Brugada Syndrome:30 years after and still learning

Josep Brugada, MD, PhD

Hospital Clínic and Pediatric Hospital Sant Joan de DéuUniversity of Barcelona

Spain

History

• 1st patient identified in 1986• 1st abstract including 4 patients in 1991

(Brugada P, Brugada J. PACE)• 1st paper including 8 patients in 1992

(Brugada P, Brugada J. JACC; 20, 1391-6)

The ECG

- Prolonged PR

- RBBB

- ST segment ↑

Ventricular arrhythmias

Definition

The Brugada syndrome is a clinical-electrocardiographic diagnosis based on the occurrence of syncopal or sudden death episodes in patients without demonstrable structural heart disease and a characteristic ECG pattern of apparent right bundle branch block and ST segment elevation in leads V1 to V3.

Original articles including in the title: Brugada syndrome

Number of articles Number of citations

Initial descriptionJ Am Coll Cardiol

1992 1997 1998 1999 2000 2001 2002 2003 2005

Clinical descriptionJ Cardiovasc Electrofisiol

Sudden deathCirculation

GeneticsNature

Temperature dependenceCirc Res

AjmalineCirculation

EPSJ Cardiovasc Electrofisiol

ICDJ Electrocardiol

AsymptomaticsJ Cardiovasc Electrofisiol

Long term follow-upCirculation

SUDS = BrugadaHum Mol Genet

Diagnostic criteriaCirculation, Eur Heart J

MutationsMol Gen Metabol

Risk stratificationCirculation

ECGCirculation

ManagementCirculation, Eur Heart J

MutationsCirculation

Type 1“Coved”

Type 2 & 3“Saddle back”

NON DIAGNOSTIC

Figure 5. Spontaneous changes on the electrocardiogram in a patient with Brugada syndrome. Note how the ST elevation changes. On February 1993 the electrocardiogram was completely normal (arrow).

basal ajmaline isoprot basal ajmaline isoprot

proband brother

Ajmaline test

Affected Non-affected

Value of the ajmaline test

• Sensitivity 80%• Specificity 94%• + PV 93%• - PV 83 %

Penetrance of the disease increases from 32,7% to 78,6% with the use of ajmaline

Major events (SD or VF) depending on gender

Mujeres

Varones

Log-rank<0.003

Type of ECG at baseline

Males Females

p < 0.001

Males Females

ST-segment elevation:

Major events (SD or VF) depending on previous symptoms

Asintomáticos

Síncope

Muerte súbita

Log-rank<0.0001

I am 28 years old, male. I was a very healthy individual.

I was on my duty about 10 p.m. I was talking on the phone when suddenly had lost my consciousness and hit the ground.

Luckily, I was seen by my co-resident … He immediately hooked me to a cardiac monitor.When I got my consciousness, I could not remember

what happened.…Can you confirm the diagnosis and tell me the steps I

need to follow to protect my family.

Cardiac arrest

Major events (SD or VF) depending on inducibility

No inducible

Inducible

Log-rank<0.0001

Programmed ventricular stimulation

N=166

EPSN= 135 (81%)

No EPSN= 31 (19%)

EPS (-)N= 89 (66%)

EPS (+)N= 46 (34%)

3 (10%) ICD1 (3%) Loop recorder

44 (96%) ICD1 (2%) Loop recorder

0 Arrhythmic events

1 (3%) SCDAsymptomaticBasal Type 1 ECG

Giustetto C et al. Europace (2009) 11,507-513.

