Multidetector CT coronary angiography: Where we are, and where we are going ...

Introduction

Coronary artery imaging has undergone major advances in recent years, the most significant being the advent of multidetector CT angiography (MDCTA). CT scanners with multiple detector rows, increased temporal and spatial resolution, and with powerful reconstruction and analysis software have enabled noninvasive coronary artery imaging to a degree never before possible. MDCTA not only allows accurate visualization and semiquantitation of coronary artery lumen stenoses [[1]], but it also provides important information about nonobstructive atherosclerotic plaque in the coronary artery wall [[2]]. While current 64-detector CT technology lacks sufficient spatial and temporal resolution to replace conventional diagnostic coronary angiography, it is nevertheless emerging as a valuable clinical adjunct [[3]]. This discussion first reviews the technical aspects of performing MDCTA and then focuses on patient selection, information currently available from MDCTA imaging, how this information is used clinically, and what the future may hold for MDCTA.

Patient preparation procedures and imaging technique

Premedication

Patients are given oral metoprolol (50 or 100 mg) 1 hr before the scan if the heart rate is 60-64 or >64, respectively. Intravenous metoprolol from 5 to a total of 40 mg can be administered at the time of the scan if the heart rate rises above 60 bpm. Just prior to the scan sublingual nitroglycerin, 0.4 mg is also administered to maximize coronary artery dilation during imaging.

If the heart rate cannot be decreased to an appropriate range, the scan quality can be compromised [[4]]. Also, if absolute contraindications to beta blockade exist (active wheezing, decompensated heart failure) and the heart rate requires lowering, scans may be cancelled on a case-by-case basis.

Scan Techniques

The technical settings and parameters of the CT scanner will vary depending on scanner type, but typically a bolus of 80-100 ml of contrast is injected into an 18 gauge IV (or 20 gauge if an 18 gauge is not possible) for a scan range that includes the native coronary arteries. To accommodate the larger scan field in patients with bypass grafts, 100-120 ml of contrast is typically used. The injection rate is 4.5-5 ml/sec using an isotonic contrast medium with an iodine content of at least 320. The contrast attenuation or brightness is the result of the product of the iodine content times the injection rate (iodine flux). A dual-head injector allows a 40-60 ml saline 'chaser' flush to follow the contrast injection. This limits streak artifacts from the otherwise more concentrated contrast in the right heart. Scanning is initiated based on either a timing bolus (15-20 ml of contrast) or an automated bolus tracking system in the ascending or descending aorta, which detects a threshold of 100-150 Hounsfield units (HU). A breath hold of 8-16 sec is required for native coronary arteries and 12-20 sec for patients with bypass grafts, depending on the scan field covered by the detectors with each gantry rotation. Longer breath holds are required for scanners with fewer detectors.

Image Reconstruction

Images may be reconstructed in overlapping increments to limit the effect of "stair-stepping" artifact (Fig. 1). An appropriate filter or kernel is chosen to reconstruct scan data depending on patient size and extent of X-ray dense objects in the field. Patients with stents, heavy calcification, or surgical clips may benefit from a noisier, but sharper kernel. Those with already poor "signal to noise" from obesity are better served from a softer, "less noisy" kernel. Figure 2 is an example of kernel selection. Retrospective EKG gating is applied first to three standard reconstructions with two diastolic (65 and 70%), and one systolic (30%) R-R interval. The coronary artery or segment of interest in the axial plane is reconstructed and viewed every 5 msec throughout the cardiac cycle. Then, a new reconstruction is performed at the interval that best stops coronary motion. If ectopy is present, the EKG should be reviewed and individual premature beats edited and/or R-R intervals manipulated. For heart rates >70 bpm, a multisegmented reconstruction algorithm can be applied to reduce the temporal resolution to a minimum of 105 msec. This algorithm uses data from two consecutive cardiac cycles to reconstruct one-half gantry rotation, thereby improving the temporal resolution. However, this often produces suboptimal results because of variable, or accelerating heart rates. This algorithm can be turned "on or off" after the data has been acquired and should only be used if the resultant images are superior.

Figure 1. "Stairstep" artifacts (white arrows) are seen representing the misregistration of axially acquired 64-slice band into the sagittal orientation. This typically occurs when the heart does not return to the exact spatial location on consecutive beats.

