Paramagnetic Contrast Agents
Despite the excellent soft tissue contrast shown by CMR, some situations may benefit from increased tissue contrast. The paramagnetic CMR contrast agents predominantly affect the image contrast by shortening the longitudinal relaxation time, T1, which is measured in milliseconds. The effects induced by magnetic resonance (MR) contrast agents are typically discussed in terms of 1/T1, called R1, the relaxation rate (ms–1), which is increased in the presence of paramagnetic contrast agents.70,71 Importantly, the contrast agent itself is not visualized by CMR. Rather, CMR visualizes the relaxation-altering effect that the paramagnetic agent exerts on the hydrogen protons in its immediate vicinity. This effect depends on the number of protons available to affect, the distance to these protons, and the rotational tumbling frequency of the water-particle complex72 and is related to the contrast agent concentration and its relaxivity (ie, how "good" the contrast agent is at affecting the protons) (Fig. 6–5). The relaxivity in vitro for the agents most often used today is approximately 4 s–1 mM–1 at 20 MHz and 37°C. The contrast agent concentration in a certain tissue depends on the pharmacokinetics of the contrast agent and tissue architecture. In vitro, the contrast agent concentration is considered to be linearly related to relaxivity. In vivo, however, this is limited by additional relaxation effects.73 The signal intensity in the image is therefore not necessarily linearly related to the relaxation rate. Contrast agent concentration in a tissue, however, is proportional to the change in R1 (ΔR1), defined as the difference between R1 before and after contrast administration. Thus, R1 and ΔR1 can be quantified by using a Look-Locker sequence74 or modified Look-Locker sequence for pixel mapping of R1.75 A Look-Locker sequence uses an inversion pulse followed by multiple small flip angle excitation pulses. Thereby the longitudinal relaxation rate of the tissue can be estimated. This may be used in order to determine contrast agent concentrations in different regions within the myocardium, such as infarcted and normal myocardium.
Three viability images of syringes filled with gadolinium (Gd), water, and Gd added to water. The syringe with Gd alone is dark in the image because no protons are available to affect. Also, the syringe with water alone becomes dark in the viability images. When Gd is added, the protons are affected, and the image becomes bright. This is also the case with edema and infarction where Gd affects the protons in the compartment.
The most common paramagnetic agent used today is gadolinium (Gd), which has seven unpaired electrons and thus high relaxivity.72 Because Gd is toxic, it is chelated to a ligand, such as diethylene triamine pentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), or DTPA bismethyl amide (DTPA-BMA), in order to reduce toxicity.76 Gd bound to ligands such as those mentioned distributes in the extracellular space77 in the same way as inulin78 and acts mainly on R1.
Nephrogenic Systemic Fibrosis
Recently, some Gd-based contrast agents have been suggested to be related to a rare but severe disease called nephrogenic systemic fibrosis (NSF).79 The disease is typically characterized by fibrosis of the skin and connective tissues. It is recommended that estimated glomerular filtration rate (eGFR) be assessed in patients above age 60 and patients with hypertension, diabetes, or hepatorenal disease. In cases of eGFR <30 mL/min, it is recommended that the examination using Gd-based contrast agents be cancelled. For patients with eGFR <60 mL/min, it is recommended that the dose be reduced to 0.1 mmol/kg. Patients with hepatorenal syndrome and patients with reduced renal function who have had or are awaiting liver transplantation should be considered at risk of NSF if eGFR is <60 mL/min. It is proposed that the value of the examination should be considered and that contrast agent may be administered, even in patients with low eGFR. Finally, there are macrocyclic contrast agents that have not been associated with NSF, and one might argue that these agents should be used preferentially. The numbers of proven cases of NSF are low in total, and the incidence may be decreased further by using adequate dose and choice of agent to be administered and using postexamination dialysis in certain cases.80,81
Intravascular MR Contrast Agents
Intravascular MR contrast agents have been thought to overcome some of the limitations of extravascular contrast agents (eg, in angiography where the contrast stays in the vessel without extravasation). These agents have been tested for coronary artery MR imaging (MRI),82,83 infarct imaging,84-86 and determination of microvascular obstruction.87 The most promising applications are for angiography, but their clinical potential has not yet been fully explored.
Both clinical and experimental studies of treatment for acute myocardial infarction are facilitated by accurate measurement of myocardial infarct size expressed as percentage of the myocardium at risk.88,89 The number of patients needed for a certain power is significantly lower when infarct size is normalized to myocardium at risk. The reference standard in clinical research for quantifying myocardium at risk is myocardial perfusion SPECT (MPS) (see Chapter 3). Quantifying myocardium at risk by MPS, however, requires that a radioactive tracer is injected prior to opening the occluded coronary artery. The tracers technetium 99m (99mTc) -sestamibi and 99mTc-tetrofosmin both distribute in the myocardium in proportion to blood flow90 and are taken up by the viable myocytes, probably by a potential-driven transport of the lipophilic cation91 and binding to the mitochondria. Very little change in myocardial distribution is seen over time. The tracer does not redistribute and has a half-life of 6 hours. Imaging can typically be performed up to 4 hours after injection.92 Importantly, because the myocardial uptake is fast and redistribution is minimal, image acquisition will represent the perfusion of the myocardium at the time of tracer injection. Thus, if the tracer is injected during occlusion, image acquisition undertaken following reperfusion will still represent the perfusion of the myocardium as it was during occlusion.93,94 However, there are issues with using MPS to quantify myocardium at risk, such as the logistics of radiotracer availability, need for administration before opening of the occluded coronary artery, and possible interference with post-PCI care when acquiring images. Considering these limitations with MPS imaging, other clinical methods to quantify myocardium at risk are warranted.
