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Journal of Electrocardiolog

Magnetic resonance imaging as a potential gold standard forinfarct quantification

Marcus Carlsson, MD, PhD,a,b,⁎,1 Hakan Arheden, MD, PhD,b

Charles B Higgins, MD,a Maythem Saeed, DVM, PhDa

aDepartment of Radiology and Biomedical Imaging, UCSF, San Francisco, CA, USAbDepartment of Clinical Physiology, Lund University Hospital, Lund, Sweden

Received 6 June 2008; revised 18 June 2008; accepted 27 June 2008

Abstract Accurate diagnosis, characterization, and quantification of myocardial infarction (MI) is essential to

⁎ CorrespondingUniversity Hospital, 246151769.

E-mail address: m1 Address from S

0022-0736/$ – see frodoi:10.1016/j.jelectroc

assess the impact of therapy and to aid in predicting prognosis of patients with ischemic heartdisease. Delayed contrast-enhanced magnetic resonance (DE-MR) imaging has the potential of beingthe gold standard for quantification of MI. It has also been useful in correlating electrocardiographyabnormalities with the location and transmurality of infarction. The focus of this review is to addressthe strengths and limitations of DE-MR imaging in the detection and quantification of MI forclinicians and investigators in the field of electrocardiology. The biological rationale and technicalbackground for detecting MI by DE-MR imaging were reviewed as well as the different approachesfor quantification of the DE-MR images, exemplified by patient cases.© 2008 Elsevier Inc. All rights reserved.

Keywords: Infarct; Viability; ECG; MRI; Myocardium; Heart

Introduction

Ischemic heart disease and myocardial infarction (MI)remain the main causes for death in the industrializedworld. Myocardial viability and infarct detection isimportant in the prediction of functional recovery afterrevascularization and in risk stratification of patients withischemic heart disease. The most common method to detectMI is the 12-lead electrocardiogram (ECG). It is widelyavailable, noninvasive, can be placed next to the patient'sbed, and provides information on acute and chronic MI. Thevalidation of the ECG in localizing and quantifying MI hasrelied on either postmortem studies or indirect measurementof infarct size, for example, nuclear imaging or biochemicalmarkers. Contrast enhanced magnetic resonance (MR)imaging has been used in the assessment of coronary arterydisease using the wash-in and wash-out kinetics ofgadolinium-based contrast media during the first passthrough the myocardium and delayed contrast enhancement

author. Department of Clinical Physiology, Lund2185 Lund, Sweden. Tel.: +46 46173989; fax: +46

arcus.carlsson@med.lu.seeptember 2008 (until then UCSF, San Francisco).

nt matter © 2008 Elsevier Inc. All rights reserved.ard.2008.06.010

as a hyperenhanced region due to the increased distributionvolume of the contrast media in infarcted myocardium.More recently, delayed contrast enhancement (DE) MRimaging has been introduced, which can detect and quantifyMI with high accuracy and precision in the routine clinicalsetting.1 Therefore, this technique can be used as a goldstandard for increasing the capability of ECG in localizing,determining transmurality, and quantifying the size of MI.However, there is a need for a consensus on the imageacquisition protocol and image analysis.2 Furthermore,multicenter trials with larger patient populations to furtherestablish MR as the gold standard for infarct sizing areneeded3 and such studies are now being performed.Magnetic resonance imaging, as all other diagnostic tech-niques, has strengths and limitations, which will beaddressed in this review. The focus will be on the technicalbackground and biological rationale for detection of MIusing DE-MR imaging, the potential pitfalls when collect-ing the DE-MR images, how timing of infarct depictionyields different results and the different approaches inquantification of the DE-MR images.

Magnetic resonance imaging for infarct quantification

Cardiac MR imaging has evolved from a technique givinganatomical information, morphological and structural, to a

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technique yielding quantitative physiologic information;regional and global left ventricular (LV) function, bloodflow, and infarct characterization (localization, extent, andmicrovascular obstruction) (Figs. 1 and 2). Magneticresonance imaging does not require ionizing radiation ornephrotoxic-iodinated contrast media and is therefore suitedfor longitudinal studies in patients. MR contrast media havebeen used for defining cell necrosis.4 The DE-MR imagesare usually acquired in a stack of 10 to 12 parallel short-axis slices encompassing the LV to provide a quantitativemeasure of MI as percentage of LV mass. Long-axis imagesperpendicular to the short-axis are also obtained to provideinformation on the transmural extent of infarction. Aninfarct is ideally depicted in 2 roughly perpendicular imageplanes to decrease the possibility of artifacts beinginterpreted as infarction. This is especially important forsmall infarcts (Fig. 3). The time from contrast injection to

