Polymorphic ventricular tachycardia--part II: the channelopathies.

Polymorphic Ventricular Tachycardia– Part II: The Channelopathies Indrajit Choudhuri, MD, Mamatha Pinninti, MD, Muhammad R. Marwali, MD, Jasbir Sra, MD, and Masood Akhtar, MD Abstract: In this article, we explore the clinical and cellular phenomena of primary electrical diseases of the heart, that is, conditions purely related to ion channel dysfunction and not structural heart disease or reversible acquired causes. This growing classification of conditions, once considered together as “idiopathic ventricular fibrillation,” continues to evolve and segregate into diseases that are phenotypically, molecularly, and genetically unique. (Curr Probl Cardiol 2013;38:503–548.) rimary electrical disorders are a group of diseases affecting the myocyte transmembrane ion channels that predispose to various arrhythmias including polymorphic ventricular tachycardia (PMVT). These inherited arrhythmia syndromes include long and short QT syndromes, short-coupled torsade de pointes (TdP), Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT), and there is also some fascination with early repolarization and associated sudden cardiac death (SCD). Most patients show no evidence of structural heart disease, and long-term prognosis is excellent if arrhythmia is controlled. The clinical aspects of these syndromes are detailed elsewhere.1 Although their pathological aspects are unique and distinct, management strategies include a common algorithm: implantable cardioverter-defibrillator (ICD) therapy for patients with recurrent syncope despite drug therapy, sustained ventricular tachyarrhythmia, or cardiac arrest and consideration of ICD for primary prevention of SCD when there is a strong family history of SCD or when avoidance of medical therapy is desired. In addition, as with all inherited conditions, genetic counseling and family

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The authors have no conflicts of interest to disclose. Curr Probl Cardiol 2013;38:503–548. 0146-2806/$ – see front matter http://dx.doi.org/10.1016/j.cpcardiol.2013.07.004

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planning are an important aspect of the management approach. Herein, we focus on aspects of the individual conditions that pertain to PMVT.

Long QT Syndrome Clinical Features The long QT syndromes (LQTS) are a complex spectrum of molecularly distinct but phenotypically similar ion channel disorders that are characterized by delayed ventricular repolarization, which places patients at risk for PMVT in the setting of a prolonged QT interval. There are at least 13 different genes associated with congenital LQTS, but 3 groups of mutations that lead to LQT1, LQT2, or LQT3 syndromes account for 90% of cases.2,3 The most common ones—LQT1 and LQT2—are caused by loss-of-function mutations in genes expressing potassium channels (KCNQ1 and KCNH2). In LQT1, ventricular tachycardia (VT) typically occurs during physical exertion, particularly swimming.4 In LQT2, VT is often triggered by emotional surprise, such as a loud noise. LQT3 syndrome is attributable to a mutation that enhances the sodium current; SCD during sleep is a prominent feature.

Electrocardiographic Features The phenotypic T-wave morphology often can be helpful in distinguishing LQTS genotypes: broad-based T waves are suggestive of LQT1, notched T waves are suggestive of LQT2, and narrow-based T waves with prolonged ST segment are indicative of LQT3 (Fig 1).5

Cellular Features The T-wave morphology in models of the LQTS has been suggested to correlate with action potentials of different layers of myocardial cells: the peak of the T wave with repolarization of the epicardial action potential is

FIG 1. Congenital long QT patterns. Type 1 exhibits broad-based T wave with ST segment leaving baseline immediately following J point. Type 2 exhibits low-amplitude notched T wave. Type 3 exhibits prolonged ST segment at baseline with normal or narrow T wave. 504


the earliest to repolarize; whereas the end of the T wave with repolarization of the M cells is the last to repolarize. Thus, the action potential duration of the longest M cells determines the QT interval and the interval between the peak of the T wave and the end of the T wave (TPE) serves as an index of dispersion of repolarization. The interaction between these various forces determines not only the T-wave amplitude but also the degree to which the ascending or descending limb of the T wave is interrupted, giving rise to bifurcated T waves and “apparent T-U complexes” under long QT conditions (Fig 2).6 Amplification of spatial dispersion of repolarization within the ventricular myocardium is thought to generate the principal arrhythmogenic substrate in congenital LQTS. Accentuation of spatial and transmural dispersion promotes development of early afterdepolarization-induced triggered activity that underlies development of TdP.7,8 The canine arterially perfused left ventricular wedge preparation9 has been employed to model the LQT1, LQT2, and LQT3 forms of LQTS. Salient findings include that preferential prolongation of the M-cell action potential duration leads to an increase in the QT interval and increased dispersion of repolarization, which establishes the substrate for spontaneous as well as stimulation-induced TdP.10-12 In the LQT1 model, isoproterenol infusion increases transmural dispersion of repolarization (TDR), most strikingly during the first 2 minutes and persists to a lesser extent during steady state. TdP incidence increased during the initial period as well as during steady state. In the LQT2 model, isoproterenol produces only a transient increase in TDR, and TdP incidence is increased only during this brief period. These differences in repolarization dispersion time course may underlie the differences in response to autonomic activity and other gene-specific triggers that contribute to events in patients with different LQTS genotypes13,14 as well as the genotype-specific response to treatment with β-blockers.15 Dr Scheinman: The authors correctly point out that the majority of patients with the LQTS have genetic mutations that affect the Kþ or Naþ channels. Although much less common, genetic abnormalities resulting in gain of function of the Caþþ channel may also produce the LQTS. One such syndrome is known as Timothy syndrome resulting in autosomal dominant mutations in the Cav1.2 gene (CACNA1C). This abnormality is expressed in many tissues and results in a spectrum of disorders associated with webbed fingers (or toes), developmental delays, and autism. These patients are at risk for malignant ventricular arrhythmias. (Dixon RE, Cheng EP, Mercado JL, Santana LF. L-type Ca2þ channel function during Timothy syndrome. Trends Cardiovasc Med. 2012;22(3):72-76. doi:10.1016/j.tcm.2012.06.015).


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FIG 2. Transmembrane action potentials and transmural electrocardiograms in control and LQT1 (Panel A), LQT2 (Panel B), and LQT3 (Panel C) models of LQTS (arterially perfused canine left ventricular wedge preparations). Isoproterenol þ chromanol 293B—an IKs blocker, d-sotalol þ low [Kþ]o, and ATX-II, an agent that slows inactivation of late INa, are used to mimic the LQT1, LQT2, and LQT3 phenotypes, respectively. Each panel depicts action potentials simultaneously recorded from endocardial (Endo), midmyocardial (M), and epicardial (Epi) sites together with a transmural electrocardiogram (ECG). Basic cycle length ¼ 2000 ms. TDR across the ventricular wall, defined as the difference in the repolarization time between M and Epi cells, is denoted below the ECG traces. (Modified from Shimuzu W and Antzelevitch C.10 Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome: effects of b-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation 1997;96:2038-47, with permission from Wolters Kluwer Health.)

Diagnosis The diagnosis of LQTS is based on clinical history, electrocardiographic (ECG) manifestation of prolonged corrected QT interval (QTc), and genetic testing. Clinical history may include palpitations, syncope, seizure, or documented cardiac arrhythmia or aborted cardiac arrest (ACA) in the patient or ACA or SCD in a family member of an otherwise asymptomatic individual. Typical triggers for cardiac events in LQT1 include adrenergic stimulation such as with emotion or exercise (62%), particularly swimming,4 but rarely sleep (3%).13 In LQT2, cardiac events occur during exercise (13%), emotion (43%), or sleep (29%), but also in response to auditory stimuli such as an alarm or telephone ring interrupting sleep, which may then provoke a startled response and trigger the event.16 In LQT3, most events occur at sleep or rest (39%) and few during exercise (13%).13 Exercise and mental stress have a role in triggering VT in LQT4 and hypokalemia in LQT7. QTc duration of more than 460 ms in children o15 years of age, more than 450 ms in adult men, or more than 470 ms in adult women using the Bazett formula identifies QT prolongation.17 The QT is best measured in lead II, lead V5, or lead V6. In atrial fibrillation or sinus arrhythmia, it should be taken as an average of at least 10 cardiac cycles of the lead with the longest QT interval. The QTc is dynamic and 10%-35% of patients with proven genetic LQTS can present with normal QTc. Diagnosis in this subset of patients can be particularly challenging. The diagnostic yield can be increased by analyzing multiple serial ECG recordings and Holter or event monitoring. Suggestive T-wave morphology includes flattened, notched, broad or peaked T waves, or overlapping T and U waves and T-wave alternans. The Schwartz et al.18 criteria is an LQTS scoring system that was developed using clinical and ECG criteria before genetic testing was readily available in an effort to improve phenotype-genotype correlation (Table 1). A score of at least 4 is associated with a high probability of LQTS, 2-3 correlates with intermediate probability, and 1 or less indicates low probability. ECG findings in the scoring system are valid only in the absence of acquired causes of QT prolongation such as drugs. The scoring system was correlated with genetic testing in a recent study of 541 patients and showed that 72% of patients with a score Z4 were genetically positive. Only 42% were positive with a score o4.19 This scoring system can be used as an initial evaluation tool; however, provocative and genetic testing should be performed in cases of high suspicion, even with low score. Curr Probl Cardiol, December 2013

