Diversity of ion channel expression in health and disease

Heterogeneity of action potential waveforms among differ-ent species and within specific regions of an individual’s heart is a function of the diversity of ion channel expres-sion. These species differences, mainly in repolarizing cur-rents, have to be considered in interpreting experimental studies on arrhythmogenesis in animals. Even among larger mammals, such as dog and pig, mechanisms of repolariza-tion differ significantly. Differential expression of ion chan-nels in various regions of the heart, and more specifically the transmural distribution in ventricular myocardium, is currently under close investigation. The strongest transven-tricular gradient in human ventricular myocardium exists for the calcium independent transient outward current (ITo1), with its current being 4–5-fold larger in epicardial than in endocardial cells. In hypertrophy and heart failure the hallmark feature of a prolonged action potential again reflects the altered diversity of ion channel expression. Prolonged and labile repolarization in hypertrophy and heart failure in both animal models and humans is predominantly caused by down-regulation of potassium channels. The reduction of outward potassium currents in hypertrophy and heart failure may contribute to the enhanced sensitivity of failing myocardium to proarrhythmia triggering factors such as hypokalaemia, ischaemia, antiarrhythmic drugs with class III effects and non-antiarrhythmic drugs with QT prolongation potential.