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

吸气肌力量训练可降低患有慢性肾病的中年和老年人的收缩压

基本信息

批准号：
10313126
负责人：
Michel Benjamin Chonchol
金额：
$ 59.49万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10313126
关键词：
Adherence Adult Aerobic Exercise Antioxidants Arginine Biological Availability Biomedical Research Biopsy Blood Pressure Blood Vessels Cardiovascular Diseases Cell Culture Techniques Chronic Kidney Failure Clinical Clinical Trials Devices Double-Blind Method Dropout Elderly End stage renal failure Endothelial Cells Endothelium Epidemic Functional Magnetic Resonance Imaging Funding Glomerular Filtration Rate Guidelines Hand Hour Human Hypertension Individual Inhalation Intervention Trial Life Style Modification Link Magnetic Resonance Imaging Measures Mediating NOS3 gene Nitric Oxide Nitric Oxide Synthase Oxidative Stress Patients Pharmaceutical Preparations Pharmacotherapy Pilot Projects Plasma Process Production Protocols documentation Public Health Randomized Reactive Oxygen Species Regimen Regulation Renal Blood Flow Research Priority Resistance Rest Role Safety Serum Signal Transduction Time Training Umbilical vein Vascular Diseases blood pressure intervention blood pressure reduction blood pressure regulation brachial artery cardiovascular disorder risk cardiovascular risk factor circulating biomarkers clinically relevant dehydroascorbate design high risk improved innovation insight interest lifestyle intervention metabolomics middle age modifiable risk molecular marker mortality muscle strength novel novel therapeutics older men older women pilot trial pressure primary outcome secondary outcome strength training stress reduction treatment duration vascular endothelial dysfunction

项目摘要

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.

项目概要慢性肾病（CKD）是一个重大的公共卫生问题，已达到流行病的程度。高血压是心血管疾病 (CVD) 和终末期肾病的主要可改变危险因素但 50-70% 的 CKD 成人患者未能将血压 (BP) 控制在 <130/80 mmHg。将高收缩压 (SBP) 与 CVD 联系起来的过程是血管内皮功能障碍，由过度的收缩压介导。活性氧（ROS）引起的氧化应激和一氧化氮（NO）生物利用度的降低。对肾血流 (RBF) 的调节也至关重要，肾血流与血压和血管密切相关指南建议逐步结合生活方式改变和药物治疗来降低血压。 BP，但 CKD 患者对生活方式改变（如有氧运动）的依从性较差。治疗方案通常涉及多种药物，因为高抵抗性 CKD 患者的高血压很难控制。吸气肌力量训练（IMST）是一种新颖的生活方式干预措施，涉及重复吸气使用手持设备对抗电阻负载，以随机、双盲、假控制、并行的方式进行。小组设计，R21 资助的试点研究对 36 名基线 SBP ≥120 mmHg 的中年/老年男性和女性进行，我们显示 IMST（30 次呼吸 [5 分钟]/天，最大吸气压力的 75%，6 天 [30 分钟]/周，持续 6 周）具有出色的依从性（完成了 95% 的规定疗程）并降低了休闲（静息）SBP 提高 9±2 mmHg IMST 改善内皮功能（肱动脉血流介导）。扩张 (FMDBA) 40%，与内皮 NO 合酶 (eNOS) 激活和 NO 增加有关生物利用度、ROS 产生和氧化应激减少以及循环因子的变化。 IMST 对 SBP 和 FMDBA 的影响在估计肾小球滤过的个体中更大率 (eGFR) <75 mL/min/1.73m2 确定高阻 IMST 对中年/老年人（≥50）的疗效。年）患有中重度 CKD（eGFR 20-59 mL/min/1.73m2）且高血压控制不充分（SBP 130-159 mm Hg），我们提出了一项随机、平行组、假对照、双盲临床试验评估临床相关 IMST 治疗持续时间（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） IMST 或假训练 3 个月之前（基线）和之后。目标 2：测量 IMST 或假训练前后的 FMDBA（次要结果）。目标 3：确定：a) IMST 或假血清前后内皮细胞培养物 eNOS、NO 和 ROS 的产生 b) 活检内皮细胞中氧化应激和抗氧化状态的标志物；涉及的血浆代谢物；d) 通过功能磁共振成像进行 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。