Extended atrial conduction system characterised by the expression of the HCN4 channel and connexin45

Abstract

Objective: In the heart, there are multiple supraventricular pacemakers involved in normal pacemaking as well as arrhythmias and the objective was to determine the distribution of HCN4 (major isoform underlying the pacemaker current, I_f) in the atria. Methods: In the atria of the rat, the localisation of HCN4 and connexins was determined using immunohistochemistry, and electrical activity was recorded using extracellular electrodes. Results: As expected, HCN4 and Cx45 (but not Cx43) were expressed in the sinoatrial node extending from the superior vena cava down the crista terminalis. The same pattern of expression of HCN4 and connexins was observed in a novel tract of nodal-like cells extending from the superior vena cava down the interatrial groove. Although the sinoatrial node was usually the leading pacemaker site, the novel tract of HCN4-expressing cells was capable of pacemaking and could act as the leading pacemaker site; there was evidence of a hierarchy of pacemakers. The same pattern of expression of HCN4 and connexins was also observed in the atrioventricular ring bundle (including the atrioventricular node) encircling the tricuspid valve, but not in the atrioventricular ring bundle encircling the mitral valve. HCN4 was not expressed in the pulmonary veins. Conclusions: The widespread distribution of HCN4 can explain the widespread location of the leading pacemaker site during sinus rhythm, the extensive region of tissue that has to be ablated to stop sinus rhythm, and the widespread distribution of ectopic foci responsible for atrial tachycardia.