CT of Coronary Heart Disease: Part 1, CT of Myocardial Infarction, Ischemia, and Viability

Cardiopulmonary Imaging Review Vliegenthart et al. CT of Coronary Heart Disease Cardiopulmonary Imaging Review CME SAM CT of Coronary Heart Disease FOCUS ON: Rozemarijn Vliegenthart 1,2 Thomas Henzler 1,3 Antonio Moscariello 1,4 Balazs Ruzsics 1 Gorka Bastarrika 1,5 Matthijs Oudkerk 2 U. Joseph Schoepf 1 Vliegenthart R, Henzler T, Moscariello A, et al. Keywords: CT, dual-energy CT, dual-source CT, hemodynamics, ischemia, myocardial infarction, myocardial perfusion, myocardial viability DOI:10.2214/AJR.11.7082 Received April 15, 2011; accepted after revision May 30, 2011. G. Bastarrika is a member of the speakers bureaus of Bayer-Schering, GE Healthcare, Medrad, and Siemens Healthcare. U. J. Schoepf is a consultant for and receives research support from Bayer-Schering, Bracco, GE Healthcare, Medrad, and Siemens Healthcare. 1 Department of Radiology and Radiological Science, Medical University of South Carolina, Ashley River Tower, 25 Courtenay Dr, Charleston, SC 29425-2260. Address correspondence to U. J. Schoepf (schoepf@musc.edu). 2 Center for Medical Imaging North East Netherlands, Department of Radiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 3 Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim-Heidelberg University, Mannheim, Germany. 4 Department of Bioimaging and Radiological Sciences, Catholic University of the Sacred Heart, Agostino Gemelli Hospital, Rome, Italy. 5 Department of Radiology, University of Navarra, Pamplona, Spain. CME/SAM This article is available for CME/SAM credit. AJR 2012; 198:531 547 0361 803X/12/1983 531 American Roentgen Ray Society CT of Coronary Heart Disease: Part 1, CT of Myocardial Infarction, Ischemia, and Viability OBJECTIVE. This article reviews the CT-based approaches aimed at the assessment of myocardial infarction, ischemia, and viability described in the recent literature. CONCLUSION. Rapid advances in CT technology not only have improved visualization of coronary arteries but also increasingly enable noncoronary myocardial applications, including analysis of wall motion and the state of the myocardial blood supply. These advancements hold promise for eventually accomplishing the goal of comprehensively evaluating coronary heart disease with a single noninvasive modality. I n patients with symptoms suggestive of coronary artery disease (CAD), the goal of diagnostic imaging is to detect flow-limiting coronary artery stenoses that is, lesions with a hemodynamically relevant impact on myocardial perfusion. It is surprisingly difficult to predict which coronary artery stenosis will result in impairment of myocardial blood flow, especially in the case of lesions with intermediate severity (30 80% luminal narrowing) [1]. Correct identification of patients with CAD who will benefit from coronary intervention therefore usually requires a combination of anatomic and functional testing. In the past decades, functional imaging of myocardial perfusion has mainly been the domain of nuclear scanning techniques namely, SPECT and PET. Ample evidence shows that the information obtained by these tests has considerable therapeutic and prognostic implications [2]. However, nuclear imaging techniques have limitations such as attenuation artifacts, high cost, radiation dose, and limited off-hours availability. In recent years, the importance of MRI for perfusion imaging has increased especially because of its superior spatial resolution and lack of ionizing radiation. There is evidence that MRI has better diagnostic accuracy than SPECT for significant CAD [3, 4]. Several concepts have been introduced to combine data on structural and functional information on a patient s cardiac status from different imaging modalities via image fusion [5 7] or hybrid acquisition [8 10] techniques most notably, PET/CT [9, 10]. How- ever, in view of diagnostic efficiency, patient comfort, and potential cost-effectiveness, a single noninvasive imaging modality providing a conclusive diagnosis of all aspects of coronary heart disease (CHD), including the noninvasive assessment of the coronary arteries for atherosclerosis and stenosis, is desirable. Currently, no single established imaging modality combines both functional and anatomic imaging in a manner that satisfactorily addresses these needs. Advances in CT technique may hold potential to change this reality. The rapid evolution of CT technology in recent years has significantly improved spatial and temporal resolution, thus enabling accurate noninvasive assessment of the fastmoving coronary arteries. Coronary CT angiography (CTA) has quickly gained an important role in the diagnostic workup of patients with suspected CAD. A plethora of studies have evaluated the accuracy of this test for the detection of significant coronary artery stenosis [11 13]. Currently, the strongest indication for coronary CTA is to exclude significant stenosis in patients with a low to intermediate risk of CAD [14, 15]. The ability of CT to noninvasively evaluate coronary artery morphology for atherosclerosis and luminal integrity is the most important hallmark of this test [16]. This unique capability is the cornerstone and driving force of all considerations to expand the role of CT beyond structural assessment to the evaluation of other aspects of CHD. Accordingly, deliberations about using CT as the primary method for the assessment of AJR:198, March 2012 531

Vliegenthart et al. myocardial function and perfusion outside the context of coronary artery evaluation are likely ill conceived except for rare clinical scenarios (e.g., poor echocardiographic acoustic windows, patient with a pacemaker) because of the availability of gentler imaging modalities for these purposes. Likewise, CT-based approaches aimed at enhancing ancillary information at the expense of compromising the diagnostic yield of coronary CTA are likely misguided. However, coronary CTA performed using retrospectively ECG-gated acquisition techniques [17, 18] or newer, lower-radiation-dose prospectively ECG-triggered [19] acquisition techniques inherently yields functional information. The performance of multiphasic CT reconstructions for the assessment of global and regional heart function has been extensively reviewed elsewhere [20, 21]. The intent of this article is to tally the quickly accumulating body of recent literature on CT-based approaches aimed at accomplishing the third cornerstone in the imaging evaluation of CHD namely, the assessment of myocardial infarction, ischemia, and viability. CT Technology and Techniques for Imaging the Myocardial Blood Supply and Viability CT assessment of