Abstract and Introduction
Abstract
K channels in the heart shape the cardiac action potential, and many existing drugs can inhibit or activate these currents. In particular, their potential therapeutic benefit has been explored in the treatment and prevention of abnormal heart rhythm. Their use in the management of malignant ventricular arrhythmias has been disappointing and is frequently complicated by proarrhythmia. However, K channel-blocking drugs developed for supraventricular rhythm problems, in particular atrial fibrillation, may be more successful. Agents currently in use also have a high incidence of cardiac and other side effects. Thus, the field is moving to a strategy targeting K channels that are selectively expressed in the atria, and this is particularly appealing to ameliorate ventricular proarrhythmia. Drugs targeting IKur (Kv1.5), and to a lesser extent IKACh (Kir3.1/3.4), are in various stages of development.
Introduction
Ion channels are key for the coordinated electrical activity of an excitable tissue, such as the heart. In particular, K channels are responsible for repolarization of the cardiac action potential, setting the resting membrane potential and the modulation of electrical activity in response to hormonal modulation and metabolic challenge. The biophysical and electrophysiological details of the currents underlying cardiac excitability were first developed in the 1960s and 1970s. However, during the last 25 years, our understanding has been complemented and exponentially enhanced by the identification of the large families of K channel genes and auxiliary proteins and an appreciation at a structural level of how these ion channels select for K and how they might open and close in response to voltage and Ca. These major intellectual advances have had a substantial impact on drug development and the investigation of novel targets in cardiovascular disease. In this article, we will consider this question and, in particular, focus on cardiac K channels as therapeutic targets in cardiac arrhythmia.
Abnormalities in heart rhythm are a substantial clinical burden. At the most malignant end of the spectrum, sudden cardiac death resulting from ventricular arrhythmia usually caused by heart failure and/or ischemic heart disease represents a major healthcare problem. Some 300,000 cases per year are recorded in the USA, stressing the potential clinical significance of treating those at particular risk. Supraventricular arrhythmias are also important, leading to significant morbidity and mortality. Atrial fibrillation (AF) occurs in up to 1% of the general population, and the prevalence increases eightfold in those over 80 years of age. Interventional cardiology has provided a number of new treatment modalities, including implantable cardiac defibrillators (ICDs) for the management of ventricular tachyarrhythmias, and ablation procedures, such as pulmonary vein isolation, surgery and various pacing strategies for atrial fibrillation. Even if these therapeutic approaches become pre-eminent, pharmacological therapy could still potentially have a place in management. For example, preventing abnormal event occurrence and, thus, ICD discharge in patients with malignant ventricular arrhythmias and the recurrence of AF after ablation procedures are important clinical issues. Furthermore, these procedures are major undertakings, have significant adverse effects and are not suitable for all patient groups. In this article, our argument is that drugs modulating K channels for the treatment of ventricular arrhythmia are likely to be of use in only very defined clinical scenarios. By contrast, the targeting of atrial-specific K channels in AF could be a much more profitable strategy for drug development.