It is now possible to define the molecular basis of several con-genital and acquired cardiac arrhythmias. The best example is the polymorphic ventricular tachycardia known as torsades de pointes (Figure 14–8), which is associated with prolongation of the QT interval (especially at the onset of the tachycardia), syncope, and sudden death. This represents prolongation of the action potential of at least some ventricular cells (Figure 14–1). The effect can, in theory, be attributed to either increased inward current (gain of function) or decreased outward current (loss of function) during the plateau of the action potential. Action potential prolongation is thought to generate early afterdepo-larizations (Figure 14–5) that then trigger torsades de pointes. Recent molecular genetic studies have identified up to 300 different mutations in at least eight ion channel genes that produce congenital long QT (LQT) syndrome (Table 14–1). Loss-of-function mutations in potassium channel genes (HERG, KCNE2, KCNQ1, KCNE1, and KCNJ2) result in decreased outward plateau current, while gain-of-function mutations in the sodium channel gene (SCN5A) or calcium channel gene (CACNA1c) cause increases in inward plateau current. The identification of the precise molecular mechanisms underlying various forms of the LQT syndromes now raises the possibility that specific therapies may be developed for individu-als with defined molecular abnormalities. Indeed, preliminary reports suggest that the sodium channel blocker mexiletine can correct the clinical manifestations of congenital LQT subtype 3, while β-blockers have been used to prevent arrhythmias trig-gered by sympathetic stimulation in patients with LQT subtype 1. The molecular basis of several other congenital cardiac arrhythmias associated with sudden death has also recently been identified. At least three forms of short QT syndrome have been identified that are linked to gain-of-function mutations in different potassium channel genes (KCNH2, KCNQ1, and KCNJ2). Catecholaminergic polymorphic ventricular tachycardia, a disease that is characterized by stressor emotion-induced syncope, can be caused by mutations in at least two different genes (hRyR2 and CASQ2) of proteins expressed in the sarcoplasmic reticulum that control intracellular calcium homeostasis. Mutations in two different ion channel genes (HCN4 and SCN5A) have been linked to congenital forms of sick sinus syndrome. Several forms of Brugada syndrome, which is characterized by ventricular fibrillation associated with persistent ST-segment elevation, and progressive cardiac conduction disorder (PCCD), which is characterized by impaired conduction in the His-Purkinje system and right or left bundle block leading to complete AV block, have been linked to loss-of-function mutations in the sodium channel gene (SCN5A). At least one form of familial atrial fibrillation is caused by a gain-of-function mutation in a potassium channel gene (KCNQ1).
effect can be caused by genetic mutations associated with congenital long QT (LQT) syndrome (see Box: Molecular & Genetic Basis of Cardiac Arrhythmias). A number of drugs (antiarrhythmic as well as non-antiarrhythmic agents) can produce “acquired” or drug-induced LQT syndrome, which is typically due to block of rapidly activating delayed rectifier potassium channels. Many forms of LQT syndrome are exacerbated by other factors that prolong action potential duration, including hypokalemia and slow heart rates. DADs, on the other hand, often occur when there is an excess accumulation of intracellular calcium (see Chapter 13), especially at fast heart rates. They are thought to be responsible for arrhythmias associated with digitalis toxicity, excess catecholamine stimulation, and myocardial ischemia.
Disturbances of Impulse Conduction