T2-weighted CMR has been demonstrated to show myocardium at risk in experimental studies95-97 (Fig. 6–6). Similar findings in human studies have suggested that T2-weighted imaging may be related to myocardium at risk.98-101 Recently, T2-weighted short tau inversion recovery (STIR) CMR imaging was directly validated in humans using MPS imaging as reference method and demonstrated that myocardium at risk can be quantified in humans at 1 day and at 1 week after the acute event.102 T2-STIR MRI is thus a promising tool for measuring myocardium at risk simultaneously with final infarct size 1 week after the acute event (Fig. 6–7).
Agreement between areas at risk (AAR) determined by microspheres and T2-weighted (T2W) magnetic resonance imaging in an experimental model of myocardial infarction. LV, left ventricle; SD, standard deviation; SEE, standard error of estimate. Reproduced with permission from Aletras AH, Tilak GS, Natanzon A, et al. Retrospective determination of the area at risk for reperfused acute myocardial infarction with T2-weighted cardiac magnetic resonance imaging: histopathological and displacement encoding with stimulated echoes (DENSE) functional validations. Circulation. 2006;113:1865-1870.
Myocardium at risk by single photon emission computed tomography (SPECT) and T2-weighted short tau inversion recovery (T2-STIR) cardiac magnetic resonance (CMR) and final infarct size by late gadolinium-enhanced (LGE) CMR in one typical patient. Short axis slices at the same ventricular level of SPECT on day 1, T2-STIR at week 1, and LGE CMR at week 1 in a patient with reperfused right coronary occlusion resulting in an inferior infarct. The epicardium is traced in green, the endocardium is traced in red, and the affected region is traced in yellow. Note the similarity in size of the perfusion defect during coronary occlusion by SPECT and by T2-STIR CMR 1 week later, which demonstrates that T2-STIR at week 1 can be used to quantify myocardium at risk. Reprinted from Carlsson M, Ubachs JF, Hedstrom E, Heiberg E, Jovinge S, Arheden H. Myocardium at risk after acute infarction in humans on cardiac magnetic resonance: quantitative assessment during follow-up and validation with single-photon emission computed tomography. JACC Cardiovasc Imaging. 2009;2:569-576. Copyright 2009, with permission from Elsevier.
The brightness in T2 images is believed to be mainly related to increased free-water content caused by edema, which prolongs T2 relaxation.103 This prolongation has been suggested to be related to the duration of ischemia.104 The increase in T2 following acute ischemia is relatively small. Thus, images may only show subtle signal intensity changes. As a result, surface coil intensity correction and through-plane motion need to be compensated for. Recent enhancements include black-blood T2-STIR,102,105 single-shot, bright-blood, T2-prepared steady-state free precession (SSFP) during free breathing,99 and hybrid T2 bright-blood turbo spin echo (TSE) SSFP techniques with high signal-to-noise ratio and contrast-to-noise ratio97 and single breath-hold T2 mapping.106 The bright-blood sequences may help solve the issue of difficulties differentiating slow-flowing blood from edema of the myocardial wall, whereas T2 mapping provides the ability for absolute quantification of tissue T2.
Contrast-Enhanced Ssfp MRI
In a recent study, quantification of myocardium at risk with contrast-enhanced SSFP MRI was demonstrated and validated using MPS imaging as reference method107 (Fig. 6–8).
Corresponding left ventricular short axis views from a patient with anterior ST-segment elevation myocardial infarction. Myocardium at risk determined by (A) myocardial perfusion single photon emission computed tomography, (B) gadolinium-enhanced steady-state free precession (SSFP) at end-diastole, (C) infarct size images with late gadolinium enhancement, and (D) gadolinium-enhanced SSFP at end-systole. Reproduced from Sorensson P, Heiberg E, Saleh N, et al. Assessment of myocardium at risk with contrast enhanced steady-state free precession cine cardiovascular magnetic resonance compared to single-photon emission computed tomography. J Cardiovasc Magn Reson. 2010;12:25.
Endocardial Extent of Infarction
It has been argued that the endocardial extent of infarction can be used as a surrogate measure of myocardium at risk.108,109 However, there are clinical situations with early reperfusion and a high degree of salvage or aborted infarction when the endocardial extent of infarction cannot be measured or is inaccurate.29 Thus, in these situations, salvage should not be calculated based on the endocardial extent of infarction because it is not a reliable quantitative measure of myocardium at risk (Fig. 6–9).
Myocardium at risk by T2-weighted imaging and endocardial extent of infarction. Short axis slices at the same ventricular level of T2-weighted imaging and late gadolinium-enhanced (LGE) cardiac magnetic resonance (CMR) for endocardial extent of infarction in three patients after reperfusion of an acute coronary occlusion. The endocardial borders are traced in red, the epicardial borders are traced in green, and the affected region is traced in yellow (myocardium at risk [MaR] for T2-weighted imaging and infarction for LGE CMR). The borders of the endocardial extent of infarction are indicated by dashed lines. Within each image, the total MaR is given as a percentage of left ventricular wall. The upper panel shows a patient with an aborted infarction, the middle panel shows a patient with >90% myocardial salvage, and the lower panel shows a patient with 40% myocardial salvage. Note the difference in size of the MaR by T2-weighted imaging and endocardial extent of infarction for the patient with an aborted infarction and the patient with >90% myocardial salvage. Reproduced from Ubachs JF, Engblom H, Erlinge D, et al. Cardiovascular magnetic resonance of the myocardium at risk in acute reperfused myocardial infarction: comparison of T2-weighted imaging versus the circumferential endocardial extent of late gadolinium enhancement with transmural projection. J Cardiovasc Magn Reson. 2010;12:18.
