assessing myocardial recovery following st-segment elevation myocardial infarction: short- and...

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Obraztsov and Strazhesko described survival of myocardial infarction in humans in the late 19th century [1]. Since then, enormous efforts have been made to improve outcome after myocar-dial infarction. Ever since the late 1970s when it was observed that β-blocker therapy [2] and intracoronary reperfusion strategies [3,4] enable a reduction in infarct size, the preservation of left ventricular ejection fraction (LVEF) is one of the major therapeutic targets in patients after acute ST-segment elevation myocardial infarction (STEMI). Because it is easy to measure non-invasively, LVEF is the parameter of choice to assess left ventricle (LV) recovery after STEMI. Primary percutaneous angioplasty has proven to be superior to thrombolytic strategies in STEMI

[5], and is the method of choice in the treatment of acute STEMI [6]. If performed early, primary percutaneous angioplasty not only reduces mor-tality, but also saves LV global and regional func-tion [7] and as a result, preserves quality of life. Nevertheless, there is a need for enhanced pro-cedures and advanced thrombolytic regimens, as there is ample evidence that even after epicar-dial reperfusion, in up to 60% of patients after primary percutaneous angioplasty for STEMI, microvascular hypoperfusion may persist with prognostic relevance [8–10].

MRI is one of the most advanced and expen-sive imaging techniques available to today’s cli-nician. With the invention of the FLASH [11] sequences, it became possible to acquire images

Gert Klug and Bernhard Metzler*University Clinic of Internal Medicine III (Cardiology), Medical University of Innsbruck, Innsbruck, Austria*Author for correspondence: Tel.: +43 512 504 81315 Fax: +43 512 504 22767 [email protected]

Myocardial recovery after revascularization for ST-segment elevation myocardial infarction (STEMI) remains a significant diagnostic and, despite novel treatment strategies, a therapeutic challenge. Cardiovascular magnetic resonance (CMR) has emerged as a valuable clinical and research tool after acute STEMI. It represents the gold standard for functional and morphological evaluation of the left ventricle. Gadolinium-based perfusion and late-enhancement viability imaging has expanded our knowledge about the underlying pathologies of inadequate myocardial recovery. T2-weighted imaging of myocardial salvage after early reperfusion of the infarct-related artery underlines the effectiveness of current invasive treatment for STEMI. In the last decade, the number of publications on CMR after acute STEMI continued to rise, with no plateau in sight. Currently, CMR research is gathering robust prognostic data on standardized CMR protocols with the aim to substantially improve patient care and prognosis. Beyond established CMR protocols, more specific methods such as magnetic resonance relaxometry, myocardial tagging, 4D phase-contrast imaging and novel superparamagnetic contrast agents are emerging. This review will discuss the currently available data on the use of CMR after acute STEMI and take a brief look at developing new methods currently under investigation.

Assessing myocardial recovery following ST-segment elevation myocardial infarction: short- and long-term perspectives using cardiovascular magnetic resonanceExpert Rev. Cardiovasc. Ther. 11(2), 203–219 (2013)

Expert Review of Cardiovascular Therapy

© 2013 Expert Reviews Ltd

10.1586/ERC.12.173

1477-9072

1744-8344

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Keywords: cine • CMR • first-pass perfusion • late-enhancement • STEMI • T2-weighted imaging

THeMed ArTICLe y Disorders of the Myocardium

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of moving organs like the heart within a reasonable time and with diagnostic quality that paved the way for cine cardiovascu-lar magnetic resonance (CMR) [12]. T2-weighted (T2-w) CMR discriminates acute from chronic myocardial infarcts [13] and defines salvaged myocardium after successful reperfusion [14,15]. T2*-weighted imaging is sensitive to intramyocardial iron depo-sition and therefore able to depict hemorrhage after reperfusion [16,17]. With the application of late gadolinium (Gd)-enhanced (LGE) imaging in patients after myocardial infarction, Kim et al. provided an unrivalled method to noninvasively quantify myocardial infarct size [18]. Moreover, advances in perfusion imaging allow for the detection of small subendocardial areas of microvascular obstruction (MVO) [19]. Since it is safe to perform CMR within days after primary percutaneous angioplasty and stent implantation [20], it is a unique tool for investigating the recovery of infarcted myocardium in humans with almost no side effects.

This review will describe recent CMR protocols to measure myocardial recovery after STEMI. Furthermore, it will summa-rize the current literature regarding myocardial recovery assessed with CMR and its association with CMR measurements of the infarct zone. Moreover, it will discuss the potential of CMR as a prognostic tool in patient care as well as in therapeutic research, speculate about the role of CMR in guiding therapies after STEMI and provide an outlook on emerging techniques that promise to further establish the role of CMR as the most sophisticated imaging technique after acute STEMI.

