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

项目摘要 心脏病相关的收缩压（SBP）升高和血管功能障碍是导致心脏病的主要因素。 心血管疾病（CVD）在“中年”（50-64岁）和老年人（65+）（ML/O）成人。大部分高架 CVD风险发生在偶然（静息）SBP“升高”（120-129 mmHg）和1级的ML/O成人中 高血压（130-139 mmHg）的范围和相关：a）受损的内皮功能（降低 肱动脉血流介导的扩张[FMDBA]）;和B）大弹性动脉硬化（颈动脉- 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），均由 过量的活性氧（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，SBP在这些范围内，应采用生活方式策略治疗约3个月 在考虑药物治疗之前。我们已经表明，在健康的年轻人，被动热疗法（热 将核心温度从约37.0 ° C升高到38.5-39.0°C的水浸是安全的，可以改善SBP， 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个疗程 热疗约10周安全/耐受性良好，可降低偶发SBP（约10 mmHg）， h SBP（~6 mmHg），FMDBA和NO生物利用度增加，CFPWV、颈动脉β-硬度和 血管氧化应激将培养物中的内皮细胞暴露于从受试者在（vs. 热疗法抑制基础ROS产生并增加乙酰胆碱刺激的NO产生， 这表明“循环因子”的变化可能至少部分抵消热疗法的CV益处。 作为将被动热疗法转化为最终临床实践的下一步，我们建议 一项更大规模、适当把握度、随机化、假对照、平行组设计、单中心临床试验 评估被动热疗的有效性、安全性、潜在机制和潜在的持久效应（36 x 60分钟，持续约12周）与假手术（热中性水浸泡）相比， ML/O男性和女性SBP升高/1级高血压患者的SBP和血管功能改善 确定被动热疗与假手术（对照）之前、之后以及随访4周和12周之后： 目标1：偶然（静息）和24小时BP。还将评估安全性、耐受性和实施可行性。 目的2：血管内皮功能（FMDBA）和主动脉（CFPWV）和颈动脉（β-刚度指数）刚度。 目的3：a）FMDBA的氧化应激相关的抑制（响应于超氧化应激的FMDBA的急性增加）。 ROS清除剂，维生素C的治疗性输注）; B）氧化应激的标志物，促氧化剂信号传导， 和抗氧化剂防御; c）丰度和 循环微泡（MV）的含量;和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耗尽的血浆，或3）在热疗或假手术之前与之后从受试者收集的分离MV。

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.