the myocardial blood supply uses a premise similar to myocardial perfusion MRI: The contrast agents for CT and MRI have similar contrast kinetics that allow both the assessment of the arterial blood supply and the evaluation of myocardial viability [22]. Single-Energy Coronary CT Angiography Based Techniques For the CT-based assessment of the myocardial blood supply, in general, two fundamentally very different strategies are currently in use and need to be carefully differentiated. One is the qualitative, visual evaluation of the myocardial blood content during the early arterial phase of myocardial contrast medium attenuation. During the first-pass of contrast material through the left ventricle, myocardial segments with diminished perfusion have a reduced delivery of contrast material, resulting in a characteristic area of hypoattenuation [23, 24] (Fig. 1). This ancillary evaluation is performed in most cases using the same coronary CTA image acquisition that is aimed primarily at assessing coronary artery luminal integrity, and typically the CT protocol is not changed [25, 26]. Thus, obtaining this information does not come at the expense of additional scanning time or increased radiation dose. Consequently, in principle this approach is technically feasible with every CT scanner capable of performing coronary CTA. Dedicated postprocessing techniques, such as the application of electronic filters, have been described [27] to enhance the conspicuity of myocardial blood volume defects when using this application. A C E First-pass CT depends on correct bolus timing and can suffer from beam-hardening artifacts at the interface of the endocardial border with the contrast medium filled left ventricle [28, 29]. To distinguish a true area of hypoattenuation from artifact, reconstruct multiple phases of the cardiac cycle (at least one systolic phase and one diastolic phase) whenever the acquisition technique permits. A true perfusion defect will remain throughout the cardiac cycle [30]. Fig. 1 55-year-old man with acute myocardial infarction. A and B, Contrast-enhanced CT study displayed as thin maximum intensity projections in short-axis (A) and long-axis (B) views shows hypoattenuating area (arrows) within anteroseptal wall of left ventricle and of apex; these findings suggest infarction. C and D, Maximum-intensity-projection view (C) and volume-rendered display (D) of left anterior descending coronary artery show complete occlusion of proximal segment (arrows). E, Invasive coronary angiography image confirms presence of occlusion (arrow) shown in C and D. B D 532 AJR:198, March 2012

CT of Coronary Heart Disease A D G J Fig. 2 64-year-old man with exertional dyspnea. A H, Contrast-enhanced dual-energy CT study displayed in long-axis (A and B) and short-axis (D and E) views at rest (A and D) and stress (B and E) shows reversible perfusion defects (arrows, B, E, F, and H) of lateral wall of left ventricle and of anterior papillary muscle; these findings suggest ischemia. A D depict color maps of iodine distribution based on both energy spectrum datasets superimposed onto gray-scale multiplanar reformats of left ventricle. CT images are in good correlation with stress-rest SPECT images (long-axis images, C; short-axis images, F) and with first-pass perfusion MR images obtained during rest (G) and adenosine stress (H). I, Multiplanar reformation of left circumflex coronary artery based on coronary CT angiography data displays diffuse mixed atherosclerotic disease with subtotal occlusion of mid segment (arrow) without visible distal filling. J, Maximum-intensity-projection image of proximal left coronary arteries shows narrowing of left circumflex coronary artery (lower arrow) corresponding to findings shown in I and significant stenosis in first diagonal branch of left anterior descending coronary artery (upper arrow). K, Invasive coronary angiography image confirms diffuse coronary artery disease of left circumflex coronary artery with subtotal occlusion of mid segment (arrow). L, Conventional coronary catheter angiography image obtained after percutaneous coronary intervention (stent placement) shows flow in left circumflex coronary artery has been restored. B E H K C F I L AJR:198, March 2012 533

Vliegenthart et al. Dual-Energy Coronary CT Angiography Based Techniques A variation of the approach of evaluating myocardial blood content during the first arterial pass of IV injected contrast medium is image acquisition using more than one energy x-ray spectrum. For imaging the heart, this strategy has been evaluated mainly with dual-source CT technology [31 33]. The two-tube, two-detector configuration of this scanner type enables mapping the myocardial iodine distribution based on the unique absorption characteristics of this element when penetrated with x-ray spectra of different energy levels [28]. Thus, this approach uses material decomposition and constitutes a departure from image interpretation according to the Hounsfield unit attenuation gray scale. With dual-energy CT, visualization of defects in the myocardial blood supply is ordinarily dependent on generating a map of myocardial iodine distribution based on both energy spectrum datasets, which is superimposed onto gray-scale multiplanar reformats of the left ventricle from which the contrast material has initially been electronically ( virtually ) removed (Fig. 2). Because the dataset contains a broad range of iodine concentrations, the iodine map should be normalized to areas of normal myocardial perfusion [34]. Initially, the use of dual-energy CT for cardiac applications required decreasing the temporal resolution from 83 to 165 ms [31]. This change was not in keeping with the tenet that obtaining ancillary information about the myocardial blood supply must not detract from the full diagnostic performance of coronary CTA for stenosis detection. However, this limitation has been addressed, and the full temporal resolution of 83 ms (first-generation dual-source CT) or 75 ms (second-generation dual-source CT) has been restored for cardiac dual-energy CT applications [35]. This approach does not involve additional scanning time or radiation dose compared with routine, single-energy retrospectively ECG-gated coronary CTA. Other strategies have been proposed in the interim for obtaining multiple-energy CT acquisitions, such as fast switching of kilovoltage settings, or fast kv switching, based on single-source CT [36] and compartmentalization of detected x-ray photons into energy bins by detectors of a single-source CT scanner operating at constant kilovoltage and milliampere settings [37]; however, the application of these techniques for the