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

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Abstract

Background

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.

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. Ca2+ handling properties were measured by loading atrial cardiomyocytes (CMs) with fura-2 AM. The L-type Ca2+ (ICa−L) and Na+–Ca2+ exchanger (INCX) currents of the CMs were recorded by the whole-cell patch-clamp technique. The key Ca2+ 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 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.

Conclusion

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

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Funding

This work was supported by the National Natural Science Foundation of China (no. 81870248, 81300138), Scientific Research Program of Shanghai Science and Technology Commission (no. 13430721700) and the Jiangsu Provincial Medical Youth Talent (QNRC2016761).

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Authors and Affiliations

  1. Cardiology Department, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, 1678 Dongfang Road, Pudong New Area, 200127, Shanghai, China

    Wan-Ping Zhou, Fen Li, Jin-Jin Wu, Ya-Nan Lu & Yi-Jiao Qian

  2. Cardiology Department, Children’s Hospital of Soochow University, Suzhou, China

    Wan-Ping Zhou

Authors
  1. Wan-Ping Zhou
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  2. Fen Li
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  3. Jin-Jin Wu
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  5. Yi-Jiao Qian
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Contributions

WPZ designed the study, recorded the iron currents and measured cell contraction and Ca2+ fluorescence, and wrote the paper. FL designed the study. JJW did in vivo electrophysiological study. YNL performed the procedures of Fontan operation. YJQ was involved in Western blotting and histological analysis. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Fen Li.

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Ethical approval

All animal-handling procedures followed the National Institutes of Health guidelines and were approved by the Shanghai Children’s Medical Center Animals Research Ethics Committee. No financial or nonfinancial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.

Conflict of interest

None declared.

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Zhou, WP., Li, F., Wu, JJ. et al. Calcium-handling abnormalities underlying atrial arrhythmogenesis in a Fontan operation canine model. World J Pediatr 14, 576–584 (2018). https://doi.org/10.1007/s12519-018-0177-z

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  • DOI: https://doi.org/10.1007/s12519-018-0177-z

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