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TABLE 1. Long QT syndrome diagnostic scoring system Findings Electrocardiographic Corrected QT interval, ms Z480 460-470 450 (in males) Torsade de pointes T-wave alternans Notched T wave in 3 leads Low heart rate for age Clinical history Syncope with stress Syncope without stress Congenital deafness Family history Family members with definite long QT syndrome Unexplained SCD in immediate family members o30 y

Score

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

Provocative Testing Even minor changes in adrenergic tone may be useful in identifying patients with LQTS. For instance, in response to standing, QT interval increases significantly in patients with LQTS compared with controls.20 Exercise stress testing can be useful in evaluating QT response to exercise. QTc 4500 ms at a heart rate of o100 bpm during exercise using the Bazett formula may indicate LQTS. A QTc 4445 ms at the end of recovery (4 min after cessation of exercise) identifies LQT1 and LQT2 with a sensitivity of 92% and specificity of 88%,21 whereas early-recovery QTc o460 ms has a sensitivity of 79% and specificity of 92% in differentiating LQT2 from LQT1.21,22 QT hysteresis (difference in QT interval between exercise and 1 or 2 min into recovery with similar heart rates of approximately 100 bpm)23 of 425 ms is more indicative of LQT2.24 Dr Scheinman: The authors correctly point out the importance of exercise stress testing, particularly, in those patients with LQT, who are concealed (normal QT) or have borderline prolonged QT values. It is important for the clinician to appreciate the problems in evaluation of the QTc using the Bazett formula during tachycardia. With exercise, the QT in normals will shorten but much less than the RR interval, hence the corrected QT will show an artificially long QTc especially at maximal exercise. It is therefore best to measure the QTc on standing or in recovery from exercise. (Viskin S, Postema PG, Bhuiyan ZA, Rosso R, Kalman JM, Vohra JK, Guevara-Valdivia ME, Marquez MF, Kogan E, Belhassen B, Glikson M, Strasberg B, Antzelevitch C, Wilde AA. The response of the QT interval to the brief tachycardia provoked by standing: 508


a bedside test for diagnosing long QT syndrome. J Am Coll Cardiol. 2010;55:1955-1961. doi:10.1016/j.jacc.2009.12.015 [Epub 2010 Jan 29. PMID:20116193]). (Chattha IS, Sy RW, Yee R, Gula LJ, Skanes AC, Klein GJ, Bennett MT, Krahn AD. Utility of the recovery electrocardiogram after exercise: a novel indicator for the diagnosis and genotyping of long QT syndrome? Heart Rhythm. 2010;7(7):906-911. doi:10.1016/j.hrthm.2010.03. 006 [Epub 2010 Mar 10. PMID:20226272]).

Although electrophysiology study alone has not proved useful in predicting risk of PMVT and SCD in LQTS,25 pharmacologic challenge with epinephrine has been shown to facilitate genotype-phenotype correlation.26,27 Two protocols of epinephrine infusion have been established: the bolus with brief infusion (Shimizu protocol)26 and the gradually escalating dose protocol (Mayo protocol).27 In a study of 147 genotyped patients,28 gradually increasing the doses of epinephrine (0.05, 0.1, 0.2, and 0.3 μg/kg/ min) was found to distinguish healthy control subjects from patients with concealed LQT1. The median change in QT interval during low-dose epinephrine infusion was 23 ms in the gene-negative group, þ78 ms in LQT1, 4 ms in LQT2, and 58 ms in LQT3, identifying a paradoxical QTc prolongation in patients with LQT1, no change in patients with LQT2, and shortening in patients with LQT3. The paradoxical QTc response was observed in 92% of patients with LQT1 compared with 18% of genenegative patients, 13% of patients with LQT2, and zero patients with LQT3. Overall, the paradoxical QTc response had a sensitivity of 92.5%, specificity of 86%, positive predictive value of 76%, and negative predictive value of 96% for LQT1 status. Patients receiving β-blocker therapy at the time of testing are likely to have lower diagnostic accuracy. Graded infusions of epinephrine in normal subjects can be associated with QTc prolongation in up to 79% of normal subjects27,29 and may lead to inappropriate diagnosis of LQTS. However, an absolute QT prolongation by more than 20-30 ms is not typically seen in normal patients at any dose level. With epinephrine bolus followed by brief infusion, the QTc was found to prolong remarkably as RR duration decreases with peak epinephrine infusion and remains prolonged during steady state in patients with LQT1, whereas in patients with LQT2, QTc prolongs at peak dose, but shortens during steady state. In patients with LQT3 and controls, QTc is much less prolonged during infusion.30 A positive test is identified if a paradoxical QT-QTc response is observed. Some have proposed that an increase in the absolute QT interval by 30 ms (at 0.05 μg/kg/min epinephrine),27 an increase in absolute QT interval by 35 ms26 or QTc prolongation by 30 ms31 (at 0.10 μg/kg/min Curr Probl Cardiol, December 2013

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epinephrine), and an increase in QTc by 65 ms32 or to a value above 600 ms29 during epinephrine infusion (up to 0.4 μg/kg/min) are useful adjunctive criteria in diagnosing LQTS. In general, epinephrine testing is useful in distinguishing between patients with LQT1 and LQT2 and not recommended in suspected LQT3. The test should be discontinued if systolic blood pressure exceeds 200 mm Hg or if PMVT or nonsustained VT develops. Intravenous β-blockers may be used immediately to suppress arrhythmias. Dr Scheinman: Careful studies on the effects of catecholamine infusions in normal subjects were studied by Magnano et al.4 They found a 2-fold increase in the U wave during epinephrine infusions and found that the specificity of paradoxical prolongation of the QTc Z 600 ms at any dose of epinephrine was 100%. However, the specificity of other criteria proved to be poor. In using the epinephrine criteria, the clinician should be aware that prolongation of the QT can occur in normals and that care must be taken to avoid inclusion of the augmented U-wave when assessing effects of epinephrine; finally, to my knowledge no one has compared exercise testing with epinephrine infusions. The former mode of evaluation should be safer as provocation of serious arrhythmias during exercise testing is rare. (Magnang AR, Talathoti N, Hallur R, Bloomfield DM, Garan H. Sympathomimetic infusion and cardiac repolarization: the normative effects of epinephrine and isoproterenol in healthy subjects. J Cardiovasc Electrophysiol. 2006;17(9):983-989 [Epub 2006 Jul 18]).)

Adenosine also has been investigated to identify QT changes in response to induced sudden bradycardia and subsequent heart rate acceleration, and it may have discriminative power in distinguishing patients with LQTS from controls.33 A QTc of 4410 ms at maximal bradycardia had sensitivity of 0.94 and specificity of 0.90 to detect LQTS. A QTc of 4490 ms at the time of maximal effect of adenosine on T-wave morphology had sensitivity of 0.94 and specificity of 0.85 to detect LQTS. The small number of genotyped patients in this study series precludes reaching reliable conclusions regarding the utility of adenosine testing, but the promising results warrant further study.

Genetic Testing and Screening Several mutations in 12 genes have been identified to date. Testing for LQT1-LQT3 yields associated putative mutations in 75% of clinically definite LQTS.19 Of these, LQT1, LQT2, and LQT3 mutations account for 45%, 45%, and 5%-8%, respectively. LQTS is generally transmitted through autosomal dominant inheritance with variable penetrance. The 510


Jervell and Lange-Nielsen syndrome, which has particularly poor prognosis with 93% mortality by the age of 40 years,34 is transmitted through autosomal recessive inheritance. Sporadic mutations occur in o5%-10%. Genetic testing of the proband and family members is important in LQTS for both risk stratification and treatment. Genotyping patients with high clinical suspicion and QTc o500 ms is particularly vital as patients with borderline QT prolongation or normal QT interval represent most of the underdiagnosed patients. Targeted testing of the major LQT1-LQT3 genes is more economical than comprehensive testing of all genes. However, both are acceptable strategies. Mutation-specific genetic testing of family members should be performed even if they are asymptomatic with negative ECG results. If clinical history, ECG, and genetic testing have negative results, LQTS can be ruled out in the family member. Dr Scheinman: Mutations in 13 genes have been identified to date. (Refsgaard L, Holst AG, Sadjadieh G, Haunsø S, Nielsen JB, Olesen MS. High prevalence of genetic variants previously associated with LQT syndrome in new exome data. Eur J Hum Genet. 2012;20(8):905-908. doi:10.1038/ejhg.2012.23 [Epub 2012 Feb 29]).

