Management of Brugada Syndrome 2016: Should All High Risk Patients Receive an ICD? All High-Risk Patients Should Receive an Implantable Cardiac Defibrillator.

Abstract

HomeCirculation: Arrhythmia and ElectrophysiologyVol. 9, No. 11Management of Brugada Syndrome 2016: Should All High Risk Patients Receive an ICD? Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBManagement of Brugada Syndrome 2016: Should All High Risk Patients Receive an ICD?All High-Risk Patients Should Receive an Implantable Cardiac Defibrillator Juan Sieira, MD and Pedro Brugada, MD, PhD Juan SieiraJuan Sieira From the Heart Rhythm Management Centre, UZ Brussel-VUB, Brussels, Belgium. Search for more papers by this author and Pedro BrugadaPedro Brugada From the Heart Rhythm Management Centre, UZ Brussel-VUB, Brussels, Belgium. Search for more papers by this author Originally published8 Nov 2016https://doi.org/10.1161/CIRCEP.116.004195Circulation: Arrhythmia and Electrophysiology. 2016;9:e004195IntroductionBrugada syndrome (BS) is an inherited cardiac disease associated with sudden cardiac death (SCD), mainly because of ventricular fibrillation (VF),1 in the absence of structural heart anomalies. As a consequence, the use of an implantable cardiac defibrillator (ICD) in patients at risk of arrhythmic events was an evident option since the first description of the syndrome in 1992.2 This strategy is endorsed by current clinical practice guidelines and consensus documents3,4 and is the most common option for patients at higher risk.5–7See Response by BelhassenBS is usually diagnosed in young and otherwise healthy individuals.8 ICD implantation in these patients requires a thorough evaluation. They confront to live with an ICD during several decades and, therefore, face the risk of long-term device complications.9 Furthermore, because of their active way of life, inappropriate shocks are relevant, with a negative psychological impact.An active search of an alternative to ICD implantation has been ongoing for decades. Certain drugs, quinidine being the most studied one, but also isoproterenol, sotalol, mexiletine, and disopiramide,10 are used for the treatment of arrhythmic storm in BS patients and are recommended under certain circumstances as an alternative to ICD implantation or to reduce the number of appropriate shocks.3 An electrophysiological (EP)-guided therapy based on drugs that effectively suppress the induction of VF in a given patient during electric stimulation of the heart could be a therapeutic option for these.11We defend the use of an ICD in BS patients at risk of VA. We support our recommendation in several facts: the multiple mechanisms underlying the BS, the fact that events can appear several decades after the diagnosis, the proven efficacy of ICD avoiding SCD, the more accurate risk stratification of patients available nowadays, and the frequent secondary effects of drug therapy. Nevertheless, we acknowledge that EP-guided drug therapies have an important role in BS, and they might be an alternative to ICD under certain circumstances. Importantly, the use of a device is not opposed to the use of drugs. They can be complementary: a device provides effective long-term protection, whereas drugs prevent events.Pathological Mechanisms Underlying the BSBS is a complex inherited disease. Physiopathology of BS is not yet fully understood, and its nature is still debated.12 The most extended hypotheses propose depolarization or repolarization alterations. Mechanisms underlying these can have different natures: purely genetic alterations, abnormal neural crest cell migration,13 improper gap junctional communication. or connexome abnormalities.14 Several mechanisms are likely to coexist in the BS and even vary among patients. A common phenotype might be the final result of completely different pathophysiologic mechanisms. Nevertheless, all mechanisms will ultimately lead to the occurrence of VF, which will be potentially treated by an ICD. Figure 1 shows the different hypothesis under the BS.Download figureDownload PowerPointFigure 1. Pathophysiological hypothesis underlying Brugada Syndrome (BS). A, The depolarization theory: A slow conduction in the right ventricular outflow tract (RVOT) might have a role in the development of the electrocardiographic and arrhythmic manifestations of BS. Adapted from Meregalli et al15 with permission of the publisher. Copyright © 2005, European Society of Cardiology. B, The repolarization theory: An outward shift in the balance of currents in the right ventricular epicardium can result in repolarization abnormalities. Adapted from Antzelevitch16 with permission of the publisher. Copyright © 2001, John Wiley and Sons, Inc. Authorization for these adaptations have been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. C, Neural crest migration theory: BS might be linked to an abnormal expression of the neural crest during embryological development of the RVOT. Reprinted from Elizari et al13 with permission of the publisher. Copyright © 2007, Heart Rhythm Society. AP indicates action potential; RA, right atrial; and RV, right ventricle.In past years, many pathogenic mutations in