Reperfusion injury medical therapy

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Editors-In-Chief: Anjan K. Chakrabarti, M.D. [1]; C. Michael Gibson, M.S., M.D. [2]

Overview

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.

Hypothetical assessment of reperfusion injury and role of cardioprotection and treatment:

Scenario Clinical course Infarct size (%)
Presentation Myocardial ischemia 0
Best scenario (hypothetical) Ischemia + Reperfusion (no reperfusion injury) 0
Actual Ischemia + Reperfusion + Reperfusion injury 40
GOAL (with treatment) Ischemia + Reperfusion + Reperfusion injury + Myocardial protection 5-10%

Therapies Associated with Limited Success

Pharmacotherapies that have either failed or that have met with limited success in improving clinical outcomes include: [1]

  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 [2] and other older studies[3][4][5][6][7][8][8][9][10][11][12][13][14][15][16]
  3. Sodium-hydrogen exchange inhibitors such as cariporide (Studied in the GUARDIAN [17] [18] and EXPIDITION [19] [20] trials)
  4. Adenosine (Studied in the AMISTAD I [21] and AMISTAD II [22] trials as well as the ATTACC trial [23]). 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. [24]
  5. Calcium-channel blockers
  6. Potassium–adenosine triphosphate channel openers[25][26]
  7. Antibodies directed against leukocyte adhesion molecules such as CD 18 (Studied in the LIMIT AMI trial [27])
  8. Oxygen free radical scavengers/anti-oxidants, including Erythropoietin[28][29][30][31][32], estrogen[33][34], heme-oxygenase 1[35], and hypoxia induced factor-1 (HIF-1)[36].
  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 [37] )
  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)[38].
  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.)[39]
  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)[40]
  13. Magnesium, which was evaluted by the Fourth International Study of Infarct Survival (ISIS-4)[41] and the MAGIC trial[42].
  14. Hypothermia[43]
  15. Hyperoxemia, the delivery of supersaturated oxygen after PCI (Studied in the AMIHOT II trial[44]).

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).[45][46]
    • Mechanisms of protection include formation and release of several autacoids and cytokines, maintained acidosis during early repercussion, activation of protein kinases, and attenuation of opening of the mitochondrial permeability transition pore (MPTP)
    • One study in humans demonstrated an area under the curve (AUC) of creatine kinase (C) release over the first 3 days of reperfusion (as a surrogate for infarct size) was significantly reduced by 36% in the postconditioned versus control group[47]
    • Infarct size reduction by PCI postconditioning persisted 6 months after AMI and resulted in a significant improvement in left ventricular (LV) function at 1 year[45]
  2. Inhibition of mitochondrial pore opening by cyclosporine. [48]
    • 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
    • Infarct size was 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 redundant pathways mediating reperfusion injury
  4. Inadequate dosing of the agent

References

  1. ↑ 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)
  2. ↑ 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)
  3. ↑ "Potassium, glucose, and insulin treatment for acute myocardial infarction". Lancet. 2 (7583): 1355–60. 1968. PMID 4177929. Unknown parameter |month= ignored (help)
  4. ↑ 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)
  5. ↑ 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)
  6. ↑ 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)
  7. ↑ 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)
  8. ↑ 8.0 8.1 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.
  9. ↑ 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)
  10. ↑ 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)
  11. ↑ 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)
  12. ↑ 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)
  13. ↑ 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)
  14. ↑ 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)
  15. ↑ 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)
  16. ↑ 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)
  17. ↑ 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)
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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)
  21. ↑ 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)
  22. ↑ 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)
  23. ↑ 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)
  24. ↑ 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)
  25. ↑ 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)
  26. ↑ 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)
  27. ↑ 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)
  28. ↑ 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)
  29. ↑ 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)
  30. ↑ 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)
  31. ↑ 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.
  32. ↑ 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)
  33. ↑ 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.
  34. ↑ 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)
  35. ↑ 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)
  36. ↑ 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)
  37. ↑ 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)
  38. ↑ 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)
  39. ↑ 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)
  40. ↑ 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)
  41. ↑ "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)
  42. ↑ "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)
  43. ↑ Dixon SR, Whitbourn RJ, Dae MW, Grube E, Sherman W, Schaer GL; et al. (2002). "Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction". J Am Coll Cardiol. 40 (11): 1928–34. PMID 12475451.
  44. ↑ Stone GW, Martin JL, de Boer MJ, Margheri M, Bramucci E, Blankenship JC; et al. (2009). "Effect of supersaturated oxygen delivery on infarct size after percutaneous coronary intervention in acute myocardial infarction". Circ Cardiovasc Interv. 2 (5): 366–75. doi:10.1161/CIRCINTERVENTIONS.108.840066. PMID 20031745.
  45. ↑ 45.0 45.1 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)
  46. ↑ 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.
  47. ↑ Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I; et al. (2005). "Postconditioning the human heart". Circulation. 112 (14): 2143–8. doi:10.1161/CIRCULATIONAHA.105.558122. PMID 16186417.
  48. ↑ 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)
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