Risk Stratification The clinical course and risk of cardiac events are affected by several factors, including gender, aging, QT interval duration, symptoms, genotype, and the presence of congenital deafness. During childhood, there is significant increase in the incidence of cardiac events in male probands and this is affected family members (85% and 72%, respectively),35 as well as a 3-fold increase in fatal cardiac events compared with females36 and a 71% increase in cardiac events in males with LQT1 compared with females. No apparent gender-related differences in events during childhood have been detected in patients with LQT2 and LQT3.37 Males aged 10-12 years have a 4-fold increased risk of ACA or SCD compared with females; however, there were no gender-related differences in the incidence of lethal cardiac events in the 12- to 20-year-old age group.38 Gender risk reversal for lethal events occurs during adulthood (18-40 years), when females have higher incidence (11%) of ACA or SCD vs males (3%) and higher overall rate of first cardiac event (39% vs 16%).39 The risk remains high in females even after the age of 40 years.40 Greater physical activity resulting in tachycardia in boys may explain the high incidence of cardiac events in childhood. With the onset of adolescence, androgens may have a role in QTc shortening and estrogens may have dose-dependent potassium Curr Probl Cardiol, December 2013

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channel (IKs) blocking effects that prolong QTc. Pregnancy is not a risk factor, however, the postpartum period is associated with higher incidence of ventricular arrhythmias, especially in LQT2.41 QTc duration is an important prognostic factor. QTc 4500 ms is associated with 70% incidence of cardiac events by the age of 40 years,42 although females with QTc 4500 ms during childhood do not seem to have significant risk of fatal events. During adolescence (10-20 years), QTc 4530 ms is associated with a 2-fold increase in fatal events irrespective of gender,38 and life-threatening events continue to correlate with QTc duration during adulthood. QTc duration during follow-up recordings and the maximum QTc value determine the subsequent event rate rather than the baseline value. Time-dependent syncope is the most powerful indicator for risk of future ACA or SCD in childhood. During childhood, “recent” syncope (in the previous 2 years) is accompanied by a 6-fold risk of events in males vs 28-fold increase in females, whereas remote syncope (beyond 2 years) has a 2-fold risk in males vs 12-fold in females.40 During adolescence, Z2 and 1 syncopal events in the last 2 years have 18-fold and 12-fold increases in the risk of lethal cardiac events, respectively,38 and recent syncope continues to be a risk factor into adulthood. Family history of SCD is not a risk factor. Cardiac event rates are higher in LQT1 during childhood and adolescence, whereas patients with LQT2 have higher incidence of cardiac events during adulthood. Patients with LQT3 have significantly higher rates of life-threatening events after the age of 40 years. Missense mutations have higher event rates than nonsense mutations.43 Mutations in the pore region of the hERG channel appear to have a severe course and higher incidence of cardiac events (11-fold) at earlier age.44 Jervell and Lange-Nielsen syndrome has a particularly poor prognosis with 93% mortality by the age of 40 years.34 ACA or TdP has high risk (14%), whereas syncope has intermediate risk (3%) for ACA or SCD in 5 years. Dr Scheinman: The availability of large registries of genotyped patients with the long QT syndrome allows for assessing the relationship of specific abnormalities in the channel protein with phenotypic expression of disease. Recently, for example, Barsheshet et al. found that mutations in the intracytoplasmic C-loops of the subunit of KCNQ1 was associated with a very high incidence of sudden death, but fortunately this same mutation is associated with marked efficacy of β-blocker therapy. (Moss AJ, Shimizu W, Wilde AA, Towbin JA, Zareba W, Robinson JL, Qi M, Vincent GM, Ackerman MJ, Kaufman ES, Hofman N, Seth R, Kamakura S, Miyamoto Y, Goldenberg I, Andrews ML, McNitt S. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation. 2007;115(19):2481-2489 512


[Epub 2007 Apr 30. PMID: 17470695]). (Barsheshet et al. Circulation, 122: A13466).

Treatment Lifestyle Modification Patients with LQTS should avoid extreme physical exertion such as swimming (LQT1) and sudden auditory stimuli (LQT2). Drugs that prolong the QT interval should be avoided in general.

b-Blockers β-blockers reduce the incidence of cardiac events by 60% in patients with LQTS.39 Schwartz et al.13 showed that β-blockers reduce the incidence of cardiac arrhythmia and SCD by 81% in patients with LQT1, 59% in those with LQT2 and 50% in those with LQT3. Vincent et al. followed 216 patients with LQT1 and found that 75% became asymptomatic and fatal cardiac events were reduced by 95% after β-blocker therapy. However, 12 patients had cardiac arrests.45 Priori et al.15 observed that the rates of cardiac events on β-blockers were 10% in patients with LQT1, 23% in those LQT2 and 32% in those with LQT3. In general, β-blockers are recommended (class I) for patients with clinical diagnosis compatible with LQTS (ie presence of long QT interval) and can be effective in reducing SCD in patients with molecular-proven LQTS with a normal QT interval (Class IIa recommendation).46 β-blockers have been shown to be more effective in high-risk and intermediate-risk patients with LQT, including children and adolescents who had syncope in the last 2 years or adult females with QTc Z500 ms. The role of β-blockers is not clear in LQT3 as patients exhibit baseline bradycardia, which can enhance ventricular dispersion of repolarization and precipitate PMVT. β-blockers are not effective in patients with the most virulent form of LQTS—Jervell and Lange-Nielsen syndrome.47 ICD ICD implantation with the use of β-blockers is recommended for patients with LQTS with previous cardiac arrest (class I), can be effective to reduce SCD in patients with LQTS experiencing syncope or VT while receiving β-blockers (class IIa), and may be considered for prophylaxis of SCD for patients with high risk such as those with LQT2 and LQT3 (class IIb).46 Zareba et al. followed 125 high-risk patients who received ICD, including 54 with ACA and 19 with syncope on β-blocker, and compared their outcomes to 161 high-risk patients who did not receive an ICD. They observed 1 death in the ICD group over 3 years and 26 deaths in the nonCurr Probl Cardiol, December 2013

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ICD group over a follow-up period of 8 years.48 In another study of 35 patients, no deaths were noted in patients with ICD during the mean followup of 31 months.49 Dual-chamber ICD with atrial pacing is beneficial to prevent bradycardia-induced TdP, especially in LQT3, and to prevent pausedependent TdP (commonly in LQT2), as well as to maximize β-blocking effect. Even though ICD therapy is lifesaving, it has long-term complications, such as appropriate shocks (28% over 4.6 years),50 inappropriate shocks, lead infection, generator change, and vascular stenosis, which require consideration with the patient before insertion. Device programming with longer detection intervals, higher cutoff rate for detection of VT at 200220 bpm, and concomitant use of β-blockers to decrease the sinus rate may decrease the complication rates. Single-coil ICD leads may help in ICD extractions if necessary. It was shown that primary ICD implantation is costeffective in patients with high-risk LQTS.51-53 Dr Scheinman: The authors make an important point relative to the beneficial effect of chronic pacing to prevent pause-dependent torsades. It should be stressed that overdrive atrial pacing is an effective mode of treatment to both reduce the QT interval as well as to obviate the pauses which may provoke torsades. In particularly difficult cases we initiate triple therapy, namely, β-blockers, atrial overdrive pacing (to bring the QT interval to normal or near normal levels), and a back-up defibrillator. Pacing should not be used as a substitute for defibrillator therapy. (Eldar M, Griffin JC, Abbott JA, Benditt D, Bhandari A, Herre JM, Benson DW, Scheinman MM. Permanent cardiac pacing in patients with the long QT syndrome. J Am Coll Cardiol. 198710(3):600-607.) (Dorostkar PC, Eldar M, Belhassen B, Scheinman MM. Long-term follow-up of patients with long-QT syndrome treated with beta-blockers and continuous pacing. Circulation. 1999;100 (24):2431-2436 [PMID:10595956])

Left Cardiac Sympathetic Denervation (LCSD) LCSD, in which the first 4 thoracic sympathetic nerves are removed endoscopically, may be considered for LQTS patients with syncope, TdP, or cardiac arrest while receiving β-blockers (Class IIb recommendation).46 Of the 147 high-risk patients who were followed up for 8 years after LCSD and 48% of whom had ACA, 46% became asymptomatic, 31% had further syncope, and 16% and 7% had ACA and SCD, respectively. In another study, patients requiring intravenous medications for ongoing PMVT were weaned to suppressive oral medications after LCSD.54 ICD shocks may be reduced by up to 95%.55 Given the continued event rate despite LCSD, it cannot be considered an alternative to ICD therapy, although in patients refusing ICD implant and medical therapy or in 514


whom such therapy is not possible or contraindicated, LCSD alone may be considered. LCSD should be considered for the patients who continue to be symptomatic while on β-blockers or who have ventricular storm and receive repeated ICD discharges. A limitation of LCSD is its availability in few centers. Dr Scheinman: The comment by the authors with regard to avoiding use of left sympathectomy in lieu of defibrillator bears emphasis. Our own experience showed that patients on long-term follow-up were at risk for sudden cardiac death and that evidence of sympathetic reinnervation had occurred. Moreover, even among enthusiasts for the technique, recent studies have shown a disturbingly high incidence of recurrent symptoms (50%) and the authors relegate LCSD as “an option for those with suboptimal response to drugs or to drug side effects.” Finally, the excellent work from the UCLA group (Shivkumar) has emphasized, from animal and human work, the fact that both sides of the T1-T4 ganglia innervate the heart and that there is a great deal of cross-innervation. In these studies, bilateral denervation was much more effective. Moreover, if bilateral cardiac denervation is performed, sympathetic fibers reach the heart from the middle cervical ganglion. (Bhandari AK, Scheinman MM, Morady F, Svinarich J, Mason J, Winkle R. Efficacy of left cardiac sympathectomy in the treatment of patients with the long QT syndrome. Circulation. 1984;70 (6):1018-1023 [PMID:6499140, Circulation Arrhyth Electrophysiology. May 2 or 3]). (Ajijola OA, Lellouche N, Bourke T, Tung R, Ahn S, Mahajan A, Shivkumar K. Bilateral cardiac sympathetic denervation for the management of electrical storm. J Am Coll Cardiol. 2012;59(1):91-92. doi:10.1016/j.jacc. 2011.09.043 [No abstract available. PMID: 22192676]).

