The most common myth about the [[Ischemia-reperfusion injury|ischemia-reperfusion]] injury is itself related to [[blood]] flow. One can easily think like if everything is happening due to [[ischemia]] and with the restoration of [[blood flow]], the injury should [[Healing|heal]]. Here is the trick, [[reperfusion]] in turn further exacerbates the injury mainly due to the formation of [[free radicals]]. There are few approaches that are studied widely and do play a major role in controlling the [[injury]] related to [[ischemia-reperfusion injury]]
* Prevent generation of [[free radicals]]( Oxidative stress) or Increase the [[Tissue (biology)|tissue's]] capacity to trap the [[free radicals]]
* Controlling the [[neutrophil]] activation and [[Infiltration (medical)|infiltration]] of [[Ischemic|ischemic tissue]]
* [[Hypoxic]] [[pre-conditioning]]
[[Hyperbaric oxygen]] therapy is also studied widely and best suited when used within 6 hrs of [[hypoxia]] as it helps in the reduction of local and [[Hypoxemia|systemic hypoxia]] and in turn, increases the [[Survival rate|survival]] of affected [[tissue]].
== Medical Therapy ==
[[File: Reperfusion Injury Treatment .gif|thumb|429x429px|Reperfusion injury treatment, shown at various steps the intermediates and the possible drugs and compounds that can help to inhibit those steps and in turn decresing the incidence of reperfusion injury at various steps. [https://www.pinterest.com/pin/743727325934798842/]]]
Various proposed medical managements studied are:
*'''Therapeutic hypothermia'''
** It has been shown in rats that [[Neuron|neurons]] sometimes die completely 24 hours after the [[blood flow]] returns<ref name="pmid14767591">{{cite journal |vauthors=Polderman KH |title=Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: Indications and evidence |journal=Intensive Care Med |volume=30 |issue=4 |pages=556–75 |date=April 2004 |pmid=14767591 |doi=10.1007/s00134-003-2152-x |url=}}</ref>.
**This delayed reaction is the result of the multiple [[Inflammation|inflammatory]] [[immune responses]] that occur during [[reperfusion]].
**Such inflammatory reactions cause increase in[[Intracranial pressure|ntracranial pressure]], a pressure that leads to [[Cell disruption|cell damage]] and [[cell death]] in some cases.
**[[Hypothermia]] has been shown to help reduce [[intracranial pressure]] and thus decrease the adverse effects of inflammatory immune responses during [[reperfusion]].
**Besides that, reperfusion also increases [[Free-radical theory|free radical]] development. [[Hypothermia]] has also been shown to decrease the patient's development of deadly [[free radicals]] during [[reperfusion]].
'''Editors-In-Chief:''' {{AC}}; [[C. Michael Gibson]], M.S., M.D. [mailto:Mgibson@perfuse.org]
*'''Hydrogen sulfide treatment'''
** There are several preliminary studies in mice that seem to show that treatment with [[hydrogen sulfide]] ( H2S) could have a protective effect against [[reperfusion injury]].<ref>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</ref>
==Overview==
*'''Cyclosporine'''
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.
** In addition to its well-known [[Immunosuppression|immunosuppressive]] capabilities, the one-time administration of [[cyclosporine]]<ref name="pmid18669426">{{cite journal |vauthors=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 |title=Effect of cyclosporine on reperfusion injury in acute myocardial infarction |journal=N. Engl. J. Med. |volume=359 |issue=5 |pages=473–81 |date=July 2008 |pmid=18669426 |doi=10.1056/NEJMoa071142 |url=}}</ref> at the time of [[percutaneous coronary intervention]] (PCI) has been found to deliver a 40 percent reduction in [[infarct]] size in a small group proof of concept study of [[human]] patients with [[reperfusion injury]] published in The [[New England Journal of Medicine]] in 2008.
**[[Cyclosporine]] works by inhibiting the action of [[Cyclophilin|Cyclophilin D]] which usually helps in opening [[Mitochondrial membrane transport protein]]<ref name="pmid17595511">{{cite journal |vauthors=Javadov S, Karmazyn M |title=Mitochondrial permeability transition pore opening as an endpoint to initiate cell death and as a putative target for cardioprotection |journal=Cell. Physiol. Biochem. |volume=20 |issue=1-4 |pages=1–22 |date=2007 |pmid=17595511 |doi=10.1159/000103747 |url=}}</ref><ref name="pmid18669431">{{cite journal |vauthors=Hausenloy DJ, Yellon DM |title=Time to take myocardial reperfusion injury seriously |journal=N. Engl. J. Med. |volume=359 |issue=5 |pages=518–20 |date=July 2008 |pmid=18669431 |doi=10.1056/NEJMe0803746 |url=}}</ref> ( MPT Pore). So once [[Cyclophilin|cyclophilin D]] action is inhibited, there is no more MPT pore opening and in turn, saves the [[mitochondria]] from getting damaged.
**The opening of [[Mitochondrial membrane transport protein|MTP Pore]] results in major [[cell]] destruction by causing the influx of water into [[mitochondria]], impairing its function and ultimately leading to the [[collapse]]. The strategy to protect [[mitochondria]] is the most important thing associated with the [[Treatment|treatment part]].
*'''TRO40303'''
**TRO40303 is a new [[cardio]] protective compound that was shown to inhibit the [[Mitochondrial membrane transport protein|MP]][[Mitochondrial membrane transport protein|T pore]] and reduce [[infarct]] size after [[ischemia]]-[[reperfusion]]<ref name="pmid24507657">{{cite journal |vauthors=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 |title=Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial |journal=J Transl Med |volume=12 |issue= |pages=38 |date=February 2014 |pmid=24507657 |pmc=3923730 |doi=10.1186/1479-5876-12-38 |url=}}</ref>.
