Catheter ablation in Brugada syndrome: are we missing an opportunity

This editorial refers to ‘Catheter ablation as an adjunctive therapy to ICD implantation in Brugada Syndrome’, by I. Doundoulakis et al. https://doi.org/10.1093/ehjqcco/qcae040. The good physician treats the disease; the great physician treats the patient who has the disease.—William Osler P. D. L. receives educational grants from Abbott and Boston Scientific. He is supported by UCL/UCLH Biomedicine NIHR and Barts BRC. Brugada syndrome (BrS) is an inherited ion channel disorder with a distinctive ECG pattern in the right precordial leads—J point elevation, a coved ST segment and T wave inversion—the so-called Type 1 pattern.1 Its significance lies in the association with life-threatening ventricular arrhythmias, and patients considered at high risk are recommended to undergo defibrillator implantation.2 However, defibrillators are ‘reactive’ & don't prevent ventricular arrhythmias or address the underlying aetiology. The substrate leading to ventricular arrhythmias in BrS is most likely due to areas of sub-epicardial fibrosis causing slow conduction facilitating re-entry and wavebreak initiating VF.3–5 Given that the right precordial leads overlie the right ventricular outflow tract (RVOT), it was postulated that the epicardial surface of the RVOT was the substrate, proven in 2011 by Nadamanee and colleagues, showing recurrent life-threatening ventricular arrhythmia patients had a remarkably consistent electrophysiological substrate in sinus rhythm—low amplitude, delayed, and high-frequency signals recorded on the anterior epicardial surface of the RVOT.6 They eliminated this pathological substrate with catheter ablation by targeting these signals, being highly effective in preventing arrhythmias (8 of 9 patients had no further arrhythmias), and ablation even abolished the Brugada ECG pattern indicating that homogenising the epicardial substrate interferes with the pathophysiology of this condition. Subsequent observational studies examined outcomes in larger cohorts with promising results,7–9 and yet differences in patient selection and procedural workflow highlighted some of the controversies that still remain in this challenging disease, especially identifying the most suitable subjects as low-risk asymptomatic drug induced Brugada pattern cases as were included in one series.10 In this context, Doundoulakis et al. provide a timely opportunity to evaluate the effectiveness and safety of catheter ablation to clarify how this therapy fits into our management strategy.11 They performed a structured meta-analysis of data from 14 studies including 528 patients undergoing catheter ablation for BrS. The pooled population were high risk—94% had a defibrillator, 87% had experienced prior ventricular arrhythmias, including 19% who had experienced electrical storm. The study was methodical and well conducted, carefully excluding duplicate data and case reports, and gave consideration to sources of bias. Their main findings were as follows: All patients were shown to have electrophysiological substrate in the epicardial anterior RVOT. This consistency is important, providing a reproducible target for ablation. Additional substrate was identified in some studies, however,8 especially around the inferior RV free wall, which appeared to be related to the early repolarisation pattern on the ECG, indicating that careful mapping of the entire epicardial surface is important in order not to miss arrhythmogenic substrate. Non-inducibility of ventricular arrhythmias during programmed stimulation could be achieved in 91% of patients. Normalization of the Brugada ECG pattern could be achieved in 88% of patients. Freedom of ventricular arrhythmias occurred in 87% of patients with a mean follow up duration of around 2.5 years. The best predictor of ongoing ventricular arrhythmias was a persistent Brugada pattern at the end of the procedure highlighting this as a key ablation end-point to eliminate. Complication rates less than 1% and mainly related to pericardial bleeding or inflammation, with no deaths and no major cardiovascular endpoints. The authors go on to conclude that catheter ablation reduces arrhythmia burden in patients with BrS and highlight its role as an adjunct to a defibrillator in patients with frequent ventricular arrhythmias. So, do the data support these conclusions? Certainly, in patients with recurrent ventricular arrhythmias these data are clear, and show that in experienced hands catheter ablation is highly effective, at least in the short term, and safe—with the caveat of positive reporting bias from less experienced centres will exclude failed ablations and complications. However, this group with recurrent ventricular arrhythmias is a tiny proportion of the overall cohort with BrS. Should we not be looking to offer such an effective and apparently safe treatment to a wider spectrum of cases? Does one really need to wait until they have experienced multiple episodes of ventricular fibrillation before considering catheter ablation, as recommended by the European Society of Cardiology?2 Electrophysiologists offer catheter ablation for a very wide range of arrhythmias—some benign, others malignant, but common to all procedures must be (1) an understanding of the electroanatomical substrate and (2) an ability to measure and prove the response to ablation. In patients with BrS, there is a highly reproducible substrate with abnormal signals identifiable in all patients in a well-defined anatomical area. The size of this substrate correlates with risk, and can be reproducibly defined with high density mapping in conjunction with ajmaline provocation. Moreover, we have defined procedural endpoints—non-inducibility, abolition of abnormal substrate, and critically a very strong predictor of risk of ongoing arrhythmias—persistence