Short QT Syndrome Clinical Features The short QT syndrome (SQTS) is a rare and still relatively new clinical entity characterized by a short QT interval on ECG, absence of structural heart disease, familial SCD, and arrhythmic events including resuscitated cardiac arrest, syncope, palpitations, dizziness, and atrial fibrillation.56-61

ECG Features The distinctive ECG feature is the abbreviated QTc (o320 ms), nearly absent ST segment with tall and peaked, symmetrical T waves. In experimental models of short QT syndrome, increased TDR and its electrocardiographic counterpart TPE appear to contribute to induction of PMVT. In a clinical study of acquired long QT syndrome, TPE/QT ratio 40.28 indicated arrhythmia risk, and similar observations have been made in patients with short QT.62 Curr Probl Cardiol, December 2013

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Cellular Features Extramiana et al.63 were the first to demonstrate a role for transmural heterogeneity of repolarization under conditions associated with short QT intervals in the ECG. They again made use of the canine left ventricular wedge preparation, this time to test the hypothesis that abbreviation of the QT interval, which was induced by the ATP-sensitive potassium current (IK-ATP) activator pinacidil in an effort to augment outward currents and enhance repolarization, is associated with an increase in TDR and creates the substrate for reentry and VT or ventricular fibrillation (VF). They observed that pinacidil-induced abbreviation of repolarization in the left ventricle was heterogenous and associated with an increased TDR. Isoproterenol amplified these effects with preferential abbreviation of the M-cell action potential (Fig 3). A good association between the level of TDRmax and the inducibility of PMVT also was seen.

Diagnosis The diagnosis of SQTS resides in ECG, clinical, and genetic data. Since the first description in 2000 by Gussak et al.56 there remains no clear-cut definition on the duration of QT for diagnosis of SQTS. Viskin et al.64 concluded that QTc o360 ms in males and o370 ms in females may pose an increased risk of cardiac arrhythmias in a study of idiopathic VF. However, Anttonen et al.65 followed up a Finnish population with QTc o320 ms over a period of 30 years and found no association with SCD risk. Hence, having a mere QT shortening on ECG does not constitute SQTS. A QTc duration of r360 ms (2 standard deviations below normal for the population) may be reasonable to be considered a short QT interval. Differential diagnoses of a short QT interval include hypercalcemia, hyperthermia, hyperkalemia, acidosis, acetylcholine effect, and digitalis toxicity, which should be excluded before entertaining SQTS. Other ECG findings in SQTS include tall peaked T waves, very short or absent ST segment, and prolonged TPE. In types SQT4 and SQT5, ST-segment elevation of the Brugada type can be seen along with short QT intervals.66 A unique hallmark of SQTS is that patients have a flat or less steep QT-RR relationship, and the QT remains short even at slow heart rates,67 reflecting generally poor heart rate modulation of action potential duration and refractory periods, which are short. Clinical presentation includes arrhythmic symptoms such as cardiac arrest (34%), which manifests as the initial presentation in 28%; palpitations (31%); syncope (24%); and atrial fibrillation (17%), or patients 516


FIG 3. IK-ATP activation abbreviates QT interval and accentuates TDRmax. Each panel shows transmembrane action potentials simultaneously recorded from epicardial (Epi) and deep subendocardial M-cell regions of arterially perfused left ventricular wedge preparation, together with 4 unipolar electrograms (Uni 1-4) and pseudo-ECG. Uppermost trace is stimulus (stim) marker. TDRmax is denoted by maximum difference in Vmax (repolarization time) of unipolar electrograms at 4 transmural sites. Global measure of transmural dispersion is denoted by the interval between the peak and end of the T wave (TpTe) of ECG in Panels A and C. The T wave in Panel B is too flat to measure accurately. Panel A: Control; Panel B: Pinacidil (2 mol/L); Panel C: Pinacidil þ isoproterenol (100 nmol/L). Basic cycle length ¼ 2000 ms. (Reprinted from Extramiana F and Antzelevitch C.63 Amplified transmural dispersion of repolarization as the basis for arrhythmogenesis in a canine ventricular-wedge model of short-QT syndrome. Circulation 2004;110:3661-6, with permission from Wolters Kluwer Health.)

can be asymptomatic (38%).68 In a registry of 61 patients, 35 patients (57.4%) were symptomatic, of which 5 had SCD, 15 had ACA, syncope occurred in 9, and 11 had atrial fibrillation.69 Most of the asymptomatic patients were family members of probands and had short QT duration or were genetically positive. As the diagnosis is not entirely based on ECG findings, a scoring system was developed by Gollob et al. that considers ECG, clinical presentation, family history, and genetic testing (Table 2). A score Z4 indicates high probability of detecting SQTS, whereas 3 indicates intermediate probability and r2 indicates low probability. This scoring system requires patients to have at least 1 point accumulated from the ECG section before evaluating other data.69 This is an important distinction from the LQTS scoring system in which a normal QT interval does not preclude scoring other aspects and does not exclude diagnosis. Curr Probl Cardiol, December 2013

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TABLE 2. Short QT syndrome diagnostic scoring system Findings

Points

Corrected QT interval, ms o370 o350 o330 J point peak of T-wave interval o120 ms Clinical history History of sudden cardiac arrest Documented PMVT or VF Unexplained syncope Atrial fibrillation Family history First- or second-degree relative with high probability of SQTS First- or second-degree relative with autopsy-negative SCD Sudden infant death syndrome Genotype Genotype positive Mutation of undetermined significance in a culprit gene

1 2 3 1 2 2 1 1 2 1 1 2 1

Treatment ICD ICD therapy is recommended as secondary prevention in patients who have ECG findings alone or with ACA or have syncope with strong family history of SCD.70 The role of ICD therapy as a primary preventive treatment is not well defined in asymptomatic individuals. Although ICD therapy is effective in preventing SCD, inappropriate shocks due to oversensing of tall peaked T waves (60% incidence in 30 ⫾ 26 days after implantation) or less frequently due to atrial fibrillation or sinus tachycardia complicate management. Pharmacologic Treatment Initial forays into pharmacologic therapy have identified therapeutic roles for hydroquinidine, amiodarone, disopyramide, propafenone, and isoproterenol. Hydroquinidine prolongs the QT interval to normal limits, increases the ventricular effective refractory period, and can prevent arrhythmic symptoms as well as render VF noninducible with programmed electrical stimulation.71 In a study of 10 patients with SQTS who were treated with hydroquinidine, no SCD or syncope was observed over 23 months of follow-up.68 Hydroquinidine has been shown to prevent ventricular storm in SQTS ICD recipients.72 The electrophysiologic effects of hydroquinidine involve suppressing the gain of function mainly in IKr but also IKs, Ito, and IKATP currents induced by the hERG mutation in SQT1. Disopyramide was 518


prescribed in 2 patients; it slightly prolonged the QT interval and ventricular effective refractory period.73 Amiodarone and propafenone were prescribed in small case series of SQTS and no arrhythmic symptoms were observed over 6 months and 2 years of follow-up, respectively.72,74 Nifekalant, available only in Japan, has been reported to normalize QT interval in 1 patient.75 Isoproterenol was used successfully to treat ventricular storm in a patient with SQTS and recurrent VF.76

Genetic Screening So far, mutations in 5 genes have been identified to be responsible for 5 SQTS. SQT1 and SQT3-SQT5 syndromes are transmitted through autosomal dominant inheritance, whereas the SQT2 syndrome occurs sporadically. Comprehensive or SQT1-SQT3 (KCNH2, KCNQ1, and KCNJ2)targeted genetic testing may be considered for any patient in whom a cardiologist has established a strong clinical index of suspicion for SQTS. Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the SQTS-causative mutation in an index case.2 Mutations in potassium channels were found in only 20% of index cases. Therefore, genetic testing currently has little to no role in establishing diagnosis, confirmation, or treatment, this indicates that gene abnormalities accounting for most of the cases remain to be identified.

Risk Stratification Electrophysiology studies have demonstrated very short atrial and ventricular effective refractory periods. Electrical stimulation induces atrial fibrillation and VF in only 60% of SQTS. Owing to the low sensitivity (50%), the role of electrophysiology study is limited in diagnosis and therapeutic decision making.