Hypothetical assessment of [[reperfusion injury]] and role of cardioprotection and treatment:
*[[File: Ischemic Conditioning.png|thumb|357x357px|Ischemic Conditioning Flow chart- Ischemic Conditioning Mechanism- Role of ischemic conditioning in preventing and minimizing the damage associated with Reperfusion injury. [https://openi.nlm.nih.gov/detailedresult?img=PMC4386982_bph0172-2074-f1&query=preconditioning%20in%20ischemia%20reperfusion%20injury&it=xg&req=4&npos=82]]]'''Stem cell therapy'''
** Recent investigations suggest a possible beneficial effect of [[Mesenchymal stem cell|mesenchymal stem cells]]<ref name="pmid21498423">{{cite journal |vauthors=van der Spoel TI, Jansen of Lorkeers SJ, Agostoni P, van Belle E, Gyöngyösi M, Sluijter JP, Cramer MJ, Doevendans PA, Chamuleau SA |title=Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease |journal=Cardiovasc. Res. |volume=91 |issue=4 |pages=649–58 |date=September 2011 |pmid=21498423 |doi=10.1093/cvr/cvr113 |url=}}</ref> on [[heart]] and [[kidney]] [[reperfusion injury]]<ref name="pmid24220681">{{cite journal |vauthors=Zhao JJ, Liu JL, Liu L, Jia HY |title=Protection of mesenchymal stem cells on acute kidney injury |journal=Mol Med Rep |volume=9 |issue=1 |pages=91–6 |date=January 2014 |pmid=24220681 |doi=10.3892/mmr.2013.1792 |url=}}</ref>
**[[Superoxide dismutase]] is an important [[antioxidant]] enzyme that transforms [[superoxide]] [[anions]] into water and [[hydrogen peroxide]]. Recent work has demonstrated important therapeutic effects on pre-clinical models of [[reperfusion]] damage following an [[ischemic stroke]]<ref name="pmid26928528">{{cite journal |vauthors=Jiang Y, Arounleut P, Rheiner S, Bae Y, Kabanov AV, Milligan C, Manickam DS |title=SOD1 nanozyme with reduced toxicity and MPS accumulation |journal=J Control Release |volume=231 |issue= |pages=38–49 |date=June 2016 |pmid=26928528 |doi=10.1016/j.jconrel.2016.02.038 |url=}}</ref><ref name="pmid26093094">{{cite journal |vauthors=Jiang Y, Brynskikh AM, S-Manickam D, Kabanov AV |title=SOD1 nanozyme salvages ischemic brain by locally protecting cerebral vasculature |journal=J Control Release |volume=213 |issue= |pages=36–44 |date=September 2015 |pmid=26093094 |pmc=4684498 |doi=10.1016/j.jconrel.2015.06.021 |url=}}</ref>
! Scenario
! Clinical course
! Infarct size (%)
|-
| Presentation
| Myocardial [[ischemia]]
| 80
|-
| Best scenario (hypothetical)
| [[Ischemia]] + [[Reperfusion]] (no reperfusion injury)
Pharmacotherapies that have either failed or that have met with limited success in improving clinical outcomes include: <ref name="pmid17306241">{{cite journal |author=Dirksen MT, Laarman GJ, Simoons ML, Duncker DJ |title=Reperfusion injury in humans: a review of clinical trials on reperfusion injury inhibitory strategies |journal=Cardiovasc. Res. |volume=74 |issue=3 |pages=343–55 |year=2007 |month=June |pmid=17306241 |doi=10.1016/j.cardiores.2007.01.014 |url=http://cardiovascres.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=17306241}}</ref>
**Some studies proved the role of [[metformin]] in preventing [[Ischemia-reperfusion injury|Ischemia-Reperfusion injury]] by inhibiting the opening of [[MPT Pore]] and [[Mitochondrial]] complex inhibition. Although the studies are done in [[rats]] only still the correlation can be derived [[clinically]] for humans as well.<ref name="pmid19295441">{{cite journal |vauthors=Paiva M, Riksen NP, Davidson SM, Hausenloy DJ, Monteiro P, Gonçalves L, Providência L, Rongen GA, Smits P, Mocanu MM, Yellon DM |title=Metformin prevents myocardial reperfusion injury by activating the adenosine receptor |journal=J. Cardiovasc. Pharmacol. |volume=53 |issue=5 |pages=373–8 |date=May 2009 |pmid=19295441 |doi=10.1097/FJC.0b013e31819fd4e7 |url=}}</ref><ref name="pmid18080084">{{cite journal |vauthors=Bhamra GS, Hausenloy DJ, Davidson SM, Carr RD, Paiva M, Wynne AM, Mocanu MM, Yellon DM |title=Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening |journal=Basic Res. Cardiol. |volume=103 |issue=3 |pages=274–84 |date=May 2008 |pmid=18080084 |doi=10.1007/s00395-007-0691-y |url=}}</ref>
#[[Beta-blockade]]
*'''Cannabinoids'''
#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 <ref name="pmid16631017">{{cite journal |author=Timmer JR, Svilaas T, Ottervanger JP, ''et al'' |title=Glucose-insulin-potassium infusion in patients with acute myocardial infarction without signs of heart failure: the Glucose-Insulin-Potassium Study (GIPS)-II |journal=J. Am. Coll. Cardiol. |volume=47 |issue=8 |pages=1730–1 |year=2006 |month=April |pmid=16631017 |doi=10.1016/j.jacc.2006.01.040 |url=http://linkinghub.elsevier.com/retrieve/pii/S0735-1097(06)00178-1}}</ref> and other older studies<ref name="pmid4177929">{{cite journal |author= |title=Potassium, glucose, and insulin treatment for acute myocardial infarction |journal=Lancet |volume=2 |issue=7583 |pages=1355–60 |year=1968 |month=December |pmid=4177929 |doi= |url=}}</ref><ref name="pmid4171584">{{cite journal |author=Pentecost BL, Mayne NM, Lamb P |title=Controlled trial of intravenous glucose, potassium, and insulin in acute myocardial infarction |journal=Lancet |volume=1 |issue=7549 |pages=946–8 |year=1968 |month=May |pmid=4171584 |doi= |url=}}</ref><ref