Sindrome di Brugada e QT lungo - asiam-aggiornamentomedico.it · Aritmie Fatali: Eziologia. Kaufman...

Sindrome di Brugada

e QT lungo

Paolo Pieragnoli

Università degli Studi di Firenze

Firenze – 16 Giugno 2018

Stadio Artemio Franchi

I sessione – La Morte Improvvisa

Morte Improvvisa / Definizione

Morte naturale, preceduta da

improvvisa perdita della conoscenza,

che si verifica entro 1 ora dall’inizio

dei sintomi, in soggetti con o senza

cardiopatia nota preesistente, ma in

cui l’epoca e la modalità di morte

sono imprevedibili.Myerburg RJ, Castellanos A 1980; Task-force on SD of ESC. Eur Heart J 2001; 22: 1374-1450

FILIPPIDE muore improvvisamente subito dopo aver

annunciato agli Ateniesi la vittoria di MARATONA

PROBLEMA ANTICO !

“Chi si libera spesso e

violentemente, senza apparente

motivo, muore all’improvviso.”

Ippocrate “Aforismi”

A Roncisvalle, Orlando “sente che la morte lo

prende tutto. Dalla testa, scende verso il

cuore”. Egli “sente che il suo tempo è finito”.1

Tristano “sentì che la sua vita si perdeva,

comprese che stava per morire”.2

“Nipote mia, mi sento vicino a morire”.3

1 La Chanson de Roland2 Le Roman de Tristan et Iseult3 Cervantes, Don Chisciotte

L’uomo è stato per millenni il padrone assoluto

della sua morte e delle circostanze della sua

morte . . .

Di rado la morte era improvvisa, anche in caso

di incidente o di guerra, e la morte improvvisa

era molto temuta, non solo perché non dava il

tempo di pentirsi, ma perché privava l’uomo

della sua morte.

Ariès “Storia della morte in Occidente”

MI – Epidemiologia / Italia

• Incidenza → 1 x 1000 Abit.

• Numero casi x anno → 57.000

• Numero casi x giorno → 156

• 1 caso ogni 9 minuti

• 10 % di tutte le cause di morte

• 40 % di tutti i decessi x causa cardiaca

MI-Aritmie Responsabili

Bradiaritmia

15-20%

Tachiaritmia Ventricolare (TV/FV)

75-80%

Dissociazione

Elettromeccanica 5%

80%

Malattie

Coronariche

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

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

15%Cardiomiopatie

5% Altre*

Aritmie Fatali: Eziologia

Kaufman Heart Rhythm 2009

Channelopathies (ion Channel disturbances) affect nearly every organ

system. Individuals with ion channel mutations usually are well compensated

at baseline, and their symptoms tend to be paroxysmal.

Cardiac channelopathies are characterized by genetic heterogeneity and

variable penetrance.

Several cardiac channelopathy syndromes: long QT syndrome (LQTS), short

QT syndrome, Brugada syndrome and catecholaminergic polymorphic

ventricular tachycardia (CPVT).

SINDROME DI BRUGADA

Un po’ di storia• 1953 Oshler e Wolff descrissero un sopraslivellamento ST nelle precordiali destre indipendente da

ischemia miocardica senza alcuna spiegazione “plausibile”

• 1989 Martini pubblica uno studio su 6 pazienti senza cardiopatia, resuscitati dall’arresto cardiaco per FV; l’ECG di uno di questi presentava una deflessione terminale positiva in V1-V2 con evidente sopraslivellamento del tratto ST

• 1992 Brugada P. & J.

Epidemiologia della Sindrome di Brugada

Sindrome di Brugada: responsabile dal 4% al 12% di tutte le morti SD and for up to 20% of SD in subjects withoutconcomitant cardiopathy.

Its prevalence has been estimated in 5 of 10000 inhabitants, although this rate should be understood cautiously, first, because many patients present concealed forms of the disease, thus making it likely that the real prevalence ishigher, and second, because important ethnic and geographicdifferences have been described.

