Repolarization of the cardiac action potential. Does an increase in repolarization capacity constitute a new anti‐arrhythmic principle?

The cardiac action potential can be divided into five distinct phases designated phases 0-4. The exact shape of the action potential comes about primarily as an orchestrated function of ion channels. The present review will give an overview of ion channels involved in generating the cardiac action potential with special emphasis on potassium channels involved in phase 3 repolarization. In humans, these channels are primarily K(v)11.1 (hERG1), K(v)7.1 (KCNQ1) and K(ir)2.1 (KCNJ2) being the responsible alpha-subunits for conducting I(Kr), I(Ks) and I(K1). An account will be given about molecular components, biophysical properties, regulation, interaction with other proteins and involvement in diseases. Both loss and gain of function of these currents are associated with different arrhythmogenic diseases. The second part of this review will therefore elucidate arrhythmias and subsequently focus on newly developed chemical entities having the ability to increase the activity of I(Kr), I(Ks) and I(K1). An evaluation will be given addressing the possibility that this novel class of compounds have the ability to constitute a new anti-arrhythmic principle. Experimental evidence from in vitro, ex vivo and in vivo settings will be included. Furthermore, conceptual differences between the short QT syndrome and I(Kr) activation will be accounted for.