assessment of the myocardial blood supply has not been described to date. Evaluation of CT series acquired at two energy levels requires software processing and then visual analysis of the myocardial blood supply, which ordinarily adds about 5 10 minutes of reading time to the study interpretation. Occasionally, the techniques described are imprecisely referred to as perfusion imaging, whereas in reality they constitute a static snapshot capture of contrast medium distribution within the myocardium, thus reflecting the myocardial blood pool at the time of image acquisition. In theory this approach harbors a limitation arising from the fact that different portions of the myocardium are imaged during different phases of myocardial perfusion because image acquisition proceeds across the cardiac anatomy; however, according to the existing literature [26, 31 33], this limitation does not appear to detract from the clinical performance of dual-energy CT techniques for detecting regional decreases in the myocardial blood supply in comparison with other imaging modalities. Dynamic Time-Resolved CT Techniques for Myocardial Perfusion Imaging A fundamentally different approach for the CT-based assessment of myocardial blood flow at rest and stress that indeed fulfills the principle of perfusion imaging consists of dynamic time-resolved image acquisition at multiple time points during the passage of a contrast medium bolus through the myocardium. This concept is not new; it is important to remember that the technology of electron beam CT was originally developed precisely for this purpose [38, 39]. Currently this application is seeing a renaissance with the advent of CT systems that rival or exceed the anatomic coverage of electron beam CT. Conventional CT technologies ordinarily can image organ perfusion only within a tissue volume corresponding to the detector width. The recent availability of CT systems such as 256-MDCT, 320- MDCT, and second-generation dual-source CT enables dynamic time-resolved perfusion imaging encompassing all or most of the left ventricular myocardium. With the former technologies, this is accomplished by a detector width that is broad enough to cover the entire heart [40]; the latter technology uses Fig. 3 49-year-old man with occlusion of left anterior descending coronary artery. Color-coded perfusion maps are based on dynamic perfusion CT performed during adenosine stress. Timeattenuation curves and perfusion parameters for entire myocardium (1), perfusion defect (2), and healthy control segment (3) are shown. 534 AJR:198, March 2012

CT of Coronary Heart Disease rapid back-and-forth CT scanner table movements to image the myocardium at multiple time points during contrast medium passage [33, 41, 42]. These approaches are unaffected by the mentioned theoretic limitation of image acquisition during different phases of myocardial perfusion with coronary CTA; more importantly, they enable quantitative measurements of tissue blood flow in healthy and diseased myocardium as opposed to the mostly qualitative visual assessment for defects in the myocardial blood supply with coronary CTA techniques (Fig. 3). This capability is of considerable importance because quantitative measurement of myocardial perfusion is a coveted goal [1]. The only other imaging modality currently capable of providing this information is cardiac PET with the use of dedicated (commonly rubidium-82) tracers [43]. Cardiac MRI is limited for this purpose by the nonlinear relationship between tissue signal intensity after injection of gadolinium-based contrast agents and actual tissue perfusion [44], whereas this relationship is indeed linear with iodine-based CT contrast agents [45, 46]. The disadvantage of dynamic time-resolved perfusion CT lies in relatively high levels of radiation exposure (13 18 msv, depending on the technique [33, 41, 42]). This limitation is further aggravated by the fact that these image acquisition strategies are dedicated to the measurement of myocardial perfusion and ordinarily do not allow simultaneous evaluation for coronary artery stenosis from the same dataset, as most coronary CTA based techniques. Thus, they are ordinarily performed in addition to morphologic imaging to obtain complete anatomic and functional information. In our experience, software processing of the perfusion CT data and the actual visual and quantitative analyses of myocardial perfusion require about 15 minutes of additional reading time. IV access, ECG Scout images With or without test bolus Contrast Stress CT Pharmacologic stress CT Techniques for Imaging of Myocardial Viability In the setting of acute myocardial infarction (MI), cell damage leads to the loss of membrane integrity and a subsequent increase in the distribution volume of contrast medium. Viability imaging with CT uses a premise similar to MRI given that iodine-based CT contrast agents are thought to accumulate in the intracellular space of irreversibly damaged cardiomyocytes similar to gadolinium and can subsequently be detected by delayed enhancement CT. Factors to consider when performing delayed enhancement CT are the method of ECG synchronization, tube settings, and method of contrast delivery. CT-based approaches for the assessment of myocardial viability ordinarily involve standard coronary CTA techniques with retrospective ECG-gating or prospective ECGtriggering. Prospective ECG-triggering significantly limits radiation dose compared with retrospective ECG-gating [47]. Thus, a delayed CT scan can be obtained at a low radiation dose of about 1 msv. Compared with MRI, CT has a rather low signal-to-noise ratio. MRI can null the myocardium to enhance the conspicuity of hyperenhancing areas, whereas CT generally lacks this capability at least when performed using a single-energy technique. Dedicated image acquisition protocols, such as the use of a low kilovoltage setting, have been described to improve the detection of areas of delayed contrast enhancement within the myocardium in animal experiments [48, 49]; however, such low-kilovoltage protocols quickly become limited when imaging normal-sized or obese patients because high levels of image noise interfere with the accurate delineation of segments showing delayed enhancement. An adequate amount of iodine contrast medium, approximately 120 150 ml, is a prerequisite for the detection of myocardial hyperenhancement. Although contrast material is usually administered as a bolus during coronary CTA or dedicated myocardial blood pool assessment, investigators [50] reported greater attenuation differences between infarcted tissue and normal myocardium when applying a combination of a bolus and subsequent