Cine cardiac magnetic resonanceMethodsFor cardiac cine studies, 1.5 Tesla magnetic resonance scanners with multiple phased arrays provide sufficient signal-to-noise ratio with satisfactory temporal and spatial resolution. Breath holding is man-datory if no navigator is used. ECG gating is applied retrospectively to cover the whole diastole, usually with 25 acquired phases over one cardiac cycle. In patients with arrhythmias, prospective gat-ing might be applied. Modern steady-state, free-precession, bright blood sequences are acquired with a voxel size below 2 × 2 mm and a slice thickness of 8–10 mm. Images are acquired typically in the four-chamber view (left and right atria and ventricles), the two-chamber view (left atrium and ventricle), three-chamber view (left atrium and ventricle, LV outflow tract) and a stack of 10–15 short-axis (SA) views of the left and right ventricle) (Figure 1) [7]. Alternative methods for the assessment of myocardial function after STEMI are CMR tagging [21] and velocity-encoded phase-contrast CMR [22,23], which allow for a comprehensive assessment of myo-cardial function, including strain [24] and dyssynchrony imaging [25], as well as the analysis of diastolic function [26]. Their clinical application, however, is still very limited.

Evaluation of cine CMR images consists of a visual inspection of two-, three- and four-chamber views to detect pericardial effu-sion, evidence for stenosis or regurgitation of the valves (i.e., mitral regurgitation), intracavital masses (thrombus) and gross inspection of global and regional function, morphology and extracardiac struc-tures [27,28]. SA images are then transferred to dedicated software

Figure 1. Axis in cardiovascular MRI. After acquisition of coronal, sagittal and transversal scout images (loc_cor, loc_sag, loc_tra, respectively) pseudo two-chamber (loc_2CH, red) and short axis (loc_SA, yellow) localizers are acquired. Then true four-chamber (cine_4CH, blue) and a stack of 10–15 short-axis views (cine_SA, green) are performed according to the given axis (lines). Multiple lines indicate a stack. True 2-CH and 3-CH views are not displayed.

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for further segmentation. In our laboratory, evaluation is performed on standard manufacturer software. Contouring of LV endo- and epi-cardial borders is performed semiautomatically at end-diastolic and end-systolic images. Papillary muscles are excluded from myo-cardial mass (MM) and included into LV volume. The most basal slices are excluded from evaluation [29] if the LV outflow tract repre-sents more than one-quarter of the LV circumference. Longitudinal shortening is typically taken into account by analyzing the one or two most basal and apical slices only at end-diastole but not at end-systole (Figure 2). LVEF is calculated via absolute LV end-diastolic volume (EDV, ml), end-systolic volume (ESV, ml) and stroke vol-ume (ml). Cardiac output is calculated by multiplying LV stroke volume by the heart rate where heart rate is the given by the mean of the R-R intervals during image acquisition (Table 1).

Left ventricular MM is calculated by multiplying the end-diastolic wall volume by the specific density of cardiac muscle (1.05 g/cm3) (Table 1) [30].

Myocardial end-diastolic to end-systolic segmental wall thicken-ing (SWT) analysis is performed for each slice based on the same endo- and epi-cardial contours. For each segment, end-diastolic and end-systolic wall thickness (EdWTh, end-systolic wall thickness [mm]), respectively, as well as end-diastolic to end-systolic wall thickening (SWT, [mm]) or %, SWT (% of EdWTh) are assessed and calculated. Segmentation follows the 17-segment model accord-ing to the AHA 2002 Guidelines for Tomographic Imaging [31] with no evaluation of the apical segment 17 (see Figure 3). Two to three SA images are assigned visually to basal, mid, or apical seg-ments according to anatomic landmarks (papillary muscles) and

Figure 2. Evaluation of cine short-axis views with use of semiautomatic segmentation. Endocardial (green) and epicardial (red) borders are delineated in ED and ES. Papillary muscles are excluded from left ventricle mass. As the ventricle shortens with systole (four-chamber view), the ED stack includes more images than the ES one. ED: End diastole; ES: End systole.

Assessing myocardial recovery following STEMI with CMR


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four-chamber view. SWT is then summed up and averaged for each segment from the SA slices involved in this segment.

Global LV functionToday, global LV systolic dysfunction is one of the main diagnostic criteria to guide therapy after STEMI [32,33]. LVEF assessed by CMR in the acute setting (<1 week) closely correlates with cardiac troponin [34] and creatine kinase measures of infarct size [35] as well as with acute N-terminal pro-B-type natriuretic peptide levels [36].

LVEF increases within the first 4 months after STEMI and remains statistically constant for 14 months after STEMI [37,38]. N-terminal pro-B-ype natriuretic peptide [36], cardiac troponin and creatine kinase [39] levels might serve as prognosticators for 4-month LVEF. Mid-term (<6 month) LVEF at 5 months is inversely cor-related to acute infarct size and, to a lesser extent, infarct reper-fusion [40], but recovery itself is not. Importantly, the extent of LVEF recovery within the first 4 months after STEMI is inversely correlated to the acute LVEF (Figure 4), [Klug, unpublished data]. This observation might be explained by compensatory hypercontractility in adjacent myocardium with yet unknown consequences for LV remodeling. Our previous report of increased regional function

of remote, noninfarcted, myocardium after 4 months supports this interpretation [7].

