Article

Inherited Channelopathies and Cardiomyopathies - When Is Invasive Risk Stratification Needed?

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Abstract

This article summarises the potential role of invasive electrophysiological studies (EPS) for the risk stratification and management of inherited channelopathies and cardiomyopathies based on the latest clinical evidence as well as published clinical guidelines, including the American College of Cardiology/American Heart Association guidelines and the Heart Rhythm UK 2010 position statement. Generally speaking, there is no role for EPS and genetic studies in the diagnosis and risk stratification of hereditary channelopathies. Nevertheless, the controversy over the role of EPS in asymptomatic Brugada syndrome remains. In the case of inherited cardiomyopathies, there is no role for invasive EPS in symptomatic patients with hypertrophic cardiomyopathy (HCM) and atherosclerotic renovascular disease (ARVD). On the other hand, in patients with suspected HCM or AVRD, a negative EPS might be helpful in identifying the population at low risk of sudden cardiac death.

Keywords

Long QT syndrome, Brugada, short QT syndrome, atherosclerotic renovascular disease, hypertrophic cardiomyopathy, electrophysiological study, risk stratification,

Disclosure:The authors have no conflicts of interest to declare.

Received:

Accepted:

DOI:https://doi.org/10.15420/apc.2011:3:1:64

Correspondence Details:Hung Fat Tse, Cardiology Division, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China. E: hftse@hkucc.hku.hk

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Inherited channelopathies and cardiomyopathies include diseases with a wide range of clinical manifestations, from asymptomatic gene carrier status to life-threatening cardiac arrhythmias and sudden cardiac death (SCD). Unfortunately, there is no definitive curative therapy for these diseases, which commonly affect young people. Currently, implantable cardioverter-defibrillators (ICDs) are the only option to prevent SCD in those at risk. However, ICDs impose a tremendous physical, psychological and financial burden on patients and families. It is of paramount importance to select high-risk patients who will benefit most from an ICD and to avoid overtreating low-risk groups, in whom the complications of the device outweigh the benefits. Despite advances in diagnosis and the increasingly widespread recognition of inherited channelopathies and cardiomyopathies, the risk stratification of SCD in these diseases remains challenging. The potential role of invasive electrophysiological studies (EPS) for the risk stratification and management of inherited channelopathies and cardiomyopathies based on the latest clinical evidence and published clinical guidelines is summarised in this article.1-3

Inherited Channelopathies

Currently, four types of well-described inherited channelopathy have been linked to SCD: long QT syndrome (LQTS), short QT syndrome (SQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT) and Brugada syndrome.

Long QT Syndrome

The International LQT Registry estimated a 4% overall mortality rate over 40 years for LQTS patients, yielding an average yearly mortality rate of 0.1%.4,5 The mortality rate varies depending on the baseline risk profile of LQTS patients. The annual mortality rate for LQTS patients with a history of aborted cardiac arrest, those with syncope despite beta-blockers and their asymptomatic counterparts were estimated to be around 3.37, 2.18 and <1% per year, respectively.6,7

However, irrespective of patient symptoms, a corrected QT interval (QTc) of 500-549 (compared with a QTc <499ms) has a hazard ratio (HR) of 3.34, while a QTc >550ms (compared with a QTc <499ms) has an HR of 6.35 for aborted cardiac arrest or LQTS-related sudden death.8 Therefore, a personal history of aborted SCD or syncope and QT prolongation >500ms are considered as high-risk indicators for SCD.8,9 Furthermore, patients with recent syncope (within the last two years) have a higher risk of aborted cardiac arrest/death than those with a remote history of syncope. Men have an increased risk of events during pre-adolescence, while women tend to have higher event rates in adolescence and beyond. However, the death of a sibling or the symptom severity of close relatives are not predictive of future risk of aborted cardiac arrest or death.9 The role of EPS in the risk stratification of SCD remains controversial. Bhandari et al.10 reported that the inducibility of ventricular tachycardia (VT) or the result of EPS-guided drug testing with beta-blockers have limited value in the diagnosis and management of patients with LQTS. In general, EPS are not recommended for risk stratification for SCD in patients with LQTS.1-3

Short QT Syndrome

Current guidelines are limited by the small number of patients identified to date and therefore do not provide definite recommendations regarding the diagnosis and management of SQTS. Genetic analysis may help to identify silent carriers of SQTS, but its role in diagnosis and risk stratification remains unknown. Giustetto et al.11 performed invasive EPS in a cohort of 18 patients with SQTS who presented with a history of syncope, aborted SCD or incidental diagnosis during family screening. In this study, ventricular fibrillation (VF) was induced in 11 of 18 patients (61%), but VF was inducible in only half of those patients with a history of VF and aborted SCD. This study illustrated the limited diagnostic and therapeutic value of EPS in patients with SQTS.

