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Remote intermittent ischemia before coronary artery bypass graft surgery: a strategy to reduce injury and inflammation?

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Abstract

Perioperative myocardial ischemia contributes to postoperative morbidity and mortality. Remote intermittent ischemia (RI) has been shown to benefit patients undergoing coronary artery bypass graft (CABG) surgery by decreasing postoperative cardiac troponin levels. In addition, there is evidence that volatile anesthetics may provide myocardial protection. In this prospective randomized controlled trial we tested the hypothesis that RI is cardioprotective under a strict anesthetic regime with volatile anesthesia until cardiopulmonary bypass (CPB). We also assessed whether RI modulates postoperative cytokine and growth factor concentrations. Fifty-four patients referred for elective CABG surgery without concomitant valve or aortic surgery were randomized to three 5-min cycles of left upper limb ischemia by cuff inflation (RI) or placebo without cuff inflation (Plac). All patients received the volatile anesthetic isoflurane (1.15–1.5 vol%) before CPB and the intravenous anesthetic propofol (3–4 mg/kg/h) thereafter until the end of surgery. Cardiac arrest during CPB was induced by intermittent cross-clamp fibrillation, or by blood cardioplegia. We excluded patients older than 85 years, with unstable angina, significant renal disease, and those taking sulfonylureas. Troponin I (cTnI) was measured preoperatively and after 6, 12, 24 and 48 h. In addition, brain natriuretic peptide (BNP), creatine kinase (CKMB) and a panel of cytokines and growth factors were analyzed perioperatively. Although cTnI, BNP and CKMB all increased post-CABG, there were no significant differences between RI and Plac groups; area under the curve for cTnI 189.4 (183.6) ng/mL/48 h and 183.0 (155.2) ng/mL/48 h mean (SD), p = 0.90, respectively, despite a tendency to a shorter (p < 0.07) cross-clamp time in the treatment group. Similarly, there were no differences between groups in the central venous concentrations of numerous cytokines and growth factors. In patients undergoing CABG surgery RI does not provide myocardial protection under a strict anesthetic regime with volatile anesthesia until CPB, and RI was not associated with changes in cytokines.

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References

  1. Bish LT, Morine KJ, Sleeper MM, Sweeney HL (2010) Myostatin is upregulated following stress in an Erk-dependent manner and negatively regulates cardiomyocyte growth in culture and in a mouse model. PLoS One 5:e10230. doi:10.1371/journal.pone.0010230

    Article  PubMed  Google Scholar 

  2. Bøtker HE, Kharbanda R, Schmidt MR, Bøttcher 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, Sørensen 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 

  3. Devereaux PJ, Goldman L, Cook DJ, Cook DJ, Gilbert K, Leslie K, Guyatt HG (2005) Perioperative cardiac events in patients undergoing noncardiac surgery: a review of the magnitude of the problem, the pathophysiology of the events and methods to estimate and communicate risk. CMAJ 6:627–634. doi:10.1503/cmaj.050011

    Google Scholar 

  4. Ebelt H, Jungblut M, Zhang Y, Kubin T, Kostin S, Technau A, Oustanina S, Niebrugge S, Lehmann J, Werdan K, Braun T (2007) Cellular cardiomyoplasty: improvement of left ventricular function correlates with the release of cardioactive cytokines. Stem Cells 25:236–244. doi:10.1634/stemcells.2006-0374

    Article  PubMed  CAS  Google Scholar 

  5. Fleischmann KE, Goldman L, Young B, Lee TH (2003) Association between cardiac and noncardiac complications in patients undergoing noncardiac surgery: outcomes and effects on length of stay. Am J Med 115:515–520. doi:10.1016/S0002-9343(03)00474-1

    Article  PubMed  Google Scholar 

  6. Hausenloy DJ, Baxter G, Bell R, Bøtker 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 105:677–686. doi:10.1007/s00395-010-0121-4

    Article  PubMed  Google Scholar 

  7. 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 randomised controlled trial. Lancet 370:575–579. doi:10.1016/S0140-6736(07)61296-3

    Article  PubMed  Google Scholar 

  8. Hausenloy DJ, Yellon DM (2008) Remote ischaemic preconditioning: underlying mechanisms and clinical application. Cardiovasc Res 79:377–386. doi:10.1093/cvr/cvn114

    Article  PubMed  CAS  Google Scholar 

  9. Hausenloy DJ, Yellon DM (2009) Cardioprotective growth factors. Cardiovasc Res 83:179–194. doi:10.1093/cvr/cvp062

    Article  PubMed  CAS  Google Scholar 

  10. Heusch G, Boengler K, Schulz R (2010) Inhibition of mitochondrial permeability transition pore opening: the holy grail of cardioprotection. Basic Res Cardiol 105:151–154. doi:10.1007/s00395-009-0080-9

    Article  PubMed  Google Scholar 

  11. Heusch G, Kleinbongard P, Böse D, Levkau B, Haude M, Schulz R, Erbel R (2009) Coronary microembolisation from bedside to bench and back to bedside. Circulation 120:1822–1836. doi:10.1161/circulationaha.109.888784