name="pmid10439880">{{cite journal |author=Apstein CS, Opie LH |title=Glucose-insulin-potassium (GIK) for acute myocardial infarction: a negative study with a positive value |journal=Cardiovasc Drugs Ther |volume=13 |issue=3 |pages=185–9 |year=1999 |month=May |pmid=10439880 |doi= |url=http://www.kluweronline.com/art.pdf?issn=0920-3206&volume=13&page=185}}</ref><ref name="pmid9286943">{{cite journal |author=Fath-Ordoubadi F, Beatt KJ |title=Glucose-insulin-potassium therapy for treatment of acute myocardial infarction: an overview of randomized placebo-controlled trials |journal=Circulation |volume=96 |issue=4 |pages=1152–6 |year=1997 |month=August |pmid=9286943 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=9286943}}</ref><ref name="pmid785990">{{cite journal |author=Rogers WJ, Stanley AW, Breinig JB, ''et al'' |title=Reduction of hospital mortality rate of acute myocardial infarction with glucose-insulin-potassium infusion |journal=Am. Heart J. |volume=92 |issue=4 |pages=441–54 |year=1976 |month=October |pmid=785990 |doi= |url=}}</ref><ref name="pmid7044275">{{cite journal |author=Rackley CE, Russell RO, Rogers WJ, Mantle JA, McDaniel HG, Papapietro SE |title=Glucose-insulin-potassium administration in acute myocardial infarction |journal=Annu. Rev. Med. |volume=33 |issue= |pages=375–83 |year=1982 |pmid=7044275 |doi=10.1146/annurev.me.33.020182.002111 |url=}}</ref><ref name="pmid7044275">{{cite journal |author=Rackley CE, Russell RO, Rogers WJ, Mantle JA, McDaniel HG, Papapietro SE |title=Glucose-insulin-potassium administration in acute myocardial infarction |journal=Annu. Rev. Med. |volume=33 |issue= |pages=375–83 |year=1982 |pmid=7044275 |doi=10.1146/annurev.me.33.020182.002111 |url=}}</ref><ref name="pmid3300232">{{cite journal |author=Satler LF, Green CE, Kent KM, Pallas RS, Pearle DL, Rackley CE |title=Metabolic support during coronary reperfusion |journal=Am. Heart J. |volume=114 |issue=1 Pt 1 |pages=54–8 |year=1987 |month=July |pmid=3300232 |doi= |url=}}</ref><ref name="pmid7797776">{{cite journal |author=Malmberg K, Rydén L, Efendic S, ''et al'' |title=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 |journal=J. Am. Coll. Cardiol. |volume=26 |issue=1 |pages=57–65 |year=1995 |month=July |pmid=7797776 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/073510979500126K}}</ref><ref name="pmid9867443">{{cite journal |author=Díaz R, Paolasso EA, Piegas LS, ''et al'' |title=Metabolic modulation of acute myocardial infarction. The ECLA (Estudios Cardiológicos Latinoamérica) Collaborative Group |journal=Circulation |volume=98 |issue=21 |pages=2227–34 |year=1998 |month=November |pmid=9867443 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=9867443}}</ref><ref name="pmid10439881">{{cite journal |author=Ceremuzyński L, Budaj A, Czepiel A, ''et al'' |title=Low-dose glucose-insulin-potassium is ineffective in acute myocardial infarction: results of a randomized multicenter Pol-GIK trial |journal=Cardiovasc Drugs Ther |volume=13 |issue=3 |pages=191–200 |year=1999 |month=May |pmid=10439881 |doi= |url=http://www.kluweronline.com/art.pdf?issn=0920-3206&volume=13&page=191}}</ref><ref name="pmid12957421">{{cite journal |author=van der Horst IC, Zijlstra F, van 't Hof AW, ''et al'' |title=Glucose-insulin-potassium infusion inpatients treated with primary angioplasty for acute myocardial infarction: the glucose-insulin-potassium study: a randomized trial |journal=J. Am. Coll. Cardiol. |volume=42 |issue=5 |pages=784–91 |year=2003 |month=September |pmid=12957421 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0735109703008301}}</ref><ref name="pmid12706939">{{cite journal |author=Sack MN, Yellon DM |title=Insulin therapy as an adjunct to reperfusion after acute coronary ischemia: a proposed direct myocardial cell survival effect independent of metabolic modulation |journal=J. Am. Coll. Cardiol. |volume=41 |issue=8 |pages=1404–7 |year=2003 |month=April |pmid=12706939 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0735109703001645}}</ref><ref name="pmid1199950">{{cite journal |author=Stanley AW, Moraski RE, Russell RO, ''et al'' |title=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 |journal=Am. J. Cardiol. |volume=36 |issue=7 |pages=929–37 |year=1975 |month=December |pmid=1199950 |doi= |url=}}</ref><ref name="pmid4941225">{{cite journal |author=Hjermann I |title=A controlled study of peroral glucose, insulin and potassium treatment in myocardial infarction |journal=Acta Med Scand |volume=190 |issue=3 |pages=213–8 |year=1971 |month=September |pmid=4941225 |doi= |url=}}</ref>
