallmark of LQTS. In addition, T wave abnormalities are encountered in the majority of patients.

QT Interval Measurement The QT interval is the body surface representation of the duration of ventricular depolarization and subsequent repolarization. Any deviation or dispersion of depolarization (e.g., bundle branch block) or repolarization (e.g., prolongation or dispersion of the action potential duration) results in prolongation of the QT interval. An accurate measurement of the QT interval is important for the diagnosis of LQTS. A 12-lead ECG tracing at a paper speed of 25 mm/s at 10 mm/mV is usually adequate to make accurate measurements of the QT interval. The QT interval is measured as the interval from the onset of the QRS complex, that is, the earliest indication of ventricular depolarization, to the end of the T wave, that is, the latest indication of ventricular repolarization. The QT interval is measured in all ECG leads where the end of the T wave can be clearly defined (preferably leads II and V5 or V6), with the longest value being used. The end of the T wave is the point at which the descending limb of the T wave intersects the isoelectric line. Three to five consecutive cardiac cycles are taken to derive average values for R-R, QRS, and QT intervals.22 When the end of the T wave is indistinct, or if a U wave is superimposed or inseparable from the T wave, it is recommended that the QT be measured in the leads not showing U waves (often leads aVR and aVL) or that the downslope of the T wave be extended by drawing a tangent to the steepest proportion of the downward limb of the T wave until it crosses the baseline (i.e., the T-P segment) (Fig. 31.4).

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

DPP6, CALM1

Shot coupled torsades de pointes

2013 Early repolarization syndrome

2000 Short QT syndrome

1992 Brugada syndrome

1978 CPVT

IVF

1957 Long QT syndrome

Fig. 31.4  Schematic illustration of the use of the tangent method to define the end of the T wave in normal and abnormal TU-wave morphologies. CPVT, Catecholaminergic polymorphic ventricular tachycardia; IVF, idiopathic ventricular fibrillation. (From Postema PG, Wilde AAM. The measurement of the QT interval. Curr Cardiol Rev. 2014;10:287–294.)

However, it should be recognized that defining the end of the T wave in these ways can potentially underestimate the QT interval. Some investigators advocate measurement of both the QT interval and the QTU interval (with the latter measurement taken to the end of the U wave as it intersects the isoelectric line) because the QTU interval probably reflects the total duration of ventricular depolarization. The highest diagnostic and prognostic value in LQTS families has been observed for QTc in leads II and V5 of the 12-lead ECG. Thus QTc should be obtained in one of these leads if measured in only a single ECG lead. However, other leads were found to offer similar diagnostic (aVR) or prognostic (V2/V3) value alone, and, in general, the lead with the longest QT interval is used for measurement. The QT interval should ideally be measured at a heart rate closest to 60 beats/min and definitely less than 100 beats/min. The use of beta-blockers or long-term ECG monitoring need to be considered to obtain optimal measurements.

TABLE 31.3  Formulas for Heart Rate

Correction of the QT Interval Bazett Framingham-Sagie Fridericia Hodges Nomogram-Karjalainen Rautaharju

QTcB = QT/(R-R interval)1/2 (all intervals in seconds) QTcFa = QT + 154(1 − 60/HR) QTcFi = QT/(R-R interval)1/3 QTcH = QT + 1.75(HR − 60) QTcN = QT + nomogram correction factor QTcRa = QT − 155 × (60/HR − 1) − 0.93 × (QRS − 139) + k (k = −22 msec for men, and –34 msec for women)

HR, Heart rate.

QT Interval Correction for Gender

QT Interval Correction for Heart Rate

The QT interval shortens after puberty in males but not in females, resulting in a longer QT in women than in men. The reported gender difference in various studies varies from 6 to 10 milliseconds in older age groups and from 12 to 15 milliseconds in younger adults. Overall, the gender difference in the QTc interval becomes small after 40 years of age and practically disappears in older men and women. Separate gender- and age-specific QT adjustment formulas have been proposed to accommodate these differences.

Because the heart rate (R-R cycle length) is the primary modifier of ventricular action potential, QT interval measurements must be corrected (QTc) for the baseline R-R interval to allow for comparisons. Various correction formulas have been developed (Table 31.3), the most widely used being the formula derived by Bazett in 1920 from a graphic plot of measured QT intervals in 39 young subjects. The Bazett correction, however, performs less well at high and low heart rates (undercorrects at fast heart rates and overcorrects at slow heart rates).

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies In addition to the Bazett formula, many other correction formulas, such as the Framingham-Sagie, Fridericia, Hodges, and NomogramKarjalainen formulas, have been proposed. In a study comparing the accuracy of those five different QT correction formulas for determining drug-induced QT interval prolongation, the Bazett correction formula provided the most marked QTc variations at heart rates distant from 60 beats/min. The Fridericia formula was found to overestimate QTc at faster heart rates, being more reliable at slower heart rates. Conversely, the Hodges, Nomogram, and Framingham formulas demonstrated less QTc variability over the whole range of the investigated heart rates and seemed to be similarly satisfactory at heart rates of up to 100 beats/ min. Among them, the Hodges method, followed by the NomogramKarjalainen method, appeared to be the most accurate in determining the correct QTc and subsequently in guiding clinical decisions.22 Nonetheless, the Bazett formula remains the one most commonly used to measure the QT interval for the diagnosis of LQTS. However, when a prolonged QTc is observed during faster heart rates (greater than 90 beats/min), it is important to repeat the ECG once the heart rate slows down, to minimize the error that can potentially be introduced by heart rate correction formulas. Importantly, there exists a substantial interindividual variability of the relationship between QT duration and heart rate (the QT/R-R relationship). In contrast, a high intraindividual stability of the QT/R-R pattern has been demonstrated, suggesting that a genetic component might partly determine individual QT length. Therefore populationbased and averaged QT correction cannot accurately predict a normal QT interval at a given R-R interval in a given patient. Individual-specific QT/R-R hysteresis correction in combination with individualized heart rate correction can potentially reduce intraindividual QTc variability.

QT Interval Correction to QRS Duration The QT interval prolongs in ventricular conduction defects, mainly due to a delay in depolarization (i.e., prolongation of the QRS duration) and not in repolarization. Most QT correction formulae do not take bundle branch block into consideration. Only a few formulae (such as the Rautaharju formula, the Bogossian formula, and the JT index) are designed to include bundle branch blocks in their calculations, but none of them have been widely adopted in clinical practice. A widely used approach is to apply the Bazett formula to the uncorrected QT interval and accept a longer QTc as the upper limit of acceptable (550 milliseconds rather than 500 milliseconds). Another method to adjust the QT measurement after the development of a bundle branch block is to subtract the difference in QRS widths before and after the block (when such information is available). A third method is to measure the JT interval from the end of the QRS complex to the end of the T wave. Unlike the QTc interval which describes both cardiac depolarization and repolarization, the JTc interval is independent of the QRS duration and thus represents only repolarization (JTc = QTc − QRS). If the JT interval is chosen, normal standards established specifically for the JT interval should be used. QT and JT adjustment formulas have recently been introduced for use in the setting of prolonged ventricular conduction. With confirmation, they may be incorporated into automated algorithms to provide appropriate correction factors.23,24 However, because of delay in depolarization in left bundle branch block (LBBB), repolarization begins before the end of the QRS complex (i.e., before the J point); hence, the JT interval likely underestimates the duration of repolarization, particularly when QRS duration was very prolonged (greater than 175 milliseconds).25 A recent study in a series of patients with intermittent LBBB found that the net increase in QRS duration contributes to 92% of the extra time in measured QT in LBBB, and a new formula (the Wang formula) was developed to calculate the true QT: True QT interval = measured

QT in LBBB − (0.86 * QRS in LBBB − 71). The QT so derived can then be corrected using the Bazett or other standard formulation.25

QT Interval Measurement During Right Ventricular Pacing Reliable estimation of the QT interval in ventricular paced rhythm is challenging. It has been demonstrated that the Rautaharju formula (see Table 31.3) yields QTc values during ventricular pacing that are closest with the non-paced QTc interval values; however, this formula is complex to apply and exhibits significant interaction with heart rate changes. The Framingham and Nomogram correction methods were found to offer the most optimal balance for assessing the QTc interval, including minimal interaction between pacing mode and heart rate. The use of the Bazett formula significantly exaggerates the QTc rate dependency during ventricular pacing and, therefore, is less reliable.26 A recent study suggested the use of the Framingham and Nomogram methods to calculate the corresponding nonpaced intrinsic QTc interval from the measured ventricular paced QTc interval (regardless of heart rate) by subtracting 43 milliseconds in normal-QTc patients, and 37 milliseconds (for the Framingham method) or 36 milliseconds (for the Nomogram method), in prolonged-QT patients.26 Another study found that RV pacing causes prolongation of the QT due to a paced LBBB without prolongation of the JT interval, and that QT prolongation caused by ventricular pacing constitutes about 50% of the QRS width. The Bogossian formula subtracts this value from the measured ventricular paced QT interval (QT in LBBB = measured QT interval − 50% * QRS duration).23 Although this formula can provide a simple method for estimating the nonpaced intrinsic QT interval, it tends to overcorrect the QT interval, that is, making the QT shorter than it should be. The paced JTc interval was found to more accurately represent ventricular repolarization (as compared to the paced QTc interval) and mirror repolarization changes observed during nonpaced rhythm. However, as noted previously, the sensitivity of the JT interval in identifying patients with delayed ventricular repolarization decreases with increasing QRS duration, and that can artificially shorten the calculated QT interval. Therefore the JT interval appears ineffective in predicting delayed repolarization in patients with a very wide QRS.24,25

QT Interval Prolongation The diagnosis of QT interval prolongation can be challenging because of the difficulty in defining the “end” of the T wave and the need for correction for heart rate, age, and gender. This is further complicated by the lack of linear behavior of the Bazett formula at slower and faster heart rates as well as the arbitrary definition of the gender-based diagnostic cutoff values that define an abnormally prolonged QTc (QTc of 450 milliseconds for men and QTc of 460 milliseconds for women; Table 31.4).

TABLE 31.4  Suggested Bazett-Corrected

QT Interval Values for Diagnosis of QT Prolongation Rating Normal Borderline Prolonged

1–15 Years

Adult Man

Adult Woman

<440 440–460 >460

<430 430–450 >450

<450 450–470 >470

Values given in milliseconds. From Goldenberg I, Moss AJ. Long QT syndrome. J Am Coll Cardiol. 2008;51:2291–2300.

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

LQT1

LQT2

LQT3

II

V3

V5 Fig. 31.5  Electrocardiogram Recordings From Leads II, V3, and V5 in Three Patients From Families With Long QT Syndrome (LQTS). The typical morphology of LQT3 with straight ST segment and small T wave is shown in the right panel. (From Ruan Y, Liu N, Bai R, Priori SG, Napolitano C. Congenital long QT syndrome type 3. Card Electrophysiol Clin. 2014;6:705–713.)

Furthermore, no single QTc value separates all LQTS patients from healthy controls. In fact, LQTS cannot be excluded merely by the presence of a normal QTc interval. The QT interval is subject to large variations even in healthy individuals, and substantial overlap exists with QTc values obtained from LQTS mutation carriers in the range between 410 and 470 milliseconds. In up to 40% of LQTS patients, QTc intervals fall in the normal range. On the other hand, QTc values greater than 470 milliseconds in men and greater than 480 milliseconds in women are practically not observed among healthy individuals (especially when their heart rate is 60 to 70 beats/min). Therefore unless excessive QTc prolongation (greater than 500 milliseconds, corresponding to the upper quartile among affected genotyped individuals) is present, the QTc interval should always be evaluated in conjunction with the other diagnostic criteria. Of note, a considerable variability in QTc interval duration can be observed in patients with LQTS when serial ECGs are recorded during follow-up. This time-dependent change in QTc duration is an important determinant of the phenotypic expression of the disease. Up to 40% of patients with LQTS will have QTc greater than 500 milliseconds at least once during long-term follow-up, but only 25% will have that degree of QT prolongation during their initial evaluation. The maximal QTc duration measured at any time before age 10 years was shown to be the most powerful predictor of cardiac events during adolescence, regardless of baseline, mean, or most recent QTc values. In addition, the QT interval may normally exhibit individual variations during the day. Therefore in the case of borderline QTc prolongation, serial ECG and 24-hour Holter recordings can potentially assist in establishing QT prolongation.

T Wave Morphology ST-T wave abnormalities are common among LQTS patients, and some of the ST-T changes are characteristic for a certain genotype. Specifically, “broad,” “notched,” and “late” T waves are associated with LQT1,

LQT2, and LQT3, respectively, although these features are often subtle and inconsistently observed (Fig. 31.5).27 Patients with LQT1 commonly exhibit a smooth, broad-based T wave that is present in most leads, and particularly evident in the precordial leads. The T wave generally has a normal to relatively high amplitude and often no distinct onset. LQT2 patients generally present with low-amplitude T waves, which are notched or bifid in approximately 60% of carriers. The bifid T wave can be confused with a T-U complex; however, unlike the U waves, the bifid T waves are usually present in most of the 12 ECG leads. LQT3 patients often show late-onset, narrow, peaked, and/or biphasic T waves with a prolonged isoelectric ST segment. Occasionally, the T wave is peaked and asymmetrical with a steep downslope. These ST-T wave patterns can be seen in 88% of LQT1 and LQT2 carriers and in 65% of LQT3 carriers. No specific T wave pattern has been suggested in the LQT5 and LQT6 syndromes. T-U wave abnormalities such as biphasic T waves following long pauses like those found in the LQT2 syndrome are commonly observed in the LQT4 syndrome. Enlarged U waves separated from the T wave are reported to be characteristic ECG features in the LQT7 syndrome. Severe QT interval prolongation and macroscopic T wave alternans can be observed in LQT8. Despite the initial enthusiasm in achieving a genotype-phenotype correlation for specific LQT-associated genes, this approach failed to provide a high diagnostic yield because of the frequent exceptions in T wave morphology presentation. Furthermore, the T wave pattern can vary with time, even in the same patient with a specific mutation. Therefore other T wave parameters, such as duration, amplitude, asymmetry, and flatness, as well as the interval from the peak of the T wave to the end of the T wave (Tp-e), have been used as highly specific quantitative descriptors (see later). Of note, quantitative analysis of T wave morphology in lead V6 was found in a recent report to be capable of distinguishing patients with genetically proven LQTS from matched controls and even permits

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies identification of over 80% of patients with LQTS, despite having a normal resting QTc. The potential implications of this tool for universal screening for LQTS warrant further investigation.28

Torsades de Pointes Torsades de pointes is a polymorphic VT occurring in the setting of QT interval prolongation (acquired or congenital LQTS) and is characterized by a progressive change of the electrical axis, typically rotating 180 degrees in approximately 10 to 12 cycles. This results in the characteristic sinusoidal twisting of the peaks of the QRS complexes around the isoelectric line of the recording; hence, the name torsades de pointes or “twisting of the points.” However, this characteristic pattern may not be evident in all ECG leads. Also, during a very fast VT, periodic decrease in the amplitude of the entire QRS-T complex can be observed with less distinct shifts in the QRS axis. Occasionally, a polymorphic QRS configuration is observed without displaying those characteristics. Of note, different patterns can be seen in different VT episodes from the same patient.29 The VT is frequently preceded by a variable period of bigeminal rhythm caused by one or two PVCs coupled to the prolonged QT interval of the preceding basic beat. The tachycardia rate is typically in the range of 150 to 300 beats/min. In many cases, torsades de pointes is a selflimiting arrhythmia that spontaneously dies out after a few tens of cycles; however, most patients experience multiple episodes of the VT occurring in rapid succession. Only in a minority of cases does torsades de pointes degenerate into VF, which almost without exception leads to SCD if immediate rescue intervention, including defibrillation, is not performed.

Dispersion of Repolarization Prolongation of the action potential duration (and QT interval) per se is not pathogenic, as evidenced by the fact that a homogeneous action potential duration prolongation (such as occurs following amiodarone therapy) fails to generate reentry. As demonstrated in experimental models of the LQTS, prolonged repolarization, transmural dispersion of repolarization, and EADs are the three electrophysiological (EP) components linked to the genesis of torsades de pointes. Transmural dispersion of repolarization arises from repolarization heterogeneity that exists between the epicardial and putative midmyocardial (M) cells that lie toward the endocardium of the LV wall. These midmyocardial cells are especially sensitive to a repolarization challenge and exhibit significant prolongation of the action potential duration compared with other transmural cell types. Several ECG indices have been proposed in recent years as noninvasive surrogates for transmural dispersion of repolarization, including the T wave peak to T wave end (Tp-e) interval, QT interval dispersion, and ratio of the amplitudes of the U and T waves. Tp-e interval. Although controversy exists, some experimental models suggest that the peak of the T wave coincides with the end of epicardial repolarization (the shortest action potentials), whereas the end of the T wave coincides with the end of repolarization of the M cells (the longest action potentials). Hence, the Tp-e interval in each surface ECG lead has been proposed as an index of transmural repolarization. However, subsequent investigations using intact hearts have challenged this concept and suggested that, in vivo, the Tp-e interval is a measure of “global” dispersion of repolarization of the whole ventricle rather than “transmural” dispersion. Because increased dispersion of repolarization promotes reentry and enhances arrhythmogenesis, prolongation of the Tp-e interval has been proposed as a more sensitive predictor of risk for arrhythmic events than the QT interval; the latter represents the total duration of electrical ventricular activation and not necessarily the dispersion of

989

transmural repolarization. In fact, a prolonged Tp-e interval has been shown to be a marker of increased arrhythmogenic risk in patients with Brugada syndrome, hypertrophic cardiomyopathy, and structural heart disease, as well as in certain populations. Although changes in the Tp-e interval can potentially show the dynamicity of the dispersion of repolarization in clinical settings in LQTS patients, the role of measuring the Tp-e interval in these patients has yet to be clearly defined. In fact, the normal value of the Tp-e interval on the ECG has not been established. Nonetheless, an interval of more than 100 milliseconds is uncommon in normal subjects compared with that in patients with LQTS (9% vs. 55%). On ambulatory monitoring, LQT2 exhibits a larger-degree of dispersion of repolarization, as measured by the Tp-e interval, compared with LQT1 and normal hearts. In fact, the Tp-e interval has been proposed as a diagnostic criterion in differentiation between LQT2 and LQT1 patients. Also, LQT1 patients exhibit abrupt increases in Tp-e intervals at elevated heart rates, whereas LQT2 patients exhibit increases in dispersion of repolarization at a much wider range of rates. In addition, beta-adrenergic stimulation (exercise or epinephrine infusion) increases dispersion of repolarization in both LQTS models, transiently in LQT2 and persistently in LQT1. QT interval dispersion.  An alternate approach to determine repolarization heterogeneity is provided by the dispersion of the QT interval. The QT dispersion index is obtained by the difference between the maximal and minimal QT intervals (QTmax − QTmin) measured on a 12-lead ECG. The QT dispersion index reflects the spatial heterogeneity of myocardial refractoriness more accurately than single QT values. Visualization of the differences in QT interval in the different ECG leads can be facilitated by the display of temporally aligned simultaneous ECG leads with a slight separation on the amplitude scale. Importantly, QT interval dispersion measurements are subject to similar shortcomings encountered with the QT interval assessment, as a large overlap between affected and healthy individuals is observed. Further, accurate measurement on the scalar ECG at a paper speed of 25 mm/s is difficult. The same caveat applies to measuring the Tp-e interval. U wave–to–T wave amplitude ratio.  The ratio of the amplitudes of the U and T waves has been suggested as the clinical counterpart of EADs, and a progressive increase in this ratio was found to precede the onset of torsades de pointes in an experimental model of LQTS. In addition, the increment in U wave amplitude after a PVC has been suggested as a marker for arrhythmia risk in “pause-dependent” LQTS. In patients with bifid T waves, some investigators used the late component of the T wave, rather than the U wave. The diurnal maximal ratio between late and early T wave peak amplitude was found to correlate with a history of LQTS-related symptoms better than the baseline QTc interval in both LQT1 and LQT2 patients, and the diurnal distributions of maximal T2-to-T1 wave amplitude ratios were similar to those of cardiac events.

Diagnosis of the Long QT Syndrome According to the most recent consensus statement, LQTS can be diagnosed in individuals testing positive for an unequivocally pathogenic mutation in one of the LQTS genes. In the absence of a pathogenic mutation, and in the absence of a secondary cause for QT prolongation, the diagnosis of LQTS requires the presence of one of the following: (1) QTc interval of at least 500 milliseconds (using the Bazett formula) on repeated 12-lead ECGs; (2) QTc interval between 480 and 499 milliseconds on repeated 12-lead ECGs in conjunction with unexplained syncope; or (3) Schwartz score of at least 3.5 points (see later). In addition, LQTS can be suspected in individuals with QTc values exceeding 450 milliseconds for men and exceeding 460 milliseconds

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

for women; the probability for LQTS increases if these subjects also have a history of syncope and familial SCD. On the other hand, LQTS is very unlikely among men with QTc less than 390 milliseconds and among women with QTc less than 400 milliseconds. It is important to note that the LQTS is largely a clinical diagnosis, primarily based on the clinical presentation, personal and family history, and ECG findings. A detailed family history of syncope and SCD is essential, not only in first-degree relatives (mother, father, siblings, children), but also in more distant relatives. Also, the family history should also be investigated for other potential manifestations of malignant arrhythmias that might not have been classified as cardiac in origin, such as drowning, death while driving, epileptic seizures, and SIDS. Data on comorbidities in evaluated individuals or family members (such as congenital deafness) should also be acquired. Clinical features such as triggers of syncope and specific QT morphological attributes in patients in whom the clinical diagnosis has been made can suggest the affected gene in 70% to 90% of patients. Importantly, a significant proportion (20% to 40%) of patients with genetically proven LQTS have normal or borderline QTc measurements at rest (“concealed” LQTS). It has been reported that these silent mutation carriers account for 36% of LQT1 patients, 19% of LQT2 patients, and 10% of LQT3 patients. Therefore the diagnosis of LQTS should not be excluded based solely on a QTc interval in the normal range (400 to 450 milliseconds), and additional testing is indicated whenever the clinical history requires exclusion of LQTS. In this setting, obtaining a resting ECG periodically and ambulatory ECG monitoring can sometimes uncover abnormal prolongation of the QTc interval, given the considerable day-to-day variability in QTc of patients with LQTS. In addition, reviewing the ECGs of all family members can be valuable because some family members can have obvious QT prolongation. The probability of LQTS in an index subject can be augmented if one of those family members has QTc prolongation. Several provocative tests have been used to unmask LQTS patients with normal QTc on resting ECG. These include QT measurement upon abrupt standing, in the recovery phase of exercise testing, or during infusion of epinephrine. Also, genetic testing is recommended in patients with a strong clinical index of suspicion for LQTS. Although these diagnostic tools can all contribute to identifying patients with LQTS, a gold standard diagnostic tool is still lacking. Invasive EP testing is generally not useful in the diagnosis of LQTS.1

TABLE 31.5  Diagnostic Criteria for the

Long QT Syndrome

Points Electrocardiographic Findings A QTcb

a

B C D E F

≥480 msec 460–479 msec 450–459 (male) msec QTcb fourth minute of recovery from exercise stress test ≥480 msec Torsade de pointesc T wave alternans Notched T wave in three leads Low heart rate for aged

Clinical History A Syncopec B

With stress Without stress

Congenital deafness

Family History A Family members with definite LQTSe B Unexplained sudden cardiac death younger than age 30 among immediate family memberse

3 2 1 1 2 1 1 0.5 2 1 0.5 1 0.5

Score: ≤1 point: low probability of LQTS. 1.5–3 points: intermediate probability of LQTS. ≥3.5 points high probability. a In the absence of medications or disorders known to affect these electrocardiographic features. b QTc calculated by the Bazett formula where QTc = QT/√RR. c Mutually exclusive. d Resting heart rate below the second percentile for age. e The same family member cannot be counted in A and B. (From Di Fusco SA, Palazzo S, Colivicchi F, Santini M. The influence of gender on heart rhythm disease. Pacing Clin Electrophysiol. 2014;37: 650–657.) From Schwartz PJ, Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation. 2011;124:2181–2184.

When the diagnosis of LQTS is suspected but uncertain, a clinical scoring system (Schwartz score) has been developed to enhance the diagnostic reliability of clinical parameters and to estimate the probability of LQTS. The most recent (2011) update of the Schwartz score incorporates ECG features in combination with personal clinical history and family history. Scores were arbitrarily divided into three probability categories, providing a quantitative estimate of the risk for LQTS (Table 31.5). A score of 3.5 or higher makes the diagnosis of LQTS very likely and should compel further investigation, including genetic testing when available. Among patients with suspected LQTS (based on QTc interval prolongation or clinical history), “high probability” of LQTS (score greater than or equal to 3.5) using the Schwartz criteria identified LQTS mutation carriers with a sensitivity of 89% and a specificity of 82%. Further testing is required in the group with “intermediate probability” of LQTS to confirm or exclude the diagnosis, including serial ECGs, Holter recordings, and provocative testing.30,31

rarely will show spontaneous arrhythmias in LQTS patients. However, this method can sometimes be used for the detection of extreme QT interval events that occur infrequently during the day. An important value of Holter recordings lies in showing T wave changes characteristic of LQTS, which can become evident especially during sleep or following post-extrasystolic pauses.32 A recent study described a novel computer algorithm that measures QTc in a beat-to-beat manner during 24-hour Holter monitoring. The QTc measurements for a population or for an individual patient are displayed on a plot (“QTc clock” plot) to illustrate QT dynamics and characterize the extent and duration of QT prolongation. Using this technology, unique patterns of QT prolongation were observed in patients with LQT1 and LQT2. LQT1 patients were more likely to have diagnostic QTc prolongation during the daytime hours than during the night, likely correlating with the level of sympathetic activity (eFig. 31.3). Conversely, LQT2 patients showed more QT prolongation during the night. Whether these observations can be used to distinguish between the different LQTS genotypes or to predict arrhythmogenic risk requires further investigation.33

Ambulatory Cardiac Monitoring

QT Interval Response to Abrupt Standing

Holter monitoring is not sufficiently well standardized to serve in the primary assessment for ventricular repolarization analysis, and only

The brief tachycardia associated with abrupt standing can potentially uncover patients with insufficient QT adaptation abilities and poor

Clinical Scoring Systems

MALE

FEMALE

HEALTHY (n = 101)

HEALTHY (n = 101) 00:00

450 msec median

00:00

466 msec median 600

600 550

21:00

550

21:00

03:00

450

450

400

400

350

350 300

18:00

300

06:00 18:00

15:00 450 msec median

LQT1 (n = 88)

12:00

06:00

15:00

09:00

00:00

478 msec median

09:00

LQT1 (n = 114)

12:00

497 msec median

00:00

485 msec median

600

600 550

21:00

550

21:00

03:00

450

450

400

400

350

350 300

300

06:00 18:00

15:00 470 msec median

LQT2 (n = 42)

12:00

06:00

15:00

09:00

474 msec median

505 msec median

00:00

09:00

LQT2 (n = 47)

12:00

507 msec median

00:00

600

600 550

21:00

550

21:00

03:00

450

450

400

400

350

350 300

477 msec median

12:00

300

06:00 18:00

09:00

15:00

03:00

500

500

18:00

03:00

500

500

18:00

03:00

500

500

LQT3 (n = 8)

09:00

15:00 510 msec median

06:00

12:00

LQT3 (n = 6)

eFig. 31.3  QTc Clock. QTc clock plots for long QT syndrome type 1 (LQT1) males and females (top left and right panels, respectively), LQT2 males and females (middle left and right panels, respectively), and LQT3 males and females cohorts (bottom left and right panels, respectively). Each area is defined by the middle 68th percentile of QTc values, that is, same percentage as ±1 SD, measured across all Holter recordings, for each 1-minute slice. The dark green area represents the expected range of QTc variations in our healthy cohort. The figure highlights the changes in QT prolongation in LQT2 and LQT3 cohorts during the night. This phenomenon is expressed as graph asymmetry in which the area corresponding to LQT2/3 cohort stretches away from the normal value during the night (22:00–08:00). Arrows indicate median QTc between two periods of the day: 3:00–4:00 a.m. and 3:00–4:00 p.m. Note that the LQT3 ranges are computed from only six female and eight male patients. (From Page A, Aktas MK, Soyata T, Zareba W, Couderc J-P. “QT clock” to improve detection of QT prolongation in long QT syndrome patients. Heart Rhythm. 2016;13:190–198.)

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

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repolarization reserve, which characterize LQTS. Initially, an ECG is obtained in the supine position; then, the patient is asked to stand up briskly and a second ECG is obtained. In one report, postural-induced QTc prolongation was more than 30 milliseconds in 68% of patients with “concealed” LQTS. Also, a QTc cutoff value of 490 milliseconds yielded a sensitivity of 89% and a specificity of 87% for the diagnosis of LQTS in patients with no excessive prolongation of the supine QT intervals (i.e., less than 480 milliseconds for females, less than 470 milliseconds for males).22 Postural QTc prolongation can be attenuated with beta-blockade. Furthermore, T wave morphology changes exposed by quick standing are useful for diagnosing LQTS. The diagnosis of LQTS can be made with a higher degree of confidence when QT prolongation is accompanied by abnormal T wave morphology. The value of postural changes of T wave morphology for determining the specific LQTS genotype is modest, being most useful for LQT2, less useful for LQT1, and least useful for LQT3.34

channel and augmentation of a late inward Na+ current. In fact, the QT interval in LQT3 patients shortens during exercise much more in LQT1 and LQT2 patients and even more than in healthy controls. In addition, exercise treadmill testing can reveal the characteristic T wave morphology in patients with LQT1 and LQT2 syndromes. Exercise-induced QTc prolongation and QT hysteresis can be attenuated with beta-blockade; therefore beta-blocker therapy should be discontinued before exercise testing. Importantly, induction of arrhythmias during exercise is very rare in LQTS patients. Exercise-induced ventricular ectopy exceeding isolated PVCs is observed in less than 10% of patients. The presence of exercise-induced ventricular ectopy beyond single, isolated PVCs must prompt intense evaluation because it was found to have a positive predictive value exceeding 90% for the presence of significant cardiac pathology. However, CPVT, rather than LQTS, is the far more likely diagnosis.32

QT Interval Response to Exercise

Catecholamine provocation testing can help diagnose patients with concealed LQT1, with a positive predictive value approaching 75% and a negative predictive value of 96%. Furthermore, epinephrine provocation testing was found to be a powerful test to predict the genotype of LQT1, LQT2, and LQT3 syndromes. Two major protocols have been developed for epinephrine infusion. Using the “escalating-dose infusion protocol,” epinephrine infusion is initiated at 0.025 µg/kg per minute and then increased sequentially every 10 minutes to 0.05, 0.1, and 0.2 µg/kg per minute. The 12-lead ECG is continuously recorded during sinus rhythm under baseline conditions and during epinephrine infusion. The QT interval is measured 5 minutes after each dose increase. Epinephrine infusion should be stopped for systolic blood pressure greater than 200 mm Hg, sustained or nonsustained VT, frequent PVCs (greater than 10 per minute), T wave alternans, or patient intolerance. A paradoxical QT interval response (prolongation of the absolute QT interval of greater than or equal to 30 milliseconds) during low-dose epinephrine infusion provides a presumptive clinical diagnosis of LQT1, with a positive predictive value of 75%. The diagnostic accuracy can be reduced in patients receiving beta-blockers. Using the “bolus and infusion protocol,” an epinephrine bolus (0.1 µg/kg) is administered and immediately followed by continuous infusion (0.1 µg/kg per minute) for 5 minutes. The QT interval is measured 1 to 2 minutes after the start of epinephrine infusion when the R-R interval is the shortest (which represents the peak epinephrine effect) and 3 to 5 minutes after the start of epinephrine infusion (which represents the steady-state epinephrine effect). During the epinephrine test, patients with LQT1 manifest prolongation of the QTc at the peak of the epinephrine effect, which is maintained under steady-state conditions of epinephrine. In contrast, epinephrine prolongs the QTc more dramatically at the peak of epinephrine infusion in LQT2 patients, but the QTc returns to baseline levels under steady-state conditions. A much milder prolongation of QTc at the peak of epinephrine has been described in LQT3 patients and in healthy subjects, and it returns to the baseline levels under steady-state conditions. A subject is considered to have an LQT1 response if the QTc increase in the peak phase is greater than 35 milliseconds and is maintained throughout the steady-state phase (Fig. 31.6). LQT2 response is likely if the peak QTc increase of greater than 80 milliseconds is not maintained in the steady-state phase. In one report, the sensitivity and specificity of the epinephrine test to differentiate LQT1 from LQT2 were 97% and 96%, those from LQT3 were 97% and 100%, and those from healthy subjects were 97% and 100%, respectively, when ΔQTc greater than 35 milliseconds at steady state was used. The sensitivity and specificity to differentiate LQT2 from

Exercise testing can be useful to assess QT adaptation to heart rate, a measure of the integrity of the IKs channels. Changes in QTc duration and prolonged QT hysteresis during exercise testing can be helpful in identifying patients with LQTS and even in predicting the genotype. Gradual supine bicycle testing can help minimize signal artifact from upper body motion observed during treadmill exercise. In particular, the QTc at 4 minutes of recovery after maximal exercise discriminates between patients with LQTS and healthy subjects. In one study of patients with normal or borderline QTc intervals at baseline (i.e., less than 480 milliseconds for females, less than 470 milliseconds for males), a QTc greater than or equal to 480 milliseconds during the fourth minute of recovery identified LQTS patients with a sensitivity of 94% and a specificity of 90%. However, these diagnostic strategies have not been meticulously studied in an unselected population suspected of LQTS.22 In addition, a gene-specific QTc interval behavior during exercise has been reported. Genetic mutations in LQT1 result in reduction of the amplitude of IKs, one of the dominant K+ currents responsible for repolarization especially at rapid heart rates. Attenuation of IKs results in failure of the QT to adapt (i.e., failure to shorten) in response to increasing heart rate. A maladaptive, paradoxical prolongation of the QTc interval during the recovery phase (QTc greater than 470 milliseconds or a ΔQTc [QTc at 3 minutes of recovery minus the baseline supine QTc] greater than 30 milliseconds) was found to distinguish patients with manifest or concealed LQT1 from normal subjects and those with LQT2 and LQT3 genotypes. In contrast, patients with LQT2 mutations have normal QT shortening or minimal QTc prolongation during exercise, but they characteristically demonstrate an exaggerated QT hysteresis compared with LQT1 patients and normal subjects. QT hysteresis is normally measured by comparing the QT intervals during exercise versus the recovery period at comparable heart rates (e.g., when the heart rate accelerates to approximately 100 beats/min during early exercise, and when the heart rate decelerates to approximately 100 beats/min during the recovery phase). In LQT2 patients, the QT fails to shorten at these intermediate heart rates in early exercise because of attenuated IKr (a so-called IKr zone). This is followed by recruitment of the unimpaired, sympathetically responsive IKs, resulting in appropriate QT shortening at faster heart rates through to peak exercise, which persists into the recovery phase. This leads to increased QT hysteresis, that is, the QT interval is significantly longer during exercise than during recovery at comparable heart rates. The LQT3 phenotype is characterized by a constant shortening of the QT interval with exercise because of stimulation of the intact IKs

Epinephrine QT Stress Test

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies clinical index of suspicion for LQTS (Schwartz score greater than or equal to 3.5 points) and for asymptomatic patients with QT prolongation (QTc greater than or equal to 480 milliseconds [prepuberty] or greater than or equal to 500 milliseconds [adults]) in the absence of other clinical conditions that might prolong the QT interval. In addition, LQTS genetic testing may be considered for the asymptomatic subject with a QTc greater than or equal to 470 milliseconds on serial ECGs but with negative family history.32

∆QTc (steady state— baseline)

≥35 msec

<35 msec

LQT1

∆QTc (peak–baseline)

Differential Diagnosis: Acquired Long QT Syndrome

≥80 msec

<80 msec

LQT2

LQT3 control

Fig. 31.6  Epinephrine Provocative Testing for the Diagnosis of Long QT Syndrome (LQTS). Control, Normal subjects; LQT, long QT syndrome genotype; QTc, corrected QT interval.

