Reperfusion injury

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Please Join in Editing This Page and Apply to be an Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.

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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].

Mitochondrial dysfunction plays an important role in reperfusion injury. While the mitochondrial membrane is usually impermeable to ions and metabolites, ischemia alters permeability by elevating intro-mitochondrial calcium concentrations, reducing adenine nucleotide concentrations, and causing oxidative stress. This primes the mitochondrial permeability transition pore (MPTP), which opens when reperfusion occurs[2]. This leads to an increased osmotic load into the mitochondrial body causing swelling and rupture, release of mitochondrial proteins which stimulate apoptosis. Mithochondrial function is disrupted and ATP is hydrolyzed, leading to the activation of degradative enzymes. Finally, excessive Poly ADP ribose polymerase-1 (PARP-1) activation impairs the function of other organelles and accelerates the production of reactive oxygen species[3].

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[4]. 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[4].

The myocardium

Restoration of epicardial patency can be associated with reperfusion injury in the myocardium. This can manifest in a number of ways clinically, including arrhythmia, microvascular dysfunction, myocardial stunning, and myocyte death.

Arrhythmia is mediated by mitochondrial dysfunction, as discussed above. The mitochondrion is unable to restore its inner membrane potential, leading to destabalization of the action potential[5].

Microvascular dysfunction, or "no reflow," as well as myocardial stunning, are both possible consequences of reperfusion injury. Myocardial stunning, which results from persistent anearobic metabolism that continues after reperfusion, may to some extent be mediated by impaired microvascular function[6][7][8][9].

An area of ongoing study is how much damage, or myocyte death, is attributable to ischemia vs. reperfusion injury after vessel patency has been established. Animal studies suggest that up to 50% of of infarct size can be related to reperfusion injury[10][11]. This opens the door for novel therapies that can attenuate myocyte death due to reperfusion injury.

Therapies

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.

Therapies Associated with Limited Success

Pharmacotherapies that have either failed or that have met with limited success in improving clinical outcomes include: [12]

  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 [13] and other older studies[14][15][16][17][18][19][19][20][21][22][23][24][25][26][27]
  3. Sodium-hydrogen exchange inhibitors such as cariporide (Studied in the GUARDIAN [28] [29] and EXPIDITION [30] [31] trials)
  4. Adenosine (Studied in the AMISTAD I [32] and AMISTAD II [33] trials as well as the ATTACC trial [34]). 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 improved echocardiographic and clinical outcomes in one small study. [35]
  5. Calcium-channel blockers
  6. Potassium–adenosine triphosphate channel openers[36][37]
  7. Antibodies directed against leukocyte adhesion molecules such as CD 18 (Studied in the LIMIT AMI trial [38])
  8. Oxygen free radical scavengers/anti-oxidants, including Erythropoietin[39][40][41][42][43], estrogen[44][45], heme-oxygenase 1[46], and hypoxia induced factor-1 (HIF-1)[47].
  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 [48] )
  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)[49].
  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.)[50]
  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)[51]
  13. Magnesium, which was evaluted by the Fourth International Study of Infarct Survival (ISIS-4)[52] and the MAGIC trial[53].

Therapies Associated with Improved Clinical Outcomes

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).[54]
  2. Inhibition of mitochondrial pore opening by cyclosporine. [55][56]
Specifically, the study by Piot et al demonstrated that administration of cyclosporine at the time of reperfusion was associated with a reduction in infarct size as measured by the release of creatine kinase and delayed hyperenhancement on MRI. Patients with cardiac arrest, ventricular fibrillation, cardiogenic shock, stent thrombosis, previous acute myocardial infarction, or angina within 48 hours before infarction were not included in the study. Occlusion of the culprit artery (TIMI flow 0) was part of the inclusion criteria.

