Ischemia-reperfusion injury is a composite of damage accumulated during reduced perfusion of an organ or tissue and the additional insult sustained during reperfusion. Such injury occurs in a wide variety of clinically important syndromes, such as ischemic heart disease and stroke, which are responsible for a high degree of morbidity and mortality worldwide. Basic research has identified a number of interventions that stimulate innate resistance of tissues to ischemia-reperfusion injury. Here, we summarise the experimental and clinical trial data underpinning one of these “conditioning” strategies, the phenomenon of remote ischemic preconditioning. 1. Introduction Ischemia-reperfusion injury underpins the damage of myocardial infarction, stroke, and other conditions complicated by interruption of the blood supply to tissues. Strategies to limit the duration of ischemia have achieved substantial health gains in myocardial infarction and, to a lesser degree, stroke. However door-to-needle times have probably reached the minimum that is possible in many health-care delivery systems, so further reduction in morbidity and mortality from IR injury will require strategies to increase tissue tolerance to ischemia or reduce damage that occurs on reperfusion. One such approach is ischemic preconditioning, and its variant remote ischemic preconditioning, the subject of this paper. 2. Types of Ischemic Preconditioning Ischemic preconditioning (IPC) describes the phenomenon whereby transient, brief periods of ischemia confer protection against a subsequent prolonged and injurious period of ischemia. There are a number of ways in which preconditioning can be induced. Local preconditioning occurs when the preconditioning stimulus is applied to the same organ or tissue that will subsequently sustain the ischemic injury. Remote ischemic preconditioning refers to a stimulus applied to a distant organ or tissue, which then protects against index ischemia. For example, the preconditioning stimulus might be suprasystolic blood pressure inflations on an arm or leg, which then confer myocardial protection against subsequent ischemia. Postconditioning occurs when there is staged reperfusion, for example, in the setting of balloon angioplasty. Its variant perconditioning occurs when the conditioning stimulus is applied during ischemia. 3. Ischemic Preconditioning Ischemic preconditioning was first described in 1986, when Murry et al. demonstrated that in the dog, brief episodes of ischemia (4 cycles of 5-minute occlusion followed by reperfusion) of the circumflex artery reduced
References
[1]
C. E. Murry, R. B. Jennings, and K. A. Reimer, “Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium,” Circulation, vol. 74, no. 5, pp. 1124–1136, 1986.
[2]
T. Kuzuya, S. Hoshida, N. Yamashita et al., “Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia,” Circulation Research, vol. 72, no. 6, pp. 1293–1299, 1993.
[3]
M. S. Marber, D. S. Latchman, J. M. Walker, and D. M. Yellon, “Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction,” Circulation, vol. 88, no. 3, pp. 1264–1272, 1993.
[4]
G. F. Baxter, F. M. Goma, and D. M. Yellon, “Characterisation of the infarct-limiting effect of delayed preconditioning: timecourse and dose-dependency studies in rabbit myocardium,” Basic Research in Cardiology, vol. 92, no. 3, pp. 159–167, 1997.
[5]
K. Przyklenk, B. Bauer, M. Ovize, R. A. Kloner, and P. Whittaker, “Regional ischemic “preconditioning” protects remote virgin myocardium from subsequent sustained coronary occlusion,” Circulation, vol. 87, no. 3, pp. 893–899, 1993.
[6]
B. C. G. Gho, R. G. Schoemaker, M. A. Van den Doel, D. J. Duncker, and P. D. Verdouw, “Myocardial protection by brief ischemia in noncardiac tissue,” Circulation, vol. 94, no. 9, pp. 2193–2200, 1996.
[7]
S. C. Lang, A. Els？sser, C. Scheler et al., “Myocardial preconditioning and remote renal preconditioning. Identifying a protective factor using proteomic methods,” Basic Research in Cardiology, vol. 101, no. 2, pp. 149–158, 2006.
[8]
M. Cour, L. Gomez, N. Mewton, M. Ovize, and L. Argaud, “Postconditioning: from the bench to bedside,” Journal of Cardiovascular Pharmacology and Therapeutics, vol. 16, no. 2, pp. 117–130, 2011.