longer low-flow injection. Controversy exists regarding the optimal time point during which attenuation of iodine-based contrast medium within areas of myocardial scar is the With or without delayed CT ~ 5 min ~ 10 min ~ 15 min Fig. 4 Schematic representation of CT protocol for assessment of myocardial blood supply involving pharmacologic stress. Contrast Rest CT highest; however, a delay time of 5 10 minutes after contrast medium administration is commonly described [22, 51 53]. An easy and elegant manner to perform delayed enhancement CT is directly after catheterization for reperfusion, which allows detection of hyperenhancing areas without administering additional contrast medium [54, 55]. In general, delayed enhancement CT studies are best viewed as thick (5 or 10 mm) multiplanar reformations with a narrow window width and level (e.g., width, 200 HU; level, 100 HU) or as maximum intensity projections [30]. Pharmacologic Stress as Part of a Comprehensive CT Protocol for Coronary Heart Disease Evaluation The mere presence of coronary artery diameter reduction of 50% or more, which is the threshold most commonly used to describe significant stenosis, does not necessarily result in a reduction of myocardial perfusion. In studies comparing coronary artery stenosis on coronary CTA with myocardial perfusion defects on MRI or SPECT, CTA was not accurate in predicting ischemia [56, 57]. It is generally accepted that the hemodynamic significance of coronary artery stenosis cannot be reliably determined without information about perfusion or wall motion of the myocardium during stress (by exercise or pharmacologically induced) and during rest. In the ischemic cascade, stress perfusion abnormalities occur at a much earlier stage than wall motion abnormalities [58] and are therefore considered a more sensitive sign of hemodynamically significant stenosis. Because CT evaluation at rest would, in theory, allow detection of only fixed myocardial perfusion defects (i.e., generally MI), several studies have supplemented coronary CTA acquisitions at rest with an additional AJR:198, March 2012 535

Vliegenthart et al. scan acquired during pharmacologic stress, with the goal of also detecting reversible perfusion defects (i.e., stress-induced myocardial ischemia) [32, 33, 59 64]. Analogous to the indications for coronary CTA, conceivable future indications for performing a myocardial perfusion CT study under pharmacologic stress may include evaluating a symptomatic patient with an intermediate risk of CAD who has a nondiagnostic or equivocal ECG result or is unable to exercise and to determine the hemodynamic significance of a known coronary artery stenosis. Also, this protocol may find a role in patients who have undergone bypass surgery and have recurrent chest pain to assess inducible ischemia along with the patency of grafts. For a more extensive overview of the potential future indications for adenosine stress CT, we refer to a statement explaining A the criteria for the appropriate use of cardiac CT and cardiac MRI [14]. In general, the described scanning protocols (Fig. 4) include a coronary CTA acquisition at rest for detecting coronary artery stenosis and obtaining information about the resting status of the myocardial blood supply [25, 26, 31, 33, 59, 64, 65]. During a second acquisition before or after the rest scan, pharmacologic stress is induced by continuous infusion of adenosine, most commonly at 140 µg/min/kg of body weight for 2 5 minutes. In our practice, pharmacologic stress is increasingly induced with IV injection of 0.4 mg of regadenoson as an alternative to adenosine because regadenoson is easier to administer by bolus injection than adeno sine is by pump infusion. At peak pharmacologic stress, a second bolus of iodine contrast medium is injected, and stress image acquisition is subsequently performed (Figs. B 5 and 6). Although reflex tachycardia secondary to pharmacologic stress agents is possible, the increase in average heart rate has been found to be usually limited to approximately 10 beats/min [32, 61]. In addition, the evaluation of the coronary arteries is ordinarily based on CT data acquired at rest, so a somewhat higher heart rate during stress is not likely to interfere with coronary artery evaluation. In some protocols, rest and stress imaging is followed by a delayed phase acquisition, about 5 10 minutes after the last contrast injection, for the purpose of myocardial viability imaging. Few data exist about the additional time needed to evaluate stress-rest perfusion scans. The only investigation stating evaluation time [65] to our knowledge reported 15 minutes of additional reading time, which is comparable with our experience. We expect that this additional interpretation time will decrease in C D E F Fig. 5 75-year-old man with stable angina. A L, Contrast-enhanced dual-energy CT study displayed in short-axis (A, B, D, and E) and long-axis (G, H, J, and K) views during stress (A, B, G, and H) and rest (D, E, J, and K) shows reversible perfusion defects (arrows, A C and G I) of anteroseptal wall of left ventricle; these findings suggest ischemia. CT images show good correlation with SPECT images: C and F are short-axis images obtained during stress and rest, respectively, and I and L are long-axis images obtained during stress and rest. (Fig. 5 continues on next page) 536 AJR:198, March 2012

CT of Coronary Heart Disease G J Fig. 5 (continued) 75-year-old man with stable angina. A L, Contrast-enhanced dual-energy CT study displayed in short-axis (A, B, D, and E) and long-axis (G, H, J, and K) views during stress (A, B, G, and H) and rest (D, E, J, and K) shows reversible perfusion defects (arrows, A C and G I) of anteroseptal wall of left ventricle; these findings suggest ischemia. CT images show good correlation with SPECT images: C and F are short-axis images obtained during stress and rest, respectively, and I and L are long-axis images obtained during stress and rest. the future, with newer perfusion analysis software enabling greater automatization. Preliminary patient data [33, 41, 42] show that such combined CT-based approaches for imaging of the coronary arteries, myocardial perfusion during stress and rest, and myocardial viability can be accomplished at radiation doses (? 15 msv, [Table 1]) that compare favorably with SPECT for myocardial perfusion imaging (? 10 msv for 99m Tc and 20 40 msv for 201 Tl) and dual-isotope SPECT for myocardial viability assessment (? 