Orthostatic Intolerance in Autonomic Neuropathies & Postural Tachycardia Syndrome

自主神经病的直立不耐受

• 批准号: 7892374
• 负责人: PHILLIP A LOW
• 金额: $ 24.84万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7892374
• 关键词: 6-chloropenicillanic acid S-sulfoxide; Acute; Adrenergic Agents; Adult; Affect; African American; Agonist; Anhidrosis; Antibodies; Antibody titer measurement; Asians; Autoimmune Process; Autonomic nervous system disorders; Axon; Baroreflex; Beds; Binding Sites; Blood Plasma Volume; Blood Vessels; Blood capillaries; Brain Stem; Caliber; Carbon Dioxide; Cardiac; Catecholamines; Caucasians; Caucasoid Race; Cerebrum; Cholinergic Receptors; Chronic; Clinical; Codon Nucleotides; Collaborations; Constitutional; Data; Denervation; Diagnosis; Disease; Dissection; Distal; Double-Blind Method; Down-Regulation; Dysautonomias; Epinephrine; Ethnic group; Evaluation; Failure; Fatigue; Femoral vein; Filtration; Frequencies; Functional disorder; Funding; Gender; Genetic Polymorphism; Genotype; Haplotypes; Head; Heart Rate; Hispanics; Human Resources; Hypocapnia; Hypovolemia; Immune; Immunoglobulin G; Individual; Intravenous Immunoglobulins; Isoproterenol; Label; Laboratories; Latino; Leg; Lesion; Lewy Body Disease; Limb structure; Liquid substance; Longitudinal Studies; Lower Extremity; Mails; Mediating; Mus; Neuropathy; Norepinephrine; Outcome; Patients; Perfusion; Peripheral; Phase; Phenotype; Phenylephrine; Placebos; Plasma; Plethysmography; Positioning Attribute; Pressoreceptors; Production; Prospective Studies; Proteins; Recovery; Recruitment Activity; Reflex action; Reporting; Research Personnel; Resistance; Respiration; Rest; Risk Factors; Series; Single Nucleotide Polymorphism; Site; Sweat test; Symptoms; Syndrome; System; Tachycardia; Testing; Therapeutic; Time; Tyramine; United States National Institutes of Health; Vasodilation; Vasomotor; Veins; Venous; Venous Pressure level; Work; adrenergic; arteriole; autonomic neuropathy; base; capillary; cerebral hypoperfusion; cholinergic; cohort; desensitization; falls; follow-up; functional outcomes; heart imaging; improved; improved functioning; indexing; instrument; interest; metaiodobenzylguanidine; neurotransmission; placebo controlled study; programs; prospective; pyridostigmine; receptor; research clinical testing; response; segregation; treatment trial; vasoconstriction; vigilance

The Mayo Autonomic Disorders PPG was the first autonomic disorders program project funded by NIH. In the 9 years since its inception, we have continued our focus on orthostatic intolerance and failure. Orthostatic intolerance can be unassociated with OH as in POTS. Over the past 10 years we have assembled a unique combination of personnel, patients, and instruments to facilitate the series of important studies we are proposing; some of which can only be done at Mayo. POTS: At the inception of this PPG, little information was available on the pathophysiology of POTS. Orthostatic intolerance without OH occurs much more commonly than OH in a ratio of approximately 5:1.46'47 Over the last 4 years of the current cycle, significant progress has been made in this and other autonomic programs. We reported that about 50% of POTS may be post-infectious suggesting an immune-mediated limited autonomic neuropathy. ' Since that time, the clinical features have been prospectively evaluated using a standardized instrument.58 Independent clinical and laboratory features that aid the diagnosis of POTS have been defined and its outcome evaluated.51 We have, for the first time, developed a validated instrument to evaluate autonomic symptoms.73 Significant advances have also been made on its pathophysiology. Peripheral denervation has been confirmed, and about 10% have ganglionic antibody.76 Norepinephrine spillover in the leg is reduced by 50% in POTS31 and there is denervation supersensitivity of the lower extremity veins.71 Sudomotor denervation is present in the distal lower extremity.26'48 Denervation results in an increase in vascular capacity manifested as increased venous pooling48'66 and a reduction in preload.47 Excessive venous pooling and/or a reduced plasma volume results in a hyperadrenergic state29 and there may be a component of p-receptor supersensitivity.69 Cerebral hypoperfusion occurs during HUT but not during supine rest, in part due to hypocapnia.53 HUT results in a large but transient fall in BP, with recovery within 