This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brugada, R. Articles by Brugada, P. Search for Related Content PubMed PubMed Citation Articles by Brugada, R. Articles by Brugada, P. Related Collections Clinical genetics Arrhythmias, clinical electrophysiology, drugs Arrythmias-basic studies

(Circulation. 2000;101:510.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Sodium Channel Blockers Identify Risk for Sudden Death in Patients With ST-Segment Elevation and Right Bundle Branch Block but Structurally Normal Hearts

Ramon Brugada, MD; Josep Brugada, MD; Charles Antzelevitch, PhD; Glenn E. Kirsch, PhD; Domenico Potenza, MD; Jeffrey A. Towbin, MD; Pedro Brugada, MD

From the Departments of Cardiology (R.B.) and Pediatrics (J.A.T.), Baylor College of Medicine, Houston, Texas; the Arrhythmia Unit, Cardiovascular Institute, Hospital Clínic, University of Barcelona, Barcelona, Spain (J.B.); the Masonic Medical Research Laboratory, Utica, New York (C.A.); the Rammelkamp Center for Research, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio (G.E.K); the Cardiology Department, Casa Sollievo della Sofferenza, S. Giovani Rotondo, Italy (D.P.); and the Cardiovascular Center, OLV Hospital, Aalst, Belgium (P.B.).

Correspondence to Dr Josep Brugada, Arrhythmia Unit, Cardiovascular Institute, Hospital Clínic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain. E-mail jepbrugada{at}grn.es

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background—A mutation in the cardiac sodium channel gene (SCN5A) has been described in patients with the syndrome of right bundle branch block, ST-segment elevation in leads V1 to V3, and sudden death (Brugada syndrome). These electrocardiographic manifestations are transient in many patients with the syndrome. The present study examined arrhythmic risk in patients with overt and concealed forms of the disease and the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk.

Methods and Results—The effect of intravenous ajmaline (1 mg/kg), procainamide (10 mg/kg), or flecainide (2 mg/kg) on the ECG was studied in 34 patients with the syndrome and transient normalization of the ECG (group A), 11 members of 3 families in whom a SCN5A mutation was associated with the syndrome and 8 members in whom it was not (group B), and 53 control subjects (group C). Ajmaline, procainamide, or flecainide administration resulted in ST-segment elevation and right bundle branch block in all patients in group A and in all 11 patients with the mutation in group B. A similar pattern could not be elicited in the 8 patients in group B who lacked the mutation or in any person in group C. The follow-up period (37±33 months) revealed no differences in the incidence of arrhythmia between the 34 patients in whom the phenotypic manifestation of the syndrome was transient and the 24 patients in whom it was persistent (log-rank, 0.639).

Conclusions—The data demonstrated a similar incidence of potentially lethal arrhythmias in patients displaying transient versus persistent ST-segment elevation and right bundle branch block, as well as the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk.

Key Words: electrocardiography • death, sudden • fibrillation • antiarrhythmia agents

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Approximately 5% of patients who experience sudden death have no demonstrable structural heart disease or other external cause responsible for the episode.^{1 2} These patients are generally classified as presenting with idiopathic ventricular fibrillation. Patients without demonstrable structural heart disease who have an ECG showing right bundle branch block (RBBB) and ST-segment elevation in leads V1 to V3 are at high risk for sudden death.^{3 4 5} The recent demonstration of an association with mutations in SCN5A, the cardiac sodium channel gene, provides further support for the hypothesis that this syndrome is primarily an electrical disease, separate and distinct from previously described arrhythmogenic disorders accompanied by structural changes in the heart.⁶

The ECG pattern in these patients has been extensively studied; it shows variations over time, including transient normalization. In addition, these ECG patterns are modulated by autonomic and antiarrhythmic interventions.^{7 8} Normalization of the ECG signature of this syndrome by whatever mechanism may lead to an underestimation of the prevalence of the disease, thus placing some patients at risk. It is, therefore, of some importance to identify whether patients with the concealed versus overt syndrome are at similar risks for arrhythmic events and, if so, to identify an approach to unmask those cases that are concealed. Because genetic anomalies in the cardiac sodium channel are involved in the pathophysiology of this disease,⁶ we examined the effect of 3 sodium channel blockers representing antiarrhythmia classes IA and IC.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Patients
Since 1992, we have collected data on 58 symptomatic patients who experienced episodes of sudden cardiac death due to ventricular fibrillation who did not have demonstrable structural heart disease but did have an ECG pattern of RBBB and ST-segment elevation in leads V1 to V3. Repeated ECG analysis revealed persistent anomalies in 24 of these patients (21 men; mean age, 49±15 years) and transient normalization of the ECG pattern in 34 (31 men; mean age, 42±19 years) (group A).