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 2006-08-09.
  2. ↑ Halestrap AP, Clarke SJ, Javadov SA (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. Unknown parameter |month= ignored (help)
  3. ↑ Zingarelli B, O'Connor M, Hake PW (2003). "Inhibitors of poly (ADP-ribose) polymerase modulate signal transduction pathways in colitis". Eur. J. Pharmacol. 469 (1–3): 183–94. PMID 12782201. Unknown parameter |month= ignored (help)
  4. ↑ 4.0 4.1 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.
  5. ↑ Akar FG, Aon MA, Tomaselli GF, O'Rourke B (2005). "The mitochondrial origin of postischemic arrhythmias". J. Clin. Invest. 115 (12): 3527–35. doi:10.1172/JCI25371. PMC 1280968. PMID 16284648. Unknown parameter |month= ignored (help)
  6. ↑ Iliceto S, Galiuto L, Marchese A; et al. (1996). "Analysis of microvascular integrity, contractile reserve, and myocardial viability after acute myocardial infarction by dobutamine echocardiography and myocardial contrast echocardiography". Am. J. Cardiol. 77 (7): 441–5. PMID 8629581. Unknown parameter |month= ignored (help)
  7. ↑ Iliceto S, Galiuto L, Marchese A, Colonna P, Oliva S, Rizzon P (1997). "Functional role of microvascular integrity in patients with infarct-related artery patency after acute myocardial infarction". Eur. Heart J. 18 (4): 618–24. PMID 9129892. Unknown parameter |month= ignored (help)
  8. ↑ Ito H, Maruyama A, Iwakura K; et al. (1996). "Clinical implications of the 'no reflow' phenomenon. A predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction". Circulation. 93 (2): 223–8. PMID 8548892. Unknown parameter |month= ignored (help)
  9. ↑ Sabia PJ, Powers ER, Ragosta M, Sarembock IJ, Burwell LR, Kaul S (1992). "An association between collateral blood flow and myocardial viability in patients with recent myocardial infarction". N. Engl. J. Med. 327 (26): 1825–31. doi:10.1056/NEJM199212243272601. PMID 1448120. Unknown parameter |month= ignored (help)
  10. ↑ Matsumura K, Jeremy RW, Schaper J, Becker LC (1998). "Progression of myocardial necrosis during reperfusion of ischemic myocardium". Circulation. 97 (8): 795–804. PMID 9498544. Unknown parameter |month= ignored (help)
  11. ↑ Arai M, Lefer DJ, So T, DiPaula A, Aversano T, Becker LC (1996). "An anti-CD18 antibody limits infarct size and preserves left ventricular function in dogs with ischemia and 48-hour reperfusion". J. Am. Coll. Cardiol. 27 (5): 1278–85. PMID 8609356. Unknown parameter |month= ignored (help)
  12. ↑ Dirksen MT, Laarman GJ, Simoons ML, Duncker DJ (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. Unknown parameter |month= ignored (help)
  13. ↑ Timmer JR, Svilaas T, Ottervanger JP; et al. (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. Unknown parameter |month= ignored (help)
  14. ↑ "Potassium, glucose, and insulin treatment for acute myocardial infarction". Lancet. 2 (7583): 1355–60. 1968. PMID 4177929. Unknown parameter |month= ignored (help)
  15. ↑ Pentecost BL, Mayne NM, Lamb P (1968). "Controlled trial of intravenous glucose, potassium, and insulin in acute myocardial infarction". Lancet. 1 (7549): 946–8. PMID 4171584. Unknown parameter |month= ignored (help)
  16. ↑ Apstein CS, Opie LH (1999). "Glucose-insulin-potassium (GIK) for acute myocardial infarction: a negative study with a positive value" (PDF). Cardiovasc Drugs Ther. 13 (3): 185–9. PMID 10439880. Unknown parameter |month= ignored (help)
  17. ↑ Fath-Ordoubadi F, Beatt KJ (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. Unknown parameter |month= ignored (help)
  18. ↑ Rogers WJ, Stanley AW, Breinig JB; et al. (1976). "Reduction of hospital mortality rate of acute myocardial infarction with glucose-insulin-potassium infusion". Am. Heart J. 92 (4): 441–54. PMID 785990. Unknown parameter |month= ignored (help)
  19. ↑ 19.0 19.1 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.
