PHYSIOLOGY IN MEDICINE In collaboration with The American Physiological Society, Thomas E. Andreoli, MD, Editor The Brugada Syndrome: Clinical, Genetic, Cellular, and Molecular Abnormalities Gerald V. Naccarelli, MD, and Charles Antzelevitch, PhD The Brugada syndrome is an arrhythmic syndrome character- ized by a right bundle branch block pattern and ST segment elevation in the right precordial leads of the electrocardiogram in conjunction with a high incidence of sudden death secondary to ventricular tachyarrhythmias. No evidence of structural heart disease is noted during diagnostic evaluation of these pa- tients. In 25% of families, there appears to be an autosomal dominant mode of transmission with variable expression of the abnormal gene. Mutations have been identified in the gene that encodes the alpha subunit of the sodium channel (SCN5A) on chromosome 3. This genetic defect causes a reduction in the density of the sodium current and explains the worsening of the above electrocardiographic abnormalities when patients are treated with sodium channel blocking antiarrhythmic agents, which further diminish the already reduced sodium current. The prognosis is poor with up to a 10% per year mortality. Antiarrhythmic drugs including beta-blockers and amiodarone have no benefit in prolonging survival. The treatment of choice is the insertion of an implantable cardioverter-defibrillator. Am J Med. 2001;110:573–581. q2001 by Excerpta Medica, Inc. A pproximately 5% of patients who experience sud- den cardiac death have no demonstrable struc- tural heart disease or obvious cause and are clas- sified as having idiopathic ventricular fibrillation (1– 4). A subgroup of these patients has been shown to manifest a right bundle branch block (RBBB) pattern, ST segment elevation in leads V1 to V3 (Figure 1), and a high inci- dence of sudden death. Such patients die suddenly, com- monly in their sleep, secondary to ventricular fibrillation (5–26). This combination has been labeled the Brugada syndrome (5,18). This disorder is often inherited with an autosomal dominant mode of transmission; the only mu- tations thus far linked to the syndrome appear in the gene that encodes for the alpha subunit of the sodium channel, SCN5A (5–26). This article reviews the clinical presenta- tion, the cellular and ionic bases for the syndrome, and the impact that our understanding of the molecular biol- ogy and genetics of this syndrome has had on rendering appropriate treatment to these patients. MOLECULAR GENETICS OF BRUGADA SYNDROME Genetic abnormalities have been discovered in several ar- rhythmic disorders, including the long QT (LQT) syn- drome, arrhythmogenic right ventricular dysplasia, con- duction system disease (Lenegre’s disease), and the Bru- gada syndrome (7,14,27) (Table). About 20% of patients with Brugada syndrome have documented SCN5A mu- tations (Figure 2) (17). Genetic studies have demon- strated that some cases of Brugada syndrome and chro- mosome 3–linked long-QT syndrome (LQT3) are allelic disorders of the cardiac sodium channel gene (SCN5A, 3p21). Three types of SCN5A mutations have been iden- tified in the Brugada syndrome: splice-donor, frame- shift, and missense (6,17). All of these lead to a reduction in the fast sodium channel current. In LQT3 the defect in the sodium channel causes a persistent late sodium cur- rent. An autosomal dominant SCN5A gene abnormality has also been shown to underlie a progressive cardiac conduction system disease (Lev’s or Lenegre’s disease) in two European families (27). In 1998, Chen et al (6) reported on six families and several sporadic cases of the Brugada syndrome. Linkage to known arrhythmogenic right ventricular dysplasia (ARVD) chromosomal loci was excluded at the outset. In three families, mutations in SCN5A were identified (6), including 1) a missense mutation (C-to-T base substitu- tion) causing a substitution of a highly conserved threo- nine by methionine at codon 1620 (T1620 M) in the ex- From the Division of Cardiology (GVN), Cardiovascular Center, Penn- sylvania State University College of Medicine, Hershey, Pennsylvania; and Masonic Medical Research Laboratory (CA), Utica, New York. Requests for reprints should be addressed to Gerald V. Naccarelli, MD, Department of Medicine, Division of Cardiology, Cardiovascular Center, Pennsylvania State University College of Medicine, 500 Univer- sity Drive, H047, Hershey, Pennsylvania 17033. q2001 by Excerpta Medica, Inc. 0002-9343/01/$–see front matter 573 All rights reserved. PII S0002-9343(01)00625-8
The Brugada Syndrome: Clinical, Genetic, Cellular, and Molecular Abnormalities
Oct 17, 2022
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
PII: S0002-9343(01)00625-8The American Physiological Society, Thomas E. Andreoli, MD, Editor
The Brugada Syndrome: Clinical, Genetic, Cellular, and Molecular Abnormalities
Gerald V. Naccarelli, MD, and Charles Antzelevitch, PhD
The Brugada syndrome is an arrhythmic syndrome character- ized by a right bundle branch block pattern and ST segment elevation in the right precordial leads of the electrocardiogram in conjunction with a high incidence of sudden death secondary to ventricular tachyarrhythmias. No evidence of structural heart disease is noted during diagnostic evaluation of these pa- tients. In 25% of families, there appears to be an autosomal dominant mode of transmission with variable expression of the abnormal gene. Mutations have been identified in the gene that encodes the alpha subunit of the sodium channel (SCN5A) on
chromosome 3. This genetic defect causes a reduction in the density of the sodium current and explains the worsening of the above electrocardiographic abnormalities when patients are treated with sodium channel blocking antiarrhythmic agents, which further diminish the already reduced sodium current. The prognosis is poor with up to a 10% per year mortality. Antiarrhythmic drugs including beta-blockers and amiodarone have no benefit in prolonging survival. The treatment of choice is the insertion of an implantable cardioverter-defibrillator. Am J Med. 2001;110:573–581. q2001 by Excerpta Medica, Inc.
