Exercise-induced cardioprotection is mediated by a bloodborne, transferable factor

  • M. M. MichelsenEmail author
  • N. B. Støttrup
  • M. R. Schmidt
  • B. Løfgren
  • R. V. Jensen
  • M. Tropak
  • E. Jean St-Michel
  • A. N. Redington
  • H. E. Bøtker
Original Contribution


Exercise protects against myocardial ischemia-reperfusion (I-R) injury but the mechanism remains unclear. Protection can be transferred from a remotely preconditioned human donor to an isolated perfused rabbit heart using a dialysate of plasma. We hypothesized that physical exercise preconditioning also confers cardioprotection through a humorally mediated effector dependent on opioid receptor activation. Thirteen male volunteers performed vigorous exercise (four 2-minute bouts of high-intensity exercise) and 1 week later they underwent remote ischemic preconditioning (four cycles of 5 min upper limb ischemia and reperfusion). Dialysates were prepared from blood collected before (control) and after the two interventions. Isolated rabbit hearts were perfused with the dialysates without and with co-administration of naloxone (opioid receptor antagonist) prior to 40 min regional ischemia and 2 h reperfusion. Exercise and remote ischemic preconditioning (rIPC) reduced infarct size from 60 ± 5 to 35 ± 5 % and from 57 ± 7 to 27 ± 3 % of the area at risk, respectively (p < 0.05 and < 0.01). Furthermore, post-ischemic left ventricular developed pressure was improved compared with controls (p = 0.08 for exercise and p = 0.04 for rIPC). Co-perfusion with naloxone abrogated the protective effects of exercise and remote ischemic preconditioned dialysates. In conclusion, high-intensity exercise preconditioning elicits cardioprotection through a humorally mediated dependent on opioid receptor activation, similar to rIPC.


Ischemia Reperfusion Cardioprotection Exercise Remote ischemic preconditioning Humoral factor 



Coronary artery disease


Ischemic preconditioning


Remote IPC


Exercise preconditioning


Infarct size


Ischemic preconditioning




Krebs Henseleit buffer


Left ventricular


Left ventricular developed pressure



We thank Eva Sparrewath and Bente Jacobsen for excellent technical assistance. The results of the present study do not constitute endorsement by ACSM. This study was financially supported by Foundation Leducq (CVD 06), The Danish Agency for Science, Technology and Innovation (11-108354 and 11-115818), Canadian Institutes of Health Research, The Lundbeck Foundation


