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Controversies in Brugada syndrome
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Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
Controversies in Brugada syndrome Marina Cerrone, MD* Cardiovascular Genetics Program, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY
abstra ct The Brugada syndrome is an inherited channelopathy associated with increased risk of ventricular arrhythmias and sudden death, often occurring during sleep or resting conditions. Although this entity has been described more than 20 years ago, it remains one of the most debated among channelopathies, with several open questions on its genetic substrate, arrhythmia mechanisms, and clinical management. Studies on the genetics and physiopathology bases of the Brugada syndrome have opened novel investigative pathways and concepts that are now entering the field of cardiovascular genetics and are applied to other inherited arrhythmias. In this perspective, Brugada syndrome can be seen as an example on how basic science discoveries have influenced clinical management and led to novel therapeutic approaches. & 2017 Elsevier Inc. All rights reserved.
Introduction
Clinical features and diagnosis
The Brugada syndrome (BrS) was initially described by Pedro and Josep Brugada in 1992 as a novel clinical entity characterized by “right bundle branch block, persistent ST segment elevation, and sudden cardiac death” [1]. A growing body of novel discoveries helped unravel its clinical presentation, arrhythmia mechanisms, and genetic background; still BrS remains one of the most debated among channelopathies with several open questions that makes its clinical management quite challenging. This syndrome is particularly fascinating to the physician scientist, given that it represents a clear example on how therapeutic approaches could be directly influenced by the results of basic science studies. Additionally, this has been one of the very first genetic conditions to challenge the “one gene one disease” dogma dominating the initial years of the cardiovascular genetics field. This review will offer an overview of its clinical and genetic features, focusing on the latest discoveries and open questions.
The Brugada syndrome (BrS) is characterized by increased risk of syncope, cardiac arrest, and sudden death often occurring during sleep, rest, or enhanced vagal tone situations, such as alcohol intoxication or large meals [2]. Fever is another relevant arrhythmic trigger [2], which seems to be especially dangerous in affected children, although most symptoms manifest in young adults with a peak around the 3rd/4th decade [2]. The syndrome is diagnosed based on the ECG features, as already highlighted in the original article from the Brugada brothers [1]. Currently [2], diagnosis is made in the presence of a coved morphology, or type 1, ST segment elevation 42 mm in at least one of the precordial leads V1–V2, recorded either in the conventional fourth intercostal space or in the second and third intercostal spaces. The recently revised recommendations introduced as a diagnostic procedure recording ECG leads in the second or third intercostal space, based on electro-anatomical evidence that it is the projection
This work was supported by a Scientist Development Grant from the American Heart Association (#14SDG18580014). The authors have indicated there are no conflicts of interest. n Correspondence to: 522 First Avenue SRB806, New York, NY. Tel.: þ212 263 9136; fax: þ646 754 9659. E-mail address: [email protected] (M. Cerrone). https://doi.org/10.1016/j.tcm.2017.11.003 1050-1738/& 2017 Elsevier Inc. All rights reserved.
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Fig. 1 – ECG in one patient with Brugada syndrome showing different patterns in V1–V2 when recorded in the second, third, and fourth intercostal space. of the right ventricular outflow tract (RVOT) that best reflects where the BrS ECG originates [3]; as such, by restricting the diagnosis only to the conventional fourth intercostal space, one may limit sensitivity (Fig. 1). The international consensus [2] has also excluded as diagnostic for the disease additional ST segment morphologies such as the “type 2” (“saddleback”) and the “type 3” (saddleback 41 mm), which in the past were considered sufficient to establish a suspect for the syndrome. If a type 2 or 3 ECG is noted, diagnosis of BrS is based on the conversion into a type 1 ECG during a sodium channel blocker challenge. An ECG consistent with a suspect BrS could manifest during several conditions that need to be taken into account as differential diagnosis [2,4]. Hence, some investigators proposed to introduce the concept of “Brugada Syndrome Phenocopy” [5], when the suspect ECG is associated with one or more of the following: identifiable underlying conditions; resolution of the ECG pattern after resolution of the condition; negative sodium channel blocker challenge; low clinical probability of BrS based on lack of symptoms, medical, and family history.
Sodium channel blocker test: do we really need to chase concealed ECG patterns? The hallmark ECG in BrS is known to be transitory with the coved morphology being present only sporadically in some patients [2,4] (Fig. 2). A sodium channel blocker challenge is used to unravel concealed BrS in patients with either a suspect ECG or family/medical history. Sodium channel blocker agents can worsen the conduction and repolarization abnormalities typical of BrS [6]. Different agents are used in different countries, mainly based on availability: flecainide and when possible ajmaline are used in Europe, procainamide in the USA, and pilsicainide in Asia. Several reports have suggested that the sensitivity and specificity of the agents could be different, with procainamide being potentially the least sensitive [6]. We collected data comparing for the first time flecainide and procainamide sensitivity in a
single US center [7], showing in a small group of 10 patients with a negative procainamide test that subsequent flecainide infusion was positive; of note, 7 of these patients carried a genetic mutation consistent with BrS. Recently, a group of French investigators [8] aimed to assess sensitivity of the drug challenge with either ajmaline and flecainide in obligate carriers; their data showed a higher sensitivity for ajmaline when compared with flecainide. Currently, the specificity of the test and how to assess the risk of a false positive outcome are becoming pressing issues, considering the growing number of diagnosed patients. Hasdemir et al. [9] showed that in a cohort of patients undergoing radiofrequency ablation for atrio-ventricular nodal reentrant tachycardia (AVNRT), about 27% had a type 1 BrS ECG after ajmaline infusion. Although this outcome prompted them to suggest that AVNRT may be a common manifestation in BrS, it also provided interesting data suggesting that ajmaline may have low specificity with increased risk of false positives and over-diagnosis [10]. Most asymptomatic patients carrying a diagnosis of BrS are identified after a sodium channel blocker challenge test: hence, several investigators started raising awareness of the potential risks of a false positive result [10,11]. Individuals with only a drug-induced BrS ECG and absence of symptoms maintain a low arrhythmic risk during follow-up [12]. Because of the lack of preventive medical therapy, no treatment is warranted [2]. However, individuals diagnosed based upon the pharmacological challenge often carry a significant psychologic burden due to the awareness of being at increased sudden cardiac death risk, and although the risk of proarrhythmic effects during the test remains very low if performed in expert centers, it is not nonexistent [13]. All these factors should be taken into account and could prompt a revision of the current recommendations on the use of sodium channel blockers in asymptomatic individuals. Following this evidence, there have been initial suggestions from an international expert consensus [4] that a difference should be established between a “BrS ECG” only and a full syndrome. The latter should be considered if at least one of the following is present: nocturnal agonal respiration; documented
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Fig. 2 – Transitory nature of type 1 coved ST segment elevation in the same patient. (A) ECG during fever and (B) ECG recorded after resolution of the illness and normal body temperature. VF or polymorphic VT; syncope with arrhythmic origin; family history of sudden cardiac death o45 years of age and negative autopsy, or coved-type ECG in family members.