Approximately 5% of patients who experience sud- den cardiac death have no demonstrable struc- tural heart disease or obvious cause and are clas-
sified as having idiopathic ventricular fibrillation (1– 4). A subgroup of these patients has been shown to manifest a right bundle branch block (RBBB) pattern, ST segment elevation in leads V1 to V3 (Figure 1), and a high inci- dence of sudden death. Such patients die suddenly, com- monly in their sleep, secondary to ventricular fibrillation (5–26). This combination has been labeled the Brugada syndrome (5,18). This disorder is often inherited with an autosomal dominant mode of transmission; the only mu- tations thus far linked to the syndrome appear in the gene that encodes for the alpha subunit of the sodium channel, SCN5A (5–26). This article reviews the clinical presenta- tion, the cellular and ionic bases for the syndrome, and the impact that our understanding of the molecular biol- ogy and genetics of this syndrome has had on rendering appropriate treatment to these patients.
MOLECULAR GENETICS OF BRUGADA SYNDROME
Genetic abnormalities have been discovered in several ar- rhythmic disorders, including the long QT (LQT) syn- drome, arrhythmogenic right ventricular dysplasia, con- duction system disease (Lenegre’s disease), and the Bru- gada syndrome (7,14,27) (Table). About 20% of patients with Brugada syndrome have documented SCN5A mu- tations (Figure 2) (17). Genetic studies have demon- strated that some cases of Brugada syndrome and chro- mosome 3–linked long-QT syndrome (LQT3) are allelic disorders of the cardiac sodium channel gene (SCN5A, 3p21). Three types of SCN5A mutations have been iden- tified in the Brugada syndrome: splice-donor, frame- shift, and missense (6,17). All of these lead to a reduction in the fast sodium channel current. In LQT3 the defect in the sodium channel causes a persistent late sodium cur- rent. An autosomal dominant SCN5A gene abnormality has also been shown to underlie a progressive cardiac conduction system disease (Lev’s or Lenegre’s disease) in two European families (27).
In 1998, Chen et al (6) reported on six families and several sporadic cases of the Brugada syndrome. Linkage to known arrhythmogenic right ventricular dysplasia (ARVD) chromosomal loci was excluded at the outset. In three families, mutations in SCN5A were identified (6), including 1) a missense mutation (C-to-T base substitu- tion) causing a substitution of a highly conserved threo- nine by methionine at codon 1620 (T1620 M) in the ex-
From the Division of Cardiology (GVN), Cardiovascular Center, Penn- sylvania State University College of Medicine, Hershey, Pennsylvania; and Masonic Medical Research Laboratory (CA), Utica, New York.
Requests for reprints should be addressed to Gerald V. Naccarelli, MD, Department of Medicine, Division of Cardiology, Cardiovascular Center, Pennsylvania State University College of Medicine, 500 Univer- sity Drive, H047, Hershey, Pennsylvania 17033.
q2001 by Excerpta Medica, Inc. 0002-9343/01/$–see front matter 573 All rights reserved. PII S0002-9343(01)00625-8
tracellular loop between transmembrane segments S3 and S4 of domain IV (DIVS3–DIVS4), an area important for coupling of channel activation to fast inactivation; 2) a two nucleotide insertion (AA), which disrupts the splice-donor sequence of intron 7 of SCN5A; and 3) a single nucleotide deletion (A) at codon 1397, which re- sults in an in-frame stop codon that eliminates DIIIS6, DIVS1–DIVS6, and the carboxy-terminus of SCN5A. Biophysical analysis of the mutants in Xenopus oocytes demonstrated a reduction in the number of functional sodium channels in both the splicing mutation and one- nucleotide deletion mutation, which would be expected to result in a marked reduction of sodium channel cur- rent. The T1620 M missense mutation, the most studied
of the Brugada mutations, was initially shown to shift the inactivation curve in the depolarizing direction and to accelerate the recovery of the channel from inactivation when coexpressed with the R1232W polymorphism (6). Makita et al (7) subsequently showed that when ex- pressed alone, T1620 M shifts steady-state inactivation to more positive potentials but does not accelerate recovery from inactivation. Coexpression of the b1 subunit (hB1) was found to shift the steady-state inactivation to still more positive potentials and to accelerate recovery from inactivation. These changes in the function of the channel could not adequately explain the phenotype of the Bru- gada syndrome. Dumaine et al (24) expressed the T1620 M mutation in a mammalian cell line (HEK293) and
Figure 1. Twelve-lead electrocardiogram demonstrating right bundle branch block and ST segment elevation in the right precordial leads in a patient with Brugada syndrome. Reprinted with permission from Circulation (41).
