Time-efficient inspiratory muscle strength training for improving blood pressure and vascular function in older adults with sleep-disordered breathing

项目摘要 运动对收缩压（SBP）和心血管健康有很好的好处。而 目前的指南提倡每周约150分钟的中等强度运动，我们的初步数据显示约5 6周的吸气肌肉力量训练（IMST）可使偶然（静息）SBP降低约12 mmHg。 这种简单的降低血压的方法可以应用于几乎任何人群，但我们建议 研究患有阻塞性睡眠呼吸暂停（OSA）的老年人的IMST。OSA是一个理想的目标人群， 阻塞性睡眠呼吸暂停的患病率正在上升，由于打鼾和呼吸暂停导致慢性间歇性低氧血症， 导致交感神经系统（SNS）过度活跃、内皮功能障碍和高血压。这些 心血管疾病的实质性风险因对主要治疗的依从性差而加剧 持续气道正压通气（<50%）、肥胖、疲劳和强烈的运动不耐受。 我们在健康年轻人（n=50）中的研究结果表明，IMST相关的血压降低是由以下因素介导的： 全身血管阻力降低，提示血管张力和功能改变。符合 根据这一假设，我们在OSA成人（n=24）中进行的初步临床试验的结果显示， 血浆去甲肾上腺素水平（PNE）和肌肉交感神经活动（MSNA），这两个指标的SNS 活动我们的初步机制评估表明，IMST可能会降低其他循环浓度 血管收缩因子和增加一氧化氮（NO）介导的内皮依赖性舒张。还有， 在一种新内皮细胞培养模型中，表明NO增加和活性氧减少 (ROS)和氧化应激。然而，尚不清楚：1）IMST是否降低了患者的偶然和24小时（动态）SBP， 老年OSA患者; 2）SBP的降低是持久的; 3）动脉硬化，NO介导的内皮细胞 扩张和/或氧化应激得到改善;和4）如果在该群体中的依从性长期较高。 我们提出了一个随机、双盲、安慰剂对照的临床试验，以确定IMST的疗效 (75%最大吸气压，[PImax]）5天/周，持续24周vs安慰剂（15%PImax）（n=61/组） 用于降低血压和阻塞性睡眠呼吸暂停（OSA）高于正常值的成人（>50岁）的收缩压。我们假设IMST会降低 SBP通过SNS活性和循环血管收缩因子降低，血管功能改善， 以及氧化应激/炎症的减少，并且在IMST后SBP的减少将持续。 目的1：测定IMST/安慰剂治疗前/后、治疗后4周和12周的偶然血压和24小时动态血压 训练还将评估安全性、耐受性和依从性。 目的2：测定动脉僵硬度、肱动脉血流介导的舒张功能（FMDBA）、血浆PNE、MSNA、 血管收缩因子和炎症;前/后，4周和12周后IMST/安慰剂训练。 目的3：评价FMDBA对超氧化物的抑制作用，以及氧化应激和抗氧化的标志物 在IMST/安慰剂训练之前/之后以及训练后4周和12周，受试者的内皮细胞防御。

Project Summary Exercise has well-documented benefits for systolic blood pressure (SBP) and cardiovascular health. Whereas current guidelines advocate ~150 min moderate intensity exercise/week, our preliminary data show ~5 min/day of inspiratory muscle strength training (IMST) for 6 weeks lowers casual (resting) SBP by ~12 mmHg. This simple approach to lowering BP could be applied to almost any population however we propose to study IMST in older adults with obstructive sleep apnea (OSA). OSA is an ideal population to target because OSA prevalence is growing and because snoring and apneas result in chronic intermittent hypoxemia that drives sympathetic nervous system (SNS) hyperactivity, endothelial dysfunction and hypertension. These substantive risks for cardiovascular disease are compounded by poor adherence to the mainstay treatment continuous positive airway pressure (<50%), obesity, fatigue and a robust intolerance for exercise. Our findings in healthy young adults (n=50) show IMST-related reductions in BP are mediated by decreases in systemic vascular resistance, suggesting changes in vascular tone and function. Consistent with this hypothesis, our results from a pilot clinical trial in adults with OSA (n=24) show IMST-related reductions in plasma norepinephrine levels (PNE) and muscle sympathetic nerve activity (MSNA), both markers of SNS activity. Our preliminary mechanistic assessments indicate IMST may lower circulating concentrations of other vasoconstrictor factors and increase nitric oxide (NO)-mediated endothelium-dependent dilation. And, findings in a novel endothelial cell culture model, point to increases in NO and declines in reactive oxygen species (ROS) and oxidative stress. However, it is unknown if: 1) IMST lowers casual and 24-h (ambulatory) SBP in older adults with OSA; 2) the reductions in SBP are long-lasting; 3) arterial stiffness, NO-mediated endothelial dilation and/or oxidative stress are improved; and 4) if adherence in this population is high long term. We propose a randomized, double-blind, placebo-controlled, clinical trial to establish the efficacy of IMST (75% maximum inspiratory pressure, [PImax]) 5 days/week for 24 weeks vs. placebo (15%PImax) (n=61/group) for lowering SBP in adults (>50 years) with above normal BP and OSA. We hypothesize that IMST will lower SBP via reductions in SNS activity and circulating vasoconstrictor factors, improvements in vascular function, and reductions in oxidative stress/inflammation and that reductions in SBP will be sustained after IMST. Aim 1: To determine casual and 24-h ambulatory BP; before/after, and 4- and 12-weeks post-IMST/placebo training. Safety, tolerability and adherence also will be assessed. Aim 2: To measure arterial stiffness, brachial artery flow-mediated dilation (FMDBA), plasma PNE, MSNA, vasoconstrictor factors and inflammation; before/after, and 4- and 12-weeks post-IMST/placebo training. Aim 3: To evaluate superoxide related suppression of FMDBA, and markers of oxidative stress and antioxidant defense in endothelial cells from subjects before/after, and 4- and 12-weeks post-IMST/placebo training.