Radiofrequency ablation in Brugada syndrome
Koonlawee Nademanee
Abstract
Brugada syndrome (BrS) was introduced in the early 1990s as “primary electrical disease” that caused ventricular fibrillation (VF) in relatively healthy individuals who had coved-type ST-segment elevation in right precordial electrocardiographic (ECG) leads,1Brugada P. Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report.J Am Coll Cardiol. 1992; 20: 1391-1396Crossref PubMed Scopus (2654) Google Scholar and it was thought to be due to repolarization abnormality from ion channelopathy due to molecular genetic defects.2Wilde A.A.M. Antzelevitch C. Borggrefe M. et al.Proposed diagnostic criteria for the Brugada syndrome: consensus report.Circulation. 2002; 106: 2514-2519Crossref PubMed Scopus (646) Google Scholar Around the same time, the US Centers for Disease Control and Prevention identified an alarming increase in sudden nocturnal unexplained deaths among Laotian and Cambodian refugees in the United States. Because they were otherwise healthy with normal autopsies, the Centers for Disease Control and Prevention coined the term “sudden unexplained death syndrome” (SUDS).3Parrish R.G. Tucker M. Ing R. Encarnacion C. Eberhardt M. Sudden unexplained death syndrome in Southeast Asian refugees: a review of CDC surveillance.MMWR CDC Surveill Summ. 1987; 36: 43SS-53SSPubMed Google Scholar SUDS is prevalent in Thailand and Southeast Asian countries. I was fortunate to have an opportunity to study SUDS survivors with colleagues in Thailand: We found that VF was the primary rhythm causing sudden death/cardiac arrest in SUDS, and the Brugada ECG pattern was common in SUDS survivors.4Nademanee K. Veerakul G. Nimmannit S. et al.Arrhythmogenic marker for the sudden unexplained death syndrome in Thai men.Circulation. 1997; 96: 2595-2600Crossref PubMed Scopus (456) Google Scholar Implantable cardioverter-defibrillator (ICD) treatment in SUDS survivors, as in BrS, was effective in preventing deaths from VF.5Nademanee K. Veerakul G. Mower M. et al.Defibrillator Versus beta-blockers for Unexplained Death in Thailand (DEBUT): a randomized clinical trial.Circulation. 2003; 107: 2221-2226Crossref PubMed Scopus (120) Google Scholar Unfortunately, an ICD does not prevent recurrent VF in patients with BrS. In fact, some patients have suffered ICD/VF storms and had physical and mental trauma from multiple ICD shocks. These patients, on rare occasions, have committed suicide or required cardiac transplantation.6Coronel R. Casini S. Koopmann T.T. et al.Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, histopathologic, and computational study.Circulation. 2005; 112: 2769Crossref PubMed Scopus (345) Google Scholar No antiarrhythmic drug was effective at preventing VF recurrences in BrS except quinidine, which was not available in Thailand or many other countries. And quinidine was sometimes not effective in severely symptomatic BrS. Thus, finding an alternative treatment modality for such patients with BrS became a necessity: Ablation! The Bordeaux group reported their first attempt to perform catheter ablation of VF triggers in a few patients with symptomatic BrS in 2003.7Haïssaguerre M. Extramiana F. Hocini M. et al.Mapping and ablation of ventricular fibrillation associated with long-QT and Brugada syndromes.Circulation. 2003; 108: 925-928Crossref PubMed Scopus (414) Google Scholar They found that VF triggers, once identified and ablated, yielded good outcomes.7Haïssaguerre M. Extramiana F. Hocini M. et al.Mapping and ablation of ventricular fibrillation associated with long-QT and Brugada syndromes.Circulation. 2003; 108: 925-928Crossref PubMed Scopus (414) Google Scholar This ablation approach was not practical, however, because spontaneous VF triggering premature ventricular contractions in patients with BrS are rarely present to be mapped. This led to a search for substrate sites as targets for catheter ablation. While several controversies exist in BrS, most experts agree that the right ventricular outflow tract (RVOT) epicardium is the most likely substrate site. Fortunately, 2 decades ago, advances in the tool, technology, and technical approach (ie, Sousa technique of gaining access into the pericardium, irrigated-tip ablation catheter, and electroanatomic mapping) enabled us to launch a study to map the epicardium of patients with BrS aiming to identify and ablate the BrS substrate. Our first patient had more than 20 VF episodes in 1 week before the study. When we put the mapping catheter on the RVOT epicardium, we were pleasantly surprised by the abnormal low-voltage fractionated electrograms (Abn-Egm) that were present in a wide area of the anterior RVOT epicardium and not elsewhere. When we ablated these areas, VF became noninducible and prevented VF recurrences in this patient. The experiences from this case were subsequently reproduced in 8 more patients, giving us confidence to publish our findings from the 9 patients 10 years ago.8Nademanee K. Veerakul G. Chandanamattha P. et al.Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium.Circulation. 2011; 123: 1270-1279Crossref PubMed Scopus (505) Google Scholar We then concluded that the anterior RVOT epicardium was exclusively the primary substrate site of BrS, and ablation in this area not only normalizes the ECG but also effectively prevents recurrent VF episodes in patients with BrS. However, as we expanded our experiences, we came to recognize that the above conclusions were not entirely correct; we also found that about 35% of patients with BrS have arrhythmogenic substrates, displaying Abn-Egm at the body and inferior aspect of the right ventricle (RV).9Nademanee K. Hocini M. Haïssaguerre M. Epicardial substrate ablation for Brugada syndrome.Heart Rhythm. 