63 * Ageing is associated with myocardial disarray, changes in the expression of ion channels, gap junction proteins and Ca2+ handling proteins with in the atrioventricular conduction axis

Abstract

Introduction: The inferior nodal extension (INE), compact node (CN) and penetrating/His bundle (PB/HB) form the atrioventricular (AV) conduction axis and are responsible for conduction and delay of the action potential from the atria to the ventricles. With ageing, dysfunction of the AV conduction axis results in prolongation of the PR interval and AV block. Methods: We have compared the INE, CN and PB/HB from male rats 3 months old (n 9) and 2 years old (n 8). From survival curves, 3 month old rat correspond to 20 yearr old human, whereas 2 year old rat correspond to 70 year old human. Morphological characteristics of these tissues were studied using Masson's trichrome (MT) and picrosirius red (PR) on serial histological sections. Protein expression was studied using immunofluorescence and confocal microscopy. Qualitative signal intensity of proteins investigated was measured using Volocity software. Results: MT staining showed that the cells of INE, CN and PB were more loosely packed and irregularly arranged thus showing myocardial disarray in old rats. PR staining showed that total collagen content was greater in CN and PB with ageing. There was an age dependent cellular hypertrophy in all regions of the AV conduction axis. Immunohistochemistry revealed that Cx43 (the major gap junction in the heart) down regulates in PB ( P <0.05), but Cx40 (important gap junction in the atria and AV conduction axis) up regulates in INE and CN ( P <0.05) in old rats. With ageing, there was a down regulation of Nav1.5 (major cardiac Na+channel) in CN and PB ( P <0.05), up regulation of Cav1.3 (L-type Ca2+ channel) in PB ( P <0.05) and in terms of Ca2+ handling proteins, downregulation of RyR2 in CN, PB ( P <0.05) and up regulation of SERCA2a in PB ( P <0.05). There was also trend to downregulation of HCN4 in PB/HB bundle ( P =0.051) Conclusion: Ageing is associated with structural changes to the tissues in the AV conduction axis, which include myocardial disarray, fibrosis and hypertrophy. Ageing is also associated with changes in the expression of ion channels, gap junction proteins and Ca2+ handling proteins. These changes may explain the age dependent dysfunction of AV conduction axis.