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Passive heat therapy for lowering systolic blood pressure and improving vascular function in mid-life and older adults

被动热疗可降低中年和老年人的收缩压并改善血管功能

基本信息

批准号：
10596067
负责人：
DOUGLAS R SEALS
金额：
$ 62.9万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596067
关键词：
3-nitrotyrosine Acetylcholine Acute Adult Adverse event Age Years Aging Antioxidants Aorta Arteries Ascorbic Acid Automobile Driving Biological Assay Biological Availability Biopsy Blood Pressure Blood Vessels Blood flow Body Temperature Cardiovascular Diseases Carotid Arteries Classification Clinical Clinical Trials Dementia Disease Drops Elasticity Elderly Endothelial Cells Endothelium Exposure to Femur Guidelines Hour Human Hypertension Immersion Impaired cognition Impairment Individual Infusion procedures Life Style Measures Mediating Medical Molecular Nitric Oxide Oregon Oxidative Stress Oxidative Stress Induction Pharmacotherapy Physiologic pulse Placebos Plasma Prevalence Production Randomized Reactive Oxygen Species Recommendation Rectum Rest Risk Factors Safety Serious Adverse Event Serum Signal Transduction Stroke Temperature Therapeutic heat application Translations Umbilical vein Universities Vascular Diseases Vascular Endothelium Vasodilator Agents Water Woman age group age related angiogenesis arterial stiffness blood pressure reduction brachial artery cardiovascular disorder risk cardiovascular risk factor clinical application clinical practice clinical research site comorbidity design effectiveness evaluation efficacy evaluation endothelial dysfunction exposed human population follow-up high risk population improved in vivo indexing insight lifestyle intervention men microvesicles middle age novel older men older women oxidized low density lipoprotein pharmacologic pilot trial preservation rectal response young adult

项目摘要

Project Summary Age-related increases in systolic blood pressure (SBP) and vascular dysfunction are major factors driving cardiovascular diseases (CVD) in “mid-life” (50-64 years) and older (65+) (ML/O) adults. Much of the elevated CVD risk occurs in ML/O adults with casual (resting) SBP in the “elevated” (120-129 mmHg) and stage 1 hypertension (130-139 mmHg) ranges and is associated with: a) impaired endothelial function (decreased brachial artery flow-mediated dilation [FMDBA]); and b) stiffening of the large elastic arteries (increased carotid- femoral pulse wave velocity [CFPWV], i.e., aortic stiffness, and carotid artery β-stiffness index), all mediated by excess reactive oxygen species (ROS)-related oxidative stress, which reduces nitric oxide (NO) bioavailability. Current guidelines recommend that SBP in these ranges be treated with lifestyle strategies for ~3 months prior to considering drug therapy. We have shown in healthy young adults that passive heat therapy (hot water immersion to raise core temperature from ~37.0 to 38.5-39.0°C) is safe and may improve SBP and vascular function. We recently completed a small pilot trial (n=23) in ML/O adults and found that 30 sessions of heat therapy over ~10 weeks was safe/well-tolerated, reduced casual SBP (~10 mmHg) and ambulatory 24- h SBP (~6 mmHg), increased FMDBA and NO bioavailability, and reduced CFPWV, carotid β-stiffness and vascular oxidative stress. Exposing endothelial cells in culture to serum obtained from subjects after (vs. before) heat therapy suppressed basal ROS production and increased acetylcholine-stimulated NO production, indicating that changes in “circulating factors” may, at least in part, transduce the CV benefits of heat therapy. As the required next step in translation of passive heat therapy to eventual clinical practice, we propose a larger, properly powered, randomized, sham-controlled, parallel group design, single-site clinical trial to assess the efficacy, safety, underlying mechanisms, and potential lasting effects of passive heat therapy (36 x 60-min sessions over ~12 weeks) vs. sham (thermoneutral water immersion) for decreasing casual and 24-h SBP and improving vascular function in ML/O men and women with elevated SBP/stage 1 hypertension. To determine before, after passive heat therapy vs. sham (control), and after 4 and 12 weeks of follow-up: Aim 1: Casual (resting) and 24-h BP. Safety, tolerability, and implementation feasibility will also be assessed. Aim 2: Vascular endothelial function (FMDBA) and aortic (CFPWV) and carotid (β-stiffness index) stiffness. Aim 3: a) Oxidative stress-related suppression of FMDBA (acute increase in FMDBA in response to a supra- therapeutic infusion of the ROS scavenger, vitamin C); b) markers of oxidative stress, pro-oxidant signaling, and antioxidant defenses in endothelial cells obtained from clinical endovascular biopsy; c) abundance and content of circulating microvesicles (MVs); and d) NO bioavailability, ROS production, and NO-mediated angiogenesis (functional assay of NO bioavailability) in cultured endothelial cells exposed to 1) intact plasma, 2) MV-depleted plasma, or 3) isolated MVs collected from subjects before vs. after heat therapy or sham.

