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The clinical role of Cardiovascular Magnetic Resonance (CMR) continues to expand1, supported by ongoing technological advances that have shortened acquisition times while maintaining and often improving image quality. New applications of CMR in cardiovascular imaging continue to emerge and results from larger clinical trials are beginning to define the role of CMR in a range of clinical scenarios. Current accepted indications for CMR include the assessment of congenital heart disease, the great vessels, acquired myocardial and pericardial disease and chronic coronary artery disease (CAD)1. The role of CMR in the assessment of acute coronary syndromes (ACS) is less well established. However, evidence is accumulating that CMR provides often unique information in chest pain syndromes that can aid the detection and differential diagnosis of ACS, guide clinical decision-making and improve risk-stratification after an event.
Following a review of the relevant CMR methodology, this article presents the current evidence for CMR in ACS and gives an outlook of future developments.
The following CMR methods are most commonly used for the assessment of ACS (see Figure 1) and can be incorporated into a clinical protocol that can be performed within an hour.
The assessment of global and regional left ventricular (LV) and right ventricular (RV) function by CMR is typically based on a cine data set aligned in the true LV short axis that covers the heart in 10-12 consecutive two-dimensional slices2. Alternatively, three-dimensional cine data sets covering the entire heart in a single breath-hold can be acquired3, 4. In addition to its high tissue contrast, the main advantage of CMR over other imaging modalities is that imaging planes can be freely and reproducibly defined. Consequently, CMR is the most accurate and reproducible imaging modality for the assessment of global ventricular volumes and function 5, 6. In addition, regional contractile function can be assessed either by visual interpretation of cine loops7, 8 or by measuring wall motion, thickening and strain using myocardial tagging methods9, 10. Myocardial tagging during low dose dobutamine stress has been used to measure parameters of diastolic dysfunction such as the time to peak untwist which may identify coronary stenosis11,12. Following AMI, low dose dobutamine cine CMR can be used to predict viability and functional recovery13-16. High dose dobutamine stress CMR has high diagnostic accuracy to identify inducible LV wall motion abnormalities indicative of flow-limiting coronary stenosis17-19.
Current first pass myocardial perfusion CMR methods track the passage of a bolus of a T1-shortening contrast agent injected into a peripheral vein20, 21. Data acquired during intravenous vasodilator-stress (most commonly with adenosine) delineate relatively underperfused regions associated with myocardial ischemia. The spatial resolution of CMR myocardial perfusion imaging of 2 to 3 mm is vastly superior to other imaging modalities, so that subendocardial ischemia can be more reliably identified. Recent developments have seen further improvements in spatial resolution to around 1 mm in the imaging plane22 and acquisition at 3-Tesla promises improved signal to noise ratio and diagnostic yield23, 24. Both of these developments should continue to enhance the value of CMR perfusion assessment. The interpretation of CMR myocardial perfusion studies in clinical practice is most commonly visual, but quantitative approaches that measure characteristics of myocardial signal intensity profiles are available21, 25-28 and have been validated against x-ray angiography, SPECT and PET29-31. The recent MR-IMPACT study in 234 patients reported improved detection of coronary stenosis by CMR compared with SPECT in the first multi-centre, multi-vendor comparison32. In the context of ACS, myocardial perfusion CMR imaging can be used to delineate microvascular obstruction and ischaemia, as described in subsequent sections.
Following acute ischemic injury, the myocardial distribution volume of extra-cellular gadolinium-based contrast agents is increased because of the presence of sarcrolemmal disintegration and abnormal wash-out kinetics. In chronic myocardial infarction, the presence of fibrotic tissue increases the distribution volume of the contrast agents. The resulting differences in contrast distribution between normal and injured myocardium can be delineated with T1-sensitive inversion-recovery CMR methods. Imaging within the first few minutes after contrast administration is the method of choice to delineate microvascular obstruction (MVO), which prevents contrast delivery to the infarct core and thus results in low signal on T1-weighted imaging33. Acutely injured and chronically infarcted tissue without MVO on the other hand retains contrast agent and therefore appears bright34-37. The preferred imaging time for scar is between 10 and 20 minutes after contrast agent administration, when the differences between scar, normal myocardium and blood pool are maximal. This method is referred to in the literature variably as late gadolinium enhanced CMR (the currently preferred term), late-contrast enhanced, delayed contrast-enhanced or hyperenhancement CMR. It has become the reference standard for the in vivo assessment of myocardial viability because of its very high spatial definition and high contrast to normal myocardium, which allows a detailed assessment of the spatial distribution of scar. Because of its high spatial resolution late gadolinium enhanced CMR can detect infarction in as little as 1ml of tissue, substantially less than other in vivo methods. The technique has been extensively validated in animal models showing excellent agreement with histology and has been applied in numerous recent human studies33-38. Most notably, it was shown that CMR is more sensitive in detecting subendocardial MI than SPECT or PET and in chronic CAD that the extent of scar on CMR predicts the potential for functional recovery after revascularisation 39-41. Figure 2 shows a case example of early and late gadolinium enhancement following acute MI.