[9]
D. S. Burley, P. Ferdinandy, and G. F. Baxter, “Cyclic GMP and protein kinase-G in myocardial ischaemia-reperfusion: opportunities and obstacles for survival signaling,” British Journal of Pharmacology, vol. 152, no. 6, pp. 855–869, 2007.
[10]
D. J. Hausenloy and D. M. Yellon, “New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway,” Cardiovascular Research, vol. 61, no. 3, pp. 448–460, 2004.
[11]
S. Lecour, “Activation of the protective Survivor Activating Factor Enhancement (SAFE) pathway against reperfusion injury: does it go beyond the RISK pathway?” Journal of Molecular and Cellular Cardiology, vol. 47, no. 1, pp. 32–40, 2009.
[12]
G. Heusch, K. Boengler, and R. Schulz, “Editorial: inhibition of mitochondrial permeability transition pore opening: the holy grail of cardioprotection,” Basic Research in Cardiology, vol. 105, no. 2, pp. 151–154, 2010.
[13]
I. E. Konstantinov, S. Arab, R. K. Kharbanda et al., “The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans,” Physiological Genomics, vol. 19, no. 1, pp. 143–150, 2005.
[14]
T. Murphy, P. M. Walsh, P. P. Doran, and K. J. Mulhall, “Transcriptional responses in the adaptation to ischaemia-reperfusion injury: a study of the effect of ischaemic preconditioning in total knee arthroplasty patients,” Journal of Translational Medicine, vol. 8, article 46, 2010.
[15]
L. Breivik, E. Helgeland, E. K. Aarnes, J. Mrdalj, and A. K. Jonassen, “Remote postconditioning by humoral factors in effluent from ischemic preconditioned rat hearts is mediated via PI3K/Akt-dependent cell-survival signaling at reperfusion,” Basic Research in Cardiology, vol. 106, no. 1, pp. 135–145, 2010.
[16]
D. J. Hausenloy and D. M. Yellon, “The Second Window of Preconditioning (SWOP) where are we now?” Cardiovascular Drugs and Therapy, vol. 24, no. 3, pp. 235–254, 2010.
[17]
E. W. Dickson, C. P. Reinhardt, F. P. Renzi, R. C. Becker, W. A. Porcaro, and S. O. Heard, “Ischemic preconditioning may be transferable via whole blood transfusion: preliminary evidence,” Journal of Thrombosis and Thrombolysis, vol. 8, no. 2, pp. 123–129, 1999.
[18]
E. W. Dickson, M. Lorbar, W. A. Porcaro et al., “Rabbit heart can be 'preconditioned' via transfer of coronary effluent,” American Journal of Physiology, vol. 277, no. 6, pp. H2451–H2457, 1999.
[19]
H. H. Patel, J. Moore, A. K. Hsu, and G. J. Gross, “Cardioprotection at a distance: mesenteric artery occlusion protects the myocardium via an opioid sensitive mechanism,” Journal of Molecular and Cellular Cardiology, vol. 34, no. 10, pp. 1317–1323, 2002.
[20]
M. Shimizu, M. Tropak, R. J. Diaz et al., “Transient limb ischaemia remotely preconditions through a humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection,” Clinical Science, vol. 117, no. 5, pp. 191–200, 2009.
[21]
F. Tomai, F. Crea, A. Gaspardone et al., “Effects of naloxone on myocardial ischemic preconditioning in humans,” Journal of the American College of Cardiology, vol. 33, no. 7, pp. 1863–1869, 1999.
[22]
H. H. Patel, J. Moore, A. K. Hsu, and G. J. Gross, “Cardioprotection at a distance: mesenteric artery occlusion protects the myocardium via an opioid sensitive mechanism,” Journal of Molecular and Cellular Cardiology, vol. 34, no. 10, pp. 1317–1323, 2002.
