Reperfusion injury medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Anjan K. Chakrabarti, M.D. [2] Shivam Singla, M.D.[3]

Overview

Medical Therapy

Various proposed medical managements studied are:

  • Hydrogen sulfide treatment

[10]

  • Cannabinoids
    • A research published in 2012 shows that the synthetic analog of phytocannabinoid tetrahydrocannabivarin (THCV), 8-Tetrahydrocannabivarin (THCV) and its 11-OH-8-THCV metabolite prevents hepatic ischemia/reperfusion injury by minimizing oxidative stress and inflammatory reactions through cannabinoid CB2 receptors, thereby lowering tissue damage and protective effects of inflammation. Pretreatment with a CB2 receptor antagonist, whereas a CB1 antagonist appeared to strengthen it, attenuated the defensive effects of somewhere else[15].
    • An earlier study published in 2011 found that cannabidiol (CBD) also protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signals and oxidative and nitrative stress response, resulting in cell death and tissue damage, but is independent of classic CB1 and CB2 receptors[16].

Therapies Associated with Improved Clinical Outcomes

Medical treatment in IRI

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).
  2. Inhibition of mitochondrial pore opening by cyclosporine.

Limitations to applying strategies that have demonstrated benefit in animal models are 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.

Therapies Associated with Limited Success

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

  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 and other older studies
  3. Sodium-hydrogen exchange inhibitors such as cariporide (Studied in the GUARDIAN and EXPEDITION trials)
  4. Adenosine (Studied in the AMISTAD I and AMISTAD II trials as well as the ATTACC trial ). 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.
  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 )
  8. Oxygen free radical scavengers/anti-oxidants, including Erythropoietin, estrogen, heme-oxygenase 1, and hypoxia induced factor-1 (HIF-1).
  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 )
  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).
  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 randomized trials.)
  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)
  13. Magnesium, which was evaluated by the Fourth International Study of Infarct Survival (ISIS-4) and the MAGIC trial.
  14. Hyperoxemia, the delivery of supersaturated oxygen after PCI (Studied in the AMIHOT II trial).
  15. Bendavia studied in the EMBRACE STEMI trial

