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Brugada syndrome is a rare disease first described in 1992. 1 It is a genetic disease

involving mutations in myocardial ion channels that play a major role in myocardial

depolarization and repolarization.2,   3
                                           The majority of genotyped patients have

mutations causing malfunction of the channel responsible for the inward sodium

current.4 However, the disease is genetically heterogeneous and mutations causing

malfunction of other myocardial ion channels have been recently identified. 4-9 The

phenotypic manifestations of the disease include an abnormal electrocardiogram and

a tendency to develop cardiac arrhythmias.1, 10

The abnormal electrocardiogram (ECG) consists of a right bundle branch block pattern

with ST-segment elevation in the right precordial leads (leads V1-V3). Based on the

degree of ST elevation and the morphology of the ST segment, the "Brugada

electrocardiogram" is classified as follows:2 Type 1Brugada pattern is characterized by

a coved ST-segment elevation ≥2 mm (0.2 mV) followed by a negative T wave. Type 2

ST-segment elevation has a saddleback appearance with a high takeoff ST-segment

elevation of ≥2 mm, a trough displaying <1 mm ST elevation, and then either a

positive or biphasic T wave. Type 3 has either a saddleback or coved appearance with

an ST-segment elevation of <1 mm. Type 2 and type 3 ECG are not diagnostic of the

Brugada syndrome. These 3 patterns may be observed spontaneously in serial ECG

tracings from the same patient11 but only type I is considered diagnostic of Brugada

syndrome.        Whenever Brugada syndrome is suspected and only type II and type III

electrocardiograms are recorded, the following diagnostic tests may be performed to

unravel a type I electrocardiogram: 1) placing the precordial electrodes (V1- and V2)

at the second or third intercostal space (instead of the standard location at the fourth

intercostal space).13 or 2) performing a drug challenge test (intravenous infusion of a

sodium channel blocker like flecainide or ajmaline).2, 14

The clinical manifestations of the Brugada syndrome are caused by cardiac

arrhythmias. Sinus node dysfunction or atrioventricular conduction block15 may lead to

bradycardia-related symptoms like weakness or syncope and atrial arrhythmias (like

atrial flutter or atrial fibrillation)16, 17 may lead to palpitations. However, the most

common and serious manifestations of Brugada syndrome are syncope or sudden

death to malignant (mainly polymorphic) ventricular arrhythmias. 1, 10

There is general world-wide consensus that patients with symptomatic Brugada

syndrome, including those with malignant syncope (believed to be due to malignant

ventricular arrhythmias) and those resuscitated after cardiac arrest due to ventricular

fibrillation (VF), ought to be treated with an implantable cardioverter defibrillator (ICD). 2

Quinidine has been proposed as an alternative therapy for selected patients with

symptomatic Brugada syndrome.18-20 On the other hand, the best treatment for

patients with asymptomatic Brugada syndrome is still a matter of considerable

debate.21, 22 The standard of care for such patients has involved risk stratification with
electrophysiologic studies (EPS):         Patients who have no inducible arrhythmias are

generally left without treatment whereas ICD implantation has been widely

recommended for patients who have inducible VF at EPS. 2 However, this therapeutic

approach to asymptomatic Brugada syndrome is probably causing more harm than


The problems of the present therapeutic approach.

All over the world, patients with asymptomatic Brugada syndrome are undergoing

electrophysiologic studies (EPS);25,   26
                                            depending on the aggressiveness of the EPS

protocol, 20%-80% of such patients will have inducible ventricular fibrillation (VF)23, 25-
     and many will undergo implantation of an implantable cardioverter defibrillator

(ICD).23,   25-28
                    However, the rate of spontaneous VF among patients undergoing

prophylactic ICD implantation for "asymptomatic Brugada syndrome with inducible VF"

appears to be only 1% per year according to a multicenter European study.29

Accordingly, ICD implantation might be unnecessary for the vast majority of patients.

On the other hand, 28%29 - 32%28 of these young individuals develop very serious

complications directly related to ICD implantation. Thus, the wisdom of guiding our

therapeutic approach by the results of EPS is increasingly questioned.22, 24-26

Why is it that the EPS-guided approach is not working?

There is general agreement that the risk for cardiac arrest for patients with negative

EPS is only 1-2%.24 It should be emphasized, however, that these low values relate to

a mean follow-up period of less than 4 years.26 The long-term risk for patients with

asymptomatic Brugada syndrome and negative EPS could conceivably be higher.

