Hyperpnea in Orthostatic Intolerance

描述(由申请人提供)：在许多患者中，慢性立位耐受性表现为体位性心动过速综合征(POTS)。POTS的病理生理学是不同的，但经常与交感神经激活增加有关，并经常伴随无呼吸急促的呼吸过多。低碳酸血症会减少脑血流量，全身血管调节也会受到不利影响。我们假设，在立位应激期间过度的压力感受性反射卸载是POTS的起始事件，导致1)中枢化学感受器活性抑制减少，2)由于交感诱发的颈动脉体血流量减少而刺激外周化学感受器活性。化学感受器活性增加会导致呼吸暂停。我们将通过比较患有直立性高呼吸和无直立性高呼吸的POTS患者(N=20)和健康对照组(N=15)来验证这一假设，并提出以下研究问题：1)有高呼吸暂停的POTS患者的呼吸化学反射功能是否异常，它对呼吸、交感神经活动和压力反射功能的影响是否与对照组不同？2)压力反射卸载是否产生过度的交感和化学反射活动，3)与压力反射无关的交感神经刺激是否影响POTS中的化学反射敏感性和交感神经活动？：为了回答这些问题，我们招募了40名受试者和20名年龄和性别匹配的对照组。实验将测试呼吸亢进是否由压力感受性反射卸载引发的交感兴奋引起，化学反射增强，以及肺伸展反射调制。在吸入二氧化碳和氧气的受控变化期间，将测量呼吸和肌肉交感神经活动的化学反射功能曲线(由腓骨显微神经摄影获得的MSNA)。化学感受器对压力反射的交互作用，以及压力反射对化学反射的交互作用，将使用MSNA、连续的BP评估、气动心动图以及使用阻抗方法和超声测量中心血流量来评估。改进的Oxford方法将用于间歇性地评估心脏迷走神经和交感压力反射，并将补充基于小波的心率、BP、MSNA和外周血流量的连续评估。在POTS中，呼吸暂停和脑血流量减少是一个严重的衰弱和耐受性差的发现。前瞻性数据将确定与呼吸暂停相关的病理生理学机制，以开发针对这种疾病的特异和有效的治疗方法。项目描述由于体位性心动过速综合征(POTS)导致的慢性直立不耐受影响了100多万美国人，其中大部分是年轻女性，她们无法获得有报酬的工作或上学。虽然心率过快(心动过速)是这种疾病的特征，但患者往往会出现过度换气和呼吸困难，这些仍然无法解释。在目前的建议中，我们将对循环系统和呼吸系统进行复杂的测试，以研究盆腔直立过度通风的原因、机制和可能的治疗方法。

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.