So many genes, yet so few patients genotyped: is Mendelian inheritance the only answer? The familial nature of BrS has been recognized since its initial descriptions and the first gene associated with the disease was identified in 1998 by Chen et al. [14] as the SCN5A gene that codes for the α-subunit of the cardiac sodium channel,
Nav1.5. Mutations in SCN5A linked to the BrS phenotype cause a reduced availability of depolarizing sodium current [14]. Indeed, slowed atrio-ventricular and intraventricular conduction are very often seen in these patients [15]. Still, only about 1/5 of diagnosed patients carry mutations on the SCN5A gene, even if it is the most prevalent gene linked to the disease. The fast evolving progress in next generation sequencing led to the discovery of several additional genes in patients diagnosed with BrS [4] (Table 1). Most genes are either coding for accessory proteins involved in sodium current availability, or in regulation of the calcium or of the Ito potassium currents [4]. Unfortunately, none of these new
Table 1 – Genes that have been associated with Brugada syndrome grouped by electrophysiologic effect on the sodium, calcium, potassium, and other currents. Only mutations on SCN5A have been detected in 20–25% of patients, while the occurrence of mutations on the other genes is rare. Gene
Protein
Effect
SCN5A GPDL1 SCN1b SCN2b SCN3b RANGRF SLMAP PKP2 FGF12 SCN10A TRPM4 CACNA1c CACNB2b CACNA2D1 KCNE3 KCND3 KCND2 SEMA3A KCNE5 KCNJ8 ABCC9 KCNH2 HCN4
α-subunit Nav1.5 sodium channel Glycerol-3-phosphate-dehydrogenase 1-like β-subunit Navβ1 sodium channel β-subunit Navβ2 sodium channel β-subunit Navβ3 sodium channel RAN guanine nucleotide release factor Sarcolemma-associated protein Plakophillin-2 Fibroblast growth factor 12 α-subunit Nav1.8 sodium channel Calcium-activated nonselective ion channel α-subunit α1C Cav1.2 calcium channel β-subunit Cavβ2b calcium channel δ-subunit Cavα2δ1 calcium channel β-subunit MIRP2 potassium channel α-subunit KV4.3 potassium channel α-subunit KV4.2 potassium channel Semaphorin family protein Auxiliary β-subunit potassium channel α-subunit KIR6.1 potassium channel ATP-sensitive potassium channel α-subunit HERG potassium channel Hyperpolarization-activated cyclic nucleotide-gated channel 4
↓INa ↓INa ↓INa ↓INa ↓INa ↓INa ↓INa ↓INa ↓INa ↓INa ↓INa ↓ICa ↓ICa ↓ICa ↑Ito ↑Ito ↑Ito ↑Ito ↑Ito ↑IK-ATP ↑IK-ATP ↑IKr ↓If
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Fig. 3 – PKP2 mutations associated with Brugada syndrome phenotype cause decreased sodium current. (A) ECG of the patients carrying PKP2 mutations. (B) Sodium current recorded in HL1 cells with no PKP2 (blue); PKP2 mutants (red) and PKP2 wild type (WT, black). Reproduced with permission from Ref. [18]. (Color version of figure is available online.) “minor” genes account for more than sporadic cases and only a few are being identified in even 3–5% of patients [16]. Notwithstanding the number of novel genes discovered, the overall yield of positive genetic test in BrS remains around 25–30% [16]. Additionally, the analysis from genetic dataset of healthy controls has recently shown that several variants in minor BrS genes are also found with a relatively high prevalence in the general population, thus questioning their role as the monogenic sole cause of the disease. In one study, 6% of variants previously linked to BrS were found in healthy subjects and none of them had clinical or ECG features suspect for the disease [17]. Notwithstanding the known elusive nature of clinical manifestations in BrS, these data support a cautionary approach to the use of variants in minor genes as the only diagnostic tool in this condition, especially when applied for cascade screening in unaffected family members. Indeed, it is now suggested [16] not to extend genetic test on asymptomatic relatives when variants of unknown significance (which are the majority of variants found in these genes) are detected in an index patient. The negligible clinical impact of the minor genes raised a call for caution from several investigators on how quickly scientific discoveries should enter the clinical field, especially considering that nowadays genetic test is commercially available and could be used without the necessary counseling in place. A gene disease that, although recognized in only a minority of BrS patients, has been challenging further the “one disease, one gene” dogma is the PKP2 gene, coding for plakophilin-2
(PKP2) [18]. Mutations on PKP2 account for the majority of arrhythmogenic cardiomyopathy (ACM) cases [19], a disease characterized by high incidence of ventricular arrhythmias and a progressive cardiomyopathy with fibrofatty infiltration involving predominantly the right ventricle. Although BrS was initially described as a purely electric condition in intact hearts [1], it is now recognized that structural changes especially at the right ventricular outflow tract (RVOT) are present in some patients [20,21]. These findings support the hypothesis, suggested in the past by some clinicians [22], that the two conditions could be at the bookends of a phenotypical common spectrum. PKP2 is a structural protein of the desmosome whose principal role is to maintain tissue integrity and cell-to-cell stability. However, data from cellular and mouse models demonstrated that loss of PKP2 could facilitate arrhythmias by decreasing sodium current [23,24], thus through an electrophysiologic effect. Indeed, in vitro characterization of the PKP2 mutations detected in patients with a BrS phenotype showed a decreased sodium current, consistent with the clinical phenotype [18] (Fig. 3). Super-resolution microscopy data showed that loss of PKP2 could affect proper trafficking of the sodium channel at the membrane, thus supporting the concept that proteins could have accessory roles aside from the primary one ascribed to them [18]. The role of the cardiac intercalated disc as a functional unit with both structural and electric regulatory functions has been opening new paths of investigations on the possible arrhythmogenic substrate in BrS [25]. An additional analysis on 45
