BRUGADA Syndrome BRUGADA Syndrome Stefano Nardi MD

AZIENDA OSPEDALIERA SANTA MARIA TERNIAZIENDA OSPEDALIERA SANTA MARIA TERNIDIPARTIMENTO CARDIOTORACOVASCOLAREDIPARTIMENTO CARDIOTORACOVASCOLARE STRUTTURA COMPLESSA DI CARDIOLOGIA STRUTTURA COMPLESSA DI CARDIOLOGIA

UNITA’ OPERATIVA DI ARITMOLOGIA CARDIACA UNITA’ OPERATIVA DI ARITMOLOGIA CARDIACA LABORATORIO DI ELETTROFISIOLOGIA ED ELETTROSTIMOLAZIONE LABORATORIO DI ELETTROFISIOLOGIA ED ELETTROSTIMOLAZIONE

• AUTOSOMAL DOMINANT trait and incomplete penetrance with variable expression.

BRUGADA Syndrome BRUGADA Syndrome

• Genetic defects in the α-subunit of cardiac Na+ channel, (reduction the Na+ channel current) that accentuates the epicardial action potential notch leading to ST-segment elevation.

• Abnormal EP activity in the RV epicardium that leads to the development of coupled PVCs that precipitates VT/VF.

• Mutations in the cardiac Na+ channel gene SCN5A

• RBBB and ST-segment elevation in the right precordial leads (V1 to V3), w/o evidence of structural HD.

• Exclusion of mimic diseases (hypothermia, pericarditis, myocarditis, or ischemic events).

• ECG pattern could be intermittent (variable and dynamic) and influenced by many factors (°C, ANS, Drugs) that can affect ion channel function.

BRUGADA Syndrome BRUGADA Syndrome

ST segment elevation in Brugada syndrome

• Autonomic tests– Isoproterenol, propranolol, norepinephrine, phentolamine

• Antiarrhythmic drugs– Ia (procainamide) Ib (lidocaine) Ca channel blocker (verapamil)

• Early repolarization hypothesis

• PREVALENCE: 0.1% in Europe

• DIAGNOSIS: ~ 40 years (2 to 77 years)

• MALE/FEMALE: 3:1

• TACHYARRHYTHMIAS at rest or during the night.

• RECURRENCE of arrhythmic events is as high as 40%.

• Sudden Infant Death Syndrome (SIDS) in the first mo. of life where it may be misdiagnosed as

BRUGADA Syndrome BRUGADA Syndrome

• Provocative test with Na+ channel blockers proposed to unmask the diagnostic ECG pattern.

– Ajmaline (1mg/kg IV) or– Flecainide (2mg/kg IV) or– Procainamide (10mg/kg IV) as a bolus over 10 m’.

– ST-segment further elevation > 2 mm

BRUGADA Syndrome BRUGADA Syndrome

BRUGADA Syndrome BRUGADA Syndrome

• The inducibility during the EPS was used to identify the risk of cardiac event, although its accuracy was limited

BRUGADA Syndrome BRUGADA Syndrome

BRUGADA Syndrome BRUGADA Syndrome • α-agonist, neostigmine/edrophonium and Class IA AADs

should be avoided because they consistently augmented ST segment elevation in pts with BS

• Although the number of pts was small in this study.

• Indication for ICD– symptomatic Brugada syndrome patients including syncope, cardiac arrest or documented VT

– Asymptomatic individuals with a positive ECG and a family history of sudden death and/or inducible during electrophisiological study

BRUGADA Syndrome BRUGADA Syndrome

A sudden syncope in a 35-year old man, with no prior cardiac history. The physical examination was unremarkable, the echo parameters were normal and an head-up test does not reproduced the symptoms.

The ECG shown is obtained.

At this point you would advise:

A.No specific therapy

B.Empiric B-blocker

C.EP Study with ICD implantation if positive

D.ICD implantation

A clinical and electrocardiographic syndrome

- no demonstrable structural HD

• - suffering from cardiac arrhythmias

• - a very specific ECG

• apparent RBBB

• ST elevation in leads V1-V3

Description of the syndrome

• The disease is associated with a mutation in sodium channel (SCN5A).

