Abstract 493: An Age-associated Reduction in Na V 1.5 Protein Expression Correlates With an Increase in Na V 1.8 Protein Expression in the Right Atrial Appendage of the Human Heart

Abstract

Background: Na v 1.5 is the predominantly expressed voltage-gated sodium channel (VGSC) isoform in the heart, responsible for phase 0 of the action potential. Our rodent studies have shown expression of neuronal isoform Na v 1.8 protein in the adult heart. Others have associated Na v 1.8 expression with aberrant sodium currents leading to increased frequency of arrhythmogenic episodes. Aim: To investigate age-associated changes in the protein expression of VGSCs Na v 1.5 and Na v 1.8 in the right atrial appendage of the human heart. Methods: Tissues from the right atrial appendage were obtained with NHS ethical approval (IRAS 197493) from patients undergoing routine cardiac surgery, coronary artery bypass or valve repair. The protein expression of VGSC isoforms Na v 1.5 and Na v 1.8 were quantified using specific protein-directed primary antibodies (Alomone, Israel) coupled with a secondary antibody conjugated to HRP for western blot (Abcam, UK), or Alexa Fluor 488 (ThermoFisher, UK) for immunohistochemistry with confocal microscopy (LSM 710 Zeiss, UK). Densities were quantified using Image J software. Results: Derived from 26 patients, the protein expression of Na v 1.5 arranged in chronological age order (43-87 years of age) demonstrated a negative correlation between increasing age and Na v 1.5 protein expression (Pearson correlation coefficient of -0.25). The contrary was shown for Na v 1.8, which had a positive correlation with increasing age (Pearson correlation coefficient of 0.26), as older patients show increased Na v 1.8 protein expression. This novel finding was reflected when we compared confocal images from elderly patients with their younger counterparts, as the elderly showed a higher density of labelled Na v 1.8 protein and a lower density of labelled Na v 1.5 protein, particularly located at the t-tubules and intercalated disks. Conclusion: With increasing chronological age, the human heart reduces expression of the predominant cardiac isoform Na v 1.5 whilst increasing the expression of Na v 1.8: This finding has the potential to increase the risk of an elderly person’s heart to an increased susceptibility of arrhythmias.