Structural and functional remodeling of the atrioventricular node with aging in rats: The role of hyperpolarization-activated cyclic nucleotide-gated and ryanodine 2 channels

Background Ageing is associated with an increased incidence of atrioventricular nodal (AVN) dysfunction. Objectives The aim of the study is to identify the structural and functional remodelling in the atrioventricular junction (AVJ) with ageing. Methods Electrophysiological, histology and immunohistochemistry experiments on male Wistar-Hanover rats aged 3months (n=24) and 2years (n=15) were performed. AH interval, Wenkebach cycle length (WBCL) and AVN effective refractory period (AVNERP) were measured. Cesium (2mM) was used to block hyperpolarization-activated cyclic nucleotide-gated (HCN) channels whilst ryanodine (2μM) was used to block Ryanodine-2 (RyR2) channels. Protein expression from different regions of the AVJ was studied using immunofluorescence. The expression of the connexins (Cx43, Cx40), ion channels (HCN4, Nav1.5, Cav1.3) and calcium handling proteins (RyR2, SERCA2a) were measured. Morphological characteristics were studied with histology. Results Without drugs to block the HCN and RyR2, there was prolongation of the AH, WBCL and AVNERP (p<0.05) with ageing. In young rats only, Cesium prolonged the AH, WBCL and AVNERP (p<0.01). Ryanodine prolonged the AH and WBCL (P<0.01) in both young and old rats. Immunofluorescence revealed that with ageing: Cx43, HCN4, Nav1.5 and RyR2 downregulate in the regions of AVJ and Cx40, SERCA2a and Cav1.3 upregulate (p<0.05). Ageing results in cellular hypertrophy, loosely packed cells, a decrease in the number of nuclei and an increase in the collagen content. Conclusion Heterogeneous ion channel expression changes were observed in the AVJ with ageing. For the first time, we have shown that HCN and RyR2 play an important role in AVN dysfunction with ageing.