Antzelevitch C et al. Circulation 2005

Basi genetiche

Data la bassa sensibilità la diagnosi resta prettamente clinica;inoltre il risultato dello screening genetico, non influenza né laprognosi né il trattamento.

12

30

4

4

0mVolts

-85mV

• Codes for cardiac sodium channel that opens during phase 2 of the action potential. In Brugada, it opens poorly in RV epicardial cells.

• Autosomal dominant inheritance

• 20-30% of cases have anbl SCN5A gene.

• 80+ mutations, different prognosis.

SCN5A gene

Benito B. et al. Progress in cardiovasc disease 2008

Elettrogenesi• L’onda J deriva da un alterazione del potenziale d’azione che coinvolge le celluleepicardiche durante la fase 1 (ripolarizzazione precoce) .

• Il malfunzionamento dei canali del sodio (I-Na late) fa sì che la fuoriuscita di ionipotassio non sia più controbilanciata; si determina pertanto il cosiddetto potenzialed’azione “spike-and-dome”. Si viene a creare cosi un gradiente endo/epi in fase 1,che si esprime con la onda J. L’entità del gradiente determina le differenze tra i varipattern

• Il rischio aritmico compare quando l’alterazione dei flussi ionici è di entità tale daprovocare (a livello infundibolare) perdita della fase di plateau e accorciamento delladurata del potenziale.

• Tale fenomeno è presente solo in alcune aree epicardiche; si determina pertantouna differenza di refrattarietà fra endocardio ed epicardio, e fra diverse zonedell’epicardio. Pertanto durante la fase 2 si crea un gradiente elettrico tra diversecellule (dispersione) e le cellule con potenziale accorciato e breve refrattarietàpossono essere “rieccitate”

Elettrogenesi e rischio aritmico

Oreto G 2010

Bayés de Luna A et al. J Electrocardiol. 2012

Comparison between type 1 and 2 BrP, arrhythmogenic right ventricular dysplasia,

pectus excavatum, athletes, and partial RBBB to view the presence of mismatch in

the QRS duration in V1-V2 and mid/left precordial leads. There is clear mismatch in

type 1 and 2 of BrP, and there is none in the other cases.

Bayés de Luna A et al. J Electrocardiol. 2012

Blocco di branca DX

Distinzione fra onda r’ del blocco di branca dx e l’onda J del

pattern di Brugada (G Ital Cardiol Vol 11 Suppl 2 al n 11 2010)

Blocco di branca DX e pattern di Brugada

Distinzione tra pattern di Brugada associato a blocco completo

di branca dx e il blocco di branca destra isolato (G Ital Cardiol

Vol 11 Suppl 2 al n 11 2010)

Ripolarizzazione precoce e pattern di Brugada

Utilizzo del rapporto ST/ST80 per la distinzione tra

ripolarizzazione precoce e pattern di Brugada. Un rapporto

inferiore a 1 identifica il sopraslivellamento della

ripolarizzazione precoce. (The Brugada syndrome: from bench to

bedside. Malden (MA): Blackwell, Futura, 2005: 119-29)

STEMI e pattern di Brugada

BRUGADA

STEMI

G Ital Cardiol Vol 11 Suppl 2 al n 11 2010

IPOTERMIA

Quadro elettrocardiografico tipico di ipotermia, come rivelano l’onda J

evidente in V2-V5, la bradicardia sinusale, il BAV di primo grado, il

sopraslivellamento di ST in V2-V3 e gli artefatti da tremori muscolari.

(G Ital Cardiol Vol 11 Suppl 2 al n 11 2010)

Displasia aritmogena del ventricolo destro

Rev Esp Cardiol. 2010;63(8):963-83

Sopraslivellamento del segmento ST diffuso

Sottoslivellamento del tratto P-R

Evolutività del quadro

Pericardite acuta

G Ital Cardiol Vol 11 Suppl 2 al n 11 2010

Sindrome di BrugadaCriteri diagnostici

Pattern ECG tipo 1 spontaneo o dopo farmaci AA del I

gruppo in associazione ad una delle seguenti condizioni:

FV o TV polimorfa documentate

Storia familiare di MI (età<45 anni)

Presenza di ECG di tipo 1 in membri della famiglia

Inducibilità di aritmie ventricolari con la SEP

Sincopi o respiro agonico notturno

To increase diagnostic sensitivity, the expert consensus statement of 2013 on inherited

arrhythmogenic diseases omits any clinical criterion and demands diagnostic ECG

changes in only one right precordial lead .