2017; 14: 457-461Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar The question then is: What is the underlying pathology of these substrates? The breakthrough came when our group and Prof. Akihiko Nogami’s at Tsukuba University, out of necessity, had to perform open thoracotomy in either patients with symptomatic BrS who needed open thoracotomy for infected ICD assembly or patients where gaining access into the pericardium percutaneously was not possible. The findings were truly striking: All patients had thickened epicardial fibrosis and interstitial fibrosis at the sites where we recorded Abn-Egm.9Nademanee K. Hocini M. Haïssaguerre M. Epicardial substrate ablation for Brugada syndrome.Heart Rhythm. 2017; 14: 457-461Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar These findings led to a collaborative study with Prof. Elijah R. Behr at St. George University in the United Kingdom and Prof. Arthur Wilde at Amsterdam Medical Center with their necropsy study, which showed that SUDS victims with a family history of BrS had a higher collagen content and lower connexin 43 expression in the RVOT and RV than did controls, with evidence of epicardial fibrosis and interstitial fibrosis similar to that in our in vivo study.10Nademanee K. Raju H. De Noronha S. et al.Fibrosis, connexin 43, and conduction abnormalities in the Brugada syndrome.J Am Coll Cardiol. 2015; 66: 1976-1986Crossref PubMed Scopus (210) Google Scholar The aforementioned pathological finding in our patients with BrS dovetails very well with those observed in an explanted heart by Coronel et al6Coronel R. Casini S. Koopmann T.T. et al.Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, histopathologic, and computational study.Circulation. 2005; 112: 2769Crossref PubMed Scopus (345) Google Scholar and shifts our viewpoint of BrS from a “primary electrical disease” to a more multidimensional complex interplay between subtle fibrosis and ion channel dysfunction, specifically reduced sodium current.11Nademanee K. Tei C. Two faces of Brugada syndrome: electrical and structural diseases.JACC Clin Electrophysiol. 2020; 6: 1364-1366Crossref PubMed Scopus (1) Google Scholar It also changes our viewpoint to favor depolarization abnormality as the likely underlying electrophysiological mechanism of BrS in lieu of repolarization abnormality.12Nademanee K. Wilde A.A.M. Repolarization versus depolarization defects in Brugada syndrome: a tale of two different electrophysiologic settings?.JACC Clin Electrophysiol. 2017; 3: 364-366Crossref PubMed Scopus (5) Google Scholar In recent years, in collaboration with Prof. Michel Haïssaguerre and Prof. Mélèze Hocini from Bordeaux, France, in studying VF in BrS, we found that during the first 5 seconds of VF, either spontaneously occurring or induced, VF drivers indeed located at these substrate sites where Abn-Egms were recorded, confirming that they are truly substrate sites13Nademanee K. Haïssaguerre M. Hocini M. et al.Mapping and ablation of ventricular fibrillation associated with early repolarization syndrome.Circulation. 2019; 140: 1477-1490Crossref PubMed Scopus (37) Google Scholar: Good ablation targets! After our initial report, several centers worldwide confirmed our findings that ablation of the RVOT/RV epicardium substrates is effective at preventing VF recurrences and is being increasingly used for patients with symptomatic BrS.9Nademanee K. Hocini M. Haïssaguerre M. Epicardial substrate ablation for Brugada syndrome.Heart Rhythm. 2017; 14: 457-461Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar,14Pappone C. Brugada J. Vicedomini G. et al.Electrical substrate elimination in 135 consecutive patients with Brugada syndrome.Circ Arrhythm Electrophysiol. 2017; 10e005053Crossref PubMed Scopus (105) Google Scholar Ablation of BrS substrates has become an important therapeutic modality for treatment of symptomatic BrS. Recently, several patients who had been free of VF for several years and did not want an ICD anymore requested the device to be taken out or did not want a replacement device at the end of the current ICD’s battery life. Similarly, new patients with symptomatic BrS who sought ablation treatment did not want an ICD implanted after ablation. My recommendation has always been to stay with the current guideline that ICD is a class I indication for patients with symptomatic BrS, especially those who survived aborted sudden cardiac death. However, I hypothesize that patients with symptomatic BrS who had no overlapping syndrome with combined BrS and early repolarization syndrome could be treated after substrate ablation procedures without ICD if normalization of the right precordial ECG at the higher intercostal space lead positioning after sodium channel blocker challenge could be achieved. I hope that a definitive answer to the above hypothesis and questions will be available after the multicenter randomized study Ablation in Brugada Syndrome for the Prevention of VF (BRAVE study; ClinicalTrials.gov identifier NCT02704416) is completed. Importantly, percutaneous epicardial mapping and ablation are invasive procedures that could pose significant risks to patients and thus mandate experienced operators and electrophysiology team. At present, procedures should not be carried out in patients with asymptomatic BrS. That said, undoubtedly, ablation of BrS substrates will become an important addition to the armamentarium for treatment of patients with BrS: This treatment approach will surely improve because of advances in mapping technology (including lesion assessment), ablation energy source, and ablation catheter. Thus, I hope to eventually and confidently answer the patient: “No, you do not need an ICD!” ErratumHeart RhythmVol. 19Issue 1PreviewIn the article titled “Radiofrequency ablation in Brugada syndrome” by Koonlawee Nademanee, MD, FHRS, that published in the October issue of Heart Rhythm Journal (2021: 18: 1805-1806), “Sosa technique” was misspelled as “Sousa technique” in the fifth paragraph. The author regrets the error. Full-Text PDF