LQT3 or healthy subjects were 100% and 100%, respectively, when ΔQTc greater than 80 milliseconds at peak was used. The escalating-dose infusion protocol is generally better tolerated by the patient and carries a lower incidence of false-positive responses. On the other hand, the bolus and infusion protocol offers the ability to monitor the temporal course of the epinephrine response at peak dose (during the bolus) and during steady state (during the infusion), which is particularly important in individuals with LQT2 in whom transient prolongation of the uncorrected QT interval can occur, followed by subsequent shortening.

Genetic Testing Although the diagnosis of LQTS can frequently be certain based on clinical diagnostic measures, genetic testing can still be of value; identification of the specific disease-causing mutation can potentially guide therapeutic choice, enhance risk stratification, and facilitate the identification of affected family members and implementation of lifestyle adjustment and presymptomatic treatment. Furthermore, genetic testing may be important in the identification of concealed LQTS, because a significant proportion (25% to 50%) of individuals with genetically proven LQTS can have a nondiagnostic QTc. However, genetic testing remains expensive. Depending on the stringency of clinical phenotype assessment, the yield for positive genetic results in LQTS ranges from 50% to 78%, and is highest among tested individuals with the highest clinical probability (i.e., those with longer QTc intervals and more severe symptoms). The remaining probands with a strong clinical probability of LQTS will have a negative genetic test result, probably because of technical difficulties with genotyping, noncoding variants, or as yet unidentified disease-associated genes. Therefore a negative genetic test in a subject with clinical LQTS (i.e., genotype-negative/phenotype-positive LQTS) does not provide a basis to exclude the diagnosis. Nonetheless, a negative genetic test renders the diagnosis of LQTS very unlikely in those patients with low to moderate pretest probability based on clinical findings.32 There is also the potential for false-positive results; genetic testing may identify novel mutations of unclear significance, which could represent normal variants, and require validation and further analysis (e.g., linkage within a family or in vitro studies). Currently, comprehensive or targeted (LQT1, LQT2, and LQT3) genetic testing is recommended for symptomatic patients with a strong

It is important to distinguish acquired factors that result in QT interval prolongation from the inherited form of LQTS. Acquired LQTS is far more prevalent than the congenital form. However, the occurrence of torsade de pointes is far less common than that of QT prolongation. Nonetheless, there is an increased risk for torsade de pointes whenever the QTc interval exceeds 500 milliseconds and whenever the QTc interval increases by more than 60 milliseconds from baseline, especially when the increase occurs rapidly. In contrast to the most common types of congenital LQTS (LQT1 and LQT2), a short-long-short pattern of R-R cycles constitutes the typical pattern of initiation of torsades de pointes in acquired LQTS. The long pause exaggerates the QT interval prolongation, and the shortlong-short sequence is thought to promote torsades de pointes by increasing transmural dispersion of repolarization. The short-long R-R interval is usually caused by a short-coupled PVC followed by a compensatory pause and then another PVC occurring during the T wave. However, because of the underlying QT interval prolongation, this R-on-T PVC does not have the short coupling interval that is characteristic of idiopathic VF. Torsades de pointes can also occur in association with bradycardia or frequent pauses (sometimes referred to as “pausedependent LQTS”).35

Etiology Acquired causes of abnormal prolongation of the QT interval include myocardial ischemia, cardiomyopathies, electrolyte abnormalities (hypokalemia, hypomagnesemia, and hypocalcemia), autonomic influences, drugs, hypothyroidism, hypothermia, pheochromocytoma, intracranial bleeding, and bradycardia. Hypokalemia causes prolongation of the action potential duration because of reductions in multiple K+ currents including IKr, IK1, and Ito. Low extracellular K+ levels accelerate fast inactivation of the hERG channel and further decrease IKr.36,37 Acquired LQTS is also observed in the setting of extreme bradycardia, in particular, bradycardia complicating acquired AV block (spontaneous or iatrogenic). In fact, the original description of torsade de pointes, the hallmark arrhythmia of the LQTS, was entirely based on patients with LQTS complicating atrioventricular block. It is important to note that QT prolongation in patients with complete AV block is more pronounced than that in response to similar degrees of sinus bradycardia, and it is the magnitude of this QT prolongation in response to bradycardia, rather than the bradycardia per se, that determines the risk of torsade de pointes. It has been proposed that a change in QRS morphology, commonly observed in the setting of complete AV block but not during SND, leads to T wave changes associated with cardiac memory, which contributes to excessive QT prolongation. In one report, patients who developed a change in QRS morphology at the time of AV block had a sevenfold higher incidence of torsades de pointes and a change in the QRS axis seemed to be associated with an even greater incidence. These observations suggest that repolarization changes influenced by cardiac memory play a role in arrhythmia risk during AV block. Also, premature beats that lead to short-long-short cycles can foster the development of torsade de pointes.10,38

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies By far, the most common environmental stressor resulting in acquired LQTS is drug therapy, including antiarrhythmic drugs, some antihistamines, antipsychotics, and antibiotics (www.qtdrugs.org). Noncardiovascular drugs that can potentially precipitate QT interval prolongation and arrhythmias comprise approximately 2% to 3% of total prescribed medications. Indeed, the risk of acquired LQTS is the most common cause of withdrawal or restriction of drugs that have already been marketed. For specific drugs, the incidence of torsade de pointes is difficult to quantify, and ranges from extremely low for many of the macrolide antibiotics, to 0.5% to 1% for drugs such as sotalol and azimilide, to 1.5% to 9% for quinidine.36,39 The vast majority of drugs associated with the acquired form of LQTS are known to interact with the hERG channel (which mediates IKr), likely because of unique structural properties rendering this channel unusually susceptible to blockade by a wide range of different drugs. Compared with other cardiac K+ channels, the hERG channel has a large, funnel-like vestibule that allows many small-sized molecules to enter and block the channel (see Chapter 2). The more spacious inner cavity is due to the lack of the Pro-X-Pro sequence motif in the S6 segment (which is present in most other voltage-gated K+ channels and is believed to induce a sharp bend in the inner S6 helices of voltage-gated K+ channels, reducing the inner vestibule), presumably facilitates access of drugs to the pore region from the intracellular side of the channel to block the channel current. In addition, the hERG channel contains two aromatic sites inside its pore (not present in most other K+ channels), which provide high-affinity binding sites for aromatic moieties of a wide range of structurally diverse compounds. Interaction of these compounds with the channel’s pore causes functional alteration of its biophysical properties, occlusion of the permeation pathway, or both. Other mechanisms underlying drug-induced LQTS have been recently described, including disruption of hERG channel protein trafficking, with consequent reduction of surface membrane expression of otherwise functional channels (e.g., pentamidine), or folding and assembly of channel subunits. The accessory β-subunit (MiRP1, KCNE2) of the hERG channel also determines the drug sensitivity.

Risk Factors of Drug-Induced Long QT Syndrome Several factors can potentially increase the susceptibility to drug-induced LQTS, including female gender (70% of patients with drug-induced torsades de pointes are women), advanced age, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, congestive heart failure, LV hypertrophy, recent conversion from AF, and the presence of QT interval prolongation on baseline ECG. Other risk factors include high drug doses (with the exception of quinidine), rapid IV infusion, and concurrent use of other drugs that prolong the QT interval or promote other QT-prolonging factors (such as bradycardia or electrolyte abnormalities). Also, conditions leading to accumulation of QT-prolonging drugs in plasma, such as from drug-drug interactions, are in general risk factors for torsades de pointes. These include the presence of renal or hepatic failure and the concomitant use of drugs that slow drug metabolism or impair drug excretion.10 In addition, genetically determined variability in pharmacodynamics (e.g., polymorphisms and mutations of the cytochrome system) can be responsible for significant variations in drug response. Most patients with drug-induced torsades de pointes have one or more risk factors.10,37,40 Hospitalized patients appear to be at greater risk of drug-induced QT interval prolongation and torsades de pointes than outpatients, likely due to a greater preponderance of risk factors, including structural heart disease, advanced age, electrolyte abnormalities, bradycardia, or renal or hepatic disease.41 A risk score was developed for predicting the risk of developing acquired LQTS in hospitalized patients in cardiac care units (Table 31.6). The risk score effectively distinguished hospital-

TABLE 31.6  Calculation of Risk Score for

QTc Interval Prolongation

Risk Factor Points Age ≥68 years Female sex Loop diuretic Serum potassium ≤3.5 mEq/L Admission QTc ≥450 msec Acute myocardial infarction ≥2 QTc-prolonging drugs Sepsis Heart failure One QTc-prolonging drug Maximum Risk Score

1 1 1 2 2 2 3 3 3 3 21

From Tisdale JE, Jaynes HA, Kingery JR, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes. 2016;6: 479–487.

ized patients at moderate or high risk for QTc interval prolongation from those at low risk. The occurrence of drug-induced torsades de pointes is an extremely rare event in patients without any risk factors. Over 90% of patients who develop torsades de pointes have at least one, and 71% of patients have at least two risk factors.42,43

Genetics Evidence suggests that drug-induced LQTS can represent a “forme fruste” of congenital LQTS in a significant proportion of patients, whereby drug challenge merely exposes the presence of the congenital form of the syndrome. This is likely related to a redundancy in repolarizing currents; normal repolarization is accomplished by multiple ion channels, providing a safety reserve for repolarization (the concept of “repolarization reserve”), which is genetically determined and compensates for any factor (e.g., drugs or genetic mutation) that might either decrease repolarizing or increase depolarizing currents during the action potential. As a result, a mutation or polymorphism in one of the LQTS genes can be clinically inapparent until another insult to repolarization, such as a drug, hypokalemia, or hypomagnesemia, is superimposed.36 Mutations of ion channel genes responsible for LQTS have been implicated as a risk factor. In fact, previously unrecognized congenital LQTS, of any subtype, can be identified in as many as 36% to 40% of drug-induced LQTS patients. In addition, polymorphisms (i.e., common genetic variations present in greater than 1% of the population) in cardiac ion channels can potentially increase the risk for the development of drug-induced torsades de pointes. In a recent study, druginduced LQTS patients had a greater burden of amino acid coding variants (missense, nonsynonymous, or frameshift), than the control subjects, suggesting that multiple rare variants, notably across congenital LQTS genes, predispose to drug-induced LQTS.44 In a large cohort of acquired LQTS subjects, the QTc interval remained prolonged (although to a milder degree than that observed in congenital LQTS carriers) in a significant proportion of patients even after the QT-prolonging factors are removed (withdrawal of culprit drugs or correction of serum electrolytes), suggesting that acquired LQTS could represent at least in part a latent genetic predisposition. Further, 28% of acquired LQTS subjects were found to harbor mutations in one of the major LQTS-related genes (most commonly in the KCNH2 gene). Even among the “true” acquired LQTS, i.e., those with normal QT interval outside the triggering episode, 23% had congenital LQTS-causing

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

TABLE 31.7  Predictors of the Probability

of Being Mutation Carriers in Acquired Long QT Syndrome Age, <40 vs. ≥40 years QTc, >440 vs. ≤440 msec Clinical status, symptomatic vs. asymptomatic

OR (95% CI)

P Value

2.5 (1.2–5.3) 5.2 (2.2–12.2) 10.6 (1.3–83.5)

0.020 <0.001 0.025

CI, Confidence interval; OR, odds ratio. From Itoh H, Crotti L, Aiba T, et al. The genetics underlying acquired long QT syndrome: impact for genetic screening. Eur Heart J. 2016; 37:1456–1464

mutations. Predictors for carrying a pathogenic mutation in acquired LQTS included (1) age less than 40 years, (2) baseline QTc interval exceeding 440 milliseconds, and (3) history of symptoms at the time of acquired LQTS diagnosis (Table 31.7). Of the acquired LQTS patients carrying a mutation, 88% had two or more of those predictors, while only 3% of patients with one or none of those risk factors had a mutation. Therefore some investigators have proposed genetic screening in acquired LQTS subjects with two or more of the risk factors to enable “cascade screening” in their family members and thereby prevent avoidable risks of life-threatening arrhythmias.45

Management First-line treatment approaches to torsades de pointes include removal of the offending causes, the use of IV magnesium, maintenance of high-normal serum K+ level, and avoidance of QT-prolonging agents. In some refractory cases, isoproterenol infusion or temporary transvenous overdrive pacing may be required to increase heart rate, which can shorten the QT interval and suppress torsades de pointes. Magnesium suppresses torsades de pointes without shortening the QT interval, presumably by suppressing the EADs that trigger torsades de pointes. EAD suppression by magnesium has been attributed to its Ca2+ channel–blocking effects but may also be mediated by a reduction of the late component of the sodium current (INaL). The value of acute K+ repletion is less well documented than that of IV magnesium for the acute treatment of drug-induced torsades de pointes. Normal levels of both potassium and magnesium should be maintained aggressively in hospitalized patients at risk.46 Recent studies suggested that mexiletine (a strong INaL blocker) may be an effective treatment for acute termination of torsades de pointes in several acquired causes of QT interval prolongation. Although torsades de pointes often responds to a lidocaine bolus, arrhythmias tend to recur despite continuous infusions. In contrast, ranolazine (an INaL blocker), flecainide (a strong INa blocker), and verapamil (a strong ICaL blocker) also block IKr, thus limiting their use in patients with druginduced LQTS.35 Of note, a recent report demonstrated potential benefit of oral progesterone for the prevention of drug-induced QT interval prolongation.18

Risk Stratification The clinical course in LQTS patients is not uniform and is influenced by many factors, including age, gender, genotype, environmental factors, therapy, and possibly other modifier genes.

Clinical Markers of Risk Syncope.  Nonfatal events (syncope and aborted cardiac arrest) in LQTS patients remain the strongest predictor of subsequent LQTS-

related fatal events, and the overall risk of subsequent SCD in an LQTS patient who has experienced a previous episode of syncope is approximately 5% per year. The risk of subsequent syncopal episodes can be reduced with betablocker therapy; however, patients experiencing syncope while receiving beta-blockers are at high risk of subsequent cardiac events, a risk similar to that observed in patients who are not treated with beta-blockers. Both the timing and frequency of syncopal events are related to the subsequent risk of cardiac events. Patients with recent (within the past 2 years) syncope and a higher number of syncopal events during this period carry a higher risk of subsequent cardiac events. However, it is important to distinguish between suspected arrhythmogenic and nonarrhythmogenic causes of syncope, especially given the fact that neurocardiogenic syncope is not uncommon in this patient population and its occurrence does not impact the prognosis negatively. A detailed clinical history in LQTS patients presenting with syncope is imperative, since clinical features (in particular, the occurrence of prodromes and the presence of specific triggers) can allow distinction between suspected arrhythmogenic and nonarrhythmogenic etiologies in a large proportion of cases. Family history.  The incomplete penetrance and variable expressivity in LQTS preclude predicting severity of symptoms in relatives of a symptomatic LQTS patient. In fact, SCD of a sibling (at any age) does not seem to contribute to increased personal risk of LQTS-related lifethreatening cardiac events. Instead, the risk of adverse events in relatives appears to be determined more by the individual’s own risk factors (QTc duration, personal history of syncope, and gender). Gender.  The effect of gender on outcome is age dependent, with boys exhibiting a significant (71% to 85%) increase in risk for syncope, aborted cardiac arrest, or SCD as compared with girls during childhood and early adolescence. However, a gender risk reversal occurs after age 14 years, in which girls exhibit an 87% increase in the risk of cardiac events compared with boys among probands and a 3.3-fold increase in the risk among affected family members. When only life-threatening cardiac events (aborted cardiac arrest or SCD) are considered, the onset of gender risk reversal occurs at a later age. The cumulative probability of a first life-threatening cardiac event from age 1 to 12 years is 5% in boys compared with only 1% among girls, whereas in the age range of 12 to 20 years, there is no significant gender difference in risk. Risk reversal for the endpoint of aborted cardiac arrest or SCD occurs after the age of 20 years, and women maintain higher risk than men throughout adulthood. Importantly, the effect of gender on outcome appears to be genotype dependent. Among those younger than 15 years, male LQT1 patients exhibit the highest risk of cardiac events; female LQT1 patients had intermediate risk; and both male and female LQT2 patients had the lowest risk. No significant gender-related difference in risk was shown among LQT2 and LQT3 children. In contrast, in the 15- through 40-yearold age group, the risk is highest among LQT2 women, intermediate among LQT1 women, and lowest among LQT1 and LQT2 men.19 Age.  Risk factors in LQTS are time dependent and age specific (Table 31.8). LQTS patients who experience an aborted cardiac arrest during the first year of life are at a very high risk for subsequent lifethreatening cardiac events during the first decade of life. The risk factors for a cardiac event in LQTS infants also include a QTc of at least 500 milliseconds, a heart rate not exceeding 100 beats/min, and female gender. In LQTS children, risk factors for life-threatening cardiac events include male gender, a history of syncope at any time during childhood, and a QTc duration greater than 500 milliseconds. Among adolescent patients with suspected LQTS, recent episodes of syncope (in particular within the past 2 years) and QTc greater than

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

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TABLE 31.8  Age-Specific Risk Factors for Life-Threatening Cardiac Events in Long QT

Syndrome Patientsa Age Group

Risk Factor

Childhood (1–12 years)

Male gender QTc >500 msec Prior syncope   Recent (>2 years)   Remote (≥2 years) QTc >530 msec Syncope   ≥2 syncopal events in past 2 years   1 syncopal event in past 2 years   ≥2 syncopal events in past 2–10 years   1 syncopal events in past 2–10 years Female gender QTc duration  QTc ≥500 msec  QTc = 500–549 msec Prior syncope Recent syncope (<2 years) QTc > 530 msec LQT3 genotype

Adolescence (10–20 years)

Adulthood (18–40 years)

Adulthood (41–60 years)b

Hazard Ratio (P Value) 3.96 (<0.001) 2.12 (0.02)

Beta-Blocker Efficacy, % Reduction (P Value) 73% (0.002)

14.34 (<0.001) 6.45 (<0.001) 2.3 (<0.001)

64% (0.01)

18.1 (<0.001) 11.7 (<0.001) 5.8 (<0.001) 2.7 (<0.001) 2.68 (<0.05)

60% (<0.01)

6.35 (<0.01) 3.34 (<0.01) 5.10 (<0.01) 9.92 (<0.001) 1.68 (0.06) 4.76 (0.02)

42% (0.40)c

a

Findings are from separate multivariable Cox models in each age group for the endpoint of aborted cardiac arrest or sudden cardiac death. Because long QT syndrome (LQTS)–related events are more difficult to delineate in the older age group, the endpoint in the 41- to 60-year-old age group comprised aborted cardiac arrest or death from any cause. c Lack of a statistically significant beta-blocker effect in this age group may relate to the broad endpoint of death from any cause. QTc, Corrected QT interval. From Goldenberg I, Moss AJ. Long QT syndrome. J Am Coll Cardiol. 2008;51:2291–2300. b

530 milliseconds predict increased risk of LQTS-related cardiac events. Although LQT1 genotype predicts higher risk in patients not more than 14 years of age (especially boys), the risk is higher for LQT2 in patients 15 years of age or older (especially women). In adult patients, predictors of worse outcome include a QTc greater than 500 milliseconds, female gender, and history of syncope before age 18 years. In addition, patients with LQT2 mutations appear to be at a greater risk for a cardiac event than patients with LQT1 or LQT3 genotypes. Beyond 40 years of age, recent syncope (within the past 2 years) appears to be the predominant risk factor in affected subjects, and those with a positive mutation had a significantly higher mortality, particularly those with an LQT3 mutation. Furthermore, women with a QTc greater than 470 milliseconds are at a higher risk of LQTS-related cardiac events, whereas in men, event rates are similar in the various QTc categories. After the age of 60 years, the risk of death due to LQTS competes with other disease entities that may lead to death.

Electrocardiographic Markers of Risk QT interval prolongation.  The QTc interval is the best prognostic ECG parameter in LQTS families. A QTc interval of at least 470 milliseconds is a predictor for increased risk for symptoms, whereas a QTc of at least 500 milliseconds predicts an increased risk of life-threatening cardiac events. Although there is no threshold of QTc prolongation at which torsades de pointes is certain to occur, a gradual increase in risk for torsades de pointes is observed as the QTc interval increases. Each 10-millisecond increase in QTc contributes approximately a 5% to 7% additional increase in risk for torsades de pointes. Therefore a patient with a QTc of 540 milliseconds has a 63% to 97% higher risk of

developing torsades de pointes than a patient with a QTc of 440 milliseconds. Importantly, considerable time-dependent variability and instability of ventricular repolarization exist in LQTS. Thus risk stratification should take into account the risk associated with variability in the duration of the QTc interval in the individual LQTS patient during follow-up. In fact, it has been shown that the maximum QTc duration measured at any time before age 10 was the most powerful predictor of cardiac events during adolescence, regardless of baseline, mean, or most recent QTc values. Furthermore, a considerable variability in the duration of the QTc interval exists among LQTS patients with identical mutations. Evidence suggests that mutation-specific QTc variability (defined as QTc standard deviation [QTcSD] among all carriers of a specific mutation) provide incremental prognostic information for risk stratification that is independent of those related to the individual’s own QTc. A greater degree of repolarization instability associated with specific LQTS mutations (manifesting as a high mutation-specific QTcSD) was identified as an independent risk predictor even in high-risk patients with long QTc durations. It has been reported that every 20-millisecond increment in mutation-specific QTcSD resulted in a 33% increased risk for cardiac events after adjustment for the patient-specific QTc, and patients who had mutations with QTcSD of 45 milliseconds or more experienced a significant 48% increase in the risk of cardiac events compared with patients who had mutations with QTcSD less than 45 milliseconds. These findings emphasize the importance of checking mutation-specific effects in various genetic backgrounds to identify mutations that are more susceptible to intrinsic or extrinsic modifying factors. It is important to note that the prognostic implications of QTcSD appear to be

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

genotype specific; the risk associated with a higher QTcSD was pronounced among patients with LQT1, whereas in patients with LQT2, no significant association of QTcSD with cardiac events was found.47 T-U wave morphology.  The ratio of the amplitude of the U wave to that of the T wave has been suggested as the clinical counterpart of EADs; a progressive increase in the ratio of the U wave to the T wave preceded the onset of torsades de pointes in an experimental model of LQTS. In addition, the increment in U wave amplitude after a PVC has been suggested as a marker for arrhythmia risk in “pausedependent” LQTS. In patients with bifid T waves, the diurnal maximal ratio between late and early T wave peak amplitude was found to correlate with a history of LQTS-related symptoms better than the baseline QTc interval in both LQT1 and LQT2 patients, and can potentially be used to assess the risk of symptoms in asymptomatic patients with known type 1 or 2 LQTS genotype. In LQT1 patients, a ratio of at least three suggests a high probability of being symptomatic whereas a ratio not exceeding two suggests a low probability. Among LQT2 patients, ratios suggestive of being symptomatic or asymptomatic are, respectively, at least 2.4 and not more than 1.5. Of note, the presence of macroscopic T wave alternans (bidirectional beat-to-beat changes in T wave polarity) indicates electrical instability and high acute risk of ventricular arrhythmias.

Genetic Markers of Risk The genotype is an important predictor of LQTS-related cardiac events. The risk of cardiac events has been shown to be significantly higher in LQT1 and LQT2 when compared with LQT3, with events occurring at a younger age. The cumulative mortality, however, appears to be similar regardless of the genotype, since patients with LQT3 develop arrhythmias less often, but these are more likely to be lethal when they ultimately occur. LQT1 patients exhibit a 49% increase in the risk of cardiac events as compared with LQT2 patients. However, in the 15- through 40-yearold age group, the risk of a first cardiac event is significantly higher among LQT2 patients (67% increase in the risk as compared with LQT1 patients). Among LQTS patients receiving beta-blocker therapy, the LQT2 and LQT3 genotypes are associated with increased risk of arrhythmic events as compared with LQT1. In addition to identifying the LQT genotype, knowing the specific mutation and its biophysical function can help improve risk stratification. For LQT1, patients with mutations in the transmembrane domain of the KCNQ1 channel had more frequent cardiac events (syncope, aborted cardiac arrest, or SCD) and a greater risk of the first cardiac event occurring at a younger age than did patients with C-terminal mutations. For LQT2, pore mutations have a more severe clinical course and a higher frequency of arrhythmic events occurring at a younger age when compared with nonpore mutations. In particular, missense mutations in the transmembrane pore (S5-loop-S6) region appear to be associated with the highest risk of clinical arrhythmia. Preliminary data for LQT3 patients also suggest that the location and biophysical function of the mutation can play a role in determining the severity of the clinical phenotype. Mutations with a dominantnegative effect on ion channel function (greater than 50% reduction in function) have a more severe phenotype compared with mutations exhibiting haploinsufficiency (less than or equal to 50% reduction in function). Jervell and Lange-Nielsen syndrome and the Timothy syndromes (LQT8) have a highly malignant course with poor prognosis, and are less likely to respond to beta-blocker therapy alone. In contrast, the Andersen-Tawil syndrome has a generally more benign clinical course in terms of arrhythmic death.

The presence of multiple mutations (the so-called “double hits,” observed in 8% to 11% of patients with LQTS) is associated with a significantly higher risk for life-threatening cardiac events as compared with patients with a single mutation. Also, among patients with multiple mutations, a double hit in a single gene (compound heterozygosity) was associated with a greater risk for life-threatening cardiac events than a double hit in different genes (digenic heterozygosity).48,49

Principles of Management The main therapeutic modalities for the prevention of life-threatening cardiac events include beta-blockers, left (sometimes bilateral) cervicothoracic sympathetic denervation, and implantable cardioverterdefibrillator (ICD) implantation. In nongenotyped patients, beta-blockers comprise the mainstay therapy, whereas cervicothoracic sympathetic denervation and ICD implantation are therapeutic options in high-risk LQTS patients who experience recurrent cardiac events despite betablocker therapy (Table 31.9). Renal sympathetic denervation may play a future role.

Pharmacological Therapy Treatment with beta-blockers is associated with a significant (53% to 64%) reduction in risk of LQTS-related life-threatening events (syncope, cardiac arrest, and SCD), regardless of age (see Table 31.8). The benefit appears to be most substantial in patients at highest risk for cardiac events. On the other hand, very low-risk patients (no history of syncope, QTc less than 500 milliseconds, girls younger than 14 years, LQT2 men of any age, and LQT1 women older than 14 years) have such a small frequency of events that beta-blockers may not provide a substantial benefit.50 Genetic data can be used to guide the therapeutic management plan. Given the critical role of catecholamines in precipitating arrhythmias in LQT1, beta-blocker therapy is particularly effective for this group of patients; approximately 90% of LQT1 patients treated with beta-blockers remained free from syncope and cardiac arrest after a mean follow-up time of 5.4 years and showed a total mortality rate of 1%. Although beta-blockers were generally considered to have lower efficacy in LQT2 patients as compared with LQT1 patients, recent data argue for a similar magnitude of risk reduction in LQT2 patients (beta-blocker therapy decreased cardiac events from 58% to 23% after an average follow-up of 4.9 years on therapy). The higher residual event rate in LQT2 patients while receiving beta-blocker therapy is likely due to a higher overall event rate in patients with this genotype, rather than to an attenuated efficacy of medical therapy in this high-risk population. Of note, a trigger-specific response to beta-blocker therapy exists within the LQT2 population; beta-blockers appear to be more protective against exercisetriggered cardiac events than arousal- or non–exercise-related events (see Fig. 31.3). On the other hand, the value of beta-blocker therapy in LQT3 patients is debated. These patients continue to experience high rates of cardiac events despite beta-blocker therapy. Among LQT3 patients receiving beta-blocker therapy, the adjusted risk for a cardiac event is fourfold higher than among LQT1 patients. However, when excluding LQT3 patients with the most severe phenotype (i.e., patients who had suffered a cardiac event during infancy and those with QTc greater than 600 milliseconds), beta-blocker therapy appears to be beneficial in LQT3. It is important to note, however, that prolongation of the QT intervals is aggravated at slow heart rates; thus a reduction in heart rate with beta-blockers can potentially pose a therapeutic problem in these patients.19 Currently, beta-blockers are considered the mainstay therapy for the prevention of life-threatening cardiac events and, given the approximately 12% risk of SCD as the first manifestation of LQTS, they should

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

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TABLE 31.9  Expert Consensus Recommendations on Long QT Syndrome (LQTS) Therapeutic Interventions Class I

Class IIa

Class III

1. The following lifestyle changes are recommended in all patients with a diagnosis of LQTS: a. Avoidance of QT-prolonging drugs (www.qtdrugs.org) b. Identification and correction of electrolyte abnormalities that may occur during diarrhea, vomiting, metabolic conditions, or imbalanced diets for weight loss. 2. Beta-blockers are recommended for patients with a diagnosis of LQTS who are: a. Asymptomatic with QTc ≥470 msec and/or b. Symptomatic for syncope or documented ventricular tachycardia/ventricular fibrillation (VT/VF). 3. Left cardiac sympathetic denervation (LCSD) is recommended for high-risk patients with a diagnosis of LQTS in whom: a. Implantable cardioverter-defibrillator (ICD) therapy is contraindicated or refused and/or b. Beta-blockers are not effective in preventing syncope/arrhythmias, not tolerated, not accepted, or contraindicated. 4. ICD implantation is recommended for patients with a diagnosis of LQTS who are survivors of a cardiac arrest. 5. All LQTS patients who wish to engage in competitive sports should be referred to a clinical expert for evaluation of risk. 6. Beta-blockers can be useful in patients with a diagnosis of LQTS who are asymptomatic with QTc ≤470 msec. 7. ICD implantation can be useful in patients with a diagnosis of LQTS who experience recurrent syncopal events while on beta-blocker therapy. 8. LCSD can be useful in patients with a diagnosis of LQTS who experience breakthrough events while on therapy with beta-blockers/ICD. 9. Sodium channel blockers can be useful, as add-on therapy, for LQT3 patients with a QTc >500 msec who shorten their QTc by >40 msec following an acute oral drug test with one of these compounds. 10. Except under special circumstances, ICD implantation is not indicated in asymptomatic LQTS patients who have not been tried on beta-blocker therapy.

From Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm. 2013;10:1932–1963.

be considered the first-line measure in all nongenotyped patients and in patients with LQT1 or LQT2 genotypes, regardless of their symptomatic or risk status (Fig. 31.7). Possible exceptions could include very low-risk LQTS patients (based on clinical and ECG parameters) in whom beta-blocker therapy may be considered on an individual basis. That said, it is important to understand that all these recommendations are based on observational studies and not randomized clinical trials. Propranolol and nadolol are the beta-blockers most widely used. Limited data exist regarding the effectiveness of other beta-blockers in preventing cardiac events in patients with LQTS, although some evidence suggests the superiority of nadolol and propranolol as compared to metoprolol in LQT1 and LQT2 patients. Long-acting medications are preferred to improve compliance and avoid of wide fluctuations in blood levels. The nonselective beta-blocker nadolol (which has strong negative chronotropic effect and long half-life [20 to 24 hours]) is the most preferred first-choice therapy in patients with LQTS. Propranolol is probably the preferred beta-blocker in LQT3 patients, given its direct late Na+ current blocking properties.32,51 The protective effect of beta-blockers is related to their adrenergic blockade, which diminishes the risk of cardiac arrhythmias; hence, the goal of beta-blocker therapy is to blunt the maximal heart rate during exercise, and the adequacy of beta-blockade should be assessed by exercise testing or ambulatory monitoring. It is recommended to start at a low dose and slowly up-titrate the dose (over several weeks, especially in asymptomatic patients) to help improve patient tolerance and compliance, which can potentially lead to otherwise unnecessary ICD implantation. Of note, beta-blockers do not substantially shorten the QT interval.1,52,53 Despite the beneficial effects of beta-blockers, a high rate of residual cardiac events has been reported in patients receiving beta-blocker therapy, occurring in 10%, 23%, and 32% of LQT1, LQT2, and LQT3 patients, respectively, after a mean follow-up time of 5.4 years. Therefore

patients who remain symptomatic despite treatment with beta-blockers should be considered for other therapeutic modalities. Interestingly, it has been reported that noncompliance is an important cause of events occurring during beta-blocker treatment in LQT1 patients.

Implantable Cardioverter-Defibrillator ICD therapy is highly effective to prevent SCD in high-risk LQTS patients (mortality of 1.3% in high-risk ICD patients compared with 16% in non-ICD patients during a mean follow-up time of 8 years). Therefore ICD implantation should be considered for secondary prevention in patients with prior cardiac arrest and for primary prevention in those who experience unexplained syncope or ventricular tachyarrhythmias while receiving beta-blocker therapy (Fig. 31.8).53 Although prophylactic ICD therapy used to be considered for LQTS patients with risk factors for SCD (see Table 31.8) regardless of medical therapy, recent data suggest that high-risk LQT1 and LQT2 patients should be considered for prophylactic ICD implantation only if they develop recurrent cardiac events (e.g., syncope or torsades de pointes) despite beta-blocker therapy or when compliance with or intolerance to medical therapy is a concern. Using this approach, most patients with LQTS do not need an ICD. Clear understanding by the patient and family of the relative merits of each strategy is essential. Although betablocker therapy significantly reduces the risk of SCD in this population, it is not completely protective, and residual cardiac events still occur. On the other hand, data suggest that syncopal episodes almost always precede cardiac arrest in patients receiving beta-blockers, allowing for institution of other therapeutic modalities, such as ICD implantation. In addition, ICD therapy is not without complications; infection, lead malfunction, inappropriate shocks, psychological sequelae, as well as the need for periodic device or lead revisions, have to be taken into consideration. This is especially important in children and young adults in whom the initial decision to implant an ICD carries decades-long implications, such as multiple procedures for generator replacements

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

Bidirectional VT

VF/PMVT

Early repolarization syndrome

Brugada syndrome

Assess QT interval and ST segment

Short QT syndrome

Correct precipitants

Consider CPVT

Normal QT interval and ST deviation

Long QT interval and nonischemic ST segment

Consider ischemia

Isoproterenol in acquired LQT

Isoproterenol

Idiopathic VF Quinidine No No

Beta-blocker in congenital Long QT Syndrome 1 and 2

Beta-blocker, Flecainide, Sedation

LQTS

Yes Consider coronary angiography

CPVT

Correct electrolytes, magnesium

Consider cardiomyopathy Yes

Revascularize, lidocaine, amiodarone

Amiodarone

Consider pacing

Fig. 31.7  An Algorithm for Acute Pharmacological Treatment of Arrhythmias in Suspected Channelopathies. CPVT, Catecholaminergic polymorphic ventricular tachycardia; LQTS, long QT syndrome; PMVT, polymorphic ventricular tachycardia; VF, ventricular fibrillation. (From Obeyesekere MN, Antzelevitch C, Krahn AD. Management of ventricular arrhythmias in suspected channelopathies. Circ Arrhythmia Electrophysiol. 2015;8:221–231.)