** A [[synthetic]] analog of [[cannabis]]<ref name="pmid21470208">{{cite journal |vauthors=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 |title=Δ8-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors |journal=Br. J. Pharmacol. |volume=165 |issue=8 |pages=2450–61 |date=April 2012 |pmid=21470208 |pmc=3423240 |doi=10.1111/j.1476-5381.2011.01410.x |url=}}</ref> helps to prevent [[hepatic ischemia]] and [[injury]] by reducing the [[inflammation]] and [[oxidative stress]] occurring through [[CB2]] receptors<ref name="pmid21362471">{{cite journal |vauthors=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 |title=Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death |journal=Free Radic. Biol. Med. |volume=50 |issue=10 |pages=1368–81 |date=May 2011 |pmid=21362471 |pmc=3081988 |doi=10.1016/j.freeradbiomed.2011.02.021 |url=}}</ref>. This in turn lowers the [[tissue]] [[damage]] and provides protective effects. The various [[synthetic]] analogs of [[phytocannabinoid]] that play major role are:
#Sodium-hydrogen exchange inhibitors such as cariporide (Studied in the GUARDIAN <ref name="pmid11120691">{{cite journal |author=Théroux P, Chaitman BR, Danchin N, ''et al'' |title=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 |journal=Circulation |volume=102 |issue=25 |pages=3032–8 |year=2000 |month=December |pmid=11120691 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=11120691}}</ref> <ref name="pmid11714411">{{cite journal |author=Theroux P, Chaitman BR, Erhardt L, ''et al'' |title=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 |journal=Curr Control Trials Cardiovasc Med |volume=1 |issue=1 |pages=59–67 |year=2000 |pmid=11714411 |pmc=56207 |doi= |url=http://cvm.controlled-trials.com/content/1/1/59}}</ref> and EXPIDITION <ref name="pmid12691376">{{cite journal |author=Bolli R |title=The role of sodium-hydrogen ion exchange in patients undergoing coronary artery bypass grafting |journal=J Card Surg |volume=18 Suppl 1 |issue= |pages=21–6 |year=2003 |pmid=12691376 |doi= |url=http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0886-0440&date=2003&volume=18&issue=&spage=21}}</ref> <ref name="pmid18355507">{{cite journal |author=Mentzer RM, Bartels C, Bolli R, ''et al'' |title=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 |journal=Ann. Thorac. Surg. |volume=85 |issue=4 |pages=1261–70 |year=2008 |month=April |pmid=18355507 |doi=10.1016/j.athoracsur.2007.10.054 |url=http://linkinghub.elsevier.com/retrieve/pii/S0003-4975(07)02183-2}}</ref> trials)
** THCV- [[Tetrahydrocannabivarin]]
#[[Adenosine]] (Studied in the AMISTAD I <ref name="pmid10577561">{{cite journal |author=Mahaffey KW, Puma JA, Barbagelata NA, ''et al'' |title=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 |journal=J. Am. Coll. Cardiol. |volume=34 |issue=6 |pages=1711–20 |year=1999 |month=November |pmid=10577561 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0735109799004180}}</ref> and AMISTAD II <ref name="pmid15936605">{{cite journal |author=Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW |title=A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II) |journal=J. Am. Coll. Cardiol. |volume=45 |issue=11 |pages=1775–80 |year=2005 |month=June |pmid=15936605 |doi=10.1016/j.jacc.2005.02.061 |url=http://linkinghub.elsevier.com/retrieve/pii/S0735-1097(05)00536-X}}</ref> trials as well as the ATTACC trial <ref name="pmid12743668">{{cite journal |author=Quintana M, Hjemdahl P, Sollevi A, ''et al'' |title=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 |journal=Eur. J. Clin. Pharmacol. |volume=59 |issue=1 |pages=1–9 |year=2003 |month=May |pmid=12743668 |doi=10.1007/s00228-003-0564-8 |url=http://dx.doi.org/10.1007/s00228-003-0564-8}}</ref>). 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. <ref name="pmid10801755">{{cite journal |author=Marzilli M, Orsini E, Marraccini P, Testa R |title=Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction |journal=Circulation |volume=101 |issue=18 |pages=2154–9 |year=2000 |month=May |pmid=10801755 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=10801755}}</ref>
** 8-[[Tetrahydrocannabivarin]]
#[[Calcium-channel blockers]]
** [[11-OH-8-THCV]]
#Potassium–adenosine triphosphate channel openers<ref name="pmid9192246">{{cite journal |author=Sakata Y, Kodama K, Ishikura F, ''et al.'' |title=Disappearance of the 'no-reflow' phenomenon after adjunctive intracoronary administration of nicorandil in a patient with acute myocardial infarction |journal=Jpn. Circ. J. |volume=61 |issue=5 |pages=455–8 |year=1997 |month=May |pmid=9192246 |doi= |url=}}</ref><ref name="pmid10080465">{{cite journal |author=Ito H, Taniyama Y, Iwakura K, ''et al.'' |title=Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction |journal=J. Am. Coll. Cardiol. |volume=33 |issue=3 |pages=654–60 |year=1999 |month=March |pmid=10080465 |doi= |url=}}</ref>
#Antibodies directed against leukocyte adhesion molecules such as CD 18 (Studied in the LIMIT AMI trial <ref name="pmid11733394">{{cite journal |author=Baran KW, Nguyen M, McKendall GR, ''et al'' |title=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 |journal=Circulation |volume=104 |issue=23 |pages=2778–83 |year=2001 |month=December |pmid=11733394 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=11733394}}</ref>)
