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The Brugada Syndrome Created by Ravi Parmar, Island Health Pharmacy For other health information, please visit www.viha.ca CREATED (OR UPDATED): February 16, 2022 DEPARTMENT: Pharmacy Background: - BrS is an inherited cardiac arrhythmia, which was first described as a new clinical entity in Nov 1992 by Spanish cardiologists, and brothers Josep and Pedro Brugada. 1,2 - Electrocardiographically characterized by distinct coved type ST segment elevation in the right precordial leads, the syndrome is associated with a high risk for ventricular tachyarrhythmias and sudden cardiac death in young adults, and less frequently in infants and children. 1 - Typically manifests in third or fourth decade of life (average age 41 ± 15 years). 3 - Teaming up with their third brother, and fellow cardiologist, Ramon, it took the Brugadas only 6 years to progress from describing the syndrome to a publication on its genetic basis. 4 Epidemiology: - There is not precise data available on the epidemiology of BrS. - It does tend to be much more prevalent in Asian and Southeast Asian countries, especially Thailand, Phillipines, and Japan, reaching 0.5-1 per 1000. 3 - The reason for this higher prevalence is unknown, but it has been speculated to be partly related to an Asian specific gene sequence in the promoter region of SCN5A. 3 - BrS is also 8-10 times more prevalent in males than females, which is believed to be secondary to more prominent transient outward current and higher testosterone levels. 3 Genetics: - So far, nineteen responsible genes have been reported. 1

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The Brugada Syndrome (BrS)

If you have any questions that are not answered here, please ask a care provider for more information. For other health information, please visit www.viha.ca

Created by Ravi Parmar, Island Health Pharmacy Resident 2017/2018

CREATED (OR UPDATED): May 11, 2023DEPARTMENT: Pharmacy

Background:

- BrS is an inherited cardiac arrhythmia, which was first described as a new clinical entity in Nov 1992 by Spanish cardiologists, and brothers Josep and Pedro Brugada.1,2

- Electrocardiographically characterized by distinct coved type ST segment elevation in the right precordial leads, the syndrome is associated with a high risk for ventricular tachyarrhythmias and sudden cardiac death in young adults, and less frequently in infants and children.1

- Typically manifests in third or fourth decade of life (average age 41 ± 15 years).3 - Teaming up with their third brother, and fellow cardiologist, Ramon, it took the Brugadas only 6

years to progress from describing the syndrome to a publication on its genetic basis.4

Epidemiology:

- There is not precise data available on the epidemiology of BrS. - It does tend to be much more prevalent in Asian and Southeast Asian countries, especially

Thailand, Phillipines, and Japan, reaching 0.5-1 per 1000.3

- The reason for this higher prevalence is unknown, but it has been speculated to be partly related to an Asian specific gene sequence in the promoter region of SCN5A.3

- BrS is also 8-10 times more prevalent in males than females, which is believed to be secondary to more prominent transient outward current and higher testosterone levels.3

Genetics:

- So far, nineteen responsible genes have been reported.1

- Either a decrease in the inward sodium or calcium current or an increase in one of the outward potassium currents has been shown to be associated with the BrS phenotype in all nineteen genes.1

- Genetic abnormalities of SCN5A, the gene that encodes for the alpha subunit of the cardiac sodium channel, accounts for up to 30% of clinically diagnosed BrS patients.3

Pathophysiology:

Three different pathophysiological theories:

1) The depolarization theory – consistent with mutations in the sodium channel causing slow conduction and re-entry and is partly based on observations made on a patient undergoing heart transplant because of electrical storms.2

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2) The repolarization theory – supported by mutations related to calcium or potassium genes leading to a shortened action potential and phase 2 re-entry (as opposed to re-entry because of slow conduction).2

3) The neural crest theory – Provides a potential explanation of Brugada syndrome where mutations in the germinal cells do not appear to play a role. Suggests that it may be caused by somatic mutations traceable only by local biopsy of diseased cardiac muscle.2

Clinical Manifestations:

- Many different factors can contribute to both the electrocardiographic and clinical manifestations of Brugada syndrome, which include germinal and somatic gene mutations, structural abnormalities, autonomic tone, fever, and the use illicit substances and certain medications.5

- Symptoms include VF or aborted SCD (more often at night than during the day), syncope, nocturnal agonal respiration, palpitations, and chest discomfort.3

- Symptoms typically occur during rest or sleep, during a febrile state or with vagotonic conditions, but rarely during exercise.3

- BrS is associated with no clearly apparent structural heart diseases, however several clinical studies have reported mild right and left ventricular structural abnormalities.3

Diagnosis:

1) BrS is diagnosed in patients with ST-segment elevation with type 1 morphology ≥2 mm in ≥1 lead among the right precordial leads V1, V2, positioned in the 2nd,3rd or 4th intercostal space occurring either spontaneously or after provocative drug test with intravenous administration of Class I antiarrhythmic drugs.3

2) BrS is diagnosed in patients with type 2 or type3 ST-segment elevation in ≥1 lead among the right precordial leads V1, V2 positioned in the 2nd, 3rd or 4th intercostal space when a provocative drug test with intravenous administration of Class I antiarrhythmic drugs induces a type I ECG morphology.3

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Therapeutic Recommendations:

- Thus far, the only proven effective therapeutic strategy for prevention of sudden cardiac death in BrS patients is the ICD. However ICDs may have their disadvantages, including multiple device replacements in young patients and potentially inappropriate shocks. BrS patients should have their risk factors fully assessed prior to implantation of ICD.3

- Isoproterenol (which increases the L-type calcium current), has been shown to be useful for treatment of electrical storm in BrS.3

- Quinidine, a Class Ia antiarrhythmic drug that has Ito and IKr blocker effects, has been shown to prevent induction of ventricular fibrillation and suppress spontaneous ventricular arrhythmias in a clinical setting. Quinidine is currently being used in (1) patients with ICD and multiple shocks; (2) cases in which ICD implantation is contraindicated; or (3) for the treatment of supraventricular arrhythmias.3

Prognosis:

- Since BrS was first reported, the annual rate of events has decreased.3 - The risk of lethal or near-lethal arrhythmic episodes among previously asymptomatic patients

with BrS varies among different case series of different durations from 1% - 8%.3 - The high risk of recurrence of cardiac arrest after BrS patients have survived a first episode of

ventricular fibrillation is clear, and it is generally agreed that these patients should always be protected with an ICD.3

Clinical Pearls

- Patients with BrS should be counselled to avoid excessive alcohol intake.3 - Patients with BrS with fever should be treated with antipyretic medications immediately.3 - Maintenance of normal electrolyte levels is important in preventing arrhythmias. - Patients on quinidine should have regular liver function testing done, as well as always notify

healthcare practitioners when starting new medications as there is several drug interactions with both quinidine and BrS itself.

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References:1) Antzelevitch C, Patocskai B. Brugada Syndrome. Clinical, Genetic, Molecular, Cellular and

Ionic Aspects. Curr Probl Cardiol. 2016;41(1): 7-57. 2) Brugada P. Brugada syndrome: More than 20 years of scientific excitement. Journal of

Cardiology. 2016;67(3):215-220.3) Priori S, Wilde A, Horie M, Cho Y, Behr E, Berul C et al. HRS/EHRA/APHRS Expert Consensus

Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes. Heart Rhythm. 2013;10(12):1932-1963.

4) Torjesen I. Pioneers in Cardiology: Pedro Brugada, Unravelling the Genetics of Arrhythmias and Working to Prevent and Treat Heart Failure. Circulation. 2008: f37-f39.

5) Wylie J, Garlitski A. Brugada Syndrome: Epidemiology and pathogenesis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://uptodate.com (Accessed on Sep.19,2017)

6) Postema PG, Wolpert C, Amin AS, Probst V, Borggrefe M, Roden DM, Priori SG, Tan HL, Hiraoka M, Brugada J, Wilde AA. Drugs and Brugada syndrome patients: review of the literature, recommendations and an up-to-date website (www.brugadadrugs.org). Heart Rhythm 2009;6(9):1335-1341.

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