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Brugada’s Syndrome and Sudden Brugada’s Syndrome and Sudden Cardiac Death Cardiac Death

Nitish Badhwar, MD, FACCUniversity of California, San Francisco

3rd Asian Heart and Vascular SymposiumFebruary 27, 2009

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1 Myerberg RJ, Castellanos A. Cardiac Arrest and Sud den Cardiac Death. In: Braunwald E, ed. Heart Dis ease: A Textbook of Cardiovascular Medicine. 5 th Ed. New York: WB Saunders. 1997: 742-779.

2 Circulation. 2001; 104: 2158-2163.3 Vreede-Swagemakers JJ et al. J Am Coll Cardiol 1997 ; 30: 1500-1505.

<5%400,0003W. Europe

5%450,0002U.S.

<1%3,000,0001Worldwide

SurvivalIncidence(cases/year)

Sudden Cardiac DeathSudden Cardiac DeathSudden Cardiac DeathSudden Cardiac Death

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1 U.S. Census Bureau, Statistical Abstract of the United States: 2001.2 American Cancer Society, Inc., Surveillance Research, Cancer Facts and Figures 2001.3 2002 Heart and Stroke Statistical Update, American Heart Association.4 Circulation. 2001;104:2158-2163.

SCD claims more lives each year than these other di seases combined.

Magnitude of Sudden Cardiac Magnitude of Sudden Cardiac Death (SCD) in United StatesDeath (SCD) in United StatesMagnitude of Sudden Cardiac Magnitude of Sudden Cardiac Death (SCD) in United StatesDeath (SCD) in United States

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80%Coronary Artery

Disease

Adapted from Heikki et al. N Engl J Med, Vol. 345, No. 20, 2001.

* ion-channel abnormalities, valvular or congenital heart disease, other causes

15%Cardiomyopathy

5% Other*

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Causes of Sudden Cardiac DeathCauses of Sudden Cardiac DeathCauses of Sudden Cardiac DeathCauses of Sudden Cardiac Death

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CardiomyopathyCardiomyopathyCardiomyopathyCardiomyopathy

� Dilated Cardiomyopathy

� Hypertrophic Cardiomyopathy (HCM)

� Arrhythmogenic Right Ventricular

Cardiomyopathy (ARVC)

� Left Ventricular Non-compaction

� Restrictive Cardiomyopathy

� Dilated Cardiomyopathy

� Hypertrophic Cardiomyopathy (HCM)

� Arrhythmogenic Right Ventricular

Cardiomyopathy (ARVC)

� Left Ventricular Non-compaction

� Restrictive Cardiomyopathy

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Cardiac Cardiac ChannelopathiesChannelopathiesCardiac Cardiac ChannelopathiesChannelopathies

� Brugada Syndrome

� Long QT Syndrome (LQTS)

� Short QT Syndrome

� Catecholamine induced Polymorphic

Ventricular Tachycardia (CPVT)

�� Short coupled Short coupled TorsadesTorsades

�� Idiopathic VFIdiopathic VF

� Brugada Syndrome

� Long QT Syndrome (LQTS)

� Short QT Syndrome

� Catecholamine induced Polymorphic

Ventricular Tachycardia (CPVT)

�� Short coupled Short coupled TorsadesTorsades

�� Idiopathic VFIdiopathic VF66

� First described in 1992 in 8 patients with aborted sudden cardiac death

� Characterized by:– ECG findings of RBBB and

persistent ST segment elevation in V1-V3

– Structurally normal hearts– Propensity for life threatening

ventricular arrhythmias

� First described in 1992 in 8 patients with aborted sudden cardiac death

� Characterized by:– ECG findings of RBBB and

persistent ST segment elevation in V1-V3

– Structurally normal hearts– Propensity for life threatening

ventricular arrhythmias

BrugadaBrugada SyndromeSyndromeBrugadaBrugada SyndromeSyndrome BrugadaBrugada Syndrome: ECGSyndrome: ECGBrugadaBrugada Syndrome: ECGSyndrome: ECG

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BrugadaBrugada : Clinical Features: Clinical FeaturesIncidence and DistributionIncidence and Distribution

BrugadaBrugada : Clinical Features: Clinical FeaturesIncidence and DistributionIncidence and Distribution

� Unexpected sudden death

� Syncope, seizures

� Agonal nocturnal respirations

� Affects male patients predominately (8:1)

� Cases reported worldwide

� Unexpected sudden death

� Syncope, seizures

� Agonal nocturnal respirations

� Affects male patients predominately (8:1)

� Cases reported worldwide

BrugadaBrugada : Clinical Features: Clinical FeaturesIncidence and DistributionIncidence and Distribution

BrugadaBrugada : Clinical Features: Clinical FeaturesIncidence and DistributionIncidence and Distribution

