Prognosis of Brugada syndrome

patients with ICD in Korea

Young Keun On, MD, PhD, FHRS

Samsung Medical Center

Sungkyunkwan University School of Medicine

• In 1992, Brugada brothers first reported a unique

electrocardiographic syndrome in which ventricular fibrillation

could occur without obvious structural heart disease.

• Brugada syndrome is electrocardiographically characterized

by ST-segment elevation in the right precordial leads.

• Sudden death is common and may be the first manifestation

of disease during its clinical course.

67 year-old gentleman complained of recurrent syncope

for 5 years.

During work (agriculture) or walking

No prodromal symptom

28 month-old grandson presented to the hospital for fever and sepsis.

Tachycardia of 212 bpm

Lidocaine 13 mg

28 month-old grandson

< SCN5A Gene Mutation Analysis >

SCN5A Gene Mutation : Detected

Indentified Mutation : c.3911C>T (p.Thr1304Met)

GENETIC VARIATIONS OBSERVED

-------------------------------------------------------------------------------------------------------

Exon# NT# BaseChange Codon# AA Chage Designation Mutation Type/Effect

-------------------------------------------------------------------------------------------------------

2 87 A > G 29 Ala>Ala A29A (Het) Polymorphism(rs6599230)

16 2695 T > C 899 Trp>Arg W899R (Het) Unclassified

17 3183 A > G 1061 Glu>Glu E1061E (Hom) Polymorphism(rs7430407)

22 3911 C > T 1304 Thr>Met T1304M (Het) Mutation (Known)

28 5457 T > C 1819 Asp>Asp D1819D (Het) Polymorphism(rs1805126)

------------------------------------------------------------------------------------------------------

Brugada syndrome

SCN5A Gene Mutation :

c.3911C>T (p.Thr1304Met)

67/M

38/M

2/M

Syncope

VT during fever

• Introduction as a clinical entity in 1992

• Electrocardiographically characterized by a distinct ST-segment

elevation in the right precordial leads

• Association with high risk for sudden death in young and healthy adults

• Manifests during adulthood, with a mean age of sudden death of 41 ±

15 years. (2 days old to 84 years old)

• 4% of all sudden deaths and 20% of sudden deaths in patients with

structurally normal hearts.

• Second only to automobile accidents as a cause of death among

young adults

Brugada syndrome

Second Consensus Conference Circulation 2005;111;659

Difference between epicardial and endocardial membrane

action potential (AP) morphology

Shu J, et al. J Electrocard 2005;38:26

• The epicardial AP showed “spike and dome” pattern.

• Loss of epicardial AP dome shortens AP duration.

• A difference in action potential plateau amplitude

generates a transmural voltage gradient that

manifests as ST-segment displacement in surface

ECG.

Accelerated inactivation of Na channels and

predominance of transient outward K current (Ito)

to generate a voltage gradient in the RV layers

Phase-2 reentry in the epicardium of an isolated canine right ventricular outflow

tract preparation having Brugada type ECG

Morita H, et al. Heart Rhythm 2007;4:66

Three ECG repolarization patterns in the right precordial leads

• Type I : diagnostic for Brugada syndrome

coved-type ST segment elevation greater than 2 mm, followed by a

negative T wave in at least one right precordial lead (V1 to V3).

• Type II and type III : saddleback-shaped patterns, with a high initial augmentation

followed by an ST elevation greater than 2 mm for type II and less than 2 mm for

type III. suggestive of but not diagnostic for Brugada syndrome.

Brugada syndrome is definitively diagnosed when a type 1 ST-segment

elevation is observed in >1 right precordial lead (V1 to V3)

and in conjunction with one of the following

: documented ventricular fibrillation (VF),

polymorphic ventricular tachycardia (VT),

a family history of sudden cardiac death at < 45 years old,

coved-type ECGs in family members,

inducibility of VT with programmed electrical stimulation,

syncope,

or nocturnal agonal respiration.

Diagnostic Criteria

15, May, 2001 22, May, 2001 24, Aug, 2001

Dynamic change of ECG pattern in a Brugada syndrome patient

Park DW, et al. Circ J 2003; 67: 934

Drug challenge test in Brugada syndrome

Baseline After flecainide

Precipitating Factors

The ECG manifestations of Brugada syndrome are often concealed

but can be unmasked by sodium channel blockers,

a febrile state,

vagotonic agents,

α-adrenergic agonists,

β-adrenergic blockers,

tricyclic or tetracyclic antidepressants,

a combination of glucose and insulin,

hyperkalemia, hypokalemia,

hypercalcemia,

and alcohol and cocaine toxicity.

• VF and sudden death in Brugada syndrome usually occur at rest and at night.

• Circadian variation of sympathovagal balance, hormones, and metabolic factors are

likely to contribute to this circadian pattern.

Circadian pattern of VF episodes in Brugada syndrome.

Second Consensus Conference Circulation 2005;111;659

• Syncope and sudden death are caused by fast polymorphic

ventricular tachycardia or ventricular fibrillation.

• These arrhythmias appear with no warning.

• Treatment for symptomatic patients with Brugada syndrome is

needed.

• Patients presenting with Brugada syndrome ECG at baseline

conditions have an increased risk for sudden death and need risk

stratification.

• Brugada syndrome is a genetically transmissible disease manifesting

as an autosomal dominant and age-dependent trait.

• More than 100 causative gene mutations have been identified,

mostly located on the SCN5A gene of the cardiac sodium channel.

• Further studies are needed to establish the underlying mechanism of

Brugada syndrome.

• The role of EPS in risk stratification of asymptomatic patients with

Brugada syndrome remains controversial.

