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Cardiovascular magnetic resonance in ischemic heart disease
Monique Bernard*,1, Alexis Jacquier1,2 & Frank Kober1
Abstract: Ischemic heart disease is the major cause of death in developed countries. Recently, cardiovascular magnetic resonance (CMR) has appeared as a powerful technique for diagnosis and prognosis of ischemia, as well as for postischemic therapy follow-up. The objective of this chapter is to provide an overview of the role of CMR in assessing ischemic myocardium. It reviews the most recent studies in this field and includes CMR parameters that are already well established in the clinical setting as well as promising or emerging parameters in clinical use. Ischemic heart disease is caused by obstruction of large arteries or dysfunction of small vessels. Myocardial ischemia results from an imbalance between oxygen supply and demand with a consecutive cascade of events from reversible to irreversible injury that results in cardiac cell death. These events include in particular altered energetic metabolism, mitochondrial damage, perturbation in ionic homeostasis, myocardial contractile dysfunction, intracellular edema, irreversible injury of myocytes and vascular endothelial cells with cellular necrosis and apoptosis. Ischemic heart disease, is particularly related to coronary artery disease (CAD) and is the major cause of death in developed countries. The assessment of patients with myocardial ischemia is still challenging for the physicians who need appropriate tools for prevention, early detection and characterization of ischemia on the one hand and for prognosis and follow-up of therapies on the other hand. Today, cardiovascular magnetic resonance (CMR) appears as a powerful technique not only for assessing ischemia with high diagnostic and prognostic accuracy, but also for the follow-up of postischemic therapy [1] . CMR has numerous advantages over other imaging methods, the most prominent being its high temporal and spatial resolution, the absence of ionizing radiation and its diagnostic versatility. The significant progress of CMR methods in the recent years has contributed to strengthening their position among other tools. In the recent years, CMR was indeed increasingly used to examine patients with known or suspected ischemic disease. CMR has the advantage of being multiparametric. A variety of parameters can be measured in a single imaging examination to detect myocardial ischemia, to differentiate and to determine the size of infarcted myocardium and to obtain a prognosis after ischemia. CMR can assess function and wall motion abnormalities by cine imaging, abnormal coronary flow by perfusion MRI, myocardial edema by T2-weighted techniques and it is able to determine infarcted myocardium by late gadolinium enhancement (LGE). Other emerging CMR modalities aim at obtaining new interesting information from ischemic tissue. Oxygenation-sensitive CMR, for instance, allows assessing oxygenation defects, T1 and T2 parametric mapping give deeper insight into edematous
Keywords
• CMR • coronary artery disease • imaging • ischemia • myocardium
Aix-Marseille Université, CNRS, Centre de Résonance Magnétique Biologique et Médicale (CRMBM), UMR 7339, Faculté de Médecine, 27 Bd Jean Moulin 13385 Marseille, Cedex 5, France 2 APHM, CHU Timone, Service de Radiologie Adultes, Rue Saint Pierre, 13385 Marseille, Cedex 5, France *Author for correspondence: Tel.: +33 4 91 32 48 18; Fax: +33 4 91 25 65 39; [email protected] 1
10.2217/FCA.14.39 © 2014 Future Medicine Ltd
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Special Report Bernard, Jacquier & Kober and fibrotic regions, diffusion tensor imaging aims at depicting myocardial fiber anatomy and magnetic resonance spectroscopy (MRS) of various nuclei (31P, 1H and 13C) can assess perturbations in metabolism. The different measurable parameters and the corresponding CMR modalities are summarized in Table 1. Cardiac function CMR is the reference standard technique in assessing cardiac morphology and function. Dynamic steady-state free precession (SSFP) cine MRI sequences are used to calculate ventricular volumes and function and to visualize regional wall motion. The SSFP method allows excellent delineation of the blood–myocardium interface [2] . Systolic and diastolic left and right ventricular volumes, stroke volumes, ejection fraction and myocardial mass are determined with high reproducibility on cine images. In addition, regional ventricular function can be assessed both qualitatively and quantitatively. Recommendations have been made for plane selection, slice orientation and number of myocardial segments to standardize with other imaging modalities and the 17-segment model has been proposed by the American Heart Association [3] and is considered as the reference. Evaluation of cardiac function and myocardial contractility can be performed
both at rest and under stress conditions (physical or pharmacological). Pharmacologic stress may be induced with dobutamine as inotropic agent. Left ventricular function is assessed using SSFP cine imaging at rest, and then during increasing dosages of intravenously administered dobutamine. Multiple studies have reported excellent diagnostic and prognostic performance of stress CMR [4] . Dobutamine cine CMR has been shown to provide better sensitivity and specificity than dobutamine stress echocardiography and quantitative coronary angiography for detecting >50% coronary stenosis [5,6] . Regional myocardial wall motion can be quantified using myocardial strain analysis to detect subtle wall motion abnormalities giving further insight to detect early evidence of myocardial ischemia. These techniques measure a large number of regional parameters such as strain, strain rate, torsion and velocity. As the first developed regional function technique, myo cardial tissue tagging [7] has been used in a large number of clinical applications. This method is still difficult to use routinely mainly because of long processing times, but advances in gradient technology and acquisition techniques are improving temporal resolution of this method [8] . Other methods such as displacement encoding with stimulated echoes (DENSE) and strain
Table 1. Indicators of ischemia and corresponding cardiovascular magnetic resonance modality. Ischemia parameter
CMR modality
Global function and wall motion abnormalities Regional function
Cine MRI (rest and stress) Tagging Feature and tissue tracking SENC DENSE First pass perfusion (rest and stress) Arterial spin labeling BOLD imaging T2-weighted imaging T2 mapping T1 mapping LGE LGE First pass perfusion T2-weighted imaging† T2*-weighted imaging DTI 23 Na MRI 31 1 P, H and 13C MRS
Tissue blood flow Oxygenation Edema
Delineation of infarct Microvascular obstruction Hemorrhage Microstructure Ionic homeostasis Metabolism
† Less specific than T2*-weighted imaging. BOLD: Blood oxygen level dependent; CMR: Cardiovascular magnetic resonance; DENSE: Displacement encoding with stimulated echoes; DTI: Diffusion tensor imaging; LGE: Late gadolinium enhancement; MRS: Magnetic resonance spectroscopy; SENC: Strain encoding.