Obviously, the negative predictive value of EPS will depend on the aggressiveness of

the EPS protocol used. Unfortunately, using more aggressive EPS protocols to

improve the negative predictive value, particularly if including extrastimulation with

very short coupling intervals, would inevitably reduce the positive predictive value of

the test as well.36

Understanding the significance of a positive EPS in the asymptomatic patient is even

more problematic.24 To begin with, one should realize that it is possible to induce VF

with double or triple ventricular extrastimulation in at least 6% of healthy individuals.24

In fact, the rate of accidental VF induction could be much higher than 6% because (as

explained in detail elsewhere24) 6% to 41% of the healthy individuals participating in

the 5 studies37-41 looking at the specificity of "inducible VF" did not go through the

entire EPS protocol because the study was terminated prematurely to avoid the need

for DC shock when non-sustained polymorphic ventricular tachycardia was induced.

Defining the positive predictive value of EPS in patients with asymptomatic Brugada

syndrome is even more problematic.21, 22 On the one hand, Brugada et al have

presented data showing that 12% of asymptomatic patients with inducible VF will have

cardiac arrest (or spontaneous ventricular arrhythmias triggering ICD therapy) within 3

years of follow-up.23, 27 On the other hand, data from 10 published studies

(summarized by Paul)26 including data for more than 250 patients with inducible VF

suggests that the risk is no more than 4%.24 As explained elsewhere,26 the higher

(12%-risk) figures published by Brugada probably resulted from over-representation of

patients with more severe forms of the disease in their earlier series.

Why are the complication-rates after ICD implantation for Brugada syndrome so


It is not surprising that the complication rate after ICD implantation for Brugada
syndrome (28% in a multicenter European study),           is higher than the 12%

complication rate reported in the Antiarrhythmic Versus Implantable Defibrillators

(AVID) trial.42 AVID patients had organic heart disease and, consequently, 16% of

them died within 18 months of ICD implantation.43 The much longer survival of

patients with Brugada syndrome (who are young and free of heart disease) inevitably

places them at increased risk for ICD-related complications in the long term because

the repeated need for ICD replacements significantly increases the risk of device-

related infection.44 Also, the risk for electrode fractures increases over time, especially

in young active males.45 Patients with Brugada syndrome are also at increased risk for

ICD related complications in the short term because they are physically active, tend to

have atrial arrhythmias16, 17, 46 and do not receive beta-blockers. All these factors

significantly increase their risk for inappropriate shocks,28, 29, 45 which seriously impair

quality of life.

Many patients and physicians are finding the above-mentioned morbidity intolerable,

particularly after prophylactic ICD implantation. The search for alternative therapeutic

strategies, like empiric prophylactic therapy with quinidine is therefore justifiable.

Why quinidine?

The Brugada syndrome has been associated with mutations affecting sodium, calcium

and potassium channels subunits.4-9 Irrespectively of the ion-channel involved, a

prominent ITo (transient outward potassium current) appears to play a predominant

role in arrhythmogenesis.47 Consequently, blocking the ITo channel is a logical

approach and this can be done with quinidine.47 Indeed, the following lines of

evidence support the use of quinidine for the primary prevention of arrhythmic death in

Brugada syndrome: 1) Quinidine prevents phase-II reentry and VF in the wedge-

preparation that mimics Brugada syndrome in vitro.47 2) Quinidine tends to normalize

the electrocardiogram.48 3) Quinidine is extremely effective in preventing the induction

of VF in humans during EPS (76%20-88%18 of patients who have inducible VF at

baseline EPS are rendered non-inducible by quinidine therapy). 4) Quinidine is very

effective for aborting VF-storms.49, 50 5) Non-randomized studies suggest that

quinidine prevents spontaneous arrhythmias in high-risk patients with Brugada

syndrome during long-term follow-up.18, 20 In fact, Belhassen et al have effectively

used quinidine as the sole therapy (without ICD back-up) for patients with symptomatic

Brugada syndrome, including patients who had spontaneous VF before the initiation of

therapy.18 In a recent study, none of the 50 patients with symptomatic or

asymptomatic Brugada syndrome developed symptomatic ventricular arrhythmias

during quinidine therapy.28

Risk vs. benefit considerations of empiric quinidine in Brugada syndrome.

