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Title: The ultrastructural and abnormal calcium handling in pulmonary vein sleeve cells, atrial and ventricular myocytes during ageing
Author: Masoud, Said
ISNI:       0000 0004 7661 1799
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2018
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Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, with age being a significant risk factor. It is well established now that electric activities originating from pulmonary vein sleeve cells (PVCs) initiate AF. Factors that are involved in maintaining AF include structural remodelling and abnormal Ca2+ handling in PVCs and atrial myocytes. Whilst structural changes and alterations in the Ca2+ homeostasis have been described previously in atrial myocytes, similar studies are still lacking in PVCs. Thus, this thesis investigated structural remodelling and Ca2+ handling, particularly in PVCs from 3- and 24month-old mice. Using immunohistochemical and electron microscopy (EM) studies, this thesis revealed that PVCs just like atrial and ventricular myocytes, express RyR2, Cx40, and Cx43. Whilst RyR2 and Cx43 expressions did not change with age, Cx40 expression was found to deteriorate during ageing. Additionally, EM studies showed significant alterations in mitochondria which increased in size and numbers during ageing. Unlike PVCs, mitochondria in atrial myocytes were enlarged but did not increase in numbers during ageing. Mitochondria in ventricular myocytes did not deteriorate with age. This study also showed that Ca2+ homeostasis in PVCs is disrupted during ageing. PVCs from aged mice had an increased frequency and duration of spontaneous Ca2+ waves, with reduced amplitude, less able to follow electrical pacing and had higher basal ROS levels compared to PVCs from young mice. Additional studies attempted to induce ageing chemically with hydroxyurea (HU) in neonatal rat ventricular myocytes (NRVMs). HU inhibited pacing ability, induced autophagy and increased inducible ROS. Although some changes in chemically ageing model were similar to those in aged PVCs, further studies are needed to fully establish whether HU can induce ageing in NRVMs. In conclusion, this study showed that structural remodelling and Ca2+ homeostasis differs in PVCs during ageing which may facilitate the occurrence of arrhythmias.
Supervisor: Not available Sponsor: Open University (OU)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral