no reflow phenomenon (60)

Symposium PaperThe metamorphosis of myocardial infarction followingcoronary recanalizationCristina Basso ⁎,Stefania Rizzo,Gaetano ThieneDepartment of Medical Diagnostic Sciences and Special Therapies,University of Padua Medical School,Padua,ItalyReceived 30April 2009;accepted 26June 2009AbstractThe “metamorphosis ”of acute myocardial infarction (AMI)in terms of pathological features and complications in the reperfusion era is herein discussed.Typically,the AMI following coronary artery recanalization is characterized by frequent subendocardial location,since a prompt coronary lumen recanalization is able to prevent the transmural progression of myocardial necrosis from the endocardium towards the epicardium.Transmural AMI may develop when recanalization occurs late (>6hours)or is not effective (persistent coronary occlusion).Moreover,reperfused AMI frequently appears reddish because of interstitial haemorrhage,which is thought to be caused by vascular cell damage with leakage of blood out of the injured vessels.Hemorrhage occurs always within the area of necrosis and it is significantly related to the infarct size and to the coronary occlusion time.At histology,typical features of reperfused AMI consist of contraction band necrosis and interstitial hemorrhage.Moreover,a more pronounced inflammatory cellular response is visible within the necrotic area when comparing reperfused with non-reperfused AMI.Reperfusion after prolonged coronary occlusion is also associated with secondary impairment of microcirculatory flow (“no-reflow ”phenomenon),that is due to endothelial swelling,luminal obstruction and external compression but may also be aggravated by distal embolization.Finally,the reperfused AMI with its typical subendocardial,non-trasmural location,is characterized by a lower incidence of expansive remodelling and related complications,in terms of cardiogenic shock,myocardial rupture,aneurysm and pseudoaneurysm formation and thromboembolism.Moreover,pericardial involvement is a rare occurrence.Unfavorable mechanical consequences of intramyocardial haemorrhage could consist in increased myocardial stiffness,propensity to wall rupture and delayed healing process.However,prospective in vivo large-scale studies in patients with reperfused AMI are needed to assess the prognostic value of hemorrhagic AMI in terms of morbidity and mortality.The knowledge and correct interpretation of these findings at post-mortem by the general and forensic pathologists is of great importance,to provide useful information to the clinicians.©2010Elsevier Inc.All rights reserved.Keywords:Myocardial infarction;Coronary recanalizationAcute myocardial infarction (AMI)remains a major cause of morbidity and mortality in Western countries [1].In the preinterventional era,the management of AMI focused on treatment and/or prevention of complications.After thediscovery of the “wave-front phenomenon ”[2,3]and the identification of coronary artery thrombosis as primum movens of AMI [4],multiple therapeutic strategies were developed to rapidly restore blood flow to the myocardium with the ultimate goal of infarct size reduction and improvement in clinical outcome [5].Mortality from AMI has been significantly decreasing,and this drop appears to be mainly the consequence of the decline in the incidence of ST-segment elevation myocardial infarction (STEMI)and of an absolute reduction in case fatality rate once STEMI has occurred [6].Most deaths in hospitalized patients are now due to heart failure and mechanical pared with the prereperfusion era,fatal ventricular tachyarrhyth-mias are less common,although sudden cardiac deathCardiovascular Pathology 19(2010)22–28Presented at the United States and Canadian Academy of Pathology Society for Cardiovascular Pathology Companion Meeting,Denver,CO,March 2,2008.The study was supported by the Registry for Cardio-cerebro-vascular Pathology,Veneto Region,Venice,Italy.