In 1995, we identified a familial form of the syndrome in which the disease was associated with a mutation in the cardiac sodium channel gene. The case index in the family experienced sudden death at age 23 and displayed the typical ECG pattern. The 13 living individuals of the family were screened. All members had a genotypic test, but 3 refused the intravenous administration of antiarrhythmic drugs. Two family members presented with a RBBB/ST-segment elevation ECG pattern. No other family members displayed an abnormal ECG at baseline. Since then, 2 other families with the syndrome and a mutation in the sodium channel gene have been identified and screened. One consisted of 5 members; 2 of them transiently presented with the typical ECG pattern. The other consisted of 4 members; one had the persistent ECG pattern (group B: 19 total tested, 8 men; mean age, 35±16 years).

We also evaluated the effects of sodium channel blockers in 53 patients without the syndrome (group C). Of them, 8 patients had arrhythmogenic right ventricular dysplasia, (6 men; mean age, 35±12 years), 10 patients had isolated RBBB (8 men; mean age, 43±14 years), and 35 patients had no previous history of syncope, ventricular arrhythmias, or sudden death and did have a normal ECG (30 men; mean age, 37±12 years).

Drug Administration
After written informed consent was obtained, a single intravenous dose of one sodium channel blocker was administered to all patients in the 3 groups. Each patient received a single drug. The use of each drug was determined based on the availability of the drug at each center, although the use of ajmaline was encouraged. The patients were studied in the Electrophysiology Laboratory, where continuous ECG recordings were obtained. In 77 patients, 1 mg/kg ajmaline was administered over a 5-minute period. In 14 patients, 2 mg/kg flecainide was administered over a 5-minute period, and in the remaining 15 patients, 10 mg/kg procainamide was infused at a rate of 100 mg/min. The ECG changes during the infusion were considered positive when a terminal R wave and ST-segment elevation (>1 mm) occurred in leads V1 to V3. Each ECG was reviewed blindly by 2 of the authors who did not perform the test.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Concordance between the 2 observers was 100% in patients in groups A and B. In 2 patients in group C, a discordance occurred between the 2 observers. These 2 cases were finally considered negative after consulting a third blinded observer (Figure 1). Ajmaline, flecainide, or procainamide tests were positive in all 34 patients in group A. Administration of a sodium channel blocker during transient ECG normalization resulted in an ST-segment elevation/RBBB ECG pattern in all group A patients (Figure 2). In group B, the ajmaline test was positive in 11 patients and negative in 8 patients. Genotype analysis of the family demonstrated that the ajmaline test was positive only in those 11 patients who had the mutation in the cardiac sodium channel gene (Figures 3 through 5). In contrast, sodium blockade was negative in all group C patients, including the 8 with arrhythmogenic right ventricular dysplasia, the 10 with isolated RBBB, and the 35 without a previous history of syncope or sudden death (Figure 3). In patients with a positive test, mean ST-segment elevation in lead V2 was 0.27±0.09 mV (Table). When comparing the effects of different drugs, ajmaline and flecainide tended to produce greater ST-segment elevation than procainamide, but this difference was not statistically significant.

View larger version (126K): [in this window] [in a new window]   Figure 1. Twelve surface ECG leads in a patient in control group during basal conditions (top; PRE) and after administration of 1 mg/kg IV ajmaline (bottom; POST). Note occurrence of RBBB after ajmaline administration (S wave in I and V6). One observer classified this ECG as doubtful. However, detailed analysis showed no ST segment changes after ajmaline administration, and the test was finally considered negative.

