Management of ventricular arrhythmias in suspected channelopathies.

Abstract

HomeCirculation: Arrhythmia and ElectrophysiologyVol. 8, No. 1Management of Ventricular Arrhythmias in Suspected Channelopathies Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBManagement of Ventricular Arrhythmias in Suspected Channelopathies Manoj N. Obeyesekere, MBBS, Charles Antzelevitch, PhD and Andrew D. Krahn, MD Manoj N. ObeyesekereManoj N. Obeyesekere From the Department of Cardiology, Northern Healthcare Group, Epping, Victoria, Australia (M.N.O.); Masonic Medical Research Laboratory, Utica, NY (C.A.); and Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada (A.D.K.). Search for more papers by this author , Charles AntzelevitchCharles Antzelevitch From the Department of Cardiology, Northern Healthcare Group, Epping, Victoria, Australia (M.N.O.); Masonic Medical Research Laboratory, Utica, NY (C.A.); and Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada (A.D.K.). Search for more papers by this author and Andrew D. KrahnAndrew D. Krahn From the Department of Cardiology, Northern Healthcare Group, Epping, Victoria, Australia (M.N.O.); Masonic Medical Research Laboratory, Utica, NY (C.A.); and Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada (A.D.K.). Search for more papers by this author Originally published1 Feb 2015https://doi.org/10.1161/CIRCEP.114.002321Circulation: Arrhythmia and Electrophysiology. 2015;8:221–231IntroductionAlthough structural heart disease remains the predominant substrate for ventricular arrhythmia, channelopathies including long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and early repolarization syndrome (ERS) are less common but important contributing entities. These etiologies require specific therapies potentially contrary to empirical management of arrhythmias associated with structural heart disease. Conventional therapy including antiarrhythmic drug therapy may not only fail to resolve unstable arrhythmias but worsen them. Additionally, channelopathy patients with implantable cardioverter defibrillators (ICD) and arrhythmic storms represent a major challenge, and the acute care team needs to be cognizant of unique circumstances that require specific acute therapies beyond empirical advanced life support algorithm recommendations.1Successful and considered acute management of ventricular arrhythmias is contingent on a number of variables, including knowledge of the cardiac substrate or potential substrate; form, mechanism, and precipitants of ventricular arrhythmias; and acute effect of potential therapies. In the longer term, an understanding of the natural history of the channelopathy along with the efficacy of long-term therapy will lead to superior outcomes. This review will present the risk of ventricular arrhythmias associated with these uncommon entities, the evolving understanding of the mechanism of arrhythmia, and the mechanistic basis of therapies along with a clinical approach to summarize the evidence pertaining to acute and long-term management.Long QT SyndromePatients with a prolonged QT interval are at risk of sudden cardiac death (SCD) due to Torsade de Pointes (TdP; Figure 1). Most patients with congenital LQTS are asymptomatic and diagnosed incidentally on electrocardiogram screening or following family screening. However, syncope, aborted SCD, or SCD may be the first presentation. Most arrhythmic events in congenital LQT1 occur during physical or emotional stress, at rest or in association with sudden auditory stimulation in LQT2, and during sleep or rest in LQT3 patients.2 Although typical presentations can assist in raising the suspicion of LQTS, the history alone remains insufficient to diagnose the genotype and guide management.Download figureDownload PowerPointFigure 1. Long QT syndrome with resultant Torsade de Pointes (TdP) (top, exercise-induced TdP; bottom, bradycardia-induced TdP).Although numerous variables have been reported to increase the risk of TdP in patients with LQTS, the degree of QTc prolongation remains foundational.2 SCD in patients with congenital LQTS and a normal QTc (<440 ms) is low (4% at 40 years and 10% at 70 years).3 This is significantly lower compared with patients