REVIEW

Imaging

MRI in acute myocardial infarctionMartina Perazzolo Marra1*, Joao A.C. Lima2,3, and Sabino Iliceto1

1Division of Cardiology, Department of Cardiac, Thoracic, and Vascular Sciences, University of Padua Medical School, Via Giustiniani, 2, 35128 Padua, Italy; 2Department ofRadiology, Johns Hopkins School of Medicine, Baltimore, USA; and 3Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, USA

Received 7 June 2010; revised 15 September 2010; accepted 15 October 2010; online publish-ahead-of-print 25 November 2010

Although acute myocardial infarction (AMI) is still one of the main causes of high morbidity in Western countries, the rate of mortality hasdecreased significantly. The main cause of this drop appears to be the decline of the incidence of ST-segment elevation myocardial infarction(STEMI) along with an absolute reduction in case fatality rate once STEMI has occurred. Myocardial ischaemia progresses with the duration ofcoronary occlusion and the delay in time to reperfusion determines the extent of irreversibile necrosis from subendocarial layers towardsthe epicardium in accordance with the so-called ‘wave-front phenomenon’. Coronary artery recanalization, either by thrombolitic therapy orprimary percutaneous intervention, may prevent myocardial cell necrosis increasing salvage of damaged, but still viable, myocardium withinthe area at risk. Magnetic resonance imaging (MRI) can provide a wide range of clinically useful information in AMI by detecting not onlylocation of transmural necrosis, infarct size and myocardial oedema, but also showing in vivo important microvascular pathophysiological pro-cesses associated with AMI in the reperfusion era, such as intramyocardial haemorrhage and no-reflow. The focus of this review will be onthe impact of cardiac MRI in the characterization of AMI pathophysiology in vivo in the current reperfusion era, concentrating also on clinicalapplications and future perspectives for specific therapeutic strategies.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywords Acute myocardial infarction † Pathophysiology † Magnetic resonance imaging

IntroductionAlthough acute myocardial infarction (AMI) is one of the majorcauses of morbidity in Western countries,1 mortality hasdecreased significantly and this drop appears to be the result ofthe decline in the incidence of ST-segment elevation myocardialinfarction (STEMI) along with the absolute reduction of overallmortality of AMI.2 The reduction of mortality for AMI is due tothe efficacy of current therapeutic strategies focused on an earlyreopening of the infarct-related artery, either by thrombolitictherapy or primary percutaneous coronary intervention (PCI),which represents the most effective way to limit infarct size (IS)and reduce transmural extention of necrosis. Reperfusiontherapy modifies traditional pathological features of AMI,because coronary artery recanalization can prevent the transmuralprogression of myocardial necrosis.3,4 Indeed, reperfusion afterprolonged coronary occlusion may develop into reperfusioninjury associated with impairment of microcirculatory flow andpossible further deterioration due to intramyocardial haemor-rhage. The pathological consequences of reperfusion strategiescan be currently detected in vivo by cardiac magnetic resonanceimaging (MRI), a non-invasive tool that allows the translation of

features previously studied only by experimental models frombench to bedside. Cardiac MRI can provide a wide range of infor-mation such as myocardial oedema (myocardium at risk), locationof transmural necrosis, quantification of IS and microvascularobstruction leading also to intramyocardial haemorrage.5 More-over, cardiac MRI provides an accurate and reproducible modalityfor the assessment of global ventricular volumes and function,6

representing the most powerful phenotyping tool for a globalevaluation of post-infarction remodelling. This review will demon-strate the impact of cardiac MRI in the in vivo assessment of thepathophysiology of AMI in the current reperfusion era, focusingalso on clinical applications and future perspectives for therapeuticstrategies.

Technical advantages of cardiacmagnetic resonanceCardiac MRI represents a non-invasive technique with increasingapplications in AMI providing the assessment of function, perfusionand tissue characterization in a highly reproducible manner duringa single examination even in patients with acoustic window

* Corresponding author. Tel: +1 39 049 821 8642, Fax: +1 39 049 8761 764, Email: martina.perazzolomarra.1@unipd.it

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010. For permissions please email: journals.permissions@oup.com.

European Heart Journal (2011) 32, 284–293doi:10.1093/eurheartj/ehq409

limitations (Figure 1).7 Cine MRI for evaluation of cardiac volumes,mass, and systolic function is considered a gold standard com-pared with other imaging modalities, since it does not apply geo-metric assumptions.6 The high values of reproducibility andaccuracy (standard error for left ventricular, LV, mass andvolume is about 5%) are particularly useful to reduce samplesize in clinical trials.6 –10 The steady-state free precessionsequences for cine images have replaced the older turbo gradientecho due to increased natural contrast between blood and endo-cardial border.11,12 Consecutive breath-hold short axis of theheart (temporal resolution of 50 ms or less) are used to obtainfunctional assessment: after delineation of endocardial and epicar-dial borders the summation of discs method is applied. Newthree-dimensional MRI acquisition offers the advantage to coverthe entire myocardium with a single breath hold of 20–30 s, butwith lower temporal resolution (100 ms).7 Regional myocardialfunction including wall thickening, evaluation and measures ofmyocardial strain may be perfomed.13