The saddle-back type 2 and type 3 ECG patterns are suspicious for, but not diagnostic

of BrS and the two patterns have now been grouped together into one type 2 ECG

(saddle-back pattern). When encountering a type 2 ECG the diagnosis of BrS may only

be made after drug-induced conversion to a type 1 ECG.

Because of frequent fluctuations between diagnostic, non-diagnostic, and normal ECGs

without ST-segment changes, repeated ECG recordings should be performed for

accurate risk stratification.

In asymptomatic patients, other ECG changes may support the diagnosis (5), such as:

● First-degree atrioventricular block

● Right bundle branch block

● Fragmented QRS complex

● Increased ST-segment elevation during exercise or during the recovery phase after

exercise

● Ventricular extrasystoles with left bundle branch block pattern

● Atrial fibrillation

Curcio A et al. J Cardiovasc Electrophysiol 2016

Usefulness of Multichannel Holter ECG Recording in the Third

Intercostal Space for Detecting Type 1 Brugada ECG:

Comparison with Repeated 12-Lead ECGsKENJI SHIMENO, M.D., MASAHIKO TAKAGI, M.D., Ph.D., KEIKO MAEDA, M.D., Ph.D.,

HIROAKI TATSUMI, M.D., Ph.D., ATSUSHI DOI, M.D., Ph.D.,

and MINORU YOSHIYAMA, M.D., Ph.D.

(J Cardiovasc Electrophysiol, Vol. 20, pp. 1026-1031, September 2009)

Nell’ECG registrato come di norma si osserva solo un

sopraslivellamento del punto J in V2. Lo spostamento degli elettrodi di

V1 V3 uno o due spazi più in alto mette in evidenza una chiara onda J

mentre le registrazioni eseguite al quinto spazio intercostale non rilevano

alcun segno suggestivo del pattern di Brugada (G Ital Cardiol Vol 11

Suppl 2 al n 11 2010)

Conversion of a normal ECG to a type 1 Brugada syndrome ECG during ajmaline challenge. Note the coved-

type ST segments (arrows) in the right precordial ECG leads at peak ajmaline (note that V3 is placed in the

third intercostal space above V1 [V1ic3], and V5 is placed in the third intercostal space above V2 [V2ic3]).

Pattern circadiano delle FV nella Sindrome di Brugada

Matsuo te al. Eur Heart J 1999

Età di comparsa di episodi spontanei di FV/SD

Benito B. et al. Progress in cardiovasc disease 2008

Gourrauda JB et al. Arch Cardiovasc Dis 2017

A: an S wave in D1

B: a type 1 ECG pattern in

D2

C: aVr sign

D: a prolonged Tpeak—Tend

interval in V1—V3leads

E: early repolarization in D2

and D3

F: fragmented QRS in V1—

V3 leads.

The main electrocardiogram variables associated with prognosis

Stratificazione del rischioRischio intermedio- rischio basso

• I pazienti con sincope hanno un rischio intermedio , essendo un gruppo estremamente eterogeneo potenzialmente costituito deipazienti con sincope aritmica e sincope neuromediata/non aritmica

Olde Nordkamp LR Heart Rhythm 2015

• I pazienti asintomatici hanno un rischio basso, ma non banale, di eventi cardiaci ( 0,5-1,5 % / anno ) e sono pertanto l'obiettivoprincipale della stratificazione del rischio. In questi pazienti ilvalore dello studio elettrofisiologico per la stratificazione del rischio rimane ad oggi il punto di maggior dibattito