Short-Coupled Torsade de Pointes Clinical and ECG Features A number of reports have described ACA and resuscitated SCD in the setting of structurally normal heart, normal ECG, and “short-coupled” extrasystoles that initiate TdP.77-80 The interesting characteristic observed in these patients with TdP is that the coupling interval of the precipitating ventricular activation may be unusually short (245 ⫾ 28 ms) (Fig 4).77 A distinction is made in 2 regards: first, the terminology of “torsade de pointes” implies QT prolongation and second, in TdP, initiation occurs with extrasystoles occurring at a coupling interval associated with termiCurr Probl Cardiol, December 2013

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nal repolarization, i.e. during the downslope of the T wave, which then would be expected to be long (586 ⫾ 489 ms)78 due to the presence of QT prolongation, often precipitated by ventricular pauses that accentuate QT prolongation and dispersion of repolarization. “Short-coupling,” then, refers to extrasystoles that occur before the terminal portion of the T wave, and more often at the presumed peak of the T wave, typically in the setting of a nonprolonged QT interval. However, it does not imply a short QT interval, and a normal QT interval77,79 may distinguish this entity from SQTS, which also is associated with short-coupled extrasystoles simply by virtue of the duration of the QT interval. Conversely, extrasystole coupling in the SQTS is expected to occur on the downslope of the T wave, when dispersion of repolarization is enhanced.63,81 Alternatively, a normal QT interval may not exclude SQTS, as a recent study of the entire cohort of reported cases of genetically proven SQTS has demonstrated a mean QTc value of 306.7 ms with values ranging from 248 to 381 ms in symptomatic cases.82 In 1 report, a prominent J wave in leads V3-V6 was observed as well.79

Electrophysiology Study Features In 1 case, the shortness of local ventricular effective refractory period and heterogeneity of ventricular refractoriness were felt to contribute to development and maintenance of reentrant tachycardia and PMVT.83 It has

FIG 4. Short-coupled TdP. Rhythm strip from a 17-year-old boy presenting with palpitations and found to have atrial fibrillation and initiation of TdP with short-coupled extrasystole 280 ms after QRS. TdP quickly degenerates to ventricular fibrillation. 520


been shown that when local myocardial refractoriness is short, shortcoupled premature beats may be induced; the shorter the coupling interval of the premature beat, the greater the likelihood of unidirectional block with initiation of reentrant tachycardia.84 It also was observed that overdrive ventricular pacing could inhibit TdP and short-coupled ventricular premature complexes, and verapamil could suppress the occurrence of ventricular premature complexes.84

Treatment In the case reports and small series that have been described, ICD therapy is the mainstay treatment in patients affected with ACA and resuscitated SCD given its efficacy over medical therapy. However, verapamil has repeatedly been shown to be effective in suppressing arrhythmia, supporting the theory that the verapamil-sensitive ventricular myocardium may be involved in permitting triggered activity and TdP.83 Verapamil also is effective in suppressing ventricular ectopy and shortcoupling TdP arising from the right ventricular inflow free wall, suggesting the molecular mechanisms are not sufficiently dependent on the verapamilsensitive zone of the ventricular septum for arrhythmia, but may be related in a more general manner to slow calcium channels and calcium overload. The role of mexiletine and sodium channel blockade is also suggested based on the hypothesis that inhibiting Purkinje firing due to Naþ channel dependency and enhanced postrepolarization refractoriness may play a role.83 Finally, nifekalant may prevent TdP with short-coupling by prolonging local ventricular refractoriness and reducing repolarization heterogeneity through inhibition of potassium currents, especially IKr.85 Dr Scheinman: The extremely important work by Haissaguerre and colleagues has greatly elucidated the mechanism and treatment modality for patients with short-coupled “torsades.” They found that those patients showed triggered premature ventricular contractions (PVCs) that could emanate from either the Purkinje system or from ventricular myocardia (particularly the right ventricular outflow tract). Ablation of these short-coupled PVCs resulted in arrhythmia cure with only a small incidence of recurrent arrhythmias during follow-up studies. These observations have revolutionized our treatment approach for these patients, making ablation the preferred therapeutic approach. (Haı¨ssaguerre M, Shoda M, Jaı¨s P, Nogami A, Shah DC, Kautzner J, Arentz T, Kalushe D, Lamaison D, Griffith M, Cruz F, de Paola A, Gaı¨ta F, Hocini M, Garrigue S, Macle L, Weerasooriya R, Cle´menty J. Mapping and ablation of idiopathic ventricular fibrillation. Circulation. 2002;106(8):962-967 [PMID: 12186801]).


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Brugada Syndrome Clinical Features Brugada syndrome is characterized by a prominent J wave and ST-segment elevation in the right precordial leads in the absence of myocardial ischemia or defined structural heart disease86-88 and is associated with high risk of SCD. The Brugada-pattern ECG most commonly shows J-point elevation in leads V1-V3 or inferior leads (II, III, and aVF) with an elevated but steeply negative ST segment giving the appearance of atypical right bundle branch (RBB) block with T-wave inversion, but it may be intermittent.89

ECG Features Type 1 Brugada pattern has a prominent coved ST segment with J-point amplitude or ST-segment elevation Z2 mm, followed by a negative T wave in the right precordial leads (V1-V3). RBB block may or may not be seen.90,91 Type 2 Brugada pattern is characterized by Z2 mm J-point elevation and Z1 mm ST-segment elevation with a trough or “saddleback” appearance, followed by a positive or biphasic T wave. Type 3 Brugada pattern exhibits either a saddleback or coved morphology ST segment with elevation o1 mm and is considered to be suggestive but not confirmatory of the disease. It also has been suggested that TPE may correlate with SCD risk (Fig 5).92 Dr Scheinman: It should be emphasized that not all clinical studies have validated a positive correlation between TPE differences and cardiac events. In large-scale studies of patients treated with cardiac resynchronization therapy, or long QT for example, have shown inconsistent results. (Chirag et al. PACE 10/2012). (Kanters JK, Haarmark C, Vedel-Larsen E, Andersen MP, Graff C, Struijk JJ, Thomsen PE, Christiansen M, Jensen HK, Toft E. T(peak)T (end) interval in long QT syndrome. J Electrocardiol. 2008;41(6):603-608. doi:10. 1016/j.jelectrocard.2008.07.024 [Epub 2008 Sep 25. PMID: 18822425]).

Cellular Features The proposed cellular mechanisms of the Brugada phenotype are related to net outward shift of currents during phases 1 and 2 of the right ventricular epicardial action potential, which results in depression or loss of the action potential dome and is responsible for ST-segment elevation in Brugada syndrome. The J wave on ECG is thought to be mediated by the Ito-mediated spike-and-dome morphology or notch in ventricular epicardium, but not endocardium, which thereby creates a transmural voltage gradient (Fig 6A). 522


FIG 5. Brugada electrocardiographic patterns.

If epicardial repolarization completes earlier than endocardial regions, the T wave is upright and the ST-segment shows a saddleback configuration (Fig 6A). Further accentuation of the notch associated with prolongation of the epicardial action potential reverses the transmural voltage gradients, resulting in development of a coved-type ST-segment elevation followed by an inverted T wave (Fig 6B). Complete loss of the action potential dome at some epicardial sites but not at others is responsible for the formation of the arrhythmogenic substrate (Fig 6C) in which the action potential dome spreads from sites where it is maintained to sites where it is lost and leads to development of a closely coupled extrasystole due to phase 2 reentry (Fig 6D). An increase in TDR facilitates transmural propagation of the extrasystole and provides a substrate for the development of PMVT and VF.93 Dr Scheinman: Two alternative theories exist to explain the Brugada pattern. The authors have nicely explained and illustrated the pathogeneses of this pattern using the elegant wedge preparation, which suggested that this pattern is due to abnormalities in repolarization. Alternatively, others have suggested that the J wave in the Brugada pattern is due to abnormalities in myocardial conduction particularly in the region of the right ventricular outflow tract (RVOT). The recent studies of Nademanee et al. showed that ablation of fractionated potentials over the RVOT both caused disappearance of the Brugada pattern as well as arrhythmia cure. These observations tend to support the hypothesis that the pattern may be due to regional alterations in myocardial depolarization. (Mizusawa Y, Wilde AA. Brugada syndrome. Circ Arrhythm Electrophysiol. 2012;5(3):606-616.).123


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FIG 6. Schematic representation of right ventricular epicardial action potential changes proposed to underlie the electrocardiographic manifestation of Brugada syndrome. (Modified from Antzelevitch C. The Brugada syndrome: ionic basis and arrhythmia mechanisms. J Cardiovasc Electrophysiol 2001;12:268-272, with permission from John Wiley and Sons.)

Diagnosis Brugada syndrome is diagnosed if a type 1 ECG pattern is manifested either spontaneously or with provocative testing in more than 1 right precordial leads (V1-V3) along with at least one of the following clinical criteria: 1. 2. 3. 4. 5.

Syncope or seizures or nocturnal agonal breathing; spontaneous VT/VF; inducible VT or VF on programmed electrical stimulation; family history of SCD before the age of 45 years; and type 1 ECG pattern in family members.