Legend Class I

Prior cardiac arrest?

Yes

ICD recommended

Recurrent syncope while on betablockers?

Yes

ICD can be useful

Asymptomatic not treated with betablockers

Yes

ICD is not indicateda

Class IIa Class IIb Class III

No

a

Except under special circumstances, ICD implantation is not indicated in asymptomatic patients who have not been tried on beta-blocker therapy.

Fig. 31.8  Consensus Recommendations for Implantable Cardioverter-Defibrillators (ICDs) in Patients Diagnosed With Long QT Syndrome. (From Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/ APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm. 2013;10:1932–1963.)

and lead extractions, increasing the lifetime risks of morbidity and mortality.53 Because ICD therapy does not prevent the occurrence of arrhythmias, concurrent treatment with beta-blockers is recommended for symptomatic and high-risk patients. Furthermore, careful programming of the ICD arrhythmia detection settings is recommended to reduce the risk of inappropriate shocks. This usually involves programming a single VF zone of more than 220 beats/min with or without a monitoring zone of more than 180 beats/min.1 The European registry of 233 LQTS patients with ICDs showed that 28% received appropriate ICD therapies, and that future appropriate ICD therapies could be predicted by four variables: (1) age younger than 20 years at implantation; (2) QTc greater than 500 milliseconds; (3) prior cardiac arrest; and (4) cardiac events despite therapy. The M-FACT scoring system (Table 31.10), based on those clinical variables, was developed to identify in advance those patients with the highest and lowest probability of receiving appropriate shocks, which might represent the justification for the ICD implantation. Within 7 years, appropriate ICD therapies did not occur in any patients who had none of these factors and did occur in 70% of patients with all four clinical factors. Patients with an M-FACT score of 0 are unlikely to benefit from ICD implantation.32,54 In addition, prophylactic ICD therapy should be considered in veryhigh-risk patients, including symptomatic patients with two or more gene mutations, including those with the Jervell and Lange-Nielsen syndrome variant with congenital deafness.1

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

TABLE 31.10 M-FACTa Risk Score Points Event-free on therapy for >10 years QTc 501–550 msec >550 msec Age at implantation ≤20 years Prior aborted cardiac arrest Events on therapy

−1 1 2 1 1 1

a

Acronym derived from M (minus 1 point for being free of cardiac events while on therapy for >10 years), F (500- and 550-msec QTc), A (age ≤20 years at implantation), C (cardiac arrest), and T (events on therapy).

Left Cervicothoracic Sympathectomy Left cervicothoracic sympathectomy, which involves resection of the lower half of the left stellate ganglion and the first two to four thoracic ganglia (T1–T4), is another antiadrenergic therapeutic option for patients with LQTS. Care must be taken to not damage the top half of the ganglia to avoid Horner syndrome. Currently, left cervicothoracic sympathectomy is recommended for the management of high-risk LQTS patients in whom drug therapy may not be sufficiently protective when ICD therapy is refused or not feasible (e.g., small infants) and when beta-blockers are not effective, not tolerated, or contraindicated.1,32 Although cardiac sympathetic denervation provides a significant long-term reduction in the frequency of aborted cardiac arrest and syncope (more effective in patients with LQT1 than in those with other types of LQTS), it is not completely protective against SCD. Studies of LQTS patients who have undergone left cervicothoracic sympathectomy demonstrated a residual mortality rate of 5% at 5 years. Furthermore, about 50% of high-risk LQTS patients have experienced one or more cardiac events, and patients with extremely malignant LQTS might not be responsive to cardiac sympathetic denervation. Hence, left cervicothoracic sympathectomy must not be viewed as curative or as an ICD alternative for high-risk patients.55 Importantly, postoperative morbidity is common in patients undergoing left cervicothoracic sympathectomy. A large proportion of patients experience left-sided dryness, unilateral facial flush with exercise, contralateral hyperhidrosis, differential hand temperatures, transient and permanent ptosis, and left arm paresthesia. Nonetheless, postoperative satisfaction is generally high and patients feel safer following the procedure, despite the side effects.56,57

Permanent Pacemaker Cardiac pacing, in conjunction with beta-blocker therapy, can potentially reduce the risk of bradycardia-dependent QT prolongation, decrease heart-rate irregularities (eliminating short-long-short sequences), and reduce repolarization heterogeneity. Permanent pacemakers can be of value, especially in patients who continue to be symptomatic despite beta-blocker therapy or those in whom bradycardia or AV block limits the use of such therapy. In particular, patients with documented pauseor bradycardia-induced torsades de pointes and those with the LQT3 genotype may derive significant benefit from cardiac pacing.58 Nevertheless, the high mortality in patients with recurrent symptoms (syncope or torsades de pointes) while receiving beta-blocker therapy is not adequately attenuated by the addition of cardiac pacing. Therefore

999

if cardiac pacing is being considered, the use of an ICD is more logical because it provides protection from SCD as well as the benefit of cardiac pacing. However, when ICD implantation is associated with an extremely high rate of adverse events (such as in small infants), an atrial pacemaker in combination with beta-blocker therapy can potentially serve as a bridge to ICD placement.58 When cardiac pacing is employed, atrial pacing is preferred, at a rate that shortens the QTc to less than 440 milliseconds. It is recommended to minimize ventricular pacing as possible because it can potentially increase the heterogeneity of ventricular repolarization. However, in patients with AV block, ventricular pacing is important to maintain AV synchrony and elimination of ventricular pauses and longshort cycles.

Catheter Ablation In LQTS patients, frequent episodes of torsades de pointes are occasionally triggered by focal, monomorphic PVCs. In this setting, catheter ablation of the focus of the PVCs can be valuable in reducing the burden of arrhythmias and the frequency of ICD therapies.

Lifestyle Modifications Education and lifestyle changes for the prevention of arrhythmias are critical in patients with LQTS. Patients should avoid drugs that prolong the QT interval (www.qtdrugs.org) or reduce their serum potassium or magnesium levels, and they should consult with their physician before taking any medications or over-the-counter supplements. Furthermore, patients need to be educated on conditions that can lead to potentially dangerous electrolyte abnormalities (e.g., dehydration, diarrhea, vomiting, imbalanced diets for weight loss).1 In addition, the importance of compliance with medical therapy should be emphasized. Beta-blocker noncompliance and use of QTprolonging drugs account for the vast majority of life-threatening events in LQT1 patients. Preventive measures in LQTS patients in general and LQT2 patients in particular include avoidance of unexpected auditory stimuli (such as alarm clocks, doorbells, and telephones), especially during rest or sleep. Families with LQTS may also consider basic life support training and operation of an automated external defibrillator.

Participation in Sports Physical activity and stress-related emotions frequently trigger cardiac events in patients with LQTS, especially patients with LQT1 or LQT2. Therefore all competitive sports (except those in the class IA category, such as billiards, bowling, cricket, and golf) should be restricted in symptomatic LQTS patients (regardless of the QTc duration or underlying genotype) as well as asymptomatic patients with baseline QT prolongation (QTc greater than or equal to 470 milliseconds in men, greater than or equal to 480 milliseconds in women). Swimming is particularly hazardous in LQT1 patients and should therefore be limited or performed under appropriate supervision, even in subjects with genotypepositive/phenotype-negative LQT1. Because many first cardiac events occur before the age of 15 years in male patients, particularly those with the LQT1 genotype, whereas female patients may experience first cardiac events after the age of 20 years, LQT1 male patients require stricter exercise restriction before the age of 15. Recent data suggests that sports participation is safer than previously recognized, and the restriction limiting participation to class IA activities may be liberalized for the asymptomatic patient with genetically proven LQT3 genotype and those with genotype-positive/phenotypenegative LQTS (especially patients genotyped as non-LQT1 and no family history of multiple SCDs), assuming that appropriate disease-specific

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

treatments are in place. In addition, automated external defibrillators and personnel trained in basic life support should be readily available. Furthermore, precautionary measures should be undertaken to avoid exercise-related dehydration, heat exhaustion, and electrolyte abnormalities.1,59 Sports participation may also be carefully considered in LQTS patients with QT prolongation and those rendered asymptomatic after institution of treatment. These decisions, however, should be deliberated carefully by an LQTS expert to ensure that the athletes and their family members have been well informed, well risk stratified, and well treated.60 Other considerations include the acquisition of a personal automatic external defibrillator as part of the athlete’s personal sports safety gear, and establishment of an emergency action plan with the appropriate training facility and team officials.

Gene-Specific Therapy The standard therapeutic options for LQTS (including beta-blockers, cardiac sympathetic denervation, ICD) rely on genotype to only a minor degree, yet are quite effective. Nevertheless, beta-blockers and left cervicothoracic sympathectomy have some degree of genotype specificity, being quite effective in LQT1 and LQT2 and less effective in LQT3. Similarly, lifestyle modification and exercise restriction are most helpful in LQT1 and LQT2. For practical purposes, however, this apparent genotype specificity influences therapy decisions in only a very small number of patients. Several gene-specific LQTS therapies are being evaluated, including Na+ channel blockers, K+ channel activators, alpha-adrenergic receptor blockers, protein-kinase inhibitors, and atropine. However, current experience with these drugs is limited. LQT3.  Currently, LQT3 is the only LQTS variant for which a genespecific therapy is recommended by current guidelines (see Table 31.9). Given the fact that augmentation of the late Na+ inward current (INaL) underlies the prolongation of the QT interval in patients with the LQT3 genotype, Na+ channel blockers have been successfully used in these patients. Mexiletine, a class IB Na+ channel blocker, was shown to shorten the QT interval and reduce the occurrence of arrhythmic events in LQT3 patients.61 Until prospective clinical trials confirm the effectiveness of mexiletine, it should be used in LQT3 patients with a QTc exceeding 500 milliseconds only in conjunction with beta-blockers or with the backup of an ICD. In addition, some investigators recommend testing the effectiveness of mexiletine by the administration of half the daily dose during continuous ECG monitoring. Only if the QTc is shortened by more than 40 milliseconds within 90 minutes of drug administration (when the peak plasma concentration is reached) should mexiletine be added to beta-blocker therapy. Flecainide, a class IC Na+ channel blocker, was shown to shorten the QT interval in LQT3 patients with a specific mutation (D1790G) in the SCN5A gene. However, flecainide is reported to elicit a Brugada phenotype in some LQT3 patients; therefore this drug should not be used in LQT3 patients except for those with this specific SCN5A mutation. The antianginal agent ranolazine has unique EP properties. Unlike other Na+ channel blockers, which reduce both the early (peak) and late components of the Na+ current (INa and INaL, respectively), ranolazine preferentially reduces INaL. Moreover, ranolazine reduces Ca2+ overload of myocardial cells and suppresses EAD-triggered arrhythmias in animal models of LQT3. Ranolazine was shown to shorten the QT interval without widening the QRS complex in LQT3 patients, and can potentially offer a therapeutic benefit in these patients.62 LQT2.  Potassium supplements can be of value, especially in LQT2 patients, who are particularly sensitive to low K+ levels because the

conductance of KCNH2 channels is directly related to extracellular K+ concentrations. Therefore efforts should be made to maintain a serum K+ level greater than 4 mEq/L in patients with this genotype. Acute treatment with IV potassium can be effective in suppressing torsades de pointes. Furthermore, long-term oral potassium supplements, even in patients with normal K+ levels at baseline, can potentially reduce repolarization abnormalities in LQT2. Increasing extracellular K+ concentrations enhances IKr, at least partially compensates for the loss of IKr in LQT2, and can potentially limit the development of an arrhythmogenic substrate under long QT conditions. Whether these effects translate into clinical benefit in reduction of the risk of cardiac events remains to be proven.

Family Screening Timely (often presymptomatic) identification of disease carriers is important because preventive measures and therapies can effectively avert SCD. Therefore when a patient is diagnosed with LQTS, ECGs should be obtained on all first-degree family members (i.e., parents, siblings, offspring) to determine whether others are affected. Unexplained sudden death in a young individual should trigger a similar evaluation to determine if LQTS is present in the family. When the causal mutation has been identified in the proband, firstdegree relatives should be offered genetic screening, even those with a negative clinical and ECG phenotype. Genotyping of family members can help exclude the diagnosis in some persons, and identify silent mutation carriers and allow prophylactic treatment. However, detailed genetic counseling is warranted before proceeding to this testing, particularly for asymptomatic persons for whom the option of not testing must also be recognized.

BRUGADA SYNDROME The Brugada syndrome is an autosomal dominant inherited channelopathy characterized by typical ECG changes (ST segment elevation or J waves) in the right precordial leads. Described in 1992, the syndrome is associated with a high incidence of SCD secondary to polymorphic VT or VF in the absence of structural heart disease.63

Genetics of the Brugada Syndrome The Brugada syndrome is a channelopathy that causes current dysfunction in multiple channels participating in the generation of the cardiac action potential. To date, mutations in 19 genes have been identified as associated with the Brugada phenotype (Table 31.11) with an autosomal dominant mode of transmission. These include genes related to the Na+ current (INa) and genes that affect L-type Ca2+ channels (ICaL) or transient outward K+ channels (Ito). These channelopathies cause Brugada syndrome phenotype by attenuating INa, attenuating ICaL, or enhancing Ito, resulting in an outward shift in the balance of current active during the early phases of the action potential in the right ventricular outflow tract (RVOT). The relationships between genotype and phenotype are not always predictive. Mutations in different genes can express similar Brugada syndrome phenotypes. Conversely, mutations in the same gene can lead to different syndromes.64,65 More than 65% of Brugada syndrome probands remain genetically undetermined, which suggests that unknown mutations or pathophysiological cellular regulations (such as posttranslational modulations, phosphorylation, glycosylation) may also cause similar ion current defects and clinical manifestations.66

Mutations Related to the Sodium Current Most cases of the Brugada syndrome are attributable to loss-of-function mutations in the cardiac Na+ channel resulting in a reduction of the

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

TABLE 31.11  Molecular Basis of the

Brugada Syndrome Gene

Protein

BrS1 BrS2 BrS3 BrS4 BrS5 BrS6 BrS7 BrS8 BrS9 BrS10 BrS11

SCN5A GPD1L CACNA1C CACNB2B SCN1B KCNE3 SCN3B KCNJ8 CACNA2D1 KCND3 RANGRF

BrS12

SLAMP

BrS13 BrS14 BrS15 BrS16 BrS17 BrS18 BrS19

ABCC9 SCN2B PKP2 FGF12 SCN10A HEY2 SEMA3A

Nav1.5 G3PD1L Cav1.2 Cavβ2 Navβ1 MiRP2 Navβ3 Kir6.1 Cavα2δ1 Kv4.3 MOG1, Nav1.5 cofactor Sarcolemmalassociated protein SUR2A Navβ2 Plakophillin-2 FHF-1 Nav1.8 Transcriptional factor Semaphorin

Functional Effect

% of Probands

↓ INa ↓ INa ↓ ICaL ↓ ICaL ↓ INa ↑ Ito ↓ INa ↑ IKATP ↓ ICaL ↑ Ito ↓ INa

11%–28% Rare 6.6% 4.8% 1.1% Rare Rare 2% 1.8% Rare Rare

↓ INa

Rare

↑ IKATP ↓ INa ↓ INa ↓ INa ↓ INa ↑ INa ↑ Ito

Rare Rare Rare Rare 5%–16.7% Rare Rare

BrS, Brugada syndrome; FHF-1, fibroblast growth factor homologous factor-1; ICaL, L-type Ca2+ current; IKACh, acetylcholine-activated inward rectifier K+ current; IKs, slowly activating delayed rectifier K+ current; INa, Na+ current; Ito, transient outward K+ current. Modified from Antzelevitch C, Yan GX, Ackerman MJ, et al. J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge. Heart Rhythm. 2016;13:e295–e324.

inward Na+ current (INa). INa initiates the ventricular action potential, thereby controlling cardiac excitability and electric conduction velocity. SCN5A is the first gene to be linked to Brugada syndrome. Loss-offunction mutations in the SCN5A gene (encoding the α subunit of the cardiac voltage-gated Na+ channel [Nav1.5]) account for the vast majority (greater than 75%) of genotype-positive Brugada syndrome cases (but only 11% to 28% of total Brugada syndrome probands). A higher incidence of SCN5A mutations has been reported in familial than in sporadic cases.66,67 So far, more than 300 Brugada syndrome-associated mutations have been described in the SCN5A gene. Some of these mutations result in loss of function due to impaired channel trafficking to the cell membrane, disrupted ion conductance, or altered gating function. Most of the mutations are missense mutations, whereby a single amino acid is replaced by a different amino acid. Missense mutations commonly alter the gating properties of mutant channels. Because virtually all reported SCN5A mutation carriers are heterozygous, mutant channels with altered gating can result in an up to 50% reduction of INa. Different SCN5A mutations can cause different degrees of INa reduction and, hence, different levels of severity of the clinical phenotype of the Brugada syndrome.66 SCN5A loss-of-function mutations have also been linked to patients with progressive cardiac conduction system disease (Lev-Lenègre disease). Mutated SCN5A can also impede the closure (gain of function) of the Na+ channel, leading to type 3 LQTS (LQT3). It was reported that all three syndromes (Brugada syndrome, LQT3, and Lev-Lenègre disease)

1001

occurred within a single family because of a single mutated SCN5A gene. Approximately 65% of mutations identified in the SCN5A gene are associated with the Brugada syndrome phenotype. Compared with Brugada patients without an SCN5A mutation, those with SCN5A mutations generally exhibit longer and progressive conduction delays (PQ, QRS, and HV intervals), frequent occurrences of fragmented QRS complex, and ventricular arrhythmias of extraRVOT origin. In addition to SCN5A mutations, reduction in INa can be caused by mutations in SCN1B (encoding the β1- and β1b-subunits of the Na+ channel [Nav1.5]), SCN2B (encoding the β2-subunit of the Na+ channel), and SCN3B (encoding the β3-subunit of Nav1.5), resulting in the clinical phenotype of the Brugada syndrome.66 Recently, SCN10A (which encodes Nav1.8, a neuronal Na+ channel, which appears to play a role in the heart) was identified as a major susceptibility gene for Brugada syndrome (identified in 16.7% of probands). Loss of function mutations in SCN10A lead to significant reduction in INa. The majority of patients with SCN10A Brugada syndrome present with mixed phenotypes, the most common of which is progressive cardiac conduction system disease.64 Furthermore, mutations in GPD1L (which encodes the protein glycerol-3-phosphate dehydrogenase 1-like [G3PD1L] protein) affect the trafficking of the cardiac Na+ channel to the cell surface, resulting in reduction of INa and Brugada syndrome. The Brugada phenotype associated with GPD1L mutations is characterized by progressive conduction disease, low sensitivity to procainamide, and a relatively good prognosis.64 Mutations in several other genes have been reported to cause reduction in INa and lead to the Brugada phenotype, including HEY2 (encoding the transcriptional factor HEY2). FGF12 (encoding for a fibroblast growth factor homologous factor-1, which exerts modulatory effects on cardiac Na+ and Ca2+ channels), PKP2 (encoding the desmosomal protein plakophillin-2, a known susceptibility gene for arrhythmogenic right ventricular cardiomyopathy [ARVC]), RANGRF (encoding MOG1, a protein known to modulate the Na+ channel), and SLMAP (encoding the sarcolemmal membrane–associated protein, SLMAP, a component of T-tubules and sarcoplasmic reticulum).64

Mutations Related to the Calcium Current Approximately 13% of cases of the Brugada syndrome are attributable to loss-of-function mutations in the cardiac Ca2+ channel resulting in a reduction of the depolarizing ICaL. These include CACNA1C (which encodes the pore-forming α1C-subunit [Cav1.2] of the L-type voltage-gated Ca2+ channel), CACNB2 (which encodes for the regulatory β2-subunit [Cavβ2] of Cav1.2, which modifies gating of ICaL), and CACNA2D1 (which encodes the regulatory α2δ-subunit of Cav1.2). In this setting, the mechanism of Brugada syndrome involves a reduction of the depolarizing ICaL. Loss of function mutations in these genes are also reported to contribute to SQTS, idiopathic VF, and early repolarization syndrome.65

Mutations Related to the Potassium Current Gain-of-function mutations in KCNE3 (which encodes the auxiliary β-subunit [MiRP2] of the transient outward K+ channel [Kv4.3]) and KCND3 (which encodes the α-subunit of Kv4.3) result in an increase in Ito density and causes Brugada syndrome. Furthermore, gain-of-function mutations in SCN1B (which encodes the auxiliary β1-subunit of the Na+ channel), in addition to reducing INa, can also increase Ito. In addition, mutations in KCNJ8 (which encodes Kir6.1) can augment IKATP, resulting in accentuation of the action potential notch as well as depression of the plateau, leading to Brugada syndrome phenotype. These mutations can also result in shortening of action potential duration and SQTS phenotype. Recently, mutations in ABCC9

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

(which encodes SUR2A, the adenosine triphosphate [ATP]-binding cassette transporter of the IKATP channel) has been reported to cause Brugada phenotype by augmenting IKATP, likely due to reduced channel sensitivity to the inhibitory effects of ATP.64

Other Candidate Genes New susceptibility genes recently proposed and awaiting confirmation include the transient receptor potential melastatin protein-4 gene (TRPM4, which encodes a calcium-activated nonselective cation channel) and the KCND2 gene (which encodes the voltage-gated potassium channel subfamily D, Kv4.2).65 Other genetic variants were found to be capable of modulating, but not necessarily causing, the expression of Brugada syndrome by increasing Ito (KCNE5, which encodes one of the regulatory β-subunits of the Ito and IKs channels), or by increasing IKr (KCNH2, which encodes the α-subunit of the rapid delayed rectifier potassium channel [hERG]). Further, loss-offunction mutations in HCN4 (encoding the hyperpolarization-activated cyclic nucleotide-gated channel 4 protein of the human cardiac pacemaker channel) can lead to reduction in the pacemaker current (If ) and bradycardia, which can accentuate or unmask the Brugada syndrome phenotype.64

Pathophysiology of the Brugada Syndrome The mechanisms underlying the ECG changes and arrhythmogenesis in Brugada syndrome patients remain incompletely understood. Two hypotheses have been proposed: (1) the repolarization disorder hypothesis, based on transmural dispersion in repolarization of the RVOT; and (2) the depolarization disorder hypothesis, based on activation delay in the RVOT subepicardium. It is likely that a combination of the two mechanisms plays a role in the genesis of the ECG pattern and arrhythmogenicity and that both may coexist. Also, both hypotheses recognize a central role for the RVOT as a critical arrhythmogenic substrate in Brugada syndrome.64

Repolarization Hypothesis The ST-T wave changes in Brugada syndrome likely reflect a profound change in the process of ventricular repolarization, particularly in the relationship between the endocardial and epicardial repolarization processes. The cellular basis for this phenomenon is thought to be the result of loss of function of Na+ channels (reduced INa) that differentially alters the action potential morphology in epicardial versus endocardial cells. Ito is a prominent repolarizing current; it partially repolarizes the membrane, shaping rapid (phase 1) repolarization of the action potential, setting the height of the initial plateau (phase 2), and resulting in a pronounced action potential notch and, in combination with depolarizing Ca2+ currents, in a “spike-and-dome” action potential morphology. Ito channel densities are heterogeneously distributed across the myocardial wall and in different regions of the heart, being much higher in the right ventricle (RV) than in the left ventricle (LV), in the epicardium than in the endocardium, and nearer the base than the apex of the ventricles. These regional differences are responsible for the shorter duration, the prominent phase 1 notch, and the “spike and dome” morphology of RV epicardial and midmyocardial action potentials compared with endocardium and LV. A prominent Ito-mediated action potential notch in ventricular epicardium but not endocardium produces a transmural voltage gradient during early ventricular repolarization that registers as a J wave or J point elevation on the ECG (Fig. 31.9).68,69 Na+ channel malfunction and reduction of INa associated with the Brugada syndrome accentuate the notch produced by Ito, leading to partial or complete loss of the action potential dome, premature repolarization, and significant action potential shortening, presumably by

deactivation or voltage modulation that reduces ICaL. These changes occur predominantly in regions where Ito is abundant (such as RVOT epicardium). In contrast, endocardial cells display a much smaller Ito and, consequently, INa reduction would not significantly affect action potential morphology and duration. This is likely to manifest on the ECG as an early repolarization pattern consisting of a J point elevation, slurring of the terminal part of the QRS, and mild ST segment elevation. A further increase in net repolarizing current can result in complete loss of the action potential dome in the RVOT epicardium, leading to more pronounced dispersion of repolarization (epicardial repolarization precedes repolarization in endocardial regions) and a transmural voltage gradient that manifests as greater ST segment elevation.68,69

Depolarization Hypothesis A growing body of evidence suggests that depolarization abnormalities related to ionic channelopathy and structural abnormalities in the RVOT contribute to the arrhythmogenic substrate underlying the Brugada syndrome. The reduction in INa observed in Brugada syndrome linked to an SCN5A mutation leads to a reduction in the upstroke velocity of action potential phase 0, and, as a result, slowing in atrial and ventricular electrical conduction. This is often reflected by prolongation in AV and intraventricular conduction intervals (PR interval and QRS duration) on the ECGs of Brugada syndrome patients with an SCN5A mutation. Conduction slowing preferentially involves the RVOT, likely combined with ultrastructural abnormalities of the RVOT epicardium (interstitial fibrosis and altered expression of gap junction proteins). These depolarization abnormalities likely contribute to ST elevation, thus increasing the transmural gradient of the membrane potential.68,69 The depolarization hypothesis is indirectly supported by several histological, imaging, ECG, and EP observations, including the presence of late potentials and fragmented electrograms recorded from the RVOT epicardium on high-density electroanatomical mapping, signal-averaged ECG, and body surface potential maps. Catheter ablation of these epicardial sites significantly reduced the arrhythmia vulnerability and ECG manifestation of the disease.68,69

Mechanism of Ventricular Arrhythmias The excessive increase in transmural dispersion of repolarization (between epicardium and endocardium) facilitates reentrant excitation waves between depolarized endocardium and prematurely repolarized epicardium. A significant outward shift in current can cause a prominent action potential notch causing more negative potentials during phase 1 of the action potential and loss of activation of ICaL. As a consequence, loss of the action potential dome and marked abbreviation of the action potential develop in regions where Ito is prominent (epicardium) but not in other locations. The dome can then propagate from regions where it is maintained to regions where it is lost, giving rise to a very closely coupled extrasystole (phase 2 reentry) that in turn can initiate polymorphic VT or VF (Fig. 31.10). Although the repolarization abnormalities facilitate the onset of polymorphic VT, it may be the depolarization disturbance (conduction slowing leading to wave break of the reentrant wave) that allows the VT to become sustained and to degenerate to VF. Because the RVOT is the critical area associated with depolarization and repolarization abnormalities, it is a frequent origin of VT and VF in the setting of Brugada syndrome.64

Mechanism of Age and Gender Effects The effects of age and gender on the Brugada syndrome phenotype (being more prevalent in adult males) may be due to intrinsic differences in Na+ channel expression between men and women (e.g., higher

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

Notch magnitude

Endo

Endo Epi AP

APD 90

Phase 0–Phase 2 interval (msec)

APD 90

TDR

Epi AP 1st derivative

TDR Epi1

Epi1

APD 90

APD 90 200 msec

A

AP

Epi2

Epi2

ECG

APD 90

J wave amplitude

C J wave

EDR

EDR

QRS

APD 90

D

T wave

B Fig. 31.9  Dispersion of Action Potential (AP) Repolarization in J Wave Syndromes. (A and B) Quantitation dispersion of AP and J wave parameters. (C) Measurement of dispersion of AP repolarization. (D) Measurement of dispersion of repolarization when the AP dome is lost at 1 epicardial (Epi) site but not the other. APD90, Action potential duration at 90% repolarization; ECG, electrocardiogram; EDR, epicardial dispersion of repolarization; Endo, endocardial; TDR, transmural dispersion of repolarization. (From Gurabi Z, Koncz I, Patocskai B, Nesterenko VV, Antzelevitch C. Cellular mechanism underlying hypothermia-induced ventricular tachycardia/ventricular fibrillation in the setting of early repolarization and the protective effect of quinidine, cilostazol, and milrinone. Circ Arrhythmia Electrophysiol. 2014;7:134–142.)

Ito densities in men) or due to differences in hormone levels (e.g., higher testosterone levels in men). The concentration of testosterone is reportedly higher in men with Brugada syndrome than in controls, and regression of the Brugada ECG pattern after castration in men with prostate neoplasia has been reported. The phase 1 notch potentially mediates the effects of sex hormones on the phenotypic expressions of Na+ channel dysfunction, thus contributing to the male predominance of Brugada syndrome. Estrogen suppresses the expression of the Kv4.3 channel, resulting in reduced Ito and a shallow phase 1 notch, whereas testosterone enhances the outward currents (IKr, IKs, IK1) and reduces the inward current (ICaL), thus deepening the phase 1 notch.

Mechanism of Temperature Sensitivity Fever-induced Brugada is the term used to describe the aggravation of clinical and/or ECG characteristics of this syndrome during febrile states in susceptible individuals. In fact, fever has been reported to be

the precipitating factor of ventricular arrhythmias in 18% of cases in a large series of Brugada patients presenting with cardiac arrest. In one report, the prevalence of a type I Brugada ECG pattern in patients with fever was 20 times higher than in afebrile patients, emphasizing the potency of fever in uncovering this ECG phenomenon.70 The exact mechanism by which fever triggers arrhythmias in Brugada syndrome remains unknown. It is possible that high temperatures result in worsening of the biophysical properties of the defective Na+ channels, leading to further reduction of INa. Alternatively, fever-induced arrhythmias may be mediated by the effect of temperature on the normal (unaffected) channels. According to this model, normal Na+ channels are less efficient at high temperatures, but this slight loss of function becomes clinically significant only in the presence of other factors that reduce the repolarization or depolarization reserve (e.g., heterozygosity with loss-of-function mutations). Of note, fever does not appear to prolong the PR interval or QRS duration as drug challenge does.71

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Transmural voltage gradient Epi2 Epi1

Endo Transmural and epicardial dispersion of repolarization

A 50 mV

Endo

channel blockers to unmask concealed forms of the Brugada syndrome and the potential proarrhythmic adverse effects of these and other pharmacological agents. In contrast, quinidine, in addition to blocking INa, has a relatively strong effect in blocking Ito. Hence, quinidine can effectively suppress ST elevation and ventricular arrhythmias in patients with the Brugada syndrome. Beta-adrenergic stimulation augments the inward ICaL and attenuates the excess of outward current, resulting in reduction of ST segment elevation in right precordial leads and potentially underlying the therapeutic benefit observed for isoproterenol infusion for prevention of ventricular arrhythmias in Brugada syndrome patients with electrical storm. In contrast, acetylcholine facilitates the loss of the action potential dome by suppressing ICaL and/or augmenting K+ current.

Epidemiology Epi1

50 mV

Epi2

50 mV J wave

J wave

ECG

B

500 msec

Fig. 31.10  Potential Mechanism for Arrhythmogenesis in the Brugada and Early Repolarization Syndromes. (A) With enhanced repolarization in regions with prominent transient outward current (Ito), all-or-none repolarization can occur, creating a substrate for arrhythmias. (B) Simultaneous action potentials from two epicardial sites (Epi1 and Epi2) and one endocardial site (Endo), and surface electrocardiogram (ECG). A loss of the action potential dome in Epi1, but not in Epi2, leads to apparent propagation of the dome from Epi2 to Epi1, inducing reentry. (From Benito B, Guasch E, Rivard L, Nattel S. Clinical and mechanistic issues in early repolarization of normal variants and lethal arrhythmia syndromes. J Am Coll Cardiol. 2010;56:1177–1186.)

Mechanism of Exercise-Induced Changes Exercise can aggravate the ECG abnormalities in the Brugada syndrome, but does not appear to induce ventricular arrhythmia in these patients. The mechanisms underlying the ECG responses in the Brugada syndrome to exercise are complex, which may be related to different moleculargenetic mutations underlying the Brugada syndrome phenotype. Brugada syndrome–linked loss-of-function mutations in SCN5A reduce INa more during tachycardia, likely secondary to accumulation of mutant Na+ channels in the slow inactivated state. Na+ channels activate on depolarization and inactivate within milliseconds thereafter. Before reopening, channels must recover from inactivation during diastole. At fast heart rates, the diastolic interval becomes too short for mutant channels to completely recover from the slow inactivated state, resulting in decreased availability of open channels and, as a consequence, accentuation of Na+ channel loss of function produced by SCN5A mutations. Besides tachycardia associated with exercise, other factors (e.g., autonomic nervous system, ion current imbalances) also play a role.

