Arq Bras CardiolabcArquivos Brasileiros de CardiologiaArq. Bras. Cardiol.0066-782X1678-4170Sociedade Brasileira de Cardiologia - SBCKqHPbCgF5NRtCmK6nQxG33rS0066-782X201900030021710.5935/abc.20190047EditorialProgrammed Ventricular Stimulation in the Management of Brugada Syndrome Patients0000-0001-7327-2275ScanavaccaMauricio IbrahimHachulDenise TessariolInstituto do CoraçãoSão PauloSPBrazilInstituto do Coração (Incor), São Paulo, SP - BrazilMailing Address: Mauricio Ibrahim Scanavacca, Av. Joaquim C. A. Marques, 1205. Postal Code 05688-021, Morumbi, SP - Brazil. E-mail: mibrahim@cardiol.br, mauricio.scanavacca@gmail.com0320191123217219This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly citedKeywordsBrugada SyndromeTachycardia, VentricularVentricular FibrillationDeath, Sudden, Cardiac/prevention & controlRisk FactorsDefibrilators, Implantable/utilization
Since 1980, the American College of Cardiology (ACC) and the American Heart Association (AHA), by means of a systematic methodology, have incorporated and adapted scientific evidence into practical recommendations aiming to improve preventive and therapeutic measures for cardiovascular diseases. These guidelines have become the current reference for cardiology practices and been adopted by many societies, which adapt them according to local realities.1
In 2006, the AHA/ACC, together with the Heart Rhythm Society (HRS), published the first guidelines for the management of patients with ventricular arrhythmias and prevention of sudden death (SD). In 2017, this first document was updated by the same societies and published in October 2018.2,3
Despite considerable advances in knowledge of risk stratification, prevention and treatment of SD, many gaps in its understanding still exist. Among many issues raised by the authors of the last review, two were addressed by an independent commission and recently published in an additional document.4
One of the issues is the subject of the present editorial and refers to the role of the electrophysiological study in risk stratification of asymptomatic patients with Brugada syndrome (BrS).
BrS was described in 1992 in individuals with structurally normal hearts who had recovered from a cardiac arrest from ventricular fibrillation showing a unique electrocardiographic pattern, characterized by a right bundle-branch block with ST-segment elevation in the right precordial leads V1 -V3.5
In the last 25 years, several clinical studies have shown that the BrS is a genetically determined disease, affecting one in 2,000 - 10,000 individuals with apparently normal hearts. The risk of SD is knowingly high in patients who had already had arrhythmic syncope or had recovered from cardiac arrest. There is a consensus that implantation of an automated implantable cardioverter defibrillator (ICD) is the most effective method to prevent SD in these patients.6
On the other hand, the risk of SD is apparently low in asymptomatic BrS patients, which makes the decision-making about the use of ICD in these patients difficult. Besides, most of these patients are young and at risk of receiving inappropriate shocks, and experience technical problems with generators and electrodes over the years.7
Several clinical, familial, electrophysiological and genetic aspects have been investigated in attempt to determine the risk of SD in asymptomatic individuals with BrS, who may benefit from an early ICD implantation. However, the discriminating ability of these methods is still a matter of controversy.6,8
Sustained ventricular tachycardia (SVT) induced by programmed ventricular stimulation (PVS) has been used for many years to identify patients at risk of spontaneous occurrence of SVT/ventricular fibrillation (VF) in patients with structural heart diseases, who may benefit from a prophylactic use of ICD.2,3 This approach was based on the efficacy of the method in reproducing SVT in a laboratory setting.9
Clinical observations have revealed that the capacity of the planned ventricular stimulation in reproducing ventricular arrhythmias, particularly SVT, is very high in the chronic phase of myocardial infarction, lower in non-ischemic heart diseases, and almost absent in cardiac channelopathies.2,3,9 This distinctive behavior is explained by characteristics of the arrhythmogenic substrate in sustained ventricular arrhythmias. In structural heart diseases, it depends on reentries into stable anatomic substrates, mostly represented by scars caused by diseases. Conditions that cause dense myocardial scars with preserved myocardial tissue channels favor the occurrence of reproducible SVTs. In contrast, EP has low reproducibility in conditions where these characteristics are not present.9
