Coronary Artery Calcification
The presence of coronary artery calcification (CAC) is clearly indicative of coronary atherosclerosis,14,15 serving as a marker for CAD; but importantly, the severity of angiographic coronary artery stenosis is not directly related to the total CAC. CAC is thought to begin early in life, but it progresses more rapidly in older individuals who have further advanced atherosclerotic lesions.16 Calcification is an active, organized, and regulated process occurring during atherosclerotic plaque development, where calcium phosphate in the form of hydroxyapatite precipitates in atherosclerotic coronary arteries in a fashion similar to that observed in bone mineralization.17,18 Although lack of calcification does not categorically exclude the presence of atherosclerotic plaque, calcification occurs exclusively in atherosclerotic arteries and is not found in normal coronary arteries.
The presence and extent of histologically determined plaque area has been compared with the total calcium area in individual coronary arteries derived from autopsied hearts.14 A strong linear correlation exists between total coronary artery plaque area and the extent of CAC as found in individual hearts (r = 0.93, P < .001) and in individual coronary arteries (r = 0.90, P < .001).
Detection of Coronary Artery Calcification
MDCT imaging protocols vary among different camera systems and manufacturers. Generally, 40 consecutive images, 2.5- to 3-mm thick, are acquired per cardiac study. Calcified lesions are defined as two or three adjacent pixels with a tomographic density of either greater than 90 or greater than 130 HU. Effective pixel size for a reconstruction matrix of 512 × 512 pixels with a common field of view of 26 cm is 0.26 mm2. Calcium scoring is usually based on the traditional Agatston method (ie, initial density of > 130 HU). As with electron beam computed tomography (EBCT) scoring, the total coronary artery calcium score (CACS) is calculated as the sum of each calcified plaque over all the tomographic slices.
Noninvasive techniques, such as exercise treadmill testing and myocardial perfusion imaging (MPI), aim to identify patients with abnormal coronary flow reserve either secondary to abnormal microvasculature or advanced epicardial CAD. However, unlike CT, which can detect coronary atherosclerosis at its earliest stages, these techniques can identify only patients with advanced CAD who manifest myocardial ischemia. Although the presence and extent of ischemia can accurately identify asymptomatic individuals at high risk for cardiac events, the very low prevalence of a positive test result (< 5%) precludes the use of these methodologies as primary screening tests for the early detection and treatment of CAD (Fig. 17–5).19,20
Kaplan-Meier survival curves based on exercise electrocardiogram (ECG) and thallium 201 (Tl) scan results. The highest event rate (17%) is observed in patients with ischemia (+) by both tests. The percentages of patients with each test combination are shown above the curves. CABG, coronary artery bypass grafting; MI, myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty. Reproduced from Blumenthal RS, Becker DM, Moy TF, et al. Exercise thallium tomography predicts future clinically manifest coronary heart disease in a high-risk asymptomatic population. Circulation. 1996 Mar 1;93(5):915-923.19
Several studies emphasize the effectiveness of selectively combining stress MPI with CT in the anticipated small (10%) number of asymptomatic patients who will have a high (≥ 400) CACS so as to specifically identify those with silent myocardial ischemia.20,21 This testing strategy may prove to be optimal based on the known prognostic value of perfusion imaging and the superior sensitivity of CT over the former for detecting preclinical CAD.
Coronary Artery Calcification: Prognostic Implications
Traditional risk factor assessment is routinely used to identify individuals who are at increased risk for developing cardiovascular disease based on standard clinical criteria.22 Given that the development of symptomatic cardiovascular disease occurs almost exclusively in patients with atherosclerosis, it seems advantageous, for the purposes of risk assessment, to use a technique that directly characterizes the presence and severity of atherosclerotic burden, rather than estimating its presence through indirect measures. For example, although there is a clear relationship between the number of cardiac risk factors and the presence and extent of CAC, 40% of men and 30% of women without risk factors in one series had CAC, whereas 26% of men and 36% of women with more than three traditional risk factors did not have any CAC.23 Importantly, this study and others have confirmed that CAC allows for much more accurate risk stratification than do other risk factors.
The likelihood of plaque rupture and the development of acute cardiovascular events is related to the total atherosclerotic plaque burden.24,25 There is a direct relationship between the CAC severity, the extent of atherosclerotic plaque, and the presence of silent myocardial ischemia. Many studies have now demonstrated an increased risk of cardiac events in asymptomatic patients who have extensive atherosclerosis and silent ischemia,19,26,27 Therefore, the CACS could be useful for risk assessment of asymptomatic individuals and potentially guide therapeutics.
