Skip to main content

Advertisement

Log in

Cardioprotection by remote ischemic conditioning and its signal transduction

  • Invited Review
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

An Erratum to this article was published on 03 February 2017

Abstract

Cardioprotective strategies aim to salvage myocardium from ischemia/reperfusion injury and to reduce infarct size and its consequences. Different stimuli, acting at sites remote from the heart (remote conditioning), activate molecular self-defense mechanisms at the target organ heart as well as in other parenchymal organs. Remote conditioning of the heart has been established in many experimental studies and successfully translated to patients. Remote ischemic conditioning by short repetitive cycles of ischemia/reperfusion on an extremity reduces infarct size and improves the prognosis of patients with reperfused myocardial infarction. The present review focuses on three levels of remote conditioning and its resulting cardioprotection: I) at the stimulus level, electrical stimulation, chemical/pharmacological substances, mechanical trauma and cycles of ischemia/reperfusion act at sites remote from the heart, II) at the transfer level, neuronal and humoral mediators transfer the protective signal from the periphery to the heart, and III) at the target level, receptor activation and intracellular signal transduction ultimately affect protection of the myocardium and other organs, as established in different animal models and humans/patients. Remote conditioning is obviously a systemic response. Further mechanistic understanding is mandatory to translate the protection by remote conditioning more successfully to patients with cardiovascular disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Abdul-Ghani S, Heesom KJ, Angelini GD, Suleiman MS (2014) Cardiac phosphoproteomics during remote ischemic preconditioning: a role for the sarcomeric Z-disk proteins. Biomed Res Int 2014:767812. doi:10.1155/2014/767812

    Article  PubMed  PubMed Central  Google Scholar 

  2. Albrecht M, Zitta K, Bein B, Wennemuth G, Broch O, Renner J, Schuett T, Lauer F, Maahs D, Hummitzsch L, Cremer J, Zacharowski K, Meybohm P (2013) Remote ischemic preconditioning regulates HIF-1alpha levels, apoptosis and inflammation in heart tissue of cardiosurgical patients: a pilot experimental study. Basic Res Cardiol 108:314. doi:10.1007/s00395-012-0314-0

    Article  PubMed  CAS  Google Scholar 

  3. Arroyo-Martinez EA, Meaney A, Gutierrez-Salmean G, Rivera-Capello JM, Gonzalez-Coronado V, Alcocer-Chauvet A, Castillo G, Najera N, Ceballos G, Meaney E (2016) Is local nitric oxide availability responsible for myocardial salvage after remote preconditioning? Arq Bras Cardiol 107:154–162. doi:10.5935/abc.20160100

    PubMed  PubMed Central  Google Scholar 

  4. Baars T, Skyschally A, Klein-Hitpass L, Cario E, Erbel R, Heusch G, Kleinbongard P (2014) microRNA expression and its potential role in cardioprotection by ischemic postconditioning in pigs. Pflügers Arch - Eur J Physiol 466:1953–1961. doi:10.1007/s00424-013-1429-3

    Article  CAS  Google Scholar 

  5. Barile L, Moccetti T, Marban E, Vassalli G (2016) Roles of exosomes in cardioprotection. Eur Heart J. doi:10.1093/eurheartj/ehw304

    PubMed  Google Scholar 

  6. Basalay M, Barsukevich V, Mastitskaya S, Mrochek A, Pernow J, Sjoquist PO, Ackland GL, Gourine AV, Gourine A (2012) Remote ischaemic pre- and delayed postconditioning - similar degree of cardioprotection but distinct mechanisms. Exp Physiol 97:908–917. doi:10.1113/expphysiol.2012.064923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Basalay M, Mastitskaya S, Mrochek A, Ackland GL, del Arroyo AG, Sanchez J, Sjoquist PO, Pernow J, Gourine AV, Gourine A (2016) Glucagon-like peptide-1 (GLP-1) mediates cardioprotection by remote ischaemic conditioning. Cardiovasc Res. doi:10.1093/cvr/cvw216

    PubMed  PubMed Central  Google Scholar 

  8. Birkelund T, Obad DS, Matejec R, Botker HE, Ravn HB (2015) Remote ischemic preconditioning does not increase circulating or effector organ concentrations of proopiomelanocortin derivates. Scand Cardiovasc J 49:257–263. doi:10.3109/14017431.2015.1046401

    Article  PubMed  CAS  Google Scholar 

  9. Bøtker 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

    Article  PubMed  Google Scholar 

  10. Brandenburger T, Huhn R, Galas A, Pannen BH, Keitel V, Barthel F, Bauer I, Heinen A (2014) Remote ischemic preconditioning preserves connexin 43 phosphorylation in the rat heart. J Transl Med 12:228. doi:10.1186/s12967-014-0228-8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Breivik L, Helgeland E, Aarnes EK, Mrdalj J, Jonassen AK (2011) Remote postconditioning by humoral factors in effluent from ischemic preconditioned rat hearts is mediated via PI3K/Akt-dependent cell-survival signaling at reperfusion. Basic Res Cardiol 106:135–145. doi:10.1007/s00395-010-0133-0

    Article  CAS  PubMed  Google Scholar 

  12. Cabrera-Fuentes HA, Niemann B, Grieshaber P, Wollbrueck M, Gehron J, Preissner KT, Boning A (2015) RNase1 as a potential mediator of remote ischaemic preconditioning for cardioprotection. Eur J Cardiothorac Surg 48:732–737 . doi:10.1093/ejcts/ezu519discussion 737

    Article  PubMed  Google Scholar 

  13. Cai ZP, Parajuli N, Zheng X, Becker L (2012) Remote ischemic preconditioning confers late protection against myocardial ischemia-reperfusion injury in mice by upregulating interleukin-10. Basic Res Cardiol 107:277. doi:10.1007/s00395-012-0277-1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Cai Z, Luo W, Zhan H, Semenza GL (2013) Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart. Proc Natl Acad Sci US A 110:17462–17467. doi:10.1073/pnas.1317158110

    Article  CAS  Google Scholar 

  15. Candilio L, Malik A, Hausenloy DJ (2013) Protection of organs other than the heart by remote ischemic conditioning. J Cardiovasc Med (Hagerstown) 14:193–205. doi:10.2459/JCM.0b013e328359dd7b

    Article  Google Scholar 

  16. Candilio L, Malik A, Ariti C, Barnard M, Di SC, Lawrence D, Hayward M, Yap J, Roberts N, Sheikh A, Kolvekar S, Hausenloy DJ, Yellon DM (2015) Effect of remote ischaemic preconditioning on clinical outcomes in patients undergoing cardiac bypass surgery: a randomised controlled clinical trial. Heart 10:185–192. doi:10.1136/heartjnl-2014-306178

    Article  Google Scholar 

  17. Cao Y, Zhang SZ, Zhao SQ, Bruce IC (2011) The mitochondrial Ca(2+)-activated K(+) channel contributes to cardioprotection by limb remote ischemic preconditioning in rat. Life Sci 88:1026–1030. doi:10.1016/j.lfs.2011.03.011

    Article  CAS  PubMed  Google Scholar 

  18. Cellier L, Tamareille S, Kalakech H, Guillou S, Lenaers G, Prunier F, Mirebeau-Prunier D (2016) Remote ischemic conditioning influences mitochondrial dynamics. Shock 45:192–197. doi:10.1097/SHK.0000000000000500

