Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, which is strongly correlated with patients who go on to develop a stroke. AF is thought to be originated in the myocardial sleeve of the pulmonary vein (PV) extending from left atrium (LA). Some studies have shown automaticity activity in PV cardiomyocytes generated by pacemaker-like cells, which can lead to the generation of ectopic activity that initiates AF. Sympathetic and parasympathetic nervous systems play an important role in promoting AF as both a trigger and a substrate. Atrial arrhythmogenic remodelling, defined as any change in atrial structure e.g. mechanical stretch, is considered a critical factor in AF studies. However, the underlying mechanisms for this ectopic activity remain unclear. Thus, the aims of this thesis were to examine the characteristic of cardiomyocytes and nodal cells in the rat PV using Masson's trichrome staining and immunohistochemistry. The role of adrenergic receptors in the PV was investigated with the application of noradrenaline (NA) in a contraction (twitch-tension) study. Moreover, mechanical stretch was also investigated, which changes the electrical activity of the PV potentially leading to the genesis of AF. Histological studies revealed cardiomyocytes extend from LA into the PV, which forms a myocardial sleeve, within which a non-uniform alignment of myocardial fibres was found. Sinoatrial node (SAN) cells were observed in right atrium (RA); however,they were not observed in any area of the rat PV section. Immunohistochemistry was used to identify the expression of HCN4, which is observed in SAN of the RA section but not in the rat PV section. In contractile studies, NA induced ectopic activity in the rat PVs at 37°C, although this ectopic activity decreased when temperature was reduced to 25°C. Increasing extracellular Ca2+ also increased the frequency and the duration of ectopic contractions in the rat PVs. NA-induced ectopic activity in the rat PV was decreased by prazosin, propranolol, carbachol, and verapamil. Mechanical stretch increased the incidence of spontaneous activity but had no effect on the action potential characteristics in rat PV cardiomyocytes. The application of NA increases the incidence of ectopic action potentials, prolongs APD and induces EADs in rat PV cardiomyocytes under a stretch condition. These ectopic action potentials induced bythe combination of stretch and NA were inhibited by gadolinium, ORM-10103, verapamil, prazosin and propranolol in the rat PV myocardium. In conclusion, the PV contains a myocardial sleeve extending from the LA, which is thought to be the source of ectopic electrical activity underlying AF. NA-induced ectopic activity in rat PVs was mediated via α-β-adrenergic receptors, indicating that increased catecholaminergic activity is an important mediator of enhanced automaticity in rat PV cardiomyocytes. Mechanical stretch also induces changes in electrical characteristics, leading to ectopic action potentials in the rat PVs. Stretch activated channels (SACs) may therefore be an important link between stretch and ectopic activity in the PV, potentially acting as a main factor in the development of AF. Thus, autonomic nervous system and structural remodelling in the rat PVs may be considered as an influence on the genesis of arrhythmogenic activity in the development of AF.
|Date of Award||30 Aug 2017|
- University Of Strathclyde
|Supervisor||Edward Rowan (Supervisor) & John Dempster (Supervisor)|