Endogenous circadian mechanisms underlying cardiovascular risk

心血管风险的内源性昼夜节律机制

• 批准号: 10656183
• 负责人: STEVEN A SHEA
• 金额: $ 92.4万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656183
• 关键词: Adrenergic Agents; Adult; Adverse event; Affect; Autonomic nervous system; Behavior; Behavioral; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cells; Circadian Rhythms; Clinical; Clinical Research; Discipline of Nursing; Drug Targeting; Equilibrium; Event; Exercise Physiology; Funding; Grant; Heart; Human; Hypertension; Individual; Lead; Left ventricular structure; Medicine; Myocardial Infarction; Obstructive Sleep Apnea; Paper; Pattern; Physiological; Population; Positron-Emission Tomography; Posture; Predisposition; Protocols documentation; Publications; Research; Research Personnel; Rest; Risk; Risk Factors; Services; Sleep; Stress; Stroke; System; Time; Tissues; United States National Institutes of Health; Variant; Work; cardiovascular disorder risk; cardiovascular disorder therapy; cardiovascular risk factor; circadian; circadian pacemaker; experience; improved; laboratory experiment; middle age; multidisciplinary; postsynaptic; preclinical study; presynaptic; programs; response; stressor; sudden cardiac death; tool

PROJECT SUMMARY/ABSTRACT Endogenous circadian clocks exist in all cells and tissues, including the autonomic nervous system, heart, and vasculature. The resultant rhythms prepare the cardiovascular (CV) system for optimal function to match the daily anticipated behavioral and environmental cycles, such as altered posture and increased activity after awakening in the morning. However, the morning is also the most vulnerable time for adverse CV events, including myocardial infarction, stroke and sudden cardiac death. Dr. Shea has pioneered the use of intensive, multi-day laboratory experiments and uncovered substantial endogenous circadian rhythms across the CV system in healthy humans. Dr. Shea also discovered that circadian rhythms exist in the CV reactivity to stressors (i.e., there are different CV responses to identical stressors at different times of day). Dr. Shea’s work has led to the concept that circadian rhythms in the CV system act as a ‘double-edged sword’: the normal amplified responses in the morning aid the transition from sleep to activity in healthy individuals, but such exaggerated responses are potentially perilous in individuals with underlying CV risk factors who are susceptible to adverse events. Dr. Shea will lead a multi-disciplinary team of outstanding investigators to examine the broad question of how the circadian system interacts with behavior-related CV responses to produce predictable daily variations in CV risk profiles. To compare with healthy controls, studies will be performed in populations with increased underlying susceptibility to CV disease, such as hypertension, midlife adults, and obstructive sleep apnea. The overall team has expertise in circadian, sleep, stress, exercise and CV physiology, and positron emission tomographic imaging of the balance of pre- and post-synaptic adrenergic function in the left ventricle in resting humans. The investigators will use outstanding purpose-built facilities to perform the necessary intensive, multi- day studies with nursing, bio-nutrition and clinical support services integrated with the team’s physiological expertise. Dr. Shea has >30 years’ experience performing clinical research mainly focused on circadian rhythms in healthy humans and their impact on CV disease risk factors, and he has performed the majority of the CV physiology studies in humans that use validated circadian protocols. Dr. Shea has been well-funded with 25 consecutive years as PI of investigator-initiated federal grants. Dr. Shea’s publications are well-cited with a mean relative citation ratio of 3.84 for original research papers in the past decade [2009-18], which is higher than the 90% percentile for all NIH-funded papers in the same field [NIH Office of Portfolio Analysis: iCite Tool]). Due to the fast emerging recognition of the magnitude and extent of circadian rhythms throughout the body, including circadian rhythms in drug targets, we are on the cusp of meaningful chronotherapeutic trials in CV medicine that consider internal circadian time. These preclinical studies performed in this Research Program will provide the critical and timely background needed to fully exploit these opportunities to improve therapy of CV disease.