In patients with suspected coronary disease, myocardial per-fusion reserve measured by cardiac MRI yields high diagnosticaccuracy for the detection of flow-limiting lesions.12,14 PerfusionMRI is performed at rest and again during a vasodilator stressadministration (i.e. adenosine, dipyridamole) using a ‘first-pass’technique with fast intravenous injection of a gadolinium-basedcontrast agent.15,16 The myocardial signal increases in normal well-perfused myocardium, but not in the regions of myocardialischaemia.17,18

Tissue characterization by cardiac MRI is due to the evaluationof proton relaxation times T1 and T2. Currently T2 images areused in non-contrast approaches, whereas T1 sequences are

used for contrast-enhanced studies (i.e. previous citied firstpass). Increased myocardial water content increases signal onT2-weighted images, such as inflammation. Myocardial oedema inthe acute phase of myocardial infarction can be visualized as abright signal on T2-weighted images, defining ‘myocardium atrisk’.19– 21 The major advantages of this technique are to distinguishchronic from acute infarction,22 and to quantify the proportion ofmyocardial salvaged assessed retrospectively by comparingT2-weighted oedematous size and late enhancement images.23

Late gadolinium enhancement (LGE) images are T1-weightedinversion recovery sequences acquired about 10 min after intrave-nous administration of gadolinium and the inversion time is chosento null myocardial signal24 using ‘inversion time scout’ or ‘looklocker’ sequences. Gadolinium is an extracellular agent, whichenhances its distribution volume in certain conditions such asnecrotic or fibrotic myocardium, assuming a bright signal (hyperen-hancement), opposed to dark viable myocardium.25 Cardiac MRIhighlights the region of scar or fibrosis as small as 0.16 g26,27 andthe reproducibility is high with a coefficient of reproducibilityreported equal to+2.4% of LV mass in chronic setting.28 Thepattern of LGE is useful to differentiate post-infarction necrosis(subendocardial or transmural LGE) (Figure 2) from fibrosis in non-ischaemic dilated cardiomyopathies (mid-wall LGE, subepicardialLGE), or myocarditis (subepicardial or focal LGE) (Figure 3).Delayed post-contrast sequences are currently used also to evalu-ate persistent microvascular dysfunction/damage: in the context ofwhite LGE regions (infarcted myocardium) may coexist darkhypoenhanced areas, traditionally referred to as microvascularobstruction. Microvascular obstruction has been initially definedas hypoenhancement at 1–2 min after gadolinium injection;25,29,30

Figure 1 A complete cardiac magnetic resonance protocol is summarized in this figure taking into account the pathophysiological substratesunderlying different MRI findings. SSFP indicates steady-state free precession; IR GRE, inversion recovery gradient echo; LV, left ventricle; RV,right ventricle; AAR, area of myocardium at risk.

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however, persistent microvascular damage is currently evaluatedon delayed post-contrast sequences.31

Myocardial ischaemia: area at riskDuring the early phase of a coronary occlusion, the subsequentdiscrepancy between myocardial oxygen supply and demand leadto myocardial ischaemia, characterized by a specific pattern ofmetabolic and ultrastructural alterations.32 If ischaemia persists,

myocardial injury becomes irreversibile and the necrosis extendsfrom the subendocardium towards the subepicardium in accord-ance with the ‘wavefront phenomenon’ described initially byReimer and Jennings.3,4 The final IS depends mainly on theextent of the so-called ‘risk area’, defined as the myocardial arearelated to an occluded coronary artery with complete absenceof blood flow, either antegrade or collateral.33 Up to now, myo-cardium at risk has been measured by single photon emissioncomputer tomography (SPECT)34 using the injection of a

Figure 2 Different extent of necrosis visualized by cardiac magnetic resonance. The patient represented on panel A shows a non-transmuralmyocardial infarction detected by late gadolinium enhancement extending for 25% on the entire thickness of the antero-septal wall. On thecontrary, the T1 IR post-contrast sequence of patient B shows a transmural bright anterior and septal myocardial infarction.

Figure 3 Different late gadolinium enhancement patterns. The pattern of late gadolinium enhancement is useful to differentiate necrosis dueto myocardial infarction from fibrosis in different conditions. The patient presented in panels A and B shows a typical epicardial pattern of lategadolinium enhancement in the inferior and infero-lateral wall, suggesting a myocarditis. The intramyocardial deposition of late gadoliniumenhancement on interventricular septum (‘mid-wall’ pattern) on panels C and D is typical for primary dilated cardiomyopathy.