⁎Corresponding author.Department of Medical Diagnostic Sciences and Special Therapies,University of Padua Medical School,Via A.Gabelli,61,Padua,Italy.Tel.:+390498272286;fax:+390498272284.E-mail address:cristina.basso@unipd.it (C.Basso).1054-8807/09/$–see front matter ©2010Elsevier Inc.All rights reserved.doi:10.1016/j.carpath.2009.06.010remains the main cause of death in out-of-hospital AMI and a substantial cause of late mortality in those with severe impairment of left ventricular function.This review will focus on the pathological features and complications of AMI,to address its“metamorphosis”from the pre-to the postinterventional era.The knowledge and correct interpretation of these findings at postmortem by the general and forensic pathologists are of great importance,to provide useful information to the clinicians.1.Pathobiology of acute myocardial ischemiaIschemic heart disease refers to a group of clinical-pathological conditions caused by a discrepancy between myocardial oxygen supply and demand,including acute coronary syndromes like unstable angina,non-STEMI (NSTEMI)and STEMI,and chronic ischemic heart disease[7].Occlusive or mural thrombosis due to plaque disruption/ fissuring or erosion,complicating an atherosclerotic plaque, represents the main cause of acute coronary syndromes[8]. Although spontaneous reperfusion of the infarct-related coronary artery may occur,thrombotic occlusion usually persists in the majority of patients suffering from AMI.Myocardial necrosis progresses with the duration of coronary occlusion,extending from the subendocardium towards the subepicardium,as to involve the full thickness ventricular wall.Coronary occlusion leads to transmural AMI when exceeding6h.This concept of“wavefront phenomenon of myocardial death”was established in the 1970s by Reimer and Jennings[2,3]using a canine model of acute coronary occlusion.After an acute coronary occlusion, infarct size depends mainly on the extent of the territory distal to the culprit coronary plaque(area at risk),the presence and magnitude of residual flow(subtotal occlusion, collaterals),and the duration of ischemia.The knowledge that the vast majority of AMI is caused by an occlusive coronary thrombosis and that the myocardium can be salvaged for a period of time after the onset of occlusion(“time is muscle”)has led to a revolution in the therapeutic strategies.Aggressive pharmacological or inter-ventional approaches were then searched for,with the aim to restore coronary artery patency as early as possible to produce effective myocardial reperfusion and prevent further loss of viable myocardium.The earlier the reperfusion therapy after the onset of AMI,the greater the potential for reduction of infarct size and mortality.In fact,the highest number of lives saved by reperfusion therapy is within the first hour after symptom onset,the so-called golden hour[9].In the experimental setting,myocardial ischemia results in a characteristic pattern of metabolic and ultrastructural altera-tions of the cardiomyocytes,including the mitochondria, nuclei,myofilaments,other organelles,and sarcolemma[10]. If ischemia persists,myocardial injury becomes irreversible, usually between20and45min after coronary occlusion,thus accounting for AMI.The microvasculature also shows damages,although typically postponed as compared to cardio-myocyte injury(i.e.,between45and60min),and this explains why the reperfused AMI is often hemorrhagic[11,12].At difference from data obtained from experimental animal models,we must consider that the pathologic features of human AMI are“biased”by the selection criteria,since they are obviously based upon patients who die due to AMI. Most patients with AMI who are admitted early to intensive care units and interventional labs undergo timely successful revascularization and have a good prognosis and,as a consequence,are not studied at postmortem.On the contrary, fatal AMI seen in the autopsy room usually refers to cases occurring out of the hospital or to patients who came late to the emergency room,thus receiving either no or late coronary revascularization.2.The“classic”pathology of AMI in the prerecanalization eraThe gross features of AMI and their histological counter-parts are quite variable,depending on the time interval between the onset of coronary occlusion and death and on whether coronary occlusion does exist.AMI can be divided into two major types,i.e.,transmural,when themyocardial Fig.1.Gross features of AMI in the pre-and postrecanalization era:(A) white,anemic transmural AMI with wall thinning and expansion;(B) hemorrhagic,red transmural AMI.23C.Basso et al./Cardiovascular Pathology19(2010)22–28necrosis involves the full thickness of the ventricular wall,and subendocardial (or nontransmural),when the myocardial necrosis remains confined to the inner layers.While the transmural AMI is usually precipitated by an occlusive thrombosis of the infarct-related coronary artery,the subendocardial AMI frequently occurs in the setting of multivessel