[23]
S. P. Loukogeorgakis, A. T. Panagiotidou, M. W. Broadhead, A. Donald, J. E. Deanfield, and R. J. MacAllister, “Remote ischemic preconditioning provides early and late protection against endothelial ischemia-reperfusion injury in humans: role of the autonomic nervous system,” Journal of the American College of Cardiology, vol. 46, no. 3, pp. 450–456, 2005.
[24]
T. J. Pell, G. F. Baxter, D. M. Yellon, and G. M. Drew, “Renal ischemia preconditions myocardium: role of adenosine receptors and ATP-sensitive potassium channels,” American Journal of Physiology, vol. 275, no. 5, pp. H1542–H1547, 1998.
[25]
T. Oxman, M. Arad, R. Klein, N. Avazov, and B. Rabinowitz, “Limb ischemia preconditions the heart against reperfusion tachyarrhythmia,” American Journal of Physiology, vol. 273, no. 4, pp. H1707–H1712, 1997.
[26]
A. Imani, M. Faghihi, S. S. Sadr, S. S. Niaraki, and A. M. Alizadeh, “Noradrenaline protects in vivo rat heart against infarction and ventricular arrhythmias via nitric oxide and reactive oxygen species,” Journal of Surgical Research, vol. 169, no. 1, pp. 9–15, 2010.
[27]
R. G. Schoemaker and C. L. van Heijningen, “Bradykinin mediates cardiac preconditioning at a distance,” American Journal of Physiology, vol. 278, no. 5, pp. H1571–H1576, 2000.
[28]
C. M. Pedersen, M. R. Schmidt, G. Barnes et al., “Bradykinin does not mediate remote ischaemic preconditioning or ischaemia-reperfusion injury in vivo in man,” Heart, vol. 97, no. 22, pp. 1857–1861, 2011.
[29]
Y. J. Li, Z. S. Xiao, C. F. Peng, and H. W. Deng, “Calcitonin gene-related peptide-induced preconditioning protects against ischemia-reperfusion injury in isolated rat hearts,” European Journal of Pharmacology, vol. 311, no. 2-3, pp. 163–167, 1996.
[30]
S. Wolfrum, J. Nienstedt, M. Heidbreder, K. Schneider, P. Dominiak, and A. Dendorfer, “Calcitonin gene related peptide mediates cardioprotection by remote preconditioning,” Regulatory Peptides, vol. 127, no. 1–3, pp. 217–224, 2005.
[31]
L. Xiao, R. Lu, C. P. Hu, H. W. Deng, and Y. J. Li, “Delayed cardioprotection by intestinal preconditioning is mediated by calcitonin gene-related peptide,” European Journal of Pharmacology, vol. 427, no. 2, pp. 131–135, 2001.
[32]
A. Takaoka, I. Nakae, K. Mitsunami et al., “Renal ischemia/reperfusion remotely improves myocardial energy metabolism during myocardial ischemia via adenosine receptors in rabbits: effects of 'remote preconditioning',” Journal of the American College of Cardiology, vol. 33, no. 2, pp. 556–564, 1999.
[33]
Y. F. Ding, M. M. Zhang, and R. R. He, “Role of renal nerve in cardioprotection provided by renal ischemic preconditioning in anesthetized rabbits,” Acta Physiologica Sinica, vol. 53, no. 1, pp. 7–12, 2001.
[34]
D. A. Liem, P. D. Verdouw, H. Ploeg, S. Kazim, and D. J. Duncker, “Sites of action of adenosine in interorgan preconditioning of the heart,” American Journal of Physiology, vol. 283, no. 1, pp. H29–H37, 2002.
[35]
J. H. Dong, Y. X. Liu, E. S. Ji, and R. R. He, “Limb ischemic preconditioning reduces infarct size following myocardial ischemia-reperfusion in rats,” Sheng li Xue Bao, vol. 56, no. 1, pp. 41–46, 2004.
[36]
R. K. Kharbanda, M. Peters, B. Walton et al., “Ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia-reperfusion in humans in vivo,” Circulation, vol. 103, no. 12, pp. 1624–1630, 2001.