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Cardiovascular magnetic resonance in ischemic heart disease encoding (SENC) have also been proposed more recently for measuring regional function [9] . Myocardial perfusion Impaired myocardial perfusion precedes myocardial ischemia. Extent and severity of perfusion deficits have been shown to predict clinical outcomes including cardiovascular mortality risk. In the recent years, stress CMR perfusion imaging has been shown to be a sensitive and specific means of diagnosing coronary artery disease [10] . Myocardial perfusion is assessed with MRI by monitoring the ‘first pass’ of contrast medium through the heart using a bolus injection of gadolinium. Perfusion may be assessed qualitatively, semiquantitatively or quantitatively [11] . Perfusion studies can be performed during resting conditions and/or during administration of a vasodilatatory agent. The predominant vasodilator is adenosine, but regadenoson, a selective A 2A receptor, which is administered as a single bolus, is increasingly used [12,13] . Dobutamine is also used for myocardial perfusion assessment combined to the study of wall motion abnormalities in a single examination [14–16] . Stress perfusion CMR is regarded as a safe method. The utility of stress perfusion CMR was evaluated in several multicenter studies. A meta-analysis of the diagnostic performance of stress perfusion CMR for detection of coronary artery disease has shown a high sensitivity of this method (sensitivity 89% and specificity 80% in patients with high prevalence of CAD [57%]) [17] . Improvement of S/N ratio and contrast with increasing the magnetic field to 3 T has improved the diagnostic accuracy of perfusion CMR for coronary artery disease [18] . Comparison of perfusion CMR with the other available methods for CAD detection has been performed. Magnetic resonance (MR) perfusion has been compared with single-photon emission computed tomography (SPECT) [19,20] . The large prospective trial CE-MARC has shown the superiority of CMR (including cine imaging, rest and stress perfusion and coronary angiog raphy) over SPECT [20] . The multicenter study MR-IMPACT trial also reported a superior diagnostic performance for stress CMR as compared with SPECT [21] using x-ray coronary angiography as the reference standard. Stress perfusion CMR has been shown to have comparable diagnostic accuracy to real-time myocardial contrast echocardio graphy [22] . Myocardial multislice computed
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tomography is also developing as a competitive technique to detect perfusion deficits in CAD and has been compared with CMR as the reference technique in several studies showing a good diagnostic accuracy [23,24] . PET is the gold standard in the clinical setting to quantify myocardial perfusion and comparisons between CMR and PET have been performed [25,26] and have shown that both techniques measure accurately myocardial perfusion reserve but absolute quantification of myocardial blood flow with CMR still needs validation and standardization for clinical use [25,26] . As an alternative to bolus tracking, arterial spin labeling (ASL) methods, which are already applied in routine to brain and kidney, are under development for measuring tissue blood flow in human myocardium. These methods do not require the use of an exogenous contrast agent and may be used in patients, for which contrast agents are contraindicated. ASL relies on the labeling of arterial blood thereby generating an endogenous tracer [27,28] . It can be used repeatedly and provides absolute quantification of tissue blood flow. Zun et al. [29] have demonstrated that ASL has the potential to detect myocardial ischemia in patients, since their method was able to show reduced perfusion reserve in ischemic segments of patients with CAD. The technique is rapidly evolving through improved sequences and radiofrequency coils [30] . More recent approaches may in the future allow this technique to be used while the subjects are freely breathing [28] . Edema Myocardial edema is associated with acute stage of myocardial injury. The T2-relaxation time is correlated with the percentage of free water, and edema is therefore visible on T2-weighted MR images as hyperintense areas. It is generally accepted that hyperintense signal on T2-weighted images reflects the myocardium at risk in patients with acute myocardial infarction (Figure 1) . Better T2-weighted methods are under development to increase the robustness of the technique. T2-weighted imaging methodology has recently been improved for instance with the introduction of a T2-prepared hybrid turbo-spin echo-SSFP sequence [31] . A promising technique for assessing myocardium at risk is the direct measurement of T2 relaxation times by T2 mapping [32] . T2-mapping sequences should provide
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T2 STIR
T2 map
Delayed enhancement
T1 map pre-Gd
T1 map post-Gd
Figure 1. Example of routine multiparametric cardiovascular MRI at 1.5 T in a 70-year-old patient, 4 days anterior postinfarct. Short axis images. T2-weighted imaging, T1 and T2 mapping imaging, late gadolinium enhancement imaging demo in the infarcted area. Gd: Gadolinium; STIR: Short tau inversion recovery.
more reliable detection than conventional T2-weighted imaging since these are less dependent on confounders affecting signal intensity and image quality. T2 mapping has been validated in dogs with microsphere blood analysis as a reference standard [32] . In this study, the authors have also shown that T1 mapping is a well performing method to detect edema. In patients, T2 mapping has been shown to have a higher sensitivity compared with T2-weighted dark blood TSE imaging for myocardial edema visualization in acute myocardial infarction [33] . Performance of T1 mapping to assess acute myocardial edema has been demonstrated in patients in several pathological conditions with a high diagnostic performance compared with T2 weighted [34,35] . Performance of the ShMOLLI sequence has been underlined [34] . In patients with acute myocardial infarction T1 mapping has been proposed as a complementary technique to LGE and T2-weighted imaging to assess myocardial injury [36] . Examples of T1 and T2 mapping in a patient with myocardial infarct are shown in Figure 1.
