Sarcolemmal KATP Channel Modulators and Cardiac Arrhythmias

I.      Baczko; Z.      Husti; V.      Lang; I.      Lepran; P.      E. Light

doi:10.2174/092986711796642472

Abstract

Cardiac atrial and ventricular arrhythmias are major causes of mortality and morbidity. Ischemic heart disease is the most common cause underlying 1) the development of ventricular fibrillation that results in sudden cardiac death and 2) atrial fibrillation that can lead to heart failure and stroke. Current pharmacological agents for the treatment of ventricular and atrial arrhythmias exhibit limited effectiveness and many of these agents can cause serious adverse effects - including the provocation of lethal ventricular arrhythmias. Sarcolemmal ATP-sensitive potassium channels (sarcKATP) couple cellular metabolism to membrane excitability in a wide range of tissues. In the heart, sarcKATP are activated during metabolic stress including myocardial ischemia, and both the opening of sarcKATP and mitochondrial KATP channels protect the ischemic myocardium via distinct mechanisms. Myocardial ischemia leads to a series of events that promote the generation of arrhythmia substrate eventually resulting in the development of life-threatening arrhythmias. In this review, the possible mechanisms of the anti- and proarrhythmic effects of sarcKATP modulation as well as the influence of pharmacological KATP modulators are discussed. It is concluded that in spite of the significant advances made in this field, the possible cardiovascular therapeutic utility of current sarcKATP channel modulators is still hampered by the lack of chamber-specific selectivity. However, recent insights into the chamber-specific differences in the molecular composition of sarcKATP in addition to already existing cardioselective sarcKATP channel modulators with sarcKATP isoform selectivity holds the promise for the future development of pharmacological strategies specific for a variety of atrial and ventricular arrhythmias.

Keywords: ATP-sensitive, potassium channel, atrial fibrillation, cardiac arrhythmias, KATP channel blockers, mitochondrial KATP channel, potassium channel openers, repolarization, reverse use-dependent prolongation of repolarization, sarcolemmal KATP channel