The emerging clinical role of cardiovascular magnetic resonance imaging

Abstract

Starting as a research method little more than a decade ago, cardiovascular magnetic resonance (CMR) imaging has rapidly evolved to become a powerful diagnostic tool used in routine clinical cardiology. The contrast in CMR images is generated from protons in different chemical environments and, therefore, enables high-resolution imaging and specific tissue characterization in vivo, without the use of potentially harmful ionizing radiation.

CMR imaging is used for the assessment of regional and global ventricular function, and to answer questions regarding anatomy. State-of-the-art CMR sequences allow for a wide range of tissue characterization approaches, including the identification and quantification of nonviable, edematous, inflamed, infiltrated or hypoperfused myocardium. These tissue changes are not only used to help identify the etiology of cardiomyopathies, but also allow for a better understanding of tissue pathology in vivo. CMR tissue characterization may also be used to stage a disease process; for example, elevated T2 signal is consistent with edema and helps differentiate acute from chronic myocardial injury, and the extent of myocardial fibrosis as imaged by contrast-enhanced CMR correlates with adverse patient outcome in ischemic and nonischemic cardiomyopathies.

The current role of CMR imaging in clinical cardiology is reviewed, including coronary artery disease, congenital heart disease, nonischemic cardiomyopathies and valvular disease.

Starting as a basic research tool in cardiology as recently as 10 years ago, cardiovascular magnetic resonance (CMR) imaging has become a powerful diagnostic method and has entered the clinical arena.

In general, the strengths of the technique lie in its favourable safety profile and the ability to use specific image acquisition settings (sequences) to create a tissue-specific contrast. The signal obtained depends on the magnetic properties of protons in any tissue, which are determined by tissue composition. The range of contrast patterns can be extended by the use of contrast agents, which, for example, enables the identification of contrast-enhancing lesions. Currently available standard sequences offer a spatial resolution of as high as 1.0 mm × 1.0 mm in plane – substantially higher than that achieved by single photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging. Temporal resolution is good, with the fastest sequences being able to acquire an image in approximately 15 ms to 30 ms.

A recent consensus statement of the leading international societies for cardiology and radiology (including the American College of Cardiology Foundation, the American College of Radiology and the Society for Cardiovascular Magnetic Resonance) recommended CMR imaging for a list of clinical indications (1), and the Canadian Cardiovascular Society together with leading imaging societies in Canada published a position statement summarizing the indications for CMR imaging in ischemic heart disease (2).

In the present review, we discuss the emerging role of CMR imaging in clinical cardiology.

CMR IN CONGENITAL HEART DISEASE

CMR is well suited for pre- and postoperative evaluation of congenital heart disease (CHD) because it offers advantages over other imaging modalities, including lack of ionizing radiation, which is particularly important because many CHD patients will require imaging studies in childhood or serial examinations throughout their lifetime; capacity for true three-dimensional (3D) imaging; accurate blood flow quantification; tissue characterization; and freely selectable imaging planes with wide fields of view that enable assessment of relationships between cardiac and vascular structures (3,4). Although echocardiography is the initial imaging modality for CHD in infants and children, CMR is of benefit in the presence of complex anatomy or in older patients whose echocardiographic views may be suboptimal (5,6). CMR has found an increasingly important role in the evaluation of morphology and pathophysiology of complex CHD at all ages, particularly in the assessment of great vessel anatomy, venous connections, extracardiac conduits and intracardiac baffles, and complex spatial relationships, as well as physiological evaluation of shunts, ventricular function and myocardial fibrosis (7).

The clinical use of CMR in patients with CHD – like that of any other imaging technique – is challenged by the tremendous diversity of congenital cardiac malformations and the manner in which they are repaired. Keeping in mind the versatility of CMR, the overall goals of CMR assessment of CHD include the following (8):