Mechanism of Drug Effects Pharmacological agents that primarily block INa but not Ito (flecainide, ajmaline, and procainamide) can further diminish INa that is already reduced by the Brugada mutations. This may explain the use of Na+

The prevalence of the Brugada ECG pattern in an apparently healthy population varies depending on the demographics of the patient population studied, ranging from 0.017% in Europe and 0.005% to 0.1% in North America to 0.15% to 0.27% in Japan and 0.18% in the Philippines. However, because the Brugada ECG pattern can be intermittently present or concealed, it is difficult to estimate the true prevalence of the disease in the general population. For unclear reasons, the Brugada syndrome is either more prevalent or more penetrant in Eastern countries (mainly in Southeast Asia), where the disease occurs endemically and is the leading cause of death in men younger than 40 years. The Brugada syndrome exhibits an autosomal dominant pattern of transmission with incomplete penetrance (i.e., the pathogenic mutation is inherited by 50% of the offspring, but not all will develop the disease). In up to 60% of patients the disease can be sporadic, that is, absent in parents and other relatives. A family history of unexplained SCD is present in approximately 20% to 40% of Brugada probands in Western countries and in a lower percentage of probands (15% to 20%) in Japan.65 Although the disease is inherited as an autosomal dominant trait and the prevalence of gene carriers among males and females is similar, the vast majority of patients who actually develop symptoms are male (ratio of men to women, 8 : 1). The age of onset of clinical manifestations (syncope or cardiac arrest) is the third to fourth decade of life (mean age of SCD occurrence, 41 ± 15 years). Brugada syndrome is rare in children and the elderly, but cases have been diagnosed in infancy and in patients in their 80s.64,72 The prognosis of Brugada syndrome varies widely among patients with this disorder, ranging from benign to malignant. Patients with a history of cardiac arrest are at the highest risk of recurrent events (7.7% to 13.5% per year) in the absence of drug therapy.73 The arrhythmic risk is intermediate (0.6% to 1.2% per year) for patients with “malignant” syncope, and small, but not trivial (0.5% per year) in asymptomatic patients.74

Clinical Presentation There are three main clinical presentations of the Brugada syndrome: (1) cardiac arrest secondary to polymorphic VT/VF; (2) syncope; and (3) no symptoms. Less frequently, patients can present with symptoms secondary to SND, AV conduction abnormalities, or supraventricular arrhythmias. In contemporary practice, the majority (more than 60%) of Brugada syndrome patients are asymptomatic at the time of diagnosis, often discovered during routine evaluation (preoperative or before sports participation), family screening, or upon the observation of the abnormal ECG pattern during a febrile illness. Only a minority (less than 10% to 20%) of Brugada syndrome patients diagnosed today have a history of cardiac arrest, and about one-third present with syncope.64

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies Symptoms associated with Brugada syndrome are related to polymorphic VT, VF. Cardiac arrest is often the first manifestation of arrhythmias in the Brugada syndrome. When the arrhythmia terminates spontaneously, patients can present with syncope, agonal respirations, nocturnal labored respiration with agitation, or “seizures.” About 25% of patients suffering from SCD had already experienced a syncopal episode.65 The Brugada syndrome is a leading cause of SCD in men younger than 40 years of age, particularly in countries in which the syndrome is endemic. The Brugada syndrome is believed to be responsible for 4% to 12% of all SCDs, and at least 20% of those occurring in patients with structurally normal hearts. The Brugada syndrome has even been described as responsible for SIDS and sudden unexplained nocturnal death syndrome (SUNDS; also known as SUDS). Nevertheless, the majority of Brugada syndrome patients do not manifest life-threatening events; approximately 10% to 15% of clinically affected patients experience one or more cardiac arrests before age 60. In a meta-analysis of prognostic studies, patients with a Brugada ECG pattern have an approximately 10% risk of SCD, syncope, or ICD shock at an average follow-up time of 2.5 years, or approximately 3.8% per year. More recent data suggest a lower annual event rate (approximately 1.5%); the discrepancy is likely due to selection bias, as initial reports included patients at higher risk.65 Cardiac arrhythmia and death in the Brugada syndrome seem to occur largely in the early morning hours during sleep and in the setting of bradycardia. Circadian variation of sympathovagal balance, hormones, and other metabolic factors are likely to contribute to this circadian pattern. Bradycardia resulting from altered autonomic balance or other factors likely contributes to the initiation of arrhythmia. Some episodes of syncope or SCD can be triggered by large meals (gastric distention), alcohol and cocaine toxicity, drugs, and fever. In

Type 1

1005

fact, it now appears that many previously described episodes of “febrile seizures” may in fact represent bouts of polymorphic VT in patients with temperature-sensitive mutations. Some patients with the Brugada syndrome experience an electrical storm of VF, but with no obvious precipitating factors. Syncope is common (28%) in patients with Brugada syndrome; however, a large proportion of those patients have nonarrhythmic (often vasovagal) causes of syncope. Clinical features allow distinction between suspected arrhythmogenic and nonarrhythmogenic causes of syncope in 70% of cases. The absence of prodromes, brief (less than 1 minute) loss of consciousness, and absence of specific triggers (e.g., hot and crowded surroundings, pain or other emotional stress, seeing blood, or prolonged standing) are suggestive of an arrhythmic etiology. Of note, palpitations are very common in patients with suspected nonarrhythmic syncope, likely because of the pronounced postural tachycardia occurring before an actual faint.75 Approximately 20% of patients with Brugada syndrome develop supraventricular arrhythmias. AF is the most common, observed in 10% to 20% of patients, especially in those with more advanced disease. Atrioventricular nodal reentrant tachycardia and Wolff-Parkinson-White syndrome have also been reported.76 The identification of concomitant AV and intraventricular conduction defects have been shown to correlate with the presence of SCN5A mutations. Therefore all SCN5A-positive patients should be closely monitored for the onset of conduction block.

Electrocardiographic Features

Brugada Electrocardiogram Patterns Previously, three ECG repolarization patterns in the right precordial leads were recognized (Fig. 31.11). Type 1 is characterized by ST segment

Type 2

Type 3

V1

V1

V1

V2

V2

V2

V3

V3

V3

V4

V4

V4

V5

V5

V5

V6

V6

V6

Fig. 31.11  Brugada Electrocardiogram (ECG) Patterns. Note the ventricular ectopic beat in the left panel with a QRS morphology consistent with origin from the right ventricular outflow tract. See text for discussion.

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

elevation of at least 2 mm (0.2 mV) with a coved (downward convex) morphology, associated with an incomplete or complete right bundle branch block (RBBB) pattern and followed by a descending negative T wave, with little or no isoelectric separation. The type 2 pattern has a “saddleback” appearance with a high take-off ST segment elevation of at least 2 mm, a trough displaying an ST elevation greater than or equal to 1 mm, and then either a positive or biphasic T wave. The type 3 pattern has either a saddleback or coved appearance with an ST segment elevation of less than 1 mm. These three patterns can be observed spontaneously in serial ECG tracings from the same patient or after the introduction of specific drugs. Only the type 1 ECG pattern is diagnostic of the Brugada syndrome, with type 2 and type 3 ECG patterns being suggestive but not specific.65 The most recent consensus statement recommended that only two Brugada ECG patterns be considered: type 1 (coved type) and type 2 (saddleback type). Given the minimal morphological differences between type 2 and 3 Brugada patterns and the lack of impact on prognosis and risk stratification, the new type 2 ECG pattern definition encompasses patterns 2 and 3 of the previous consensus. Type 1 remains identical to the classic type 1 described previously, but with some new measurements that may also help to quantify the difference in the r′ wave morphology (Box 31.1; Table 31.12).77,78 The ECG Brugada pattern type 1 with the above criteria is easily recognized; and when found in a patient without apparent structural heart disease, it is very specific and strongly supports the diagnosis of Brugada syndrome (see Box 31.1). The infrequent cases with a covedtype pattern that present a high takeoff of QRS-ST between 0.1 and 0.2 mV, but with negative T wave in leads V1-V2, have been considered suggestive of the type 1 Brugada pattern, and should be evaluated

with complementary ECG criteria testing to confirm the diagnosis (see Table 31.12).77,78

Electrocardiogram Electrode Locations The use of more cephalad placement of the right precordial (in the third or second intercostal spaces) can increase the sensitivity for detecting the Brugada ECG pattern (both in the presence or absence of a drug challenge), likely with no reduction in the specificity of the diagnosis. In fact, it has been reported that the superior displacement of V1-V2 leads could reveal more than 20% of new Brugada syndrome cases. This is likely related to the normal projection of the RVOT (which harbors the abnormalities underlying the ECG changes) onto the anterior chest surface.79,80 Therefore the standard position of leads V1-V2 in the fourth intercostal space is not sufficient to exclude the presence of a Brugada ECG pattern; ECG recordings need to be obtained with the V1-V2 electrodes positioned in the second and third intercostal spaces in all patients. Also, those electrodes should be positioned in the same diagnostic location when serial recordings are performed to allow comparative assessments.79

Dynamicity of the Brugada Pattern The ECG changes associated with the Brugada pattern can be dynamic, intermittent, and are sometimes concealed. In fact, it is rare for patients to present with uniformly diagnostic tracings. Therefore serial ECGs can be necessary for diagnostic evaluation in highrisk patients. Continuous Holter monitoring also can help assess ST segment elevation at night because such changes can be modified by autonomic tone.77

BOX 31.1  ECG Alterations in Brugada Syndrome ECG Diagnostic Criteria in Precordial Leads • Brugada pattern: (usually, the pattern is seen only in leads V1-V2; but in some cases, it is recorded only in V1 or V2; and, in others, it is observed from V1 to V3). • Type 1 Brugada pattern (coved pattern): Initial ST elevation ≥2 mm, slowly descending and concave or rectilinear with respect to the isoelectric baseline, with negative symmetric T wave (see other characteristics in Table 31.12). • Type 2 Brugada pattern (saddleback pattern): The high take-off terminal positive wave (r′) is ≥2 mm with respect to the isoelectric line and is followed by ST elevation; convex with respect to the isoelectric baseline (saddleback pattern) with elevation ≥0.05 mV with positive/flat T wave in lead V2, and variable (mildly positive, flat, or mildly negative) T wave in lead V1. If there is some doubt (i.e., r′ < 2 mm), it is necessary to record the ECG in the second and third intercostal space (see other characteristics in Table 31.12). • New ECG criteria: • Corrado index (2010): The ratio between the peak height of the take-off of QRS-ST to the height of ST segment at 80 msec later in leads V1-V2 is >1 (because the ST is downsloping). In athletes, the ST especially in lead V2 is upsloping; hence, the index is <1. The end of QRS (J point) often does not coincide with the high take-off of QRS-ST as was suggested by Corrado. However, using the high takeoff of QRS-ST for the application of the Corrado index is valid for discriminating the Brugada pattern and other conditions mimicking the Brugada pattern.

• The β angle formed by ascending S and descending r′ is >58 degrees in the type 2 Brugada pattern (in athletes, it is much lower) (sensitivity, 79%; specificity, 84%). • Duration of the base triangle of r′ at 5 mm from the high takeoff is more than 3.5 mm in the type 2 Brugada pattern (sensitivity, 81%; specificity, 82%). This measurement is much shorter in healthy athletes with incomplete RBBB. Other ECG Findings • QT generally is normal but can be prolonged in right precordial leads. • Conduction disorders: Sometimes, prolonged PR interval (long HV interval). The conduction delay located in the RV explains the r′ and longer QRS duration in right precordial leads compared with mid/left precordial leads. • Supraventricular arrhythmias. Mostly atrial fibrillation. • Some other ECG findings may be seen: the presence of r′ wave in lead aVR >3 mm, early repolarization pattern in inferior leads, fractioned QRS, alternans of T wave after ajmaline injection, etc. Other ECG Techniques • In some occasions, it is necessary or convenient to find some new diagnostic clues with exercise testing, late potentials, and impaired QT dynamics studied by Holter. Electrophysiological studies remain controversial for diagnosis and for risk stratification.

ECG, Electrocardiogram; RBBB, right bundle branch block; RV, right ventricle. Modified from Bayés De Luna A, Brugada J, Baranchuk A, et al. Current electrocardiographic criteria for diagnosis of Brugada pattern: a consensus report. J Electrocardiol. 2012;45:433–442.

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

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TABLE 31.12  Brugada Electrocardiogram Patterns in Leads V1-V2 Type 1: Coved Pattern

Type 2: Saddleback Pattern

High takeoff 40 msec 80 msec

β

Base at 5 mm from high takeoff

Characteristics of the typical coved pattern in leads V1-V2: • At the end of QRS, an ascending and quick slope with a high takeoff ≥2 mm followed by concave or rectilinear downsloping ST. There are few cases of coved pattern with a high takeoff between 1 and 2 mm. • There is no clear r′ wave. • The high takeoff often does not correspond with the J point. • At 40 msec of high takeoff, the decrease in amplitude of ST is ≤4 mm (≤0.4 mV). This is much less than the decrease observed in right bundle branch block because the downslope is slower. • ST at high takeoff > ST at 40 msec > ST at 80 msec. • ST is followed by negative and symmetric T wave • QRS duration “mismatch:” The QRS duration is longer in V1-V2 than in mid/ left precordial leads (because of evidence of RV conduction delay), although this is sometimes difficult to determine.

Characteristics of the typical saddleback pattern in leads V1-V2: • High takeoff of r′ (that often does not coincide with J point) ≥2 mm. • Descending arm of r′ coincides with beginning of ST (often is not well seen). • Minimum ST ascent ≥0.5 mm • ST is followed by positive T wave in lead V2 (Tpeak > ST minimum >0) and of variable morphology in lead V1. • The characteristics of triangle formed by r′ allow definition of different criteria useful for diagnosis. • β angle >58 degrees • Duration of the base of the triangle of r′ at 5 mm from the high takeoff greater than 3.5 mm • The duration of QRS is longer in the type 2 Brugada pattern than in other cases with r′ in lead V1, and there is a mismatch between V1 and V6.

From Bayés De Luna A, Brugada J, Baranchuk A, et al. Current electrocardiographic criteria for diagnosis of Brugada pattern: a consensus report. J Electrocardiol. 2012;45:433–442.

When concealed, the ECG manifestations of the Brugada syndrome can be unmasked by stress, fever, various vagal stimuli (including gastric distention), vagotonic agents, a combination of glucose and insulin, electrolyte abnormalities (e.g., hyperkalemia, hypokalemia, hypercalcemia, hyponatremia), alcohol and cocaine toxicity, class I antiarrhythmic medications, and a number of other noncardiac medications.81 Furthermore, the ECG phenotype in the Brugada syndrome can be modified by autonomic changes. Adrenergic stimulation attenuates whereas acetylcholine accentuates the ECG abnormalities in affected individuals. Clinically, this correlates well with the propensity for cardiac events to occur at rest or during sleep.

QT Interval Prolongation A slight prolongation of the QT interval is sometimes observed in association with ST segment elevation in patients with the Brugada syndrome. The QT interval is prolonged more in the right precordial leads than it is in the left leads, presumably because of a preferential prolongation of action potential duration in RV epicardium secondary to accentuation of the action potential notch.78

QRS Fragmentation In addition to the repolarization abnormality, the Brugada syndrome is associated with depolarization abnormalities and conduction disturbances. Fragmentation of the QRS complex (manifesting as multiple small spikes within the QRS complex) can be observed in 40% of patients with the Brugada syndrome and in the majority (85%) of those who had VF episodes. It has been proposed that the multiple

spikes within the fragmented QRS complex suggest the presence of an arrhythmogenic substrate that has multiple areas of conduction slowing, and can potentially predict a high risk of life-threatening ventricular arrhythmias. Notably, fragmentation of the QRS occurs preferentially in the right precordial leads, especially in the higher intercostal spaces, suggesting a localized conduction abnormality within the RVOT region. The use of a low-pass filter with a low cutoff frequency (greater than 25 Hz), as commonly employed to remove the electromyogram signal, can eliminate the QRS fragmentation. Thus a low-noise amplifier and a relatively high cutoff low-pass filter frequency (150 Hz) need to be used.78 Of note, epsilon-like waves and localized prolongation of the QRS complex in the right precordial leads have been observed in some patients with a spontaneous or drug-induced type 1 Brugada ECG pattern, likely reflecting RV activation delay.

Conduction Abnormalities Depolarization abnormalities, including prolongation of P wave duration, PR interval, and QRS duration, are frequently observed, particularly in patients with SCN5A mutations. PR interval prolongation likely reflects infranodal conduction delay. Of note, loss-of-function SCN5A mutations can also lead to isolated cardiac conduction defects or LevLenègre disease, characterized by disturbances in any part of the conduction system without QT interval prolongation or Brugada ST segment elevation. In addition, prolonged sinus node recovery time and sinoatrial conduction time, slowed atrial conduction, and atrial standstill have been reported in association with the Brugada syndrome.78

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies arrest, unexplained syncope, or family screening). Up to 30% to 50% of the patients are diagnosed with Brugada syndrome after a positive drug challenge. Provocative drug testing is generally not performed if a patient displays an intermittently spontaneous type 1 ECG because the test does not offer additional diagnostic or prognostic value in these patients, and it is not devoid of risk for provoking arrhythmic events. It is also important to recognize that a negative provocative drug test does not exclude a latent form of Brugada syndrome. The drug challenge test involves administration of ajmaline, flecainide, procainamide, or pilsicainide (Table 31.14) under close cardiac monitoring and in a setting that is fully equipped for resuscitation. The drug challenge test is terminated when (1) the diagnostic type 1 ST segment elevation develops (Fig. 31.13), (2) the ST segment elevation in the type 2 ECG pattern increases by at least 2 mm, (3) PVCs or other arrhythmias develop, or (4) the QRS widens by 30% or more. Although the drug challenge test is considered safe if performed in a controlled environment, it can potentially precipitate malignant cardiac arrhythmias or advanced AV block, particularly in patients with preexisting AV or intraventricular conduction abnormalities. Ventricular arrhythmias during or shortly after drug challenge have been reported in 0.3% to 15% of the tests, but are predominantly nonsustained and self-terminating. Sustained ventricular arrhythmias occur in about 1.8% of the patients during ajmaline challenge. Notably, such an occurrence in patients with Brugada syndrome does not appear to identify a category at higher risk of spontaneous arrhythmic events. Isoproterenol and sodium lactate can be effective antidotes in this setting. The different Na+ channel blockers exhibit different efficacies in unmasking the Brugada pattern ECG, mostly secondary to the different potency of inhibition of Ito and INa. Data suggest that ajmaline (a class IA Na+ channel blocker) is the most efficacious and is likely safer than others because of its shorter half-life and stronger rate-dependent Na+ channel blocking effects. In SCN5A-positive subjects with Brugada

Diagnosis of the Brugada Syndrome The 2013 consensus report recommended that Brugada syndrome is definitively diagnosed when a type 1 ECG pattern is observed, either spontaneously or after provocative drug testing (with IV administration of a sodium channel blocker such as ajmaline, flecainide, pilsicainide, or procainamide), in at least one right precordial lead (V1 or V2), placed in a standard or a superior position (i.e., in the fourth, third, or second intercostal space) (Fig. 31.12).1,82 Although symptoms are no longer mandatory for diagnosis according to the consensus report, several investigators have suggested that when a type 1 ECG pattern is unmasked using a sodium channel blocker, a definitive diagnosis of Brugada syndrome should require that the patient also present with either symptoms (cardiac arrest, agonal nocturnal respiration, documented polymorphic VT or VF, or unexplained syncope) or positive family history (unexplained SCD at age younger than 45 years or diagnosed Brugada syndrome in a first-degree relative). Inducibility of VT/VF with 1 or 2 ventricular extrastimuli (VESs) at EP study supports the diagnosis of Brugada syndrome under these circumstances.65,77,82 The type 2 Brugada ECG pattern is suspicious, but not diagnostic for Brugada syndrome, and requires further investigation. A drug challenge test to unmask a type 1 Brugada ECG pattern is recommended in those individuals only when the type 2 ECG pattern is accompanied by symptoms or positive family history, as specified above.65 A diagnostic score system for Brugada syndrome (the Shanghai Brugada syndrome score, (Table 31.13) has been proposed based on the available literature, but validation by large-scale trials is lacking.65

Provocative Drug Testing Provocative testing with Na+ channel blockers is used to unmask a Brugada ECG pattern in nondiagnostic cases (e.g., unexplained cardiac

4th-ICS

V1

3rd-ICS

Baseline

A

Baseline

V1

V1 V1

V2

Ajmaline

V2

V2

B

V1

V2

V2

Ajmaline

V1

V2

C

Fig. 31.12  Diagnosis of the Brugada Electrocardiogram (ECG) Patterns. ECG leads V1 and V2 are shown. (A) Single-lead coved-type ECG exceeding 2 mm only in the third intercostal space (ICS). (B) Single-lead coved-type ECG exceeding 2 mm only at baseline and further accentuated upon 1 mg/kg ajmaline; in (A) and (B) Brugada syndrome can be diagnosed according to 2013 criteria. (C) Incomplete right bundle branch block with minimal ST segment abnormalities at baseline that are converted to a coved pattern after ajmaline, but ST segment elevation remains less than 2 mm. In this case the challenge is considered negative. Horizontal blue lines represent 2 mm. (From Curcio A, Mazzanti A, Bloise R, et al. Clinical presentation and outcome of Brugada syndrome diagnosed with the new 2013 criteria. J Cardiovasc Electrophysiol. 2016;27:937–943.)

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

TABLE 31.13  Proposed Shanghai Score

System for Diagnosis of Brugada Syndrome Points I. ECG (12-Lead/Ambulatory) A. Spontaneous type 1 Brugada ECG pattern at nominal or 3.5 high leads B. Fever-induced type 1 Brugada ECG pattern at nominal or 3 high leads C. Type 2 or 3 Brugada ECG pattern that converts with 2 provocative drug challenge Only award points once for highest score within this category. One item from this category must apply. II. Clinical History A. Unexplained cardiac arrest or documented VF/ 3 polymorphic VT B. Nocturnal agonal respirations 2 C. Suspected arrhythmic syncope 2 D. Syncope of unclear mechanism/unclear etiology 1 E. Atrial flutter/fibrillation in patients <30 years without 0.5 alternative etiology Only award points once for highest score within this category. III. Family History A. First- or second-degree relative with definite BrS 2 B. Suspicious SCD (fever, nocturnal, Brugada aggravating 1 drugs) in a first- or second-degree relative C. Unexplained SCD <45 years in first- or second-degree 0.5 relative with negative autopsy Only award points once for highest score within this category. IV. Genetic Test Result A. Probable pathogenic mutation in BrS susceptibility gene 0.5   Score (requires at least one ECG finding)   ≥3.5 points: Probable/definite BrS   2–3 points: Possible BrS   <2 points: Nondiagnostic BrS, Brugada syndrome; ECG, electrocardiogram; SCD, sudden cardiac death; VF, ventricular fibrillation; VT, ventricular tachycardia. From Antzelevitch C, Yan GX, Ackerman MJ, et al. J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge. Heart Rhythm. 2016;13:e295–e324.

TABLE 31.14  Drugs Used to Unmask

Brugada Electrocardiogram Pattern Drug

Dose

Ajmaline Flecainide

1 mg/kg IV infusion over 10 min 2 mg/kg IV infusion over 10 min, maximum 150 mg; or 200–300 mg oral 10 mg/kg IV infusion over 10 min 1 mg/kg IV infusion over 10 min

Procainamide Pilsicainide IV, Intravenous.

syndrome and their relatives, ajmaline was reported to have a sensitivity of 80% and a specificity of 94%. Flecainide has been shown to have a lower efficacy compared with ajmaline, likely due to a greater inhibition of Ito. Pilsicainide, a pure class IC drug, is believed to be more potent than flecainide. The class IA Na+ channel blocker procainamide is traditionally regarded as the least potent, likely due to a more rapid dissociation of the drug from the Na+ channels resulting in comparatively less inhibition of INa. The choice of Na+ channel blocker used, however,

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is usually based on availability. Procainamide remains the only choice for IV pharmacological induction protocols in the United States.83,84 Of note, the response to flecainide infusion exhibits time-dependent variability of ECG patterns and intervals. Although most of the induced type I ECG patterns are observed during the first 30 minutes of the initiation of provocative testing, a recent study showed that extended periods of recording time (100 to 120 minutes) increased the percentage of positive testing from 12% to 19%.85

Signal-Averaged Electrocardiography Signal-averaged ECG demonstrates late potentials in approximately 60% to 70% of clinically affected Brugada syndrome patients. In this setting, late potentials can be a clinical marker of the disease, representing the delayed second upstroke of the epicardial action potential, a local phase 2 reentry (failing to trigger transmural reentry), or an intraventricular conduction delay.64

Exercise Testing Treadmill exercise testing can potentially aggravate the ECG abnormalities in the Brugada syndrome, including widening of the QRS, prolongation of the QTc duration, and augmentation of precordial peak ST segment elevation (which reaches its maximal amplitude during the early phase of recovery from exercise). Nonetheless, exercise was not found to induce ventricular arrhythmias in Brugada patients.86

Genetic Testing Genetic testing is recommended to support the diagnosis in patients manifesting the clinical phenotype of the Brugada syndrome. Although the knowledge of a specific mutation may not provide guidance for determining prognosis or treatment in the index patient, identification of a disease-causing mutation in the family can lead to genetic identification of at-risk family members who are clinically asymptomatic and who may have a normal ECG. However, it is important to remember that a negative result of genetic testing does not exclude the presence of the disease and, therefore, only a positive genetic diagnosis is informative. Genetic screening of SCN5A in unselected patients with a diagnosis of Brugada syndrome has low yield (less than 30%) and may not be cost-effective. The yield of genotyping increases substantially in patients with type 1 Brugada ECG pattern and prolonged PR interval, suggesting that this subset of patients with Brugada syndrome should be screened.64 Genetic testing is not recommended in the setting of an isolated type 2 Brugada ECG pattern. It is important to recognize that genetic testing can produce “false-positive” results. Although SCN5A mutations are the most common genetic cause of Brugada syndrome, SCN5A genetic testing is complicated by an approximately 3% to 5% “benign” variant frequency in the general population.65

Electrophysiological Testing In patients with Brugada syndrome, EP testing may be considered for: (1) risk stratification to guide ICD implantation decisions in patients who have no history of cardiac arrest (including asymptomatic patients and those presenting with syncope); (2) evaluation of the efficacy of quinidine to suppress inducibility of VF in patients with inducible VF who do not prefer ICD therapy; and (3) assessment of sinus node function, conduction disturbances, and inducibility of supraventricular arrhythmias in patients with syncope.87

Differential Diagnosis

Acquired Brugada Phenotype ECG patterns identical to the type 1 or type 2 Brugada pattern can be seen in the absence of known genetic factors and family history. Some

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

Type 3 Brugada ECG Pattern: Baseline I

aVR

V1

V4

II

aVL

V2

V5

III

aVF

V3

V6

II

A Type 1 Brugada ECG Pattern: Post Flecainide I

aVR

V1

V4

II

aVL

V2

V5

III

aVF

V3

V6

II

B Fig. 31.13  Provocative Drug Testing to Unmask Brugada Electrocardiogram (ECG) Pattern. (A) ECG showing type 3 Brugada ECG pattern at baseline. (B) Type 1 Brugada ECG pattern developed post administration of flecainide.

investigators have labeled these “phenocopies,” indicating that they mimic the phenotype without a genetic predisposition. These acquired forms of Brugada phenotype can be elicited by a variety of pathological and physiological conditions (e.g., acute ischemia, pericarditis, myocarditis, pulmonary embolism, metabolic disorders, acidosis, ionic abnormalities, cocaine ingestion, some drugs, surgical RVOT manipulation) and disappear upon resolution of the underlying condition (Box 31.2). Characteristically, these patients lack symptoms, medical history, and family history suggestive of the true Brugada syndrome. Also, the ECG returns to normal upon resolution of the inciting environmental factors.20 In some doubtful cases of type 2 Brugada pattern, provocative testing with a Na+ channel blocker is recommended, which is typically negative in Brugada phenocopies.77 Genetic testing may also be considered to rule out true Brugada syndrome, although it should be recognized that a negative genetic test result does not exclude the congenital Brugada syndrome.78

Drug-Induced Brugada Electrocardiogram Pattern A variety of pharmacological agents have been implicated in druginduced Brugada ECG phenotype, although the likelihood of arrhythmias is unclear. In general, factors that increase outward currents (e.g., Ito, IKATP, IKr, IKs) or decrease inward currents (e.g., INa, ICaL) at the end of phase 1 of the action potential can potentially accentuate or unmask ST segment elevation similar to the ECG pattern observed in patients with the Brugada syndrome.39

Among antiarrhythmic drugs, class IC agents (flecainide, propafenone, pilsicainide) and class IA drugs (ajmaline and procainamide) most effectively amplify or unmask ST segment elevation. On the other hand, class IB antiarrhythmic drugs (lidocaine, mexiletine) block fast INa primarily at fast heart rates (because of the rapid dissociation of these drugs from Na+ channels). Therefore these drugs have little or no effect on fast INa at moderate or slow heart rates.39 Several noncardiac drugs can potentially induce a Brugada-like ECG pattern secondary to block of INa, including psychotropic drugs, lithium, and cocaine. In addition, verapamil, H1 antihistamines, propofol, alcohol intoxication, vagomimetic agents, and beta-blockers and potentially nitrates can induce a Brugada-like ECG pattern (Table 31.15). Druginduced Brugada syndrome from noncardiac drugs occurs predominantly in adult males, is frequently due to drug toxicity, and occurs late after the onset of therapy. However, the likelihood of drug-induced Brugada syndrome is difficult to predict in routine clinical practice.88 Na+ channel blocker provocation testing, family screening for Brugada syndrome, and possibly genetic analysis may be performed in a subject with an acquired form of Brugada ECG phenotype by noncardiac agents. Subjects with drug-induced Brugada syndrome by noncardiac agents should be advised to avoid the majority of class I and class III antiarrhythmic agents as well as beta-blockers and calcium channel blockers. Rigorous treatment of fever, a well-known trigger of arrhythmic events in Brugada syndrome, is also advised in subjects with an acquired Brugada syndrome ECG pattern by noncardiac agents.89

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

BOX 31.2  Conditions Associated With

Brugada-Like Electrocardiogram Pattern

Acute Conditions • Acute pericarditis/myocarditis • Acute myocardial ischemia or infarction (especially of the right ventricle) • Pulmonary thromboembolism • Prinzmetal angina • Dissecting aortic aneurysm • Hypothermia • Postdefibrillation electrocardiogram • Metabolic disorders • Electrolyte abnormalities Persistent Conditions • Atypical right bundle branch block • Left ventricular hypertrophy • Early repolarization • Athlete’s heart • Central and autonomic nervous system abnormalities • Duchenne muscular dystrophy • Friedreich ataxia • Spinobulbar muscular atrophy • Myotonic dystrophy • Arrhythmogenic right ventricular dysplasia • Chagas disease • Mechanical compression of the right ventricular outflow tract (e.g., pectus excavatum, mediastinal tumor, hemopericardium) Modified from Antzelevitch C, Yan GX, Ackerman MJ, et al. J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge. Heart Rhythm. 2016;13:e295–e324.

TABLE 31.15  Drug-Induced Brugada

Electrocardiogram Pattern Drug Group

Example(s)

Class IC antiarrhythmic drugs Class IA antiarrhythmic drugs Calcium channel blockers Beta-blockers H1-Antihistamines Tricyclic antidepressants Tetracyclic antidepressants Selective serotonin reuptake inhibitors Phenothiazines Local anesthetics Other drugs

Flecainide, propafenone, pilsicainide Ajmaline, procainamide, disopyramide Verapamil, diltiazem, nifedipine Propranolol Dimenhydrinate Amitriptyline, nortriptyline, desipramine Maprotiline Fluoxetine Perphenazine, trifluoperazine Bupivacaine Lithium, nitrates, propofol

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from the type 1 or type 2 Brugada ECG pattern. These include RBBB, LV hypertrophy, early repolarization, athlete’s heart, and ARVC. Right bundle branch block.  Complete RBBB and the type 1 Brugada pattern are characterized by the presence of positive terminal deflections of the QRS and negative T waves in leads V1-V2. It is possible to distinguish between the two entities on the basis of the following77,78: 1. The positive terminal r′ wave is peaked in RBBB (β angle less than 58 degrees). Conversely, the high takeoff of r′ in the Brugada pattern is rounded, wide, and usually of relatively low voltage, with a gradual slope of the descending arm of r′. 2. The terminal wave (r′ or R′) in RBBB observed in leads V1-V2 is synchronous with the broad S wave observed in leads I and V6, and the QRS complex duration in leads V1-V2 is identical to that observed in lead V6. In contrast, the QRS duration in the Brugada syndrome is longer in leads V1-V2 than in mid/left precordial leads (“QRS duration mismatch”) because the terminal deflection observed in lead V1 (the r′ wave overlying the RVOT) is not recorded by the V6 electrode. 3. The ST segment in RBBB is not elevated in the right precordial leads. Healthy athletes.  Although lead V1 in athletes can exhibit an r′ wave, this wave is usually peaked and sharp (β angle less than 58 degrees) with no or only mild ST elevation (less than 1 mm), and the ST segment starts after the clear end of QRS and is often followed by a negative and sometimes deep T wave in lead V1. Furthermore, the ST segment elevation observed in healthy athletes is upsloping, especially in lead V2 (Corrado index less than or equal to 1).77,78 Pectus excavatum.  Mechanical compression of the RVOT in the setting of pectus excavatum can produce right precordial ECG abnormalities mimicking the Brugada pattern. The ECG pattern observed in pectus excavatum usually presents a narrow, very well defined r′ wave in lead V1, followed by a slight ST segment elevation. The T wave is usually negative or positive/negative in lead V1 and positive in lead V2.78 Arrhythmogenic right ventricular cardiomyopathy.  ARVC can produce repolarization and depolarization ECG abnormalities than can occasionally mimic the Brugada pattern. The depolarization abnormalities are caused by cellular uncoupling and altered tissue architecture due to fibrofatty infiltration, and typically manifest on the ECG as epsilon waves, RBBB, QRS fragmentation, localized QRS widening, and terminal S wave prolongation in right precordial leads. Repolarization abnormalities typically manifest as T wave inversion in the right precordial leads. T wave inversion in ARVC is observed in several precordial leads (V1 to V3-V5), and not limited to leads V1-V2 as seen in the Brugada syndrome. In addition, the ECG pattern in ARVC is always fixed, in contrast to the dynamic Brugada pattern.78 Although positive late potentials can be observed on signal-averaged ECG in both Brugada syndrome and ARVC, the prevalence is much higher in ARVC, and wavelet analysis demonstrates that the frequency level is higher in ARVC.77,78

Risk Stratification Whether the “acquired” form of Brugada syndrome unmasks clinically inapparent Brugada syndrome (“forme fruste”) or merely represents one end of a broad spectrum of responses to Na+ channel blockers is not known. The prognosis for asymptomatic patients with a druginduced Brugada ECG pattern, but without a family history of SCD, appears to be benign once the offending agent is discontinued, provided the full-blown Brugada syndrome is not uncovered.82

Conditions Associated With Right Precordial ST Elevation A variety of pathophysiological conditions are associated with distinct right precordial abnormalities on the ECG that need to be distinguished

As noted, the risk of arrhythmic events varies widely among patients with Brugada syndrome, and is highest in patients with a history of cardiac arrest and intermediate in those with syncope. The risk of lifethreatening arrhythmic events in patients who are asymptomatic when diagnosed is small, but not trivial (0.5% to 1.5% per year); therefore these patients are the main target of risk stratification strategies. However, risk stratification in these patients remains difficult because the event rate is low but the presenting symptom is often cardiac arrest.74 Several criteria have been proposed for selecting asymptomatic patients with Brugada syndrome prone to a significant risk of malignant ventricular arrhythmias (Box 31.3). Gender, multiple ECG parameters,

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

BOX 31.3  Established and Potential

Markers of Risk in Brugada Syndrome Clinical Markers • Aborted SCD • Documented VT/VF • Syncope likely due to VT/VF • Nocturnal agonal respiration • Male gender Electrocardiogram Markers • Spontaneous type 1 Brugada ECG pattern • Early repolarization pattern in the inferolateral leads • Increased Tpeak-Tend interval • Fragmented QRS • Prominent R wave in lead aVR • Prominent S wave in lead I • QRS duration ≥90 msec in lead V6 • r–J interval ≥90 msec in lead V2 • QRS duration ≥120 msec in lead V2 • Late potentials on epicardial bipolar electrogram or signal-averaged ECG Electrophysiological Markers • Inducible VT/VF • Short ventricular refractory period <200 msec ECG, Electrocardiogram; SCD, sudden cardiac death; VF, ventricular fibrillation; VT, ventricular tachycardia.

and VT/VF inducibility by programmed electrical stimulation have been reported to be useful in identifying high-risk patients; however, individual prediction performances of these parameters are limited. The presence of multiple independent risk factors likely provides additive prognostic information. Nevertheless, it is important to recognize that risk stratification in asymptomatic patients with Brugada syndrome has been a matter of continuous controversy.74,73

Cardiac Arrest Patients with a history of cardiac arrest are at the highest risk of recurrent events (35% at 4 years, 44% at 7 years, and 48% at 10 years). In a meta-analysis, the annual rate of arrhythmic events or SCD in these patients was estimated at 13.5%. The mean time from presentation to VF recurrence is 1.5 to 2 years, but late recurrence (5 years after the initial event) also can happen.73

Syncope Unexplained syncope (presumed to be of arrhythmogenic etiology, based on clinical characteristics) is considered a risk marker in patients with a spontaneous type I ECG at baseline (without conditions known to unmask the signature sign, i.e., drugs and fever).1 In these patients, the risk of arrhythmic events during follow-up appears to be intermediate: about four times higher than the risk of asymptomatic patients but four times lower than that of patients presenting with cardiac arrest. In contrast, “nonarrhythmogenic” syncope (such as neurocardiogenic syncope, which is relatively common in Brugada patients) does not predict an increased arrhythmic risk. Therefore it is important to obtain a detailed clinical history because clinical features allow distinction between suspected arrhythmogenic and nonarrhythmogenic causes of syncope in 70% of cases.75 Current guidelines state that ICD implantation can be useful in patients with a spontaneous type I ECG who have a history of syncope presumed to be of arrhythmic origin.73

Gender Male gender has consistently been shown to be associated with more arrhythmic events. However, male predominance is also observed in asymptomatic patients, which leads to a nonsignificant association with SCD.73

Family History Familial forms of the Brugada syndrome do not appear to be associated with a worse prognosis than are sporadic cases. In other words, a positive family history of Brugada syndrome does not predict outcome. Similarly, a positive family history for SCD is not a reliable predictor for poor outcome in asymptomatic patients with Brugada syndrome.