The ECG pattern is dynamic and type 2 or type 3 ECG patterns are not diagnostic of Brugada syndrome unless there is conversion to type 1 ECG either spontaneously or under provocation.94 Precipitating factors include 524


fever, cocaine use, vagotonic agents, electrolyte disturbances such as hypercalcemia or hyperkalemia, psychotropic agents, or antiarrhythmic drugs (class 1a or class 1c sodium channel blockers, calcium channel blockers, or β-blockers), which may unmask a type 1 ECG by accentuating inactivation of sodium or calcium channels or by increasing Ito. Provocative Testing The purpose of provocative testing is to manifest a type 1 Brugada ECG pattern and to facilitate spontaneous or induced ventricular arrhythmias. The typical ECG features can be unmasked with sodium channel blockers. Autonomic tone can also modulate the ECG phenotype: isoproterenol attenuates and acetylcholine accentuates the ECG changes in affected patients.95 Several agents (sodium channel blockers) can be used, including ajmaline, flecainide, procainamide, disopyramide, propafenone, or pilsicainide. Ajmaline, with sensitivity of 80%, specificity of 94%, and positive and negative predictive values of 93 and 83%, respectively,96 is the drug of choice where available, followed by flecainide, which has a sensitivity and specificity of 77% and 80%, respectively.97 Placement of right precordial leads in the second and third intercostal spaces increases the diagnostic yield98-100 but does not affect prognosis.101 The provocative drug challenge should be terminated once a type 1 ECG develops, premature beats or other arrhythmias develop, or if QRS prolongs more than 130% of baseline. If the patient develops ventricular storm, intravenous isoproterenol (inhibits Ito current) can be used.99 Overall, the sensitivity of provocative tests in patients with an SCN5A mutation (which represents only 20% of all patients with Brugada syndrome96,97) is estimated to be 71%-80%. The available study by Brugada et al.102 in non-SCN5A patients with Brugada syndrome, found the sodium channel blocker test to be highly sensitive and specific in patients with transitory type 1 ECG resuscitated from SCD.

Risk Stratification Patients with symptoms including aborted SCD or VT or VF or syncope and spontaneous type 1 ECG are at the greatest risk for future cardiac events. Brugada syndrome patients with aborted SCD have a recurrence rate of 17%-62% at 48-84 months follow-up, and the event rate with history of syncope is 6%-19% at 24-39 months in various studies.103-109 Conversely, cardiac events in asymptomatic patients range from 0.5% to 2% annually among different series.103-105 Family history of SCD, type 1 ECG pattern in the family, male sex, or positive genetic tests or provocative tests failed to Curr Probl Cardiol, December 2013

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show any role in risk stratification. Priori et al.110 have showed that ventricular effective refractory period o200 ms and QRS fragmentation in V1 and V2 may help identify high-risk patients. A study showed that TPE and TPE dispersion times were significantly prolonged in patients with recurrent cardiac events.92 Signal-averaged ECG to identify presence of late potentials also can predict arrhythmic events in Brugada syndrome.107 The role of electrophysiology study in risk stratification is controversial. It has been shown to have a low positive predictive value (23%), although it had a high negative predictive value (93%) over 3 years of follow-up in some studies,87,111,112 reaching up to 98%-99% in asymptomatic patients.113 Brugada et al.105 initially showed that VT or VF inducibility is an independent predictor of future cardiac events. However, subsequent studies have not confirmed these observations.103,110,114 Priori et al.111,115 reported electrophysiology testing does not predict subsequent cardiac arrest and have advocated noninvasive risk stratification based on ECG and symptoms. Currently, guidelines indicate “electrophysiology testing may be considered for risk stratification in asymptomatic Brugada syndrome patients with spontaneous type 1 ECG with or without genetic mutation” (class IIb). Electrophysiology study should not be done in asymptomatic patients with drug-induced Brugada pattern as the follow-up event rate is o1%.

Treatment ICD therapy is the only prophylactic measure that prevents SCD, though emerging evidence suggests a role for quinidine.116 The ICD is the mainstay of therapy in Brugada syndrome to prevent SCD. However, the high inappropriate shock rate (20%-36% over 21-47 months of follow-up) compared with low annual appropriate discharges (2.6%) (2-2.5-fold),117-119 along with physical and social limitations to prevent lead damage, should be considered when ICD therapy is discussed with an asymptomatic patient. Belhassen et al.120 showed that quinidine sulfate at a dose of 1500 mg/day was effective in prevention of VF in 22 of 25 patients (88%) over a period of 6 months to 22.2 years of follow-up, although with 36% incidence of side effects. In another study by Hermida et al.121 hydroquinidine (300 mg twice daily) was effective in preventing VT or VF inducibility in 76% of asymptomatic patients and VT or VF recurrence in Brugada syndrome patients with multiple ICD shocks. Marquez et al.122 showed that lower doses of quinidine (o600 mg/day) were well tolerated and prevented ventricular arrhythmias in 6 patients with appropriate ICD shocks (including 4 patients with ventricular storm) over a period of 4 years. Isoproterenol (class IIa) or quinidine (class IIb) can be used for immediate treatment of ventricular storm in patients with Brugada syndrome.46 526


Other drugs that can be useful in Brugada syndrome include denopamine, cilostazol, bepridil, disopyramide, and orciprenaline. Epicardial right ventricular outflow tract ablation of a fractionated electrogram may be an option for severely affected patients with recurrent VF.123

Genetic Screening Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the Brugada-causative mutation in an index case (class I). Comprehensive or type 1 Brugada syndrome (SCN5A)-targeted genetic testing can be useful for any patient in whom a cardiologist has established a clinical index of suspicion for Brugada syndrome based on examination of the patient's clinical history, family history, and spontaneous or provoked ECG type 1 (class IIa). Genetic testing is not indicated in the setting of an isolated type 2 or type 3 Brugada ECG pattern (class III).2 To date, there are 10 causative genes identified for Brugada syndrome. SCN5A is the most commonly identified gene (accounting for 75% of mutation-positive Brugada syndrome); however, the test yield is only 20%25% in clinical cases.124 Brugada syndrome is transmitted via autosomal dominant inheritance and de novo mutations account for o1% of patients with clinical Brugada syndrome. Brugada syndrome is a clinical diagnosis and genetic testing has no role in establishing the diagnosis. However, identification of a particular mutation may help confirm a diagnosis in uncertain index cases and for screening of family members (parents first, if results are positive, siblings need to be tested as there is a 50% chance of inheritance). Genetic testing has no value in risk stratification or prognosis in Brugada syndrome and does not affect the treatment strategy in symptomatic patients. In asymptomatic mutation carriers, precautions against the aforementioned provocative scenarios should be advised. Genetic counseling should be offered to families of the gene-positive proband.

Early Repolarization Syndrome Clinical Features The ECG pattern of early repolarization is characterized by a distinct J wave and ST-segment elevation predominantly in the left precordial leads and is generally accepted as a benign ECG phenomenon.125 However, several clinical studies have demonstrated an increased association of the early repolarization ECG pattern with SCD in the absence of structural heart disease or other identified reversible cause,126 perhaps justifying classification as a true syndrome. Curr Probl Cardiol, December 2013

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ECG Features The early repolarization pattern with elevated J point and ST segment of at least 0.1 mV from baseline in the inferior or lateral leads was found in 31% of patients affected VF vs 2%-5% of the asymptomatic normal population.126 Subsequent studies have confirmed an association between early repolarization and VF events or SCD, thereby posing a clinical challenge in evaluating patients with nonspecific but potentially alarming symptoms such as palpitations, dizziness, and syncope who manifest the early repolarization pattern.

Cellular Features J-point and ST-segment elevation in this syndrome are thought to be due to depression (partial loss) of the Ito-mediated action potential dome in the left ventricular epicardium.127 This is supported by clinical observations that heart rate and autonomic tone, which influence Ito, L-type calcium current (ICa), and perhaps inward sodium current (INa), modify ST-segment elevation in early repolarization syndrome.125 As with Brugada syndrome, an increase in TDR related to electrical heterogeneity during early ventricular repolarization facilitates transmural propagation of an extrasystole and provides the substrate for development of PMVT and VF (Fig 7).93

Diagnosis and Associated Features Early repolarization syndrome is diagnosed based on the ECG criteria of J-point elevation of at least 0.1 mV, QRS slurring or notching, ST-segment elevation with upward concavity, and prominent T waves in at least 2 contiguous leads. The prevalence is 5.8% in general population if J-point elevation Z0.1 mV is used and mortality, over a follow-up of 30 ⫾ 11 years, may be as high as 10%. The incidence decreases to 0.3% if J-point elevation criterion is increased to Z0.2 mV.128 However, in patients with idiopathic VF, the prevalence of early repolarization was 31%.126 The early repolarization syndrome may be considered a diagnosis of idiopathic VF in patients with the early repolarization ECG pattern, although a mechanistic relation between VF and early repolarization, though proposed, remains unconfirmed. No pharmacologic provocative testing has been established to aid in confirming a suspected diagnosis, though sodium channel blockers may attenuate early repolarization.129 The only genetic abnormality found to date is in KCNJ8 encoding the pore-forming subunit Kir6.1 of the IK-ATP ion channel.130 528


FIG 7. Polymorphic ventricular tachycardia initiated by phase 2 reentry in a canine right ventricular wedge in the presence of 2.5 mmol/l pinacidil. The action potentials were simultaneously recorded from 2 epicardial sites (Epi 1 and Epi 2) and 1 endocardial (Endo) site. A loss of the action potential dome in Epi 1, but not in Epi 2, led to phase 2 reentry capable of initiating polymorphic ventricular tachycardia. (Modified from Yan et al. Ventricular repolarization components on the electrocardiogram: cellular basis and clinical significance. J Am Coll Cardiol 2003;42:401-409, with permission from Elsevier.)

