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

Abstract

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 14days, an electrophysiological study was performed to evaluate the AT vulnerability. Ca2+ handlingproperties were measured by loading atrial cardiomyocytes (CMs) with fura-2 AM. The L-type Ca2+ (ICa-L) and Na+-Ca2+exchanger (INCX) currentsof 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 INCX density were increased, but ICa-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.