Several studies in both symptomatic28,29 and asymptomatic30,31,32,33,34 patients have studied whether the extent of CAC can predict subsequent patient outcomes. In 422 symptomatic patients followed for 30 ± 12 months,28 cardiac events were 10-fold higher in patients with a CACS above the 75th percentile for age (9.5%) versus patients with a CACS below the 25th percentile (0.9%). These results were also adjusted for age, gender, and race. Another study of 288 symptomatic patients referred for coronary angiography29 showed that patients with a CACS of more than 100 had a 3.2-fold higher relative risk of death or MI than those with a lower CACS.
Large trials have reported an approximately 10-fold increased risk with the presence of CAC.34,35 In one of the largest observational trials to date, Shaw and colleagues36 reported all-cause mortality in 10,377 asymptomatic patients (4191 women and 6186 men) who had a baseline CAC and were then followed for 5.0 ± 3.5 years. Most patients had cardiac risk factors including a family history of CAD (69%), hyperlipidemia (62%), hypertension (44%), and current cigarette smoking (40%). The CACS was a strong independent predictor of mortality, with 43% additional predictive value contained within the CACS beyond risk factors alone. Mortality significantly increased with increasing CACS.
Similarly, in a younger cohort of asymptomatic persons, the 3-year mean follow-up in 2000 participants (mean age, 43 years) showed that coronary calcium was associated with an 11.8-fold increased risk of incident coronary heart disease (P < .002) in a Cox model controlling for the Framingham risk score.37 The Rotterdam Heart Study38 investigated 1795 asymptomatic participants (mean age, 71 years) who had CAC and measured risk factors. During a mean follow-up of 3.3 years, the multivariate-adjusted relative risk of coronary events was 3.1 for calcium scores of 101 to 400, 4.6 for calcium scores of 401 to 1000, and 8.3 for calcium scores greater than 1000, compared with calcium scores of 0 to 100.
Multiple studies have demonstrated that the relationship between CAC and outcomes is similar in men and women and across different ethnic groups.39,40,41,42,43 Each of these studies demonstrated that the area under the curve to predict coronary artery events is significantly higher with CAC than either Framingham or Prospective Cardiovascular Munster (PROCAM) risk stratification. Studies comparing predictive capacity of conventional and newer biomarkers for prediction of cardiovascular events consistently demonstrate that adding a number of newer biomarkers (such as C-reactive protein, interleukins, and other proposed risk stratifiers) only changes the C statistic by 0.009 (P = .08).39,40,44 Small changes such as these in the C statistic suggest limited or modest improvement in risk discrimination. However, CAC scanning has been shown to markedly improve the C statistic, suggesting robust improvement in risk discrimination.
In another study, 9715 individuals underwent CAC imaging and were followed for a mean of 14.6 years. A warranty period was defined as less than a 1% death rate. It was demonstrated that the warranty period in patients with CACS of 0 and low and intermediate risk was almost 15 years, with no significant differences regarding age and sex. A CACS of 0 was associated with a vascular age of 1, 10, 20, and 30 years less than the chronological age of individuals between 50 and 59, 60 and 69, 70 and 79, and 80 years of age and older, respectively. CAC was the strongest predictor of death when compared to both Framingham Risk Score and National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III).45
Overall, CAC score appears to provide complementary prognostic information to that obtained by the Framingham risk model or other risk assessment methods. Furthermore, multiple studies consistently demonstrate that CAC scanning confers more precise risk prediction than other alternatives such as C-reactive protein or carotid intimal-medial thickness.39,40,44
Coronary Artery Calcification Progression
Much interest has been directed at using CAC to measure plaque burden and then remeasuring at some point after treatment is applied to assess for progression of disease.46 Callister and coworkers47 performed one of the first studies to demonstrate a relationship between cholesterol lowering and atherosclerosis progression. There was a significant net increase in mean calcium volume score among individuals not treated with cholesterol-reducing medications (mean change, 52% ± 36%; P < .001). There was a graded response depending on the low-density lipoprotein (LDL) reduction with statin therapy, with those treated to LDL less than 120 mg/dL demonstrating an average diminution of coronary calcium (7% ± 23%) and those treated less aggressively (LDL > 120 mg/dL) showing a calcium volume score increase of 25% ± 22% (P < .001 for comparison with aggressively treated patients).
The Multi-Ethnic Study of Atherosclerosis (MESA) measured baseline CACSs and repeated this measurement after 3.5 years in 5756 patients. Of these, 2948 patients (51%) had a CACS of 0 at onset and were followed for development of incident positive CACS. The percentage developing positive scores was 16%. Another 2808 patients had a detectable CACS at baseline and were followed for progression. Their average rate of progression was 17.5 Agatston units per year. Risk factors associated with CAC progression were older age, male sex, white race/ethnicity, hypertension, higher body mass index, diabetes mellitus, and family history of heart attack. The associations that persisted after adjustment for baseline CAC were body mass index, family history of MI, diabetes mellitus, microalbuminuria, and blood glucose level.48
A new post hoc analysis49 of eight intravascular ultrasound (IVUS) studies that assessed the effect of medical therapies on serial changes in coronary atheroma burden suggests that there is a paradoxical relationship between calcification of the coronary artery and atheroma volume among individuals treated with statin therapy. This study demonstrates that high-intensity statin therapy promotes coronary calcification despite inducing regression of overall coronary atheroma volume. One interpretation of such results could be that the increase in coronary calcification among patients treated with a statin might be suggestive of coronary plaque stabilization. Therefore, the interpretation of results demonstrating CAC progression in a setting of high-intensity therapy could change from plaque progression to plaque stabilization.