Table. Genetic Defects in Arrhythmic Syndromes
Gene or Chromosomal Locus
Brugada syndrome 1 SCN5A Decreased INa
Brugada syndrome 2 3p22-25 Unknown Long QT syndrome 1 KVLQT1 Decreased IKs
Long QT syndrome 2 HERG Decreased IKr
Long QT syndrome 3 SCN5A Increased INa
Long QT syndrome 5 KCNE1 Decreased IKs
Long QT syndrome 6 KCNE2 Decreased IKr
Conduction system disease SCN5A Decreased INa
Familial atrial fibrillation 10q22–q24 Unknown Arrhythmogenic right ventricular
dysplasia/cardiomyopathy 1q42–q43 Unknown 2q32.1–q32.3 Unknown 3p23 Unknown 14q12–q22 Unknown 14q23–q24 Unknown 17q21 (Naxos) Plakoglobin
Molecular Biology of Brugada Syndrome/Naccarelli and Antzelevitch
574 May 2001 THE AMERICAN JOURNAL OF MEDICINEt Volume 110
showed that at more physiological temperatures (32 to 408 C) the sodium channel inactivates prematurely and recovers from inactivation more slowly. The accelerated decay of sodium channel current is temperature sensitive and can be missed if studied at room temperature (24,25). The authors suggested that this temperature de- pendence might predispose patients with this mutation to the development of ventricular tachycardia/fibrillation during a febrile state. Subsequent experiments by Wang et al (25) coexpressed T1620 M with the b1 subunit and showed that the mutation causes the channel to enter an intermediate inactivation state from which it recovers more slowly. Wan et al (28) further demonstrated that when T1620 M, R1232W, and the b1 subunit are coex- pressed in HEK cells, sodium channel density is dramat- ically reduced because of failure of much of the channel protein to reach the cell membrane. These reports served to highlight the fact that the results of such studies are a sensitive function of the expression system, incubation temperature of the cell culture, recording temperature, as well as the presence or absence of the b1 subunit. The common denominator of the findings obtained from the studies performed in the HEK cells is that the T1620 M mutation importantly reduces sodium channel current density.
Veldkamp et al (20) demonstrated that the insertion of an amino acid (aspartic acid) at codon 1795 of SCN5A (1795insD) leads to a reduction of sodium channel cur- rent. This change is the result of a positive shift of the activation curve and negative shift of the inactivation curve coupled with a slowing of recovery of the sodium channel from inactivation. The insertion mutation also
caused a defect in inactivation of the channel, leading to augmentation of late sodium channel current. The effect of the mutation to reduce the early sodium current but augment late sodium current is consistent with the pre- sentation of both Brugada and LQT3 syndrome features in patients with this mutation.
CELLULAR BASIS FOR THE BRUGADA SYNDROME
Under normal conditions, the presence of an Ito-medi- ated action potential notch or spike and dome morphol- ogy in ventricular epicardium, but not endocardium, cre- ates a transmural voltage gradient responsible for the electrocardiographic J wave or J point elevation (29). A reduction in the density of the sodium channel current, as occurs with the inherited mutations discussed above, is known to accentuate the epicardial action potential notch leading to ST segment elevation secondary to the accen- tuation of the transmural voltage gradients normally re- sponsible for inscription of the J wave. If the epicardial repolarization precedes repolarization of the cells in M and endocardial regions, the T wave will remain positive and the result will be a saddleback form of ST segment elevation (Figure 3B). Further accentuation of the notch as a consequence of additional reduction of INa may be accompanied by a prolongation of the epicardial action potential such that the direction of the transmural voltage gradient is reversed, thus leading to the development of a coved-type of ST segment elevation and inversion of the T wave (Figure 3C), typically observed in the electrocar- diograms (ECG) of patients with Brugada syndrome. A delay in epicardial activation can also contribute to inver- sion of the T wave. Although the typical Brugada mor- phology is present at this juncture, the substrate for reen- try is not. A further shift in the balance of currents leads to loss of the action potential dome at some epicardial sites, which manifests in the ECG as a further ST segment ele- vation (Figure 3D). Loss of the action potential dome in epicardium but not endocardium results in the develop- ment of a marked transmural dispersion of repolariza- tion, which is responsible for the development of a vul- nerable window during which a premature impulse or extrasystole can induce a reentrant arrhythmia. More- over, loss of the epicardial action potential dome at some sites but not others creates a dispersion of repolarization within epicardium (Figure 3D) (30). Propagation of the action potential dome from sites at which it is maintained to sites at which it is lost causes local re-excitation by means of a phase 2–reentry mechanism. This causes the development of a very closely coupled extrasystole, which is capable of initiating circus movement reentry (Figures 3E and 4) (30,31). The phase 2 reentrant beat coincides with the negative T wave of the basic response causing
Figure 2. Mutations in the cardiac sodium gene SCN5A from different arrhythmic syndromes. In the Brugada syndrome, a splicing error at the donor site of intron 7 affects the first trans- membrane segment of domain I (6). In Lenegre’s disease, a splicing error at exon 22 is associated with the disease (17). In long QT3, there is a delta KPQ deletion at position 1505–1507 in the intercellular linker between domains III and IV (27). Re- printed with permission from J Cardiovasc Electrophysiol (66).
Molecular Biology of Brugada Syndrome/Naccarelli and Antzelevitch
May 2001 THE AMERICAN JOURNAL OF MEDICINEt Volume 110 575
fusion of the QRS of the extrasystole with the T wave of the preceding beat.
CLASS I AGENTS EXPRESSING BRUGADA SYNDROME ELECTROCARDIOGRAPHIC ABNORMALITY
The use of sodium channel blockers in an already dis- eased sodium channel can facilitate loss of the epicardial action potential dome and slowing conduction. These antiarrhythmics can cause the appearance of a RBBB pat- tern and ST elevation, and may even provoke spontane- ous premature ventricular contractions, ventricular
tachycardia, and/or ventricular fibrillation (Figure 5). The mechanism responsible for class I antiarrhythmic agents expressing the ECG abnormalities associated with the Brugada syndrome has been studied extensively (8,9,20,32–34). Recently, Priori et al (21) reported that there was an overlap between the LQT3 and the Brugada syndromes. In 12 of 13 patients with LQT3 syndrome, flecainide shortened the QT interval. In 6 of these 13 pa- tients, flecainide produced ST segment elevation in V1 through V3.