Viability and Infarct Imaging
In vivo and ex vivo experiments have demonstrated that infarct size can be accurately assessed using late Gd-enhanced (LGE) CMR (Figs. 6–10 and 6–11).110-112 Depiction of myocardial infarction relies on the pharmacokinetics and biodistribution of Gd chelate (ie, Gd-DTPA, Gd-DOTA, or Gd-DTPA-BMA). Importantly, the Gd chelates are small enough to readily pass across the vessel wall into the interstitial space but large enough that they will not pass across the cell wall. Thus, these Gd chelates are referred to as extracellular contrast agents. Healthy cells have intact cell membranes and exclude the tracers. Thus, extracellular MR contrast media distributes in proportion to the extracellular space.77 Animal experiments using echoplanar MR with isotope validation indicate that the extracellular space is approximately 20% in normal myocardium, 30% in myocardium at risk or salvaged myocardium, and 90% in necrosis where cells with ruptured sarcolemmas can no longer exclude the contrast agent15 (Fig. 6–12).
Comparison between ex vivo and in vivo viability images. Top four rows: T1-weighted short axis ex vivo cardiac magnetic resonance (CMR) images (repetition time/echo time, 20 ms/3.2 ms; flip angle, 70°; number of signal averages, two; isotropic resolution, 0.5 mm) in an image stack of 16 consecutive thin 0.5-mm thick ex vivo sections. Sections are arranged from base to apex starting at upper left and advancing left to right, then top to bottom. The arrow with circle shows a region that is not completely infarcted in the top row and almost completely infarcted in the bottom row. Bottom left: Image shows average of 16 thin ex vivo sections corresponding to one 8-mm thick section. Bottom right: In vivo inversion-recovery CMR image (repetition time/echo time/inversion time, 3.8 ms/1.1 ms/230-290 ms; flip angle, 15°; resolution, 1.56 x 1.56 mm) shows good agreement with averaged ex vivo image. Note partial volume effect seen as the relatively intermediate signal intensity on bottom right image where arrow with circle shows same region as for the corresponding ex vivo images. Reproduced from Heiberg E, Ugander M, Engblom H, et al. Automated quantification of myocardial infarction from MR images by accounting for partial volume effects: animal, phantom, and human study. Radiology. 2008;246:581-588.
Graphs show results for performance of automatic algorithm for calculation of myocardial infarct size where partial volume is taken into account (see Fig. 6–10). Top: Results comparing algorithm with reference infarct size. Dotted line is line of identity. Bottom: Difference calculated by subtracting result with algorithm from reference infarct volume. A. Animal data. B. Computer phantom data. C. Patient data. Consensus infarct size denotes the mean of manual measurements from three observers. LVM, left ventricular mass; MR, magnetic resonance. Reproduced from Heiberg E, Ugander M, Engblom H, et al. Automated quantification of myocardial infarction from MR images by accounting for partial volume effects: animal, phantom, and human study. Radiology. 2008;246:581-588.
Light microscopic (LM, top; magnification, 380×) and electron microscopic (EM, bottom; magnification, 32,500×) sections of hearts subjected to regional moderate (20-minute) and severe (60-minute) ischemia and then reperfusion. The LM sections obtained from normal and injured regions are stained with 1% toluidine blue dye. The normal myocardium (0-minute ischemia, top left) is compact and consists of darkly stained myocytes and intact microvasculature; at EM (bottom left), it shows abundant contractile bands, mitochondria of normal size, and intact sarcolemma. At LM, after 20 minutes of ischemia (top middle), most cells appear to be normal. Some cells, however, are lightly stained, which is consistent with intracellular edema, and appear as scattered small islands of grouped cells. In some areas, the myocardium is less compact, with increased distance between the myocyte bundles, which is suggestive of increased extracellular volume. At EM, after 20 minutes of ischemia (bottom middle), most of the cells are viable. A few cells show irreversible injury. At LM, after 60 minutes of ischemia (top right), the majority of cells are lightly stained and swollen. The space between the myocyte bundles is increased compared with that in the normal myocardium. At EM, after 60 minutes of ischemia (bottom right), irreversible injury in all cells is evident, as reflected in the presence of amorphous matrix densities in the mitochondria and discontinuous sarcolemma. fDV, fractional distribution volume. Reproduced with permission from Arheden H, Saeed M, Higgins CB, et al. Reperfused rat myocardium subjected to various durations of ischemia: estimation of the distribution volume of contrast material with echo-planar MR imaging. Radiology. 2000;215:520-528.
The concept of using paramagnetic agents for enhancement of image contrast was illustrated already by Bloch in 1946.70 The use of Gd-DTPA as a nonspecific contrast agent for CMR was discussed in 1984 by Weinmann et al,71 and the basics for using segmented inversion-recovery gradient-recalled echo imaging was described in 1990 by Edelman et al113 for enhanced image contrast originally for liver imaging. This was further developed by Simonetti et al114 who introduced the technique for imaging of myocardial infarction. Image contrast between the infarcted region and normal myocardium was further accentuated by both using an extracellular contrast agent and adjusting the image acquisition so that the inversion time (TI) was set to null the signal from normal myocardium. To reduce motion artifacts, the acquisition is synchronized to diastasis during the latter part of diastole in order to minimize the effect of cardiac movement on image quality. General motion artifacts are also reduced by adding gradient-moment refocusing. The normal myocardium shows up as black in a magnitude-based inversion-recovery image, because the TI is set to null the signal from normal myocardium. Because normal myocardium has a distribution volume of approximately 20%,77 the infarcted region with a distribution volume of approximately 90% will show as bright due to the increased relaxation rate related to the relatively higher contrast agent concentration in this region (Fig. 6–13). It should be noted that the contrast agents most often used distribute passively into the extracellular space and do not accumulate in or bind to the injured myocardium.115 Furthermore, in cases of acute occlusion, the ischemic region may still appear bright despite absence of contrast agent116 (Fig. 6–14). This is related to the use of magnitude images where a region lacking contrast agent will display an image intensity that is similar for reperfused infarction and nonreperfused ischemia. However, this ischemic region does not necessarily represent infarction because if this ischemic region is reperfused in a timely manner, a high degree of salvage can be expected. This potential pitfall may be avoided when imaging with a phase-sensitive inversion-recovery sequence, as described below.
