Reperfusion injury

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Overview

Reperfusion injury refers to damage to tissue caused when blood supply returns to the tissue after a period of ischemia. The absence of oxygen and nutrients from blood creates a condition in which the restoration of circulation results in inflammation and oxidative damage through the induction of oxidative stress rather than restoration of normal function.

Mechanisms of reperfusion injury

The damage of reperfusion injury is due in part to the inflammatory response of damaged tissues. White blood cells carried to the area by the newly returning blood release a host of inflammatory factors such as interleukins as well as free radicals in response to tissue damage [1].The restored blood flow reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma membrane. Damage to the cell's membrane may in turn cause the release of more free radicals. Such reactive species may also act indirectly in redox signaling to turn on apoptosis. Leukocytes may also build up in small capillaries, obstructing them and leading to more ischemia[1]. Other pathophysiologic disturbances include intracellular calcium overload and the opening of mitochondrial permeability transition pores. [2]

In prolonged ischemia (60 minutes or more), hypoxanthine is formed as breakdown product of ATP metabolism. The enzyme xanthine dehydrogenase is converted to xanthine oxidase as a result of the higher availability of oxygen. This oxidation results in molecular oxygen being converted into highly reactive superoxide and hydroxyl radicals. Xanthine oxidase also produces uric acid, which may act as both a prooxidant and as a scavenger of reactive species such as peroxinitrite. Excessive nitric oxide produced during reperfusion reacts with superoxide to produce the potent reactive species peroxynitrite. Such radicals and reactive oxygen species attack cell membrane lipids, proteins, and glycosaminoglycans, causing further damage. They may also initiate specific biological processes by redox signaling.

Specific organs affected by reperfusion injury

The central nervous system

Reperfusion injury plays a part in the brain's ischemic cascade, which is involved in stroke and brain trauma. Repeated bouts of ischemia and reperfusion injury also are thought to be a factor leading to the formation and failure to heal of chronic wounds such as pressure sores and diabetic foot ulcers[3]. Continuous pressure limits blood supply and causes ischemia, and the inflammation occurs during reperfusion. As this process is repeated, it eventually damages tissue enough to cause a wound[3].

The myocardium

Restoration of epicardial patency can be associated with reperfusion injury in the myocardium. While many pharmacotherapies are successful in limiting reperfusion injury in animal studies or ex-vivo, many have failed to improve clinical outcomes in randomized clinical trials in patients. Pharmacotherapies that have either failed or that have met with limited success in improving clinical outcomes include: [4]

  1. Beta-blockade
  2. GIK (glucose-insulin-potassium infusion) (Studied in the Glucose-Insulin-Potassium Infusion in Patients With Acute Myocardial Infarction Without Signs of Heart Failure: The Glucose-Insulin-Potassium Study (GIPS)-II [5] and other older studies[6][7][8][9][10][11][11][12][13][14][15][16][17][18][19]
  3. Sodium-hydrogen exchange inhibitors such as cariporide (Studied in the GUARDIAN [20] [21] and EXPIDITION [22] [23] trials)
  4. Adenosine (Studied in the AMISTAD I [24] and AMISTAD II [25] trials as well as the ATTACC trial [26]). It should be noted that at high doses in anterior ST elevation MIs, adenosine was effective in the AMISTAD trial. Likewise, intracoronary administration of adenosine prior to primary PCI has been associated with imporved ehcocardiographic and clinical outcomes in one small study. [27]
  5. Calcium-channel blockers
  6. Potassium–adenosine triphosphate channel openers
  7. Antibodies directed against leukocyte adhesion molecules such as CD 18 (Studied in the LIMIT AMI trial [28])
  8. Oxygen free radical scavengers
  9. Pexelizumab, a humanized monoclonal antibody that binds the C5 component of complement (Studied in the Pexelizumab for Acute ST-Elevation Myocardial Infarction in Patients Undergoing Primary Percutaneous Coronary Intervention (APEX AMI) trial [29] )
  10. KAI-9803, a delta-protein kinase C inhibitor (Studied in the Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction trial or DELTA AMI trial)[30].
  11. Human atrial natriuretic peptide (Studied in the Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials.)[31]
  12. FX06, an anti-inflammatory fibrin derivative that competes with fibrin fragments for binding with the vascular endothelial molecule VE-cadherin which deters migration of leukocytes across the endothelial cell monolayer (studied in the F.I.R.E. trial (Efficacy of FX06 in the Prevention of Myocardial Reperfusion Injury)[32]

Therapies that have been associated with improved clinical outcomes include

  1. Post conditioning (short repeated periods of vessel opening by repeatedly blowing the balloon up for short periods of time).[33]
  2. Inhibition of mitochondrial pore opening by cyclosporine [34]

Limitations to applying strategies that have demonstrated benefit in animal models is the fact that reperfusion therapy was administered prior to or at the time of reperfusion. In the management of STEMI patients, it is impossible to administer the agent before vessel occlusion (except during coronary artery bypass grafting). Given the time constraints and the goal of opening an occluded artery within 90 minutes, it is also difficult to administer experimental agents before reperfusion in STEMI.

