ReviewPathogenesis of Myocardial Ischemia-Reperfusion Injury and Rationale for Therapy
Section snippets
Historical Perspective
The seminal observation that reperfusion after ischemia was associated with myocardial injury was made in 1960 by Jennings et al.2 Their report was based on experiments with canine hearts subjected to coronary ligation in which reperfusion appeared to accelerate the development of necrosis. For example, those investigators noted that the histologic changes seen after only 30 to 60 minutes of ischemia-reperfusion (IR) were comparable to the degree of necrosis normally seen after 24 hours of
Mechanisms of Ischemia-Reperfusion Injury
Molecular and cellular events underlying IR injury are complex, representing the confluence of divergent biologic pathways. Furthermore, the extent to which each of these pathways is relevant to human disease remains unclear, as animal models do not always faithfully recapitulate the IR disease process in humans. These limitations notwithstanding, several key pathophysiologic features of clinically relevant IR have emerged (Table 1).
Ischemia induces the accumulation of intracellular sodium,
Ischemia-Reperfusion in Acute Myocardial Infarction
Although “reperfusion injury” in the most general sense refers to that component of the infarction process related to restoration of epicardial patency and anterograde blood flow, in the catheterization laboratory, “IR injury” is often synonymous with the “no-reflow” phenomenon. The term was first applied to myocardial ischemia after coronary ligation in dogs.36 Regarded as a dreaded complication of acute MI intervention, it is estimated to occur in >30% of cases and is associated with adverse
Therapeutic Interventions Targeting Ischemia-Reperfusion Injury in Acute Myocardial Infarction
Despite the substantial progress in understanding mechanisms of IR on the basis of models of acute MI, and the associated enthusiasm for translating these findings into patient care, the results of clinical studies have been largely disappointing. Whether this reflects our still incomplete understanding of the biology of IR or just a naive belief that a single intervention could be protective against a process involving multiple major pathophysiologic components is not clear. Initial pilot
Ischemia-Reperfusion Injury During Cardiac Surgery
IR stress caused by cardiac surgery is distinctly different from that occurring during spontaneous MI. Ischemia is induced artificially by aortic cross clamping, and myocardial preservation strategies are used throughout this ischemic period. Cardioplegia is achieved via hyperkalemic, hypothermic cardiac arrest and maintained with the intermittent use of a glucose-containing cardioplegic solution (usually mixed with blood) delivered anterograde in the aortic root and/or retrograde via the
Interventions Targeting Ischemia-Reperfusion Injury After Cardioplegic Arrest
Although the operating theater may appear daunting given the number of personnel, environmental factors, and pieces of equipment needed to successfully manage a patient through cardiac surgery, it is, in many ways, an ideal place to perform research. The duration of ischemia is known, electrolytes and glucose concentrations are meticulously regulated, and hemodynamics can be followed throughout the procedure, including the pre- and postoperative phases. Furthermore, local drug delivery, as
Acknowledgment
We thank Lynne Isbell, PhD, at Discovery Chicago, for editorial support.
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This work was supported by grants HL-075173, HL-080144, and HL-090842 from the National Institutes of Health, Bethesda, Maryland; grant 0640084N from the American Heart Association, Dallas, Texas; grant 7-08-MN-21-ADA from the American Diabetes Association, Alexandria, Virginia; and grant 0970518N from the AHA-Jon Holden DeHaan Foundation, Naples, Florida. Editorial support was funded by Schering-Plough Corporation, Kenilworth, New Jersey.