1. Evaluation of the anatomy and severity of the defect(s);

2. Assessment of the functional consequences of the defect(s) before and after surgical repair; and

3. Identification of associated and incidental lesions.

The first goal, anatomical evaluation, is achieved by imaging the heart and vascular structures in several planes to produce a multidimensional representation of the anatomy. Transverse, coronal, sagittal and oblique multislice images using black-blood sequences (fast spin echo) (Figure 1A) or static bright-blood sequences (static single-shot or segmented steady-state free precession [SSFP]) (Figure 1B) provide excellent anatomical definition and serve as reference images for accurate location of piloted breath-hold SSFP cine images, which are useful for assessment of anatomy and function. Contrast-enhanced magnetic resonance angiography with gadolinium, which has comparable diagnostic accuracy to x-ray angiography in complex CHD (9), is valuable for 3D assessment of extracardiac structures such as the aorta, main and branch pulmonary arteries, pulmonary veins and collateral vessels (Figure 1D). Time-resolved 3D contrast-enhanced magnetic resonance angiography is a newer angiographic technique that captures information about the dynamics of blood flow through the right and left heart using a small volume of contrast (10). Additionally, 3D static SSFP acquisitions may be obtained, either with single breath-hold or diaphragmatic monitoring, for visualization of the coronary arteries or 3D anatomy of the whole heart and vessels.

Figure 1).

Examples of cardiovascular magnetic resonance imaging of congenital heart disease. A Sagittal black-blood image of a patient with repaired tetralogy of Fallot, showing right ventricular dilation and an aneurysm (A) of the right ventricular outflow tract patch. B Transverse static bright-blood image (steady-state free precession) of the pulmonary arteries (PAs) lying anterior to the aorta (Ao) following arterial switch repair with the Lecompte manoeuvre in transposition of the great arteries. C Diastolic frame of a steady-state free precession cine image series in a patient with repaired tetralogy of Fallot and pulmonary regurgitation showing severe right ventricular dilation. D Volume rendering of a gadolinium-enhanced magnetic resonance angiogram of the right ventricle (RV) and PAs in a patient with an RV-to-PA-valved conduit for repair of pulmonary atresia and ventricular septal defect. LA Left atrium; LV Left ventricle; RA Right atrium

The second goal, assessment of the functional consequences of CHD, is achieved with a number of techniques including cine imaging using SSFP and phase-contrast velocity mapping. Cine imaging with SSFP offers an excellent contrast between blood and myocardium and, hence, is very useful for the analysis of right ventricular (RV) and left ventricular (LV) function (described in greater detail below), for quantification of ventricular volume and mass, and for the visualization of valve leaflets and high-velocity stenotic jets (Figure 1C). There are particular advantages of cine SSFP CMR imaging over echocardiographic evaluation of the right heart in CHD; CMR is independent of geometrical assumptions for evaluation of RV volume and function, and the wide field of view provides good visualization of the RV outflow tract and anterior RV wall. CMR quantification of the right ventricle is therefore becoming increasingly important in the management of patients with repaired tetralogy of Fallot and pulmonary regurgitation (11,12).

Evaluation of blood flow and velocity by CMR imaging is achieved with the use of phase-contrast velocity mapping, a technique that is based on magnetic resonant properties acquired from blood flowing in a magnetic field gradient. Phase-contrast maps acquired parallel to blood flow are used to measure peak velocities or assess turbulent jets. Phase-contrast velocity mapping allows measurement of blood flow as well as velocity. In this regard, phase-contrast techniques are useful for evaluation of flow, stenosis and regurgitation in the systemic and pulmonary circulations (13,14), and in shunt quantification in CHD (15).

The third goal, identification of associated and incidental lesions, relates to the complexity of many types of CHD. Because CMR produces images independent of acoustic windows and provides additional information about tissue characteristics such as myocardial scarring or fibrosis (described in greater detail in following sections of the present review), it may provide additional new diagnoses or insight into the pathophysiology of a patient’s condition. For example, CMR is valuable in the detection of previously unrecognized shunts, aberrant arterial vessels (16) or anomalous pulmonary veins (17). Additionally, CMR findings of myocardial fibrosis or infarction in repaired transposition of the great arteries (18) and in tetralogy of Fallot (19) appear to have prognostic significance with respect to ventricular function, exercise tolerance, arrhythmia or sudden death in these types of CHD.