项目摘要/摘要 内源性生物钟存在于所有细胞和组织中，包括自主神经系统、心脏和 脉管系统。由此产生的节律使心血管(CV)系统准备好最佳功能，以匹配 每天预期的行为和环境周期，如姿势改变和术后活动增加 在清晨醒来。然而，上午也是不利的简历事件最容易发生的时候， 包括心肌梗塞、中风和心脏性猝死。谢伊博士率先使用了密集的， 多天的实验室实验和发现了跨CV的大量内源性昼夜节律 在健康人类中的系统。谢伊博士还发现，简历对应激源的反应存在昼夜节律 (即，在一天中的不同时间，对相同的压力源有不同的简历反应)。谢伊博士的研究已经导致 CV系统中的昼夜节律就像一把“双刃剑”：放大的正常 早晨的反应有助于健康人从睡眠到活动的转变，但这种反应夸大其词 对于具有潜在的CV风险因素的个人来说，反应是潜在的危险，他们容易受到不利因素的影响 事件。谢伊博士将领导一个由杰出研究人员组成的多学科团队来研究这个广泛的问题 昼夜节律系统如何与行为相关的CV反应相互作用以产生可预测的日变化 在简历风险配置文件中。为了与健康对照组相比，研究将在增加的人群中进行 对心血管疾病的潜在易感性，如高血压、中年成年人和阻塞性睡眠呼吸暂停。这个 整个团队在昼夜节律、睡眠、压力、运动和心血管生理学以及正电子发射方面都有专长。 静息状态下左室突触前、后肾上腺素能平衡的断层成像 人类。调查人员将使用专门建造的出色设施来执行必要的密集、多任务 与护理、生物营养和临床支持服务相结合的日间学习与团队的生理 专业知识。Shea博士有30年的临床研究经验，主要从事昼夜节律的临床研究 在健康人及其对心血管疾病危险因素的影响方面，他已经完成了大部分的心血管疾病 使用有效的昼夜节律方案的人体生理学研究。谢伊博士已经获得了充足的资金， 连续几年担任调查员发起的联邦拨款的PI。谢伊博士的出版物被大量引用，但引用的频率很低 近十年来原创研究论文的相对引文率为3.84[2009-18]，高于 NIH资助的同一领域所有论文的90%百分位数[NIH投资组合分析办公室：iCite工具])。由于 对全身昼夜节律的大小和范围的快速认识，包括 药物靶点的昼夜节律，我们正处于CV医学中有意义的时间治疗试验的尖端 考虑一下内部昼夜节律时间。在本研究计划中进行的这些临床前研究将提供 关键和及时的背景需要充分利用这些机会来改进心血管疾病的治疗。

项目成果

The Tech4Rest Randomized Controlled Trial: Applying the Hierarchy of Controls to Advance the Sleep, Health, and Well-being of Team Truck Drivers.

Tech4Rest 随机对照试验：应用控制层次来改善卡车司机的睡眠、健康和福祉。

• DOI: 10.1097/jom.0000000000002941
• 发表时间: 2023
• 期刊: Journal of occupational and environmental medicine
• 影响因子: 3.2
• 作者: Olson,Ryan;Johnson,PeterW;Shea,StevenA;Marino,Miguel;Springer,Rachel;Rice,SeanPM;Rimby,Jarred;Donovan,Courtney
• 通讯作者: Donovan,Courtney

Understanding Circadian Mechanisms of Sudden Cardiac Death: A Report From the National Heart, Lung, and Blood Institute Workshop, Part 1: Basic and Translational Aspects.

• DOI: 10.1161/circep.121.010181
• 发表时间: 2021-11
• 期刊: Circulation. Arrhythmia and electrophysiology
• 作者: Delisle BP;George AL Jr;Nerbonne JM;Bass JT;Ripplinger CM;Jain MK;Hermanstyne TO;Young ME;Kannankeril PJ;Duffy JF;Goldhaber JI;Hall MH;Somers VK;Smolensky MH;Garnett CE;Anafi RC;Scheer FAJL;Shivkumar K;Shea SA;Balijepalli RC
• 通讯作者: Balijepalli RC

Slow wave synchronization and sleep state transitions.

• DOI: 10.1038/s41598-022-11513-0
• 发表时间: 2022-05-06
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Guo, Dan;Thomas, Robert J.;Liu, Yanhui;Shea, Steven A.;Lu, Jun;Peng, Chung-Kang
• 通讯作者: Peng, Chung-Kang

Chronobiology of Exercise: Evaluating the Best Time to Exercise for Greater Cardiovascular and Metabolic Benefits.

• DOI: 10.1002/cphy.c210036
• 发表时间: 2022-06-29
• 期刊: COMPREHENSIVE PHYSIOLOGY
• 影响因子: 5.8
• 作者: Brito, Leandro C.;Marin, Thais C.;Azevedo, Luan;Rosa-Silva, Julia M.;Shea, Steven A.;Thosar, Saurabh S.
• 通讯作者: Thosar, Saurabh S.

Chronological distribution of readings in ambulatory blood pressure monitoring exams affects the nighttime average and the magnitude of blood pressure dipping.

动态血压监测检查中读数的时间分布会影响夜间平均值和血压下降的幅度。

• DOI: 10.1152/ajpheart.00542.2023
• 发表时间: 2023
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Brito,LeandroCamposde;Bowles,NicoleP;McHill,AndrewW;Rice,SeanPM;Butler,MatthewP;Emens,JonathanS;Shea,StevenA;Thosar,SaurabhS
• 通讯作者: Thosar,SaurabhS