of the Brugada ECG pattern, with or without ajmaline provocation. Provided we can abolish the induced Brugada pattern, and demonstrate a negative response to ajmaline provocation, the published data indicate extremely low recurrence rates. In this series, complication rates appear to be low. Pericardial bleeding and pericardial inflammation are the most commonly encountered complications, affecting less than 1% in the published series and none required surgery. There were no life-threatening complications recorded in 528 procedures in this study, although life threatening complications relating to ajmaline administration are recognized and have been reported in the context of catheter ablation.12 Therefore, if catheter ablation and substrate modification in BrS is effective and safe, why are the current guidelines so restrictive? Why do we feel comfortable offering a patient an implantable cardioverter defibrillator (ICD) implant, with the well-recognized lifetime risks of device related complications, and yet feel uncomfortable offering a potentially curative catheter ablation procedure? Indeed, with risk stratification being so challenging in this condition, the logic of ablating the underlying substrate seems very appealing especially if ICD implantation could be avoided. A key issue is the perception that epicardial catheter ablation is a high risk procedure with complication rates to match, plus the unknown long-term effects of epicardial ablation in this disease, including the possibility that it may be proarrhythmic. This isn't borne out by the Brugada ablation data so far; however—less than 1% of patients had a complication, albeit in highly experienced hands. In a broad cohort of patients with various aetiologies undergoing epicardial catheter ablation, complications include needle puncture of the right ventricle in approximately 10% of patients, tamponade in approximately 5%, and injury to abdominal viscera or coronary arteries in around 1% We can't necessarily extrapolate from patients with underlying structural heart disease; however—as BrS patients are often relatively young, often have few comorbidities, more compliant right ventricles in the event of inadvertent puncture, and of course, new techniques are offering novel approaches to access the pericardial space while reducing the risks of inadvertent damage to adjacent structures.13 So, what is the balance of the risks from the condition and the risks of the proposed treatment? This question is analogous to the situation of pre-excitation in Wolf–Parkinson White syndrome where the end-point is clearly defined but the criteria to justify ablation to prevent sudden death in asymptomatic cases were hotly debated for many years. In the case of asymptomatic BrS with a resting Type 1 ECG, the annual risk of sudden death is <1% that is below the proposed comparative threshold for ICD implantation in hypertrophic cardiomyopathy of 6% over 5 years.2 Therefore, targeting such lower risk cases has to be carefully appraised, since unless epicardial access is performed judiciously in very experienced centres the potential benefits will be abrogated. Indeed, more mature risk stratification strategies utilising genetics may enable suitable higher risk asymptomatic cases to be targeted.14 This risk-benefit balance is clearly met in favour of catheter ablation in patients experiencing recurrent ICD therapy for ventricular fibrillation. But perhaps there should be a role in patients having undergone a single episode of ventricular fibrillation, as an adjunct to ICD implantation? There are data to support this approach,10 although not randomized, and this series also included patients with no prior history of ventricular arrhythmia. This creates the false impression of low subsequent ventricular arrhythmia event rates as the pre-procedural risk of events in such asymptomatic cases is low. Given the well-recognized risks associated with long-term device implantation, the role of catheter ablation as an alternative to ICD implantation needs to be considered and needs to be evaluated in well-designed structured multicentre studies. BRAVE,5 randomly allocating BrS patients with ≥1 VF episode to implantable cardioverter-defibrillator—only versus implantable cardioverter-defibrillator plus ablation therapy is underway. Indeed, with the alternative option of quinidine to suppress ventricular arrhythmias, such studies should include this pharmacological arm with appropriate long term follow-up if the drug is tolerated. In QUIDAM (Hydroquinidine vs. Placebo in Patients with BrS), a crossover trial of hydroquinidine vs. placebo in high-risk patients with BrS that was terminated prematurely, the annual risk of VF was 1% for patients on placebo and zero during quinidine therapy (P = not significant).16 However, diarrhoea, thrombocytopenia, and liver damage are important side effects & occurred in 68% patients in the trial (mainly gastrointestinal) leading to discontinuation of the therapy in 26%. However, efficacy in preventing arrhythmic storm is well documented making it a reasonable option in asymptomatic type 1 ECG patients with high-risk ECG features and short coupled PVCs.17 Studying asymptomatic resting Type 1 Brugada cases will require sizeable international studies including SE Asia as event rates are so low—a sample size of around 600 patients would be required to demonstrate the expected reduction of VF risk at 5 years from 5% with no therapy to 1% with ablation therapy.18 Therefore, we await the data, but while it is vital to exercise caution when adopting new treatments, and we must always follow the evidence, it is equally important that as a community we don't miss an opportunity in developing this strategy so that more appropriately selected patients may benefit from it in the future. The authors declare no conflict of interest.