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

项目摘要 高血压（BP），特别是收缩压（SBP），是主要的可改变的危险因素， 心血管疾病和相关的衰老障碍。SBP随着女性年龄的增长而显著增加， 高于正常SBP的患病率（即，≥120 mmHg），超过绝经后（PM）女性 年龄匹配的男性。收缩压的增加与血管内皮功能障碍有关， 过量的活性氧（ROS）诱导的氧化应激和随后的一氧化氮减少 (NO)生物利用度每周150分钟的中等强度有氧运动（AE）是基于临床指南的 （标准治疗）生活方式疗法降低SBP。然而，在雌激素缺乏的PM（PME-）妇女中， AE对SBP的影响是适度的，并且在AE停止后不会持续超过4周。AE也不 持续增强内皮功能，并与该组中的不良依从性（<30%）相关。 高阻力吸气肌肉力量训练（IMST）是一种新的生活方式干预， 使用手持装置对抗阻力负载重复吸入。在一项随机、双盲、假- 在中年/老年男性和女性中进行的对照、平行组设计R21资助的试点研究（n=36 [17 PME-21]） 女性]），我们发现IMST（30次呼吸[5分钟]/天，75%的最大吸气压力，6天 [30分钟]/周，持续6周），偶然（静息）SBP降低9±2 mmHg（6±2 mmHg，6周后 IMST停止）和24小时SBP降低3±3 mmHg。IMST改善内皮功能（肱动脉血流- 介导的扩张，FMDBA），约40%，同时促进良好的依从性（95%的处方会话 完成）。重要的是，IMST对PME女性的SBP和FMDBA的影响均≥男性。 在这里，我们提出了一个更大的，随机的临床试验与指南为基础的治疗时间（3个月）， 直接比较IMST与标准治疗AE（150分钟/周快走）降低 PME中的SBP和FMDBA改善-基线时SBP高于正常值（≥120 mmHg）的女性。我们假设 IMST将减少并在很大程度上维持SBP减少，并增加FMDBA > AE。FMDBA增加 IMST将通过减少ROS/氧化应激介导，IMST后血清将减少ROS， AE后内皮细胞NO含量增加。IMST的依从性、安全性和耐受性将> AE。 目的1：测量偶然SBP（主要结局）和24小时（动态）SBP（次要结局） IMST或AE之前（基线）、3个月后和IMST或AE停止后6周; 目的2：在IMST或AE之前、之后和IMST或-AE之后6周测量FMDBA（次要结局）; 目的3：确定体内ROS介导的FMDBA抑制（FMDBA ±维生素C输注）; 活检内皮细胞中的氧化应激和抗氧化状态;以及内皮细胞培养物NO和ROS IMST或AE血清暴露前后的产生以及相关血浆代谢物的鉴别; 目的4：评估IMST与AE的依从性（已完成：处方疗程）、安全性和耐受性。

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.