[ARVD-FORUM] ARVD and Brugada Syndrome. Dr. Perez Riera II

[ARVD Symposium]

English - Portuguese

Recently Morimoto et al sowed a 30-year-old man with Brugada syndrome(BrS)
died suddenly. The heart weighed 380 g. The left ventricular wall showed
mild thickening, and marked fatty tissue deposition was noted in the Right
Ventricular Outflow Tract (RVOT). Neither ventricle was enlarged.
Contraction band necrosis was diffuse in both ventricles. In the ventricles
no cardiac muscle cell hypertrophy or atrophy, or significant interstitial
fibrosis was observed. In the sinus node half, with fatty tissue and
fibrosis prominent, reduced the number of nodal cells. But no lesions were
evident in the right bundle branch.( Morimoto S, Uemura A, Hishida H. An
autopsy case of Brugada syndrome with significant lesions in the sinus node.
J Cardiovasc Electrophysiol. 2005; 16:345-347.).

Recently Papavassiliu T et al (Papavassiliu T, Wolpert C, Fluchter
S, Magnetic resonance imaging findings in patients with Brugada
syndrome.Cardiovasc Electrophysiol. 2004; 15:1133-1138) prospectively
evaluated Cardiac Magnetic Resonance Images in 20 consecutive patients
diagnosed with BrS. Compared with normal controls, the RVOT area was
significantly enlarged in patients with BrS . There was a trend toward
larger right ventricular (RV) end-diastolic and end-systolic volumes and
lower RV ejection fraction in patients with BrS compared to controls. High
intramyocardial T1 signals similar to fat signal was observed in 20% of the
BrS patients, compared to none in controls. Antzelevitch (Antzelevitch C.
Brugada syndrome: historical perspectives and observations. E Heart J. 2002;
23: 676-678) hypothesized that BrS could begin as a primary electrical or
functional disease without structural heart disease, and evolve over time to
develop structural alterations, as observed with electrical remodeling
during chronic atrial fibrillation (Ausma J, Wijffels M, Vaneys G, et al.
Differentiation of atrial cardiomyocytes as a result of chronic atrial
fibrillation. Am J Pathol. 1997; 151:985-97.) as well as in hibernating
myocardium. In human hibernating myocardium, intracellular degeneration
reduces cellular protein synthesis, and the replacement fibrosis contributes
to structural abnormalities (Elsasser A, Vogt AM, Nef H, Kostin S, Mollmann
H, Skwara W, et al. Human hibernating myocardium is jeopardized by apoptotic
and autophagic cell death.J Am Coll Cardiol. 2004; 43:2191-2199.).

The authors explain that in the sinus node half, with fatty tissue and
fibrosis prominent, reduced the number of nodal cells. There is a report a
case of ARVC/D in a 60-year-old man who developed sick sinus syndrome during
evolution (sinus node recovery time of 6113 mseg). The authors explain
atrial arrhythmias by gradual replacement of right atrium myocytes by
adipose tissue. (Balderramo DC, Caeiro AA. Arrhythmogenic right ventricular
dysplasia and sick sinus syndrome Medicina (B Aires). 2004; 64: 439-441.).

Sick sinus syndrome could be caused by recessive mutations in the cardiac
sodium channel gene SCN5A (Benson DW, Wang DW, Dyment M, Knilans TK, Fish
FA, Strieper MJ, et al. Congenital sick sinus syndrome caused by recessive
mutations in the cardiac sodium channel gene (SCN5A). J Clin Invest. 2003;
112: 1019-1028.) the same gene affected in BrS.
Sick sinus syndrome is characterized by inappropriate sinus bradycardia,
sinus arrest, or chronotropic incompetence. Some forms of "idiopathic" sinus
node dysfunction are related to inherited dysfunctions of cardiac pacemaker
ion channels. In children a previous history of cardiac surgery for
congenital heart malformation is noted in approximately 80% of SSS cases.
In a candidate gene approach, a heterozygous 1-bp deletion (1631delC) in
exon 5 of the human HCN4 gene was detected in a patient with idiopathic
sinus node dysfunction. The mutant HCN4 protein (HCN4-573X) had a truncated
C-terminus and lacked the cyclic nucleotide-binding domain. COS-7 cells
transiently transfected with HCN4-573X cDNA indicated normal intracellular
trafficking and membrane integration of HCN4-573X subunits. Patch-clamp
experiments showed that HCN4-573X channels mediated I(f)-like currents that
were insensitive to increased cellular cAMP levels. Coexpression experiments
showed a dominant-negative effect of HCN4-573X subunits on wild-type
subunits. The cardiac I(f) channels are functionally expressed but with
altered biophysical properties. Taken together, the clinical, genetic, and
in vitro data provide a likely explanation for the patient's sinus
bradycardia and the chronotropic incompetence. (Schulze-Bahr E, Neu A,
Friederich P, Kaupp UB, Breithardt G, Pongs O, Isbrandt D.Pacemaker channel
dysfunction in a patient with sinus node disease. J Clin Invest. 2003;
111:1537-1545).

Best Regard

Andrés Ricardo Pérez Riera & Edgardo Schapachnik and Sergio Dubner.