View larger version (112K): [in this window] [in a new window]   Figure 2. Surface ECG from patient with no demonstrable structural heart disease but who experienced ventricular fibrillation. One week after arrhythmic event, ECG showed RBBB and ST-segment elevation in leads V1 through V3 (Basal). One month after arrhythmic event, ECG was normalized (PRE); however, administration of 1 mg/kg IV ajmaline unmasked electrocardiographic abnormalities (POST).

View larger version (15K): [in this window] [in a new window]   Figure 3. Genealogical tree of familial form of syndrome of RBBB and ST-segment elevation in V1 through V3. Filled symbols indicate affected members; open symbols, unaffected members; slashed symbols, uncertain data; NEG, negative; POS, positive; N/A, not available; WT, wild type; and T/M, T1640M mutation in cardiac sodium channel in chromosome 3. The star and the dot refer to Figure 4.

View larger version (24K): [in this window] [in a new window]   Figure 4. Electrocardiographic leads V1, V2, and V3 from 2 members of family shown in Figure 3, before (PRE) and after (POST) administration of single intravenous dose of 1 mg/kg ajmaline. Left panels are from an affected patient (marked with star in Figure 3), and right panels are from an unaffected patient (marked with dot in Figure 3).

View larger version (79K): [in this window] [in a new window]   Figure 5. Twelve-lead surface ECG from an asymptomatic family member of a patient with syndrome who has a proven mutation. Administration of single intravenous dose of 1 mg/kg ajmaline resulted in abrupt occurrence of electrocardiographic abnormalities. Ten minutes after end of ajmaline administration, ECG became normal again. Numbers indicate minutes (’) and seconds (") after initiation of drug administration (START). END denotes end of drug administration.

View this table: [in this window] [in a new window]   Table 1. Effects of Class I Antiarrhythmic Drugs on ECG Parameters

One patient in group A developed spontaneous ventricular fibrillation during the infusion of the drug. Frequent ventricular premature beats were observed during infusion in 5 other patients with a positive test (4 in group A and 1 in group B).

Follow-Up
During a mean follow-up of 43±32 months in the 34 patients in group A diagnosed with a transiently concealed syndrome, 12 (35%) experienced recurring arrhythmic events consisting of ventricular fibrillation or sudden death. Among the 24 patients who displayed a persistent RBBB/ST-segment elevation, 5 (21%) experienced recurrent ventricular fibrillation or sudden death during a mean follow-up of 28±34 months (P=0.23). Kaplan-Meier analysis showed no differences in outcome between both groups (log-rank, 0.639) (Figure 6).

View larger version (12K): [in this window] [in a new window]   Figure 6. Kaplan-Meier curves of recurring arrhythmic events (sudden death or aborted sudden death due to ventricular fibrillation [VF] or appropriate shock from implantable defibrillator) in patients with permanent electrocardiographic abnormalities (solid line) and patients with transient normalization of ECG pattern (dotted line).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Since the initial description of the syndrome of RBBB, ST-segment elevation in leads V1 to V3, and sudden cardiac death,³ many patients with it have been identified worldwide.^{4 5 9 10 11 12} Discovery of a genetic basis associated with an ion channel defect confirms the primarily electrical nature of the disease.⁶ Transient normalization and modulation of the ECG pattern by antiarrhythmic drugs has been described.^{7 8 12} Our results demonstrate that patients with the concealed form of the disease are at a similar risk for ventricular fibrillation and sudden death as those who manifest ST-segment elevation and RBBB persistently. These findings suggest that the syndrome may be underdiagnosed and that failure to unmask the disease may place patients at considerable risk. The high degree of concordance among different observers shows that the anomalies are easily recognized and could be identified by nonspecialists.

Our data demonstrated the ability of ajmaline, flecainide, and procainamide to identify patients in whom the syndrome is concealed. Administration of the drug during transient normalization of the ECG in patients previously recognized as having the syndrome unmasked the ECG pattern characteristic of the syndrome. However, administration of the drug did not result in a similar pattern in any of the controls, even if they presented with isolated RBBB or arrhythmogenic right ventricular dysplasia. Moreover, in a given family, only individuals with a proven mutation of the cardiac sodium channel tested positive. Thus, the data demonstrated both a high sensitivity and specificity for the ability of these sodium channel blockers to unmask the syndrome.

