Channel structure and drug-induced cardiac arrhythmias.

E lectrical activity underlies the control of the frequency, strength, and duration of contraction of the heart. During the cardiac cycle, a regular rhythmic pattern must be established in time-dependent changes in ionic conductances to ensure events that underlie normal cardiac function. Electrical impulses, originating at the sino atrial node are conducted throughout the atria until they converge at the atrio-ventricular node, pass through the bundle of His and the Purkinje fiber conducting system, and eventually excite the working myocardial cells of both ventricles. Current f low through a large number of ion channels, exchange mechanisms, and pumps underlies and coordinates these electrical signals and alteration of the critical balance of these multiple current pathways can lead to disruptive, often fatal, rhythm disturbances: the cardiac arrhythmias. Although the cardiac arrhythmias form a complicated and diverse group reflecting the complexities of the ionic mechanisms underlying the electrical activity of the human heart, a surprisingly large number of rhythm disturbances are caused either directly or indirectly by mechanisms that prolong the duration of the action potential of the working myocardium (1, 2). Whereas prolongation of the cardiac ventricular action potential under controlled conditions can be, in principle, an effective mechanism to prevent certain types of re-entrant arrhythmias (3), excessive prolongation can be fatal. In this issue of PNAS, Mitcheson et al. (4) provide the first detailed report of a structural basis for the most common form of arrhythmia that is caused by drug-induced prolongation of the cardiac action potential that is reflected in prolongation of the QT interval of the electrocardiogram. This important study thus paves the way for a rational approach to the development of compounds that can be safely administered with minimum risk of QT prolongation and the induction of life-threatening arrhythmias. Action potentials of the heart are long lasting, and particularly in the ventricle, they are characterized by a period of slowly changing and maintained depolarization, the action potential plateau. The plateau is crucial in determining the strength and duration of contraction of the myocardium, in setting the proper relationship between systolic contraction and diastolic filling times, and in providing a cardio-protective window in which reexcitation cannot take place via voltagedependent sodium or calcium channels (5). The duration of the plateau phase is controlled in part by the activation of two types of delayed potassium channel currents IKr and IKs (6). The congenital long QT syndrome (LQTS) is a disease that prolongs ventricular repolarization and predisposes individuals to episodes of syncope, polymorphous ventricular tachycardia (torsades de pointes), and sudden death (7, 8). Multiple genes that encode ion channel subunits are linked to LQTS (9–11), including KCNQ1 (KvLQT1) and KCNE1 (minK) KCNH2 and KCNE2, the genes encoding the a and b subunit of the delayed rectifier potassium channels that conduct IKr and IKs (12–16). It is clear that mutationinduced reduction in these key currents underlies the disease phenotype (17); however, the prevalence of these inherited disorders is rare (18). A more common and related disorder is excessive delay in repolarization caused inadvertently by drug-induced inhibition of HERG channels by commonly used medications. This disorder is referred to as drug-induced LQTS (19). As shown schematically in Fig. 1, the essence of this disorder is that drug-induced action potential prolongation may vary within a patient population. A drug concentration, which may slightly prolong the action potential plateau and actually be antiarrhythmic in some patients, may produce excessive prolongation in others, leading to arrhythmogenic activity (3). This drug activity is not limited to cardiac antiarrhythmic drugs but also has been reported for antianginal agents such as bepridil and prenylamine as well as nonsedating antihistamines such as terfenadine and astemizole (20, 21). Previous investigations have identified sporadic ion channel mutations in patients with drug-induced torsades de pointes (22, 23), indicating that patients with ‘‘acquired’’ LQTS can have a genetic predisposition to arrhythmia because of mutation in subunits of their IKr potassium channels.