The first speaker in this ESC state-of-the-art session was Pascale Guicheney (Paris, F) who reported on genetic findings in stress-induced polymorphic ventricular tachycardia (CPVT). The majority of gene mutations are in distinct functional domains of the ryanodine receptor-2 gene (Ryr2), whereas only a minority are identified in the human calsequestrin gene (CASQ2). In contrast to Ryr2, mutations are predominantly found in homozygous state, because this subtype (CPVT-2) is recessively inherited. Thus, affected individuals are threatened by sudden cardiac death already in early childhood. Interestingly, heterozygous mutation carriers appear to be mildly or not affected.
Carlo Napolitano (Pavia, IT) pointed out the various phenotypic consequences of Cav1.2 (CACNA1c) mutations that are gain-of-function mutations. In addition to the eletrocardiographic phenotype (QTc often >600 ms, functional 2:1 AVB) in a lower instance cardiac malformations are reported. Children can be recognised by prominent digital and facial abnormalities that are a hallmark of Timothy syndrome. So far, mutations are restricted to the gene’s exon 8/8a. Disease onset is also very early in childhood and aside from ventricular tachycardia some patients suffered from severe hypoglycaemia. The relation of Ca++ channel dysfunction to the developmental and non-cardiac phenotypes is only understood in part so far.
Christoffer George (Cardiff, UK) reported that Ryr2 channel dysfunction in CPVT-1 is more complex than anticipated, since a variety of mechanisms can be involved. The notion that mutations are located within distinct gene regions so far is probably to configurational instability of protein interacting sites. On a functional level, there is a sensitized Ryr2 channel activation with an increased open probability that causes a more than normal Ca++ release from SR. The frequency of Ryr2 mutations in patients with ventricular fibrillation is probably underestimated. It is unclear whether mutations can also been identified in other gene regions.
Shane Cunha (Iowa City, US) explained the multiple interactions of ankyrins with ion channels and other receptor. For the human heart, two ankyrins (Ank) are of relevance: Ank-2 (also AnkB) that causes long-QT syndrome of type 4, and Ank-3 (also AnkG) that is functionally linked to Brugada syndrome. Whereas AnkB mutations led to a reduced membrane localisation of target proteins NCX, NKA and IPR3, a cardiac sodium channel mutation in the AnkG binding site was found that causes a lack of AnkG interaction and mutant SCN5A protein retention in ER. However, other than AnkG-related mutations in SCN5A have been identified that independently can lead to ER retention of the mutant protein. So far, no AnkG mutations have been found in an arrhythmia syndrome.