Inherited cardiac arrhythmia syndromes: What have they taught us about arrhythmias and anti-arrhythmic therapy?

SUMMARY 1. In recent years, the identification of the gene defects in a vast array of monogenic disorders has revolutionized our understanding of the basic mechanisms underlying numerous disease processes. 2. Mutations in cardiac ion channels have been identified as the basis of a wide range of inherited arrhythmia syndromes, including the congenital long QT syndromes, Brugada syndrome, Lenegre syndrome, Andersen's disease and familial atrial fibrillation. 3. Identification of mutations in the human‐ether‐a‐go‐go‐related gene (HERG) K+ channel as the molecular basis of congenital long QT syndrome type 2 also led to the discovery that HERG is the molecular target for the vast majority of drugs (both cardiac and non‐cardiac) that cause drug‐induced arrhythmias. This has had profound implications not only for the development of anti‐arrhythmic agents, but also for drug development in general. 4. The sequencing of the human genome in a sense represents the pinnacle of the reductionist era of molecular medicine. The great challenge now is to re‐integrate the information gathered during the ‘reductionist era’ to provide a better understanding of the intact organism. Computer modelling is likely to be a key component of that re‐integration process.