Calcium-Handling Abnormalities Underlying Atrial Arrhythmogenesis and Contractile Dysfunction in Dogs With Congestive Heart Failure

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 x2 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 Ca-i(2+) 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 II delta 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. (Circ Arrhythmia Electrophysiol. 2008;1:93-102.)