Abstract 3859: Connexin Changes, Atrial Fibrosis and the Atrial Fibrillation Substrate in Congestive Heart Failure (CHF)
Connexin alterations occur in various atrial fibrillation (AF) paradigms, but their functional significance remains unclear. No data are available regarding the effects of CHF on atrial connexin expression and phosphorylation. We therefore analyzed connexin changes and their contribution to the AF substrate during the development and reversal of CHF. Dogs were allocated to three groups: CHF induced by 2-week ventricular tachypacing (CHF, n=15); CHF dogs allowed to recover for 4 weeks after 2-week tachypacing (REC, n=15) and non-paced shams (CTL, n=11). Left ventricular end-diastolic pressure increased with CHF (14.5±1.0*** vs. 3.7±0.7, ***P<0.001 vs. CTL) and normalized upon CHF recovery (5.1±1.0†††, †††P<0.001 vs. CHF). Real-time RT-PCR and Western-blot analyses revealed connexin43 (Cx43) and connexin40 (Cx40) mRNA and protein expression to be unchanged by CHF and REC. However, CHF caused Cx43 dephosphorylation (by ~73%***) and increased Cx40/Cx43 protein ratio (by ~35%***), with both alterations completely reversing in REC. Immunofluorescent confocal microscopy confirmed connexin protein trends, with a reduction in phosphorylated Cx43 (by ~68%*** in CHF) that returned to control in REC. CHF caused conduction abnormalities (phase delay-range and heterogeneity index, both P<0.01) and burst pacing-induced AF prolongation (CTL 22±7s, CHF 1100±171s***, REC 884±220s***) which persisted in the recovery period, along with residual fibrosis (CTL 3.6±0.7%, CHF 14.7±1.5%***, REC 13.3±2.3%***). Fibrosis physically interrupted muscle bundle continuity and an ionically-based action potential model of canine atrium showed that fibrosis was able to account for the conduction abnormalities seen. CHF causes connexin-dephosphorylation and Cx40/Cx43 ratio increases. With CHF reversal, atrial connexin alterations recover completely, but tissue fibrosis, conduction abnormalities and a substrate for AF remain, with fibrosis accounting for conduction abnormalities. Thus, although atrial connexin changes occur with CHF, they are not essential for conduction disturbances and AF promotion, which appear rather to be related primarily to fibrotic interruption of muscle-bundle continuity.