7 VF (15%) interrupted by the ICD

1 VF (3%)interrupted by the ICD

FOLLOW-UP: 30 ± 21 months

Multivariate analysis

Variable HR 95% IC P

Male 2,13 1,2-3,9 0,01

Syncope 3,77 2,2-6,3 < 0,001

SD 5,28 3,3-8,4 < 0,001

Inducibility 2,73 1,5-4,9 0,001

ECG AT

BASELINE

ECG WITH AJMALINE

- - - + - - - - - - - - + - - + + + - - + N/A - N/A

MUTATION ANALYSIS WT WT T/M T/M T/M T/M WT WT T/M T/M WT T/M T/M

AFFECTEDNON AFFECTEDDEAD

Family K005

WT: Wild typeT/M:

T1620M

Phenotypic-Genotypic correlation

I II III IV

Extracellular

Domains

COOH

NH2

*****

* R1623Q**R1644H***T1645M

S1710L1786

*

T1620M

R15

12W E1784K

D1790GN13

25S

ΔKPQ

150

5-15

07

G14

06R

1795insDY1795H

A19

24T

A19

24T

D15

95N

ΔK15

00

*

R1232W

T130

4MIV

S22+

2T>C

L567

Q T632MIVS7+4insAA

R1432G1397*

R11

92Q

A73

5V

R36

7H

G29

8S

G51

4C

Brugada syndromeLong QT syndromeConduction Disease

Brugada /Conduction DiseaseBrugada / LQT3 / Conduction Disease

• Identification of first gene in 19981:SCN5A (α-subunit of sodium channel) on chrom. 3

GENETICS

1. Chen, Brugada et al. Nature 1998

To date, > 200 different mutations identified in SCN5A2.

Loss of function of sodium channelOnly identified in ≈ 18-30% of

cases

MOLECULAR STUDIESLow incidence SCN5A mutations/BS→genetic heterogeneity

Calcium cardiac channelsPotassium cardiac channelsSodium cardiac channels

IV

COOH

▪↓ I Na+ ↓ ICa++ AND/OR ↑ Ito ↑ Other IK

Role of additional variations in Brugada Syndrome

Exon 28Exon 9

Exon 28

Exon 28 Exon 9

RB6043 RB6061

RB6042 RB6044

RB6045

?

RB6046

Exon 9

Cordeiro, Brugada et al. Circulation, 2006

Role of additional variations in Brugada Syndrome

RB6043 RB6061

RB6042 RB6044

RB6045

RB6046

Cordeiro, Brugada et al. Circulation, 2006

• Brugada syndrome (BS) = Na+ CHANNELOPATHY

MOLECULAR STUDIES

Ca++

- 90 mV

0 mV

Na+

Ito(K)

K+

AP in Brugada Syndrome SCN5A Mutation

Loss of functionNa+ channel

↓Na+ voltage-dependent current (INa)↑ K+ transient outward current (Ito)

•Loss of dome/AP

•ECG changes

•VT/VF

Ionic mechanisms responsible for the phenotype of the Brugada syndrome are temperature dependent. Circ Res. 1999.

39.5°C 36.4°C

Appropriate ICD therapies

CLINICAL RECOMMENDATION FOR BRUGADA SYNDROME

• Ito blockers:– QUINIDINE1 (Ito blocker with anticholinergic effects):

• 25 BS patients with inducible VF.• 22/25 (88%) not inducible after treatment.• 19/19 with no arrhythmias in follow-up.• 36% side effects → drug discontinuation.

– Other: tedisamil, 4-aminopyridine.• Activators of ICa:

– Isoproterenol (for electrical storm)2.– Cilostazol3.– Orciprenaline (for electrical storm) 4

PHARMACOLOGICAL TREATMENT

1. Belhassen et al. Circ 20042. Tanaka et al. PACE 2001

3. Tsuchiya et al. JCE 20024. Kyriasis et al. Europace 2009

Reduction in the median number of ICD shocks before and after Quinidine administration.