We have previously shown that there is a poor correlation of echocardiographic and CMR derived LVEF in the acute phase of STEMI. This correlation improves in the chronic state [41]. Reasons for this observa-tion might be an overestimation of LVEF by echocardiographic methods, especially in posterior wall infarcts [42]. Although the prognostic value of LVEF may depend on the method that was used for its assessment [43,44], so far, no studies compared the prog-nostic value of LVEF assessed by echocar-diography and CMR. Furthermore, despite its excellent reproducibility [45], the clinical net benefit or even the cost–effectivenesss of CMR over echocardiography have not yet been proven, which hampers its clinical use. Nevertheless, the use of CMR-derived LVEF as a surrogate end point [46,47] may allow for a reduction in sample sizes in clinical trials and thus a reduction in costs [48]. Therefore, CMR for measuring global systolic function after STEMI is mainly used for research purposes or in patients with poor echocar-diography windows, which occurs in up to 20% of cases [49].

LV volumes are mainly used as measures of LV remodeling after myocardial infarc-tion. An increase in EDV (EDV, EDV index, EDV-to-MM) is commonly used to define remodeling due to structural changes of the LV and diastolic filling. ESV is sometimes

used to define remodeling [50], but in contrast to EDV, it depends mainly on EDV and systolic function [51]. A study by Tarantini et al. described an increase in EDVI from 64 to 75 ml/m2 within the first 6 months after STEMI. Major determinants of LV dilatation are infarct size and transmurality as well as the presence of MVO [52,53]. Lund et al. observed an increase in EDV within the first 8 months after STEMI mainly in patients with an infarct size >24% of left ventricular MM [54]. Recent studies suggest an impact of infarct hemorrhage [50] and myocardial salvage on LV remodeling [55]. In contrast to functional recovery after STEMI, LV remodeling is an ongoing process even 1 year after myocardial infarction [56].

Regional systolic functionStudies have demonstrated the additional prognostic value of regional wall motion abnormalities after STEMI as assessed by echocardiography [57]. CMR has the advantage of combining LGE infarct visualization and regional wall motion quantification (Figure 3).

The measurement of regional systolic function is typically expressed as the percentage of thickening of the myocardium from end-diastole to end-systole (SWT, %). Remote myocardium

Table 1 Calculations used in cardiac magnetic resonance imaging after ST-segment elevation myocardial infarction.

Parameter (unit) CMR protocol

Calculation

LVEDV (ml) Cine –

LVESV (ml) Cine –

LVSV (ml) Cine EDV (ml) - ESV (ml)

LVEF (% of EDV) Cine SV (ml)

EDV (ml)× 100

CO (ml/min) Cine SV × heart rate (beat/min)

LVMM (g) Cine LV wall volume (cm3) × 1.05 (g/cm3)

SWT (mm) Cine EsWth (mm) - EdWth (mm)

SWT (%) Cine SWT (mm)

EdWth× 100

Infarct volume (cm3) LE ∑Infarct areaSLICE (cm2) × slice thickness (cm3)

Infarct mass (g) LE Infarct volume (cm3) × 1.05 (g/cm3)

Infarct mass (%) LE Infarct mass (g)

LVMM (g)× 100

Salvaged myocardium (cm3) LE/T2-w Volume at risk (cm3) - Infarct volume (cm3)

Myocardial salvage index (%) LE/T2-w Salvaged myocardium (cm3)

Volume at risk (cm3)× 100

CO: Cardiac output; CMR: Cardiovascular magnetic resonance; EDV: End-diastolic volume; EdWth: End-diastolic wall thickness; ESV: End-systolic volume; EsWth: End-systolic wall thickness; LE: Late enhancement; LV: Left ventricle; LVEDV: Left ventricular end-diastolic volume; LVEF: Left ventricular ejection fraction; LVESV: Left ventricular end-systolic volume; LVMM: Left ventricular myocardial mass; LVSV: Left ventricular stroke volume; SV: Stroke volume; SWT: Segmental wall thickening; T2-w: T2-weighted.

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exhibits values of around 80–100%, which is in the range of normal, healthy myo-cardium. Infarcted segments, as defined by LGE, exhibit a SWT between 20 and 40%, and may improve after STEMI by 15–20% [7,58,59].

Several factors influence regional myo-cardial recovery. The authors have shown that infarcted segments with a pain-to-balloon time <6 h have a significantly better recovery of regional systolic wall motion than segments with a longer treat-ment delay [7]. As treatment delay impacts myocardial salvage [60], our data suggest an important role of myocardial salvage on myocardial regional recovery after STEMI (Figure 3). A direct comparison of myocardial salvage indices and regional functional recovery after acute STEMI is so far lacking.

Furthermore, the authors and oth-ers have shown that the improvement of regional function occurs within 4 months after acute STEMI and mainly depends, (beside treatment delay), on the presence of MVO [37,53,61], which may be a more powerful predictor than infarct transmu-rality [61]. Nevertheless, while myocardial segments with an acute infarct transmural-ity ≤25% show complete recovery of up to 80%, segments with a transmurality >75% are very unlikely to recover [29,62]. Low-dose dobutamin stress CMR has been used early after STEMI to predict myocardial recovery, but its use is limited. Its additional value over LGE imaging is still under discussion [63–65] and does not seem to justify the more extensive CMR protocol.

Right ventricular & left atrial functionCine CMR is able to assess right ventricular mass and volumes with high accuracy [66]. Right ventricular involvement is observed in up to 50% of STEMI patients and it decreases right ventricular ejection fraction by 30%, compared with patients with anterior myocardial infarc-tions without any right ventricular involvement [67]. A right ven-tricular ejection fraction <40% has been shown to add prognostic information to LVEF after STEMI [68].