CMR FOR THE ASSESSMENT OF RV AND LV SIZE AND FUNCTION

CMR provides accurate measurements of LV and RV mass, volumes and systolic function. SSFP sequences are commonly used and provide excellent contrast of myocardium over intracavitary blood, and cine movies covering one cardiac cycle with 25 frames are typically acquired over 15 heartbeats (with acquisition of up to six slices during one breath-hold) (20). Using the multiple short-axis slice-summation method, contiguous slices of short-axis cine datasets are acquired from the base of the left ventricle to the apex, covering the myocardium completely. This approach has been shown to provide excellent accuracy (21) and low interstudy variability (22); normal values are available for healthy subjects (23). A less commonly used approach covers the entire LV myocardium with multiple radial long-axis slices, and has been shown to yield similarly robust values of interobserver variability (24). Imaging time for the acquisition of a complete LV or RV data set takes in the range of 3 min to 5 min, and approximately 5 min to 10 min are required for quantitative data analysis. In the absence of arrhythmia, CMR yields a consistently stable image quality, and the reproducibility of CMR for anatomical and functional parameters is higher than that of echocardiography (25). This translates into a sample size reduction in research studies when CMR is used to measure treatment effects on ventricular volumes, function or mass (26–28), and it allows higher accuracy in the assessment of smaller changes of these parameters in patients. Furthermore, two-dimensional (2D) echocardiographic studies have been shown to overestimate LV mass and underestimate LV volume when compared with CMR imaging (29). This is explained by the technical approach to volumetric assessment. While 2D echocardiography obtains quantitative data in two imaging planes, these are subsequently extrapolated to obtain 3D data, under the assumption that the patient’s ventricle has a geometrical ellipsoid shape. This, however, may not perfectly represent the patient’s anatomy. CMR overcomes this limitation by using a 3D imaging method; here, volumes are measured, not extrapolated, and anatomical variances are respected. In summary, while 2D echocardiography can provide an estimate of LV volumes and function, CMR can provide an actual measurement of LV volumes and function; therefore, it is often regarded as the gold standard for the assessment of ventricular volumes and function.

Few approaches have been undertaken to examine diastolic dysfunction with CMR, but none is currently being widely used in routine clinical imaging. One promising approach uses a technique known as tagging. Here, magnetic field saturation is applied to the myocardium in a grid-like fashion, and the deformation of this grid is used to assess regional wall motion and strain (30,31). However, analysis software is currently too complex for daily routine use. One working group has suggested tissue phase mapping of the myocardium as an alternative for diastolic function assessment. This method measures myocardial tissue velocity in 3D space, which can be used to measure diastolic wall motion with low interobserver variability (32).

DETECTION OF STRESS-INDUCED MYOCARDIAL ISCHEMIA

CMR currently offers two clinically used methods for the detection of stress-induced myocardial ischemia – first-pass perfusion studies with a vasodilatory stress agent (adenosine) (Figure 2), and wall motion analysis with an adrenergic agent (usually dobutamine). Both are routinely used in experienced CMR centres, with modern cardiac scanners allowing for continuous real-time electrocardiographic and respiratory monitoring, blood-pressure measurements and intercom systems for optimal patient supervision.

Figure 2).

Adenosine stress perfusion imaging of a patient with coronary artery disease. A patient with a high-grade stenosis of a diagonal branch artery. The left image shows a short-axis view of an apical short-axis slice (still frame extracted from a movie). There is no significant perfusion deficit during contrast infusion at rest. When the examination is repeated 20 min later during the continuous infusion of adenosine, the second contrast infusion shows a stress-induced subendocardial perfusion deficit of the anterolateral wall (arrows). LV Left ventricle

Adenosine causes microvascular vasodilation by acting on the A2 receptors of the muscularis layer of coronary resistance vessels. Although adenosine is used to unmask hypoperfused myocardium at perfusion scans, the underlying mechanism of action is not well understood. It is commonly believed that adenosine causes a ‘steal phenomenon’ by increasing perfusion in coronary territories not affected by epicardial artery stenosis, which leads to relative hypoperfusion of the territory subtended by a stenosed coronary artery (33). Several research papers (34–38), including one multicentre study, have assessed the role of adenosine stress perfusion for the diagnosis of coronary artery disease and consistently demonstrated high sensitivity for CMR imaging to diagnose epicardial coronary artery stenoses. When CMR perfusion was compared with x-ray coronary angiography, its specificities to detect coronary stenoses were only moderately high (62% to 90%) (34–38). However, when PET or fractional flow reserve on x-ray angiography were used as standards of truth, specificities were higher (94% [34] and 90% [38], respectively). This is explained by the fact that CMR assesses perfusion on a tissue level, which includes not only perfusion deficits caused by macrovascular epicardial coronary artery disease, but also those due to microvascular disease as it occurs, for example, in diabetes or chronic arterial hypertension. The method can be used to quantify myocardial perfusion reserve with good inter-observer and intraobserver variabilities (36). In patients presenting to the emergency room with chest pain and exclusion of acute myocardial infarction, abnormal findings on adenosine stress perfusion were shown to predict adverse cardiovascular events independently and stronger than the combination of known risk factors; furthermore, negative adenosine stress perfusion tests had a negative predictive value of 100% for cardiovascular events at one-year follow-up in one study (39). A high negative predictive value was recently confirmed in another study involving more than 450 stable outpatients who were referred for a CMR stress test (40).