Myocardial edema is a feature of many forms of acute myocardial injury that are associated with inflammation. Edema alters myocardial T2-relaxation and can therefore be detected with T2-weighted CMR imaging42. Following acute myocardial infarction, T2-weighted CMR can be used to delineate the ischemic risk region, which typically extends beyond the scar (see Figure 3). This is discussed in greater detail later. However, both the relatively small contrast-to-noise ratio between edematous and normal myocardium (around 2 to 3) and artefacts from slow flowing blood at the subendocardial border can make interpretation of T2-weighted images more challenging than other CMR methods, although recent methodological developments promise to improve these limitations43.
CMR imaging can be used to delineate coronary morphology and detect at least proximal coronary stenosis44. Coronary MR angiography, however, is rarely used in ACS, where invasive angiography is a routine test and non-invasive coronary imaging has little to add to the diagnostic process.
In summary, CMR offers a wide range of tools that can be utilized for the detection, differential diagnosis and management of patients with acute and chronic manifestations of CAD. Data acquisition times for most CMR methods continue to be reduced, allowing multi-parametric assessment in a single imaging session. In the following sections the established and evolving clinical applications of CMR in ACS will be discussed.
Patients with suspected ACS are increasingly managed with early interventional strategies45. However, in low-risk patients or in the presence of concomitant medical problems that increase the risk of complications from cardiac catheterization, an initial non-invasive functional test may be preferred45. In this context, CMR presents an attractive alternative to established diagnostic methods. A study by Kwong and colleagues suggested that CMR imaging may more accurately identify ACS than conventional markers46. In 161 consecutive patients presenting to the emergency room with cardiac chest pain but no evidence for MI, CMR was performed within 12 hours of presentation. The CMR protocol comprised myocardial perfusion at rest, cine imaging and late gadolinium enhancement. The study reports a sensitivity and specificity of 84% and 85%, respectively, of CMR for detecting subsequent ACS defined as 70% coronary stenosis or positive stress test within 8 weeks of the index event. Detection of regional wall motion abnormalities was the most powerful part of the CMR study in this setting where perfusion abnormalities may be normal in between episodes of pain and infarction may not yet be established. CMR was more sensitive than ECG, troponin and the Thrombolysis in Myocardial Infarction (TIMI) risk score and was the strongest predictor of ACS on multivariate logistic regression analysis.
CMR is also helpful in differentiating acute from chronic MI by combining late gadolinium enhancement with T2-weighted imaging, which will delineate the edema associated with acute infarction. In a study of 73 patients with acute and chronic MI by Abdel Aty and colleagues, CMR was 96% sensitive in differentiating acute from chronic MI42. The incremental value of T2-weighted imaging for the detection of ACS was the subject of a recent study of 64 consecutive patients47 presenting with chest pain to the emergency room with negative cardiac enzymes and no ECG changes suggestive of coronary ischemia. Adding T2-weighted imaging and left ventricular wall thickness measurements to a core CMR protocol of cine and late gadolinium enhancement imaging increased the specificity, positive predictive value, and overall accuracy in detecting ACS from 84% to 96%, 55% to 85%, and 84% to 93%, respectively. CMR provided incremental value in the detection of ACS over and above traditional risk stratification with the changes detected by CMR occurring before the rise in cardiac enzymes (6±12 hours).
As well as detecting early changes following ACS, CMR is useful in the setting of delayed presentations where cardiac markers may have returned to normal, while abnormalities on T2-weighted CMR can persist for several weeks48.