obstructive coronary atherosclerosis,without lumen occlusion [13].According to the recent definition [7],AMI can be classified by size —microscopic (focal necrosis),small (b 10%of the left ventricular myocardium),moderate (10–30%),and large (N 30%)—and by location.Moreover,myocardial infarction can be defined “pathologically ”as acute,healing,or healed,and “temporally ”as evolving (b 6h),acute (6h –7days),healing (7–28days),and healed (29days and beyond).Noteworthy,the clinical and electrocardiographic timing of an AMI may not correspond exactly with the pathological timing.It takes several hours before myocardial necrosis can be identified by macroscopic or microscopic postmortem examination [14,15].At gross examination,myocardial changes are in fact difficult to identify in the early hours after coronary occlusion (b 6h from onset)and histochemical methods are available to help in the identification of AMI in the acute phase.They consist in the immersion of a slice of the myocardium in a solution of nitro blue tetrazolium or triphenyiltetrazolium that imparts a blue or red stain,respectively,to the noninfarcted area preserving the dehydrogenase enzymes.From 6to 12h,the infarcted region is pale,anemic,and turns grayish from 18to 24h.From days 1to 3,the infarct area is centered by a yellow-tan core,then surrounded by the hyperemic borders on days 3–7and eventually involving the entire infarct area on days 7–10(Fig.1A).Fibrous gray scar starts to develop from the periphery to the center from the second week,to be completed after the secondmonth.Fig.2.Histological features of AMI.(A)Waviness of cardiomyocytes;(B)coagulative cardiomyocyte necrosis and neutrophil infiltrates;(C)macrophage infiltrates;(D)contraction band necrosis (reperfused AMI);(E)interstitial hemorrhage (reperfused AMI);(F)small vessel damage and massive interstitial hemorrhage (reperfused AMI)Hematoxylin and eosin stain.24 C.Basso et al./Cardiovascular Pathology 19(2010)22–28The histological features also reflect the age of AMI (Fig.2A–C).The characteristic findings cannot be recognized on light microscopic examination until6–8h after coronary occlusion,with the only exception of the so-called myocyte waviness,especially at the periphery of the infarct.After8h,interstitial edema becomes evident.After 12h,early neutrophilic infiltrates appear and coagulative necrosis(hypereosinophilic changes in myocytes and nuclear pyknosis)starts and progresses with loss of the nuclei(days1–3).Between days1and3,polymorpho-nuclear leukocytes accumulate first at the periphery and then in the center of the infarct,with release of lytic enzymes.Between days3and7,early removal of necrotic debris by macrophages begins,and then a progressive infiltration of lymphocytes and fibroblasts occurs.By8 days,the necrotic cardiomyocytes are dissolved.Finally, granulation tissue and neo-vessel formation first appear at the periphery on day10,evolving through loose(week2) and dense collagen deposition(from3to6weeks).plications of AMI in the prerecanalization eraMajor complications of AMI in terms of mortality and morbidity include ventricular arrhythmias,cardiogenic shock,cardiac rupture,and electromechanical dissociation [16].Moreover,infarct expansion with wall thinning and aneurysm formation,mitral valve incompetence,mural thrombosis,and thromboembolism can occur(Table1).Postinfarction remodeling has been divided into an early phase(b72h)and a late phase(N72h).The early phase involves expansion of the infarct zone,which may result inearly ventricular rupture or aneurysm te remode-ling involves the left ventricle globally and is associated with dilatation and mural compensatory hypertrophy,which are adaptive responses during postinfarction remodeling[17].Infarct expansion,thinning,and disproportionate dilation of the infarct segment seem to begin within hours of AMI and to be associated with hypertension,anterior transmural location,persistent occlusion of the infarct artery,and poor collaterals.Wall rupture and late aneurysm formation are structural consequences of infarct expansion.True ventricular aneurysms are circumscribed,thin-walled fibrous,noncontractile outpouchings of the ventricle and occur as a consequence of transmural AMI[18].They are mostly apical(in the setting of anteroseptal AMI),since the apex is the thinnest region of the ventricle and is an area of the heart that is particularly vulnerable to expansion,and their clinical sequelae include congestive heart