Therefore, the initial suggestion of using PVS for risk stratification of SD in patients with BrS caused surprise among traditional electrophysiologists,10 since BrS was until then considered a channelopathy without anatomic substrate based on gadolinium-enhanced magnetic resonance. Subsequent studies revealed that BrS patients have an arrhythmogenic substrate characterized, by invasive electrophysiological mapping, by late electrical potential, identified predominantly in subepicardial fibers in the right ventricular outflow tract.11
Although in some cases, these electrical features have been associated with persistent anatomical changes,12 in most of the cases, electrophysiologic changes are transient, modulated or induced by hormonal, autonomic, metabolic and drug-related conditions.6
This could explain why patients with persistent, spontaneous type 1 Brugada electrocardiographic pattern have higher risk of events compared with patients in whom the BrS pattern occurs occasionally.5 The possible explanation for that is the fact that, in the former patients, the arrhythmogenic substrate is more extensive and stable, detectable in the ECG, and thereby more suitable to SVT and VF in external modulation, whereas in the second condition, a milder substrate would be found, and hence the possibility of malignant arrhythmias would be lower, detected only in very special conditions. In this case, the substrate would be only identified by analysis of electrograms obtained from the epicardial surface or by infusion of potent sodium-channel blockers.
In line with this hypothesis, recent studies on radiofrequency catheter ablation of the subepicardial substrate in BrS have shown that the induction of SVT or VF is common in patients with spontaneous type 1 pattern; these arrhythmias became noninducible after ablation of the arrhythmogenic substrate with normalization of the typical pattern.11,13 The extension of the BrS substrate at the moment of the ES could then explain the differences in the results reported in several clinical studies and current controversies.14
Therefore, patients with BrS recovered from cardiac arrest or patients with persistent type 1 electrocardiographic pattern would have a higher rate of induction of ventricular arrhythmias as compared with those without electrocardiographic manifestations. However, so far, there is not enough information regarding the EKG presentation at the time of the electrophysiological study.15
The first study to use programmed ventricular stimulation for screening of asymptomatic BrS patients for ICD implantation involved 252 patients; 116 of them had a history of syncope or had recovered from cardiac arrest, and 136 were asymptomatic at diagnosis. Polymorphic ventricular tachycardia or VF were induced in 130 (51%) patients. induction of ventricular arrhythmias was more frequent (73%) in sympomtatic than asymptomatic (33%) patients (p = 0.0001). Spontaneous arrhythmic event occurred in 52 individuals (21%) in a mean follow-up of 34 ± months, 45 (39%) of 116 symptomatic patients and 7 (5%) of 136 asymptomatic patients. On the other hand, only 1 patient in 91 (1.1%) of the asymptomatic group presented spontaneous arrhythmic event when the ventricular pacing was negative.15
These data were corroborated by a second study by the same group, in which patients were followed for up to 20 years. Induction of SVT/VF in the ES had a sensitivity of 75% and specificity of 91.3% for spontaneous occurrence of malignant arrhythmias in asymptomatic patients. Despite the low positive predictive value (18.2%), the procedure had a negative predictive value of 98.3%.16
Clinical studies by other authors did not reproduce these findings, generating a debate that persists up to the present days. The PRELUDE was a multicenter prospective study including 273 asymptomatic patients. During the clinical follow-up, with a median of 34 months, there was no significant difference in the rates of events between patients with and without induced ventricular arrhythmias in the ES.17 In the FINGER BrS registry involving 654 asymptomatic patients, followed by 31.9 (14 to 54.4) months, there was a low rate of events (0.5%). Although this rate was higher in patients with induced ventricular arrhythmias in the ES, there was no statistical significance in the multivariate analysis.18
In the meta-analysis by Kusumoto et al.,2 organized by the AHA/ACC/HRS, six studies on BrS patients were selected of a total of 236 titles retrieved from traditional databases. To minimize possible patient overlap, the primary analysis included five of six studies selected, with exclusion of one study conducted in the same institution. Of 1,138 patients included, SVT or sustained VF was induced in 390 (34.3%) with occurrence of major arrhythmic events (SVT, VF, cardiac MS or appropriate ICD therapy) in 13 (3.3%) patients, compared with 12 events (1.6%) in 748 patients without induced arrhythmia, resulting in an odds ratio (OR) of 2.3 (95%IC: 0.63-8.66; p = 0.2).