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candidate genes in BrS patients not carrying a SCN5A mutation showed enrichment for another desmosomal gene, the DSC2 coding for desmocollin-2 [26], further supporting the hypothesis of a possible continuum between the 2 diseases. Although BrS is commonly referred to as an autosomal dominant Mendelian disease, several recent studies challenged this concept and proposed a role for a cumulative effect of common variants in modulating the phenotype. In 2009, Probst et al. [27] showed that in 5 large families, 8 mutation-negative family members had a diagnostic type 1 ECG pattern and they did not carry additional mutations on the SCN5A gene, questioning for the first time the pure Mendelian inheritance pattern and suggesting that the interaction of modulating factors could influence the ECG pattern and clinical presentation, such as it happens for complex diseases. Following up on these observations, Dr. Bezzina led a collaborative genome-wide association study of 312 BrS patients and 1115 controls providing evidence that some SNPs on the SCN10a and SCN5A genes had a cumulative effect in associating with likelihood of carrying a BrS phenotype [28]. More importantly, this study also identified SNPs in the Hey2 gene as associated with likelihood of disease. The Hey2 gene encodes for a transcription factor modulating transmural expression of ion channels, including Nav1.5, especially in the right ventricle [28]. Following up on this discovery, the same group recently demonstrated [29] that in the human heart, expression of Hey2 is correlated to one of the KCNIP2 genes, encoding for the Ito current and that in a mouse model Hey2 impacts the transmural depolarization
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and repolarization gradients across the ventricular wall, one of the most important mechanisms supposedly at the base of arrhythmias in BrS. This finding corroborated the prevalent involvement of the RVOT as the vulnerable area in BrS and substantiated the role of genetic modifiers as modulators of arrhythmic risk in the setting of the disease. This hypothesis is also offering a possible justification for the low percentage of patients with a positive genotype by conventional Mendelian genetics.
What is determining the ECG pattern and how are arrhythmias facilitated? The debate on which are the arrhythmogenic mechanisms in this disease is still ongoing with strong and compelling arguments from different groups [30]; as such, offering a definite answer is beyond the scope of this review. Certainly, which factors determine the peculiar ST segment pattern in humans remain a puzzling question. So far, no animal model has been able to reproduce a type 1 ECG morphology. Genetically engineered mice had provided some interesting data, but fail to reproduce all features of the BrS phenotype [31]. Our group recently developed the only large animal model carrying a truncated SCN5A mutation, an engineered knock-in minipig [32]. Even if the minipig showed marked conduction delay and increased susceptibility to ventricular fibrillation, especially in the setting of elevated body temperature (mimicking a fever-like trigger), no spontaneous coved ST segment elevation was recorded [32] (Fig. 4).
Fig. 4 – ECG and arrhythmias in the SCN5A E558X/þ knock-in minipig. (A) Left: baseline ECG and after administration of flecainide iv. Right: arrhythmias elicited by flecainide administration. (B) Volume conducted ECG in wild type (WT) and E558X/ þ minipig Langendorff perfused isolated hearts exposed to high temperature to mimic fever, showing occurrence of spontaneous arrhythmias in the E558X/þ hearts. (Reproduced with permission from Ref. [32].)
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Dr. Antzelevitch’s studies have proposed that the ST segment elevation pattern in BrS is determined by a transmural repolarization gradient between the RVOT epicardium and endocardium [30,33]; arrhythmias would arise when a trigger elicits a further shift in the balance of currents in the early phases of action potential through a phase 2 reentry mechanism. Most of the gradient imbalance is determined by either decreased sodium current (such as mediated by genetic mutations), which would cause a relative increase in the Ito current magnitude or by recently described gain of function mutations increasing the Ito current. Accordingly, the lack of Ito in the minipig action potential is argued by this group as one of the reasons as to why the animal did not show type 1 ECG pattern, although several other factors could have played a role. There is also a growing body of evidence that supports the hypothesis that the arrhythmogenic features in BrS are caused by delayed depolarization and that fibrosis and structural alterations at the RVOT play an important role [21,25,30,34]. Conduction slowing is recognized as one of the features of the disease and often patients present clinically with prolonged PR interval, some degree of right bundle branch block, and/or positive late potential at the SAECG [1,15]. Additionally, reports from explanted hearts or biopsies showed presence of right ventricular focal myocardial fibrosis, reduced connexin-43 signal and apoptosis, although overt structural abnormalities are rare [25,35]. This evidence also favors the argument of a possible tight correlation between BrS and ARVC. Genetic mutations linked to the disease are thought to decrease sodium current availability and increase conduction delay, and SCN5A mutations also have been associated with structural alterations [36–38]. Following this hypothesis, arrhythmias in BrS would be facilitated by conduction block and reentry caused by tissue discontinuity. Late activation at the RVOT may create a gradient between RVOT and RV resulting in the coved ST elevation and negative T wave seen in the type 1 ECG [30]. Although contrasting, probably the 2 advocated mechanisms are not necessarily mutually exclusive; for instance, there is agreement on the role that the RVOT exerts in defining the pathophysiology of BrS [34]. Importantly, these studies have provided an essential contribution to develop recent novel diagnostic approaches and therapeutic strategies. One peculiar feature typical only of BrS and early repolarization syndromes is the susceptibility to arrhythmias during enhanced parasympathetic tone. One interesting theory [39] is that high parasympathetic activity, such as during sleep or bradycardia, could increase the Ito current, facilitating ST elevation and arrhythmias. Paul et al. [40] showed in a preliminary study small samples of cardiac biopsies that BrS patients have lower levels of norepinephrine and cAMP, which they attributed to impaired stimulation of β-adrenoceptors; the reduced level of adrenergic impulse could create a predominant vagal tone facilitating arrhythmias. Although these are only preliminary studies, they open an interesting perspective on the role of sympathovagal imbalance and autonomic innervation as the arrhythmic substrate of the disease.