Computed Tomography Angiography
Anatomical Assessment of Coronary Arteries
Assessment of Native Coronary Arteries
The explosive growth of cardiovascular imaging over the past few decades has facilitated the noninvasive detection of CAD. CCTA has the ability to accurately detect luminal stenosis in the coronary arteries and characterize coronary artery plaques. Advances in MDCT technology have resulted in high spatial and temporal resolution capable of detecting coronary atherosclerosis approximating that seen with invasive catheter-based coronary angiography. However, invasive coronary angiography (ICA) carries procedural risk (0.1%-0.2%), as well as high procedural cost.50 It has been estimated that approximately up to 40% of patients who undergo coronary angiography have normal angiograms, and many patients with CAD do not require revascularization procedures.51,52,53 CCTA has the potential to obviate the need for invasive procedures in select patients by demonstrating the absence of significant CAD, as well as improve risk stratification through detection of coronary atherosclerosis, assessment of ventricular function, and provision of information on cardiac structure.
MDCT scanners produce images by rotating an x-ray tube around a circular gantry through which the patient advances on a moving table. Pitch is the speed of the table relative to the speed of the gantry rotation, which allows each cross-sectional level of the heart to be imaged during more than one cardiac cycle. The number of image slices acquired during each gantry rotation (4–320) determines the overall duration of the MDCT scan. Developments in MDCT technology have led to the rapid advancement from four-slice MDCT machines in 1998 to 64 slices in 2004 and 256-slice and 320-detector row scanners in 2007. The latest technology contains 0.5-mm-wide detector elements yielding a maximum of 16-cm z-axis coverage. This configuration allows three-dimensional (3D) volumetric whole heart imaging during the diastole of one R-R interval, which opens the possibility of CCTA usage in the settings of higher heart rates and even arrhythmia.54 This progression is ongoing, with 640-detector row scanners now citing even less radiation and scanning time, as well as improved image quality.55
Cardiac CT is performed with ECG gating in either prospective or retrospective mode. ECG gating synchronizes image acquisition with the cardiac cycle. The optimal phase or interval for image analysis is the period during which the heart is the least mobile (usually end-diastole) and therefore the least degraded by motion artifact. Prospective ECG gating entails scan initiation at a defined interval after the R wave, continues for a prespecified duration, and then stops until the same optimal period is reached in the subsequent cardiac cycle, at which time scanning resumes. Retrospective ECG gating uses continuous acquisition of images throughout the cardiac cycle. The images from multiple consecutive heartbeats are then reconstructed at various percentages of the R-R interval (eg, from 0%-90% of an R-R cycle at 10% intervals). With retrospective gating, several thousand images can be acquired during a single cardiac study, allowing the interpreting physician to select the images with the least amount of motion-related distortion prior to final image reconstruction. Gating is the most advantageous at relatively slower heart rates (< 60 beats/min), where the R-R interval is more than 1000 milliseconds and the fastest imaging protocols may be used.
The coronary arteries move independently throughout the cardiac cycle and, even at relatively slower heart rates (ie, < 70 beats/min), exhibit significant translational motion of up to 60 mm/s for the RCA and 20 to 40 mm/s for the LAD and circumflex coronary arteries (Fig. 17–6).1,2 The velocity of coronary artery motion increases significantly with increasing heart rates. Image acquisition of less than 50 milliseconds is truly required to completely avoid cardiac motion artifacts.1 Cardiac motion is minimized with the use of oral and/or intravenous β-blockers prior to scanning, thereby reducing the heart rate and prolonging the time during the cardiac cycle at which coronary artery velocity is low. For individuals without contraindication to β blockade, these drugs are the medication of choice because they not only decrease the heart rate through the reduction of sympathetic tone, but may also reduce the number of premature atrial or ventricular beats, which adversely affect the overall quality of the images. Another crucial element for obtaining high-quality coronary images is to maximally dilate coronary vessels with nitroglycerin through the use of sublingual tablets or spray (Fig. 17–7). Respiratory motion is excluded by performing the scan during a breath-hold.