    Article  CAS  PubMed  Google Scholar 

  19. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864. doi:10.1038/nm1075

    Article  CAS  PubMed  Google Scholar 

  20. Chao de la Barca JM, Bakhta O, Kalakech H, Simard G, Tamareille S, Catros V, Callebert J, Gadras C, Tessier L, Reynier P, Prunier F, Mirebeau-Prunier D (2016) Metabolic signature of remote ischemic preconditioning involving a cocktail of amino acids and biogenic amines. J Am Heart Assoc 5. doi:10.1161/JAHA.116.003891

  21. Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD, Mochly-Rosen D (2008) Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science 321:1493–1495. doi:10.1126/science.1158554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chen CH, Ferreira JC, Gross ER, Mochly-Rosen D (2014) Targeting aldehyde dehydrogenase 2: new therapeutic opportunities. Physiol Rev 94:1–34. doi:10.1152/physrev.00017.2013

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Contractor H, Stottrup NB, Cunnington C, Manlhiot C, Diesch J, Ormerod JO, Jensen R, Bøtker HE, Redington A, Schmidt MR, Ashrafian H, Kharbanda RK (2013) Aldehyde dehydrogenase-2 inhibition blocks remote preconditioning in experimental and human models. Basic Res Cardiol 108:343. doi:10.1007/s00395-013-0343-3

    Article  PubMed  CAS  Google Scholar 

  24. Contractor H, Haarup Lie R, Cunnington C, Li J, Støttrup NB, Manlhiot C, Bøtker HE, Schmidt MR, Forfar JC, Ashrafian H, Redington A, Kharbanda RK (2016) Adenosine receptor activation in the “trigger” limb of remote pre-conditioning mediates human endothelial conditioning and release of circulating cardioprotective factor(s). J Am Coll Cardiol Basic Trans Science. doi:10.1016/j.jacbts.2016.06.002

    Google Scholar 

  25. Davidson SM, Selvaraj P, He D, Boi-Doku C, Yellon RL, Vicencio JM, Yellon DM (2013) Remote ischaemic preconditioning involves signalling through the SDF-1alpha/CXCR4 signalling axis. Basic Res Cardiol 108:377. doi:10.1007/s00395-013-0377-6

    Article  PubMed  CAS  Google Scholar 

  26. Davidson SM, Takov K, Yellon DM (2016) Exosomes and cardiovascular protection. Cardiovasc Drugs Ther. doi:10.1007/s10557-016-6698-6

    PubMed Central  Google Scholar 

  27. Diaz RJ, Harvey K, Boloorchi A, Hossain T, Hinek A, Backx PH, Wilson GJ (2014) Enhanced cell volume regulation: a key mechanism in local and remote ischemic preconditioning. Am J Physiol Cell Physiol 306:C1191–C1199. doi:10.1152/ajpcell.00259.2013

    Article  CAS  PubMed  Google Scholar 

  28. Dickson EW, Reinhart CP, Renzi FP, Becker RC, Porcaro WA, Heard SO (1999) Ischemic preconditioning may be transferable via whole blood transfusion: preliminary evidence. J Thromb Thrombolysis 8:123–129

    Article  CAS  PubMed  Google Scholar 

  29. 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

    Article  CAS  PubMed  Google Scholar 

  30. Donato M, Buchholz B, Rodriguez M, Perez V, Inserte J, Garcia-Dorado D, Gelpi RJ (2012) Role of the parasympathetic nervous system in cardioprotection by remote hindlimb ischemic preconditioning. Exp Physiol 98:425–434. doi:10.1113/expphysiol.2012.066217

    Article  PubMed  Google Scholar 

  31. Donato M, Goyeneche MA, Garces M, Marchini T, Perez V, Del Mauro J, Hocht C, Rodriguez M, Evelson P, Gelpi RJ (2016) Myocardial triggers involved in activation of remote ischaemic preconditioning. Exp Physiol 101:708–716. doi:10.1113/EP085535

    Article  CAS  PubMed  Google Scholar 

  32. Duan X, Ji B, Wang X, Liu J, Zheng Z, Long C, Tang Y, Hu S (2012) Expression of microRNA-1 and microRNA-21 in different protocols of ischemic conditioning in an isolated rat heart model. Cardiology 122:36–43. doi:10.1159/000338149

    Article  CAS  PubMed  Google Scholar 

  33. Dubin AE, Patapoutian A (2010) Nociceptors: the sensors of the pain pathway. J Clin Invest 120:3760–3772. doi:10.1172/JCI42843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ferdinandy P, Hausenloy DJ, Heusch G, Baxter GF, Schulz R (2014) Interaction of risk factors, comorbidities and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol Rev 66:1142–1174. doi:10.1124/pr.113.008300

    Article  CAS  PubMed  Google Scholar 

  35. Ferko M, Kancirova I, Jasova M, Carnicka S, Murarikova M, Waczulikova I, Sumbalova Z, Kucharska J, Ulicna O, Ravingerova T, Ziegelhoffer A (2014) Remote ischemic preconditioning of the heart: protective responses in functional and biophysical properties of cardiac mitochondria. Physiol Res 63(Suppl 4):S469–S478

    CAS  PubMed  Google Scholar 

  36. Foley RN (2008) Erythropoietin: physiology and molecular mechanisms. Heart Fail Rev 13:405–414. doi:10.1007/s10741-008-9083-0

    Article  CAS  PubMed  Google Scholar 

  37. Gao J, Fu W, Jin Z, Yu X (2007) Acupuncture pretreatment protects heart from injury in rats with myocardial ischemia and reperfusion via inhibition of the beta(1)-adrenoceptor signaling pathway. Life Sci 80:1484–1489. doi:10.1016/j.lfs.2007.01.019

    Article  CAS  PubMed  Google Scholar 

  38. Gao Y, Song J, Chen H, Cao C, Lee C (2015) TRPV1 activation is involved in the cardioprotection of remote limb ischemic postconditioning in ischemia-reperfusion injury rats. Biochem Biophys Res Commun 463:1034–1039. doi:10.1016/j.bbrc.2015.06.054

    Article  CAS  PubMed  Google Scholar 

  39. Gedik N, Thielmann M, Kottenberg E, Peters J, Jakob H, Heusch G, Kleinbongard P (2014) No evidence for activated autophagy in left ventricular myocardium at early reperfusion with protection by remote ischemic preconditioning in patients undergoing coronary artery bypass grafting. PLoS One 9:e96567. doi:10.1371/journal.pone.0096567

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Gedik N, Maciel L, Schulte C, Skyschally A, Heusch G, Kleinbongard P (2016) Cardiomyocyte mitochondria as targets of humoral factors released by remote ischemic preconditioning. Arch Med Sci. doi:10.5114/aoms.2016.61789

    Google Scholar 

  41. Gho BCG, 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

    Article  CAS  PubMed  Google Scholar 

  42. Giricz Z, Varga ZV, Baranyai T, Sipos P, Paloczi K, Kittel A, Buzas EI, Ferdinandy P (2014) Cardioprotection by remote ischemic preconditioning of the rat heart is mediated by extracellular vesicles. J Mol Cell Cardiol 68:75–78. doi:10.1016/j.yjmcc.2014.01.004