[37]
R. K. Kharbanda, U. M. Mortensen, P. A. White et al., “Transient limb ischemia induces remote ischemic preconditioning in vivo,” Circulation, vol. 106, no. 23, pp. 2881–2883, 2002.
[38]
S. P. Loukogeorgakis, A. T. Panagiotidou, M. W. Broadhead, A. Donald, J. E. Deanfield, and R. J. MacAllister, “Remote ischemic preconditioning provides early and late protection against endothelial ischemia-reperfusion injury in humans: role of the autonomic nervous system,” Journal of the American College of Cardiology, vol. 46, no. 3, pp. 450–456, 2005.
[39]
J. C. Cleveland, D. R. Meldrum, B. S. Cain, A. Banerjee, and A. H. Harken, “Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium: two paradoxes revisited,” Circulation, vol. 96, no. 1, pp. 29–32, 1997.
[40]
H. Klepzig, G. Kober, C. Matter et al., “Sulfonylureas and ischaemic preconditioning. A double-blind, placebo-controlled evaluation of glimepiride and glibenclamide,” European Heart Journal, vol. 20, no. 6, pp. 439–446, 1999.
[41]
S. J. Clarke, I. Khaliulin, M. Das, J. E. Parker, K. J. Heesom, and A. P. Halestrap, “Inhibition of mitochondrial permeability transition pore opening by ischemic preconditioning is probably mediated by reduction of oxidative stress rather than mitochondrial protein phosphorylation,” Circulation Research, vol. 102, no. 9, pp. 1082–1090, 2008.
[42]
C. Weinbrenner, F. Schulze, L. Sárváry, and R. H. Strasser, “Remote preconditioning by infrarenal aortic occlusion is operative via δ1-opioid receptors and free radicals in vivo in the rat heart,” Cardiovascular Research, vol. 61, no. 3, pp. 591–599, 2004.
[43]
D. M. Yellon and J. M. Downey, “Preconditioning the myocardium: from cellular physiology to clinical cardiology,” Physiological Reviews, vol. 83, no. 4, pp. 1113–1151, 2003.
[44]
B. Günaydin, I. ？akici, H. Soncul et al., “Does remote organ ischaemia trigger cardiac preconditioning during coronary artery surgery?” Pharmacological Research, vol. 41, no. 4, pp. 493–496, 2000.
[45]
M. M. H. Cheung, R. K. Kharbanda, I. E. Konstantinov et al., “Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans,” Journal of the American College of Cardiology, vol. 47, no. 11, pp. 2277–2282, 2006.
[46]
Z. Wenwu, Z. Debing, C. Renwei et al., “Limb ischemic preconditioning reduces heart and lung injury after an open heart operation in infants,” Pediatric Cardiology, vol. 31, no. 1, pp. 22–29, 2010.
[47]
D. J. Hausenloy, P. K. Mwamure, V. Venugopal et al., “Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial,” The Lancet, vol. 370, no. 9587, pp. 575–579, 2007.
[48]
V. Venugopal, D. J. Hausenloy, A. Ludman et al., “Remote ischaemic preconditioning reduces myocardial injury in patients undergoing cardiac surgery with cold-blood cardioplegia: a randomised controlled trial,” Heart, vol. 95, no. 19, pp. 1567–1571, 2009.
[49]
I. A. Rahman, J. G. Mascaro, R. P. Steeds et al., “Remote ischemic preconditioning in human coronary artery bypass surgery: from promise to disappointment?” Circulation, vol. 122, no. 11, pp. S53–S59, 2010.
[50]
D. Brevoord, M. W. Hollmann, S. G. De Hert et al., “Effect of remote ischemic conditioning on atrial fibrillation and outcome after coronary artery bypass grafting (RICO-trial),” BMC Anesthesiology, vol. 11, article 11, 2011.
[51]
E. K. Iliodromitis, S. Kyrzopoulos, I. A. Paraskevaidis et al., “Increased C reactive protein and cardiac enzyme levels after coronary stent implantation. Is there protection by remote ischaemic preconditioning?” Heart, vol. 92, no. 12, pp. 1821–1826, 2006.
