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Transcutaneous vagus nerve stimulation attenuates autoantibody-mediated cardiovagal dysfunction and inflammation in a rabbit model of postural tachycardia syndrome

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Journal of Interventional Cardiac Electrophysiology Aims and scope Submit manuscript

Abstract

Purpose

Previous studies demonstrated M2 muscarinic acetylcholine receptor-activating autoantibodies (M2R-AAb) were present in some patients with postural tachycardia syndrome (POTS). This study examines how these autoantibodies might contribute to the pathophysiology of POTS, and whether low-level tragus stimulation (LLTS) can ameliorate autoantibody-mediated autonomic dysregulation in the rabbit.

Methods

Five New Zealand white rabbits were immunized with a M2R second extracellular loop peptide to produce cholinomimetic M2R-AAb. Tilt test and infusion studies were performed on conscious rabbits before immunization, 6 weeks after immunization, and 8 weeks after immunization with 2-week daily LLTS treatment. Each rabbit served as its own control.

Results

Compared to preimmune state, an enhanced heart rate increase and decreased parasympathetic activity upon tilting were observed in immunized rabbits. Furthermore, these rabbits demonstrated an attenuated heart rate-slowing response to infusion of the M2R orthosteric agonist arecaidine propargyl ester (APE), suggesting an inhibitory allosteric effect of M2R-AAb. There was also a significant increase in serum inflammatory cytokines in immunized rabbits. LLTS treatment suppressed the postural tachycardia, improved the sympathovagal balance with increased acetylcholine secretion, reduced the levels of inflammatory cytokines, and reversed the attenuated heart rate response to APE in immunized rabbits. No suppression of M2R-AAb expression by LLTS was found during this short-term study period. Receptor-modulating activity of M2R-AAb produced in immunized rabbits was confirmed with in vitro bioassay.

Conclusions

Autoantibody inhibition of cholinergic ligand activity may be involved in the development of cardiovagal dysfunction and inflammation associated with POTS, both of which can be improved by vagal stimulation.

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Funding

This work was supported in part by funding from the National Heart, Lung, and Blood Institute (R01HL128393), an Exploratory Grant award from Harold Hamm Diabetes Center at the University of Oklahoma, grants from Dysautonomia International, and by individual donations from Christy and Aaron Jagdfeld and from Francie Fitzgerald and family through the OU Foundation Webster Fund. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73117, USA

    Jielin Deng, Hongliang Li, Yankai Guo, Gege Zhang, Hayley Fischer, Stavros Stavrakis & Xichun Yu

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  1. Jielin Deng
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  2. Hongliang Li
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Correspondence to Xichun Yu.

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This study protocol was approved by the Institutional Animal Care and Use Committee of the University of Oklahoma Health Sciences Center, and conforms to international standards for animal safety and comfort.

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Deng, J., Li, H., Guo, Y. et al. Transcutaneous vagus nerve stimulation attenuates autoantibody-mediated cardiovagal dysfunction and inflammation in a rabbit model of postural tachycardia syndrome. J Interv Card Electrophysiol 66, 291–300 (2023). https://doi.org/10.1007/s10840-022-01144-w

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