Circadian rhythms and cardiovascular risk

昼夜节律和心血管风险

• 批准号: 9109679
• 负责人: STEVEN A SHEA
• 金额: $ 68.29万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109679
• 关键词: Adult; Adverse event; Affect; Age; Aldosterone; Apnea; Arousal; Autonomic nervous system; Behavior; Behavior Control; Behavioral; Biological; Biological Clocks; Blood; Blood Platelets; Blood Pressure; Blood coagulation; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Catecholamines; Cessation of life; Chronotherapy; Circadian Rhythms; Coagulation Process; Comorbidity; Continuous Positive Airway Pressure; Data; Development; Dilatation - action; Environment; Epinephrine; Equilibrium; Event; Exercise; General Population; Health; Heart Rate; Hemostatic function; Hormones; Hour; Human; Hydrocortisone; Hypertension; Incidence; Laboratories; Lead; Life; Light; Link; Malondialdehyde; Measures; Mediating; Modeling; Myocardial Infarction; Norepinephrine; Obesity; Obstructive Sleep Apnea; Outcome; Oxidative Stress; P-Selectin; Patients; Pattern; Periodicity; Pharmaceutical Preparations; Phase; Physiology; Plasma; Plasminogen Activator Inhibitor 1; Plasminogen Inactivators; Platelet Activation; Platelet aggregation; Play; Population; Posture; Predisposition; Protocols documentation; Rest; Risk Factors; Risk Marker; Role; Schedule; Sleep; Sleep Apnea Syndromes; Sleep Wake Cycle; Stress; Surface; System; Techniques; Testing; Thrombosis; Thrombus; Time; Ventricular Arrhythmia; Vulnerable Populations; Wakefulness; Withdrawal; age group; awake; base; cardiovascular disorder risk; cardiovascular risk factor; clinically relevant; heart rate variability; hemodynamics; indexing; interest; novel; research study; response; sex; stressor; sudden cardiac death; treatment strategy

 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.

 描述(申请人提供)：心血管不良事件，包括心脏性猝死、心肌梗死和室性心律失常，都在上午9点左右出现最高发生率。在健康的人类中，我们发现我们体内的生物钟导致许多心血管疾病的风险标记物在这个时候达到峰值。这些包括对压力的交感迷走神经反应，血栓形成或血栓形成的标记物(PAI-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发的额外压力：睡眠唤醒、姿势改变和活动增加也会引发大量的CV反应。一些因素，如增加交感神经-迷走神经平衡和血液凝固性，可能对健康人有益，但在易患心血管疾病的人群中代表着危险因素，如高血压或阻塞性睡眠呼吸暂停(OSA)患者。从心血管风险和昼夜节律的角度来看，OSA患者特别感兴趣，因为OSA增加了心血管疾病的易感性，与危险的夜间非低血压(BP)的发生率相关，并导致心肌梗死和心脏性猝死的发生率完全不同的昼夜模式--高峰在夜间而不是早上。我们的具体目标是确定与接受持续气道正压治疗(CPAP)和匹配的对照组相比，未经治疗的阻塞性睡眠呼吸暂停患者在静息清醒时(目标1)的心血管功能的内源性昼夜节律是否受到干扰，以及心血管功能对标准化应激源(姿势、运动；目标2)的反应性是否受到干扰。相关的心血管风险标记物将包括血液动力学、止血、自主神经系统活动、内皮功能和氧化应激的测量。为了记录昼夜节律，受试者将在包括昏暗光线在内的恒定环境中在实验室中度过5天。为了测试体内生物钟所有阶段的CV功能，同时控制测试前的行为，如进餐或清醒的时间，受试者将在行为受到严格控制的重复出现的5小时20分钟“天”中存活。在这样的方案中，我们在睡眠期间连续测量血压。这项技术将使我们能够从体内生物钟、睡眠本身或呼吸暂停引起的睡眠中断的影响方面确定与OSA相关的非降压的原因。我们假设OSA患者将有：(I)BP及其调节因子(包括儿茶酚胺和皮质醇)的昼夜节律异常提前，以及(Ii)关键心血管风险标记物的有害昼夜节律幅度。假设这两种影响是为了解释OSA中不良心血管事件的易感性增加和更早发生的时间。这项研究将首次提供内部昼夜节律和特定行为应激源对阻塞性睡眠呼吸暂停综合征患者心血管功能的相对作用的证据。通过指出OSA与其共病相关的新机制，这项研究可能会更好地揭示夜间心肌梗死和心脏性猝死，帮助制定基于一天中不同时间的治疗策略，并最终减少与心血管相关的死亡。