    Article  CAS  PubMed  Google Scholar 

  43. Gourine A, Gourine AV (2014) Neural mechanisms of cardioprotection. Physiology (Bethesda) 29:133–140. doi:10.1152/physiol.00037.2013

    CAS  Google Scholar 

  44. Grau M, Kollikowski A, Bloch W (2016) Remote ischemia preconditioning increases red blood cell deformability through red blood cell-nitric oxide synthase activation. Clin Hemorheol Microcirc 63:185–197. doi:10.3233/CH-152039

    Article  CAS  PubMed  Google Scholar 

  45. Gross GJ, Baker JE, Moore J, Falck JR, Nithipatikom K (2011) Abdominal surgical incision induces remote preconditioning of trauma (RPCT) via activation of bradykinin receptors (BK2R) and the cytochrome P450 epoxygenase pathway in canine hearts. Cardiovasc Drugs Ther 25:517–522. doi:10.1007/s10557-011-6321-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gross ER, Hsu AK, Urban TJ, Mochly-Rosen D, Gross GJ (2013) Nociceptive-induced myocardial remote conditioning is mediated by neuronal gamma protein kinase C. Basic Res Cardiol 108:381. doi:10.1007/s00395-013-0381-x

    Article  PubMed  CAS  Google Scholar 

  47. Hausenloy DJ, Mwamure PK, Venugopal V, Harris J, Barnard M, Grundy E, Ashley E, Vichare S, Di Salvo C, Kolvekar S, Hayward M, Keogh B, MacAllister RJ, Yellon DM (2007) Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomized controlled trial. Lancet 370:575–579. doi:10.1016/S0140-6736(07)61296-3

    Article  PubMed  Google Scholar 

  48. Hausenloy DJ, Iliodromitis EK, Andreadou I, Papalois A, Gritsopoulos G, Anastasiou-Nana M, Kremastinos DT, Yellon DM (2012) Investigating the signal transduction pathways underlying remote ischemic conditioning in the porcine heart. Cardiovasc Drugs Ther 26:87–93. doi:10.1007/s10557-011-6364-y

    Article  CAS  PubMed  Google Scholar 

  49. Hausenloy DJ, Candilio L, Evans R, Ariti C, Jenkins DP, Kolvekar S, Knight R, Kunst G, Laing C, Nicholas J, Pepper J, Robertson S, Xenou M, Clayton T, Yellon DM, Investigators ET (2015) Remote ischemic preconditioning and outcomes of cardiac surgery. N Engl J Med 373:1408–1417. doi:10.1056/NEJMoa1413534

    Article  CAS  PubMed  Google Scholar 

  50. Hausenloy DJ, Kharbanda R, Rahbek Schmidt M, Moller UK, Ravkilde J, Okkels Jensen L, Engstrom T, Garcia Ruiz JM, Radovanovic N, Christensen EF, Sorensen HT, Ramlall M, Bulluck H, Evans R, Nicholas J, Knight R, Clayton T, Yellon DM, Botker HE (2015) Effect of remote ischaemic conditioning on clinical outcomes in patients presenting with an ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Eur Heart J 36:1846–1848

    PubMed  Google Scholar 

  51. Headrick JP, See Hoe LE, Du Toit EF, Peart JN (2015) Opioid receptors and cardioprotection - 'opioidergic conditioning' of the heart. Br J Pharmacol 172:2026–2050. doi:10.1111/bph.13042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Helgeland E, Breivik LE, Vaudel M, Svendsen OS, Garberg H, Nordrehaug JE, Berven FS, Jonassen AK (2014) Exploring the human plasma proteome for humoral mediators of remote ischemic preconditioning - a word of caution. PLoS One 9:e109279. doi:10.1371/journal.pone.0109279

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Hendgen-Cotta UB, Merx MW, Shiva S, Schmitz J, Becher S, Klare JP, Steinhoff HJ, Goedecke A, Schrader J, Gladwin MT, Kelm M, Rassaf T (2008) Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury. Proc Natl AcadSci USA 105:10256–10261. doi:10.1073/pnas.0801336105

    Article  CAS  Google Scholar 

  54. Hepponstall M, Ignjatovic V, Binos S, Monagle P, Jones B, Cheung MH, d'Udekem Y, Konstantinov IE (2012) Remote ischemic preconditioning (RIPC) modifies plasma proteome in humans. PLoS One 7:e48284. doi:10.1371/journal.pone.0048284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hepponstall M, Ignjatovic V, Binos S, Attard C, Karlaftis V, d'Udekem Y, Monagle P, Konstantinov IE (2015) Remote ischemic preconditioning (RIPC) modifies the plasma proteome in children undergoing repair of tetralogy of fallot: a randomized controlled trial. PLoS One 10:e0122778. doi:10.1371/journal.pone.0122778

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Heusch G (2015) Molecular basis of cardioprotection: signal transduction in ischemic pre-, post- and remote conditioning. Circ Res 116:674–699. doi:10.1161/CIRCRESAHA.116.305348

    Article  CAS  PubMed  Google Scholar 

  57. Heusch G (2016) Remote ischemic conditioning – the enigmatic transfer of protection. Cardiovasc Res in press

  58. Heusch G (2016) The coronary circulation as a target of cardioprotection. Circ Res 118:1643–1658. doi:10.1161/CIRCRESAHA.116.308640

    Article  CAS  PubMed  Google Scholar 

  59. Heusch G, Gersh BJ (2016) ERICCA and RIPHeart: two nails in the coffin for cardioprotection by remote ischemic conditioning? Probably not! Eur Heart J 37:200–202. doi:10.1093/eurheartj/ehv606

    Article  PubMed  Google Scholar 

  60. Heusch G, Gersh BJ (2016) The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge. Eur Heart J. doi:10.1093/eurheartj/ehw224

    Google Scholar 

  61. Heusch G, Rassaf T (2016) Time to give op on cardioprotection? A critical appraisal of clinical studies on ischemic pre-, post-, and remote conditioning. Circ Res 119:676–695. doi:10.1161/CIRCRESAHA.116.308736

    Article  CAS  PubMed  Google Scholar 

  62. Heusch G, Liu GS, Rose J, Cohen MV, Downey JM (2000) No confirmation for a causal role of volume-regulated chloride channels in ischemic preconditioning in rabbits. J Mol Cell Cardiol 32:2279–2285. doi:10.1006/jmcc.2000.1259

    Article  CAS  PubMed  Google Scholar 

  63. Heusch G, Cohen MV, Downey JM (2001) Ischemic preconditioning through opening of swelling-activated chloride channels ? Circ Res 89:e48

    CAS  PubMed  Google Scholar 

  64. Heusch G, Boengler K, Schulz R (2008) Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation 118:1915–1919. doi:10.1161/CIRCULATIONAHA.108.805242

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  66. Heusch G, Libby P, Gersh B, Yellon D, Böhm M, Lopaschuk G, Opie L (2014) Cardiovascular remodeling in coronary artery disease and heart failure. Lancet 383:1933–1943. doi:10.1016/S0140-6736(14)60107-0