CMR can facilitate the differential diagnosis of ACS, in particular in the context of a normal coronary angiogram. In a study of 27 patients with troponin-positive chest pain and normal x-ray coronary angiogram, half showed subepicardial or mid-wall late gadolinium enhancement, suggesting myocarditis, while the other half demonstrated subendocardial or transmural enhancement typical of myocardial infarction49. Another study of 61 patients presenting with troponin positive chest pain and normal coronary angiography showed that contrast enhanced CMR was able to identify a cause in 65% of cases with the commonest being myocarditis (50%), followed by myocardial infarction and cardiomyopathy50. Laissy and colleagues came to similar results in a study of 55 patients, which included 24 patients with clinically suspected myocarditis and normal coronary angiography and 31 with a history of atypical myocardial infarction and coronary stenosis51. In all but one patient with myocarditis, CMR perfusion was normal and late gadolinium enhanced CMR showed either epicardial or diffuse non-segmental enhancement, while MI patients showed typical endocardial enhancement. The pattern of CMR abnormalities in myocarditis may even predict long-term outcome52. Figure 4 shows an example of enhancement in a patient with myocarditis.
Tako Tsubo cardiomyopathy, or apical ballooning syndrome, is a syndrome with distinctive features such as acute chest pain and shortness of breath, ST-segment elevation on electrocardiogram and release of cardiac enzymes. Consequently it can mimic acute myocardial infarction (AMI) at clinical presentation. The diagnosis is usually suspected during invasive coronary angiography, which typically reveals non-obstructed coronary arteries and an apical wall motion abnormality crossing coronary supply territories. CMR can reliably make the diagnosis of abnormal apical contraction that characterizes the syndrome and late gadolinium enhanced CMR shows absence of myocardial necrosis in this syndrome and reliably predicts recovery (Figure 5) 53, 54. A study by Eitel et al demonstrated the ability of CMR to distinguish acute apical myocardial infarction from apical ballooning syndrome without infarction and myocarditis in patients with angiographically normal coronary arteries and characteristic wall motion abnormalities55.
In summary, CMR may be a useful and accurate test to detect the presence of ACS and can be considered as an additional diagnostic tool to differentiate ACS from chronic MI and from disease entities with similar clinical presentations.
Current guidelines for the management of non-ST elevation ACS recommend that low risk patients with normal biomarkers should undergo a stress test (nuclear perfusion imaging or stress echocardiography) within 72 hours as an alternative to inpatient admission45. Plein et al showed that CMR can also be used safely in the context of ACS56. A CMR study incorporating cine imaging, rest and stress perfusion, coronary MRA and late gadolinium enhancement was performed within 2-5 days of non-ST elevation ACS in 72 patients. CMR reliably predicted the presence of coronary stenosis requiring revascularisation on subsequent X-ray coronary angiography, in particular when several of the CMR modules were interpreted in combination (sensitivity 96%, specificity 83%). Furthermore, this was superior to the prediction based on the TIMI risk score. Figure 6 gives a case example of a patient presenting with a biomarker-negative ACS, in whom CMR identified unknown previous MI and inducible ischemia in two separate coronary territories.
Ingkanisorn et al. showed subsequently that CMR adds significant prognostic value in predicting future diagnosis of CAD, MI, or death over clinical risk factors57. They studied 135 troponin-negative patients presenting to the emergency room with chest pain using adenosine stress perfusion CMR. CMR had 100% sensitivity and 93% specificity to predict the development of CAD at one-year follow-up.
Following acute ST-elevation MI (STEMI) patients may not receive definitive revascularisation at the time of initial presentation for a variety of reasons, including late presentation, concomitant medical problems that exclude reperfusion strategies or widespread or complex coronary disease that is not suitable for percutaneous revascularisation. The detection and quantification of scar by late gadolinium enhanced CMR is increasingly used to guide revascularisation decisions in these patients in particular. In a group of 50 patients with myocardial infarction, of which 6 were studied within two weeks of infarction, Kim et al. showed that late gadolinium enhanced CMR predicts reversible myocardial dysfunction. Ninety percent of the myocardial segments studied that contained hyperenhancement between 51% and 75% of tissue and virtually all of those with transmural infarction did not improve after revascularization. Conversely, 256 out of 339 (78%) of hypokinetic segments containing no hyperenhancement had improved contractility after revascularization 34. A subsequent study by Nijveldt et al. in 60 patients with recent AMI confirmed that segments with >75% transmural enhancement are unlikely to function completely at follow-up, while in about half of the segments with less than 25% transmural enhancement function improved completely58. These results were supported by Bodi et al. who showed that the amount of viable myocardium on CMR predicts functional recovery in thrombolysed STEMI patients who receive post-hoc revacularisation59.