Quinidine often causes side effects (like diarrhea, thrombocytopenia, hepatitis) that

resolve following drug discontinuation. When high doses of quinidine are used,18 one

of 3 patients receiving empiric quinidine have to discontinue the medication because

of drug-intolerance. On the other hand, excellent long-term tolerability has been

reported for patients with Brugada syndrome receiving low doses of quinidine. 51

The main concern relates to the potential proarrhythmic risks of quinidine. A 2%-

8%.risk for torsade de pointes from quinidine has been estimated and this risk

appears to be dose-independent 52 However, these figures mainly reflect the risk for

patients with organic heart disease.52 Also, male gender decreases the risk of drug-

induced torsade de pointes53 and the vast majority of patients with Brugada syndrome

are males. Finally, most cases of quinidine-induced torsade occur soon after the onset

of therapy54 and close monitoring during the first 3 days of therapy should prevent

proarrhythmic complications. Torsade de pointes occurring long after the onset of

therapy is often due to drug interactions or hypokalemia55 and meticulous avoidance

of such risk factors should reduce the risk of torsade de pointes from quinidine in

patients with Brugada syndrome to a minimum.

The present study:


Study overview.

This Prospective International Registry will recruit patients with asymptomatic Brugada

syndrome (NIH-Clinical Trial Registry number pending). Brugada syndrome will be

defined according to the Second Consensus Conference 2 and patients will be

considered "asymptomatic" if they do not have a history of cardiac arrest or a history

of syncope with malignant clinical characteristics suggesting arrhythmic origin. In other

words, patients reporting palpitations, atypical chest pain and/or a history of syncope

with clinical characteristics suggestive of benign vasovagal syncope will be counted as

"asymptomatic" and will be accepted to the trial (Figure 1). The Registry encourages

empiric therapy with Hydroquinidine hydrochloride (Serecor, Sanofi-Aventis, France)

600 to 900 mg/day; Lower doses of

quinidine have been associated with higher incidence of inducibility of VF during

repeated EPS.51 However, the effects of low-dose quinidine for preventing

spontaneous arrhythmias is less clear and reduced doses are clearly associated with

better long-term tolerability.51 Therefore, patients developing adverse events have the

option of continuing low doses of quinidine (like 300 mg at bed-time). Also, such

patients may then opt to undergo EPS (with subsequent ICD implantation if the EPS is

positive) or may prefer follow-up with no therapy. It is difficult to say at this point which

of all these options will prove to be better in the long-term. Finally, in view of recent

data suggesting that unselected patients with asymptomatic Brugada syndrome are at

low risk for developing spontaneous VF, it is recognized that physicians and patients

may prefer to avoid antiarrhythmic therapy altogether. Such patients are welcomed to

join the Registry (Figure 1).

Aim of the study.

To collect prospective data of patients with asymptomatic Brugada syndrome that will

help define what is the best therapeutic approach for this disease.

Study design.

Prospective registry. Mode of therapy is not randomized. Instead, the therapeutic

approach (including the option of clinical follow-up with no therapy) is selected by the

physician and primary care physician.

Inclusion criteria.

    1. Patients with Asymptomatic Brugada syndrome.

       "Brugada syndrome" is defined as the presence of a Type-I Brugada

        electrocardiogram [coved ST-segment elevation ≥2 mm (0.2 mV) in V1, V2 or

        V3] either spontaneously (at rest, in the baseline state or during a febrile

        episode) or following a standard drug-challenge test (with flecainide, ajmaline,

        procainamide, or pilsicainide) and recorded either with standard electrode

        position or with the precordial electrodes placed on the second or third

        intercostal space.

       "Asymptomatic patients" will be defined as patients without a history of cardiac

        arrest, a history of "arrhythmic syncope" or a history of "suspected arrhythmic

        syncope." Arrhythmic syncope" is a syncope occurring during documented

        ventricular tachyarrhythmias. "Suspected arrhythmic syncope" is a syncope

        without documented arrhythmias believed to be caused by a tachyarrhythmia

        based on clinical judgment. In other words, patients with typical vagal syncope

        will be counted as "asymptomatic" and will be accepted to the registry whereas

          patients with a clinical history suggesting "syncope other than vagal syncope"

          will not be accepted to this Registry.

         Genetic confirmation (identification of a disease-causing mutation) will not be

          required for establishing the diagnosis of Brugada syndrome but will be

          recorded when present.

