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.