    Article  PubMed  Google Scholar 

  12. Jakobsen CJ, Berg H, Hindsholm KB, Faddy N, Sloth E (2007) The influence of propofol versus sevoflurane anesthesia on outcome in 10, 535 cardiac surgical procedures. J Cardiothorac Vasc Anesth 21:664–671. doi:10.1053/j.jvca.2007.03.002

    Article  PubMed  CAS  Google Scholar 

  13. Kersten JR, Schmeling TJ, Pagel PS, Gross GJ, Warltier DC (1997) Isoflurane mimics ischemic preconditioning via activation of KATP channels: reduction of myocardial infarct size with an acute memory phase. Anesthesiology 87:361–370

    Article  PubMed  CAS  Google Scholar 

  14. Kleinbongard P, Heusch G, Schulz R (2010) TNF-alpha in atherosclerosis, myocardial ischemia/reperfusion and heart failure. Pharmacol Ther 127:295–314. doi:10.1016/j.pharmathera.2010.05.002

    Article  PubMed  CAS  Google Scholar 

  15. Lacerda L, McCarthy J, Mungly SFK, Lynn EG, Sack MN, Opie LH, Lecour S (2010) TNFα protects cardiac mitochondria independently of its cell surface receptors. Basic Res Cardiol 105:751–762. doi:10.1007/s00395-010-0113-4

    Article  PubMed  CAS  Google Scholar 

  16. Landesberg G, Shatz V, Akopnik I, Wolf YG, Mayer M, Berlatzky Y, Weissman C, Mosseri M (2003) Association of cardiac troponin, ck-mb, and postoperative myocardial ischemia with long-term survival after major vascular surgery. J Am Coll Cardiol 42:1547–1554. doi:10.1016/S0735-1097(03)01069-6

    Article  PubMed  CAS  Google Scholar 

  17. Landoni G, Biondi-Zoccai GG, Zangrillo A, Bignami E, D’Avolio S, Marchetti C, Calabro MG, Fochi O, Guarracino F, Tritapepe L, De Hert S, Torri G (2007) Desflurane and sevoflurane in cardiac surgery: a meta-analysis of randomized clinical trials. J Cardiothorac Vasc Anesth 21:502–511. doi:10.1053/j.jvca.2007.02.013

    Article  PubMed  CAS  Google Scholar 

  18. Lim SJ, 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 

  19. Matheny RW Jr, Nindl BC, Adamo ML (2010) Minireview: Mechano-growth factor: a putative product of IGF-I gene expression involved in tissue repair and regeneration. Endocrinology 151:865–875. doi:10.1210/en.2009-1217

    Article  PubMed  CAS  Google Scholar 

  20. Niu J, Kolattukudy PE (2009) Role of MCP-1 in cardiovascular disease: molecular mechanisms and clinical implications. Clin Sci (Lond) 117:95–109. doi:10.1042/CS20080581

    Article  CAS  Google Scholar 

  21. Pelosi L, Giacinti C, Nardis C, Borsellino G, Rizzuto E, Nicoletti C, Wannenes F, Battistini L, Rosenthal N, Molinaro M, Musaro A (2007) Local expression of IGF-1 accelerates muscle regeneration by rapidly modulating inflammatory cytokines and chemokines. Faseb J 21:1393–1402. doi:10.1096/fj.06-7690com

    Article  PubMed  CAS  Google Scholar 

  22. Pravdic D, Sedlic F, Mio Y, Vladic N, Bienengraeber M, Bosnjak ZJ (2009) Anesthetic-induced preconditioning delays opening of mitochondrial permeability transition pore via protein kinase C-epsilon-mediated pathway. Anesthesiology 111:267–274. doi:10.1097/ALN.0b013e3181a91957

    Article  PubMed  CAS  Google Scholar 

  23. 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

    PubMed  CAS  Google Scholar 

  24. Rahman IA, Mascaro JG, Steeds RP, Frenneaux MP, Nightingale P, Gosling P, Townsend P, Townend JN, Green D, Bonser RS (2010) Remote ischaemic pre-conditioning in human coronary artery bypass surgery: from promise to disappointment. Circulation 122:S53–S59. doi:10.1161/circulationaha.109.926667

    Article  PubMed  Google Scholar 

  25. Santini MP, Tsao L, Monassier L, Theodoropoulos C, Carter J, Lara-Pezzi E, Slonimsky E, Salimova E, Delafontaine P, Song YH, Bergmann M, Freund C, Suzuki K, Rosenthal N (2007) Enhancing repair of the mammalian heart. Circ Res 100:1732–1740. doi:10.1161/circresaha.107.148791

    Article  PubMed  CAS  Google Scholar 

  26. Scarci M, Fallouh HB, Young CP, Chambers DJ (2009) Does intermittent cross-clamp fibrillation provide equivalent myocardial protection compared to cardioplegia in patients undergoing bypass graft revascularisation? Interact Cardiovasc Thorac Surg 9:872–878. doi:10.1510/icvts.2009.209437