    2. Patients with Questionable Brugada Syndrome who are asymptomatic.

         Patients with "Questionable Brugada Syndrome" are defined as patients with

          type II or III electrocardiogram who have an inconclusive result during a drug

          challenge with a sodium channel blocker. "asymptomatic" is defined as above.

         Genetic testing will not be required. However, patients with "Questionable

          Brugada" based on electrocardiographic criteria will be defined as "Patients

          with Brugada Syndrome" if a disease-causing mutation is identified.

Exclusion criteria.

        1. A history of cardiac arrest, "arrhythmic syncope" or "suspected arrhythmic

           syncope" (as defined above).

        2. Evidence of organic heart disease. The evaluation considered mandatory for

           excluding heart disease will consist of electrocardiogram, echocardiogram and

           exercise stress testing. Additional tests will be performed only if clinically


        3. Evidence of non-cardiac disease likely to affect 5-year survival.


    1. Patients will receive a complete explanation of the risk and benefits of the

          different therapeutic approaches to asymptomatic Brugada syndrome, including

          the risk and benefits of a) clinical follow-up with no therapy; b) empiric therapy

       with quinidine; c) EPS-based risk stratification and EPS-based therapy with

       quinidine or ICD. In view of the conflicting evidence regarding the predictive

       value of EPS that emerges from recent trials, performance of EPS studies will

       not be recommended.

    2. Patients agreeing to participate in this Registry will be entered into the Registry

       data base. "Agreeing to participate" means signing the informed consent form.

       The informed consent form will specifically emphasize that – at the present time

       – the optimal therapeutic approach for asymptomatic Brugada syndrome is

       unknown. The informed consent form will emphasize the risk and benefits of

       each potential therapy (including observation with no therapy, quinidine therapy

       and ICD implantation). The informed consent form will also specifically mention

       that the patient and his/her physician agree to provide sufficient contact

       information to allow for adequate collection of follow-up data for a minimum of 5

       years of follow-up. The contact information will include the patient's full name

       and contact information as well as those of the primary care physician and an

       immediate relative that could be contacted by the Registry if contact with the

       patient is lost.

    3. Patients entering the Registry will authorize their physician to enter clinical data

       and scanned electrocardiograms to the Registry data-base. The Registry

       principal investigators will review this information. The Registry principal

       investigators may decide that the patient does not qualify for the Registry

       according to the inclusion/exclusion criteria and will define the patient as "Not

       Registered." Alternatively, based on the clinical and electrocardiographic data

       the principal investigators will define the patient as "Registered" and will classify

       the patient into one of the following categories:

                                           - 10 -
       Based on the clinical history the patient will be classified as "totally

        asymptomatic" or as "patient with syncope believed to be of vagal etiology"

        (patients with syncope believed to be of arrhythmic origin are excluded).

       The electrocardiogram will be classified as: a) Type-I Brugada at baseline ECG;

        b) Type-I electrocardiogram recorded only during a febrile episode; c) Type-I

        electrocardiogram recorded only with the electrodes positioned at a high

        intercostal space; d) Type I electrocardiogram recorded only during a challenge

        test with sodium channel blocker; e) Questionable Brugada (when Type I

        electrocardiogram is not recorded and the drug-challenge with sodium channel

        blocker is inconclusive.

    4. Patients accepted to the Registry will be encouraged to start empiric quinidine

        therapy with hydroquinidine hydrochloride (Serecor, Sanofi-Aventis, France)

        900 mg/day or with equivalent doses of quinidine. However, patients preferring

        to avoid antiarrhythmic therapy will also be welcomed to join the Registry as

        long as informed consent is provided as above.

    5. For patients opting to start quinidine therapy, hospitalization to provide

        electrocardiographic monitoring for 48 - 72 hours during the onset of quinidine

        therapy will be encouraged for males and mandatory for females. There is no

        clear-cut definition of "excessive QT prolongation" during quinidine therapy and

        the degree of QT prolongation that accurately distinguishes "therapeutic" from

        "proarrhythmic" effects of quinidine have not been defined. Therefore, the

        decision to discontinue quinidine because of "excessive QT prolongation" will

        be the responsibility of the primary attending physician. However, the principal

        investigators of the Registry will provide expert opinion in this regard.

                                             - 11 -
    6. Patients on quinidine therapy will be requested to perform blood tests (including

       a complete blood count, liver function tests, kidney function tests and sodium

       and potassium serum levels) within one week after initiation of therapy, one

       month after the initiation of therapy and twice a year thereafter.