#Oxygen free radical scavengers/anti-oxidants, including [[Erythropoietin]]<ref name="pmid15862410">{{cite journal |author=Namiuchi S, Kagaya Y, Ohta J, ''et al.'' |title=High serum erythropoietin level is associated with smaller infarct size in patients with acute myocardial infarction who undergo successful primary percutaneous coronary intervention |journal=J. Am. Coll. Cardiol. |volume=45 |issue=9 |pages=1406–12 |year=2005 |month=May |pmid=15862410 |doi=10.1016/j.jacc.2005.01.043 |url=}}</ref><ref name="pmid15946993">{{cite journal |author=Hanlon PR, Fu P, Wright GL, Steenbergen C, Arcasoy MO, Murphy E |title=Mechanisms of erythropoietin-mediated cardioprotection during ischemia-reperfusion injury: role of protein kinase C and phosphatidylinositol 3-kinase signaling |journal=FASEB J. |volume=19 |issue=10 |pages=1323–5 |year=2005 |month=August |pmid=15946993 |doi=10.1096/fj.04-3545fje |url=}}</ref><ref name="pmid15944807">{{cite journal |author=Bullard AJ, Govewalla P, Yellon DM |title=Erythropoietin protects the myocardium against reperfusion injury in vitro and in vivo |journal=Basic Res. Cardiol. |volume=100 |issue=5 |pages=397–403 |year=2005 |month=September |pmid=15944807 |doi=10.1007/s00395-005-0537-4 |url=}}</ref><ref name="pmid15943180">{{cite journal |author=Xu B, Dong GH, Liu H, Wang YQ, Wu HW, Jing H |title=Recombinant human erythropoietin pretreatment attenuates myocardial infarct size: a possible mechanism involves heat shock Protein 70 and attenuation of nuclear factor-kappaB |journal=Ann. Clin. Lab. Sci. |volume=35 |issue=2 |pages=161–8 |year=2005 |pmid=15943180 |doi= |url=}}</ref><ref name="pmid15883754">{{cite journal |author=Hirata A, Minamino T, Asanuma H, ''et al.'' |title=Erythropoietin just before reperfusion reduces both lethal arrhythmias and infarct size via the phosphatidylinositol-3 kinase-dependent pathway in canine hearts |journal=Cardiovasc Drugs Ther |volume=19 |issue=1 |pages=33–40 |year=2005 |month=January |pmid=15883754 |doi=10.1007/s10557-005-6895-1 |url=}}</ref>, [[estrogen]]<ref name="pmid16607102">{{cite journal |author=Jeanes HL, Wanikiat P, Sharif I, Gray GA |title=Medroxyprogesterone acetate inhibits the cardioprotective effect of estrogen in experimental ischemia-reperfusion injury |journal=Menopause |volume=13 |issue=1 |pages=80–6 |year=2006 |pmid=16607102 |doi=10.1097/01.gme.0000196593.44335.eb |url=}}</ref><ref name="pmid12706470">{{cite journal |author=Sbarouni E, Iliodromitis EK, Bofilis E, Kyriakides ZS, Kremastinos DT |title=Estrogen alone or combined with medroxyprogesterone but not raloxifene reduce myocardial infarct size |journal=Eur. J. Pharmacol. |volume=467 |issue=1-3 |pages=163–8 |year=2003 |month=April |pmid=12706470 |doi= |url=}}</ref>, heme-oxygenase 1<ref name="pmid16449792">{{cite journal |author=Liu X, Pachori AS, Ward CA, ''et al.'' |title=Heme oxygenase-1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function |journal=FASEB J. |volume=20 |issue=2 |pages=207–16 |year=2006 |month=February |pmid=16449792 |doi=10.1096/fj.05-4435com |url=}}</ref>, and hypoxia induced factor-1 (HIF-1)<ref name="pmid10679484">{{cite journal |author=Jung F, Palmer LA, Zhou N, Johns RA |title=Hypoxic regulation of inducible nitric oxide synthase via hypoxia inducible factor-1 in cardiac myocytes |journal=Circ. Res. |volume=86 |issue=3 |pages=319–25 |year=2000 |month=February |pmid=10679484 |doi= |url=}}</ref>.
#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 <ref name="pmid17200474">{{cite journal |author=Armstrong PW, Granger CB, Adams PX, ''et al'' |title=Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial |journal=JAMA |volume=297 |issue=1 |pages=43–51 |year=2007 |month=January |pmid=17200474 |doi=10.1001/jama.297.1.43 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=17200474}}</ref> )
# 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)<ref name="pmid18250271">{{cite journal |author=Bates E, Bode C, Costa M, ''et al'' |title=Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction |journal=Circulation |volume=117 |issue=7 |pages=886–96 |year=2008 |month=February |pmid=18250271 |doi=10.1161/CIRCULATIONAHA.107.759167 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=18250271}}</ref>.
#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.)<ref name="pmid17964349">{{cite journal |author=Kitakaze M, Asakura M, Kim J, ''et al'' |title=Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials |journal=Lancet |volume=370 |issue=9597 |pages=1483–93 |year=2007 |month=October |pmid=17964349 |doi=10.1016/S0140-6736(07)61634-1 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(07)61634-1}}</ref>
#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)<ref name="pmid19232907">{{cite journal |author=Atar D, Petzelbauer P, Schwitter J, ''et al'' |title=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 |journal=J. Am. Coll. Cardiol. |volume=53 |issue=8 |pages=720–9 |year=2009 |month=February |pmid=19232907 |doi=10.1016/j.jacc.2008.12.017 |url=http://linkinghub.elsevier.com/retrieve/pii/S0735-1097(09)00023-0}}</ref>
#[[Magnesium]], which was evaluted by the Fourth International Study of Infarct Survival (ISIS-4)<ref name="pmid7661937">{{cite journal |author= |title=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 |journal=Lancet |volume=345 |issue=8951 |pages=669–85 |year=1995 |month=March |pmid=7661937 |doi= |url=}}</ref> and the MAGIC trial<ref name="pmid12401244">{{cite journal |author= |title=Early administration of intravenous magnesium to high-risk patients with acute myocardial infarction in the Magnesium in Coronaries (MAGIC) Trial: a randomised controlled trial |journal=Lancet |volume=360 |issue=9341 |pages=1189–96 |year=2002 |month=October |pmid=12401244 |doi= |url=}}</ref>.