    Article  PubMed  PubMed Central  Google Scholar 

  67. Heusch G, Botker HE, Przyklenk K, Redington A, Yellon DM (2015) Remote ischemic conditioning. J Am Coll Cardiol 65:177–195. doi:10.1016/j.jacc.2014.10.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Heyman SN, Leibowitz D, Mor-Yosef Levi I, Liberman A, Eisenkraft A, Alcalai R, Khamaisi M, Rosenberger C (2016) Adaptive response to hypoxia and remote ischaemia pre-conditioning: a new hypoxia-inducible factors era in clinical medicine. Acta Physiol 216:395–406. doi:10.1111/apha.12613

    Article  CAS  Google Scholar 

  69. Hibert P, Prunier-Mirebeau D, Beseme O, Chwastyniak M, Tamareille S, Lamon D, Furber A, Pinet F, Prunier F (2013) Apolipoprotein A-I is a potential mediator of remote ischemic preconditioning. PLoS One 8:e77211. doi:10.1371/journal.pone.0077211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hibert P, Prunier-Mirebeau D, Beseme O, Chwastyniak M, Tamareille S, Pinet F, Prunier F (2014) Modifications in rat plasma proteome after remote ischemic preconditioning (RIPC) stimulus: identification by a SELDI-TOF-MS approach. PLoS One 9:e85669. doi:10.1371/journal.pone.0085669

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Hildebrandt HA, Kreienkamp V, Gent S, Kahlert P, Heusch G, Kleinbongard P (2016) Kinetics and signal activation properties of circulating factor(s) from healthy volunteers undergoing remote ischemic pre-conditioning. J Am Coll Cardiol Basic Trans Science 1:3–13. doi:10.1016/j.jacbts.2016.01.007

    Google Scholar 

  72. Holst JJ (2007) The physiology of glucagon-like peptide 1. Physiol Rev 87:1409–1439. doi:10.1152/physrev.00034.2006

    Article  CAS  PubMed  Google Scholar 

  73. Hu Q, Luo W, Huang L, Huang R, Chen R (2016) Apoptosis-related microRNA changes in the right atrium induced by remote ischemic perconditioning during valve replacement surgery. Sci Rep 6:18959. doi:10.1038/srep18959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Iaconetti C, Sorrentino S, De Rosa S, Indolfi C (2016) Exosomal miRNAs in heart disease. Physiology (Bethesda) 31:16–24. doi:10.1152/physiol.00029.2015

    Google Scholar 

  75. Ibanez B, Heusch G, Ovize M, Van de Werf F (2015) Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol 65:1454–1471. doi:10.1016/j.jacc.2015.02.032

    Article  PubMed  Google Scholar 

  76. Jeanneteau J, Hibert P, Martinez MC, Tual-Chalot S, Tamareille S, Furber A, Andriantsitohaina R, Prunier F (2012) Microparticle release in remote ischemic conditioning mechanism. Am J Physiol Heart Circ Physiol 303:H871–H877. doi:10.1152/ajpheart.00102.2012

    Article  CAS  PubMed  Google Scholar 

  77. Jensen RV, Stottrup NB, Kristiansen SB, Bøtker 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

    Article  PubMed  CAS  Google Scholar 

  78. Johnsen J, Pryds K, Salman R, Lofgren B, Kristiansen SB, Botker HE (2016) The remote ischemic preconditioning algorithm: effect of number of cycles, cycle duration and effector organ mass on efficacy of protection. Basic Res Cardiol 111:10. doi:10.1007/s00395-016-0529-6

    Article  PubMed  Google Scholar 

  79. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413:203–210. doi:10.1038/35093019

    Article  CAS  PubMed  Google Scholar 

  81. Kaelin WG Jr, Ratcliffe PJ (2008) Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30:393–402. doi:10.1016/j.molcel.2008.04.009

    Article  CAS  PubMed  Google Scholar 

  82. Kakinuma Y, Akiyama T, Sato T (2009) Cholinoceptive and cholinergic properties of cardiomyocytes involving an amplification mechanism for vagal efferent effects in sparsely innervated ventricular myocardium. FEBS J 276:5111–5125. doi:10.1111/j.1742-4658.2009.07208.x

    Article  CAS  PubMed  Google Scholar 

  83. Kalakech H, Tamareille S, Pons S, Godin-Ribuot D, Carmeliet P, Furber A, Martin V, Berdeaux A, Ghaleh B, Prunier F (2013) Role of hypoxia inducible factor-1alpha in remote limb ischemic preconditioning. J Mol Cell Cardiol 65:98–104. doi:10.1016/j.yjmcc.2013.10.001

    Article  CAS  PubMed  Google Scholar 

  84. Kalakech H, Hibert P, Prunier-Mirebeau D, Tamareille S, Letournel F, Macchi L, Pinet F, Furber A, Prunier F (2014) RISK and SAFE signaling pathway involvement in apolipoprotein A-I-induced cardioprotection. PLoS One 9:e107950. doi:10.1371/journal.pone.0107950

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Kalogeris T, Baines CP, Krenz M, Korthuis RJ (2012) Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol 298:229–317. doi:10.1016/B978-0-12-394309-5.00006-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  87. Kiss K, Csonka C, Paloczi J, Pipis J, Gorbe A, Kocsis GF, Murlasits Z, Sarkozy M, Szucs G, Holmes CP, Pan Y, Bhandari A, Csont T, Shamloo M, Woodburn KW, Ferdinandy P, Bencsik P (2016) Novel, selective EPO receptor ligands lacking erythropoietic activity reduce infarct size in acute myocardial infarction in rats. Pharmacol Res 113:62–70. doi:10.1016/j.phrs.2016.08.013

    Article  CAS  PubMed  Google Scholar 

  88. Kleinbongard P, Heusch G (2015) Extracellular signalling molecules in the ischaemic/reperfused heart - druggable and translatable for cardioprotection? Br J Pharmacol 172:2010–2025. doi:10.1111/bph.12902

    Article  CAS  PubMed  Google Scholar 

  89. Kono Y, Fukuda S, Hanatani A, Nakanishi K, Otsuka K, Taguchi H, Shimada K (2014) Remote ischemic conditioning improves coronary microcirculation in healthy subjects and patients with heart failure. Drug Des Devel Ther 8:1175–1181. doi:10.2147/DDDT.S68715

    PubMed  PubMed Central  Google Scholar 

  90. Konstantinov IE, Arab S, Li J, Coles JG, Boscarino C, Mori A, Cukerman E, Dawood F, Cheung MM, Shimizu M, Liu PP, Redington AN (2005) The remote ischemic preconditioning stimulus modifies gene expression in mouse myocardium. J Thorac Cardiovasc Surg 130:1326–1332. doi:10.1016/j.jtcvs.2005.03.050

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  92. 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 147:376–382. doi:10.1016/j.jtcvs.2013.01.005

    Article  CAS  PubMed  Google Scholar 

  93. Kristiansen SB, Henning O, Kharbanda RK, Nielsen-Kudsk JE, Schmidt MR, Redington AN, Nielsen TT, Bøtker HE (2005) Remote preconditioning reduces ischemic injury in the explanted heart by a KATP channel-dependent mechanism. Am J Physiol Heart Circ Physiol 288:H1252–H1256. doi:10.1152/ajpheart.00207.2004

    Article  CAS  PubMed  Google Scholar 

  94. Lambert EA, Thomas CJ, Hemmes R, Eikelis N, Pathak A, Schlaich MP, Lambert GW (2016) Sympathetic nervous response to ischemia-reperfusion injury in humans is altered with remote ischemic preconditioning. Am J Physiol Heart Circ Physiol 311:H364–H370. doi:10.1152/ajpheart.00369.2016

