Calcium-handling abnormalities underlying atrial arrhythmogenesis in a Fontan operation canine model

Background Atrial tachyarrhythmia (AT) is a common complication in patients who have undergone a Fontan operation. In this study, we investigated whether abnormal Ca 2+ handling contributes to the Fontan operation-related atrial arrhythmogenic substrate. Methods Mongrel dogs were randomly assigned to sham and Fontan groups. The Fontan operation model was developed by performing an atriopulmonary anastomosis. After 14 days, an electrophysiological study was performed to evaluate the AT vulnerability. Ca 2+ handling properties were measured by loading atrial cardiomyocytes (CMs) with fura-2 AM. The L -type Ca 2+ ( I Ca−L ) and Na + –Ca 2+ exchanger ( I NCX ) currents of the CMs were recorded by the whole-cell patch-clamp technique. The key Ca 2+ handling proteins expression was assessed by Western blotting. Results The AT inducibility was higher in the Fontan group than in the sham group (85.71 vs. 14.29%, P < 0.05). The Fontan operation resulted in decreased Ca 2+ transient (CaT) amplitude and sarcoplasmic reticulum (SR) Ca 2+ content, but in enhanced diastolic intracellular Ca 2+ concentration and SR Ca 2+ leak in the atrial CMs. The spontaneous CaT events, triggered ectopic activity and I NCX density were increased, but I Ca−L density was reduced in CMs from the Fontan atria (all P < 0.05). Additionally, the Fontan operation resulted in decreased SR Ca 2+ ATPase expression and Cav1.2 expression, but in increased NCX1 and Ser2814-phosphorylated ryanodine receptor 2. The calmodulin-dependent protein kinase II expression and function were markedly enhanced in the Fontan atria. Conclusion The Fontan operation caused atrial CM Ca 2+ handling abnormalities that produced arrhythmogenic-triggered activity and increased vulnerability to AT in experimental Fontan dogs.