Our findings also serve to further distinguish this syndrome from that of arrhythmogenic right ventricular dysplasia. Although structural heart disease could not be demonstrated in any of our patients, some authors have suggested that the ECG pattern could be the expression of right ventricular cardiomyopathy.¹³ However, the changing nature of the ECG pattern, the lack of ECG modification during class I drug testing in patients with proven right ventricular dysplasia, and the genetic data associating the syndrome with mutations in the cardiac sodium channel gene that are completely different from the loci thus far identified in familial forms of right ventricular dysplasia argue against this.

The occurrence of frequent ventricular premature beats in 5 patients and the spontaneous development of ventricular fibrillation in 1 patient during ajmaline administration indicate the need to perform such tests in an appropriate environment, where cardiopulmonary resuscitation facilities are available.

The mechanisms responsible for the electrocardiographic actions of class I antiarrhythmia agents in patients with Brugada syndrome have been the subject of extensive study by Antzelevitch and others.^{14 15} On the basis of these studies, our working hypothesis is that a strong sodium channel block facilitates the loss of the right ventricular epicardial action dome (plateau phase) by altering the balance of current at the end of phase 1 of the action potential from inward to outward. The result is an all or none repolarization of the right ventricular epicardial action potential and marked abbreviation of the epicardial action potential duration. The loss of the dome in right ventricular epicardium but not endocardium creates a transmural voltage gradient that manifests as an ST-segment elevation in the right precordial leads of the ECG and a transmural dispersion of refractoriness that can serve as the substrate for the development of functional reentry.

Loss of the action potential dome at some right ventricular epicardial sites but not others leads to the development of closely coupled extrasystoles via phase 2 reentry. When these extrasystoles capture the vulnerable window created by the transmural dispersion of refractoriness, they precipitate ventricular arrhythmias.

Because a prominent I_to (transient outward current) is pivotal to this mechanism, inhibition of I_to (with 4-aminopyridine) can restore the dome and normalize ST-segment elevation. Isoproterenol and dobutamine are also capable of restoring the dome via augmentation of I_Ca (calcium current). The much greater density of I_to in right versus left ventricular epicardium may also explain why Brugada syndrome is a right ventricular disease.

Limitations of the Study
The major limitation of this study is the limited number of patients with a known genotype. This group of patients is the only one in which we have a certain diagnosis; this allows the study of the sensitivity and specificity of the test. Also, results on genotyped patients are limited to individuals with a mutation in the coding region of the sodium channel. It is not known if the test performed in patients with Brugada syndrome and a different genetic defect will have the same power to unmask concealed forms of the disease.

	Footnotes

 
Guest editor for this article was Dan M. Roder, MD, Vanderbilt University, Nashville, Tennessee.

Received February 23, 1999; revision received August 30, 1999; accepted September 15, 1999.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Wever EFD, Hauer RNW, Oomen A, Peters RHJ, Bakker PFA, Robles de Medina EO. Unfavorable outcome in patients with primary electrical disease who survived an episode of ventricular fibrillation. Circulation. 1993;88:1021–1029.[Abstract/Free Full Text]
   
2. Viskin S, Belhassen B. Idiopathic ventricular fibrillation. Am Heart J. 1990;120:661–671.[Medline] [Order article via Infotrieve]
   
3. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. J Am Coll Cardiol. 1992;20:1391–1396.[Abstract]
   
4. Brugada J, Brugada R, Brugada P. Right bundle branch block and ST segment elevation in leads V1 through V3: a marker for sudden death in patients without demonstrable structural heart disease. Circulation. 1998;97:457–460.[Abstract/Free Full Text]
   
5. Nademannee K, Veerakul G, Nimmannit S, Chaowakul V, Bhuripanyo K, Likittanasombat K, Tunsanga K, Kuasirikul S, Malasit P, Tansupasawadikul S, Tatsanavivat P. Arrhythmogenic marker for the sudden unexplained death syndrome in Thai men. Circulation. 1997;96:2595–2600.[Abstract/Free Full Text]
   
6. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, Ortiz-López R, Wang Z, Antzelevitch C, O’Brien RE, Schulze-Bahr E, Keating M, Towbin JA, Wang Q. Genetic basis and molecular mechanisms for idiopathic ventricular fibrillation. Nature. 1998;392:293–296.[Medline] [Order article via Infotrieve]
   