The assessment of left atrial function by cine CMR requires a stack of 4–6 additional SA slices covering not only the LV but also the entire left atrium [69]. Left atrial emptying measured as left atrial fractional change has recently been shown to provide incremental prognostic information after STEMI [70].

T2-weighted imagingMethodsIn the last years, T2-w CMR imaging of myocardial edema [15,71] and hemorrhage [50] with spin-echo sequences has been rediscov-ered after its first description in 1983 [72]. Today turbo-spin-echo or inversion-recovery spin-echo sequences with fat- and blood-suppression are mainly used, but T2-prepared steady-state free-precession sequences [73] have been described to be more robust [74]. Contrast-enhanced steady-state free-precession protocols provide

Figure 3. Regional functional recovery measured by cine cardiovascular magnetic resonance. (A) Late gadolinium-enhanced images at day 2 after ST-segment elevation myocardial infarction (d2, left column) show diffuse transmural enhancement in the septal wall after left descending artery occlusion and reperfusion by primary percutaneous angioplasty within 60 min (arrows). The open arrow shows a small area of endocardial LGE with 50% transmurality. Diffuse septal LGE resolves within 4 months (right column). (B) T2-weighted images at baseline (left column) show edema in the territory of the left descending artery (arrowheads), which is most prominent in the septal area (arrow), and completely resolves within 124 days (right row). (C) Regional wall thickening is impaired during the acute phase in areas with LGE and T2-weighted hyperintensity (left column, arrow). After 4 months, septal and anterior wall motion shows recovery (right column). White line: anterior insertion point of the right ventricle. d: Day.

A

d2 d124

B

C



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T2 contrast and functional information within one scan [75,76]. Turbo-spin-echo sequences, however, provide good reliability and sufficient spatial and temporal resolution [77]. Most of the clinical experience was obtained by turbo-spin-echo or inversion-recovery spin-echo sequences.

T1- and T2-mapping of myocardial relaxation rates might pro-vide a new approach to determine myocardial edema and area-at-risk [78] and a better understanding of persisting T2-enhanced areas, as it might differentiate between water and lipid deposition in the infarct territory [79]. Its clinical use is still limited.

Early Gd enhancement obtained 2 min after contrast application with an inversion-recovery technique allows for estimation of the area-at-risk in good agreement with established techniques [80]. Myocardial salvage has also been assessed by endocardial surface area method on LGE images [81]. Assessment of myocardium-at-risk using the endocardial surface area underestimates the area-at-risk compared with angiographic scores and T2-w imaging [82]. T2-w imaging is nowadays the preferred method to assess myocar-dium-at-risk. The endocardial surface area should only be used in patients without aborted myocardial infarction and a low amount of myocardial salvage as a surrogate for the myocardium-at-risk [81].

T2-w images are typically acquired in SA views with an in-plane resolution of 1.5–2 mm and a slice thickness of 8–10 mm, to match results to LGE images. As a threshold for defining edema on T2-w images, the authors propose a mean signal intensity >2 standard deviations above remote myocardium, based on literature [79,83]. Manual and other semiautomatic segmentation modes may pro-vide similar results [84,85]. A bias of up to 20% may result from the use of different segmentation techniques [84]. Myocardial edema

is delineated in SA views, whereby hypointense cores are included in the area-at-risk, and the volume-at-risk is calculated by multi-plying the area by the slice thickness. Myocardial salvage is then calculated as the difference between the area-at-risk determined by T2-w imaging and final myocardial infarct size obtained from LGE images. Furthermore, the myocardial salvage index is calculated to define the percentage of myocardium at-risk that is ‘saved’ by reperfusion (Table 1).

The paramagnetic effects of deoxyhemoglobin cause T2 short-ening of hemorrhagic myocardial tissue [86]. As MVO may also decrease signals in T2-w CMR [87], hypointense areas within the infarct zone should be further evaluated with the use of T2*-sensitive protocols. Either T2*-sensitive gradient echo sequences [88] or T2*-mapping [16] have been proposed for this purposed, but their clinical utility is still limited.

Myocardial salvageIntracellular as well as extracellular edema causes a prolongation of myocardial T2 times, which appears as bright transmural zones in the territory below the infarct-related artery. Numerous studies have validated these areas as a retrospective quantification of the area-at-risk in animal models [89] as well as against angiographic [82] and single-photon emission computed tomography measures [15]. In dogs, T2-w imaging has recently been shown to correlate well with microsphere measurements [78].

There is a close association of acute myocardial infarct size with the area-at-risk and an inverse correlation to the myocardial salvage index. The area-at-risk is a major determinant of myocardial infarct size as both depend on the perfusion bed of the infarct-related artery [90]. As the myocardial salvage index represents ‘rescued’ myocardium and depends on treatment delay [91] and success [92], some authors claim that myocardial salvage index is a more valuable end point in therapeutic STEMI studies than infarct size [48]. This may indeed be the case, since the prognostic impact of myocardial salvage index has recently been demonstrated [83,93]. The inverse association of acute myocardial infarct size with myocardial salvage index has mainly mathematical reasons as myocardial infarct size is one variable to calculate myocardial salvage index (see Table 1) [55]. Interestingly, Eitel et al. observed a reduction in MVO size in patients with a myocardial salvage index above median, which may be explained by a protective effect of myocardial salvage on the integrity of the reperfused microvasculature [83].

