Luca Soattin1, Zoltan Borbas1,2,3, Jane Caldwell2,4,5, Brian Prendergast2, Akbar Vohra1,2, Yawer Saeed1,2,6, Andreas Hoschtitzky7,8,9, Joseph Yanni1, Andrew Atkinson1, Sunil Jit Logantha1,10, Balint Borbas1, Clifford Garratt1,2, Gwilym Matthew Morris1,2, Halina Dobrzynski1,11. 1. Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom. 2. Manchester Heart Centre, Central Manchester University Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom. 3. Liverpool Heart and Chest Hospital, Liverpool, United Kingdom. 4. Hull University Teaching Hospitals, Hull, United Kingdom. 5. Hull York Medical School, Hull, United Kingdom. 6. Department of Medicine, Aga Khan University, Karachi, Pakistan. 7. Adult Congenital Heart Disease Unit, Manchester Royal Infirmary, Manchester Academic Health Science Centre, Manchester, United Kingdom. 8. Royal Brompton Hospital, London, United Kingdom. 9. Imperial College London, London, United Kingdom. 10. Liverpool Centre for Cardiovascular Sciences, Department of Cardiovascular and Metabolic Medicine, University of Liverpool, Liverpool, United Kingdom. 11. Department of Anatomy, Jagiellonian University, Krakow, Poland.
Abstract
BACKGROUND: The sinoatrial/sinus node (SAN) is the primary pacemaker of the heart. In humans, SAN is surrounded by the paranodal area (PNA). Although the PNA function remains debated, it is thought to act as a subsidiary atrial pacemaker (SAP) tissue and become the dominant pacemaker in the setting of sinus node disease (SND). Large animal models of SND allow characterization of SAP, which might be a target for novel treatment strategies for SAN diseases. METHODS: A goat model of SND was developed (n = 10) by epicardially ablating the SAN and validated by mapping of emergent SAP locations through an ablation catheter and surface electrocardiogram (ECG). Structural characterization of the goat SAN and SAP was assessed by histology and immunofluorescence techniques. RESULTS: When the SAN was ablated, SAPs featured a shortened atrioventricular conduction, consistent with the location in proximity of atrioventricular junction. SAP recovery time showed significant prolongation compared to the SAN recovery time, followed by a decrease over a follow-up of 4 weeks. Like the SAN tissue, the SAP expressed the main isoform of pacemaker hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) and Na+/Ca2+ exchanger 1 (NCX1) and no high conductance connexin 43 (Cx43). Structural characterization of the right atrium (RA) revealed that the SAN was located at the earliest activation [i.e., at the junction of the superior vena cava (SVC) with the RA] and was surrounded by the paranodal-like tissue, extending down to the inferior vena cava (IVC). Emerged SAPs were localized close to the IVC and within the thick band of the atrial muscle known as the crista terminalis (CT). CONCLUSIONS: SAN ablation resulted in the generation of chronic SAP activity in 60% of treated animals. SAP displayed development over time and was located within the previously discovered PNA in humans, suggesting its role as dominant pacemaker in SND. Therefore, SAP in goat constitutes a promising stable target for electrophysiological modification to construct a fully functioning pacemaker.
BACKGROUND: The sinoatrial/sinus node (SAN) is the primary pacemaker of the heart. In humans, SAN is surrounded by the paranodal area (PNA). Although the PNA function remains debated, it is thought to act as a subsidiary atrial pacemaker (SAP) tissue and become the dominant pacemaker in the setting of sinus node disease (SND). Large animal models of SND allow characterization of SAP, which might be a target for novel treatment strategies for SAN diseases. METHODS: A goat model of SND was developed (n = 10) by epicardially ablating the SAN and validated by mapping of emergent SAP locations through an ablation catheter and surface electrocardiogram (ECG). Structural characterization of the goat SAN and SAP was assessed by histology and immunofluorescence techniques. RESULTS: When the SAN was ablated, SAPs featured a shortened atrioventricular conduction, consistent with the location in proximity of atrioventricular junction. SAP recovery time showed significant prolongation compared to the SAN recovery time, followed by a decrease over a follow-up of 4 weeks. Like the SAN tissue, the SAP expressed the main isoform of pacemaker hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) and Na+/Ca2+ exchanger 1 (NCX1) and no high conductance connexin 43 (Cx43). Structural characterization of the right atrium (RA) revealed that the SAN was located at the earliest activation [i.e., at the junction of the superior vena cava (SVC) with the RA] and was surrounded by the paranodal-like tissue, extending down to the inferior vena cava (IVC). Emerged SAPs were localized close to the IVC and within the thick band of the atrial muscle known as the crista terminalis (CT). CONCLUSIONS: SAN ablation resulted in the generation of chronic SAP activity in 60% of treated animals. SAP displayed development over time and was located within the previously discovered PNA in humans, suggesting its role as dominant pacemaker in SND. Therefore, SAP in goat constitutes a promising stable target for electrophysiological modification to construct a fully functioning pacemaker.
Authors: Natalie Chandler; Oleg Aslanidi; David Buckley; Shin Inada; Steven Birchall; Andrew Atkinson; Danielle Kirk; Oliver Monfredi; Peter Molenaar; Robert Anderson; Vinod Sharma; Daniel Sigg; Henggui Zhang; Mark Boyett; Halina Dobrzynski Journal: Anat Rec (Hoboken) Date: 2011-04-28 Impact factor: 2.064
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