Sodium channelopathy with an overlap of Brugada syndrome, paroxysmal atrial fibrillation, and progressive cardiac conduction system dysfunction

Abstract

Brugada syndrome is a rare diagnosis with a prevalence of 3 to 5 per 10,000 accounting for 4% of all sudden cardiac deaths. It can present with ventricular tachyarrhythmia and sudden cardiac deaths in structurally normal hearts. The inheritance pattern is autosomal dominant. An ECG showing a Brugada type 1 pattern with other clinical features is required for diagnosis. Different genes have been associated with the disease, the commonest being the voltage-gated sodium channel alpha type V gene (SCN5A) (1Sarquella-Brugada G. Campuzano O. Arbelo E. Brugada J. Brugada R. Brugada syndrome: clinical and genetic findings.Genet Med. 2016; 18: 3-12https://doi.org/10.1038/gim.2015.35Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). We report a 21-year-old male presented twice to the hospital from the prison following being found in a collapsed status. The patient suffered cardiac arrest, and was resuscitated using an Automated External Defibrillator (AED), resulting in a return of spontaneous circulation (ROSC). AED printouts were reviewed and showed Ventricular Fibrillation (VF). Electrocardiogram (ECG) showed Atrial Fibrillation (AF) with coved ST elevation in V1-V2 consistent with a Brugada-type 1 pattern (Figure 1). Reaching a correct diagnosis and consulting the appropriate experts led to the best possible outcome for the patient. We present a 21-year-old gentleman inmate with no past medical history of note and no family history of sudden cardiac death, who had two hospital admissions following episodes of loss of consciousness. On the first admission, he was intubated, ventilated, and admitted to the Intensive Care Unit. A brain CT was done, which was unremarkable and was treated for presumed meningitis based on positive blood culture. Drug and toxicology screening was requested to look for evidence of illicit drug use. The screening included (synthetic cannabinoids, cannabis, amphetamine, benzodiazepine, cocaine, methadone metabolites and opiates). All were negative, apart from benzodiazepine. A referral to the community adult psychiatry was suggested for suspected drug use/overdose. On the second admission, a similar presentation of a sudden loss of consciousness was witnessed by his cellmate. Prison officers initiated CPR, and AED delivered four shocks, achieving ROSC. AED confirmed that the underlying rhythm was Ventricular Fibrillation (VF) (Figure 2). He was admitted to the CCU; the supplementary material file provides a flow-chart describing our approach to diagnosing and managing this patient with recurrent Transient Loss of Consciousness (TLOC) or syncope. Initial ECG showed AF with coved ST elevation in leads V1 and V2, compatible with the Brugada-type 1 pattern. Repeated ECGs showed inferolateral J waves at the terminal portion of the QRS complexes, paroxysmal AF, compatible with a sodium channelopathy overlap syndrome. An echocardiogram showed a structurally normal heart and blood tests were unremarkable. In CCU, he had three early morning in-hospital VF arrests, requiring multiple shocks and treatment with intravenous amiodarone and beta blockers. The ECG post-cardioversion showed sinus rhythm with prolonged PR interval. The patient was referred to the electrophysiology and inherited cardiac conditions (ICC) team. A cardiac MRI showed a structurally normal heart. He was first established on isoprenaline infusion, and the amiodarone and beta-blocker therapy were stopped, then transitioned to oral quinidine therapy with excellent effect. The inferolateral J waves disappeared, and the quinidine-induced QT prolongation remained manageable around 470-480ms. He also displayed evidence of AV conduction disease with PR prolongation of 260-280ms initially and then further prolongation to 346ms (Figure 3). A dual-chamber ICD was implanted for secondary prevention of arrhythmic death. ICD was programmed as follows: Cut-off interval: VT 167bpm (360 msec), FVT 240bpm (250 msec), VF 200 bpm (300 msec). Therapy VT = OFF; FVT therapy: ATP1 (type: Burst), ATP2 (type: Ramp), Shocks x4 35J. VF therapy: ATP during charging, Shocks x6 35J. The patient was followed up in the