30 msv) [66, 67]. Stress MRI has a major advantage over both SPECT and CT in terms of radiation dose; however, to date MRI cannot accurately and consistently evaluate the coronary arteries. H K CT of Myocardial Infarction: Clinical Evidence In many cases, standard CT techniques can identify healed MI because the site of chronic MI will have reduced capillary density, can contain fatty metaplasia or calcium, and may show remodeling including wall thinning [68] and aneurysm formation (Fig. 7). Many of these features may even be discernible on unenhanced CT studies performed for coronary calcium scoring [69, 70]. Gupta et al. [69] showed that hypoattenuating myocardial regions suggestive of chronic MI can be detected in patients with fixed perfusion defects on nuclear myocardial perfusion imaging with a sensitivity of 92% and a specificity of 72% on a per-patient basis. The strong and incremental prognostic value of coronary calcium scoring for CHD in asymptomatic populations is well known [71, 72]. Data are too limited to promote the use of unenhanced CT as a primary modality to detect chronic MI. However, in individuals undergoing coronary calcium scanning, the recognition of silent, chronic MI has considerable implications because the prognosis for this entity is similar to that of patients with clinically manifested nonfatal MI [73]. On contrast-enhanced cardiac CT, chronic MI can ordinarily be recognized as a hypoattenuating region (> 50% HU decrease compared with surrounding myocardium) [74] in a subendocardial or transmural distribution that persists in systole and diastole and is concordant with a coronary territory [75]. In the first systematic analysis of the potential usefulness of dual-energy CT for comprehensive CAD imaging [76], rest dual-energy CT correctly identified 26 of 29 fixed myocardial perfusion defects (90%) on SPECT. In their study of 122 patients with chronic MI, Rubinshtein et al. [75] found that 75% of infarcts in 20 vessel territories detected by SPECT were also visible on coronary CTA images. Four of five missed chronic infarcts were relatively small. On the other hand, CT showed I L AJR:198, March 2012 537

Vliegenthart et al. seven areas of chronic MI that were not visible on SPECT; these findings can be viewed as false-positive CT results, but also can be interpreted as false-negative SPECT findings in view of the limited sensitivity of this test [77]. In a study of 69 patients with healed infarcts, CT detected areas of hypoattenuation in all patients with perfusion defects on gated A D G Fig. 6 64-year-old man with history of myocardial infarction in right coronary artery territory. A I, Stress (A) and rest (B) SPECT images in long axis and stress (D) and rest (E) SPECT images in short axis views illustrate fixed defect in inferior wall (arrows, A, B, D, and E); this finding is suggestive of myocardial infarction. Color-coded perfusion maps based on dynamic perfusion CT imaging during adenosine stress (C and F) display corresponding perfusion defect (arrows, C and F). Good correlation is seen with adenosine stress perfusion MR images (G and H), which show fixed perfusion defect (arrows, G and H) in inferior wall. Delayed enhancement MR image (I) confirms myocardial infarction (arrow, I). rest SPECT (62 patients), with good correlation between infarct scores [78]. One study compared CT findings with delayed enhancement MRI [79]: 36 patients with coronary artery bypass grafts were examined with dual-energy CT and 3-T MRI, and 22 (61%) showed delayed enhancement on MRI. In this patient population, the dual-energy CT B E H studies suffered from artifacts arising from sternal wires and implanted metallic devices, affecting sensitivity. A vessel-based analysis yielded the following diagnostic performance indexes for CT in that study: 77% sensitivity, 97% specificity, 85% positive predictive value, 96% negative predictive value, and 94% accuracy [79]. C F I 538 AJR:198, March 2012

CT of Coronary Heart Disease TABLE 1: Overview of Patient Studies Comparing CT With Other Imaging Techniques for the Assessment of Myocardial Blood Supply Imaging Modality First Author [Reference No.] Study Population and Presenting Condition or Imaging Findings CT Technique Rest CT b only Nagao [25] 34 Patients with suspected CAD 28 Control subjects with normal CTA results Rest CT b only Kachenoura [65] 64 Patients undergoing CAG 20 Control subjects with normal CTA and MPI results Rest CT b only Ruzsics [31] 36 Patients with equivocal or incongruous SPECT results Rest CT b only Cheng [26] 55 Patients with clinical symptoms and SPECT findings suspicious for CAD Stress and rest CT c George [59] 40 Patients with positive SPECT results Stress and rest CT c Blankstein [60] Stress and rest CT c Rocha-Filho [61] 34 Patients who underwent SPECT < 3 mo earlier scheduled to undergo CAG or who exhibited high-risk signs for CAD 35 Patients who underwent SPECT < 3 mo earlier scheduled to undergo CAG or who exhibited high-risk signs for CAD 64-MDCT Rest CT 64-MDCT Rest CT Dual-source CT Rest dual-energy CT Dual-source CT Rest CT 24 patients, 64-MDCT 16 patients, 256-MDCT Stress CT and rest CT (256-MDCT) Dual-source CT Stress CT Rest CT CT Dose (msv) Comparison a Results Stress-rest SPECT CT within < 2 wk of SPECT 7 15 CAG Mean of 44 d after CT 14 ± 5 Stress-rest SPECT CT within < 4 d of SPECT 16 ± 7 Stress-rest SPECT CT within < 3 wk of SPECT 17 22 10 2 Stress-rest SPECT CAG (27) Stress-rest SPECT CAG Systolic CT attenuation and difference between systolic and diastolic attenuations of diseased segments were significantly lower than healthy segments (15/17 segments). Ischemia was characterized by systolic hypoattenuation and normal diastolic attenuation Addition of so-called CT subendocardial perfusion index to CTA improved diagnostic accuracy (per patient): sensitivity from 0.87 to 0.96 and accuracy 0.84 from 0.88; however, specificity decreased from 0.79 to 0.68 mostly because of image quality Diagnostic accuracy (per segment) of CT iodine maps compared with any perfusion defect on SPECT: sensitivity, 92%; specificity, 93%; accuracy, 93%. Dual-energy CT detected 96% of fixed and 88% of reversible defects shown by SPECT Diagnostic accuracy (per patient) of CT compared with: Perfusion defects on rest SPECT: sensitivity, 100%; specificity, 78%; accuracy, 84% Perfusion defects on stress SPECT: sensitivity, 83%; specificity, 90%; accuracy, 87% Diagnostic accuracy (per vessel) of rest CT versus perfusion defects on SPECT: sensitivity, 70%; specificity, 51% Diagnostic accuracy (per patient) of CTA and CT myocardial assessment compared with SPECT or CAG results: sensitivity, 86%; specificity, 92% Sensitivity and specificity (per vessel) for stenosis 50% on CAG: 79% and 80%, respectively, with CT myocardial assessment and 67% and 83% with SPECT Compared with CTA alone, addition of CT myocardial assessment increased sensitivity from 83% to 91% and specificity from 71% to 91% (Table 1 continues on next page) AJR:198, March 2012 539