Dobutamine stress studies for ischemia-induced wall motion abnormalities can be performed with CMR protocols identical to those established for transthoracic dobutamine stress echocardiography, with a similar safety profile (41–43). Because wall motion abnormalities occur later in the ischemic cascade than perfusion deficits (44), dobutamine stress tests may be less sensitive but more specific for inducible ischemia than perfusion tests.

An advantage of CMR imaging over transthoracic echocardiography for dobutamine stress testing is that state-of-the-art CMR sequences offer consistently high image quality for visualization of all RV and LV wall segments. Additionally, CMR is not limited by the restrictions of an acoustic window. In a head-to-head comparison of more than 200 patients, this was shown to translate into superior accuracy of dobutamine stress CMR imaging (accuracy 86%) over echocardiography (accuracy 73%) for the diagnosis of epicardial coronary artery disease (45). Overall, published sensitivities for the diagnosis of epicardial coronary artery stenosis using dobutamine stress CMR imaging are reported to be in the range of 78% to 89%, with specificities in the range of 80% to 87% (45–47).

Few working groups have studied blood oxygen level-dependent CMR imaging as a method to detect adenosine-dependent ischemia in coronary artery disease. This approach does not depend on a contrast agent, and derives image contrast from the concentrations of oxygenated versus deoxygenated hemoglobin. While early studies (48,49) demonstrated the feasibility of this approach, they were limited by image artifacts; recent technical developments have overcome this problem, and more recent research (50,51) suggests that blood oxygen level-dependent CMR imaging may be entering the clinical arena in the next few years as a test for myocardial hypoxemia.

ASSESSMENT OF MYOCARDIAL VIABILITY IN ISCHEMIC HEART DISEASE

The detection of viable myocardium plays a crucial role in clinical cardiology because it has been shown that myocardial infarction patients only benefit from revascularization therapy if the reperfused tissue is viable (52,53).

In a clinical setting, there are two ways to assess myocardial viability with CMR – cine imaging, which allows for wall motion analysis at rest and during low-dose dobutamine stress; and ‘late enhancement’ imaging, which identifies nonviable tissue (fibrosis and scar).

Low-dose dobutamine stress CMR imaging for viability assessment is performed with protocols similar to low-dose dobutamine stress echocardiography. An improvement of regional contractility during a continuous infusion of dobutamine at a dose of 10 μg/kg body weight/min or less has been shown to be a powerful predictor of functional recovery after revascularization therapy (54), and is a better predictor of LV functional recovery after revascularization than end-diastolic wall thickness (55). However, this method is limited by assessing viability indirectly through an assessment of function as a surrogate, which can be hampered in the presence of dysfunctional (eg, stunned or hibernating) tissue (56).

A more recently developed approach allows for viability assessment at the tissue level and is known as ‘late enhancement’ imaging. The method, first described by Simonetti et al (57) and first used by Kim et al (58), is based on gadolinium contrast enhancement of nonviable cardiac tissue (Figure 3); it accurately reflects infarction tissue when compared with ex vivo pathology in animal models (57–60) and is highly reproducible (61). The underlying mechanism is an increased volume of distribution for the extracellular contrast agent gadolinium-diethylene triamine penta-acetic acid in nonviable tissue as opposed to healthy myocardium, leading to delayed washout of contrast in nonviable tissue (60,62). In addition to contrast enhancement of myocardial necrosis or collagenous scar, late enhancement imaging sequences suppress the signal derived from remote noninfarcted myocardium, leading to very high image contrast. Image voxel size obtained with these sequences is typically 1.5 mm² × 1.3 mm² in plane with a slice thickness of 8 mm or 10 mm, which allows the detection of myocardial infarcts involving as little as 0.7 g of tissue (63). The method is established in acute as well as chronic myocardial infarction.

Figure 3).

