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National Cerebral and Cardiovascular Center

Brugada syndrome – nothing, Quinidine, ICD, or AblationWhat to do in the storm

6/13/2016Kenichiro Yamagata

National Cerebral and Cardiovascular Center, Japan


✓Diagnosing Brugada syndrome

✓Treating Brugada syndrome

✓SCN5A mutation in Brugada syndrome

Today’s Talk





Today’s Talk


Brugada syndrome (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.

2013, Heart Rhythm


(Europace, 2017, 19, 665–694)


Shanghai Score System for diagnosis of Brugada syndrome

ECG

Spontaneous type 1 Brugada ECG pattern at nominal or high leads 3.5

Fever-induced type 1 Brugada ECG pattern at nominal or high leads 3

Type 2 or 3 Brugada ECG pattern that converts with provocative drug

challenge

2

Clinical History

Unexplained cardiac arrest or documented VF/polymorphic VT 3

Nocturnal agonal respirations 2

Suspected arrhythmic syncope 2

Syncope of unclear mechanism/unclear etiology 1

Atrial flutter/fibrillation in patients, 30 years without alternative etiology 0.5

Family History

First- or second- degree relative with definite BrS 2

Suspicious SCD (fever, nocturnal, Brugada aggravating drugs) in a first-

or second-degree relative

1

Unexplained SCD, 45 years in first- or second- degree relative with

negative autopsy

0.5

Genetic Test Result

Probable pathogenic mutation in BrS susceptibility gene 0.5

≥3.5 points: Probable/definite BrS2–3 points: Possible BrS2 points: Nondiagnostic

Score(requires at least 1 ECG finding)

J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge

(Europace, 2017, 19, 665–694)

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Shanghai Score System for Diagnosis of Brugada SyndromeValidation of the Score System and Reclassification of the Patients

(Kawada et al., JACC CE 2018)

The Shanghai Score System for the diagnosis and risk stratification of patients with BrS





Today’s Talk





Today’s Talk


Ⅰ

Ⅱ

Ⅲ

aVR

aVL

aVF

V1

V2

V3

V4

V5

V6

Brugada syndrome

Ⅰ

Ⅱ

Ⅲ

aVR

aVL

aVF

V1

V2

V3

V4

V5

V6

ICD is highly recommended


Are we always happy with ICD when it saves life?

VF storm…

Brugada syndrome


Pharmacological Treatment

Evaluate the precipitating factors• Fever• Hypokalemia

• Ishchemia• Drug

Catheter Ablation

How to treat Brugada Syndrome Storms

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Pharmacological Treatment of BrS

• Quinidine →Ito block

• Isoproterenol →PKA activate→Increase Ica-L

• Cilostazol →PDE block→cAMP increase→Increase Ica-L

Quinidine or isoproterenol should be considered inpatients with Brugada syndrome to treat electrical storms(IIa)

Quinidine should be considered in patients who qualifyfor an ICD but present a contraindication or refuse it andin patients who require treatment for supraventricular

arrhythmias (IIa)(EHJ(2015) 36, 2793–2867)


Pharmacological Treatment• Isoproterenol• Quinidine

• Cilostazole



Catheter Ablation• Trigger• Substrate



Purkinje potentials

First report to succeeded eliminating PVCs and no recurrence of VF

Mapping and Ablation of Ventricular Fibrillation Associated

With Long-QT and Brugada Syndromes

Most BrS patients don’t have frequent PVCs

(Haissaguerre, Circulation. 2003;108:925-928.)


Prevention of Ventricular Fibrillation Episodes in Brugada Syndrome by Catheter

Ablation Over the Anterior Right Ventricular Outflow Tract Epicardium

purple represents the longest duration (160 ms) during

sinus rhythm

• 8 out of 9 patients had normalized BrS type ECG• 9 out of 9 patients had no recurrence of VF events

(Nademanee et al., Circulation. 2011;123:1270-1279.)


4ICS

43y.o. maleDiagnosed as BrS at 29 y.o.Implanted ICD for secondary prevention

Experienced VF storm and prescribed Quinidine

VF storm reccured 3 years after

Case


Fragmented / delayed potential

Voltage map

RAO LAO

RAO LAO

<Epi>

<Endo>

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Bordeline of FP area

Ablation site

Ablation site

Pre Post

No recurrence after 5years of f/u


Electrical Substrate Elimination in 135 Consecutive

Patients With Brugada Syndrome

(Pappone et al., Circ Arrhythm Electrophysiol. 2017;10:e005053.)