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technetium-based tracer before opening of the occluded vessel,and by contrast echocardiography.35 Recently, cardiac MRI isused to visualize and to quantify the area at risk since increasedmyocardial signal intensity depicted by T2-weighted sequencesare very sensitive to water-bound protons indicating an increasedwater content with an active myocardial inflammation and tissueoedema. The concept of infarct-related oedema was initially eval-uated on animal models of AMI, in which a linear correlationbetween myocardial-free water content of the infarcted regionand prolongation of its T2 relaxation time is demonstrated.19 Sub-sequent experimental studies have shown that the area of high T2signal abnormality closely matched the area at risk determined onhistology.36,20 In particular, Aletras et al.20 have demonstrated in ananimal model, with 90 min of coronary occlusion followed byreperfusion, that the area at risk measured by microspheres wascomparable with the area of increased signal on T2-weightedimages 2 days later. At first, the application of T2-weightedimaging in the clinical setting is used to differentiate acute fromchronic myocardial infarction.22 However, the most importantapplication of MRI ischaemia-related oedema regards the

evaluation of ‘salvaged myocardium’ (Figure 4). Cury et al.37 haverecently applied T2-weighted imaging to improve the accuracy inthe diagnosis of myocardial ischaemia in patients arriving to theemergency room with acute chest pain, negative biomarkers andinconclusive ECG. However, the most intriguing application isthe possibility to assess quantitatively the reversible and irrevers-ible injury in reperfused AMI. Experimental data have shown thatin AMI the area with high T2 signal exceeds that of irreversibleinjury. In fact, Choi et al.38 have demontrated in a pig model thehigh signal on T2-weighted images reflects both irreversible andreversibly injured, but essentially the viable, peri-infarct zone. Onthis basis, Friedrich et al.23 have compared T2-weighted imageswith LGE to visualize reversible and irreversible myocardialinjury, respectively. Thereafter, many clinical studies have evaluatedthe potential of MRI to assess myocardial oedema39 –41 in compari-son with well-established techniques.42 However, the recent inter-ventional study performed by Francone et al.43 represents acornerstone for future investigation for the application of thecounterwise area of myocardium at risk in the clinical setting. Inthis study,43 the concept of reduction of total viable myocardium

Figure 4 Myocardium at risk represents the myocardial area related to an occluded coronary artery with complete absence of blood flow.An example of ‘risk area’ on septal wall (hyperenhancement) is described on panel A on T2-weighted images, the so-called ‘remote myocar-dium’ with normal blood flow appears dark, without signs of oedema, on the lateral wall. In the example B myocardial at risk (oedema) onanterior, septal and inferior wall is shown: note inside the hyperenhancement on T2-weitghted images the presence of a hypoenhancementcore suggesting intramyocardial haemorrhage. Panels C and D represent a case of acute septal myocardial infarction. Panel C shows T2-weightedimages with transmural oedema extending toward all septal wall even partially in the inferior and anterior wall (black asterisk). Panel D showsthe same slice after delayed contrast injection: note that the bright signal intensity shows a late gadolinium enhancement extent of 75% of theentire segment only in the anterior septal wall. Note the absence of late gadolinium enhancement in the previous areas involved by oedema(white arrows), representing area of myocardium at risk.

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amount in proportion to the delay on time-to-reperfusion isdemonstrated in vivo: in particular, the salvaged myocardium (quan-tified as the difference between area of increase T2 signal and areaof LGE) is markedly reduced (2.1%) when reperfusion occurs .

90 min after coronary occlusion in contrast with 8.5% in patientswith ≤90 min of delay.

Progression of necrosis: viabilityAccording to the concept of ‘wavefront phenomenon of myocardialdeath’,4 IS increases, extending from the endo to the epicardiumwith an increasing duration of coronary occlusion. If ischaemia per-sists, myocardial injury becomes irreversible, usually between 20and 45 min after coronary occlusion: a prompt coronary lumenrecanalization is able to prevent the progression of necrosisleading in some cases to an ‘aborted AMI’. The major determinantof final transmural necrosis and microvascular damage is the dur-ation of ischaemia, as recently demonstrated in vivo by MRI.43,44

Beyond the potentially reversible events (ischaemia andoedema), cardiac MRI can be used for assessment of the extentof the irreverrsible necrosis using delayed contrast-hyperenhancedimages. Non-viable infarcted tissue is usually seen on MRI as a‘hyperenhanced’ area after contrast injection, so-called LGE(Figure 2). In the setting of AMI, the extracellular space is expanded,also by oedema and inflammation, and the contrast agent entersthe intracellular space through damaged cell membranes. TheLGE assessment has been validate against animal models25 and rep-resents a permanent memory of myocardial injury even after theacute phase of infarction.45 However, in the first days after AMI,LGE is more extensive compared with the chronic phase, whenthe healing process is complete. Oshinski et al.46 using a ratmodel of AMI, showed that, immediately after contrast injection,the enhanced region overestimates the true IS, on histology, by20–40%. Saeed et al.47 have suggested that LGE does not occurexclusively in regions with myocardial necrosis but also involvesthe border zones of injured but viable myocardium surroundingAMI. Other clinical studies have observed an initial overestimationof IS that gradually decreases over time. Recently, Ingkanisornet al.48 have found that IS on MRI appeared to diminish in sizeon follow-up from 16+12 to 11+ 9% (P , 0,003). The samereduction on IS was noted by Hombach et al.31 in a large popu-lation study. Baks et al.49 evaluating the effects of primary PCI onearly and late IS described a 31% decrease in LGE between5 days and 5 months. More recently, LGE extent has been evalu-ated during the hyperacute phase of STEMI: Larose et al.50 haveperformed in STEMI patients a cardiac MRI within 12 h ofprimary PCI and at 6 months discovering a reduction in LGEvolume from 22 to 16% (P ¼ 0.01).