    7. Patients with dose-dependent adverse events from quinidine (like diarrhea) will

       be encouraged to reduce the dosage and continue therapy with the maximally

       tolerated dosage. Patients who cannot tolerate more than 300 mg serecor daily

       will be encouraged to take the medication at bedtime.

    8. Patients with dose-independent adverse events from quinidine (like

       thrombocytopenia) will discontinue the medication and will select one of the

       following therapeutic approaches: a) clinical follow-up with no therapy or b)

       EPS-guided risk stratification and therapy with ICD if inducible. The selection of

       therapy will be the responsibility of the patient and his primary physician but the

       Registry will encourage clinical observation with no therapy at this point,

       especially for patients who do not have a Type-I electrocardiogram at rest.

    9. All patients and their immediate family members will be encouraged to undergo

       training in basic cardiopulmonary resuscitation (CPR) techniques and will be

       advices about the availability of External Automatic Defibrillators (EAD) for

       home use. Patients will also be advised of the availability of Implantable Holter

       and home-monitoring devices that could potentially detect asymptomatic

       arrhythmias during long-term follow-up.

    10. All patients will be informed of the possibility that some medications may be

       proarrhythmic and dangerous for patients with Brugada syndrome. The use of

       these medications will be strongly discouraged: class 1C antiarrhythmic drugs

                                           - 12 -
       (like propafenone and flecainide); beta-blockers, calcium-channel blockers and


    11. The Registry will provide no funding for medications, hospitalizations, EAD or


    12. The Registry will collect follow-up information twice yearly from each patient,

       his/her physician and (if needed) from the patient's immediate relative if


                                           - 13 -

1.    Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac

      death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol.


2.    Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus

      conference. Heart Rhythm. 2005;2:429-440.

3.    Meregalli PG, Wilde AA, Tan HL. Pathophysiological mechanisms of Brugada syndrome: depolarization

      disorder, repolarization disorder, or more? Cardiovasc Res. 2005;67:367-378.

4.    Chen Q, Kirsch G, Zhang D, et al. Genetic basis and molecular mechanism for idiopathic ventricular

      fibrillation. Nature. 1998;392:293.

5.    Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium

      channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and

      sudden cardiac death. Circulation. 2007;115:442-449.

6.    London B, Michalec M, Mehdi H, et al. Mutation in glycerol-3-phosphate dehydrogenase 1 like gene

      (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias. Circulation. 2007;116:2260-


7.    Schulze-Bahr E, Eckardt L, Breithardt G, et al. Sodium channel gene (SCN5A) mutations in 44 index

      patients with Brugada syndrome: different incidences in familial and sporadic disease. Hum Mutat.


8.    Delpón E, Cordeiro JM, Núñez L, et al. Functional effects of KCNE3 mutation and its role in the

      development of Brugada syndrome. Circ Arrhythmia Electrophysiol, doi:10.1161/CIRCEP.107.748103


9.    Watanabe H, Koopmann TT, Le Scouarnec S, et al. Sodium channel beta1 subunit mutations associated

      with Brugada syndrome and cardiac conduction disease in humans. J Clin Invest. 2008;118:2260-2268.

10.   Alings M, Wilde A. "Brugada" syndrome. Clinical data and suggested pathophysiological mechanism.

      Circulation. 1999;99:666-673.

11.   Wilde AA. Spontaneous electrocardiographic fluctuations in Brugada syndrome: does it matter? Eur

      Heart J. 2006;27:2493-2494.

                                                    - 14 -
12.   Wilde AA, Antzelevitch C, Borggrefe M, et al. Proposed diagnostic criteria for the Brugada syndrome:

      consensus report. Circulation. 2002;106:2514-2519.

13.   Shimizu W, Matsuo K, Takagi M, et al. Body surface distribution and response to drugs of ST segment

      elevation in Brugada syndrome: clinical implication of eighty-seven-lead body surface potential mapping

      and its application to twelve-lead electrocardiograms. J Cardiovasc Electrophysiol. 2000;11:396-404.

14.   Meregalli PG, Ruijter JM, Hofman N, et al. Diagnostic value of flecainide testing in unmasking SCN5A-

      related Brugada syndrome. J Cardiovasc Electrophysiol. 2006;17:857-864.

