The sinus node (SN) is the natural pacemaker of the heart. In the human, the SN is surrounded by the paranodal area (PNA), the function of which is currently unknown. The PNA may act as subsidiary atrial pacemakers (SAP) and become the dominant pacemaker during sinus node dysfunction (SND). Creation of an animal model of SND allows characterisation of SAP, which can be a target for novel treatment strategies other than the currently available electronic pacemakers. I developed a large animal model of SND by ablating the SN in the goat and validated it by mapping the location of the newly emergent SAP. Functional characterisation of the SAP revealed reduced atrioventricular (AV) conduction time consistent with a location of the SAP close to the AV junction. SAP recovery time showed an initially significant prolongation compared to the SN recovery time, followed by a gradual decrease over 4 weeks. SAP pauses, and temporary reliance on electronic pacemaker activity have also been demonstrated then disappeared over time, suggesting possible modulation, maturation of the SAP. Structural characterisation of the SN revealed an extensive pacemaking complex within the right atrium (RA); the SN was surrounded by the PNA, extending down to the inferior vena cava (IVC) and into the interatrial groove. The PNA had a histological appearance that is intermediate to the SN and the RA. 3D reconstruction demonstrated, for the first time in a large animal model, an extensive and almost complete circle of pacemaking tissue at the junction of the embryologically different sinus venosus and the muscular right atrium. The SAP emerged in a location close to the IVC along the crista terminalis. Expression of key ion channel proteins in the SAP showed abundance of the pacemaker channel (HCN4) and the sodium/calcium exchanger (NCX1) compared to RA, similar to the expression pattern of the SN. The expression of the main high conductance connexin (Cx43) was not significantly different between SAP and RA, and both expressed Cx43 more abundantly than the SN.Conclusion: Destruction of the sinus node in this experimental model resulted in the generation of chronic SAP activity in the majority of the animals. The SAP displayed maturation over time and located in the inferior part of the RA, in the same area where the PNA was found in controls, suggesting the role of PNA as the dominant pacemaker in sinus node dysfunction. The SAP in the goat constitutes a promising stable target for electrophysiological modification to construct a fully functioning biological pacemaker.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:668554 |
| Date | January 2015 |
| Creators | Borbas, Zoltan |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/characterisation-of-the-structural-and-functional-properties-of-subsidiary-atrial-pacemakers-in-a-goat-model-of-sinus-node-dysfunction(56e73040-f88e-4e14-942e-553b8d90d779).html |
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