Figure 2.

(a) Reconstruction of a LAD stent with a "soft" B25f kernel. Note the blurring of not only the stent itself but also detail within the stent.

(b) Reconstruction of the same stent using a "sharp" B46f kernel and a wider window width. Note the improved in-stent luminal death.

Methods of scanning and image analysis

Image Evaluation

MDCTA data sets can be displayed in various formats, each format providing valuable information for scan interpretation. Multiplanar reconstruction (MPR) provides the thinnest reconstructed slices acquired from the scanner. Each rotation of the CT gantry creates axial data, which then is stacked into a volume. These stacks of data are registered or aligned. The isotropic voxels (equal x, y, and z sizes for a truly cubic voxel) allow reconstruction of data in multiple oblique orientations and can be viewed using MPR. Misregistration may occur and can be a source of pseudo-lesions from discontinuity of contrast when viewed across misregistered slices. As a result, image evaluation is done by comparing the axial with coronal and sagittal MPR images to check for slice misregistration. The thinnest two-dimensional (2D) MPR images provide the best spatial resolution for visualization of fine details in the coronary wall and lumen. However, the smallest voxels (0.6 mm) also have the most compromised signal to noise ratio. One can use thicker slices (5 mm or more) with axial and oblique 2D maximum intensity projection (MIP) slices for an improved signal to noise ratio and to more rapidly scroll through large datasets (Fig. 3). However, thicker slices may also obscure subtle and sometimes discrete coronary lesions. If a coronary lesion is suspected, review with a thin slice MPR or MIP should follow.

Figure 3.

(a) Orthogonal long and a short axis view of a severe proximal LAD lesion (white arrow). This is seen using a multiplanar reconstruction with a 0.6 mm slice thickness.

(b) The LAD is seen with a 5-mm maximum intensity projection. The volume of data is quickly reviewed, but the spatial resolution is lower.

Assuming adequate slice registration, analysis of the coronary lumen and wall along the z axis is improved with appropriate software that automatically acquires a center-line within each major vessel. These images are displayed in a curved MPR (Fig. 4) or in orthogonal long-axis views. The latter improves the ability to evaluate the noncalcified arterial wall adjacent to areas of calcification (Fig. 5).

Figure 4. Curved multiplanar reformat (MPR) image of a LIMA-LAD graft and distal LAD. In this curved MPR format, the plane of view is composed of multiple spatial planes, allowing a complex path such as that of the LIMA-LAD to appear in a single plane.

Figure 5. Orthogonal long axis views of a proximal LAD vessel showing calcified and noncalcified (arrow) wall in an arterial segment.

The volume rendered technique (VRT) displays cardiac anatomy in three dimensions and allows visualization of the coronary artery tree in relation to the adjacent cardiac structures (Fig. 6). The VRT display is developed by segmenting the image using HU values and creates artificially large structures when bright objects such as calcium, stents, or metallic clips are analyzed due to X-ray 'blooming' artifact. This may obscure adjacent coronary lesions and, as a result, the VRT provides a general overview of coronary and graft anatomy, but other analysis tools are required for final interpretation. Overall, many patients require all the available techniques for accurate and rapid scan interpretation.

Figure 6. Volume rendered technique showing three coronary bypass grafts and insertion into the native LAD, LCx, and OM.

Calcium Score

A calcium score is typically obtained with an unenhanced CT technique using a 3-mm collimator and prospective EKG gating with tube current modulation in systole. The calcium score is calculated using the Agatston method modified for MDCT. MDCT calcium scores correlate highly with those obtained by electron beam CT [[5]].

Coronary calcium is useful as a marker of coronary artery disease (CAD) and is a valuable predictor of CAD events independent of standard risk factors [[6-11]]. It may also be helpful in further stratifying patients at intermediate Framingham risk into either a low or high risk group [[12]]. Patients with a Framingham risk of 10-15% and a calcium score above 300 had a 19.5% incidence of myocardial infarction or coronary death over a median of 7 years, whereas patients with the same Framingham risk and a lower calcium score had an incidence of only 4.2% over the same time period [[12]]. Coronary artery calcium scoring is less useful in patients who are at very low or very high risk for coronary events [[12-14]]. Therefore, in patients who are known to have significant CAD, and thus at high risk for clinical events, coronary artery calcium score is not necessarily performed prior to contrast-enhanced MDCTA.

