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Cardiac arrhythmias: from gene to bedside

  • Shaping molecular electrophysiology: a decade of progress, presented by S G Priori (Pavia, IT) - Slides
  • J-wave syndromes: update on ventricular fibrillation mechanisms, presented by M Naebauer (Munich, DE) - Slides
  • Channelopathy or structural heart disease: what is the Brugada syndrome? Presented by A A M Wilde (Amsterdam, NL) - Slides
  • Desmosome and arrhythmogenic cardiomyopathies, presented by W J McKenna (London, GB) - Slides

 

Arrhythmias



The session aimed to give a translational view on genetically transmitted diseases and to provide new information on diseases such as J-wave syndromes including Brugada-syndrome.

First of all, Prof Silvia Priori reminded us that it was Mark Keating and his team who took the first step in molecular genetics, by identifying the genetic defect for Long QT 1, 2 and 3, leading to the elucidation of the cause for inherited sudden death. A long period of generating genotype-phenotype correlations followed in order to identify high and low risk mutation carriers. She stressed that the story of the various defects of calcium currents is especially interesting due the heterogeneity of phenotypes caused by the different mutations both on the cardiac but also the extracardiac level.

Prof Priori stated that the biggest challenge after defining a candidate gene and identifying the mutations is risk prediction in the setting of variable penetration and better understanding the role of modifiers. Research directed towards disease-modifying common polymorphisms may help to tailor therapy better to individuals with a potentially disease-causing mutation.

Prof Naebauer discussed the so-called 'J-wave syndromes' which summarize all diseases in which there is a change of the repolarisation at the point of the J-wave. The difference of the outward transient potassium current between endo and epicardial layers has been shown to be the reason for the occurrence of J-waves in the presence of abnormal conditions such as hypothermia. Prof Naebauer also entered into the discussion of the two different hypotheses for the generation of J-waves, namely the depolarisation and repolarisation theory. He said that the beneficial effect of quinidine does not really support the depolarisation theory, since conduction slowing by quinidine should exacerbate conduction and increase depolarisation abnormalities. He also mentioned experiments that demonstrated J-waves after administration of a substance that enhances the transient potassium outward current.

Prof Wilde replied that for him the term J-waves syndromes does not appropriately summarize the different etiologies such as early repolarisation syndrome, Brugada syndrome and IVF. From his experience, it makes more sense to treat them as completely different entities. To support the depolarisation hypothesis for the generation of J-waves, he showed data from studies that identified long conduction delays and severe degree of fragmentation at the epicardial aspect of the right ventricle in patients with Brugada syndrome and recurrent ventricular fibrillation, in whom both arrhythmias were eliminated and the J-wave normalised after extensive ablation in this area. Finally he brought up the fact that there is no linkage data for SCN5A in Brugada syndrome in contrast to Long QT syndrome and concluded that this disease may be a developmental disorder in which fibrosis and mutations in the sodium channel gene may act as modifiers.

Prof McKenna gave first an overview on the molecular composition of the desmosome. He could show that the decrease in plakoglobin is not seen in LV cardiomyopathy of ischaemic or hypertrophic origin, and therefore not an unspecific marker of right ventricular cardiomyopathy. However, he also showed that in cardiac sarcoidosis a rarification of plakoglobin could be observed in one study. Finally, he showed a case of a gene carrier of Naxos Diseas with a clear ECG pehonytpe with severe T wave negativity, more than 15000 PVS but a completely normal heart at autopsy, showing that the arrhythmia problem, may occur long before macroscopic changes occur in ARVC and does not necessarily mean major changes in the cardiac texture.

References


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SessionTitle:

Cardiac arrhythmias: from gene to bedside

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.