Fig. 1. A patient with a small myocardial infarct in the left anterior descendingadditional large infarct in the right coronary artery (RCA)-territory (white arrowheadviews of the heart. None of the infarcts are transmural, but the large subendocard

imaging is usually 10 to 40 minutes; therefore, these imagesare called delayed contrast-enhanced MR imaging. Thetime between contrast delivery and imaging allows forwashing out of the contrast medium from normal myo-cardium and diffusion of the contrast medium into infarctedmyocardium. The quantification of infarct size with DE-MR imaging has been extensively validated against trueinfarct size as verified by histochemical staining withtriphenyl tetrozolium chloride (TTC) in animal models(Fig. 2).5-9

Biological background

Myocardial viability can be demonstrated on Tl201 orTc99 single-photon emission computed tomography as apreserved cellular fraction, fluorodeoxyglucose-positronemission tomography as preserved glucose metabolism,

artery (LAD)-territory (gray arrowheads, anterior and apical wall) and ans, inferior wall). Left panels show long-axis and right panels show short-axisial infarct of the inferior wall will cause Q waves in the inferior leads.

Fig. 3. Small infarct (arrow) resulting from occlusion of septal coronarybranch demonstrated in long-axis (left) and short-axis (right) views. Toconfirm the presence of infarction on DE-MR imaging, images should beacquired in 2 planes perpendicular to each other. This minimizes the falsepositive reports of infarction.

Fig. 2. Comparison of DE-MR images acquired at 3 days after infarction and 50 days after infarction compared with histochemical staining (TTC) in a swinemodel. Microvascular obstruction is seen in the acute phase (arrow) as a dark (hypoenhanced) region surrounded by bright (hyperenhanced) infarct. There is asignificant decrease in infarct size (infarct resorption) between the acute and chronic phase (black arrowheads). The size and location of infarction does not differbetween DE-MR imaging and TTC (white arrowheads) performed at the same day (50 days after infarction).

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and on MR imaging as fractional distribution volume ofcontrast media. Gadolinium-based MR contrast media areused for delineation of acute and chronic MI. Theseextracellular agents distribute in the interstitium of themyocardium through diffusion because of their lowmolecular weight (0.8 kDa). Normal myocardium ismainly composed of 3 compartments, namely intravas-cular (approximately 10%), extravascular (interstitium,approximately 10%), and intracellular (approximately80%).10,11 Extracellular contrast media nonspecificallydistribute in the extracellular compartment that constitutes20% of the normal myocardial tissue. In an acuteinfarction, the cell membranes are disrupted and theformerly intracellular compartment is no longer separatedfrom the interstitium. In combination with interstitialedema, this results in a dramatic increase of space wherethe contrast media can distribute.10,11 In chronic infarc-tion, the abundance of collagen and the scarcity of cellsprovide a large interstitium for contrast media distribution.Additional cause for the differential enhancement ofinfarcted myocardium is that the myocardial kinetics ofthe contrast media differs in infarcted compared to normalmyocardium, with a delayed wash-out of contrast mediafrom the infarct.12 The DE-MR imaging depicts thisdifference in contrast media levels between normal andinfarcted myocardium.

Technical background

The DE-MR imaging gives the ability to detect small(Fig. 3) and large MI (Fig. 4) in the acute and chronic phase(Fig. 2). The ability to show differences in contrast levelsbetween infarcted and normal myocardium was firstdemonstrated in computed tomography,13 although thepercentage difference in attenuation between the infarctedand normal myocardium limited the technique. Thedifference in signal intensity between normal and infarctedmyocardium on MR imaging can be enhanced by applyingan “inversion-recovery pulse.” The time between theinversion-recovery pulse and image acquisition is calledinversion time. At this time point, the infarct has muchhigher signal intensity (typically 500%) compared tonormal myocardium. The in-plane resolution of the

acquired images is in the order of 1.5 × 1.5 mm in patientstudies. The resolution in the z-plane however is muchlower, typically 8 mm, which results in partial volumeeffects.9 Three major technical factors affect the size ofinfarction on DE-MR imaging: (1) the dose of contrast,14