Vliegenthart et al. TABLE 1: Overview of Patient Studies Comparing CT With Other Imaging Techniques for the Assessment of Myocardial Blood Supply (continued) Imaging Modality First Author [Reference No.] Stress and rest CT c Okado [62] 47 Patients who underwent SPECT < 3 mo earlier scheduled to undergo CAG or who exhibited high-risk signs for CAD Stress and rest CT c Tamarappoo [63] 30 Patients with positive SPECT results< 2 mo earlier Stress and rest CT c Ko [32] 50 Symptomatic patients with CAD on CTA Stress and rest CT c Weininger [33] 20 Patients with acute chest pain: 10 underwent FPCT and 10 underwent dynamic CT Stress and rest CT c Cury [64] 36 Patients with positive SPECT results < 2 mo earlier Study Population and Presenting Condition or Imaging Findings CT Technique CT Dose (msv) Comparison a Results Dual-source CT Stress CT Rest CT Dual-source CT Stress CT (6 also Rest CT) Dual-source CT Stress CT Rest CT Dual-source CT Stress dual-energy CT Rest dual-energy CT 64-MDCT Dipyridamole stress CT Rest CT or CTA 10 2 Stress-rest SPECT Good correlation between CT myocardial assessment and SPECT on a per-vessel basis (Pearson r = 0.56 for stress and 0.66 for rest) and on a per-patient basis (Pearson r = 0.60 for stress and 0.76 for rest) 18 Stress-rest SPECT Good agreement between CT myocardial assessment and SPECT on a per-segment basis (k = 0.71). Magnitude of myocardial defect on CT similar to SPECT 6 9 Stress-rest MRI (36) CAG 15 Stress-rest MRI and stress-rest SPECT 12 3 Stress-rest SPECT CAG (26) Diagnostic accuracy (per segment) of stress CT compared with reversible perfusion defect on MRI: sensitivity, 89%; specificity, 72%; accuracy, 89% Diagnostic accuracy (per vessel) of stress CT compared with CAG findings: sensitivity, 89%; specificity, 76%; accuracy, 83% Diagnostic accuracy (per segment) of CT myocardial assessment compared with: MRI: sensitivity, 93%; specificity, 99%; PPV, 96%; NPV, 92% SPECT: sensitivity, 94%; specificity, 98%; PPV, 94%; NPV, 92% Good agreement between CT and SPECT (75%) for myocardial assessment Diagnostic accuracy (per vessel) for stenosis 70% on CAG: CT myocardial assessment: sensitivity, 88%; specificity, 79%; PPV, 67%; NPV, 93% SPECT: sensitivity, 69%; specificity, 76%; PPV, 67%; NPV, 78% Note CAD = coronary artery disease, CTA = CT angiography, CAG = coronary angiography, MPI = myocardial perfusion imaging, PPV = positive predictive value, NPV = negative predictive value. a Numbers in parentheses indicate number of patients. b Same scan data as used to reconstruct CTA images. c Unless otherwise indicated, stress was induced by adenosine. 540 AJR:198, March 2012

CT of Coronary Heart Disease TABLE 2: Overview of Patient Studies Comparing CT Infarct Imaging With MRI First Author [Reference No.] Nikolaou [87] Mahnken [88] Gerber [22] Boussel [54] Nieman [51] Study Popluation and Presenting Condition or Imaging Findings CT MRI Results 30 patients: 18 with known CAD and 12 with suspected CAD 28 patients with reperfused acute MI 37 patients: 16 with acute MI (reperfused in 9 patients) and 21 with chronic MI 19 patients with reperfused acute MI 21 patients with reperfused acute MI Choe [52] 80 CT studies of 63 patients: 40 of reperfused acute MI and 40 of reperfused chronic MI Jacquier [53] 19 patients with reperfused acute MI FPCT FPCT and DECT performed < 2 wk after MI FPCT and DECT performed mean of 11 d after MI in acute MI patients DECT; CT with no additional contrast material performed immediately after reperfusion (mean, 22 min later) FPCT in all patients and DECT in 15 patients < 5 d after MI FPCT and DECT performed < 3 wk after MI in acute MI patients DECT at 5 and 10 min < 3 15 d after reperfusion DEMRI performed mean of 10 d after CT DEMRI performed < 2 wk after MI FPMRI and DEMRI; performed mean of 1 d after CT DEMRI < 8 d after MI FPMRI and DEMRI < 5 d after MI FPMRI and DEMRI < 1 d of CT DEMRI at 5 and 10 min < 1 7 d of CT Detection of MI by CT compared with MRI on per-patient basis: sensitivity, 91%; specificity, 79%; accuracy, 83% Detection of ischemia by CT: sensitivity, 50% MI volume underestimated 19% by FPCT versus DEMRI Differentiation of ischemia from MI not possible by FPCT Good agreement between DECT (infarct size = 33%) and DEMRI (infarct size = 31%) MI size underestimated 25% by FPCT DE seen on CT in 34 of 37 patients PD seen on CT in more patients with acute MI (11/16) than in those with chronic MI (7/21) Concordance of DECT and DEMRI 92% for PD, 82% for DE; slightly better in acute MI cases than in chronic MI Concordance of DECT and DEMRI was excellent for infarct location per patient: k = 0.90 Good agreement for number of involved segments, infarct size, and transmural extent of enhancement with both techniques (r2 = 0.74, 0.67 and 0.76, respectively) No reflow found less by DECT than DEMRI (9 vs 16 patients, respectively) DE on MRI in all patients and on CT in 11 of 15; DE area similar (13% vs 15%, respectively) PD on CT and MRI in all patients; PD area on FPCT larger than FPMRI (11% vs 7%) CNR ratio better for MRI than CT Correlation coefficient for MI size was 0.81 for DECT and DEMRI and 0.62 for FPCT and FPMRI Mean MI volume larger on DEMRI than DECT (26% vs 23%, respectively) but similar on FPMRI and FPCT (11% vs 12%) Decrease in MI volume from acute to chronic stage DE on all scans DE area on CT and MRI closely related at 5 and 10 min (r = 0.80 0.85) Hypoattenuating area (no reflow) on DE imaging: better correlation for CT and MRI at 5 min than at 10 min For CT, SNR and image quality better at 5 min than at 10 min (Table 2 continues on next page) AJR:198, March 2012 541