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Detection of myocardial infarction The LGE or delayed enhancement method allows visualizing irreversible myocardial injury. The introduction of this method has been an important milestone in the development of CMR for clinical use [37] . This method relies on a T1-weighted segmented inversion recovery gradient echo sequence and the use of gadolinium-based contrast agents. After injection, the contrast agent concentration gradually increases in the damaged myocardium. In acute infarction gadolinium diffuses into myocytes because of the rupture of the sarcolemmal membrane. In chronic infarction, the distribution of gadolinium increases with the loss of myocytes and the associated increase in extracellular collagen content. The higher gadolinium concentration induces T1 shortening, which in turn appears as higher signal on the MR images (Figure 1) . Lack of contrast at the tissue–blood interface is a limitation of the technique, and new sequences are currently proposed to improve the method. As an example, multicontrast delayed enhancement (MCODE)
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Cardiovascular magnetic resonance in ischemic heart disease sequence based on a T2-weighted image combined with a phase-sensitive inversion recovery (PSIR) LGE image has recently been proposed to better discriminate subendocardial MI from blood pool [38] . Free-breathing motioncorrected LGE techniques are emerging for risk stratification of vulnerable patients [39] . Microvascular obstruction Microvascular obstruction (MVO), angio graphically evidenced by the ‘no-reflow’ phenomenon indicates poor prognosis after reperfusion following myocardial ischemia. When restoring the flow to the ischemic tissue, perfusion may not be uniform. Areas of no-reflow are characterized by ultrastructural changes to the microvasculature and irreversible myocardial cell injury [40] . MVO predicts adverse cardiac remodeling and can be assessed either with gadolinium enhancement (early or late) or perfusion MR. No reflow is visualized as a hypointense, dark region inside the enhanced area of infarcted myocardium. Ultrafast inversion-recovery gradient echo sequences for early and LGE and accelerated high-resolution sequences for perfusion allow total coverage of the ventricle and have improved the detection of MVO [41] . In a large prospective trial, de Waha and coworkers [42] have provided good evidence that late rather than early MVO predicts outcome after myocardial infarction. Hemorrhage Reperfusion injury is also characterized by hemorrhage which can be assessed with T2-weighted and T2*-weighted imaging. Hemorrhage is detected on MRI images based on the paramagnetic effects of hemoglobin degradation products. These paramagnetic effects lead to reduced T2 and T2* relaxation times and therefore to hypo-enhanced regions in CMR images [41] . The signal intensity of hemorrhage in T2-weighted images undergoes various changes and a low signal intensity area is less specific to hemorrhage than T2*-weighted imaging. Kumar et al. [43] have demonstrated the accuracy of quantifying hemorrhage with T2*-weighted imaging and suggested that it may be used as a marker of severe tissue injury in addition to the CMR markers for the other components of tissue injury (edema, necrosis, MVO). Zia et al. [44] have shown the value of quantitative T2* mapping to characterize hemorrhage postacute myocardial infarction.
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Myocardial microstructure Microstructure of the left ventricular myocardium can be analyzed using diffusion tensor MRI (DTI), which measures parameters that describe the restricted water molecule diffusion in the tissue. Microstructural changes in the myocardium can then be quantified by measuring mean diffusivity, fractional anisotropy and the orientation (helix angle, HA) of the myofibers. Microstructural changes after infarction have been measured with DTI by Wu et al. [45] who showed that these changes were indeed correlated with changes in myocardial wall thickness and wall thickening. Further optimization of the method has to be performed, but good reproducibility of this method, which is challenging in the human heart in vivo, has been demonstrated recently [46] . Myocardial oxygenation While perfusion MRI assesses oxygen supply, myocardial oxygen demand is an equally important parameter, which may be assessed with blood oxygen level dependent (BOLD) imaging. This technique is based on detecting differences in magnetic susceptibility between oxyhemoglobin and deoxyhemoglobin. In ischemic tissue, decreased oxyhemoglobin and increased deoxyhemoglobin tissue content induce lower T2* or T2 values that lead to signal changes on T2*or T2-weighted images. Oxygenation-sensitive CMR can be performed during rest and under pharmacological stress conditions. The potential of oxygenation-sensitive CMR has been shown in animals [47] and then in human studies [48–50] . Karamitsos et al. [51] have assessed the relationship between BOLD changes and myocardial perfusion measurement by PET. They have shown that reduced perfusion is not always associated to deoxygenation. Arnold et al. [52] evaluated the performance of BOLD imaging for the detection of CAD in the clinical setting. They showed additional value of this parameter over myocardial blood flow in characterizing ischemia. However, further advances in BOLD techniques are needed for routine clinical use. MR coronary angiography MR coronary angiography offers an interesting perspective as a noninvasive method which can be combined with other parameters such as perfusion imaging or scar determination in one single examination but is challenging compared with computed tomography angiography.
