Dr. David Sedmera
The session “Developmental mechanisms of arrhythmias” brought the participants an update on basic mechanisms of arrhythmogenesis from a developmental perspective. Four basic scientists delivered presentations on current state of the art on genes involved in etiopathogenesis of various arrhythmias.The first speaker, Prof. Vincent Christoffels from AMC Amsterdam focused on transcriptional regulation of cardiac conduction via T-box transcription factors TBX3 and TBX5. TBX3 reduces conductivity, inducing pacemaking activity, and negatively regulates sodium channel genes SCN5a and SCN10a. Studies in his lab discovered the crucial role of 3D genome organization for transcriptional regulation, and uncovered one common single nucleotide polymorphism in an otherwise conserved enhancer region that is associated with atrial arrhythmias. Thomas Brand from Harefield, UK followed with an update on the role of popeye domain proteins 1, 2, and 3 in arrhythmogenesis. All these transmembrane proteins are expressed in myocyte membrane, can form homo- and heterodimers, and have a partially redundant function. The mutants show an age-dependent progression of sinus bradycardia during stress conditions, which is exacerbated in double nulls. Similarity of these proteins to cAMP binding proteins helped to decipher that one of the partners is ion channel TREK1.Next, Diego Franco from Jaen, ES provided an overview of the role of ion channels in atrial fibrillation. He focused on the Pitx2 gene regulatory network, which apart from controlling the location of the pacemaker through laterality control also influences miRNA 208 and 133. Other downstream targets are enzymes involved in protein phosphorylation regulation. Importantly, this cascade is not involved in the fibrosis pathway.The last speaker of the session, Luigi Venetucci from Manchester, UK delivered a talk on hereditary channelopathies with a special focus on the Brugada syndrome. Most mutations associated with this syndrome are linked again to SCN5A. The data presented showed that the site of ventricular ectopies in this disease lies in the right ventricular outflow tract, a region of the heart with reduced expression of fast conduction genes (Connexin43, SCN5A), and has a different developmental history. Having thus a reduced safety margin for conduction, it is particularly prone to development of conduction slowing or block leading to reentry tachyarrhythmias.The audience from a well-packed room contributed to a stimulating discussion that helped to put these new findings into the clinical context. While not yet ready for bedside applications, identification of novel genetic targets can lead to improved diagnosis, risk prediction, counselling, and ultimately development of new therapeutic strategies for arrhythmias.
Developmental mechanisms of arrhythmias
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