Rhythms in the beat: Circadian Clock Regulation of Cardiac Electrophysiology

每年，英国都有数以百万计的人遭遇心律失常。鉴于心律失常是心血管相关死亡的主要原因，了解导致心律失常发生的遗传、生物和生活方式因素显然是及时和重要的。众所周知，不良心脏事件和心律失常更有可能在一天中的某些时间发生。最近的研究表明，心脏在其功能中表现出固有的每日节律，这不仅仅是我们行为的结果(夜间睡眠和低心率，白天高活动和心率)。相反，这种节奏在一定程度上是由身体内部的生物钟(昼夜节律)系统驱动的，该系统由位于大脑和外周器官(包括心脏)的时钟网络组成。然而，昼夜节律系统是如何与心脏功能相联系的还不是很清楚。我们认为，心脏内的局部时钟，特别是在心脏传播电信号的部分(心脏传导系统)，对一天中的心脏反应和对扰动的反应产生强烈的影响。我们最近的工作表明，在老鼠和人类中，时钟的影响在整个传导系统中并不是一致的(对于高度耦合的系统来说是意外的)，心脏传导受到影响人体时钟的范例的干扰。此外，我们首次提供证据表明，心脏本身(即心脏本身的一种属性，而不是对行为或系统因素的变化做出反应)在一天中的特定时间更容易发生心律失常。这些发现对心血管健康具有重要意义，特别是考虑到昼夜节律紊乱(与倒班工作、夜间光线、衰老等有关)。在我们的现代社会中很常见。在更基本的层面上，我们和其他人的发现表明，我们大脑和心脏中的生物钟对心脏功能非常重要。了解不同时钟的作用以及它们在心脏内的相互作用，对于深化我们对心血管生理学的理解至关重要。为了解决昼夜生物学和心脏功能的这些重要方面，我们将使用独特的小鼠模型，允许大脑、心脏或整个身体的时钟被选择性地关闭。通过研究这些模型中的心脏传导，我们可以揭示体内不同的时钟如何帮助调节心脏罕见(HR)和传导，并确定一天中不同时间心脏功能的差异。我们还将确定体内的时钟如何帮助(或阻碍)心脏处理破坏性事件的能力，例如日常光暗(LD)周期的突然变化和改变的进食时间表(类似于倒班工作的经历)。我们还将直接测试心脏的电反应和基因表达在一天中的不同时间以及时钟被禁用时的不同。由于我们的试点工作表明时钟确实对心脏功能有很大的影响，我们将确定心脏时钟本身是否受到LD环境的快速变化的干扰，以及副交感神经系统(大脑引导心脏活动的主要途径)中是否存在时钟功能。最后，我们将确定破坏性行为模式(模仿轮班工作)是否会增加心脏发生电子故障的可能性。这些研究将极大地促进我们对心脏生理学的理解，并让公众、医疗保健部门和监管机构了解我们的行为、社交和工作惯例如何影响我们的心脏。这项工作还可能打开潜在的新的治疗选择，以药理学或非药理学(例如，用光)的生物钟为目标。

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).