Top

Published in:

01-05-2014 | Original Contribution

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

Authors: Anthony C. Merlocco, Kathrine L. Redington, Tara Disenhouse, Samuel C. Strantzas, Rachel Gladstone, Can Wei, Michael B. Tropak, Cedric Manlhiot, Jing Li, Andrew N. Redington

Published in: Basic Research in Cardiology | Issue 3/2014

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.

Birnbaum Y, Hale SL, Kloner RA (1997) Ischemic preconditioning at a distance: reduction of myocardial infarct size by partial reduction of blood supply combined with rapid stimulation of the gastrocnemius muscle in the rabbit. Circulation 96:1641–1646. doi:10.1161/01.CIR.96.5.1641 PubMedCrossRef

Boengler K, Buechert A, Heinen Y, Roeskes C, Hilfiker-Kleiner D, Heusch G, Schulz R (2008) Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice. Circ Res 102:131–135. doi:10.1161/CIRCRESAHA.107.164699 PubMedCrossRef

Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sorensen HT, Redington AN, Nielsen TT (2010) Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 375:727–734. doi:10.1016/S0140-6736(09)62001-8 PubMedCrossRef

Celander O, Folkow B (1953) The nature and the distribution of afferent fibres provided with the axon reflex arrangement. Acta Physiol Scand 29:359–370. doi:10.1111/j.1748-1716.1953.tb01031.x PubMedCrossRef

Cheung MM, Kharbanda RK, Konstantinov IE, Shimizu M, Frndova H, Li J, Holtby HM, Cox PN, Smallhorn JF, Van Arsdell GS, Redington AN (2006) Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol 47:2277–2282. doi:10.1016/j.jacc.2006.01.066 PubMedCrossRef

Conti A, Scala S, D’Agostino P, Alimenti E, Morelli D, Andria B, Tammaro A, Attanasio C, Della Ragione F, Scuderi V, Fabbrini F, D’Esposito M, Di Florio E, Nitsch L, Calise F, Faiella A (2007) Wide gene expression profiling of ischemia–reperfusion injury in human liver transplantation. Liver Transplant 13:99–113. doi:10.1002/lt.20960 CrossRef

Dickson EW, Blehar DJ, Carraway RE, Heard SO, Steinberg G, Przyklenk K (2001) Naloxone blocks transferred preconditioning in isolated rabbit hearts. J Mol Cell Cardiol 33:1751–1756. doi:10.1006/jmcc.2001.1436 PubMedCrossRef

Dickson EW, Lorbar M, Porcaro WA, Fenton RA, Reinhardt CP, Gysembergh A, Przyklenk K (1999) Rabbit heart can be “preconditioned” via transfer of coronary effluent. Am J Physiol 277:H2451–H2457PubMed

Ding YF, Zhang MM, He RR (2001) Role of renal nerve in cardioprotection provided by renal ischemic preconditioning in anesthetized rabbits. Sheng Li Xue Bao 53:7–12PubMed

10.

Dong JH, Liu YX, Ji ES, He RR (2004) Limb ischemic preconditioning reduces infarct size following myocardial ischemia–reperfusion in rats. Sheng Li Xue Bao 56:41–46PubMed

11.

Dong JH, Liu YX, Zhao J, Ma HJ, Guo SM, He RR (2004) High-frequency electrical stimulation of femoral nerve reduces infarct size following myocardial ischemia–reperfusion in rats. Sheng Li Xue Bao 56:620–624PubMed

12.

Evans MS, Reid KH, Sharp JB Jr (1993) Dimethylsulfoxide (DMSO) blocks conduction in peripheral nerve C fibers: a possible mechanism of analgesia. Neurosci Lett 150:145–148. doi:10.1016/0304-3940(93)90522-m PubMedCrossRef

13.

Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, Verdouw PD (1996) Myocardial protection by brief ischemia in noncardiac tissue. Circulation 94:2193–2200. doi:10.1161/01.CIR.94.9.2193 PubMedCrossRef

14.

Han JS, Chen XH, Sun SL, Xu XJ, Yuan Y, Yan SC, Hao JX, Terenius L (1991) Effect of low- and high-frequency TENS on Met-enkephalin-Arg-Phe and dynorphin A immunoreactivity in human lumbar CSF. Pain 47:295–298PubMedCrossRef

15.

Heusch G, Musiolik J, Kottenberg E, Peters J, Jakob H, Thielmann M (2012) STAT5 activation and cardioprotection by remote ischemic preconditioning in humans: short communication. Circ Res 110:111–115. doi:10.1161/CIRCRESAHA.111.259556 PubMedCrossRef

16.