(2) the time from contrast injection to imaging,15 and (3)the inversion time.16 However, as long as the inversiontime is set correctly to null the signal of normalmyocardium, infarct size will be unchanged using 0.1 to0.2 mmol/kg contrast, between 5 and 30 minutes afterinfarction.16,17 For each examination, the inversion timeneeds to be adapted individually to null the signal of normalmyocardium to obtain an optimal contrast between normaland infarcted myocardium.18

Image analysis

There are at least 3 different approaches to quantify MI onDE-MR images: (1) manual delineation, (2) automatedsegmentation, and (3) visual scoring (“semiquantification”).Manual delineation of the infarct is performed on DE-MRimages and the LV mass is obtained by delineation of theepicardium and endocardium, to get the hyperenhancedinfarct as a percentage of the left ventricle (LV). Thisapproach has apparent limitations such as interobserver and

-

Fig. 4. Patient with large apical aneurysm (arrowheads) caused by occlusion of the left anterior descending (LAD) coronary artery. Top row shows long-axisviews and bottom row short-axis views (as depicted by lines A, B, and C). In the basal short-axis slice (A), there is no infarct but in the midventricular view (B)transmural infarct is seen in the septum and anterior wall, 50 to 75 percent transmurality of the infarct of the lateral wall and no infarct in the inferior wall. In theapical short-axis view (C), there is a transmural infarct around the entire circumference of the LV. It is not difficult for an observer or a computer algorithm todifferentiate the infarct from normal myocardium. However, correct sizing of the infarct is dependent on an accurate delineation of the entire LV including thethin wall of the aneurysm.

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intraobserver variability, especially when comparing obser-vers from different centers. Furthermore, manual delineationis time-consuming. Automated segmentation of the DE-MRimages has been used to minimize operator dependence,decrease analysis time, and decrease the interobservervariability.19-21 Automated segmentations, using a thresholdof signal intensity (a fixed number of SDs above the normalmyocardium), have been used routinely, although differentnumbers of SD above normal myocardium have been

ig. 5. Example of the variability in infarct size measured by different analytical methods in a patient with infarct in the left anterior descending artery (LAD)rritory. Infarct quantification by manual delineation resulted in 24% of the LV, 2SD = 32%, 3SD = 29%, algorithm I = 21%, and algorithm II = 27%. Thesesults were obtained when using the same epicardial and endocardial contours for all infarct quantification methods. In addition, differences in the outline of theV contour can add further variability to infarct measurement. Therefore, it is important to standardize the analysis method of DE-MR imaging.

FtereL

proposed. Kim et al9 found excellent correlation (r = 0.97-0.99) with TTC in ex vivo MR images with high spatialresolution (0.5 × 0.5 × 0.5 mm) using 2SD above remotemyocardium. This approach has been used in several clinicalstudies.16,22-24 Heiberg et al19 and Bondarenko et al25 foundthat 2SD from remote on automated segmentation over-estimates infarct size in patients when compared to manualdelineation of infarction. Bondarenko et al also found that5SD above remote myocardium gave the most accurate

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results.25 In contrast, a study in dogs using in vivo imag-ing with image resolution similar to clinical scans andTTC, as gold standard, showed no significant correlationbetween infarction size by MR and TTC when using 5SDfrom remote.17 Most accurate results were obtained in thisstudy using thresholding with full-width at half maximum.Several more or less automated algorithms have beendescribed.19,26-29 Recently, the first algorithm that takesthe heterogeneity of the infarct as well as the partial volumeeffect into account was described and incorporated into afreely available software.21 The differences when quantify-ing the infarct size using different methods (Fig. 5) illustratethe need for consensus.2 It should be noted that even if theinfarct quantification per se is automated, the methods arestill dependent on a delineation of the endocardium andepicardium to calculate LV mass. Semiquantification ofinfarction using visual scoring has been used to expedite theanalysis of large clinical studies. In this techniques, themyocardium is divided into the 17 segments as proposed bythe American Heart Association,30 and each segment isgiven a score from 0 to 4 depending on the transmurality ofinfarct in the segment. Infarct size as percentage of LV iscalculated by summing the segments with delayed enhance-ment weighted by the visually scored transmurality ofenhancement for each segment divided by 17.31