Patient selection

MDCTA is a powerful tool, but as with other novel tests it must be applied to the appropriate clinical question and patient subset. Heart rate remains an important issue and, therefore, reduction of heart rates with beta blocker premedication improves the image quality of MDCT coronary angiography [[15]]. Most centers utilize a beta-blocker protocol to safely attain reduced heart rates. The R-R interval should be constant for proper image reconstruction, and thus it is vital that patients undergoing coronary artery evaluation be in sinus rhythm or paced regularly. Large anatomic structures such as the atria or large vessels can be imaged in patients with atrial fibrillation, though it is best to perform a nongated scan to avoid marked slice misregistration in this situation. With a 64-detector scanner, a patient may need a breath hold of up to 16 sec. Breath holding is a critical part of a scan. Poor breath holding results in a compromised scan that cannot be easily improved with data postprocessing. Renal function and contrast allergies should be known prior to a study to avoid potential complications. A noncontrast scan, to quantitate coronary calcium, can be performed prior to the contrast-enhanced CT scan. Very high coronary calcium scores typically limit the ability to interrogate all coronary segments because of partial volume effects causing a 'blooming' artifact of the coronary calcium. Contrast-enhanced MDCTA may be cancelled in the setting of a very high calcium burden, as these patients may be exposed to unnecessary radiation and contrast, given the increased likelihood of an uninterpretable scan.

Risks of ct angiography

MDCTA is a noninvasive examination and, therefore, patients are not subject to the risk of arterial vascular complications as they are with invasive angiography. The intravenous contrast dose is usually 80-100 ml, which is only slightly more than a typical invasive coronary angiogram. Despite the relatively small volume of intravenous contrast given, a theoretical risk remains for both contrast-induced nephropathy and contrast-mediated anaphylactic reactions. However, in a cohort of more than 1,000 patients with normal renal function (creatinine <= 1.4) and using isosmolar contrast, serious adverse renal effects were rare. Furthermore, the risk of severe and fatal anaphylactic reactions due to intravenous contrast is reported to be only 0.04% [[16]]. Pretreatment with antihistamines and corticosteroids for patients with a "contrast reaction" history is thus recommended and effective.

The effective radiation dose with 64-detector CTA was estimated to be between 6.4 and 21.4 millsieverts (mSv) per study for various scan protocols [[17][18]]. This dose may be comparable, or slightly higher than those seen with invasive diagnostic coronary angiography in which the dose is between 2.1 and 7 mSv [[18]]. For comparison, the effective radiation dose for a technetium Tc99m sestamibi myocardial perfusion stress test is estimated at 9 mSv [[19][20]]. The effective radiation dose of MDCTA can be reduced using ECG-dependent dose modulation and reduced tube voltage. Dose modulation protocols allow for reduced tube current during the systolic phase of the cardiac cycle, since systolic intervals are less commonly utilized for image interpretation due to increased cardiac motion. Hausleiter et al. showed a 53-64% reduction in estimated radiation dose using these modalities, leading to an estimated effective dose of 11.0 ± 4.1 mSv for a 64-detector CTA [[17]]. The lifetime risk of dying from cancer due to the dose of radiation absorbed during a 64-detector CT scan is estimated to be less than 0.1%, nevertheless, radiation exposure should be taken into consideration when subjecting a patient to a MDCTA [[21]].

The risk of administering pre-scan beta-blockers is minimal. Of 654 patients who received beta-blockers per protocol at our institution, two patients had significant bradycardia (<= 40 bpm), and only one of these patients was symptomatic.