    Article  PubMed  Google Scholar 

  95. Lang SC, Elsässer A, Scheler C, Vetter S, Tiefenbacher CP, Kübler W, Katus HA, Vogt AM (2006) Myocardial preconditioning and remote renal preconditioning. Identifying a protective factor using proteomic methods? Basic Res Cardiol 101:149–158. doi:10.1007/s00395-005-0565-0

    Article  CAS  PubMed  Google Scholar 

  96. Lanza GA, Stazi A, Villano A, Torrini F, Milo M, Laurito M, Flego D, Aurigemma C, Liuzzo G, Crea F (2016) Effect of remote ischemic preconditioning on platelet activation induced by coronary procedures. Am J Cardiol 117:359–365. doi:10.1016/j.amjcard.2015.10.056

    Article  CAS  PubMed  Google Scholar 

  97. Leung CH, Wang L, Nielsen JM, Tropak MB, Fu YY, Kato H, Callahan J, Redington AN, Caldarone CA (2014) Remote cardioprotection by transfer of coronary effluent from ischemic preconditioned rabbit heart preserves mitochondrial integrity and function via adenosine receptor activation. Cardiovasc Drugs Ther 28:7–17. doi:10.1007/s10557-013-6489-2

    Article  CAS  PubMed  Google Scholar 

  98. Li J, Rohailla S, Gelber N, Rutka J, Sabah N, Gladstone RA, Wei C, Hu P, Kharbanda RK, Redington AN (2014) MicroRNA-144 is a circulating effector of remote ischemic preconditioning. Basic Res Cardiol 109:423. doi:10.1007/s00395-014-0423-z

    Article  PubMed  CAS  Google Scholar 

  99. Liem DA, Verdouw PD, Ploeg H, Kazim S, Duncker D (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.01031.2001

    Article  CAS  PubMed  Google Scholar 

  100. Lim SY, Yellon DM, Hausenloy DJ (2010) The neural and humoral pathways in remote limb ischemic preconditioning. Basic Res Cardiol 105:651–655. doi:10.1007/s00395-010-0099-y

    Article  PubMed  Google Scholar 

  101. Ling Ling J, Wong GT, Yao L, Xia Z, Irwin MG (2010) Remote pharmacological post-conditioning by intrathecal morphine: cardiac protection from spinal opioid receptor activation. Acta Anaesthesiol Scand 54:1097–1104. doi:10.1111/j.1399-6576.2010.02295.x

    Article  CAS  PubMed  Google Scholar 

  102. Lonborg J, Vejlstrup N, Kelbaek H, Holmvang L, Jorgensen E, Helqvist S, Saunamaki K, Ahtarovski KA, Botker HE, Kim WY, Clemmensen P, Engstrom T (2013) Final infarct size measured by cardiovascular magnetic resonance in patients with ST elevation myocardial infarction predicts long-term clinical outcome: an observational study. Eur Heart J Cardiovasc Imaging 14:387–395. doi:10.1093/ehjci/jes271

    Article  PubMed  Google Scholar 

  103. 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

    Article  CAS  PubMed  Google Scholar 

  104. Loukogeorgakis SP, Williams R, Panagiotidou AT, Kolvekar SK, Donald A, Cole TJ, Yellon DM, Deanfield JE, MacAllister RJ (2007) Transient limb ischemia induces remote preconditioning and remote postconditioning in humans by a KATP channel dependent mechanism. Circulation 116:1386–1395. doi:10.1161/CIRCULATIONAHA.106.653782

    Article  CAS  PubMed  Google Scholar 

  105. Lu Y, Wong GT, Zhang Y, Hu J, Dong C (2014) Remote intrathecal morphine preconditioning is ineffective in the presence of neuraxial blockade with lidocaine. Kaohsiung J Med Sci 30:68–72. doi:10.1016/j.kjms.2013.10.007

    Article  PubMed  Google Scholar 

  106. Martin-Puig S, Tello D, Aragones J (2015) Novel perspectives on the PHD-HIF oxygen sensing pathway in cardioprotection mediated by IPC and RIPC. Front Physiol 6:137. doi:10.3389/fphys.2015.00137

    Article  PubMed  PubMed Central  Google Scholar 

  107. Mastitskaya S, Marina N, Gourine A, Gilbey MP, Spyer KM, Teschemacher AG, Kasparov S, Trapp S, Ackland GL, Gourine AV (2012) Cardioprotection evoked by remote ischaemic preconditioning is critically dependent on the activity of vagal pre-ganglionic neurones. Cardiovasc Res 95:487–494. doi:10.1093/cvr/cvs212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Mastitskaya S, Basalay M, Hosford PS, Ramage AG, Gourine A, Gourine AV (2016) Identifying the source of a humoral factor of remote (pre)conditioning cardioprotection. PLoS One 11:e0150108. doi:10.1371/journal.pone.0150108

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Mei B, Li W, Cheng X, Liu X, Gu E, Zhang Y (2016) Activating mu-opioid receptors in the spinal cord mediates the cardioprotective effect of remote preconditioning of trauma. Cardiol J. doi:10.5603/CJ.a2016.0062

    PubMed  Google Scholar 

  110. Merlocco AC, Redington KL, Disenhouse T, Strantzas SC, Gladstone R, Wei C, Tropak MB, Manlhiot C, Li J, Redington AN (2014) Transcutaneous electrical nerve stimulation as a novel method of remote preconditioning: in vitro validation in an animal model and first human observations. Basic Res Cardiol 109:406. doi:10.1007/s00395-014-0406-0

    Article  PubMed  CAS  Google Scholar 

  111. Meybohm P, Bein B, Brosteanu O, Cremer J, Gruenewald M, Stoppe C, Coburn M, Schaelte G, Boning A, Niemann B, Roesner J, Kletzin F, Strouhal U, Reyher C, Laufenberg-Feldmann R, Ferner M, Brandes IF, Bauer M, Stehr SN, Kortgen A, Wittmann M, Baumgarten G, Meyer-Treschan T, Kienbaum P, Heringlake M, Schon J, Sander M, Treskatsch S, Smul T, Wolwender E, Schilling T, Fuernau G, Hasenclever D, Zacharowski K, Collaborators RIS (2015) A multicenter trial of remote ischemic preconditioning for heart surgery. N Engl J Med 373:1397–1407. doi:10.1056/NEJMoa1413579

    Article  CAS  PubMed  Google Scholar 

  112. Nilius B, Owsianik G, Voets T, Peters JA (2007) Transient receptor potential cation channels in disease. Physiol Rev 87:165–217. doi:10.1152/physrev.00021.2006

    Article  CAS  PubMed  Google Scholar 

  113. Oba T, Yasukawa H, Nagata T, Kyogoku S, Minami T, Nishihara M, Ohshima H, Mawatari K, Nohara S, Takahashi J, Sugi Y, Igata S, Iwamoto Y, Kai H, Matsuoka H, Takano M, Aoki H, Fukumoto Y, Imaizumi T (2015) Renal nerve-mediated erythropoietin release confers cardioprotection during remote ischemic preconditioning. Circ J 79:1557–1567. doi:10.1253/circj.CJ-14-1171

