Inspiratory muscle strength training for lowering blood pressure and improving endothelial function in postmenopausal women: comparison with "standard of care" aerobic exercise

用于降低绝经后妇女血压和改善内皮功能的吸气肌力量训练：与“标准护理”有氧运动的比较

• 批准号: 10414050
• 负责人: DOUGLAS R SEALS
• 金额: $ 58.06万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10414050
• 关键词: Acute; Adherence; Adult; Aerobic Exercise; Age; Aging; Antioxidants; Ascorbic Acid; Back; Biological Availability; Biopsy; Blood Pressure; Cardiovascular Diseases; Cell Culture Techniques; Chronic Kidney Failure; Clinical; Clinical Trials; Devices; Diastolic blood pressure; Disease; Double-Blind Method; Dropout; Elderly; Endothelial Cells; Endothelium; Estrogens; Exhibits; Facility Accesses; Funding; Guidelines; Hand; Health; Home; Hour; Human; Hypertension; Infusion procedures; Inhalation; Lifestyle Therapy; Link; Measures; Mediating; Molecular; Nitric Oxide; Oxidative Stress; Pilot Projects; Plasma; Postmenopause; Premenopause; Prevalence; Process; Production; Public Health; Randomized; Randomized Clinical Trials; Reactive Oxygen Species; Resistance; Rest; Risk; Role; Safety; Serum; Signal Transduction; Time; Training; Translating; Travel; Umbilical vein; Vascular Endothelium; Walking; Woman; base; brachial artery; cardiovascular disorder risk; cardiovascular health; cardiovascular risk factor; clinical practice; clinically relevant; comparative efficacy; design; effective intervention; evidence base; exercise program; exercise training; health goals; improved; in vivo; insight; lifestyle intervention; men; metabolomics; middle age; modifiable risk; molecular marker; muscle strength; novel; older men; older women; pilot trial; portability; post intervention; pressure; primary outcome; secondary outcome; standard of care; strength training; stress reduction; treatment duration; vascular endothelial dysfunction

PROJECT SUMMARY High blood pressure (BP), particularly systolic BP (SBP), is the major modifiable risk factor for cardiovascular diseases and related disorders of aging. SBP increases markedly with aging in women such that the prevalence of above-normal SBP (i.e., ≥120 mmHg) in postmenopausal (PM) women exceeds rates in age-matched men. This increase in SBP is associated with vascular endothelial dysfunction, mediated by excessive reactive oxygen species (ROS)-induced oxidative stress and consequent reductions in nitric oxide (NO) bioavailability. Moderate-intensity aerobic exercise (AE) of 150 min/week is a clinical guideline-based (standard-of-care) lifestyle therapy for reducing SBP. However, in estrogen-deficient PM (PME-) women, the effects of AE on SBP are modest and do not persist >4 weeks after AE cessation. AE also does not consistently enhance endothelial function and is associated with poor adherence (<30%) in this group. High-resistance inspiratory muscle strength training (IMST) is a novel lifestyle intervention involving repeated inhalations against a resistive load using a hand-held device. In a randomized, double-blind, sham- controlled, parallel group design R21-funded pilot study in midlife/older men and women (n=36 [17 PME- women]), we showed that IMST (30 breaths [5 minutes]/day at 75% of maximal inspiratory pressure, 6 days [30 minutes]/week for 6 weeks), lowered casual (resting) SBP by 9±2 mmHg (6±2 mmHg 6 weeks after cessation of IMST) and 24-hour SBP by 3±3 mmHg. IMST improved endothelial function (brachial artery flow- mediated dilation, FMDBA), by ~40%, while promoting excellent adherence (95% of prescribed sessions completed). Importantly, the effects of IMST on SBP and FMDBA in the PME- women were all ≥ those in men. Here we propose a larger, randomized clinical trial with a guideline-based treatment duration (3 months) to directly compare the efficacy of IMST vs. standard-of-care AE (150 min/week brisk walking) for decreasing SBP and improving FMDBA in PME- women with above-normal SBP (≥120 mmHg) at baseline. We hypothesize that IMST will reduce and largely sustain reductions in SBP and increase FMDBA > AE. Increases in FMDBA with IMST will be mediated by reduced ROS/oxidative stress, and serum post-IMST will decrease ROS and increase NO in endothelial cells > post-AE. Adherence, safety and tolerability will be > with IMST vs. AE. Aim 1: To measure casual SBP (primary outcome) and 24-hour (ambulatory) SBP (secondary outcome) before (baseline), after 3 months of IMST or AE, and 6 weeks following cessation of IMST or AE; Aim 2: To measure FMDBA (secondary outcome) before, after IMST or AE, and 6 weeks post-IMST or -AE; Aim 3: To determine in vivo ROS-mediated suppression of FMDBA (FMDBA ± vitamin C infusion); markers of oxidative stress and antioxidant status in biopsied endothelial cells; and endothelial cell culture NO and ROS production pre-post IMST or AE serum exposure and the identity of the plasma metabolites involved; Aim 4: To assess adherence (completed:prescribed sessions), safety and tolerability with IMST vs. AE.

