Reperfusion injury medical therapy: Difference between revisions

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'''Editors-In-Chief:''' {{AC}}; [[C. Michael Gibson]], M.S., M.D. [mailto:Mgibson@perfuse.org]
'''Editors-In-Chief:''' {{AC}}; [[C. Michael Gibson]], M.S., M.D. [mailto:Mgibson@perfuse.org]


==Overview==
== Medical Therapy ==
While many pharmacotherapies are successful in limiting reperfusion injury in animal studies or ex-vivo, the majority have failed to improve clinical outcomes in randomized clinical trials in patients. Strategies may have failed as a result of targeting the wrong mechanism, because an inadequate dose was studied, because patients with insufficient potential for benefit were studied, and because the drug was administered too late (after reperfusion had already occurred).
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. Some claim that this delayed reaction is the result of the multiple inflammatory immune responses that occur during reperfusion. Such inflammatory reactions cause intracranial pressure, a pressure that leads to 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 development. Hypothermia has also been shown to decrease the patient's development of deadly free radicals during reperfusion.  
 
* '''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.
 
* '''Cyclosporine'''
** In addition to its well-known immunosuppressive capabilities, the one-time administration of cyclosporine 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 has been confirmed in studies to inhibit the actions of cyclophilin D, a protein which is induced by excessive intracellular calcium flow to interact with other pore components and help open the MPT pore. Inhibiting cyclophilin D has been shown to prevent the opening of the MPT pore and protect the mitochondria and cellular energy production from excessive calcium inflows.
** Reperfusion leads to biochemical imbalances within the cell that lead to cell death and increased infarct size. More specifically, calcium overload and excessive production of reactive oxygen species in the first few minutes after reperfusion set off a cascade of biochemical changes that result in the opening of the so-called mitochondrial permeability transition pore (MPT pore) in the mitochondrial membrane of cardiac cells.
** The opening of the MPT pore leads to the inrush of water into the mitochondria, resulting in mitochondrial dysfunction and collapse. Upon collapse, the calcium is then released to overwhelm the next mitochondria in a cascading series of events that cause mitochondrial energy production supporting the cell to be reduced or stopped completely. The cessation of energy production results in cellular death. Protecting mitochondria is a viable cardio protective strategy.
** Cyclosporine is currently in a phase II/III (adaptive) clinical study in Europe to determine its ability to ameliorate neuronal cellular damage in traumatic brain injury.
 
* '''TRO40303'''
** TRO40303 is a new cardio protective compound that was shown to inhibit the MPT pore and reduce infarct size after ischemia-reperfusion.
 
* '''Stem cell therapy'''
** Recent investigations suggest a possible beneficial effect of mesenchymal stem cells on heart and kidney reperfusion injury
 
* '''Superoxide dismutase'''
** Superoxide dismutase is an important antioxidant enzyme that transforms superoxide anions to water and hydrogen peroxide. Recent work has demonstrated important therapeutic effects on pre-clinical models of reperfusion damage following an ischemic stroke .
 
* '''Metformin'''
** A series of 2009 studies published in the Journal of Cardiovascular Pharmacology indicate that metformin may prevent injury to cardiac reperfusion by inhibiting Mitochondrial Complex I and opening up MPT pore and in rats.
 
* '''Cannabinoids'''
** A research published in 2012 shows that the synthetic analog of phytocannabinoid tetrahydrocannabivarin (THCV), 8-Tetrahydrocannabivarin (THCV) and its 11-OH-8-THCV metabolite prevents hepatic ischemia / reperfusion injury by minimizing oxidative stress and inflammatory reactions through cannabinoid CB2 receptors, thereby lowering tissue damage and protective effects of inflammation. Pretreatment with a CB2 receptor antagonist, whereas a CB1 antagonist appeared to strengthen it, attenuated the defensive effects of somewhere else.
** An earlier study published in 2011 found that cannabidiol (CBD) also protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signals and oxidative and nitrative stress response, resulting in cell death and tissue damage, but is independent of classic CB1 and CB2 receptors.


==Therapies Associated with Limited Success==
==Therapies Associated with Limited Success==
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>
Pharmacotherapies that have either failed or that have met with limited success in improving clinical outcomes include:  


#[[Beta-blockade]]
#[[Beta-blockade]]
#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>
#GIK (glucose-insulin-potassium infusion) (Studied in the Glucose-Insulin-Potassium Infusion in Patients With Acute Myocardial Infarction Without Signs of Heart Failure: The Glucose-Insulin-Potassium Study (GIPS)-II and other older studies<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>
#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)
#Sodium-hydrogen exchange inhibitors such as cariporide (Studied in the GUARDIAN   and EXPIDITION   trials)
#[[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>
#[[Adenosine]] (Studied in the AMISTAD I and AMISTAD II trials as well as the ATTACC trial ). It should be noted that at high doses in anterior ST elevation MIs, adenosine was effective in the AMISTAD trial.  Likewise, intracoronary administration of adenosine prior to primary PCI has been associated with improved echocardiographic and clinical outcomes in one small study.  
#[[Calcium-channel blockers]]
#[[Calcium-channel blockers]]
#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>
#Potassium–adenosine triphosphate channel openers
#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>)
#Antibodies directed against leukocyte adhesion molecules such as CD 18 (Studied in the LIMIT AMI trial )
#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>.
#Oxygen free radical scavengers/anti-oxidants, including [[Erythropoietin]], [[estrogen]], heme-oxygenase 1, and hypoxia induced factor-1 (HIF-1).
#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> )
#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 )
# 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>.
# 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).
#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>
#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.)
#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>
#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]], 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>.
#[[Magnesium]], which was evaluted by the Fourth International Study of Infarct Survival (ISIS-4) and the MAGIC trial.
#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>
#Hypothermia
#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>).
#Hyperoxemia, the delivery of supersaturated oxygen after PCI (Studied in the AMIHOT II trial).
#Bendavia studied in the EMBRACE STEMI trial
#Bendavia studied in the EMBRACE STEMI trial


