Autonomic Determinants of Postural Tachycardia Syndrome

姿势性心动过速综合征的自主决定因素

• 批准号: 9898448
• 负责人: Andre Diedrich
• 金额: $ 42.33万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898448
• 关键词: Adrenergic beta-Antagonists; Affect; Agonist; Blood Plasma Volume; Blood Pressure; Blood Volume; Characteristics; Chronic Obstructive Airway Disease; Clinical; Confidence Intervals; Congestive Heart Failure; Disease; Dose; Double-Blind Method; Functional disorder; Hypovolemia; Imidazolines; Impairment; Individual; Inpatients; Logistic Models; Metabolic; Muscle; Nature; Neck; Nerve; Neuropathy; Norepinephrine; Orthostatic tachycardia; Patients; Peripheral; Phase; Phenotype; Placebos; Plasma; Postural Orthostatic Tachycardia Syndrome; Public Health; Quality of life; Randomized; Reflex action; Rest; Sodium; Sodium Chloride; Sodium-Restricted Diet; Suction; Supination; Sympatholytics; Symptoms; Techniques; Testing; Valsalva Maneuver; deconditioning; disability; effective therapy; hemodynamics; high salt diet; improved; new therapeutic target; patient population; patient subsets; personalized medicine; response; secondary analysis; sedative; young woman

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.

抽象的 后心动过速综合征（POTS）是一种相对常见的条件，主要是健康的 年轻女性。 可与慢性阻塞性肺部疾病或充血性心力衰竭的患者相提并论 大多数患者的病理生理学是异质的。 响应对条件，部分神经病或低血容量。 非常高的盐饮食在受控条件下在代谢单元中无法解析体积的盐饮食 另一方面，POTS患者的缺陷或交感神经激活。 由肌肉交感神经活动（MSNA）确定的高静息仰卧中心交感神经流出 高于该组的95％置信区间。 与UPR血压和对Valsalva的压力反应的矛盾增加增加有关，并且出现 为了改善临床上的交感神经。因此，我们的总体假设是 中央交感神经活化为主要病理生理学的POTS患者。 该假设在使用中央交响曲的双盲，安慰剂对照，随机研究中 莫克森丁。 血量（特定的目标2），如果同志激活是 自然界的赔偿。 与老年人相比，镇静作用较小的交感性咪唑啉激动剂。 如果高盐饮食将是在特定AIM 3的情况下对锅的一种更有效的治疗方法。 提出一个侵犯，以确定中央处理增益和外围效应子的增益 通过随机颈部和小波的分类环识别技术通过分类循环识别技术的交感神经流出 从交感神经仪中提取单个峰值的分解。 增益在pspot中的高幅度，可以通过与莫克森丁的交感神经能够归一化。 使用Logistic模型进行二级分析来回归每个患者的PSPOTS状态，取决于 针对临床变量的微功能学，以识别可以使用的可读性可访问特性 在临床上识别肾上腺素能的盆中。 帮助我们的表型室内场所并开发新的治疗靶标。 研究将推进该领域，并最终帮助我们的患者。