Background: Atrial fibrillation (AF) is sustained by reentrant mechanisms that depend, in part, on atrial structural remodeling. Increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity occurs in persistent AF. A general consensus has been that electrophysiological actions of CaMKII must be the contributing factor, but electrical remodeling in AF differs considerably with electrophysiological effects of CaMKII. CaMKII has been associated with structural remodeling in several tissues, but not the cardiac atria. The role of CaMKII in sustaining AF remains undefined. Objective: The purpose of this study was to assess the effects of CaMKII on AF-related structural remodeling. Methods: We evaluated the objective in a porcine AF–heart failure model using atrial gene transfer of the CaMKII inhibitory peptide CaMKIIn. We used conventional methods including in vivo electrophysiological study, telemetry, western blot, echocardiography, and histology to quantify rhythm, function, microstructure, and signaling pathways relevant to CaMKII and structural remodeling. Results: CaMKII levels and activity increased progressively in the early stages of AF–heart failure. Inhibiting CaMKII preserved atrial contractile function and attenuated atrial hypertrophy, fibrosis, and apoptosis but did not affect inflammation or myolysis. These effects were accompanied by significantly decreased phosphorylation of HDAC4, decreased expression of p38MAP-kinase, and alterations in the phosphorylation pattern and relative ratios of JNK isoforms. Conclusion: Our findings suggest that CaMKII mediates signaling pathways related to atrial contractile function and structural remodeling in AF. CaMKII inhibition is potentially a novel therapy for AF. These findings are of importance because no clinically relevant mediators of either atrial contractile function or structural remodeling have yet been identified.
- Atrial fibrillation
- Ca/calmodulin-dependent protein kinase
- Gene therapy
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)