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

• 批准号: 10375083
• 负责人: DOUGLAS R SEALS
• 金额: $ 65.5万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375083
• 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; Body Temperature; Cardiovascular Diseases; Carotid Arteries; Clinical; Clinical Trials; Dementia; Disease; Drops; Elderly; Endothelial Cells; Endothelium; Exposure to; Guidelines; Hour; Human; Hypertension; Immersion; Impaired cognition; Impairment; Individual; Infusion procedures; Life Style; Measures; Mediating; Medical; Molecular; Nitric Oxide; Oregon; Oxidative Stress; Pharmacology; Pharmacotherapy; Physiologic pulse; Placebos; Plasma; Prevalence; Production; Randomized; Reactive Oxygen Species; Rest; Risk Factors; Safety; Serious Adverse Event; Serum; Signal Transduction; Stroke; Temperature; Therapeutic; 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; endothelial dysfunction; exposed human population; follow-up; high risk population; improved; in vivo; indexing; insight; lifestyle intervention; men; microvesicles; middle age; novel; oxidized low density lipoprotein; pilot trial; preservation; rectal; response; young adult

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.

项目摘要 年龄相关的收缩压(SBP)升高和血管功能障碍是主要的驱动因素 “中年”(50-)和65岁以上(ML/O)成年人的心血管疾病。大部分高架飞机 心血管疾病风险发生在ML/O成人中，且SBP临时(静息)处于“升高”(120-129毫米汞柱)和第1期 高血压(130-139毫米汞柱)范围和与：a)内皮功能受损(降低 肱动脉血流介导的扩张[FMDBA])；以及b)大的弹性动脉硬化(增加的颈动脉- 股骨脉搏波速度[CFPWV]，即主动脉硬度和颈动脉β硬度指数)，均由 过量的活性氧物种(ROS)相关的氧化应激，这降低了一氧化氮(NO)的生物利用度。 目前的指南建议，在这些范围内的SBP应采用生活方式策略治疗约3个月 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(热疗 将心脏温度从~37.0摄氏度提高到38.5-39.0摄氏度的浸水是安全的，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)，发现有30个疗程 超过10周的热疗是安全的/耐受性良好的，降低了随意的SBP(~10毫米汞柱)和24- HSBP(~6毫米汞柱)，增加FMDBA和NO的生物利用度，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(vs. 在此之前，热疗抑制了基础ROS的产生，增加了乙酰胆碱刺激的NO产生， 这表明，“循环因子”的改变至少在一定程度上可以传递热疗的心血管益处。 作为将被动热疗转化为最终临床实践所需的下一步，我们建议 一项规模更大、动力适当、随机、假对照、平行分组设计、单部位临床试验 评估被动热疗的有效性、安全性、潜在机制和潜在的持久影响(36 在约12周的时间内进行60分钟的治疗)与假的(温中压水浸泡)相比，可减少随意性和24小时 SBP升高的ML/O男性和女性患者的SBP和改善血管功能。 为了确定被动热疗前、被动热疗后与假手术(对照组)的对比，以及4周和12周的随访后： 目标1：随意(休息)和24小时血压。还将对安全性、耐受性和实施可行性进行评估。 目的2：血管内皮细胞功能(FMDBA)、主动脉血流速度(CFPWV)和颈动脉硬度(β-Stiffness Index)。 目的3：a)氧化应激相关的抑制FMDBA(FMDBA的急剧增加响应于超... 治疗性输注ROS清除剂，维生素C)；b)氧化应激标志物，促氧化信号， 从临床血管内活检中获得的内皮细胞中的抗氧化防御；c)丰富和 循环微泡(MVS)的含量；以及d)NO的生物利用度、ROS的产生和NO介导的 血管生成(NO生物利用度的功能测定)暴露于1)完整血浆的培养内皮细胞， 2)MV耗竭的血浆，或3)从受试者热疗前或假手术后采集的MV。