Non-invasive vagus nerve stimulation and exercise capacity in healthy volunteers: a randomized trial.

Background and aims

Vagal parasympathetic dysfunction is strongly associated with impaired exercise tolerance, indicating that coordinated autonomic control is essential for optimizing exercise performance. This study tested the hypothesis that autonomic neuromodulation by non-invasive transcutaneous vagus nerve stimulation (tVNS) can improve exercise capacity in humans.

Methods

This single-centre, randomized, double-blind, sham-controlled, crossover trial in 28 healthy volunteers evaluated the effect of bilateral transcutaneous stimulation of vagal auricular innervation, applied for 30 min daily for 7 days, on measures of cardiorespiratory fitness (peak oxygen consumption (VO2peak)) during progressive exercise to exhaustion. Secondary endpoints included peak work rate, cardiorespiratory measures, and the whole blood inflammatory response to lipopolysaccharide ex vivo.

Results

tVNS applied for 30 min daily over 7 consecutive days increased VO2peak by 1.04 mL/kg/min (95% CI: .34-1.73; P = .005), compared with no change after sham stimulation (-0.54 mL/kg/min; 95% CI: -1.52 to .45). No carry-over effect was observed following the 2-week washout period. tVNS increased work rate (by 6 W; 95% CI: 2-10; P = .006), heart rate (by 4 bpm; 95% CI: 1-7; P = .011), and respiratory rate (by 4 breaths/min; 95% CI: 2-6; P < .001) at peak exercise. Analysis of the whole blood transcriptomic response to lipopolysaccharide in serial samples obtained from five participants showed that tVNS reduced the inflammatory response.

Conclusions

Non-invasive vagal stimulation improves measures of cardiorespiratory fitness and attenuates inflammation, offering an inexpensive, safe, and scalable approach to improve exercise capacity.

References:

• Kohl  HW, Craig  CL, Lambert  EV, Inoue  S, Alkandari  JR, Leetongin  G, et al.  The pandemic of physical inactivity: global action for public health. Lancet Lond Engl  2012;380:294–305. 10.1016/S0140-6736(12)60898-8
• Valenzuela  PL, Ruilope  LM, Santos-Lozano  A, Wilhelm  M, Kränkel  N, Fiuza-Luces  C, et al.  Exercise benefits in cardiovascular diseases: from mechanisms to clinical implementation. Eur Heart J  2023;44:1874–89. 10.1093/eurheartj/ehad170
• Mandsager  K, Harb  S, Cremer  P, Phelan  D, Nissen  SE, Jaber  W. Association of cardiorespiratory fitness with long-term mortality among adults undergoing exercise treadmill testing. JAMA Netw Open  2018;1:e183605. 10.1001/jamanetworkopen.2018.3605
• Blodgett  JM, Ahmadi  MN, Atkin  AJ, Chastin  S, Chan  H-W, Suorsa  K, et al.  Device-measured physical activity and cardiometabolic health: the prospective physical activity, sitting, and sleep (ProPASS) consortium. Eur Heart J  2024;45:458–71. 10.1093/eurheartj/ehad717
• Bauman  AE, Reis  RS, Sallis  JF, Wells  JC, Loos  RJ, Martin  BW. Correlates of physical activity: why are some people physically active and others not?  Lancet  2012;380:258–71. 10.1016/S0140-6736(12)60735-1