failure,throm-boembolism,and ventricular tachyarrhythmias(Fig.3).Postinfarction cardiac ruptures include free wall rupture, ventricular septal defects,and papillary muscle rupture [19,20].After ventricular arrhythmias and cardiogenic shock,cardiac rupture is the third most common cause of death in AMI.Free wall rupture occurs10times more frequently than septal or papillary muscle ruptures.Old age, female gender,hypertension,first AMI,and long interval between symptoms onset and treatment are independent factors of free wall rupture.Rupture usually occurs in the first4days after AMI onset,when coagulation necrosis and neutrophilic infiltration are at their peak,accounting for a fragile wall.At difference from nonruptured AMI,those with rupture show a more extensive inflammation and ofteneosinophils.Fig. plications of transmural AMI:aneurysm,mural thrombus formation,and pericarditis.(A)Anteroseptal transmural white AMI with expansion,aneurysm formation,and mural endocardial thrombosis;(B) fibrinous pericarditis(hematoxylin and eosin stain).Table1Pathologic features of AMI in the pre-and postrecanalization eraNonreperfused AMI Reperfused AMI Extension Transmural Subendocardial Aspect White,anemic Red,hemorrhagic Expansion and relatedcomplicationsRare–Aneurysm Frequent Rare–Cardiogenic shock Frequent Rare–Cardiac rupture Frequent Rare–Mural thrombosis Frequent Rare–Embolism Frequent Rare Pericardial involvement Frequent RareRight ventricular infarction Frequent RareHistologic features–Contraction band necrosis Rare Frequent–Interstitial hemorrhage Rare Frequent–Microembolization Rare Frequent 25C.Basso et al./Cardiovascular Pathology19(2010)22–28Three types of post-AMI cardiac ruptures have been identified:an abrupt tear in the wall without thinning(Type I), erosion of the necrotic myocardium covered by thrombus (Type II),and marked thinning of the necrotic wall with expansion and aneurysm formation(Type III)[21],the last one being particularly frequent in the prereperfusion era(Fig.4).Some patients may have a subacute course as a result of a “contained”rupture by adhesion of the surrounding pericardium,with pseudoaneurysm formation[22].Emboli-zation from thrombotic material entrapped in the cavity of the pseudoaneurysm,congestive heart failure,and late cardiac rupture have been reported.Ventricular septal defects complicate1–2%of all nonreperfused AMI[23]and are more common in females and in those with advanced age and single-vessel disease with poorly developed collaterals.In cases of anterior transmural AMI,the rupture is usually located in the anteroapical part of the interventricular septum,whereas in inferior AMI the defect occurs in its basal part.Fibrinous pericarditis complicates up to25%of trans-mural AMI[24](Fig.3B).The organization of fibrinous pericarditis may lead to pericardial adhesion and prevent late cardiac rupture.In3–4%of patients suffering from AMI, Dressler syndrome appears weeks or months after the onset of AMI,probably due to immune response.Right ventricular AMI occurs exclusively in transmural posteroseptal infarc-tion in the setting of concomitant obstructive disease of the left anterior descending coronary artery[25].3.The pathology of AMI in the reperfusion era:a metamorphosisThe amount of salvaged myocardium is related to the duration of total coronary artery occlusion,the level of myocardial oxygen consumption,and the collateral blood flow.In other words,the effects of reperfusion are quite variable and depend on the duration and severity of preceding ischemia.Typically,the AMI following coronary artery recanalization is characterized by frequent subendo-cardial location,since a prompt coronary lumen recanaliza-tion,either pharmacological or interventional,is able to prevent the transmural progression of myocardial necrosis from the endocardium towards the epicardium.Transmural AMI may develop when recanalization occurs late(N6h)or is not effective(persistent coronary occlusion)(Table1).Reperfused AMI frequently appears reddish because of interstitial hemorrhage[26–28](Fig.1B).Experimental plications of transmural AMI:cardiac rupture.(A)Diagram illustrating the three types of post-AMI cardiac rupture:an abrupt tear in the wall without thinning(Type I),erosion of the necrotic myocardium(Type II),and marked thinning of the necrotic wall with expansion and aneurysm formation(Type III). Modified from Becker and van Mantgem[21].(B)Gross features of Type I postinfarction free wall rupture.