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Special Report Bernard, Jacquier & Kober Nevertheless, it is evolving with improvements of the MR techniques including in particular the development of multichannel coils, magnetic field increase, improved sequences and breathing correction. In 2010, Kato et al. [53] have conducted a multicenter trial in Japan with promising results showing a sensitivity of 88%,
a specificity of 72% and positive and negative predictive values of 71 and 88%, respectively. Hamdan et al. [54] have compared 3 T MR angiography with a 32-channel coil and 64 multislice computed tomography and have shown comparable accuracy in the diagnosis of coronary stenosis. An interesting perspective is to combine
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Figure 2. 31P 3D chemical-shift imaging in a patient with anterior myocardial infarction. On the left are proton short axis images showing voxel selection. On the right are typical human cardiac 31P spectra acquired using 3D chemical shift imaging showing resonances of PCr, ATP (three resonances), 2,3-DPG and Pi. PCr/ATP ratio is decreased in the infarcted area. DPG: Diphosphoglycerate; PCr: Phosphocreatine; Pi: Inorganic phosphate.
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Cardiovascular magnetic resonance in ischemic heart disease coronary angiography and perfusion MR. Heer et al. [55] were able to show that combining both methods improves the specificity for the diagnosis of CAD without compromising the sensitivity. Technical developments in MR may improve the robustness of MR coronary angio graphy, as a matter of fact Soleimanifard et al. [56] have recently shown the value of a 3D volumetargeted high-resolution balanced steady-state free-precession sequence in a breath hold at 3 T using a 32-channel cardiac coil, a multitransmit system and localized RF shimming. Ionic homeostasis Nonviable myocardium can be characterized without contrast agent by 23Na MRI. Sandstede et al. have shown an increased signal on sodium images after infarction in myocardial areas with wall motion abnormalities [57]. Total sodium increase is attributed to increased intracellular sodium and higher extracellular volume. This increase in sodium is attributed to loss of cell membrane integrity. Spatial resolution is currently a limitation for clinical applications. Myocardial metabolism MRS provides quantitative information on metabolic compounds in the myocardium [58] . In particular 31P MRS gives access to high energy metabolism (PCr and ATP) whose changes are an early marker of cellular ischemia as levels of high-energy phosphates fall when energy supply is decreased. Localization sequences such as chemical shift imaging allow the identification of areas of the myocardium in which highenergy phosphates are decreased corresponding to ischemic myocardium (Figure 2) . It is also possible to measure creatine kinase flux with 31 P MRS. Bottomley et al. [59] demonstrated a 50% lower creatine kinase flux in myocardial infarcts. 31P MRS is currently limited by its low spatial resolution, but improvements are expected from higher magnetic fields. 1H MRS with the measurement of creatine has also the potential to identify infarcted myocardium. Bottomley and Weiss [60] have shown that creatine concentration was significantly lower in infarct myocardium. The development of hyperpolarisation techniques with 13C MRS is promising to follow important metabolites that are markers of ischemia such as lactate or bicarbonate [61] . Metabolic information by 31P MRS or 13C MRS is complementary to those afforded by PET combined to radiolabeled tracers such
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as for instance 18F-fluorodeoxyglucose or C-11 actetate to study myocardial glucose metabolism or TCA cycle [62] . Besides spectroscopy, molecular imaging with parametric probes which target specific cellular pathways such as, for instance, apoptosis, necrosis or angiogenesis may have significant diagnostic, prognostic and therapeutic value but still need to be translated from animal models to clinics [63,64] . Conclusion Numerous clinical data support the application of CMR in ischemic diseases. CMR is a noninvasive method with the possibility to assess a variety of parameters on tissue alterations, function and perfusion for early detection, risk stratification and guidance of patient therapy. It offers the advantage of a comprehensive examination including contractile function, morphology, perfusion, angiography and tissue characterization. It is becoming more and more an alternative to other imaging modalities. Cost efficiency for CAD diagnosis of CMR method compared with other methods such as SPECT, fractional flow reserve or coronary angiography has been shown in studies involving several countries [65–67] . Future perspective There are still challenges to increase the robustness and accuracy of CMR, but the workflow in clinical routine is continuously being improved, and the technique is evolving rapidly with ongoing developments in hardware and software. CMR is currently mainly performed at a magnetic field strength of 1.5 T while 3 T systems are increasingly used. Moving toward higher field strengths will increase S/N ratio and will lead to higher spatial and temporal resolution and faster imaging techniques. 7 T systems are now installed in an increasing number of centers, but cardiac MR at ultra-high field is challenging and will have to be validated in the future in clinical applications such as ischemic heart disease. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
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Special Report Bernard, Jacquier & Kober Executive summary ●●
The assessment of patients with myocardial ischemia is still challenging and physicians need appropriate tools for prevention, early detection and characterization of ischemia as well as for prognosis and follow-up of therapies.
