Transcutaneous electrical nerve stimulation as a novel method of remote preconditioning: in vitro validation in an animal model and first human observations

Abstract

Remote ischemic preconditioning (rIPC) induced by transient limb ischemia (li-rIPC) leads to neurally dependent release of blood-borne factors that provide potent cardioprotection. We hypothesized that transcutaneous electrical nerve stimulation (TENS) is a clinically relevant stimulus of rIPC. Study 1: seven rabbits were subjected to lower limb TENS; six to li-rIPC, and six to sham intervention. Blood was drawn and used to prepare a dialysate for subsequent analysis of cardioprotection in rabbit Langendorff preparation. Study 2: 14 healthy adults underwent upper limb TENS stimulation on one study day, 10 of whom also underwent li-rIPC on another study day. Blood was drawn before and after each stimulus, dialysate prepared, and cardioprotective activity assessed in mouse Langendorff preparation. The infarct size and myocardial recovery were measured after 30min of global ischemia and 60 or 120min of reperfusion. Animal validation: compared to control, TENS induced marked cardioprotection with significantly reduced infarct size (TENS vs. sham p<0.01, rIPC vs. sham p<0.01, TENS vs. rIPC p=ns) and improved functional recovery during reperfusion. Human study: compared to baseline, dialysate after rIPC (pre-rIPC vs. post-rIPC, p<0.001) and TENS provided potent cardioprotection (pre-TENS vs. post-TENS p<0.001) and improved myocardial recovery during reperfusion. The cardioprotective effects of TENS dialysates were blocked by pretreatment of the receptor heart with the opioid antagonist naloxone. TENS is a novel method for inducing cardioprotection and may provide an alternative to the limb ischemia stimulus for induction of rIPC clinically.