Molecular mechanisms of arrhythmias.

Most arrhythmias occur in patients with structural heart disease, where anatomical factors play an important role. Patients without structural heart disease may also suffer from arrhythmias, and recently the genetic basis for such so-called idiopathic arrhythmias has been elucidated. In the congenital long QT syndrome, characterized by a prolonged QT interval, torsade de pointes and sudden death, three aberrant ionic currents have been identified, resulting in a prolongation of the ventricular action potential, which in its turn may cause early afterdepolarization and torsade de pointes. In LQTS1, mutations in the KvLQT1 gene reduce the slow component of the delayed rectifier Iks; in LQTS, mutations in the Human Ether a-go-go Related Gene (HERG) reduce the rapid component of the delayed rectifier Iks. Both potassium currents are important determinants of repolarization: a reduction in outward currents carried by K+ ions prolongs the action potential. In LQTS3, there are mutation in the NA+ channel gene (SCN5A) which causes the channel to inactivate incompletely; the persistent inward current carried by Na+ ions also prolongs the action potential. In the Brugada syndrome, characterized by right bundle branch block, ST elevation in V1-V3 and sudden death, mutations have been observed in the Na+ channel gene, but it is as yet unclear which functional changes in the NA+ channel are responsible for the typical ECG changes and the arrhythmias. Various cardiac disorders may lead to changes in gene expression that modify channel function. In hypertrophy, the ventricular action potential is prolonged by a decrease in the inward rectifier and the transient outward current. After prolonged episodes of rapid electrical activity, the atrial action potential is shortened, because of a reduction in the Iks type calcium current. Finally, many carriers of mutated genes display no abnormalities on the ECG. It is conceivable that such individuals may show excessive QT prolongation when taking cardiac or noncardiac drugs (such as neuroleptics, antidepressants, antihistamines, antimicrobials, antimalarials) that block potassium currents.