    Article  PubMed  Google Scholar 

  114. Oikawa S, Mano A, Takahashi R, Kakinuma Y (2015) Remote ischemic preconditioning with a specialized protocol activates the non-neuronal cardiac cholinergic system and increases ATP content in the heart. Int Immunopharmacol 29:181–184. doi:10.1016/j.intimp.2015.06.004

    Article  CAS  PubMed  Google Scholar 

  115. Okerson T, Chilton RJ (2012) The cardiovascular effects of GLP-1 receptor agonists. Cardiovasc Ther 30:e146–e155. doi:10.1111/j.1755-5922.2010.00256.x

    Article  CAS  PubMed  Google Scholar 

  116. Olenchock BA, Moslehi J, Baik AH, Davidson SM, Williams J, Gibson WJ, Pierce KA, Miller CM, Hanse EA, Kelekar A, Sullivan LB, Wagers AJ, Clish CB, Vander Heiden MG, Kaelin WG Jr (2016) EGLN1 inhibition and rerouting of alpha-ketoglutarate suffice for remote ischemic protection. Cell 164:884–895. doi:10.1016/j.cell.2016.02.006

    Article  CAS  PubMed  Google Scholar 

  117. Ovize M, Baxter GF, Di Lisa F, Ferdinandy P, Garcia-Dorado D, Hausenloy DJ, Heusch G, Vinten-Johansen J, Yellon DM, Schulz R (2010) Postconditioning and protection from reperfusion injury: where do we stand? Cardiovasc Res 87:406–423. doi:10.1093/cvr/cvq129

    Article  CAS  PubMed  Google Scholar 

  118. Pedersen CM, Cruden NL, Schmidt MR, Lau C, Bøtker HE, Kharbanda RK, Newby DE (2011) Remote ischemic preconditioning prevents systemic platelet activation associated with ischemia-reperfusion injury in humans. J Thromb Haemost 9:404–407. doi:10.1111/j.1538-7836.2010.04142.x

    Article  CAS  PubMed  Google Scholar 

  119. Pedersen CM, Schmidt MR, Barnes G, Bøtker HE, Kharbanda RK, Newby DE, Cruden NL (2011) Bradykinin does not mediate remote ischaemic preconditioning or ischaemia-reperfusion injury in vivo in man. Heart 97:1857–1861. doi:10.1136/heartjnl-2011-300323

    Article  CAS  PubMed  Google Scholar 

  120. Pickard JM, Botker HE, Crimi G, Davidson B, Davidson SM, Dutka D, Ferdinandy P, Ganske R, Garcia-Dorado D, Giricz Z, Gourine AV, Heusch G, Kharbanda R, Kleinbongard P, MacAllister R, McIntyre C, Meybohm P, Prunier F, Redington A, Robertson NJ, Suleiman MS, Vanezis A, Walsh S, Yellon DM, Hausenloy DJ (2015) Remote ischemic conditioning: from experimental observation to clinical application: report from the 8th biennial hatter cardiovascular institute workshop. Basic Res Cardiol 110:453. doi:10.1007/s00395-014-0453-6

    Article  PubMed  Google Scholar 

  121. Pickard JM, Davidson SM, Hausenloy DJ, Yellon DM (2016) Co-dependence of the neural and humoral pathways in the mechanism of remote ischemic conditioning. Basic Res Cardiol 111:50. doi:10.1007/s00395-016-0568-z

    Article  PubMed  PubMed Central  Google Scholar 

  122. Pryds K, Nielsen RR, Hoff CM, Tolbod LP, Bouchelouche K, Li J, Schmidt MR, Redington AN, Frokiaer J, Botker HE (2016) Effect of remote ischemic conditioning on myocardial perfusion in patients with suspected ischemic coronary artery disease. J Nucl Cardiol. doi:10.1007/s12350-016-0709-7

    PubMed  Google Scholar 

  123. 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

    Article  CAS  PubMed  Google Scholar 

  124. Randhawa PK, Jaggi AS (2015) TRPV1 and TRPV4 channels: potential therapeutic targets for ischemic conditioning-induced cardioprotection. Eur J Pharmacol 746:180–185

    Article  CAS  PubMed  Google Scholar 

  125. Randhawa PK, Jaggi AS (2016) Opioids in remote ischemic preconditioning-induced cardioprotection. J Cardiovasc Pharmacol Ther. doi:10.1177/1074248416660621

    PubMed  Google Scholar 

  126. Randhawa PK, Jaggi AS (2016) Unraveling the role of adenosine in remote ischemic preconditioning-induced cardioprotection. Life Sci 155:140–146. doi:10.1016/j.lfs.2016.05.009

    Article  CAS  PubMed  Google Scholar 

  127. Rassaf T, Ferdinandy P, Schulz R (2014) Nitrite in organ protection. Br J Pharmacol 171:1–11. doi:10.1111/bph.12291

    Article  CAS  PubMed  Google Scholar 

  128. Rassaf T, Totzeck M, Hendgen-Cotta UB, Shiva S, Heusch G, Kelm M (2014) Circulating nitrite contributes to cardioprotection by remote ischemic preconditioning. Circ Res 114:1601–1610. doi:10.1161/CIRCRESAHA.114.303822

    Article  CAS  PubMed  Google Scholar 

  129. 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

    Article  PubMed  CAS  Google Scholar 

  130. Redington KL, Disenhouse T, Li J, Wei C, Dai X, Gladstone R, Manlhiot C, Redington AN (2013) Electroacupuncture reduces myocardial infarct size and improves post-ischemic recovery by invoking release of humoral, dialyzable, cardioprotective factors. J Physiol Sci 63:219–223. doi:10.1007/s12576-013-0259-6

    Article  PubMed  Google Scholar 

  131. Reed GW, Rossi JE, Cannon CP (2016) Acute myocardial infarction. Lancet. doi:10.1016/S0140-6736(16)30677-8

    PubMed Central  Google Scholar 

  132. Rentoukas I, Giannopoulos G, Kaoukis A, Kossyvakis C, Raisakis K, Driva M, Panagopoulou V, Tsarouchas K, Vavetsi S, Pyrgakis V, Deftereos S (2010) Cardioprotective role of remote ischemic periconditioning in primary percutaneous coronary intervention: enhancement by opioid action. J Am Coll Cardiol Cardiovasc Interv 3:49–55. doi:10.1016/j.jcin.2009.10.015

    Article  Google Scholar 

  133. Sanchis-Gomar F, Garcia-Gimenez JL, Pareja-Galeano H, Romagnoli M, Perez-Quilis C, Lippi G (2014) Erythropoietin and the heart: physiological effects and the therapeutic perspective. Int J Cardiol 171:116–125. doi:10.1016/j.ijcard.2013.12.011

    Article  PubMed  Google Scholar 

  134. Sardar P, Chatterjee S, Kundu A, Samady H, Owan T, Giri J, Nairooz R, Selzman CH, Heusch G, Gersh BJ, Abbott JD, Mukherjee D, Fang JC (2016) Remote ischemic preconditioning in patients undergoing cardiovascular surgery: evidence from a meta-analysis of randomized controlled trials. Int J Cardiol 221:34–41. doi:10.1016/j.ijcard.2016.06.325

