Over the last decade, we have witnessed a revolution in the understanding of primary cardiac arrhythmia syndromes. These remarkable advances stemmed from the discovery of mutations, primarily in ion channel genes, underlying a number of these disorders. Only 10 years ago the long QT syndrome (LQTS) was considered one disease entity, the Brugada syndrome had just been described, and the short QT syndrome (SQTS) had never been heard of. Moreover, it immediately became obvious that genetic heterogeneity in these disorders is not the exception but the rule.

The recognition of the genetic substrate underlying the inherited arrhythmia syndromes has provided remarkable insight into the molecular basis of cardiac electrophysiology, including the role of the various ion channels and mechanisms of arrhythmias. The availability of a genetic diagnostic test has added an important diagnostic tool, providing new opportunities for patient management such as early (presymptomatic) identification and treatment of individuals at risk of developing fatal arrhythmias. Studies into genotype–phenotype relationships, carried out mostly for the LQTS, have uncovered important gene specific aspects of disease and indicated that patient management must take the nature of the gene affected into consideration. Initial thoughts that the genetic dissection of these disorders would facilitate therapeutic management of these patients have, however, not been substantiated. On the contrary, the heterogeneous (genetic, pathophysiological) character of all primary arrhythmia syndromes precludes uniform treatment.

Herein we review these developments at large, with emphasis on the issues that are relevant for understanding the pathophysiology of these syndromes and daily management of affected individuals.

CARDIAC ION CHANNELS AND THE ECG

The cardiac action potential is mediated by the exceptionally well orchestrated activity of a diversity of ion channels (fig 1). Cardiac ion channels¹ are protein complexes in the sarcolemma of cardiomyocytes which, via highly regulated opening and closing (gating), conduct a selective and rapid flow of …