Circadian rhythms and cardiovascular risk

 描述（由申请人提供）：不良心血管事件，包括心源性猝死、心肌梗死和室性心律失常，均在上午9点左右发生率最高。在健康人群中，我们发现我们的内部生物钟会导致许多心血管（CV）疾病风险标志物在此时达到峰值。这些包括对压力的交感迷走神经反应，血栓形成或凝块形成的标志物（派-1和血小板聚集），以及应激激素皮质醇。正是在这个脆弱的生物钟时间，人们会遇到由行为引起的额外压力：从睡眠中唤醒，改变姿势，增加活动也会引起许多CV反应。一些，如交感神经-迷走神经平衡和血液凝固性增加，可能对健康人群有益，但在易患心血管疾病的人群中代表风险因素，如高血压或阻塞性睡眠呼吸暂停（OSA）人群。从CV风险和昼夜节律的角度来看，OSA受试者特别值得关注，因为OSA增加了对CV疾病的易感性，与危险性夜间非下降血压（BP）的发生率较高相关，并导致心肌梗死和心源性猝死发生率的完全不同的日/夜模式-峰值在夜间而不是早晨。我们的具体目标是确定与接受持续气道正压通气（CPAP）治疗的患者和匹配对照组相比，未接受治疗的OSA患者在休息觉醒期间CV功能（目标1）和CV功能对标准化应激源（姿势、运动;目标2）的反应性中的内源性昼夜节律是否受到干扰。依赖性CV风险标志物将包括血流动力学、止血、自主神经系统活动、内皮功能和氧化应激指标。为了记录昼夜节律，受试者将在实验室中在包括昏暗光线的恒定环境中度过5天。为了在内部时钟的所有阶段测试CV功能，同时控制测试前的行为，例如进餐或清醒时间的持续时间，受试者将生活在重复的5小时20分钟“天”中，在此期间行为受到严格控制。在这样的协议中，我们在睡眠期间连续测量血压。这项技术将使我们能够确定阻塞性睡眠呼吸暂停相关的非下降血压的原因，从内部生物钟，睡眠本身或呼吸暂停引起的睡眠中断的影响。我们假设OSA患者将具有：（i）BP及其调节因子（包括儿茶酚胺和皮质醇）的异常提前昼夜节律相位，以及（ii）关键CV风险标志物的有害昼夜节律幅度。假设这两种效应可以解释OSA患者的易感性增加和不良CV事件发生时间提前。这项研究将提供第一个证据的相对作用，内部昼夜节律和特定的行为压力对CV功能的阻塞性睡眠呼吸暂停。通过指出OSA与其合并症相关的新机制，这项研究可能会更好地揭示夜间心肌梗死和心源性猝死，有助于制定基于一天中时间的治疗策略，并最终减少CV相关死亡。

 DESCRIPTION (provided by applicant): Adverse cardiovascular events, including sudden cardiac death, myocardial infarction and ventricular arrhythmias all have their highest incidence around 9 AM. In healthy humans, we discovered that our internal body clock causes many cardiovascular (CV) disease risk markers to peak at this time. These include sympatho-vagal responses to stress, markers of thrombosis or clot formation (PAI-1 and platelet aggregation), and the stress hormone cortisol. It is precisely at this vulnerable body clock time that people encounter additional stresses elicited by behaviors: arousal from sleep, altered posture, and increased activity also induce numerous CV responses. Some, such as increased sympatho-vagal balance and blood coagulability, might be beneficial in healthy people but represent risk factors in populations vulnerable to CV disease, such as those with hypertension or obstructive sleep apnea (OSA). Subjects with OSA are of particular interest from both CV risk and circadian rhythms perspectives because OSA increases vulnerability to CV disease, is associated with greater incidence of a perilous nocturnal non-dipping blood pressure (BP), and leads to completely different day/night patterns in incidence of myocardial infarction and sudden cardiac death - with peaks during the night rather than the morning. Our specific aims are to determine if endogenous circadian rhythms in CV function during rested wakefulness (Aim 1) and in the reactivity of CV function to standardized stressors (posture, exercise; Aim 2) are disturbed in people with untreated OSA compared to people treated with continuous positive airway pressure (CPAP) and matched controls. Dependent CV risk markers will include measures of hemodynamics, hemostasis, autonomic nervous system activity, endothelial function, and oxidative stress. To document circadian rhythms, subjects will spend 5 days in a laboratory in a constant environment including dim light. To test CV function at all phases of the internal clock while controlling for behaviors that precede the tests, such as meals or the duration of time awake, subjects will live on recurring 5 hour 20 minute `days' during which behavior is tightly controlled. In protocols like this, we have measured BP continuously during sleep. This technique will allow us to determine the causes of OSA-associated non-dipping BP in terms of effects from the internal body clock, sleep itself, or the sleep disruptions caused by apneas. We hypothesize that people with OSA will have: (i) abnormally advanced circadian phase in BP and its regulators including catecholamines and cortisol, and (ii) deleterious circadian amplitudes in key CV risk markers. These two effects are hypothesized to explain the increased vulnerability and earlier timing of adverse CV events in OSA. This study will provide the first evidence of the relative role of internal circadian rhythms and specific behavioral stressors on CV function in OSA. By pointing to novel mechanisms by which OSA is linked to its comorbidities, this study may shed better light on nocturnal myocardial infarction and sudden cardiac death, help lead to treatment strategies based on time of day, and ultimately lead to a reduction in CV-related deaths.