Cardiac motion artifact. Top left panel: Three-dimensional (3D) rendering image of a heart with significant motion artifact affecting the interpretation of the distal right coronary artery (RCA). This patient was scanned with a dual-source computed tomography (CT) (temporal resolution of 83 ms), and the heart rate in the time of the scan was 105 beats/min. Top right panel: Maximum-intensity projection (MIP) image of the same patient showing significant transitional motion artifact in the proximal and mid RCA. Bottom left panel: 3D rendering image of a heart without motion artifact showing the distal RCA. The heart rate was 75 beats/min, and the patient was scanned with a dual-source CT. Bottom right panel: MIP image of the same patient showing only slight transitional motion artifact in the mid RCA.
Effect of optimal coronary vasodilation with nitroglycerin. A. Three-dimensional (3D) rendering image showing only the portion of the left anterior descending coronary artery (LAD) with evidence of calcified plaques in the mid LAD. The study was performed without nitroglycerin. B. 3D rendering image of the same patient who was given an oral sublingual nitroglycerin prior to the scan. In contrast to the image in A, there is a significant improvement of the LAD with clear showing of all the side branches and the mid to distal portion of the vessel.
Coronary CTA requires the intravenous administration of an iodinated contrast medium. Approximately 50 to 100 mL of contrast medium is necessary for adequate coronary artery enhancement. The accurate timing of image acquisition relative to the contrast injection is a major determinant of overall image quality. A test bolus or bolus tracking technique is used to optimize this timing by determining the amount of time necessary to peak enhancement in the aorta.
Advancements in MDCT technology have led to shorter scan times, reduced breath-hold duration, smaller intravenous contrast injections, and decreased motion-related artifacts, resulting in lower radiation exposure and improved diagnostic accuracy.
The coronary vasculature on CCTA is evaluated through axial images, multiplanar (coronal, sagittal, or oblique) reformations, and 3D data sets constructed from specific phases during the cardiac cycle (Fig. 17–8). Maximum-intensity projection images allow the evaluation of longer segments of the coronary vessels but can be limited by overlapping structures adjacent to the artery of interest. Curved multiplanar reformations are reconstructed on a plane to fit a curve and allow display of the entire vessel in a single image. 3D volume-rendered images are useful for selecting images with the least motion artifact and for assessing the relationships among different anatomic structures (Fig. 17–9).
Evaluation of coronary atherosclerosis. A. Longitudinal maximum-intensity projection view of the mid left anterior descending coronary artery showing a calcified plaque. B. Axial multiplanar reconstruction view of the same nonobstructive plaque.
A. Three-dimensional volume rendering image of severe proximal left anterior descending coronary artery (LAD) disease. B. Maximum-intensity projection (15-mm thickness) of the same heart showing diffuse proximal LAD and diagonal branch stenoses. C. Multiplanar reconstruction of the same heart focusing on the proximal LAD stenosis demonstrating total occlusion of the vessel segment with in situ thrombus (~ 20 HU).
The spatial resolution of the image depends on the size of the 3D pixels or volume elements (voxels) that constitute the image. Slice thickness affects the spatial resolution of CCTA. Temporal resolution is determined by the speed of rotation of the gantry around the patient. A temporal resolution of 50 milliseconds or less is desirable for coronary artery imaging. The 64-slice MDCT scans have a spatial resolution of 0.4 mm and temporal resolution of 83 to 165 milliseconds, which limits the sensitivity and diagnostic accuracy for detecting stenosis in vessels less than 1.5 mm in diameter.56,57 In comparison, invasive angiography has both a superior spatial resolution of 0.2 mm and a temporal resolution of 5 to 20 milliseconds, whereas magnetic resonance angiography has decreased spatial resolution (0.7 mm) compared with MDCT but a better temporal resolution of 20 milliseconds.56
Diagnostic Accuracy of Cardiac Computed Tomography Angiography
Although there is still room for improvement in terms of image quality and elimination of artifacts, the diagnostic performance of the CCTA is now well established. A meta-analysis including nine studies totaling 566 patients using scanners with 64 or fewer detectors revealed a per-patient pooled sensitivity of 95% (95% confidence interval [CI] 90%–98%) and specificity of 90% (95% CI 87%-93%) in detecting acute coronary syndromes (ACS) in comparison with ICA.58 Another meta-analysis including 16 studies and 1119 patients found sensitivity and specificity of 96% (95% CI 93%-98%) and 92% (95% CI 89%-94%), respectively.59 Both studies demonstrate higher diagnostic accuracy for ACS with CCTA than with other previously studied modalities, including exercise treadmill, stress magnetic resonance imaging (MRI), stress nuclear imaging, and stress echocardiography.
