Autonomic Determinants of Postural Tachycardia Syndrome

摘要 体位性心动过速综合征（POTS）是一种相对常见的疾病， 年轻女性。它是造成严重残疾和严重损害生活质量的原因 与慢性阻塞性肺疾病或充血性心力衰竭患者相当， 病理生理学是异质的。在大多数患者中，交感神经激活可能是一种适当的代偿性反应。 对去适应、部分神经病变或血容量不足的反应。然而，我们的初步研究表明， 在代谢单位中在受控条件下给予的极高盐饮食不能解决体积问题， 缺陷或交感神经激活。另一方面，我们已经确定了一部分患者 静息仰卧位中枢交感神经流出量高，由肌肉交感神经活动（MSNA）确定 高于该组的95%置信区间上限。该“初级交感神经”（psPOTS）子集是 与直立血压和对Valsalva的升压反应的矛盾增加相关，并且似乎 改善中枢交感神经阻滞剂的临床疗效因此，我们的总体假设是，有一个子集， POTS患者以中枢交感神经激活为主要病理生理机制。我们建议测试 在一项使用中枢交感神经阻滞剂的双盲、安慰剂对照、随机研究中， 莫索尼定如果我们的假设是正确的，交感神经抑制将改善直立症状（具体目标1）， 血容量（特定目标2）。如果交感神经激活被阻断， 补偿性的莫索尼定被选择用于这项概念验证研究，因为它是一种有效的 交感神经阻滞咪唑啉激动剂，与较老的药物相比，具有较低的镇静作用。我们还将确定 高盐饮食是否是存在莫昔尼定的POTS的更有效的治疗。在具体目标3中，我们 提出了一种互补的方法来确定中央处理增益和外围效应器增益， 交感神经流出，通过使用随机颈部抽吸和小波的闭环识别技术 分解以从交感神经图中提取单个尖峰。我们假设中心弧 psPOTS中的增益较高，并且可以通过用莫索尼定的交感神经松解来正常化。我们还将执行一项 二次分析，使用逻辑模型回归每例患者的psPOTS状态，通过 显微神经造影术，针对临床变量，以确定可使用的易于获得的特征 临床上识别肾上腺素能亢进的POTS。我们相信这些研究将推动这一领域的发展， 通过提高我们目前的表型分析能力和开发新的治疗靶点来帮助我们的患者。 研究将推动这一领域的发展，最终帮助我们的病人。

Abstract Postural tachycardia syndrome (POTS) is a relatively common condition affecting mostly otherwise healthy young women. It is the cause of significant disability and an impairment in quality of life of a magnitude comparable to patients with chronic obstructive pulmonary disease or congestive heart failure but the underlying pathophysiology is heterogeneous. In most patients sympathetic activation is likely an appropriate compensatory response to deconditioning, partial neuropathy or hypovolemia. Our preliminary studies, however, show that a very high salt diet administered under controlled conditions in a metabolic unit does not resolve the volume deficits or sympathetic activation in POTS patients. On the other hand, we have identified a subset of patients with high resting supine central sympathetic outflow, as determined by muscle sympathetic nerve activity (MSNA) above the upper 95% confidence interval for the group. This “primary sympathetic” (psPOTS) subset is associated with a paradoxical increase in upright blood pressure and pressor responses to Valsalva, and appear to improve clinically on central sympatholytics. Thus, our overarching hypothesis is that there is a subset of POTS patients with a central sympathetic activation as the primary pathophysiology. We propose to test this hypothesis in a double blind, placebo-controlled, randomized study using the central sympatholytic moxonidine. If our hypothesis is true, sympathetic inhibition will improve orthostatic symptoms (Specific Aim 1), blood volume (Specific Aim 2). We would expect worsening of all these parameters if sympathetic activation is compensatory in nature. Moxonidine was selected for this proof-of-concept study because it is an effective sympatholytic imidazoline agonist that has less sedative effect compared to older agents. We will also determine if a high salt diet will be a more effective treatment for POTS in the presence of moxnidine. In Specific Aim 3, we propose a complementary approach to determine the central processing gain and peripheral effector gain of sympathetic outflow, by closed loop identification techniques using randomized neck suction and wavelet decomposition to extract individual spikes from sympathetic neurograms. We hypothesize that the central arc gain is higher in psPOTS and can be normalized by sympatholysis with moxonidine. We will also perform a secondary analysis using a logistic model to regress each patient's psPOTS status, as determined by microneurography, against clinical variables, to identify readilly accessible characteristics that can be used clinically to identify hyperadrenergic POTS. We believe the proposed studies will advance this field and ultimately help our patients by improving our current phenotyping capabilities and developing new therapeutic targets. studies will advance this field and ultimately help our patients.