Identification of Region-Specific Myocardial Gene Expression Patterns in a Chronic Swine Model of Repaired Tetralogy of Fallot
Sabine Charron 1 , François Roubertie 2 , David Benoist 1 , Virginie Dubes 1 , Stephen H Gilbert 3 , Marion Constantin 1 , Delphine Vieillot 4 , Delphine Elbes 5 , Bruno Quesson 1 , Pierre Bordachar 2 , Michel Haissaguerre 2 , Olivier Bernus 1 , Jean-Benoit Thambo 2 , Caroline Rooryck 6
1 L'Institut de Rythmologie et Modélisation Cardiaque LIRYC, Université de Bordeaux, Pessac, France; Inserm U1045 CRCTB, Université de Bordeaux, Bordeaux, France.
2 L'Institut de Rythmologie et Modélisation Cardiaque LIRYC, Université de Bordeaux, Pessac, France; Inserm U1045 CRCTB, Université de Bordeaux, Bordeaux, France; Hôpital cardiologique Haut-Lévêque, CHU de Bordeaux, Pessac, France.
3 L'Institut de Rythmologie et Modélisation Cardiaque LIRYC, Université de Bordeaux, Pessac, France; Inserm U1045 CRCTB, Université de Bordeaux, Bordeaux, France; Max Delbrück Center for Molecular Medicine, Berlin, Germany.
4 Plateforme Technologique d'Innovation Biomédicale, Université de Bordeaux, Pessac, France.
5 L'Institut de Rythmologie et Modélisation Cardiaque LIRYC, Université de Bordeaux, Pessac, France; Inserm U1045 CRCTB, Université de Bordeaux, Bordeaux, France; University of Oxford, Institute of Biomedical Engineering, Oxford, United-Kingdom.
6 L'Institut de Rythmologie et Modélisation Cardiaque LIRYC, Université de Bordeaux, Pessac, France; Hôpital cardiologique Haut-Lévêque, CHU de Bordeaux, Pessac, France; Laboratoire Maladies Rares: Génétique et Métabolisme (MRGM), EA 4576, Université de Bordeaux, Bordeaux, France.
Surgical repair of Tetralogy of Fallot (TOF) is highly successful but may be complicated in adulthood by arrhythmias, sudden death, and right ventricular or biventricular dysfunction. To better understand the molecular and cellular mechanisms of these delayed cardiac events, a chronic animal model of postoperative TOF was studied using microarrays to perform cardiac transcriptomic studies. The experimental study included 12 piglets (7 rTOF and 5 controls) that underwent surgery at age 2 months and were further studied after 23 (+/- 1) weeks of postoperative recovery. Two distinct regions (endocardium and epicardium) from both ventricles were analyzed. Expression levels from each localization were compared in order to decipher mechanisms and signaling pathways leading to ventricular dysfunction and arrhythmias in surgically repaired TOF. Several genes were confirmed to participate in ventricular remodeling and cardiac failure and some new candidate genes were described. In particular, these data pointed out FRZB as a heart failure marker. Moreover, calcium handling and contractile function genes (SLN, ACTC1, PLCD4, PLCZ), potential arrhythmia-related genes (MYO5B, KCNA5), and cytoskeleton and cellular organization-related genes (XIRP2, COL8A1, KCNA6) were among the most deregulated genes in rTOF ventricles. To our knowledge, this is the first comprehensive report on global gene expression profiling in the heart of a long-term swine model of repaired TOF.