Inspiratory muscle strength training for lowering systolic blood pressure in midlife and older adults with chronic kidney disease

项目总结 慢性肾脏疾病(CKD)是一个已经达到流行程度的主要公共卫生问题。 高血压是心血管疾病(CVD)和终末期肾脏的主要可改变危险因素 然而，50-70%的CKD成人无法将血压控制在130/80毫米汞柱。一把钥匙 高收缩压(SBP)与心血管疾病的联系过程是血管内皮功能障碍，由过度收缩介导 活性氧(ROS)诱导的氧化应激和一氧化氮(NO)生物利用度的降低。不是 在调节与血压和血管密切相关的肾血流量(RBF)方面也起着关键作用 功能。指南建议循序渐进地结合改变生活方式和药物治疗来降低 然而，CKD患者对有氧运动等生活方式改变的依从性很差。药效 治疗方案通常涉及多种药物，因为高血压在慢性肾脏病中很难控制。高阻 吸气肌力训练(IMST)是一种新的生活方式干预方法，需要反复吸气 使用手持设备对抗阻性负载。在随机、双盲、假控制、平行试验中 分组设计，R21资助的36名中老年男性和女性的基础收缩压≥为120毫米汞柱的先导性研究 结果显示，在最大吸气压力的75%下，每天30次呼吸[5分钟]，6天[30 分钟]/周，持续6周)具有极好的依从性(完成了95%的规定疗程)，并降低了 随意(静息)SBP降低9±2 mm Hg。IMST改善内皮功能(肱动脉血流介导 扩张，FMDBA)增加40%，与内皮一氧化氮合酶(ENOS)活性和一氧化氮的增加有关 生物利用度、ROS生成减少和氧化应激，以及循环因素的变化。重要的是 在估计有肾小球滤过的个体中，IMST对SBP和FMDBA的影响更大 剂量(EGFR)：75毫升/分钟/1.73米~2。在中老年人群中建立高抵抗力IMST的疗效(≥50 年)，患有中到重度CKD(EGFR 20-59毫升/分钟/1.73平方米)和高血压控制不充分 (SBP 130-159 mm Hg)，我们提出了一项随机、平行、假对照、双盲的临床试验。 评价临床相关的IMST疗程(3个月)对SBP、FMDBA、NO的影响 生物利用度、eNOS激活、ROS/氧化应激、循环因子和RBF。 目标1：测量临时SBP(主要结果)和24小时(动态)SBP(次要结果) 在IMST或Sham训练前(基线)和3个月后。 目的2：测量IMST或Sham训练前后的FMDBA(次要结果)。 目的3：测定：a)内皮细胞培养前eNOS、NO和ROS的产生 暴露；b)活组织内皮细胞氧化应激和抗氧化状态的标志物；c)识别 所涉及的血浆代谢物；d)功能磁共振成像的RBF。 目标4：评估Imst与Sham的依从性(已完成：规定疗程)、安全性和耐受性。

PROJECT SUMMARY Chronic kidney disease (CKD) is a major public health concern that has reached epidemic proportions. Hypertension is a leading modifiable risk factor for cardiovascular disease (CVD) and end-stage kidney disease, yet 50-70% of adults with CKD fail to achieve blood pressure (BP) control to <130/80 mmHg. A key process linking high systolic BP (SBP) to CVD is vascular endothelial dysfunction, mediated by excessive reactive oxygen species (ROS)-induced oxidative stress and reductions in nitric oxide (NO) bioavailability. NO is also critical in the regulation of renal blood flow (RBF), which is intimately related to BP and vascular function. Guidelines recommend a stepwise combination of lifestyle modifications and drug therapy to lower BP, yet adherence to lifestyle modifications such as aerobic exercise is poor in patients with CKD. Drug regimens often involve multiple medications, as hypertension is challenging to control in CKD. 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 36 midlife/older men and women with baseline SBP ≥120 mmHg, we showed that IMST (30 breaths [5 minutes]/day at 75% of maximal inspiratory pressure, 6 days [30 minutes]/week for 6 weeks) had excellent adherence (95% of prescribed sessions completed) and lowered casual (resting) SBP by 9±2 mmHg. IMST improved endothelial function (brachial artery flow-mediated dilation, FMDBA) by 40%, linked to increased endothelial NO synthase (eNOS) activation and NO bioavailability, reduced ROS production and oxidative stress, and changes in circulating factors. Importantly, the effects of IMST on SBP and FMDBA were even greater in individuals with an estimated glomerular filtration rate (eGFR) <75 mL/min/1.73m2. To establish the efficacy of high-resistance IMST in midlife/older adults (≥50 years) with moderate-to-severe CKD (eGFR 20-59 mL/min/1.73m2) and inadequately controlled hypertension (SBP 130-159 mm Hg), we propose a randomized, parallel group, sham-controlled, double-blind, clinical trial to evaluate the effects of a clinically relevant treatment duration of IMST (3 months) on SBP, FMDBA, NO bioavailability, eNOS activation, ROS/oxidative stress, circulating factors, and RBF. Aim 1: To measure casual SBP (primary outcome) and 24-hour (ambulatory) SBP (secondary outcome) before (baseline) and after 3 months of IMST or Sham training. Aim 2: To measure FMDBA (secondary outcome) before and after IMST or Sham training. Aim 3: To determine: a) endothelial cell culture eNOS, NO and ROS production pre-post IMST or Sham serum exposure; b) markers of oxidative stress and antioxidant status in biopsied endothelial cells; c) the identity of the plasma metabolites involved; d) RBF by functional magnetic resonance imaging. Aim 4: To assess adherence (completed:prescribed sessions), safety, and tolerability of IMST vs. Sham.