Probst V et al FINGER registry Circulation 2010

Priori SG et al PRELUDE registry JACC 2012

Management of patients with Brugada Syndrome: Results of the PRELUDE Registry

Survival According to VTs/VF Inducibility

Priori S et al.J Am Coll Cardiol 2012;59:37–45


Survival According to History of Syncope

Priori S et al.J Am Coll Cardiol2012;59:37–45


Survival According to Presence of Spontaneous type 1 ECG



Survival According to Presence of Ventricular Refractory < 200 ms

Priori S et al.J Am Coll Cardiol2012;59:37–45


Survival According to Presence of QRS fragmentation



CONCLUSION: Our data show that VT/VF inducibility is unable

to identify high-risk patients, whereas the presence of a

spontaneous type I ECG, history of syncope, ventricular

effective refractory period 200 ms, and QRS fragmentation

seem useful to identify candidates for prophylactic implantable

cardioverter defibrillator.

Sroubek J et al. Circulation. 2016

Survival curves demonstrating freedom

from sudden cardiac arrest or VT

resulting in ICD shock for patients

according to induction with single or

double extrastimuli in the following clinical

subgroups:

A. syncope and spontaneous type 1 ECG

pattern

B. syncope and drug-induced type 1

ECG pattern

C. asymptomatic and spontaneous type 1

ECG pattern

D. asymptomatic and drug-induced type

1 ECG pattern.

Programmed stimulation may identify patients at

increased risk for cardiac arrest, but the association

appears most apparent in individuals induced with

single or double extrastimuli rather than more

aggressive stimulation protocols. Importantly, the

absence of induction with programmed

stimulation alone is not sufficient to identify low-

risk individuals. We submit that EP studies in

patients with Brugada syndrome are reasonable but

that the decision to proceed should be

individualized after clinical risk stratification and

detailed counseling with patients about the

implications of a positive or negative result.

Sroubek J et al. Circulation. 2016

Event probability according to Kaplan-Meier method

for different risk factors

Sieira J et al. European Heart Journal 2017

(A) Score corresponding to each item. SCD refers to presentation as aborted sudden

cardiac death. (B) Event probability according to Kaplan–Meier method in each score

category.

Selected risk model to predict events

Sieira J et al. European Heart Journal 2017

Risk of Sudden Cardiac Death in

Brugada Syndrome

Gourrauda JB et al. Arch Cardiovasc Dis 2017

Expert Consensus Recommendations on

BrS Therapeutic Interventions

Algorithm for diagnosis, risk stratification, and

treatment of Brugada syndrome

http://www.brugadadrugs.org

http://www.brugadadrugs.org

Drugs to be avoid Drugs preferably avoided

Ohgo T et al. Heart Rhythm 2007

Acute and chronic management in patients with Brugada syndrome

associated with electrical storm of ventricular fibrillation

Acute and chronic management in patients with Brugada syndrome

associated with electrical storm of ventricular fibrillation

No specifically clinical, laboratory, electrocardiographic, and electrophysiologic

characteristics were recognized in patients with Brugada syndrome associated with

electrical storm of VF.

Ohgo T et al. Heart Rhythm 2007

Successful treatment of electrical storm

with oral quinidine in Brugada syndrome

A: electrocardiographic tracing of the patient; a typical St segment elevation is present

in the right precordial leads. B: ST segment normalizes after quinidine administration.

Bettiol K et al. Ital Heart J 2005

Excellent Long-Term Reproducibility of the Electrophysiologic Efficacy of

Quinidine in Patients with Idiopathic Ventricular Fibrillation and Brugada

Syndrome

BELHASSEN B et al PACE 2009

Farmaci antiaritmici nella S di Br

• Chinidina: blocca la corrente Ito; elimina i rientri in fase 2; effettovagolitico

Belhassen 2004: chinidina 1500 mg/die;

Hermida 2004: chinidina 600-900 mg/die;

Mitzurawo 2006: chinidina 300-600 mg/die; prevenzione inducibiltàrispettivamente nel 88%,76%, 44%.

• Procainamide: proaritmia.

• Disopiramide: blocca i canali K+ ed anche Ito;effetto vagolitico.