(C)Gross features of Type III postinfarction free wall rupture.26 C.Basso et al./Cardiovascular Pathology19(2010)22–28models first showed myocardial hemorrhage in the setting of prolonged coronary occlusion and reperfusion[2,24,26]. Then,myocardial hemorrhage after reperfusion has been described also in humans,following cardiac surgery, percutaneous transluminal coronary angioplasty,and fibri-nolysis.Hemorrhagic infarcts are thought to be caused by vascular cell damage with leakage of blood out of the injured vessels.It is well known that vascular cell damage occurs after myocardial cell necrosis and thus it represents a relatively late event in the course of AMI at the time of already irreversible myocyte damage.Moreover,infarct hemorrhage occurs always within the area of necrosis and it is significantly related to the infarct size and to the coronary occlusion time.As such,hemorrhage is not related to the type of recanalization as it was originally thought,since hemorrhagic infarcts can develop both after percutaneous coronary interventions and after thrombolysis.In each instance,the major determinant of hemorrhage is the time interval between the onset of coronary occlusion and the reflow,which is the extent of hemorrhage increased by the delay in reperfusion.At histology,typical features of reperfused AMI consist of contraction band necrosis and interstitial hemorrhage [5,26,29](Fig.2D–F).During the earliest minutes of reperfusion,contraction band necrosis has been ascribed to cardiomyocyte calcium overload.Although ischemic myo-cytes following reperfusion suddenly develop ultrastruc-tural changes indicative of cell death,they are still apparently normal from a histological point of view;it is likely that most of the myocytes are already irreversibly injured by the time reperfusion occurred,due to loss of plasma membrane integrity,and reperfusion simply accel-erates the phenomenon.When comparing reperfused with nonreperfused AMI at the same time intervals,besides interstitial hemorrhage,a more pronounced inflammatory cellular response is visible within the necrotic area in the former.Finally,reperfusion after prolonged coronary occlusion is associated with secondary impairment of microcirculatory flow(“no-reflow”phenomenon),which is due to endothelial swelling,luminal obstruction(viscosity,neutrophil plug-ging,platelet),and external compression(edema,hemor-rhage,myocyte swelling),but may also be aggravated by distal embolization of plaque debris and thrombus into the microvasculature.This embolization can occur sponta-neously or as a result of intracoronary manipulation[5]. plication of reperfused AMIEarly mortality due to ventricular arrhythmias is reduced after successful percutaneous coronary intervention[30]. Overall,the reperfused AMI with its typical subendocar-dial,nontrasmural location,is characterized by a lower incidence of expansive remodeling and related complica-tions,in terms of cardiogenic shock,myocardial rupture, aneurysm and pseudo-aneurysm formation,and throm-boembolism[29].Moreover,pericardial involvement is a rare occurrence[31,32].Although reperfusion therapy has decreased the inci-dence of cardiac rupture,and particularly that of ventricular septal defect(0.2%of reperfused AMI)[33],this complica-tion has a higher rate among patients subjected to late fibrinolysis(i.e.,several hours after the onset of symptoms), in comparison to those with early drug administration (within6–8h of the onset of symptoms)[34].Moreover,it manifests earlier in the postinfarct period(within the first 24h),in contrast with the nonreperfused AMI.Typically, early ruptures are of Type I and occur in AMI with large intramural hematomas that dissect the myocardium and rupture[35].Further unfavorable mechanical consequences of intra-myocardial hemorrhage could consist in increased myocar-dial stiffness,propensity to wall rupture,and delayed healing process.However,at present,the clinical implications of hemorrhagic vs.anemic infarcts remain undetermined and are based almost exclusively upon postmortem data. Prospective in vivo large-scale studies in patients with reperfused AMI are needed to assess the prognostic value of hemorrhagic AMI in terms of morbidity and mortality. Cardiac imaging techniques able to provide not only morpho-functional but also tissue characterization informa-tion,such as magnetic resonance with gadolinium enhance-ment[28],will be of help in solving these issues. 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