15.   van den Berg MP, Wilde AA, Viersma TJW, et al. Possible bradycardic mode of death and successful

      pacemaker treatment in a large family with features of long QT syndrome type 3 and Brugada syndrome. J

      Cardiovasc Electrophysiol. 2001;12:630-636.

16.   Kusano KF, Taniyama M, Nakamura K, et al. Atrial fibrillation in patients with Brugada syndrome

      relationships of gene mutation, electrophysiology, and clinical backgrounds. J Am Coll Cardiol.


17.   Morita H, Kusano-Fukushima K, Nagase S, et al. Atrial fibrillation and atrial vulnerability in patients with

      Brugada syndrome. J Am Coll Cardiol. 2002;40:1437-1444.

18.   Belhassen B, Glick A, Viskin S. Efficacy of quinidine in high-risk patients with Brugada syndrome.

      Circulation. 2004;110:1731-1737.

19.   Belhassen B, Viskin S, Antzelevitch C. The Brugada syndrome: is an implantable cardioverter

      defibrillator the only therapeutic option? Pacing Clin Electrophysiol. 2002;25:1634-1640.

20.   Hermida JS, Denjoy I, Clerc J, et al. Hydroquinidine therapy in Brugada syndrome. J Am Coll Cardiol.


21.   Brugada P, Brugada R, Brugada J. Should patients with an asymptomatic Brugada electrocardiogram

      undergo pharmacological and electrophysiological testing? Circulation. 2005;112:279-292; discussion


22.   Priori SG, Napolitano C. Should patients with an asymptomatic Brugada electrocardiogram undergo

      pharmacological and electrophysiological testing? Circulation. 2005;112:279-292; discussion 279-292.

23.   Brugada P, Geelen P, Brugada R, et al. Prognostic value of electrophysiologic investigations in Brugada

      syndrome. J Cardiovasc Electrophysiol. 2001;12:1004-1007.

                                                    - 15 -
24.   Viskin S, Rogowski O. Asymptomatic Brugada syndrome: a cardiac ticking time-bomb? Europace.


25.   Gehi AK, Duong TD, Metz LD, et al. Risk stratification of individuals with the Brugada

      electrocardiogram: a meta-analysis. J Cardiovasc Electrophysiol. 2006;17:577-583.

26.   Paul M, Gerss J, Schulze-Bahr E, et al. Role of programmed ventricular stimulation in patients with

      Brugada syndrome: a meta-analysis of worldwide published data. Eur Heart J. 2007;28:2126-2133.

27.   Brugada P, Brugada R, Mont L, et al. Natural history of Brugada syndrome: the prognostic value of

      programmed electrical stimulation of the heart. J Cardiovasc Electrophysiol. 2003;14:455-457.

28.   Rosso R, Glick A, Glikson M, et al. Outcome after implantation of ICD in patients with Brugada

      syndrome: a multicenter Israeli study (ISRABRU). Isr Med Assoc J. 2008;10:435-439.

29.   Sacher F, Probst V, Iesaka Y, et al. Outcome after implantation of a cardioverter-defibrillator in patients

      with Brugada syndrome: a multicenter study. Circulation. 2006;114:2317-2324.

30.   Schwartz PJ, Periti M, Malliani A. The long Q-T syndrome. Am Heart J. 1975;89:378-390.

31.   Priori SG, Napolitano C, Schwartz PJ, et al. Association of long QT syndrome loci and cardiac events

      among patients treated with beta-blockers. JAMA. 2004;292:1341-1344.

32.   Chatrath R, Bell CM, Ackerman MJ. Beta-blocker therapy failures in symptomatic probands with

      genotyped long-QT syndrome. Pediatr Cardiol. 2004;25:459-465.

33.   Moss AJ, Zareba W, Hall WJ, et al. Effectiveness and limitations of beta-blocker therapy in congenital

      long-QT syndrome. Circulation. 2000;101:616-623.

34.   Moss AJ, Shimizu W, Wilde AA, et al. Clinical aspects of type-1 long-QT syndrome by location, coding

      type, and biophysical function of mutations involving the KCNQ1 gene. Circulation. 2007;115:2481-


35.   Villain E, Denjoy I, Lupoglazoff JM, et al. Low incidence of cardiac events with beta-blocking therapy in

      children with long QT syndrome. Eur Heart J. 2004;25:1405-1411.