• Farmaci AA classe 1C: proaritmia

• Farmaci AA classe 2: betabloccanti. Non prevengono la MI

Sacher F et al, Circulation 2006

The aim of this study was to evaluate long-term outcome in a

large series of patients implanted with an ICD for a diagnosis of

Brugada syndrome.

The major finding of this study is that during a follow-up period of

> 3 years after implantation, there is a 2.5 fold greater

frequency of inappropriate (20%) than appropriate shocks

(8%), with an overall complication rate of 28%.

No arrhythmic death occurred at implantation or during

follow-up in this young, otherwise healthy population.

Brugada syndrome is characterized by young age of ICD carriers with a high likelihood of

experiencing inappropriate shocks. The highest risk of inappropriate therapy is in the early

post-implantation period, and mostly occurred in asymptomatic younger patients receiving

ICD for primary prevention. The absence of arrhythmic events in our recipients of ICD for

primary prevention as well as reports of other registries after a long term follow-up warrants a

more careful evaluation of these young and otherwise “healthy” individuals before implanting an

ICD. This approach can minimize the incidence of complications.

Bonny A et al. Ind Pac and Electrophysiol J 2017

Pappone C et al. J Am Coll Cardiol. 2018


Unlike variables such as clinical presentation,

type 1 Brugada syndrome ECG pattern, and

genetic test results, only substrate size was

the variable retained as an independent

predictor of VT/VF inducibility.

A substrate size of 4 cm2 best differentiated

patients with inducible VT or VF from

patients without inducible ventricular

tachycardia or ventricular fibrillation (area

under the curve: 0.98; p < 0.001).

This study considered whether the

arrhythmic substrate was an

independent predictor of lethal

ventricular tachyarrhythmias in patients

with or without Brugada syndrome -

related symptoms.

This study demonstrates that among patients with BrS

the extent of substrate is the only independent

predictor of inducibility of VT or VF and may serve

as a new marker for risk stratification and therapy.

Substrate elimination by RF catheter ablation is

associated with no VT or VF inducibility.

Understanding the site and electrophysiology of

arrhythmic substrate can facilitate recognition of

patients at higher risk for VT or VF, thus providing

an understanding of therapeutic options and limitations

and suggesting avenues for future investigations.

Conclusions


Pappone C et al. Circ Arrhythm Electrophysiol. 2017


The epicardial map shows a concentric

onion-like” substrate distribution after ajmaline.

White lines delimitate multiple areas exhibiting

electrograms with different duration (A ≥300

ms; B ≥250 ms; and C ≥200 ms ). Areas with

the longest potential duration (≥300 ms) are in

the inner circle, whereas relatively

shorter areas (≥250 and ≥200 ms) are in the

outer circle. Red regions represent areas with

electrogram potential duration of ≤110 ms.


RF ablation in the

inner circle

determined initial

ascending and

horizontal ST-

segment elevation in

the high right

precordial leads.

The complete set of

lesions has been delivered

in the whole area ≥200 ms

resulting in persistent

horizontal and flat ST

elevation in the right

precordial leads, which

are not showing the

Brugada type 1 pattern at

the end of ablation

In summary, the results of this prospective study in a large cohort

of consecutive BrS patients with various clinical

presentations, who represent the vast majority of patients

currently diagnosed with BrS, have provided new information and

insights into understanding of the pathophysiological substrate,

mechanism, and management of the disease. We conclude that

electro-physiologically and anatomically welldefined extensive

abnormal epicardial areas, as exposed by ajmaline administration,

are the primary site for BrS substrate and are responsible for type

1 BrS-ECG pattern and VT/VF inducibility. Persistent ECG pattern

normalization without VF inducibility even after repeated

ajmaline challenge suggests that substrate ablation can be

considered as a potential therapy for preventing recurrent

VT/VF.

Conclusions


The ECG at baseline (A) and after flecainide infusion (B). Note that

flecainide infusion results in type I Br ECG pattern.

Brugada J et al. Circ Arrhythm Electrophysiol. 2015

Immediately after RFA application, there is an increase of type I BrS ECG

pattern (A, arrows), which after further applications is progressively replaced

by an ascendant ST segment elevation (B and C, arrows).