Huda R, Chung DH, Mathru M (2005) Ischemic preconditioning at a distance: altered gene expression in mouse heart and other organs following brief occlusion of the mesenteric artery. Heart Lung Circ 14:36–43. doi:10.1016/j.hlc.2004.11.006 PubMedCrossRef

17.

Jensen RV, Stottrup NB, Kristiansen SB, Botker HE (2012) Release of a humoral circulating cardioprotective factor by remote ischemic preconditioning is dependent on preserved neural pathways in diabetic patients. Basic Res Cardiol 107:285. doi:10.1007/s00395-012-0285-1 PubMedCrossRef

18.

Jones WK, Fan GC, Liao S, Zhang JM, Wang Y, Weintraub NL, Kranias EG, Schultz JE, Lorenz J, Ren X (2009) Peripheral nociception associated with surgical incision elicits remote nonischemic cardioprotection via neurogenic activation of protein kinase C signaling. Circulation 120:S1–S9. doi:10.1161/CIRCULATIONAHA.108.843938 PubMedCentralPubMedCrossRef

19.

Kharbanda RK, Mortensen UM, White PA, Kristiansen SB, Schmidt MR, Hoschtitzky JA, Vogel M, Sorensen K, Redington AN, MacAllister R (2002) Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation 106:2881–2883. doi:10.1161/01.CIR.0000043806.51912.9B PubMedCrossRef

20.

Kharbanda RK, Nielsen TT, Redington AN (2009) Translation of remote ischaemic preconditioning into clinical practice. Lancet 374:1557–1565. doi:10.1016/S0140-6736(09)61421-5 PubMedCrossRef

21.

Konstantinov IE, Arab S, Kharbanda RK, Li J, Cheung MM, Cherepanov V, Downey GP, Liu PP, Cukerman E, Coles JG, Redington AN (2004) The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans. Physiol Genomics 19:143–150. doi:10.1152/physiolgenomics.0 0046.2004PubMedCrossRef

22.

Konstantinov IE, Li J, Cheung MM, Shimizu M, Stokoe J, Kharbanda RK, Redington AN (2005) Remote ischemic preconditioning of the recipient reduces myocardial ischemia–reperfusion injury of the denervated donor heart via a Katp channel-dependent mechanism. Transplantation 79:1691–1695PubMedCrossRef

23.

Kottenberg E, Musiolik J, Thielmann M, Jakob H, Peters J, Heusch G (2014) Interference of propofol with signal transducer and activator of transcription 5 activation and cardioprotection by remote ischemic preconditioning during coronary artery bypass grafting. J Thorac Cardiovasc Surg 147(1):376–382. doi: 10.1016/j.jtcvs.2013.01.005 PubMedCrossRef

24.

Kottenberg E, Thielmann M, Bergmann L, Heine T, Jakob H, Heusch G, Peters J (2012) Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol—a clinical trial. Acta Anaesthesiol Scand 56:30–38. doi:10.1111/j.1399-6576.2011.02585.x PubMedCrossRef

25.

Liem DA, Verdouw PD, Ploeg H, Kazim S, Duncker DJ (2002) Sites of action of adenosine in interorgan preconditioning of the heart. Am J Physiol Heart Circ Physiol 283:H29–H37. doi:10.1152/ajpheart.0 1031.2001PubMed

26.

Linden MD, Whittaker P, Frelinger AL 3rd, Barnard MR, Michelson AD, Przyklenk K (2006) Preconditioning ischemia attenuates molecular indices of platelet activation-aggregation. J Thromb Haemost 4:2670–2677. doi:10.1111/j.1538-7836.2006.02228.x PubMedCrossRef

27.

Loukogeorgakis SP, Panagiotidou AT, Broadhead MW, Donald A, Deanfield JE, MacAllister RJ (2005) Remote ischemic preconditioning provides early and late protection against endothelial ischemia–reperfusion injury in humans: role of the autonomic nervous system. J Am Coll Cardiol 46:450–456. doi:10.1016/j.jacc.2005.04.044 PubMedCrossRef

28.

Lu Y, Zhou J, Xu C, Lin H, Xiao J, Wang Z, Yang B (2008) JAK/STAT and PI3 K/AKT pathways form a mutual transactivation loop and afford resistance to oxidative stress-induced apoptosis in cardiomyocytes. Cell Physiol Biochem 21:305–314. doi:10.1159/000129389 PubMedCrossRef

29.

