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| __NOTOC__ | | __NOTOC__ |
| | {{Reperfusion injury}} |
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| {{SI}} | | {{CMG}} {{AE}} {{AC}} {{Shivam Singla}} |
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| {{CMG}} | | {{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 |
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| ==Overview== | | ==[[Reperfusion injury overview|Overview]]== |
| '''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 pathophysiology|Pathophysiology]]== |
| 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" />. Other pathophysiologic disturbances include intracellular calcium overload and the opening of mitochondrial permeability transition pores. <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=http://cardiovascres.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=14962470}}</ref>
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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. 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. 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>
| | '''[[Reperfusion injury medical therapy|Medical Therapy]]''' |
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| #[[Beta-blockade]]
| | '''[[Reperfusion injury future or investigational therapies|Future or Investigational Therapies]]''' |
| #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>
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| <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>
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| <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>
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| <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 imporved ehcocardiographic 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
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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
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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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| Therapies that have been associated with improved clinical outcomes include
| | ==Related Chapters== |
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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>
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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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| 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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| * [http://www.newsweek.com/id/35045 Docs Change the Way They Think About Death]
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| [[Category:Physiology]] | | [[Category:Physiology]] |
| [[Category:Neurotrauma]] | | [[Category:Neurotrauma]] |
| | [[Category:Cardiology]] |
| | [[Category:Up-To-Date]] |
| | [[Category:Up-To-Date cardiology]] |