Sympatho-inhibition with Mindfulness in Chronic Kidney Disease

美国约有3000万人患有慢性肾脏疾病（CKD）， 心血管（CV）疾病和死亡率。在这种情况下，导致CV风险增加的一个主要机制是 患者群体是交感神经系统（SNS）的慢性过度激活。SNS过度活跃， 慢性肾脏病导致血压（BP）难以控制，并且血压昼夜节律异常，其特征为 夜间血压下降失败（即非下降），与CV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、安全且 在这一高度流行且 越来越多的CKD患者。一种改善血液动力学和自主神经功能的新方法 在CKD中起作用的是正念冥想（MM）。多项先前的研究表明，MM，特别是 基于正念的减压（MBSR）在各种患者人群中显著降低了血压。 然而，MM降血压作用的机制尚不清楚。使用间接法的小型研究 测量表明MM可能调节自主神经系统;然而，没有先前的研究 已经使用直接的，金标准的方法来询问基于MM的干预措施的持续影响， SNS.我们进行了第一次研究，使用直接的，神经内测量肌肉交感神经 活性（MSNA），证明MM急性降低CKD中的BP和MSNA。在Aim 1（R61）中，我们将测试 假设8周的正念减压疗法导致MSNA持续下降，这与改善有关 改善CKD患者夜间血压下降。在这些研究之后，我们将确定 经皮迷走神经刺激（tVNS）是一种简单、无创、自我管理的连续疗法， 增强MM在CKD中的交感神经抑制作用。迷走神经，主要的效应器， 副交感神经系统（PNS）由连接到核的传入神经纤维组成 孤束（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。无论是实验性的还是人类的 研究表明，tVNS减少SNS活动，改善压力反射敏感性（BRS），并降低 我们的初步数据表明，tVNS减少了CKD中的MSNA并改善了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， 动态血压曲线，并通过改善动脉BRS和降低 CKD的炎症。这些研究将阐明的自主机制的有益影响， CKD中的MM，同时满足开发安全、耐受性良好和有效治疗的迫切需求 改善CKD患者SNS过度活动、降低BP和改善CV风险特征的方法。

~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.