7. Miyazaki T, Mitamura H, Miyoshi S, Soejima K, Aizawa Y, Ogawa S. Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome. J Am Coll Cardiol. 1996;27:1061–1070.[Abstract]
   
8. Brugada J, Brugada P. Further characterization of the syndrome of right bundle branch block, ST segment elevation and sudden cardiac death. J Cardiovasc Electrophysiol. 1997;8:325–331.[Medline] [Order article via Infotrieve]
   
9. Viskin S, Belhassen B. When you only live twice. N Engl J Med. 1995;332:1221–1225.[Free Full Text]
   
10. Bjerregaard P, Gussak I, Kotar SL, Gessler JE, Janosik D. Recurrent syncope in a patient with a prominent J wave. Am Heart J. 1994;127:1426–1430.[Medline] [Order article via Infotrieve]
    
11. Proclemer A, Facchin D, Feruglio GA, Nucifora R. Recurrent ventricular fibrillation, right bundle branch block and persistent ST segment elevation in V1–V3: a new arrhythmia syndrome? G Ital Cardiol. 1993;23:1211–1218.[Medline] [Order article via Infotrieve]
    
12. Chinushi M, Aizawa Y, Ogawa Y, Shiba M, Takahashi K. Discrepant drug action of disopyramide on ECG abnormalities and induction of ventricular arrhythmias in a patient with Brugada syndrome. J Electrocardiol. 1997;30:133–136.[Medline] [Order article via Infotrieve]
    
13. Corrado D, Nava A, Buja G, Martini B, Fasoli G, Oselladore L, Turrini P, Thiene G. Familial cardiomyopathy underlies syndrome of right bundle branch block, ST segment elevation and sudden death. J Am Coll Cardiol. 1996;27:443–448.[Abstract]
    
14. Antzelevitch C. The Brugada syndrome. J Cardiovasc Electrophysiol. 1998;9:513–516.[Medline] [Order article via Infotrieve]
    
15. Gussak I, Antzelevitch C, Bjerregaard P, Towbin JA, Chaitman BR. The Brugada syndrome: clinical, electrophysiologic and genetic aspects. J Am Coll Cardiol. 1999;33:5–15.[Abstract/Free Full Text]
    

This article has been cited by other articles:

				L. Baty, J. Hollister, and J. D. Tobias Perioperative Management of a 7-Year-Old Child With Brugada Syndrome J Intensive Care Med, May 1, 2008; 23(3): 210 - 214. [Abstract] [PDF]

				S. Nagase, K. F. Kusano, H. Morita, N. Nishii, K. Banba, A. Watanabe, S. Hiramatsu, K. Nakamura, S. Sakuragi, and T. Ohe Longer Repolarization in the Epicardium at the Right Ventricular Outflow Tract Causes Type 1 Electrocardiogram in Patients With Brugada Syndrome J. Am. Coll. Cardiol., March 25, 2008; 51(12): 1154 - 1161. [Abstract] [Full Text] [PDF]

				P.-S. Chen and S. G. Priori The Brugada Syndrome J. Am. Coll. Cardiol., March 25, 2008; 51(12): 1176 - 1180. [Full Text] [PDF]

				R. Veeraraghavan and S. Poelzing Mechanisms underlying increased right ventricular conduction sensitivity to flecainide challenge Cardiovasc Res, March 1, 2008; 77(4): 749 - 756. [Abstract] [Full Text] [PDF]

				I. Six, J.-S. Hermida, H. Huang, L. Gouas, V. Fressart, N. Benammar, B. Hainque, I. Denjoy, M. Chahine, and P. Guicheney The occurrence of Brugada syndrome and isolated cardiac conductive disease in the same family could be due to a single SCN5A mutation or to the accidental association of both diseases Europace, January 1, 2008; 10(1): 79 - 85. [Abstract] [Full Text] [PDF]

				B. London, M. Michalec, H. Mehdi, X. Zhu, L. Kerchner, S. Sanyal, P. C. Viswanathan, A. E. Pfahnl, L. L. Shang, M. Madhusudanan, et al. Mutation in Glycerol-3-Phosphate Dehydrogenase 1 Like Gene (GPD1-L) Decreases Cardiac Na+ Current and Causes Inherited Arrhythmias Circulation, November 13, 2007; 116(20): 2260 - 2268. [Abstract] [Full Text] [PDF]