• The early theory was that the syndrome reflected an increase in the Ito channel (governing the potassium current in phase 1 of the ECG).

• In fact, the Ito current is only increased relative to the sodium current, because the sodium channel

closes prematurely.

Ionic basis of disease

• ECG definition has become more and more strict.

• ST elevation of a coved type of at least 2 mm or ST elevation of saddleback type if it becomes coved type under stress with anti-arrhythmics.

• Elevation is always present in V2, and either V1 or V3 (usually both).

Diagnosing the syndrome

• Flecainide used now that ajmaline is no longer available.

• Given in an IV in Europe, but maybe 200mg orally but patient must be monitored for 8 hours because of the long half-life.

• Procainamide is effective in unmasking the syndrome, but the ECGs are much less spectacular. May have less specificity and sensitivity than ajmaline.

Drugs for diagnosis

• In all pts where we had genetic confirmation of the disease, we did not have a single false negative or false positive with ajmaline.

• The ajmaline test was consistently reproducible in over 100 pts.

• Pts’ hearts are different and the positioning of the leads can play an important role in

diagnosis since the syndrome is localized in a specific region of the heart.

Sensitivity and specificity

EP testing

• Every single patient that has a classic Brugada ECG gets an EP test.

• Asymptomatic patients who have a normal basal ECG have 0% events in follow-up so far.

• So we don’t do EP tests in these patients.

• Wait and watch because there is no evidence they are at risk.

Asymptomatics • If the base ECG is abnormal, then we follow with

EP testing.

• In these pts, 2/3 are non-inducible.

• If non-inducible, we do nothing, because the event rate is extremely low.

• Events in asymptomatic pts with abnormal basal ECG occurred in pts who were inducible by EP testing.

• Pt with a father who died of SD – no ECG available.

• The pt has abnormal ECG, which becomes classic Brugada after stressing with flecainide.

• This pt should get EP study due to family history.

• If the study is positive, give them a defibrillator. If negative, do nothing.

Clinical decision making

• Only 60% of SD in families with known Brugada syndrome can be attributed to the syndrome.

• ECGs can normalize over time. A completely normal ECG in one moment doesn’t mean it will always be normal.

• If the ECG ever becomes abnormal, you then follow up with drug tests and then EP testing.

Clinical decision making

• A 28 year old uncle who died suddenly, no ECG available. My father died suddenly at 46.

No autopsy.

• The kid has a classic Brugada ECG but is non-inducible to EP testing.

• I would suggest a defibrillator due to the strong family history, but there is no evidence that the risk is extremely high.

• But with the strong family history and the baseline Brugada ECG, I would be nervous.

Clinical decision making

Definition of Brugada ECG• RBBB in V1-V3 (V2 most important)

• Coved ST-segment elevation of > 2mm

• If not present at baseline, ECG can be induced by flecainide or procainamide.

• ICD is treatment of choice for pts with documented cases of serious arrhythmias

• In general if the EP study shows no inducible VT, watch and wait.

Review

Brugada - Circulation ‘05

547 “coved type”

124 Sincope 170

Routine

253 Familiarità

391 Spontanei

156 dopo ajmalina

28±42 mesi Follow Up 45 (8%) eventi

Età media 40 aa

Brugada - Circulation ‘05

ECG spontaneo coved type, %

(95% IC)

ECG dopo test ajmalina, % (95% IC)

Sincope•Inducibilità

•Non inducibilità

Asintomatici•Inducibilità

•Non inducibilità

27.2 (17.3-40.0)

4.1 (1.4-11.7)

4.5 (1.0-17.1)

0.5 (0.1-2.7)

14.0 (8.1-23.0)

1.8 (0.6-5.1)

9.7 (2.3-33.1)

1.2 (0.2-6.6)

• FU 28±42 mo

• 45 FV (8%)

• Inducibilità durante PES/ storia di sincope

Analisi di REGRESSIONE LOGISTICA: Sincope sufficiente rischio da giustificare un ICD (1.2 % -27.2 %)

COVED TYPE: sopralsivell punto J ≥ 2 mm con onda T negativa.

