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)和心血管健康的益处是有据可查的。鉴于 目前的指导方针主张每周进行约150分钟的中等强度运动，我们的初步数据显示 每天一分钟的吸气肌力训练(IMST)持续6周，可使安静时的SBP降低约12毫米汞。 这种降低血压的简单方法可以应用于几乎任何人群，无论我们如何建议 研究老年阻塞性睡眠呼吸暂停(OSA)患者的IMST。OSA是理想的目标人群，因为 OSA的患病率正在上升，因为打鼾症和呼吸暂停会导致慢性间歇性低氧血症， 导致交感神经系统(SNS)过度活动、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方法的不良坚持而变得更加复杂 持续气道正压(&lt；50%)、肥胖、疲劳和强烈的运动不耐受。 我们在健康年轻人(n=50)中的发现表明，与IMST相关的血压下降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发生改变。与一致 这一假设，我们在成人阻塞性睡眠呼吸暂停综合征(n=24)的试点临床试验中的结果显示，与IMST相关的OSA减少 血浆去甲肾上腺素水平(PNE)和肌交感神经活动(MSNA)均为SNS的标志 活动。我们的初步机械评估表明，IMST可能会降低循环中其他物质的浓度 血管收缩因子和增加一氧化氮(NO)介导的内皮依赖性扩张。以及，调查结果 在一种新的内皮细胞培养模型中，指出一氧化氮的增加和活性氧的减少 (ROS)和氧化应激。然而，目前尚不清楚：1)IMST是否会降低非卧床和24小时(动态)SBP 患有OSA的老年人；2)SBP的降低是持久的；3)动脉僵硬，NO介导的血管内皮细胞 扩张和/或氧化应激得到改善；以及4)如果长期坚持在这一人群中很高。 我们建议进行一项随机、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])每周5天，共24周，与安慰剂(15%PImax)(n=61/组)比较 用于降低血压和OSA高于正常水平的成年人(50岁)的SBP。我们假设Imst会降低 SBP通过降低SNS活性和循环血管收缩因子，改善血管功能， 氧化应激/炎症的减少，SBP的降低将在IMST后持续。 目标1：测定服药前/服药后、服药后4周和12周的随机和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：测量动脉僵硬、肱动脉血流介导的扩张(FMDBA)、血浆PNE、MSNA、 血管收缩因子和炎症；IMST/安慰剂训练前/后以及4周和12周后。 目的3：评价超氧自由基对FMDBA的抑制作用，以及氧化应激和抗氧化剂的标记物 受试者在IMST/安慰剂训练前/后以及4周和12周后内皮细胞的防御。

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.