Genotype Large registries have not found an association between specific genetic mutations and the risk of VF. Therefore genetic testing is not recommended for the sole purpose of risk stratification.73

Invasive Electrophysiological Testing The value of inducibility of ventricular arrhythmias by programmed stimulation as a predictor of poor outcome has been debated and remains unresolved. VF or sustained polymorphic VT can be induced in approximately 50% to 70% of Brugada patients during EP testing. Although large registries agree that VT/VF inducibility at EP study is greatest among Brugada syndrome patients with previous cardiac arrest or syncope, different studies arrived at different conclusions regarding the value of the EP testing for risk stratification in asymptomatic patients. These discrepancies are likely the result of differences in patient characteristics, subtle differences in the diagnostic criteria, and the use of nonstandardized or noncomparable stimulation protocols. It is important to recognize that VF can be induced by programmed electrical stimulation in 6% to 9% of apparently healthy individuals and can represent a false-positive and nonspecific response, particularly when aggressive stimulation protocols are used. Limiting programmed ventricular stimulation to a maximum of two extrastimuli (while disregarding the induction of VF with three extrastimuli) delivered only from the RV apex (while avoiding pacing from the RVOT) has been suggested to increase the specificity of EP testing in Brugada patients. Although a negative study is a sign of good prognosis, the yield of a positive study remains controversial. Current guidelines consider the use of ventricular arrhythmia inducibility at EP study as an indication for ICD implantation in asymptomatic patients a class IIb indication.73,90 In one report, a short ventricular effective refractory period (less than 200 milliseconds) was found to be a significant risk marker, but its use for clinical decision making awaits corroboration by further studies.

Electrocardiographic Parameters Type 1 Brugada ECG pattern.  In asymptomatic patients, spontaneous type 1 Brugada ECG pattern (recorded in whichever intercostal space) is a risk marker for fatal arrhythmias (0.5% to 0.8% per year), while the event rate of patients with drug-induced type 1 ECG is much lower (less than or equal to 0.35% per year). This observation is true for asymptomatic patients and for patients presenting with syncope.73 A recent report found that the presence of a type 1 ECG pattern conferred a 3.5-fold increased risk of arrhythmic events in previously asymptomatic subjects. Because the Brugada ECG pattern is highly variable over time, it is imperative to obtain serial 12-lead ECG Holter recordings (at the fourth, third, and second intercostal spaces) to detect a spontaneous ECG pattern in asymptomatic subjects.73 The risk of arrhythmic events in patients with fever-induced type 1 ECG pattern appears to be affected by the clinical presentation: the

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies annual event rate was 3.0% in patients with a history of VF, 1.3% in patients with a history of syncope, and 0.9% in asymptomatic patients. Type 2 Brugada ECG pattern.  Patients with a type 2 ECG pattern that did not convert to type 1 during drug challenge testing were found to have a good prognosis. However, in a recent report, the prognosis of probands with a type 2 Brugada ECG pattern (even after challenge with a Na+ channel blocker) was similar to that of patients with spontaneous or drug-induced type 1 ST elevation. Patients presenting with aborted cardiac arrest had a grim prognosis (annual rate of arrhythmic events of 10.6%), whereas those presenting with syncope or no symptoms had an excellent prognosis (annual rate of arrhythmic events less than or equal to 1.2%) irrespective of their ECG pattern (that is, type 1 vs. non–type 1). Also, a family history of SCD at an age younger than 45 years and coexistence of early repolarization in the inferolateral leads (observed in 8% to 11% of Brugada patients) were predictors of poor outcome. In contrast, VT/VF inducibility during programmed stimulation was not a predictor of outcome. Furthermore, men with a spontaneous type 1 ECG recorded only at the higher leads V1 and V2 showed a prognosis similar to that of men with a type 1 ECG when using standard leads. Early repolarization.  The prevalence of early repolarization in inferolateral leads is relatively high (11% in one report) among Brugada patients, and it appears to be associated with a worse outcome in both symptomatic and asymptomatic patients. The location of J waves in the inferior and lateral leads and horizontal ST segment morphology after the J wave may be related to a highly arrhythmogenic substrate in patients with Brugada syndrome. Interval between the peak and the end of the T wave.  The time interval between the peak and the end of the T wave (Tp-e interval) is thought to represent the difference in repolarization times between subendocardial and subepicardial myocardial cells and has been proposed as an ECG marker of transmural dispersion of repolarization when measured in the precordial leads. An increased Tp-e interval in the precordial leads has been shown to identify patients at higher risk of malignant arrhythmic events in various settings.91 The Tp-e interval was shown to be significantly longer from lead V1 to V4 in patients with Brugada syndrome presenting with malignant ventricular arrhythmia or syncope than in asymptomatic patients. A maximum Tp-e interval of at least 100 milliseconds in the precordial leads has been found to be highly and independently related to arrhythmic events in a large series of unselected patients with Brugada syndrome.92 Furthermore, Tp-e interval dispersion (defined as the difference between the maximum and the minimum value of the Tp-e interval in leads V1-V6) has been reported to be useful in identifying high-risk patients.74 S wave in lead I.  The presence of a deep (greater than 0.1 mV) and/or large (greater than 40 milliseconds) S wave in lead I was found to be an independent predictor of arrhythmic events during follow-up. The S wave in lead I is generated by the terminal vector of ventricular activation, which is directed upward and somewhat to the right and backward. This vector is determined by electrical activation of the basal region of both ventricles and by depolarization of the RVOT. A prominent S wave in lead I is typically observed in cases of congenital heart disease, valvular heart disease, and cor pulmonale, which cause RV enlargement and fibrosis. Of note, a large and prominent S wave in leads I and V6 in adults is also a diagnostic criterion for RBBB, whereas an SISIISIII pattern (i.e., an S wave is present in all three leads I, II, and III) and an SIRIIRIII pattern with a QRS interval of less than 120 milliseconds can be produced by RV enlargement or zonal RV block. In the setting of Brugada syndrome, the presence of a prominent S wave in lead I could be related

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to conduction delay over the RVOT and could be used to identify highrisk patients.68 aVR sign.  A prominent R wave in lead aVR (denoted “aVR sign”), defined as an R wave equal to or greater than or equal to 0.3 mV or an R/q ratio greater than or equal to 0.75 in lead aVR, has been suggested to reflect RV conduction delay. This association has not been confirmed in large studies. Other ECG markers.  QRS duration greater than or equal to 90 milliseconds in lead V6, r–J interval greater than or equal to 90 milliseconds in lead V2, QRS duration greater than or equal to 120 milliseconds in lead V2, and fragmented QRS (defined as greater than or equal to 2 spikes within the QRS complex in leads V1-V3) have been reported to be useful in identifying high-risk patients.73,74,93

Signal-Averaged Electrocardiogram The presence of late potentials on signal-averaged ECG (which reflect ventricular conduction delay) has been reported to predict arrhythmic events during follow-up on univariate analysis; however, this finding remains unconfirmed.73

Principles of Management

Implantable Cardioverter-Defibrillator Currently, an ICD is the most effective treatment modality for the prevention of SCD in patients with Brugada syndrome. There is general consensus that ICD implantation is recommended in patients with type 1 Brugada ECG (either spontaneously or after Na+ channel blockade) and a history of aborted SCD (class I indication) (Fig. 31.14). The cumulative efficacy of ICD therapy (at least one appropriate defibrillation) in these patients is 18%, 24%, 32%, 36%, and 38% at 1, 2, 3, 4, and 5 years of follow-up, respectively.64,94 In addition, ICD therapy is considered useful in Brugada patients with syncope, seizure, or nocturnal agonal respiration judged to be likely caused by ventricular tachyarrhythmias (class IIa indication). This group of patients, however, requires a thorough clinical assessment to exclude noncardiac causes of these symptoms before recommending ICD implantation. This is particularly important given the fact that most cases of syncope in Brugada patients have a nonarrhythmic mechanism, in whom the risk of life-threatening arrhythmic events is not higher than that in completely asymptomatic patients. On the other hand, there is no similar consensus regarding the management of asymptomatic patients with the Brugada syndrome. Although some experts advocate close follow-up, others propose the evaluation of VT/VF inducibility by programmed stimulation for risk stratification in patients with spontaneous type 1 Brugada ECG. ICD implantation in those with inducible VT/VF is controversial and has a class IIb indication. For asymptomatic patients with normal baseline ECG and those with spontaneous type 1 Brugada ECG but noninducible VT/VF during programmed stimulation, a conservative approach (i.e., general precautions and follow-up) and reassurance are adequate management.82 It is important to recognize that ICD therapy is not without complications, and the decision to implant an ICD prophylactically in asymptomatic patients must be examined in the context of the low rate of cardiac events (0.5% per year) and the high long-term risk of devicerelated complications (16%). This is relevant given that Brugada patients enjoy extended longevity post ICD implantation, and because of younger age and more activity, they have a greater propensity for lead fractures, require multiple generator exchanges over a lifetime, and experience quality-of-life issues from inappropriate shocks.95 Inappropriate shocks are among the most important adverse effects of ICD therapy, occurring 2.5 times more frequently than appropriate shocks. In one report, inappropriate shocks at 10-years post ICD

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

Legend Class I Class IIa

Prior cardiac arrest or sustained VT?

Yes

ICD recommended

Class IIb No

Class III

Spontaneous type I ECG and hx of syncope judged Yes to be caused by vent arrhythmias?

ICD can be useful

No

Inducible VF on EP study?

Yes

ICD may be considered

substrate before ablation, and to ensure complete substrate elimination post ablation (Fig. 31.16).96,97 The mechanism of the ameliorative effects of epicardial ablation in the setting of Brugada syndrome remains uncertain; nonetheless, recent experimental studies suggest that catheter ablation abolishes the cells with the most prominent action potential notch, thus eliminating sites of abnormal repolarization and the substrate for ventricular arrhythmias.98 Catheter ablation therapy can be lifesaving in patients with refractory arrhythmias or those in whom ICD implantation is not feasible or not desired. The most recent expert consensus guidelines recommend ablation (class IIb) for patients with Brugada syndrome and frequent appropriate ICD shocks due to recurrent electrical storms (see Fig. 31.15).96 Importantly, despite normalization of the spontaneous type 1 Brugada ECG pattern after epicardial ablation, VT/VF recurrence was observed in 27% of patients in one report, suggesting that ICD remains the cornerstone therapy for Brugada syndrome patients.99

Pharmacological Therapy No or No EP study Asymptomatic with druginduced type I ECG and family history of SCD?

Yes

ICD is not indicated

Fig. 31.14  Consensus Recommendations for Implantable Cardioverter-Defibrillators in Patients Diagnosed With Brugada Syndrome. ECG, Electrocardiogram; ICD, implantable cardioverter defibrillator; SCD, sudden cardiac death; VF, ventricular fibrillation; VT, ventricular tachycardia. (From Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm. 2013;10:1932–1963.)

implantation were observed in 37% of ICD recipients. Inappropriate ICD therapies are usually triggered by supraventricular arrhythmias, lead fracture, and T wave oversensing. Several strategies can potentially reduce the frequency of inappropriate shocks, such as adding an atrial lead (for better discrimination between ventricular and supraventricular arrhythmias), modifying the arrhythmia detection settings (programming a single VF zone of more than 210 beats/min with or without a monitoring zone of more than 180 beats/min), and aggressive treatment of supraventricular arrhythmias. Of note, high rates of inappropriate shock have been reported even after careful device programming.1,95

Catheter Ablation In Brugada patients with frequent episodes of VT/VF, monomorphic PVCs originating predominantly in the RVOT or RV Purkinje network are often the trigger for VT, and focal radiofrequency (RF) ablation of the PVCs can be valuable in reducing the burden of arrhythmias and ICD therapies (Fig. 31.15). Furthermore, recent studies suggest that extensive ablation of the epicardial arrhythmogenic substrate in the RVOT and RV anterior wall can significantly reduce arrhythmia vulnerability and ECG manifestation of the disease in most patients. Ablation targets include sites displaying late potentials and low-voltage, fractionated bipolar electrograms, potentially representing depolarization abnormalities or concealed phase 2 reentry secondary to heterogeneous repolarization. Na+ channel blockade challenge (e.g., with flecainide, ajmaline, or procainamide) has been used to delineate the arrhythmic

Several pharmacological agents have been used for treatment and prevention of ventricular arrhythmias in patients with Brugada syndrome (see Fig. 31.15). Because of the critical role of Ito and ICaL in the arrhythmogenesis in the Brugada syndrome, drugs such as quinidine that inhibit Ito or augment ICaL have been shown to have a therapeutic value. Both groups of drugs can potentially restore the RV epicardial action potential dome, thus normalizing the ST segment and preventing phase 2 reentry and ventricular arrhythmias in the Brugada syndrome. Of note, amiodarone and beta-blockers are ineffective. Also, class IC (flecainide, propafenone) and some class IA antiarrhythmic agents (procainamide) with predominant Na+ channel blocking effects are contraindicated, as they can worsen ST elevation and arrhythmogenesis. Ito blockade.  No cardioselective Ito-specific blockers are currently available. Nonetheless, quinidine, a class IA Na+ channel blocker, has a relatively strong effect in blocking Ito and has been found effective in suppressing arrhythmia inducibility on EP testing in up to 76% of Brugada syndrome patients and in preventing the occurrence of spontaneous arrhythmias. In particular, quinidine has been extraordinarily effective in the treatment of VF storms in Brugada patients. Doses between 600 and 900 mg are recommended, if tolerated, but even lower doses can be beneficial.100 The use of quinidine is recommended as adjunctive chronic treatment in ICD patients with frequent appropriate ICD therapies, and in patients with electrical storm. Also, quinidine should be considered in high-risk Brugada patients in whom ICD implantation is not feasible or not desired. Although quinidine has been proposed as a preventative measure in asymptomatic patients displaying a spontaneous type 1 ECG pattern, this has not been evaluated in large clinical trials. Nonrandomized clinical studies suggest that EP-guided therapy with quinidine (or alternatively disopyramide) that effectively suppresses the induction of VF by programmed electrical stimulation can potentially be used as an alternative to ICD therapy under certain circumstances, especially in those patients who do not prefer device implantation. This approach requires that sustained polymorphic VT or VF is induced during EP testing, and that arrhythmia inducibility is eliminated by drug therapy despite aggressive stimulation protocol (less than or equal to 3 extrastimuli, less than or equal to 5 diastolic threshold, 2 RV sites, 2 pacing drive cycle lengths [CLs]). This strategy also requires tolerance and compliance to long-term drug therapy.100–102 The experience with disopyramide (a class IA Na+ channel blocker) is much more limited but its efficacy seems to be acceptable. More recently, bepridil was shown to suppress VT/VF, mainly through Ito inhibition and INa augmentation. Tedisamil, an experimental potent Ito

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies blocker without the relatively strong inward current-blocking actions of quinidine, may become a therapeutic option. ICaL augmentation.  Several drugs that augment ICaL can potentially be effective for the treatment of ventricular arrhythmias associated with the Brugada syndrome. Beta-adrenergic agonists, such as isoproterenol, denopamine, and orciprenaline, have been shown to be useful. Isoproterenol infusion (dose titrated to achieve a 20% increase in heart rate), alone or in combination with quinidine, has been successfully used to decrease ST elevation and suppress repetitive episodes of VF in patients presenting with electrical storms (see Fig. 31.7). Before consideration of isoproterenol therapy, however, it is critical that the diagnosis of Brugada syndrome be clearly established as the underlying etiology of VF storm. Isoproterenol infusion can be devastating in patients with VF due to other mechanisms, especially CPVT. This is especially important to recognize because a Brugada-like ST segment elevation can occasionally appear for a brief period in a patient successfully defibrillated from VF. The phosphodiesterase III inhibitors cilostazol and milrinone are other promising agents for suppressing ST elevation and arrhythmogenesis in Brugada syndrome, likely by augmenting ICaL and by reducing Ito secondary to an increase in cAMP and heart rate. INa augmentation.  Agents that augment INa, including bepridil and dimethyl lithospermate B, have also been suggested to be of value in the pharmacological approach to therapy of Brugada syndrome. As noted, the antiarrhythmic effects of bepridil are likely mediated by inhibition of Ito as well as augmentation of peak and late INa.

Lifestyle Modifications Education and lifestyle changes for the prevention of arrhythmias are critical in patients with Brugada syndrome (see Fig. 31.15). Patients need to be educated about the importance of seeking medical attention during febrile illnesses to ensure the rapid and aggressive treatment of pyrexia (often with cardiac monitoring in place). In addition, several drugs have been reported to exacerbate the ECG pattern of ST segment elevation in the Brugada syndrome and to trigger arrhythmias (as outlined at www.brugadadrugs.org), and should be avoided. Family members may consider basic life support training and operation of an automated external defibrillator for home use.

Participation in Sports Currently available data are insufficient to make definitive recommendations for participation of asymptomatic Brugada patients in competitive sports. A clear association between exercise and SCD has not been established. Given the fact that the risk of an arrhythmic event in asymptomatic patients with Brugada syndrome is small and that malignant ventricular arrhythmias are usually unrelated to physical activity, participation of asymptomatic athletes with Brugada syndrome in competitive sports is not prohibited.103 Competitive sports participation may also be considered for an athlete with previously symptomatic Brugada syndrome assuming appropriate disease-specific treatments are in place and that the athlete has been asymptomatic on treatment for at least 3 months.103

Type 1 Brugada pattern • Avoid drugs that may induce or aggravate ST segment elevation in right precordial leads (www.brugadadrugs.org) • Avoid cocaine and excessive alcohol intake • Immediately treat fever with antipyretic drugs (class I). Symptomatic

Electrical storm

Asymptomatic

Prior cardiac arrest sustained VT

Isoproterenol +/− quinidine (class IIa)

Syncope seizure NAR Presumably arrhythmic origin − +

ICD (class I)

ICD (class IIa)

Repeated appropriate shocks

Spontaneous and fever-induced type 1 Brugada pattern or Based on patient and Inducible VT/VF ECG characteristics with up to 2 ES (age, gender, Jp amplitude, QRS fragmentation,...) − +

Close follow-up with/without ILR

1015

Close follow-up

Quinidine

Type 1 Brugada pattern induced by sodium channel blocker

+

ICD

Close follow-up

ICD (class IIb)

Quinidine, if ICD indicated but refused or contraindicated (class IIa)

Quinidine (class IIa) RVOT ablation (class IIb) Cilostazol Fig. 31.15  Indications for Therapy of Patients With Brugada Syndrome. Recommendations with class designations are taken from Priori et al.1 and Priori and Blomström-Lundqvist.154 Recommendations without class designations are derived from expert consensus. ECG, Electrocardiogram; ES, extrastimuli at right ventricular apex; ICD, implantable cardioverter-defibrillator; ILR, implantable loop recorder; NAR, nocturnal agonal respiration; RVOT, right ventricular outflow tract; VF, ventricular fibrillation; VT, ventricular tachycardia. (From Antzelevitch C, Yan GX, Ackerman MJ, et al. J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge. Heart Rhythm. 2016;13:e295–e324.)

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

Fig. 31.16  Brugada Syndrome (BrS) Phenotype Abolition by Epicardial Substrate Ablation. Top, Baseline BrS electrocardiogram (ECG) pattern and epicardial color-coded duration CARTO maps. A saddleback pattern is evident in V2 (II intercostal space) with a corresponding small (2.2 cm2) purple area of abnormally prolonged potentials (210 msec in the example). The border-zone area (green/blue area >110 msec and <200 msec) shows potentials with relatively shorter duration (136 msec). Middle, BrS ECG pattern and color-coded duration maps after ajmaline. After type 1 ajmaline-induced ECG pattern, the abnormal purple area significantly increased to 21.5 cm2. Examples of abnormal and prolonged electrograms found in the purple area after ajmaline test are shown beside the map (289 and 219 msec). Bottom, BrS ECG pattern and color-coded duration maps after radiofrequency ablation of epicardial substrate. After ajmaline rechallenge at the end of the procedure, the ECG showed a horizontal and ascendant ST segment elevation, with minimal intraventricular conduction delay characterized by slight QRS broadening with a more pronounced S wave in leads I and II and qR morphology in aVR. Abnormally prolonged fragmented and delayed electrograms disappeared (87 and 96 msec, light blue color). The two examples of ventricular electrograms were recorded from the previously abnormal area, and the red asterisks indicate disappearance of the late components. Electrogram panels are from the CARTO system and show ECG lead V2 (white), distal (light blue), and proximal bipolar (yellow) and unipolar signals (yellow) at 200 mm/s speed, from top to bottom, respectively. Of note, in the middle, lead V2 shows a typical coved-type pattern, which after ablation was modified into a horizontal and at ST segment elevation. (From Pappone C, Brugada J, Vicedomini G, et al. Electrical substrate elimination in 135 consecutive patients with Brugada syndrome. Circ Arrhythmia Electrophysiol. 2017;10:e005053.)

Importantly, appropriate precautionary measures should be undertaken to avoid exercise-related hyperthermia, dehydration, and electrolyte abnormalities, which can potentially trigger ventricular arrhythmias in Brugada patients. Also, athletes should be aware of the potential impact of postexercise increase in vagal tone on triggering cardiac events. Other considerations include the acquisition of a personal automatic external defibrillator as part of the athlete’s personal sports safety gear, and establishment of an emergency action plan with the appropriate training facility and team officials.103

Family Screening Most individuals diagnosed with the Brugada syndrome have inherited the disease-causing mutation from a parent. Although a proband with the Brugada syndrome may have the disorder as the result of a de novo gene mutation, this is very rare (approximately 1%). Because the disease is caused by an autosomal dominant genetic defect, every offspring has a 50% chance of inheriting the disease-causing mutation. Nonetheless, the family history may appear to be negative because of failure to recognize the disorder in family members, low penetrance, early death of the parent before the onset of warning symptoms, or late onset of symptoms in the affected parent. Therefore the lack of a family history does not rule out a heritable disease. When the causative mutation in the index patient is identified, genetic testing is recommended in all first-degree relatives. Family members who test positive for the familial mutation should receive baseline ECG and annual ECG screening examinations, and should be instructed to avoid medications that can induce ventricular arrhythmias and to seek medical attention immediately on occurrence of symptoms. On the other hand, mutation-negative family members and their descendants have no risk for developing the disease and do not need further evaluation. Genetic testing also can be used for prenatal diagnosis. All patients who undergo genetic testing should receive pretest and posttest genetic counseling to understand the implications of testing. When genetic testing is not performed in the proband, or when genetic analysis fails to identify a definite disease-causing mutation (or only reveals one or more genetic variants of unknown significance), genetic testing in the related family members is not recommended. In this setting, it is recommended that at-risk individuals with a family history of Brugada syndrome should undergo ECG monitoring every 1 to 2 years. The presence of type 1 ST elevation should be further investigated.

TABLE 31.16  Molecular Basis of the Short

QT Syndrome

SQT1 SQT2 SQT3 SQT4 SQT5 SQT6

Gene

Protein

Functional Effect

KCNH2 (HERG) KCNQ1 (KvLQT1) KCNJ2 CACNA1C CACNB2B CACNA2D1

Kv11.1 Kv7.1 Kir2.1 Cav1.2 Cavβ2b Cavα2δ1

↑IKr ↑IKs ↑IK1 ↓ICaL ↓ICaL ↓ICaL

ICaL, L-type Ca2+ current; IK1, inward rectifier K+ current; IKr, rapidly activating delayed rectifier K+ current; IKs, slowly activating delayed rectifier K+ current; SQT1 to SQT6, short QT syndrome types 1 to 6, respectively.

SHORT QT SYNDROME The SQTS, first described in 2000, is a highly arrhythmogenic inherited channelopathy occurring in young individuals with structurally normal hearts. Affected patients are characterized by constantly short QT intervals associated with AF, syncope, and/or SCD.104

Genetics of the Short QT Syndrome To date, mutation analysis has implicated six distinct genes in the etiology of a proportion of patients diagnosed with SQTS, although the majority of diagnosed cases do not have reported genetic associations. It is expected that further genes will be identified. Genetic studies reveal a genetically heterogeneous disease with gain-of-function mutations of voltage-gated K+ channel genes (Table 31.16). Loss-of-function mutation in the L-type Ca2+ channel genes have also been linked to SQTS, but in some cases might represent a clinical spectrum of Brugada or early repolarization syndromes. These mutations cause either an increase in the outward repolarizing K+ currents or a decrease in the inward depolarizing Ca2+ currents, leading to shortening of the action potential duration, the QT interval, and the effective refractory period.

Mutations Related to the Potassium Current SQT1, the most common genotype, is caused by mutations of the KCNH2 gene (HERG, encoding the α-subunit Kv11.1 of the IKr). A

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

gain-of-function mutation on KCNH2 causes a shift of voltage dependence of inactivation of IKr by +90 mV out of the range of the action potential, which results in a significant increase in IKr during the action potential plateau. The resulting IKr augmentation achieved by altered gating hastens repolarization, thereby shortening the action potential duration and QT interval and facilitating reentrant excitation waves to induce atrial and/or ventricular arrhythmias. Of note, loss-of-function mutations in the KCNH2 gene are responsible for LQT2. SQT2 is caused by mutations of the KCNQ1 gene (KvLQT1, encoding the α-subunit Kv7.1 of the IKs). A gain-of-function mutation of KCNQ1 causes a shift in the voltage dependence of IKs activation by −20 mV and acceleration of activation kinetics, leading to enhancement of IKs and shortening of the action potential duration and QT interval. Of note, loss-of-function mutations in the KCNQ1 gene are responsible for LQT1. SQT3 is caused by a mutation in the KCNJ2 gene (encoding the strong inwardly rectifying channel protein Kir2.1 of the IK1). A gainof-function mutation causes a significant increase in the outward IK1 at potentials between −75 and −45 mV, leading to shortening of the QT interval and asymmetrical T waves, with a normal ascending component and a rapid descending terminal phase. On the other hand, loss-offunction mutations in the KCNJ2 gene, identified in patients with the Andersen syndrome, generate prolongation of the QT intervals (LQT7). Because IKr, IKs, and IK1 each contribute differentially to cardiac repolarization, gene-specific mutations will differentially influence repolarization and the susceptibility to arrhythmia. However, detailed information regarding the genotype-phenotype correlation is currently limited by the rare nature of this disorder.

Mutations Related to the Calcium Current SQT4–6 is caused by mutations in the CACNA1C, CACNB2, and CACNA2D1 genes, encoding the α1C-, β2b-, and α2δ1-subunits of the cardiac L-type Ca2+ channel Cav1.2, respectively. Loss-of-function mutations of those genes result in major attenuation in ICaL amplitude, leading to shortening of the action potential duration, and are associated with asymmetrical T waves, an attenuated QT–heart rate relationship, and AF. Three patients reported to harbor these mutations had a Brugada type 1 phenotype. In addition, loss-of-function mutations of the CACNA1C and CACNB2 genes have recently been linked to a sudden death syndrome that combines the features of Brugada syndrome, including the characteristic ECG pattern, and a short QT interval. It was speculated that these mutations cause Brugada syndrome by aggravating transmural voltage gradients. Of note, loss-of-function mutations in L-type Ca2+ channel proteins can also, in certain cases, cause early repolarization syndromes. Conversely, a gain-of-function mutation of the L-type Ca2+ channel is known to generate the LQT8 (Timothy syndrome).104

Pathophysiology of Short QT Syndrome Reduced wavelength of activation and heterogeneous shortening of action potential duration (preferentially more in epicardial and endocardial layers, causing increased transmural dispersion of repolarization), predispose to functional reentry and play a role in the increased atrial and ventricular susceptibility to premature stimulation, leading to AF and VF.1,104

Epidemiology SQTS has been described in very few families worldwide; therefore all the information available is based on small numbers of cases. The majority (more than 75%) of affected subjects have been men, suggesting a sex-dependent penetrance (similar to the Brugada syndrome). Nonetheless, the prevalence of cardiac arrest appears equal in both genders,

suggesting that females should not be regarded at a lower risk for malignant arrhythmias. The age of presentation is quite variable, ranging from infancy to the eighth decade of life, with a mean age of 20 to 30 years. There seems to exist an age dependency in the susceptibility to arrhythmias, with a peak in the occurrence of cardiac arrest in the first year of life (incidence, 4% per year) and a second peak between 20 and 40 years of age (incidence, 1.3% per year). Up to 72% of patients with SQTS have a family history of SQTS or SCD.105,106

Clinical Presentation More than 60% of the subjects have symptoms at presentation, with cardiac arrest being the most frequent symptom, representing the first clinical manifestation in one-third of patients. Syncope is observed as a first clinical presentation less frequently (14%). AF has been documented in approximately 30% of patients with SQTS. No information is available on whether specific triggers precipitate cardiac events, and the majority of cardiac events appear to occur under resting conditions or during sleep.107

Electrocardiographic Features A short QT interval is the hallmark of SQTS. However, the definition of the lower limit of a “normal” QT interval and the diagnostic criteria sufficient to establish the diagnosis of SQTS remain to be determined unequivocally. Based on ECG analysis of 14,379 healthy individuals, some investigators proposed that a QTc interval less than 350 milliseconds (which is less than 88% of the mean predicted value, or less than 2 standard deviations below the mean) be considered short, and a QTc interval less than 320 milliseconds (which is less than 80% of the mean predicted value) be considered abnormally short. The prevalence of a QTc interval less than 88% of the mean was 2.5% and that of a QTc interval less than 80% of the mean was 0.03%.104 Importantly, the mere presence of a short QT interval on the surface ECG does not necessarily translate into an increased risk of arrhythmias. In fact, in a study in a middle-aged Finnish population (n = 10,822) followed up for 29 ± 10 years, the prevalence of QTc less than 320 milliseconds (using the Bazett formula) was 0.1% and that of QTc less than 340 milliseconds was 0.4%. There was no difference in the all-cause or cardiovascular mortality between subjects with a very short QTc (less than or equal to 320 milliseconds) or short QTc (less than or equal to 340 milliseconds) and those subjects with a normal QTc interval (360 to 450 milliseconds). On the other hand, in a recent epidemiological study of a cohort of 1.7 million persons with 6.4 million ECGs, a QTc of 300 milliseconds or less was extraordinarily rare (0.7 per 100,000 ECGs) and was associated with significant ECG abnormalities and a 2.6-fold increased risk of death.108 Of note, the physiological shortening of the QT interval during exercise-induced tachycardia can be blunted in patients with SQTS. This is relevant because impaired QT adaptation to heart rate changes makes the correction formulas such as those of Bazett or Fredericia inappropriate or of limited value in SQTS patients with heart rates above 100 beats/min or below 60 beats/min. The poor performance of correction formulas, in addition to the lack of a universal diagnostic cutoff value for an SQTS, makes it difficult to establish a diagnosis in cases of borderline shortened QT intervals. Several other ECG markers can potentially be helpful to support the diagnosis of SQTS especially in patients with borderline QTc intervals (QTc intervals 330 to 370 milliseconds). In addition to constantly short QTc intervals, affected patients have in common a short or even absent ST segment, with the T wave initiating immediately from the S wave. Extreme abbreviation of the Jpoint-Tpeak interval (less than 120 milliseconds) can help distinguish patients with SQTS from healthy subjects with an apparent abbreviation of the ST segment and shortened QT

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies intervals (mean Jpoint-Tpeak interval of 188 ± 11 milliseconds). Furthermore, the increase in dispersion of repolarization in patients with SQTS results in increased Tp–e interval and ratio of Tp–e/QT. In addition, high-amplitude, narrow, and symmetrical T waves in the precordial leads are frequently observed in SQTS patients; but asymmetrical T waves also can be observed, especially in SQT3 patients. Another ECG characteristic observed in most (81%) SQTS patients is PQ segment depression (greater than or equal to 0.05 mV), likely caused by heterogeneous shortening of atrial repolarization.109

Diagnosis of the Short QT Syndrome A diagnostic scoring system to facilitate the diagnosis of SQTS was proposed in 2011 by Gollob et al., based on a comprehensive review of 61 reported cases of the SQTS. The Gollob score incorporates ECG findings, clinical history, family history, and genotype findings (Table 31.17). In this system, all patients should have a QTc interval (using the Bazett formula) of no more than 370 milliseconds. Clinical events (cardiac arrest, nonsustained polymorphic VT or VF, syncope, AF) must occur in the absence of other identified clinical pathologies. Although these diagnostic criteria can potentially facilitate evaluation in suspected cases of SQTS, their value for evaluation of family members can poten-

TABLE 31.17  Diagnostic Criteria of the

Short QT Syndrome

QTc • <370 msec • <350 msec • <330 msec • Jpoint-Tpeak interval <120 msec

1 2 3 1

Clinical History • History of sudden cardiac arrest • Documented polymorphic VT or VF • Unexplained syncope • Atrial fibrillation

2 2 1 1

Family History • First- or second-degree relative with high-probability SQTS • First- or second-degree relative with autopsy-negative sudden cardiac death • Sudden infant death syndrome Genotype • Genotype positive • Mutation of undetermined significance in a culprit gene

1019

tially be limited because of incomplete disease penetrance. Importantly, treatment considerations should be reserved for subjects receiving a high-probability score, whereas medical surveillance or expert opinion should be considered for intermediate- or low-probability cases. More recently, in 2013, an expert consensus recommended that SQTS is diagnosed in the presence of a QTc of 330 milliseconds or less. SQTS also can be diagnosed in the presence of a QTc between 330 and 360 milliseconds in conjunction with at least one additional criterion including: (1) a pathogenic mutation, (2) family history of SQTS, (3) family history of SCD below age 40, or (4) survival of a VT/VF episode in the absence of heart disease.1

Electrophysiology Testing The role of EP study in diagnosis and risk stratification is not yet fully defined. During EP testing, atrial and ventricular effective refractory periods are significantly shortened, and VT/VF is inducible in 60% to 91% of patients. However, inducibility of ventricular arrhythmias does not appear to be predictive of adverse clinical outcome.

