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| __NOTOC__ | | __NOTOC__ |
| {{SI}} | | {{Reperfusion injury}} |
| {{EJ}}
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| '''Editors-In-Chief:''' [[AC]]; [[C. Michael Gibson]], M.S., M.D. [mailto:Mgibson@perfuse.org]
| | {{CMG}} {{AE}} {{AC}} {{Shivam Singla}} |
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| ==Overview==
| | {{SK}} Reperfusion Damage; Damage, Reperfusion; Damages, Reperfusion; Reperfusion Damages; Ischemia-Reperfusion Injury; Ischemia-Reperfusion Injury; Injury, Ischemia-Reperfusion; Injuries, Ischemia-Reperfusion; Injury, Ischemia-Reperfusion; Ischemia-Reperfusion Injuries; Injury, Reperfusion; Injuries, Reperfusion; Reperfusion Injuries |
| '''Reperfusion injury''' refers to damage to [[tissue (biology)|tissue]] caused when [[blood]] supply returns to the tissue after a period of [[ischemia]]. The absence of [[oxygen]] and [[nutrient]]s from blood creates a condition in which the restoration of [[circulatory system|circulation]] results in [[inflammation]] and [[oxidation|oxidative]] damage through the induction of [[oxidative stress]] rather than restoration of normal function.
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| ==Mechanisms of reperfusion injury== | | ==[[Reperfusion injury overview|Overview]]== |
| The damage of reperfusion injury is due in part to the [[inflammatory response]] of damaged tissues. [[White blood cell]]s carried to the area by the newly returning blood release a host of [[cytokine|inflammatory factors]] such as [[interleukin]]s as well as [[reactive oxygen species|free radicals]] in response to tissue damage
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| <ref name="WMClark">{{cite web | last = Clark | first = Wayne M. | title = Reperfusion Injury in Stroke | work = eMedicine | publisher = WebMD | date = January 5, 2005 | url = http://www.emedicine.com/neuro/topic602.htm | accessdate = 2006-08-09 }}</ref>.The restored blood flow reintroduces oxygen within [[cell (biology)|cell]]s that damages cellular [[protein]]s, [[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 [[capillary|capillaries]], obstructing them and leading to more ischemia<ref name="WMClark" />.
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| 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 ([[Mitochondrial permeability transition|MPTP]]), which opens when reperfusion occurs<ref name="pmid14962470">{{cite journal |author=Halestrap AP, Clarke SJ, Javadov SA |title=Mitochondrial permeability transition pore opening during myocardial reperfusion--a target for cardioprotection |journal=Cardiovasc. Res. |volume=61 |issue=3 |pages=372–85 |year=2004 |month=February |pmid=14962470 |doi=10.1016/S0008-6363(03)00533-9 |url=}}</ref>. 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<ref name="pmid12782201">{{cite journal |author=Zingarelli B, O'Connor M, Hake PW |title=Inhibitors of poly (ADP-ribose) polymerase modulate signal transduction pathways in colitis |journal=Eur. J. Pharmacol. |volume=469 |issue=1-3 |pages=183–94 |year=2003 |month=May |pmid=12782201 |doi= |url=}}</ref>.
| | ==[[Reperfusion injury pathophysiology|Pathophysiology]]== |
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| In prolonged ischemia (60 minutes or more), [[hypoxanthine]] is formed as breakdown product of [[Adenosine triphosphate|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]] [[Radical (chemistry)|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]].
| | ==[[Reperfusion injury risk factors|Risk Factors]]== |
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| ==Specific organs affected by reperfusion injury== | | ==[[Reperfusion injury natural history|Natural History, Complications & Prognosis]]== |
| ===The central nervous system===
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| 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 [[wound healing|heal]] of [[chronic wound]]s such as [[pressure sore]]s and [[diabetic foot]] [[ulcer]]s<ref name="TMustoe">{{cite journal | author=Mustoe T. | title=Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy | journal=AMERICAN JOURNAL OF SURGERY | volume=187 | issue=5A | year=2004 | pages=65S-70S | id=PMID 15147994}}</ref>. 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]]<ref name="TMustoe" />.
