Short and long term effects of a two-week transcutaneous vagus nerve stimulation in hyperadrenergic postural orthostatic tachycardia syndrome: a proof-of-concept trial

Background and aims: Hyperadrenergic POTS (Hyper-POTS) is characterized by excessive central sympathetic activity and impaired cardiovagal modulation. A single transcutaneous vagus nerve stimulation (tVNS) rebalanced cardiovascular autonomic control in previous studies. Repetitive tVNS may similarly restore autonomic balance and improve symptoms in Hyper-POTS. Methods: Twenty-two Hyper-POTS were studied at baseline (Pre-tVNS), after 14 days of tVNS (tVNS), and within 24 months post-discontinuation (Post-tVNS). The modified Vanderbilt Orthostatic Symptoms Score (mVOSS) quantified symptoms. ECG, arterial pressure, respiratory activity, and muscle sympathetic nerve activity (MSNA) were continuously recorded while supine and during 75° head-up tilt (HUT). Cardiac vagal modulation (high frequency power,HFRR), sinoatrial node sympatho-vagal interaction (low-to high-frequency ratio,LF/HF), sympathetic vasomotor control (LFSAP) and arterial baroreflex sensitivity (αLF) were assessed by spectral analysis. Baroreflex sensitivity was also evaluated by spontaneous sequences (BRS) technique. Results: At tVNS, MSNA decreased in both positions. tVNS increased HFRR and decreased LF/HF in supine. During HUT, αLF increased, HFRR increased, and HR decreased compared to Pre-tVNS. Total symptom score declined in both positions, with improvements in multiple mVOSS domains during tilt. At Post-tVNS, HFRR and BRS increased in both positions. During HUT, αLF increased, HR and LFSAP decreased. MSNA returned to Pre-tVNS in both positions. Total symptom score showed sustained improvement. Conclusions: Fourteen-day tVNS enhanced cardiovagal modulation, reduced sympathetic activity, and improved orthostatic symptoms in Hyper-POTS patients. Additionally, some benefits persisted beyond the stimulation period. Thus, tVNS could potentially be used as an additional therapeutic tool in Hyper-POTS.