A second analysis included all six studies, with potential data duplication. Of 1,401 patients, 481 (34.2%) had SVT or VF induced in the ES. In patients with induced SVT/VF, there were 23 arrhythmic events (5.0%), whereas among those without SVT/VF induction, 14 events occurred (1.5%), resulting in an OR of 3.3 (95%CI: 1.03-10.4; p = 0.04).
Based on these data, the 2017 AHA/ACC/HRS guidelines issued a 2B recommendation with level of evidence B for indication of ES to asymptomatic BrS patients, using less aggressive ventricular stimulation protocols when performed (up to two extrastimulation).2
In summary, these data do not establish the real role of SVT/VF induction in asymptomatic patients with BrS, probably due to the lack of homogeneity of samples and methods used in the studies. These data also indicate the need for prospective, multicenter studies involving a larger number of patients.
References1 Halperin JL, Levine GN, Al-Khatib SM, Birtcher KK, Bozkurt B, Brindis RG, et al. Further evolution of the ACC/AHA clinical practice guideline recommendation classification system: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2016;67(13):1572-4.HalperinJLLevineGNAl-KhatibSMBirtcherKKBozkurtBBrindisRGFurther evolution of the ACC/AHA clinical practice guideline recommendation classification system: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice GuidelinesJ Am Coll Cardiol20166713157215742 European Heart Rhythm Association; Heart Rhythm Society, Zipes DP, Camm AJ, Borggrefe M, Buxton AE, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol. 2006;48(5):e247-346.European Heart Rhythm AssociationHeart Rhythm SocietyZipesDPCammAJBorggrefeMBuxtonAEACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death)J Am Coll Cardiol2006485e247e3463 Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.. J Am Coll Cardiol. 2018;72(14):e91-220.Al-KhatibSMStevensonWGAckermanMJBryantWJCallansDJCurtisAB2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm SocietyJ Am Coll Cardiol20187214e912204 Kusumoto FM, Bailey KR, Chaouki AS, Deshmukh AJ, Gautam S, Kim RJ, et al.. Systematic Review for the 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2018;72(14):1653-76.KusumotoFMBaileyKRChaoukiASDeshmukhAJGautamSKimRJSystematic Review for the 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm SocietyJ Am Coll Cardiol20187214165316765 Brugada 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(6):1391-6.BrugadaPBrugadaJRight bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter reportJ Am Coll Cardiol1992206139113966 Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013;10(12):1932-63.PrioriSGWildeAAHorieMChoYBehrERBerulCHRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013Heart Rhythm20131012193219637 van Rees JB, de Bie MK, Thijssen J, Borleffs CJ, Schalij MJ, van Erven L. Implantation-related complications of implantable cardioverter-defibrillators and cardiac resynchronization therapy devices: a systematic review of randomized clinical trials. J Am Coll Cardiol. 2011;58(10):995-1000.van ReesJBde BieMKThijssenJBorleffsCJSchalijMJvan ErvenLImplantation-related complications of implantable cardioverter-defibrillators and cardiac resynchronization therapy devices: a systematic review of randomized clinical trialsJ Am Coll Cardiol2011581099510008 Takagi M, Yokoyama Y, Aonuma K, Aihara N, Hiraoka M, Japan Idiopathic Ventricular Fibrillation Study (J-IVFS) Investigators. Clinical characteristics and risk stratification in symptomatic and asymptomatic patients with Brugada syndrome: multicenter study in Japan. J Cardiovasc Electrophysiol. 