Longitudinal magnetization recovery curves in the situation when contrast agent has access to the injured myocardium. The reperfused infarct is enhanced in the magnetic resonance (MR) image, due to a larger tissue distribution volume for contrast agent in this region. Optimal inversion time (TI) is chosen as the time when the signal from viable myocardium is nulled. This time point is indicated by the intensity bar, which also indicates the MR image contrast, where black in the MR image corresponds to an Mz of 0, whereas bright regions in the MR image correspond to an Mz closer to −1 or 1. Gd, gadolinium; LV, left ventricle; Mz, magnetic moment in the z direction. Reproduced with permission from Hedström E, Arheden H, Eriksson R, Johansson L, Ahlstrom H, Bjerner T. Importance of perfusion in myocardial viability studies using delayed contrast-enhanced magnetic resonance imaging. J Magn Reson Imaging. 2006;24:77-83.
Longitudinal magnetization recovery curves after administration of an extracellular gadolinium (Gd)-based contrast agent, in the situation when contrast agent does not have access to the injured myocardium (nonperfused). Infarcted or not, in the absence of contrast agent, this region would still be hyperintense if the signal from perfused myocardium were nulled (see Fig. 6–19B). The higher signal intensity in nonperfused myocardium is related to the modulus reconstruction of the magnetic resonance image and is due to absence of contrast agent in this region. The signal intensity bars A, B, and C indicate nulling of the signal from blood, perfused myocardium, and nonperfused myocardium, respectively, and correspond to Fig. 6–19. Curves are derived from measured relaxation rate (R1) values applying a Look-Locker sequence 21 minutes after contrast agent administration but are presented as real data for clarity. LV, left ventricle; Mz, magnetic moment in z direction; TI, inversion time. Reproduced with permission from Hedström E, Arheden H, Eriksson R, Johansson L, Ahlstrom H, Bjerner T. Importance of perfusion in myocardial viability studies using delayed contrast-enhanced magnetic resonance imaging. J Magn Reson Imaging. 2006;24:77-83.
Extracellular MR Contrast Dynamics
The enhancement of an infarcted region by LGE CMR is initially (during approximately the first 5 minutes after injection) related primarily to blood flow.117 After approximately 10 minutes, a pseudo–steady-state is reached (Fig. 6–15), and contrast agent concentration throughout the body declines with renal clearance and is fully cleared after approximately 24 hours in a person with normal renal function. At this pseudo–steady-state, extracellular MR contrast agents are distributed in body tissues according to their fractional tissue distribution volume (the fraction of the tissue volume in which the contrast agent can distribute).77 In the case of extracellular contrast agents, the fractional distribution volume corresponds to the extracellular space available in the compartment. For instance, normal myocardium has approximately 20% extracellular space (Fig. 6–16), whereas the blood pool has approximately 50% extracellular space (1-hematocrit). Acutely infarcted myocardium has undergone sarcolemmal rupture, and thus, the formerly intracellular space is exposed to and has become contiguous with the extracellular space, totaling approximately 90%.77 Moreover, the tissue subjected to ischemia and reperfusion is swollen due to edema for hours to days.
Change in relaxation rate (ΔR1) ratios are illustrated as a function of time after injection of 0.2 mmol/kg gadodiamide in hearts subjected to 20, 30, 40, and 60 minutes of coronary arterial occlusion followed by 1 hour of reperfusion. Note that the ΔR1 ratios in normal and injured myocardium are constant for 30 minutes after the injection; this suggests that the ΔR1 ratios represent the partition coefficient. The ΔR1 ratios increased with the duration of occlusion. Reproduced with permission from Arheden H, Saeed M, Higgins CB, et al. Reperfused rat myocardium subjected to various durations of ischemia: estimation of the distribution volume of contrast material with echo-planar MR imaging. Radiology. 2000;215:520-528.
Schematic drawing of contrast agent distribution. The contrast agent distributes passively in the extracellular space, indicated in yellow. In reperfused infarction (right), the tissue distribution volume is increased compared with viable myocardium. This is mainly due to loss of cellular membrane integrity and to some extent related to edema. RBC, red blood cell. Adapted with permission from Arheden H, Saeed M, Higgins CB, et al. Measurement of the distribution volume of gadopentetate dimeglumine at echo-planar MR imaging to quantify myocardial infarction: comparison with 99mTc-DTPA autoradiography in rats. Radiology. 1999;211:698-708.
The first pass of MR contrast agent is usually used to acquire short axis images for assessment of myocardial perfusion at rest and stress to determine presence of stress-induced ischemia (see later section "Myocardial Perfusion MRI").
An MR contrast agent that has been injected into a peripheral vein, usually the brachial vein, enters the right atrium from the superior vena cava, continues sequentially to the right ventricle and the lungs, and then appears in the left atrium, left ventricle, aorta, the coronary arteries, and the myocardium. If structures like thrombi or tumors are present anywhere in the great vessels or cardiac chambers, these exclude the MR contrast during the first pass and therefore appear dark. If they stay dark after the myocardium has enhanced, they are likely thrombi or other structures with low vascularization. If they enhance intermediately, they may be sparsely vascularized tumors like lipomas or fibromas. If they enhance to the same extent as myocardium or more, they may represent highly vascularized tumors such as sarcomas. First-pass images acquired in the four-chamber view may therefore be used to diagnose these conditions.