These observations are notable from a clinical point of view,even if the measurement of IS by MRI is highly reproducible,28

the chosen time of imaging along the healing process can yielddifferent results. The reduction of IS associated with the healingprocess is 25% of initial size over 4–6 weeks. However, theimproved reproducibility of LGE with detection of smallerchanges in IS allows for substantial reduction in sample size forclinical trials,51 even when one takes into consideration variabilitybetween patients.52

Another technical issue to take into account when comparingISs in different AMI populations is the dose of gadolinium used.In a recent international multicentre trial,53 the sensitivity of LGErose with increased gadolinium dose, reaching 99 and 94% inacute and chronic myocardial infarction, respectively, with the0.3 mmol/kg dose.

The measurement of LGE seems to provide additive value as apredictor of adverse outcomes after AMI above ejection fraction.Before recent studies on AMI,50,54 IS within 1 week from AMIwas directly related to LV remodelling and was a stronger predic-tor of future events than measures of LV systolic performance.55

More recently, Larose et al.50 demonstrated that the occurrenceof LV dysfunction at 6 months invariably increased with greaterLGE: a cut-off of ≥23% LGE measured on hyperacute MRIshowed the best accuracy for late LV dysfunction (sensitivity89%, specificity 74%).

After the healing process is completed and necrotic tissue hasbeen replaced by a scar,56 MRI provides clinically relevant infor-mation concerning viability. Cardiac MRI offers a unique tool toassess multiple interrelated clinical markers of viability in a singletest with a limited time consumption, moreover considering thatLGE technique together with cine MRI takes no more than30 min to perform. Scintigraphic techniques and stress echocardio-graphy have been so far considered the mainstay of viability diag-nosis. However, the role of MRI in the assessment of myocardialviability is rapidly increasing as it has the advantage of being per-formed under resting conditions, without exposing the patient toradiation. Stress echocardiography with low dose of dobutaminerepresents an inexpensive imaging tool for viability evaluation.However, the high inter-observer variability and inter-individualdifferences in image quality for echo-stress imaging explain thelower sensitivity compared with LGE technique.57 Moreover, inthe setting of AMI a pharmacological stress is not usually indicated.Initially in an experimental model, Hillenbrand et al.58 have demon-strated that LGE is not detected in regions with severe but revers-ible ischaemic injury and that there is an inverse relationshipbetween the transmural extent of necrosis and recovery of func-tion. The first clinical application of MRI to identify reversible myo-cardial dysfunction has been made by Kim et al.59 who havedetermined the accuracy of MRI in predicting recovery in aseries of patients with chronic coronary artery disease and LV dys-function undergoing myocardial revascularization. In the assess-ment of myocardial viability in AMI patients, when the extent ofLGE is ,50% the likelihood for functional recovery is efficient.60

Direct comparison with PET, as a gold standard, has shown excel-lent results.61,62 In particular, Klein et al.,61 performing MRI andPET within 1 week in patients with ischaemic disease and LV sys-tolic dysfunction, have found a good correlation between thetwo tests. Notably, more than half of subendocardial infarcts,which have been detected by MRI, have been classified asnormal by PET. Kuhl et al.62 have found similar results with 36%of segments normal by PET, but showing subendocardial LGE onMRI. When comparing SPECT imaging, the main advantage ofMRI LGE is its spatial resolution of 1–2 mm (in plane), contraryto about 10 mm with SPECT scans.63 Therefore, MRI can identifysubendocardial necrosis when perfusion by SPECT appears unal-tered.37,64 Wagner et al.63 discovered the improvement in infarct

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detection for LGE vs. SPECT with an elegant animal and clinicalstudy. Similar to animal data, this study has shown that SPECTdetection of LGE-evidenced infarcts varied according to transmuralextent: among segments with near transmural LGE (involving.75% wall thickness), all show evidence of infarct by SPECT, onthe contrary segments with subendocardial LGE (involving,50% wall thickness), SPECT detected infarct only in 53%.Other studies have provided further evidence that LGE identifiesmyocardial infarctions that are undetected by SPECT.65,66 Evaluat-ing patients early after AMI, Ibrahim et al.64 have compared MRIwith SPECT using troponin elevation as the reference standard,and has discovered that cardiac MRI was significantly more sensi-tive than SPECT for the detection of small infarcts and infarctionin non-anterior region.