2007;18(12):1244-51.TakagiMYokoyamaYAonumaKAiharaNHiraokaMJapan Idiopathic Ventricular Fibrillation Study InvestigatorsClinical characteristics and risk stratification in symptomatic and asymptomatic patients with Brugada syndrome: multicenter study in JapanJ Cardiovasc Electrophysiol20071812124412519 Buxton AE, Lee KL, DiCarlo L, Gold MR, Greer GS, Prystowsky EN, et al. Electrophysiologic testing to identify patients with coronary artery disease who are at risk for sudden death. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med. 2000;342(26):1937-45.BuxtonAELeeKLDiCarloLGoldMRGreerGSPrystowskyENElectrophysiologic testing to identify patients with coronary artery disease who are at risk for sudden death. Multicenter Unsustained Tachycardia Trial InvestigatorsN Engl J Med2000342261937194510 Brugada P, Brugada R, Mont L, Rivero M, Geelen P, Brugada J. Natural history of Brugada syndrome: the prognostic value of programmed electrical stimulation of the heart. J Cardiovasc Electrophysiol. 2003;14(5):455-7.BrugadaPBrugadaRMontLRiveroMGeelenPBrugadaJNatural history of Brugada syndrome: the prognostic value of programmed electrical stimulation of the heartJ Cardiovasc Electrophysiol200314545545711 Nademanee K, Veerakul G, Chandanamattha P, Chaothawee L, Ariyachaipanich A, Jirasirirojanakorn K, et al. Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation. 2011;123(12):1270-9.NademaneeKVeerakulGChandanamatthaPChaothaweeLAriyachaipanichAJirasirirojanakornKPrevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardiumCirculation2011123121270127912 Nademanee K, Raju H, de Noronha SV, Papadakis M, Robinson L, Rothery S, et al. Fibrosis, connexin-43, and conduction abnormalities in the Brugada Syndrome. J Am Coll Cardiol. 2015;66(18):1976-86.NademaneeKRajuHde NoronhaSVPapadakisMRobinsonLRotherySFibrosis, connexin-43, and conduction abnormalities in the Brugada SyndromeJ Am Coll Cardiol201566181976198613 Pappone C, Brugada J, Vicedomini G, Ciconte G, Manguso F, Saviano M, et al. Electrical substrate elimination in 135 consecutive patients with Brugada Syndrome. Circ Arrhythm Electrophysiol. 2017;10(5):e005053.PapponeCBrugadaJVicedominiGCiconteGMangusoFSavianoMElectrical substrate elimination in 135 consecutive patients with Brugada SyndromeCirc Arrhythm Electrophysiol2017105e00505314 Brugada J, Pappone C, Berruezo A, Vicedomini G, Manguso F, Ciconte G, et al. Brugada Syndrome phenotype elimination by epicardial substrate ablation. Circ Arrhythm Electrophysiol. 2015;8(6):1373-81.BrugadaJPapponeCBerruezoAVicedominiGMangusoFCiconteGBrugada Syndrome phenotype elimination by epicardial substrate ablationCirc Arrhythm Electrophysiol2015861373138115 Brugada P, Geelen P, Brugada R, Mont L, Brugada J. Prognostic value of electrophysiologic investigations in Brugada Syndrome. J Cardiovasc Electrophysiol. 2001;12(9):1004-7.BrugadaPGeelenPBrugadaRMontLBrugadaJPrognostic value of electrophysiologic investigations in Brugada SyndromeJ Cardiovasc Electrophysiol20011291004100716 Sieira J, Conte G, Ciconte G, de Asmundis C, Chierchia GB, Baltogiannis G, et al. Prognostic value of programmed electrical stimulation in Brugada syndrome: 20 years experience. Circ Arrhythm Electrophysiol. 