Sodium channel blockade appears to facilitate the loss of the right ventricular epicardial action dome by shifting the balance of current at the end of phase I of the action potential from inward to outward. Sodium channel blockers further diminish INa already reduced by Bru- gada mutations that speed up inactivation of INa. Some LQT3 mutations, including delta KPQ, accelerate inacti- vation of the early sodium current in addition to slowing inactivation of late INa. In both situations, the premature inactivation of the early current can leave Ito unopposed in the epicardium of the right ventricle, which has a denser Ito current than the left ventricular myocardium (29). This will cause a transmural voltage gradient that manifests itself as ST segment elevation in the right pre- cordial leads (Figure 3) (35,36). Pharmacological and/or pathophysiological changes in other currents can con- tribute to loss of the action potential dome in the right ventricle and thus precipitate the Brugada syndrome (Figure 4).
Figure 4. Cellular mechanisms proposed to underlie arrhyth- mogenesis in the Brugada syndrome.
Figure 3. Schematic showing right ventricular epicardial action potential changes thought to underlie the electrocardiographic manifestation of the Brugada syndrome. Modified from Eur Heart J (67), with permission.
Molecular Biology of Brugada Syndrome/Naccarelli and Antzelevitch
576 May 2001 THE AMERICAN JOURNAL OF MEDICINEt Volume 110
Because of the pivotal role of the transient outward current, agents that block Ito, including 4-aminopyridine and quinidine, have been shown to restore the action po- tential dome and electrical homogeneity, thus suppress- ing all arrhythmic activity in experimental models (30,37). Agents that potently block INa, but not Ito (fle- cainide, ajmaline, and procainamide), exacerbate or un- mask the Brugada syndrome, whereas those with actions to block both INa and Ito (eg, quinidine and disopyr- amide) may exert a therapeutic effect (30). The anticho- linergic effects of quinidine may also contribute to its effectiveness. In patients with the Brugada syndrome and various forms of idiopathic ventricular fibrillation, anec- dotal evidence exists for an ameliorative effect of quini- dine, an agent with Ito blocking actions (38 – 40).
CLINICAL GENETICS OF BRUGADA SYNDROME
Patients are usually male, Caucasian, and Asian with no reported cases in black Africans. In 25% of patients the genetics are unclear, and in 15% there is no family his- tory; these cases may represent sporadic mutations. In the Brugada syndrome, 25% of families have apparent auto- somal dominant inheritance with variable expression of the abnormal gene (41). Approximately 50% of offspring of affected patients develop the disease. Family members should be screened for the disease.
CLINICAL ASPECTS OF BRUGADA SYNDROME
Osher and Wolff (42) first identified the ECG pattern of RBBB with ST elevation in leads V1 to V3 (Figure 1). Shortly thereafter, Edeiken (43) identified persistent ST elevation without RBBB in 10 asymptomatic males and Levine et al (44) described ST elevation in the right chest leads and conduction block in the right ventricle in pa- tients with severe hyperkalemia. Several authors de- scribed the association of this ECG pattern with sudden death (45,46). In 1992, Josep and Pedro Brugada (5) de-
scribed 8 patients with a history of aborted sudden death and a distinct ECG pattern of RBBB, ST segment eleva- tions in the right precordial leads, and a normal QT in- terval in the absence of any structural heart disease. In 4 of the 8 patients, a family history was suggested. The finding of ST-elevation in the right chest leads has been observed in a variety of clinical and experimental settings and is not unique or diagnostic of Brugada syndrome itself. Situa- tions in which these ECG findings occur include electro- lyte or metabolic disorders, pulmonary or inflammatory diseases, and abnormalities of the central or peripheral nervous system. In the absence of these abnormalities, the term idiopathic ST elevation is often used.
The above ECG findings and associated sudden and unexpected death had been reported as a common prob- lem in Japan and Southeast Asia where it most commonly affects men during sleep (47–53). This disorder has been labeled as sudden and unexpected death syndrome (SUDS) or sudden unexpected nocturnal death syn- drome (SUNDS). General characteristics of SUDS in- clude young, healthy men in whom death occurs sud- denly with a groan, usually during sleep late at night. No precipitating factors are identified, and autopsy findings are generally negative (8). Life-threatening ventricular tachyarrhythmias as a primary cause of SUDS has been demonstrated, with ventricular fibrillation occurring in most cases. This syndrome probably is the same as Bru- gada syndrome, because the ECG in these patients typi- cally displays a RBBB morphology and a precordial injury pattern in V1 through V3.
Typically, medical histories and physical examinations are unremarkable. In a review of 163 cases reported in the literature up to 1998, men (n 5 150) far outnumbered women (n 5 13) (41). In this same review, 58% of pa- tients were of Asian ancestry. A family history of syncope, documented ventricular fibrillation, or sudden death was reported in 22% of the population. Among the 104 pa- tients who presented with symptoms, 76 had ventricular fibrillation and 28 had syncope. The remaining patients in this series had the typical electrocardiographic findings noted during screening of family members of the pro- band. Of 21 patients whose activity was reported at the
Figure 5. Antiarrhythmic provocation of right bundle branch block and ST segment elevation in the right precordial leads by intravenous ajmaline in a patient with Brugada syndrome whose baseline electrocardiogram (left panel) demonstrated no electro- cardiographic abnormalities. Panels 2 through 8 are changes noted over 5 minutes after intravenous ajmaline. The last panel on the right shows resolution of changes 10 minutes after administration of the drug. Modified from Am J Cardiol (64), with permission.
