Inflammation, Proinflammatory Mediators and Myocardial Ischemia–reperfusion Injury

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Ischemic myocardium must be reperfused to terminate the ischemic event; otherwise the entire myocardium involved in the area at risk will not survive. However, there is a cost to reperfusion that may offset the intended clinical benefits of minimizing infarct size, postischemic endothelial and microvascular damage, blood flow defects, and contractile dysfunction. There are many contributors to this reperfusion injury. Targeting only one factor in the complex web of reperfusion injury is not effective because the untargeted mechanisms induce injury. An integrated strategy of reducing reperfusion injury in the catheterization laboratory involves controlling both the conditions and the composition of the reperfusate. Mechanical interventions such as gradually restoring blood flow or applying postconditioning may be used independently in or conjunction with various cardioprotective pharmaceuticals in an integrated strategy of reperfusion therapeutics to reduce postischemic injury.

Section snippets

The Pathophysiology of Myocardial Ischemia—Reperfusion Injury

In 2002, there were over 3,480,000 heart attacks in the United States alone. There were 1,121,000 angioplasties performed in the United States; this number is estimated to increase to 2.4 million in 2004 to 2005. Angioplasty is the primary approach to achieving reperfusion and is the definitive treatment for coronary occlusive disease to reduce the extent of myocardial infarction. Without reperfusion, the entire area at risk involved in a coronary occlusion will become necrotic.

In the 1970s,

Attenuating Reperfusion Injury in Acute Myocardial Ischemia with Reperfusion Therapeutics: Going Beyond Restoring Blood Flow

The questions must be asked: (1) whether infarct size and other manifestations of postischemic damage can be reduced by therapies applied at reperfusion, and (2) is it important to limit infarct size in the setting of percutaneous coronary intervention or cardiac surgery? Acute myocardial ischemia is used here instead of acute myocardial infarction because reperfusion contributes to the ultimate infarct size (and other injuries), and therefore there is the potential for infarction depending on

Nitric Oxide Therapy

Numerous experimental studies have tested agents with anti-inflammatory properties delivered at the time of reperfusion as a therapeutic approach. Nitric oxide [130], nitric oxide donor agents [131], and the physiologic precursor l-arginine [132], [133] have been effective at reducing postischemic injury by reducing neutrophil activation, accumulation, superoxide anion generation, and endothelial cell activation. Nitric oxide has also been used in cardioplegia solutions to protect hearts from

Summary

Although ischemic myocardium must be reperfused to survive, there is a cost to reperfusion that offsets the intended clinical benefits of minimizing infarct size, postischemic blood flow defects, and contractile dysfunction. There is a multiplicity of contributors to reperfusion injury. Proinflammatory mediators and inflammatory cells play an integral part by not only triggering deleterious responses but also by amplifying ongoing responses to build a cascade of injury. This cascade may be

Acknowledgments

The authors thank the Carlyle Fraser Heart Center Foundation for their continued support of the research effort.

References (156)

  • D.S. Schwartz et al.

    Regional topical hypothermia of the beating heart: preservation of function and tissue

    Ann Thorac Surg

    (2001)
  • O.I. Pisarenko et al.

    Effects of gradual reperfusion on postischemic metabolism and functional recovery of isolated guinea pig heart

    Biochem Med Metab Biol

    (1993)
  • H. Sato et al.

    Gradual reperfusion reduces infarct size and endothelial injury but augments neutrophil accumulation

    Ann Thorac Surg

    (1997)
  • M.E. Halkos et al.

    Myocardial protection with postconditioning is not enhanced by ischemic preconditioning

    Ann Thorac Surg

    (2004)
  • L.J. Feldman et al.

    Reperfusion syndrome: relationship of coronary blood flow reserve to left ventricular function and infarct size

    J Am Coll Cardiol

    (2000)
  • N. Kobayashi et al.

    Further ST elevation at reperfusion by direct percutaneous transluminal coronary angioplasty predicts poor recovery of left ventricular systolic function in anterior wall AMI

    Am J Cardiol

    (1997)
  • M. Ochiai et al.

    Relation of duration of ST re-elevation at reperfusion and improvement of left ventricular function after successful primary angioplasty of the left anterior descending coronary artery in anterior wall acute myocardial infarction

    Am J Cardiol

    (1997)
  • A. Shah et al.

    Prognostic implications of TIMI flow grade in the infarct related artery compared with continuous 12-lead ST-segment resolution analysis. Reexamining the “gold standard” for myocardial reperfusion assessment

    J Am Coll Cardiol

    (2000)
  • G. Ambrosio et al.

    The relationship between oxygen radical generation and impairment of myocardial energy metabolism following post-ischemic reperfusion

    J Mol Cell Cardiol

    (1991)
  • W. Ko et al.

    Myocardial reperfusion injury. Platelet-activating factor stimulates polymorphonuclear leukocyte hydrogen peroxide production during myocardial reperfusion

    J Thorac Cardiovasc Surg

    (1991)
  • W.J. Dreyer et al.