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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>
#Post conditioning (short repeated periods of vessel opening by repeatedly blowing the balloon up for short periods of time).
#*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)
#*Mechanisms of protection include formation and release of several autacoids and cytokines, maintained acidosis during early repercussion, activation of protein kinases, and attenuation of opening of the mitochondrial permeability transition pore (MPTP)
#*One study in humans demonstrated an area under the curve (AUC) of creatine kinase (C) release over the first 3 days of reperfusion (as a surrogate for infarct size) was significantly reduced by 36% in the postconditioned versus control group<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>
#*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
#*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>
#*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>
#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>
#Inhibition of mitochondrial pore opening by cyclosporine.  
#*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
#*Specifically, the study by Piot et al demonstrated that administration of cyclosporine at the time of reperfusion was associated with a reduction in infarct size
#*Infarct size was measured by the release of creatine kinase and delayed hyperenhancement on MRI
#*Infarct size was measured by the release of creatine kinase and delayed hyperenhancement on MRI
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[[Category:Up-To-Date]]
[[Category:Up-To-Date]]
[[Category:Up-To-Date cardiology]]
[[Category:Up-To-Date cardiology]]
<references />

Revision as of 17:11, 14 August 2020


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

Medical Therapy

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. Some claim that this delayed reaction is the result of the multiple inflammatory immune responses that occur during reperfusion. Such inflammatory reactions cause intracranial pressure, a pressure that leads to 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 development. Hypothermia has also been shown to decrease the patient's development of deadly free radicals during reperfusion.  
  • 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.
  • Cyclosporine
    • In addition to its well-known immunosuppressive capabilities, the one-time administration of cyclosporine 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 has been confirmed in studies to inhibit the actions of cyclophilin D, a protein which is induced by excessive intracellular calcium flow to interact with other pore components and help open the MPT pore. Inhibiting cyclophilin D has been shown to prevent the opening of the MPT pore and protect the mitochondria and cellular energy production from excessive calcium inflows.
    • Reperfusion leads to biochemical imbalances within the cell that lead to cell death and increased infarct size. More specifically, calcium overload and excessive production of reactive oxygen species in the first few minutes after reperfusion set off a cascade of biochemical changes that result in the opening of the so-called mitochondrial permeability transition pore (MPT pore) in the mitochondrial membrane of cardiac cells.
    • The opening of the MPT pore leads to the inrush of water into the mitochondria, resulting in mitochondrial dysfunction and collapse. Upon collapse, the calcium is then released to overwhelm the next mitochondria in a cascading series of events that cause mitochondrial energy production supporting the cell to be reduced or stopped completely. The cessation of energy production results in cellular death. Protecting mitochondria is a viable cardio protective strategy.
    • Cyclosporine is currently in a phase II/III (adaptive) clinical study in Europe to determine its ability to ameliorate neuronal cellular damage in traumatic brain injury.
  • TRO40303
    • TRO40303 is a new cardio protective compound that was shown to inhibit the MPT pore and reduce infarct size after ischemia-reperfusion.
  • Stem cell therapy
    • Recent investigations suggest a possible beneficial effect of mesenchymal stem cells on heart and kidney reperfusion injury
  • Superoxide dismutase
    • Superoxide dismutase is an important antioxidant enzyme that transforms superoxide anions to water and hydrogen peroxide. Recent work has demonstrated important therapeutic effects on pre-clinical models of reperfusion damage following an ischemic stroke .
  • Metformin
    • A series of 2009 studies published in the Journal of Cardiovascular Pharmacology indicate that metformin may prevent injury to cardiac reperfusion by inhibiting Mitochondrial Complex I and opening up MPT pore and in rats.
  • Cannabinoids
    • A research published in 2012 shows that the synthetic analog of phytocannabinoid tetrahydrocannabivarin (THCV), 8-Tetrahydrocannabivarin (THCV) and its 11-OH-8-THCV metabolite prevents hepatic ischemia / reperfusion injury by minimizing oxidative stress and inflammatory reactions through cannabinoid CB2 receptors, thereby lowering tissue damage and protective effects of inflammation. Pretreatment with a CB2 receptor antagonist, whereas a CB1 antagonist appeared to strengthen it, attenuated the defensive effects of somewhere else.
    • An earlier study published in 2011 found that cannabidiol (CBD) also protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signals and oxidative and nitrative stress response, resulting in cell death and tissue damage, but is independent of classic CB1 and CB2 receptors.

