[ARVD-FORUM] ARVD and Brugada Syndrome. Dr. Martini

Thu Apr 14 13:43:29 ART 2005

English - Spanish

One more case of organic heart disease underlying the syndrome!

Bortolo Martini

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Un caso mas de enfermedad organica del corazon subyacente al sindrome!

Bortolo Martini

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>
> 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.
>
>
> _______________________________________________
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-- 
Dr. Sergio Dubner
Director

Dr. Edgardo Schapachnik
Director