Sympatho-inhibition with Mindfulness in Chronic Kidney Disease

慢性肾病中正念的交感抑制

• 批准号: 10706603
• 负责人: Jeanie Park
• 金额: $ 67.04万
• 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706603
• 关键词: Acute; Address; Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; African American; Anti-Inflammatory Agents; Antihypertensive Agents; Autonomic nervous system; Baroreflex; Binding; 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; Electric Stimulation; Equilibrium; Event; Failure; Fatigue; Health; Hour; Human; Hyperlipidemia; Hypertension; 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; Persons; Pharmaceutical Preparations; Phase; Physiological; Population; Randomized; Randomized Controlled Clinical Trials; Regulation; Renal function; Rest; Risk Reduction; Role; Safety; Self Administration; Sympathetic Nervous System; Sympatholytics; Techniques; Testing; Therapeutic; Vagus nerve structure; active control; afferent nerve; blood pressure control; blood pressure reduction; cardiovascular disorder risk; cardiovascular risk factor; cholinergic; 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; pharmacologic; 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疾病(CKD)，患慢性肾病的风险显著增加 心血管疾病和死亡率。导致这一风险增加的一个主要机制是 患者群体是交感神经系统(SNS)慢性过度激活。SNS过度活跃在 慢性肾脏病导致难以控制的血压，以及异常的血压昼夜节律，特征是 夜间未能降低血压(即不降低血压)，这与心血管风险增加独立相关。 然而，目前对抗SNS过度激活的策略仅限于以下交感神经溶解药物 通常耐受性差，有不良副作用。因此，迫切需要开发新颖、安全和 耐受性良好的策略，用于减少SNS活动，以改善这种高度流行和 CKD患者的人口不断增加。一种改善血流动力学和自主神经的新方法 CKD的功能是正念冥想(MM)。先前的多项研究表明，MM，特别是 基于正念的压力减轻(MBSR)显著降低了各种患者的血压。 然而，MM的降压作用机制尚不清楚。使用间接的小型研究 已有研究表明多发性骨髓瘤可能调节自主神经系统；然而，之前没有研究 使用直接的黄金标准方法来询问以MM为基础的干预措施对 社交网络。我们使用直接的神经内测量肌肉交感神经进行了第一次研究。 活动度(MSNA)表明MM能显著降低CKD患者的BP和MSNA。在Aim1(R61)中，我们将测试 假设8周的MBSR会导致MSNA持续减少，这与改善有关 改善CKD患者夜间血压的变化。在这些研究之后，我们将确定是否 经皮迷走神经刺激(TVNS)是一种简单、非侵入性的自我给药辅助疗法， 增强MM对CKD的交感神经抑制作用。迷走神经，迷走神经的主要效应器 副交感神经系统(PNS)是由连接到核团的传入神经纤维组成的 孤束(NTS)和其他影响中枢SNS输出和压力感受器反射的脑干区，以及 能激活胆碱能抗炎途径的传出神经纤维。无论是实验性的还是人类的 研究表明，tVNS降低了SNS的活性，提高了压力感受器反射敏感性(BRS)，并降低了 炎症，我们的初步数据表明，tVNS减少了MSNA，改善了CKD的BRS。在……里面 目的2(R33)，我们将检验tVNS增强MBSR对MSNA和 动态血压描记，通过改善动脉BRS和降低SNS过度激活 慢性肾脏病的炎症反应。这些研究将阐明潜在的自主神经机制的有益影响 慢性肾脏病中的MM，同时满足开发安全、耐受性好和有效的治疗的迫切需要 改善慢性肾脏病患者SNS过度活动、降低血压和改善心血管风险的方法。