P<0.001

Total numberof shocks n= 203

Total numberof shocks n= 41

Anguera I. et al, JACC 2016

The Brugada ECG Pattern Ablation

Circulation 2002

Incidental abolition of Brugada pattern during endocardial ablation of ventricular ectopy for VF prevention in the RVOT

Journal of Cardiovascular Electrophysiology Vol. 22, pp. 1290-1291, November 2011

• 17 arterially perfused canine RV preparations

• Pinacidil (5 μM) and pilsicaine (5 μM) → BS model

• RFCA earliest activation site of PVCs in EPI or ENDO

(N= 9)

(N= 8)

Morita H et al. Heart Rhythm, Vol 6, Nº 5, May 2009

RFCA:AP heterogeneity still presentDisconnection of areas with long (EPI1) and short AP (EPI2) eliminated arrhythmia

Circulation 2011

The Brugada ECG Pattern Ablation

- 9 patients were treated -In 7/9 pts no VT/VF was inducible-In 5/9 pts BrS pattern disappeared immediately after the procedure

-In 3/9 pts BrS pattern disappears during FUP

-In 8/9 patients no VT/VF recurrences occurred

Brugada J, Pappone C, et al. Circ Arrhythm Electrophysiol 2015

-14 patients were enrolled (ICD was implanted in all patients)-We target fragmented and delayed potentials and low voltage areas in basal condition and after flecainide test

-In 14/14 pts Brugada pattern disappeared immediately after the RFA. -In 14/14 pts pharmacological test (flecainide or ajmaline) after RFA resulted negative-In 14/14 pts VT/VF was not inducible after RFA (EP Test up to three extrastimuli untill refractoriness or to 200 msec)

-In 14/14 pts during FUP Brugada ECG pattern was not evident anymore in basal condition and after drug challenge

-In 14/14 pts during FUP no recorded VT/VF episodes

23/3/16 Gia

Basal Flecainide

Duration MAP

23/3/16 Tar

Basal Flecainide RF on Flecainide Final

23/3/16 Tar

Start RF RF on RF on RF on RF on RF on Final

23/3/16 Tar

Basal

Flecainide

200 250 300

200 250 300

Duration MAP

23/3/16 Tar

Basal

Final post RF

VOLTAGE DURATION ACTIVATION

VOLTAGE DURATION ACTIVATION

Electrograms characterizationDiscrete double and late component

Wide duration, high voltage and delayed component

Wide duration, low voltage and late component

Uni - distal

Bip - distal

Bip - prox

V1 ECG lead

V2 ECG lead

Potential Duration Map (PDM)Electrograms with longer duration, low voltage and late or consistent and discrete component are shown in purple color.

>200 ms >250 ms >280 ms252 ms

216 ms 252 ms 290 ms

Automatic Potential Duration AnnotationAutomatic detectionRed Calipers

Onset Offset

Color-code Map Potential Duration Map (PDM)

Electrograms characterizationDiscrete double and late component

Wide duration, high voltage and delayed component

Wide duration, low voltage and late component

Uni - distal

Bip - distal

Bip - prox

V1 ECG lead

V2 ECG lead

23/3/16 Gia

proximal

distal

proximal

distal

proximal

distalproximal

distal

proximal

distal

proximal

distal

Case 2 SEE and Ajmaline Test pre ablationBASELINE AJMALINE 1 mg/Kg

IIIIII

aVRaVLaVFV1 II ic

V2 II icV1 III ic

V2 III icV1 IV ic

V2 IV ic

6-months Follow-up - Ajmaline TestBASELINE

I

II

III

aVR

aVL

aVF

V1 II ic

V2 II icV1 III ic

V2 III ic

V1 IV ic

V2 IV ic

AJMALINE 1 mg/Kg

Case 2

Bangungot = Lai Tai = Pokkuri = Brugada syndrome

“In Thailand, the being to fear is the phi am or ‘widow ghost’ who comes to steal away the souls of young men. Some villages think that bangungot appears in form of a huge and fat female demon, that sits over men’s face suffocating them, causing agonal respiration and ultimately death .Some men defend themselves from phi am by wearing lipstick at night, so that the ghost mistakes them for women and leaves them alone.”

The Brugada family

Ramon Pedro Georgia Josep