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Brugada Syndrome: Clinical Care Amidst Pathophysiological Uncertainty

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Brugada Syndrome: Clinical Care Amidst Pathophysiological Uncertainty Heart, Lung and Circulation (2020) 29, 538–546 REVIEW 1443-9506/19/$36.00 https://doi.org/10.1016/j.hlc.2019.11.016 Brugada Syndrome: Clinical Care Amidst Pathophysiological Uncertainty Julia C. Isbister, MBBS a,b,c, Andrew D. Krahn, MD d, Christopher Semsarian, MBBS, PhD, MPH a,b,c, Raymond W. Sy, MBBS, PhD b,c,* aAgnes Ginges Centre for Molecular Cardiology at Centenary Institute, University of Sydney, Sydney, NSW, Australia bFaculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia cDepartment of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia dDivision of Cardiology, University of British Columbia, Vancouver, Canada Received 16 August 2019; received in revised form 14 November 2019; accepted 25 November 2019; online published-ahead-of-print 17 December 2019 Brugada syndrome (BrS) is a complex clinical entity with ongoing conjecture regarding its genetic basis, underlying pathophysiology, and clinical management. Within this paradigm of uncertainty, clinicians are faced with the challenge of caring for patients with this uncommon but potentially fatal condition. This article reviews the current understanding of BrS and highlights the “known unknowns” to reinforce the need for flexible clinical practice in parallel with ongoing scientific discovery. Keywords Brugada syndrome Risk stratification Sudden death Arrhythmogenesis Implantable cardioverter- defibrillator Non-device management Introduction more commonly affected than females, and the average age at diagnosis is in the fourth decade [5]. Brugada syndrome (BrS) is an inherited arrhythmogenic heart disease defined by the classic electrocardiographic feature of coved ST-segment elevation in the right precordial leads and an increased risk of sudden death. Although some Pathophysiology of BrS suspicion of an association of right bundle branch block, A schema of our current understanding of the pathophysi- early repolarisation and idiopathic VF had been raised by ology of BrS is summarised in Figure 1. Despite the recog- Martini et al. in 1989 [1], the first formal description of the nition of BrS as a clinical entity for almost three decades [2], clinical syndrome was reported by Brugada et al. in 1992 [2]. the underlying pathophysiological mechanisms remain Nademanee et al. [3] reported the same electrocardiographic contentious. Brugada syndrome has historically been features in those resuscitated from the Sudden Unexplained considered a channelopathy, requiring a structurally normal Nocturnal Death Syndrome. heart by definition and there has been vibrant debate be- The prevalence of type 1 Brugada electrocardiogram tween the predominant electrophysiological theories of (ECG) pattern has been reported to be in the range of 1 in abnormal repolarisation and depolarisation [6]. Recent ad- 2,000, but the true incidence of BrS is difficult to define vances in non-invasive imaging, improved electrophysio- because of variable penetrance, dynamic electrocardio- logical characterisation and potentially curative ablation, graphic features and concealed phenotypes. Moreover, large as well as histological observations have prompted a reas- ethnic differences exist with prevalence reported to be 10- sessment of the interplay between structural and functional fold higher in South-East Asian populations compared to changes and the complex heterogenous drivers of BrS and European and North American cohorts [4]. Males are much its phenocopies. *Corresponding author at: Associate Professor Raymond W Sy, Department of Cardiology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia., Email: [email protected] Ó 2019 Published by Elsevier B.V. on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Brugada Syndrome 539 Figure 1 Pathophysiology of Brugada Syndrome. Abbreviation: ECG, electrocardiograph. The repolarisation hypothesis is based upon the regional inducibility during stimulation from the RVOT [12]. Cardiac variation in electrophysiological properties of cardiac myo- magnetic resonance (CMR) imaging has shown significantly cytes. Data from in vitro studies using perfused sections of increased RVOT size in BrS patients compared with controls canine myocardium demonstrated differential expression of [13] and recent studies have confirmed that these structural fl transient outward potassium current (Ito) between endocar- changes are isolated to the out ow tract, as opposed to the dial and epicardial myocytes which, when coupled with a more generalised right ventricular changes seen in arrhyth- reduced phase 0 inward sodium current (INa) due to sodium mogenic right ventricular cardiomyopathy [14]. channel