Catecholaminergic Polymorphic Ventricular Tachycardia

The reported incidence of SCD in patients with CPVT was found to be about 1.36-2.8% per year over a follow-up period of two to seven years.12-16 Interestingly, the fatal event rate among probands and asymptomatic family members was similar, suggesting a high penetrance of the genetic mutation of CPVT.14

For patients not on beta-blockers, the estimated annual risk of death or near-fatal events was 3.1% per year, reduced to 1.2% per year for patients on beta-blockers.14 Therefore, oral beta-blockers are recommended for all patients with CPVT. Nevertheless, the use of beta-blockers does not eliminate the risk of SCD in patients with CPVT. Priori et al.13 reported no deaths in a cohort of patients with CPVR treated with beta-blockers after a mean follow-up of 46 months. However, half of the patients had arrhythmia recurrence and half of the patients with an ICD (six out of 12) had appropriate shocks for VT/VF. In patients with CPVT, EPS have low sensitivity and specificity for the diagnosis of CPVT. Priori at al.13 performed EPS in 19 patients with CPVT, and polymorphic non-sustained VT was induced in only two patients (11%) at baseline. Even during isoproterenol infusion, polymorphic non-sustained VT was induced by EPS in only six patients (31%). In up to half of the patients with CPVT, VT/VF were not inducible during EPS. Therefore, EPS have low sensitivity and specificity for diagnosis and risk stratification in symptomatic CPVT patients. As a result, EPS are not recommended for the risk stratification of SCD in CPVT patients.1-3

Brugada Syndrome

The cardiac event rate of Brugada syndrome patients (defined as SCD, VF or appropriate ICD shock) per annum varies from 0% in asymptomatic patients without spontaneous type I electrocardiogram (ECG) to 13.8% in patients with a prior cardiac arrest.17-21 A recent pooled analysis by Heart Rhythm UK of a series of studies by Brugada,17,22-25 a series of studies by Priori,26,27 studies by the Joint European Group led by Wilde and Eckardt and colleagues,18,28,29 the Japan Idiopathic VF Study Investigators,19 a Franco-Japanese study20 and a Belgian series21 concluded that a personal history of aborted SCD or syncope (HR 3.51), spontaneous type I ECG (as opposed to a drug-induced type I pattern: relative risk [RR] 4.65), male gender (RR 3.47) and South-East Asian origin are predictors of a high RR of SCD; however, a family history of SCD and SCN5A mutation status do not carry an increased risk of SCD.3

The clinical value of invasive EPS in Brugada syndrome is highly controversial. In the initial series by Brugada, a higher risk of VT/VF among individuals with spontaneous type I ECG, syncope and sustained VT/VF at EPS was reported. Furthermore, asymptomatic carriers with a positive EPS were also found to be at higher risk, irrespective of their baseline ECG.17,25 However, subsequent studies yielded conflicting conclusions regarding the role of EPS in Brugada syndrome. Benito et al.30 showed that the inducibility of EPS in asymptomatic patients with non-diagnostic basal ECG was very low. Even for patients with syncope and spontaneous type I ECG, the inducibility of EPS was still <40%. Priori et al.29 also reported that EPS had a low positive predictive value for cardiac events and SCD. In pooled data31 from studies in patients with asymptomatic Brugada syndrome, the risk of arrhythmic events during follow-up ranged from 0.8 to 27%. Similarly, EPS non-inducibility conferred a high negative predictive value: VF occurred in only 1-2% of asymptomatic Brugada patients with negative EPS. However, a positive EPS among asymptomatic patients predicted VF in only 4-12% of patients, suggesting a very low positive predictive value. The discrepancies between the Brugada series and other studies could be due to the early referral bias of more severe cases to the Brugada registry31,32 as well as the differences among the study protocols for EPS.

The limited role of EPS in asymptomatic Brugada patients was further demonstrated in recent studies in Japan33 and Europe.18 In the Japanese Brugada study,33 91 asymptomatic Brugada patients were studied, and VF was inducible in 56 and 58% of patients with spontaneous type I ECG and patients with drug-induced type I ECG, respectively. At four-year follow-up, VF occurred in only one patient (2%). In the European France, Italy, Netherlands, Germany (FINGER study), the largest series of Brugada syndrome patients to date,18 1,029 consecutive individuals (64% of whom were asymptomatic) with either spontaneous or drugprovoked type I ECG were recruited. During a median follow-up of 31.9 months, the cardiac event rate per year was 7.7% in patients with aborted SCD, 1.9% in patients with syncope and 0.5% in asymptomatic patients. In this study, EPS inducibility of VT/VF, SCN5A mutation and family history of SCD were not predictors of a cardiac event.