Molecular Biology of Brugada Syndrome/Naccarelli and Antzelevitch
May 2001 THE AMERICAN JOURNAL OF MEDICINEt Volume 110 577
time of their arrhythmic event, 17 events occurred at rest or during sleep.
ELECTROCARDIOGRAPHIC FINDINGS
The typical ECG findings (5,8,18) of the Brugada syn- drome suggest premature repolarization and/or conduc- tion delay in the right ventricle as noted by the ST seg- ment elevation in the right precordial leads and in some cases other leads (Figure 1). The ST segment elevation is typically down sloping and followed by a negative T wave, which differentiates it from early repolarization syn- drome (ERS). ST segment elevation in leads V2 to V4 with upward concavity and a positive T wave characterize ERS. No reciprocal ST segment depression is noted in most cases of the Brugada syndrome. Widened S waves in the lateral leads are usually absent, suggesting the absence of true right bundle branch block.
The presence of a right bundle branch block pattern in the right precordial leads was present in 12 of 22,027 sub- jects (.05%) in one study (54) and in 0.1% in another study of 3,585 asymptomatic subjects (55). The ECG can normalize transiently in up to 40% of cases, and this in- termittent nature can make diagnosis difficult. Sodium channel blocking agents, such as ajmaline, procainamide, flecainide, and propafenone, can accentuate the changes and be used as a diagnostic test (Figure 5) (8,9,20,32–34). Class IB sodium channel blockers have no effect on the ST segment elevation. Class IA or IC sodium channel blocker challenge can cause spontaneous ventricular fibrillation. Therefore, this testing should be done in a laboratory with cardiopulmonary resuscitation facilities. Stress test- ing and isoproterenol may normalize the abnormal ECG findings noted above (8,32).
BRUGADA SYNDROME AND ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA (ARVD)
Controversy exists concerning the possible association…
The Brugada Syndrome: Clinical, Genetic, Cellular, and Molecular Abnormalities
Gerald V. Naccarelli, MD, and Charles Antzelevitch, PhD
The Brugada syndrome is an arrhythmic syndrome character- ized by a right bundle branch block pattern and ST segment elevation in the right precordial leads of the electrocardiogram in conjunction with a high incidence of sudden death secondary to ventricular tachyarrhythmias. No evidence of structural heart disease is noted during diagnostic evaluation of these pa- tients. In 25% of families, there appears to be an autosomal dominant mode of transmission with variable expression of the abnormal gene. Mutations have been identified in the gene that encodes the alpha subunit of the sodium channel (SCN5A) on
chromosome 3. This genetic defect causes a reduction in the density of the sodium current and explains the worsening of the above electrocardiographic abnormalities when patients are treated with sodium channel blocking antiarrhythmic agents, which further diminish the already reduced sodium current. The prognosis is poor with up to a 10% per year mortality. Antiarrhythmic drugs including beta-blockers and amiodarone have no benefit in prolonging survival. The treatment of choice is the insertion of an implantable cardioverter-defibrillator. Am J Med. 2001;110:573–581. q2001 by Excerpta Medica, Inc.
Approximately 5% of patients who experience sud- den cardiac death have no demonstrable struc- tural heart disease or obvious cause and are clas-
sified as having idiopathic ventricular fibrillation (1– 4). A subgroup of these patients has been shown to manifest a right bundle branch block (RBBB) pattern, ST segment elevation in leads V1 to V3 (Figure 1), and a high inci- dence of sudden death. Such patients die suddenly, com- monly in their sleep, secondary to ventricular fibrillation (5–26). This combination has been labeled the Brugada syndrome (5,18). This disorder is often inherited with an autosomal dominant mode of transmission; the only mu- tations thus far linked to the syndrome appear in the gene that encodes for the alpha subunit of the sodium channel, SCN5A (5–26). This article reviews the clinical presenta- tion, the cellular and ionic bases for the syndrome, and the impact that our understanding of the molecular biol- ogy and genetics of this syndrome has had on rendering appropriate treatment to these patients.
MOLECULAR GENETICS OF BRUGADA SYNDROME
Genetic abnormalities have been discovered in several ar- rhythmic disorders, including the long QT (LQT) syn- drome, arrhythmogenic right ventricular dysplasia, con- duction system disease (Lenegre’s disease), and the Bru- gada syndrome (7,14,27) (Table). About 20% of patients with Brugada syndrome have documented SCN5A mu- tations (Figure 2) (17). Genetic studies have demon- strated that some cases of Brugada syndrome and chro- mosome 3–linked long-QT syndrome (LQT3) are allelic disorders of the cardiac sodium channel gene (SCN5A, 3p21). Three types of SCN5A mutations have been iden- tified in the Brugada syndrome: splice-donor, frame- shift, and missense (6,17). All of these lead to a reduction in the fast sodium channel current. In LQT3 the defect in the sodium channel causes a persistent late sodium cur- rent. An autosomal dominant SCN5A gene abnormality has also been shown to underlie a progressive cardiac conduction system disease (Lev’s or Lenegre’s disease) in two European families (27).
