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 所有细胞和组织中都存在内源性昼夜节律，包括自主神经系统，心脏和 脉管系统。最终的节奏准备心血管（CV）系统以使其最佳功能与 每日预期的行为和环境周期，例如改变的姿势和活动增加 早上醒来。但是，早晨也是预先简历活动的最脆弱的时间， 包括心肌梗塞，中风和心脏突然死亡。 Shea博士率先使用密集型， 多日实验室实验并发现了CV跨CV的大量内源性昼夜节律 健康人的系统。 Shea博士还发现，CV对压力源的反应性存在昼夜节律 （即，在一天中的不同时间对相同的压力源有不同的CV响应）。 Shea博士的工作导致 简历系统中昼夜节律的概念充当“双刃剑”：正常放大器 早晨的回应有助于健康个体从睡眠到活动的过渡，但如此夸张 在具有基本简历风险因素的个体中，反应可能是危险的 事件。 Shea博士将领导一支多学科的杰出调查员团队，以研究一个广泛的问题 昼夜节律与行为相关的简历响应如何相互作用以产生可预测的每日变化 在简历风险概况中。为了与健康对照相比，将在增加的人群中进行研究 对CV疾病的敏感性，例如高血压，中年成年人和阻塞性睡眠呼吸暂停。 总体团队在昼夜节律，睡眠，压力，运动和简历生理学以及正电子排放方面具有专业知识 静止左心室中突触前和突触后肾上腺功能的平衡的层析成像 人类。调查人员将使用出色的专用设施来执行必要的密集，多重 与护士的一日研究，与团队的生理学集成的护士，生物营养和临床支持服务 专业知识。 Shea博士拥有> 30年的经验进行临床研究，主要集中于昼夜节律 在健康的人类及其对简历疾病危险因素的影响中，他已经进行了大多数简历 在人类中使用经过验证的昼夜节律方案的生理学研究。 Shea博士拥有25 连续担任调查员发起的联邦赠款的PI。 Shea博士的出版物引人注目的是 在过去的十年中，原始研究论文的相对引文比率为3.84 [2009-18]，高于 同一领域中所有NIH资助的论文[NIH投资组合分析办公室：ICITE工具]的90％百分点。由于 对整个身体的昼夜节律的大小和程度的快速认识，包括 在药物靶标中的昼夜节律，我们正处于有意义的CV医学中有意义的年代治疗试验的风口浪尖 考虑内部昼夜节时间。在本研究计划中进行的这些临床前研究将提供 充分探索这些机会改善简历疾病治疗的机会所需的关键和及时背景。

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