Molecular basis for ion current heterogeneity in normal and diseased hearts

Abstract

Cardiac action potential characteristics are known to vary in different species, but also in the different regions of the heart within a given species and in cardiovascular disease. The heterologous expression of voltage-gated ion currents is believed to underlie these differences. The purpose of this thesis is to elucidate the molecular mechanisms which may underlie some of the observed current changes in different species, as well as regions and diseases of the heart.Here, we describe the variable dependence on repolarizing K+ currents in different species as being the result of the lack of Ito subunits in guinea pig heart with a greater expression of IK subunits, while rabbits express all hypothesized Ito subunits, but express IK subunits at low levels. Humans are found to lie in between these two species in terms of the expression of these voltage-gated K+ channel subunits. The specialized function of certain regions of the heart, such as the ventricles and the SAN, have been attributed to the heterologous expression of Ito and the pacemaker current (I f) respectively. Here were demonstrate that both Kv4.3 and KchIP2 gradients underlie an observed Ito transmural gradient and contribute to the dispersion of repolarization, while a greater expression of HCN2 and HCN4 subunits in the SAN compared to the right atrium account for the larger I f current in this region. Cardiovascular diseases such as congestive heart failure (CHF) have been associated with ion channel remodelling. Here, we report the finding of changes in Nav1.5, Kv4.3, HCN2 and HCN4 expression which may underlie some of the electrophysiological changes associated with this disease. Furthermore, we characterise a genetic polymorphism which is associated with another disease, atrial fibrillation.The heterologous expression of voltage-gated ion channel subunits may account for many of the species-, region- and disease-specific differences which have been observed in the heart. Such heterogeneity contributes to the proper functioning of the heart under normal conditions, but may also contribute to the pathogenesis of cardiovascular disease