Sleep and circadian mechanisms in hypertension

项目摘要 高血压（HTN）是美国发病率和死亡率的主要原因， 45%的美国成年人。血压（BP）在白天几乎总是较高;然而， 夜间血压比日间血压更能预测总体CV风险。一般来说，HTN患者被分类为 分为：（1）下降，其中夜间平均血压较日间平均值下降≥10%;和（2）非下降， 平均夜间血压不会下降10%。超过30%的HTN患者有非浸渍 血压特征，与不良结局（包括终末器官）风险显著增加相关 损伤和死亡率。目前还不清楚是什么原因导致非浸渍HTN，但 昼夜节律系统和睡眠可能起作用，因为这两个系统都影响BP的昼夜变化。我们 目的是确定未经治疗的HTN患者体内昼夜节律系统的单独作用 和睡眠与非下降血压曲线和相关CV变量的日/夜变异性之间的关系，包括 估计交感神经和副交感神经活性、肾素-血管紧张素-醛固酮系统活性，以及 血管内皮功能 我们的具体目标是确定：1）血压的昼夜节律是否在非倾斜HTN中改变，2） 在非浸渍HTN中的睡眠。我们假设：1）血压昼夜节律改变，在非浸渍相比， 降低HTN，导致夜间血压下降减少; 2）睡眠持续时间在非浸渍比 浸渍HTN，和3）睡眠的缺乏减弱浸渍HTN比非浸渍过夜血压下降 HTN。一个探索性的目的是确定两周的睡眠规律是否会增加夜间血压下降。 32名受试者（16名杓型、16名非杓型、16名女性和16名男性）将参与所有研究。我们将 首先在参与者的家中使用无人值守的多导睡眠图来量化睡眠持续时间。第二，我们将揭开 采用40小时恒定常规方案，监测所有参与者的血压昼夜节律 在实验室中，在不间断的休息清醒状态下，以半卧位姿势，昏暗的光线， 时间线索第三，我们将在实验室昏暗的灯光下进行随机交叉试验， 睡眠是允许的，还是不允许的。在昼夜节律研究中连续测量BP和机械CV标志物， 交叉试验在交叉试验中，我们还将使用显微神经造影术测量交感神经活动， 试验当天的24小时血压。最后，我们将试点测试两周的睡眠规律化时间表，包括 保持一个自我选择的就寝时间，以其对夜间血压下降的影响。 这些高度受控的实验将使我们能够记录昼夜节律系统的不同作用， 睡在不沾水的HTN里了解潜在的CV机制将提供潜在的药理学 HTN循证时间疗法的目标。了解睡眠的作用将为未来提供 有机会正式测试睡眠延长或规律化作为非浸渍HTN的行为疗法。

Project Summary Hypertension (HTN) is a leading cause of morbidity and mortality in the United States and affects approximately 45% of US adults. Blood pressure (BP) is almost invariably higher during the day; however, the relative drop in overnight BP is a better predictor of overall CV risk than daytime BP. Generally, patients with HTN are classified into: (1) dipping, where the average nighttime BP drops by ≥10% from the daytime average; and (2) non-dipping, where the average nighttime BP does not dip by 10%. More than 30% of patients with HTN have a non-dipping BP profile, which is associated with a significantly increased risk for adverse outcomes, including end-organ damage, and mortality, compared to patients with dipping HTN. It is unclear what causes non-dipping HTN, but the circadian system and sleep likely play a role because both systems affect the day-night variation in BP. Our goal is to determine, in patients with untreated HTN, the separate contributions of the internal circadian system and sleep to the non-dipping BP profile and the day/night variability in associated CV variables, including estimates of sympathetic and parasympathetic activity, renin-angiotensin-aldosterone system activity, and vascular endothelial function. Our specific aims are to determine: 1) if circadian rhythms in BP are altered in non-dipping HTN and 2) the role of sleep in non-dipping HTN. We hypothesize that: 1) BP circadian rhythms are altered in non-dipping compared to dipping HTN, resulting in a reduced nocturnal BP decline; 2) sleep duration is shorter in non-dipping than dipping HTN, and 3) the absence of sleep attenuates overnight BP drop in dipping HTN more than non-dipping HTN. An exploratory aim is to determine if two weeks of sleep regularization increases overnight BP dipping. Thirty-two participants (16 dippers, 16 non-dippers, 16 females, and 16 males) will partake in all studies. We will first quantify sleep duration using unattended polysomnography in participants’ homes. Second, we will uncover circadian rhythms in BP by employing a 40-h constant routine protocol, where all participants will be monitored in the laboratory during uninterrupted rested wakefulness in a semi-recumbent posture, dim light, and without time cues. Third, we will conduct a randomized crossover trial in dim light in the laboratory, during which overnight sleep is permitted or not. BP and mechanistic CV markers are continuously measured in the circadian study and the crossover trial. In the crossover trial, we will also measure sympathetic activity using microneurography and 24-h BP on the days of the trials. Finally, we will pilot test a two-week sleep regularization schedule, including maintaining a self-selected bedtime, to its impact on overnight BP dipping. These highly controlled experiments will enable us to document the separate roles of the circadian system and sleep in non-dipping HTN. Understanding underlying CV mechanisms will provide potential pharmacological targets for evidence-based chronotherapy in HTN. Understanding the role of sleep will provide future opportunities to formally test sleep extension or regularization as behavioral therapies for non-dipping HTN.