  20. ↑ Satler LF, Green CE, Kent KM, Pallas RS, Pearle DL, Rackley CE (1987). "Metabolic support during coronary reperfusion". Am. Heart J. 114 (1 Pt 1): 54–8. PMID 3300232. Unknown parameter |month= ignored (help)
  21. ↑ Malmberg K, Rydén L, Efendic S; et al. (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. Unknown parameter |month= ignored (help)
  22. ↑ Díaz R, Paolasso EA, Piegas LS; et al. (1998). "Metabolic modulation of acute myocardial infarction. The ECLA (Estudios Cardiológicos Latinoamérica) Collaborative Group". Circulation. 98 (21): 2227–34. PMID 9867443. Unknown parameter |month= ignored (help)
  23. ↑ Ceremuzyński L, Budaj A, Czepiel A; et al. (1999). "Low-dose glucose-insulin-potassium is ineffective in acute myocardial infarction: results of a randomized multicenter Pol-GIK trial" (PDF). Cardiovasc Drugs Ther. 13 (3): 191–200. PMID 10439881. Unknown parameter |month= ignored (help)
  24. ↑ van der Horst IC, Zijlstra F, van 't Hof AW; et al. (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. Unknown parameter |month= ignored (help)
  25. ↑ Sack MN, Yellon DM (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. Unknown parameter |month= ignored (help)
  26. ↑ Stanley AW, Moraski RE, Russell RO; et al. (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. Unknown parameter |month= ignored (help)
  27. ↑ Hjermann I (1971). "A controlled study of peroral glucose, insulin and potassium treatment in myocardial infarction". Acta Med Scand. 190 (3): 213–8. PMID 4941225. Unknown parameter |month= ignored (help)
  28. ↑ Théroux P, Chaitman BR, Danchin N; et al. (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. Unknown parameter |month= ignored (help)
  29. ↑ 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. PMC 56207. PMID 11714411.
  30. ↑ 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.
  31. ↑ Mentzer RM, Bartels C, Bolli R; et al. (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. Unknown parameter |month= ignored (help)
  32. ↑ Mahaffey KW, Puma JA, Barbagelata NA; et al. (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. Unknown parameter |month= ignored (help)
  33. ↑ Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW (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. Unknown parameter |month= ignored (help)
  34. ↑ Quintana M, Hjemdahl P, Sollevi A; et al. (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. Unknown parameter |month= ignored (help)
  35. ↑ Marzilli M, Orsini E, Marraccini P, Testa R (2000). "Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction". Circulation. 101 (18): 2154–9. PMID 10801755. Unknown parameter |month= ignored (help)
  36. ↑ Sakata Y, Kodama K, Ishikura F; et al. (1997). "Disappearance of the 'no-reflow' phenomenon after adjunctive intracoronary administration of nicorandil in a patient with acute myocardial infarction". Jpn. Circ. J. 61 (5): 455–8. PMID 9192246. Unknown parameter |month= ignored (help)
  37. ↑ Ito H, Taniyama Y, Iwakura K; et al. (1999). "Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction". J. Am. Coll. Cardiol. 33 (3): 654–60. PMID 10080465. Unknown parameter |month= ignored (help)
  38. ↑ Baran KW, Nguyen M, McKendall GR; et al. (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. Unknown parameter |month= ignored (help)
  39. ↑ Namiuchi S, Kagaya Y, Ohta J; et al. (2005). "High serum erythropoietin level is associated with smaller infarct size in patients with acute myocardial infarction who undergo successful primary percutaneous coronary intervention". J. Am. Coll. Cardiol. 45 (9): 1406–12. doi:10.1016/j.jacc.2005.01.043. PMID 15862410. Unknown parameter |month= ignored (help)