				H. Furushima, M. Chinushi, K. Okamura, K. Iijima, S. Komura, Y. Tanabe, S. Okada, D. Izumi, and Y. Aizawa Comparison of conduction delay in the right ventricular outflow tract between Brugada syndrome and right ventricular cardiomyopathy: investigation of signal average ECG in the precordial leads Europace, October 1, 2007; 9(10): 951 - 956. [Abstract] [Full Text] [PDF]

				C. Antzelevitch Role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2024 - H2038. [Abstract] [Full Text] [PDF]

				C. LASKE, S. R. SOEKADAR, R. LASZLO, and C. PLEWNIA Brugada Syndrome in a Patient Treated With Lithium Am J Psychiatry, September 1, 2007; 164(9): 1440 - 1441. [Full Text] [PDF]

				E. A. Stephenson and C. I. Berul Electrophysiological Interventions for Inherited Arrhythmia Syndromes Circulation, August 28, 2007; 116(9): 1062 - 1080. [Full Text] [PDF]

				R. K. Riezebos, K. de Man, M. S. Patterson, and G. S. de Ruiter A bridge to Brugada Europace, June 1, 2007; 9(6): 398 - 400. [Abstract] [Full Text] [PDF]

				K. S. Stokoe, R. Balasubramaniam, C. A. Goddard, W. H. Colledge, A. A. Grace, and C. L.-H. Huang Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a+/ murine hearts modelling the Brugada syndrome J. Physiol., May 15, 2007; 581(1): 255 - 275. [Abstract] [Full Text] [PDF]

				C. Veltmann, R. Schimpf, C. Echternach, L. Eckardt, J. Kuschyk, F. Streitner, S. Spehl, M. Borggrefe, and C. Wolpert A prospective study on spontaneous fluctuations between diagnostic and non-diagnostic ECGs in Brugada syndrome: implications for correct phenotyping and risk stratification Eur. Heart J., November 1, 2006; 27(21): 2544 - 2552. [Abstract] [Full Text] [PDF]

				M. Abello, J. L. Merino, R. Peinado, and M. Gnoatto Negative flecainide test in Brugada syndrome patients with previous positive response Europace, October 1, 2006; 8(10): 899 - 900. [Abstract] [Full Text] [PDF]

				Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J. Am. Coll. Cardiol., September 5, 2006; 48(5): e247 - e346. [Full Text] [PDF]

				Writing Committee Members, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 746 - 837. [Full Text] [PDF]

				D. I. Keller, H. Huang, J. Zhao, R. Frank, V. Suarez, E. Delacretaz, M. Brink, S. Osswald, N. Schwick, and M. Chahine A novel SCN5A mutation, F1344S, identified in a patient with Brugada syndrome and fever-induced ventricular fibrillation Cardiovasc Res, June 1, 2006; 70(3): 521 - 529. [Abstract] [Full Text] [PDF]

				T. Aiba, W. Shimizu, I. Hidaka, K. Uemura, T. Noda, C. Zheng, A. Kamiya, M. Inagaki, M. Sugimachi, and K. Sunagawa Cellular Basis for Trigger and Maintenance of Ventricular Fibrillation in the Brugada Syndrome Model: High-Resolution Optical Mapping Study J. Am. Coll. Cardiol., May 16, 2006; 47(10): 2074 - 2085. [Abstract] [Full Text] [PDF]

				M C S Hall and D M Todd Modern management of arrhythmias Postgrad. Med. J., February 1, 2006; 82(964): 117 - 125. [Abstract] [Full Text] [PDF]

				R. Ogawa, R. Kishi, K. Mihara, H. Takahashi, A. Takagi, N. Matsumoto, K. Masuhara, K. Nakazawa, F. Miyake, S. Kobayashi, et al. Population Pharmacokinetic and Pharmacodynamic Analysis of a Class IC Antiarrhythmic, Pilsicainide, in Patients With Cardiac Arrhythmias J. Clin. Pharmacol., January 1, 2006; 46(1): 59 - 68. [Abstract] [Full Text] [PDF]

