Electrophysiology Study Testing in Brugada Syndrome: A Shocking Surprise?

Brugada syndrome is a relatively rare genetic disease that can lead to ventricular arrhythmias, syncope, or sudden cardiac death. It was first described in 1992 as a clinical entity.1 Since that time, specific diagnostic criteria for the Brugada syndrome have been defined.2,3 Symptomatic patients with Brugada syndrome should probably receive an implantable cardioverter-defibrillator (ICD), although the treatment plan for asymptomatic Brugada syndrome patients remains elusive. Programmed electrical stimulation (PES) with electrophysiology (EP) studies has been proposed as a risk-stratification tool by some,3,4 but not all Brugada syndrome researchers.5,6 This article will examine the current literature on the use of PES for Brugada syndrome patients, including highlighting the possible need to update the 2005 Brugada syndrome Consensus Statement.3 Background Brugada syndrome (BS) is an ion channelopathy linked to mutations in the SCN5A (sodium channel) gene.1-6 Affected patients have a “loss of function” mutation, meaning that the sodium channel is “closed.” However, only 20-30% of all BS patients ultimately will have a genetic mutation identified, so other ion channel mutations may underlie BS. Although the mutation affects men and women equally, most symptomatic BS patients are male, for unclear reasons.1-6 Brugada syndrome has been described in virtually every ethnic group. Symptoms of BS can include asymptomatic (most commonly) syncope, bradyarrhythmias, ventricular fibrillation, and cardiac arrest leading to sudden death.1-6 Other ion channelopathies that have been described include long QT syndrome (which is one of the most common such diseases), catecholaminergic polymorphic ventricular tachycardia (CPVT or the ryanodine receptor mutation), and arrhythmogenic right ventricular dysplasia (ARVD).7 The classic ECG findings include the characteristic ST-segment elevation in the right precordial ECG-leads.1-6 Diagnosis of the Brugada Syndrome Three ECG repolarization patterns in the right precordial leads have been described.1-6 Type 1 is the most diagnostic of BS and shows a coved ST-segment elevation of ≥ 2 mm followed by a negative T wave. Type 2 shows a saddleback-type ST-segment elevation in V1 and V2 followed by a positive or biphasic T wave. Type 3 has either appearance with an ST-segment elevation of Brugada Syndrome Prognosis As you might expect, in the initial clinical series, patients with BS did poorly.1-4 In retrospect, the initial studies included the clinically most dramatic of all such patients, leading us to believe that BS was a very lethal disease. A high percentage of affected patients went on to experience sudden cardiac arrest or syncope over a short time frame in these early reports. In one of the earliest papers from 1998, 27% of initially asymptomatic BS patients experienced ventricular fibrillation or sudden cardiac death in the 34 months of average follow-up.9 This led to a very high 10% per year rate of occurrence in BS patients.9 In another study described in Circulation 2005, Brugada et al reported on 724 affected BS patients.4 Of these initial patients, 75% were asymptomatic. Over a follow-up period on average of only 28 months, 8% of the affected patients experienced a cardiac arrest. Using multivariate analysis, the authors found that patients who had inducible ventricular arrhythmias during PES (programmed electrical stimulation or electrophysiology study) were at some heightened risk in the future to experience a sudden cardiac arrest or even death, as compared with those BS patients who were not inducible with PES.4 This study opened the veritable Pandora’s Box on the utility of PES at risk-stratifying asymptomatic BS patients. Multiple studies have shown that an aborted cardiac arrest, presence of a spontaneous Brugada syndrome EKG pattern, or a history of syncope are high-risk features in BS patients.1-6 Yet the use of PES remains controversial. Another well-done study looked at 212 BS patients from four centers in Europe.6 In this cohort, 58% of the patients were initially asymptomatic, 31% had experienced a syncopal event, and 11% had suffered ventricular fibrillation. Most of the patients (88%) underwent PES. During nearly four years of follow-up, the authors found that 4 of 65 (6%) with a prior syncopal event and 4 of 24 (17%) with a previous aborted cardiac arrest experienced another arrhythmic event. Thus, a previous history of symptoms again predicted a possible bad outcome for these BS patients. However, 4 of 9 patients who went on to have an arrhythmic event (even aborted cardiac arrest) were completely non-inducible at PES! The authors in this study concluded that PES “showed very little accuracy in predicting outcome.”6 Device Therapy for Brugada Patients At this point, you may be thinking, why not give everyone with Brugada syndrome an ICD? Since we cannot always know who will go on to have a cardiac arrest, and since these patients are oftentimes young, this line of reasoning is quite attractive. One elegant study from Circulation in 2006 examined the utility of ICD therapy in BS patients.10 This was a multicenter study from 14 hospitals looking at BS patients who received ICDs from 1993-2005; there were 220 patients in total. Roughly half (n = 114 patients) were initially asymptomatic. Over three years of follow-up, 8% of the patients had appropriate shocks from the ICD, indicating that the ICD therapy potentially saved them from a malignant, BS-related arrhythmia. The annual rate of appropriate shocks was 2.6% in previously symptomatic patients and 1.5% in asymptomatic patients. However, interestingly, 28% of the BS patients had device complications related to their ICD.10 The complications included inappropriate shocks in 20% of the patients. Two patients developed psychological issues from having the ICD in place, which led to a loss of employment simply due to having the device. A total of 90% of the patients had PES in this study. Again, PES did not seem to be particularly predictive at seeing if BS subjects would go on to have future arrhythmias. Of the 11 patients who previously had an aborted cardiac arrest and also had PES, only 4 had a positive PES; the other 7 such patients had a normal PES. Thus, PES alone would have missed most of the patients in this study who had symptomatic BS. The authors of this study estimated that they would have to implant 23 ICDs to save one Brugada patient’s life.10 As always with these studies, the follow-up is relatively short. No one really knows if the incidence of sudden death in BS patients keeps increasing over time. If these patients were followed for 50 years, would more Brugada patients receive appropriate ICD shocks? The FINGER Brugada Syndrome Registry The 2005 Consensus Statement on the Brugada syndrome considers PES to be a gold standard risk-stratification tool.3 If PES is positive in a BS patient, one should strongly consider placing a prophylactic ICD. However, the 2010 FINGER Brugada syndrome registry calls this suggestion into question (again).11 In one of the largest BS studies to date, the authors studied 1,029 BS patients from 11 centers in four European countries.11 A total of 638 patients (or 62%) underwent PES. The PES protocol was standardized to three ventricular extrastimuli from two ventricular pacing sites. As with other studies, the authors found that BS patients with a previously aborted cardiac arrest or a history of syncope with the presence of a spontaneous Type 1 ECG pattern were at increased risk of future arrhythmia events over a median follow-up of 31.9 months. However, the presence of a positive PES or family history of sudden death was not predictive of future events.11 The authors also found that the risk of arrhythmic events was low in initially asymptomatic patients, at only 0.5% per year. Future Directions The BS pendulum has swung back and forth over the years regarding the usefulness of PES in asymptomatic patients, as we have learned more from ongoing research efforts. In the largest, most comprehensive BS cohort yet to date, we are advised not to perform PES as a gold standard tool to risk-stratify these patients, in direct contradiction to the current 2005 Consensus Statement on Brugada syndrome.3,11 Perhaps it is time to revisit the Consensus Statement and address these recommendations in view of newer literature, which suggests that PES is not such a shocking surprise anymore.