Risk stratification and therapeutic approaches Due to the lack of prophylactic medical treatment, identification of high-risk patients in BrS is of pivotal importance.
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Several studies agree on the presence of spontaneous coved ST segment elevation and history of syncope as the factors that select individuals at higher risk, for whom an implantable cardioverter defibrillator (ICD) is indicated [2,4,12,41–43]. Similarly, several studies have confirmed that individuals that are asymptomatic and are diagnosed based on a druginduced ECG remain at low arrhythmic risk throughout follow-up (event rate ranging from 0.27 [42] to 0.5 [12]). A still unresolved controversy remains the role of programmed electrical stimulation (PES) as a risk indicator. While data from a large cohort of 403 patients followed by a single center showed increased arrhythmic risk in inducible patients [43], several series from different investigators [12,41,42] failed to confirm that the test could have a positive and especially a negative predictive value. The latest results from a pooled analysis of 8 studies and ~1300 patients [42] showed that indeed arrhythmia inducibility with PES may indicate increased arrhythmic risk at follow-up, with the lower number of extrastimuli identifying the patients at higher risk. However, a negative PES was not a good indicator of a low risk. Indeed, subjects with no inducible arrhythmias, but showing type 1 ECG and history of syncope, still had a 2.55% risk of experiencing fatal arrhythmias at follow-up. These data emphasize the need for standardized PES protocols and reinforce the concept that an aggressive stimulation protocol may lead to an excess of false positive results. Overall, consensus has emerged on the need for additional clinical indicators that could sub-stratify those individuals that fall within the “intermediate risk” category. In the PRELUDE study [41], QRS fragmentation was a novel risk indicator, then confirmed by additional series [44]. Until preventive therapeutic approaches (beyond ICDs) become available, the quest for additional clinical parameters to identify patients at risk remains one of the open challenges in the management of BrS. The use of subcutaneous ICD, a device that has become available in the past few years, could potentially be a better approach in BrS, due to the relative young age of the patients and the existing reports of increased rate of complications with endocardial ICDs in the young population. Concerns have been raised [45], however, on the risk of reduced detection accuracy due to the peculiarity of the type 1 ECG morphology and QRS-to-T ratio, as well as the intermittent nature of the ECG and of a right bundle branch block pattern, which could all increase the possibility of inappropriate shocks. However, accurate pre-implant selection may limit if not completely control these risks and help identify those individuals that are more likely to benefit from a subcutaneous ICD. So far, the only medical therapy that could have some potential as a preventive approach for the disease is quinidine [2]. This drug blocks several ionic channels, with a recognized strong blockage effect on the Ito current, which is proposed to be the mechanism by which quinidine could control arrhythmias in BrS [33]. Several reports confirmed the effectiveness of quinidine, as well as of isoproterenol, to treat electric VT/VF storms [46]. The drug is also used to limit the incidence of shocks in symptomatic patients with an ICD [46]. Some encouraging data on the use of chronic quinidine therapy as an alternative to the ICD come from recent
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studies: the long-term experience of the Israeli group showed that patients inducible at PES were no longer inducible nor had arrhythmic events after quinidine therapy at 10 years follow-up [47]. Encouraging data on drug effectiveness also came from the results of the QUIDAM study, the first multicenter prospective randomized double-blind study with cross-over phases drug/placebo [48]. Unfortunately, the study had to be terminated prematurely because of the high number of discontinuation due to side effects, and because of the very low adverse event rate, which is typical of the natural history of BrS and a major limitation in gathering effective long-term data on drug effectiveness. Probably one of the most innovative approaches that could significantly change how to treat patients, if confirmed in large series and by different groups, is the use of right ventricular radiofrequency ablation therapy. Initially, Nademanee et al. [49] demonstrated in few high-risk patients that they were able to alter the arrhythmic substrate and obtain non-inducibility of VT/VF by using epicardial ablation in the RVOT aimed to sites with abnormal low voltage, prolonged duration and fractionated late potentials. They were also the first group to show that RVOT epicardial ablation could modify the type 1 ECG pattern in the majority of patients. Subsequently, this and other groups [49,50] further extended the epicardial ablation field using the sodium channel blockers challenge to select all areas with low voltage beyond the RVOT and often including the RV area to limit recurrences. The elimination of the type 1 ECG was also corroborated by repeating the pharmacologic challenge after the procedure [50]. Although these data still need to be supported by additional evidence, they have provided a new potential therapeutic venue offering a much-needed alternative to the management of BrS patients. It is also worth emphasizing how these clinical studies stemmed from decades of investigation in cellular and animal models that unraveled the role of the RVOT as the culprit anatomical area responsible for arrhythmias in BrS.
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Acknowledgments This work was supported by a Scientist Development Grant from the American Heart Association (#14SDG18580014).
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Conclusions The field of cardiovascular genetics is continuously evolving and BrS has been at the forefront of this progress. Several recent discoveries have been put forward by investigating this disease, from the evidence that minor genes may have been accepted too precipitously into clinical practice, to the possibility that Mendelian inheritance may not be the sole mode of transmission. Concepts learned from this experience are now explored and applied to other channelopathies. Furthermore, studies in the pathophysiology of this fascinating condition have been able to move from basic science experiments into the clinical sphere, providing a compelling argument into the need for translational studies in order to find better management strategies for patients.