Detection of obstructive CAD

Since its clinical debut several years ago, the application of MDCTA has focused primarily on the detection of coronary artery luminal stenosis. This resulted from the fact that CAD detection with invasive coronary angiography is limited by its ability to visualize only the lumen, and not vessel wall or plaque. Most populations reported in MDCTA studies include only patients already selected for coronary angiography, and therefore have a very high pretest probability of obstructive CAD. A multicenter study by Garcia et al. with 16-detector MDCTA showed a sensitivity of 89% in a segment-based analysis, but a specificity of only 65% with 29% of segments being unevaluable [[22]]. Recent reports utilizing 64-detector technology have shown segment-based analyses with sensitivities of 73-99% and specificities of 86-97% [[18][23-27]] (Table I). It remains unclear how MDCTA will perform in low-intermediate risk patients, which is the population that MDCTA will likely be most utilized clinically. Lesser and coworkers used 16-detector MDCTA in a clinical population of 994 consecutive patients. Most patients had atypical symptoms, equivocal stress test results, or had multiple risk factors. One hundred and sixty of these patients were referred for coronary angiography based on their MDCTA result. The accuracy of MDCTA in this setting was 87% by patient-based analysis and 89% by vessel-based analysis. Referral and verification bias were present, but of the remaining patients who were not referred for invasive coronary angiography, 6-month clinical follow-up revealed an event rate of 0.2% [[28]]. These results suggest that in addition to accurately defining coronary artery stenoses, MDCTA may also be a useful tool for risk stratification in a population at low to intermediate risk for events.

Table I. MDCTA Performance in Coronary Artery Disease

Detection of nonobstructive CAD

Although digital cardiac fluoroscopy provides excellent resolution (0.3 mm), visualization is limited to that of the coronary artery lumen. It is only with advanced CAD that the coronary plaque begins creating luminal obstruction, and thus is detectable by invasive coronary angiography. Plaques that are 'vulnerable' to rupture may not always be those which are severely stenotic [[29]]. MDCTA allows visualization of the coronary artery wall in addition to the lumen as illustrated in a study by Caussin et al. [[30]]. Patients who were seen with an acute coronary syndrome (ACS) and normal coronary angiogram were studied with MDCTA and were found to have a significant amount of nonobstructive CAD [[30]]. Glagov et al. described the progression of early CAD as outward plaque growth, or positive remodeling with minimal narrowing of the lumen [[31]]. MDCTA permits assessing coronary artery remodeling, making detection of the earliest form of CAD possible [[2][32]]. MDCTA has also shown good correlation with intravascular ultrasound in measuring plaque area and volume [[1][23]]. Thus, MDCTA may be a means of detecting patients with early CAD, as well as those with CAD, and only minimal luminal obstruction who may be at risk for coronary artery plaque rupture.

Coronary plaque characterization

Electron beam CT localizes and quantifies calcified plaque, however, MDCTA enables both calcified and noncalcified plaque visualization [[2][33]]. Software is currently in development for quantification of noncalcified plaque; however, current technology allows assessment of plaque density using HU, a measure of tissue density relative to water. When compared with intravascular ultrasound, MDCTA is able to categorize plaque as lipid-rich, fibrous, or calcified based on density measurements [[1][34-36]]. Coronary plaque burden is estimated by quantitation of coronary calcium, however, when reviewing 124 symptomatic patients undergoing MDCTA who had no coronary calcium present, 56% had noncalcified coronary plaque, with significant obstruction in 5% (unpublished data). A small autopsy study by Schroeder et al. also showed good correlation with coronary artery histology. In this study, coronary plaques were characterized postmortem by a modified Stary's classification. Lipid-rich plaques had a mean density of 42 ± 22 HU, with intermediate and calcified plaques having a mean density of 70 ± 21 HU and 715 ± 328 HU, respectively [[33]].

The majority of ACSs are caused by rupture or erosion of moderately stenotic, lipid-rich plaques with thin, fibrous caps [[37-39]]. MDCTA, by allowing evaluation of plaque morphology, may provide a method in which these plaques are preemptively identified. Identification of plaques which have already undergone disruption has also been described. A retrospective analysis in our experience of 176 ambulatory patients who underwent MDCTA found 39 patients with high density lesions (>130 HU) within the extraluminal space. In those patients (30 of 39) who had a noncontrast MDCTA scan available to exclude calcium deposition, seven patients were determined to have contrast infiltration of a coronary plaque, and thus coronary artery plaque rupture (Fig. 7) [[40]]. Caussin et al. made similar observations when comparing MDCTA with IVUS, detecting plaque disruption in 9 of 21 patients seen with ACS [[34]]. It has become clear that MDCTA will likely be a tool for characterizing coronary artery plaque, and with further study, the potential for screening patients to detect those vulnerable to coronary plaque rupture may be substantial.