The extent of myocardial edema as assessed by CMR decreases 1 week after STEMI (Figure 5) and thus may be underestimated if imaged later. The decrease of edema is accompanied by a resolu-tion of LGE and improvement of regional function, suggesting that LGE after acute STEMI may, in part, also represent viable myocardium(see Figure 3) [79]. Accordingly, the authors have observed recovery of regional myocardial function in segments reperfused within 3 h, although they initially showed LGE [7]. In any case, the independent impact of the myocardial salvage index on global or regional functional recovery within the first 6 months after STEMI has not yet been determined. Masci et al. report that myocardial salvage index correlates with acute LVEF and adverse remodeling (15% change in ESV) after a 4-month follow-up, but

Figure 4. Global functional improvement and baseline left ventricular ejection fraction. There is an inverse correlation of the change in LVEF within 4 months after ST-segment elevation myocardial infarction and the baseline LVEF. LVEF: Left ventricular ejection fraction.

20

20 30 40 50 60 70 80LVEF, baseline (%)

LV

EF

, bas

elin

e to

4 m

on

ths

(∆%

)

10

-10

-20

0

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gives no information on differences in LVEF at follow-up [55]. Another study observed an impaired regional function in 95% of segments with trans mural edema, and a functional improvement in 65% of segments in which LGE resolves over a period of 6 months [79], but only identifies myocardial infarct size as an independent predictor of regional functional recovery.

Gd-enhanced CMRGd-enhanced CMR at 1.5 Tesla offers the possibility to access rest perfusion and infarct size within one examination. Currently, the use of 3 Tesla scanners is under investigation for perfusion imaging and promises whole-cardiac coverage with 3D imaging [94]. A standard sequence is depicted in Figure 6.

Perfusion imagingAfter assessing T2-w images and cine CMR, a bolus injection of 0.1 mmol/kg Gd-based contrast agent [27] is administered with an infusion pump at 2–3 ml/s. First-pass perfusion images are obtained in three SA sections centered on the mid-papillary muscle as well as in two- and four-chamber view [19]. The authors use an ECG-triggered T1-weighted inversion-recovery true-Fast Imaging with Steady State Precession sequence. Sixty dynamic images are acquired simultaneously at each of the three sections during the first-pass of the contrast agent within the myocardium.

Early MVO is considered qualitatively to be present if a region of hypoperfusion persists for 60 s after the contrast bolus arrival in the LV and if it is located in the subendocardial layer of the infarct core in at least one of the SA slices (see Figure 7) [95].

A further approach allows for semiquan-titative estimation of myocardial blood flow by measuring signal intensity curves. An observer contours LV endo- and epicardial borders manually throughout the whole first-Gd-pass sequence (0–60 s). Each SA slice can again be divided in six equiangu-lar segments, starting at the anterior septal insertion of the right ventricle and counting contraclockwise [31]. Analysis is performed on a standard manufacturer console using a standard software package (Figure 7) [19].

Late-enhancement CMRAfter obtaining perfusion images, LGE-CMR images are acquired by using an ECG-triggered, phase-sensitive inversion-recovery true-Fast Imaging with Steady State Precession sequence with consecutive slices perpendicular to the SA using the same slice thickness and position as the cine CMR study. The authors use a spatial reso-lution of 2.2 × 1.6 × 8.0 mm. The use of the phase-sensitive inversion-recovery sequence does not require the use of inversion time

optimization [96]. Alternatively, inversion-recovery gradient echo sequences with prior inversion time determination via look-locker sequences are widely used to asses LGE [97].

The area of late-enhancement (LE) is evaluated quantitatively for each slice using a commercially available software tool. Visual assessment of LGE may overestimate the area of the infarct com-pared with automated segmentation [98]. The authors define ‘hyperenhancement’ using a threshold of +5 standard deviations above the signal intensity of normal myocardium in the opposite myocardial segment based on literature and our own experience (Figure 8) [29,99,100].

Infarct area is assessed quantitatively for each slice and AHA segment. Infarct volume is calculated by multiplying the hyper-enhanced area with slice thickness (including the inter-slice gap). Infarct mass is assessed by multiplying the volume with the specific density of cardiac muscle (1.05 g/cm3). To assess the percentage of infarcted myocardium, infarct mass is divided by a hundredth of MM according to LE images (Table 1) [101].

Furthermore, on LE images, a persisting area of hypoenhance-ment, surrounded by hyperenhanced myocardial tissue is consid-ered as late MVO and quantified by manual contouring of the unenhanced myocardium. Late MVO mass as well as the percent-age of late MVO myocardium are calculated according to the LE images. The optimal time point to achieve high contrast between

Figure 5. T2-weighted imaging differentiates acute from chronic infarct. Edema is clearly depicted by T2-w imaging 3 days after an acute posterior ST-segment elevation myocardial infarction in 2011 (arrows, lower row). LGE in the anterior wall is due to an old anterior non-ST-segment elevation myocardial infarction (upper row) previously imaged in 2007. LGE: Late gadolinium-enhanced; T2-w: T2-weighted.



