Circadian rhythms and cardiovascular risk

昼夜节律和心血管风险

• 批准号: 8965062
• 负责人: STEVEN A SHEA
• 金额: $ 50.3万
• 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/8965062
• 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; 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; Relative (related person); 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; public health relevance; 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（适用提供）：不良心血管事件，包括心脏猝死，心肌梗死和心室心律不齐，所有这些事件均在上午9点左右发生最高。在健康的人类中，我们发现我们的内部时钟会导致许多心血管疾病风险标记在此时达到顶峰。这些包括对压力的交感反应，血栓形成或凝块形成的标志物（PAI-1和血小板聚集）以及应力同性皮质醇。正是在这个脆弱的身体时钟时间，人们会遇到行为引起的其他压力：睡眠唤醒，姿势改变和活动增加也会引起许多简历反应。有些人，例如增加交感神经平衡和血液凝结能力，可能对健康的人有益，但代表了容易患有简历疾病的人群的危险因素，例如患有高血压或阻塞性睡眠呼吸暂停（OSA）的危险因素。从简历风险和昼夜节律的角度来看，患有OSA的受试者特别感兴趣，因为OSA增加了对CV疾病的脆弱性，与夜间夜间非浸血血压（BP）的发生率更大有关，并且会导致心肌梗死和突然的心脏梗死和峰值死亡的夜间/夜晚完全不同的白天/夜晚模式。我们的具体目的是确定在休息觉醒期间CV功能中的内源性昼夜节律（AIM 1）以及CV功能对标准压力源的反应性（姿势，锻炼； AIM 2）在未经处理的OSA中受到了与经过连续的正气道（CPAP）和匹配对照的人相比，未经处理的OSA受到干扰。依赖的简历风险标记将包括血液动力学，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的光线在内的恒定环境中在实验室中度过5天。在控制测试之前的行为（例如饭菜或清醒的时间）之前，在内部时钟的所有阶段测试CV功能，受试者将生活在5小时的20分钟20分钟“天”中，在此过程中，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了BP。这项技术将使我们能够从内部时钟，睡眠本身或apneas引起的睡眠中断的影响方面确定与OSA相关的非浸泡BP的原因。我们假设OSA患者将拥有：（i）BP及其调节剂中的昼夜节律阶段，包括儿茶酚胺和皮质醇，以及（ii）关键CV风险标记中有害的昼夜节律放大器。假设这两种效果可以解释OSA中不良CV事件的脆弱性和更早的时间。这项研究将提供第一个证据，证明内部昼夜节律和特定行为应力源对OSA中CV功能的相对作用。通过指出OSA与合并症有关的新型机制，这项研究可能会更好地阐明夜间心肌梗死和猝死，有助于根据一天中的时间导致治疗策略，并最终导致与CV相关的死亡减少。