ICC clinic post-discharge, with no further events. The PR interval was 200ms, showing a hint of a type 1 Brugada pattern in lead V1. A home monitor has not transmitted any therapies from the ICD, and ICD interrogation was satisfactory. A three-generation family history was taken, and there was no evidence of anyone else with cardiac issues or early sudden death. No genetic cause was identified on Genomics laboratory report; the panel applied included SCN5A. The patient was advised not to drive for six months and must inform the Driver and Vehicle Licensing Agency (DVLA). A discussion about the dangers of illicit drug use in causing arrhythmia in Brugada was made with the patient due to his previous history of illicit drug use. He was also advised regarding over-the-counter medications and advised not to exercise alone. There is a difference between the Brugada pattern and Brugada syndrome. Asymptomatic patients with typical ECG findings and no other clinical features are said to have a Brugada pattern. On the other hand, those with typical ECG features with ventricular arrhythmias or sudden cardiac death or associated clinical criteria are labelled as Brugada syndrome (2Wylie J, 2021. Brugada syndrome: Epidemiology and pathogenesis. UpToDate. [online] Available from: https://www.uptodate.com/contents/brugada-syndrome-epidemiology-and-pathogenesis#! (Accessed 01 April 2023)Google Scholar). Factors such as mutations in the cardiac sodium channel SCN genes, right ventricle (RV) abnormalities, autonomic tone, fever, cocaine use, and some psychotropic drugs – may contribute to the ECG changes and clinical manifestation of Brugada syndrome. For example, cocaine, neuroleptic drugs and cyclic antidepressant overdose can block cardiac sodium channels resulting in a transient Brugada ECG pattern (2Wylie J, 2021. Brugada syndrome: Epidemiology and pathogenesis. UpToDate. [online] Available from: https://www.uptodate.com/contents/brugada-syndrome-epidemiology-and-pathogenesis#! (Accessed 01 April 2023)Google Scholar). Mutations in SCN genes SCN5A and SCN10A, encoding a cardiac sodium channel’s subunit, have been identified by genetic analysis. SCN1B mutations have been identified in Brugada syndrome probands. Reduction in sodium inflow currents due to the defective myocardial sodium channel reduces the duration of normal action potentials. I(to), the transient outward current prominent in the right ventricle outflow tract (RVOT) epicardium causes significant shortening of the action potential (2Wylie J, 2021. Brugada syndrome: Epidemiology and pathogenesis. UpToDate. [online] Available from: https://www.uptodate.com/contents/brugada-syndrome-epidemiology-and-pathogenesis#! (Accessed 01 April 2023)Google Scholar). Brugada syndrome was identified in 3 to 24 % of patients with idiopathic ventricular fibrillation; this was a study by Remme CA et al. Almost 89% had documented VF during resuscitation by ambulance crew, 86% of patients had myocardial biopsies, which showed no evidence of structural heart disease, and some patients had ECG features of Brugada syndrome. (3Remme C.A. Wever E.F. Wilde A.A. Derksen R. Hauer R.N. Diagnosis and long-term follow-up of the Brugada syndrome in patients with idiopathic ventricular fibrillation.Eur Heart J. 2001; 22: 400-409https://doi.org/10.1053/euhj.2000.2366Crossref PubMed Scopus (105) Google Scholar). There is a male predominance, 2 to 9 times more likely in men. Men carry a greater risk than women, with a worse prognosis (4Priori S.G. Wilde A.A. Horie M. 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: 1932-1963https://doi.org/10.1016/j.hrthm.2013.05.014Abstract Full Text Full Text PDF PubMed Scopus (1299) Google Scholar, 5Benito B. Sarkozy A. 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Andorin A. et al.Gender differences in patients with Brugada syndrome and arrhythmic events: Data from a survey on arrhythmic events in 678 patients.Heart Rhythm. 