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

项目摘要 慢性肾脏病（CKD）是一个主要的公共卫生问题，已达到流行病的比例。 高血压是心血管疾病（CVD）和终末期肾病的主要可改变风险因素 然而，50 - 70%患有CKD的成年人无法将血压（BP）控制在<130/80 mmHg。一个关键 将高收缩压（SBP）与CVD联系起来的过程是血管内皮功能障碍，由过度的 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。没有 在肾血流量（RBF）的调节中也是至关重要的，这与血压和血管密切相关。 功能指南建议逐步结合生活方式的改变和药物治疗，以降低 然而，CKD患者坚持改变生活方式，如有氧运动的能力较差。药物 治疗方案通常涉及多种药物，因为CKD患者的高血压难以控制。高电阻 吸气肌肉力量训练（IMST）是一种新型的生活方式干预，包括重复吸气 使用手持设备抵抗电阻性负载。在一项随机、双盲、假手术对照、平行 分组设计，R21资助的在36名基线SBP ≥ 120 mmHg的中年/老年男性和女性中进行的初步研究，我们 显示IMST（30次呼吸[5分钟]/天，75%最大吸气压，6天[30 分钟]/周，持续6周）具有良好的依从性（95%的规定疗程完成）， 偶然（静息）SBP降低9 ± 2 mmHg。IMST改善内皮功能（肱动脉血流介导的 扩张，FMDBA）40%，与增加内皮NO合酶（eNOS）活化和NO 生物利用度，减少ROS产生和氧化应激，以及循环因子的变化。重要的是， IMST对SBP和FMDBA的影响在估计肾小球滤过的个体中甚至更大 eGFR <75 mL/min/1.73m2。确定中老年人（≥ 50岁）中高阻力IMST的疗效 中重度CKD（eGFR 20 - 59 mL/min/1.73 m2）和高血压控制不佳 (SBP 130 - 159 mm Hg），我们提出了一项随机、平行组、假对照、双盲临床试验， 评价IMST的临床相关治疗持续时间（3个月）对SBP、FMDBA、NO的影响 生物利用度、eNOS活化、ROS/氧化应激、循环因子和RBF。 目的1：测量偶然SBP（主要结局）和24小时（动态）SBP（次要结局） IMST或假训练前（基线）和3个月后。 目的2：测量IMST或假训练前后的FMDBA（次要结局）。 目的3：测定：a）IMST前后或假血清中内皮细胞培养eNOS、NO和ROS的产生 暴露; B）活检内皮细胞中氧化应激和抗氧化状态的标志物; c） 涉及的血浆代谢物; d）通过功能性磁共振成像的RBF。 目的4：评估IMST与假手术的依从性（已完成：处方疗程）、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.