dysfunction, creates a transmural gradient across the Histopathological studies have revealed structural changes myocardium causing the characteristic ST-segment elevation in BrS patients but no pathognomonic pattern has been of BrS [7]. This dispersion of repolarisation between identified [1,15]. Resolution of BrS ECG changes and reduc- myocardial layers has also been implicated in the develop- tion of spontaneous arrhythmic events have been reported ment of phase 2 re-entry mediated extrasystolic events; a following catheter ablation in the RVOT [10,16,17]. This is proposed mechanism for ventricular arrhythmias in BrS [7]. perhaps the most compelling evidence for the importance of By contrast, the depolarisation hypothesis, based largely the RVOT in arrhythmogenesis in BrS. Collectively, this has on clinical observations, postulates that reduced phase 0 INa led to the proposal that BrS may be considered an inherited causes conduction delay across the right ventricle, most cardiomyopathy rather than a primary arrhythmia syn- marked in the right ventricular outflow tract (RVOT) [6]. drome in some cases. The ECG phenotype of BrS may be the This leads to the development of a gradient between the right final common pathway for expression of a potential gradient ventricle (RV) and the more delayed RVOT causing initial ST of structural and electrical changes affecting both depolar- elevation in the high precordial leads which overlie the isation and repolarisation, resulting in an arrhythmogenic RVOT. In the later stage of the action potential, the gradient RVOT [18]. No single hypothesis fits all of the clinical reverses, shifting net membrane potential back from the observations. RVOT to RV accounting for T-wave inversion as current travels away from the high precordial leads [8]. A unifying point between these two apparently divergent Genetic Basis of BrS hypotheses is that the RVOT is the primary site of arrhyth- mogenesis. Electrophysiological studies have demonstrated Brugada syndrome has endured a tortuous journey of ge- delayed conduction [9,10], electro-anatomical abnormalities netic discovery since the first report of causative mutations in characterised by low voltage, fractionated electrograms the sodium channel gene SCN5A in 1998 [19]. Even at this localised to the RVOT [11] and increased arrhythmic early stage, the mechanistic complexity of genotype- 540 J.C. Isbister et al. Type 1 – “Coved Type” Type 2 – “Saddle-back Type” Type 3 ≥2 mm coved ST elevation in ≥1 right Saddle-back ST-segment elevation with ST-segment elevation <1 mm in ≥1 right precordial lead (V1–V3) ≥1 mm trough (may be ≥2 mm at J-point) precordial lead (V1–V3), either coved or in ≥1 right precordial lead (V1–V3) saddle-back followed by an upright/biphasic T wave Figure 2 Electrocardiographic Features of Brugada Syndrome. phenotype interaction in BrS was apparent, with func- various sodium channel related genes and genes encoding tionally different variants producing electrocardiographic transcription regulator function [23]. heterogeneity, hinting at the likely role for modifying factors. Technological advances in genetic testing and the advent Diagnosis and Risk Stratification of high throughput, next generation sequencing led to an explosion of genetic data and a new set of challenges sur- Features of BrS rounding variant interpretation. Determining the pathoge- The ECG is the cornerstone of diagnosis in BrS and three nicity of a variant is a complex and dynamic process that ECG patterns are described (Figure 2). The type 1 pattern is takes into account evolving evidence such as population characterised by 2 mm ST-segment elevation in at least one data, functional assessment and family studies. At present, of V1 or V2. Type 2 and 3 morphologies are suspicious for the role of diagnostic genetic testing in BrS is limited, with a BrS but non-diagnostic. The ECG pattern can be mimicked reported yield of w20% typically contingent upon the by various pathologies (Table 1) and these should be finding of a recognised pathogenic variant in SCN5A [20]. It excluded prior to conferring a diagnosis of BrS [4]. Electro- is noteworthy that missense variants in SCN5A occur cardiographic changes of BrS fluctuate and are not present in frequently, and may be present in 2–5% of healthy in- affected patients at all times. Modifiers of the BrS ECG dividuals [20]. The pathogenicity of a variant is generally morphology are also listed in Table 1 [4]. supported when it segregates within a family, but genotype- Prolonged ECG monitoring is useful given the dynamic phenotype mismatch has been reported in families with BrS nature of the BrS ECG and high precordial lead placement [21]. Beyond SCN5A, hundreds of variants in over 20 genes (V1 and V2 in the second and third intercostal spaces) has have
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