several genes have been found. These genes encode for subunits of cardiac sodium, potassium, and calcium channels, as well as genes involved in the regulation of these channels,17–19 but to date, there is a suspicion that most of these gene defects identified may not be directly responsible of the disease, at least alone. Mutations in the cardiac sodium channel gene SCN5A, which encodes the α-subunit of the human cardiac sodium channel, are identified in 11% to 28% of patients with BS. Over 300 different mutations of SCN5A have been identified, and the list is growing.17,18,20 The great spectrum in the severity of the electrocardiographic and clinical manifestations of BS correlates with the existence of a wide spectrum in the severity of the underlying genetic and cellular abnormalities of the right ventricle outflow tract and of the surrounding structures.EP-guided drug therapy relies on the antiarrhythmic effect of certain drugs (quinidine being the most representative) and its capacity to suppress VA induced by electric stimulation of the heart. This implies 2 important considerations: that one single pathophysiological mechanism is responsible of the disease and the ability of EP study in detecting all patients at risk of SCD.Quinidine effects on BS are mainly driven by the inhibition of the transient outward K+ current (Ito). One of the mechanisms proposed in BS is the loss of the action potential dome in the initial plateau of the right ventricular epicardium. This is attributed to an outward shift in the balance of currents at the end of phase 1 of the action potential (principally Ito and ICa). This phenomenon results in differences in the duration of action potentials between the endocardium and epicardium, resulting in marked differences between initial domes21,22 and, therefore, generating a transmural voltage gradient,22,23 inducing phase 2 reentry and VF. Quinidine would normalize the transmural gradient and even restore the ST-segment elevation.24However, as most antiarrhythmic drugs, quinidine has multiple ionic effects. It blocks the delayed rectifier current, the inward rectifier current, the adenosine triphosphate–sensitive current, the steady-state window current, the slow inward calcium current, and muscarinic receptor, in addition to INa.24,25 The effect of quinidine is a result of complex interactions among multiple effects on cardiac membrane currents with theoretical potential proarrhythmic effects.Quinidine and other drugs with blocking effects on the Ito current would, therefore, only act on one of the multiple proposed mechanisms of BS, not guarantying a complete protective effect. Furthermore, as will be presented later, some patients might have paradoxical responses to quinidine because of particular sodium channel mutations.Conduction slowing based on interstitial fibrosis has been postulated as an alternative explanation to transmural repolarization difference. This fibrosis might be the effect of gap junction or connexome pathologies.14,26 Therefore, quinidine would have no effect on this mechanism.Quinidine might suppress arrhythmias in patients with specific pathogenic mutations but it cannot guarantee a full protection to all patients. In some patients, the VA could be secondary to a sum of mechanisms, and even several might coexist in the same patient, in which case quinidine might offer a partial protection. A better understanding of mechanisms responsible of BS could lead in the future to a personalized approach to the disease. In the meantime, only ICD implantation can guarantee a full protection.Risk Stratification of BSIdentifying those patients at risk of arrhythmic events is key in the management of BS. Although it remains a challenging and sometimes controversial issue, great scientific progress has been recently made.Accurate risk stratification will select those patients at higher risk, in whom an ICD will be lifesaving and reduce the number of patients who will not benefit of it and who might suffer device-related complications in the long term. To date, the strategy to stratify patients is not clear. Clinical guidelines and consensus offer recommendations for those patients at the highest risk. Certainly, these will benefit the most of an ICD. Among BS patients who have presented an aborted SCD, >50% will receive an appropriate shock after 5 years.5Identifying patients at low risk is more challenging; there is no consensus strategy for these patients. Unfortunately, they are the most common patients diagnosed nowadays.It is not the purpose of this article to deeply treat the risk stratification process, but it should briefly be addressed. Furthermore, a shift in the presentation of BS patients has been produced.27 From more expressive and severe manifestation of the syndrome in the early patients, nowadays, BS is diagnosed more frequently in asymptomatic and lower-risk patients. Nevertheless, these patients are not at zero risk because some might suffer an SCD. Identifying them is important and challenging.Some risk factors are widely accepted, while others remain under deep controversy. Among the first ones, we can find a spontaneous type I ECG