Review

normal myocardium and myocardium with acute infarction or MVO seems to be 10–15 min after contrast application [97].

Microvascular obstructionMVO after primary percutaneous angioplasty for acute STEMI is a no-reflow phenomenon in coronary vessels smaller than 200 µm, despite adequate epicardial reperfusion [102]. CMR with its concepts of first-pass perfusion and LE imaging is a unique tool to investigate MVO [7,103–105]. Early MVO especially has been shown to correlate well with angiographic blush grade [106]. MVO can be studied by CMR up to at least 1 week after primary percutaneous angioplasty for STEMI [107].

The authors have previously shown the relation between cardiac and inflammatory markers and MVO after successful primary percutaneous angioplasty for STEMI [95]. MVO is pre-dicted by the extent of the ischemic region and is associated with decreased baseline ejection fraction and wall motion scores [108]. The role of treatment delay and MVO is under discussion, and is, if present, marginal [9,60]. This is because other factors like the morphological type of coronary lesion, a large vessel diam-eter and a high thrombus load impact the occurrence of slow

or no-reflow phenomenon after primary angioplasty [109].

Early [110], as well as late [9,10,105], MVO have been shown to be significant and independent prognostic factors affecting clinical outcomes. Recent data favors the use of late MVO as a prognostic marker over early MVO [10]. As both surrogates are likely to represent the same pathophysi-ological phenomenon, the authors think that the clinical significance of different results is marginal, especially because the differences in total event rates are small [10]. The higher number of SA slices as well

as the higher spatial resolution may favor late MVO in clinical practice.

Myocardial infarct sizeThe concept of LGE has been widely studied in acute and chronic infarcts. An approximated steady state of Gd-contrast distribution between the blood volume and the interstitial space is reached 8–30 min after contrast application. Bright subendo-cardial regions represent an increased distribution volume for extracellular Gd-contrast agents in the area of the myocardial infarction. The proposed underlying mechanism is an expansion of the extracellular space and a loss of the integrity of the myo-cardial cell membrane, which allows for an intracellular contrast uptake [111]. Extracellular volumes are increased by fibrosis in the chronic state [112].

Troponin levels, except for admission values, after myocar-dial infarction correlate well with CMR-derived measures of myocardial infarct size [35,113,114]. Anatomically, infarct size depends on the location of the coronary artery occlusion [90]. Acute infarct size is further correlated with time-to-treatment [60], preprocedural thrombolysis in myocardial infaction flow

Figure 7. Types of microvascular obstruction assessed by cardiovascular magnetic resonance. (A) First-pass perfusion imaging depicts areas of hypoenhanced Microvascular obstruction (early MVO) 60 s after contrast application. Regions of interest drawn in infracted (R1, blue, *) and remote areas (R2, pink). The derived signal intensity curves (B) show lower contrast enhancement in the infracted area, which suggests MVO. (C) Late gadolinium-enhanced imaging depicts a hypoenhanced core within the lateral infarct area (*: late MVO). *: area of MVO

A B C

Figure 6. Standard cardiovascular magnetic resonance protocol. It allows the assessment of LV function, perfusion, scar and edema imaging within a scan time of approximately 35 min. 4CH: Four-chamber view; BW: Bodyweight; CMR: Cardiovascular magnetic resonance; LV: Left ventricle; PSIR: Phase-sensitive inversion-recovery; SA: Short axis; T2-w: T2-weighted.

Scouts

5 min 5 min 10 min 1–2 min 10 min

T2-w‘Edema’

Gd-bolus:0.1 mmol/kg BW

Σ ~35 min

Cine SA/4CH ‘Function’

First-pass‘Perfusion’

PSIR ‘Late enhancement’

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and ST-segment resolution [115], which implies an important role of early and complete myocardial salvage in infarct size reduc-tion. The influence of time-to-treatment on infarct size is still controversial [39,60,116–118], but the impact on infarct transmu-rality is undisputed even in large unselected cohorts [119]. This finding corresponds to the established ‘wavefront phenomenon of myocardial death’ [120]. The authors conclude from the exist-ing data that a short treatment delay reduces infarct size relative to its individual area-at-risk in optimally treated STEMI patients (see above T2-w imaging). In studies with an even distribution of infarct-related arteries, this results in a statisticall significant reduction of the absolute infarct size [61,115]. This point is important, since the extent of LGE might be a more powerful predictor of mortality after STEMI [121] than LVEF [122].

LGE then decreases over the f irst 4 months, with the main changes occur-ring in the first week after the acute event [59]. The fact that acute LGE ‘overestimates’ final infarct size has thus to be considered when performing LGE in acute STEMI patients. In analogy with LVEF, the amount of infarct shrinkage is inversely correlated to baseline infarct size (see Figure 9), [Metzler,

unpublished data, 54]. The reasons for infarct ‘shrinkage’ within the first 4 months after STEMI are still under debate, but increased myocardial thickness due to acute edema and myocardial salvage may play an impor-tant role [7,59,79,123]. Accordingly, the authors and others [124], observed increased EdWTh in STEMI patients immediately after the acute event compared with follow-up, as well as an impact of treatment delay on infarct size 1 week and 4 months after STEMI [39]. These data suggest an important role for ischemia time in optimally treated patients even after the acute event.