Vliegenthart et al. TABLE 2: Overview of Patient Studies Comparing CT Infarct Imaging With MRI (continued) First Author [Reference No.] Habis [55] Study Popluation and Presenting Condition or Imaging Findings CT MRI Results 26 patients with acute MI; reperfused (less 3) A DECT; CT with no additional contrast material performed immediately after PCI (mean, 22 min later) DEMRI performed mean of 10 d after MI C CT of Myocardial Ischemia: Clinical Evidence The clinical evidence on CT of myocardial ischemia [25, 26, 31 33, 59 65] (Table 1) generally shows good agreement between findings on adenosine stress-rest CT and MRI as well as on SPECT. Studies based on dual-source CT [32, 33, 42, 62] showed sensitivity and specificity values for reversible perfusion defects on MRI ranging from 89% to 93% and from 72% to 99%, respectively. The sensitivity and specificity of SPECT for abnormalities were 94% and 98%, respectively [33]. Compared with CTA alone, the addition of perfusion CT was found to im- D prove the diagnostic accuracy of CT for the detection of stenosis on conventional coronary angiography [61], with increases in sensitivity from 83% to 91% and in specificity from 71% to 91%. However, the studies available to date include relatively small patient populations and are often limited by selection bias due to the specific recruitment of subjects with known positive SPECT results, which leads to overoptimistic assessments of test characteristics. Interestingly, in studies acquiring only rest perfusion CT images, the majority of perfusion defects on both rest and stress SPECT scans were detected [26, 31]. The fact that B Transmurality of MI by CT compared with MRI on a per-patient basis: sensitivity, 90%; specificity, 80%; PPV, 95%; NPV, 67%; accuracy, 88% MI size on CT and MRI highly correlated (r = 0.94) Note CAD = coronary artery disease, FP = first-pass, DE = delayed enhancement, MI = myocardial infarction, CNR = contrast-to-noise ratio, SNR = signal-to-noise ratio, PCI = percutaneous coronary intervention, PPV = positive predictive value, NPV = negative predictive value. Fig. 7 46-year-old woman with prior myocardial infarction in left anterior descending coronary artery territory. A D, Unenhanced (A and C) and contrast-enhanced (B and D) CT studies shown in long-axis (A and B) and short-axis (C and D) views show chronic myocardial infarction of septum and apex (arrows), with myocardial wall thinning, fatty replacement and calcification, as well as apical aneurysm formation. rest CT can identify reversible perfusion defects that are visible only on stress SPECT may be related to different factors. The spatial resolution of CT is superior to SPECT and may allow detection of smaller, especially subendocardial, areas of severe ischemia or infarction that are not noticed on rest SPECT. Furthermore, the iodine contrast medium injected for CT acquisitions is thought to have a vasodilatory effect that may cause a degree of hyperemia like the response to vasodilator drugs in myocardial perfusion imaging [80]. Last, the kinetics of iodinated contrast media may have a wider dynamic range [39] at increasing coronary perfusion rates on CT than on SPECT, with potential to detect more subtle reductions in myocardial perfusion in cases of significant stenoses. CT of Myocardial Viability: Clinical Evidence Early evaluation of myocardial damage after reperfused acute MI is important because patient prognosis is linearly correlated to the extent of residual MI [81]. For a long time, SPECT was considered the best available modality for determining infarct size, as measured by the number of residual cardiac segments with perfusion defects [82, 83]. However, SPECT has been shown to have suboptimal sensitivity for small infarcts and for nontransmural, subendocardial infarcts especially in comparison with cardiac MRI [75]. Accordingly, delayed enhancement MRI has more recently become the reference standard for viability imaging. MRI is unsurpassed in its ability to differentiate viable from nonviable myocardial tissue, whether in the acute, subacute, or chronic 542 AJR:198, March 2012

CT of Coronary Heart Disease A C E G Fig. 8 46-year-old man with history of myocardial infarction in right coronary artery territory. A H, First-pass rest perfusion CT images (A and B) and MR images (C and D) in short-axis (A and C) and longaxis (B and D) views show perfusion defect (arrows) in inferior wall. Delayed enhancement CT images (E and F) show inferior hyperenhancement, indicating myocardial infarction, which is in good agreement with findings shown on delayed enhancement MR images (G and H). B D F H phase of MI [84]. The transmural extent of delayed enhancement was found to be strongly related to the probability of improved contractility after revascularization: Segments showing delayed enhancement of more than 75% of the myocardial thickness were unlikely to benefit from revascularization [85]. Furthermore, MRI has excellent soft-tissue differentiation, which allows detection and evaluation of more expressions of myocardial injury than SPECT. Recent studies have shown that, apart from infarct dimensions on delayed enhancement MRI, interstitial edema, periinfarct penumbra, microvascular obstruction, and interstitial hemorrhage are important components of reperfusion damage that can be used to predict short- and long-term survival [86]. A number of studies [22, 51 55, 87, 88] of patients with MI have compared the accuracy of the detection of hyperenhancing areas on delayed CT with delayed enhancement MRI or the presence of perfusion defects on first-pass imaging with CT and MRI (Table 2). These studies have shown that CT can characterize acute and chronic MI with contrast patterns similar to first-pass perfusion and delayed enhancement MRI and that infarct size can be reasonably well quantified. Furthermore, the presence and size of both delayed enhancement and perfusion defects on CT were found to be predictive of myocardial dysfunction 3 months after acute MI [89] (Fig. 8). As we know from MRI studies, the area of delayed enhancement diminishes somewhat from the acute to the subacute phase of MI, probably because of resorption of periinfarct edema. In the acute phase, the core of the MI can become necrotic as a result of profound and sustained ischemia. Despite reopened coronary arteries, this core is not perfused probably because of severe obstruction of the microvasculature. This obstruction can be recognized as a central area of hypoattenuation within the hyperenhancing region (i.e., no reflow phenomenon). In fact, this hypoattenuating core as seen on CT may be the finding that is most predictive of a residual perfusion defect 6 weeks after successful reperfusion of acute MI [90]. The decrease in infarct size over time is a process that can also be observed with CT [91]. Furthermore, a recent study showed that periinfarct edema in large acute MIs can be assessed on unenhanced CT [92]. In animal studies, nonreperfused acute MIs showed persistent hypoattenuation on first-pass and delayed CT [93, 94]. In chronic MI, whether reperfused or not, necrotic myocardial cells are replaced by scar tissue with increased interstitial space, AJR:198, March 2012 543