� Responsible for up to 50% of sudden death in victims with structurally normal hearts in Thailand

� Recognized in Asia for decades:– Bangungut: “scream followed by

sudden death during sleep” (Philippines)

– Lai tai: “death during sleep” (Thailand)– Pokkuri: “unexpected death during

sleep” (Japan)

� Responsible for up to 50% of sudden death in victims with structurally normal hearts in Thailand

� Recognized in Asia for decades:– Bangungut: “scream followed by

sudden death during sleep” (Philippines)

– Lai tai: “death during sleep” (Thailand)– Pokkuri: “unexpected death during

sleep” (Japan)

Type 1 Type 2 Type 3

BrugadaBrugada Syndrome: ECGSyndrome: ECGBrugadaBrugada Syndrome: ECGSyndrome: ECGBrugadaBrugada Syndrome: Before (A) and Syndrome: Before (A) and

After (B) After (B) ProcainamideProcainamideBrugadaBrugada Syndrome: Before (A) and Syndrome: Before (A) and

After (B) After (B) ProcainamideProcainamide

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�� Na+ channel blockersNa+ channel blockers�� Alpha agonists, Alpha agonists, VagotonicVagotonic agents,Betaagents,Beta--

blockersblockers�� FeverFever�� TricyclicTricyclic antidepressants, antidepressants, antihistaminicsantihistaminics�� HypercalcemiaHypercalcemia, , HyperkalemiaHyperkalemia�� Alcohol, CocaineAlcohol, Cocaine�� Severe ischemiaSevere ischemia

�� Na+ channel blockersNa+ channel blockers�� Alpha agonists, Alpha agonists, VagotonicVagotonic agents,Betaagents,Beta--

blockersblockers�� FeverFever�� TricyclicTricyclic antidepressants, antidepressants, antihistaminicsantihistaminics�� HypercalcemiaHypercalcemia, , HyperkalemiaHyperkalemia�� Alcohol, CocaineAlcohol, Cocaine�� Severe ischemiaSevere ischemia

Factors / Drugs that enhance ECG Factors / Drugs that enhance ECG PatternPattern

Factors / Drugs that enhance ECG Factors / Drugs that enhance ECG PatternPattern

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� 20% Atrial Fibrillation

� Prolonged PR interval (prolonged HV interval)

� AV nodal reentrant tachycardia

� WPW

� 20% Atrial Fibrillation

� Prolonged PR interval (prolonged HV interval)

� AV nodal reentrant tachycardia

� WPW

BrugadaBrugada Syndrome: Other Syndrome: Other ArrhythmiasArrhythmias

BrugadaBrugada Syndrome: Other Syndrome: Other ArrhythmiasArrhythmias

� Autosomal dominant

� 60 different mutations in the SCN5A (chromosome 3) gene have been linked to the syndrome.

� Failure of alpha subunit of Sodium channel to express

� Shift in voltage and time dependence of INA+ activation, inactivation or reactivation

� Autosomal dominant

� 60 different mutations in the SCN5A (chromosome 3) gene have been linked to the syndrome.

� Failure of alpha subunit of Sodium channel to express

� Shift in voltage and time dependence of INA+ activation, inactivation or reactivation

BrugadaBrugada Syndrome: GeneticsSyndrome: GeneticsBrugadaBrugada Syndrome: GeneticsSyndrome: Genetics

More pronounced AP notch (red arrow) due to greater Ito mediated outward current in RVMore pronounced AP notch (red arrow) due to greater Ito mediated outward current in RV

BrugadaBrugada: : PathophysiologyPathophysiologyVariation Between LV and RV Action Potentials Variation Between LV and RV Action Potentials

BrugadaBrugada: : PathophysiologyPathophysiologyVariation Between LV and RV Action Potentials Variation Between LV and RV Action Potentials

BrugadaBrugada: : PathophysiologyPathophysiologyHeterogeneous Loss of Action Potential DomeHeterogeneous Loss of Action Potential Dome

BrugadaBrugada: : PathophysiologyPathophysiologyHeterogeneous Loss of Action Potential DomeHeterogeneous Loss of Action Potential Dome

Transmural voltage gradient

EndocardiumEpicardium

Transmembrane dispersion of repolarization

Epicardial dispersion of repolarization

Normal

Brugada

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BrugadaBrugada: Diagnosis: DiagnosisBrugadaBrugada: Diagnosis: Diagnosis

� Symptoms: syncope, SCD (usually during sleep)� Physical exam: normal� Family history: strong history of SCD� ECG: best test to identify Brugada patients

– May require Flecainide or Procainamide to bring out typical findings

– ST elevation more predictive of SCD than RBBB

� Imaging tests: usually no underlying structural disease

� Stress tests: symptoms and ECG findings not usually reproducible with exercise

� SAECG: can show late potentials in 80%

� Symptoms: syncope, SCD (usually during sleep)� Physical exam: normal� Family history: strong history of SCD� ECG: best test to identify Brugada patients

