ABSTRACT
Cardiac arrhythmias arise from disturbances in the normal spread of cellular excitability and/or regional refractoriness, and can result from localized tissue damage (e.g., ischemia), anatomical anomalies or drug treatment. In the United States alone, sudden cardiac death is estimated to account for over half a million deaths yearly, and about 80% are believed to be caused by ventricular tachyarrhythmias (Morganroth and Bigger, 1990; Panidis and Morganroth, 1983). Modulation of K channel activity has been shown in numerous animal models and in some clinical studies to represent beneficial therapy in the treatment of arrhythmias that arise from such disturbances. The rationale for use of these agents is rather simplistic. Activation of K + conductance reduces electrical excitability, an effect useful in arrhythmias arising from enhanced automaticity. Block of K + conductance delays repolarization of action potentials, a useful mechanism to terminate some forms of reentrant-based tachyarrhythmias. The key to successful termination or prevention of an arrhythmia by either approach is to match the correct drug (and dosage) with an arrhythmia of defined origin, a difficult and often impossible clinical task. For example, lengthening of action potential duration (APD) with a K channel blocker (KCB) can prolong the refractory period sufficiently to slow or prevent a tachyarrhythmia based upon a reentrant circuit. However, excessive lengthening of action potential duration can result in the triggering of early afterdepolarizations (EADs), one probable cellular mechanism of torsades de pointes arrhythmias (Janse and Wit, 1989; Surawicz, 1989) (Figure 10.1 ). Druginduced torsades de pointes is a polymorphic ventricular tachycardia that is preceded by excessive QT lengthening and is characterized by a sinusoidal twisting of the QRS axis around the isoelectric line, with a cycle length that varies between 5-20 beats (Keren and Tzivoni, 1991; Surawicz, 1989). Several class lA (e.g., quinidine, procainamide, disopyramide, aprindine) and class III (e.g., amiodarone, sotalol) antiarrhythmic drugs have been reported to induce this arrhythmia. However, no useful correlation between plasma concentrations, or extent of QT prolongation by these drugs and their propensity to cause torsades de pointes has been established
Block of cardiac K current(s)
---------------Modest prolongation of APD (and QT interval)
+ Decreased dispersion of ventricular refractoriness
+ Decreased vulnerability to
ventricular fibrillation
Excessive prolongation of APD ( and QT interval)
+ Early Afterdepolarizations at several sites in ventricle
arrhythmia +
(Surawicz, 1989). Treatment of torsades de pointes usually consists of cardiac pacing, or infusion of isoproterenol or magnesium sulfate (Keren and Tzivoni, 1991; Surawicz, 1989). In animal and tissue models, these drug-induced arrhythmias can also be terminated with an activator of A TP-sensitive K channels (KATP), e.g. cromakalim (CRK). Evidence from animal studies suggest that excessive doses of K channel openers are equally proarrhythmic, caused by an increased dispersion in refractoriness. Obviously, there is not a single mechanism that will terminate all types of arrhythmias and as discussed above, most K channel modulators (KCMs) can also induce arrhythmias when used inappropriately. This can easily be demonstrated in animal models. For example, in anesthetized rabbits infused with the a-agonist methoxamine, there is a striking correlation between doses of various class III agents required to prolong QTU interval by 20% and doses required to induce arrhythmias with features akin to torsades de pointes (Carlsson et al., 1990). Despite the obvious limitations of KCBs as antiarrhythmic agents there has been much recent effort directed towards their development. In large part this can be traced to the publishing of interim results of the Cardiac Arrhythmia Suppression Trial (CAST), where it was reported that encainide and fiecainide (class IC agents) increased mortality relative to placebo (The Cardiac Arrhythmia Suppression Trial (CAST) Investigators, 1989). The CAST report obviously raised questions regarding the risk versus benefit of all then currently available antiarrhythmic agents, and provided great impetus to develop new drugs that acted via mechanisms other than slowed conduction.
