title: 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 30 min of global ischemia and 60 or 120 min 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.
authors.affiliation: The Division of Cardiology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, M5G1X8, Canada.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Merlocco
authors.forename: Kathrine L
authors.initials: KL
authors.lastname: Redington
authors.forename: Tara
authors.initials: T
authors.lastname: Disenhouse
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Strantzas
authors.forename: Rachel
authors.initials: R
authors.lastname: Gladstone
authors.forename: Can
authors.initials: C
authors.lastname: Wei
authors.forename: Michael B
authors.initials: MB
authors.lastname: Tropak
authors.forename: Cedric
authors.initials: C
authors.lastname: Manlhiot
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Redington
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000097:blood / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011817:Rabbits; D012039:Regional Blood Flow; D013997:Time Factors; D004561:Transcutaneous Electric Nerve Stimulation; D034941:Upper Extremity / Q000098:blood supply*; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
chemical_list: D015415:Biomarkers; D009292:Narcotic Antagonists