2015;8(4):777-84.SieiraJConteGCiconteGde AsmundisCChierchiaGBBaltogiannisGPrognostic value of programmed electrical stimulation in Brugada syndrome: 20 years experienceCirc Arrhythm Electrophysiol20158477778417 Priori SG, Gasparini M, Napolitano C, Della Bella P, Ottonelli AG, Sassone B, et al. Risk stratification in Brugada syndrome: results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) registry. J Am Coll Cardiol. 2012;59(1):37-45.PrioriSGGaspariniMNapolitanoCDella BellaPOttonelliAGSassoneBRisk stratification in Brugada syndrome: results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) registryJ Am Coll Cardiol2012591374518 Probst V, Veltmann C, Eckardt L, Meregalli PG, Gaita F, Tan HL, et al. Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry. Circulation. 2010;121(5):635-43.ProbstVVeltmannCEckardtLMeregalliPGGaitaFTanHLLong-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome RegistryCirculation20101215635643Estimulação Ventricular Programada no Manejo de Pacientes com Síndrome de Brugada0000-0001-7327-2275ScanavaccaMauricio IbrahimHachulDenise TessariolInstituto do Coração (Incor), São Paulo, SP - BrasilCorrespondência: Mauricio Ibrahim Scanavacca, Av. Joaquim C. A. Marques, 1205. CEP 05688-021, Morumbi, SP - Brasil. E-mail: mibrahim@cardiol.br, mauricio.scanavacca@gmail.comPalavras-chaveSíndrome de BrugadaTaquicardia VentricularFibrilação VentricularMorte Súbita/prevenção & controleFatores de RiscoDesfibriladores Implantáveis/utilização
Desde 1980, as sociedades médicas americanas American College of Cardiology (ACC) e American Heart Association (AHA) vem incorporando e adaptando, por meio de métodos sistemáticos, evidências científicas em recomendações práticas para aprimorar condutas na prevenção e tratamento de doenças cardiovasculares. Essas diretrizes se tornaram a base atual das condutas em cardiologia e utilizadas por muitas sociedades, que as adaptam de acordo com suas realidades regionais.1
Em 2006, as AHA/ACC, em conjunto com a Heart Rhythm Society (HRS), publicaram a primeira diretriz para o manejo de pacientes com arritmias ventriculares e para prevenção da morte súbita (MS). Em 2017, as mesmas sociedades se reuniram para atualizar o documento inicial, publicado em outubro de 2018.2,3
Apesar dos inúmeros avanços no conhecimento para estratificação do risco, prevenção e tratamento das patologias que levama a MS, muitas lacunas em seu entendimento ainda permanecem. Dentre as várias questões levantadas pelo grupo de estudo da última revisão, duas foram tratadas por um comitê independente e publicadas recentemente em um documento adicional.4
Uma das questões revisadas e motivo desse editorial refere-se ao papel do estudo eletrofisiológico (EEF) na estratificação de risco de pacientes assintomáticos com síndrome de Brugada (SBr).
A SBr foi descrita em 1992 em indivíduos com o coração estruturalmente normal que foram recuperados de parada cardíaca por fibrilação ventricular e que apresentavam aspectos eletrocardiográficos singulares, caracterizados por distúrbio de condução pelo ramo direito e elevação persistente do segmento ST nas derivações V1 - V3.5
Ao longo dos últimos 25 anos, inúmeros estudos clínicos revelaram que a SBr é uma doença geneticamente determinada, que ocorre em 1 entre 2.000 a 10.000 indivíduos com coração aparentemente normal. O risco de MS é reconhecidamente alto nos pacientes que já apresentaram síncope arrítmica ou foram recuperados de parada cardíaca. Existe consenso de que o implante do cardioversor e desfibrilador automático (ICD) é o método mais efetivo para evitar a MS nesses pacientes.6