Although the 2005 Brugada Syndrome Second Consensus Conference34 recommended EPS testing for all asymptomatic patients with spontaneous type I ECG and ICD implantation for those with a positive EPS, this is not fully supported by the American Heart Association (AHA)/American College of Cardiology (ACC)/European Society of Cardiology (ESC) guideline and the Heart Rhythm UK position statement.1-3 In the AHA/ACC guidelines,1 EPS is only a class IIb indication for risk stratification in asymptomatic Brugada syndrome patients with spontaneous ST elevation with or without a mutation in the SCN5A gene. Based on current evidence, a negative EPS study in asymptomatic patients with suspected Brugada syndrome should have a high negative predictive value for SCD in those in whom prophylactic ICD is not warranted. However, the clinical predictive value of a positive EPS study in asymptomatic patients with suspected Brugada syndrome remains unclear.

Inherited Cardiomyopathies

Two common inherited cardiomyopathies with SCD will be discussed: hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular dysplasia (ARVD).

Hypertrophic Cardiomyopathy

The reported annual risk of SCD in HCM patients has declined from 2-4% to 1% per year.35 This might be due to the early identification of more patients with milder phenotypes. The risk of SCD occurs throughout life, but is at its maximum in adolescence and young adulthood. The major risk factors for SCD include VF, spontaneous sustained VT, family history of SCD, unexplained syncope, left ventricular thickness 30mm, abnormal blood pressure during exercise and non-sustained spontaneous VT. Potential risk factors include atrial fibrillation, myocardial ischaemia, left ventricular outflow tract obstruction, high-risk mutations and competitive physical exercise.

In HCM patients with aborted SCD or sustained VT, the cumulative survival rate (death or ICD discharge) was 59% at five years.36,37 Registry data from multiple centres reported a yearly discharge rate of 10-11% for secondary prevention in patients with a history of resuscitated VT/VF.37

Current guidelines1-3 recommend ICDs for HCM patients with sustained VT/VF or aborted SCD. In patients with two or more risk factors, the annual sudden death risk is around 3%, whereas the presence of a single risk factor (which is the case in ~25% of HCM patients) confers an annual risk of ~1%.38 In patients with HCM, EPS inducibility predicted a higher event rate but with very low predictive accuracy, irrespective of patient symptoms. Fananapazir et al.39 showed that only 36% of patients with HCM had inducible sustained VT, and the predictive value for SCD was very low. Accordingly, current guidelines do not recommend the use of EPS for the risk stratification of HCM patients. Nevertheless, recent studies suggest that the ventricular electrogram fragmentation provoked by EPS might have greater positive predictive value for SCD than the use of single or combined conventional risk factors.40 However, the role of EPS in the selection of patients for ICD remains to be defined.

Arrhythmogenic Right Ventricular Dysplasia

In a multicentre observational study by Corrado et al.,41 it was demonstrated that the rate of subsequent SCD or a life-saving shock from an ICD was up to 21% per year in ARVC patients who had an ICD implanted for secondary prevention (10% for those with a history of cardiac arrest, 62% for those with sustained VT and 16% for those with syncope without ECG documentation). However, in the Johns Hopkins Registry42,43 the overall annual incidence of 'life-saving' shock in ARVD patients with an ICD was only 5% per year. Current guidelines1-3 recommend ICDs for the prevention of SCD in ARVD patients with documented sustained VT/VF or SCD. However, the risk of SCD is much lower in asymptomatic patients with mild disease.45 In patients with ARVD, EPS is of limited value in risk stratification, and is only a class IIb recommendation in the AHA/ACC/ESC guideline.1,2 In patients with confirmed ARVD and VT, EPS has a false-positive and false-negative rate of 50%.43 Furthermore, EPS is also of limited value in predicting appropriate shocks in ARVD patients after ICD implantation.43 Nevertheless, in patients with suspected ARVD, a negative EPS might predict a low-risk population for SCD.43

Conclusion

Risk stratification for SCD using EPS in subjects with inherited channelopathies and cardiomyopathies remains challenging. In the case of inherited channelopathies, there is no role for invasive EPS in symptomatic patients with LQTS, SQTS and CPVT. However, the role of EPS in asymptomatic subjects remains unclear. Similarly, there is no role for invasive EPS in symptomatic patients with Brugada syndrome, but controversy remains over the role of EPS in asymptomatic Brugada syndrome patients. In the case of inherited cardiomyopathies, there is no role for invasive EPS in symptomatic patients with HCM or ARVD. However, in patients with suspected HCM or AVRD, a negative EPS might be helpful in identifying a low-risk population for SCD.

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