Vliegenthart et al. again resulting in a larger distribution volume and delayed enhancement. Although the role of CT for viability imaging still needs to be defined, CT may have a future role for dedicated viability imaging in patients with contraindications to MRI, such as patients with pacemakers, defibrillators, or other metal implants. Also, because CT is more time-efficient than MRI and is available in an emergency setting, CT may be useful to evaluate myocardial viability immediately after percutaneous revascularization [54, 55] or as part of a comprehensive CT protocol for a complete evaluation of CHD. An additional application of CT namely, evaluation of left ventricular function and (inducible) wall motion abnormalities is beyond the scope of this review. However, the possibility that CT can show regional wall motion abnormalities as an aid for diagnosing MI has been well established [95]. CT of Myocardial Infarction, Ischemia, Viability: Future Outlook Advanced mechanical CT techniques for the assessment of myocardial infarction, ischemia, and viability only very recently left the stage of animal experiments and transitioned into actual human studies. As detailed earlier, the current evidence base for this approach largely consists of feasibility and initial accuracy studies, most of which are limited by select, small patient populations. Substantial future work will be required before this test can be considered a mature, robust method for routine clinical application. Even more time will pass before appropriate scenarios for its use can be determined on the basis of comparative efficacy and patient outcome studies. Except very preliminary analyses about the potential cost-effectiveness of CT-based approaches [96], such data are not available to date. The only study on this topic available to date suggests that dual-energy CT as a first-line imaging test for myocardial perfusion assessment in the workup of patients with CAD has the potential to provide gains in quality-adjusted life-years while lowering costs compared with routine myocardial perfusion SPECT. However, these findings need to be confirmed by larger future investigations. Decades of evidence support the high prognostic value of nuclear myocardial perfusion imaging, whereas data on the routine clinical use of coronary CTA have been accumulating only since the introduction of 64-MDCT in 2004, albeit at a very rapid pace. Although promising, CT of the myocardial state of perfusion currently is at the very beginning of this curve. The usefulness of comprehensive CAD imaging with CT, as with other imaging tests, will likely be highly dependent on the pretest probability of CAD. For combined testing of both coronary artery stenosis and the hemodynamic effects on myocardial perfusion of stenotic lesions to be efficient, the risk of significant CAD must be at least intermediate or high. In patients with lower suspicion of CAD, coronary CTA with the aim to rule out significant stenoses may be a more appropriate imaging test. In conclusion, rapid advances in technology enhance the attractiveness of CT as a single noninvasive imaging modality for obtaining conclusive information about all aspects of CHD, built around the noninvasive assessment of the coronary arteries for atherosclerosis and stenosis. Future studies are needed to refine and validate the CT assessment of infarction, ischemia, and viability to determine suitable patient populations in whom these CT applications can contribute to diagnostic efficiency and improved outcomes. References 1. Kern MJ, Samady H. Current concepts of integrated coronary physiology in the catheterization laboratory. J Am Coll Cardiol 2010; 55:173 185 2. Klocke FJ, Baird MG, Lorell BH, et al.; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American Society for Nuclear Cardiology. ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imaging: executive summary a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging). Circulation 2003; 108:1404 1418 3. Schwitter J, Wacker CM, van Rossum AC, et al. MR-IMPACT: comparison of perfusion-cardiac magnetic resonance with single-photon emission computed tomography for the detection of coronary artery disease in a multicenter, multivendor, randomized trial. Eur Heart J 2008; 29:480 489 4. Chung SY, Lee KY, Chun EJ, et al. Comparison of stress perfusion MRI and SPECT for detection of myocardial ischemia in patients with angiographically proven three-vessel coronary artery disease. AJR 2010; 195:356 362 5. Gaemperli O, Schepis T, Valenta I, et al. Cardiac image fusion from stand-alone SPECT and CT: clinical experience. J Nucl Med 2007; 48:696 703 6. Santana CA, Garcia EV, Faber TL, et al. Diagnostic performance of fusion of myocardial perfusion imaging (MPI) and computed tomography coronary angiography. J Nucl Cardiol 2009; 16:201 211 7. Pazhenkottil AP, Nkoulou RN, Ghadri JR, et al. Prognostic value of cardiac hybrid imaging integrating single-photon emission computed tomography with coronary computed tomography angiography. Eur Heart J 2011; 32:1465 1471 8. Rispler S, Keidar Z, Ghersin E, et al. Integrated single-photon emission computed tomography and computed tomography coronary angiography for the assessment of hemodynamically significant coronary artery lesions. J Am Coll Cardiol 2007; 49:1059 1067 9. Namdar M, Hany TF, Koepfli P, et al. Integrated PET/CT for the assessment of coronary artery disease: a feasibility study. J Nucl Med 2005; 46:930 935 10. Di Carli MF, Dorbala S, Curillova Z, et al. Relationship between CT coronary angiography and stress perfusion imaging in patients with suspected ischemic heart disease assessed by integrated PET- CT imaging. J Nucl Cardiol 2007; 14:799 809 11. Miller JM, Rochitte CE, Dewey M, et al. Diagnostic performance of coronary angiography by 64-row CT. N Engl J Med 2008; 359:2324 2336 12. Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol 2008; 52:1724 1732 13. Vanhoenacker PK, Heijenbrok-Kal MH, Van Heste R, et al. Diagnostic performance of multidetector CT angiography for assessment of coronary artery disease: meta-analysis. Radiology 2007; 244:419 428 14. Hendel RC, Patel MR, Kramer CM, et al.; American College of Cardiology Foundation Quality Strategic Directions Committee Appropriateness Criteria Working Group; American College of Radiology; Society of Cardiovascular Computed Tomography; Society for Cardiovascular Magnetic Resonance; American Society of Nuclear Cardiology; North American Society for Cardiac Imaging; Society for Cardiovascular Angiography and Interventions; Society of Interventional Radiology. ACCF/ACR/ SCCT/SCMR/ASNC/NASCI/SCAI/SIR 2006 appropriateness criteria for cardiac computed tomography and cardiac magnetic resonance imaging: a report of the American College of Cardiology Foundation Quality Strategic Directions Committee Appropriateness Criteria Working Group, American College of Radiology, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, American Society of Nuclear Cardiology, North American Society for Cardiac Imaging, Society for Cardiovascular Angiography and 544 AJR:198, March 2012