After RFA, the 12-lead ECG

shows a diffuse ST segment

elevation (A), which

disappears one month later

(B).


30 BrS patients compared with 30

sex-,body surface area-, and age-

matched normal volunteers.

RV WALL MOTION

CONTRACTILITY

RV and LV mono-dimensional

parameters: RV inflow tract diameter (short-axis);

RV inflow tract diameter (four-chamber long-axis);

RV outflow tract diameter (short axis).

RV inflow and outflow tracts area

mild right ventricle (RV) wall-motion abnormalities [15

(50%) vs. 5 (17%) subjects (P ¼ 0.006) with reduced

radial fractional shortening in more than two segments

- 81 consecutive genetically screened BrS patients and 30

healthy controls.

- Left ventricular (LV) and right ventricular (RV) volumes and

dimensions were assessed by CMR and compared with respect

to the genotype.

Brugada syndrome patients with an SCN5A mutation (16

patients; 20%) revealed significantly larger RV volumes, along

with lower RV ejection fraction, than patients without a

mutation or controls, indicating a more severe phenotype in

patients with a mutation.

ROC analysis indicated good predictive performance of RV end-

diastolic volume, RV end-systolic, and LV cardiac output (area

under the curve ¼ 0.81, 0.81, and 0.2), with respect to the

presence of an SCN5A mutation.

Conclusion Brugada syndrome patients with an SCN5A mutation

reveal distinct changes in RV volumes and function when

compared with those without an SCN5A mutation.

Cardiovascular magnetic resonance may provide additional

insight to distinguish between SCN5A mutation-positive and

-negative BrS patients.

- 78 BrS patients were compared with

78 healthy controls

- 26% BrS patients carried SCN5A

mutations.

RVEF was slightly lower (61±8% vs

64±5%; p=0.004)

RV end-systolic volume greater

(31±10mL/m2 vs 28±6mL/m2; p=0.038)

in BrS compared with controls.

LGE was demonstrated in 8% BrS

patients (left ventricular midwall LGE in

5%) but not in controls (p=0.028).

Late gadolinium enhancement in

Brugada

syndrome: A marker for subtle

underlying

cardiomyopathy?

Rachel Bastiaenen, Andrew T. Cox, Silvia Castelletti,

Yanushi D. Wijeyeratne, Nicholas Colbeck, Nadia

Pakroo, Hammad Ahmed, Nick Bunce, Lisa Anderson,

James C. Moon, Sanjay

Prasad, Sanjay Sharma, Elijah R. Behr

Heart Rhythm. 2017 Apr;14(4):583-589.

Atrial Fibrillation and Brugada SyndromeJ Am Coll Cardiol 2008;51:1149–53

The arrhythmogenic substrate in Brugada syndrome may not

be restricted to the ventricles, and atrial arrhythmias are being

increasingly reported (from 6% to 38%)

The presence of a prominent transient outward current in atria

and the observation that episodes of AF are triggered by

closely coupled atrial extrasystoles point to the possibility that

a substrate similar to that responsible for ventricular

arrhythmogenesis underlies the development of AF in patients

with Brugada syndrome.

Nonsustained ventricular tachycardia in a patient who was given

flecainide for paroxysmal atrial fibrillation. Note the coved-type ST

segments (arrow). The patient was diagnosed with Brugada syndrome

during an ajmaline provocation test.

Efficacy of Pulmonary Vein Isolation in

Paroxysmal Atrial Fibrillation Patients With a

Brugada Electrocardiogram

Conclusions

Because of the concerns of proarrhythmias with antiarrhythmic

drugs, PVI may be an effective strategy for highly symptomatic

patients with AF who have a Brugada ECG pattern.

Yamada T et al. Circ J 2008

Zareba Progress in Cardiovascula Disease 2008

Roden DM et al, NEJM 2008

Forme più frequenti di LQT

Zareba Progress in Cardiovascular Disease 2008

Goldenberg and Moss , JACC 2008

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