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Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
Controversies in Brugada syndrome Marina Cerrone, MD* Cardiovascular Genetics Program, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY
abstra ct The Brugada syndrome is an inherited channelopathy associated with increased risk of ventricular arrhythmias and sudden death, often occurring during sleep or resting conditions. Although this entity has been described more than 20 years ago, it remains one of the most debated among channelopathies, with several open questions on its genetic substrate, arrhythmia mechanisms, and clinical management. Studies on the genetics and physiopathology bases of the Brugada syndrome have opened novel investigative pathways and concepts that are now entering the field of cardiovascular genetics and are applied to other inherited arrhythmias. In this perspective, Brugada syndrome can be seen as an example on how basic science discoveries have influenced clinical management and led to novel therapeutic approaches. & 2017 Elsevier Inc. All rights reserved.
Introduction
Clinical features and diagnosis
The Brugada syndrome (BrS) was initially described by Pedro and Josep Brugada in 1992 as a novel clinical entity characterized by “right bundle branch block, persistent ST segment elevation, and sudden cardiac death” [1]. A growing body of novel discoveries helped unravel its clinical presentation, arrhythmia mechanisms, and genetic background; still BrS remains one of the most debated among channelopathies with several open questions that makes its clinical management quite challenging. This syndrome is particularly fascinating to the physician scientist, given that it represents a clear example on how therapeutic approaches could be directly influenced by the results of basic science studies. Additionally, this has been one of the very first genetic conditions to challenge the “one gene one disease” dogma dominating the initial years of the cardiovascular genetics field. This review will offer an overview of its clinical and genetic features, focusing on the latest discoveries and open questions.
The Brugada syndrome (BrS) is characterized by increased risk of syncope, cardiac arrest, and sudden death often occurring during sleep, rest, or enhanced vagal tone situations, such as alcohol intoxication or large meals [2]. Fever is another relevant arrhythmic trigger [2], which seems to be especially dangerous in affected children, although most symptoms manifest in young adults with a peak around the 3rd/4th decade [2]. The syndrome is diagnosed based on the ECG features, as already highlighted in the original article from the Brugada brothers [1]. Currently [2], diagnosis is made in the presence of a coved morphology, or type 1, ST segment elevation 42 mm in at least one of the precordial leads V1–V2, recorded either in the conventional fourth intercostal space or in the second and third intercostal spaces. The recently revised recommendations introduced as a diagnostic procedure recording ECG leads in the second or third intercostal space, based on electro-anatomical evidence that it is the projection
This work was supported by a Scientist Development Grant from the American Heart Association (#14SDG18580014). The authors have indicated there are no conflicts of interest. n Correspondence to: 522 First Avenue SRB806, New York, NY. Tel.: þ212 263 9136; fax: þ646 754 9659. E-mail address: [email protected] (M. Cerrone). https://doi.org/10.1016/j.tcm.2017.11.003 1050-1738/& 2017 Elsevier Inc. All rights reserved.
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Fig. 1 – ECG in one patient with Brugada syndrome showing different patterns in V1–V2 when recorded in the second, third, and fourth intercostal space. of the right ventricular outflow tract (RVOT) that best reflects where the BrS ECG originates [3]; as such, by restricting the diagnosis only to the conventional fourth intercostal space, one may limit sensitivity (Fig. 1). The international consensus [2] has also excluded as diagnostic for the disease additional ST segment morphologies such as the “type 2” (“saddleback”) and the “type 3” (saddleback 41 mm), which in the past were considered sufficient to establish a suspect for the syndrome. If a type 2 or 3 ECG is noted, diagnosis of BrS is based on the conversion into a type 1 ECG during a sodium channel blocker challenge. An ECG consistent with a suspect BrS could manifest during several conditions that need to be taken into account as differential diagnosis [2,4]. Hence, some investigators proposed to introduce the concept of “Brugada Syndrome Phenocopy” [5], when the suspect ECG is associated with one or more of the following: identifiable underlying conditions; resolution of the ECG pattern after resolution of the condition; negative sodium channel blocker challenge; low clinical probability of BrS based on lack of symptoms, medical, and family history.
Sodium channel blocker test: do we really need to chase concealed ECG patterns? The hallmark ECG in BrS is known to be transitory with the coved morphology being present only sporadically in some patients [2,4] (Fig. 2). A sodium channel blocker challenge is used to unravel concealed BrS in patients with either a suspect ECG or family/medical history. Sodium channel blocker agents can worsen the conduction and repolarization abnormalities typical of BrS [6]. Different agents are used in different countries, mainly based on availability: flecainide and when possible ajmaline are used in Europe, procainamide in the USA, and pilsicainide in Asia. Several reports have suggested that the sensitivity and specificity of the agents could be different, with procainamide being potentially the least sensitive [6]. We collected data comparing for the first time flecainide and procainamide sensitivity in a
single US center [7], showing in a small group of 10 patients with a negative procainamide test that subsequent flecainide infusion was positive; of note, 7 of these patients carried a genetic mutation consistent with BrS. Recently, a group of French investigators [8] aimed to assess sensitivity of the drug challenge with either ajmaline and flecainide in obligate carriers; their data showed a higher sensitivity for ajmaline when compared with flecainide. Currently, the specificity of the test and how to assess the risk of a false positive outcome are becoming pressing issues, considering the growing number of diagnosed patients. Hasdemir et al. [9] showed that in a cohort of patients undergoing radiofrequency ablation for atrio-ventricular nodal reentrant tachycardia (AVNRT), about 27% had a type 1 BrS ECG after ajmaline infusion. Although this outcome prompted them to suggest that AVNRT may be a common manifestation in BrS, it also provided interesting data suggesting that ajmaline may have low specificity with increased risk of false positives and over-diagnosis [10]. Most asymptomatic patients carrying a diagnosis of BrS are identified after a sodium channel blocker challenge test: hence, several investigators started raising awareness of the potential risks of a false positive result [10,11]. Individuals with only a drug-induced BrS ECG and absence of symptoms maintain a low arrhythmic risk during follow-up [12]. Because of the lack of preventive medical therapy, no treatment is warranted [2]. However, individuals diagnosed based upon the pharmacological challenge often carry a significant psychologic burden due to the awareness of being at increased sudden cardiac death risk, and although the risk of proarrhythmic effects during the test remains very low if performed in expert centers, it is not nonexistent [13]. All these factors should be taken into account and could prompt a revision of the current recommendations on the use of sodium channel blockers in asymptomatic individuals. Following this evidence, there have been initial suggestions from an international expert consensus [4] that a difference should be established between a “BrS ECG” only and a full syndrome. The latter should be considered if at least one of the following is present: nocturnal agonal respiration; documented
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Fig. 2 – Transitory nature of type 1 coved ST segment elevation in the same patient. (A) ECG during fever and (B) ECG recorded after resolution of the illness and normal body temperature. VF or polymorphic VT; syncope with arrhythmic origin; family history of sudden cardiac death o45 years of age and negative autopsy, or coved-type ECG in family members.
