Arrhythmogenesis in the ageing atria

Abstract

Atrial Fibrillation (AF) is rare amongst young people whilst epidemic in the elderly.Whilst much is known about the pathophysiology of AF, the mechanisms underlyingthe vulnerability to AF amongst older people in incompletely understood. Young (8 years, last quintile of life) Welsh mountainsheep 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 correctedsinus node recovery time increased with age, suggesting deteriorating sinus nodefunction. These findings confirmed the validity of sheep as a model for human ageing.In isolated atrial myocytes, action potentials (APs) were recorded using the perforatedpatch clamp technique. AP duration increased with age, and an increase in APamplitude was also seen at the lowest stimulation rates. Right atrial AP durationswere prolonged compared to those from left atrial myocytes, and the inter-atrialdifference was similar between old and young. However, when right atrialmonophasic APs were recorded from anaesthetised sheep in vivo, no difference in APduration was seen between age groups.Alternans occurred at lower stimulation rates in old compared to young myocytes andwas of greater magnitude. These age-related differences were present in isolatedmyocytes and in vivo. Alternans mechanisms were explored by simultaneouslyrecording APs and intracellular calcium concentration. Atrial alternans was driven byalternans of Ca2+ cycling at low stimulation rates. However, despite disabling Ca2+cycling using thapsigargin, alternans could still be elicited from myocytes during rapidstimulation.Right atrial conduction velocity (CV) was assessed in vivo and found to increase withage. A key determinant of CV, the Na+ current INa was investigated using the whole cellpatch clamp technique. INa increased with age in left atrial myocytes and recoveredfaster from inactivation. Protein expression was investigated using Western blotting.Expression of the Na+ channel alpha-subunit did not change with age. The gap junctionprotein 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 theeffects of age have not been thoroughly investigated. The longer cellular APs seenwith age decrease the wavelength of potential re-entrant circuits which could be seenas protective against AF. However, AP prolongation is also associated withafterdepolarisations which could serve to trigger AF. The increase in alternansbehaviour 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 itincreases arrhythmia wavelength, and is likely to be caused by the increased INa.

Date of Award	31 Dec 2015
Original language	English
Awarding Institution	The University of Manchester
Supervisor	David Eisner (Supervisor) & Katharine Dibb (Supervisor)