Electrical auricular tragus stimulation induces release of circulating cardioprotective factors in healthy human volunteers

Abstract Background Vagal activation during remote ischemic conditioning (RIC) with subsequent release of cardioprotective factors from the spleen into the circulation reduces infarct size. These humoral cardioprotective factors can be transferred with plasma-dialysate from human donors undergoing RIC to isolated recipient hearts where they reduce infarct size. Electrical auricular tragus stimulation (ATS) has been demonstrated to reduce the release of cardiac injury biomarkers and ventricular arrhythmias and to improve contractile function in patients with acute myocardial infarction. Purpose To determine whether ATS, as RIC, induces release of cardioprotective factors into the circulation. Methods Healthy volunteers (3 females, 7 males, 26±5 years) were randomized to receive ATS or RIC, respectively, with an interval of at least two weeks between protocols. ATS was induced by bipolar electrical rectangular pulses of 200 µs width and a frequency of 30 Hz. The amplitude (5.5 ± 0.81 mA) was set for each volunteer to not be perceived as uncomfortable. A microprocessor-controlled circuit periodically interrupted the stimulation signal after 5 s of stimulation for 5 s. ATS was continued over 30 min. RIC served as a reference to induce the release of cardioprotective factors by 3 x 5 min blood pressure cuff inflation at 200 mmHg on the left upper arm/ 5 min deflation. Venous blood samples were taken before and 60 min after ATS or RIC, respectively, and used to prepare plasma-dialysates (1:10 dialysis against buffer for 24 h, cut-off 12-14 kDa). Male Lewis rats were sacrificed and their hearts isolated and perfused at constant pressure with buffer. Plasma-dialysates from samples taken before and 60 min after ATS or RIC, respectively, were infused for 8 min into rat hearts followed by 2 min washout before global 30 min ischemia/ 120 min reperfusion. Infarct size was demarcated by triphenyl tetrazolium chloride staining and calculated as percent of ventricular mass. Results With infusion of plasma-dialysate before ATS, infarct size was 30.9 ± 4.5% of ventricular mass and not different from that with infusion of plasma-dialysate before RIC (35.8 ± 5.8 %). Infusion of plasma-dialysate after ATS reduced infarct size to 18.3 ± 3.9 %. This cardioprotective effect was similar to that seen with infusion of plasma-dialysate after RIC (20.1 ± 3.5 %). Conclusion ATS induces the release of cardioprotective factors into the circulation of healthy volunteers. Plasma-dialysates after ATS or RIC, respectively, reduce myocardial infarct size by the same magnitude in ex vivo isolated perfused rat hearts with global ischemia/ reperfusion.