36.   Eckardt L, Probst V, Smits JP, et al. Long-term prognosis of individuals with right precordial ST-

      segment-elevation Brugada syndrome. Circulation. 2005;111:257-263.

37.   Belhassen B, Shapira I, Sheps D, et al. Programmed ventricular stimulation using up to two extrastimuli

      and repetition of double extrastimulation for induction of ventricular tachycardia: a new highly sensitive

      and specific protocol. Am J Cardiol. 1990;65:615-622.

                                                     - 16 -
38.   Brugada P, Green M, Abdollah H, et al. Significance of ventricular arrhythmias initiated by programmed

      ventricular stimulation: the importance of the type of ventricular arrhythmia induced and the number of

      premature stimuli required. Circulation. 1984;69:87-92.

39.   Buxton AE, Waxman HL, Marchlinski FE, et al. Role of triple extrastimuli during electrophysiologic

      study of patients with documented sustained ventricular tachyarrhythmias. Circulation. 1984;69:532-540.

40.   Morady F, Shapiro W, Shen E, et al. Programmed ventricular stimulation in patients without spontaneous

      ventricular tachycardia. Am Heart J. 1984;107:875-882.

41.   Stevenson WG, Brugada P, Waldecker B, et al. Can potentially significant polymorphic ventricular

      arrhythmias initiated by programmed stimulation be distinguished from those that are nonspecific? Am

      Heart J. 1986;111:1073-1080.

42.   Kron J, Herre J, Renfroe EG, et al. Lead- and device-related complications in the antiarrhythmics versus

      implantable defibrillators trial. Am Heart J. 2001;141:92-98.

43.   The Antiarrhythmic Versus Implantable Defibrillators (AVID) Investigators. A comparison of

      antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal

      ventricular arrhythmias. N Engl J Med. 1997;337:1576-1583.

44.   Klug D, Balde M, Pavin D, et al. Risk factors related to infections of implanted pacemakers and

      cardioverter-defibrillators: results of a large prospective study. Circulation. 2007;116:1349-1355.

45.   Sarkozy A, Boussy T, Kourgiannides G, et al. Long-term follow-up of primary prophylactic implantable

      cardioverter-defibrillator therapy in Brugada syndrome. Eur Heart J. 2007;28:334-344.

46.   Bigi MA, Aslani A, Shahrzad S. Clinical predictors of atrial fibrillation in Brugada syndrome. Europace.


47.   Antzelevitch C. The Brugada syndrome: ionic basis and arrhythmia mechanisms. J Cardiovasc

      Electrophysiol. 2001;12:268-272.

48.   Alings M, Dekker L, Sadee A, et al. Quinidine induced electrocardiographic normalization in two patients

      with Brugada syndrome. Pacing Clin Electrophysiol. 2001;24:1420-1422.

49.   Ohgo T, Okamura H, Noda T, et al. Acute and chronic management in patients with Brugada syndrome

      associated with electrical storm of ventricular fibrillation. Heart Rhythm. 2007;4:695-700.

50.   Marquez MF, Salica G, Hermosillo AG, et al. Ionic basis of pharmacological therapy in Brugada

      syndrome. J Cardiovasc Electrophysiol. 2007;18:234-240.

                                                    - 17 -
51.   Mizusawa Y, Sakurada H, Nishizaki M, et al. Effects of low-dose quinidine on ventricular

      tachyarrhythmias in patients with Brugada syndrome: low-dose quinidine therapy as an adjunctive

      treatment. J Cardiovasc Pharmacol. 2006;47:359-364.

52.   Jackman WM, Friday KJ, Anderson JL, et al. The long QT syndromes: a critical review, new clinical

      observations and a unifying hypothesis. Prog Cardiovasc Dis. 1988;31:115-172.

53.   Viskin S. The long QT syndromes and torsade de pointes. Lancet. 1999;354:1625-1633.

54.   Viskin S, Barron HV, Heller K, et al. The treatment of atrial fibrillation: pharmacologic and

      nonpharmacologic strategies. Curr Prob Cardiol. 1997;22:44-108.

55.   Viskin S, Fish R, Roden DM. Drug induced torsade de pointes. In: Braunwald E, Fauci SA, Isselbacher

      KJ, Kasper DL, Hauser SL, Longo DL, Jameson JL, eds. Harrison's principles of internal medicine.

      Harrison's on-line. http// 14 ed; 2000:231.

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