Extravasation of an extracellular MR contrast medium during the first pass through the capillary bed is high, up to 40%, which challenges imaging of vessels and direct quantification of myocardial perfusion (see earlier section "Intravascular MR Contrast Agents").
Early Images and Microvascular Obstruction
A dark core of microvascular obstruction may be seen in larger infarcts at first-pass perfusion, early Gd enhancement (EGE), and LGE MR imaging118 (Fig. 6–17). This core is visualized with a much slower initial rise of enhancement and is typically located at the subendocardial level. This hypoenhanced core usually persists for several minutes but starts to decrease in size after approximately 5 minutes. The optimal time to detect and quantify microvascular obstruction is therefore suggested to be approximately 2 to 4 minutes after contrast injection.119 The term microvascular obstruction comes from the severe capillary damage due to microemboli obstructing the microvasculature, endothelial damage, and myocardial inflammation. Administration of a GPIIb/IIIa inhibitor seems to increase blood flow on the microvascular level,7 and microvascular obstruction is seen to a lesser extent in patients receiving this treatment early after pain onset.
A. Cardiac magnetic resonance (CMR) images from a patient with acute lateral myocardial infarction. Arrows point to microvascular obstruction (MO; areas of hypoenhancement) on first-pass perfusion (left), early gadolinium enhancement (EGE; middle), and late gadolinium enhancement (LGE; right). B. CMR images from a patient with acute anterior myocardial infarction. Arrows point to MO on (areas of hypoenhancement) first-pass perfusion (left), EGE (middle), and LGE (right). Reproduced from Mather AN, Lockie T, Nagel E, et al. Appearance of microvascular obstruction on high resolution first-pass perfusion, early and late gadolinium enhancement CMR in patients with acute myocardial infarction. J Cardiovasc Magn Reson. 2009;11:33.
A CMR report should include information on the amount of microvascular obstruction because this determines outcome, predicts event-free survival,120 and is more common in larger infarcts.121 The region of microvascular obstruction is resorbed and heals to thin scar over time.122
LGE CMR images are acquired for visualization and quantification of myocardial necrosis, microvascular obstruction, healed myocardial infarction (scar), and other types of fibrosis due to cardiomyopathies or myocarditis.
LGE CMR has emerged as a powerful tool for accurate and high-resolution assessment of myocardial viability.123 Validation studies have demonstrated the ability of LGE CMR to differentiate between viable and nonviable myocardium independent of wall motion, reperfusion status, or infarct age.110,124,125 Studies in humans have shown infarct transmurality to be predictive of recovery of regional function following acute infarction,126,127 elective revascularization,128-132 and β-blocker therapy.133 Infarct size by LGE CMR is prognostically significant independent of measures of systolic function.134 It has been shown that myocardial infarction by LGE CMR exceeding approximately one quarter of the left ventricle in the acute setting will predict negative remodeling (increased end-diastolic volume and reduced ejection fraction) over time.135
LGE CMR images are typically acquired 10 to 30 minutes after Gd-based contrast agent administration.136 The size of measured infarct on LGE CMR images does not change if images are acquired between 10 and 30 minutes after contrast agent injection (see "Extracellular MR Contrast Dynamics" earlier).136 Myocardial infarct size overestimation has been suggested when imaging is performed too early after Gd administration (<10 minutes), and therefore, this should be taken into consideration.
LGE CMR performed within the first 24 hours after an acute infarction may result in overestimation of infarct size in experimental137,138 and human135,139-142 studies. This might be ascribed to edema within the core of the infarction but may also be attributed to edema of the peri-infarction zone. The core of the infarction is known to shrink over the first 24 hours. Infarct size continues to decline over the first year142 (Fig. 6–18). The time line for when infarct size is no longer overestimated has not been fully evaluated, and the pathophysiologic background of enhancement and its overestimation of myocardial infarction size during the first week after infarction are not completely understood. Notably, LGE CMR accurately depicts infarct size in the setting of chronic fibrotic scar.110 Because LGE may be used both for acute and chronic infarction, a T2-weighted sequence sensitive for edema may be added to differentiate one from the other.98
Hyperenhancement caused by acute infarction decreases over time with the most pronounced decrease during the first week. Vertical bars indicate standard error of the mean. *P = .05 versus day 1; †P = .05 versus day 7; ‡P = .05 versus day 42. Published with permission from Engblom H, Hedstrom E, Heiberg E, Wagner GS, Pahlm O, Arheden H. Rapid initial reduction of hyperenhanced myocardium after reperfused first myocardial infarction suggests recovery of the peri-infarction zone: one-year follow-up by MRI. Circ Cardiovasc Imaging. 2009;2:47-55.
Importance of Finding the Optimal Inversion Time
Usually, infarct size by LGE CMR is considered adequate for clinical applications if imaging is undertaken using the optimal TI for nulling the signal from normal myocardium. The optimal value of TI for nulling the signal from normal myocardium depends on the scanner manufacturer and sequence timing parameters, as well as contrast agent dose, time after contrast agent administration, and renal clearance. To facilitate finding the optimal TI for nulling signal from normal myocardium, a Look-Locker sequence may be applied74 (Fig. 6–19). In this sequence, the images are acquired as described earlier for determination of relaxation rate, and each image acquired is associated with the time after the inversion pulse. Thus, one can choose the TI when the signal from the normal myocardium is nulled in the image. To facilitate finding the optimal TI using a Look-Locker sequence, one needs to acquire representative images while choosing imaging parameters similar to those that are to be used for the subsequent viability sequence.