项目概要 高血压（BP），特别是收缩压（SBP），是主要的可改变危险因素 心血管疾病和相关的衰老疾病在女性中随着年龄的增长而显着增加。 绝经后 (PM) 女性中 SBP 高于正常值（即 ≥120 mmHg）的患病率超过了 在年龄匹配的男性中，收缩压的增加与血管内皮功能障碍有关，由血管内皮功能障碍介导。 过多的活性氧 (ROS) 引起的氧化应激和随之而来的一氧化氮减少 (NO) 生物利用度 150 分钟/周的中等强度有氧运动 (AE) 是基于临床指南的。 （标准护理）生活方式疗法可降低 SBP 然而，对于缺乏雌激素的 PM (PME-) 女性， AE 对 SBP 的影响不大，并且在 AE 停止后不会持续超过 4 周。 持续增强内皮功能，并且与该组中依从性差（<30%）相关。 高阻吸气肌力量训练（IMST）是一种新颖的生活方式干预措施，涉及 在随机、双盲、假实验中，使用手持设备反复吸入阻力负载。 R21 资助的对照平行小组设计试点研究，针对中年/老年男性和女性（n=36 [17 PME- 女性]），我们展示了 IMST（30 次呼吸 [5 分钟]/天，最大吸气压力的 75%，6 天 [30 分钟]/周，持续 6 周），将休闲（静息）SBP 降低 9±2 mmHg（6 周后降低 6±2 mmHg） IMST 停止）和 24 小时收缩压 3±3 mmHg IMST 改善内皮功能（肱动脉血流）。 介导扩张（FMDBA）约 40%，同时促进良好的依从性（规定疗程的 95%） 重要的是，IMST 对 PME 女性 SBP 和 FMDBA 的影响均≥男性。 在此，我们提出一项更大规模的随机临床试验，其治疗持续时间基于指南（3 个月），以 直接比较 IMST 与标准护理 AE（150 分钟/周快走）对于减少 基线时 SBP 高于正常值 (≥120 mmHg) 的 PME 女性的 SBP 和 FMDBA 的改善。 IMST 将减少并在很大程度上维持 SBP 的降低并增加 FMDBA > AE 的增加。 IMST 的治疗将通过减少 ROS/氧化应激来介导，IMST 后的血清将减少 ROS 和 增加内皮细胞中的 NO > AE 后的依从性、安全性和耐受性 > IMST 与 AE 相比。 目标 1：测量临时 SBP（主要结果）和 24 小时（动态）SBP（次要结果） 之前（基线）、IMST 或 AE 3 个月后以及 IMST 或 AE 停止后 6 周； 目标 2：在 IMST 或 AE 之前、之后以及 IMST 或 AE 后 6 周测量 FMDBA（次要结果）； 目标 3：确定体内 ROS 介导的 FMDBA 抑制（FMDBA ± 维生素 C 输注）； 活检内皮细胞和内皮细胞培养物中的氧化应激和抗氧化状态； IMST 或 AE 血清暴露前后的生产以及所涉及血浆代谢物的身份； 目标 4：评估 IMST 与 AE 的依从性（已完成：规定疗程）、安全性和耐受性。