  1. 1.
    Akil H, Owens C, Gutstein H, Taylor L, Curran E, Watson S (1998) Endogenous opioids: overview and current issues. Drug Alcohol Depend 51:127–140PubMedCrossRefGoogle Scholar
  2. 2.
    Ali ZA, Callaghan CJ, Ali AA, Sheikh AY, Akhtar A, Pavlovic A, Nouraei SA, Dutka DP, Gaunt ME (2008) Perioperative myocardial injury after elective open abdominal aortic aneurysm repair predicts outcome. Eur J Vasc Endovasc Surg 35:413–419PubMedCrossRefGoogle Scholar
  3. 3.
    Bijnen FC, Caspersen CJ, Mosterd WL (1994) Physical inactivity as a risk factor for coronary heart disease: a WHO and international society and federation of cardiology position statement. Bull World Health Organ 72:1–4PubMedGoogle Scholar
  4. 4.
    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 375:727–734PubMedCrossRefGoogle Scholar
  5. 5.
    Bowles DK, Farrar RP, Starnes JW (1992) Exercise training improves cardiac function after ischemia in the isolated, working rat heart. Am J Physiol 263:H804–H809PubMedGoogle Scholar
  6. 6.
    Brown DA, Jew KN, Sparagna GC, Musch TI, Moore RL (2003) Exercise training preserves coronary flow and reduces infarct size after ischemia-reperfusion in rat heart. J Appl Physiol 95:2510–2518PubMedGoogle Scholar
  7. 7.
    Chatham JC, Des RC, Forder JR (2001) Evidence of separate pathways for lactate uptake and release by the perfused rat heart. Am J Physiol Endocrinol Metab 281:E794–E802PubMedGoogle Scholar
  8. 8.
    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 47:2277–2282PubMedCrossRefGoogle Scholar
  9. 9.
    Debruille C, Luyckx M, Ballester L, Brunet C, Odou P, Dine T, Gressier B, Cazin M, Cazin JC (1999) Serum opioid activity after physical exercise in rats. Physiol Res 48:129–133PubMedGoogle Scholar
  10. 10.
    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 33:1751–1756PubMedCrossRefGoogle Scholar
  11. 11.
    Dickson EW, Hogrefe CP, Ludwig PS, Ackermann LW, Stoll LL, Denning GM (2008) Exercise enhances myocardial ischemic tolerance via an opioid receptor-dependent mechanism. Am J Physiol Heart Circ Physiol 294:H402–H408PubMedCrossRefGoogle Scholar
  12. 12.
    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–H2457PubMedGoogle Scholar
  13. 13.
    Dickson EW, Porcaro WA, Fenton RA, Heard SO, Reindhardt CP, Renzi FP, Przyklenk K (2000) “Preconditioning at a distance” in the isolated rabbit heart. Acad Emerg Med 7:311–317PubMedCrossRefGoogle Scholar
  14. 14.
    Dickson EW, Reinhardt CP, Renzi FP, Becker RC, Porcaro WA, Heard SO (1999) Ischemic preconditioning may be transferable via whole blood transfusion: preliminary evidence. J Thromb Thrombolysis 8:123–129PubMedCrossRefGoogle Scholar
  15. 15.
    Finegan BA, Lopaschuk GD, Gandhi M, Clanachan AS (1995) Ischemic preconditioning inhibits glycolysis and proton production in isolated working rat hearts. Am J Physiol 269:H1767–H1775PubMedGoogle Scholar
  16. 16.
    Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, Verdouw PD (1996) Myocardial protection by brief ischemia in noncardiac tissue. Circulation 94:2193–2200PubMedGoogle Scholar
  17. 17.
    Guth BD, Wisneski JA, Neese RA, White FC, Heusch G, Mazer CD, Gertz EW (1990) Myocardial lactate release during ischemia in swine. Relation to regional blood flow. Circulation 81:1948–1958PubMedCrossRefGoogle Scholar
  18. 18.
    Hamilton KL, Staib JL, Phillips T, Hess A, Lennon SL, Powers SK (2003) Exercise, antioxidants, and HSP72: protection against myocardial ischemia/reperfusion. Free Radic Biol Med 34:800–809PubMedCrossRefGoogle Scholar
  19. 19.
    Hausenloy DJ, Baxter G, Bell R, Botker HE, Davidson SM, Downey J, Heusch G, Kitakaze M, Lecour S, Mentzer R, Mocanu MM, Ovize M, Schulz R, Shannon R, Walker M, Walkinshaw G, Yellon DM (2010) Translating novel strategies for cardioprotection: the Hatter workshop recommendations. Basic Res Cardiol 105:677–686PubMedCrossRefGoogle Scholar
  20. 20.
    Hausenloy DJ, Mwamure PK, Venugopal V, Harris J, Barnard M, Grundy E, Ashley E, Vichare S, Di SC, 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 randomised controlled trial. Lancet 370:575–579PubMedCrossRefGoogle Scholar
  21. 21.