A short-axis image of the left ventricle acquired 21 minutes after contrast agent administration using a Look-Locker sequence consisting of 70 images, in a setting of coronary artery occlusion in pig. Three different inversion times have been chosen when the signal was nulled from blood (A), perfused myocardium (B), and non-perfused myocardium (C). The correct inversion time to choose for viability studies would be the one depicted in B. Compare Fig. 6–14 for longitudinal relaxation curves. Reproduced with permission from Hedström E, Arheden H, Eriksson R, Johansson L, Ahlstrom H, Bjerner T. Importance of perfusion in myocardial viability studies using delayed contrast-enhanced magnetic resonance imaging. J Magn Reson Imaging. 2006;24:77-83.
The inversion-recovery sequence adapted by Simonetti et al114 was further developed by Kellman et al.143-145 They introduced a reconstructed image considering not only the magnitude, but also the phase of the magnetization during recovery. The phase-sensitive inversion-recovery (PSIR) sequence is therefore not so dependent on selecting the optimal TI for nulling the signal from normal myocardium (Fig. 6–20). The normal myocardium is presented as black in the image, and contrast/brightness can be adjusted for enhancing the image contrast further. The phase-sensitive reconstructed image is typically the image that is most useful for diagnosis. In cases with artifactual nulling of the signal from structures other than normal myocardium in the phase-sensitive reconstructed image, however, the standard magnitude image acquired simultaneously may be used for diagnosis. In such cases, this image is still dependent on the optimal TI for nulling the signal from normal myocardium. Therefore, the aim should be to select an appropriate TI to facilitate diagnosis, even when using a PSIR sequence.
The standard magnitude image (left) and the reconstructed phase-sensitive image (right) in a patient with anterior and septal infarction. The inversion time is not correctly chosen to null the signal from normal myocardium. Despite this, the reconstructed image shows excellent image contrast with a homogeneous dark myocardial wall with bright infarction (arrowheads).
In patients with arrhythmias, the standard magnitude or PSIR images may be difficult to interpret due to different timings of acquisition in the cardiac cycle resulting in motion artifacts. In the case of arrhythmias, it is also of value to image every other heart beat to allow recovery of the signal before the next inversion pulse.
In these situations, a single-shot SSFP sequence may also be applied.146 This yields higher image contrast due to decreased blurriness and less motion artifacts (Fig. 6–21). Moreover, this sequence can be acquired during free breathing with respiratory gating or with a very short breath-hold (1 second) and may therefore also be applied in patients who are not able to hold their breath for the duration of a typical breath-hold sequence (15 to 25 seconds).147 The downside of the single-shot SSFP sequence is a decreased sensitivity to detect small areas of fibrosis/infarct.
A T1-weighted single-shot steady-state free precession sequence applied in a patient with arrhythmia (left). The signal from normal myocardium is well nulled, and the bright inferior infarction is easily delineated (arrowheads). For comparison regarding motion artifacts, a standard sequence is shown (right).
Relation of Lge CMR to Other Methods for Viability Assessment
An important challenge in the identification of dysfunctional but viable myocardium is the determination of myocardial viability, particularly in the setting of chronic IHD. Several noninvasive imaging techniques offer this possibility, and they include thallium-201 and 99mTc tracers used for MPS, 18-fluorodeoxyglucose (18-FDG) positron emission tomography (PET), dobutamine stress echo-cardiography, dobutamine stress CMR, and LGE CMR.
A comprehensive review of non-CMR techniques for viability assessment was undertaken for 105 studies of just over 3000 patients. In these studies, regional functional improvement following revascularization occurred in 53% of the evaluated segments that were identified as dysfunctional but viable prior to intervention. The overall mean weighted sensitivity and specificity of the techniques was 84% and 69%, respectively, for identification of regional functional improvement after revascularization.148 Furthermore, pooled data have highlighted the prognostic importance of viability testing by showing that patients with significant viability who were revascularized showed a greater than 50% reduction in cardiac event rate compared with both patients who were treated medically and patients without viability who were treated either medically or with revascularization.149
Human LGE CMR studies have demonstrated excellent repeatability137 and good agreement compared with 18-FDG PET,129,150,151 MPS,152-154 and myocardial contrast echocardiography.155 The assessment of infarct size by MPS, however, can both overestimate153 and underestimate152 infarct size by LGE CMR. Importantly, one study showed that 47% of subendocardial infarcts identified by LGE CMR were missed by MPS152; this is likely attributable to the limited resolution in MPS. In addition, LGE CMR can be used to definitively assess viability in patients with suspected attenuation artifacts by MPS.156 The spatial resolution in LGE CMR is much greater than in MPS and can resolve small periprocedural infarctions not detected by other techniques.157,158
Low-dose dobutamine stress CMR imaging involves an infusion of a low dose of dobutamine in order to assess whether or not an improvement can be seen in regional contractile function, as a measure of dysfunctional but viable myocardium. Improvement in regional function assessed by low-dose dobutamine stress CMR has shown close agreement with viability by PET159 and a sensitivity of 89% and specificity of 94% for predicting improvement in function following revascularization.160 Moreover, assessment using grid tagging161 and dobutamine has shown a similarly high sensitivity of 89% and specificity of 93% for predicting functional improvement after revascularization.162
Studies comparing low-dose dobutamine stress and LGE CMR have shown conflicting results. Two studies have shown similar or better results with LGE CMR compared with low-dose dobutamine when it comes to predicting functional recovery following revascularization.163,164 However, other studies have shown that contractile reserve with dobutamine is superior to LGE CMR for predicting functional recovery165 and may add information particularly regarding the potential for functional recovery of segments with intermediate infarct transmurality.166 Thus, the relative contributions of contractile reserve and viability by LGE CMR to functional recovery and prognostic benefit following revascularization are worthy of further study.167
In summary, LGE CMR has developed as the reference standard for assessment of transmurality and extent of infarction. It offers the advantages of increased spatial resolution over alternative techniques. In particular, LGE CMR is an imaging technique whereby nonviable infarction is imaged directly through an increased tissue distribution volume of contrast agent in nonviable tissue, as opposed to relying on the absence of signal or analysis of regional function as with nuclear and echocardiographic techniques, respectively.