Multiple trials have assessed the diagnostic accuracy of 64-slice CCTA compared with ICA.60,61,62,63,64 Subsequent meta-analyses have found that in patient-based analysis for the detection of obstructive CAD (> 50% stenosis), 64-slice MDCT had a pooled sensitivity of 94% to 100%, a specificity of 89% to 100%, a positive predictive value (PPV) of 93% to 97%, and a negative predictive value (NPV) of 93% to 100%.65,66,67,68 These observational results suggest that CCTA has good diagnostic accuracy for the detection of obstructive CAD. This was corroborated by two ensuing multicenter prospective clinical trials: Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography (ACCURACY)69 and Coronary Artery Evaluation Using 64-Row Multidetector CT Angiography (CORE-64).70 The ACCURACY trial enrolled 230 patients with chest pain, who underwent both CCTA and ICA. In a patient-based model, the ability of CCTA to detect obstructive CAD (>70% stenosis) had a sensitivity of 94%, specificity of 83%, PPV of 48%, and NPV of 99%.69 The high NPV of CCTA makes 64-slice MDCT a valuable tool in the exclusion of obstructive CAD. Therefore, CCTA is useful in the risk stratification of symptomatic patients and can reduce the need for invasive diagnostic coronary angiography in patients without obstructive CAD. A recent scientific statement from the American Heart Association (AHA) on CCTA concluded that “CT coronary angiography is reasonable for the assessment of obstructive disease in symptomatic patients (class IIa, Level of Evidence: B).”71
In particular, CCTA is an accurate tool in the assessment of chest pain in patients with intermediate risk of CAD or in patients with uninterpretable or equivocal stress tests.72 Other important clinical roles of MDCT include the assessment of congenital heart disease, suspected coronary anomalies, and significant CAD as a cause of new-onset heart failure.
Cardiac Computed Tomography Angiography, Plaque Composition, and Noninvasive Identification of High-Risk Plaques
In contrast to ICA, CCTA can assess the composition of the vessel wall, in addition to characterizing the degree of narrowing of the coronary artery lumen. MDCT can detect coronary plaque extent, distribution, location, and composition. Necropsy and coronary IVUS studies have shown that ICA consistently underestimates the amount of atherosclerotic plaque.73,74
Most ACS are caused by atherosclerotic plaque rupture, causing sudden luminal thrombosis. Pathological and anatomical features of high-risk or vulnerable plaques have been reviewed extensively in the literature75 and in Chap. 32.
These features include presence of large necrotic core, thin fibrous cap, positive remodeling (PR), spotty calcifications (SC), and perivascular inflammation.76 Some of these features are identifiable in vivo utilizing various invasive and noninvasive imaging modalities, such as IVUS, optical coherence tomography (OCT) and positron emission tomography (PET).77,78,79,80,81,82,83,84,85 In the past decade, noninvasive identification of such features using CCTA has been a major focus of research.
A study by Leber and colleagues86 assessed the capability of 64-slice CT to detect and quantify coronary plaques compared with IVUS. For the detection of coronary plaque, 64-slice MDCT had a sensitivity of 84% and specificity of 91%. In addition, 64-slice MDCT showed good correlation with IVUS in determining the mean plaque area (r = 0.73) and mean lumen area (r = 0.81).
In 2007, Motayama and Narula77 compared the CCTA plaque features of 38 patients with ACS to 33 patients with stable angina. Presence of PR, low attenuation plaque (LAP) (< 30 HU), and SC were associated with plaque rupture and ACS. In a prospective study by the same authors,87 1059 patients were followed for 27 months after the initial CCTA. The copresence of LAP and PR was associated with a 22.5% chance of ACS, whereas absence of these features was associated with 0.5% event rates. There were no significant differences in the degree of stenosis between the plaques that led to ACS and those that did not. The long-term follow-up (10 years) of this study88 showed that ACS occurred in 23.0% of patients with two high-risk features, 10.7% of patients with one high-risk feature, 1.6% of patients with no such features, and 0.6% of patients without any plaque (log-rank P < .0001). The other CT finding suggestive of plaque vulnerability, the so-called “napkin ring” sign, was reported for the first time in 2010.78 It was defined as a coronary plaque with a napkin ring–like attenuation pattern and SC (Fig. 17–10). The circumferential outer rim (red dashed line) of noncalcified plaque has a higher CT attenuation in both the noncontrast (A) and contrast-enhanced (B) images as compared to the attenuation within the central part of the plaque. These features of the “napkin ring” sign most likely identify a very similar histological pattern as the thin cap fibroatheroma. The “napkin ring” sign has also been shown to be predictive of events in a study of 895 patients80 who had a CCTA and were followed for up to 5 years thereafter. Patients with plaques with no high-risk features had no events, whereas there was a 40% event rate for patients with lesions with the following three high-risk features: “napkin ring” sign, PR, and LAP.
