Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73117, USA.
J Interv Card Electrophysiol. 2023 Mar;66(2):291-300. doi: 10.1007/s10840-022-01144-w. Epub 2022 Feb 4.
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.
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.
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.
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.
先前的研究表明，一些体位性心动过速综合征（POTS）患者存在 M2 毒蕈碱乙酰胆碱受体激活自身抗体（M2R-AAb）。本研究探讨了这些自身抗体如何促成 POTS 的病理生理学，以及低水平耳轮刺激（LLTS）是否可以改善兔的自身抗体介导的自主神经调节障碍。
用 M2R 第二细胞外环肽免疫 5 只新西兰白兔，产生拟胆碱能 M2R-AAb。在免疫前、免疫后 6 周和免疫后 8 周（每天进行 2 周 LLTS 治疗）对清醒兔进行倾斜试验和输注研究。每只兔子作为自己的对照。
与免疫前状态相比，免疫兔在倾斜时观察到心率增加增强和副交感神经活动减少。此外，这些兔子对 M2R 变构激动剂槟榔碱丙炔酯（APE）的输注显示出心率减慢反应减弱，表明 M2R-AAb 的抑制变构效应。免疫兔的血清炎症细胞因子也显著增加。LLTS 治疗抑制了体位性心动过速，改善了交感神经-副交感神经平衡，增加了乙酰胆碱分泌，降低了炎症细胞因子水平，并逆转了免疫兔对 APE 的心率减慢反应。在这个短期研究期间，没有发现 LLTS 对 M2R-AAb 表达的抑制。用体外生物测定证实了免疫兔产生的 M2R-AAb 的受体调节活性。
自身抗体抑制胆碱能配体活性可能参与了与 POTS 相关的心脏迷走神经功能障碍和炎症的发生，而迷走神经刺激可以改善这两种情况。
