Abstract 13782: Atrioventricular Junction Elongation and Ion Channel Remodelling Leads to Slowing of Atrioventricular Conduction in Heart Failure
The atrioventricular junction (AVJ) maintains synchronised atrioventricular conduction and protects from ventricular tachycardia, as well as bradycardia. Heart failure (HF) is a major killer worldwide. Slowing of atrioventricular conduction in HF is associated with increased morbidity and mortality. The hypothesis of this study was that anatomical and ion channel changes cause slowing of atrioventricular conduction in HF. Three-month old male New Zealand rabbits underwent destruction of the aortic valve (week 0) followed by banding of the abdominal aorta (week 3). Echocardiography confirmed reduction in ejection fraction prior to termination (week 8). In-vivo electrocardiographic recordings showed prolongation of the PR interval in HF before and after autonomic blockade (n=12; Student’s t-test, *p<0.05). AVJ preparations were dissected and serial histological sectioning used for three-dimensional anatomical modelling of the AVJ. Laser-microdissection, real-time PCR and immunohistochemistry were used for molecular mapping of ion channel expression in seven regions across the AVJ (atrial septum, transitional tissue, compact node, penetrating bundle, His bundle, left and right ventricular septum). A significant 30% elongation of the AVJ was observed in HF (n=16; 2.4 ± 0.23 cm control vs.3.0 ± 0.19 cm HF, Student’s t-test p=0.03) with no change in transverse cell diameter or collagen content. HCN1, Cx40 and Cx43 mRNA transcripts were significantly downregulated across all regions (n=9; 2-way ANOVA, FDR-adjusted significance *p<0.1), Cav1.3 was also significantly downregulated in transitional tissue (n=9; Limma test, p=0.03). A compensatory increase in CLCN2, Nav1.1, Navβ1, SUR2A and PAK1 was seen (n=9; 2-way ANOVA, FDR-adjusted significance *p<0.1). In conclusion, anatomical remodelling with marked elongation of the AVJ in HF leads to slowing of atrioventricular conduction. Downregulation of HCN1, Cav1.3 (in transitional tissue) and gap-junction proteins Cx40 and Cx43 further delays conduction by decreasing excitability, action potential upstroke and cell coupling, respectively. Targeting these transcripts by modulating transcription factors or gene therapy may prevent atrioventricular block and bradycardic deaths in HF.
- © 2013 by American Heart Association, Inc.