Age-Associated Changes in Voltage-Gated Sodium Channels Within the Right Atrium Predispose the Elderly to Atrial Fibrillation

Isaac, Emmanuel Salib

Abstract

Atrial Fibrillation (AF) is the most common cardiac arrhythmia worldwide with sufferers of the condition facing significant morbidity and mortality. Ageing alone is identified as the most significant risk factor for developing the arrhythmia. As such, an ageing global population has, and will continue to give rise to a marked prevalence of AF, placing enormous pressure on healthcare systems around the world. Ionic remodelling of sodium channels has been observed in animal studies with regards to the ageing process which drive the arrhythmogenic pathology, with parallel observations made with regards to AF. This study will examine, and potentially unify, the narratives of ionic remodelling in AF and ageing, focusing specifically on the expression of two voltage-gated sodium channel (VGSC) isoforms within the human heart; Nav1.5 & Nav1.8. The former being the native cardiac isoform and principal driver for phase 0 of the action potential, and the latter a neuronal isoform implicated in pathological late currents which predispose the cardiomyocyte to electrical instability. This study involved sampling human right atrial appendage from patients undergoing routine cardiac surgery at Castle Hill Hospital.
With increasing age, expression of Nav1.5 declined with a Pearson’s correlation coefficient of -0.25. Comparing the extremes in age of these samples, protein expression was decreased by 18.8% in the older group (P=0.18). The inverse trend was noted with regards to Nav1.8 with a positive correlation of +0.259. When comparing the extremes of age an increase of 32% was observed (P=0.039). These results suggest that the ageing process remodels the human heart in a manner which diminishes the capacity for sodium ion influx critical for conduction during action potential upstroke, meanwhile upregulating ion channels which enhance the aberrant late currents. To investigate the ionic landscape of cardiac tissue in AF, patients with the arrhythmia were matched on age with patients in sinus rhythm. AF patients were found to have significantly reduced expression of Nav1.5 (P=<0.05). These results suggest that the loss of native cardiac sodium channels may be a key step in the pathophysiology of cardiac arrhythmia in humans, and a process in which the ageing heart undergoes which underpins development of AF.
In order to investigate the precise mechanics modulating the ionic redistribution observed, this study examined the role JNK may have as a potential regulator of sodium channel expression in the human heart. JNK has been suggested as having a strong influence in the expression of other ion channel proteins-specifically Cx43. Total expression of JNK was found to be 56 % greater in the oldest population compared to younger patients (P=0.05). Examination of the direct role increased levels of JNK may have on VGSC expression was investigated using pharmacological manipulation of this pathway through Anisomycin (JNK activator) and SP600125 (JNK inhibitor). Subjectively, it has been noted that inhibition of JNK markedly reduced the expression of Nav1.8, whereas upregulation of this protein seemed to increase the density of expression of the neuronal isoform.

Citation

Isaac, E. S. Age-Associated Changes in Voltage-Gated Sodium Channels Within the Right Atrium Predispose the Elderly to Atrial Fibrillation. (Thesis). Hull York Medical School. https://hull-repository.worktribe.com/output/4508137

• Thesis Type: Thesis
• Deposit Date: Jan 9, 2024
• Publicly Available Date: Jan 9, 2024
• Keywords: Medicine
• Public URL: https://hull-repository.worktribe.com/output/4508137
• Additional Information: Hull York Medical School; University of Hull and University of York
• Award Date: Nov 1, 2022