FINGER (France, Italy, Netherlands, Germany)

Brugada Syndrome Registry

• to evaluate the prognosis and risk factors of SCD in Brugada syndrome

patients

• 11 tertiary centers in 4 European countries

• 1,029 consecutive individuals (men; 72%), median age of 45 (35~55) years

• aborted SCD (6%); unexplained syncope (30%); asymptomatic (64%)

• median follow-up of 32 months, 51 cardiac events (5%, appropriate shock

44 patients, SCD 7 patients)

• Cardiac event rate per year; 7.7% in patients with aborted SCD,

1.9% in patients with syncope,

0.5% in asymptomatic patients

• Symptoms and spontaneous type 1 ECG were predictors of arrhythmic

events

FINGER Brugada Syndrome Registry Circulation. 2010;121:635

FINGER Brugada Syndrome Registry Circulation. 2010;121:635

The presence of symptoms and a spontaneous type 1 ECG are the only independent

predictors of arrhythmic events.

FINGER (France, Italy, Netherlands, Germany) Brugada Syndrome Registry

FINGER Brugada Syndrome Registry Circulation. 2010;121:635

Gender, family history of SCD, inducibility of ventricular tachyarrhythmias during EPS,

and presence of a mutation in the SCN5A gene have no predictive value.

FINGER (France, Italy, Netherlands, Germany) Brugada Syndrome Registry

Absolute and annual event rate in the major Brugada syndrome registries

Napolitano C, Priori SG. Circulation. 2012;125:2027

Devices

ICD - only established effective therapy

? Ablation or cryosurgery

? Pacemaker

Drugs

Amiodarone: does not protect

β-Blockers: do not protect

α-Adrenergic agonists (isoproterenol)

Phosphodiesterase inhibitors (cilostazol)

Class IC antiarrhythmics (flecainide, propafenone):contraindicated

Class IA antiarrhythmics

Procainamide: contraindicated

? Disopyramide

Quinidine (nonspecific Ito blocker)

? Tedisamil

Ito blockers: cardioselective and ion channel–specific

Therapy in Brugada Syndrome

• No drug has been definitely proven effective in reducing the cardiac

arrest burden.

• Risk assessment is a key issue to tailor the use of ICD therapy.

• Annual incidence of cardiac arrest was between 1%/y and 2%/y.

• The event rate is time dependent with events peaking in the third to

fourth decade of life.

• The presence of a spontaneous type 1 ECG with history of

syncope could identify subjects who warrant an ICD.

• Genotype-phenotype correlation is scanty in Brugada syndrome.

Second Consensus Conference Circulation 2005;111:659

FINGER Brugada Syndrome Registry Circulation. 2010;121:635

• Risk stratification and treatment strategy for asymptomatic patients

with Brugada syndrome remain to be defined.

• Studies for follow-up of ICD therapy and risk stratification for sudden

cardiac death in Korean patients with Brugada syndrome are limited.

• Korea Survey of Brugada syndrome patients with ICD

• The objective of the Survey was

to evaluate the prognosis of Korean patients with Brugada

syndrome after implantation of ICD

and to search for predictor of adverse cardiac outcomes.

• N=69 patients of Brugada syndrome with ICD implantation

• Jan 1998 ~ Apr 2012

• Male : 68, Female : 1

• 4 university hospitals

Asan Medical Center,

Chunnam National University Hospital,

Korea University Anam Hospital,

Samsung Medical Center

• Follow up duration: mean 59 ± 46 months

median 4.1 years (IQR 2.0-7.7)

Korea Survey of Brugada syndrome patients with ICD

N (%)

n 69

Male gender 68 (99%)

Age 46 ± 14

FHx. of Brugada syndrome 4 (6%)

FHx. of SCD 13 (19%)

ECG ST elevation type

Type 1 44 (64%)

Type 2 18 (26%)

Type 3 3 (4%)

Clinical presentation

Cardiac arrest 38 (55%)

Syncope 17 (25%)

Presyncope 3

Palpitation 10

Chest pain 7

Nocturnal agonal respiration 6

Dyspnea 4

Baseline characteristics

Cardiac arrest

Syncope

Asymptomatic17 명 (25%)

14 명 (20%)

38 명 (55%)

Indication for ICD implantation

Clinical outcome

Cardiac event N (%)

Composite cardiac event 30 (44%)

Annual event rate 8.8%

Appropriate shock 19 (28%)

Annual event rate 5.6%

Inappropriate shock 14 (20%)

Hospitalization for cardiac cause 6 ( 9%)

Cardiac death 0

Follow up duration: mean 59 ± 46 months

Appropriate shock : 19 (28%)

Inappropriate shock : 14 (20%)

Hospitalization for cardiac cause : 6 (9%)

Cardiac death : 0

Composite cardiac event free survival

Appropriate shock free survival

Composite cardiac event free survival

Appropriate shock free survival

Appropriate shock free survival

Inappropriate shock

• 73 events in 14 patients (20%)

Cause of

inappropriate shock

Number of patients

AF, AFL 4

SVT 3

Abnormal sensing 2

Lead failure 2

NA 3

• Brugada syndrome is electrocardiographically characterized by a distinct

ST-segment elevation in the right precordial leads.

• Manifests during adulthood, with a mean age of sudden death of 41 yrs

• Korean Brugada syndrome patients with ICD implantation : 69 patients

Composite cardiac events during mean follow up of 59 mo: 44%

Appropriate shock : 28%

Inappropriate shock : 20%

Hospitalization for cardiac cause : 9%

Cardiac death : 0

• Predictor of cardiac events : history of aborted cardiac arrest

• The presence of spontaneous type 1 ECG demonstrated no statistical

differences in cardiac event.

Summary