So many genes, yet so few patients genotyped: is Mendelian inheritance the only answer? The familial nature of BrS has been recognized since its initial descriptions and the first gene associated with the disease was identified in 1998 by Chen et al. [14] as the SCN5A gene that codes for the α-subunit of the cardiac sodium channel,
Nav1.5. Mutations in SCN5A linked to the BrS phenotype cause a reduced availability of depolarizing sodium current [14]. Indeed, slowed atrio-ventricular and intraventricular conduction are very often seen in these patients [15]. Still, only about 1/5 of diagnosed patients carry mutations on the SCN5A gene, even if it is the most prevalent gene linked to the disease. The fast evolving progress in next generation sequencing led to the discovery of several additional genes in patients diagnosed with BrS [4] (Table 1). Most genes are either coding for accessory proteins involved in sodium current availability, or in regulation of the calcium or of the Ito potassium currents [4]. Unfortunately, none of these new
Table 1 – Genes that have been associated with Brugada syndrome grouped by electrophysiologic effect on the sodium, calcium, potassium, and other currents. Only mutations on SCN5A have been detected in 20–25% of patients, while the occurrence of mutations on the other genes is rare. Gene
Protein
Effect
SCN5A GPDL1 SCN1b SCN2b SCN3b RANGRF SLMAP PKP2 FGF12 SCN10A TRPM4 CACNA1c CACNB2b CACNA2D1 KCNE3 KCND3 KCND2 SEMA3A KCNE5 KCNJ8 ABCC9 KCNH2 HCN4
α-subunit Nav1.5 sodium channel Glycerol-3-phosphate-dehydrogenase 1-like β-subunit Navβ1 sodium channel β-subunit Navβ2 sodium channel β-subunit Navβ3 sodium channel RAN guanine nucleotide release factor Sarcolemma-associated protein Plakophillin-2 Fibroblast growth factor 12 α-subunit Nav1.8 sodium channel Calcium-activated nonselective ion channel α-subunit α1C Cav1.2 calcium channel β-subunit Cavβ2b calcium channel δ-subunit Cavα2δ1 calcium channel β-subunit MIRP2 potassium channel α-subunit KV4.3 potassium channel α-subunit KV4.2 potassium channel Semaphorin family protein Auxiliary β-subunit potassium channel α-subunit KIR6.1 potassium channel ATP-sensitive potassium channel α-subunit HERG potassium channel Hyperpolarization-activated cyclic nucleotide-gated channel 4
↓INa ↓INa ↓INa ↓INa ↓INa ↓INa ↓INa ↓INa ↓INa ↓INa ↓INa ↓ICa ↓ICa ↓ICa ↑Ito ↑Ito ↑Ito ↑Ito ↑Ito ↑IK-ATP ↑IK-ATP ↑IKr ↓If
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Fig. 3 – PKP2 mutations associated with Brugada syndrome phenotype cause decreased sodium current. (A) ECG of the patients carrying PKP2 mutations. (B) Sodium current recorded in HL1 cells with no PKP2 (blue); PKP2 mutants (red) and PKP2 wild type (WT, black). Reproduced with permission from Ref. [18]. (Color version of figure is available online.) “minor” genes account for more than sporadic cases and only a few are being identified in even 3–5% of patients [16]. Notwithstanding the number of novel genes discovered, the overall yield of positive genetic test in BrS remains around 25–30% [16]. Additionally, the analysis from genetic dataset of healthy controls has recently shown that several variants in minor BrS genes are also found with a relatively high prevalence in the general population, thus questioning their role as the monogenic sole cause of the disease. In one study, 6% of variants previously linked to BrS were found in healthy subjects and none of them had clinical or ECG features suspect for the disease [17]. Notwithstanding the known elusive nature of clinical manifestations in BrS, these data support a cautionary approach to the use of variants in minor genes as the only diagnostic tool in this condition, especially when applied for cascade screening in unaffected family members. Indeed, it is now suggested [16] not to extend genetic test on asymptomatic relatives when variants of unknown significance (which are the majority of variants found in these genes) are detected in an index patient. The negligible clinical impact of the minor genes raised a call for caution from several investigators on how quickly scientific discoveries should enter the clinical field, especially considering that nowadays genetic test is commercially available and could be used without the necessary counseling in place. A gene disease that, although recognized in only a minority of BrS patients, has been challenging further the “one disease, one gene” dogma is the PKP2 gene, coding for plakophilin-2
(PKP2) [18]. Mutations on PKP2 account for the majority of arrhythmogenic cardiomyopathy (ACM) cases [19], a disease characterized by high incidence of ventricular arrhythmias and a progressive cardiomyopathy with fibrofatty infiltration involving predominantly the right ventricle. Although BrS was initially described as a purely electric condition in intact hearts [1], it is now recognized that structural changes especially at the right ventricular outflow tract (RVOT) are present in some patients [20,21]. These findings support the hypothesis, suggested in the past by some clinicians [22], that the two conditions could be at the bookends of a phenotypical common spectrum. PKP2 is a structural protein of the desmosome whose principal role is to maintain tissue integrity and cell-to-cell stability. However, data from cellular and mouse models demonstrated that loss of PKP2 could facilitate arrhythmias by decreasing sodium current [23,24], thus through an electrophysiologic effect. Indeed, in vitro characterization of the PKP2 mutations detected in patients with a BrS phenotype showed a decreased sodium current, consistent with the clinical phenotype [18] (Fig. 3). Super-resolution microscopy data showed that loss of PKP2 could affect proper trafficking of the sodium channel at the membrane, thus supporting the concept that proteins could have accessory roles aside from the primary one ascribed to them [18]. The role of the cardiac intercalated disc as a functional unit with both structural and electric regulatory functions has been opening new paths of investigations on the possible arrhythmogenic substrate in BrS [25]. An additional analysis on 45