#Hypothermia<ref name="pmid12475451">{{cite journal| author=Dixon SR, Whitbourn RJ, Dae MW, Grube E, Sherman W, Schaer GL et al.| title=Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction. | journal=J Am Coll Cardiol | year= 2002 | volume= 40 | issue= 11 | pages= 1928-34 | pmid=12475451 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12475451 }} </ref>
#Hyperoxemia, the delivery of supersaturated oxygen after PCI (Studied in the AMIHOT II trial<ref name="pmid20031745">{{cite journal| author=Stone GW, Martin JL, de Boer MJ, Margheri M, Bramucci E, Blankenship JC et al.| title=Effect of supersaturated oxygen delivery on infarct size after percutaneous coronary intervention in acute myocardial infarction. | journal=Circ Cardiovasc Interv | year= 2009 | volume= 2 | issue= 5 | pages= 366-75 | pmid=20031745 | doi=10.1161/CIRCINTERVENTIONS.108.840066 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20031745 }} </ref>).
==Therapies Associated with Improved Clinical Outcomes==
==Therapies Associated with Improved Clinical Outcomes==
[[File: Reperfusion injury management - Via pre-conditioning & Post-conditioning.jpg|thumb|400x400px|Pre-conditioning and Post-conditioning benefits in preventing severe damage to tissue during the ischemia-reperfusion injury. [https://www.bing.com/images/search?view=detailV2&ccid=eQhDbs0j&id=E5D50872E33073701294D73698E657322D493F6C&thid=OIP.eQhDbs0jRxuHDz57WodwIAHaFj&mediaurl=http%3A%2F%2Fpharmrev.aspetjournals.org%2Fcontent%2Fpharmrev%2F59%2F4%2F418%2FF1.large.jpg%3Fwidth%3D800&height=600&carousel=1&exph=1349&expw=1800&q=ischmeia+reperfusion+injury+pre+conditioning&simid=608021275909228002&ck=1C020A344040E2AA2DCE159454A45C5D&selectedindex=1&form=EX0023&adlt=demote&shtp=GetUrl&shid=6e60ffe4-72bc-4043-b4fd-3ca4bd90be10&shtk=SW50ZXJhY3Rpb24gb2YgQ2FyZGlvdmFzY3VsYXIgUmlzayBGYWN0b3JzIHdpdGggTXlvY2FyZGlhbCAuLi4%3D&shdk=Rm91bmQgb24gQmluZyBmcm9tIHBoYXJtcmV2LmFzcGV0am91cm5hbHMub3Jn&shhk=DXEQg8avhNPCm%2F1MxBprUKaui1s1sFcmif0yLoXbVMs%3D&shth=OSH.WALe8DIkA3SxhBs2CEuIQA&vt=0&sim=11]]]
Therapies that have been associated with improved clinical outcomes include:
Therapies that have been associated with improved clinical outcomes include:
#Post conditioning (short repeated periods of vessel opening by repeatedly blowing the balloon up for short periods of time).<ref name="pmid18268150">{{cite journal |author=Thibault H, Piot C, Staat P, ''et al'' |title=Long-term benefit of postconditioning |journal=Circulation |volume=117 |issue=8 |pages=1037–44 |year=2008 |month=February |pmid=18268150 |doi=10.1161/CIRCULATIONAHA.107.729780 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=18268150}}</ref><ref name="pmid20448097">{{cite journal| author=Ovize M, Baxter GF, Di Lisa F, Ferdinandy P, Garcia-Dorado D, Hausenloy DJ et al.| title=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. | journal=Cardiovasc Res | year= 2010 | volume= 87 | issue= 3 | pages= 406-23 | pmid=20448097 | doi=10.1093/cvr/cvq129 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20448097 }} </ref>
# "Preconditioning" - [[Preconditioning]] is basically an adaptive response in which [[ischemia]] is exposed for a brief period of time before the actual [[ischemia]] phase to the [[tissue]]. This phenomenon markedly increases the ability of the [[heart]] to withstand subsequent [[ischemic]] insults<ref name="pmid26629140">{{cite journal |vauthors=Dong S, Cao Y, Li H, Tian J, Yi C, Sang W |title=Impact of ischemic preconditioning on ischemia-reperfusion injury of the rat sciatic nerve |journal=Int J Clin Exp Med |volume=8 |issue=9 |pages=16245–51 |date=2015 |pmid=26629140 |pmc=4659028 |doi= |url=}}</ref>. In addition to that, the application of brief episodes of [[ischemia]] at the onset of [[reperfusion]] is termed as "postconditioning" which reduces the extent of [[injury]] that is supposed to happen.
#*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)
#"Postconditioning" (short repeated periods of [[Blood vessel|vessel]] opening by repeatedly blowing the balloon up for short periods of time)<ref name="pmid26140711">{{cite journal |vauthors=Heusch G |title=Treatment of Myocardial Ischemia/Reperfusion Injury by Ischemic and Pharmacological Postconditioning |journal=Compr Physiol |volume=5 |issue=3 |pages=1123–45 |date=July 2015 |pmid=26140711 |doi=10.1002/cphy.c140075 |url=}}</ref>.
#*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<ref name="pmid16186417">{{cite journal| author=Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I et al.| title=Postconditioning the human heart. | journal=Circulation | year= 2005 | volume= 112 | issue= 14 | pages= 2143-8 | pmid=16186417 | doi=10.1161/CIRCULATIONAHA.105.558122 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16186417 }} </ref>
#*Mechanisms of protection include formation and release of several [[autacoids]] and [[cytokines]], maintained [[acidosis]] during early repercussion, activation of [[Kinases|protein kinases]], and attenuation of the opening of the [[mitochondrial permeability transition pore]] (MPTP)
#*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<ref name="pmid18268150">{{cite journal| author=Thibault H, Piot C, Staat P, Bontemps L, Sportouch C, Rioufol G et al.| title=Long-term benefit of postconditioning. | journal=Circulation | year= 2008 | volume= 117 | issue= 8 | pages= 1037-44 | pmid=18268150 | doi=10.1161/CIRCULATIONAHA.107.729780 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18268150 }} </ref>
#*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 [[Surrogacy|surrogate]] for infarct size) was significantly reduced by 36% in the post conditioned versus a control group
#Inhibition of mitochondrial pore opening by cyclosporine. <ref name="pmid18669426">{{cite journal |author=Piot C, Croisille P, Staat P, ''et al'' |title=Effect of cyclosporine on reperfusion injury in acute myocardial infarction |journal=N. Engl. J. Med. |volume=359 |issue=5 |pages=473–81 |year=2008 |month=July |pmid=18669426 |doi=10.1056/NEJMoa071142 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=18669426&promo=ONFLNS19}}</ref>
#*[[Infarct]] size reduction by PCI postconditioning persisted 6 months after [[Acute myocardial infarction|AMI]] and resulted in a significant improvement in [[left ventricular]] (LV) function at 1 year
#*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
#Inhibition of mitochondrial pore opening by [[cyclosporine]].