A patient with an acute posterolateral myocardial infarction. The image to the left displays a short-axis view using the ‘late enhancement’ sequence after application of gadolinium-diethylene triamine penta-acetic acid contrast. There is contrast enhancement indicating myocardial necrosis of the inferior lateral wall (bold arrows), but not in the anterior and septal wall. There is an area of microvascular obstruction, highlighted with the slim arrow. The image to the right is a T2-weighted spin-echo image, showing a regionally high signal in the inferior lateral wall (arrows), consistent with myocardial edema in the area of necrosis. The presence of edema indicates that the infarction is acute

The high spatial resolution viability imaging allows for the in vivo assessment of the transmural extent of viable myocardium as well as the amount of viable tissue within one segment of myocardium. The spatial resolution is superior to what is achieved by SPECT or PET imaging and, consequently, subendocardial infarctions that are missed by SPECT (59,64,65) and PET imaging (66,67) are detected by late enhancement CMR imaging.

The transmural extent of late enhancement contains clinically relevant information because it can be used to predict the functional recovery of myocardial contractility after vascularization. In a study performed by Choi et al (68) in patients with acute reperfused myocardial infarction, only 5% of segments demonstrated improved contractility at eight to 12 weeks follow-up if the transmural extent of necrosis was greater than 75%; however, it was 63% when the transmural extent of necrosis was 50% or less. Other investigators confirmed the correlation of functional recovery with transmural extent of viable tissue in acute myocardial infarction (69) as well as in chronic ischemic disease (70,71). Equally, in chronic systolic heart failure, the recovery of function after initiation of beta-blocker therapy was shown to be a measure of the transmural extent of viable myocardium (72). CMR imaging is therefore a useful tool to assess stunned as well as hibernating (73) myocardium, when functional cine imaging is combined with late enhancement imaging. CMR imaging has a higher accuracy than SPECT for the prediction of functional recovery, which is explained by the higher spatial resolution of CMR (65).

More recently, the concept of peri-infarct zone imaging was introduced using CMR imaging. Electrophysiology studies have suggested that in ischemic heart disease, the infarct border zone may be the origin of ventricular tachycardia due to micro re-entry. Initial CMR studies have shown an association between the extent of the heterogeneous infarct border zone and inducible ventricular tachycardia (74) and mortality, independent of ejection fraction, infarct size and ventricular volume (75).

The same technique applied early after contrast injection is used for visualization of microvascular obstruction or no reflow, which presents as absence of contrast enhancement in the subendocardium, surrounded by contrast enhancement in the infarcted but successfully reperfused tissue (Figure 3). The presence of no reflow, as displayed on CMR imaging, predicts adverse outcome independent of infarct size (76).

While late enhancement CMR imaging is highly accurate for the detection of viable myocardium, it is unable to differentiate between acute necrosis and chronic fibrotic scar.

Advancement in CMR imaging was achieved when T2-weighted spin-echo imaging was shown to yield a signal increase specific to acute, but not chronic, myocardial infarction (77). The signal intensity in T2-weighted images is influenced by the tissue water content, and myocardial edema is believed to be the main underlying pathology that causes the T2 signal change. Myocardial edema precedes myocardial necrosis (78), and is a marker of the area at risk in acute ischemia (79,80). T2 signal changes persist after reperfusion, and this method can therefore be used to determine the area at risk retrospectively after reperfusion therapy. In conjunction with infarct size measurement, the myocardial salvage can be measured in grams of tissue (77,79–81). A recent study (82) suggested that edema in reversibly injured myocardium may be the cause of myocardial stunning in acute ischemic injury.

In summary, the combination of functional studies, sequences for stress-inducible ischemia, viability and edema allow for the comprehensive assessment of a patient with coronary artery disease within 30 min to 40 min of examination time. Example images of a viability study in a patient with acute myocardial infarction are shown in Figure 3.

CMR FOR PATIENT ASSESSMENT BEFORE CARDIAC RESYNCHRONIZATION THERAPY

Two types of CMR parameters have been assessed for patient evaluation before cardiac resynchronization therapy (CRT) – functional parameters that assess different aspects of ventricular wall motion, and tissue characterization parameters that assess myocardial scar. In terms of functional LV assessment, velocity-encoded CMR of LV contraction has been shown to yield similar results as tissue Doppler echocardiography (83). Moreover, CMR tagging allows for the assessment of regional function, which can be used to assess circumferential shortening and regional quantification of myocardial strain. A recent study suggested that strain imaging may be more effective at predicting response to CRT than the assessment of mechanical dyssynchrony (84); however, another study demonstrated that a CMR function-derived dyssynchrony index is of prognostic value and useful for the prediction of mortality and morbidity after CRT (85).