Risk Stratification Patients with J-point elevation Z0.2 mV have a 3-fold increased risk of death from cardiac arrhythmia compared with those with J-point elevation Z0.1 mV.128 J-point height is dynamic and has diurnal variation due to autonomic activity. Ventricular tachyarrhythmias, including cardiac arrest, and appropriate ICD shocks peak between midnight and early morning in early repolarization syndrome, suggesting a role for heightened parasympathetic tone in J-wave inscription131 as with other conditions associated with prominent J waves, including hypothermia, hypervagotonia, and spinal cord injuries with sympathetic denervation. Spontaneous accentuation of J-wave magnitude and increased beat-to-beat variation of the J-wave morphology are indicators of impending VF.126 Patients with J waves and ST-segment elevation in the inferolateral leads126 or globally in all leads132 are at high risk for developing VF. Merchant et al.133 showed that QRS notching was more prevalent in patients with VF and early repolarization compared with patients with benign early repolarization. Abe et al.134 showed that early repolarization is 10 times more common in patients presenting with syncope without any organic etiology compared with controls. Presence of late potentials by signal averaging of ambulatory ECG monitoring indicates high risk for future ventricular tachyarrhythmic Curr Probl Cardiol, December 2013

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events in early repolarization syndrome.135 Electrophysiology testing demonstrates VT inducibility in only 34% of the patients with history of VT on programmed electrical stimulation, hence electrophysiology study is of limited use in identifying high-risk patients.126

Dr Scheinman: Recent observations from Dr Viskin’s group have shown important parameters for distinguishing “benign” from malignant ECG patterns in patients with aborted or sudden cardiac death associated with the J-wave syndrome compared to age matched control. While the presence of J waves was associated with a 4-fold increase in risk for sudden cardiac death, addition of both J waves and horizontal ST depression was associated with an odds ratio of 13.8 for experiencing VF. This important observation adds an important component to the evaluation of subjects with J waves.

Treatment ICD is the first-line treatment for secondary prevention of SCD in patients with ACA due to VF, and this may be attributed to early repolarization syndrome when an early repolarization pattern is the only clinical observation made after thorough investigation. Haïssaguerre et al. followed up 122 patients who were resuscitated from VF with ECG early repolarization and subsequently received ICD. Of these, 16 patients had 1-3 episodes of VF and 33 patients had more than 3 ICD appropriate shocks for VF over a period of 69 months. Patients with history of syncope, inducibility on programmed electrical stimulation, and higher amplitude of J waves had higher incidence of recurrent VF. Efficacy of pharmacologic therapy has been described in 33 patients who had more than 3 episodes of VF.136 Only quinidine or hydroquinidine at a dose of 450 mg/day was effective, without any recurrence of VF in any of the 9 patients over 25 months of follow-up. Quinidine reduced J-point elevation and normalized the ECG. Amiodarone, Class Ic antiarrhythmic drugs, and β-blockers were partially effective in very few patients. Of 33 patients, 16 had electrical storm, and isoproterenol infusion at a rate of 1-5 mg/min that achieved a sinus rate of 120 bpm was effective in suppressing VF storm in all 7 patients. Amiodarone was effective in 3 of 10 patients. Lidocaine, verapamil, β-blockers, and mexiletine were completely ineffective in suppressing VF and electrical storm. Catheter ablation of ectopy-initiated VF was successful in preventing frequent ICD discharge in resistant cases not controlled by pharmacologic therapy.136 530


Catecholaminergic Polymorphic Ventricular Tachycardia Clinical Features CPVT is characterized by ventricular arrhythmias that develop in association with physical or emotional stress. Structural heart disease is invariably absent, given the young age of presentation.

ECG Features The induced VT is often polymorphic, but the hallmark is bidirectional VT (Fig 8). This can be seen in other conditions as well, including digoxin toxicity and Andersen-Tawil syndrome. The resting ECG is usually completely normal. VT patterns are reproducible with exercise or catecholamine infusion and appear during sinus tachycardia rates of 120-130 bpm, with increasing frequency of premature ventricular complexes followed by bursts of PMVT or bidirectional VT.137

Theoretical Mechanisms of Bidirectional VT An optical mapping study in a mouse model showed that bidirectional VT occurred as a result of 2 foci in the His-Purkinje system firing alternately.138 The location of these foci was shown to be 1 in each ventricle. The evidence was further supported by conversion of bidirectional VT into monomorphic VT following ablation of one of the foci. Moreover, alternating pacing from right and left ventricles was shown to be compatible with bidirectional VT. However, this does not explain the ability of 2 independent foci to operate separately without being overdrive suppressed by the faster focus, unless dual parasystolic foci are invoked. A more recently proposed “ping-pong” theory postulates alternating bigeminy as the possible mechanism behind bidirectional VT.139 It states that a normally paced action potential is followed by a triggered action potential from the RBB at a slower heart rate and assumes the RBB to have a lower heart rate threshold for triggered activity than the left bundle branch (LBB). The triggered action potential from the RBB assumes LBB block QRS morphology on ECG. As bigeminy results in increased heart rate, the LBB heart rate threshold for triggered activity is reached and the following triggered action potential is elicited by LBB, showing an RBB block morphology on ECG. The RBB is stimulated to trigger another action potential upon arrival of this beat, resulting in sustained alternating LBB block-RBB block morphology VT if repeated triggering of action potentials continues. Curr Probl Cardiol, December 2013

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FIG 8. Bidirectional ventricular tachycardia.

Risk Stratification Determining risk levels in CPVT has not been investigated given the relatively small number of patients reported, but most clinical descriptions indicate β-blockers can be effective in preventing VT and ICD therapy is reasonable when recurrence of sustained VT, hemodynamically untolerated VT, or syncope attributable to ventricular tachyarrhythmias occurs despite β-blockers. Patients with VF and ACA are considered at high risk and are usually treated with ICD in addition to β-blocker therapy. Electrophysiology testing is generally not useful in the management of patients with CPVT, as the arrhythmia is usually not inducible with programmed ventricular stimulation.

Diagnosis A history of adrenergic- or exertion-induced syncope with spontaneous or induced PMVT in a young patient is highly suggestive of CPVT. Resting ECG and echocardiogram are normal. Holter monitor or implantable loop recorders are useful in the diagnosis, although they are generally of low yield. Usually VT develops at a threshold tachycardia of approximately 110-120 bpm, initially as monomorphic ventricular ectopy (Fig 9A) followed by bidirectional VT (with alternating LBB and RBB block patterns; Fig 9B) and then PMVT (Fig 9C and D), which can lead to VF, syncope, and collapse. VT is usually selflimiting with discontinuation of exercise or the specific circumstance that precipitated VT (Fig 9E). 532


FIG 9. Progression of ventricular ectopy in CPVT. With sinus tachycardia, monomorphic premature ventricular complexes are first seen (Panel A), followed by more complex ectopy (Panel B), then bidirectional VT (Panel C), and then polymorphic VT (Panel D) that resolves with rest and use of b-blockers (Panel E).

Provocative Testing in CPVT Sympathetic stimulation with exercise or by epinephrine infusion accentuates abnormalities in intracellular calcium handling and can lead to arrhythmias mediated by delayed afterdepolarizations.140 Ventricular ectopy, bidirectional VT, and PMVT can occur in a progressively predictable order with increasing heart rate. Tachyarrhythmias disappear with discontinuation of testing, and intravenous β-blocker therapy can suppress ventricular arrhythmias after provocative testing. Development of complex ventricular ectopy (including bidirectional VT) or PMVT or both defines a positive test, but not if only simple isolated monomorphic ectopy is seen. PMVT or bidirectional VT can be provoked in 63% of patients during exercise and in 82% of patients with epinephrine.141 Hence, the diagnosis of CPVT is not excluded by a normal provocative test. In a large series of patients with CPVT (n ¼ 101), exercise testing was negative in 12 of 17 asymptomatic family members with a positive CPVT genotype.142 In another study of 30 CPVTCurr Probl Cardiol, December 2013

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genotyped patients, exercise stress testing induced ventricular arrhythmias in only 23.143

Treatment and Prognosis There is a typical delay of 2-3 years between first presentation and diagnosis, and most patients with CPVT are wrongly diagnosed as having seizures without significant improvement on maximal seizure medication. If untreated, the rate of mortality by the age of 30 years in CPVT patients is 31%. The younger the patient is at initial presentation, the worse is the prognosis. The 4- and 8-year cardiac event rates were 33% and 58%, respectively, in a series of 31 patients not receiving β-blockers. Younger age at the time of diagnosis, absence of β-blockers, and ACA are independent risk factors for cardiac events. There is no difference in the incidence of arrhythmia and fatal or near-fatal cardiac events between probands and affected family members, regardless of their symptoms or lack thereof. Therefore, treatment is recommended for all.142 Lifestyle Modification In most cases, cardiac events are triggered by physical activity or emotion. Intensive sports and exercise should be avoided by all symptomatic patients to prevent the adrenergic response. Exercise tolerance in asymptomatic carriers should be guided by stress testing. β-Blockers β-blockers are the mainstay of treatment in every CPVT patient with either positive genotype or positive stress test whether the patient is a symptomatic proband or an asymptomatic affected family member. In the largest study of 101 patients with CPVT, β-blockers reduced the incidence of cardiac events from 58% to 27% and of fatal or near-fatal events from 25% to 11%, respectively, over 8 years of follow-up. Nonadherence accounted for most cardiac events in the β-blocker group and patients must be counseled about the consequences of noncompliance and sudden cardiac death. Nadolol at a dose of 1.6 mg/kg was found to be superior to other β-blockers (event rate of 19% vs 39%), partly because of its lack of sympathomimetic activity and long half-life. The medication dosage has to be titrated based on the heart rate response during exercise testing so that the patient never reaches the level of tachycardia that induces the VT.142 Asymptomatic exercise test-negative patients should be recommended the maximally tolerated β-blocker dose. 534