Genetic Testing Genetic analysis may be considered for patients with a strong clinical index of suspicion for SQTS based on the personal and family history and the ECG phenotype. A mutation in genes related to SQTS is observed in 23% of probands, with SQTS1 being the most common. Genetic testing can help identify silent carriers of SQTS-related mutations; however, the risk of cardiac events in genetically affected individuals with a normal ECG is currently not known. Similarly, given the limited number of patients with SQTS so far identified, genetic analysis at present does not contribute to risk stratification.

Differential Diagnosis Shortening of the QT interval can be encountered in a variety of pathophysiological states, including hyperkalemia, hypercalcemia, hyperthermia, acidosis, digitalis overdose, androgen use, increased vagal tone, administration of acetylcholine and catecholamines, and carnitine deficiency (an autosomal recessive disorder due to a defective transport of carnitine into the cell).104,110

Risk Stratification 2 1 1 2 1

Notes: • High-probability SQTS, ≥4 points; intermediate-probability SQTS, 3 points; low-probability SQTS, ≤2 points. • Electrocardiogram: Must be recorded in the absence of modifiers known to shorten the QT. • Jpoint-Tpeak interval must be measured in the precordial lead with the greatest amplitude T wave. • Clinical history: Events must occur in the absence of an identifiable etiology, including structural heart disease. • Points cannot be combined for the following three markers: cardiac arrest, documented polymorphic VT, and unexplained syncope. • Family history: Points can only be received once in this section. • A minimum of 1 point must be obtained in the electrocardiographic section to obtain additional points. QTc, Corrected QT interval; SQTS, short QT syndrome; VF, ventricular fibrillation; VT, ventricular tachycardia.

The optimal strategy for risk stratification of asymptomatic SQTS patients remains uncertain. SQTS patients with prior cardiac arrest are considered at high risk for SCD. However, no independent risk factors for lifethreatening arrhythmias have been identified in asymptomatic patients. The degree of shortening of the QT interval at faster heart rates has not been found to be a prognostic indicator in asymptomatic patients. Although mutation carriers exhibited a significantly shorter QTc interval compared with noncarriers, this finding did not correlate with a different outcome. As noted, inducibility of ventricular arrhythmia during EP testing was found ineffective for predicting cardiac arrest (sensitivity of 37% and a negative predictive value of 58%). Also, the Gollob score was not a predictor of adverse cardiac events in this patient population.106

Principles of Management

Implantable Cardioverter-Defibrillator At present, ICD implantation is the therapy of choice for the prevention of SCD in symptomatic SQTS patients (survivors of cardiac arrest and those with spontaneous VT). The role of ICD therapy for primary prevention is uncertain, although ICD implantation may be reasonable in asymptomatic SQTS patients with a strong family history of SCD (class IIb). Importantly, patients with SQTS are potentially susceptible to inappropriate shocks because of oversensing of the tall, narrow T

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

waves and the high prevalence of AF. Therefore appropriate programming of the ICD is necessary.1

Pharmacological Therapy Of the pharmacological agents tested to date, quinidine seems the most effective at prolonging the QT interval in patients with SQTS. Quinidine was shown to prolong the QT interval, normalize atrial and ventricular effective refractory periods, and prevent inducibility of ventricular arrhythmias during EP testing in patients with SQT1, with a weaker and variable effect in the non-SQT1 patients. In a recent report, the incidence of arrhythmic events during follow-up was 4.9% per year in the patients without pharmacological prophylaxis, whereas no arrhythmic events occurred in those receiving hydroquinidine (even if previously symptomatic). Hence, quinidine can potentially serve as an adjunct to ICD therapy in the treatment of paroxysmal AF or recurrent ventricular tachyarrhythmias in this subgroup of patients or as an alternative option to ICD in patients who cannot receive it (small children) or who decline the implant. Quinidine may also be considered primary prevention of cardiac arrest in asymptomatic SQTS patients with a family history of SCD.1 Other drugs, including class III agents (e.g., sotalol), are not effective in prolonging the QTc interval in SQT1 patients, and efficacy in the other subtypes is unknown.1

Participation in Sports Until the phenotype of SQTS is better understood, a universal restriction from competitive sports, with the possible exception of class IA activities, seems to represent the most prudent recommendation.

CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA CPVT, also known as familial polymorphic VT, is a rare but highly malignant inherited arrhythmia disorder characterized by exercise- and stress-induced polymorphic or bidirectional VT. CPVT is an important cause of syncope and SCD in individuals with a structurally normal heart.111

Genetics of Catecholaminergic Polymorphic Ventricular Tachycardia Mutations in genes that encode for four key Ca2+ regulatory proteins are currently implicated in the pathogenesis of CPVT (Table 31.18).

TABLE 31.18  Molecular Basis of

Catecholaminergic Polymorphic Ventricular Tachycardia Disease

Gene

Protein

Inheritance

% Probands

CPVT1

RyR2 CASQ2

CPVT3

Unknown

Unknown

CPVT4

CALM1

Calmodulin

CPVT5

TRDN

Triadin

Autosomal dominant Autosomal recessive Autosomal recessive Autosomal dominant Autosomal recessive

50%–55%

CPVT2

Ryanodine receptor 2 Calsequestrin

2%–5% Rare <1% 1%–2%

CPVT, Catecholaminergic polymorphic ventricular tachycardia.

CPVT1 is the most common genetic variant and is caused by mutations in the RyR2 gene. RyR2 is the major calcium release channel of the sarcoplasmic reticulum, mediating excitation-contraction coupling. Approximately 50% to 70% of patients with CPVT harbor RyR2 mutations. CPVT mutant RyR2s typically show gain-of-function defects following channel activation by PKA phosphorylation (in response to beta-adrenergic stimulation or caffeine), resulting in uncontrolled Ca2+ release from the sarcoplasmic reticulum during electrical diastole, which facilitates the development of DADs and triggered arrhythmias. Of note, missense mutations in RyR2 have also been linked to a form of arrhythmogenic cardiomyopathy (ARVC-2) characterized by exercise-induced polymorphic VT that does not appear to have a reentrant mechanism, occurring in the absence of significant structural abnormalities. Patients do not develop characteristic features of ARVC on the 12-lead ECG or signal-averaged ECG, and global RV function remains unaffected. ARVC-2 shows a closer resemblance to familial CPVT in both etiology and phenotype; its inclusion under the umbrella term of ARVC remains controversial. CPVT2 is much less common (accounting for less than 5% of CPVT index cases), and is associated with homozygous mutations in the CASQ2 gene. Heterozygous carriers of one CASQ2 mutation are usually healthy. Although CASQ2 mutations are typically identified in consanguineous families, compound heterozygosity has been observed in nonconsanguineous families. CASQ2 is a sarcoplasmic reticulum Ca2+ buffering protein associated with RyR2. CASQ2 plays an active role in the control of Ca2+ release from the sarcoplasmic reticulum to the cytosol. Although some of CASQ2 mutations are thought to compromise CASQ2 synthesis and result in reduced expression or complete absence of CASQ2 in the heart, other mutations seem to cause expression of defective CASQ2 proteins with abnormal regulation of cellular Ca2+ homeostasis. CPVT3 is caused by a mutation mapped to chromosome 7. The exact gene has not yet been identified. CPVT4 is caused by a mutation of the CALM1 gene (encoding calmodulin). Calmodulin is a Ca2+-binding protein that directly interacts with and regulates RyR2 and L-type Ca2+ channels. Like CPVT1, CPVT4 is autosomal dominant. Of note, three genes (CALM1–3) in the human genome encode exactly the same calmodulin protein. Mutations in CALM1–3 have also been linked to LQTS. In addition, mutations in CALM1 were identified in a family with idiopathic VF. CPVT5 is caused by mutations of the TRDN gene (encoding triadin). Triadin is a transmembrane sarcoplasmic reticulum anchoring protein of calsequestrin to the ryanodine channel. CPVT2, CPVT3, and CPVT5 are autosomal recessive. Recently, three novel loss-of-function mutations of the KCNJ2 gene (encoding for the strong inwardly rectifying channel Kir2.1 of the IK1) have been found in patients with CPVT, and may represent a CPVT phenocopy. These patients had prominent U waves, ventricular ectopy, and polymorphic VT, but no dysmorphic features or skeletal muscle abnormalities. IK1 reduction may trigger arrhythmia by allowing inward currents, which are no longer counterbalanced by the strong outward IK1, to gradually depolarize the membrane potential during phase 4. Membrane depolarization during phase 4 induces arrhythmia by facilitating spontaneous excitability.

Pathophysiology of Catecholaminergic Polymorphic Ventricular Tachycardia Mechanism of Ventricular Arrhythmias

Abnormalities in the control of sarcoplasmic reticulum Ca2+ release constitute the central pathogenic abnormality in CPVT, although considerable controversy exists about the molecular mechanisms causing these defects. RyR2 and CASQ2 are both critically involved in the regulation of cardiac excitation-contraction coupling. Ca2+ influx via the

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies L-type Ca2+ channels in the cell membrane during the action potential plateau triggers more massive Ca2+ release (Ca2+ transients) from the sarcoplasmic reticulum into the cytosol via activation of RyR2. This amplifying process, termed calcium-induced calcium release (CICR), causes a rapid increase in cytosolic Ca2+ concentration to a level required for optimal binding of Ca2+ to troponin C and induction of contraction. During diastole, most of the surplus Ca2+ in the cytosol is resequestered into the sarcoplasmic reticulum by the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), the activity of which is controlled by the phosphoprotein phospholamban. In addition, some of the Ca2+ is extruded from the cell by the Na+-Ca2+ exchanger to balance the Ca2+ that enters with the Ca2+ current. Recurring Ca2+ release-uptake cycles provide the basis for periodic elevations of the cytosolic Ca2+ concentration and contractions of myocytes, and hence for the orderly beating of the heart (see Fig. 1. 7). The molecular mechanisms by which RyR2 mutations alter the physiological properties and function of RyR2 are not completely defined. It has been suggested that CPVT mutations in RyR2 reduce the binding affinity of RyR2 for the regulatory protein FKBP12.6 (calstabin-2), which stabilizes the closed conformational state of the RyR2 channel, thus enabling the channel to close completely during diastole (at low intracellular Ca2+ concentrations) and preventing aberrant Ca2+ leakage from the sarcoplasmic reticulum, ensuring muscle relaxation. PKA phosphorylation (induced by beta-adrenergic stimulation) of the mutant channels results in further worsening of the binding affinity of FKBP12.6 for the mutant RyR2, thus increasing the probability of an open state at diastolic Ca2+ concentrations. As a consequence, the mutant RyR2 channel fails to completely close during diastole, resulting in diastolic Ca2+ leak from the sarcoplasmic reticulum during stress or exercise. An alternative hypothesis is that RyR2 mutations sensitize the channel to luminal (within the sarcoplasmic reticulum) Ca2+ such that under baseline conditions, where sarcoplasmic reticulum load is normal, there is no Ca2+ leak. Under beta-adrenergic (sympathetic) stimulation, sarcoplasmic reticulum Ca2+ concentration becomes elevated above the reduced threshold, causing Ca2+ to leak out of the sarcoplasmic reticulum. A third hypothesis is that mutations in RyR2 impair the intermolecular interactions between discrete RyR2 domains necessary for proper folding of the channel and self-regulation of channel gating.112 Calsequestrin is the most important Ca2+ storage protein in the sarcoplasmic reticulum and it forms a part of a large quaternary complex with RyR2, triadin, and junctin; together, these proteins play a major role in regulating intracellular Ca2+. Calsequestrin represents a highcapacity, low-affinity Ca2+-binding protein that is able to bind luminal Ca2+ (40 to 50 Ca2+ ions per molecule) during diastole, buffering Ca2+ within the sarcoplasmic reticulum and preventing diastolic Ca2+ release via RyR2 into the cytosol. CASQ2 mutations result in disruption of the control of RyR2s by luminal Ca2+ required for effective termination of sarcoplasmic reticulum Ca2+ release and prevention of spontaneous Ca2+ release during diastole, leading to diminished Ca2+ signaling refractoriness and generation of arrhythmogenic spontaneous Ca2+ releases (eFig. 31.4).112 Dysregulation of RyR2 likely underlies the disease mechanisms of calmodulin mutation-associated CPVT. Calmodulin is a small cytoplasmic Ca2+-binding protein that regulates, directly or indirectly, the activity of proteins that play a key role in excitation–contraction coupling, and in particular, those responsible for the release and subsequent sequestration of cytosolic Ca2+ into the sarcoplasmic reticulum. The main binding partner of calmodulin in cardiac cells is the RyR2, which regulates Ca2+ release from the sarcoplasmic reticulum. Calmodulin inhibits RyR2 channel open probability. CPVT-linked calmodulin mutations result in defective calmodulin–RyR2 binding and impaired

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calmodulin inhibition of RyR2 function. This can lead to excessive Ca2+ release from RyR2 channels, primarily from insufficient termination of RyR2-mediated Ca2+ release.5,6 DADs and triggered activity have been proposed as the arrhythmogenic mechanism in CPVT because the bidirectional ECG pattern of this VT closely resembles the arrhythmias associated with intracellular Ca2+ overload and the DADs observed during digitalis toxicity. CPVTrelated mutations lead to cytosolic Ca2+ overload, which results in activation of the Na+-Ca2+ exchanger, which in turn generates a net inward current (the so-called transient inward current [Iti]). Iti underlies DADs, which may reach the threshold for Na+ channel activation and trigger abnormal beats. When the DADs are of low amplitude, they are usually not apparent or clinically significant. Probably the most important influence that causes subthreshold DADs to reach threshold is a decrease in the initiating cycle length; fast heart rates increase both the amplitude and rate of the DADs. In addition, catecholamines can facilitate the development of DADs via several mechanisms, including (1) increasing the L-type Ca2+ current through stimulation of beta-adrenergic receptors and increasing cAMP, which results in an increase in transsarcolemmal Ca2+ influx and intracellular Ca2+ overload; (2) enhancing the activity of the Na+-Ca2+ exchanger, thus increasing the likelihood of DADmediated triggered activity; (3) enhancing the uptake of Ca2+ by the sarcoplasmic reticulum, leading to increased Ca2+ stored in the sarcoplasmic reticulum and the subsequent release of an increased amount of Ca2+ from the sarcoplasmic reticulum during contraction; and (4) increasing the heart rate. These effects underlie the increased susceptibility to ventricular arrhythmias in CPVT patients during exercise and emotional stress associated with increased sympathetic stimulation and increased heart rates. Importantly, in the setting of digitalis poisoning, the abnormal RyR2 behavior leading to spontaneous Ca2+ release and DADs is secondary to the elevation of the sarcoplasmic reticulum Ca2+ content (store overload–induced Ca2+ release, SOICR). In CPVT, on the other hand, spontaneous Ca2+ release and DADs can occur without Ca2+ overload. Mutations in RyR2 or CASQ2 lead to defective Ca2+ signaling that reduces the sarcoplasmic reticulum Ca2+ threshold for spontaneous Ca2+ release below the normal baseline level (“perceived” Ca2+ overload). A similar mechanism may underlie triggered arrhythmias in other disease conditions, including heart failure and ischemic heart disease, in which sarcoplasmic reticulum Ca2+ release regulation is compromised because of acquired defects in components of the RyR2 channel complex. As expected with DAD-mediated triggered activity, a positive direct correlation has been observed between the coupling interval of ventricular arrhythmias and the preceding R-R interval. This observation can also suggest that supraventricular arrhythmias commonly observed prior to the onset of ventricular arrhythmias during exercise in CPVT patients may act as a trigger for the development of DADs and triggered activity in the ventricle.

Mechanism of the Bidirectional Morphology of Ventricular Tachycardia The EP mechanisms leading to the characteristic bidirectional morphology of the VT are not clear. Changes in conduction direction from a single ventricular focus with every other beat, VT originating from one focus that triggers another focus, and double ventricular foci (from the right and left apical portions of the heart) are some of the proposed mechanisms. The QRS morphology of bidirectional VT is inconsistent in the same recording lead, suggesting that the focus of the arrhythmia can vary to some extent. Some investigators suggested that CPVT starts from a single focus or double foci, usually originating from the RVOT, whereas the ensuing beats tend to originate from the LV. Others found

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies Normal

CPVT

DAD

MP 3Na+

LCC

NCX

Ca2+

[Ca2+]c Time

SR

SERCA

RyR2

A

TRD CASQ2

[Ca2+]SR Refractoriness

B

eFig. 31.4  Calcium Cycling in Normal Myocytes and Myocytes Harboring Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Calsequestrin (CASQ2) Mutations. (A) In normal myocytes, Ca2+ influx through L-type Ca2+ channels (LCC) during the action potential activates ryanodine receptor type 2s (RyR2s) and initiates the release of Ca2+ stored in the sarcoplasmic reticulum (SR) on CASQ2 polymers. SR Ca2+ release terminates when the drop in intra-SR [Ca2+] causes RyR2s to close because of inhibition by CASQ2 monomers at reduced [Ca2+]SR. The RyR2s stay refractory until [Ca2+]SR is restored by sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). The rate of [Ca2+]SR recovery and thus the rate of restitution from luminal Ca2+dependent refractoriness depends on both SERCA activity and the Ca2+binding capacity of CASQ2. Ca2+ signaling refractoriness prevents spontaneous Ca2+ release during diastole. (B) Arrhythmogenic CASQ2 mutations disrupt Ca2+ handling through either one or a combination of decreased CASQ2 expression, reduced CASQ2 Ca2+ binding capacity (via disruption of CASQ2 polymerization), and impaired CASQ2 interaction with the RyR2 complex (via triadin [TRD]). Alterations in CASQ2 abundance and/or behavior result in diminished and shortened Ca2+ signaling refractoriness after each release through accelerating recovery of [Ca2+]SR, altering RyR2 gating dependency on [Ca2+]SR, or both. PKAmediated stimulation of SERCA (via PLB) further accelerates SR refilling, accounting for the dependency of CPVT on adrenergic stimulation. Compromised RyR2 refractoriness results in spontaneous SR Ca2+ release, which in turn elicits delayed afterdepolarizations (DADs) through stimulation of Na+-Ca2+ exchange (NCX). PKA, Protein kinase A; PLB, phospholamban. (Reproduced with permission from Györke S. Molecular basis of catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm. 2009;6:123–129.)

1021.e1

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

that a left posterior inferior origin accounts for the majority of cases. In addition, the Purkinje network has been suggested as the site of origin of bidirectional VT, with alternating firing from the right and left branches of the Purkinje fibers. A recent experimental model suggested a “ping-pong” mechanism may underlie ventricular arrhythmias in CPVT, whereby DAD-induced triggered activity develops at different heart rate thresholds in different regions of the His-Purkinje system (HPS) or ventricles. First, once the heart rate exceeds a certain threshold, ventricular bigeminy develops from a single site in the HPS or ventricular myocardium. The shortened R-R cycle length due to ventricular bigeminy induces DAD-triggered beats from a second focus within the HPS, with the latter reciprocally activating PVCs from the first focus; a process that is repeated back and forth, in a ping-pong pattern. “Reciprocating bigeminy” from the two sites produces the bidirectional VT characteristic of CPVT. Polymorphic VT results when three or more sites concurrently develop bigeminy, whereas monomorphic VT develops when repetitive DADs generate a run of triggered activity from a single site.

Mechanism of Drug Effects As noted, activation of the adrenergic nervous system exerts profound effects on Ca2+ handling, and it is often the initiator of Ca2+-mediated arrhythmogenesis. Hence, beta-adrenergic blockade plays an important role in the management of CPVT. It is likely that beta-blocker therapy inhibits the increase of Ca2+ content of the sarcoplasmic reticulum with reduced propensity to aberrant Ca2+ leakage from the sarcoplasmic reticulum during diastole. Also, beta-blockers attenuate the effect of adrenergic stimulation induced by exercise or emotion. In addition, because the amplitude of DADs is directly related to heart rate, the bradycardia induced by beta-blockers reduces the probability that a DAD would reach the threshold for triggering PVCs. Accordingly, the lower the heart rate achieved with beta-blocker therapy, the higher the probability of preventing malignant arrhythmias. Flecainide (a Na+ channel blocker) has recently been demonstrated to prevent lethal ventricular arrhythmias in CPVT. The mechanisms mediating those effects are still debated. It has been speculated that flecainide suppresses spontaneous sarcoplasmic reticulum Ca2+ release events via direct blockade of RyR2 channels, reducing Ca2+ spark amplitude. An alternative hypothesis is that flecainide prevents the development of abnormal threshold potentials through the inhibition of the Na+-Ca2+ exchange pump that contributes to the formation of premature and arrhythmogenic Ca2+ waves. The negative chronotropic effects of flecainide can also reduce ventricular arrhythmias during exercise by keeping the heart rate below the threshold of PVC initiation.

Epidemiology The prevalence of CPVT has been roughly estimated at 1 : 10,000. Despite the low prevalence, CPVT is an important cause of sudden cardiac arrest in young individuals, and cardiac event rates as high as 80% before the age of 40 years have been reported if left untreated. The mean age at clinical presentation is between 7 and 9 years, although later onset has been reported. Approximately 30% of probands have a family history of stress-related syncope, seizure, or SCD before age 40 years. There is a high level of penetrance of the RYR2-related disease (75% to 80%); therefore asymptomatic individuals with RYR2-related CPVT are a minority.1

Clinical Presentation CPVT patients typically present with syncope triggered by exercise or emotion, and a distinctive pattern of reproducible, stress-related, bidirectional VT in the absence of structural heart disease or QT interval prolongation.

CPVT is one of the most malignant forms of ventricular arrhythmia. The majority of untreated CPVT patients develop symptoms (syncope, VT or VF) by age 40 and overall mortality is 30% to 50%. SCD can be the first manifestation of the disease in a significant proportion of cases.

Electrocardiographic Features The resting ECG of patients with CPVT is often normal, without prolongation or shortening of the QT interval, atrioventricular and intraventricular conduction defects, or Brugada-like ST elevation. Sinus bradycardia and prominent U waves can be observed in some patients. “Bidirectional VT,” the hallmark of CPVT, is characterized by an alternating QRS axis with 180-degree rotation on a beat-to-beat basis (Fig. 31.17). The typical bidirectional VT, however, is not present in all patients. In one report, bidirectional VT was documented in only 35% of probands, whereas other patients showed polymorphic VT or VF. Single PVCs during an exercise test can be the only finding recorded in some CPVT patients. Importantly, the morphology of VT, which is polymorphic or bidirectional, is strongly dependent on the ECG recording lead. When the maximal QRS vector changes in one lead during bidirectional VT, the axis perpendicular to the former lead shows polymorphic VT. However, unlike other polymorphic VTs, such as torsades de pointes, the QRS morphology is not chaotic but has some regularity. A characteristic feature of CPVT is the progressive worsening of arrhythmias with increasing exercise workload. Ventricular arrhythmias during exercise stress testing appear quite consistently at a heart rate of 110 to 130 beats/min. Initially, monomorphic PVCs appear, which become polymorphic with continued exercise. Typically, the PVCs in CPVT are late-coupled and can exhibit an LBBB pattern with an inferior axis or RBBB pattern with a superior axis. Notably, PVC morphologies are usually reproducible in an individual patient. With increasing heart rates, ventricular bigeminy, ventricular couplets, and nonsustained VT develop. If exercise is not promptly discontinued, bidirectional VT may degenerate into polymorphic VT and VF. On termination of exercise, arrhythmias progressively diminish in terms of VT rate and VT duration until they disappear. Isolated premature atrial complexes (PACs), nonsustained SVT, and short runs of AF are usually observed during exercise, with an onset at a range of heart rates similar to or slower than that of ventricular arrhythmias.113 PVCs also can be observed in healthy subjects in response to exercise testing. Certain features of PVCs during an exercise test can potentially assist in distinguishing CPVT from healthy controls, including a larger number of PVCs, first appearance at higher workload, an LBBB pattern and an inferior axis, bigeminy or trigeminy at peak stress, QRS duration of more than 120 milliseconds, a coupling interval of more than 400 milliseconds, and disappearance in the first minute of the recovery.114

Diagnosis of Catecholaminergic Polymorphic Ventricular Tachycardia A clinical diagnosis of CPVT is made based on symptoms (syncope or aborted SCD), family history, and unexplained exercise or catecholamineinduced bidirectional VT or polymorphic PVCs or VT in an individual (especially those younger than 40 years), in the presence of a structurally normal heart and normal baseline ECG. Ventricular arrhythmias can be observed (using a combination of Holter monitoring, exercise testing, and drug provocation) in more than 80% of patients.1 In patients presenting with syncope or cardiac arrest, the CPVT diagnosis is frequently missed or delayed, unless exercise stress testing or ambulatory cardiac monitoring is performed to document ventricular arrhythmias. Not infrequently, syncopal episodes are considered as vasovagal in origin, and no further workup is performed. If the loss of consciousness is associated with convulsions, it can be misdiagnosed as epileptic seizures if a prolonged circulatory arrest resulted in brain

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

I

aVR

V1

V3

II

aVL

V2

V5

III

aVF

V3

V6

1023

II

Fig. 31.17  Ventricular Arrhythmias in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). This 12-lead electrocardiogram from a 9-year-old boy with ryanodine-positive CPVT shows a transition from bidirectional ventricular tachycardia followed by brief polymorphic ventricular tachycardia to ventricular fibrillation. (From Roses-Noguer F, Jarman JWE, Clague JR, Till J. Outcomes of defibrillator therapy in catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm. 2014;11:58–66.)

ischemia. Unexplained cardiac arrest is also frequently misdiagnosed as idiopathic VF. CPVT should be suspected when a syncopal episode induced by exercise or emotion occurs in a child or in a young patient with a normal resting ECG and no structural heart disease. In addition, CPVT should be considered in all cases of idiopathic VF and unexplained cardiac arrest (normal coronary arteries, normal ventricular function, and normal ECG), especially if an adrenergic trigger is present.115

Exercise Stress Testing A standardized exercise stress test is the most important step for diagnosis of CPVT. In at least 80% of CPVT patients, exercise stress testing induces ventricular arrhythmias, which typically appear when the sinus rate exceeds an individual threshold rate (usually at 110 to 130 beats/ min). The progressive worsening of arrhythmias during exercise is highly reproducible and is a diagnostic marker of CPVT. Sometimes, the exercise-provoked arrhythmias can be demonstrated only after a delay of months or more after the first syncopal episode has occurred, emphasizing the necessity of repeated exercise stress tests when there is a high suspicion of CPVT.

Ambulatory Cardiac Monitoring Continuous ambulatory monitoring can reveal arrhythmias typical for CPVT if the sinus rate of the patient exceeds the individual arrhythmiainducing threshold during monitoring. Ambulatory monitoring can be very useful in young children, whenever performing a maximal exercise stress test is difficult. Implantation of a loop recorder can also be valuable in some cases.

Provocative Drug Testing Catecholamine provocation testing can help diagnose patients with concealed CPVT. Progressive ventricular arrhythmias can also be provoked by IV infusion of isoproterenol or epinephrine. The protocol for epinephrine infusion is similar to that described for LQTS. The test is considered positive for CPVT if epinephrine provoked three or more beats of polymorphic VT or bidirectional VT and borderline if polymorphic couplets, PVCs, or nonsustained monomorphic VT is induced.

Electrophysiological Testing Invasive EP testing is of no value in the diagnosis or risk stratification in patients with CPVT. Arrhythmias are seldom inducible by programmed electrical stimulation.

Genetic Testing Genetic testing is recommended in all probands with definitive clinical diagnosis of CPVT and is also considered in subjects with idiopathic VF when an adrenergic trigger is identified. Using a comprehensive screening approach, the percentage of successfully genotyped CPVT patients is approximately 55% to 60%. Mutations in RYR2 are identified in approximately 60% of patients with a strong CPVT phenotype. The yield of RYR2 genetic testing drops to 5% to 38% in patients with a possible clinical diagnosis in CPVT. Of note, because the RyR2 gene (which underlies the most common form of CPVT) is one of the largest genes in the human genome, genetic testing can be time-consuming and costly. Genetic screening for disease-causing mutations in the calsequestrin (CASQ2) and triadin (TRDN) genes, which underlie the

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

autosomal recessive form of CPVT, is advisable in all pedigrees compatible with a recessive pattern of inheritance but also in all apparently sporadic CPVT cases with negative RyR2 screening even in the absence of parental consanguinity.

Differential Diagnosis Other inherited arrhythmogenic cardiac disorders that can cause malignant ventricular tachyarrhythmias should also be excluded. A QTc interval less than 320 milliseconds should raise a suspicion of SQTS. On the other hand, a prolonged QTc suggests LQTS. Although the onset of clinical symptoms of LQTS is often around puberty, the first syncopal events in CPVT patients tend to occur during childhood. Importantly, induction of arrhythmias during exercise is very rare in LQTS patients. Furthermore, LQTS patients develop torsades de pointes (characterized by the twisting of the points of the QRS complexes), in contrast to CPVT patients who manifest with the typical bidirectional VT with a beat-to-beat 180-degree rotation of the QRS complex. Bidirectional VT can also occur in patients with LQT7 (AndersenTawil syndrome) linked to mutations in the KCNJ2 gene, which may be considered a CPVT phenocopy, particularly in patients with Andersen-Tawil syndrome having borderline QT interval prolongation and lacking the extracardiac features of the syndrome (e.g., periodic paralysis, facial and limb dysmorphism). Distinguishing between LQT7 and CPVT is important; patients with Andersen-Tawil syndrome show a much more benign course than those with other forms of CPVT, and SCD is rare among Andersen-Tawil syndrome patients and KCNJ2 mutation carriers. Ankyrin-B syndrome can also manifest with catecholamine-mediated ventricular arrhythmias. Loss-of-function mutations in the ANK2 gene (encoding cardiac ankyrin-B, a structural membrane adapter protein) result in increased intracellular concentration of Ca2+ and, sometimes, fatal arrhythmia. Although this syndrome has been categorized under LQTS (LQT4), the inconsistent QT interval prolongation and the varying degrees of cardiac dysfunction and arrhythmias observed (including bradycardia, sinus arrhythmia, idiopathic VF, adrenergically mediated VT, and SCD) distinguishes ankyrin-B syndrome as a clinical entity distinct from classic LQTS. Exercise-provoked arrhythmias also can develop in ARVC, but the typical ECG pattern of ARVC and the structural abnormalities of the RV distinguish ARVC from CPVT. The typical arrhythmia in ARVC, monomorphic VT with an LBBB pattern, is clearly different from the polymorphic PVCs or VT in CPVT. In contrast to CPVT, patients with Brugada syndrome do not manifest polymorphic PVCs on physical effort; rather, arrhythmias in Brugada syndrome usually appear at rest or during sleep. Furthermore, the absence of ST segment elevation in the precordial ECG leads at baseline and after provocation testing with Na+ channel blockers helps distinguish CPVT from Brugada syndrome.