●●
Cardiovascular magnetic resonance (CMR) has numerous advantages over other imaging methods and in particular
high temporal and spatial resolution, absence of ionizing radiation and diagnostic versatility. It has indeed become a powerful technique to assess ischemia with high diagnostic and prognostic accuracy. ●●
A variety of parameters can be measured in a single imaging examination to detect myocardial ischemia and to obtain
a prognosis after infarct. CMR can assess function and wall motion abnormalities by cine imaging, abnormal coronary flow by perfusion MRI, myocardial edema by T2-weighted techniques and it is able to determine infarcted myocardium by late gadolinium enhancement. Other emerging techniques have the potential to afford further interesting information on ischemic tissue. Among these emerging techniques are blood oxygen level dependent imaging to assess oxygenation defects, T1 and T2 mapping for edema, diffusion tensor imaging for fiber anatomy or magnetic resonance spectroscopy of various nuclei (31P, 1H, 23Na and 13C) for assessing perturbations in metabolism. ●●
There are still challenges to increase the robustness and accuracy of CMR, but its workflow in clinical routine is
continuously being improved, and the technique is evolving rapidly with ongoing developments in both hardware and software. References 1
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Cardiovascular magnetic resonance in ischemic heart disease
Monique Bernard*,1, Alexis Jacquier1,2 & Frank Kober1
Abstract: Ischemic heart disease is the major cause of death in developed countries. Recently, cardiovascular magnetic resonance (CMR) has appeared as a powerful technique for diagnosis and prognosis of ischemia, as well as for postischemic therapy follow-up. The objective of this chapter is to provide an overview of the role of CMR in assessing ischemic myocardium. It reviews the most recent studies in this field and includes CMR parameters that are already well established in the clinical setting as well as promising or emerging parameters in clinical use. Ischemic heart disease is caused by obstruction of large arteries or dysfunction of small vessels. Myocardial ischemia results from an imbalance between oxygen supply and demand with a consecutive cascade of events from reversible to irreversible injury that results in cardiac cell death. These events include in particular altered energetic metabolism, mitochondrial damage, perturbation in ionic homeostasis, myocardial contractile dysfunction, intracellular edema, irreversible injury of myocytes and vascular endothelial cells with cellular necrosis and apoptosis. Ischemic heart disease, is particularly related to coronary artery disease (CAD) and is the major cause of death in developed countries. The assessment of patients with myocardial ischemia is still challenging for the physicians who need appropriate tools for prevention, early detection and characterization of ischemia on the one hand and for prognosis and follow-up of therapies on the other hand. Today, cardiovascular magnetic resonance (CMR) appears as a powerful technique not only for assessing ischemia with high diagnostic and prognostic accuracy, but also for the follow-up of postischemic therapy [1] . CMR has numerous advantages over other imaging methods, the most prominent being its high temporal and spatial resolution, the absence of ionizing radiation and its diagnostic versatility. The significant progress of CMR methods in the recent years has contributed to strengthening their position among other tools. In the recent years, CMR was indeed increasingly used to examine patients with known or suspected ischemic disease. CMR has the advantage of being multiparametric. A variety of parameters can be measured in a single imaging examination to detect myocardial ischemia, to differentiate and to determine the size of infarcted myocardium and to obtain a prognosis after ischemia. CMR can assess function and wall motion abnormalities by cine imaging, abnormal coronary flow by perfusion MRI, myocardial edema by T2-weighted techniques and it is able to determine infarcted myocardium by late gadolinium enhancement (LGE). Other emerging CMR modalities aim at obtaining new interesting information from ischemic tissue. Oxygenation-sensitive CMR, for instance, allows assessing oxygenation defects, T1 and T2 parametric mapping give deeper insight into edematous
Keywords
• CMR • coronary artery disease • imaging • ischemia • myocardium
Aix-Marseille Université, CNRS, Centre de Résonance Magnétique Biologique et Médicale (CRMBM), UMR 7339, Faculté de Médecine, 27 Bd Jean Moulin 13385 Marseille, Cedex 5, France 2 APHM, CHU Timone, Service de Radiologie Adultes, Rue Saint Pierre, 13385 Marseille, Cedex 5, France *Author for correspondence: Tel.: +33 4 91 32 48 18; Fax: +33 4 91 25 65 39; [email protected] 1
10.2217/FCA.14.39 © 2014 Future Medicine Ltd
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Special Report Bernard, Jacquier & Kober and fibrotic regions, diffusion tensor imaging aims at depicting myocardial fiber anatomy and magnetic resonance spectroscopy (MRS) of various nuclei (31P, 1H and 13C) can assess perturbations in metabolism. The different measurable parameters and the corresponding CMR modalities are summarized in Table 1. Cardiac function CMR is the reference standard technique in assessing cardiac morphology and function. Dynamic steady-state free precession (SSFP) cine MRI sequences are used to calculate ventricular volumes and function and to visualize regional wall motion. The SSFP method allows excellent delineation of the blood–myocardium interface [2] . Systolic and diastolic left and right ventricular volumes, stroke volumes, ejection fraction and myocardial mass are determined with high reproducibility on cine images. In addition, regional ventricular function can be assessed both qualitatively and quantitatively. Recommendations have been made for plane selection, slice orientation and number of myocardial segments to standardize with other imaging modalities and the 17-segment model has been proposed by the American Heart Association [3] and is considered as the reference. Evaluation of cardiac function and myocardial contractility can be performed
both at rest and under stress conditions (physical or pharmacological). Pharmacologic stress may be induced with dobutamine as inotropic agent. Left ventricular function is assessed using SSFP cine imaging at rest, and then during increasing dosages of intravenously administered dobutamine. Multiple studies have reported excellent diagnostic and prognostic performance of stress CMR [4] . Dobutamine cine CMR has been shown to provide better sensitivity and specificity than dobutamine stress echocardiography and quantitative coronary angiography for detecting >50% coronary stenosis [5,6] . Regional myocardial wall motion can be quantified using myocardial strain analysis to detect subtle wall motion abnormalities giving further insight to detect early evidence of myocardial ischemia. These techniques measure a large number of regional parameters such as strain, strain rate, torsion and velocity. As the first developed regional function technique, myo cardial tissue tagging [7] has been used in a large number of clinical applications. This method is still difficult to use routinely mainly because of long processing times, but advances in gradient technology and acquisition techniques are improving temporal resolution of this method [8] . Other methods such as displacement encoding with stimulated echoes (DENSE) and strain
Table 1. Indicators of ischemia and corresponding cardiovascular magnetic resonance modality. Ischemia parameter
CMR modality
Global function and wall motion abnormalities Regional function
Cine MRI (rest and stress) Tagging Feature and tissue tracking SENC DENSE First pass perfusion (rest and stress) Arterial spin labeling BOLD imaging T2-weighted imaging T2 mapping T1 mapping LGE LGE First pass perfusion T2-weighted imaging† T2*-weighted imaging DTI 23 Na MRI 31 1 P, H and 13C MRS
Tissue blood flow Oxygenation Edema
Delineation of infarct Microvascular obstruction Hemorrhage Microstructure Ionic homeostasis Metabolism
† Less specific than T2*-weighted imaging. BOLD: Blood oxygen level dependent; CMR: Cardiovascular magnetic resonance; DENSE: Displacement encoding with stimulated echoes; DTI: Diffusion tensor imaging; LGE: Late gadolinium enhancement; MRS: Magnetic resonance spectroscopy; SENC: Strain encoding.