BS

Sindrome di Brugada

•Storia di sincope

•Un episodio di arresto cardiacoICD

Ma qual è il RISCHIO degli altri pazienti?

•NON ESISTE una terapia medica di sicura e documentata efficacia.

• ICD funziona in pazienti che SVILUPPANO o SVILUPPERANNO una VF

• Altrimenti ……….. tutti i rischi dell’impianto e nessun beneficio

Sindrome di Brugada CONSIDERAZIONI

Possibile strategia “insertable LR + ICD esterno”

BRUGADA syndrome: stratificazione

Alto rischioRapporto di rischio: 6.4

Rischio intermedio Rapporto di rischio: 2.1

Basso rischio

Priori et al - Circulation ‘02

RischioSincope e pattern

ECG positivo

Pattern ECG positivo

Pattern ECG negativo con o senza sincope

Percentuale popolazione

10 %

41 %

49 %ICD

Terapie

Ulteriori controlli in caso di sintomi

Sindrome di Brugada

I IIa IIb

•Sincope•Familiarità per SCD

• VF - VT• Inducibilita VT-S/ VF

Classe

Priori et al. Eur Heart J ‘01Priori et al. Eur Heart J ‘01

STRATIFICAZSTRATIFICAZdel RISCHIOdel RISCHIO

I IIa IIb

• ICD in Pz. con Sincope/ TV

•ICD

•ICD in pz asintomatici EPS inducibili

PrevenzionePrimaria

PrevenzioneSecondaria

Classi

Priori et al. Eur Heart J ‘01Priori et al. Eur Heart J ‘01

Sindrome di BrugadaSindrome di Brugada

Necessità:Bilanciare costi-efficacia in pz con indicazione non ancora consolidata, stratificando i pz a rischio.

Genetic disease: ICD or hybrid approach?

Sindromi più note:- Brugada (classe II-b) - QTLS (classe II-b) - Distrofia (a seconda del tipo genetico, varia la probabilità di una futura insorgenza di VTs or blocco cardiaco)- Catecholaminergic Polymorphic VT: new possible indication ?

Possible options Impianto di ICD in pazienti a maggior rischio, altrimenti “implantable loop recorder” per monitorare aritmie spontanee + defibrillazione precoce (home defibrillation)

Genetic disease: ICD or hybrid approach?

ConclusioniMalattie geneticheStratificazione pts a rischio e applicazione di possibili strategie con miglior resa costo-efficacia

• Percezione del problema non ottimale Campagna di sensibilizzazione inconsistente

Quali sono le indicazioni accettate:

• La clinica sta facendo emergere nuove consapevolezze che però si scontrano con problemi di natura economica.• L’impegno nel coniugare le opposte esigenze è, rappresentato dalla ottimizzazione delle risorse, dal miglioramento della prevenzione e dalla riduzione di spesa sia in termini di terapia e costi sociali.

Conclusioni

Sindrome di Brugada

COVED TYPE: sopralsivellamento punto J ≥ 2 mm con onda T negativa.

Tipo 2 e 3

CLINICA

Parametri ECG

Sincope Morte improvvisa

Brugada - Circulation ‘05

547 “coved type”

124 Sincope 170

Routine

253 Familiarità

391 Spointanei

156 dopo ajmalina

28±42 mesi Follow Up 45 (8%) eventi

Età media 40 aa

Brugada - Circulation ‘05

ECG spontaneo coved type, %

(95% IC)

ECG dopo test ajmalina, % (95% IC)

Sincope•Inducibilità

•Non inducibilità

Asintomatici•Inducibilità

•Non inducibilità

27.2 (17.3-40.0)

4.1 (1.4-11.7)

4.5 (1.0-17.1)

0.5 (0.1-2.7)

14.0 (8.1-23.0)

1.8 (0.6-5.1)

9.7 (2.3-33.1)

1.2 (0.2-6.6)

Sindrome di Brugada

•Storia di sincope

•Un episodio di arresto cardiacoICD

Ma qual è il RISCHIO degli altri pazienti?

Esiste un modo per stratificare i pazienti?

45 (8%) eventi durante FU medio di 28 mesi

547 pazienti senza precedenti di arresto

cardiaco

167 casi fortuiti

•NON ESISTE una terapia medica di sicura e documentata efficacia.