Risk Stratification CPVT is one of the most malignant forms of ventricular arrhythmias, with a high mortality rate. CPVT patients with prior cardiac arrest and those in whom symptoms are not completely suppressed by pharmacological therapy are considered at high risk for SCD. Also, diagnosis in childhood is a predictor of adverse outcome. However, the optimal strategy for risk stratification for SCD in asymptomatic CPVT patients or mutation carriers remains uncertain. Programmed electrical stimulation typically fails in inducing ventricular arrhythmias, and is of no value for risk stratification. Furthermore, the predictive value of inducibility of ventricular arrhythmias by catecholamine infusion or exercise for risk stratification has not been demonstrated.1

Principles of Management Pharmacological Therapy

Beta-blockers.  Beta-blockers without intrinsic sympathomimetic activity combined with exercise restriction are the first line of treatment for CPVT and should be promptly initiated to prevent occurrence of ventricular tachyarrhythmias (see Fig. 31.7). Because of the poor prognosis of untreated CPVT, drug therapy is indicated for all clinically diagnosed patients and usually also for all silent carriers of a CPVT mutation. Differences in the pharmacodynamics and pharmacokinetics of the various beta-blockers (including their beta-1 selectivity, half-life, and lipophilicity) appear to be relevant. Studies found nadolol superior to beta-1 selective (cardioselective) beta-blockers (e.g., metoprolol succinate and bisoprolol) in preventing arrhythmias in patients with CPVT. This may be explained, at least in part, by a stronger negative chronotropic effect as well as the longer half-life (20 to 24 hours) of nadolol, which reduces the risk of breakthrough symptoms during potential drug noncompliance. Nonetheless, other mechanisms, such as membranestabilizing effects of nadolol, have been speculated. The efficacy of other nonselective beta-blockers (such as propranolol and carvedilol) has not been investigated. Presently, there is a strong consensus that the nonselective betablocker nadolol (1 to 2.5 mg/kg per day) is the preferred antiarrhythmic, antiadrenergic therapy for CPVT patients. When nadolol is not available or not tolerated, the choice should be guided by the ability of the beta-blocker to suppress ventricular ectopy on the exercise test. Propranolol (3 to 4 mg/kg per day) has been widely used in these situations. IV propranolol is the treatment of choice for acute management of CPVT.52,116,117 Exercise stress testing and Holter monitoring can help determine the adequate beta-blocker dosage for arrhythmia control. It should be noted, however, that the absence of exercise-provoked arrhythmias does not completely exclude the risk of arrhythmia recurrence, and the maximal tolerated dose of beta-blockers should be prescribed to maximize control of arrhythmias with a goal to avoid the heart rate exceeding the threshold rate for CPVT. Furthermore, compliance with regular therapy is extremely important because missing even a single dose can potentially lead to arrhythmias and increase the risk of SCD. In fact, in one report, poor adherence contributed to 48% of arrhythmic events in children with CPVT. It should be recognized that the efficacy of beta-blockers in CPVT is not sufficiently protective and appears to be lower than that seen in patients with LQT1. The annual rate of arrhythmic events on betablocker therapy ranges between 3% and 11% per year (27% over 8 years).1 Of note, recent reports found that beta-blocker therapy was unable to modify the arrhythmic pattern during exercise testing in 30% to 43% of patients, especially those with less severe arrhythmias.113 Flecainide.  Recent studies show that the addition of flecainide to beta-blocker therapy can effectively reduce exercise-induced ventricular arrhythmias in CPVT patients not controlled by beta-blocker therapy alone. Thus flecainide should be regarded as the first addition to betablockers when control of arrhythmias seems incomplete.1 Flecainide monotherapy may be considered in selected CPVT patients truly intolerant of beta-blockade.118 Verapamil.  Limited data suggest that verapamil (an inhibitor of RyR2) can be an alternative option for treatment of CPVT. Also, verapamil can potentially provide additional protection when used in combination with beta-blockers. However, because of the small number of patients and the limited follow-up in these studies, there is no conclusive evidence for recommending verapamil alone or in combination with beta-blockers, and its impact on prognosis remains unknown.1

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

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Implantable Cardioverter-Defibrillator

Family Screening

Given that no drugs can be effective in providing complete protection from SCD, ICD therapy is recommended for CPVT patients who have survived a cardiac arrest and those who continue to have symptoms (syncope or sustained or hemodynamically unstable VT) despite adequate beta-blocker therapy.115 Patients with CPVT experience a high rate of appropriate ICD therapies; approximately half of ICD recipients experience an appropriate shock to terminate VT during 2 years of follow-up. Importantly, the efficacy of ICD therapy in CPVT patients depends on the mechanism of the arrhythmia treated. VF episodes are almost always terminated by ICD shocks; in contrast, ICD discharges nearly always fail to terminate polymorphic and bidirectional VT.115,119,120 Therefore it is important to maintain the maximal tolerated dose of beta-blockers in ICD patients to help reduce the risk of arrhythmic storms and ICD shocks. The risks and benefits of ICD therapy in patients with CPVT should be carefully considered before device implantation, particularly for primary prevention. Inappropriate shocks, electrical storm, and ICD complications are common. Inappropriate ICD therapy is often triggered by supraventricular arrhythmias or spontaneous termination of a ventricular arrhythmia before the ICD discharge. Also, it is important to note that ICDs can potentially have proarrhythmic effects in patients with CPVT. The stress and catecholamine surge caused by the painful ICD shocks (whether appropriate or inappropriate) can evoke an electrical storm.115 Careful device programming can help improve effectiveness of ICD therapies and decrease related comorbidities. Extending detection intervals and altering reconfirmation rates (to avoid therapy delivery in response to frequent PVCs and spontaneously terminating arrhythmias), as well as adjusting ICD detection rates to shorter CLs (for detection of VF rather than VT) can potentially improve outcomes for CPVT patients.120

Given the severe clinical manifestations and poor prognosis of CPVT, once CPVT diagnosis is made in a proband, it is essential to expand the evaluation to both first- and second-degree relatives to find other potential CPVT patients. Exercise testing and Holter monitoring are used for screening family members. Importantly, some CPVT patients may not have arrhythmias during exercise testing during early childhood, but a change in the phenotype occurs later in life. Therefore regular follow-up with repeated exercise stress tests is indicated, for example, for younger siblings of a CPVT patient. Screening of family members by genetic testing is recommended when a gene mutation has been identified in the proband. Considering the early age of manifestation of CPVT and its association with SIDS, confirmatory genetic testing should be performed at birth. Genetic evaluation facilitates diagnosis in silent carriers and allows implementation of preventive pharmacological therapy and reproductive risk assessment. Approximately 50% of RYR2 mutation–carrying relatives identified by cascade screening have a CPVT phenotype. It is suggested that genetically positive family members without clinical manifestations of CPVT (concealed mutation-positive patients) should receive beta-blockers, even after a negative exercise test, although the natural history of these individuals and the efficacy of beta-blockers on their prognosis have not been studied.1

Catheter Ablation When ventricular arrhythmias are triggered by monomorphic PVCs, catheter ablation of the focus of PVCs can be attempted to help reduce the frequency and burden of arrhythmias and ICD shocks. Not infrequently, the initiating beat of VT exhibits an LBBB–inferior axis pattern, suggestive of a ventricular outflow tract origin.

Left Cervicothoracic Sympathectomy Left cervicothoracic sympathectomy involves resection of the lower half of the left stellate ganglion and the first two to four thoracic ganglia (T1 to T4). In recent reports, left cardiac sympathetic denervation successfully reduces major arrhythmic events by almost 90%, including cardiac arrest and SCD, in CPVT patients. Therefore left cardiac sympathetic denervation can be considered in patients with recurrent symptoms despite pharmacological therapy or those experiencing frequent ICD shocks or intractable arrhythmic storms.121 Although left cervicothoracic sympathectomy can be associated with frequent side effects (including left-sided dryness, unilateral facial flush with exercise, contralateral hyperhidrosis, and ptosis), generally these symptoms are fairly tolerated and patient satisfaction with surgical outcome remains high.56,57

Participation in Sports Symptomatic CPVT patients and asymptomatic patients (detected as part of familial screening) with documented exercise- or isoproterenolinduced VT should refrain from all competitive sports with the possible exception of minimal contact, class IA activities. A less restrictive approach may be possible for the genotype-positive/phenotype-negative (asymptomatic, no provocable VT) athlete.

IDIOPATHIC VENTRICULAR FIBRILLATION Idiopathic VF is a rare primary arrhythmia syndrome of unknown genetic origin.122 The 2013 expert consensus on inherited arrhythmia defined idiopathic VF as “a resuscitated cardiac arrest victim, preferably with documentation of VF, in whom known cardiac, respiratory, metabolic and toxicological etiologies have been excluded through clinical evaluation.”1

Genetics of Idiopathic Ventricular Fibrillation Three familial forms of idiopathic VF have recently been linked to the DPP6 gene (encoding dipeptidyl-peptidase 6), the CALM1 gene (encoding calmodulin), and the RYR2 gene (encoding ryanodine receptor). In several Dutch families heavily affected by SCD attributed to familial idiopathic VF, the arrhythmic events were associated with a risk haplotype on chromosome 7 harboring the arrhythmia gene DPP6 gene as a founder effect (i.e., the families are descendants of the same ancestor). Higher DPP6 expression in DPP6 risk haplotype-positive individuals was proposed as a likely pathogenetic mechanism. DPP6 is a putative regulatory β-subunit of the transient outward current (Ito) channel complex in the heart. The arrhythmia syndrome typically occurs between the age of 20 and 60 years, with an autosomal dominant inheritance. The penetrance of idiopathic VF is high: 50% of the male DPP6 haplotype carriers experienced (aborted) SCD before the age of 58 years. Importantly, despite comprehensive cardiac evaluation, no relevant differences between haplotype-positive and haplotype-negative individuals were observed, and no clinical parameters could be linked to SCD risk other than their genetic predisposition.123 Another familial form of idiopathic VF was linked to mutations in the CALM1 gene, with autosomal dominant transmission. Calmodulin is a Ca2+-binding protein with ubiquitous expression that has a regulatory function for numerous calcium-dependent processes. Calmodulin inhibits RyR2 channel open-state probability. Defective calmodulin–RyR2 binding results in impaired calmodulin inhibition of RyR2 function and consequent dysregulation of sarcoplasmic reticulum Ca2+ release. Calmodulin mutations have been previously described in LQTS and CPVT4.5,6

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

Recently, two different heterozygous mutations in the RYR2 gene have been identified in a family with multiple idiopathic VF victims. Those mutations resulted in a phenotype distinct from classic RYR2related CPVT.124,125

Pathophysiology of Idiopathic Ventricular Fibrillation The mechanism(s) underlying idiopathic VF remain to be elucidated. Monogenic mutations have been identified in a small subset of patients with idiopathic VF. Polygenic mutations (i.e., mutations involving two or more genes) and subclinical structural abnormalities currently undetectable with the available diagnostic modalities, have also been speculated. Those underlying substrates can be silent and manifest with VF only during particular pathophysiological processes (e.g., minimal electrolyte disturbances). Recent evidence suggests that the Purkinje network and the RVOT play a pivotal role in both the initiation and perpetuation of VF. PVCs with short-coupled intervals (i.e., R-on-T phenomenon) originating from the RVOT or HPS have been frequently implicated as the trigger of VF or torsades de pointes, at least in a subset of patients with idiopathic VF. The short-coupled PVCs can cause phase 2 reentry and thereby elicit VF. It is likely that idiopathic VF is initiated by an interaction between triggering PVCs and a susceptible ventricular substrate that is prone to transmural reentry.123,126 The exact arrhythmogenic mechanism of how DPP6 overexpression causes idiopathic VF is uncertain. Idiopathic VF associated with the DPP6 risk haplotype is predominantly elicited by monomorphic shortcoupled PVCs from the RV apex or inferior free wall. It has been hypothesized that DPP6 overexpression in DPP6 risk haplotype-positive individuals significantly alters the inactivation kinetics of both Kv4.2 and Kv4.3 channels and preferably increases Ito in the Purkinje network more so than in ventricular cardiomyocytes, resulting in a more negative phase 1 and an abnormal plateau phase of the Purkinje action potentials. Because the Ito only increases in the Purkinje fibers, a strong local repolarization gradient is created with the adjacent ventricular myocardium that results in local ectopy and short-coupled PVCs. DPP6 overexpression does not result in discernible ECG changes, as Purkinje activity is not recorded on the surface ECG.122 Dysregulation of RyR2 likely underlies the disease mechanisms of RYR2 and CAM1 mutation-associated CPVT. These mutations can lead to excessive Ca2+ release from RyR2 channels and DADs.5,6

Epidemiology Idiopathic VF accounts for up to 10% of victims of SCD, mainly in the young. The proportion of “unexplained” or “idiopathic” VF among victims of cardiac arrest has been declining, thanks to the advances in genetic testing and cardiac imaging techniques, and the expanding recognition of new disease entities, which improved the ability to diagnose distinct primary inherited arrhythmia syndromes, thereby excluding idiopathic VF (Fig. 31.18).122,127 The mean age at presentation is approximately 35 to 45 years, and two-thirds of patients are men. A family history of SCD or idiopathic VF is present in up to 20% of patients, suggesting that at least a subset of idiopathic VF is hereditary.

Clinical Presentation Idiopathic VF manifests as syncope or cardiac arrest that is typically not related to physical or emotional stress. VF often occurs at night, when heart rate is slower and vagal tone is augmented. The recurrence of VF in patients with idiopathic VF is approximately 30%, and the proportion of patients presenting with cardiac arrest as opposed to syncope appears to be much higher in idiopathic VF than in other channelopathies, suggesting that ventricular arrhythmias in other chan-

RR interval

T

P Lead II or V5

U

OT interval Tangent End of T

baseline

QTc = QT / √ RR (sec) 450 msec QRS

Fig. 31.18  Schematic Illustration of the Evolution of the Diagnosis Idiopathic Ventricular Fibrillation (IVF). CALM1, Calmodulin 1 gene mutation; CPVT, catecholaminergic polymorphic ventricular tachycardia; DPP6, Dutch DPP6 risk haplotype associated with sudden cardiac death. (From Visser M, van der Heijden JF, Doevendans PA, Loh P, Wilde AA, Hassink RJ. Idiopathic ventricular fibrillation: the struggle for definition, diagnosis, and follow-up. Circ Arrhythm Electrophysiol. 2016;9:e003817.)

nelopathies are more likely to terminate spontaneously, whereas idiopathic VF tends to be sustained. Electrical storm occurs in approximately 10% of patients.

Electrocardiographic Features Typically, the resting ECG of patients with idiopathic VF is normal, without prolongation or shortening of the QT interval, AV and intraventricular conduction defects, or Brugada-like ST elevation. Nonetheless, VF storms in idiopathic VF patients appear to be associated with J waves that show augmentation prior to VF onset. The J waves disappear during follow-up. However, the early repolarization pattern in patients with idiopathic VF does not fulfill the criteria for “early repolarization syndrome,” which is considered a separate disease entity with a distinctive phenotype.128 VF onset is not related to bradycardia or preceding ventricular pauses.122 Arrhythmic events in idiopathic VF frequently occur at rest or during sleep (similar to Brugada and early repolarization syndromes). A circadian pattern of VF occurrence has been observed in idiopathic VF patients, with two peaks: early morning and late evening. J waves also exhibit circadian rhythmicity, with nocturnal augmentation, likely a result of enhanced vagal activity or slowing of the heart rate.126,129 Characteristically, idiopathic VF is triggered by short-coupled PVCs predominantly originating from the HPS or from the RVOT. Shortcoupled PVCs may elicit torsades de pointes or immediate VF. PVCs originating from the RVOT display an inferior axis with an LBBB pattern. PVCs originating in the right Purkinje system display relatively uniform ECG morphologies and typically have an LBBB pattern with a left superior axis and a relatively short QRS duration. On the other hand, PVCs arising in the left Purkinje system produce more variable 12-lead ECG patterns, and generally exhibit a positive vector in lead V1 and a relatively narrow QRS duration (less than 120 milliseconds).

Diagnosis of Idiopathic Ventricular Fibrillation The diagnosis of idiopathic VF is based on exclusion of an underlying structural or primary electrical heart disease, and exclusion of respiratory, metabolic, and toxicological causes (Fig. 31.19). Therefore the

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

Minimal required diagnostics ECG Blood chemistry Toxicological screening Holter monitoring Echocardiography Exercise ECG (including QTc posture test)

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Fig. 31.19  Proposed Flowchart for the Diagnosis and Follow-up (FU) of Patients With Idiopathic Ventricular Fibrillation (IVF). aIn young patients (less than 45 years) without risk factors for coronary artery disease, coronary computed tomography (CT) angiography is an alternative diagnostic tool to exclude coronary artery disease. The sensitivity is 85% and 99%, respectively, the specificity is 90% and 64%, respectively, the positive predictive value is 91% and 86%, respectively, and the negative predictive value is 83% and 90%, respectively. Coronary CT angiography has a higher sensitivity compared with MRI in detecting coronary stenosis; therefore CT is a better alternative for coronary angiography. bProposed genetic testing consists of a basic panel of SCN5A, the most common LQTS genes (KCNQ1 and KCNH2), RyR2, and CALM1 in patients with exercise-induced VF. In patients with a negative phenotype, SCN5A, KCNQ1, and KCNH2 screening is recommended. ECG, Electrocardiogram. (From Visser M, van der Heijden JF, Doevendans PA, Loh P, Wilde AA, Hassink RJ. Idiopathic ventricular fibrillation: the struggle for definition, diagnosis, and follow-up. Circ Arrhythm Electrophysiol. 2016;9:e003817.)

Coronary angiography/ventriculographya MRI No diagnosis Sodium channel blocker provocation Ergonovine provocation Independent of results provocation testing Targeted genetic testing based on phenotypeb No pathogenic mutation

Diagnosis IVF

FU: ECG/echocardiography every 2 years After 6 years prolongation of FU interval Screening first degree family members: ECG, echocardiography, exercise ECG

diagnosis of idiopathic VF requires extensive diagnostic testing. Systematic advanced testing allows determination of a specific diagnosis in approximately half of initially unexplained cardiac arrest patients, with the majority (more than two-thirds) having a potentially inherited mechanism of disease.130 Differentiation from structural cardiac disease and other primary arrhythmia syndromes is critical to provide targeted medical treatment and prevention of arrhythmic events in the proband and to identify other potentially treatable cases in family members.1

Exclusion of Structural Heart Disease Echocardiography, stress testing, coronary angiography, and cardiac magnetic resonance (CMR) need to be considered to exclude structural cardiac disease, such as coronary artery disease, congenital coronary anomalies, dilated or hypertrophic cardiomyopathy, ARVC, cardiac sarcoidosis, myocarditis, and left apical ballooning. In addition, ergonovine or acetylcholine provocation can be necessary to exclude coronary artery spasm. Metabolic disorders, electrolyte abnormalities, and drug intoxication also need to be excluded.1,122

Exclusion of Primary Arrhythmia Syndromes A thorough clinical and family history is critical; subtle information regarding the triggers and circumstances of arrhythmic events can point to distinct arrhythmia syndromes. Also, careful analysis of the surface 12-lead ECG is mandatory to exclude primary electrical heart disease. Abnormal shortening or prolongation of the QT interval can suggest SQTS or LQTS, respectively. Repolarization abnormalities in the right precordial leads can suggest the Brugada syndrome. The presence of ventricular preexcitation can suggest preexcited supraventricular tachyarrhythmias, usually AF with very rapid ventricular rates, as the underlying cause of VF. It is important to understand that all these disorders can manifest with minor or borderline ECG abnormalities, and recording serial ECGs, recording of modified precordial leads (such as in the Brugada ECG pattern), recording the ECG during exercise or after drug challenge, and/or continuous ambulatory cardiac monitoring can be necessary to unmask diagnostic ECG abnormalities. Pharmacological drug challenge to exclude the Brugada syndrome, and exercise stress testing or catecholamine infusion to exclude CPVT, should be considered.122 Given the variable penetrance among gene carriers in the same family, some studies have suggested a role for family screening with ECG and echocardiogram as a diagnostic tool when conventional tests, including pharmacological tests, have not identified the cause of unexplained cardiac arrest in the proband.131

Electrophysiological Testing Invasive EP testing may be considered, especially when SND, AV conduction abnormalities, or the presence of a bypass tract (BT) is suspected. However, routine invasive EP testing is not currently recommended for the diagnosis and risk stratification of idiopathic VF. Inducibility of VF with programmed electrical stimulation is associated with limited sensitivity and specificity (43% and 64% respectively).122

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

Genetic Testing

Implantable Cardioverter-Defibrillator

The role of extensive genetic testing in patients with idiopathic VF is uncertain. Currently, the routine screening of large gene panels is not recommended because of the relatively low yield (about 15%) and the frequent detection of variants of uncertain clinical significance, which can potentially lead to unnecessary treatment and anxiety among patients. Nonetheless, targeted genetic testing is recommended when certain electrical syndromes are suspected based on clinical evaluation of the patient or family members. Testing for idiopathic VF-related mutations is only recommended in the presence of a strong family history of idiopathic VF or unexplained SCD. It should be recognized, however, that a negative genetic test result does not exclude concealed primary arrhythmia syndromes or a genetic origin of idiopathic VF.1,122,127 Certain clinical information can help guide targeted genetic testing. For example, arrhythmic events (VF or prior syncope episodes) triggered by exercise should point to CPVT or LQT1, whereas those triggered by emotion suggest CPVT or LQT2. Arrhythmic events occurring during sleep suggest Brugada syndrome or LQTS. Fever-associated arrhythmias favor Brugada syndrome. Furthermore, polymorphic PVCs on Holter monitoring or exercise test suggest CPVT. The concomitant potentially arrhythmogenic drugs should raise the suspicion of LQTS and Brugada syndrome.131

ICD implantation is recommended in patients with prior cardiac arrest due to VF given the high risk of recurrence of ventricular arrhythmias (11% to 45% mean follow-up of 3.2 to 5.3 years) and the fact that neither medical therapy nor catheter ablation provides absolute protection from SCD.1,122,127 In patients with ICDs and frequent nonsustained ventricular arrhythmias or recurrent sustained arrhythmias precipitating frequent ICD therapies, adjuvant antiarrhythmic therapy with quinidine can be helpful. Of note, patients with VF and early repolarization have shown a higher risk of VF recurrence than those without early repolarization (43% vs. 23% during 5 years of follow-up). ICD recipients also experience a high rate of inappropriate shocks (14% to 44%; mean follow-up, 1.9 to 8.8 years), frequently precipitated by AF.1,122,127 In view of the lack of specific risk factors and the absence of abnormalities on the ECG or imaging studies in patients with idiopathic VF, identification of at-risk asymptomatic subjects is currently not possible. In addition, the optimal management of asymptomatic family relatives and mutation carriers is uncertain. Nonetheless, ICD implantation may be considered in the presence of unexplained syncope in a first-degree relative of an idiopathic VF victim, but only after careful work-up of the cause of syncope and patient counseling.1,123

Principles of Management

Catheter Ablation

Data from controlled trials or experimental studies are largely lacking. Preliminary clinical experience with quinidine (a class IA antiarrhythmic agent with potent inhibition of Ito) is promising. Beta-adrenergic agonists are beneficial in idiopathic VF, particularly for arrhythmic storm. Amiodarone has limited efficacy. Beta-blockers, lidocaine, mexiletine, and verapamil are generally not beneficial (see Fig. 31.7).1 Acceleration of the heart rate (up to 120 beats/min) by isoproterenol infusion or by atrial or ventricular pacing can be very effective for the acute control of ventricular arrhythmias. Deep sedation may also be considered in refractory cases.

Recent evidence suggests an important role of specific triggers for initiation of idiopathic VF (Fig. 31.20). Distal Purkinje fibers have been recognized as the most frequent site of VF-triggering PVCs occurring during the vulnerable period of cardiac repolarization. The culprit PVCs have also been demonstrated to originate from sites other than the HPS, including the RVOT, LVOT, and papillary muscles.132 PVCs originating from the RVOT, although generally considered “benign,” can initiate polymorphic VT and VF in some patients with idiopathic VF. Distinguishing between the “malignant” forms and the benign form of RVOT PVCs is often challenging. Data suggest that shorter CLs during monomorphic VT, short coupling intervals

Pharmacological Therapy

1 mV II

1 mV V2

1 mV II

1 mV V2 Fig. 31.20  Polymorphic Ventricular Tachycardia (VT) Triggered by Premature Ventricular Complexes (PVCs). The telemetry rhythm strips show normal sinus rhythm with PVCs that trigger an episode of polymorphic VT. Note that the morphology of the triggering PVCs is similar to that of the isolated PVC.

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies of the PVCs, and a history of syncope with malignant characteristics, can potentially predict the coexistence of VF or polymorphic VT in patients with idiopathic RVOT VT/PVCs. However, significant overlap exists. When ventricular arrhythmias are triggered by monomorphic PVCs, catheter ablation of the PVC focus can potentially prevent further episodes of VF or reduce the burden of arrhythmias. In the setting of PVCs arising from the Purkinje network, a presystolic low-amplitude and high-frequency signal (Purkinje potential) is typically recorded at the successful ablation site, whereby the Purkinje potential precedes and is closely coupled with the ventricular signal of the culprit PVC (eFig. 31.5). Abolition of the local Purkinje potentials and suppression of the targeted PVCs have been shown in a small series to significantly reduce the frequency of VF.132 The presence of frequent PVCs during the ablation procedure can significantly improve the success of ablation. Not infrequently, the optimal time for ablation is at the time of an arrhythmic storm when the PVCs tend to be frequent. When the PVCs are absent at the time of the procedure, provocative maneuvers (including the use of isoproterenol or programmed electrical stimulation) are not usually helpful. Pace mapping can be used in cases of monomorphic ventricular ectopy when a clear 12-lead recording of the clinical PVCs initiating VF has been obtained (eFigs. 31.6 and 31.7).132 Catheter ablation of focal PVCs may be considered especially in patients with frequent episodes of syncope or repeated ICD shocks refractory to drug therapy. Nonetheless, ablation therapy is not a substitute for ICD therapy because of the risk of recurrence of VF (in 18% of patients) triggered by PVCs either from the original focus or from new foci.1 It is worth noting that recent studies found a concordance between the site of origin of VF-triggering PVCs and the location of the early repolarization pattern on the surface ECG. Patients with early repolarization recorded in inferior leads alone had PVCs originating from the inferior LV wall, whereas those with early repolarization recorded in both inferior and lateral leads had PVCs originating from multiple regions.

Participation in Sports Restriction from competitive sports is appropriate in patients with idiopathic VF.60

Periodic Evaluation Importantly, the initial diagnosis of idiopathic VF can change during follow-up, despite comprehensive clinical investigation at the time of the index event. Phenotypic findings of other primary electric diseases or latent structural causes are often dynamic and may not be present at initial evaluation.130 In fact, 11% to 38% of patients initially diagnosed with idiopathic VF reveal a specific disease (e.g., ARVC or Brugada syndrome) during follow-up. Therefore the diagnosis of idiopathic VF should be periodically reassessed with clinical history, physical examination, ECG, and possibly other tests, as guided by clinical suspicion. An annual assessment including an ECG is recommended, with repeat imaging, ambulatory monitoring, and exercise testing every 2 to 3 years, and with any change in arrhythmia burden.127,133

Family Screening Unlike other arrhythmia syndromes, such as Brugada syndrome and LQTS, no cardiac abnormalities are observed in idiopathic VF patients, apart from the early repolarization ECG pattern, which is also not infrequently observed in the general population. Hence, family members who may be at risk cannot be identified and the penetrance of idiopathic VF cannot be assessed on the basis of an ECG phenotype.122

As noted, phenotype penetrance of inherited arrhythmogenic syndromes can vary among gene carriers in the same family; hence, it is recommended to evaluate first-degree relatives of all idiopathic VF victims with resting ECG, exercise stress testing, and echocardiography.131 In addition, Holter monitoring, and signal-averaged ECGs, CMR, and provocative testing with class IC antiarrhythmic drugs and epinephrine infusion may also be considered, especially in relatives with unexplained syncope. Furthermore, even when the initial assessment is normal, periodic clinical assessment is indicated in young family members of idiopathic VF victims (as young patients may only manifest symptoms or signs of the disease at an older age and certain diseases have agerelated penetrance) and in all family members whenever additional suspicious sudden deaths are identified in the family.1 The recent identification of mutations of the DPP6 and CALM1 genes as a potential familial component in idiopathic VF may allow presymptomatic identification of individuals at risk. Cascade family screening should be considered when a pathogenic mutation is found (e.g., DPP6 or CALM1) or a specific diagnosis is revealed.122

EARLY REPOLARIZATION SYNDROMES Early repolarization ECG patterns, consisting of a distinct J wave or J point elevation, or a notch or slur of the terminal part of the QRS, are predominantly found in healthy young men and have traditionally been viewed as totally benign, “normal variants.” However, this concept has been challenged by several recent studies, which demonstrated that early repolarization patterns in apparently healthy subjects could represent a marker of increased dispersion of repolarization and arrhythmogenesis, and of the presence of a relationship between certain repolarization patterns and some cases of unexplained VF and SCD.65,134

Genetics of Early Repolarization Syndrome Several studies have suggested the early repolarization pattern is a heritable phenotype. Familial early repolarization has been reported to have an autosomal dominant inheritance pattern with incomplete penetrance. Variants in genes encoding cardiac ion channels have been identified in individuals and families with early repolarization syndrome (Table 31.19). Gain-of-function mutations in KCNJ8 and ABCC9 genes (encoding the pore-forming and ATP-sensing subunits of the IK-ATP channel) and the KCNE5 gene (encoding the Ito channel) have been reported in patients with early repolarization syndrome. Loss-of-function variations in the α1, β2, and α2δ subunits of the cardiac L-type Ca2+ channel (encoded respectively by the CACNA1C, CACNB2, and CACNA2D1 genes) and the α1 subunit of Nav1.5 and Nav1.8 (SCN5A, SCN10A) have been reported in patients with early repolarization syndrome.

TABLE 31.19  Molecular Basis of the Early

Repolarization Syndrome

ERS1 ERS2 ERS3 ERS4 ERS5 ERS6 ERS7

Gene

Protein

Functional Effect

% of Probands

KCNJ8 CACNA1C CACNB2B CACNA2D1 ABCC9 SCN5A SCN10A

Kir6.1 Cav1.2 Cavβ2b Cavα2δ SUR2A Nav1.5 Nav1.8

↑ IKATP ↓ ICaL ↓ ICaL ↓ ICaL ↑ IKATP ↓ INa ↓ INa

4.1% 8.3% 4.1% Rare Rare

ICaL, L-type Ca2+ current; IKATP, ATP-activated inward rectifier K+ current; INa, Na+ current; ERS1 to ERS7, early repolarization syndrome types 1 to 7, respectively.

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

I II III aVR aVL aVF V1 V2 V3

V4 V5 V6 Hisprox Hismid Hisdist RVA Abluni Abldist Ablprox Ablunip

200 msec

eFig. 31.5  Sinus Rhythm (Left) and Premature Ventricular Complexes (PVCs, Right) in a Patient With Idiopathic Ventricular Fibrillation. Dashed lines denote the onset of QRS complexes. Blue arrows indicate Purkinje potentials, and red arrows indicate His potentials. During sinus rhythm, His potentials precede Purkinje potentials, the sequence of which is reversed in the PVCs.

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

SR

PVC

Pace mapping

I II III aVR aVRL aVF V1 V2 V3

V4 V5

V6 400 msec eFig. 31.6  Pace Mapping of Premature Ventricular Complexes (PVCs) in a Patient With Idiopathic Ventricular Fibrillation. Left, Sinus rhythm (SR) and a PVC in a patient with idiopathic ventricular fibrillation are shown. Right, Pacing at the PVC site of origin closely mimics the PVC.

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

I II III aVR aVL aVF V1 V2 V3 V4 V5 V6 Hisprox Hismid Hisdist RVA Abluni

Abldist Ablprox Ablunip

400 msec eFig. 31.7  Catheter Ablation of Premature Ventricular Complexes (PVCs) in a Patient With Idiopathic Ventricular Fibrillation. Three seconds after the onset of radiofrequency energy delivery at the site of PVC origin, a burst of ectopy occurs having the same QRS configuration as the spontaneously occurring PVC (see eFigs. 31.5 and 31.6).

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

Recently, gain-of-function mutations in the genes encoding the major channel subunits of Ito, KCND2 and KCND3, have been described in Brugada syndrome and an atypical anterior J wave syndrome associated with SCD.134–136

Pathophysiology of Early Repolarization Syndromes Mechanism of Early Repolarization and J Waves

The exact ionic and cellular mechanisms for the J wave and early repolarization pattern are still under investigation. Heterogeneity in the distribution of Ito channels across the myocardial wall, being more prominent in ventricular epicardium than endocardium, results in the shorter duration, prominent phase 1 notch, and “spike and dome” morphology of the epicardial action potential as compared with the endocardial action potential. The resultant transmural voltage gradient during the early phases (phases 1 and 2) of the action potential is thought to be responsible for the inscription of the J wave on the surface ECG (see Fig. 31.9).137,138 An outward shift of currents, secondary to a decrease in the inward currents (INa and ICaL), an increase in the outward K+ currents (Ito, IKr, IKs, IKACh, IKATP), or both, can cause accentuation of the action potential notch, leading to augmentation of the J wave or the appearance of ST segment elevation on the surface ECG. An outward shift of currents that extends beyond the action potential notch not only can accentuate the J wave, but also lead to partial or complete loss of the dome of the action potential, leading to a protracted transmural voltage gradient that manifests as greater ST segment elevation and gives rise to J wave syndromes. The type of ion current affected and its regional distribution in the ventricles determines the particular phenotype (including the Brugada syndrome, early repolarization syndrome, hypothermiainduced ST segment elevation, and infarction-induced ST segment elevation).139 Male predominance can potentially result from larger epicardial Ito density versus that in women.135 It should be mentioned that not all investigators are in complete agreement about the EP basis of J waves and whether the mechanism responsible for abnormal J waves is related to depolarization abnormalities (i.e., slow impulse conduction) rather than repolarization abnormalities.135 However, while there is evidence that depolarization abnormalities are involved in the formation of a Brugada-type ECG (i.e., conduction delay to the RVOT) and ischemia-related early repolarization (conduction delay through ischemic myocardial zones) and contribute to the arrhythmias in those diseases, there is less evidence for depolarization abnormalities in patients with inferolateral early repolarization and hypothermia-related early repolarization.140

Mechanism of Arrhythmogenesis The exact relationship of an early repolarization pattern and malignant ventricular arrhythmias remains unclear. It is likely that the increased transmural heterogeneity of ventricular repolarization (i.e., dispersion of repolarization between epicardium and endocardium), which is responsible for J point elevation and the early repolarization pattern on the surface ECG, is also responsible for the increased vulnerability to ventricular tachyarrhythmias. A significant outward shift in current can cause partial or complete loss of the dome of the action potential in regions where Ito is prominent (epicardium), with the consequent loss of activation of ICaL. The dome of the action potential can then propagate from regions where it is preserved (midmyocardium and endocardium) to regions where it is lost (epicardium), giving rise to phase 2 reentry, which can generate short-coupled PVCs (falling on the descending limb of the T wave: the R-on-T phenomenon) that interacts with a susceptible ventricular substrate to trigger transmural reentry and polymorphic VT or VF (see Fig. 31.10). This phenomenon is also observed during “ischemic VF,” Brugada syndrome, and idiopathic

VF. J wave appearance represents an initial response to acute ischemia, resulting from the loss of the transient outward potassium current– mediated epicardial action potential dome triggering VF. This might explain why early repolarization is a marker for increased arrhythmic mortality across a heterogeneous clinical spectrum.139,141,142 Notably, this pathophysiology is analogous to the mechanism operative in the Brugada syndrome. Although the ECG location of early repolarization in Brugada syndrome is thought to be secondary to the presence of increased transmural dispersion of repolarization in the RVOT mediated by increased epicardial Ito, the location of early repolarization and associated J waves involving inferolateral leads caused by heterogeneity in action potential morphology and duration across the LV wall. Higher intrinsic levels of Ito in the inferior LV wall likely accounts for the greater vulnerability of this region for developing VF.134 Importantly, the J wave in early repolarization syndrome increases markedly just before arrhythmic events, an occurrence which is now recognized as a hallmark of the disease. J wave amplitude is augmented by slow heart rate and increased vagal activity, which can potentially explain why VF in these patients often occurs during sleep or at a low level of physical activities.134

Modulation of Early Repolarization Pattern Patients with early repolarization syndrome can display dynamic J point elevation. Factors that influence the kinetics of Ito or the other repolarization currents (including heart rate, heart rhythm, autonomic tone, and drugs) can modify the manifestation of the J wave on the ECG. J wave amplitude increases during slow heart rates as well as a shortlong-short sequence and a pause, which is likely related to augmentation of IKACh and IK-A P (secondary to increased vagal tone) as well as augmentation of Ito (facilitated by bradycardia). It is important to note that during episodes of high vagal tone, a degree of elevation of the J point can be a physiological finding in normal individuals. In patients with early repolarization syndrome, however, bradycardia-mediated J point elevation is markedly amplified. On the other hand, acceleration of the heart rate, which is associated with reduction of Ito (because of the slow recovery of Ito from inactivation), results in a decrease in the magnitude of the J wave.143 Circadian variation of the J- wave amplitude is also known to occur, and its augmentation is in concordance with a vagal tone. J waves can be augmented or induced by hypothermia and fever; however, the development of arrhythmias in early repolarization syndrome is much more sensitive to hypothermia, whereas arrhythmogenesis in Brugada syndrome appears to be promoted only by fever. Quinidine, which inhibits both Ito and INa, reduces the magnitude of the J wave and normalizes ST segment elevation. Quinidine was found to be effective in partially reversing the repolarization abnormalities, thus restoring electric homogeneity and abolishing the arrhythmogenic substrate.135,144 Na+ channel blockers (ajmaline, procainamide, pilsicainide, propafenone, flecainide, and disopyramide), which reduce the inward INa, unmask or accentuate J wave manifestation in Brugada syndrome but attenuate the J wave amplitude in early repolarization patients. Although this differential effect of Na+ channel blockers initially invoked a potentially different pathophysiology of early repolarization from that of the Brugada syndrome, a recent study demonstrated that J waves recorded with unipolar LV epicardial leads introduced into the left lateral coronary vein in early repolarization syndrome patients were indeed augmented, even though J waves recorded in the lateral precordial leads were diminished, principally because of engulfment of the surface J wave by the widened QRS. Na+ channel blockade results in slowing of conduction and delay of the terminal ventricular activation whereby the S waves superimpose the J waves. These S waves represent an opposing force

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies to the J waves and depending on their amplitude and duration, can decrease or completely obscure the J waves.144,145 Via beta-adrenergic stimulation, isoproterenol augments ICaL by increasing the mean channel open time and probability of channel opening. In addition, because of slow recovery from inactivation, Ito is rate dependent with decreasing current magnitude at higher heart rates, and isoproterenol decreases Ito via an acceleration of heart rate. The combined effect of increasing Ca2+ influx (via ICaL augmentation) and reducing K+ efflux (via Ito inhibition) counteracts some of the primary mechanisms thought to underlie the formation of J waves and early repolarization. The observed effects of isoproterenol are most compatible with the repolarization disorder hypothesis for early repolarization. Depolarization abnormalities are expected to worsen, rather than improve, at faster heart rates. Cilostazol and milrinone inhibit the activity of phosphodiesterase III, increasing the intracellular concentrations of cAMP, which in turn results in augmentation of ICaL. Milrinone has much greater potency than cilostazol, possibly because milrinone blocks both phosphodiesterase III and phosphodiesterase IV.138,144 Bepridil is a Ca2+ channel antagonist with lidocaine-like rapid kinetic blocking effects of Na+ channels. Bepridil also blocks most types of K+ currents, including Ito. Bepridil can decrease the number of VF episodes in patients with idiopathic VF (including those with Brugada syndrome).

