Neuromodulation of innate immunity by remote ischaemic conditioning in humans: Experimental cross-over study.
Experimental animal studies on the mechanisms of remote ischaemic conditioning (RIC)-induced cardioprotection against ischaemia/reperfusion injury demonstrate involvement of both neuronal and humoral pathways. Autonomic parasympathetic (vagal) pathways confer organ protection through both direct innervation and/or immunomodulation, but evidence in humans is lacking. During acute inflammation, vagal release of acetylcholine suppresses CD11b expression, a critical β2-integrin regulating neutrophil adhesion to the endothelium and transmigration to sites of injury. Here, we tested the hypothesis that RIC recruits vagal activity in humans and has an anti-inflammatory effect by reducing neutrophil CD11b expression. Participants (age:50 ± 19 years; 53% female) underwent ultrasound-guided injection of local anaesthetic within the brachial plexus before applying 3 × 8 min cycles of brachial artery occlusion using a blood pressure cuff (RICblock). RIC was repeated 6 weeks later without brachial plexus block. Masked analysers quantified vagal activity (heart rate, heart rate variability (HRV)) before, and 10 min after, the last cycle of RIC. RR-interval increased after RIC (reduced heart rate) by 40 ms (95% confidence intervals (95%CI):13-66; n = 17 subjects; P = 0.003). RR-interval did not change after brachial plexus blockade (mean difference: 20 ms (95%CI:-11 to 50); P = 0.19). The high-frequency component of HRV was reduced after RICblock, but remained unchanged after RIC (P < 0.001), indicating that RIC preserved vagal activity. LPS-induced CD16+CD11b+ expression in whole blood (measured by flow cytometry) was reduced by RIC (3615 median fluorescence units (95%CI:475-6754); P = 0.026), compared with 2331 units (95%CI:-3921 to 8582); P = 0.726) after RICblock. These data suggest that in humans RIC recruits vagal cardiac and anti-inflammatory mechanisms via ischaemia/reperfusion-induced activation of sensory nerve fibres that innervate the organ undergoing RIC.