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Title: Arrhythmogenesis in the ageing atria
Author: Pearman, Charles
ISNI:       0000 0004 7429 6596
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2015
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Atrial Fibrillation (AF) is rare amongst young people whilst epidemic in the elderly. Whilst much is known about the pathophysiology of AF, the mechanisms underlying the vulnerability to AF amongst older people in incompletely understood. Young (< 18 months, first quintile of life) and old (> 8 years, last quintile of life) Welsh mountain sheep were used to investigate changes in atrial electrophysiology with age. Old sheep were more vulnerable to induced AF than young sheep. On the surface ECG, p-wave duration increased with age suggesting increasing atrial size. The corrected sinus node recovery time increased with age, suggesting deteriorating sinus node function. These findings confirmed the validity of sheep as a model for human ageing. In isolated atrial myocytes, action potentials (APs) were recorded using the perforated patch clamp technique. AP duration increased with age, and an increase in AP amplitude was also seen at the lowest stimulation rates. Right atrial AP durations were prolonged compared to those from left atrial myocytes, and the inter-atrial difference was similar between old and young. However, when right atrial monophasic APs were recorded from anaesthetised sheep in vivo, no difference in AP duration was seen between age groups. Alternans occurred at lower stimulation rates in old compared to young myocytes and was of greater magnitude. These age-related differences were present in isolated myocytes and in vivo. Alternans mechanisms were explored by simultaneously recording APs and intracellular calcium concentration. Atrial alternans was driven by alternans of Ca2+ cycling at low stimulation rates. However, despite disabling Ca2+ cycling using thapsigargin, alternans could still be elicited from myocytes during rapid stimulation. Right atrial conduction velocity (CV) was assessed in vivo and found to increase with age. A key determinant of CV, the Na+ current INa was investigated using the whole cell patch clamp technique. INa increased with age in left atrial myocytes and recovered faster from inactivation. Protein expression was investigated using Western blotting. Expression of the Na+ channel α-subunit did not change with age. The gap junction protein Cx43 was expressed less in older subjects, but Cx40 expression was similar. This work has cast light on several aspects of atrial electrophysiology in which the effects of age have not been thoroughly investigated. The longer cellular APs seen with age decrease the wavelength of potential re-entrant circuits which could be seen as protective against AF. However, AP prolongation is also associated with afterdepolarisations which could serve to trigger AF. The increase in alternans behaviour may set the stage for wavebreak, leading to re-entrant circuit formation. The increase in CV was surprising and might be seen as protective against AF as it increases arrhythmia wavelength, and is likely to be caused by the increased INa.
Supervisor: Eisner, David ; Dibb, Katharine Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Conduction Velocity ; Alternans ; Atrial Fibrillation ; Ageing