with LQTS with prolonged QTc (>440 ms, 15% at 40 years and 24% at 70 years).3 However, the risk of death in patients with LQTS and a normal QTc is still 10-fold compared with unaffected family members (0.4% at 40 years and 1% at 70 years).3 Risk of TdP is directly related to QTc with QTc values >500 ms requiring prompt attention even in the absence of arrhythmias.Mechanism of ArrhythmiaQT prolongation can be due to common genetic variants or acquired, commonly due to QT-prolonging medications.Decreased outward potassium current mediated by loss-of-function mutations in IKs (slowly activating delayed rectifier potassium current) channels leads to LQT1 (Figure 2). Decreased outward potassium current, mediated by loss-of-function mutations in IKr (rapidly activating delayed rectifier current) channels, leads to LQT2. Increased inward sodium current, mediated by gain-of-function mutations in the cardiac sodium channel, causes slowed or incomplete channel inactivation leading to LQT3.Download figureDownload PowerPointFigure 2. The ionic currents of the action potential (AP). Epicardial (Epi) AP and current are shown by dotted lines and endocardial (Endo) by solid lines. Depolarizing inward currents are depicted downward and repolarizing outward currents upward. The Epi AP has a characteristic notch caused by larger phase 1 Ito compared with Endo. ECG indicates electrocardiogram; ICaL, inward calcium currents; IK1, inward rectifier current; IKACh, acetylcholine-activated current; IKATP, adenosine triphosphate–sensitive current; IKr, rapid delayed rectifier current; IKs, slow delayed rectifier current; INa, inward sodium current; INa/Ca, sodium calcium exchange; and Ito, transient outward current.The dysfunction of the ion channels results in prolonged repolarization and can lead to development of early after depolarizations due to an inward shift in the balance of current flowing during phases 2 and 3 of the cardiac action potential (AP). When the early after depolarizations reach the threshold for activation of the inward calcium current, they generate triggered extrasystoles. Differences in the degree of AP prolongation among the 3 cell types that comprise the ventricular wall lead to development of transmural dispersion of repolarization (TDR), thus creating a vulnerable window across the ventricular wall and other regions of the ventricular myocardium, which can lead to development of reentrant arrhythmias. When an early after depolarization–induced triggered response falls within this vulnerable window, the result is an atypical polymorphic ventricular tachycardia (PMVT), known as TdP.4 To date, mutations in 15 different genes have been identified in patients clinically diagnosed with LQTS (Table 1). LQT1 to LQT3 account for an estimated 85% to 95% of genotype-positive LQTS cases.2Table 1. Gene Defects Responsible for Long QT SyndromeChromosomeGeneIon ChannelLQT111KCNQ1, KvLQT1↓ IKs30%–35%LQT27KCNH2, HERG↓ IKr20%–25%LQT33SCN5A, Nav1.5↑ Late INa 5%–10%LQT44Ankyrin-B, ANK2↑ Cai, ↑ Late INa1%–2%LQT521KCNE1, MinK↓ IKs1%LQT621KCNE2, MiRP1↓ IKrRareLQT7*17KCNJ2, Kir 2.1↓ IK1RareLQT8†6CACNA1C, Cav1.2↑ ICaRareLQT93CAV3, Caveolin-3↑ Late INaRareLQT1011SCN4B, NavB4↑ Late INaRareLQT117AKAP9, Yatiao↓ IKsRareLQT1220SNTA1, a1 Syntrophin↑ Late INaRareLQT1311KCNJ5, Kir 3.4↓ IKAChRareLQT1414CALM1, CalmodulinRareLQT152CALM2, CalmodulinRare*Andersen–Tawill syndrome.†Timothy syndrome.Medications that prolong the QT interval are the best-characterized risk factors for acquired LQT, which is far more common than congenital LQTS. The vast majority of QT-prolonging drugs act by blocking IKr (Figure 2). Some IKr blockers can augment late INa via inhibition of the phosphoinositide 3-kinase pathway. Thus, the torsadogenic actions of these IKr blockers are mediated by both a reduction in outward current and an increase in inward current.5 An up-to-date list of drugs associated with QTc prolongation and cardiac arrhythmias can be found at www.qtdrugs.org. Pharmacodynamic and pharmacokinetic drug–drug interactions may also lead to QTc prolongation.Acquired LQTS is commonly associated with multiple risk factors. In 1 series of 11 patients with acquired LQT (9/11 with TdP), there were ≥2 risk factors for the development of LQT, which always included ≥1 known QT-prolonging medication and ≥1 electrolyte disturbance (hypokalemia, hypocalcemia, and hypomagnesaemia).6 Patients were taking an average of 2.8±0.3 QT-prolonging medications in this series. Average QTc interval at presentation was 633.8±29.2 ms. A QTc >500 to 550 ms should prompt clinicians to assess the risk/benefit ratio of continuing QT-prolonging pharmacotherapy, depending on contributing arrhythmic variables and competing clinical indications for QT-prolonging pharmacotherapy.Therapeutic StrategiesThe management principles hinge on pharmacological and nonpharmacological attempts to produce an outward shift in the balance of currents to overcome the abnormally prolonged repolarization and suppress triggers. Acutely, correction of electrolyte abnormalities, such as hypokalemia and hypomagnesemia, is essential in both acquired and congenital LQTS. Studies have reported the safety and utility of intravenous magnesium sulfate for the treatment of TdP associated with acquired and congenital LQTS.7β-blockers are considered first-line therapy for patients with LQT1 and LQT2, but remain controversial in LQT3. Metoprolol seems to be less effective than propranolol and nadolol.8 The longer half-life of nadolol also allows twice-a-day administration and is preferable. Similarly sustained release propranolol should be preferred. Limited data suggest that atenolol may be less effective compared with propranolol.9 Additional data suggest that in LQT1, the risk reduction is similar among atenolol, metoprolol, propranolol, and nadolol, but in LQT2, nadolol provided the only significant risk reduction.10 Currently evidence is lacking to recommend cardioselective over noncardioselective β-blockers.Experimental data indicate β-blockade (propranolol) to be effective in preventing ventricular tachycardia (VT)/ventricular fibrillation (VF) in a validated LQT3 model.11 However, other experimental data suggest β-blockade may facilitate TdP in LQT3.12 The apparent lack of clinical efficacy in small populations of patients with LQT3 on β-blockers has been suggested to be due to analysis including patients with LQT3 who had suffered a cardiac arrest in the first year of life who remained at high risk compare with patients who did not have events early in life who appeared to remain protected by β-blockers.13 The largest clinical series from 9 registries worldwide (published in conference abstract form) included 403 patients with LQT3 and concluded β-blocker therapy to be effective in significantly reducing the risk of aborted cardiac arrest or SCD.14Preliminary data suggest that patients with LQT3 could benefit more from Na+ channel blockers, such as mexiletine, flecainide, and ranolazine, although long-term data are not available as yet.15–17 Experimental data have shown that mexiletine reduces TDR and prevents TdP in LQT3, as well as LQT1 and LQT2, suggesting that agents that block late sodium current may be effective in all forms of LQTS.18 In rare cases, cautious use of mexiletine has been advocated due to reported prolongation of the QT interval by facilitating trafficking of mutant proteins in LQT3.19 Flecainide, a potent blocker of the open sodium channel, in low dose consistently shortened the QTc interval (565±60 ms to 461±23 ms; P<0.04) and normalized QTc in patients with LQT3 (n=5) with a DKPQ mutation.15 Class 1b and 1c agents may also be tried acutely intravenously in patients with TdP due to LQT3, although no study has reported safety or efficacy.The late INa blocker ranolazine is effective in abbreviating QT interval and suppressing TdP in experimental models of LQT317 and in significantly abbreviating QTc in patients with LQT3.20 In patients with DKPQ-mediated LQT3, ranolazine has been shown to cause a dose-dependent abbreviation of the QTc interval with no change in PR or QRS intervals.20 The lack of effect of ranolazine on PR interval and QRS duration is consistent with the finding that ranolazine does not significantly inhibit peak INa in the ventricle at therapeutic concentrations.20 Clinical trials of ranolazine in LQT1 and LQT2 are not as yet available.Adrenergic stimulation may be of benefit