In 1998, Chen et al (6) reported on six families and several sporadic cases of the Brugada syndrome. Linkage to known arrhythmogenic right ventricular dysplasia (ARVD) chromosomal loci was excluded at the outset. In three families, mutations in SCN5A were identified (6), including 1) a missense mutation (C-to-T base substitu- tion) causing a substitution of a highly conserved threo- nine by methionine at codon 1620 (T1620 M) in the ex-
From the Division of Cardiology (GVN), Cardiovascular Center, Penn- sylvania State University College of Medicine, Hershey, Pennsylvania; and Masonic Medical Research Laboratory (CA), Utica, New York.
Requests for reprints should be addressed to Gerald V. Naccarelli, MD, Department of Medicine, Division of Cardiology, Cardiovascular Center, Pennsylvania State University College of Medicine, 500 Univer- sity Drive, H047, Hershey, Pennsylvania 17033.
q2001 by Excerpta Medica, Inc. 0002-9343/01/$–see front matter 573 All rights reserved. PII S0002-9343(01)00625-8
tracellular loop between transmembrane segments S3 and S4 of domain IV (DIVS3–DIVS4), an area important for coupling of channel activation to fast inactivation; 2) a two nucleotide insertion (AA), which disrupts the splice-donor sequence of intron 7 of SCN5A; and 3) a single nucleotide deletion (A) at codon 1397, which re- sults in an in-frame stop codon that eliminates DIIIS6, DIVS1–DIVS6, and the carboxy-terminus of SCN5A. Biophysical analysis of the mutants in Xenopus oocytes demonstrated a reduction in the number of functional sodium channels in both the splicing mutation and one- nucleotide deletion mutation, which would be expected to result in a marked reduction of sodium channel cur- rent. The T1620 M missense mutation, the most studied
of the Brugada mutations, was initially shown to shift the inactivation curve in the depolarizing direction and to accelerate the recovery of the channel from inactivation when coexpressed with the R1232W polymorphism (6). Makita et al (7) subsequently showed that when ex- pressed alone, T1620 M shifts steady-state inactivation to more positive potentials but does not accelerate recovery from inactivation. Coexpression of the b1 subunit (hB1) was found to shift the steady-state inactivation to still more positive potentials and to accelerate recovery from inactivation. These changes in the function of the channel could not adequately explain the phenotype of the Bru- gada syndrome. Dumaine et al (24) expressed the T1620 M mutation in a mammalian cell line (HEK293) and
Figure 1. Twelve-lead electrocardiogram demonstrating right bundle branch block and ST segment elevation in the right precordial leads in a patient with Brugada syndrome. Reprinted with permission from Circulation (41).
Table. Genetic Defects in Arrhythmic Syndromes
Gene or Chromosomal Locus
Brugada syndrome 1 SCN5A Decreased INa
Brugada syndrome 2 3p22-25 Unknown Long QT syndrome 1 KVLQT1 Decreased IKs
Long QT syndrome 2 HERG Decreased IKr
Long QT syndrome 3 SCN5A Increased INa
Long QT syndrome 5 KCNE1 Decreased IKs
Long QT syndrome 6 KCNE2 Decreased IKr
Conduction system disease SCN5A Decreased INa
Familial atrial fibrillation 10q22–q24 Unknown Arrhythmogenic right ventricular
dysplasia/cardiomyopathy 1q42–q43 Unknown 2q32.1–q32.3 Unknown 3p23 Unknown 14q12–q22 Unknown 14q23–q24 Unknown 17q21 (Naxos) Plakoglobin
Molecular Biology of Brugada Syndrome/Naccarelli and Antzelevitch
574 May 2001 THE AMERICAN JOURNAL OF MEDICINEt Volume 110
showed that at more physiological temperatures (32 to 408 C) the sodium channel inactivates prematurely and recovers from inactivation more slowly. The accelerated decay of sodium channel current is temperature sensitive and can be missed if studied at room temperature (24,25). The authors suggested that this temperature de- pendence might predispose patients with this mutation to the development of ventricular tachycardia/fibrillation during a febrile state. Subsequent experiments by Wang et al (25) coexpressed T1620 M with the b1 subunit and showed that the mutation causes the channel to enter an intermediate inactivation state from which it recovers more slowly. Wan et al (28) further demonstrated that when T1620 M, R1232W, and the b1 subunit are coex- pressed in HEK cells, sodium channel density is dramat- ically reduced because of failure of much of the channel protein to reach the cell membrane. These reports served to highlight the fact that the results of such studies are a sensitive function of the expression system, incubation temperature of the cell culture, recording temperature, as well as the presence or absence of the b1 subunit. The common denominator of the findings obtained from the studies performed in the HEK cells is that the T1620 M mutation importantly reduces sodium channel current density.
Veldkamp et al (20) demonstrated that the insertion of an amino acid (aspartic acid) at codon 1795 of SCN5A (1795insD) leads to a reduction of sodium channel cur- rent. This change is the result of a positive shift of the activation curve and negative shift of the inactivation curve coupled with a slowing of recovery of the sodium channel from inactivation. The insertion mutation also
caused a defect in inactivation of the channel, leading to augmentation of late sodium channel current. The effect of the mutation to reduce the early sodium current but augment late sodium current is consistent with the pre- sentation of both Brugada and LQT3 syndrome features in patients with this mutation.
