Background— Congestive heart failure (CHF) is a common cause of atrial fibrillation. Focal sources of unknown mechanism have been described in CHF-related atrial fibrillation. The authors hypothesized that abnormal calcium (Ca²⁺) handling contributes to the CHF-related atrial arrhythmogenic substrate.

Methods and Results— CHF was induced in dogs by ventricular tachypacing (240 bpm 2 weeks). Cellular Ca²⁺-handling properties and expression/phosphorylation status of key Ca²⁺ handling and myofilament proteins were assessed in control and CHF atria. CHF decreased cell shortening but increased left atrial diastolic intracellular Ca²⁺ concentration ([Ca²⁺]_i), [Ca²⁺]_i transient amplitude, and sarcoplasmic reticulum (SR) Ca²⁺ load (caffeine-induced [Ca²⁺]_i release). SR Ca²⁺ overload was associated with spontaneous Ca²⁺ transient events and triggered ectopic activity, which was suppressed by the inhibition of SR Ca²⁺ release (ryanodine) or Na⁺/Ca²⁺ exchange. Mechanisms underlying abnormal SR Ca²⁺ handling were then studied. CHF increased atrial action potential duration and action potential voltage clamp showed that CHF-like action potentials enhance Ca²⁺_i loading. CHF increased calmodulin-dependent protein kinase II phosphorylation of phospholamban by 120%, potentially enhancing SR Ca²⁺ uptake by reducing phospholamban inhibition of SR Ca²⁺ ATPase, but it did not affect phosphorylation of SR Ca²⁺-release channels (RyR2). Total RyR2 and calsequestrin (main SR Ca²⁺-binding protein) expression were significantly reduced, by 65% and 15%, potentially contributing to SR dysfunction. CHF decreased expression of total and protein kinase A–phosphorylated myosin-binding protein C (a key contractile filament regulator) by 27% and 74%, potentially accounting for decreased contractility despite increased Ca²⁺ transients. Complex phosphorylation changes were explained by enhanced calmodulin-dependent protein kinase IIδ expression and function and type-1 protein-phosphatase activity but downregulated regulatory protein kinase A subunits.

Conclusions— CHF causes profound changes in Ca²⁺-handling and -regulatory proteins that produce atrial fibrillation–promoting atrial cardiomyocyte Ca²⁺-handling abnormalities, arrhythmogenic triggered activity, and contractile dysfunction.