#*Infarct size was measured by the release of creatine kinase and delayed hyperenhancement on MRI
#*Specifically, the study by Piot et al demonstrated that administration of [[cyclosporine]]<ref name="pmid17070837">{{cite journal |vauthors=Sharov VG, Todor A, Khanal S, Imai M, Sabbah HN |title=Cyclosporine A attenuates mitochondrial permeability transition and improves mitochondrial respiratory function in cardiomyocytes isolated from dogs with heart failure |journal=J. Mol. Cell. Cardiol. |volume=42 |issue=1 |pages=150–8 |date=January 2007 |pmid=17070837 |pmc=2700715 |doi=10.1016/j.yjmcc.2006.09.013 |url=}}</ref> at the time of reperfusion was associated with a reduction in infarct size
#*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.
#*[[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|TIMI flow 0]]) was part of the inclusion criteria.
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:
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.
# [[Beta-blockade]]<ref name="pmid12605018">{{cite journal |vauthors=Frances C, Nazeyrollas P, Prevost A, Moreau F, Pisani J, Davani S, Kantelip JP, Millart H |title=Role of beta 1- and beta 2-adrenoceptor subtypes in preconditioning against myocardial dysfunction after ischemia and reperfusion |journal=J. Cardiovasc. Pharmacol. |volume=41 |issue=3 |pages=396–405 |date=March 2003 |pmid=12605018 |doi=10.1097/00005344-200303000-00008 |url=}}</ref>
# GIK ([[glucose-insulin-potassium infusion]]) (Studied in the [[Glucose]]-[[Insulin]]-[[Potassium]] Infusion in Patients With [[Acute myocardial infarction|Acute Myocardial Infarction]] Without Signs of [[Heart Failure]]: The Glucose-Insulin-Potassium Study (GIPS)-II and other older studies
# [[Sodium]]-[[hydrogen]] exchange inhibitors such as [[cariporide]]<ref>Selective retroinfusion of GSH and cariporide attenuates myocardial ischemia–reperfusion injury in a preclinical pig modelhttps://doi.org/10.1016/j.cardiores.2003.11.012 </ref>(Studied in the GUARDIAN and EXPEDITION trials)
# [[Adenosine]] (Studied in the AMISTAD I and AMISTAD II trials as well as ATTACC trial ). It should be noted that at high doses in anterior [[ST elevation myocardial infarction]]|[[ST elevation MI]] adenosine was effective in the AMISTAD trial. Likewise, [[Intracoronary route|intracoronary]] administration of [[adenosine]] prior to [[primary PCI]] has been associated with improved [[echocardiographic]] and clinical outcomes in one small study.
#[[Calcium-channel blockers]]<ref name="pmid1992940">{{cite journal |vauthors=Nauta RJ, Tsimoyiannis E, Uribe M, Walsh DB, Miller D, Butterfield A |title=The role of calcium ions and calcium channel entry blockers in experimental ischemia-reperfusion-induced liver injury |journal=Ann. Surg. |volume=213 |issue=2 |pages=137–42 |date=February 1991 |pmid=1992940 |pmc=1358386 |doi=10.1097/00000658-199102000-00008 |url=}}</ref>
#[[Potassium–adenosine triphosphate channel]]<ref name="pmid25386080">{{cite journal |vauthors=Nogueira MA, Coelho AM, Sampietre SN, Patzina RA, Pinheiro da Silva F, D'Albuquerque LA, Machado MC |title=Beneficial effects of adenosine triphosphate-sensitive K+ channel opener on liver ischemia/reperfusion injury |journal=World J. Gastroenterol. |volume=20 |issue=41 |pages=15319–26 |date=November 2014 |pmid=25386080 |pmc=4223265 |doi=10.3748/wjg.v20.i41.15319 |url=}}</ref> openers
#[[Antibodies]] directed against [[leukocyte]] adhesion molecules such as [[CD 18]] (Studied in the LIMIT [[AMI]] trial )
# Oxygen free radical scavengers/[[anti-oxidants]], including [[Erythropoietin]], [[estrogen]], heme-oxygenase 1, and [[hypoxia]] [[Hypoxia Induced factor-1|induced factor-1]] (HIF-1).
#[[Pexelizumab]], a humanized [[monoclonal antibody]] that binds the C5 component of complement (Studied in the [[Pexelizumab]] for [[ST elevation myocardial infarction]]|[[Acute ST-Elevation Myocardial Infarction]] in Patients Undergoing Primary [[Percutaneous Coronary Intervention]] (APEX AMI) trial )
# KAI-9803, a [[delta-protein kinase C inhibitor]](Studied in the Intracoronary KAI-9803 as an adjunct to [[primary percutaneous coronary intervention]] for [[ST elevation myocardial infarction|acute ST-segment elevation myocardial infarction]] trial or DELTA AMI trial).