Figure 7. Volume rendered technique showing three coronary bypass grafts and insertion into the native LAD, LCx, and OM.

Current role in clinical cardiology

MDCTA has shown improvements in spatial and temporal resolution with the introduction of 64-detector MDCTA technology. Despite these advances, invasive angiography continues to have superior spatial and temporal resolution, and as a result, MDCTA is not yet ready to replace conventional diagnostic angiography in the clinical setting. This is reflected by the marginal sensitivity and positive predictive value in categorizing the degree of stenosis in a coronary artery segment-based analysis [[23]]. However, 64-detector MDCTA has excellent sensitivity and negative predictive value in most patient-based analyses [[18][24]], which is clinically important when evaluating patients for CAD. In current practice, low and intermediate risk symptomatic patients typically undergo cardiac stress testing. Two of the most frequently used modalities are stress echocardiography and SPECT, both of which rely on coronary artery flow abnormalities to detect stenotic lesions. These tests have adequate sensitivity and specificity for diagnosing hemodynamically significant CAD by flow limitation, but are unable to diagnose nonobstructive CAD, which may also be clinically important. One of the most common indications for MDCTA is an "indeterminate" or "equivocal" cardiac stress test result. Lesser et al. studied a population of 492 patients with "unclear" stress test results, and MDCTA had a high sensitivity (98%) in effectively triaging these patients for coronary angiography. This also led to a total estimated cost that was roughly 1/3 of that had such patients been sent directly for coronary angiography [[41]]. Based on these data, MDCTA has a role as an adjunctive diagnostic test in patients at low to intermediate risk of CAD and an "indeterminate" cardiac stress test result. An MDCTA which shows no significant stenosis (>50%) predicts an excellent short-term prognosis in this population (event rate of 0.2% at 6 months) [[40]]. MDCTA has also been studied in patients who have undergone coronary artery stenting, but due to the "blooming artifact" and partial volume effects of the stent struts, the sensitivity for detecting in-stent restenosis remains suboptimal [[42][43]]. Conversely, bypass grafts are well-visualized due to their larger diameter and relative lack of motion. Studies show MDCTA to be accurate in evaluating bypass grafts [[44]], although surgical clip artifact is a potential pitfall leading to some unevaluable graft segments [[45]].

MDCTA is also helpful in identifying anomalous coronary arteries [[46]]. Coronary artery anomalies are seen in 1% of all autopsies and ˜ 0.5% of patients undergoing coronary arteriography [[47]]. Most coronary artery anomalies are benign and remain clinically silent, allowing a patient to have a normal lifespan. However, if the anomalous coronary artery course is between the aorta and pulmonary artery, or travels intramyocardially, the individual may be at risk for sudden death, myocardial ischemia, or congestive heart failure (Fig. 8). Typically, the evaluation of a young patient with syncope will not include coronary angiography, as the likelihood of obstructive CAD is low, however, 13% of young athletes who experience sudden death have anomalous coronary arteries [[48]]. MDCTA not only shows the origin of the coronary artery, but it also delineates the course of the coronary artery in three dimensions as it relates to the great vessels and other cardiac structures.

Figure 8. Curved maximum intensity projection showing a common ostium for the RCA and LMCA originating from the left coronary cusp. The RCA course bifurcates the aorta and pulmonary artery resulting in an oblique takeoff, as well as vulnerability to compression.