[52]
S. P. Hoole, P. M. Heck, L. Sharples et al., “Cardiac remote ischemic preconditioning in coronary stenting (CRISP stent) study. A prospective, randomized control trial,” Circulation, vol. 119, no. 6, pp. 820–827, 2009.
[53]
S. P. Hoole, S. N. Khan, P. A. White et al., “Remote ischaemic pre-conditioning does not attenuate ischaemic left ventricular dysfunction in humans,” European Journal of Heart Failure, vol. 11, no. 5, pp. 497–505, 2009.
[54]
H. E. B？tker, R. Kharbanda, M. R. Schmidt et al., “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,” The Lancet, vol. 375, no. 9716, pp. 727–734, 2010.
[55]
K. Munk, N. H. Andersen, M. R. Schmidt et al., “Remote ischemic conditioning in patients with myocardial infarction treated with primary angioplasty impact on left ventricular function assessed by comprehensive echocardiography and gated single-photon emission CT,” Circulation, vol. 3, no. 6, pp. 656–662, 2010.
[56]
Z. A. Ali, C. J. Callaghan, E. Lim et al., “Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial,” Circulation, vol. 116, no. 11, pp. I98–I105, 2007.
[57]
S. R. Walsh, U. Sadat, J. R. Boyle et al., “Remote ischemic preconditioning for renal protection during elective open infrarenal abdominal aortic aneurysm repair: randomized controlled trial,” Vascular and Endovascular Surgery, vol. 44, no. 5, pp. 334–340, 2010.
[58]
S. R. Walsh, J. R. Boyle, T. Y. Tang et al., “Remote ischemic preconditioning for renal and cardiac protection during endovascular aneurysm repair: a randomized controlled trial,” Journal of Endovascular Therapy, vol. 16, no. 6, pp. 680–689, 2009.
[59]
S. R. Walsh, S. A. Nouraei, T. Y. Tang, U. Sadat, R. H. Carpenter, and M. E. Gaunt, “Remote ischemic preconditioning for cerebral and cardiac protection during carotid endarterectomy: results from a pilot randomized clinical trial,” Vascular and Endovascular Surgery, vol. 44, no. 6, pp. 434–439, 2010.
[60]
S. Hu, H. L. Dong, Y. Z. Li et al., “Effects of remote ischemic preconditioning on biochemical markers and neurologic outcomes in patients undergoing elective cervical decompression surgery: a prospective randomized controlled trial,” Journal of Neurosurgical Anesthesiology, vol. 22, no. 1, pp. 46–52, 2010.
[61]
V. Venugopal, C. M. Laing, A. Ludman, D. M. Yellon, and D. Hausenloy, “Effect of remote ischemic preconditioning on acute kidney injury in nondiabetic patients undergoing coronary artery bypass graft surgery: a secondary analysis of 2 small randomized trials,” American Journal of Kidney Diseases, vol. 56, no. 6, pp. 1043–1049, 2010.
[62]
R. F. Zimmerman, P. U. Ezeanuna, J. C. Kane et al., “Ischemic preconditioning at a remote site prevents acute kidney injury in patients following cardiac surgery,” Kidney International, vol. 80, no. 8, pp. 861–867, 2011.
[63]
K. R. Pedersen, H. B. Ravn, J. V. Povlsen, M. R. Schmidt, E. J. Erlandsen, and V. E. Hjortdal, “Failure of remote ischemic preconditioning to reduce the risk of postoperative acute kidney injury in children undergoing operation for complex congenital heart disease: a randomized single-center study,” Journal of Thoracic and Cardiovascular Surgery. In press.
[64]
Y. S. Choi, J. K. Shim, J. C. Kim et al., “Effect of remote ischemic preconditioning on renal dysfunction after complex valvular heart surgery: a randomized controlled trial,” Journal of Thoracic and Cardiovascular Surgery, vol. 142, no. 1, pp. 148–154, 2011.