in the case of acquired LQTS associated with bradycardia and long pauses. Isoproterenol or epinephrine may exacerbate arrhythmias in patients with acquired LQT with a concurrent congenital defect but may be beneficial in patients with acquired LQT with no concurrent gene mutation by recruiting functional IKs channels and accelerating heart rate21 (Table 1; Figure 3). β-adrenergic stimulation induces TdP by increasing TDR in canine models of LQT1 and 2 but suppresses TdP by reducing dispersion in the LQT3 canine model.12 Thus acutely, β-adrenergic stimulation can be beneficial in LQT3 and β-blockers in LQT1 and LQT2. Acute temporary pacing can minimize pause-dependent TdP in both acquired and congenital LQT patients.22Download figureDownload PowerPointFigure 3. An algorithm for acute pharmacological treatment of arrhythmias in suspected channelopathies. CPVT indicates catecholaminergic polymorphic ventricular tachycardia; LQT, long QT; LQTS, long QT syndrome; PMVT, polymorphic ventricular tachycardia; and VF, ventricular fibrillation.The implantation of an ICD is pivotal secondary prevention in LQTS and a reasonable primary prevention approach in select cases.2 Thoughtful ICD programming to prevent inappropriate shocks is important and usually requires a VF-only zone (detect rate, >220–240 beats per minute).Left cardiac sympathetic denervation (LCSD) is generally limited to the treatment of patients with LQT1 or LQT2 with recurrent syncope despite β-blocker therapy, in patients who experience arrhythmic events with an ICD, and considered in patients intolerant to β-blocker therapy.2 LCSD has been performed both as primary and secondary prevention in LQTS with excellent outcomes in select patients.23 Marked reduction in number of cardiac events is usually seen following LCSD. However, nearly 50% of patients with high-risk LQTS continue to experience breakthrough events. Thus, LCSD should not be viewed as curative or as an alternative to ICDs for high-risk patients. Furthermore, in appropriate patients, LCSD is initially favored, with subsequent right cardiac sympathetic denervation if there is arrhythmia recurrence.24Short QT SyndromeThe SQTS is characterized by an abbreviated QTc interval (<330 ms), with J-point to T-wave peak <120 ms (measured in the precordial leads with the T-wave of greatest amplitude), with a relatively large amplitude peaked T-wave with a steep downward slope, ventricular and atrial arrhythmias (due to short atrial and ventricular effective refractory periods), and SCD/syncope.2 The majority of affected individuals typically have a personal or family history of syncope or autopsy-negative SCD in a first- or second-degree young relative.25 SQTS is relatively rare with <60 cases reported in a recent expert consensus statement.2 There are no validated diagnostic criteria, although a scoring system for diagnosis has been proposed.26 It is likely that the severity of QT abbreviation is related to prognosis, although this has not been validated.In contrast to the mutations that underlie LQTS, SQT1 is caused by mutations that cause a gain of function of outward currents or loss of function of inward currents. The increased net outward current accelerates repolarization of the AP, thus abbreviating the QT interval. Gain-of-function mutations in the KCNH2 (IKr), KCNQ1 (IKs), and KCNJ2 (IK1) genes account for SQT1, 2, and 3, respectively. Loss-of-function mutations in the CACNA1C, CACNB2, and CACNA2D1 genes encoding for the a1, b, and a2δ subunits of the cardiac L-type calcium channel account for SQT4, 5, and 6, respectively (Figure 2).27Mechanism of Arrhythmia in SQTSAbbreviation of the AP in SQTS is heterogeneous, most commonly displaying preferential abbreviation in epicardium, thus giving rise to an increase in TDR. Augmented TDR as the basis for arrhythmogenesis in SQTS has been demonstrated in experimental models in which repolarization is abbreviated using the IKr agonist, PD-118057,28 thus mimicking the cellular conditions created by the genetic defect associated with SQT1. Dispersion of repolarization and refractoriness serve as substrates for reentry by promoting unidirectional block. Marked abbreviation of wavelength (product of refractory