The importance of assessing stress-induced ischemia in the detection of coronary artery disease is paramount. The data on stress perfusion testing are extensive in the setting of MPS, which is the clinically most prevalent imaging modality for myocardial ischemia stress testing. Numerous studies using MPS have shown that the risk of cardiac events increases with the extent and severity of stress perfusion defects assessed by MPS.41 Furthermore, the number of lives saved due to treatment with revascularization compared with medical treatment increases with the amount of ischemic myocardium identified by MPS.168
Pooled analysis of 79 studies (8964 patients) using MPS to detect coronary artery disease by invasive angiography showed a weighted mean sensitivity of 86% and specificity of 74%.31 Of patients with normal MPS studies, only those with a high suspicion for coronary artery disease are referred for invasive coronary angiography. Therefore, the relatively low specificity for MPS may reflect such a referral bias. The percentage of normal MPS studies in a population with a low likelihood of coronary artery disease is called the normalcy rate. Thus, normalcy is a better descriptor of the performance of a test in a population without disease. The normalcy rate for MPS in 10 studies (543 patients) was 89%.31
For CMR, stress by external work has limitations because it is awkward to attempt physical exertion when lying supine in an MR scanner. Importantly, this inevitably leads to motion artifacts from both breathing and bulk motion. Thus, image interpretation becomes difficult, and sensitivity and specificity of the examination during external work are low.
Pharmacologic stress can be undertaken using either a vasodilator agent, such as adenosine or dipyridamole, for assessment of perfusion or a β-agonist, such as dobutamine with or without the addition of atropine, for assessment of regional contractile function. In CMR, these agents are used in the same fashion as they are used in MPS and stress echocardiography.
Stress Perfusion with Adenosine or Dipyridamole
CMR has an emerging role in the assessment of perfusion. Quantitative analysis of first-pass contrast kinetics has been used to identify stenosis by invasive coronary angiography and has been shown to correspond to perfusion by PET169 and perfusion by microspheres.170 Stress perfusion CMR is hampered by a lack of standardization with regard to the most optimal sequence parameters for image acquisition. There is continued development in the field, with the ultimate goal of achieving a method that can provide quantitative pixel maps of the absolute blood flow in the myocardium in units of mL/min/g tissue, analogous to PET.171,172 In the absence of that level of methodologic maturity, CMR perfusion assessment is performed by visual analysis, which yields sensitivity in excess of 90% and specificity of approximately 70%.
Adenosine and dipyridamole have almost identical effects. Adenosine acts directly on vascular smooth muscle, causing nearly maximal vasodilatation, whereas dipyridamole prevents breakdown of adenosine that is produced naturally in tissue. The basic principle of vasodilator stress perfusion CMR is that the vasodilator causes an up to five-fold increase in blood flow to healthy myocardium, whereas myocardium subtended by a stenotic artery will have an impeded ability to upregulate blood flow and thus exhibits a relatively delayed arrival of the first pass of an intravenously administered bolus of a contrast agent. This delayed arrival is visualized as a hypointense region corresponding to the distribution of a coronary artery (Fig. 6–22).
Myocardial perfusion magnetic resonance imaging (MRI) in a patient with significant stenosis in the left circumflex coronary artery (LCx) at the basal, midventricular, and apical level. Upper row shows first-pass perfusion at adenosine stress, middle row shows corresponding images at rest, and lower row shows corresponding late gadolinium-enhanced (LGE) MRIs. A region in the lateral wall is dark at all levels during adenosine stress (arrowheads). This perfusion defect is less prominent at rest. LGE MRIs show smaller regions of LGE. The difference between perfusion defect at stress and LGE is the region with stress-induced ischemia.
A multicenter multivendor trial comparing MPS and CMR stress perfusion found that CMR outperformed MPS with regard to overall diagnostic accuracy.169 However, that study had several limitations in design. Most notably, gated MPS was not used in the MPS analysis, despite it being known that gated MPS adds significantly to the diagnostic accuracy of MPS.173-175 Despite the challenges with CMR stress perfusion imaging, prognostic studies have begun to be published that show similar results to MPS. Importantly, a positive CMR stress perfusion examination performed on patients being evaluated for unclear chest pain in the emergency department is independently associated with poor prognosis.176 By comparison, a normal CMR stress perfusion study is associated with a greater than 99% probability of 3-year event-free survival.176-179 In addition, the presence of a reversible perfusion defect by CMR is prognostically poor in a way that is complementary to the prognostic value of LGE CMR for identifying myocardial infarction.180
Adenosine infusion is safe.181 During the stress study, patients should be monitored regarding heart rate and rhythm, blood pressure, and symptoms. Adenosine/dipyridamole should not be used in patients with poor pulmonary function or atrioventricular block IIa or higher due to the risk of adenosine-induced complete atrioventricular block.
Stress Function with High-Dose Dobutamine
The results from dobutamine stress CMR are reproducible, and high levels of specificity and sensitivity have been shown (~80%-90%).182 Imaging is undertaken at rest and during increased stress levels. Because dobutamine and atropine are used for increasing contractility, they are primarily useful for assessment of abnormalities of myocardial contraction177,182,183 (Fig. 6–23).