Future role in clinical cardiology

As the temporal and spatial resolution of MDCTA continues to improve, the utility of this technology will broaden. Further advances in MDCTA technology will allow more accurate luminal stenosis quantitation and may provide a noninvasive alternative to diagnostic coronary angiography. In addition to accurately classifying luminal obstruction, characterization of nonobstructive coronary plaque as either "stable" or "vulnerable to rupture" may also be possible with this technology. This would likely allow therapeutic targeting based on the plaque character. Further studies will need to be done to show whether prophylactic stenting, aggressive statin therapy, or another novel medical therapy will be most beneficial in the primary treatment of vulnerable coronary artery plaque. MDCTA may also play a role in identifying asymptomatic patients with very early CAD who could benefit from aggressive preventive measures. Given the high negative predictive value with the current MDCTA technology, a rapid ACS "rule-out" protocol utilized in the emergency department may help reduce healthcare costs related to chest pain evaluation. Annual evaluation and follow-up of post heart transplant vasculopathy is another research area in which several groups have proposed that MDCTA may provide a lower risk alternative to invasive coronary angiography [[49][50]]. The high negative predictive value and MDCTA capability to assess the coronary artery wall and lumen, both which tend to be affected by transplant vasculopathy, have lent support to such a proposal. Protocols that rule-out coronary obstruction, pulmonary embolism and aortic dissection in a single scan, (so-called "triple rule-out") are underway. MDCTA can provide detailed assessment of the pulmonary and coronary venous anatomy that may also be extremely valuable in planning electrophysiologic procedures [[51]].

In addition to coronary vasculature imaging, CT also has the potential to evaluate myocardial perfusion and viability by integrating SPECT or PET techniques. The combination of a perfusion study with coronary artery imaging (particularly, if both acquired in a single scan) would likely be a valuable mode for the evaluation of CAD by providing both anatomic and physiologic data in one study. MDCTA has shown good correlation with cardiac pathology in animal models and with cardiac MRI for detecting infarct size [[52][53]]. MDCTA also has the potential to augment or replace several other functions currently served by cardiac MRI. MDCTA slice thickness provides very good assessment of LV anatomy, including wall thickness and mass, atrial anatomy, and ventricular function, that is rivaling cardiac MRI [[54]]. With MDCTA, both coronary artery anatomy and left ventricular ejection fraction can be obtained with data from a single breath hold [[55]]. The speed and inexpensive nature of MDCTA when compared with cardiac MRI is attractive, although the lack of ionizing radiation with MRI remains an important advantage to this technology over MDCTA.

Imaging other cardiac structures by MDCTA is the focus of several research groups. In a small study of 20 patients, MDCTA had a sensitivity of 100% and specificity of 86% in detecting left atrial appendage thrombus compared with transesophageal echocardiography [[56]]. Other studies show value for MDCTA to monitor left atrial size and remodeling in chronic atrial fibrillation and its response after the MAZE procedure [[56][57]]. Detection, quantitation, and follow-up of valvular lesions, including aortic stenosis and mitral valve disease, are the other promising areas of MDCTA research [[58][59]]. In a study of 50 patients, a correlation of 0.92 was reported between planimetry of aortic stenosis by 64-slice MDCTA and continuity equation transthoracic echocardiography [[60]].

Targeted and molecular imaging techniques are emerging for MDCTA. Winter et al. reported the development of fibrin-targeted nanoparticles to visualize human plasma clots via anti-fibrin monoclonal antibodies. This holds promise for early detection, localization, and characterization of unstable plaque with developing thrombus [[61]]. Other groups are investigating the use of MDCTA to monitor delivery and response to injection of labeled gene and cell therapy in ischemic cardiomyopathy and heart failure. Tadros et al. reported preliminary results of using iodinated contrast agents to serve as a vehicle of delivery of gene and cell therapy. Using ex vivo swine hearts, iodixanol was injected using various injectate volumes, pressures, and different needle designs. MDCTA was used to quantitate the retention and tissue diffusion of the contrast as indicators for successful delivery [[62][63]]. Future protocols using MDCTA as a clinically applicable tool to document delivery success, retention monitoring, and to serve as a surrogate measure for comparison of different delivery approaches, needles, and techniques are currently under development.

Summary

MDCTA technology is revolutionizing cardiac imaging with increasingly detailed assessment of coronary artery stenoses that will soon rival invasive coronary angiography. MDCTA also allows for plaque characterization, a technique that may lead to early detection of vulnerable coronary artery plaques. In addition, MDCTA may also provide information about myocardial viability, infarct size, wall motion, wall thickness, and even valve function. Although it is potentially limited by the ionizing radiation dose and intravenous contrast administration, MDCTA is a relatively inexpensive tool which can provide a broad range of valuable clinical information.

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