The second way to predict response to CRT using CMR imaging is the assessment of scar burden using late enhancement CMR imaging. Several studies have demonstrated that an increased scar burden, measured as total scar or transmural extent of scar, decreases the likelihood of a patient to respond to CRT. The relationship between scar burden and LV end-systolic volume at six months post-CRT appears to be linear (86), but scar location in the septum (87) or transmural extent of the scar (88) may be more powerful predictors of response than global scar burden.

While these approaches yield very promising initial data, the best possible way to assess CRT response and to predict mortality after this procedure using CMR is still a matter of ongoing research.

VALVULAR HEART DISEASE

CMR can quantify the severity of regurgitant and stenotic valvular lesions. Several methods are available for this purpose – phase-contrast sequences quantify anterograde and retrograde flow volumes and velocities in any desired imaging plane, within a vessel or a valvular plane (89,90). The accuracy of phase-contrast measurements as assessed with in vitro models is excellent (91,92) and good correlations have been documented between CMR flow measurements and Doppler echocardiography (93), as well as cardiac catheterization (94,95). Cine imaging is applied to quantify the orifice of a stenotic valve (96).

Aortic valve stenosis can be accurately quantified by planimetry of the aortic valve (96,97) (Figure 4), a method that does not depend on pressure gradient measurement-derived calculations, and that therefore may be less susceptible to pre- and afterload variations. Another established way to assess the aortic valve area is by flow measurements using phase-contrast CMR imaging, analogous to Doppler echocardiography. This CMR method allows calculation of the pressure gradient and valve area, but does not directly measure the orifice; it shows good correlation with the values obtained by Doppler echocardiography (93). Aortic regurgitation can be measured by characterization of blood flow immediately adjacent to the aortic valve, using phase-contrast magnetic resonance imaging. This allows for the calculation of regurgitant volume and regurgitant fraction. The method is highly reproducible (98), and the results agree well with aortic root angiography (94). Similar principles are applied to the assessment of the mitral and right-sided heart valves (95,99,100).

Figure 4).

A patient with aortic valve stenosis. Both images are still frames extracted from steady-state free precession cine movies. The orifice of the aortic valve can be measured from the systolic image to the right. The contour of the orifice is marked in yellow. AoV Aortic valve; LA Left atrium; RA Right atrium; RV Right ventricle

CMR IMAGING OF NONISCHEMIC CARDIOMYOPATHIES

CMR imaging can principally make two contributions to the workup of patients with nonischemic cardiomyopathies:

1. Identification of the etiology of the nonischemic cardiomyopathy; and

2. Quantification of volume, mass and systolic function of the right and left ventricles, and quantification of scar tissue as measures of disease severity.

Identification of etiology

Hypertrophic cardiomyopathy:

In hypertrophic cardiomyopathy, CMR can identify the pattern of hypertrophy (eg, differentiation between global and regional hypertrophy, with or without LV outflow tract obstruction) using the aforementioned sequences for ventricular function. The accuracy of the method for quantification of LV mass and systolic function makes it an appropriate tool for the serial follow-up of a patient with sensitive evaluation of the effects of pharmacological therapy. LV outflow tract obstruction can be identified (101) and quantified before and after therapeutic septal artery embolization; the change in outflow tract dimensions was shown to correlate with the improvement of the patient’s symptoms (Figure 5) (102). On histology, the disease is known to cause myofibrillar disarray and fibroses at the insertion sites of the RV wall; this is reflected by a signal increase on late enhancement imaging in those regions (103–105). Some studies (104) suggested that an increasing amount of fibrotic areas correlates with increasing clinical predictors for sudden cardiac death in patients with hypertrophic cardiomyopathy. A large prospective study (106) demonstrated an association between the extent of late enhancement and the occurrence of ventricular arrhythmia. Late enhancement may, therefore, emerge as a prognostic tissue marker in hypertrophic cardiomyopathy. However, more prospective mortality data are needed.

Figure 5).