Reperfusion injury: no-reflowphenomenon, microvascularobstruction and haemorrhageEven if coronary artery flow recanalization represents the mosteffective way to reduce IS, the process of reperfusion may itselfproduce a series of consequences described in experimentalsetting,67 including myocyte death, microvascular damage with‘no reflow’ phenomenon, stunned myocardium and reperfusionarrhythmias. The clinical relevance and also the most accuratetool to visualize and quantify microvascular damage secondary ornot to reperfusion injury remains to be identified and so far,there is no definitive consensus regarding the best imagingmodality. In this clinical scenario, it is reasonable to assume thatcardiac MRI may represent a cornerstone imaging tool yet vali-dated against established traditional techniques (i.e.contrast-echocardiography). In one of the first experimentalstudies Judd et al.25 correlated the MRI findings with pathology,by thiflavin-S staining, using a reperfused canine infarct model.The authors demonstrated that hypoenhancement within brightregions of LGE on delayed post-contrast sequences, so-called‘dark zones’, were areas of no-reflow. In humans, Lima et al.29

described a well-defined time–intensity curve of different areasof enhancement occurring in human myocardial infarcts, on thebasis of the wash-in and wash-out kinetics of contrast agent. Inagreement with these observations, the assessment of microvascu-lar damage had been performed using MRI first-pass perfusion andthe delayed post-contrast sequences.68 However, Lund et al.69

found differences in sensitivity between first-pass and delayedhypoenhancement, which was confirmed by recent studies.70 Cur-rently, it is generally accepted that delayed hypoenhancement isless sensitive than first pass because small no-reflow zonesbecome rapidly enhanced owing to diffusion of the extracellularcontrast medium from surrounding regions without impairedmicrovasculature. Moreover, the persistence of a hypoenhance-ment on delayed contrast sequences (10–20 min after injection)seems to characterize a persistent miscrovascular damage31

(Figure 5). In conclusion, a complete protocol, including both tech-niques, should be performed in the current evaluation of AMI bycardiac MRI.

More recently, microvascular damage detected by MRI has beenevaluated in comparison with coronary Doppler flow reserve.Hirsch et al.71 found that the typical presence of early systolic ret-rograde flow associated with no-reflow on intracoronary flowmeasurements was associated with the presence of microvascularobstruction assessed on LGE images. Furthermore, multivariateregression analysis revealed that the extent of microvascularobstruction on MRI was the only independent factor related toearly systolic retrograde flow and diastolic deceleration rate.Cardiac MRI features of reperfusion injury have been comparedalso with well-known angiographic perfusion parameters likeTIMI (thrombolysis in myocardial infarction) flow and myocardialblush grade (MBG). In a recent study by Appelbaum et al.72 in21 patients who underwent successful primary PCI and MRI, evi-dence of impaired perfusion at first pass was present in 90% ofcases with post-PCI myocardial perfusion grade (0/1/2), but onlyin 18.2% with normal one. Porto et al.,73 by analysing 27 patientswith AMI, found a linear correlation between decreasing MBGand MRI signs of vascular obstruction, thus confirming the relation-ship between post-PCI reperfusion index and MRI measures ofmicrovascular impairment. However, recently Nijveldt et al.70 didnot find any statistically significant relationship between early orlate microvascular obstruction and TIMI flow or MBG in 60patients with AMI treated with primary PCI. Larger multi-centrepopulation studies are needed to verify the relationship betweenangiographic perfusion indexes and MRI for the detection of micro-vascular damage.

Cardiac MRI features of no-reflow also have prognostic signifi-cance in terms of clinical outcome30,31 and changes in LVvolumes.31,74 Even if the ‘dark zones’ on MRI indicate poor prog-nostic significance, the real mechanism underlying these featuresis not yet well understood in human AMI, since no-reflow rep-resents a complex time-sensitive phenomenon, which remains tobe fully understood. In fact, the ‘no-reflow phenomenon’ refersto absent distal myocardial reperfusion after a prolonged periodof ischaemia, despite the culprit coronary artery’s successful reca-nalization,75 and likely secondary to both luminal obstruction (i.e.neutrophil plugging, platelets, atherothrombotic emboli) and exter-nal compression by oedema and haemorrhage. The haemorrhagicAMI reflects the metamorphosis of ischaemic infarcts in the ‘reper-fusion era’,76 and are commonly observed after prolonged ischae-mia once myocardial cell necrosis is well established.Garcia-Dorado et al.77 have discovered in an experimental modelthat microvascular damage is an early event, and that intramyocar-dial haemorrhage plays a role later in reperfusion injury. Microvas-cular cell damage causes leakage of blood out of the injured vesseland the subsequent healing process is characterized by haemo-globin degradation. As for intracranial haemorrhage, MRI canenhance tissue characterization through changes in relaxationtimes T1 and T2, reflecting changes in image signal intensity.19 Byassessing the paramagnetic susceptibility effects of deoxyhemoglo-bin, we have recently78 confirmed previous experimental obser-vations79 in which dark areas on post-contrast inversionrecovery sequences indicate not only the presence of microvascu-lar obstruction, but also of intramyocardial haemorrhage. Asshown in experimental models80 the extent of the hemorrhagicarea correlates with the size of ‘dark zones’ on LGE sequences;

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these preliminary results are confirmed by clinical studies81,82 andelucidate the clinical significance of intramyocardial haemorrhage.In a large population study, patients with haemorrhagic AMI haveshown a lower pre-PCI TIMI flow; moreover the area at risk, ISand ratio of IS to area at risk were significantly larger.5 Further-more, the size of ‘dark zones’ on post-contrast images islarger, and interestingly present in all patients with haemorrhagicAMI. Recently, Beek et al.83 have confirmed that the hypoenhance-ment on T2-weighted images, suggesting intramyocardial haemor-rhage, is present in the majority of patients with dark zones on LGEand also closely related to markers of IS and function. However, ithas no prognostic significance beyond delayed hypoenhancement.

