Aldosterone and Sodium Regulation in Postural Tachycardia Syndrome

描述（由申请人提供）：体位性心动过速综合征（POTS）是一种衰弱的临床症状，其特征是对直立姿势的不耐受至少持续6个月，伴有持续的至少30bpm的直立性心动过速，并且直立性症状通过躺下缓解。POTS主要是一种女性疾病（发病率是男性的4-5倍），易患于年轻人，通常是育龄人群。我们和其他人发现，POTS患者的健康相关生活质量显著下降，与充血性心力衰竭或慢性阻塞性肺病患者相当。虽然心率明显升高是POTS的标志性生理表现，但还有其他一些重要的生理异常。我们发现大多数POTS患者血浆容量低。这会触发交感神经激活，从而导致心动过速。低血容量的确切原因尚未阐明，但我们的初步研究表明醛固酮水平矛盾地降低，这可能导致低血容量。令人惊讶的是，在低醛固酮和低血容量的情况下，血管紧张素II水平在POTS患者中升高。这些数据提示POTS患者肾上腺对血管紧张素II的敏感性降低。血管紧张素-醛固酮轴的扰动可能在POTS的病理生理中起关键作用。我们的初步研究还表明，POTS患者在压力或衰竭时保留钠的能力受损。除了POTS患者循环醛固酮水平不足外，这些患者对矿化皮质激素刺激的肾脏敏感性可能降低。鉴于许多POTS患者血浆量低，其管理的一个常见策略是要求患者遵循高钠饮食，以努力增加血浆量。不幸的是，没有公开的数据表明这种简单的策略对这类患者有效。我们的主要假设是醛固酮和钠处理的问题导致血浆容量减少，这些因素在POTS的病理生理中起重要作用。为了检验这些假设，我们提出以下具体目标：1。为了验证在POTS患者中AT1受体介导的醛固酮释放减弱的假设。2. 目的：探讨POTS患者对醛固酮的抗利钠反应。3. 为了验证高钠饮食对POTS患者血浆容量扩张迟钝（不足）的影响。4. 验证慢性矿化皮质激素刺激可恢复POTS血容量的假说。

DESCRIPTION (provided by applicant): Postural Tachycardia Syndrome (POTS) is a debilitating clinical condition characterized by intolerance to upright posture of at least 6 months duration, associated with consistent orthostatic tachycardia of at least 30 bpm, and with orthostatic symptoms relieved by lying down. POTS is primarily a disorder of women (4-5 fold incidence over men) with predisposition for younger individuals, often of child-bearing age. We and others have found that patients with POTS have significantly diminished health-related quality of life, to levels comparable to patients with congestive heart failure or chronic obstructive pulmonary disease. While grossly elevated heart rates are the hallmark physiologic findings in POTS, there are several other important physiological abnormalities. We have found low plasma volume in the majority of patients with POTS. This can trigger the sympathetic activation that drives the tachycardia. The exact cause of the hypovolemia has not been elucidated, but our preliminary studies indicate that aldosterone levels are paradoxically diminished, and this likely contributes to the low blood volume. Quite surprisingly in light of the low aldosterone and blood volume, angiotensin II levels were elevated in patients with POTS. These data suggest a decreased adrenal sensitivity to angiotensin II in patients with POTS. Perturbations in the Angiotensin-Aldosterone Axis may play a critical role in the pathophysiology of POTS. Our preliminary studies also indicate that patients with POTS have an impaired ability to retain sodium at times of stress or depletion. In addition to an inadequate level of circulating aldosterone in POTS, there could be diminished renal sensitivity to mineralocorticoid stimulation in these patients. Given the low plasma volume in many patients with POTS, a common strategy in their management is to ask patients to follow a high sodium diet, in an effort to increase their plasma volume. Unfortunately, there are no published data demonstrating that this simple strategy is effective in this patient population. Our overarching hypothesis is that problems in aldosterone and sodium handling lead to reduced plasma volume and that these factors play an important role in the pathophysiology of POTS. To the test these hypotheses we propose the following Specific Aims: 1. To test the hypothesis that in patients with POTS that AT1 Receptor mediated aldosterone release is blunted. 2. To determine the anti-natriuretic response to aldosterone in patients with POTS. 3. To test the hypothesis that patients with POTS have a blunted (inadequate) plasma volume expansion in response to a high sodium diet. 4. To test the hypothesis that chronic mineralocorticoid stimulation can restore blood volume in POTS.