A patient with hypertrophic obstructive cardiomyopathy. Both images are extracted from functional steady-state free precession cine movies, at diastole (left) and mid-systole (right). The diastolic image displays marked thickening of the anterior septal wall. At mid-systole, there is an anterior movement of the anterior mitral valve leaflet, causing left ventricular outflow tract obstruction and a jet of high-velocity flow (arrow). Cardiovascular magnetic resonance imaging allows for quantification of the obstruction by planimetry of the left ventricular outflow tract and flow velocity quantification of the jet (not shown)

Idiopathic dilated cardiomyopathy:

Idiopathic dilated cardiomyopathy is characterized by an increase in end-diastolic volume and, usually, reduced systolic function of the left and right ventricles; histopathology reveals partial replacement of cardiomyocytes by fibrotic tissue. LV dilation is readily identified by CMR using 3D assessment of ventricular volumes and systolic function. Further insight can be obtained by adding tissue characterization sequences to the CMR examination. Idiopathic dilated cardiomyopathy does not display any late enhancement in two-thirds of patients, but in one-third of patients, focal fibrosis of the septum is observed at the mid-wall level, commonly termed the ‘mid-wall sign’ (107,108). The presence of this finding was recently identified as a prognosticator of adverse outcome, and it is also a substrate of ventricular tachycardia (108,109).

A diagnostic challenge that cardiologists face frequently is the need for differentiation of idiopathic dilated cardiomyopathy from phenotypic dilated cardiomyopathy as a secondary result of an unidentified primary disease. The phenotype of dilated cardiomyopathy is frequently caused by ischemic cardiomyopathy, but among many others, may be caused by myocarditis (110), exposure to cardiotoxic agents such as drugs (eg, anthracyclines) (111), alcohol abuse (112) and autoimmune diseases (113).

CMR tissue characterization can play a crucial role in this situation, because the pattern of fibrosis seen on late enhancement CMR imaging allows differential diagnosis of the underlying disease. In ischemic cardiomyopathy, CMR imaging displays infarction-type scar tissue usually restricted to the perfusion territory of one coronary artery, extending across the myocardium from the subendocardium. In anthracycline toxicity, late enhancement has been observed in a global subendocardial fashion (114), and early enhancement (a measure of hyperemia and capillary leak) is increased (115). Myocarditis is diagnosed using a comprehensive tissue assessment.

Myocarditis

Myocarditis leads to inflammatory tissue changes including hyperemia, capillary leak, edema and, in severe cases, cardiomyocyte necrosis that remodels to fibrosis.

For the diagnosis of inflammatory tissue changes in myocarditis, several CMR sequences are available that specifically address these different aspects of tissue pathology:

• T1-weighted early contrast-enhanced sequences assess myocardial hyperemia and capillary leak (116);

• T2-weighted sequences assess myocardial edema (117,118); and

• Late enhancement assesses cardiomyocyte necrosis or fibrosis (119,120).

Therefore, a comprehensive in vivo assessment of tissue pathology is possible, beyond the analysis of myocardial volumes and function.

The fibrosis and edema patterns observed in myocarditis are often patchy and, unlike in myocardial infarction, do not necessarily involve subendocardial areas (Figure 6) (117). Some studies observed that the epicardium of the inferior lateral wall was affected more often than other areas (119); other studies linked certain fibrosis patterns to specific causative viruses (120). It was shown that early enhancement changes are detectable soon after the clinical onset of disease and vanish with declining symptoms at follow-up (121). Two studies from independent working groups have shown that sequences that assess edema and hyperemia are more sensitive, while late enhancement imaging is more specific for the diagnosis of myocarditis (117,118). This is in accordance with the current understanding of pathophysiology. While inflammatory changes with edema and hyperemia are a mandatory component of inflammation in myocarditis, tissue necrosis may only occur in more severe cases. Both studies showed that the highest diagnostic accuracy is achieved by combining different tissue characterization methods in one diagnostic study and, therefore, assessing several aspects of tissue pathology at the same time. In a recent expert consensus conference on the CMR diagnosis of myocarditis, a combination of functional imaging, T2-weighted imaging, and early and late enhancement was recommended as the approach of choice for patients with suspected myocarditis (122). This combined approach yielded a sensitivity of 76%, a specificity of 95.5% and an accuracy of 85% for the diagnosis of acute myocarditis in a study applying comprehensive clinical information as a reference standard (117). Another study of patients with chronic active myocarditis, using myocardial biopsy with histology and immunohistology as a reference standard, yielded a sensitivity of 62%, a specificity of 89% and a diagnostic accuracy of 74% (118). In a recent review paper (123), CMR imaging was considered to be the most powerful noninvasive tool for determining whether active myocarditis is present.

Figure 6).