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candidate genes in BrS patients not carrying a SCN5A mutation showed enrichment for another desmosomal gene, the DSC2 coding for desmocollin-2 [26], further supporting the hypothesis of a possible continuum between the 2 diseases. Although BrS is commonly referred to as an autosomal dominant Mendelian disease, several recent studies challenged this concept and proposed a role for a cumulative effect of common variants in modulating the phenotype. In 2009, Probst et al. [27] showed that in 5 large families, 8 mutation-negative family members had a diagnostic type 1 ECG pattern and they did not carry additional mutations on the SCN5A gene, questioning for the first time the pure Mendelian inheritance pattern and suggesting that the interaction of modulating factors could influence the ECG pattern and clinical presentation, such as it happens for complex diseases. Following up on these observations, Dr. Bezzina led a collaborative genome-wide association study of 312 BrS patients and 1115 controls providing evidence that some SNPs on the SCN10a and SCN5A genes had a cumulative effect in associating with likelihood of carrying a BrS phenotype [28]. More importantly, this study also identified SNPs in the Hey2 gene as associated with likelihood of disease. The Hey2 gene encodes for a transcription factor modulating transmural expression of ion channels, including Nav1.5, especially in the right ventricle [28]. Following up on this discovery, the same group recently demonstrated [29] that in the human heart, expression of Hey2 is correlated to one of the KCNIP2 genes, encoding for the Ito current and that in a mouse model Hey2 impacts the transmural depolarization
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and repolarization gradients across the ventricular wall, one of the most important mechanisms supposedly at the base of arrhythmias in BrS. This finding corroborated the prevalent involvement of the RVOT as the vulnerable area in BrS and substantiated the role of genetic modifiers as modulators of arrhythmic risk in the setting of the disease. This hypothesis is also offering a possible justification for the low percentage of patients with a positive genotype by conventional Mendelian genetics.
What is determining the ECG pattern and how are arrhythmias facilitated? The debate on which are the arrhythmogenic mechanisms in this disease is still ongoing with strong and compelling arguments from different groups [30]; as such, offering a definite answer is beyond the scope of this review. Certainly, which factors determine the peculiar ST segment pattern in humans remain a puzzling question. So far, no animal model has been able to reproduce a type 1 ECG morphology. Genetically engineered mice had provided some interesting data, but fail to reproduce all features of the BrS phenotype [31]. Our group recently developed the only large animal model carrying a truncated SCN5A mutation, an engineered knock-in minipig [32]. Even if the minipig showed marked conduction delay and increased susceptibility to ventricular fibrillation, especially in the setting of elevated body temperature (mimicking a fever-like trigger), no spontaneous coved ST segment elevation was recorded [32] (Fig. 4).
Fig. 4 – ECG and arrhythmias in the SCN5A E558X/þ knock-in minipig. (A) Left: baseline ECG and after administration of flecainide iv. Right: arrhythmias elicited by flecainide administration. (B) Volume conducted ECG in wild type (WT) and E558X/ þ minipig Langendorff perfused isolated hearts exposed to high temperature to mimic fever, showing occurrence of spontaneous arrhythmias in the E558X/þ hearts. (Reproduced with permission from Ref. [32].)
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Dr. Antzelevitch’s studies have proposed that the ST segment elevation pattern in BrS is determined by a transmural repolarization gradient between the RVOT epicardium and endocardium [30,33]; arrhythmias would arise when a trigger elicits a further shift in the balance of currents in the early phases of action potential through a phase 2 reentry mechanism. Most of the gradient imbalance is determined by either decreased sodium current (such as mediated by genetic mutations), which would cause a relative increase in the Ito current magnitude or by recently described gain of function mutations increasing the Ito current. Accordingly, the lack of Ito in the minipig action potential is argued by this group as one of the reasons as to why the animal did not show type 1 ECG pattern, although several other factors could have played a role. There is also a growing body of evidence that supports the hypothesis that the arrhythmogenic features in BrS are caused by delayed depolarization and that fibrosis and structural alterations at the RVOT play an important role [21,25,30,34]. Conduction slowing is recognized as one of the features of the disease and often patients present clinically with prolonged PR interval, some degree of right bundle branch block, and/or positive late potential at the SAECG [1,15]. Additionally, reports from explanted hearts or biopsies showed presence of right ventricular focal myocardial fibrosis, reduced connexin-43 signal and apoptosis, although overt structural abnormalities are rare [25,35]. This evidence also favors the argument of a possible tight correlation between BrS and ARVC. Genetic mutations linked to the disease are thought to decrease sodium current availability and increase conduction delay, and SCN5A mutations also have been associated with structural alterations [36–38]. Following this hypothesis, arrhythmias in BrS would be facilitated by conduction block and reentry caused by tissue discontinuity. Late activation at the RVOT may create a gradient between RVOT and RV resulting in the coved ST elevation and negative T wave seen in the type 1 ECG [30]. Although contrasting, probably the 2 advocated mechanisms are not necessarily mutually exclusive; for instance, there is agreement on the role that the RVOT exerts in defining the pathophysiology of BrS [34]. Importantly, these studies have provided an essential contribution to develop recent novel diagnostic approaches and therapeutic strategies. One peculiar feature typical only of BrS and early repolarization syndromes is the susceptibility to arrhythmias during enhanced parasympathetic tone. One interesting theory [39] is that high parasympathetic activity, such as during sleep or bradycardia, could increase the Ito current, facilitating ST elevation and arrhythmias. Paul et al. [40] showed in a preliminary study small samples of cardiac biopsies that BrS patients have lower levels of norepinephrine and cAMP, which they attributed to impaired stimulation of β-adrenoceptors; the reduced level of adrenergic impulse could create a predominant vagal tone facilitating arrhythmias. Although these are only preliminary studies, they open an interesting perspective on the role of sympathovagal imbalance and autonomic innervation as the arrhythmic substrate of the disease.