    Article  PubMed  Google Scholar 

  27. Sharma M, Kambadur R, Matthews KG, Somers WG, Devlin GP, Conaglen JV, Fowke PJ, Bass JJ (1999) Myostatin, a transforming growth factor-beta superfamily member, is expressed in heart muscle and is upregulated in cardiomyocytes after infarct. J Cell Physiol 180:1–9. doi:10.1002/(SICI)1097-4652(199907)180:1<1:AID-JCP1>3.0.CO;2-V

    Article  PubMed  CAS  Google Scholar 

  28. Skyschally A, Gres P, Hoffmann S, Haude M, Erbel R, Schulz R, Heusch G (2007) Bidirectional role of tumor necrosis factor-alpha in coronary microembolization progressive contractile dysfunction versus delayed protection against infarction. Circ Res 100:140–146. doi:10.1161/01.RES.0000255031.15793.86

    Article  PubMed  CAS  Google Scholar 

  29. Smith C, Kruger MJ, Smith RM, Myburgh KH (2008) The inflammatory response to skeletal muscle injury: illuminating complexities. Sports Med 38:947–969. doi:10.2165/00007256-200838110-00005

    Article  PubMed  Google Scholar 

  30. Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L’Huillier I, Aupetit JF, Bonnefoy E, Finet G, André-Fouët X, Ovize M (2005) Postconditioning the human heart. Circulation 112:2143–2148. doi:10.1161/circulationaha.105.558122

    Article  PubMed  Google Scholar 

  31. Suleiman MS, Zacharowski K, Angelini GD (2008) Inflammatory response and cardioprotection during open-heart surgery: the importance of anaesthetics. Br J Pharmacol 153:21–33. doi:10.1038/sj.bjp.0707526

    Article  PubMed  CAS  Google Scholar 

  32. Symons JA, Myles PS (2006) Myocardial protection with volatile anaesthetic agents during coronary artery bypass surgery: a meta-analysis. Br J Anaesth 97:127–136. doi:10.1093/bja/ael149

    Article  PubMed  CAS  Google Scholar 

  33. Takahashi M, Li TS, Suzuki R, Kobayashi T, Ito H, Ikeda Y, Matsuzaki M, Hamano K (2006) Cytokines produced by bone marrow cells can contribute to functional improvement of the infarcted heart by protecting cardiomyocytes from ischemic injury. Am J Physiol Heart Circ Physiol 291:H886–H893. doi:10.1152/ajpheart.00142.2006

    Article  PubMed  CAS  Google Scholar 

  34. Tarant JM (2010) Blood cytokines as biomarkers of in vivo toxicity in preclinical safety assessment: considerations for their use. Toxicol Sci 117:4–16. doi:10.1093/toxsci/kfq134

    Article  Google Scholar 

  35. Teoh LK, Grant R, Hulf JA, Pugsley WB, Yellon DM (2002) A comparison between ischemic preconditioning, intermittent cross-clamp fibrillation and cold crystalloid cardioplegia for myocardial protection during coronary artery bypass graft surgery. Cardiovasc Surg 10:251–255. doi:10.1016/S0967-2109(02)00007-8

    Article  PubMed  CAS  Google Scholar 

  36. 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 cristalloid cardioplegic arrest. Basic Res Cardiol 105:657–664. doi:10.1007/s00395-010-0104-5

    Article  PubMed  CAS  Google Scholar 

  37. Venugopal V, Hausenloy DJ, Ludman A, Di Salvo C, 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 95:1567–1571. doi:10.1136/hrt.2008.155770

    Article  PubMed  CAS  Google Scholar 

  38. Wilson EM, Diwan A, Spinale FG, Mann DL (2004) Duality of innate stress responses in cardiac injury, repair, and remodeling. J Mol Cell Cardiol 37:801–811. doi:10.1016/j.yjmcc.2004.05.028

    Article  PubMed  CAS  Google Scholar 

  39. Zaugg M, Lucchinetti E, Uecker M, Pasch T, Schaub MC (2003) Anaesthetics and cardiac preconditioning. Part I. Signalling and cytoprotective mechanisms. Br J Anaesth 91:551–565. doi:10.1093/bja/aeg205

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors acknowledge the support of all nursing staff at the Cardiac Recovery and Victoria and Albert High Dependency Units, and the additional statistical advice by Dr Toby Prevost. The financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust is also acknowledged. This study was supported by a grant from the Department of Research and Development, King’s College Hospital Foundation Trust, London.

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The authors declare that they have no conflict of interest.

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Correspondence to Gudrun Kunst.

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Karuppasamy, P., Chaubey, S., Dew, T. et al. Remote intermittent ischemia before coronary artery bypass graft surgery: a strategy to reduce injury and inflammation?. Basic Res Cardiol 106, 511–519 (2011). https://doi.org/10.1007/s00395-011-0185-9

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  • DOI: https://doi.org/10.1007/s00395-011-0185-9

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