Infarct evolution

The process of infarct healing involves regression ofedema in infarcted and periinfarcted myocardium, inflam-mation, resorption of necrotic tissue, and collagen scarformation—a process that takes about 1 month inhumans.32 During this period, a decrease in infarct size(infarct resorption) occur as well as LV remodeling. Infarctresorption has been described in animal models33,34 as wellas in humans.35,36 The LV remodeling is manifested by LVhypertrophy and increase in chamber volumes. Theopportunity to longitudinally depict infarct healing can beused in future studies making serial comparisons with ECG.Differentiation of acute from chronic MR is also importantin decision-making on revascularization in patients, butboth acute and chronic MI exhibit hyperenhancementregardless of age. Therefore, a technique using a triple-inversion-pulse sequence has been employed in patients toseparate acute from chronic infarction in patient withmultiple MI.37 This noncontrast technique can be used inadjunct with DE-MR imaging.

In more than 20% of the patients, MI does not necessarilyappear as a homogenous hyperenhanced region on DE-MRimaging in the first week after infarction, due to theoccurrence of microvascular obstruction. Microvascularobstruction38 is caused by microemboli as well as cellular,and extracellular edema that leads to inability of the contrastmedia to reach the core of the infarction. Therefore, theinfarct core appears dark surrounded by hyperenhancedinfarcted myocardium (Fig. 2). The size of no-reflow zonedepicted on MR imaging has prognostic significance and isan important determinant of LV remodeling in patients.39

When quantifying MI, the no-reflow zone should beincluded as infarct.

Magnetic resonance and ECG

The ability to use DE-MR imaging as a gold standardfor infarct size and location has enabled a new field ofclinical studies of the ECG in infarct characterization.40,41

The International Society for Holter and NoninvasiveElectrocardiography has introduced new terminology forthe location of MI in the LV wall that present Q waves.42

Quantification of infarct size with the Selvester QRSscoring system has been compared with DE-MR imagingas gold standard showing that QRS score was related toboth MI size and transmurality in patients with first-timereperfused MI.43,44 Presence of Q waves, however, was notindicative of transmural MI in these patients. Other studieshave demonstrated that Q waves are related to the size ofthe infarct size on DE-MR imaging45-47 and that theendocardial extent of reperfused first-time acute MI is morepredictive of pathologic Q waves than MI transmurality.48

ECG studies of the ST segment have also used DE-MRimaging as a gold standard. Martin et al49 showed thatconsiderations of both ST elevation and ST depression inthe acute phase increased sensitivity for acute MI detectionwith only a slight decrease in specificity. Tibrewala et al50

used DE-MR imaging to demonstrate the associationbetween infarct size and persisting ST elevation after MIin the chronic setting.

Recent studies have shown that the presence of aperiinfarction zone detected by DE-MR imaging in patientsinfluence the electrophysiology of the myocardium, makingit more prone to ventricular arrythmias and death.51-53

Furthermore, researchers found that the periinfarction zonegeometry determined the reentry circuits in postinfarctionarrhythmogenic dogs.54 Therefore, further studies on therelationship between the periinfarction zone and the electro-physiology are warranted.

Limitations of DE-MR imaging

The major limitations of DE-MR imaging are as follows:(1) it is not a bedside technique, (2) special devices (suchas defibrillator and ECG for ST monitoring) cannot be usedin the MR environment, (3) patients with contraindicationsfor MR imaging cannot be subjected to scanning, (4)patients with claustrophobia are not well suited for MRimaging, and (5) there is a need for cardiac MR-trainedtechnicians and cardiologists/radiologists. Initially, DE-MRimaging required a stable heart rhythm and the ability toperform a breath hold. However, technical advances inrecent years speeding up image acquisition have enabledDE-MR imaging even in patients with arrhythmia andinability to hold their breath. However, the image quality isoften comprised in these patients.

Conclusion

It can be concluded that DE-MR imaging is an accuratenoninvasive method for quantifying MI in patients andtherefore DE-MR imaging can be used as a gold standardin this regard. Because of the different image protocols(acquisition and analysis) and doses of contrast media being

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used, there is a need for establishment of a single protocol forassessment of MI. The advantages of the DE-MR imagingtechnique include the absence of ionizing radiation exposure,high spatial resolution and 3-dimensional coverage of theheart. Magnetic resonance also offers the advantages ofdemonstrating microvascular obstruction, edema, and infarctresorption. The precise quantification of acute and chronic MIcan be directly correlated to LV function and perfusion.

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