Mechanism of Chemoreflex and Baroreflex alterations causing Postural Tachycardia Syndrome in POTS patients with orthostatic hyperpnea and hypocapnia.

化学反射和压力感受反射改变引起体位性心动过速综合征的 POTS 患者直立性呼吸过度和低碳酸血症的机制。

基本信息

批准号：
10705326
负责人：
MARVIN S MEDOW
金额：
$ 70.86万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-23 至 2024-08-31
项目状态：
已结题

项目摘要

Project Summary/Abstract Postural tachycardia syndrome (POTS) is chronic orthostatic intolerance with excessive upright tachycardia without hypotension and occurs mostly in young females (>85%). Symptoms are lightheadedness, fatigue, cognitive loss, and dyspnea with hyperpneic hypocapnia and ventilatory instability in approximately 50% of our new POTS patients. Our recent studies support an increased hypoxic ventilatory response, sympathoexcitation with sensitization of the carotid body peripheral chemoreflex. Hypocapnia alone produces tachycardia and reduces cerebral blood flow (CBF) engendering many POTS symptoms. Unlike voluntary hyperventilation, hyperpneic POTS is related to decreased central blood volume and cardiac output, increased systemic vascular resistance and BP, splanchnic blood pooling, and a shift in the sigmoidal baroreflex relation that favors tachycardia even while supine. Carotid body sensitivity is highly plastic and can be rapidly conditioned by chronic intermittent hypoxia or by “stagnant hypoxia” - recurrent ischemia of the carotid body. Stagnant hypoxia can be produced by “initial orthostatic hypotension” (IOH) comprising a transient fall in BP and CBF on standing. IOH is abnormal in POTS with a paradoxical decrease in cerebral conductance indicating impaired cerebral autoregulation. We hypothesize that a mechanism for the genesis of POTS involves carotid body sensitization initiated by recurrent IOH results in hyperpneic hypocapnia driving tachycardia directly and indirectly by resetting arterial baroreflexes. We will compare female POTS patients aged 15 to 39 years with (N=40) and without (N=40) orthostatic hyperpnea, to healthy volunteers (N=40) with the following aims: 1. To test orthostatic cardiorespiratory responses to determine whether prolonged IOH precedes upright hypocapnia in hyperpneic POTS but not in controls or non-hyperpneic POTS. Cerebral blood flow, respiratory and hemodynamic measurements, investigating splanchnic blood flow and measuring changes of CBV, regional blood volumes, and cardiac output during a 10 min stand to quantify IOH, and a 10 min tilt test to 70⁰ to quantitate cardiorespiratory changes will allow us to stratify hyperpneic and non-hyperpneic POTS patients. 2.To test if chemoreflex sensitization of ventilation and sympathetic activity are abnormal when supine and upright (at 45o) and how that interacts with Oxford measured cardiovagal and sympathetic baroreflexes under controlled gas conditions: isocapnic hypoxia and isocapnic hyperoxia to measure carotid body reflex; hyperoxic isocapnia and hyperoxic hypercapnia to measure central chemoreflexes. Hyperoxia silences peripheral chemoreceptors and will normalize baroreflex and tilt responses. 3. To employ pharmaceutical modulation of the chemoreflex to elucidate mechanisms of hyperpneic POTS, with the potential of determining treatment modalities to reduce chemoreflex sensitivity and hyperpnea – using an angiotensin type 1 receptor blocker, dietary nitrate to donate NO, and an adenosine receptor antagonist.

项目概要/摘要姿势性心动过速综合征 (POTS) 是一种慢性直立不耐受症，伴有过度直立心动过速不伴有低血压，主要发生在年轻女性中（>85%）。疲劳、认知丧失和呼吸困难，伴有高呼吸性低碳酸血症和通气不稳定，大约我们最近的研究支持 50% 的新 POTS 患者缺氧通气反应增加。交感兴奋与颈动脉体周围化学反射的敏化单独产生低碳酸血症。与自愿不同，心动过速减少和脑血流量 (CBF) 会导致许多 POTS 症状。过度通气、呼吸过度 POTS 与中心血容量和心输出量减少、增加全身血管阻力和血压、内脏血液汇集以及乙状结肠压力反射关系的转变即使在仰卧时也有利于心动过速颈动脉体敏感性具有高度可塑性并且可以迅速变化。慢性间歇性缺氧或“停滞性缺氧”——颈动脉体反复缺血。停滞性缺氧可能是由“初始直立性低血压”（IOH）造成的，包括血压短暂下降 POTS 中的 IOH 和站立时的 CBF 异常，并伴有脑电导的反常降低。表明大脑自动调节功能受损。我们追寻 POTS 发生的机制涉及颈动脉体敏化启动反复发生的 IOH 会导致高呼吸性低碳酸血症，直接或间接通过复位驱动心动过速我们将比较 15 至 39 岁的女性 POTS 患者有（N=40）和没有的情况。 (N=40) 直立性呼吸过度，针对健康志愿者 (N=40)，目的如下： 1. 测试立位心肺反应以确定长时间IOH是否先于直立呼吸过度的 POTS 中出现低碳酸血症，但对照组或非呼吸过度的 POTS 中则没有。脑血流、呼吸。和血流动力学测量，研究内脏血流并测量 CBV 的变化， 10 分钟站立期间的局部血容量和心输出量以量化 IOH，以及 10 分钟倾斜测试至 70⁰ 量化心肺变化将使我们能够对呼吸过度和非呼吸过度的 POTS 患者进行分层。 2.检测仰卧位和交感神经活动的化学反射敏化和交感神经活动是否异常。直立（45°）以及它如何与牛津测量的心迷走神经和交感压力反射相互作用受控气体条件：等二氧化碳低氧和等二氧化碳高氧以测量颈动脉体反射；等碳酸血症和高氧高碳酸血症可测量中枢化学反射。化学感受器并使压力反射和倾斜反应正常化。 3. 采用化学调节药物调节来阐明呼吸过度 POTS 的机制，具有确定治疗方式以降低化学反射敏感性和呼吸过度的潜力 - 使用 1 型血管紧张素受体阻滞剂、提供 NO 的膳食硝酸盐和腺苷受体拮抗剂。