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

项目总结 高血压(BP)，特别是收缩压(SBP)是高血压的主要可改变的危险因素 心血管疾病及相关的衰老障碍。SBP随着年龄的增长而显著增加 绝经后(PM)妇女血压高于正常水平(即≥120毫米汞柱)的患病率高于正常水平 在年龄相仿的男性中。SBP的这种增加与血管内皮功能障碍有关，这种功能是通过 过量的活性氧(ROS)诱导的氧化应激和随后的一氧化氮减少 (否)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 (标准护理)降低SBP的生活方式疗法。然而，在雌激素缺乏的PM(PME-)女性中， AE对SBP的影响不大，且在AE停止后4周不再持续。Ae也不会 始终如一地增强内皮功能，并与这一组中粘附性差(30%)相关。 高阻力吸气肌力训练(IMST)是一种新的生活方式干预，包括 使用手持设备反复吸气以对抗阻力负荷。在一个随机的，双盲的，假的- 对照平行分组设计R21资助的中年/老年男性和女性先导性研究(n=36[17 PME- 女性)，我们发现Imst(每天30次呼吸[5分钟]，最大吸气压力的75%，6天 [30分钟/周，持续6周]，将随意(静息)SBP降低9±2 mm Hg(6周后为6±2 mm Hg 即刻停止)，24小时SBP下降3±3 mm Hg。IMST改善内皮功能(肱动脉血流- 中介扩张，FMDBA)，提高~40%，同时促进良好的依从性(95%的处方疗程 已完成)。重要的是，IMST对PME女性的SBP和FMDBA的影响都是≥男性的。 在这里，我们提出了一个更大的随机临床试验，基于指南的治疗持续时间(3个月)为 直接比较IMST和标准护理AE(150分钟/周快走)对减少 在基线时SBP高于正常(≥120毫米汞柱)的PME妇女中，SBP和改善的FMDBA。我们假设 IMST将降低并在很大程度上维持SBP的下降，并增加FMDBA和AE。FMDBA增加 IMST通过降低ROS/氧化应激而介导，IMST后血清将降低ROS和 AE后血管内皮细胞中NO含量升高。依从性、安全性和耐受性将与IMST和AE相比较。 目标1：测量临时SBP(主要结果)和24小时(动态)SBP(次要结果) 治疗前(基线)、治疗后3个月、治疗结束后6周； 目的2：测量IMST或AE前、后及IMST或AE后6周的FMDBA(次级结局)； 目的3：测定体内ROS对FMDBA(FMDBA±维生素C输注)的抑制作用； 活体内皮细胞的氧化应激和抗氧化状态；以及内皮细胞培养中的NO和ROS IMST或AE血清暴露前的生产和所涉及的血浆代谢物的特性； 目标4：评估依从性(已完成：规定疗程)、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.