Dobutamine stress magnetic resonance in a patient with significant in-stent left anterior descending artery stenosis. Arrows point to region with decreased contractility at high dose. ED, end-diastole; ES, end-systole; max, maximum. Reproduced with permission from Paetsch I, Jahnke C, Wahl A, et al. Comparison of dobutamine stress magnetic resonance, adenosine stress magnetic resonance, and adenosine stress magnetic resonance perfusion. Circulation. 2004;110:835-842.
The administration of dobutamine usually follows a scheme with an increased body weight–adjusted infusion rate over time. High-dose dobutamine increases myocardial oxygen demand, and thus, myocardial regions supplied by a stenotic coronary artery typically develop abnormalities in myocardial contractility due to inadequate ability to upregulate the supply of oxygenated blood. The high-dose regimen is needed to increase sensitivity and specificity for visualizing wall motion abnormalities.
Adverse effects are rare184; however, patients should be monitored regarding heart rate and rhythm, blood pressure, wall motion abnormalities, and symptoms. Because wall motion abnormalities precede ST-segment changes in the ischemic cascade, and wall motion may be visualized during scanning, a standard single-lead ECG, as available at the scanner, is adequate for rhythm monitoring. However, the dobutamine regimen should not be used in patients with severe hypertension, significant aortic stenosis, unstable angina pectoris, or other debilitating systemic disease.
Images are acquired during rest and increased pharmacologic stress. To image the contractility defects, fast imaging is required. Either SSFP or real-time images are used, often as a short breath-hold sequence of approximately 5 seconds acquiring approximately 30 to 40 images per heartbeat with a spatial resolution of 1.5 × 1.5 mm. When using real-time imaging, the wall motion abnormalities can be visualized during the examination and thus can be used for monitoring the patient.185 However, the real-time images have lower spatial and temporal resolution than breath-hold images, and thus breath-hold images are preferred. Improved parallel real-time imaging may enhance image quality despite faster acquisition and thus facilitate evaluation of wall motion, while also shortening the scan time.186 Similar to CMR stress perfusion, a normal CMR high-dose dobutamine stress study is associated with a greater than 99% probability of 3-year event-free survival.177
Sensitivity of the examination may be increased by adding tagging prepulses to the acquisition.187 The tagging prepulses are applied perpendicular to the imaging plane and appear in the images as dark lines. Thus, local tissue deformation and contractility may be visualized and assessed. Recent developments include other tissue tracking methods such as displacement encoding with stimulated echoes (DENSE),188 harmonic phase imaging (HARP),189 and strain-encoded CMR.190 The dysfunctional region by strain-encoded CMR has been shown to correspond to region of infarction by LGE CMR.191 Furthermore, phase-contrast strain measurements can be performed for assessment of regional function.192 However, these acquisitions are currently too time consuming to be used for monitoring the patient during stress imaging.
To evaluate the images for diagnosis, the cine loops of the left ventricle are usually analyzed in 17 segments according to the American Heart Association.193 Because these segments are based on a standard coronary anatomy, one should be aware that the segments shown may be supplied by other coronary arteries than expected. In particular, there is considerable overlap between the perfusion territories subtended by the left circumflex and right coronary arteries.194 Collateral vessels also may contribute to variations from typical patterns. Thus, it is not possible to define which coronary artery has a stenosis or occlusion based on wall motion alone. The images in each segment are usually first graded by quality as good, acceptable, or poor. The wall motion is graded as normal, hypokinetic, akinetic, or dyskinetic. The wall motion score is thereafter divided by the number of diagnostic segments. The findings are considered to be diagnostic for ischemia either if wall motion is not increasing during increased stress or if systolic wall thickening is lacking. A reduction in wall motion or wall thickening is also considered to be indicative of ischemia.
Noninvasive Coronary Angiography
CMR can be used to perform noninvasive coronary angiography analogously to computed tomography (CT). A recent comprehensive meta-analysis confirmed that CT with 16-slice detectors or more shows a significantly better sensitivity and specificity for significant stenosis compared with CMR, although only five head-to-head studies exist.195 One head-to-head study showed that CT had a greater number of evaluable coronary artery segments compared with CMR.196 Interestingly, CMR was able to provide an accurate diagnosis in two thirds of the cases in which coronary segments were unevaluable by CT due to extensive calcification. CMR coronary angiography has also been shown to be able to quantify an increased coronary artery wall thickness in patients with nonsignificant coronary artery disease compared with controls.197
A whole-heart SSFP coronary artery MR angiography was described in 2003 that enables coronary imaging in three dimensions without the use of MR contrast agent198 (Fig 6–24). This sequence has been used in clinical trials with promising results.199,200
Coronary arteries of a volunteer that were imaged using a transverse targeted sequence (top row) and reformatted from a whole-heart sequence (middle row). Note that by using the whole-heart sequence, image contrast to the background is improved, especially in the more distal segments of the left anterior descending (LAD) and left circumflex (LCx) arteries. The bottom row shows three-dimensional (3D) reconstructions following computer-assisted image segmentation, which enables the major coronary vessels (right coronary artery [RCA], LAD, and LCx) to be visualized. Reproduced with permission from Weber OM, Martin AJ, Higgins CB. Whole-heart steady-state free precession coronary artery magnetic resonance angiography. Magn Reson Med. 2003;50:1223-1228.
Advantages with CMR include the lack of radiation exposure, but drawbacks include longer examination time and lower spatial resolution, in addition to the lower diagnostic accuracy. Evaluation of suspected anomalous coronary artery anatomy is possibly the strongest indication for CMR coronary angiography.201