#[[Atrial natriuretic peptide|Human atrial natriuretic peptide]]<ref name="pmid8636398">{{cite journal |vauthors=Matsumura T, Kugiyama K, Sugiyama S, Ohgushi M, Amanaka K, Suzuki M, Yasue H |title=Neutral endopeptidase 24.11 in neutrophils modulates protective effects of natriuretic peptides against neutrophils-induced endothelial cytotoxity |journal=J. Clin. Invest. |volume=97 |issue=10 |pages=2192–203 |date=May 1996 |pmid=8636398 |pmc=507298 |doi=10.1172/JCI118660 |url=}}</ref> (Studied in the [[Atrial natriuretic peptide|Human atrial natriuretic peptide]] and [[nicorandil]] as adjuncts to reperfusion treatment for [[acute myocardial infarction]] (J-WIND): two randomized trials.)
# FX06, an [[anti-inflammatory]] fibrin derivative that competes with f[[Fibrin|ibrin fragment]]<nowiki/>s 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)
# [[Magnesium]]<ref name="pmid18806932">{{cite journal |vauthors=Gormus ZI, Ergene N, Toy H, Baltaci AK, Mogulkoc R |title=Preventive role of magnesium on skeletal muscle ischemia-reperfusion injury-an experimental study |journal=Biol Trace Elem Res |volume=127 |issue=2 |pages=183–9 |date=February 2009 |pmid=18806932 |doi=10.1007/s12011-008-8228-2 |url=}}</ref>, which was evaluated by the Fourth International Study of Infarct Survival (ISIS-4) and the MAGIC trial.
# Hyperoxemia, the delivery of supersaturated [[oxygen]] after [[Percutaneous coronary intervention|PCI]] (Studied in the AMIHOT II trial).
# Bendavia studied in the EMBRACE STEMI trial
There are several explanations for why trials of experimental agents have failed in this area:
There are several explanations for why trials of experimental agents have failed in this area:
#The therapy was administered after reperfusion and after reperfusion injury had set in
#The therapy was administered after [[reperfusion]] and after [[reperfusion injury]] had set in
#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
#The greatest benefit is observed in [[ST elevation myocardial infarction|anterior ST-elevation myocardial infarctions]] (as demonstrated in the AMISTAD study), and inclusion of non-anterior locations minimizes the potential benefit
#There are uninhibited redundant pathways mediating reperfusion injury
#There are uninhibited redundant pathways mediating [[reperfusion injury]]
The most common myth about the ischemia-reperfusion injury is itself related to blood flow. One can easily think like if everything is happening due to ischemia and with the restoration of blood flow, the injury should heal. Here is the trick, reperfusion in turn further exacerbates the injury mainly due to the formation of free radicals. There are few approaches that are studied widely and do play a major role in controlling the injury related to ischemia-reperfusion injury
Reperfusion injury treatment, shown at various steps the intermediates and the possible drugs and compounds that can help to inhibit those steps and in turn decresing the incidence of reperfusion injury at various steps. [1]
Various proposed medical managements studied are:
Therapeutic hypothermia
It has been shown in rats that neurons sometimes die completely 24 hours after the blood flow returns[1].
There are several preliminary studies in mice that seem to show that treatment with hydrogen sulfide ( H2S) could have a protective effect against reperfusion injury.[2]
The opening of MTP Pore results in major cell destruction by causing the influx of water into mitochondria, impairing its function and ultimately leading to the collapse. The strategy to protect mitochondria is the most important thing associated with the treatment part.
Ischemic Conditioning Flow chart- Ischemic Conditioning Mechanism- Role of ischemic conditioning in preventing and minimizing the damage associated with Reperfusion injury. [2]Stem cell therapy
Therapies Associated with Improved Clinical Outcomes
Pre-conditioning and Post-conditioning benefits in preventing severe damage to tissue during the ischemia-reperfusion injury. [3]
Therapies that have been associated with improved clinical outcomes include:
"Preconditioning" - Preconditioning is basically an adaptive response in which ischemia is exposed for a brief period of time before the actual ischemia phase to the tissue. This phenomenon markedly increases the ability of the heart to withstand subsequent ischemic insults[15]. In addition to that, the application of brief episodes of ischemia at the onset of reperfusion is termed as "postconditioning" which reduces the extent of injury that is supposed to happen.
"Postconditioning" (short repeated periods of vessel opening by repeatedly blowing the balloon up for short periods of time)[16].
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 post conditioned versus a control group
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
Inhibition of mitochondrial pore opening by cyclosporine.
Specifically, the study by Piot et al demonstrated that administration of cyclosporine[17] 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
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:
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)
Magnesium[23], which was evaluated by the Fourth International Study of Infarct Survival (ISIS-4) and the MAGIC trial.
Hyperoxemia, the delivery of supersaturated oxygen after PCI (Studied in the AMIHOT II trial).
Bendavia studied in the EMBRACE STEMI trial
There are several explanations for why trials of experimental agents have failed in this area:
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
↑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. PMID14767591.
↑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. PMID18669426.
↑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. PMID17595511.
↑Hausenloy DJ, Yellon DM (July 2008). "Time to take myocardial reperfusion injury seriously". N. Engl. J. Med. 359 (5): 518–20. doi:10.1056/NEJMe0803746. PMID18669431.
↑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. PMID21498423.
↑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. PMID24220681.
↑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. PMID26928528.
↑Frances C, Nazeyrollas P, Prevost A, Moreau F, Pisani J, Davani S, Kantelip JP, Millart H (March 2003). "Role of beta 1- and beta 2-adrenoceptor subtypes in preconditioning against myocardial dysfunction after ischemia and reperfusion". J. Cardiovasc. Pharmacol. 41 (3): 396–405. doi:10.1097/00005344-200303000-00008. PMID12605018.
↑Selective retroinfusion of GSH and cariporide attenuates myocardial ischemia–reperfusion injury in a preclinical pig modelhttps://doi.org/10.1016/j.cardiores.2003.11.012
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