PHARMACOLOGIC PROBES IN NEURALLY-MEDIATED SYNCOPE

这些研究的总体目标是确定神经介导性晕厥亚型的关键病理生理特征，这是一种在中青年患者中引起大量发病率的疾病。晕厥是一个常见的问题，占所有急诊科就诊的3%。虽然注意力适当地集中在危及生命的原因上，但30-65%被归类为“反射性”或“未知”原因的患者也承受着巨大的痛苦。最近的初步数据支持了这些研究的基本假设，即神经介导性晕厥患者可以通过自主心血管调节的不同异常来分类，这将预测治疗反应。我们将在假设驱动的临床研究中探讨中枢和外周自主神经机制，并根据这些研究结果进行为期2年的临床试验。我们将研究患者和匹配的正常对照对象，通过记录肌肉交感神经活动，测定去甲肾上腺素溢出和清除，以及血浆中循环儿茶酚胺及其代谢物的水平，直接评估自主神经反应，包括酵母和对交感神经刺激的反应，以及对特征明确的皮质应激源（修正的Stroop和心算与人际刺激）的反应。生理应激源（等距握力和寒冷）和梯度平视倾斜。我们还将确定周围血管反应是否被改变。在交感神经反应减弱的患者中，我们将评估增强这种反应的替代方法，使用育亨宾对抗alpha2受体或使用去丙咪嗪抑制去甲肾上腺素转运体。我们将定义亚急性（5d）治疗这些药物对中枢和外周α -肾上腺素能反应的影响，并确定是否存在戒断现象。最后，根据这些研究的结果，我们将对这些药物进行为期24个月的安慰剂对照随机临床试验，评估它们在预防晕厥发作方面的功效，它们对心律的影响，它们可能的中枢副作用，以及通过超声心动图评估交感神经张力增加对心脏质量和心室大小的潜在不良影响。这些研究将直接适用于这些失能性疾病患者的评估和治疗。

The overall goal of these studies is to define the critical pathophysiological features of subtypes of neurally-mediated syncope, a disorder that cause substantial morbidity in young and middle-aged patients. Syncope is a common problem, accounting for as many as 3% of all emergency department visits. While attention has appropriately focused on life-threatening causes, the 30-65% of patients who are categorized as having either "reflex" or "unknown" causes suffer significant capacity as well. The underlying hypothesis of these studies, supported by recent preliminary data, is that patients with neurally- mediated syncope may be categorized by differential abnormalities of autonomic cardiovascular regulation that will predict therapeutic responses. We will address both central and peripheral autonomic mechanisms in hypothesis-driven clinical studies, and follow with a 2- year clinical trial, based on the results of these investigations. We will study patients and matched normal control subjects, assessing autonomic responses directly using recordings of muscle sympathetic nerve activity and determination of norepinephrine spillover and clearance, as well as plasma levels of circulating catecholamines and their metabolites, both at yeast and in response to sympathetic stimulation with well-characterized cortical stressors (modified Stroop and mental arithmetic with interpersonal provocation), physiological stressors (isometric handgrip and cold) and graded head-up tilt. We will also define whether peripheral vascular responses are altered. In patients with reduced sympathetic responses, we will assess alternative approaches to enhancing such responses, using alpha2 receptor antagonism with yohimbine or inhibition of the norepinephrine transporter with desimipramine. We will define the effect of sub-acute (5d) treatment with these agents on central and peripheral alpha-adrenergic responses, and determine whether a withdrawal phenomenon exists. Finally, depending on the results of these studies, we will conduct a 24 month, placebo-controlled, randomized clinical trial of these agents, assessing their efficacy in preventing syncopal episodes, their effect on cardiac rhythm, their possible central side effects, and the potential adverse effects of increased sympathetic tone on cardiac mass and chamber size with echocardiography. These studies will be directly applicable to the evaluation and treatment of patients with these incapacitating disorders.