CELLULAR BASIS FOR THE BRUGADA SYNDROME
Under normal conditions, the presence of an Ito-medi- ated action potential notch or spike and dome morphol- ogy in ventricular epicardium, but not endocardium, cre- ates a transmural voltage gradient responsible for the electrocardiographic J wave or J point elevation (29). A reduction in the density of the sodium channel current, as occurs with the inherited mutations discussed above, is known to accentuate the epicardial action potential notch leading to ST segment elevation secondary to the accen- tuation of the transmural voltage gradients normally re- sponsible for inscription of the J wave. If the epicardial repolarization precedes repolarization of the cells in M and endocardial regions, the T wave will remain positive and the result will be a saddleback form of ST segment elevation (Figure 3B). Further accentuation of the notch as a consequence of additional reduction of INa may be accompanied by a prolongation of the epicardial action potential such that the direction of the transmural voltage gradient is reversed, thus leading to the development of a coved-type of ST segment elevation and inversion of the T wave (Figure 3C), typically observed in the electrocar- diograms (ECG) of patients with Brugada syndrome. A delay in epicardial activation can also contribute to inver- sion of the T wave. Although the typical Brugada mor- phology is present at this juncture, the substrate for reen- try is not. A further shift in the balance of currents leads to loss of the action potential dome at some epicardial sites, which manifests in the ECG as a further ST segment ele- vation (Figure 3D). Loss of the action potential dome in epicardium but not endocardium results in the develop- ment of a marked transmural dispersion of repolariza- tion, which is responsible for the development of a vul- nerable window during which a premature impulse or extrasystole can induce a reentrant arrhythmia. More- over, loss of the epicardial action potential dome at some sites but not others creates a dispersion of repolarization within epicardium (Figure 3D) (30). Propagation of the action potential dome from sites at which it is maintained to sites at which it is lost causes local re-excitation by means of a phase 2–reentry mechanism. This causes the development of a very closely coupled extrasystole, which is capable of initiating circus movement reentry (Figures 3E and 4) (30,31). The phase 2 reentrant beat coincides with the negative T wave of the basic response causing
Figure 2. Mutations in the cardiac sodium gene SCN5A from different arrhythmic syndromes. In the Brugada syndrome, a splicing error at the donor site of intron 7 affects the first trans- membrane segment of domain I (6). In Lenegre’s disease, a splicing error at exon 22 is associated with the disease (17). In long QT3, there is a delta KPQ deletion at position 1505–1507 in the intercellular linker between domains III and IV (27). Re- printed with permission from J Cardiovasc Electrophysiol (66).
Molecular Biology of Brugada Syndrome/Naccarelli and Antzelevitch
May 2001 THE AMERICAN JOURNAL OF MEDICINEt Volume 110 575
fusion of the QRS of the extrasystole with the T wave of the preceding beat.
CLASS I AGENTS EXPRESSING BRUGADA SYNDROME ELECTROCARDIOGRAPHIC ABNORMALITY
The use of sodium channel blockers in an already dis- eased sodium channel can facilitate loss of the epicardial action potential dome and slowing conduction. These antiarrhythmics can cause the appearance of a RBBB pat- tern and ST elevation, and may even provoke spontane- ous premature ventricular contractions, ventricular
tachycardia, and/or ventricular fibrillation (Figure 5). The mechanism responsible for class I antiarrhythmic agents expressing the ECG abnormalities associated with the Brugada syndrome has been studied extensively (8,9,20,32–34). Recently, Priori et al (21) reported that there was an overlap between the LQT3 and the Brugada syndromes. In 12 of 13 patients with LQT3 syndrome, flecainide shortened the QT interval. In 6 of these 13 pa- tients, flecainide produced ST segment elevation in V1 through V3.
Sodium channel blockade appears to facilitate the loss of the right ventricular epicardial action dome by shifting the balance of current at the end of phase I of the action potential from inward to outward. Sodium channel blockers further diminish INa already reduced by Bru- gada mutations that speed up inactivation of INa. Some LQT3 mutations, including delta KPQ, accelerate inacti- vation of the early sodium current in addition to slowing inactivation of late INa. In both situations, the premature inactivation of the early current can leave Ito unopposed in the epicardium of the right ventricle, which has a denser Ito current than the left ventricular myocardium (29). This will cause a transmural voltage gradient that manifests itself as ST segment elevation in the right pre- cordial leads (Figure 3) (35,36). Pharmacological and/or pathophysiological changes in other currents can con- tribute to loss of the action potential dome in the right ventricle and thus precipitate the Brugada syndrome (Figure 4).
Figure 4. Cellular mechanisms proposed to underlie arrhyth- mogenesis in the Brugada syndrome.
Figure 3. Schematic showing right ventricular epicardial action potential changes thought to underlie the electrocardiographic manifestation of the Brugada syndrome. Modified from Eur Heart J (67), with permission.
Molecular Biology of Brugada Syndrome/Naccarelli and Antzelevitch
576 May 2001 THE AMERICAN JOURNAL OF MEDICINEt Volume 110
Because of the pivotal role of the transient outward current, agents that block Ito, including 4-aminopyridine and quinidine, have been shown to restore the action po- tential dome and electrical homogeneity, thus suppress- ing all arrhythmic activity in experimental models (30,37). Agents that potently block INa, but not Ito (fle- cainide, ajmaline, and procainamide), exacerbate or un- mask the Brugada syndrome, whereas those with actions to block both INa and Ito (eg, quinidine and disopyr- amide) may exert a therapeutic effect (30). The anticho- linergic effects of quinidine may also contribute to its effectiveness. In patients with the Brugada syndrome and various forms of idiopathic ventricular fibrillation, anec- dotal evidence exists for an ameliorative effect of quini- dine, an agent with Ito blocking actions (38 – 40).
