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Original article
Proarrhythmic remodelling of the right ventricle in a porcine model of repaired tetralogy of Fallot
  1. David Benoist1,2,
  2. Virginie Dubes1,2,
  3. François Roubertie1,2,3,
  4. Stephen H Gilbert1,2,4,
  5. Sabine Charron1,2,
  6. Marion Constantin1,2,
  7. Delphine Elbes1,2,5,
  8. Delphine Vieillot6,
  9. Bruno Quesson1,2,
  10. Hubert Cochet1,2,3,
  11. Michel Haïssaguerre1,2,3,
  12. Caroline Rooryck7,
  13. Pierre Bordachar1,2,3,
  14. Jean-Benoit Thambo1,2,3,
  15. Olivier Bernus1,2
  1. 1 IHU LIRYC, L'Institut de Rythmologie et Modélisation Cardiaque, Fondation Bordeaux Université, Bordeaux, France
  2. 2 Inserm U1045, Centre de Recherche Cardio-Thoracique de Bordeaux, Université de Bordeaux, Bordeaux, France
  3. 3 CHU de Bordeaux, Hôpital Cardiologique du Haut-Lévêque, Pessac, France
  4. 4 Max Delbrück Center for Molecular Medicine, Mathematical Cell Physiology, Berlin, Germany
  5. 5 Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, UK
  6. 6 Plateforme Technologique d'Innovation Biomédicale, Université de Bordeaux, Pessac, France
  7. 7 Inserm U1211, Maladies Rares: Génétique et Métabolisme, Université de Bordeaux, Bordeaux, France
  1. Correspondence to Dr David Benoist, IHU LIRYC, PTIB—Hôpital Xavier Arnozan, Avenue Haut Leveque, Pessac 33604, France; david.benoist{at}u-bordeaux.fr

Abstract

Objective The growing adult population with surgically corrected tetralogy of Fallot (TOF) is at risk of arrhythmias and sudden cardiac death. We sought to investigate the contribution of right ventricular (RV) structural and electrophysiological remodelling to arrhythmia generation in a preclinical animal model of repaired TOF (rTOF).

Methods and results Pigs mimicking rTOF underwent cardiac MRI functional characterisation and presented with pulmonary regurgitation, RV hypertrophy, dilatation and dysfunction compared with Sham-operated animals (Sham). Optical mapping of rTOF RV-perfused wedges revealed a significant prolongation of RV activation time with slower conduction velocities and regions of conduction slowing well beyond the surgical scar. A reduced protein expression and lateralisation of Connexin-43 were identified in rTOF RVs. A remodelling of extracellular matrix-related gene expression and an increase in collagen content that correlated with prolonged RV activation time were also found in these animals. RV action potential duration (APD) was prolonged in the epicardial anterior region at early and late repolarisation level, thus contributing to a greater APD heterogeneity and to altered transmural and anteroposterior APD gradients in rTOF RVs. APD remodelling involved changes in Kv4.3 and MiRP1 expression. Spontaneous arrhythmias were more frequent in rTOF wedges and more complex in the anterior than in the posterior RV.

Conclusion Significant remodelling of RV conduction and repolarisation properties was found in pigs with rTOF. This remodelling generates a proarrhythmic substrate likely to facilitate re-entries and to contribute to sudden cardiac death in patients with rTOF.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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Footnotes

  • DB and VD contributed equally.

  • Contributors DB, VD, FR, SHG, SC, MC, DE, DV, BQ performed the experiments; DB, VD, SHG, SC, OB analysed the data; DB, VD, FR, BQ, HC, MH, CR, PB, J-BT, OB designed the experimental protocol; DB, VD and OB wrote the manuscript.

  • Funding This work was funded by the Agence Nationale de la Recherche through the grant ANR-10-IAHU04-LIRYC, the ERC Advanced grant SYMPHONY (no 322886) and the EU FP7 IRSES programme CORDIS3D grant (IRSES-GA-2013-317767). DB was funded by a Fondation Recherche Médicale fellowship and SHG was funded by a European Union Marie Curie fellowship.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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