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| ===The myocardium=== | | ==Treatment== |
| 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.
| | '''[[Reperfusion injury medical therapy|Medical Therapy]]''' |
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| 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<ref name="pmid16284648">{{cite journal |author=Akar FG, Aon MA, Tomaselli GF, O'Rourke B |title=The mitochondrial origin of postischemic arrhythmias |journal=J. Clin. Invest. |volume=115 |issue=12 |pages=3527–35 |year=2005 |month=December |pmid=16284648 |pmc=1280968 |doi=10.1172/JCI25371 |url=}}</ref>.
| | '''[[Reperfusion injury future or investigational therapies|Future or Investigational Therapies]]''' |
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| 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<ref name="pmid8629581">{{cite journal |author=Iliceto S, Galiuto L, Marchese A, ''et al.'' |title=Analysis of microvascular integrity, contractile reserve, and myocardial viability after acute myocardial infarction by dobutamine echocardiography and myocardial contrast echocardiography |journal=Am. J. Cardiol. |volume=77 |issue=7 |pages=441–5 |year=1996 |month=March |pmid=8629581 |doi= |url=}}</ref><ref name="pmid9129892">{{cite journal |author=Iliceto S, Galiuto L, Marchese A, Colonna P, Oliva S, Rizzon P |title=Functional role of microvascular integrity in patients with infarct-related artery patency after acute myocardial infarction |journal=Eur. Heart J. |volume=18 |issue=4 |pages=618–24 |year=1997 |month=April |pmid=9129892 |doi= |url=}}</ref><ref name="pmid8548892">{{cite journal |author=Ito H, Maruyama A, Iwakura K, ''et al.'' |title=Clinical implications of the 'no reflow' phenomenon. A predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction |journal=Circulation |volume=93 |issue=2 |pages=223–8 |year=1996 |month=January |pmid=8548892 |doi= |url=}}</ref><ref name="pmid1448120">{{cite journal |author=Sabia PJ, Powers ER, Ragosta M, Sarembock IJ, Burwell LR, Kaul S |title=An association between collateral blood flow and myocardial viability in patients with recent myocardial infarction |journal=N. Engl. J. Med. |volume=327 |issue=26 |pages=1825–31 |year=1992 |month=December |pmid=1448120 |doi=10.1056/NEJM199212243272601 |url=}}</ref>.
| | ==Related Chapters== |
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| 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<ref name="pmid9498544">{{cite journal |author=Matsumura K, Jeremy RW, Schaper J, Becker LC |title=Progression of myocardial necrosis during reperfusion of ischemic myocardium |journal=Circulation |volume=97 |issue=8 |pages=795–804 |year=1998 |month=March |pmid=9498544 |doi= |url=}}</ref><ref name="pmid8609356">{{cite journal |author=Arai M, Lefer DJ, So T, DiPaula A, Aversano T, Becker LC |title=An anti-CD18 antibody limits infarct size and preserves left ventricular function in dogs with ischemia and 48-hour reperfusion |journal=J. Am. Coll. Cardiol. |volume=27 |issue=5 |pages=1278–85 |year=1996 |month=April |pmid=8609356 |doi= |url=}}</ref>. This opens the door for novel therapies that can attenuate myocyte death due to reperfusion injury.
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| ==Therapies==
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| 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.
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| ===Therapies Associated with Limited Success===
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| 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>
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| #[[Beta-blockade]]
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| #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>
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| #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)
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| #[[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>
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| #[[Calcium-channel blockers]]
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| #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>
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| #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>)
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| #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>.
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| #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> )
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| # 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>.
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| #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>
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| #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>
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| #[[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>.
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| ===Therapies Associated with Improved Clinical Outcomes===
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| Therapies that have been associated with improved clinical outcomes include:
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| #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>
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| #*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)
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| #*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>
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| #*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>
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| #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>
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| #*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
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| #*Infarct size was measured by the release of creatine kinase and delayed hyperenhancement on MRI
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| #*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.
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| 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.
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| There are several explanations for why trials of experimental agents have failed in this area:
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| #The therapy was administered after reperfusion and after reperfusion injury had set in
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| #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
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| #There are uninhibited reduncant pathways mediating reperfusion injury
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| #Inadequate dosing of the agent
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| ==See also==
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| * [[Ischemia]] | | * [[Ischemia]] |
| * [[Myocardial_infarction#Reperfusion|Myocardial infarction -- Reperfusion]] | | * [[Myocardial_infarction#Reperfusion|Myocardial infarction -- Reperfusion]] |
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| ==References==
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| {{reflist|2}}
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| ==External links==
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| * [http://www.benbest.com/cryonics/ischemia.html#reperfuse Reperfusion Injury and "No Reflow"]
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| [[Category:Physiology]] | | [[Category:Physiology]] |
| [[Category:Neurotrauma]] | | [[Category:Neurotrauma]] |
| [[Category:Cardiology]] | | [[Category:Cardiology]] |
| | [[Category:Up-To-Date]] |
| | [[Category:Up-To-Date cardiology]] |