The cross-sectional computed tomography (CT) images show a coronary plaque with napkin ring–like attenuation pattern and spotty calcification. The circumferential outer rim (red dashed line) of the noncalcified plaque has a higher CT attenuation in both the noncontrast (A) and contrast-enhanced (B) images (44.0 ± 8.8 HU, range 23.0-61.0 HU vs 48.6 ± 5.8 HU, range 34.0-60.5 HU; respectively) as compared to the attenuation within the central part of the plaque (27.9 ± 4.2 HU, range 20.7-36.4 HU and 31.0 ± 6.6 HU, range 19.0-44.0 HU on noncontrast and contrast-enhanced images; respectively). The corresponding histological section (panels C, D, and E) revealed a late fibroatheroma, with spotty calcification (E). The lesion is characterized by a necrotic core (star), which is consistent with the low attenuation core of the plaque and a significant amount of fibrous plaque tissue, which is consistent with the high attenuation rim on the CT images (red dashed line). HU, Hounsfield units; L, lumen. Reproduced with permission from Maurovich-Horvat P, Hoffmann U, Vorpahl M, et al: The napkin-ring sign: CT signature of high-risk coronary plaques? JACC Cardiovasc Imaging. 2010 Apr;3(4):440-444.76
Diagnostic Accuracy of Cardiac Computed Tomography Angiography for the Evaluation of Acute Coronary Syndrome
The diagnostic accuracy of CCTA for the clinical diagnosis of ACS has been investigated in several studies that included more than 3000 patients presenting with acute chest pain to the emergency department.89,90,91,92 In a prospective study by Rubinshtein and colleagues,89 58 patients (mean age, 56 years; 36% women) with chest pain and initially negative biomarkers in the absence of new ECG changes underwent 64-slice MDCT. Twenty-three patients were found to have obstructive CAD (> 50% luminal narrowing) on CCTA. Of these 23 patients, 20 were subsequently diagnosed with ACS. Thus, 64-slice MDCT was found to have a sensitivity of 100%, specificity of 92%, PPV of 87%, and NPV of 100% for diagnosing ACS in emergency department patients presenting with chest pain. Normal and nonobstructive CCTA results were predictive of a low rate of major adverse cardiovascular events (MACE; 2.8%) and a favorable outcome during a 15-month follow-up period.89
The Rule Out Myocardial Infarction using Computer Assisted Tomography (ROMICAT)90 study was a larger prospective trial evaluating the role of CCTA in patients presenting to the hospital with possible ACS. Overall, 368 patients (mean age, 53 years; 61% men), were studied from a lower risk population. For CCTA, sensitivity and NPV for ACS were both 100%.93 In addition, this study demonstrated that CCTA independently predicts risk for ACS and has additive value for assessing risk in patients presenting with chest pain, when used in combination with traditional risk factors and clinical estimates of the probability of ACS.93
All trials demonstrated that absence of any coronary atherosclerosis by CCTA, which was observed in about half of the population, has an excellent NPV for presence of ACS. However, presence of significant stenosis by CCTA was only moderately diagnostic for ACS. In combination with the low prevalence of ACS in the acute chest pain population in the emergency department (2%-8%),11 CCTA reveals a low PPV for ACS (~ 35%-50%).
In order to improve the PPV, different strategies have been pursued94:
Assessment of plaque morphology. As mentioned earlier, CCTA has the potential to visualize select high-risk plaque features. Even though the assessment of such features is not part of current routine clinical practice, a plaque morphology-based score developed by Motayama and Narula resulted in a PPV of 100% for ACS and could potentially enhance the diagnostic accuracy of CCTA in the setting of acute chest pain.2
Assessment of LV function. It has been demonstrated that the identification of regional wall motion abnormalities incrementally improves the diagnostic accuracy of CCTA for ACS.95 However, this comes at the expense of higher radiation exposure.
Physiologic assessment of coronary artery disease by CT perfusion (CTP) or CT fractional flow reserve (FFR; see below). Functional testing, including rest and stress myocardial perfusion, is possible using CTP, but stress testing is not recommended in the acute setting considering the potential adverse effects of stressing a patient with ACS. Similar to the nuclear literature, an incremental value of assessing rest myocardial perfusion by CT has been observed, particularly in improving PPV.96,97
In summary, the absence of coronary atherosclerosis on CCTA, as observed in 50% of the acute chest pain population, has a NPV of close to 100%. On the other hand, presence of significant stenosis, even though superior to clinical risk score such as thrombolysis in myocardial infarction (TIMI),98 has a moderate diagnostic accuracy for ACS. Additional assessment of plaque morphology, LV function or physiological assessment of CAD with CTP perfusion and CT FFR might prove beneficial in improving diagnostic accuracy of CCTA for the assessment of acute chest pain.
Effectiveness of Cardiac Computed Tomography Angiography in the Emergency Department
Because CT has an excellent NPV and can be conducted in a timely manner, it has been hypothesized that CT may allow for rapid assessment of acute chest pain in the emergency department and lead to safe rapid discharge. Based on this hypothesis, three large clinical trials have been conducted.