pattern and symptomatic patients (either with a previous SCD or syncope).5,6 Others that might have a value but still under investigation include male sex, proband status, sinus node dysfunction, familial antecedents of SCD, and induction of VA during EP study.8,28–32 Some ECG parameters have been identified as a marker of an increased arrhythmic risk, such as QRS fragmentations, early repolarization, and a prominent S wave in lead I, among others.33–36 Unfortunately, these are mainly found in patients with a more severe clinical presentation and, therefore, easily recognizable to be at high risk.A strategy with both high power to predict events and able to identify patients at no risk is desirable. Furthermore, symptoms can also be confusing in BS; an exhaustive clinical evaluation (including invasive tests if appropriate) to clarify their etiology is sometimes needed. In this scenario, implantation of a cardiac monitor could be useful.We have always endorsed the role of electrophysiological study in the stratification of BS patients. Great concerns still exist around its value. Recent reports support its utility,8,32 but we acknowledge that some registries have failed to support its usefulness.6,7 Reasons under such discrepancies are not clear. The key might be the heterogeneous protocols used in each registry. The protocol used in our institution has remained unchanged since the first reports,37 conferring, therefore, a homogenous and long-term experience. This is not present in other studies, some of which even mix different protocols.6,32 Interestingly, the one we propose is the one of least aggressive that can be found in the literature. We only stimulate at one site of the RV as compared with 2 sites approach of most of the published studies (including the PRELUDE registry [Programmed Electrical Stimulation Predictive Value]7). This mild stimulation could increase the specificity of the test.The management of BS patients with an EP-guided strategy implies the usefulness of EP study in identifying patients at high risk. Protocols used under this approach are also heterogeneous.38–40 Furthermore, some are the most aggressive ones described in BS literature.39 The purpose is to maximize its sensitivity and positive predictive value but at the cost of a reduced specificity. This poses 2 main problems: they use protocols that have failed to demonstrate its value,7 and they might falsely identify as high-risk patients at low risk. As a consequence, these will receive unneeded drugs, with significant and frequent adverse reactions and even proarrhythmic effects. Furthermore, because of the aggressive stimulation protocol, those patients who remain inducible under the drug therapy will receive an ICD, some of which would not be needed because of a lower specificity of the protocol.Despite that we think that electrophysiological study is a useful tool in identifying patients at high risk, it is not a diagnostic tool. Some high-risk patients might not be inducible. In our experience, not all patients diagnosed after an SCD are inducible,8 and the same circumstance is found by other groups.6 Using aggressive stimulation protocols11 might avoid this issue, but it remains a problem in less aggressive ones.40Furthermore, risk profile of patients has changed in the last decade.30 BS is nowadays more frequently diagnosed in asymptomatic patients or after a drug challenge test. These patients have a lower risk of arrhythmic events, but they are not risk free.30 Some groups are questioning the value of stratification in these patients.41 In our experience, electrophysiological study is highly useful in this setting. An aggressive electrophysiological study might identify all of them but at the cost of increasing false positives. Furthermore, experience achieved with quinidine is based on a heterogeneous group of patients, including initial high-risk patients. Its value in this new lower-risk population is yet to be demonstrated. Because of lower incidence of events and that some event might present decades after the diagnosis of patients,5 clinical studies with enough power to elucidate this question are difficult to conduct.Efficacy of Drug and ICD TherapyQuinidine used under an EP-guided approach by experienced groups is safe and has excellent long-term prognosis. About 90% of patients are quinidine responders.39 This impressive figure contrasts with the high arrhythmic events recurrence rate of BS patients under quinidine in real-world registries,42 where around 33% present further arrhythmic episodes. Reasons under such discrepancy are not clear; they might be related to the high experience of the first groups, with careful follow-up of the patients.Total dose of the antiarrhythmic drug might be of importance. Experimental studies suggest that high doses of quinidine, 1 g per day, must be prescribed to obtain transient outward potassium current (Ito) block and to prevent torsades de pointes secondary to inhibition of the rapidly activating delayed rectifier current.43 Of note, a differential effect of quinidine exists depending on its route and frequency of administration.44 To avoid quinidine effect on