Distinct circadian mechanisms govern rhythms in cardiac electrophysiology and susceptibility to arrhythmia

Abstract

In mammals, cardiac functions, such as heart rate, exhibit pronounced daily rhythms to facilitate the changing energy demands of the body across the day and night. Moreover, potentially fatal cardiac arrhythmias are more likely to occur at certain times of day, with many types of arrhythmia occurring most frequently in the morning hours. Importantly, fluctuations in heart activity are not simply determined by changes in our behavioural state, with recent evidence revealing an important role for the circadian timing system (our internal body clock). The circadian system is hierarchical in nature, orchestrated by a dominant clock within the suprachiasmatic nuclei (SCN) in the hypothalamus, yet influential molecular clocks are located in cells throughout the body, including muscle and pacing cells of the heart (cardiomyocytes). Evidence suggests a role for the cardiomyocyte clock in dictating rhythms in metabolic processes and aspects of ionic conduction. However, it remains unclear how timing information from central (SCN) and local tissue clocks is integrated with changes in behavioural state to impart daily rhythms in electrical properties of the heart and arrhythmia susceptibility; here lies the central objective of this PhD. To examine circadian dynamics in cardiac electrophysiology, we first developed a robust method for automated analysis of longitudinal electrocardiographic (ECG) recordings. Using this approach, we demonstrate in two tightly controlled human laboratory studies that activity at key sites of the cardiac conduction system, namely the sinoatrial (SA) and atrioventricular (AV) nodes, are strongly rhythmic, yet are differentially responsive to behavioural and sleep states. This renders them susceptible to misalignment in response to abrupt changes in behavioural routine. We go on to show that mice exhibit similar conduction dynamics, and define the relative contributions of behavioural state, and central and peripheral clocks in dictating rhythms in electrophysiology. We show that the balance of circadian inputs to the SA and AV nodes differ; while rhythms in SA nodal pacemaking are driven by central and local clocks, and behavioural state, rhythms in AV nodal delay are dictated principally by central clocks via parasympathetic signalling. Remarkably, we observed a time-of-day dependent susceptibility to ventricular tachycardia, and demonstrate that cardiomyocyte clocks drive rhythms in excitability at the cost of increased arrhythmia susceptibility at the start of the active phase. This work reveals fundamental new understanding regarding circadian influences over cardiac physiology.

Date of Award	1 Aug 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Timothy Brown (Supervisor), Andrew Trafford (Supervisor) & David Bechtold (Supervisor)