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.

项目摘要/摘要姿势心动过速综合征（POTS）是慢性静态肠道，过量直立心动过速没有低血压，主要发生在年轻女性中（> 85％）。症状是头晕，疲劳，认知损失和呼吸困难，呼吸症和通气不稳定性大约我们的新锅患者中有50％。我们最近的研究支持增加的低氧通气反应，颈动脉体外周化学反射的敏感性。单独产生的低碳酸氢菌就会产生心动过速并减少了脑血流（CBF），引起了许多花盆症状。与自愿过度换气，蜂窝盆与中枢血量减少和心脏输出有关，增加全身性血管抗性和BP，固定型血液集合以及Sigmoidal baroreflex关系的变化即使在仰卧时，这也有利于心动过速。颈动脉身体灵敏度高度塑性，可以迅速由慢性间歇性缺氧或“停滞缺氧” - 颈动脉体的复发性缺血来调节。停滞的缺氧可以通过“初始体位低血压”（IOH）产生，以完成BP的瞬时下降和CBF站立。 IOH的盆中异常，脑电导矛盾降低表明脑自动调节受损。我们假设盆栽起源的一种机制涉及颈动脉身体灵敏度通过反复发作的IOH导致直接和间接地驱动心动过速的超脑肾上腺素。动脉压力反射。我们将比较15至39岁的雌性锅患者（n = 40），没有（n = 40）正静态嗜睡，对健康的志愿者（n = 40），其目的是： 1。测试定位性心脏呼吸反应以确定延长ioH是否直立蜂窝盆中的低碳酸盐，但没有在对照或非hy骨盆中。脑血流，呼吸道和血液动力学测量，研究模脑血流并测量CBV的变化，区域血量和10分钟内的心脏输出以量化IOH，并进行10分钟的倾斜测试至70⁰ 为了量化心肺变化，我们可以分层呼吸症和非脾盆患者。 2.测试仰卧和交感神经的化学反射敏感性是否异常直立（45o）以及与牛津的相互作用如何测量的心脏和富有同情心受控气体条件：异位症缺氧和等含量高氧，以测量颈动脉体反射；高氧气高氧沉默周围化学感受器并将标准化压力反射和倾斜反应。 3。采用化学反射的物理调节来阐明蜂窝盆的机制，具有确定治疗方式的潜力，以降低化学反射敏感性和倍增性 - 使用血管紧张素1型受体阻滞剂，饮食中的硝酸盐捐赠NO和腺苷受体拮抗剂。