INa, the drug has to be administered in fractionated oral doses. Some authors advocate for high doses (≤1.5 g per day) and routine measurement of serum levels. However, high doses of quinidine may be dangerous. Furthermore, methods of quantification are not specific for the unmetabolized drug, and there is no correlation between drug concentration and maximum effect.10Conversely, low doses of quinidine (600 mg per day) might be useful based on the beneficial results of such doses in abolishing arrhythmic storms.45,46 Clinical experience and long-term follow-up of patients treated with low doses of quinidine is limited. Some groups present an excellent long-term efficacy,47 but long-term arrhythmic events were still present. Conversely, other groups report a lower effectiveness of quinidine because only 40% of patients become noninducible in the electrophysiological study, and recurrent arrhythmic events are present during a relatively short follow-up.38Patients under quinidine can still present arrhythmic events during long-term follow-up. Furthermore, it has been described that VA in BS can occur decades after the diagnosis. A long-term follow-up is limited in patients under drug treatment. Series of the most experienced groups limit to a mean follow-up of around 10 years.39Figure 2 shows time event occurrence in our series. When a patient under an EP-guided drug therapy presents an arrhythmic event, it is usually endorsed to a noncompliance of the treatment. This might be true in certain cases, but in others it can be a drug failure. Hermida et al presented an interesting figure where a patient under quinidine suffered a spontaneous VA.40 Careful analysis of the illustration of this arrhythmia suggests that the polymorphic VT recorded was not typical pause-dependent torsade de pointes, suggesting that this was an example of relative quinidine failure and not a proarrhythmic effect of the drug.10Download figureDownload PowerPointFigure 2. Survival free of arrhythmic events according to Kaplan–Meier method in our series.Pediatric population would be the most benefited in finding an effective alternative to ICD implantation. Quinidine might not be an effective treatment in these patients. Fortunately, prevalence of BS in pediatric age is low. Nevertheless, among the 8 patients that constituted the initial BS report, 3 were children.2 Pediatric BS patients who present symptoms have an especial bad prognosis.48 Conversely, asymptomatic patients seem to have good outcomes, even more when they do not show the type I pattern spontaneously, but they are not risk free.49 A recent study involving 106 patients under 19 years old showed that among 11 patients treated with quinidine, 3 had events during follow-up.48 Quinidine, therefore, has a limited role among pediatric population.Conversely, ICD has proven to be an effective treatment5,50 for arrhythmic events in BS patients. Cumulative experience involves thousands of patients, spanning for >20 years in some cases. Overall, arrhythmic mortality of BS patients with an ICD implanted is anecdotic. Furthermore, risk of ICD-related complications that lead to the death of the patient is also low. Only one patient in a series of 378 patients died because of inappropriate shock,50 and in our own experience, no patients suffered a device-related death.5 We acknowledge a case description of the necessity of several ICD therapies for the resolution of a VF episode51 or, from our own experience, a VF episode resistant to both internal and external defibrillation.5BS patients are usually otherwise healthy individuals. Furthermore, as stated before, an evolution in the clinical characteristics of patients has been produced in the last decade. From the more symptomatic and expressive patients reported in the first studies, nowadays typical BS patient is usually asymptomatic with a drug-induced type 1 ECG pattern, of whom a high proportion are women.28,30 Clearly, we are treating and evaluating a lower risk population, but not a risk-free one. Implantation of an ICD in these patients has to be based in an accurate risk stratification and deep evaluation of benefits and risks. They confront to the possibility of long-term ICD-related complications, and inappropriate shocks is not unneglectable.In a recent meta-analysis, 20% of BS patients presented inappropriate shocks and 20% device-related complications (12% of which were electrode dysfunction).9 Our group and others have published similar figures.5,50 These complications are relevant and should be taken into consideration when evaluating BS patients. Nevertheless, life-threatening complications are extremely infrequent. Benefits and risks of ICD implantation must be carefully considered in the management of BS. Clearly, in high-risk patients, benefits exceed risks. In the lower risk asymptomatic population, this decision has to be taken with extreme caution.Patients with BS with ICDs are more difficult to manage, not only because of the high incidence of inappropriate therapies but also because of their long life expectancy compared with the conventional ICD patient population. It is well established that ICD placement in