Michelsen MM, Stottrup NB, Schmidt MR, Lofgren B, Jensen RV, Tropak M, St-Michel EJ, Redington AN, Botker HE (2012) Exercise-induced cardioprotection is mediated by a bloodborne, transferable factor. Basic Res Cardiol 107:260. doi:10.1007/s00395-012-0260-x PubMedCrossRef

30.

Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136. doi:10.1161/01.CIR.74.5.1124 PubMedCrossRef

31.

Peart JN, Gross GJ (2006) Cardioprotective effects of acute and chronic opioid treatment are mediated via different signaling pathways. Am J Physiol Heart Circ Physiol 291:H1746–H1753. doi:10.1152/ajpheart.0 0233.2006PubMedCrossRef

32.

Pell TJ, Baxter GF, Yellon DM, Drew GM (1998) Renal ischemia preconditions myocardium: role of adenosine receptors and ATP-sensitive potassium channels. Am J Physiol 275:H1542–H1547PubMed

33.

Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P (1993) Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 87:893–899. doi:10.1161/01.CIR.87.3.893 PubMedCrossRef

34.

Raza A, Dikdan G, Desai KK, Shareef A, Fernandes H, Aris V, de la Torre AN, Wilson D, Fisher A, Soteropoulos P, Koneru B (2010) Global gene expression profiles of ischemic preconditioning in deceased donor liver transplantation. Liver Transplant 16:588–599. doi:10.1002/lt.22049

35.

Redington KL, Disenhouse T, Strantzas SC, Gladstone R, Wei C, Tropak MB, Dai X, Manlhiot C, Li J, Redington AN (2012) Remote cardioprotection by direct peripheral nerve stimulation and topical capsaicin is mediated by circulating humoral factors. Basic Res Cardiol 107:241. doi:10.1007/s00395-011-0241-5 PubMedCrossRef

36.

Saade NE, Massaad CA, Ochoa-Chaar CI, Jabbur SJ, Safieh-Garabedian B, Atweh SF (2002) Upregulation of proinflammatory cytokines and nerve growth factor by intraplantar injection of capsaicin in rats. J Physiol 545:241–253. doi:10.1113/jphysiol.2002.028233 PubMedCentralPubMedCrossRef

37.

Saxena P, Shaw OM, Misso NL, Naran A, Shehatha J, Newman MA, d’Udekem Y, Thompson PJ, Konstantinov IE (2011) Remote ischemic preconditioning stimulus decreases the expression of kinin receptors in human neutrophils. J Surg Res 171:311–316. doi:10.1016/j.jss.2009.11.011 PubMedCrossRef

38.

Schoemaker RG, van Heijningen CL (2000) Bradykinin mediates cardiac preconditioning at a distance. Am J Physiol Heart Circ Physiol 278:H1571–H1576PubMed

39.

Serejo FC, Rodrigues LF Jr, da Silva Tavares KC, de Carvalho AC, Nascimento JH (2007) Cardioprotective properties of humoral factors released from rat hearts subject to ischemic preconditioning. J Cardiovasc Pharmacol 49:214–220. doi:10.1097/FJC.0b013e3180325ad9 PubMedCrossRef

40.

Sergeev P, da Silva R, Lucchinetti E, Zaugg K, Pasch T, Schaub MC, Zaugg M (2004) Trigger-dependent gene expression profiles in cardiac preconditioning: evidence for distinct genetic programs in ischemic and anesthetic preconditioning. Anesthesiology 100:474–488PubMedCrossRef

41.

Shimizu M, Saxena P, Konstantinov IE, Cherepanov V, Cheung MM, Wearden P, Zhangdong H, Schmidt M, Downey GP, Redington AN (2010) Remote ischemic preconditioning decreases adhesion and selectively modifies functional responses of human neutrophils. J Surg Res 158:155–161. doi:10.1016/j.jss.2008.08.010 PubMedCrossRef

42.

Shimizu M, Tropak M, Diaz RJ, Suto F, Surendra H, Kuzmin E, Li J, Gross G, Wilson GJ, Callahan J, Redington AN (2009) Transient limb ischaemia remotely preconditions through a humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection. Clin Sci (Lond) 117:191–200. doi:10.1042/CS20080523 CrossRef

43.

Sjolund BH (1988) Peripheral nerve stimulation suppression of C-fiber-evoked flexion reflex in rats. Part 2: parameters of low-rate train stimulation of skin and muscle afferent nerves. J Neurosurg 68:279–283PubMedCrossRef

44.

Soond SM, Townsend PA, Barry SP, Knight RA, Latchman DS, Stephanou A (2008) ERK and the F-box protein betaTRCP target STAT1 for degradation. J Biol Chem 283:16077–16083. doi:10.1074/jbc.M800384200 PubMedCentralPubMedCrossRef

45.

