Autoimmune Basis for Postural Tachycardia Syndrome

项目摘要 体位性心动过速综合征（POTS）是一种由心血管自主神经系统引起的衰弱性疾病， 功能障碍，有很多原因，很难有效治疗。这一更新建议建立在 支持POTS中功能性肾上腺素能自身抗体的病理生理作用的工作。的 这些抗体对天然配体的不同变构作用提供了对增加的免疫应答的解释。 交感神经活动和POTS特征性过度直立性心动过速。但 POTS患者中副交感神经活性降低的机制尚未阐明。这 一项提案检验了毒蕈碱自身抗体介导的副交感神经功能障碍的假设， 有助于POTS的发病机制，副交感神经（迷走神经）刺激可改善POTS 症状、自身免疫和炎症。长期目标是评估 自身免疫介导的交感迷走神经失衡在POTS的病理生理学，并建立 经皮迷走神经刺激（tVNS）作为POTS的一种安全有效的治疗选择。的 具体目标是：1）确定毒蕈碱的患病率、负担和临床意义， POTS患者的良好表型队列和健康对照的匹配队列中的自身抗体 2）检查毒蕈碱自身抗体对兔心迷走神经活动的体内影响 在当前资助期间开发的自身免疫模型;和3）研究潜在的 tVNS在POTS患者和动物模型中的治疗机制。tVNS是一种重要的治疗方法， 需要跨越基础科学和临床研究之间的转化桥梁的形式。 这些研究的结果将提供关于病原学的新知识的现实期望。 这种致残性疾病，并为治疗POTS的范式转变奠定了基础。

Project Summary Postural tachycardia syndrome (POTS) is a debilitating disorder resulting from cardiovascular autonomic dysfunction, has many causes and is very difficult to treat effectively. This renewal proposal builds on the work that supports a pathophysiological role for functional adrenergic autoantibodies in POTS. The differing allosteric effects of these antibodies on the natural ligands provide an explanation for increased sympathetic activity and exaggerated orthostatic tachycardia characteristic of POTS. However, the mechanism for decreased parasympathetic activity in POTS patients is yet to be elucidated. This proposal tests the hypothesis that muscarinic autoantibody-mediated parasympathetic dysfunction contributes to the pathogenesis of POTS, and that parasympathetic (vagal) stimulation improves POTS symptoms, autoimmunity and inflammation. The long-term goal is to evaluate the significance of autoimmune-mediated sympathovagal imbalance in the pathophysiology of POTS and to establish transcutaneous vagus nerve stimulation (tVNS) as a safe and effective treatment option for POTS. The specific aims are to: 1) determine the prevalence, burden, and clinical significance of muscarinic autoantibodies in a well-phenotyped cohort of POTS patients and a matched cohort of healthy control subjects; 2) examine the in vivo impact of muscarinic autoantibodies on cardiovagal activity in a rabbit autoimmune model developed during the current funding period; and 3) investigate the potential therapeutic mechanisms of tVNS in POTS patients and in animal model. tVNS is an important treatment modality that needs to cross the translational bridge between basic science and clinical research. Findings from these studies will provide realistic expectation of new knowledge regarding the etiology of this disabling disorder and lay the foundation for a paradigm shift for the treatment of POTS.