CLINICAL GENETICS OF BRUGADA SYNDROME
Patients are usually male, Caucasian, and Asian with no reported cases in black Africans. In 25% of patients the genetics are unclear, and in 15% there is no family his- tory; these cases may represent sporadic mutations. In the Brugada syndrome, 25% of families have apparent auto- somal dominant inheritance with variable expression of the abnormal gene (41). Approximately 50% of offspring of affected patients develop the disease. Family members should be screened for the disease.
CLINICAL ASPECTS OF BRUGADA SYNDROME
Osher and Wolff (42) first identified the ECG pattern of RBBB with ST elevation in leads V1 to V3 (Figure 1). Shortly thereafter, Edeiken (43) identified persistent ST elevation without RBBB in 10 asymptomatic males and Levine et al (44) described ST elevation in the right chest leads and conduction block in the right ventricle in pa- tients with severe hyperkalemia. Several authors de- scribed the association of this ECG pattern with sudden death (45,46). In 1992, Josep and Pedro Brugada (5) de-
scribed 8 patients with a history of aborted sudden death and a distinct ECG pattern of RBBB, ST segment eleva- tions in the right precordial leads, and a normal QT in- terval in the absence of any structural heart disease. In 4 of the 8 patients, a family history was suggested. The finding of ST-elevation in the right chest leads has been observed in a variety of clinical and experimental settings and is not unique or diagnostic of Brugada syndrome itself. Situa- tions in which these ECG findings occur include electro- lyte or metabolic disorders, pulmonary or inflammatory diseases, and abnormalities of the central or peripheral nervous system. In the absence of these abnormalities, the term idiopathic ST elevation is often used.
The above ECG findings and associated sudden and unexpected death had been reported as a common prob- lem in Japan and Southeast Asia where it most commonly affects men during sleep (47–53). This disorder has been labeled as sudden and unexpected death syndrome (SUDS) or sudden unexpected nocturnal death syn- drome (SUNDS). General characteristics of SUDS in- clude young, healthy men in whom death occurs sud- denly with a groan, usually during sleep late at night. No precipitating factors are identified, and autopsy findings are generally negative (8). Life-threatening ventricular tachyarrhythmias as a primary cause of SUDS has been demonstrated, with ventricular fibrillation occurring in most cases. This syndrome probably is the same as Bru- gada syndrome, because the ECG in these patients typi- cally displays a RBBB morphology and a precordial injury pattern in V1 through V3.
Typically, medical histories and physical examinations are unremarkable. In a review of 163 cases reported in the literature up to 1998, men (n 5 150) far outnumbered women (n 5 13) (41). In this same review, 58% of pa- tients were of Asian ancestry. A family history of syncope, documented ventricular fibrillation, or sudden death was reported in 22% of the population. Among the 104 pa- tients who presented with symptoms, 76 had ventricular fibrillation and 28 had syncope. The remaining patients in this series had the typical electrocardiographic findings noted during screening of family members of the pro- band. Of 21 patients whose activity was reported at the
Figure 5. Antiarrhythmic provocation of right bundle branch block and ST segment elevation in the right precordial leads by intravenous ajmaline in a patient with Brugada syndrome whose baseline electrocardiogram (left panel) demonstrated no electro- cardiographic abnormalities. Panels 2 through 8 are changes noted over 5 minutes after intravenous ajmaline. The last panel on the right shows resolution of changes 10 minutes after administration of the drug. Modified from Am J Cardiol (64), with permission.
Molecular Biology of Brugada Syndrome/Naccarelli and Antzelevitch
May 2001 THE AMERICAN JOURNAL OF MEDICINEt Volume 110 577
time of their arrhythmic event, 17 events occurred at rest or during sleep.
ELECTROCARDIOGRAPHIC FINDINGS
The typical ECG findings (5,8,18) of the Brugada syn- drome suggest premature repolarization and/or conduc- tion delay in the right ventricle as noted by the ST seg- ment elevation in the right precordial leads and in some cases other leads (Figure 1). The ST segment elevation is typically down sloping and followed by a negative T wave, which differentiates it from early repolarization syn- drome (ERS). ST segment elevation in leads V2 to V4 with upward concavity and a positive T wave characterize ERS. No reciprocal ST segment depression is noted in most cases of the Brugada syndrome. Widened S waves in the lateral leads are usually absent, suggesting the absence of true right bundle branch block.
The presence of a right bundle branch block pattern in the right precordial leads was present in 12 of 22,027 sub- jects (.05%) in one study (54) and in 0.1% in another study of 3,585 asymptomatic subjects (55). The ECG can normalize transiently in up to 40% of cases, and this in- termittent nature can make diagnosis difficult. Sodium channel blocking agents, such as ajmaline, procainamide, flecainide, and propafenone, can accentuate the changes and be used as a diagnostic test (Figure 5) (8,9,20,32–34). Class IB sodium channel blockers have no effect on the ST segment elevation. Class IA or IC sodium channel blocker challenge can cause spontaneous ventricular fibrillation. Therefore, this testing should be done in a laboratory with cardiopulmonary resuscitation facilities. Stress test- ing and isoproterenol may normalize the abnormal ECG findings noted above (8,32).
BRUGADA SYNDROME AND ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA (ARVD)
Controversy exists concerning the possible association…
Related Documents