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Cardiovascular magnetic resonance in ischemic heart disease encoding (SENC) have also been proposed more recently for measuring regional function [9] . Myocardial perfusion Impaired myocardial perfusion precedes myocardial ischemia. Extent and severity of perfusion deficits have been shown to predict clinical outcomes including cardiovascular mortality risk. In the recent years, stress CMR perfusion imaging has been shown to be a sensitive and specific means of diagnosing coronary artery disease [10] . Myocardial perfusion is assessed with MRI by monitoring the ‘first pass’ of contrast medium through the heart using a bolus injection of gadolinium. Perfusion may be assessed qualitatively, semiquantitatively or quantitatively [11] . Perfusion studies can be performed during resting conditions and/or during administration of a vasodilatatory agent. The predominant vasodilator is adenosine, but regadenoson, a selective A 2A receptor, which is administered as a single bolus, is increasingly used [12,13] . Dobutamine is also used for myocardial perfusion assessment combined to the study of wall motion abnormalities in a single examination [14–16] . Stress perfusion CMR is regarded as a safe method. The utility of stress perfusion CMR was evaluated in several multicenter studies. A meta-analysis of the diagnostic performance of stress perfusion CMR for detection of coronary artery disease has shown a high sensitivity of this method (sensitivity 89% and specificity 80% in patients with high prevalence of CAD [57%]) [17] . Improvement of S/N ratio and contrast with increasing the magnetic field to 3 T has improved the diagnostic accuracy of perfusion CMR for coronary artery disease [18] . Comparison of perfusion CMR with the other available methods for CAD detection has been performed. Magnetic resonance (MR) perfusion has been compared with single-photon emission computed tomography (SPECT) [19,20] . The large prospective trial CE-MARC has shown the superiority of CMR (including cine imaging, rest and stress perfusion and coronary angiog raphy) over SPECT [20] . The multicenter study MR-IMPACT trial also reported a superior diagnostic performance for stress CMR as compared with SPECT [21] using x-ray coronary angiography as the reference standard. Stress perfusion CMR has been shown to have comparable diagnostic accuracy to real-time myocardial contrast echocardio graphy [22] . Myocardial multislice computed
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tomography is also developing as a competitive technique to detect perfusion deficits in CAD and has been compared with CMR as the reference technique in several studies showing a good diagnostic accuracy [23,24] . PET is the gold standard in the clinical setting to quantify myocardial perfusion and comparisons between CMR and PET have been performed [25,26] and have shown that both techniques measure accurately myocardial perfusion reserve but absolute quantification of myocardial blood flow with CMR still needs validation and standardization for clinical use [25,26] . As an alternative to bolus tracking, arterial spin labeling (ASL) methods, which are already applied in routine to brain and kidney, are under development for measuring tissue blood flow in human myocardium. These methods do not require the use of an exogenous contrast agent and may be used in patients, for which contrast agents are contraindicated. ASL relies on the labeling of arterial blood thereby generating an endogenous tracer [27,28] . It can be used repeatedly and provides absolute quantification of tissue blood flow. Zun et al. [29] have demonstrated that ASL has the potential to detect myocardial ischemia in patients, since their method was able to show reduced perfusion reserve in ischemic segments of patients with CAD. The technique is rapidly evolving through improved sequences and radiofrequency coils [30] . More recent approaches may in the future allow this technique to be used while the subjects are freely breathing [28] . Edema Myocardial edema is associated with acute stage of myocardial injury. The T2-relaxation time is correlated with the percentage of free water, and edema is therefore visible on T2-weighted MR images as hyperintense areas. It is generally accepted that hyperintense signal on T2-weighted images reflects the myocardium at risk in patients with acute myocardial infarction (Figure 1) . Better T2-weighted methods are under development to increase the robustness of the technique. T2-weighted imaging methodology has recently been improved for instance with the introduction of a T2-prepared hybrid turbo-spin echo-SSFP sequence [31] . A promising technique for assessing myocardium at risk is the direct measurement of T2 relaxation times by T2 mapping [32] . T2-mapping sequences should provide
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T2 STIR
T2 map
Delayed enhancement
T1 map pre-Gd
T1 map post-Gd
Figure 1. Example of routine multiparametric cardiovascular MRI at 1.5 T in a 70-year-old patient, 4 days anterior postinfarct. Short axis images. T2-weighted imaging, T1 and T2 mapping imaging, late gadolinium enhancement imaging demo in the infarcted area. Gd: Gadolinium; STIR: Short tau inversion recovery.
more reliable detection than conventional T2-weighted imaging since these are less dependent on confounders affecting signal intensity and image quality. T2 mapping has been validated in dogs with microsphere blood analysis as a reference standard [32] . In this study, the authors have also shown that T1 mapping is a well performing method to detect edema. In patients, T2 mapping has been shown to have a higher sensitivity compared with T2-weighted dark blood TSE imaging for myocardial edema visualization in acute myocardial infarction [33] . Performance of T1 mapping to assess acute myocardial edema has been demonstrated in patients in several pathological conditions with a high diagnostic performance compared with T2 weighted [34,35] . Performance of the ShMOLLI sequence has been underlined [34] . In patients with acute myocardial infarction T1 mapping has been proposed as a complementary technique to LGE and T2-weighted imaging to assess myocardial injury [36] . Examples of T1 and T2 mapping in a patient with myocardial infarct are shown in Figure 1.