Por outro lado, o risco de MS é aparentemente baixo nos indivíduos com SBr assintomáticos, o que torna difícil, na prática clínica, a tomada de decisão de indicação do implante do CDI nesses indivíduos. Além disso, a maioria desses pacientes são jovens e em risco de recebem choques inapropriados, terem problemas técnicos com os geradores e eletrodos ao longo dos anos.7
Vários aspectos clínicos, familiares, eletrofisiológicos e genéticos têm sido estudados tentando determinar o risco de MS nos indivíduos assintomáticos com SBr e que poderiam se beneficiar com o implante precoce do CDI. No entanto, a capacidade discriminatória desses métodos permanece controversa.6,8
A indução de taquicardia ventricular sustentada (TVS) pela estimulação ventricular programada (EP) tem sido utilizada por vários anos para identificar os pacientes em risco de ocorrência espontânea de TVS/fibrilação ventricular (FV) em pacientes com cardiopatias estruturais, nos quais haveria justificativa para o implante profilático do CDI.2,3 Essa conduta baseou-se na eficácia do método em reproduzir TVS clínicas no ambiente do laboratório de eletrofisiologia.9
Observações clínicas revelaram que a capacidade EP em reproduzir arritmias ventriculares, em particular a TVS, é muito alta na fase crônica do infarto do miocárdio, menor nas cardiopatias não isquêmicas, e praticamente nula nas canalopatias.2,3,9 Esse comportamento distinto deve-se às características do substrato arritmogênico das arritmias ventriculares sustentadas, que nas cardiopatias estruturais depende de reentradas em substratos anatômicos estáveis, na maioria representados por cicatrizes provocadas pelas doenças. Condições que provoquem cicatrizes miocárdicas densas, entremeadas por canais de tecido miocárdico viável, favorecem a ocorrência de TVS reprodutíveis; ao contrário, a EP apresenta baixa reprodutibilidade nas condições em que essas características não estão presentes.9
Assim, a sugestão inicial do uso da EP para estratificação de risco de MS em indivíduos com SBr causou surpresa aos eletrofisiologistas tradicionais,10 uma vez que a síndrome era considerada até então uma canalopatia que não apresentava substrato anatômico nas avaliações pela ressonância nuclear magnética com gadolíneo e realce tardio. Estudos posteriores, revelaram que os pacientes com SBr apresentam substrato arritmogênico caracterizado, no mapeamento eletrofisiológico invasivo, por potenciais elétricos tardios, identificados predominantemente nas fibras miocárdicas subepicárdicas da via de saída do ventrículo direito.11
Em alguns casos, foi possível relacionar essas características elétricas com alterações anatômicas persistentes,12 mas na sua maioria, as alterações eletrofisiológicas são transitórias, moduladas ou induzidas por condições hormonais, autonômicas, metabólicas e medicamentosas.6
Isso poderia explicar por que indivíduos com SBr tipo 1 espontâneo e persistente apresentam maior risco de eventos em comparação com aqueles em que o padrão de SBr ocorre ocasionalmente.5 A justificativa seria que nos primeiros, o substrato arritmogênico mais extenso e estável, perceptível até pelo ECG, seria mais propenso a sustentar TVS e FV frente a modulações externas; na segunda condição, o substrato seria muito discreto, com menor probabilidade de sustentação de arritmias malignas que ocorreriam apenas em condições muito especiais. Nessa condição, a presença do substrato poderia ser identificada apenas pela análise dos eletrogramas obtidos diretamente na superfície epicárdica ou com infusão de potentes bloqueadores dos canais de sódio.