A patient with myocarditis. The quantitative measurements of signal intensities in the myocardium normalized to skeletal muscle using a T1-weighted spin-echo sequence, before and after application of gadolinium contrast, allow for identification of patients with inflammatory myocardial disease (left image). In patients with acute severe myocarditis, patchy foci of delayed enhancement can be visualized, corresponding to foci of acute myocardial necrosis (right image, arrows)

Other nonischemic cardiomyopathies

The principle of using different imaging sequences to enable tissue characterization of the myocardium is also useful in other cardiomyopathies. CMR imaging detects myocardial involvement in amyloidosis; late enhancement involves the myocardium globally, usually with a predominant involvement of the subendocardium (124,125). Cardiac involvement in sarcoidosis can be diagnosed by early and late contrast enhancement. Early enhancement reflecting hyperemia is a more sensitive method (126), and late enhancement may identify patients with a worse clinical course. The late enhancement pattern involves the lateral wall more frequently than other areas of the myocardium (126–128).

Myocardial involvement in Anderson-Fabry disease leads to myocardial fibrosis, which can be visualized by late enhancement CMR imaging (129,130). The amount of fibrotic tissue as defined by late enhancement imaging correlates well with the extent of LV hypertrophy, and it is more frequently observed in the inferior lateral wall. The subendocardium is usually spared, which helps to differentiate this disease from others.

In thalassemia, progressive iron deposition in the myocardium can lead to heart failure. Dedicated T2-star (T2*)-weighted CMR sequences can create image contrast depending on the iron content of the myocardium (131). These are used to detect cardiac involvement in thalassemia, and furthermore measure the T2* magnetic resonance value to quantify the amount of iron deposits in the myocardium. The amount of iron as assessed by in vivo T2* quantification correlates with LV systolic function (131). CMR imaging can be used to guide therapy in these patients, and a therapy-related reduction in iron content, as measured by CMR imaging, correlates with improvement in LV systolic function (132,133)

Noncompaction cardiomyopathy is caused by genetic abnormalities of the desmoglein gene and leads to a phenotype with regional LV wall thinning of the compact myocardium and increased trabeculation in the same area. However, a similar phenotype may also evolve as the result of remodelling in other cardiomyopathies. A CMR study comparing noncompaction cardiomyopathy to hypertrophic cardiomyopathy, aortic valve stenosis, dilated cardiomyopathy and hypertensive cardiomyopathy showed that CMR imaging is able to diagnose noncompaction with 86% sensitivity and has 99% specificity to differentiate it from other causes of hypertrabeculation, using simple diagnostic criteria (134). The increased trabeculation may be subject to fibrosis or hypoperfusion (135).

Few studies (136) have been published using CMR imaging in patients with transient LV apical ballooning (takotsubo cardiomyopathy). One case study (137) demonstrated edema and hyperemia in a patient with a typical takotsubo-like presentation. Late enhancement may also be present (138), indicating that cardiomyocyte necrosis can occur.

FURTHER CLINICAL APPLICATIONS OF CMR

In clinical practice, CMR is of important value for the diagnosis of aortic diseases. 3D contrast angiography is an excellent tool for the assessment of aortic aneurysms, and has high sensitivities and specificities for the diagnosis of aortic dissection (139). The combined use of different sequences providing T1 and T2 contrast, with and without fat suppression, perfusion imaging and assessment of contrast uptake, allow for noninvasive tissue characterization of cardiac and paracardiac masses (140). Additionally, high-resolution images can be obtained to exactly assess the spatial extent of a tumour.

Considerable effort is being invested in the development of CMR coronary angiography. Although the diagnostic accuracy appears to be comparable with computed tomography (141), the technique is not widely accepted as a routine clinical tool. Most studies agree on a limited image quality for middle and distal segments of the large epicardial vessels, while image quality in the proximal segments is usually good (142).

SUMMARY AND CONCLUSION

Starting as a research tool little more than a decade ago, CMR imaging has entered the arena of routine clinical imaging applications. Specific imaging sequences and protocols are now available for a wide range of heart diseases, including ischemic and nonischemic heart disease, as well as valvular disease. The high accuracy of flow measurements, freedom to deliberately choose an imaging plane and the lack of ionizing radiation make it the imaging modality of choice for CHD in children and adults. The unique ability to obtain information on disease-specific tissue characteristics provides the clinician with new insight into pathology and pathophysiology in vivo. Although long-term follow-up studies with very large patient numbers remain scarce, there is evolving evidence that some pathological CMR imaging findings, such as fibrosis, may be of value as predictors of patient outcome.