There are several explanations for why trials of experimental agents have failed in this area:

  1. The therapy was administered after reperfusion and after reperfusion injury had set in
  2. The greatest benefit is observed in anterior ST elevation myocardial infarctions (as demonstrated in the AMISTAD study), and inclusion of non anterior locations minimizes the potential benefit
  3. There are uninhibited reduncant pathways mediating reperfusion injury
  4. Inadequate dosing of the agent

See also

References

  1. ↑ 1.0 1.1 Clark, Wayne M. (January 5, 2005). Reperfusion Injury in Stroke. eMedicine. WebMD. Retrieved on 2006-08-09.
  2. ↑ Halestrap AP, Clarke SJ, Javadov SA (February 2004). "Mitochondrial permeability transition pore opening during myocardial reperfusion--a target for cardioprotection". Cardiovasc. Res. 61 (3): 372–85. doi:10.1016/S0008-6363(03)00533-9. PMID 14962470.
  3. ↑ 3.0 3.1 Mustoe T. (2004). "Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy". AMERICAN JOURNAL OF SURGERY 187 (5A): 65S-70S. PMID 15147994.
  4. ↑ Dirksen MT, Laarman GJ, Simoons ML, Duncker DJ (June 2007). "Reperfusion injury in humans: a review of clinical trials on reperfusion injury inhibitory strategies". Cardiovasc. Res. 74 (3): 343–55. doi:10.1016/j.cardiores.2007.01.014. PMID 17306241.
  5. ↑ Timmer JR, Svilaas T, Ottervanger JP, et al (April 2006). "Glucose-insulin-potassium infusion in patients with acute myocardial infarction without signs of heart failure: the Glucose-Insulin-Potassium Study (GIPS)-II". J. Am. Coll. Cardiol. 47 (8): 1730–1. doi:10.1016/j.jacc.2006.01.040. PMID 16631017.
  6. ↑ (December 1968) "Potassium, glucose, and insulin treatment for acute myocardial infarction". Lancet 2 (7583): 1355–60. PMID 4177929.
  7. ↑ Pentecost BL, Mayne NM, Lamb P (May 1968). "Controlled trial of intravenous glucose, potassium, and insulin in acute myocardial infarction". Lancet 1 (7549): 946–8. PMID 4171584.
  8. ↑ Apstein CS, Opie LH (May 1999). "Glucose-insulin-potassium (GIK) for acute myocardial infarction: a negative study with a positive value". Cardiovasc Drugs Ther 13 (3): 185–9. PMID 10439880.
  9. ↑ Fath-Ordoubadi F, Beatt KJ (August 1997). "Glucose-insulin-potassium therapy for treatment of acute myocardial infarction: an overview of randomized placebo-controlled trials". Circulation 96 (4): 1152–6. PMID 9286943.
  10. ↑ Rogers WJ, Stanley AW, Breinig JB, et al (October 1976). "Reduction of hospital mortality rate of acute myocardial infarction with glucose-insulin-potassium infusion". Am. Heart J. 92 (4): 441–54. PMID 785990.
  11. ↑ 11.0 11.1 Rackley CE, Russell RO, Rogers WJ, Mantle JA, McDaniel HG, Papapietro SE (1982). "Glucose-insulin-potassium administration in acute myocardial infarction". Annu. Rev. Med. 33: 375–83. doi:10.1146/annurev.me.33.020182.002111. PMID 7044275.
  12. ↑ Satler LF, Green CE, Kent KM, Pallas RS, Pearle DL, Rackley CE (July 1987). "Metabolic support during coronary reperfusion". Am. Heart J. 114 (1 Pt 1): 54–8. PMID 3300232.
  13. ↑ Malmberg K, Rydén L, Efendic S, et al (July 1995). "Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year". J. Am. Coll. Cardiol. 26 (1): 57–65. PMID 7797776.
  14. ↑ Díaz R, Paolasso EA, Piegas LS, et al (November 1998). "Metabolic modulation of acute myocardial infarction. The ECLA (Estudios Cardiológicos Latinoamérica) Collaborative Group". Circulation 98 (21): 2227–34. PMID 9867443.
  15. ↑ Ceremuzyński L, Budaj A, Czepiel A, et al (May 1999). "Low-dose glucose-insulin-potassium is ineffective in acute myocardial infarction: results of a randomized multicenter Pol-GIK trial". Cardiovasc Drugs Ther 13 (3): 191–200. PMID 10439881.
  16. ↑ van der Horst IC, Zijlstra F, van 't Hof AW, et al (September 2003). "Glucose-insulin-potassium infusion inpatients treated with primary angioplasty for acute myocardial infarction: the glucose-insulin-potassium study: a randomized trial". J. Am. Coll. Cardiol. 42 (5): 784–91. PMID 12957421.
  17. ↑ Sack MN, Yellon DM (April 2003). "Insulin therapy as an adjunct to reperfusion after acute coronary ischemia: a proposed direct myocardial cell survival effect independent of metabolic modulation". J. Am. Coll. Cardiol. 41 (8): 1404–7. PMID 12706939.