Corroborando essa hipótese, estudos recentes de ablação com radiofrequência (RF) do substrato subepicárdico da SBr indicam que indução de TVS ou FV é frequente nos pacientes com padrão tipo 1 espontâneo, com perda da indução dessas arritmias após a ablação do substrato arritmogênico, com desaparecimento do padrão típico.11,13 A extensão do substrato da SBr no momento do EEF poderia então explicar as diferenças nos resultados encontrados nos diversos estudos clínicos e motivo da controvérsia atual.14
Assim, pacientes com SBr recuperados de parada cardíaca ou com padrão tipo 1 persistente no ECG teriam maior taxa de indução de arritmias ventriculares quando comparados com aqueles sem manifestação no ECG no momento do EEF. Entretanto, não há, até o momento, informações claras de qual era a apresentação do ECG no momento de realização do EEF para tal análise.15
O estudo inicial que deu origem à utilização da estimulação ventricular programada na seleção de pacientes assintomáticos com SBr para implante de CDI envolveu 252 pacientes; desses, 116 já haviam apresentado sincope ou tinham sido recuperados de parada cardíaca e 136 eram assintomáticos no momento do diagnóstico. Taquicardia ventricular polimórfica ou FV foram induzidas em 130 (51%) pacientes. A indução de arritmias ventriculares foi mais frequente (73%) nos pacientes sintomáticos do que nos assintomáticos (33%) (p = 0.0001). Evento arrítmico espontâneo ocorreu em 52 indivíduos (21%) em seguimento médio de 34 +/- 40 meses; 45 (39%) dos 116 sintomáticos e 7 (5%) dos 136 pacientes assintomáticos. Por outro lado, apenas 1 paciente em 91 (1,1%) do grupo assintomático apresentou evento arrítmico espontâneo quando a estimulação ventricular foi negativa.15
Esses dados foram corroborados por um segundo estudo do mesmo grupo com seguimento dos pacientes por um período de até 20 anos. A indução de TVS/VF no EEF apresentou sensibilidade de 75,0%, especificidade de 91,3% para ocorrência espontânea de arritmias malignas nos pacientes assintomáticos. Embora o valor preditivo positivo tenha sido baixo (18,2%), o valor preditivo negativo foi de 98,3%.16
Estudos clínicos realizados por outros investigadores não reproduziram esses achados, levando a um debate que se mantém nos dias atuais. O PRELUDE foi um registro prospectivo e multicêntrico, que incluiu 273 pacientes assintomáticos. Durante o seguimento clínico, com mediana de 34 meses, não houve diferença significativa nas taxas de eventos entre pacientes com arritmias ventriculares induzidas ou não no EEF.17 No registro FINGER de pacientes com SBr, que envolveu 654 pacientes assintomáticos, seguidos por 31,9 (14 a 54,4) meses, houve baixa taxa de eventos (0,5%). Embora essa taxa tenha sido mais alta naqueles com arritmia ventricular induzida no EEF, não houve significância estatística na análise multivariada.18
Na metanálise elaborada por Kusumoto et al.,2 organizada pela AHA/ACC/HRS, foram selecionados seis estudos envolvendo pacientes com SBr a partir de 236 títulos identificados nas bases de dados tradicionais. Para minimizar a sobreposição de pacientes, a análise primária incluiu os pacientes de cinco dos seis estudos selecionados, excluindo-se um estudo da mesma instituição. Dos 1138 pacientes incluídos, TVS ou FV sustentada foram induzidas em 390 (34,3%), com ocorrência de eventos arrítmicos maiores (TVS e FV, MS cardíaca ou terapia com CDI) em 13 (3,3%), em comparação à ocorrência de 12 eventos (1,6%) nos 748 pacientes sem indução de arritmias, resultando em uma razão de chance (OR) de 2,3 (95% CI: 0,63-8,66; p = 0,2).
Em uma segunda análise foram incluídos todos os seis estudos, com possível duplicação dados. Dos 1401 pacientes, 481 (34,3%) tiveram TV ou FV sustentadas induzidas no EEF. Nos pacientes com TVS/FV induzidas ocorreram 24 eventos arrítmicos (5,0%) e entre os pacientes sem indução ocorreram 14 eventos (1,5%), resultando em um OR de 3,3 (95% CI: 1,03-10,4; p = 0,04).
Frente a essas informações, a diretriz da AHA/ACC/HRS 2017 emitiu a recomendação 2B com nível de evidência B para a indicação do EEF em pacientes assintomáticos com SBr, sugerindo que a estimulação ventricular, quando realizada, deva ser feita de modo menos agressivo (até dois extra-estímulos).2
Em resumo, os dados atuais ainda não esclarecem o real papel preditivo da indução de TV/FV em pacientes assintomáticos com SBr, provavelmente pela falta de homogeneidade das amostras e metodologias utilizadas nas investigações. Os dados apontam para a necessidade de trabalhos prospectivos, multicêntricos, envolvendo um número mais expressivos de pacientes.