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Ischaemia, reperfusion and cardioprotection: successes and failures in the journey from molecule to man

D.J. Hearse1

The Rayne Institute, St Thomas' Hospital, London, UK

1 Correspondence: Professor David J. Hearse, Director of Cardiovascular Research, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, U.K.

Abstract

In response to the increasing toll of ischaemic heart disease, the last 50 years have seen an enormous amount of research aimed at understanding the biology of ischaemia and developing methods to control it. Much of this research has used animal models; in some instances the findings have been translated successfully to man, in others they have failed to apply to human ischaemia. Some of the failures may be due to animal models inadequately mimicking the clinical situation - a problem arising from there being is no consensus on a definition of ischaemia. Despite these difficulties, laboratory research has led to a detailed molecular and cellular characterization of experimental ischaemia. From this has emerged the concept of cardioprotection: identifying key changes in the progression of ischaemic injury and developing anti-ischaemic agents to combat these changes, thereby increasing the tolerance of the heart to ischaemia. Effective cardioprotection has been established in the laboratory and has been translated very successfully to man in the arena of cardiac surgery. Unfortunately, because of fundamental conceptual flaws, the application of anti-ischaemic therapy to management of evolving myocardial infarction has, so far, failed.

Laboratory research has revealed the phenomenon of reperfusion injury and, in doing so, established the importance of free radicals and oxidant stress in the genesis of injury during ischaemia and reperfusion. From this, the concept of limiting reperfusion injury has emerged and surgeons have again exploited this concept for the benefit of patients, although cardiologists appear reluctant to combine such an approach with thrombolysis.

Recent research has also revealed the remarkable adaptive powers of the heart and its ability to increase its tolerance to ischaemia through phenomena such as preconditioning. Although preconditioning undoubtedly occurs in man, many hurdles must be overcome before this alternative approach to cardioprotection can impact the management of heart disease.