    Article  PubMed  Google Scholar 

  135. Saxena P, Aggarwal S, Misso NL, Passage J, Newman MA, Thompson PJ, d'Udekem Y, Praporski S, Konstantinov IE (2013) Remote ischaemic preconditioning down-regulates kinin receptor expression in neutrophils of patients undergoing heart surgery. Interact Cardiovasc Thorac Surg 17:653–658. doi:10.1093/icvts/ivt279

    Article  PubMed  PubMed Central  Google Scholar 

  136. Schoemaker RG, van Heijningen CL (2000) Bradykinin mediates cardiac preconditioning at a distance. Am J Physiol Heart Circ Physiol 278:H1571–H1576

    CAS  PubMed  Google Scholar 

  137. Schulte G, Sommerschild H, Yang J, Tokuno S, Goiny M, Lovdahl C, Johansson B, Fredholm BB, Valen G (2004) Adenosine a receptors are necessary for protection of the murine heart by remote, delayed adaptation to ischaemia. Acta Physiol Scand 182:133–143. doi:10.1111/j.1365-201X.2004.01350.x

    Article  CAS  PubMed  Google Scholar 

  138. 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

    Article  CAS  PubMed  Google Scholar 

  139. Shahid M, Tauseef M, Sharma KK, Fahim M (2008) Brief femoral artery ischaemia provides protection against myocardial ischaemia-reperfusion injury in rats: the possible mechanisms. Exp Physiol 93:954–968. doi:10.1113/expphysiol.2007.041442

    Article  CAS  PubMed  Google Scholar 

  140. Shigematsu S, Ishida S, Gute DC, Korthuis RJ (1999) Concentration-dependent effects of bradykinin on leukocyte recruitment and venular hemodynamics in rat mesentery. Am J Physiol Heart Circ Physiol 277:H152–H160

    CAS  Google Scholar 

  141. Shimizu M, Konstantinov IE, Kharbanda RK, Cheung MH, Redington AN (2007) Effects of intermittent lower limb ischaemia on coronary blood flow and coronary resistance in pigs. Acta Physiol (Oxf) 190:103–109. doi:10.1111/j.1748-1716.2007.01667.x

    Article  CAS  Google Scholar 

  142. 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

    Article  CAS  Google Scholar 

  143. 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

    Article  CAS  PubMed  Google Scholar 

  144. Silvani A, Calandra-Buonaura G, Dampney RA, Cortelli P (2016) Brain-heart interactions: physiology and clinical implications. Philos Trans A Math Phys Eng Sci 374. doi:10.1098/rsta.2015.0181

  145. Skyschally A, Gent S, Amanakis G, Schulte C, Kleinbongard P, Heusch G (2015) Across-species transfer of protection by remote ischemic preconditioning with species-specific myocardial signal transduction by reperfusion injury salvage kinase and survival activating factor enhancement pathways. Circ Res 117:279–288. doi:10.1161/CIRCRESAHA.117.306878

    Article  CAS  PubMed  Google Scholar 

  146. Slagsvold KH, Moreira JB, Rognmo O, Hoydal M, Bye A, Wisloff U, Wahba A (2014) Remote ischemic preconditioning preserves mitochondrial function and activates pro-survival protein kinase Akt in the left ventricle during cardiac surgery: a randomized trial. Int J Cardiol 177:409–417. doi:10.1016/j.ijcard.2014.09.206

    Article  PubMed  Google Scholar 

  147. Slagsvold KH, Rognmo O, Hoydal M, Wisloff U, Wahba A (2014) Remote ischemic preconditioning preserves mitochondrial function and influences myocardial microRNA expression in atrial myocardium during coronary bypass surgery. Circ Res 114:851–859. doi:10.1161/CIRCRESAHA.114.302751

    Article  CAS  PubMed  Google Scholar 

  148. Sloth AD, Schmidt MR, Munk K, Kharbanda RK, Redington AN, Schmidt M, Pedersen L, Sorensen HT, Bøtker HE (2014) Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention. Eur Heart J 35:168–175. doi:10.1093/eurheartj/eht369

    Article  PubMed  Google Scholar 

  149. Southerland EM, Milhorn DM, Foreman RD, Linderoth B, Dejongste MJ, Armour JA, Subramanian V, Singh M, Singh K, Ardell JL (2007) Preemptive, but not reactive, spinal cord stimulation mitigates transient ischemia-induced myocardial infarction via cardiac adrenergic neurons. Am J Physiol Heart Circ Physiol 292:H311–H317. doi:10.1152/ajpheart.00087.2006

    Article  CAS  PubMed  Google Scholar 

  150. Stazi A, Scalone G, Laurito M, Milo M, Pelargonio G, Narducci ML, Parrinello R, Figliozzi S, Bencardino G, Perna F, Lanza GA, Crea F (2014) Effect of remote ischemic preconditioning on platelet activation and reactivity induced by ablation for atrial fibrillation. Circulation 129:11–17. doi:10.1161/CIRCULATIONAHA.113.005336

    Article  CAS  PubMed  Google Scholar 

  151. 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.00396.2010

    Article  CAS  PubMed  Google Scholar 

  152. Stone GW, Selker HP, Thiele H, Patel MR, Udelson JE, Ohman EM, Maehara A, Eitel I, Granger CB, Jenkins PL, Nichols M, Ben-Yehuda O (2016) Relationship between infarct size and outcomes following primary PCI: patient-level analysis from 10 randomized trials. J Am Coll Cardiol 67:1674–1683. doi:10.1016/j.jacc.2016.01.069

    Article  PubMed  Google Scholar 

  153. Surendra H, Diaz RJ, Harvey K, Tropak M, Callahan J, Hinek A, Hossain T, Redington A, Wilson GJ (2013) Interaction of delta and kappa opioid receptors with adenosine A1 receptors mediates cardioprotection by remote ischemic preconditioning. J Mol Cell Cardiol 60:142–150. doi:10.1016/j.yjmcc.2013.04.010

    Article  CAS  PubMed  Google Scholar 

  154. Svennerholm K, Rodsand P, Hellmand U, Lundholm M, Waldenström A, Biber B, Ronquist G, Haney M (2015) Myocardial ischemic preconditioning in a porcine model leads to rapid changes in cardiac extracellular vesicle messenger RNA content. Int J Cardiol 8:62–67. doi:10.1016/j.ijcha.2015.05.006

    Google Scholar 

  155. Svennerholm K, Rodsand P, Hellman U, Waldenstrom A, Lundholm M, Ahren D, Biber B, Ronquist G, Haney M (2016) DNA content in extracellular vesicles isolated from porcine coronary venous blood directly after myocardial ischemic preconditioning. PLoS One 11:e0159105. doi:10.1371/journal.pone.0159105

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Thielmann M, Kottenberg E, Kleinbongard P, Wendt D, Gedik N, Pasa S, Price V, Tsagakis K, Neuhäuser M, Peters J, Jakob H, Heusch G (2013) Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: a single-Centre randomised, double-blind, controlled trial. Lancet 382:597–604. doi:10.1016/S0140-6736(13)61450-6

