Hyperpnea in Orthostatic Intolerance

描述（由申请人提供）：慢性体位不耐受在许多患者中表现为体位性心动过速综合征（POTS）。POTS的病理生理是异质的，但通常与交感神经激活增加有关，并常伴有呼吸急促而无呼吸急促。低碳酸血症使脑血流量减少，全身血管调节也受到不利影响。我们假设，直立应激时过度的压力反射卸载是POTS的起始事件，导致1)中枢化学受体活性抑制降低，2)交感诱导颈动脉体血流量减少导致外周化学受体活性刺激。化学感受器活性增加导致呼吸急促。我们将通过将有直立性呼吸困难（N=20）和无直立性呼吸困难（N=20）的POTS患者与健康对照（N=15）进行比较来验证这一假设，并提出以下研究问题：1)有呼吸困难的POTS患者的呼吸化学反射功能是否异常，其对通气、交感神经活动和气压反射功能的影响是否与对照组不同？2)与无呼吸困难的POTS患者和对照组相比，有呼吸困难的POTS患者是否产生过度的交感神经和化学反射活动以及肺伸展反应？3)与压力反射无关的交感刺激是否影响化学反射敏感性和交感神经活动？为了回答这些问题，我们将招募40名受试者和20名年龄和性别匹配的对照受试者。实验将检验呼吸急促是否由由气压反射卸荷引发的交感神经兴奋引起，由化学反射增强，并由肺伸展反射调节。在吸入二氧化碳和氧气的控制变化期间，将测量通气和肌肉交感神经活动的化学反射功能曲线（MSNA，由腓神经微神经造影获得）。化学感受器对压力反射的相互作用，以及压力反射对化学反射的相互作用将通过MSNA、连续血压评估、气相造影术、使用阻抗法和超声测量中心血流来评估。改进的Oxford法将用于间歇评估心血管和交感压力反射，并辅以基于小波的连续评估心率、BP、MSNA和外周血流量。呼吸急促和脑血流量减少是POTS患者严重衰弱和难以耐受的症状。前瞻性数据将明确高压氧性POTS的病理生理机制，以便开发特异性和有效的治疗方法。由于体位性心动过速综合征（POTS）引起的慢性直立性不耐受影响了超过一百万的美国人，其中大多数是年轻女性，她们无法获得有报酬的工作或上学。虽然心率加快（心动过速）是该病的标志，但患者通常会出现换气过度和呼吸困难，目前仍无法解释。在目前的建议中，我们将对循环和呼吸系统进行复杂的测试，以研究POTS直立过度通气的原因、机制和潜在的治疗方法。

DESCRIPTION (provided by applicant): Chronic orthostatic intolerance takes the form of postural tachycardia syndrome (POTS) in many patients. POTS pathophysiology is heterogeneous but frequently related to increased sympathetic activation and often accompanied by hyperpnea without tachypnea. Cerebral blood flow is reduced by hypocapnia and systemic vasoregulation is also detrimentally affected. We hypothesize that excessive baroreflex unloading during orthostatic stress is the initiating event in POTS resulting in 1) reduced inhibition of chemoreceptor activity centrally and 2) stimulation of peripheral chemoreceptor activity due to sympathetically induced reductions in blood flow to the carotid body. Increased chemoreceptor activity leads to hyperpnea. We will test this hypothesis by comparing POTS patients with orthostatic hyperpnea (N=20) and without orthostatic hyperpnea (N=20), to healthy control subjects (N=15) asking the following research questions: 1) Is the respiratory chemoreflex function abnormal in POTS with hyperpnea and does it affect ventilation, sympathetic activity and baroreflex function differently compared to control subjects? 2) Does baroreflex unloading produce excessive sympathetic and chemoreflex activity, and pulmonary stretch response in POTS patients with hyperpnea compared to POTS patients without hyperpnea and to control subjects? 3) Does sympathetic stimulation unrelated to the baroreflexes affect chemoreflex sensitivity and sympathetic nerve activity in POTS? : To answer these questions we will enroll 40 subjects and 20 age and gender matched control subjects. Experiments will test whether hyperpnea is caused by sympathoexcitation initiated by baroreflex unloading, potentiated by chemoreflexes, and modulated by pulmonary stretch reflexes. Chemoreflex function curves for ventilation and muscle sympathetic nerve activity (MSNA, obtained by peroneal microneurography) will be measured during controlled changes in inhaled CO2 and oxygen. Interactive effects of chemoreceptors on baroreflexes, and baroreflexes on chemoreflexes will be assessed using MSNA, continuous BP assessment, pneumotachography, and measures of central blood flow using impedance methods, and ultrasound. The modified Oxford method will be used to intermittently assess the cardiovagal and sympathetic baroreflex, and will be supplemented by wavelet based continuous assessment of heart rate, BP, MSNA and peripheral blood flow. Hyperpnea and reduced cerebral blood flow is a severely debilitating and poorly tolerated finding in POTS. Prospective data will define the pathophysiological mechanisms involved in hyperpneic POTS in order to develop specific and effective therapy for the illness. Project Narrative Chronic orthostatic intolerance due to the postural tachycardia syndrome (POTS) affects over a million Americans, mostly young women, who are prevented from gainful employ or school attendance. While a rapid heart rate (tachycardia) is the hallmark of the illness, patients often develop hyperventilation and respiratory difficulty which remain unexplained. In the current proposal we will perform sophisticated tests of the circulation and respiration systems to study the causes, mechanisms and potential treatments of upright hyperventilation in POTS.