Of note, in both studies, no differences in time from onset ofsymptoms to revascularization between haemorrhagic and non-haemorrhagic AMI patients has been found, suggesting thatfactors such as the magnitude of collateral flow, preconditioning,and others may influence the final outcome of myocardial revascu-larization. In this regard, cardiac MRI is currently the only non-invasive, reliable and reproducible imaging technique that maydetect the presence of haemorrhage. Despite emerging studiesabout the presence of intramyocardial haemorrhage onT2-hypoenhancement, experimental validation by histology islacking. Further studies with comparable protocols and reperfusion

strategies are necessary to clarify the clinical role of haemorrhagebeyond microvascular obstruction, since it still remains unclearwhether haemorrhagic AMI are at increased risk of rupture orwhether they are just a marker of myocardial reperfusion.75

Significance of MRI findings toventricular remodellingDelayed reperfusion therapy may increase IS and lead to adverse LVremodelling due to infarct expansion, thinning of the necroticsegment associated with dilatation, as well as compensatory hyper-trophy of remote myocardium. Cardiac MRI measures of ventricularvolumes and mass are more accurate and reproducible than otherimaging techniques (Figure 6). In this regard, MRI is particularly suit-able for the study of large infarcts with aneursimatic ventricularchamber dilatation since LV volume and mass evaluations are inde-pendent from geometric assumptions. Since the first clinicalstudies by Wu et al.30 and Hombach et al.,31 it has become clearthat IS, transmural infarction and persistent microvascular damageon delayed post-contrast images are strong predictors of adversepost-infarct remodelling over and above other clinical parameters.Further clinical studies confirmed that IS was the main determinant

Figure 5 After a prolonged ischaemia the necrosis becomes transmural and as final consequences a microvascular damage may appear insideinfarction. On T1 inversion recovery post-contrast sequences, the persistent microvascular damage appears dark (so-called ‘dark zones’) (whiteasterisks) in the middle of late gadolinium enhancement, representing the myocardial necrosis on the inferior wall on panel A (note the involve-ment of right ventricular inferior wall seen as an intense late gadolinium enhancement), and antero-spetal wall on panel B. Panels C and D showthe same patient: on C a transmural late gadolinium enhancement on the antero-septal wall with a dark zone is shown, smaller than exampleB. Panel D represents the T2-weighted sequences of the same patient: inside the oedema (bright signal on anterior and septal wall) can bedetected a hypoenhancement core suggesting intramyocardial haemorrhage and corresponding to the dark zone on delayed post-contrastsequence.

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of LV volumes.84,85 In a 76 patient population86 we have also demon-strated that the (per patient) number of LV segments with trans-mural necrosis have additional predictive value for early LVremodelling independently of microvascular damage; by receiveroperating characteristic analysis, the presence of four LV segmentswith transmural necrosis represents a powerful predictor ofadverse remodelling after primary PCI. Recently, Lund et al.87 haveconfirmed that IS on MRI is a stronger predictor of remodellingthan microvascular damage; on the contrary Nijveldt et al.70 havefound that the presence of microvascular obstruction, and not itsextent, is the most powerful predictor of changes in global functionand LV end-systolic volume at follow-up. The more severe microvas-cular damage indexed by intramyocardial haemorrhage onT2-weighted images also has a prognostic role relative to adverseremodelling. Indeed, Ganame et al.5 have demonstrated on multi-variate analysis that myocardial haemorrhage is an independent pre-dictor of adverse LV remodelling, independently of the initial IS.

Novel cardiac MRI parameters have emerged as possible potentialindices of adverse remodelling, and the most attractive, from aphysiopathological point of view, is myocardial salvaged. So far,the most widely practiced technique for measurement of myocardialsalvaged is SPECT.88 However, using SPECT there are some limit-ations, such as poor spatial resolution. Furthermore, this techniquerequires the injection of the tracer immediately and the SPECTimaging within a few hours after revascularization. Another tech-nique may be contrast echocardiography with intravenous or intra-coronary injection of microbubbles before revascularization of theinfarct-related artery.89 Cardiac MRI is a simple ‘one-stop-shop’tool to evaluate myocardium at risk and myocardial necrosisduring the same examination early after AMI, evaluating oedemaon T2-weighted images. Francone et al.43 recently showed thatthe presence and the extent of salvaged myocardium markedlydecreases when reperfusion occurs after . 90 min of coronaryocclusion. Therefore, only the patients reperfused early (within90 min) have shown a significant increase in LV ejection fraction.Based on this concept, Masci et al.90 have recently found in a

prospective cohort of 137 patients that ‘myocardial salvage index’is independently associated with adverse LV remodelling. These find-ings remain unchanged after multivariate analysis and correction forthe occurrence of microvascular obstruction, infarct transmuralityand baseline ejection fraction. More recently, Eitel et al.54 have con-firmed that myocardial salvaged index is the strongest predictor ofmajor cardiac events and mortality at 6-months follow-up.