    Heusch G, Boengler K, Schulz R (2008) Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation 118:1915–1919PubMedCrossRefGoogle Scholar
  22. 22.
    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 110:111–115PubMedCrossRefGoogle Scholar
  23. 23.
    Hoole SP, Heck PM, Sharples L, Khan SN, Duehmke R, Densem CG, Clarke SC, Shapiro LM, Schofield PM, O’Sullivan M, Dutka DP (2009) Cardiac remote ischemic preconditioning in coronary stenting (CRISP stent) study: a prospective, randomized control trial. Circulation 119:820–827PubMedCrossRefGoogle Scholar
  24. 24.
    Karuppasamy P, Chaubey S, Dew T, Musto R, Sherwood R, Desai J, John L, Shah AM, Marber MS, Kunst G (2011) Remote intermittent ischemia before coronary artery bypass graft surgery: a strategy to reduce injury and inflammation? Basic Res Cardiol 106:511–519PubMedCrossRefGoogle Scholar
  25. 25.
    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 106:2881–2883PubMedCrossRefGoogle Scholar
  26. 26.
    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 79:1691–1695PubMedCrossRefGoogle Scholar
  27. 27.
    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 56:30–38PubMedCrossRefGoogle Scholar
  28. 28.
    Kristiansen SB, Henning O, Kharbanda RK, Nielsen-Kudsk JE, Schmidt MR, Redington AN, Nielsen TT, Botker 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–H1256PubMedCrossRefGoogle Scholar
  29. 29.
    Libonati JR, Gaughan JP, Hefner CA, Gow A, Paolone AM, Houser SR (1997) Reduced ischemia and reperfusion injury following exercise training. Med Sci Sports Exerc 29:509–516PubMedCrossRefGoogle Scholar
  30. 30.
    Libonati JR, Kendrick ZV, Houser SR (2005) Sprint training improves postischemic, left ventricular diastolic performance. J Appl Physiol 99:2121–2127PubMedCrossRefGoogle Scholar
  31. 31.
    Lim SY, Yellon DM, Hausenloy DJ (2010) The neural and humoral pathways in remote limb ischemic preconditioning. Basic Res Cardiol 105:651–655PubMedCrossRefGoogle Scholar
  32. 32.
    McElroy CL, Gissen SA, Fishbein MC (1978) Exercise-induced reduction in myocardial infarct size after coronary artery occlusion in the rat. Circulation 57:958–962PubMedGoogle Scholar
  33. 33.
    Miller TD, Christian TF, Hopfenspirger MR, Hodge DO, Gersh BJ, Gibbons RJ (1995) Infarct size after acute myocardial infarction measured by quantitative tomographic 99mTc sestamibi imaging predicts subsequent mortality. Circulation 92:334–341PubMedGoogle Scholar
  34. 34.
    Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136PubMedCrossRefGoogle Scholar
  35. 35.
    Patel HH, Moore J, Hsu AK, Gross GJ (2002) Cardioprotection at a distance: mesenteric artery occlusion protects the myocardium via an opioid sensitive mechanism. J Mol Cell Cardiol 34:1317–1323PubMedCrossRefGoogle Scholar
  36. 36.
    Peters J (2011) Remote ischaemic preconditioning of the heart: remote questions, remote importance, or remote preconditions? Basic Res Cardiol 106:507–509PubMedCrossRefGoogle Scholar
  37. 37.
    Powers SK, Quindry JC, Kavazis AN (2008) Exercise-induced cardioprotection against myocardial ischemia-reperfusion injury. Free Radic Biol Med 44:193–201PubMedCrossRefGoogle Scholar
  38. 38.
    Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P (1993) Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 87:893–899PubMedGoogle Scholar
  39. 39.
    Rahman IA, Mascaro JG, Steeds RP, Frenneaux MP, Nightingale P, Gosling P, Townsend P, Townend JN, Green D, Bonser RS (2010) Remote ischemic preconditioning in human coronary artery bypass surgery: from promise to disappointment? Circulation 122:S53–S59PubMedCrossRefGoogle Scholar
  40. 40.
    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. JACC Cardiovasc Interv 3:49–55PubMedCrossRefGoogle Scholar
  41. 41.
    Schmidt MR, Smerup M, Konstantinov IE, Shimizu M, Li J, Cheung M, White PA, Kristiansen SB, Sorensen K, Dzavik V, Redington AN, Kharbanda RK (2007) Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism: first demonstration of remote ischemic perconditioning. Am J Physiol Heart Circ Physiol 292:H1883–H1890PubMedCrossRefGoogle Scholar
  42. 42.