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Detection of myocardial infarction The LGE or delayed enhancement method allows visualizing irreversible myocardial injury. The introduction of this method has been an important milestone in the development of CMR for clinical use [37] . This method relies on a T1-weighted segmented inversion recovery gradient echo sequence and the use of gadolinium-based contrast agents. After injection, the contrast agent concentration gradually increases in the damaged myocardium. In acute infarction gadolinium diffuses into myocytes because of the rupture of the sarcolemmal membrane. In chronic infarction, the distribution of gadolinium increases with the loss of myocytes and the associated increase in extracellular collagen content. The higher gadolinium concentration induces T1 shortening, which in turn appears as higher signal on the MR images (Figure 1) . Lack of contrast at the tissue–blood interface is a limitation of the technique, and new sequences are currently proposed to improve the method. As an example, multicontrast delayed enhancement (MCODE)
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Cardiovascular magnetic resonance in ischemic heart disease sequence based on a T2-weighted image combined with a phase-sensitive inversion recovery (PSIR) LGE image has recently been proposed to better discriminate subendocardial MI from blood pool [38] . Free-breathing motioncorrected LGE techniques are emerging for risk stratification of vulnerable patients [39] . Microvascular obstruction Microvascular obstruction (MVO), angio graphically evidenced by the ‘no-reflow’ phenomenon indicates poor prognosis after reperfusion following myocardial ischemia. When restoring the flow to the ischemic tissue, perfusion may not be uniform. Areas of no-reflow are characterized by ultrastructural changes to the microvasculature and irreversible myocardial cell injury [40] . MVO predicts adverse cardiac remodeling and can be assessed either with gadolinium enhancement (early or late) or perfusion MR. No reflow is visualized as a hypointense, dark region inside the enhanced area of infarcted myocardium. Ultrafast inversion-recovery gradient echo sequences for early and LGE and accelerated high-resolution sequences for perfusion allow total coverage of the ventricle and have improved the detection of MVO [41] . In a large prospective trial, de Waha and coworkers [42] have provided good evidence that late rather than early MVO predicts outcome after myocardial infarction. Hemorrhage Reperfusion injury is also characterized by hemorrhage which can be assessed with T2-weighted and T2*-weighted imaging. Hemorrhage is detected on MRI images based on the paramagnetic effects of hemoglobin degradation products. These paramagnetic effects lead to reduced T2 and T2* relaxation times and therefore to hypo-enhanced regions in CMR images [41] . The signal intensity of hemorrhage in T2-weighted images undergoes various changes and a low signal intensity area is less specific to hemorrhage than T2*-weighted imaging. Kumar et al. [43] have demonstrated the accuracy of quantifying hemorrhage with T2*-weighted imaging and suggested that it may be used as a marker of severe tissue injury in addition to the CMR markers for the other components of tissue injury (edema, necrosis, MVO). Zia et al. [44] have shown the value of quantitative T2* mapping to characterize hemorrhage postacute myocardial infarction.
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Myocardial microstructure Microstructure of the left ventricular myocardium can be analyzed using diffusion tensor MRI (DTI), which measures parameters that describe the restricted water molecule diffusion in the tissue. Microstructural changes in the myocardium can then be quantified by measuring mean diffusivity, fractional anisotropy and the orientation (helix angle, HA) of the myofibers. Microstructural changes after infarction have been measured with DTI by Wu et al. [45] who showed that these changes were indeed correlated with changes in myocardial wall thickness and wall thickening. Further optimization of the method has to be performed, but good reproducibility of this method, which is challenging in the human heart in vivo, has been demonstrated recently [46] . Myocardial oxygenation While perfusion MRI assesses oxygen supply, myocardial oxygen demand is an equally important parameter, which may be assessed with blood oxygen level dependent (BOLD) imaging. This technique is based on detecting differences in magnetic susceptibility between oxyhemoglobin and deoxyhemoglobin. In ischemic tissue, decreased oxyhemoglobin and increased deoxyhemoglobin tissue content induce lower T2* or T2 values that lead to signal changes on T2*or T2-weighted images. Oxygenation-sensitive CMR can be performed during rest and under pharmacological stress conditions. The potential of oxygenation-sensitive CMR has been shown in animals [47] and then in human studies [48–50] . Karamitsos et al. [51] have assessed the relationship between BOLD changes and myocardial perfusion measurement by PET. They have shown that reduced perfusion is not always associated to deoxygenation. Arnold et al. [52] evaluated the performance of BOLD imaging for the detection of CAD in the clinical setting. They showed additional value of this parameter over myocardial blood flow in characterizing ischemia. However, further advances in BOLD techniques are needed for routine clinical use. MR coronary angiography MR coronary angiography offers an interesting perspective as a noninvasive method which can be combined with other parameters such as perfusion imaging or scar determination in one single examination but is challenging compared with computed tomography angiography.
