Sympatho-inhibition with Mindfulness in Chronic Kidney Disease

慢性肾病中正念的交感抑制

基本信息

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
项目类别：
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

项目摘要

~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.

美国约有 3000 万人患有慢性肾病 (CKD)，并且患慢性肾病的风险显着增加心血管（CV）疾病和死亡率。导致心血管风险增加的一个主要机制患者群体的交感神经系统（SNS）慢性过度激活。 SNS 过度活跃 CKD 导致血压 (BP) 难以控制，并且血压昼夜节律异常，其特征是未能在夜间降低血压（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抗交感神经药物。通常耐受性差，并伴有不良副作用。因此，迫切需要开发新颖、安全、减少 SNS 活动的耐受性良好的策略，以改善这一高度普遍和常见的临床心血管结果 CKD 患者数量不断增加。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，特别是基于正念的减压（MBSR）可显着降低各种患者群体的血压。然而，MM 降压作用的机制尚不清楚。使用间接法进行的小型研究测量表明MM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探讨基于 MM 的干预措施的持续影响社交网络。我们使用直接的神经内测量肌肉交感神经进行了第一项研究活性 (MSNA) 表明 MM 可以急剧降低 CKD 患者的血压和 MSNA。在 Aim1 (R61) 中，我们将测试假设 8 周的 MBSR 会导致 MSNA 持续降低，从而改善症状白天血压下降，并且改善了 CKD 患者的夜间血压下降。经过这些研究，我们将确定是否经皮迷走神经刺激（tVNS），一种简单、无创、自我管理的辅助疗法，增强 MM 在 CKD 中的交感神经抑制作用。迷走神经，主要效应器副交感神经系统 (PNS) 由连接至细胞核的传入神经纤维组成孤立束 (NTS) 和影响中枢 SNS 输出和压力反射的其他脑干区域，以及激活胆碱能抗炎通路的传出神经纤维。既有实验性的，也有人类性的研究表明，tVNS 可降低 SNS 活性，提高压力反射敏感性 (BRS)，并降低炎症，我们的初步数据表明 tVNS 可以减少 MSNA 并改善 CKD 中的 BRS。在目标 2 (R33)，我们将检验 tVNS 增强 MBSR 对 MSNA 的有益作用的假设，以及动态血压曲线，并通过改善动脉 BRS 和减少 SNS 过度激活来改善 CKD 中的炎症。这些研究将阐明潜在有益作用的自主神经机制 MM 治疗 CKD，同时满足开发安全、耐受性良好且有效的治疗方法的迫切需求改善 CKD 患者 SNS 过度活跃、降低血压和改善 CV 风险状况的方法。