    Schultz JE, Hsu AK, Gross GJ (1998) Ischemic preconditioning in the intact rat heart is mediated by delta1- but not mu- or kappa-opioid receptors. Circulation 97:1282–1289PubMedGoogle Scholar
  43. 43.
    Schultz JE, Rose E, Yao Z, Gross GJ (1995) Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts. Am J Physiol 268:H2157–H2161PubMedGoogle Scholar
  44. 44.
    Schulz R, Gres P, Heusch G (2001) Role of endogenous opioids in ischemic preconditioning but not in short-term hibernation in pigs. Am J Physiol Heart Circ Physiol 280:H2175–H2181PubMedGoogle Scholar
  45. 45.
    Schwartz LL, Kloner RA, Arai AE, Baines CP, Bolli R, Braunwald E, Downey J, Gibbons RJ, Gottlieb RA, Heusch G, Jennings RB, Lefer DJ, Mentzer RM, Murphy E, Ovize M, Ping P, Przyklenk K, Sack MN, Vander Heide RS, Vinten-Johansen J, Yellon DM (2011) New horizons in cardioprotection: recommendations from the 2010 national heart, lung, and blood institute workshop. Circulation 124:1172–1179CrossRefGoogle Scholar
  46. 46.
    Selimoglu O, Ugurlucan M, Basaran M, Gungor F, Banach M, Cucu O, Ong LL, Gasparyan AY, Mikhailidis D, Ogus TN (2008) Efficacy of remote ischaemic preconditioning for spinal cord protection against ischaemic injury: association with heat shock protein expression. Folia Neuropathol 46:204–212PubMedGoogle Scholar
  47. 47.
    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 49:214–220PubMedCrossRefGoogle Scholar
  48. 48.
    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) 190:103–109CrossRefGoogle Scholar
  49. 49.
    Shimizu M, Tropak M, Diaz RJ, Suto F, Surendra H, Kuzmin E, Li J, Gross G, Wilson GJ, Callahan JW, Redington AN (2009) Transient limb ischemia remotely preconditions through a humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection. Clin Sci (Lond) 117:191–200CrossRefGoogle Scholar
  50. 50.
    Shimojo N, Naka K, Nakajima C, Yoshikawa C, Okuda K, Okada K (1989) Test-strip method for measuring lactate in whole blood. Clin Chem 35:1992–1994PubMedGoogle Scholar
  51. 51.
    Skyschally A, van Caster P, Boengler K, Gres P, Musiolik J, Schilawa D, Schulz R, Heusch G (2009) Ischemic postconditioning in pigs: no causal role for RISK activation. Circ Res 104:15–18PubMedCrossRefGoogle Scholar
  52. 52.
    Takasaki Y, Wolff RA, Chien GL, van Winkle DM (1999) Met5-enkephalin protects isolated adult rabbit cardiomyocytes via delta-opioid receptors. Am J Physiol 277:H2442–H2450PubMedGoogle Scholar
  53. 53.
    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 105:657–664PubMedCrossRefGoogle Scholar
  54. 54.
    Venugopal V, Hausenloy DJ, Ludman A, Di SC, Kolvekar S, Yap J, Lawrence D, Bognolo J, Yellon DM (2009) Remote ischaemic preconditioning reduces myocardial injury in patients undergoing cardiac surgery with cold-blood cardioplegia: a randomised controlled trial. Heart 95:1567–1571PubMedCrossRefGoogle Scholar
  55. 55.
    Vogt AM, Poolman M, Ackermann C, Yildiz M, Schoels W, Fell DA, Kubler W (2002) Regulation of glycolytic flux in ischemic preconditioning. A study employing metabolic control analysis. J Biol Chem 277:24411–24419PubMedCrossRefGoogle Scholar
  56. 56.
    Yamashita N, Baxter GF, Yellon DM (2001) Exercise directly enhances myocardial tolerance to ischaemia-reperfusion injury in the rat through a protein kinase C mediated mechanism. Heart 85:331–336PubMedCrossRefGoogle Scholar
  57. 57.
    Yamashita N, Hoshida S, Otsu K, Asahi M, Kuzuya T, Hori M (1999) Exercise provides direct biphasic cardioprotection via manganese superoxide dismutase activation. J Exp Med 189:1699–1706PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • M. M. Michelsen
    • 1
    • 2
    • 3
    Email author
  • N. B. Støttrup
    • 1
    • 2
  • M. R. Schmidt
    • 1
    • 2
    • 3
  • B. Løfgren
    • 1
    • 2
  • R. V. Jensen
    • 1
    • 2
  • M. Tropak
    • 3
  • E. Jean St-Michel
    • 3
  • A. N. Redington
    • 3
  • H. E. Bøtker
    • 1
    • 2
  1. 1.Department of CardiologyAarhus University HospitalAarhus NDenmark
  2. 2.Institute of Clinical MedicineAarhus UniversityAarhus NDenmark
  3. 3.Division of CardiologyHospital for Sick ChildrenTorontoCanada

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