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

Atrial tachyarrhythmia (AT) is a common complication in patients who have undergone a Fontan operation. In this study, we investigated whether abnormal Ca²⁺ handling contributes to the Fontan operation-related atrial arrhythmogenic substrate.

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. Ca²⁺ handling properties were measured by loading atrial cardiomyocytes (CMs) with fura-2 AM. The L-type Ca²⁺ (I_Ca-L) and Na⁺-Ca²⁺ exchanger (I_NCX) currents of the CMs were recorded by the whole-cell patch-clamp technique. The key Ca²⁺ handling proteins expression was assessed by Western blotting.

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 Ca²⁺ transient (CaT) amplitude and sarcoplasmic reticulum (SR) Ca²⁺ content, but in enhanced diastolic intracellular Ca²⁺ concentration and SR Ca²⁺ 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 Ca²⁺ 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.

The Fontan operation caused atrial CM Ca²⁺ handling abnormalities that produced arrhythmogenic-triggered activity and increased vulnerability to AT in experimental Fontan dogs.