Abstract 1235: Molecular Basis for Sympathetic Remodeling in the Left Atrium in the Ventricular Tachypacing Canine Model of Congestive Heart Failure
Background: The sympathetic nervous system (SNS) is thought to play an important role in promoting atrial fibrillation (AF) initiation and maintenance, especially in the setting of congestive heart failure (CHF). However, it is unclear as to which components of the SNS are altered in atria isolated from failing hearts. These studies are essential, as they will delineate potential molecular targets that may be probed for therapeutic intervention in order to reduce AF pathogenesis.
Methods: CHF was induced by ventricular tachypacing (240 beats/minute) for 4 weeks in hound dogs. A total of 4 CHF and 5 control dogs were used. Immunoblot analysis was performed on left atrial appendage (LAA) homogenates to examine the protein expression of Gsα, Gi2α, and the catalytic subunit of protein kinase A (PKA). Catalytic activities of PKA and protein phosphatase type 2a (PP2a) were determined using non-radioactive enzyme activity assay systems. Cyclic AMP (cAMP) accumulation was assessed by an enzyme linked immunoabsorbant assay and phosphorylation of cardiac troponin I (cTnI) was determined using a phosphospecific antibody against cTnI.
Results: Gsαconcentrations were increased approximately 4-fold in failing left atrial preparations relative to control. In contrast, expression of Gi2αwas modestly increased ~1-fold in failing LAA relative to non-failing atrial muscles. PKA activity was significantly increased in failing LAA preparations compared to control (124.7 vs. 42.1 pmole phosphate/minute, P<0.05); while, PP2a activity was substantially decreased in failing LAA (4.60 vs. 7.06 pmole phosphate/μg protein/minute, P<0.05). cAMP concentrations were increased and expression of the catalytic subunit of PKA was upregulated (~1.5-fold increase) in failing LAA. Lastly, phosphorylation of cardiac troponin I (cTnI) was enhanced in failing LAA preparations.
Conclusions: Our data are the first to characterize sympathetic remodeling in left atrial muscles isolated from an experimental model of CHF. Additionally, our results support the hypothesis that augmented sympathetic signaling and activation may contribute to the AF substrate in a canine model of CHF characterized by increased AF susceptibility.