Litt and colleagues99 performed the largest trial of these series. A total of 1370 patients with acute chest pain in the emergency department were enrolled and randomized into CCTA versus standard care in 2:1 fashion in the American College of Radiology Imaging Network–Pennsylvania Department of Health (ACRIN-PA) study. The results met the prespecified safety threshold of below 1% for missed ACS or death during the 30 days follow-up in the CCTA group. Importantly, this study was positive regarding its primary end point establishing CCTA as a safe alternative to traditional ischemia testing, such as MPI and exercise echocardiography, in a cost-effective and time-efficient fashion.
Both the Coronary Computed Tomographic Angiography for Systematic Triage of Acute Chest Pain Patients to Treatment (CT-STAT)100 and the ROMICAT II101 trials demonstrated that the CCTA-based strategy resulted in a shorter length of stay without lower safety (2.9 vs 6.2 hours for time to diagnosis [CT-STAT] and 23 vs 31 hours for time to hospital discharge [ROMICAT II] for CCTA vs control strategy). These findings were supported by other studies, indicating that the rate of direct discharge from the emergency department increased to about 50% by using a CCTA strategy, while a typical rate of 15% to 25% is observed for standard care.99,100,101
Prognostic Value of Cardiac Computed Tomography Angiography
CCTA yields independent prognostic information in addition to clinical risk factors in patients with suspected or known CAD.102 In 100 patients referred for cardiac evaluation, the cardiac event rate in the year following CCTA was 0% in patients without evidence of CAD, 8% in patients with nonobstructive CAD, and 63% when obstructive lesions were present.102 In patients with chest pain, CCTA can identify obstructive lesions, such as proximal LAD stenosis, as well as the number of vessels with moderate-to-severe stenosis, which predict an increased risk for all-cause mortality.103
In a meta-analysis of 11 studies, including a total of 7335 mostly symptomatic patients with suspected CAD followed for a median of 20 months, the presence of any greater than 50% stenosis at CCTA was associated with a 10-fold higher risk of cardiovascular events. In addition, the finding of any CAD inferred a 4.5-fold risk, and each coronary segment involved increased the risk of adverse outcomes by 23%.104 In the Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter (CONFIRM) registry, 27,125 patients underwent CCTA and were followed for a mean follow-up time of 22.5 months. Multivariable analysis demonstrated CCTA measures of CAD severity and LVEF have independent prognostic value. Incorporation of CAD severity had incremental value for predicting all-cause death over routine clinical predictors and LVEF in patients with suspected obstructive CAD.105
In a more recent analysis of 17,793 patients from the CONFIRM registry, the majority of whom had chronic chest pain, the number of proximal segments with mixed or calcified plaques and the number of proximal segments with 50% or more stenosis were the CCTA parameters with the strongest predictive value for all-cause mortality at a median follow-up of 2.3 years.106 Evidence of the more long-term prognostic value of CCTA is beginning to accumulate. Hadamitzky and colleagues107 followed up 1584 patients for a median of 5.6 years and described annual rates of MACE of 0.2% for patients with no CAD and 1.1% in patients with obstructive CAD. In another recent study reporting on a median 6.9-year follow-up period in 218 patients, annual MACE rates were 0.3%, 2.7%, and 6.0% in patients with normal CCTA, nonobstructive CAD, and obstructive CAD, respectively.108
While CCTA is shown to be an extremely powerful prognostic tool, it has been shown only to improve prognostication for asymptomatic populations with intermediate CACS and is not incremental to CACS for asymptomatic patients with lower or higher CACS levels.109
CCTA has also shed light on the important prognostic value of nonobstructive CAD. Lin and colleagues110 evaluated 2583 primarily symptomatic (85%) adults (mean age 52.7 years; 58% women) without known CAD or obstructive disease (50% stenosis) on 64-slice coronary CTA. Over a mean follow-up period of 3.1 years, it was demonstrated that the extent of nonobstructive CAD has a strong association with risk for all-cause mortality. The presence of any plaque increased the risk factor–adjusted mortality risk (hazard ratio [HR], 1.98), and risk was increased with multivessel nonobstructive disease (HR of 4.75 for three-vessel nonobstructive disease and HR of 5.12 when five or more segments were involved). Of importance, the increased risk from nonobstructive CAD was also seen in patients with low Framingham Risk Scores (FRS), a patient subset that does not typically qualify for aggressive primary cardiovascular preventive therapies. Similarly, the presence of any plaque demonstrated an improvement in the net reclassification index when compared with risk estimates using the FRS alone. Ahmadi and colleagues111 similarly demonstrated in 1102 consecutive symptomatic patients with nonobstructive (< 50%) CAD on coronary CTA, nonobstructive disease independently predicted all-cause mortality. Moreover, mortality incrementally increased according to the type of nonobstructive disease present (mortality given in parentheses): purely calcified plaque (1.4%), partially calcified plaque (3.3%), or noncalcified plaque (9.6%) (P < .001). On the same note, one of the analyses of the CONFIRM registry demonstrated that patients with two or more noncalcified or partially calcified plaques have a prognosis similar to that of patients with one or two obstructive plaques. However, patient with up to seven calcified nonobstructive plaques had an excellent prognosis with a less than 3% event rate in 2.3 years.112
In summation, the data available to date suggest that (1) the warranty period of a negative coronary CT angiogram appears to extend to at least 5 years, (2) the presence of any CAD and the burden of atherosclerotic changes at CCTA is strongly predictive for MACE and all-cause mortality in those with stable chest pain, and (3) plaque morphology by CT confers incremental prognostic information beyond that provided by percent stenosis alone.