  40. ↑ Hanlon PR, Fu P, Wright GL, Steenbergen C, Arcasoy MO, Murphy E (2005). "Mechanisms of erythropoietin-mediated cardioprotection during ischemia-reperfusion injury: role of protein kinase C and phosphatidylinositol 3-kinase signaling". FASEB J. 19 (10): 1323–5. doi:10.1096/fj.04-3545fje. PMID 15946993. Unknown parameter |month= ignored (help)
  41. ↑ Bullard AJ, Govewalla P, Yellon DM (2005). "Erythropoietin protects the myocardium against reperfusion injury in vitro and in vivo". Basic Res. Cardiol. 100 (5): 397–403. doi:10.1007/s00395-005-0537-4. PMID 15944807. Unknown parameter |month= ignored (help)
  42. ↑ Xu B, Dong GH, Liu H, Wang YQ, Wu HW, Jing H (2005). "Recombinant human erythropoietin pretreatment attenuates myocardial infarct size: a possible mechanism involves heat shock Protein 70 and attenuation of nuclear factor-kappaB". Ann. Clin. Lab. Sci. 35 (2): 161–8. PMID 15943180.
  43. ↑ Hirata A, Minamino T, Asanuma H; et al. (2005). "Erythropoietin just before reperfusion reduces both lethal arrhythmias and infarct size via the phosphatidylinositol-3 kinase-dependent pathway in canine hearts". Cardiovasc Drugs Ther. 19 (1): 33–40. doi:10.1007/s10557-005-6895-1. PMID 15883754. Unknown parameter |month= ignored (help)
  44. ↑ Jeanes HL, Wanikiat P, Sharif I, Gray GA (2006). "Medroxyprogesterone acetate inhibits the cardioprotective effect of estrogen in experimental ischemia-reperfusion injury". Menopause. 13 (1): 80–6. doi:10.1097/01.gme.0000196593.44335.eb. PMID 16607102.
  45. ↑ Sbarouni E, Iliodromitis EK, Bofilis E, Kyriakides ZS, Kremastinos DT (2003). "Estrogen alone or combined with medroxyprogesterone but not raloxifene reduce myocardial infarct size". Eur. J. Pharmacol. 467 (1–3): 163–8. PMID 12706470. Unknown parameter |month= ignored (help)
  46. ↑ Liu X, Pachori AS, Ward CA; et al. (2006). "Heme oxygenase-1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function". FASEB J. 20 (2): 207–16. doi:10.1096/fj.05-4435com. PMID 16449792. Unknown parameter |month= ignored (help)
  47. ↑ Jung F, Palmer LA, Zhou N, Johns RA (2000). "Hypoxic regulation of inducible nitric oxide synthase via hypoxia inducible factor-1 in cardiac myocytes". Circ. Res. 86 (3): 319–25. PMID 10679484. Unknown parameter |month= ignored (help)
  48. ↑ Armstrong PW, Granger CB, Adams PX; et al. (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. Unknown parameter |month= ignored (help)
  49. ↑ Bates E, Bode C, Costa M; et al. (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. Unknown parameter |month= ignored (help)
  50. ↑ Kitakaze M, Asakura M, Kim J; et al. (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. Unknown parameter |month= ignored (help)
  51. ↑ Atar D, Petzelbauer P, Schwitter J; et al. (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. Unknown parameter |month= ignored (help)
  52. ↑ "ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group". Lancet. 345 (8951): 669–85. 1995. PMID 7661937. Unknown parameter |month= ignored (help)
  53. ↑ "Early administration of intravenous magnesium to high-risk patients with acute myocardial infarction in the Magnesium in Coronaries (MAGIC) Trial: a randomised controlled trial". Lancet. 360 (9341): 1189–96. 2002. PMID 12401244. Unknown parameter |month= ignored (help)
  54. ↑ Thibault H, Piot C, Staat P; et al. (2008). "Long-term benefit of postconditioning". Circulation. 117 (8): 1037–44. doi:10.1161/CIRCULATIONAHA.107.729780. PMID 18268150. Unknown parameter |month= ignored (help)
  55. ↑ Piot C, Croisille P, Staat P; et al. (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. Unknown parameter |month= ignored (help)
  56. ↑ Ovize M, Baxter GF, Di Lisa F, Ferdinandy P, Garcia-Dorado D, Hausenloy DJ; et al. (2010). "Postconditioning and protection from reperfusion injury: where do we stand? Position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology". Cardiovasc Res. 87 (3): 406–23. doi:10.1093/cvr/cvq129. PMID 20448097.

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