In patients receiving thrombolytic therapy for the treatment of acute STEMI, functional assessment with exercise testing or a pharmacological imaging study is recommended for low risk patients before discharge from hospital60. Greenwood and colleagues showed in a small sample of 35 patients that CMR imaging with adenosine stress perfusion, viability and function assessment can be safely performed within a few days of acute STEMI and is more accurate than an exercise tolerance test for detecting residual ischemia61.
In addition to supporting management decision-making in ACS, CMR reliably detects important complications of AMI. Ventricular aneurysms and ventricular septum defects are clearly identified on cine images. With late gadolinium enhanced CMR, these pathologies can be further characterized in the context of the acute injury and may aid planning of surgical or percutaenous procedures 62. Early or late gadolinium enhanced imaging is also very useful to identify LV thrombus 63, 64 (Figure 7).
In summary, there is early evidence that using CMR in ACS patients is safe and provides a comprehensive assessment of the sequelae of AMI that can help to guide patient management. CMR has the benefit over other imaging modalities of providing the most accurate information on cardiac morphology, function and scar. In addition, CMR can determine the presence of residual myocardial ischemia and reliably detects complications associated with ACS.
In patients with known or suspected coronary artery disease CMR has comparable predictive value for future adverse cardiac events with nuclear scintigraphy or stress echocardiography65. Even small amounts of scar on late gadolinium enhanced CMR provide incremental prognostic value beyond the usual clinical, angiographic, and functional predictors66. In the context of ACS, several CMR measures are associated with prognosis (see Table 1).
Infarct size measured by late gadolinium enhancement is directly associated with outcome. Tarantini and colleagues71 showed in 76 patients with acute revascularized MI that the amount of transmural necrosis on late gadolinium enhanced CMR predicted adverse LV remodelling, with significant additional predictive value to infarct size and microvascular obstruction. These findings were confirmed by Roes et al who showed in 231 patients with healed myocardial infarction that infarct size on late gadolinium enhanced CMR was a stronger predictor of all-cause mortality than LVEF and LV volumes. Transmurality of infarction was also associated with worse outcome73. Wu et al showed that acute infarct size as determined by CMR, which was independent of LV stunning and loading, directly relates to LV remodeling and is a stronger predictor of future events than measures of LV systolic performance74.
On late gadolinium enhanced CMR images, a border zone of intermediate signal can be observed between the infarct and surrounding tissue. This peri-infarct zone may reflect partial volume or partial myocardial necrosis and edema. A study by Kwong et al. suggested that the extent of the peri-infarct zone is an independent predictor of post-MI mortality. In 144 patients with documented coronary artery disease and previous MI, they found that the amount of myocardium exhibiting an intermediate signal on late gadolinium enhanced CMR images was a strong predictor of all-cause mortality75. A subsequent study suggested that one mechanism for this increased mortality may be that the peri-infarct zone is a substrate for arrhythmias76. CMR data on scar and peri-infarct zone could thus prove useful in the future to identify patients for implantable cardioverter/defibrillator and cardiac resynchronisation therapy (CRT)77, 78.
Early contrast-enhanced CMR can reliably demonstrate the presence and extent of MVO following reperfused AMI. MVO results in poor tissue perfusion despite restoration of epicardial blood flow to the infarcted region. It is the consequence of clogging of the small myocardial arterioles with embolic debris, acute inflammation, platelet aggregation and vasospasm. Studies have shown that the presence and extent of MVO following AMI as measured by early gadolinium enhancement CMR is associated with adverse ventricular remodelling16, 68, 79-81 and clinical outcome that is independent of the infarct size67, 69. Baks et al examined patients with CMR soon after primary percutaneous revascularisation for STEMI and again at five months. They found that dysfunctional segments without MVO had early increased wall thickness and late partial functional recovery compared to segments with MVO that showed late wall thinning and no functional recovery 70. Nijveldt et al demonstrated that MVO had incremental diagnostic value over transmurality of infarction in particular in segments with 75-100% transmural enhancement58.
The area at risk (AAR) is defined as hypoperfused myocardium at the time of an ischemic episode82. Currently the gold-standard for determining the AAR is single photon emission tomography with injection of Technitium-99m tracer into the occluded coronary artery prior to revascularisation83. In the experimental setting, myocardial contrast echo has also been used84.