				K. Terajima, T. Yamamoto, H. Onodera, S. Takeda, K. Tanaka, and A. Sakamoto Unmasking of Brugada Syndrome by an Antiarrhythmic Drug in a Patient with Septic Shock Anesth. Analg., January 1, 2006; 102(1): 233 - 236. [Abstract] [Full Text] [PDF]

				K. A. Marill and P. T. Ellinor Case 37-2005 -- A 35-Year-Old Man with Cardiac Arrest while Sleeping N. Engl. J. Med., December 8, 2005; 353(23): 2492 - 2501. [Full Text] [PDF]

				T. Makiyama, M. Akao, K. Tsuji, T. Doi, S. Ohno, K. Takenaka, A. Kobori, T. Ninomiya, H. Yoshida, M. Takano, et al. High Risk for Bradyarrhythmic Complications in Patients With Brugada Syndrome Caused by SCN5A Gene Mutations J. Am. Coll. Cardiol., December 6, 2005; 46(11): 2100 - 2106. [Abstract] [Full Text] [PDF]

				A. D. Krahn, M. Gollob, R. Yee, L. J. Gula, A. C. Skanes, B. D. Walker, and G. J. Klein Diagnosis of Unexplained Cardiac Arrest: Role of Adrenaline and Procainamide Infusion Circulation, October 11, 2005; 112(15): 2228 - 2234. [Abstract] [Full Text] [PDF]

				E Aksay, T Okan, and S Yanturali Brugada syndrome, manifested by propafenone induced ST segment elevation Emerg. Med. J., October 1, 2005; 22(10): 748 - 750. [Abstract] [Full Text] [PDF]

				D. Darbar, T. Yang, K. Churchwell, A. A.M. Wilde, and D. M. Roden Unmasking of Brugada Syndrome by Lithium Circulation, September 13, 2005; 112(11): 1527 - 1531. [Abstract] [Full Text] [PDF]

				P. G. Meregalli, A. A.M. Wilde, and H. L. Tan Pathophysiological mechanisms of Brugada syndrome: Depolarization disorder, repolarization disorder, or more? Cardiovasc Res, August 15, 2005; 67(3): 367 - 378. [Abstract] [Full Text] [PDF]

				D. M. Roden Proarrhythmia as a pharmacogenomic entity: A critical review and formulation of a unifying hypothesis Cardiovasc Res, August 15, 2005; 67(3): 419 - 425. [Abstract] [Full Text] [PDF]

				P. Brugada, R. Brugada, J. Brugada, S. G. Priori, C. Napolitano, P. Brugada, R. Brugada, J. Brugada, S. G. Priori, and C. Napolitano Should patients with an asymptomatic Brugada electrocardiogram undergo pharmacological and electrophysiological testing? Circulation, July 12, 2005; 112(2): 279 - 292. [Full Text] [PDF]

				C. ANTZELEVITCH Modulation of Transmural Repolarization Ann. N.Y. Acad. Sci., June 1, 2005; 1047(1): 314 - 323. [Abstract] [Full Text] [PDF]

				T. T. Beery The Genetics of Cardiac Arrhythmias Biol Res Nurs, April 1, 2005; 6(4): 249 - 261. [Abstract] [PDF]

				M. Inamura, H. Okamoto, M. Kuroiwa, and S. Hoka General anesthesia for patients with Brugada syndrome. A report of six cases: [L'anesthesie generale chez des patients atteints du syndrome de Brugada. Presentation de six cas] Can J Anesth, April 1, 2005; 52(4): 409 - 412. [Abstract] [Full Text] [PDF]

				C. Antzelevitch, P. Brugada, M. Borggrefe, J. Brugada, R. Brugada, D. Corrado, I. Gussak, H. LeMarec, K. Nademanee, A. R. Perez Riera, et al. Brugada Syndrome: Report of the Second Consensus Conference: Endorsed by the Heart Rhythm Society and the European Heart Rhythm Association Circulation, February 8, 2005; 111(5): 659 - 670. [Abstract] [Full Text] [PDF]

				C. E. Clancy and R. S. Kass Inherited and Acquired Vulnerability to Ventricular Arrhythmias: Cardiac Na+ and K+ Channels Physiol Rev, January 1, 2005; 85(1): 33 - 47. [Abstract] [Full Text] [PDF]