References

  1. Hearse DL. Myocardial ischaemia: can we agree on a definition for the 21st century? Cardiovasc Res. 1994;28:1737–1744
  2. Hearse DL, Garlick PB, Humphrey SM. Ischemic contracture of the myocardium: mechanisms and prevention. Am J Cardiol. 1977;39:986–993[Web of Science][Medline]
  3. Hearse DJ, Braimbridge MV, Jynge P. Protection of the Ischemic Myocardium: Cardioplegia. New York: Raven Press; 1981.
  4. Hearse DL, Stewart DA, Braimbridge MV. Myocardial protection during ischaemic cardiac arrest: the importance of magnesium in cardioplegic infusates. J Thorac Cardiovasc Surg. 1978;75:877–885[Abstract]
  5. Hearse DJ, Yellow DM. Therapeutic Approaches to Myocardial Infarct Size Limitation. New York: Raven Press; 1984.
  6. Maroko PR, Kjekshus JK, Sobel BE, et al. Factors influencing infarct size following experimental coronary artery occlusion. Circulation. 1971;43:67–82[Abstract/Free Full Text]
  7. Braunwald E. Reduction of myocardial infarct size. N Engl J Med. 1974;291:525–526
  8. Hearse DL. The protection of the ischaemic myocardium: surgical success versus clinical failure. Progr Cardiovasc Dis. 1988;6:381–402
  9. Chambers DE, Yellow DM, Hearse DJ, Downey JM. Effects of flurbiprofen in altering the size of myocardial infarcts in dogs: reduction or delay? Am J Cardiol. 1983;51:884–890[CrossRef][Web of Science][Medline]
  10. Reimer KA, Jennings RB, Cobb FR. Animal models for protecting ischaemic myocardium. Results of the NHLBI cooperative study. Circ Res. 1985;56:651–665[Abstract/Free Full Text]
  11. Hearse DL. Reperfusion of the ischaemic myocardium. J Mol Cell Cardiol. 1977;9:605–616[Web of Science][Medline]
  12. Hearse DJ, Humphrey SM, Bullock GR. The oxygen paradox and the calcium paradox: two facets of the same problem? J Mol Cell Cardiol. 1978;10:641–668[CrossRef][Web of Science][Medline]
  13. Hearse DJ, Humphrey SM, Chain EB. Abrupt reoxygenation of the anoxic potassium-arrested perfused rat heart: a study of myocardial enzyme release. J Mol Cell Cardiol. 1973;5:395–407[CrossRef][Web of Science][Medline]
  14. Kuroda H, Ishiguro S, Mari T. Optimal calcium concentration in the initial reperfusate for post-ischaemic myocardial performance. J Mol Cell Cardiol. 1986;18:625–633[CrossRef][Web of Science][Medline]
  15. Bernier M, Hearse DL, Manning AS. Reperfusion-induced arrhythmias and oxygen-derived free radicals: studies with ‘anti-free radical’ interventions and a free radical generating system in the isolated perfused rat heart. Circ Res. 1986;58:331–340[Abstract/Free Full Text]
  16. Avkiran M, Ibuki C. Reperfusion-induced arrhythmias: a role for washout of extracellular protons? Circ Res. 1992;71:1429–1440[Abstract/Free Full Text]
  17. Yasutake M, Ibuki C, Hearse DL, Avkiran M. Na+/H+ exchange and reperfusion arrhythmias: protection by intracoronary infusion of a novel inhibitor. Am J Physiol. 1994;267:H2430–H2440
  18. Galiñanes M, Lawson CS, Ferrari R, Limb GA, Derias NW, Hearse DJ. Early and late effects of leukopenic reperfusion on the recovery of cardiac contractile function: studies in the transplanted and isolated blood-perfused rat heart. Circulation. 1993;88:673–683[Abstract/Free Full Text]
  19. Hearse DL, Bolli R. Reperfusion-induced injury: manifestations, mechanisms and clinical relevance. Trends Cardiovasc Med. 1991;1:233–240
  20. Hearse DL. Stunning: a radical re-view. Cardiovasc Drugs Ther. 1991;5:853–876[CrossRef][Web of Science][Medline]
  21. Hayashi Y, Sawa Y, Nishimura M, et al. Clinical Investigation of leukocyte-depleted blood cardioplegia for pediatric open heart operations. Ann Thorac Surg. 2000;69:1914–1919[Abstract/Free Full Text]
  22. Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine. Oxford: Clarendon Press; 1993.
  23. Bolli R, Jeroudi MO, Patel BS, et al. Marked reduction of free radical generation and contractile dysfunction by anti-oxidant therapy begun at the time of reperfusion. Circ Res. 1989;65:607–622[Abstract/Free Full Text]
  24. Chen Z, Siu B, Ho Y-S, et al. Overexpression of MnSOD protects against myocardial ischaemia/reperfusion injury in transgenic mice. J Mol Cell Cardiol. 1998;30:2281–2289[CrossRef][Web of Science][Medline]
  25. Yoshida T, Maulik N, Engleman RM, et al. Targeted disruption of the mouse SOD 1 gene makes the heart vulnerable to ischaemic reperfusion injury. Circ Res. 2000;86:264–269[Abstract/Free Full Text]
  26. Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med. 1993;328:1444–1449[Abstract/Free Full Text]
  27. Rimm EB, Stampfer ML, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Vitamin E consumption and the risk of coronary disease in men. N Engl J Med. 1993;328:1450–1456[Abstract/Free Full Text]
  28. Stephens N. Anti-oxidant therapy for ischaemic heart disease: where do we stand? Lancet. 1997;349:1710–1711[CrossRef][Web of Science][Medline]
  29. Muury CE, Jennings RB, Reimer KA. Preconditioning with ischaemia: a delay of lethal cell injury in ischaemic myocardium. Circulation. 1986;74:1124–1136[Abstract/Free Full Text]
  30. Lawson CS, Coltart DJ, Hearse DJ. ‘Dose’-dependency and temporal characteristics of protection by ischaemic preconditioning against ischaemia-induced arrhythmias in rat hearts. J Mol Cell Cardiol. 1993;25:1391–1402[CrossRef][Web of Science][Medline]
  31. Kolocassides KG, Galinanes M, Hearse DJ. Ischemic preconditioning, cardioplegia or both? Differing approaches to myocardial and vascular protection. J Mol Cell Cardiol. 1996;28:623–634[CrossRef][Web of Science][Medline]
  32. Kolocassides KG, Galinanes M, Hearse DJ. Dichotomy of ischaemic preconditioning: improved post-ischaemic contractile function despite intensification of ischaemic contracture. Circulation. 1996;93:1725–1733[Abstract/Free Full Text]
  33. Cohen MV, Downey JM. Myocardial preconditioning promises to be a novel approach to the treatment of ischaemic heart disease. Ann Rev Med. 1996;47:21–29[CrossRef][Web of Science][Medline]
  34. Noda T, Minatoguchi S, Fujii J, et al. Evidence for the delayed effect in human ischaemic preconditioning: prospective multicentre study for preconditioning in acute myocardial infarction. J Am Coll Cardiol. 1999;34:1966–1974[Abstract/Free Full Text]
  35. Hearse DJ, Ferrari R, Sutherland FJ. Cardioprotection: intermittent ventricular fibrillation and rapid pacing can induce preconditioning in the blood-perfused rat heart. J Mol Cell Cardiol. 1999;31:1961–1973[CrossRef][Web of Science][Medline]

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