• ICD funziona in pazienti che SVILUPPANO o SVILUPPERANNO una VF

• Altrimenti ……….. tutti i rischi dell’impianto e nessun beneficio

Sindrome di Brugada CONSIDERAZIONI

28 +- 42 mesi

45 FV (8%)

Inducibilità durante PES/ storia di sincope

Analisi di regressione logistica

Sincope sufficiente rischio da giustificare un ICD

1.2 % -27.2 %

Brugada syndrome: RISK stratifiactionSindrome ereditaria caratterizzata da un tipico pattern ECG (ST elevation da V1 a V3, RBBB), spesso in presenza di mutazione genetica.

‘98: EPS positive for VTG/VF inducible come criterio di stratificazione di pazienti sintomatici e non 1

1 Brugada, Circulation ‘98; 2-3 Priori et al - Circulation ’00 – ‘02

‘00-’01 ≈75% pts inducibile, quindi LARGO USO dell’ICD Studi clinici, confermando la prognosi per pts sintomatici, ne hanno dimostrato una più BENIGNA di quanto ritenuto per gli asintomatici, così come un basso valore predittivo di EPS 2 ‘02: possibile stratificazione: ST ELEVATION V1 V3 e storia di sincope3 2-3 Priori, Circulation ’00 – ‘02

Brugada syndrome: RISK stratifiaction

Possibile strategia “insertable LR + ICD esterno”

BRUGADA syndrome: stratificazione

Alto rischioRapporto di rischio: 6.4

Rischio intermedio Rapporto di rischio: 2.1

Basso rischio

Priori et al - Circulation ‘02

RischioSincope e pattern

ECG positivo

Pattern ECG positivo

Pattern ECG negativo con o senza sincope

Percentuale popolazione

10 %

41 %

49 %ICD

Terapie

Ulteriori controlli in caso di sintomi

Esiste un modo per stratificare i pazienti?Survival curve showing occurrence of arrhythmicevents (SCD or VF)during FU in 547 pts with a Brugada ECG pattern “coved-type” and no previous CA.

Necessità:Bilanciare costi-efficacia in pts con indicazione non ancora consolidata, stratificando i pz a rischio.

Genetic disease: ICD or hybrid approach?

Sindromi più note:- Brugada (classe II-b) - QTLS (classe II-b) - Distrofia (a seconda del tipo genetico, varia la probabilità di una futura insorgenza di VTs or blocco cardiaco)- Catecholaminergic Polymorphic VT: new possible indication ?

Possible optionsImpianto di ICD in pts a maggior rischio, altrimenti “implantable loop recorder” per monitorare aritmie spontanee + defibrillazione precoce (home defibrillation)

Genetic disease: ICD or hybrid approach?

Malattie geneticheStratificazione pts a rischio e applicazione di possibili strategie con miglior resa costo-efficacia

• Percezione del problema non ottimale Campagna di sensibilizzazione inconsistente

Quali sono le indicazioni accettate:

• La clinica sta facendo emergere nuove consapevolezze che però si scontrano con problemi di natura economica.

• L’impegno nel coniugare le opposte esigenze è, rappresentato dalla ottimizzazione delle risorse, dal miglioramento della prevenzione e dalla riduzione di spesa sia in termini di terapia e costi sociali.

Conclusioni

• Ventricular arrhythmias w/o demonstrable structural HD have long been recognized. A specific subgroups include L-QTc S, ARVD, and Brugada.

• Firstly described by Martini in survivors of CA (’89).

• ‘92 systematic collection of cases by Brugada established this ECG pattern as a distinctive new syndrome associated with augmented risk of SD.

• Provocative test with Na+ channel blockers proposed to unmask the diagnostic ECG pattern.

– Ajmaline (1mg/kg IV) or Flecainide (2mg/kg IV) or Procainamide (10mg/kg IV) as a bolus over 10 m’.

– ST-segment further elevation > 2 mm

• The inducibility during the EPS was used to identify the risk of cardiac event, although its accuracy was limited

BRUGADA Syndrome BRUGADA Syndrome