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.

Project Narrative Postural tachycardia syndrome is a common and disabling disorder that can significantly interfere with the quality of life of affected subjects. We have discovered an antibody-mediated autoimmune reaction that can cause orthostatic symptoms and make it difficult for treatment. This project is directed toward elucidating an autoimmune mechanism of this debilitating disorder and to develop a safe, effective and non-invasive treatment option.