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Special Report Bernard, Jacquier & Kober Nevertheless, it is evolving with improvements of the MR techniques including in particular the development of multichannel coils, magnetic field increase, improved sequences and breathing correction. In 2010, Kato et al. [53] have conducted a multicenter trial in Japan with promising results showing a sensitivity of 88%,
a specificity of 72% and positive and negative predictive values of 71 and 88%, respectively. Hamdan et al. [54] have compared 3 T MR angiography with a 32-channel coil and 64 multislice computed tomography and have shown comparable accuracy in the diagnosis of coronary stenosis. An interesting perspective is to combine
PCr ATP 2,3-DPG Pi
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Figure 2. 31P 3D chemical-shift imaging in a patient with anterior myocardial infarction. On the left are proton short axis images showing voxel selection. On the right are typical human cardiac 31P spectra acquired using 3D chemical shift imaging showing resonances of PCr, ATP (three resonances), 2,3-DPG and Pi. PCr/ATP ratio is decreased in the infarcted area. DPG: Diphosphoglycerate; PCr: Phosphocreatine; Pi: Inorganic phosphate.
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Cardiovascular magnetic resonance in ischemic heart disease coronary angiography and perfusion MR. Heer et al. [55] were able to show that combining both methods improves the specificity for the diagnosis of CAD without compromising the sensitivity. Technical developments in MR may improve the robustness of MR coronary angio graphy, as a matter of fact Soleimanifard et al. [56] have recently shown the value of a 3D volumetargeted high-resolution balanced steady-state free-precession sequence in a breath hold at 3 T using a 32-channel cardiac coil, a multitransmit system and localized RF shimming. Ionic homeostasis Nonviable myocardium can be characterized without contrast agent by 23Na MRI. Sandstede et al. have shown an increased signal on sodium images after infarction in myocardial areas with wall motion abnormalities [57]. Total sodium increase is attributed to increased intracellular sodium and higher extracellular volume. This increase in sodium is attributed to loss of cell membrane integrity. Spatial resolution is currently a limitation for clinical applications. Myocardial metabolism MRS provides quantitative information on metabolic compounds in the myocardium [58] . In particular 31P MRS gives access to high energy metabolism (PCr and ATP) whose changes are an early marker of cellular ischemia as levels of high-energy phosphates fall when energy supply is decreased. Localization sequences such as chemical shift imaging allow the identification of areas of the myocardium in which highenergy phosphates are decreased corresponding to ischemic myocardium (Figure 2) . It is also possible to measure creatine kinase flux with 31 P MRS. Bottomley et al. [59] demonstrated a 50% lower creatine kinase flux in myocardial infarcts. 31P MRS is currently limited by its low spatial resolution, but improvements are expected from higher magnetic fields. 1H MRS with the measurement of creatine has also the potential to identify infarcted myocardium. Bottomley and Weiss [60] have shown that creatine concentration was significantly lower in infarct myocardium. The development of hyperpolarisation techniques with 13C MRS is promising to follow important metabolites that are markers of ischemia such as lactate or bicarbonate [61] . Metabolic information by 31P MRS or 13C MRS is complementary to those afforded by PET combined to radiolabeled tracers such
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as for instance 18F-fluorodeoxyglucose or C-11 actetate to study myocardial glucose metabolism or TCA cycle [62] . Besides spectroscopy, molecular imaging with parametric probes which target specific cellular pathways such as, for instance, apoptosis, necrosis or angiogenesis may have significant diagnostic, prognostic and therapeutic value but still need to be translated from animal models to clinics [63,64] . Conclusion Numerous clinical data support the application of CMR in ischemic diseases. CMR is a noninvasive method with the possibility to assess a variety of parameters on tissue alterations, function and perfusion for early detection, risk stratification and guidance of patient therapy. It offers the advantage of a comprehensive examination including contractile function, morphology, perfusion, angiography and tissue characterization. It is becoming more and more an alternative to other imaging modalities. Cost efficiency for CAD diagnosis of CMR method compared with other methods such as SPECT, fractional flow reserve or coronary angiography has been shown in studies involving several countries [65–67] . Future perspective There are still challenges to increase the robustness and accuracy of CMR, but the workflow in clinical routine is continuously being improved, and the technique is evolving rapidly with ongoing developments in hardware and software. CMR is currently mainly performed at a magnetic field strength of 1.5 T while 3 T systems are increasingly used. Moving toward higher field strengths will increase S/N ratio and will lead to higher spatial and temporal resolution and faster imaging techniques. 7 T systems are now installed in an increasing number of centers, but cardiac MR at ultra-high field is challenging and will have to be validated in the future in clinical applications such as ischemic heart disease. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
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Special Report Bernard, Jacquier & Kober Executive summary ●●
The assessment of patients with myocardial ischemia is still challenging and physicians need appropriate tools for prevention, early detection and characterization of ischemia as well as for prognosis and follow-up of therapies.
●●
Cardiovascular magnetic resonance (CMR) has numerous advantages over other imaging methods and in particular
high temporal and spatial resolution, absence of ionizing radiation and diagnostic versatility. It has indeed become a powerful technique to assess ischemia with high diagnostic and prognostic accuracy. ●●
A variety of parameters can be measured in a single imaging examination to detect myocardial ischemia and to obtain
a prognosis after infarct. CMR can assess function and wall motion abnormalities by cine imaging, abnormal coronary flow by perfusion MRI, myocardial edema by T2-weighted techniques and it is able to determine infarcted myocardium by late gadolinium enhancement. Other emerging techniques have the potential to afford further interesting information on ischemic tissue. Among these emerging techniques are blood oxygen level dependent imaging to assess oxygenation defects, T1 and T2 mapping for edema, diffusion tensor imaging for fiber anatomy or magnetic resonance spectroscopy of various nuclei (31P, 1H, 23Na and 13C) for assessing perturbations in metabolism. ●●
There are still challenges to increase the robustness and accuracy of CMR, but its workflow in clinical routine is
continuously being improved, and the technique is evolving rapidly with ongoing developments in both hardware and software. References 1
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