  18. ↑ Stanley AW, Moraski RE, Russell RO, et al (December 1975). "Effects of glucose-insulin-potassium on myocardial substrate availability and utilization in stable coronary artery disease. Studies on myocardial carbohydrate, lipid and oxygen arterial-coronary sinus differences in patients with coronary artery disease". Am. J. Cardiol. 36 (7): 929–37. PMID 1199950.
  19. ↑ Hjermann I (September 1971). "A controlled study of peroral glucose, insulin and potassium treatment in myocardial infarction". Acta Med Scand 190 (3): 213–8. PMID 4941225.
  20. ↑ Théroux P, Chaitman BR, Danchin N, et al (December 2000). "Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations. Main results of the GUARDIAN trial. Guard during ischemia against necrosis (GUARDIAN) Investigators". Circulation 102 (25): 3032–8. PMID 11120691.
  21. ↑ Theroux P, Chaitman BR, Erhardt L, et al (2000). "Design of a trial evaluating myocardial cell protection with cariporide, an inhibitor of the transmembrane sodium-hydrogen exchanger: the Guard During Ischemia Against Necrosis (GUARDIAN) trial". Curr Control Trials Cardiovasc Med 1 (1): 59–67. PMID 11714411.
  22. ↑ Bolli R (2003). "The role of sodium-hydrogen ion exchange in patients undergoing coronary artery bypass grafting". J Card Surg 18 Suppl 1: 21–6. PMID 12691376.
  23. ↑ Mentzer RM, Bartels C, Bolli R, et al (April 2008). "Sodium-hydrogen exchange inhibition by cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting: results of the EXPEDITION study". Ann. Thorac. Surg. 85 (4): 1261–70. doi:10.1016/j.athoracsur.2007.10.054. PMID 18355507.
  24. ↑ Mahaffey KW, Puma JA, Barbagelata NA, et al (November 1999). "Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction: results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial". J. Am. Coll. Cardiol. 34 (6): 1711–20. PMID 10577561.
  25. ↑ Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW (June 2005). "A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II)". J. Am. Coll. Cardiol. 45 (11): 1775–80. doi:10.1016/j.jacc.2005.02.061. PMID 15936605.
  26. ↑ Quintana M, Hjemdahl P, Sollevi A, et al (May 2003). "Left ventricular function and cardiovascular events following adjuvant therapy with adenosine in acute myocardial infarction treated with thrombolysis, results of the ATTenuation by Adenosine of Cardiac Complications (ATTACC) study". Eur. J. Clin. Pharmacol. 59 (1): 1–9. doi:10.1007/s00228-003-0564-8. PMID 12743668.
  27. ↑ Marzilli M, Orsini E, Marraccini P, Testa R (May 2000). "Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction". Circulation 101 (18): 2154–9. PMID 10801755.
  28. ↑ Baran KW, Nguyen M, McKendall GR, et al (December 2001). "Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study". Circulation 104 (23): 2778–83. PMID 11733394.
  29. ↑ Armstrong PW, Granger CB, Adams PX, et al (January 2007). "Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial". JAMA 297 (1): 43–51. doi:10.1001/jama.297.1.43. PMID 17200474.
  30. ↑ Bates E, Bode C, Costa M, et al (February 2008). "Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction". Circulation 117 (7): 886–96. doi:10.1161/CIRCULATIONAHA.107.759167. PMID 18250271.
  31. ↑ Kitakaze M, Asakura M, Kim J, et al (October 2007). "Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials". Lancet 370 (9597): 1483–93. doi:10.1016/S0140-6736(07)61634-1. PMID 17964349.
  32. ↑ Atar D, Petzelbauer P, Schwitter J, et al (February 2009). "Effect of intravenous FX06 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction results of the F.I.R.E. (Efficacy of FX06 in the Prevention of Myocardial Reperfusion Injury) trial". J. Am. Coll. Cardiol. 53 (8): 720–9. doi:10.1016/j.jacc.2008.12.017. PMID 19232907.
  33. ↑ Thibault H, Piot C, Staat P, et al (February 2008). "Long-term benefit of postconditioning". Circulation 117 (8): 1037–44. doi:10.1161/CIRCULATIONAHA.107.729780. PMID 18268150.
  34. ↑ Piot C, Croisille P, Staat P, et al (July 2008). "Effect of cyclosporine on reperfusion injury in acute myocardial infarction". N. Engl. J. Med. 359 (5): 473–81. doi:10.1056/NEJMoa071142. PMID 18669426.

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Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .

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