period and conduction velocity) is an additional factor promoting the maintenance of reentry. Tpeak–Tend interval and Tpeak–Tend/QT ratio, an electrocardiographic index of spatial dispersion of repolarization, including TDR, are significantly augmented in cases of SQTS.29,30 This ratio is greater in symptomatic patients.31Therapeutic StrategiesIsoproterenol has been reported to suppress VF due to SQTS32 in 1 case report. This beneficial action was secondary to a reduction of Tpeak–Tend, suggesting a reduction in TDR. However, this observation is in contrast to some experimental models of SQTS, which have shown a significant further abbreviation of QT interval and increase in TDR with isoproterenol, leading to more inducible PMVTs.33 Thus, strong evidence is lacking regarding isoproterenol in SQTS.Fifty-three patients from the European Short QT Registry were followed up for 64 months and found to have an incidence of arrhythmic events of 5% per year in patients without pharmacological prophylaxis compared with no arrhythmic events in those administered hydroquinidine,25 suggesting patients with SQTS should be considered for pharmacological prophylaxis at the least. Quinidine can normalize the QT interval but has not been evaluated in large long-term or comparative studies. Flecainide, sotalol, ibutilide, and quinidine were studied in 6 patients with SQTS. Only quinidine was associated with significant QT prolongation (263±12 ms to 362±25 ms), resulting in a longer ventricular effective refractory period and noninducibility of VF during provocative testing.34There are no data to support implantation of ICDs in asymptomatic patients. An ICD may be considered in patients with a genotype or phenotype diagnosis of SQTS and a family history of SCD with evidence of a short QTc in relative/s with SCD (class IIb).2 Appropriate programming is needed to prevent inappropriate shocks from T-wave over sensing.Brugada SyndromeThe majority of patients with a Brugada electrocardiogram pattern are asymptomatic, diagnosed incidentally, and may remain asymptomatic for life. Others may present with VF or SCD (particularly at night), nocturnal agonal breathing, syncope, and palpitations. Patients with a Brugada type-1 electrocardiogram (Figure 4) have an approximate cardiac event-rate per year of 7.7% in patients with aborted SCD, 1.9% in patients with syncope, and 0.5% in asymptomatic patients.35Download figureDownload PowerPointFigure 4. Brugada electrocardiogram types and precipitants of ventricular arrhythmia in Brugada syndrome. Type 1 is characterized by a coved-type ST-segment elevation of ≥2 mm in the right precordial leads (V1–V3) followed by a negative T-wave. In type 2, ST-segment elevation has a saddleback appearance with a high takeoff ST-segment elevation of >2 mm, a trough displaying >1-mm ST-elevation followed by a positive or biphasic T-wave. Type 3 has an ST-segment morphology that is either saddleback or coved with an ST-segment elevation of <1 mm. PMVT indicates polymorphic ventricular tachycardia; PVC, premature ventricular contraction; and VF, ventricular fibrillation.Mechanism of ArrhythmiaMutations in 19 genes have been associated with the Brugada electrocardiogram, and in each, a decrease in the inward sodium or calcium current or an increase in an outward potassium current has been demonstrated, resulting in an outward shift in the balance of current during the early phases of the AP (Table 2). The reduction in INa allows the transient outward (Ito) current to repolarize the cell during phase 1 beyond the voltage range at which L-type Ca+2 channels activate. Failure of the Ca+2 channels to activate results in loss of the AP plateau, predominantly in the subepicardial cells where Ito is most prominent. Conduction of the AP dome from epicardial sites at which it is maintained to sites at which it is lost results in the development of phase 2 reentry, giving rise to a closely coupled extrasystole.Table 2. Gene Defects Responsible for Brugada SyndromeLocusGeneIon ChannelBrS13p21SCN5A, Nav1.5↓ INa11%–28%BrS23p24GPD1L↓ INaRareBrS312p13.3CACNA1C, Cav1.2↓ ICa6.6%BrS410p12.33CACNB2b, Cavß2b↓ ICa4.8%BrS519q13.1SCN1B, Navß1↓ INa1.1%BrS611q13-14KCNE3, MiRP2↑ ItoRareBrS711q23.3SCN3B, Navß3↓ INaRareBrS812p11.23KCNJ8, Kir6.1↑ IKATP2%BrS97q21.11CACNA2D1, Cavα2δ↓ ICa1.8%BrS101p13.2KCND3, Kv4.3↑ ItoRareBrS1117p13.1RANGRF, MOG1↓ INaRareBrS123p21.2-p14.3SLMAP↓ INaRareBrS1312p12.1ABCC9, SUR2A↑ IKATPRareBrS1411q23SCN2B, Navß2↓ INaRareBrS1512p11PKP2, Plakophillin-2↓ INaRareBrS163q28FGF12, FHAF1↓ INaRareBrS173p22.2SCN10A, Nav1.8↓ INa16.7%BrS186qHEY2 (transcriptional factor)↑ INaRareBrS197p12.1SEMA3A, Semaphorin↑ ItoRareInterestingly, these repolarization abnormalities give rise to low-voltage fractionated electrogram activity and high-frequency late potentials when a bipolar electrogram is recorded in the epicardial region of the right ventricular outflow tract (RVOT) in an experimental model.36 The low-voltage fractionated electrogram activity, initially thought to be due to delayed conduction in the RVOT,37 has more recently been shown in an experimental model to be due to dyssynchrony in the appearance of the epicardial AP dome secondary to accentuation of the AP notch, and the high-frequency late potentials are due to concealed phase 2 reentry, both the result of repolarization abnormalities in the RVOT epicardium.36Therapeutic StrategiesFever should be treated promptly with antipyretics, and drugs that unmask or aggravate BrS (www.brugadadrugs.org) should be avoided. A number of precipitants for ventricular arrhythmias have been reported (Figure 4) and should be addressed acutely. Isoproterenol has been used successfully to control VF storm.38 The occurrence of spontaneous VF in patients with BrS is often related to increases in vagal tone, and correspondingly, electrical storm is sometimes treatable by the increase of sympathetic tone via isoproterenol administration (Figure 3).Quinidine may have a role in asymptomatic patients; however, this has not been evaluated in large double-blinded clinical trials.39 Quinidine is effective as adjunctive therapy in symptomatic patients, with recurrent arrhythmias and frequent ICD discharges.40 Effectiveness of quinidine or hydroquinidine in doses ≤600 mg/d is 85% (median follow-up of 4 years).41 A prospective registry of empirical quinidine for asymptomatic BrS has been established (http://clinicaltrials.gov/ct2/show/NCT00789165?term_brugada&rank_2). Doses between 600 and 900 mg are recommended by the study, if tolerated.39The relatively low annual rate of arrhythmic events in asymptomatic patients (0.5% versus 7.7%–10.2% in patients with VF and 0.6%–1.2% in patients with syncope) warrants careful consideration for ICDs in asymptomatic patients.42 In the recent HRS/EHRA/APHRS (Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society) guidelines, ICDs are not recommended in asymptomatic patients.2 However, the ICD is first-line therapy for BrS patients with a history of VT/VF or arrhythmic syncope. Long detect durations and high detect rates along with careful programming of discriminators may minimize inappropriate ICD therapy.In 9 patients with VF storm due to BrS, electroanatomic mapping has demonstrated abnormally low, prolonged voltages and fractionated late potentials clustering exclusively in the anterior aspect of the RVOT epicardium.43 Ablation at these sites rendered VT/VF noninducible and normalized the Brugada electrocardiogram pattern in the majority. Long-term outcomes (20±6 months) were excellent, with no recurrent VT/VF with only 1 patient on medical therapy with amiodarone.43 One recent study (10 patients) reports late activation in the endocardium of the RVOT as a potential VF substrate in BrS patients with VF episodes.44 Radiofrequency ablation within the RVOT endocardium normalized the electrocardiogram, suppressed VF storm, and reduced VF recurrence.Early Repolarization SyndromeAlthough early repolarization (ER; Figure 5) was historically considered benign, this perception changed in 2000 when experimental data in wedge models of ER were shown to be capable of generating rapid PMVT.45 Validation of this hypothesis came with the landmark study of Haïssaguerre et al46 and coworkers demonstrating a high prevalence of ER in patients with idiopathic VF. Numerous studies have shown a clear increased representation of the ER pattern in patients with idiopathic VF, with