    Invited letter concerning: neutrophil activation during cardiopulmonary bypass

    J Thorac Cardiovasc Surg

    (1991)
  • A.M. Gillinov et al.

    Neutrophil adhesion molecule expression during cardiopulmonary bypass with bubble and membrane oxygenators

    Ann Thorac Surg

    (1993)
  • A.M. Gillinov et al.

    Complement inhibition with soluble complement receptor type 1 in cardiopulmonary bypass

    Ann Thorac Surg

    (1993)
  • A.M. Gillinov et al.

    Complement and neutrophil activation during cardiopulmonary bypass: a study in the complement-deficient dog

    Ann Thorac Surg

    (1994)
  • A.M. Gillinov et al.

    Inhibition of neutrophil adhesion during cardiopulmonary bypass

    Ann Thorac Surg

    (1994)
  • K. Prasad et al.

    Increased oxygen free radical activity in patients on cardiopulmonary bypass undergoing aortocoronary bypass surgery

    Am Heart J

    (1992)
  • H.M. Piper et al.

    Prime cause of rapid cardiomyocyte death during reperfusion

    Ann Thorac Surg

    (1999)
  • A.P. Halestrap et al.

    Elucidating the molecular mechanism of the permeability transition pore and its role in reperfusion injury of the heart

    Biochim Biophys Acta

    (1998)
  • B.S. Cain et al.

    Adenosine reduces cardiac TNF-alpha production and human myocardial injury following ischemia-reperfusion

    J Surg Res

    (1998)
  • X.-M. Yang et al.

    Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways

    J Am Coll Cardiol

    (2004)
  • K.A. Reimer et al.

    The wavefront phenomenon of ischemic cell death. 1. Myocardial infarct size vs duration of coronary occlusion in dogs

    Circulation

    (1977)
  • M.A. DeWood et al.

    Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction

    N Engl J Med

    (1980)
  • C. Duilio et al.

    Neutrophils are primary source of 02 radicals during reperfusion after prolonged myocardial ischemia

    Am J Physiol Heart Circ Physiol

    (2001)
  • M. Quintana et al.

    Pharmacological prevention of reperfusion injury in acute myocardial infarction a potential role for adenosine as a therapeutic agent

    Am J Cardiovasc Drugs

    (2004)
  • J. Vinten-Johansen

    Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury

    Cardiovasc Res

    (2004)
  • J. Vinten-Johansen et al.

    A simple, clinically applicable procedure to improve revascularization in acute myocardial infarction

    Circulation

    (2005)
  • J. Vinten-Johansen et al.

    Myocardial protection in reperfusion with postconditioning

    Expert Rev Cardiovasc Ther

    (2005)
  • R.B. Jennings et al.

    Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog

    Arch Pathol Lab Med

    (1960)
  • E. Braunwald et al.

    Myocardial reperfusion: a double-edged sword?

    J Clin Invest

    (1985)
  • J. Vinten-Johansen

    Reperfusion injury: idle curiosity or therapeutic vector?

    J Thromb Thrombolysis

    (1997)
  • C. Cobbaert et al.

    Thrombolysis-induced coronary reperfusion causes acute and massive interstitial release of cardiac muscle cell proteins

    Cardiovasc Res

    (1997)
  • P. Staat et al.

    Postconditioning the human heart

    Circulation

    (2005)
  • W.J. Powell et al.

    The protective effect of hyperosmotic mannitol in myocardial ischemia and necrosis

    Circulation

    (1976)
  • R.D. Reynolds et al.

    Effects of propranolol on myocardial infarct size with and without coronary artery reperfusion in the dog

    Cardiovasc Res

    (1981)
  • D.M. Follette et al.

    Advantages of blood cardioplegia over continuous coronary perfusion and intermittent ischemia

    J Thorac Cardiovasc Surg

    (1978)
  • J. Vinten-Johansen et al.

    Immediate functional recovery and avoidance of reperfusion injury with surgical revascularization of short-term coronary occlusion

    Circulation

    (1985)
  • B.H. Bulkley et al.

    Myocardial consequences of coronary artery bypass graft surgery. The paradox of necrosis in areas of revascularization

    Circulation

    (1977)
  • T. Miki et al.

    Mild hypothermia reduces infarct size in the beating rabbit heart: a practical intervention for acute myocardial infarction

    Basic Res Cardiol

    (1998)
  • J. Vinten-Johansen et al.

    Controlled coronary hydrodynamics at the time of reperfusion reduces postischemic injury

    Coron Artery Dis

    (1992)
  • Z.-Q. Zhao et al.

    Reduction in infarct size and preservation of endothelial function by ischemic postconditioning: comparison with ischemic preconditioning

    Circulation

    (2002)
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    This study was supported in part by a grant from the National Heart Lung and Blood Institute of the National Institutes of Health to JV-J (HL069487).

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