30 seconds. During this interval, the depth but not rate of respiration increases53 and pCO2 falls resulting in a large fall in cerebral perfusion. Reversing hypocapnia with rebreathing CO2 will normalize cerebral perfusion.53 POTS is heterogenous in its manifestations. The term mild orthostatic intolerance is often applied to a heterogeneous group of subjects that include constitutional orthostatic intolerance, deconditioning, and mild hypovolemia. A hyperadrenegic state is typical,29'32'47'61 characterized by a heart rate increment >30 bpm, an absolute orthostatic heart rate >120 b.p.m, orthostatic plasma norepinephrine >600 pg/ml and is the most likely group to have reduced plasma volume. There is commonly some evidence of peripheral denervation and sometimes the term neuropathic POTS is used. Baroreflex vasoconstriction is often reduced or absent on the Valsalva maneuver47'61 and total systemic resistance is reduced.68 Pressor response to tyramine is reduced and response to phenylephrine increased, suggestive of postganglionic denervation.32 Symptoms suggestive of dysregulation are also seen, manifested as excessive increases in diastolic BP, excessive oscillations in BP on HUT, and spontaneous episodes of dysautonomia.48 It has been .suggested that these patients have a brain-stem disorder. One patient responded dramatically to decompression of the rostral ventrolateral medulla.46'48 Vasomotor, especially venomotor, tone can be impaired in an autonomic neuropathy.61 Excessive sequestration of labeled protein was demonstrated in the calves with standing, correctable by venous compression.48'70 An excessive fall in enddiastolic volume on head-up tilt (HUT) also suggests venous pooling.47 Venous pooling would result in a reduction in preload and excessive baroreceptor unloading in the upright position, with a resultant increase in sympathetic outflow. HUT results in excessive transcapillary efflux in POTS 7 and can be reflected in a progressive fall in plasma volume with continuation of standing.15 Venous occlusion plethysmography has been utilized to separately evaluate the venous and capillary components of fluid segregation and transfer. When the limb is occluded above venous pressure, the increase in limb volume evolves through two phases. There is an initial volume increase that corresponds to venous filling. This phase is followed by a slower phase representing net capillary filtration.22 A large increase in orthostatic norepinephrine is well documented in POTS (see above). Less well known is that orthostatic and supine epinephrine can also be increased in POTS. The vasoreactivity of (32-adrenoreceptors to epinephrine is important in orthostatic preload. Of particular interest is the relationship between certain polymorphisms of $2- adrenoreceptors and function. Significant interest has focussed on the relationship between two common polymorphisms, one at codon 16 and one at codon 27, on agonist-mediated vasodilatation and desensitization in the venous bed. Subjects who were homozygous for Argl6 had almost complete desensitization; venodilatation in response to isoproterenol in this group returned to normal much more quickly than subjects who were homozygous for Glyl6 who had more sustained venodilation.9 Subjects who were homozygous for Glu27 had higher maximal venodilatation in response to isoproterenol than those who were homozygous for Gln27. Some investigators have expanded interest from single nucleotide polymorphisms (SNPs) to chromosomally phased SNPs (haplotypes).11 The distribution of some haplotypes are quite different in Caucasian, African-American, Asian, and Hispanic-Latino ethnic groups with >20-fold differences among the frequencies of the four major haplotypes. Functional differences were shown to be more dependent on haplotype pairs than to individual SNPs. The results indicate that the unique interactions of multiple SNPs within a haplotype ultimately can affect biologic and therapeutic phenotype. Applied to POTS, and based on our preliminary data, it appears that there is an overrepresentation of a certain haplotype that results in sustained venodilatation (preliminary data). We will systematically explore the relationship among the interplay of epinephrine, polymorphic (32AR with its association with resistance to agonist-mediated desensitization leading to prolonged vasodilatation, and studies on veins and HUT indices.