2018; 15: 1457-1465https://doi.org/10.1016/j.hrthm.2018.06.019Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). It is usually diagnosed in adulthood. Atrial arrhythmias have been detected with Brugada syndrome, mostly AF. In two studies by Brodachar et al. & Kusano et al., 10-20% of patients with Brugada syndrome had AF, associated with a higher risk of VF and a more severe disease process (9Bordachar P. Reuter S. Garrigue S. et al.Incidence, clinical implications and prognosis of atrial arrhythmias in Brugada syndrome.Eur Heart J. 2004; 25: 879-884https://doi.org/10.1016/j.ehj.2004.01.004Crossref PubMed Scopus (134) Google Scholar, 10Kusano K.F. Taniyama M. Nakamura K. Miura D. Banba K. Nagase S. et al.Atrial Fibrillation in Patients With Brugada Syndrome. Relationships of Gene Mutation, Electrophysiology, and Clinical Backgrounds.Journal of the American College of Cardiology. 2008; 51: 1169-1175https://doi.org/10.1016/j.jacc.2007.10.060Crossref PubMed Scopus (142) Google Scholar). In a large study by Brugada J et al., 547 patients with ECG suggestive of Brugada and no previous cardiac arrest were studied. Around 75% were male, with an average patient age of 41 years old. They concluded from the study that a higher risk of sudden cardiac death (SCD) was seen in patients with Brugada syndrome and no previous cardiac arrest. In patients who underwent programmed ventricular stimulation, sustained ventricular arrhythmia and a history of previous syncope were markers of poor prognosis. Absence of syncopal episodes, a diagnostic ECG after drug challenge and non-inducibility with ventricular stimulation was considered the lowest-risk group (11Brugada J. Brugada R. Brugada P. Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.Circulation. 2003; 108: 3092-3096https://doi.org/10.1161/01.CIR.0000104568.13957.4FCrossref PubMed Scopus (455) Google Scholar). In another study by Yan GX and Antzelevitch C to demonstrate the cellular basis of Brugada syndrome, they identified that the trigger of ventricular arrhythmias could result from extrasystolic activity due to phase 2 re-entry arising in the intact wall of the canine RV. Their data showed that medications that block I(to), such as quinidine and 4-aminopyridine, are proven effective (12Yan G.X. Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation.Circulation. 1999; 100: 1660-1666https://doi.org/10.1161/01.cir.100.15.1660Crossref PubMed Google Scholar). This is compared to our case, where the J waves inferolaterally disappeared following quinidine initiation. Drug challenge is sometimes required for patients with ECG changes suspicious of Brugada pattern or syndrome. The drugs usually used to unmask the ECG changes are sodium channel blockers such as ajmaline, flecainide, procainamide or pilsicainide (2Wylie J, 2021. Brugada syndrome: Epidemiology and pathogenesis. UpToDate. [online] Available from: https://www.uptodate.com/contents/brugada-syndrome-epidemiology-and-pathogenesis#! (Accessed 01 April 2023)Google Scholar). However, in our case, the diagnosis was made based on ECG findings, clinical presentation, and VF arrest; a drug challenge was unnecessary, and treatment with medications and ICD implantation was crucial. Regarding pharmacological treatment, Isoproterenol is considered helpful for treating electrical storms, the mechanism being a reduction in the QT interval by increasing rate (13Maury P. Hocini M. Haïssaguerre M. Electrical storms in Brugada syndrome: review of pharmacologic and ablative therapeutic options.Indian Pacing Electrophysiol J. 2005; 5: 25-34PubMed Google Scholar). As per the HRS/EHRA/APHRS expert consensus recommendation, ICD implantation is considered a Class 1 recommendation for patients with Brugada syndrome who survived a cardiac arrest and or have spontaneously sustained VT with or without syncope. Class Ia antiarrhythmic drugs, such as quinidine, help prevent VF induction and suppressing spontaneous ventricular arrhythmias (14Priori S.G. Wilde A.A. Horie M. et al.Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes.Europace. 2013; 15: 1389-1406https://doi.org/10.1093/europace/eut272Crossref PubMed Scopus (422) Google Scholar). This case described a patient admitted following a successfully resuscitated VF arrest by CPR and AED defibrillation. The patient had a significant sodium channel disorder with evidence of Brugada, paroxysmal AF, and AV nodal conduction disorder with prolonged first-degree AV block. He was started on quinidine sulphate 600mg twice daily, had a dual chamber ICD fitted, and his ECG showed significant improvement with the help of medications.