    Article  PubMed  Google Scholar 

  157. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Thygesen K, Alpert JS, White HD, Jaffe AS, Katus HA, Apple FS, Lindahl B, Morrow DA, Chaitman BR, Clemmensen PM, Johanson P, Hod H, Underwood R, Bax JJ, Bonow RO, Pinto F, Gibbons RJ, Fox KA, Atar D, Newby LK, Galvani M, Hamm CW, Uretsky BF, Gabriel SP, Wijns W, Bassand JP, Menasche P, Ravkilde J, Ohman EM, Antman EM, Wallentin LC, Armstrong PW, Simoons ML, Januzzi JL, Nieminen MS, Gheorghiade M, Filippatos G, Luepker RV, Fortmann SP, Rosamond WD, Levy D, Wood D, Smith SC, Hu D, Lopez-Sendon JL, Robertson RM, Weaver D, Tendera M, Bove AA, Parkhomenko AN, Vasilieva EJ, Mendis S, Bax JJ, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S, Morais J, Aguiar C, Almahmeed W, Arnar DO, Barili F, Bloch KD, Bolger AF, Bøtker HE, Bozkurt B, Bugiardini R, Cannon C, de Lemos J, Eberli FR, Escobar E, Hlatky M, James S, Kern KB, Moliterno DJ, Mueller C, Neskovic AN, Pieske BM, Schulman SP, Storey RF, Taubert KA, Vranckx P, Wagner DR (2012) Third universal definition of myocardial infarction. Eur Heart J 33:2551–2567. doi:10.1093/eurheartj/ehs184

    Article  PubMed  Google Scholar 

  158. Tsai HJ, Huang SS, Tsou MT, Wang HT, Chiu JH (2015) Role of opioid receptors signaling in remote electrostimulation -induced protection against ischemia/reperfusion injury in rat hearts. PLoS One 10:e0138108. doi:10.1371/journal.pone.0138108

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Tsou MT, Huang CH, Chiu JH (2004) Electroacupuncture on PC6 (Neiguan) attenuates ischemia/reperfusion injury in rat hearts. Am J Chin Med 32:951–965. doi:10.1142/S0192415X04002557

    Article  PubMed  Google Scholar 

  160. Uitterdijk A, Yetgin T, Te Lintel HM, Sneep S, Krabbendam-Peters I, van Beusekom HM, Fischer TM, Cornelussen RN, Manintveld OC, Merkus D, Duncker DJ (2015) Vagal nerve stimulation started just prior to reperfusion limits infarct size and no-reflow. Basic Res Cardiol 110:508. doi:10.1007/s00395-015-0508-3

    Article  PubMed  Google Scholar 

  161. Vicencio JM, Yellon DM, Sivaraman V, Das D, Boi-Doku C, Arjun S, Zheng Y, Riquelme JA, Kearney J, Sharma V, Multhoff G, Hall AR, Davidson SM (2015) Plasma exosomes protect the myocardium from ischemia-reperfusion injury. J Am Coll Cardiol 65:1525–1536. doi:10.1016/j.jacc.2015.02.026

    Article  CAS  PubMed  Google Scholar 

  162. Wang L, Oka N, Tropak M, Callahan J, Lee J, Wilson G, Redington A, Caldarone CA (2008) Remote ischemic preconditioning elaborates a transferable blood-borne effector that protects mitochondrial structure and function and preserves myocardial performance after neonatal cardioplegic arrest. J Thorac Cardiovasc Surg 136:335–342. doi:10.1016/j.jtcvs.2007.12.055

    Article  PubMed  Google Scholar 

  163. 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

    Article  CAS  PubMed  Google Scholar 

  164. Whittaker P, Przyklenk K (2014) From ischemic conditioning to 'hyperconditioning': clinical phenomenon and basic science opportunity. Dose Response 12:650–663. doi:10.2203/dose-response.14-035

    Article  PubMed  PubMed Central  Google Scholar 

  165. Wong GT, Lu Y, Mei B, Xia Z, Irwin MG (2012) Cardioprotection from remote preconditioning involves spinal opioid receptor activation. Life Sci 91:860–865. doi:10.1016/j.lfs.2012.08.037

    Article  CAS  PubMed  Google Scholar 

  166. Xin P, Zhu W, Li J, Ma S, Wang L, Liu M, Li J, Wei M, Redington AN (2010) Combined local ischemic postconditioning and remote perconditioning recapitulate cardioprotective effects of local ischemic preconditioning. Am J Physiol Heart Circ Physiol 298:H1819–H1831. doi:10.1152/ajpheart.01102.2009

    Article  CAS  PubMed  Google Scholar 

  167. Yellon DM, Davidson SM (2014) Exosomes: nanoparticles involved in cardioprotection? Circ Res 114:325–332. doi:10.1152/ajpheart.01102.2009

    Article  CAS  PubMed  Google Scholar 

  168. Yellon DM, Hausenloy DJ (2007) Myocardial reperfusion injury. N Engl J Med 357:1121–1135. doi:10.1056/NEJMra071667

    Article  CAS  PubMed  Google Scholar 

  169. Zangrillo A, Musu M, Greco T, Di Prima AL, Matteazzi A, Testa V, Nardelli P, Febres D, Monaco F, Calabro MG, Ma J, Finco G, Landoni G (2015) Additive effect on survival of anaesthetic cardiac protection and remote ischemic preconditioning in cardiac surgery: a Bayesian network meta-analysis of randomized trials. PLoS One 10:e0134264. doi:10.1371/journal.pone.0134264

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Zarbock A, Schmidt C, Van Aken H, Wempe C, Martens S, Zahn PK, Wolf B, Goebel U, Schwer CI, Rosenberger P, Haeberle H, Gorlich D, Kellum JA, Meersch M, Renal RI (2015) Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial. JAMA 313:2133–2141. doi:10.1001/jama.2015.4189

    Article  CAS  PubMed  Google Scholar 

  171. Zernecke A, Preissner KT (2016) Extracellular ribonucleic acids (RNA) enter the stage in cardiovascular disease. Circ Res 118:469–479. doi:10.1161/CIRCRESAHA.115.307961

    Article  CAS  PubMed  Google Scholar 

  172. Zhang SZ, Wang NF, Xu J, Gao Q, Lin GH, Bruce IC, Xia Q (2006) Kappa-opioid receptors mediate cardioprotection by remote preconditioning. Anesthesiology 105:550–556

    Article  CAS  PubMed  Google Scholar 

  173. Zhou C, Li L, Li H, Gong J, Fang N (2014) Delayed remote preconditioning induces cardioprotection: role of heme oxygenase-1. J Surg Res. doi:10.1016/j.jss.2014.03.054

    Google Scholar 

  174. Zitta K, Meybohm P, Gruenewald M, Cremer J, Zacharowski KD, Scholz J, Steinfath M, Albrecht M (2015) Profiling of cell stress protein expression in cardiac tissue of cardiosurgical patients undergoing remote ischemic preconditioning: implications for thioredoxin in cardioprotection. J Transl Med 13:34. doi:10.1186/s12967-015-0403-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgments

PK and GH were supported by the German Research Foundation (GH: He 1320/18-1, 3; PK and GH: SFB 1116, B8).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Petra Kleinbongard.

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/s00424-017-1936-8.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kleinbongard, P., Skyschally, A. & Heusch, G. Cardioprotection by remote ischemic conditioning and its signal transduction. Pflugers Arch - Eur J Physiol 469, 159–181 (2017). https://doi.org/10.1007/s00424-016-1922-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-016-1922-6

Keywords

Navigation