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引起的衰弱疾病。 功能障碍，原因很多，很难有效治疗。此续订提案建立在 支持功能性肾上腺素能自身抗体在POTS中的病理生理学作用的工作。这个 这些抗体在天然配体上的不同变构效应为增加 交感神经活动和夸张的直立性心动过速是POTS的特征。然而， POTS患者副交感神经活性降低的机制尚不清楚。这 该提案验证了毒鼠碱自身抗体介导的副交感神经功能障碍的假说 副交感神经(迷走神经)刺激改善POTS的发病机制 症状、自身免疫和炎症。我们的长期目标是评估 自身免疫介导的交感迷走神经失衡在POTS病理生理学中的作用 经皮迷走神经刺激(TVNS)是一种安全有效的POTS治疗选择。这个 具体目标是：1)确定毒鼠强的患病率、负担和临床意义 一组表型良好的POTS患者和一组匹配的健康对照中的自身抗体 受试者；2)检测M胆碱自身抗体对兔心脏迷走神经活动的影响 在当前筹资期间开发的自身免疫模型；以及3)调查潜在的 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换桥梁的模式。 这些研究的发现将为关于该病病因的新知识提供现实的期望。 这种致残障碍为POTS治疗模式的转变奠定了基础。

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.