----------------------------------------------------

Português

Recentemente Morimoto e col mostraram um homem de 30 anos portador da
síndrome da Brugada (SBr) que falecera subitamente. O coração pesava 380 g.
O ventrículo esquerdo mostrava paredes  moderadamente hipertróficas e
marcado depósito de gordura na VSVD. Os ventrículos não estavam dilatados e
havia bandas de necrose difusas em ambos. Não havia hipertrofia ou atrofia
nos miócitos ou significativa fibrose intersticial. Dentro do Nó sinusal se
contava a metade em número das células nodais com gordura e fibrose
proeminentes.  Não se verificou  lesões nos ramos do feixe de His. (Morimoto
S, Uemura A, Hishida H. An autopsy case of Brugada syndrome with significant
lesions in the sinus node. J Cardiovasc Electrophysiol. 2005; 16:345-347.).

Recentemente Papavassiliu T e col (Papavassiliu T, Wolpert C, Fluchter
S,Magnetic resonance imaging findings in patients with Brugada
syndrome.Cardiovasc Electrophysiol. 2004; 15:1133-1138) em forma prospectiva
avaliaram com a Resonância Nuclar magnética (RNM) 20 pacientes com
diagnóstico da SBr que foram comparados com controles normais.  A VSVD
estava significativamente maior nos pacientes com SBr. O VD era mais largo,
os volumes de fim de sístole e diástoles e a FE do VD eram menores do que
nos controles. Observou-se adicionalmente sinal intramiocárdico T1 alto
indicando presença gordura na parede da VSVD em 20% dos portadores da SBr
comparados com nenhuma mudança nos controles.

Antzelevitch (Antzelevitch C. Brugada syndrome: historical perspectives and
observations. E Heart J. 2002; 23: 676-678) levanta a hipótese de que na SBr
inicia como uma doença elétrica primária ou funcional sem cardiopatia
estrutural e com o evoluir do tempo desenvolve alterações estruturais como o
observado no remodelamento ventricular durante a fibrilação atrial
crônica (Ausma J, Wijffels M, Vaneys G, et al. Differentiation of atrial
cardiomyocytes as a result of chronic atrial fibrillation. Am J Pathol.
1997; 151:985-97.) ou como o miocárdio hibernado onde se verifica
degeneração intracelular com redução na síntese de proteínas e substituição
por fibrose contribuindo para as alterações (Elsasser A, Vogt AM, Nef H,
Kostin S, Mollmann H, Skwara W, et al. Human hibernating myocardium is
jeopardized by apoptotic and autophagic cell death.J Am Coll Cardiol. 2004;
43:2191-2199.).

Os autores explicam que a quantidade de células nodais estava reduzida pela
metade.

Há um reporte de um homem de 60 anos portador de DAVD que desenvolvera
doença do Nó sinusal com tempo de recuperação muito prolongado (6113 ms.) Os
autores especulam que o fenômeno obedeceria a gradual substituição do
miócitos atriais por tecido adiposo  (Balderramo DC, Caeiro AA.
Arrhythmogenic right ventricular dysplasia and sick sinus syndrome Medicina
(B Aires). 2004; 64: 439-441.).

A doença no Nó sinusal pode ser causada por uma mutação recessiva no canal
de sódio no gene SCN5A  (Benson DW, Wang DW, Dyment M, Knilans TK, Fish FA,
Strieper MJ, et al. Congenital sick sinus syndrome caused by recessive
mutations in the cardiac sodium channel gene (SCN5A). J Clin Invest. 2003;
112: 1019-1028.) o mesmo gene da SBr.

A doença no Nó sinusal está caracterizada por bradicadia inapropriada,
parada sinusal, ou incompetência cronotrópica. Algumas formas "idiopáticas"
da doença no Nó sinusal obedecem a entidades hereditárias no canal
marcapasso. Em crianças uma história de cirurgia cardíaca por cardiopatia
congênita é referida em aproximadamente 80% dos casos.

Em pacientes com doença no Nó sinusal idiopática se ha verificado deleição
(1631delC) no exón 5 do gene humano HCN4 . A mutação HCN4 na proteína
(HCN4-573X) tem sido truncada no C-terminal com perda do domínio de ligação
do nucleotídeo cíclico.

O domínio de ligação do nucleotídeo cíclico COS-7 transfere transitoriamente
com HCN4-573X cDNA indicando tráfico intracelular normal e integração com a
subunidade HCN4-573X  normal.

Experimento com a técnica de Patch-clamp mostraram que HCN4-573X media o
canal semelhante I(f) que fica insensível com o aumento dos níveis
intracelulares de AMPc

Experimentos de coexpressão mostraram um efeito negativo dominante da
subunidade HCN4-573X  sobre a subunidade selvagem. O canal I(f) está
expresso funcionalmente, porém, com alterações nas suas propriedades
biofísicas.  Feito exame junto, o clínico, genética e dados in vivo dão uma
explicação para os pacientes com bradicardia sinusal e incompetência
cronotrópica.(Schulze-Bahr E, Neu A, Friederich P, Kaupp UB, Breithardt G,
Pongs O, Isbrandt D.Pacemaker channel dysfunction in a patient with sinus
node disease. J Clin Invest. 2003; 111:1537-1545).

Saudações

Andrés Ricardo Pérez Riera & Edgardo Schapachnik and Sérgio Dubner.