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. Adler, Jerry. "Back From the Dead." Newsweek. July 23, 2007
  2. Polderman KH (April 2004). "Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: Indications and evidence". Intensive Care Med. 30 (4): 556–75. doi:10.1007/s00134-003-2152-x. PMID 14767591.
  3. Elrod J.W., J.W. Calvert, M.R. Duranski, D.J. Lefer. "Hydrogen sulfide donor protects against acute myocardial ischemia-reperfusion injury." Circulation 114(18):II172, 2006
  4. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, André-Fouët X, Revel D, Kirkorian G, Monassier JP, Derumeaux G, Ovize M (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.
  5. Javadov S, Karmazyn M (2007). "Mitochondrial permeability transition pore opening as an endpoint to initiate cell death and as a putative target for cardioprotection". Cell. Physiol. Biochem. 20 (1–4): 1–22. doi:10.1159/000103747. PMID 17595511.
  6. Cung TT, Morel O, Cayla G, Rioufol G, Garcia-Dorado D, Angoulvant D, Bonnefoy-Cudraz E, Guérin P, Elbaz M, Delarche N, Coste P, Vanzetto G, Metge M, Aupetit JF, Jouve B, Motreff P, Tron C, Labeque JN, Steg PG, Cottin Y, Range G, Clerc J, Claeys MJ, Coussement P, Prunier F, Moulin F, Roth O, Belle L, Dubois P, Barragan P, Gilard M, Piot C, Colin P, De Poli F, Morice MC, Ider O, Dubois-Randé JL, Unterseeh T, Le Breton H, Béard T, Blanchard D, Grollier G, Malquarti V, Staat P, Sudre A, Elmer E, Hansson MJ, Bergerot C, Boussaha I, Jossan C, Derumeaux G, Mewton N, Ovize M (September 2015). "Cyclosporine before PCI in Patients with Acute Myocardial Infarction". N. Engl. J. Med. 373 (11): 1021–31. doi:10.1056/NEJMoa1505489. PMID 26321103.
  7. Sullivan PG, Sebastian AH, Hall ED (February 2011). "Therapeutic window analysis of the neuroprotective effects of cyclosporine A after traumatic brain injury". J. Neurotrauma. 28 (2): 311–8. doi:10.1089/neu.2010.1646. PMC 3037811. PMID 21142667.
  8. Le Lamer S, Paradis S, Rahmouni H, Chaimbault C, Michaud M, Culcasi M, Afxantidis J, Latreille M, Berna P, Berdeaux A, Pietri S, Morin D, Donazzolo Y, Abitbol JL, Pruss RM, Schaller S (February 2014). "Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial". J Transl Med. 12: 38. doi:10.1186/1479-5876-12-38. PMC 3923730. PMID 24507657.
  9. van der Spoel TI, Jansen of Lorkeers SJ, Agostoni P, van Belle E, Gyöngyösi M, Sluijter JP, Cramer MJ, Doevendans PA, Chamuleau SA (September 2011). "Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease". Cardiovasc. Res. 91 (4): 649–58. doi:10.1093/cvr/cvr113. PMID 21498423.
  10. Zhao JJ, Liu JL, Liu L, Jia HY (January 2014). "Protection of mesenchymal stem cells on acute kidney injury". Mol Med Rep. 9 (1): 91–6. doi:10.3892/mmr.2013.1792. PMID 24220681.
  11. Jiang Y, Arounleut P, Rheiner S, Bae Y, Kabanov AV, Milligan C, Manickam DS (June 2016). "SOD1 nanozyme with reduced toxicity and MPS accumulation". J Control Release. 231: 38–49. doi:10.1016/j.jconrel.2016.02.038. PMID 26928528.
  12. Jiang Y, Brynskikh AM, S-Manickam D, Kabanov AV (September 2015). "SOD1 nanozyme salvages ischemic brain by locally protecting cerebral vasculature". J Control Release. 213: 36–44. doi:10.1016/j.jconrel.2015.06.021. PMC 4684498. PMID 26093094.
  13. Paiva M, Riksen NP, Davidson SM, Hausenloy DJ, Monteiro P, Gonçalves L, Providência L, Rongen GA, Smits P, Mocanu MM, Yellon DM (May 2009). "Metformin prevents myocardial reperfusion injury by activating the adenosine receptor". J. Cardiovasc. Pharmacol. 53 (5): 373–8. doi:10.1097/FJC.0b013e31819fd4e7. PMID 19295441.
  14. Bhamra GS, Hausenloy DJ, Davidson SM, Carr RD, Paiva M, Wynne AM, Mocanu MM, Yellon DM (May 2008). "Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening". Basic Res. Cardiol. 103 (3): 274–84. doi:10.1007/s00395-007-0691-y. PMID 18080084.
  15. Bátkai S, Mukhopadhyay P, Horváth B, Rajesh M, Gao RY, Mahadevan A, Amere M, Battista N, Lichtman AH, Gauson LA, Maccarrone M, Pertwee RG, Pacher P (April 2012). "Δ8-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors". Br. J. Pharmacol. 165 (8): 2450–61. doi:10.1111/j.1476-5381.2011.01410.x. PMC 3423240. PMID 21470208.
  16. Mukhopadhyay P, Rajesh M, Horváth B, Bátkai S, Park O, Tanchian G, Gao RY, Patel V, Wink DA, Liaudet L, Haskó G, Mechoulam R, Pacher P (May 2011). "Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death". Free Radic. Biol. Med. 50 (10): 1368–81. doi:10.1016/j.freeradbiomed.2011.02.021. PMC 3081988. PMID 21362471.