Mayo自主疾病PPG是NIH资助的第一个自主疾病计划项目。在9年 自成立以来，我们一直致力于直达不宽容和失败。体位不耐受可能是 与锅中的OH无关。在过去的十年中，我们组装了独特的人员，患者， 和促进我们提出的一系列重要研究的工具；其中一些只能在Mayo上完成。 花盆：在此PPG的成立之初，几乎没有关于盆栽病理生理学的信息。原位 在过去的4年中，不耐受性oh的发生比OH的比率大约为5：1.46'47 当前周期和其他自主计划已经取得了重大进展。我们报告说约有50％ 盆中可能是感染后的，暗示免疫介导的有限的自主神经病。从那时起， 临床特征已经使用标准化仪器进行了前瞻性评估。58独立的临床和实验室 已经定义了有助于诊断盆栽的特征并评估了其结果。51我们首次拥有 开发了一种经过验证的工具来评估自主症状。73在其它的 病理生理学。周围神经支配已得到证实，约有10％的神经节抗体。76去甲肾上腺素 腿的溢出量在POTS31中减少了50％，下肢静脉的神经敏感性。71 下肢远端存在促瘤的神经支配。26'48神经支配导致血管能力增加 表现为增加的静脉浮花48'66，预紧力降低。47静脉池过多和/或减少 血浆体积会导致超肾上腺素能状态29，并且可能有P受体超敏的成分。69 脑部灌注不足是在小屋期间发生的，但在仰卧休息期间不发生，部分原因是低脑造成的。53小屋导致较大的 但是瞬态降低了BP，在30秒内恢复。在此时间间隔，深度但不是呼吸速率 增加了53和PCO2，导致大脑灌注大幅下降。用重新呼吸的二氧化碳逆转下降二氧化碳将 标准化脑灌注53 花盆的表现是异质的。术语中温和的矫置不耐受通常应用于异质 包括宪法正常不稳定的受试者组，调节性和轻度性低血症。一个 高铁元状态是典型的，29'32'47'61的特征是心率增量> 30 bpm，绝对的体位性心率 > 120 B.P.M，正静静脉血浆去甲肾上腺素> 600 pg/ml，是最有可能减少血浆体积的组。 通常有一些证据表明周围神经支配，有时使用神经性盆栽一词。 在Valsalva Maneuver47'61上，经常降低或不存在BaroreFlex血管收缩，并且全身电阻为 68压压对酪胺的反应减少，对苯肾上腺素的反应增加，暗示了爆炸后。 32表明失调的症状也表现为舒张压的过度增加， BP在小屋上的过度振荡和动力学自发发作。48已经说明了这些 患者患有脑干疾病。一名患者对腹侧腹侧的减压作出反应巨大 髓46'48 血管舒缩，尤其是毒液，张力可能会在自主神经病中受损。61标记的过度隔离 在犊牛中证明了蛋白质，可通过静脉压缩来校正。48'70末期末期过度下降 头部倾斜（小屋）还表明静脉池。47静脉合并会导致减少 预紧力和过度的压力受体在直立位置卸载，从而增加交感神经流出。 小屋导致POTS 7的过度经毛细血管外排过多，可以反映在等离子体体积的渐进性下降中 15静脉闭塞散布物质学已被用来单独评估静脉和 流体分离和转移的毛细管成分。当肢体被遮挡在静脉压力高于静脉压力上时， 肢体体积通过两个阶段演变。初始体积增加与静脉填充相对应。这 阶段之后是一个较慢的相，代表净毛细管过滤。22 锅中有充分的文献记载了体位化的去甲肾上腺素（见上文）。鲜为人知的是 盆中也可以增加定位和仰卧肾上腺素。 （32-肾上腺受体对肾上腺素的血管反应性） 在体位前很重要。特别有趣的是某些多态性$ 2-之间的关系 肾上腺受体和功能。重大兴趣集中在两种常见的多态性之间的关系上， 一个在密码子16，一个在密码子27上的一个，是针对静脉床的激动剂介导的血管舒张和脱敏的。主题 对Argl6纯合的人几乎完全脱敏；响应于异丙肾上腺素的静脉穿刺 小组比对Glyl6纯合的受试者更快地恢复正常 静脉 比那些对GLN27纯合的人。一些研究者扩大了单核苷酸的兴趣 多态性（SNP）至染色体分阶段SNP（单倍型）。11一些单倍型的分布非常 高加索人，非裔美国人，亚洲人和西班牙裔拉丁裔种族不同，在 四个主要单倍型的频率。功能差异显示出更依赖于单倍型对 而不是单个SNP。结果表明，单倍型中多个SNP的唯一相互作用最终 可以影响生物学和治疗性表型。应用于锅，并基于我们的初步数据 是某种单倍型的过分代表性，导致持续的静脉脱裂（初步数据）。我们将 系统地探索肾上腺素，多态性的相互作用之间的关系（32AR与与之相关 对激动剂介导的脱敏的耐药性导致长时间血管舒张，以及对静脉和小屋指数的研究。