Circadian and behavioral factors of cardiovascular risk

描述（由申请人提供）：大量流行病学研究已经证实，上午9点左右不良心血管事件（如心源性猝死、心肌梗死）的发生频率高得不成比例。这种机制被粗略地归因于一天中特定时间发生的行为压力源（例如，姿势或活动的改变）。但是，人体内部时钟（昼夜节律起搏器）在这种昼夜模式中的独立作用从未被适当的技术研究过。我们的初步数据显示，在一些心血管风险标志物中存在明显的内源性昼夜节律，这可能与心血管不良事件的昼夜模式有关。因此，我们有两个具体的目标：(1)确定昼夜节律起搏器对心血管危险标志物的影响（独立于行为）；(2)确定昼夜节律和行为对心血管危险指标的影响之间的相互作用（即行为应激源在不同昼夜节律阶段产生不同影响的相互作用）。为了实现这些目标，我们将采用为期12天的强化“强制去同步”方案，其中受试者的标准化行为和睡眠发生在昼夜节律周期的所有阶段。由于这将是该领域的首次正式研究，我们将从研究健康个体开始，以确定可能涉及心血管风险昼夜模式的正常人类生理节律和反应。在治疗过程中，标准化的行为压力源包括姿势（倾斜桌子）、活动（骑自行车运动）和睡眠/清醒状态的改变。在易感个体中可能涉及触发不良心血管事件的措施包括：(i)自主神经系统活动（儿茶酚胺，交感神经-迷走神经平衡）；（ii）血流动力学因素（心率、血压）；（iii）止血因子（血小板聚集性和计数）；（iv）血管内皮功能（血流介导的血管舒张）。根据初步数据，我们预计行为压力源将在昼夜节律周期的特定阶段产生不同的影响，揭示某些行为的脆弱时间（可能与流行病学研究中心血管脆弱性的峰值相对应）。这个项目可能最终帮助我们在行为改变和定时药物干预方面合理化心血管疾病的时间生物学治疗。

DESCRIPTION (provided by applicant): Numerous epidemiological studies have established that there is a disproportionately high frequency of adverse cardiovascular events around 9 AM (e.g., sudden cardiac death, myocardial infarction). The mechanisms have been loosely attributed to behavioral stressors occurring at specific times of day (e.g., change in posture or activity). But, the independent role of the internal body clock (circadian pacemaker) in this day/night pattern has never been studied with appropriate techniques. Our preliminary data show a marked endogenous circadian rhythm in some markers of cardiovascular risk that may be implicated in the day/night pattern of adverse cardiovascular events. Thus, we have two Specific Aims: (1) Determine the effect upon cardiovascular risk markers of the circadian pacemaker (independent from behaviors); (2) Determine the interaction between circadian and behavioral influences upon cardiovascular risk markers (i.e., an interaction by which behavioral stressors have different effects at different circadian phases). To achieve these aims, we will utilize an intensive 12-day "Forced Desynchrony" protocol, wherein subjects' standardized behaviors and sleep occur at all phases of the circadian cycle. As this will be the first formal study in this area, we will begin by studying healthy individuals to define the normal human physiological rhythms and responses that could be implicated in the day/night pattern of cardiovascular risk. During the protocol standardized behavioral stressors include changes in posture (tilt table), activity (bicycle exercise) and sleep/wake state. The measures that can be implicated in triggering adverse cardiovascular events in vulnerable individuals, will include (i) autonomic nervous system activity (catecholamines, sympatho-vagal balance); (ii) hemodynamic factors (heart rate, blood pressure); (iii) Hemostatic factors (platelet aggregability and count); and (iv) vascular endothelial function (flow mediated vasodilatation). Based on preliminary data, we anticipate that behavioral stressors will have different effects at specific phases of the circadian cycle revealing vulnerable times for certain behaviors (likely corresponding to the peak in cardiovascular vulnerability from epidemiological studies). This project may ultimately help us to rationalize chronobiological therapies for cardiovascular diseases in terms of modification of behavior and timed pharmacological intervention.