Risk stratification and therapeutic approaches Due to the lack of prophylactic medical treatment, identification of high-risk patients in BrS is of pivotal importance.
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Several studies agree on the presence of spontaneous coved ST segment elevation and history of syncope as the factors that select individuals at higher risk, for whom an implantable cardioverter defibrillator (ICD) is indicated [2,4,12,41–43]. Similarly, several studies have confirmed that individuals that are asymptomatic and are diagnosed based on a druginduced ECG remain at low arrhythmic risk throughout follow-up (event rate ranging from 0.27 [42] to 0.5 [12]). A still unresolved controversy remains the role of programmed electrical stimulation (PES) as a risk indicator. While data from a large cohort of 403 patients followed by a single center showed increased arrhythmic risk in inducible patients [43], several series from different investigators [12,41,42] failed to confirm that the test could have a positive and especially a negative predictive value. The latest results from a pooled analysis of 8 studies and ~1300 patients [42] showed that indeed arrhythmia inducibility with PES may indicate increased arrhythmic risk at follow-up, with the lower number of extrastimuli identifying the patients at higher risk. However, a negative PES was not a good indicator of a low risk. Indeed, subjects with no inducible arrhythmias, but showing type 1 ECG and history of syncope, still had a 2.55% risk of experiencing fatal arrhythmias at follow-up. These data emphasize the need for standardized PES protocols and reinforce the concept that an aggressive stimulation protocol may lead to an excess of false positive results. Overall, consensus has emerged on the need for additional clinical indicators that could sub-stratify those individuals that fall within the “intermediate risk” category. In the PRELUDE study [41], QRS fragmentation was a novel risk indicator, then confirmed by additional series [44]. Until preventive therapeutic approaches (beyond ICDs) become available, the quest for additional clinical parameters to identify patients at risk remains one of the open challenges in the management of BrS. The use of subcutaneous ICD, a device that has become available in the past few years, could potentially be a better approach in BrS, due to the relative young age of the patients and the existing reports of increased rate of complications with endocardial ICDs in the young population. Concerns have been raised [45], however, on the risk of reduced detection accuracy due to the peculiarity of the type 1 ECG morphology and QRS-to-T ratio, as well as the intermittent nature of the ECG and of a right bundle branch block pattern, which could all increase the possibility of inappropriate shocks. However, accurate pre-implant selection may limit if not completely control these risks and help identify those individuals that are more likely to benefit from a subcutaneous ICD. So far, the only medical therapy that could have some potential as a preventive approach for the disease is quinidine [2]. This drug blocks several ionic channels, with a recognized strong blockage effect on the Ito current, which is proposed to be the mechanism by which quinidine could control arrhythmias in BrS [33]. Several reports confirmed the effectiveness of quinidine, as well as of isoproterenol, to treat electric VT/VF storms [46]. The drug is also used to limit the incidence of shocks in symptomatic patients with an ICD [46]. Some encouraging data on the use of chronic quinidine therapy as an alternative to the ICD come from recent
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studies: the long-term experience of the Israeli group showed that patients inducible at PES were no longer inducible nor had arrhythmic events after quinidine therapy at 10 years follow-up [47]. Encouraging data on drug effectiveness also came from the results of the QUIDAM study, the first multicenter prospective randomized double-blind study with cross-over phases drug/placebo [48]. Unfortunately, the study had to be terminated prematurely because of the high number of discontinuation due to side effects, and because of the very low adverse event rate, which is typical of the natural history of BrS and a major limitation in gathering effective long-term data on drug effectiveness. Probably one of the most innovative approaches that could significantly change how to treat patients, if confirmed in large series and by different groups, is the use of right ventricular radiofrequency ablation therapy. Initially, Nademanee et al. [49] demonstrated in few high-risk patients that they were able to alter the arrhythmic substrate and obtain non-inducibility of VT/VF by using epicardial ablation in the RVOT aimed to sites with abnormal low voltage, prolonged duration and fractionated late potentials. They were also the first group to show that RVOT epicardial ablation could modify the type 1 ECG pattern in the majority of patients. Subsequently, this and other groups [49,50] further extended the epicardial ablation field using the sodium channel blockers challenge to select all areas with low voltage beyond the RVOT and often including the RV area to limit recurrences. The elimination of the type 1 ECG was also corroborated by repeating the pharmacologic challenge after the procedure [50]. Although these data still need to be supported by additional evidence, they have provided a new potential therapeutic venue offering a much-needed alternative to the management of BrS patients. It is also worth emphasizing how these clinical studies stemmed from decades of investigation in cellular and animal models that unraveled the role of the RVOT as the culprit anatomical area responsible for arrhythmias in BrS.
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Acknowledgments This work was supported by a Scientist Development Grant from the American Heart Association (#14SDG18580014).
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Conclusions The field of cardiovascular genetics is continuously evolving and BrS has been at the forefront of this progress. Several recent discoveries have been put forward by investigating this disease, from the evidence that minor genes may have been accepted too precipitously into clinical practice, to the possibility that Mendelian inheritance may not be the sole mode of transmission. Concepts learned from this experience are now explored and applied to other channelopathies. Furthermore, studies in the pathophysiology of this fascinating condition have been able to move from basic science experiments into the clinical sphere, providing a compelling argument into the need for translational studies in order to find better management strategies for patients.
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