Steensrud T, Li J, Dai X, Manlhiot C, Kharbanda RK, Tropak M, Redington A (2010) Pretreatment with the nitric oxide donor SNAP or nerve transection blocks humoral preconditioning by remote limb ischemia or intra-arterial adenosine. Am J Physiol Heart Circ Physiol 299:H1598–H1603. doi:10.1152/ajpheart.0 0396.2010PubMedCrossRef

46.

Steinbeck JA, Methner A (2005) Translational downregulation of the noncatalytic growth factor receptor TrkB.T1 by ischemic preconditioning of primary neurons. Gene Expr 12:99–106PubMedCrossRef

47.

Stenzel-Poore MP, Stevens SL, Xiong Z, Lessov NS, Harrington CA, Mori M, Meller R, Rosenzweig HL, Tobar E, Shaw TE, Chu X, Simon RP (2003) Effect of ischaemic preconditioning on genomic response to cerebral ischaemia: similarity to neuroprotective strategies in hibernation and hypoxia-tolerant states. Lancet 362:1028–1037. doi:10.1016/S0140-6736(03)14412-1 PubMedCrossRef

48.

Stephanou A, Scarabelli TM, Brar BK, Nakanishi Y, Matsumura M, Knight RA, Latchman DS (2001) Induction of apoptosis and Fas receptor/Fas ligand expression by ischemia/reperfusion in cardiac myocytes requires serine 727 of the STAT-1 transcription factor but not tyrosine 701. J Biol Chem 276:28340–28347. doi:10.1074/jbc.M101177200 PubMedCrossRef

49.

Takaoka A, Nakae I, Mitsunami K, Yabe T, Morikawa S, Inubushi T, Kinoshita M (1999) Renal ischemia/reperfusion remotely improves myocardial energy metabolism during myocardial ischemia via adenosine receptors in rabbits: effects of “remote preconditioning”. J Am Coll Cardiol 33:556–564. doi:10.1016/S0735-1097(98)00559-2 PubMedCrossRef

50.

Thielmann M, Kottenberg E, Boengler K, Raffelsieper C, Neuhaeuser M, Peters J, Jakob H, Heusch G (2010) Remote ischemic preconditioning reduces myocardial injury after coronary artery bypass surgery with crystalloid cardioplegic arrest. Basic Res Cardiol 105:657–664. doi:10.1007/s00395-010-0104-5 PubMedCrossRef

51.

Weinbrenner C, Nelles M, Herzog N, Sarvary L, Strasser RH (2002) Remote preconditioning by infrarenal occlusion of the aorta protects the heart from infarction: a newly identified non-neuronal but PKC-dependent pathway. Cardiovasc Res 55:590–601. doi:10.1016/S0008-6363(02)00446-7 PubMedCrossRef

52.

Wolfrum S, Schneider K, Heidbreder M, Nienstedt J, Dominiak P, Dendorfer A (2002) Remote preconditioning protects the heart by activating myocardial PKCepsilon-isoform. Cardiovasc Res 55:583–589. doi:10.1016/S0008-6363(02)00408-X PubMedCrossRef

53.

Xuan YT, Tang XL, Banerjee S, Takano H, Li RC, Han H, Qiu Y, Li JJ, Bolli R (1999) Nuclear factor-kappaB plays an essential role in the late phase of ischemic preconditioning in conscious rabbits. Circ Res 84:1095–1109. doi:10.1161/01.RES.84.9.1095 PubMedCrossRef

Title: Transcutaneous electrical nerve stimulation as a novel method of remote preconditioning: in vitro validation in an animal model and first human observations
Authors: Anthony C. Merlocco
Kathrine L. Redington
Tara Disenhouse
Samuel C. Strantzas
Rachel Gladstone
Can Wei
Michael B. Tropak
Cedric Manlhiot
Jing Li
Andrew N. Redington
Publication date: 01-05-2014
Publisher: Springer Berlin Heidelberg
Published in: Basic Research in Cardiology / Issue 3/2014
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-014-0406-0

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2014

Adiponectin promotes coxsackievirus B3 myocarditis by suppression of acute anti-viral immune responses

The role of capillary transit time heterogeneity in myocardial oxygenation and ischemic heart disease

Characterization of functional ion channels in human cardiac c-kit+ progenitor cells

The adapter protein c-Cbl-associated protein (CAP) protects from acute CVB3-mediated myocarditis through stabilization of type I interferon production and reduced cytotoxicity

Erratum to: Role of endothelial Nox2 NADPH oxidase in angiotensin II-induced hypertension and vasomotor dysfunction

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page