Calcium Channel Blockers Some limited data suggest that verapamil, in combination with βblockers, suppresses the VT immediately after exercise testing. However, long-term follow-up studies are lacking. Flecainide Flecainide has ryanodine receptor (RyR2)-blocking properties and reduces the Ca2þ-wave propagation between the adjacent Ca2þ-release units by reducing the RyR2 open probability.144 Flecainide also suppresses spontaneous calcium release events in a RyR2 mutant mouse model of CPVT145 and, by its Naþ channel blocking action, prevents triggered beats and delayed afterdepolarizations. In a clinical study, flecainide was started for 33 patients who were having exercise-induced ventricular arrhythmias while on β-blocker therapy. The dose was optimized based on ventricular arrhythmia score on exercise testing. The primary outcome of suppression of exercise-induced ventricular arrhythmias was achieved in 22 patients (76%), partially in 8 and completely in 14 patients over follow-up of 20 months, with the therapeutic dose for flecainide of 150 mg (range 100-300 mg) daily. None experienced worsening of ventricular arrhythmia scores. One patient received an appropriate ICD discharge in the setting of low serum flecainide levels at the time of the event, suggesting noncompliance, and 1 patient had complete suppression for 29 years. Flecainide and β-blockers should be used in conjunction in CPVT patients with no structural heart disease to improve the cardiac outcomes.146 ICD Implantation of an ICD with use of β-blockers is considered a class I indication for patients with CPVT who are survivors of cardiac arrest and have good functional status.111 Patients with CPVT who experience syncope or sustained VT while receiving β-blockers are considered to have a class IIa indication for ICD implantation. There are currently no guidelines for ICD insertion in asymptomatic patients with CPVT. However, in high-risk patients with very strong family history of SCD, ICD implantation may be considered. It is important to recognize the ICD can be proarrhythmic in patients with CPVT, as stress caused by ICD shocks can result in adrenergic release and precipitate VT with subsequent ICD shocks that spiral into a vicious cycle and progress to ventricular storm and even death. Maximizing β-blockers may mitigate this phenomenon. LCSD LCSD interrupts adrenergic input to the heart and thereby decreases arrhythmic events and increases threshold for VF. LCSD may be Curr Probl Cardiol, December 2013

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considered in patients with poor medication compliance, if ICD therapy is not desired or contraindicated, and in patients with VT storm and recurrent ICD shocks. There is extensive evidence supporting LCSD in LQTS; however, long-term data in CPVT is limited. In 1 study, LCSD was associated with 93% acute success rate.147 In another, 13 patients with CPVT underwent surgery, of whom 10 were symptomatic and 3 asymptomatic before surgery. After surgery, 12 patients had no breakthrough cardiac events and 1 patient experienced a reduction in events over a follow-up period of 1.3 years. However, LCSD does not obviate ICD therapy in very high-risk patients.148 As mentioned, LCSD is available only in few centers. New Developments A benzothiazepine derivative, JTV519 (Rycals family), normalizes the RyR2 channel function without blocking the channel completely during Ca2þ-induced Ca2þ release and reduces the RyR2 open probability, thereby preventing VT in a FKBP12.6 deficient mouse model.149 A new carvedilol analogue VK-II-36 prevents triggered activity through suppression of sarcoplasmic reticulum calcium leak and prevents early afterdepolarization in mice.150 Other carvedilol analogues are under active investigation for CPVT treatment.

Genes and Genetic Screening RyR2 mutations are found in 65% of index cases and CASQ2 in 3%5%.87 RyR2 is a large gene with 105 exons and the mutations largely affect specific cluster regions of the gene primarily encoding FKBP12.6-binding domain, though mutations outside these clusters have been identified as well. Hence, testing for the common mutations first, followed by the entire gene in a tiered screening fashion, is recommended.151 CASQ2 mutations are transmitted via autosomal recessive inheritance, therefore index cases with an autosomal recessive inheritance pattern or sporadic RyR2 negative cases should be screened for CASQ2 mutations. The yield of genetic testing is highest (65%) in patients presenting with typical bidirectional VT but low with atypical clinical presentations (15%).152 When a pathogenic mutation is detected, all the siblings and parents should be screened for the specific mutation and with exercise stress testing, irrespective of symptom burden. Lethal cardiac events are similar between probands and affected family members,142 hence screening family members is a priority. Because of the association between CPVT and sudden infant death syndrome, infants need to be screened at birth if there 536


is a CPVT mutation-positive family history. In addition, it should be noted that though neither a negative provocative test nor a negative genetic screen exclude the diagnosis of CPVT, evaluation for Andersen-Tawil syndrome should be considered in patients with negative evaluation for CPVT because of the similarity in presentation.

Summary Polymorphic ventricular tachycardia and its subform, TdP, remain enigmatic ventricular tachyarrhythmias despite the extensive work investigating and elucidating their mechanisms, some of which has been presented here in an abbreviated and simplistic form. Unlike monomorphic VT, and most other arrhythmias for that matter, the majority of exploration of PMVT remains in animal and computer models. Until human PMVT can be safely studied, our observations and insights into this arrhythmia remain narrow and limited. Studying the ECG during PMVT and the repolarization components of the surface ECG in sinus rhythm offers a view into the cellular underpinnings and processes that predispose to PMVT. In fact, the ECG components may not be as dangerous or benign as previously thought, referring to the QT interval and J wave, respectively, and the underlying cellular heterogeneities that these are purported to represent appear to hold the true key to risk and arrhythmia. The recognition of ion channel dysfunction over the past 60 or more years since the first case descriptions of the long QT syndrome and their associated disease states has now given way to an even more fascinating phenomenon—that of the genetic or molecular overlap syndromes, such as in a patient with Brugada syndrome who may have sudden death risk mitigated by a mutation for short QT syndrome. The ionic mechanisms of upright and inverted T waves; ST-segment deviation, both elevated and depressed; and even the processes that lead to the benign or malignant J wave on ECG have all been explored in the literature to various degrees and provide a foundation to begin understanding cardiac dysrhythmias, particularly PMVT from a cellular, molecular, and genetic or genomic perspective. More questions arise as our understanding grows, and at least 1 question begs asking in the context of this review and as food for thought—might there be an S-wave syndrome? Dr Scheinman: We are greatly indebted to the authors for a true “tour de force.” They have taken a very complex and oft not well-understood corner of cardiology (namely polymorphous VT) with a superb review emphasizing both basic pathogenic processes as well as up to date clinical review of the various syndromes that comprise the subject. They are to be complimented on the Curr Probl Cardiol, December 2013

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clarity of presentation as well as judicious use of figures to clarify complicated concepts. The article will be appreciated by medical students, cardiologists interested in arrhythmias, and provides an excellent overall review for the EP specialist. We thank the authors for all their hard work and congratulate them on a job well done.

Acknowledgments: The authors gratefully acknowledge Dr Dreema

Awan for her contribution on mechanisms of bidirectional ventricular tachycardia. We also recognize Joe Grundle and Katie Klein of Aurora Cardiovascular Services for editorial assistance and Brian Miller and Brian Schurrer of Aurora Sinai Medical Center for their help with figures.

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Polymorphic ventricular tachycardia (PMVT). Foreword.

Catheter ablation for ventricular tachyarrhythmia in patients with channelopathies.

Catheter Ablation of Polymorphic Ventricular Tachycardia and Ventricular Fibrillation.

The renal channelopathies.

Current topics in catecholaminergic polymorphic ventricular tachycardia.

Complex diagnosis of catecholaminergic polymorphic ventricular tachycardia.

Disruption of the Purkinje Network Causing Polymorphic Ventricular Tachycardia.

Stochastic spontaneous calcium release events and sodium channelopathies promote ventricular arrhythmias.

Percutaneous renal sympathetic denervation in catecholaminergic polymorphic ventricular tachycardia.

Polymorphic ventricular tachycardia due to change in pacemaker programming.

Postexertional supraventricular tachycardia in children with catecholaminergic polymorphic ventricular tachycardia.

Delay to diagnosis amongst patients with catecholaminergic polymorphic ventricular tachycardia.

Trigger elimination of polymorphic ventricular tachycardia and ventricular fibrillation by catheter ablation: trigger and substrate modification.

Episodic disorders: channelopathies and beyond.

Chloride channelopathies of ClC-2.

Reply: Takotsubo syndrome and polymorphic ventricular tachycardia: The chicken or the egg.

The effect of the physical activity on polymorphic premature ventricular complexes in chronic kidney disease.

The Role of Flecainide in the Management of Catecholaminergic Polymorphic Ventricular Tachycardia.

Channelopathies of skeletal muscle excitability.

Potassium Channelopathies and Gastrointestinal Ulceration.

Arrhythmogenic mechanisms in ryanodine receptor channelopathies.

Sympathectomy for Patients With Catecholaminergic Polymorphic Ventricular Tachycardia: Should We Have the Nerve?

Questioning flecainide's mechanism of action in the treatment of catecholaminergic polymorphic ventricular tachycardia.

Channelopathies - emerging trends in the management of inherited arrhythmias.