Therapies Associated with Limited Success

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

  1. Beta-blockade
  2. GIK (glucose-insulin-potassium infusion) (Studied in the Glucose-Insulin-Potassium Infusion in Patients With Acute Myocardial Infarction Without Signs of Heart Failure: The Glucose-Insulin-Potassium Study (GIPS)-II and other older studies[1]
  3. Sodium-hydrogen exchange inhibitors such as cariporide (Studied in the GUARDIAN and EXPIDITION trials)
  4. Adenosine (Studied in the AMISTAD I and AMISTAD II trials as well as the ATTACC trial ). It should be noted that at high doses in anterior ST elevation MIs, adenosine was effective in the AMISTAD trial. Likewise, intracoronary administration of adenosine prior to primary PCI has been associated with improved echocardiographic and clinical outcomes in one small study.
  5. Calcium-channel blockers
  6. Potassium–adenosine triphosphate channel openers
  7. Antibodies directed against leukocyte adhesion molecules such as CD 18 (Studied in the LIMIT AMI trial )
  8. Oxygen free radical scavengers/anti-oxidants, including Erythropoietin, estrogen, heme-oxygenase 1, and hypoxia induced factor-1 (HIF-1).
  9. Pexelizumab, a humanized monoclonal antibody that binds the C5 component of complement (Studied in the Pexelizumab for Acute ST-Elevation Myocardial Infarction in Patients Undergoing Primary Percutaneous Coronary Intervention (APEX AMI) trial )
  10. KAI-9803, a delta-protein kinase C inhibitor (Studied in the Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction trial or DELTA AMI trial).
  11. Human atrial natriuretic peptide (Studied in the Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials.)
  12. FX06, an anti-inflammatory fibrin derivative that competes with fibrin fragments for binding with the vascular endothelial molecule VE-cadherin which deters migration of leukocytes across the endothelial cell monolayer (studied in the F.I.R.E. trial (Efficacy of FX06 in the Prevention of Myocardial Reperfusion Injury)
  13. Magnesium, which was evaluted by the Fourth International Study of Infarct Survival (ISIS-4) and the MAGIC trial.
  14. Hypothermia
  15. Hyperoxemia, the delivery of supersaturated oxygen after PCI (Studied in the AMIHOT II trial).
  16. Bendavia studied in the EMBRACE STEMI trial

Therapies Associated with Improved Clinical Outcomes

Therapies that have been associated with improved clinical outcomes include:

  1. Post conditioning (short repeated periods of vessel opening by repeatedly blowing the balloon up for short periods of time).
    • Mechanisms of protection include formation and release of several autacoids and cytokines, maintained acidosis during early repercussion, activation of protein kinases, and attenuation of opening of the mitochondrial permeability transition pore (MPTP)
    • One study in humans demonstrated an area under the curve (AUC) of creatine kinase (C) release over the first 3 days of reperfusion (as a surrogate for infarct size) was significantly reduced by 36% in the postconditioned versus control group
    • 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[2]
  2. Inhibition of mitochondrial pore opening by cyclosporine.
    • Specifically, the study by Piot et al demonstrated that administration of cyclosporine at the time of reperfusion was associated with a reduction in infarct size
    • Infarct size was measured by the release of creatine kinase and delayed hyperenhancement on MRI
    • Patients with cardiac arrest, ventricular fibrillation, cardiogenic shock, stent thrombosis, previous acute myocardial infarction, or angina within 48 hours before infarction were not included in the study #*Occlusion of the culprit artery (TIMI flow 0) was part of the inclusion criteria.

Limitations to applying strategies that have demonstrated benefit in animal models is the fact that reperfusion therapy was administered prior to or at the time of reperfusion. In the management of STEMI patients, it is impossible to administer the agent before vessel occlusion (except during coronary artery bypass grafting). Given the time constraints and the goal of opening an occluded artery within 90 minutes, it is also difficult to administer experimental agents before reperfusion in STEMI.

There are several explanations for why trials of experimental agents have failed in this area:

  1. The therapy was administered after reperfusion and after reperfusion injury had set in
  2. The greatest benefit is observed in anterior ST elevation myocardial infarctions (as demonstrated in the AMISTAD study), and inclusion of non anterior locations minimizes the potential benefit
  3. There are uninhibited redundant pathways mediating reperfusion injury
  4. Inadequate dosing of the agent

References

  1. ↑ Rackley CE, Russell RO, Rogers WJ, Mantle JA, McDaniel HG, Papapietro SE (1982). "Glucose-insulin-potassium administration in acute myocardial infarction". Annu. Rev. Med. 33: 375–83. doi:10.1146/annurev.me.33.020182.002111. PMID 7044275.
  2. ↑ Thibault H, Piot C, Staat P, Bontemps L, Sportouch C, Rioufol G; et al. (2008). "Long-term benefit of postconditioning". Circulation. 117 (8): 1037–44. doi:10.1161/CIRCULATIONAHA.107.729780. PMID 18268150.
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