The capability of cardiac MRI to be a comprehensive phenotyp-ing tool to demonstrate in vivo the complex pathophysiology ofAMI opens new perspectives in the evaluation of the efficacy ofnovel reperfusion strategies and therapies.

Role of MRI on mechanical andarrhythmic complications afterAMICardiac MRI allows the possibility to detect the majority of mech-anical complications following AMI. Isolated case reports havedefined the role of MRI in myocardial wall rupture detection91

moreover, in clinical studies other complications such as pericar-dial enhancement suggesting inflammation, as well as pericardialeffusion have been described. Interestingly, LGE on MRI hasdetected right ventricular involvement in association with inferiorAMI more frequently than current standard techniques:92 this isimportant because in these patients, the right ventricular ejectionfraction represents a significant predictor of prognosis.93

In addition, the detection of ventricular thrombi by MRI, in par-ticular with early gadolinium enhancement is superior to that ofechocardiography, defining morphological delineation and spatialextent (Figure 1). Application of LGE sequences for LV thrombosisdetection has been reported to be superior than cine MRI and echo-cardiography.94 In patients undergoing surgical LV reconstruction, acomplete cardiac MRI protocol has shown higher sensitivity (88%)and specificity (99%) compared with transthoracic (23%, 96%) andtransoesophageal (40%, 96%) echocardiography. Long-inversion-time imaging has been suggested to increase accuracy for thrombidetection.95 Moreover, the total amount of LGE by MRI has beendemonstrated to be a risk factor for thrombus deposition.95

A novel potential application of MRI regards the identification ofpossible arrhythmic risk areas. In preliminary clinical studies,96,97

through MRI, the peri-infarct zone is portrayed by the visualizationof a grey border zone near the central infarcted core. This ‘greyzone’ has been related to post-infarction mortality as well as induci-bility, during electrophysiological studies. Further studies in the acutesetting of AMI, possibly using novel molecular imaging techniques,may clarify the role of the peri-infarct zone as an early predictorof ventricular arrhythmias as well as giving a more complete under-standing of the substrate for arrhythmias in the heterogeneous ‘greyzone’ including the potential roles of oedema and inflammation.

Cardiac MRI value for differentialdiagnosis assessmentCardiac MRI may be very useful in the emergency room for therapid assessment of extra-cardiac causes of chest pain and

Figure 6 The adverse left ventricle remodelling after myocar-dial infarction. Cardiac magnetic resonance shows a large apicalaneurism of left ventricle: the bright late gadolinium enhancementdelineates the thinned infarcted wall, note the massive thrombo-sis inside the aneurism (white asterisk).

MRI in acute myocardial infarction 291

mostly because it offers the opportunity to identify areas of in vivoinflammation and replacement fibrosis. Combining cine-images andtissue characterization sequences (T1, T2 weighted), Assomullet al.98 have evaluated the role of cardiac MRI in patients withchest pain, elevated troponins and unobstructed coronary arteries.The most common diagnosis has been myocarditis (50%), followedby myocardial infarction despite coronary angiography (11.6%),thus providing a new diagnosis in 65% of patients, and excludingsignificant pathologies in the others. Recently, Bacchoucheet al.99 have elucidated the diagnostic performance of MRI andendomyocardial biopsy in patients with troponin-I positive acutechest pain in the absence of significant coronary artery disease.In these 82 subjects a MRI diagnosis of myocarditis has beenmade in 58%; typical LGE for infarction in 5%, 1% hypertrophic car-diomyopathy, 1% dilated cardiomyopathy, and non-conclusive MRIin 20%. Typical apical ballooning findings without LGE depositionhave been found in 15% and have been considered diagnostic fortako-tsubo cardiomyopathy. Moreover, comparison of diagnosticMRI procedures with the corresponding diagnostic endomyocar-dial biopsies have demonstrated a substantial match of diagnoses(kappa ¼ 0.70).

Further studies to evaluate the accuracy of cardiac MRI vs. his-tology and the prognostic significance of LGE patterns in patientswith normal coronary arteries are needed to improve the clinicalimpact of MRI.