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Early repolarization appears to be a heritable phenotype; offspring of early repolarization–positive parents have a 2.5-fold increased risk of presenting with early repolarization on the surface ECG. In addition, genetic contributions to SCD-associated early repolarization are suggested by common familial SCD histories in symptomatic early repolarization patients. Several reports demonstrated a high familial aggregation of sudden death in early repolarization syndrome patients; a family history of sudden death is reported in about one-fifth of patients with VF and early repolarization. Geographic differences in distribution have also been described, with early repolarization–related SCD being particularly prevalent among Southeast Asians.136

Clinical Presentation The vast majority of individuals with an early repolarization ECG pattern remain asymptomatic, and are usually found to have an early repolarization pattern as an incidental finding. Idiopathic VF patients (e.g., survivors of unexplained cardiac arrest) who are found to have clear ECG evidence of early repolarization are now defined as early repolarization syndrome patients. Early repolarization syndrome is extremely rare, but these patients have a high risk of recurrent cardiac events. Life-threatening arrhythmias are often the first and unexpected manifestation of early repolarization syndrome, and usually occur at a young age (typically less than 40 years).1,135

Epidemiology

Electrocardiographic Features

The prevalence of the early repolarization pattern in the general population varies from 1% to 13%, depending on age (predominant in children and young adults), race (highest among African-Americans and Southeast Asians), gender (predominant in men), and the criterion for J point elevation (0.05 mV vs. 0.1 mV).1 The prevalence of an early repolarization pattern is several-fold higher in athletes (ranging from 10% to 90%) than in the general population. In athletes, this ECG pattern is thought to be related, at least in part, to heightened vagal tone.146 Early repolarization is more frequent in patients with idiopathic VF than in control subjects, occurring in 15% to 70% of the idiopathic VF cases. Further, the prevalence of inferolateral J point elevation is higher in the family members of sudden arrhythmic death syndrome probands compared with the general population (23% vs. 11%). Importantly, among patients with idiopathic VF, those with early repolarization are more likely to have a history of syncope or SCD than those without early repolarization. Moreover, the presence of an early repolarization pattern, especially in the inferior or inferolateral leads, has recently been recognized as associated with vulnerability to VF and a 1.7 relative risk for SCD. In the 35- to 45-year-old age range of maximal early repolarization-related SCD incidence, a J wave is estimated to increase idiopathic VF risk from 3.4 per 100,000 to 11 per 100,000.135,146 However, it is important to recognize that although early repolarization is a common entity, idiopathic VF itself is very rare. Therefore the incidental discovery of a J wave on routine screening should not be interpreted as a marker of “high risk” for SCD because the odds for this fatal disease would still be approximately 0.01% (and well less than 0.1% among asymptomatic individuals with J waves with the most “malignant” morphology), which is significantly less than the estimated 1% annual risk of spontaneous VF among asymptomatic adults with a type I Brugada ECG.1 In addition to reports of SCD in otherwise healthy patients, the presence of early repolarization on the ECG appears to be a modulator of arrhythmic risk in patients with other cardiac disorders. An early repolarization ECG pattern has been associated with an increased risk of malignant arrhythmias and SCD in patients with Brugada syndrome, acute myocardial infarction (MI), chronic ischemic heart disease, heart failure, and hypothermia.134

There has been considerable variation in the use of the terms “early repolarization” and “J point.” Historically, the term “early repolarization” was used to describe two ECG phenomena: (1) an upward deflection of the J point (or terminal part of the QRS complex) termed “J point elevation” or “J wave” and (2) ST segment elevation not associated with pathological conditions such as MI. More recently, after the emergence of reports associating early repolarization with idiopathic VF, most studies used the term “early repolarization” to describe an elevation of the QRS-ST segment junction (J point) greater than or equal to 0.1 mV in greater than or equal to 2 contiguous inferolateral leads (I, II, III, aVL, aVF, and V4 to V6), excluding right precordial leads. The morphology of the J point can be slurring (a smooth transition from the QRS segment to the ST segment) or notching (a positive J deflection inscribed on the S wave). Also, there is a consensus that the pattern of end-QRS notching and slurring may, on occasion, be due to late depolarization rather than early repolarization. Therefore some investigators suggest that the term “early repolarization” should be replaced by “J waves.”135,147

Terminology An expert consensus report published in 2015 proposed a standardized terminology and definition of ECG manifestations of early repolarization. It is recommended that the peak of an end-QRS notch and/or the onset of an end-QRS slur be designated as Jp, and that the onset of the end-QRS notch or J wave be designated as Jo and the end of a notch or slur as Jt. In the case of a slur, Jo and Jp are electrocardiographically the same point (Fig. 31.21).65,147 The pattern of ST segment elevation after the J point can be classified as horizontal or downward sloping (if the amplitude of the ST segment 100 milliseconds after Jt is less than or equal to the amplitude at Jt) or upward sloping (if the amplitude of the ST segment 100 milliseconds after Jt is greater than the amplitude at Jt). ST segment elevation in the absence of a slur or notch should not be reported as early repolarization.65,147

Definition Early repolarization is present if all of the following criteria are met:65,147 1. There is an end-QRS notch or slur on the downslope of a prominent R wave (with and without ST segment elevation). If there is a notch,

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A

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

JoJp Jt

Jp

B

it should lie entirely above the baseline. The onset of a slur must also be above the baseline. 2. The peak of the notch or J wave (Jp) is greater than or equal to 0.1 mV in more than two contiguous leads of the 12-lead ECG, excluding leads V1 to V3. 3. QRS duration (measured in leads in which a notch or slur is absent) is less than 120 milliseconds. If the ST segment is upward sloping and followed by an upright T wave, the pattern should be described as “early repolarization with an ascending ST segment.” If the ST segment is horizontal or downward sloping, the pattern should be described as “early repolarization with a horizontal or descending ST segment.” Right precordial leads (V1 to V3) have been excluded from the new definition of early repolarization to avoid confusion with the Brugada pattern. An end-QRS notch is a notch that occurs on the final 50% of the downslope of an R wave occurring as the final segment of the QRS complex; that is, it links with the ST segment of the waveform (Fig. 31.22A). It should be distinguished from a notch midway on the downslope of an R wave (see Fig. 31.22B) because this may be due to

Jt

Fig. 31.21  Standardized Terminology and Definition of Electrocardiogram Manifestations of Early Repolarization. (A) In case of an end-QRS notch, the peak of the notch is designated as Jp, the onset of the notch is designated as J-onset (Jo), and the end of a notch as J-termination (Jt). (B) In the case of an end-QRS slur, Jo and Jp are electrocardiographically the same point. (Modified from MacFarlane PW, Antzelevitch C, Haissaguerre M, et al. The early repolarization pattern: a consensus paper. J Am Coll Cardiol. 2015;66:470–477.)

I

V1

I

V1

II

V2

II

V2

III

V3

III

V3

aVR

V4

aVR

V4

aVL

V5

aVL

V5

aVF

V6

aVF

V6

A

B

Fig. 31.22  QRS Notching and Slurring. (A) Electrocardiographic leads showing end-QRS notching in lead V4 progressing to end-QRS slurring in lead V6. End-QRS slurring is also present in leads I and aVL. The arrows localize the notching or slurring. (B) Leads III and aVF show notching. In lead III, the notch peak is greater than 50% of the R wave amplitude and could be regarded as fragmentation. In lead II, appearances on the R wave downslope take the form of a slur, and there is also a notch in lead aVF. They are most probably due to the same underlying physiological process. The arrows indicate the location of the notches and slur. (From MacFarlane PW, Antzelevitch C, Haissaguerre M, et al. The early repolarization pattern: a consensus paper. J Am Coll Cardiol. 2015;66:470–477.)

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies fragmentation. Similarly, an end-QRS slur is an apparent slowing of the inscription of the waveform at the end of the QRS complex that merges with the ST segment of the complex. Likewise, a slur should occur in the final 50% of the R wave downslope.147 Importantly, ST segment elevation is not a required criterion (Fig. 31.23). In the absence of any end-QRS notching or slurring, it is recommended that the finding of ST segment elevation be described as nonspecific ST segment elevation and not described as early repolarization (Fig. 31.24).147 The early repolarization pattern can vary in response to autonomic tone and heart rate. Bradycardia and increased vagal tone (e.g., during sleep) accentuate ST segment elevation. Contrariwise, tachycardia and adrenergic stimulation (e.g., exercise testing or the infusion of isoproterenol) suppress J wave amplitude and ST segment elevation. In addition, hypothermia can induce prominent J waves (“Osborn waves”).

QRS slurring without ST elevation

QRS notching without ST elevation

Jp amplitude

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Localization of Early Repolarization Based on the localization of the early repolarization pattern on the 12-lead ECG and its potential association with risk for life-threatening arrhythmias, some investigators classified early repolarization patterns into three types134: Type 1: The early repolarization pattern manifests predominantly in the lateral precordial leads (V4–V6). This pattern is rarely seen in cases of idiopathic VF, is highly prevalent among healthy young adults and athletes, and is thought to be associated with a relatively low level of risk for arrhythmic events. Type 2: The early repolarization pattern is localized to the inferior or inferolateral leads. This pattern is less common in the general

I

V1

II

V2

III

V3

aVR

V4

aVL

V5

aVF

V6

QRS slurring with ST elevation

QRS notching with ST elevation

QRS onset (reference level)

Fig. 31.23  End-QRS Notching and Slurring With and Without ST Segment Elevation. The upper salmon line indicates the notch or slur amplitude, J peak (Jp), while the lower purple line indicates the baseline used as a reference with respect to which amplitudes should be measured. The blue lines indicate tangents to the initial component of the R wave downslope. All of these waveforms are illustrations of the early repolarization pattern. (From MacFarlane PW, Antzelevitch C, Haissaguerre M, et al. The early repolarization pattern: a consensus paper. J Am Coll Cardiol. 2015;66:470–477.)

Fig. 31.24  Nonspecific ST Segment Elevation. An illustration of an electrocardiogram showing moderate ST segment elevation in leads I, II, and aVF and more marked ST segment elevation in leads V4–V6, in the absence of any end-QRS notching or slurring. It is recommended that this finding not be described as early repolarization. The arrows indicate the points of ST segment elevation. (From MacFarlane PW, Antzelevitch C, Haissaguerre M, et al. The early repolarization pattern: a consensus paper. J Am Coll Cardiol. 2015;66:470–477.)

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

population, but is observed in approximately 50% of cases of idiopathic VF. Early repolarization in the inferior leads is also associated with an increased risk of cardiovascular death from any cause. Type 3: Early repolarization is more global, involving the inferior, lateral, and right precordial leads. This pattern is the rarest and carries the highest risk of malignant ventricular arrhythmias.

Diagnosis of Early Repolarization Syndrome According to a recent expert consensus, an “early repolarization pattern” can be diagnosed in the presence of J point elevation greater than or equal to 1 mm in more than two contiguous inferior and/or lateral leads of a standard 12-lead ECG. An “early repolarization syndrome” is diagnosed in the presence of early repolarization pattern in a patient resuscitated from otherwise unexplained VF/polymorphic VT or in an SCD victim with a negative autopsy and medical chart review.1 A scoring system (the Shanghai Score) has been proposed for the diagnosis of early repolarization syndrome (Table 31.20). This system is based on evidence available in the literature to date, but is yet to be validated in future studies.

TABLE 31.20  Shanghai Score System for

Diagnosis of Early Repolarization Syndrome Points I. Clinical History A. Unexplained cardiac arrest, documented VF or polymorphic VT B. Suspected arrhythmic syncope C. Syncope of unclear mechanism/unclear etiology Only award points once for highest score within this category. II. Twelve-Lead ECG A. ER >0.2 mV in >2 inferior and/or lateral ECG leads with horizontal/descending ST segment B. Dynamic changes in J point elevation (≥0.1 mV) in ≥2 inferior and/or lateral ECG leads C. ≥0.1 mV J point elevation in at least 2 inferior and/or lateral ECG leads Only award points once for highest score within this category. III. Ambulatory ECG Monitoring A. Short-coupled PVCs with R on ascending limb or peak of T wave IV. Family History A. Relative with definite ERS B. ≥2 first-degree relatives with a II.A. ECG pattern C. First-degree relative with a II.A. ECG pattern D. Unexplained sudden cardiac death <45 years in a first- or second-degree relative Only award points once for highest score within this category. V. Genetic Test Result A. Probable pathogenic ERS susceptibility mutation Score (requires at least one ECG finding)   ≥5 points: Probable/definite ERS   3–4.5 points: Possible ERS   <3 points: Nondiagnostic

3 2 1

2 1.5 1

2

2 2 1 0.5

0.5

ECG, Electrocardiogram; ER, early repolarization; ERS, early repolarization syndrome; PVC, premature ventricular contraction; VF, ventricular fibrillation; VT, ventricular tachycardia. From Antzelevitch C, Yan GX, Ackerman MJ, et al. J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge. Heart Rhythm. 2016;13:e295–e324.

Importantly, the diagnosis of “early repolarization syndrome” in survivors of cardiac arrest requires a complete evaluation to exclude underlying structural or other primary electrical heart disease, and exclusion of respiratory, metabolic, and toxicological etiologies. This typically necessitates extensive diagnostic testing, as discussed previously for idiopathic VF.1 Furthermore, other causes of J point elevation (ischemia, hypokalemia, hypercalcemia, hypothermia) need to be excluded. Genetic testing for early repolarization syndrome is still of questionable benefit and, until validated in future studies, is considered investigational.1,135,147 No consensus exists regarding the evaluation of asymptomatic individuals incidentally found to have an early repolarization pattern on the surface ECG. Currently, in the absence of syncope or a strong family history of juvenile SCD, the finding of the early repolarization pattern does not merit further investigation.1,135,147

Differential Diagnosis Early repolarization ECG patterns can be observed in a spectrum of acquired and congenital disorders, collectively referred to as “J wave syndromes,” which include the Brugada syndrome, hypothermia, and acute myocardial ischemia, in addition to the early repolarization syndrome. Those syndromes appear to share similar pathophysiology and arrhythmogenic mechanisms characterized by polymorphic VT or VF triggered by short-coupled PVCs.134,140 In hypothermia (including therapeutic hypothermia), J waves (Osborne waves) can manifest diffusely in all leads or be confined to selected leads. Rarely, hypothermia can induce ECG changes that mimic those of Brugada syndrome.140 The early repolarization syndrome shares a number of features with Brugada syndrome (Table 31.21). Both syndromes are associated with vulnerability to polymorphic VT and VF in young adults without apparent structural heart disease. However, in the Brugada syndrome, the region most affected by the disease is the anterior RVOT, and ST segment elevation is limited to the right precordial leads. Of note, a Brugada pattern on the surface ECG can be missed in patients with an inferolateral early repolarization pattern unless appropriate ECG recordings from the high intercostal space region are obtained. The presence of the Brugada ECG pattern was found to be a marker of poor outcome in patients with early repolarization; similarly, the presence of an inferolateral early repolarization ECG pattern was found to be a marker of poor outcome in patients with Brugada syndrome.134,148 In addition, several cardiac and noncardiac conditions can produce ECG changes that can potentially thus masquerade as a J wave (Box 31.4).

Risk Stratification Despite the reports linking early repolarization with sudden death, only a very small minority (1 : 10,000) of patients with this pattern on the ECG will have sudden cardiac arrest, while the majority remain asymptomatic. The identification of this minority of patients before they experience sudden death continues to be a challenge. Currently, the identification of the “malignant” variant of the early repolarization pattern relies on several parameters, including the amplitude, distribution, and dynamicity of J point elevation, as well as the morphology of the ST segment, pause-dependent augmentation of J point elevation, and the presence of short-coupled PVCs, among others. However, the sensitivity and specificity of these parameters remain limited. Although the presence of those markers is predicted to progressively augment the cumulative risk of SCD (Fig. 31.25), the absolute risk conferred for an asymptomatic patient remains too small to justify an aggressive approach in the absence of symptoms. Nonetheless, the presence of early repolarization should attract careful attention in certain groups of patients.

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

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TABLE 31.21  Similarities and Differences Between BrS and ERS and Possible Underlying

Mechanisms

BrS

ERS

Possible Mechanism(s)

Yes (>75%)

Yes (>80%)

Testosterone modulation of ion currents underlying the epicardial AP notch

Average age of first event Associated with mutations or rare variants in KCNJ8, CACNA1C, CACNB2, CACNA2D, SCN5A, ABCC9, SCN10A Relatively short QT intervals in subjects with Ca channel mutations Dynamicity of ECG

30–50 Yes

30–50 Yes

Yes

Yes

Loss of function of ICa

High

High

VF often occurs during sleep or at a low level of physical activity VT/VF trigger Ameliorative response to quinidine and bepridil Ameliorative response to isoproterenol denopamine and milrinone Ameliorative response to cilostazol Ameliorative response to pacing Vagally mediated accentuation of ECG pattern

Yes

Yes

Short-coupled PVC Yes Yes

Short-coupled PVC Yes Yes

Autonomic modulation of ion channel currents underlying early phases of the epicardial AP Higher level of vagal tone and higher levels of Ito at the slower heart rates Phase 2 reentry Inhibition of Ito and possible vagolytic effect Increased ICa and faster heart rate

Yes Yes Yes

Yes Yes Yes

Effect of sodium channel blockers on unipolar epicardial electrogram Fever

Augmented J waves

Hypothermia

Augmented J waves mimicking BrS

Augmented J wave Augmented J waves (rare) Augmented J waves

Similarities Between BrS and ERS Male predominance

Differences Between BrS and ERS Region most involved Leads affected

Regional difference in prevalence Incidence of late potential in signal-averaged ECG Prevalence of atrial fibrillation Effect of sodium channel blockers on surface ECG

Structural changes, including mild fibrosis and reduced expression of Cx43 in RVOT or fibrofatty infiltration in cases of arrhythmogenic right ventricular cardiomyopathy. Imaging studies have also revealed wall motion abnormalities and mild dilation in the region of the RVOT.

Augmented J waves

Gain of function in outward currents (IK-ATP) or loss of function in inward currents (ICa or INa)

RVOT V1-V3

Inferior LV wall II, II a, VF, V4, V5, V6; I, aVL, Both: inferolateral

Higher Higher Increased J wave manifestation

Lower Lower Reduced J wave manifestation

Higher in some forms of the syndrome

Unknown

Increased ICa, reduced Ito and faster heart rate Reduced availability of Ito due to slow recovery from inactivation Direct effect to inhibit ICa and indirect effect to increase Ito (due to slowing of heart rate) Outward shift of balance of current in the early phases of the epicardial AP Accelerated inactivation of INa and accelerated recovery of Ito from inactivation. Slowed activation of ICa leaving Ito unopposed. Increased phase 2 reentry but reduced pVT due to prolongation of APD.358 Higher levels of Ito and/or differences in conduction

Europe: BrS = ERS Asia: BrS > ERS

Reduction of J wave in the setting of ER is thought to be due largely to prolongation of QRS. Accentuation of repolarization defects predominates in BrS, whereas accentuation of depolarization defects predominates in ERS. Some investigators have hypothesized that some of these changes may be the result of, rather than the cause of, the BrS substrate, which may create a hibernation-like state due to loss of contractility in the RVOT secondary to loss of the AP dome.

AP, Action potential; APD, action potential duration; BrS, Brugada syndrome; ECG, electrocardiogram; ERS, early repolarization syndrome; RVOT, right ventricular outflow tract; PVC, premature ventricular contraction; pVT, polymorphic ventricular tachycardia; VF, ventricular fibrillation; VT, ventricular tachycardia. From Antzelevitch C, Yan GX, Ackerman MJ, et al. J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge. Heart Rhythm. 2016;13:e295–e324.

J Wave Amplitude Evidence suggests that the height of J point elevation, rather than its mere presence, can potentially provide important risk stratification information. A slurred or notched J point elevation greater than 0.2 mV in the inferior leads predicts a 2.9-fold increase in SCD risk, whereas

an elevation of at least 0.1 mV predicts a more modest (1.4-fold) increase in risk of arrhythmic death. A similar phenomenon was also observed in survivors of primary VF. It is worth noting that J point elevation greater than 0.2 mV seems to be rare (0.3% to 0.7%) in the normal population, but was observed in 16% of patients with idiopathic VF.1,139

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

BOX 31.4  Differential Diagnosis of Early

Repolarization Pattern

• Juvenile ST pattern • Pericardial disease (pericarditis, pericardial cyst, pericardial tumor) • Hypothermia • Hyperthermia • Myocardial tumor (lipoma) • Hypertensive heart disease • Athlete’s heart • Myocardial ischemia • ST segment elevation myocardial infarction • Fragmented QRS (terminal notching) • Hypocalcemia • Hyperkalemia • Thymoma • Aortic dissection • Arrhythmogenic right ventricular cardiomyopathy • Takotsubo cardiomyopathy • Neurological causes (intracerebral bleeding, acute brain injury) • Myocarditis • Chagas disease • Cocaine use From Antzelevitch C, Yan GX, Ackerman MJ, et al. J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge. 2016;13, e295–e324.

Short coupled VPBs Family history of sudden cardiac death Dynamic J point elevation; augmented at slower heart rates

Increasing risk

Associated pathology; Brugada syndrome, SQTS, fragmented QRS More widespread J wave distribution Increased J wave amplitude Horizontal/descending ST segment

Prevalence Fig. 31.25  Risk Stratification of Patients With Early Repolarization. The highest risk corresponds to the top of the pyramid, whereas the lowest risk is at the bottom. The estimated prevalence of the risk factor corresponds to the width of the pyramid. SQTS, Short QT syndrome; VPBs, ventricular premature beats. (From Mahida S, Derval N, Sacher F, et al. History and clinical significance of early repolarization syndrome. Heart Rhythm. 2015;12:242–249.)

wave distribution confers a progressively increased risk of arrhythmic death. Also, in asymptomatic individuals, early repolarization is most prominent in midprecordial leads (V2 to V4), a pattern that is especially predominant among athletes and is thought to confer a more benign prognosis.139

J Wave Morphology A recent report suggested a potential role of J wave duration and slope as markers of an increased arrhythmic risk. A delayed and prolonged J wave, a marker of a transmural dispersion of repolarization, may represent a new discriminant able to distinguish between benign and malignant early repolarization.149

J Wave Amplitude Fluctuation Although the pattern of J point elevation on baseline measurement remains constant during long-term follow-up in the majority of subjects, the magnitude of J point elevation can fluctuate even without drug provocation or exercise. Marked spontaneous accentuation of J wave amplitude, bradycardia- or pause-dependent dynamicity of the J wave, and spontaneous beat-to-beat fluctuation in the morphological pattern of early repolarization are frequently observed during periods of electrical storm (including frequent PVCs and episodes of VF). Transient and marked augmentation of J wave amplitude can potentially portend a high risk for VF in patients with early repolarization.135,139

ST Segment and T Wave Morphology For early repolarization patterns in the inferior or lateral leads, the presence of horizontal or downward-sloping ST segments after the J point predicts an increased risk for arrhythmic death, especially if accompanied by a high-amplitude (greater than 0.2 mV) J point elevation. In contrast, the presence of rapidly upsloping ST segments after the J point, followed by an upright T wave (which is the most common pattern observed in young athletes) is associated with a benign prognosis.134,147 The rapidly ascending ST segment variant is universal in populations with benign prognosis (such as athletes); in contrast, cohorts with increased arrhythmic risk (such as patients with ischemic VF or idiopathic VF) have J waves predominantly followed by a horizontal ST segment without ST segment elevation. A recent study reported that in patients with idiopathic VF, the prominent J wave is followed not only by a flat ST segment but also by a low-amplitude T wave (defined as T waves in leads I, II, or V4-V6 that were inverted, biphasic, or smaller than 1 mm), and a low T wave– to–R wave amplitude ratio (in lead II or V5). In fact, a low-amplitude ratio (T wave amplitude less than or equal to 10% of the R wave amplitude in the same lead) performed superior to J wave amplitude and ST segment pattern in differentiating malignant from benign inferolateral early repolarization.150

Short-Coupled Premature Ventricular Complexes The presence of frequent and short-coupled PVCs (which can potentially act as a trigger of polymorphic VT or VF) on ECG or during cardiac monitoring confers a significantly increased arrhythmic risk in early repolarization patients.

Syncope J Wave Distribution The distribution of J waves has been reported to influence the risk of sudden death in early repolarization patients. Several studies demonstrated that a lateral distribution of early repolarization portends the lowest risk, whereas an inferior and combined inferior and lateral J

More than one-third of early repolarization syndrome patients with SCD have experienced a previous episode of syncope. However, the presence of syncope has a low specificity in predicting future events and, although syncope is common in the early repolarization population, sudden death is a rare event. Nonetheless, a history of syncope in a patient with early repolarization merits detailed evaluation. The

CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies presence of unexplained syncope, especially when occurring at rest or agonal respiration while sleeping, especially in a patient with a strong family history of sudden death, may identify a subset of early repolarization patients who are at high risk for arrhythmic events.

Family History A number of studies have reported familial clustering of early repolarization syndrome and SCD. Approximately one-fifth of early repolarization syndrome patients with VF have a family history of sudden death. However, there is currently insufficient evidence to quantify the risk conferred by a positive family history in asymptomatic individuals.

Coexisting Arrhythmia Syndromes In the presence of other cardiac conditions, the EP substrate leading to early repolarization and J wave formation can potentially reduce the threshold for malignant ventricular arrhythmias. Besides idiopathic VF, recent studies showed that the presence of a J wave was associated with a higher incidence of malignant ventricular arrhythmias in patients with Brugada syndrome and SQTS.148 Furthermore, the presence of early repolarization (especially early repolarization in the inferior leads and without ST segment elevation) appears to increase the vulnerability to fatal arrhythmia risk in patients with structural cardiac disease, and was found to be a predictor of increased VT/VF or sudden death in patients with chronic ischemic heart disease, acute and subacute MI, vasospastic angina, heart failure (regardless of the etiology), noncompaction cardiomyopathy, and Takotsubo cardiomyopathy.151,152

Exercise Testing Exercise suppresses the early repolarization pattern both in symptomatic and asymptomatic subjects, especially early repolarization patterns in the lateral leads or those with an ascending ST segment. Therefore exercise testing does not seem to provide prognostic information.145

Invasive Electrophysiological Testing Invasive EP testing is not helpful for risk stratification. VF induction by programmed ventricular stimulation has been found to be a poor predictor of arrhythmic risk in symptomatic and asymptomatic patients with early repolarization. Patients with early repolarization do not exhibit significantly higher inducibility with programmed ventricular stimulation than those without early repolarization. Furthermore, VF is inducible during EP testing in only 22% to 34% of the patients with a clinical history of cardiac arrest secondary to VF. In addition, VF inducibility is not correlated with known risk factors, such as the degree of J point elevation, the distribution of J waves, or the ST segment morphology on the surface ECG.136

Genetic Screening The early repolarization pattern is associated with sudden death and has been shown to be heritable. Genetic contributions to SCD-associated early repolarization are suggested by common familial SCD histories in symptomatic early repolarization patients. As noted, several genes have been associated with early repolarization. However, so far, the genetic markers to differentiate benign and arrhythmic forms of early repolarization have not been identified, and the clinical benefit of genetic testing in these patients is currently questionable.

Principles of Management

Patients With Early Repolarization Syndrome ICD implantation is recommended for secondary prevention in survivors of cardiac arrest or those with documented sustained ventricular arrhythmias and early repolarization pattern. Quinidine is considered an alter-

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native therapy when an implanted ICD is not feasible or not preferred. A proposed algorithm for an approach to patients with early repolarization is shown in Fig. 31.26.1,135,147 For acute suppression of ventricular arrhythmias in a patient with an electrical storm, acceleration of the heart rate (20% increase in heart rate or an absolute heart rate greater than 90 beats/min) by isoproterenol infusion or by atrial or ventricular pacing can be very effective. Deep sedation may also be considered in refractory cases (see Fig. 31.7).1,134 For long-term suppression of VF in patients with recurrent arrhythmias or frequent ICD therapies, quinidine has been shown to ameliorate the early repolarization pattern and prevent VF recurrence. The combination therapy of cilostazol and bepridil may be considered an alternative therapy when quinidine is not available or not tolerated.135

Syncope Patients With Early Repolarization Pattern Management decisions for patients with syncope and family history of SCD in the context of early repolarization can be problematic, and should be individualized. The underlying etiology of syncope should be thoroughly investigated. Vasovagal syncope is not uncommon in patients with early repolarization patterns. When etiology of syncope is equivocal, ambulatory cardiac monitoring and loop recorder implantation should be considered. If malignant arrhythmias are highly suspected, ICD implantation may be considered in the patient with a strong family history of SCD.1,135,146,147

Asymptomatic Patients With Early Repolarization Pattern There is not yet a clear consensus on the specific risk factors that identify asymptomatic early repolarization subjects in whom the probability of SCD is sufficiently high to warrant an ICD for primary prevention. Pending further research, the finding of the early repolarization pattern in the absence of syncope or a strong family history of juvenile SCD does not merit further investigation, regardless of J wave amplitude or ST segment slope. With a strong family history for juvenile SCD, ICD implantation may be considered in subjects with high-risk ECG features of early repolarization.1,135,147

Participation in Sports Restriction from competitive sports is appropriate in patients with idiopathic VF. However, no information is available about lifestyle modification in asymptomatic patients with early repolarization ECG pattern. Given the high prevalence of early repolarization patterns (especially in leads V2 to V6) in athletes, occurring in 20% of noncompetitive athletes and in up to 90% of high-performance athletes, and because the midprecordial location of early repolarization is generally believed to be benign, and in the absence of reliable risk-stratifying parameters, a universal restriction from competitive sports does not seem warranted in asymptomatic athletes with early repolarization and a negative family history of SCD.146 Nonetheless, certain restrictions may be considered in highly active patients with resting bradycardia and prominent early repolarization patterns localized to the inferior or inferolateral leads and a strong family history of SCD, although definitive guidelines are still lacking.146

Family Screening No consensus exists concerning the screening of families of individuals with symptomatic or asymptomatic early repolarization pattern. There are no established provocative tests to diagnose a concealed early repolarization ECG pattern in family members of early repolarization syndrome patients, although preliminary observations suggest that the Valsalva maneuver can potentially assist in identifying concealed early repolarization cases.

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CHAPTER 31  Ventricular Arrhythmias in Inherited Channelopathies

ER pattern >0.1 mV in at least two contiguous inferolateral leads

Asymptomatic

Symptomatic

Electrical storm

Prior cardiac arrest sustained VT

Isoproterenol (class IIa) +/− quinidine

High-risk ER ECG pattern (prominent J waves, horizontal/descending ST-segment, high dynamicity) and strong family history of unexplained sudden death at young age

Presumably arrhythmic origin

ICD (class I) If ICD refused or contraindicated quinidine Repeated appropriate shocks

Syncope, seizure NAR and strong family history of sudden death at young age

+ ICD (class IIb)

Yes

No

− Close follow-up with/without ILR

ICD (class IIb)

Close follow-up

Quinidine (class IIa) Cilostazol Fig. 31.26  Indications for Therapy of Patients With Early Repolarization Syndrome. ECG, Electrocardiogram; ER, early repolarization; ICD, implantable cardioverter-defibrillator; NAR, nocturnal agonal respiration; VT, ventricular tachycardia. (From Antzelevitch C, Yan GX, Ackerman MJ, et al. J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge. Heart Rhythm. 2016;13:e295–e324.)

A number of drugs also have been tested as potential provocative agents, including verapamil, epinephrine, ATP, cibenzoline, and pilsicainide, and have been reported to have a minimal effect on the degree of J point elevation. In contrast to the Brugada syndrome, Na+ channel blockers result in a paradoxical attenuation, rather than accentuation, of J point elevation in early repolarization syndrome patients.139,145

VIDEOS The following video accompanies this chapter: See Video 22.1. Ventricular Fibrillation Triggered by Coronary Artery Spasm

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