Rhythms in the beat: Circadian Clock Regulation of Cardiac Electrophysiology

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Each year, millions of people in the UK experience heart rhythm problems (arrhythmias). Given that cardiac arrhythmias are a leading cause of cardiovascular-related deaths, understanding the genetic, biological, and lifestyle factors which contribute to the occurrence of cardiac arrhythmias is clearly timely and important. It is well-established that adverse cardiac events and arrhythmias are more likely to occur at certain times of the day. Recent work has demonstrated that the heart exhibits an inherent daily rhythm in its function, which is not simply a consequence of our behaviour (sleep and low heart rate at night, high activity and heart rate in the day). Rather this rhythm is in part driven by the body's internal clock (circadian) system, which consists of a network of clocks located in the brain and peripheral organs (including the heart). However, how the circadian system is coupled to heart function is not well understood. We believe that a local clock within the heart, and specifically within the parts of the heart which propagate electrical signals (the cardiac conduction system), exerts a strong effect on cardiac responses across the day and in response to perturbation. Our recent work demonstrates that in mice and humans, influence of the clock is not uniform across the conduction system (unexpected for a highly coupled system), and that cardiac conduction is disturbed by paradigms that affect the body's clocks. Moreover, we provide evidence for the first time that the heart is inherently (i.e. a property of the heart itself, not in response to changes in behaviour or systemic factor) more vulnerable to arrhythmias at specific times of day. These findings have an important implication for cardiovascular health, especially given that circadian disruption (linked to shift work, light at night, aging, etc.) is common within our modern society. On a more fundamental level, our findings and that of others demonstrates that the circadian clocks in our brain and heart are important for cardiac function. Understanding the role of different clocks and how they interact within the heart, is critical to deepening our understanding of cardiovascular physiology.To address these important aspects of circadian biology and cardiac function, we will use unique mouse models that allow clocks within the brain, the heart, or throughout the body to be selectively turned off. By studying cardiac conduction in these models, we can unravel how different clocks in the body help regulate heart rare (HR) and conduction, and define differences in heart function at different times of the day. We will also determine how clocks in the body help (or hinder) the heart's ability to deal with disruptive events, such as sudden shifts in the daily light-dark (LD) cycle and altered feeding schedules (similar to experiences of shift work). We will also test directly how the heart's electrical responses and gene expression differ at different times of day, and when the clock has been disabled. Since our pilot work indicates that the clock does indeed have a strong impact on heart function, we will determine whether the heart clock itself is disturbed by rapid changes in the LD environment, and whether clock function exists within the parasympathetic nervous system (a primary route through which the brain directs heart activity). Finally, we will determine whether disruptive behaviour patterns (mimicking rotating shift work) can increase the likelihood of electrical malfunction in the heart.Together, these studies will greatly advance our understanding of cardiac physiology and inform the general public, health care sector and regulatory bodies with regard to how our behavioural, social and work routines can impact our heart. The work may also open potential new therapeutic options which target the body clock pharmacologically or non-pharmacologically (e.g. with light).