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An arrhythmia (also known as cardiac dysrhythmia) is defined as an irregular heartbeat, and results from abnormal electrical activity in the heart. There are various different types of arrhythmia, often resulting in a heartbeat that is too fast (tachycardia) or too slow (bradycardia). Atrial and ventricular fibrillation, which are the most common cardiac arrhythmias, account for 10-20% of all deaths among adults in the Western world. The incidence of atrial fibrillation increases with age; it not only affects cardiac function, but also increases the risk of stroke and may worsen heart failure.
A normal heartbeat is driven by various stages of membrane depolarization and repolarization in single heart cells, propagating from the sinoatrial (SA) node to the atrium and the ventricle. There are two types of action potentials: the fast response action potential, which occurs in cardiac muscle and Purkinje fibers; and the slow response, evident in the SA and atrioventricular (AV) nodes. Action potentials enable rapid changes in heart rate. Contraction of the cardiac muscle occurs in response to depolarization. By generating action potentials and setting off a wave of depolarization, the SA node thus acts as a pacemaker, setting the rate of contraction of the heart. Dysfunction of the SA node may therefore result in an irregular heartbeat. The effective refractory period (ERP) is a mechanism that helps protect the heart from arrhythmias, by preventing the generation of new action potentials during the propagation of an existing one.
In addition to SA node dysfunction, arrhythmias can also occur as a result of abnormalities in the electrophysiology of heart cells or in cell-to-cell (impulse) propagation, which takes place through gap junctions. These enable conduction of a wave of depolarization between cells. Ion channels are responsible for the conduction of coordinated electrical impulses, and consequently dysregulation of their activity has been linked to the development of arrhythmias. For example, mutations in genes encoding the KV11.1 (hERG) potassium channel, the sodium NaV1.5 channel, and the calcium CaV1.2 channel have been linked to long QT syndrome (LQTS).
Antiarrhythmic drug therapy aims to restore normal cardiac rhythm and conduction, and to prevent more serious arrhythmias from occurring. Vaughan Williams created one of the most widely used classification schemes for antiarrhythmic drugs. The scheme divides antiarrhythmic drugs into five classes (I-V), each of which concerns a different target:
The lack of new molecular targets and toxicity problems has resulted in few novel antiarrhythmic agents being introduced in recent years, and further research is needed to develop novel, more efficacious antiarrhythmic drugs with greater selectivity and lower toxicity.