项目概要与年龄相关的收缩压（SBP）升高和血管功能障碍是导致血压升高的主要因素 “中年”（50-64 岁）和老年人（65 岁以上）(ML/O) 成年人的心血管疾病 (CVD)。大部分高位休闲（静息）SBP“升高”（120-129 mmHg）和第 1 阶段的 ML/O 成人存在 CVD 风险高血压 (130-139 mmHg) 范围并与以下因素相关：a) 内皮功能受损（血压下降）肱动脉血流介导的扩张[FMDBA]）； b）大弹性动脉硬化（颈动脉增加）股动脉脉搏波速度 [CFPWV]，即主动脉僵硬度和颈动脉 β-僵硬度指数），全部由过量的活性氧（ROS）相关的氧化应激，会降低一氧化氮（NO）的生物利用度。目前的指南建议，在这些范围内的 SBP 需要通过生活方式策略进行约 3 个月的治疗在考虑药物治疗之前。我们已经在健康的年轻人身上证明了被动热疗法（热疗法）浸水以将核心温度从 ~37.0°C 提高到 38.5-39.0°C）是安全的，并且可以改善 SBP 和血管功能。我们最近在 ML/O 成人中完成了一项小型试点试验 (n=23)，发现 30 次治疗约 10 周的热疗是安全的/耐受性良好，可降低休闲收缩压 (约 10 mmHg) 和动态 24- h SBP (~6 mmHg)，增加 FMDBA 和 NO 生物利用度，并降低 CFPWV、颈动脉 β 硬度和血管氧化应激。将培养的内皮细胞暴露于从受试者获得的血清中（与之前）热疗法抑制了基础ROS的产生并增加了乙酰胆碱刺激的NO的产生，表明“循环因素”的变化可能至少部分改变热疗对心血管的益处。作为被动热疗转化为最终临床实践所需的下一步，我们建议更大规模、适当动力、随机、假对照、平行组设计、单中心临床试验评估被动热疗的功效、安全性、潜在机制和潜在的持久影响（36 x 60 分钟疗程（约 12 周）与假手术（热中性水浸泡），以减少休闲和 24 小时 SBP 和改善 SBP 升高/1 期高血压的 ML/O 男性和女性的血管功能。为了确定被动热疗与假治疗（对照）之前、之后以及 4 周和 12 周随访后的情况：目标 1：休闲（休息）和 24 小时血压。还将评估安全性、耐受性和实施可行性。目标 2：血管内皮功能 (FMDBA) 以及主动脉 (CFPWV) 和颈动脉（β-硬度指数）硬度。目标 3：a) 与氧化应激相关的 FMDBA 抑制（FMDBA 因超量反应而急剧增加） ROS 清除剂、维生素 C 的治疗性输注； b) 氧化应激标记物、促氧化信号传导、临床血管内活检获得的内皮细胞的抗氧化防御能力； c) 丰富性和循环微泡（MV）的含量； d) NO 生物利用度、ROS 产生和 NO 介导的暴露于 1) 完整血浆的培养内皮细胞中的血管生成（NO 生物利用度的功能测定）， 2) MV 耗尽血浆，或 3) 在热疗或假手术之前与之后从受试者收集的分离 MV。