Future perspectivesThe authors believe that, despite advances in other sophisticated techniques like coronary-CMR [124] and nuclear mag-netic resonance spectroscopy [27,125–128], three main ideas will impact the mid-term future of CMR imaging of myocardial recovery after STEMI: tissue characteriza-tion by CMR relaxometry, the application of superparamagnetic contrast agents for cellular or molecular imaging and the use of strain, blood flow and velocity mapping, which enables detection of subtle changes in myocardial wall stress and morphology after STEMI.

Tissue characterizationMagnetic resonance imaging allows for the absolute quantifica-tion of longitudinal and transversal relaxation rates of different tissues [129,130]. Changes in relaxation rates represent a change in tissue composition or contrast agent distribution. Examples are T1-mapping to detect expansion of the extracellular space [131], T2-mapping as a more sophisticated method to detect edema and T2*-mapping for the detection of susceptibility changes caused by deoxyhemoglobin [132,133]. One interesting application of T2/T2*-weighted imaging is blood oxygen level-dependent imaging,

Figure 8. Infarct size quantification. Visual assessment of infarct size on short-axis late gadolinium-enhanced images (left column) of a posterior myocardial infarction 1, 161 and 371 days after ST-segment elevation myocardial infarction. Thinning of the infarcted area, corresponding to scar formation is clearly visible. Thresholding for signal intensities >5 standard deviations above remote myocardium allows for infarct area quantification (right row, grey area): day 1: 589 mm2; day 161: 324 mm2; day 371: 335 mm2.

1 day

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which is able to measure the density, size and deoxyhemoglobin content of the myocardial capillaries [132]. Although it is sensitive to susceptibility and motion artifacts, first clinical experiences have been made in animal models [134] and patients [135] after myocardial infarction.

Particularly, T1-mapping of the extracellular volume may gain importance in post-STEMI imaging, since precontrast T1-mapping allows for the detection of acute myocardial infarction with a reported sensitivity of 96% and a specificity of 91%, especially in the first week after infarction [131]. This effect is likely to be caused by the T1- and T2-prolonging effects of myocardial edema [136]. Increased postcontrast T1-shortening is thought to represent increased volumes of distribution for T1-shortening Gd-contrast agents, which may occur in myocardial infarction, atypical diffuse fibrosis and subtle myocardial abnormalities not clinically apparent on LGE images [137]. An increase in the volume of the noninfarcted extracellular matrix has recently been linked to increased mortal-ity [138]. The authors speculate that expansion of the extracellular volume of remote myocardium may favor maladaptive remodeling.

Superparamagnetic contrast agentsIn the last years, a great effort has been made to allow for cellular or even molecular imaging with CMR [129,130]. The major limita-tion of CMR compared with single-photon emission computed tomography or PET techniques is its low sensitivity, which is in the micromolar range for Gd agents. Superparamagnetic ultra-small iron oxide nanoparticles promise to overcome this limitation as they may increase MR sensitivity into the nanomolar range. In animal models, uptake of nonspecific ultrasmall particles of iron oxide (USPIOs) occurs in macrophages, which are believed to then be recruited into inflammatory areas such as atherosclerotic plaques [130] or acute myocardial infarction [139]. Specific USPIOs bound to peptides specific for adhesion molecules (i.e., VCAM-1) [140] have been reported to detect upregulated expression of these molecules in atherosclerotic mice [141]. Recently, the first feasibil-ity studies in humans showed an uptake of USPIOs into acute myocardial infarction [142,143].

Phase-contrast CMRVelocity-encoded phase-contrast MRI allows for absolute quanti-fication of flow velocities [144,145] and myocardial wall motion and strain [146]. Furthermore, with the use of phase contrast, CMR quantification of hemodynamic indices (stroke volume, cardiac output or cardiac index) as well as global LV-perfusion quantifica-tion measurements are possible within a short scan time (~5 min) noninvasively [147,148]. Recently, the use of a 4D (equivalent to 3D-cine) protocol has been described that can measure cardiac motion as well as ventricular and aortic blood flow [149]. The 3D assessment of the LV might provide more detailed informa-tion on LV remodeling after myocardial infarction than conven-tional parameters [150]. Furthermore, aortic hemodynamics can be assessed [151]. Ventricular–vascular coupling may cause maladap-tive remodeling after STEMI [152]. Although the used sequences are robust, valid and fast, only few studies have investigated their use for prognostic purposes after STEMI [153].

Figure 9. Baseline infarct size and 4-month follow-up. The scatter plot shows the correlation of the reduction in infarct size within 4 months after ST-segment elevation myocardial infarction with baseline infarct size. Larger infarcts show a larger amount of infarct size reduction. LVMM: Left ventricular myocardial mass.

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Figure 10. Schematic view on the evolution of myocardial recovery after ST-segment elevation myocardial infarction (t = 0). As myocardial edema resolves after the acute phase (>1 week) late-gadolinium enhanced estimates of infarct size decline and myocardial function improves. Most trials report that myocardial recovery and infarct zone remodeling is completed after 4–6 months after ST-segment elevation myocardial infarction. Afterwards, chronic maladaptive remodeling of the remote myocardium may occur as indicated by a steady increase in EDVI. The bars above the graph indicate the reasonable time points for CMR imaging protocols in long-term patient follow-up. CMR: Cardiovascular magnetic resonance; EDVI: End-diastolic volume index; IS: Infarct size; LVEF: Left ventricular ejection fraction; LVMM: Left ventricular myocardial mass; T2-w: T2-weighted.