augmentation of the amplitude of ER preceding the development of ventricular arrhythmias.47Download figureDownload PowerPointFigure 5. A, Early repolarization pattern in the inferior and lateral leads. Isoproterenol-mediated attenuation of inferolateral early repolarization; early repolarization is apparent at a heart rate of 54 beats per minute (B) with gradual attenuation as heart rate increases (C and D).The early repolarization pattern should be viewed as largely benign.47 In some, ER is a modifier of risk of underlying cardiac conditions, and rarely ER represents as a primary arrhythmogenic disorder (ie, the ERS when other etiologies have been systematically excluded and when ER is associated with otherwise unexplained VF). The risk of arrhythmia is reported to depend on the location, pattern, and magnitude of ER. A relatively high risk is associated with ER in the inferior limb leads with a high amplitude J-point/wave (>0.2 mV) and a horizontal or descending ST segment after the J-point (compared with rapidly ascending/upsloping ST segments).48 These high-risk features are observed in <0.3% of the population.48 In the general population, ER is associated with a 1.3- to 6-fold increased relative risk of death.48 The highest risk is associated with global ER, in which ER is apparent in inferior, lateral, and anterior (right precordial) leads. Despite the high overall prevalence of ER in the general population (6%–13%) and the even higher prevalence of ER in patients with idiopathic VF (>20%–30%, ≤50%–60%), VF itself is rare (ER is estimated to increase VF risk from 3.4 per 100 000 to 11 per 100 000).49 The ideal method to accurately identifying individuals with ER with an increased risk of death or VF compared with the benign ER observed in a substantial proportion of the population remains elusive.Mechanism of ArrhythmiaER is reported to be due to steep transmural AP gradients that predispose to arrhythmogenesis.47 The normal epicardial AP differs from the endocardial in having a prominent phase 1 notch or spike-and-dome morphology (Figure 2). The difference is due primarily to a larger Ito in the epicardium, which results in greater net repolarizing (outward) current flow during phase 1. In ER, a further enhancement in epicardial net outward current results in an enhancement of the endocardial-to-epicardial AP differences that manifests as J-waves, which reflects current flow resulting from transmural voltage gradients generated by the presence of a prominent AP notch in epicardium but not endocardium.50Recent studies have provided insight into how the repolarization gradients in ER translate into arrhythmogenesis.51 The study by Koncz et al51 suggest that the AP dome of cells within LV epicardium become accentuated giving rise to phase 2 reentry and PMVT. This study showed that repolarization defects can be accentuated by acetylcholine, explaining the deleterious influence of elevated vagal tone, and that relatively high intrinsic levels of Ito account for the greater sensitivity of the inferior LV wall to development of VT/VF. Quinidine and isoproterenol were shown to ameliorate effects by reversing the repolarization abnormalities. The mechanism underlying development of arrhythmias in these models of ERS has been shown to be nearly identical to those of BrS.52Therapeutic StrategiesBecause of their similar pathophysiological mechanism, it is not surprising that the approach to therapy of ERS is similar to that of BrS. β-adrenergic activation with isoproterenol is effective in suppressing ER arrhythmias by enhancing inward calcium current (Figures 2 and 5).53 Quinidine via its effects to inhibit Ito is effective as well.53 A multicenter observational cohort study has demonstrated that isoproterenol in acute cases and quinidine in chronic cases is effective for suppression of VF related to ERS.54 In this study (n=122; 90 male patients; mean age, 37±12 years), patients with ER in the inferolateral leads with >3 episodes of idiopathic VF (including those with electrical storms) had empirical antiarrhythmic drug therapy prescribed by the treating physicians. Follow-up data were obtained for all patients using an ICD. Isoproterenol infusion immediately su