Circadian rhythms in electrophysiology and pro-arrhythmic activity of pulmonary vein and left atrial cardiomyocytes

Abstract

The burden of atrial fibrillation (AF) in patients demonstrates a night-time preponderance.
Cardiomyocytes in the pulmonary vein (PV) sleeves are a major source of ectopic activity and
are important initiators of AF. The proximal PV at the PV/LA (Left atrium) junction is highly
innervated by the autonomic nervous system (ANS) which is known to play a role in the onset
of AF. Circadian rhythms in the electrophysiology and pro-arrhythmic activity of LA and PV
cardiomyocytes were examined under control conditions and following administration of the
key ANS neurotransmitters, noradrenaline (NA) and acetylcholine (ACh). Male Wistar rats
were sacrificed at 4 time points throughout the 24-hour cycle. (ZT 0,6,12,18). Whole-cell
current clamp, voltage clamp and calcium transient recordings were made from isolated cells
under control conditions and following administration of NA (1 µM) and ACh (1 µM). RNA
sequencing and RT-qPCR were conducted on tissue extracted from the left atrial appendage
(LAA) and proximal PV at the LA/PV junction. Circadian rhythms in the electrophysiology and
proarrhythmic activity in the form of EADs, DADs and TAs (including associated calcium
transients) were demonstrated in LAA and PV cardiomyocytes. The responses to the ANS
neurotransmitters NA and ACh were circadian and showed the greatest effects during the
lights-on resting phase. ACh had a greater effect on LAA than on PV cardiomyocytes whereas
NA had a greater effect on PV than on LAA cardiomyocytes. Automatic activity was observed
in a subpopulation of PV cardiomyocytes following the administration of NA. RNA sequencing
and RT-qPCR demonstrated circadian rhythms in components of the clock and other
transcripts which suggests that LAA and PV cells are intrinsically circadian. Collectively, these
data demonstrate for the first time the existence of circadian rhythms in PV cardiomyocyte
electrophysiology and pro-arrhythmia. Understanding these mechanisms is important in
development of future therapeutic options for AF.

Date of Award	20 Jan 2026
Original language	English
Awarding Institution	University of Bristol
Supervisor	Andrew F James (Supervisor) & Hugh D Piggins (Supervisor)