Why does ablation work?


Fibrosis, Connexin-43, and Conduction Abnormalitiesin the Brugada Syndrome

(Nademanee et al, JACC, VOL. 66, NO. 18, 2015)

Control BrS (BrS)In Vivo

BrS is associated with epicardial surface and interstitial fibrosis and reduced Connexin 43 gap junction


Pharmacological Treatment• Isoproterenol• Quinidine

• Cilostazole



Catheter Ablation• Trigger• Substrate






Today’s Talk





Today’s Talk

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How should we perform risk stratification for BrS?

Most supported risk factor

Other risk factors

Fragmented QRSEffective refractory period <200ms during EPSMale gender

Documented AFEPS

SCN5A mutation

Spontaneous type 1 ECG

HRS/EHRA/APHRS expert consensus statement


NaV1.5 (SCN5A)

Nature Reviews Neuroscience 7, 548-562 (July 2006)

S5

S6


BrS and SCN5A mutation

HRS, EHRA, and APHRS (2011)Expert consensus Statement on the State of Genetic Testing for the Channelopathises and Cardiomyopathies

Mutation-specific genetic testing is recommended for family members andappropriate relatives following the identification of the BrS-causative mutation in an

index case (Class I).

Comprehensive or BrS1 (SCN5A) targeted BrS genetic testing can be useful forany patient in whom a cardiologist has established a clinical index of suspicion forBrS based on examination of the patient’s clinical history, family history, and

expressed electrocardiographic phenotype (Class II).

Genetic testing is not indicated in the setting of an isolated type 2 or type 3Brugada ECG pattern (Class III).

The presence of a BrS-associated mutation does not impact the treatment ofan index case with BrS.


BrS and SCN5A mutation

HRS, EHRA, APHRS (2013)Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia

Syndromes

SCN5A mutation has not been proven to be a risk marker in large studies. However, some specific types of mutations, such as those that result in atruncated protein, or some common SNPs, might have prognostic

significance.


All SCN5A (+) SCN5A (-) P value

(n) 415 60 (14%) 355 (86%)

Age (years) 46 ± 14 44 ± 16 47 ± 13 0.210

Male Gender 403 (97%) 58 (97%) 345 (97%) 0.687

History of syncope

(without ACA) 99 (24%) 15 (25%) 84 (24%) 0.822

History of ACA 88 (21%) 15 (25%) 73 (21%) 0.437

Age of first syncopal

episode or ACA (years) 41 ± 16 34 ± 17 42 ± 15 0.013

Pore mutation of SCN5A 25 (42%)

FH of SCD 64 (15%) 11 (18%) 53 (15%) 0.500

ICD implantation 240 (58%) 37 (62%) 203 (57%) 0.515

Genotype-Phenotype Correlation of SCN5A Mutation for the Clinical and Electrocardiographic Characteristics of Probands With Brugada SyndromeA Japanese Multicenter Registry

(Yamagata et al., Circulation. 2017;135:2255–2270)


Follow up (months)

20

40

60

80

100

0

20

40

60

80

100

0

0 100 200 300 0 100 200 300

nonpore-SCN5A (+)

P=0.110

SCN5A (-)

pore-SCN5A (+)

P=0.002

Pro

bability o

f Surv

ival (%

)

Overall Survival among All cases

SCN5A (-)

SCN5A (+)

P=0.017

SCN5A (-)

SCN5A (+)

P=0.017

SCN5A (-)

pore-SCN5A (+)

P=0.002

(Yamagata et al., Circulation. 2017;135:2255–2270)

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SCN5A Mutations in Brugada Syndrome Are Associated with Increased Cardiac Dimensions and Reduced Contractility

(van Hoorn et al., 2012 | Volume 7 | Issue 8 | e42037)

SCN5A mutation in BrS


Comparison of Long-Term Follow-Up of Electrocardiographic

Features in Brugada Syndrome Between the SCN5A-Positive

Probands and the SCN5A-Negative Probands

(Yokokawa et al., Am J Cardiol 2007; 100:649–655)

SCN5A mutation in BrS





Today’s Talk


• Managing BrS VF storm is important

• Ablation can be a curable therapy for BrS

• BrS with SCN5A mutation can be a risk for cardiac event

Conclusion


Thank you for your attention!!!

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