Cardiac MRI safety implicationsCardiac MRI has been traditionally considered a non-invasiveimaging tool; however the presence of a magnetic field and con-trast administration involves even safety issues that need to beexplained. Also the MRI scanner room, with the presence ofstatic and gradient fields may interact with ferromagnetic objectsand this may cause electric currents. Finally, the body scannermay transmit radiofrequency waves into the patients. Because ofthese factors patients are screened for implanted cardiovasculardevices prior to undergoing MRI.100 Potential complications ofMRI examinations in patients with pacemaker or implantablecardioverter defibrillator (ICD) include damage or movement ofthe device, inhibition of the pacing output, induction of life-threatening arrhythmias, cardiac stimulation, heating of the elec-trode tips.101 –103 Currently, an MRI terminology has beenintended to elucidate matters related to biomedical implants anddevices to ensure the safe use of MRI technology. This classificationincludes the following definitions: (i) ‘MRI safe’, no hazards in allmagnetic resonance environments, (ii) ‘MRI conditional’, noknown hazards in a specific MRI environment with constraintson the specific conditions of use, and (iii) ‘MR unsafe’, hazards inall magnetic resonance environments.104 Recently, a now commer-cially available Advisa DR MRITM MRI device (Medtronic, Inc., Min-neapolis, MN) has been implanted, and it is the second generationSureScan pacemaker designed to minimize the potential inter-actions with the electromagnetic fields used for MRI systems.Moreover, the patient positioning restriction for the Advisa MRISureScan Pacing System has been removed, allowing for the firsttime scans of the chest area. However, cardiac MRI examinationof patients with pacemakers is discouraged and the European

position paper specified a group at very high risk (pacemaker-dependent) in which indication has to be re-considered, andlow-risk patients (pacemaker- non-dependent). Cardiac MRI exam-ination in patients with ICD should not be performed unless thecentre is highly experienced and only when the benefits expectedoutweigh the risks taking into account even the possibility of arte-facts due to device.105 However, for both devices a full interrog-ation prior and immediately after MRI scan has to be done andrepeated 1 week and 3 months later.

Finally, regarding coronary artery stents, data currently availableindicate that many of these could be considered as ‘safe’,106,107

including drug-eluting stents.108

The second important issue on safety regards contrast adminis-tration related to nephrogenic systemic fibrosis (NSF) that mayoccur after exposure to the extracellular non-ionic low osmolargadolinium-based contrast agent gadodiamide. Nephrogenic sys-temic fibrosis is a systemic fibrosing disorder that principallyaffects the skin, but can involve virtually any tissue in the humanbody. In subjects with normal renal function, free gadolinium isremoved through the kidney with a half-life of approximately 3 h;in patients with impaired renal function, this half-time is significantlylonger.109 So far, NSF has not been described in patients with pre-served renal function. Current risk factors for NSF include princi-pally acute or severe renal failure due to advanced chronic kidneydisease (glomerular filtration rate ,30 mL/min/1.73 m2). More-over, other clinical characteristics possibly implied are severeliver failure, peri-operative liver transplant, kidney transplant,hepatorenal-syndrome, thrombophilia. Taking into account allthese risk factors and gadolinium exposure, the 1-year incidenceof NSF has been estimated to be between 1 and 4.6%.7 Since atherapy for NSF is not yet established, it is fundamental to evaluaterenal function in the context of AMI since patients treated withprimary PCI may have kidney failure for nephrotoxicity of iodinecontrast media.

Future perspectives:developments and clinicalapplicationsCardiac MRI represents a promising modality for a tissue charac-terization of AMI, beyond traditional morpho-functional indexes.Moreover, cardiac MRI parameters may in the future be usedwith greater frequency as surrogate imaging end points of morbid-ity and mortality for testing novel therapeutic strategies as in thecase of pharmacologic interventions and cellular-based therapies.Another important question to address in the future is thefurther determination of the true prognostic significance of themany parameters evaluated by MRI in patients with AMI. Prognos-tic stratification is important for STEMI to better stratify patients atrisk of negative ventricular remodelling. However, even for non-STsegment elevation acute coronary syndromes cardiac MRI rep-resents a promising tool to identify new prognostic parametersto select patients for an early invasive management.110

The most well-recognized MRI features used to evaluate noveltherapies are IS and microvascular obstruction. For example, theeffect of cyclosporine, administrated at the time of reperfusion,

M.P. Marra et al.292

has been tested using IS and LV remodelling as end points of thera-peutic intervention.111 In addition, contrast-enhanced MRI has alsobeen used to define the effect of intracoronary stem celltherapy.112 Similarly, MRI is applied to assess the next generationof techniques utilized to manage no-reflow, including the appli-cation of devices to prevent distal microembolization. In thisregard, IS measured by MRI has been recently used to evaluatethe impact of a manual thrombectomy device.113

Ongoing research will be directed to standardizing the cardiacMRI protocol and to evaluating in large multi-centre populationstudies the significance of different imaging features for clinicaloutcome, arrhythmogenic risk stratification and remodelling.Finally, future technical improvements, such as molecular imaging,will likely enable a better understanding of reperfusion injury andthe natural repair mechanisms following AMI as well as the biologicdeterminants of LV remodelling including neovascularizationthrough angiogenesis.114

AcknowledgementsThe authors thank Barbara Hildenbrand for her professionalsupport and Dr Francesco Corbetti for the images obtained.

Conflict of interest: none declared.

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