Sympatho-inhibition with Mindfulness in Chronic Kidney Disease

慢性肾病中正念的交感抑制

• 批准号: 9796614
• 负责人: Jeanie Park
• 金额: $ 48.49万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9796614
• 关键词: Acute; Address; Adrenergic alpha-Antagonists; African American; Anti-Cholinergics; Anti-inflammatory; Antihypertensive Agents; Autonomic nervous system; Baroreflex; Blood Pressure; Brain Stem; Cardiovascular system; Cervical; Chronic; Chronic Kidney Failure; Circadian Dysregulation; Circadian Rhythms; Clinical; Clonidine; Controlled Clinical Trials; Data; Development; Devices; Efferent Neurons; Equilibrium; Failure; Fatigue; Gold; Health; Hour; Human; Hyperlipidemia; Inferior; Inflammation; Insulin Resistance; Intervention; Knowledge; Link; Masks; Measurement; Measures; Metabolic; Methods; Muscle; Nerve; Nerve Fibers; Nervous System Physiology; Nucleus solitarius; Orthostatic Hypotension; Outcome; Output; Parasympathetic Nervous System; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Population; Randomized; Randomized Controlled Clinical Trials; Regulation; Renal function; Rest; Role; Safety; Self Administration; Sympathetic Nervous System; Sympatholytics; Techniques; Testing; Therapeutic; Vagus nerve structure; active control; afferent nerve; base; blood pressure reduction; blood pressure regulation; cardiovascular disorder risk; cardiovascular risk factor; combat; design; effective therapy; experimental study; heart rate variability; hemodynamics; high risk; improved; men; mindfulness; mindfulness intervention; mindfulness meditation; mindfulness-based stress reduction; mortality; mortality risk; novel; novel strategies; novel therapeutic intervention; patient population; profiles in patients; programs; side effect; vagus nerve stimulation

~30 million people in the US have chronic kidney disease (CKD) and are at significantly increased risk of cardiovascular (CV) disease and mortality. One major mechanism contributing to increased CV risk in this patient population is chronic over-activation of the sympathetic nervous system (SNS). SNS overactivity in CKD leads to difficult-to-control blood pressure (BP), and an abnormal circadian rhythm of BP characterized by failure to decrease BP at night (i.e. nondipping), that is independently associated with increased CV risk. Current strategies to combat SNS overactivation, however, are limited to sympatholytic medications that are often poorly tolerated with adverse side effects. Therefore, there is a critical need to develop novel, safe, and well-tolerated strategies for reducing SNS activity to improve clinical CV outcomes in this highly prevalent and growing population of CKD patients. One such novel approach at improving hemodynamics and autonomic function in CKD is mindfulness meditation (MM). Multiple prior studies have shown that MM, and specifically mindfulness-based stress reduction (MBSR), significantly reduces BP in a variety of patient populations. However, the mechanisms underlying the BP-lowering effect of MM are unclear. Small studies using indirect measures have suggested that MM may modulate the autonomic nervous system; however, no prior studies have used direct, gold-standard methods to interrogate the sustained effects of MM-based interventions on SNS. We performed the first studies using direct, intraneural measurements of muscle sympathetic nerve activity (MSNA) that demonstrate that MM acutely reduces BP and MSNA in CKD. In Aim1 (R61), we will test the hypothesis that 8 weeks of MBSR leads to sustained reductions in MSNA that are linked to improvements in daytime BP, and improved nocturnal dipping of BP in CKD. Following these studies, we will determine if transcutaneous vagus nerve stimulation (tVNS), a simple, noninvasive, self-administered adjunctive therapy, enhances the sympatho-inhibitory effects of MM in CKD. The vagus nerve, the major effector of the parasympathetic nervous system (PNS), is comprised of afferent nerve fibers that connect to the nucleus tractus solitarii (NTS) and other brainstem regions that influence central SNS output and baroreflexes, and efferent nerve fibers that activate the cholinergic anti-inflammatory pathway. Both experimental and human studies have demonstrated that tVNS reduces SNS activity, improves baroreflex sensitivity (BRS), and lowers inflammation, and our preliminary data demonstrate that tVNS reduces MSNA and improves BRS in CKD. In Aim 2 (R33), we will test the hypothesis that tVNS augments the beneficial effects of MBSR on MSNA and ambulatory BP profiles, and ameliorates SNS overactivation by improving arterial BRS and reducing inflammation in CKD. These studies will elucidate autonomic mechanisms underlying the beneficial effects of MM in CKD, while addressing a critical need for the development of safe, well-tolerated and effective treatment approaches to ameliorating SNS overactivity, reducing BP and improving CV risk profiles in patient with CKD.

在美国，约有3000万人患有慢性肾脏病（CKD），并有明显增加的风险 心血管疾病和死亡率。在此导致CV风险增加的一种主要机制 患者人群是交感神经系统（SNS）的慢性过度激活。 SNS过度活动 CKD导致难以控制的血压（BP），而BP的昼夜节律异常为特征 晚上未能降低BP（即非注销），这与CV风险的增加是独立的。 然而，当前打击SNS过度活化的策略仅限于交感神经药物 通常耐受性不良而受到不利副作用。因此，迫切需要开发新颖，安全和 在这种高度普遍的和 CKD患者人数不断增长。一种这种新颖的方法来改善血液动力学和自主教 CKD的功能是正念冥想（MM）。多个先前的研究表明MM，特别是 基于正念的压力减轻（MBSR）可显着降低各种患者人群的BP。 但是，MM降低BP降低作用的机制尚不清楚。使用间接的小型研究 措施表明，MM可以调节自主神经系统。但是，没有先前的研究 已经使用直接的金标准方法来询问基于MM的干预措施的持续影响 SNS。我们使用直接的，肌肉交感神经的直接内部测量进行了第一批研究 活性（MSNA）表明MM急性降低CKD中的BP和MSNA。在AIM1（R61）中，我们将测试 8周MBSR导致MSNA的持续减少的假设与改进有关 在白天的BP中，并改善了CKD中BP的夜间浸入。遵循这些研究，我们将确定是否 经皮神经刺激（TVNS），一种简单，无创，自我管理的辅助疗法， 增强了MM在CKD中的交汇抑制作用。迷走神经，是 副交感神经系统（PNS）由连接到细胞核的传入神经纤维组成 影响中央SNS输出和刺； 激活胆碱能抗炎途径的传出神经纤维。实验和人类 研究表明，TVN会减少SNS活性，改善Baroreflex敏感性（BRS）并降低 炎症，我们的初步数据表明，TVN会降低MSNA并改善CKD中的BRS。在 AIM 2（R33），我们将测试TVNS增强MBSR对MSNA和MSNA的有益影响的假设 卧床BP剖面，并通过改善动脉BR和减少来减轻SN的过度活化 CKD的炎症。这些研究将阐明具有有益作用的自主机制 CKD中的MM，同时满足了对安全，耐受性良好和有效治疗的开发的关键需求 改善SN的过度活动，减少BP并改善CKD患者的简历风险特征的方法。