patients with BS is not without potential problems. Of note, in a study from our group, complications affected ≤33% of children with ICDs. In this particularly active category of patients, lead fracture can more frequently occur. Moreover, their long life expectancy leads to multiple generator change procedures, with a potential increased rate of device-related complications.Development of completely extravascular devices might reduce the risk of systemic device-related infections. However, the dynamic ECG pattern that can occur in BS patients might lead to inappropriate shocks or exclude patients at the screening test.52,53 Furthermore, a small percentage of BS patients might need atrial or ventricular pacing. We have demonstrated that a small percentage of BS patients might have concomitant sinus node dysfunction,30 which has prognostic importance and can appear in a pediatric age. Furthermore, monomorphic VT might happen in BS and effectively respond to antitachycardia pacing.1 Consequently, subcutaneous ICD implantation in BS should be considered after taking into account these facts.Epicardial radiofrequency substrate ablation has emerged as a promising tool for the management of BS. First described by Nademanee et al54 in 2011, radiofrequency ablation of the anterior aspect of the right ventricle outflow tract rendered arrhythmias during electrophysiological testing noninducible, normalized ECG patterns, and had an excellent prognosis at 20 months. Similar results have also been reported by others.55 To date, this technique is an accepted and useful option in arrhythmic storm or repeated appropriate shocks. Published data limit to relatively short follow-ups. Long-term follow-up and multicentre studies will clarify its efficacy and safety.Adverse Drug EffectsDrugs usually used in EP-guided therapy have a high rate of adverse events. Despite that their incidence differs between series, side effects can appear in ≤40% of patients, requiring withdrawal of the drug in most of the patients presenting them.39 Some adverse effects are mild: digestive intolerance or photosensitivity, that can appear in ≤24% of patients39,56 and without the need to discontinue the treatment. Others are serious: thrombocytopenia, allergic reactions, esophagitis, sinus node dysfunction, lupus erythematosus-like syndrome, and hepatitis among others.The proarrhythmic effect of antiarrhythmic drugs used to prevent VAs is well known and worrisome. Quinidine, as other drugs used in BS, prolongs the QT interval. Some cases of development of ventricular arrhythmias have been described, with no further VA after its withdrawal.56 To solve this issue, the use of low doses of quinidine has been proposed. They are well tolerated, but as stated before, long-term efficacy is reduced.47 Furthermore, clinical experience is limited, with studies supporting its use based on small number of patients.Furthermore, effects of antiarrhythmic drugs can vary among patients. BS might be the common phenotype of different pathophysiological mechanisms. Not all mutations responsible to the syndrome might respond equally drugs. As an example, a paradoxical effect to quinidine has been demonstrated with certain mutations, with significant further ST elevation when it was administered.57 The protective effect of the drug in such patients is not guaranteed.Defining High-Risk PatientsWhether an ICD or an EP-guided therapy should be the standard of care of patients with BS is relevant only at the moment we have identified that a patient with BS is at risk of SCD. Identifying these patients is the key issue in the management of BS patients.The struggle is how are we going to define a patient at high risk. The cut off is not clear and even controversial. In our own series, even patients without any high risk characteristics have a 3% risk of events at 10 years (unpublished data). This figure is low but is 100× the risk of SCD in a matched healthy person.58–60Therefore, just the diagnosis of BS confers a single patient a worse prognosis as compared with someone without the disease. As shown previously, some will be at high risk of events and others, fortunately the majority, will have a low risk. An accurate stratification of patients is of utmost importance. It will allow us to treat aggressively those patients who would likely present a spontaneous VA and avoid device or drug long-term complications.ConclusionICD implantation confers full protection for those patients at risk of SCD. Great experience and evidence is available supporting its value. Risk stratification is a key element in managing BS patients, and great advance has been made in the recent years. EP-guided drug therapy is useful and effective under the hands of experienced groups. Evidence of its effectiveness by less experienced groups is yet to be demonstrated, and therefore, its generalization should be made with caution.DisclosuresProf Brugada has received institutional grants from Biotronik, St Jude Medical, and Medtronic.FootnotesCorrespondence to Pedro Brugada, MD, PhD, Heart Rhythm Management Centre, UZ Brussel-VUB, Laarbeeklaan 101, 1090 Brussels, Belgium. E-mail [email protected]