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Expert commentaryIn the last 10 years, the application of CMR after acute STEMI has expanded enormously. After imaging of the human heart became feasible within reasonable scan times and diagnostic accuracy in the 1980s and 1990s, the use of Gd-contrast agents for first-pass perfusion and LE imaging established CMR as a comprehensive and reliable research tool. Beside its role as a gold standard in morphological and functional assessment of the LV, in the last decade, a huge amount of data have confirmed that infarct characterization with CMR is a valid method compared with established biochemical, imaging and clinical markers. In a large number of scenarios, it even surpasses its cheaper counterparts, making it the new in vivo reference standard for imaging after STEMI. This evolution was paralleled by an increasing number of prognostic studies, which paved the way for CMR to become an accepted surrogate end point in large prospective multicenter STEMI trials.

CMR provided new insights into the evolution of the infarct zone (Figure 10) and prognostic factors after STEMI (Figure 11). Its clinical use, however, is still hampered by the lack of therapeutic consequence.

Five-year viewThe role of CMR in imaging myocardial recovery after STEMI will depend on whether it is used as a research tool or as a decision aid in clinical practice. Both sce-narios have their own obstacles to overcome in the next 5–10 years.

The greater availability of 3 Tesla scan-ners will open a lot of new possibilities due to higher spatial and temporal resolution. Within the next 5 years it is very likely that manufacturers and researchers will provide novel sequences that allow for robust T1-, T2- and T2*-relaxometry within reasonable time. It is likely that the first feasibility stud-ies on the use of targeted contrast agents and contrast-enhanced cellular imaging will be successful in humans. The use of higher automation in segmentation software, as well as more sophisticated methods to assess myocardial function such as phase-contrast velocity-encoded imaging, will provide new insights in myocardial hemodynamics after STEMI. Moreover, single center experi-ences are often inconsistent and therefore should be expanded by registries [154] and multicenter trials [155] to strengthen the confidence in the data accumulated so far.

The role of CMR after STEMI in clinical practice is not very likely to change substan-tially within the next 5 years, but the num-ber of applications is very likely to grow. The high costs and the low availability of CMR

will be reduced due to the higher numbers of magnetic resonance scanners in general. Pacemakers might be CMR-safe in 5 years. 3D-cine real-time imaging (4D-imaging) is likely to become a standard and will shorten clinical CMR studies. This may be of interest in the critically ill. Although current treatment strategies aim at reducing CMR end points – that is, MVO and infarct size, so far therapeutic studies using infarct characteristics defined by CMR as inclusion criteria are lacking. It is likely that such studies will be planned and performed within the next 5 years, but the authors think that it will take 5–10 years until CMR is a regular imaging modality with therapeutic and prognostic impact in, at least some patients after STEMI.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial con-flict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Figure 11. A schematic view on the impact of clinical variables and CMR-derived parameters on prognosis after STEMI. For references, please see text. AAR: Area at risk; BNP: B-type natriuretic peptide; CMR: Cardiovascular magnetic resonance; CK: Creatine kinase; cTnT: Cardiac troponin; EDVI: End-diastolic volume index; Gd: Gadolinium; IRA: Infarct-related artery; IS: Infarct size; LVEF: Left ventricular ejection fraction; LVMM: Left ventricular myocardial mass; MSI: Myocardial salvage index; MVO: Microvascular obstruction; STEMI: ST-segment elevation myocardial infarction; SWT: Segmental wall thickening; T2-w: T2-weighted; y/n: Yes/no.

AAR, % LVMM

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Review

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

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Key issues

• Cardiovascular magnetic resonance (CMR) is a safe and radiation-free method with few contraindications that allows for a ‘one-stop-shop’ assessment of myocardial function, perfusion, viability and morphology after ST-segment elevation myocardial infarction (STEMI).

• CMR is the current gold standard in the assessment of global and regional myocardial function after STEMI.

• Left ventricle (LV) functional recovery after STEMI is completed within 4 months, while LV remodeling is a chronic process.

• There is growing evidence that CMR measures of infarct characteristics, such as infarct size, transmurality, microvascular obstruction, hemorrhage or salvaged area, are of higher functional and prognostic relevance after STEMI than LV ejection fraction.

• In the acute phase (<1 week), late gadolinium-enhanced overestimates final infarct size. ‘Bright is not dead’ within the first weeks after STEMI. Late enhancement >1 month after STEMI represents nonviable myocardium.

• T2-weighted imaging is a novel and promising tool to assess salvaged myocardium after primary percutaneous angioplasty for STEMI. Myocardial salvage should be assessed within 1 week after STEMI.

• Future applications of CMR after STEMI will allow for comprehensive tissue characterization, cell tracking, molecular imaging and assessment of detailed hemodynamics after STEMI.

• The role of CMR in the clinical scenario will depend on studies providing evidence on its therapeutic impact.

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