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，主要影响其他方面的健康。 年轻女性。它是导致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，但潜在的 病理生理学是异质性的。在大多数患者中，交感神经的激活可能是一种适当的代偿 对解除条件、部分神经病变或血容量减少的反应。然而，我们的初步研究表明， 在代谢单元的受控条件下给予极高盐饮食并不能解决体积 POTS患者的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 由肌肉交感神经活动(MSNA)决定的高静息仰卧位中枢交感神经流出 高于该组的上限95%的可信区间。这个“初级交感神经”(PsPOTS)子集是 与对Valsalva的直立性血压和升压反应的矛盾增加有关，并出现 以改善临床对中枢交感神经的影响。因此，我们最重要的假设是，存在 POTS患者以中枢交感神经激活为主要病理生理机制。我们打算测试一下 这一假设是在一项使用中枢交感神经的双盲、安慰剂对照随机研究中提出的。 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，我们预计所有这些参数都会恶化 在性质上是补偿的。莫索尼定被选为这项概念验证研究的原因是它是一种有效的 交感神经溶解的咪唑啉激动剂，与较老的药物相比，镇静效果较差。我们还将确定 如果高盐饮食将是一种更有效的治疗POTS存在莫索尼定。在具体目标3中，我们 提出了一种确定中央处理增益和外围效应增益的互补方法 交感神经流出，利用随机颈吸力和小波的闭环识别技术 分解以从交感神经图中提取单个棘波。我们假设中央弧线 PSPOTS的增益较高，可通过莫索尼定的交感神经松解而归一化。我们还将表演一场 使用Logistic模型进行二次分析，以回归每个患者的psPOTS状态，由 对照临床变量进行显微神经学检查，以确定可以使用的易于获得的特征 临床上用来识别肾上腺素能亢进症。我们相信，拟议的研究将推动这一领域的发展，并最终 通过改进我们目前的表型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，并最终帮助我们的患者。

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.