T2-weighted CMR offers a potentially attractive alternative for the non-invasive measurement of AAR. The increased water content of myocardium following acute ischemia-reperfusion injury85 leads to high signal on T2-weighted images86 and combined with late gadolinium enhancement allows the delineation of areas that are injured but not infarcted following reperfusion87, 88. The areas of T2 enhancement are invariably transmural and subsequently larger than the regions of late gadolinium enhancement89 88 and the difference between the two likely represents myocardial salvage90. The advantages of this method are that such a region can be retrospectively determined days after the acute event87 and without the need for direct injection of agents into the coronary artery at the time of primary reperfusion. So far, no outcome studies based on a CMR assessment of AAR have been published.
It is well recognized that involvement of the right ventricle (RV) in acute MI is associated with adverse clinical outcome. RV function is difficult to assess reliably with most imaging modalities, while it poses no particular challenge to CMR cine imaging (Figure 8). Kaandorp et al. showed that RV infarction can be detected by late gadolinium enhancement and that the extent of scar tissue is linearly related to the severity of RV dilatation at 6 months follow-up91. Kumar et al. found in 37 patients that acute RV infarction is more frequently detected by late gadolinium enhancement than by ECG and echocardiography92. Finally, Larose et al. have shown that RV ejection fraction measured by CMR is an important predictor of prognosis after AMI72. In 147 consecutive patients studied late after MI, RVEF <40% was strongly associated with mortality (hazard ratio 4.02), independent of patient age, LV infarct size and LVEF.
In summary, CMR imaging provides several independent measures of prognosis after ACS that can all be obtained in a single imaging procedure and cannot be assessed equally with other imaging modalities. A potential role for CMR may thus be to offer an improved method for risk stratification in the early post ACS period.
Owing to ongoing technological advances (faster gradients, multi-channel receiver coils, transform coding to accelerate data acquisition) scan times for many CMR methods continue to be shortened. Until now, this development has usually been invested into obtaining higher quality images (e.g. better spatial resolution, better temporal resolution, better signal to noise ratio). However, given the image quality achieved today, future improvements of imaging speed are likely to be reinvested into shortening scan time for a given CMR method. This speed up can be used to evaluate more patients per time for chronic disease, but also to answer numerous questions within a single short setting for patients with acute coronary syndromes. A likely scenario for MR imaging in these patients will resemble one of the current utilizations of CCT in patients with chest pain– the triple rule out of pulmonary embolism, aortic dissection and myocardial infarction in a single imaging session. Such an approach would look at wall motion abnormalities, edema and resting perfusion first, then use a higher bolus of contrast agent for a time resolved 3D angiography which allows assessment of the anatomy of the pulmonary arteries and the aorta within a single scan and the final assessment of late gadolinium enhancement to visualize scar tissue.
In vivo MRI of advanced plaques in human carotid arteries using contrast-enhanced techniques has identified lipid core with 85% sensitivity and 92% sensitivity93. In addition, thin and ruptured plaques can be identified in vivo by MRI in a high proportion of patients in whom it was subsequently identified on examination of post-atherectomy specimens94. Improving methods95-97 and the introduction of 3-Tesla clinical imaging98 raise the possibility that in the near future such techniques may be applied to the coronary arteries.
More specific techniques to visualize activation within a plaque using targeted (molecular) contrast agents could be used as a potential predictor of plaque rupture, with the potential for identification of specific disease processes in vivo. This has already been demonstrated in animal models for fibrin specific contrast agents, which allow the highlighting of ruptured plaques and thrombosis within the coronary arteries99, 100. Similarly, contrast agents designed to show earlier processes of plaque vulnerability such as myeloperoxidase activity101 and macrophage activation102,103 have been applied in animal models If translated into clinical application, the ability to assess non-invasively plaque activity may overcome a major limitation of the current practice of cardiology.
CMR imaging is emerging as a versatile diagnostic tool for the management of the patient with suspected or established ACS. It provides additional information over other clinical tests for the detection, differential diagnosis and prognostication after ACS, owing to the high spatial definition and multi-modal data it provides. Future larger studies will determine more fully the role of CMR in the setting of ACS.
Funding Sources The authors acknowledge financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London.
Dr Lockie is supported by a fellowship from the British Heart Foundation. Dr Plein is support by a Wellcome Trust fellowship (WT078288).
Conflict of Interest Disclosures
Dr Lockie none
Prof Nagel Research grant (Philips Healthcare, Bayer Shering Pharma); speakers bureau (Bayer Shering Pharma, GE Healthcare); consultant advisory board (Philips Healthcare, Bayer Sherling Pharma, GE Healthcare)
Dr Redwood none
Dr Plein Research grant (Wellcome Trust, British Heart Foundation)