– May require Flecainide or Procainamide to bring out typical findings

– ST elevation more predictive of SCD than RBBB

� Imaging tests: usually no underlying structural disease

� Stress tests: symptoms and ECG findings not usually reproducible with exercise

� SAECG: can show late potentials in 80%

Major criteria

1. Presence of the ECG marker of Brugada syndrome i n patients with structurally normal heart

2. Appearance of the ECG marker of Brugada syndrome after administration of sodium channel blockers

Minor criteria

1. Family history of sudden cardiac death

2. Syncope of unknown origin

3. Documented episodes of ventricular tachycardia/v entricular fibrillation

4. Positive programmed electrocardiostimulation tes t on ventricular tachycardia/ventricular fibrillation

5. Genetic mutations of ion channels

BrugadaBrugada Syndrome: Diagnostic Syndrome: Diagnostic CriteriaCriteria

BrugadaBrugada Syndrome: Diagnostic Syndrome: Diagnostic CriteriaCriteria

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BrugadaBrugada : Prognosis: PrognosisRecurrence of VF or SCD in Asymptomatic vs. Recurrence of VF or SCD in Asymptomatic vs.

Symptomatic PatientsSymptomatic Patients

BrugadaBrugada : Prognosis: PrognosisRecurrence of VF or SCD in Asymptomatic vs. Recurrence of VF or SCD in Asymptomatic vs.

Symptomatic PatientsSymptomatic PatientsRisk StratificationRisk StratificationRisk StratificationRisk Stratification

� Risk factors for asymptomatic individuals– Male - 5.5 fold– Spontaneous positive ECG - 7.7 fold– Inducible VT/VF – 8 fold

� Asymptomatic, drug induced type 1 Brugada ECG pattern and no inducible VT during Electrophysiology study - 0.5% probability of event

� Asymptomatic, Spontaneous type 1 Brugada ECG pattern and inducible sustained VT during EP study - 14% probability of event

� Syncope, Spontaneous type 1 Brugada ECG pattern , and inducible sustained VT during EP study- 27% probability of event

� Risk factors for asymptomatic individuals– Male - 5.5 fold– Spontaneous positive ECG - 7.7 fold– Inducible VT/VF – 8 fold

� Asymptomatic, drug induced type 1 Brugada ECG pattern and no inducible VT during Electrophysiology study - 0.5% probability of event

� Asymptomatic, Spontaneous type 1 Brugada ECG pattern and inducible sustained VT during EP study - 14% probability of event

� Syncope, Spontaneous type 1 Brugada ECG pattern , and inducible sustained VT during EP study- 27% probability of event

Brugada et al. Circulation. 2003;108. 3092-3096.

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BrugadaBrugada: Treatment: TreatmentBrugadaBrugada: Treatment: Treatment

�� Symptomatic patients with the disease: Symptomatic patients with the disease: ICDICD

�� Asymptomatic patients with a family Asymptomatic patients with a family history of SCD: with normal ECG and history of SCD: with normal ECG and negative EP study negative EP study OBSERVEOBSERVE

�� Asymptomatic pt with prolonged HAsymptomatic pt with prolonged H--V V interval, and inducible VT/VF: interval, and inducible VT/VF: controversial controversial ICDICD

�� Symptomatic patients with the disease: Symptomatic patients with the disease: ICDICD

�� Asymptomatic patients with a family Asymptomatic patients with a family history of SCD: with normal ECG and history of SCD: with normal ECG and negative EP study negative EP study OBSERVEOBSERVE

�� Asymptomatic pt with prolonged HAsymptomatic pt with prolonged H--V V interval, and inducible VT/VF: interval, and inducible VT/VF: controversial controversial ICDICD

Potential Potential antiarrhythmicantiarrhythmic drugs in drugs in BrugadaBrugada SyndromeSyndrome

Potential Potential antiarrhythmicantiarrhythmic drugs in drugs in BrugadaBrugada SyndromeSyndrome

� Quinidine (non specific I to blocker)

� Isoproterenol (open L typecalcium channel)

� Cilostazol (augment I ca )

� Tedisamil (I to blocker)

� Quinidine (non specific I to blocker)

� Isoproterenol (open L typecalcium channel)

� Cilostazol (augment I ca )

� Tedisamil (I to blocker)

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�Sudden Cardiac Death in Southeast Asia

�Characteristic ECG pattern

� ICD implantation in symptomatic patients

�Sudden Cardiac Death in Southeast Asia

�Characteristic ECG pattern

� ICD implantation in symptomatic patients

BrugadaBrugada Syndrome: SummarySyndrome: SummaryBrugadaBrugada Syndrome: SummarySyndrome: Summary

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