Use of Cardiac Computed Tomography Angiography versus Other Modalities in Evaluation of Patients with Stable Coronary Artery Disease
Three recent randomized prospective studies have evaluated the role of CCTA compared to other commonly used noninvasive modalities for the evaluation of patients with stable CAD.113,114,115
In a multicenter European study,113 475 patients with stable chest pain and low prevalence of CAD underwent CCTA and stress MPI by single-photon emission computed tomography (SPECT) or positron emission tomography, as well as ventricular wall motion imaging by stress echocardiography or CMR for detection of obstructive (> 50%) CAD. CCTA had the highest diagnostic accuracy; the area under the receiver operating characteristics curve was 0.91 (95% CI, 0.88-0.94), with sensitivity of 91%, and specificity 92%.
In the Scottish Computed Tomography of the Heart Trial (SCOT-HEART)114,116 a total of 4146 patients assessed for new-onset chest pain were randomized to CTA in addition to standard care or to standard care alone. The standard care included documentation of the clinical history of angina pectoris and objective demonstration of exercise-induced myocardial ischemia through exercise stress testing. At 6 weeks, use of CTA reclassified the diagnosis of coronary heart disease in 27% of patients and the diagnosis of angina in 23% of patients. Use of CTA increased the certainty of attributing the patient's symptoms to angina caused by CAD compared with usual care alone (relative risk [RR] 1.79, 95% CI 1.62-1.96). The certainty of diagnosing CAD was also significantly improved (RR 2.56, 95% CI 2.33-2.79). Adding CTA to usual care changed planned investigations and treatment options and was associated with a trend toward a reduction in fatal and nonfatal MI.
The PROspective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial115 randomized a total of 10,003 patients and no prior diagnosis of CAD to a strategy of initial anatomical testing with CCTA or to functional testing (exercise electrocardiography, nuclear stress testing, or stress echocardiography). The study showed no difference in the primary end point, a composite rate of death, MI, major procedural complications or hospitalization for chest pain. However, select secondary end points, including level of radiation exposure and rate of subsequent procedures that did not reveal significant heart disease, favored CCTA.
Assessment of Coronary Bypass Grafts
Saphenous vein grafts are relatively easier to image with CCTA (because of their larger diameter and decreased mobility) compared with native coronary arteries. CCTA has high diagnostic accuracy for evaluating arterial and venous bypass graft stenosis. The diagnostic efficacy of 64-slice MDCT in detecting angiographically significant stenosis in bypass grafts has been demonstrated by several studies, yielding sensitivity ranging from 97% to 100% and specificity ranging from 89% to 100%.117,118,119,120 However, the assessment of bypass graft stenosis has several important limitations, namely the image artifacts caused by surgical clips and the presence of extensive coronary calcification in the native coronary arteries. These limitations can particularly hinder the evaluation in distal runoff vessels and nongrafted native coronary arteries.118,120 The percentage of uninterpretable segments can be as high as 31% with 16-slice MDCT121 but is significantly reduced, to approximately 2% or less, with 64-slice MDCT.120 Furthermore, the percentage of segments of native coronary vessels that cannot be evaluated may be less relevant in the clinical decision-making process because the most extensively calcified vessels are often bypassed.
Therefore, CCTA may be clinically useful for the evaluation of coronary bypass grafts and coronary anatomy in symptomatic patients.119,120 In the case of reoperation or revascularization, coronary CT angiography may provide critically important information on the status and anatomic location of the bypass grafts. The AHA Scientific Statement on CCTA states, “It might be reasonable in most cases to not only assess the patency of bypass graft but also the presence of coronary stenoses in the course of the bypass graft or at the anastomotic site as well as in the native coronary artery system (class IIb, Level of Evidence: C).”71 In summary, CCTA using 64-slice MDCT may be appropriate in properly selected patients by providing diagnostic information on the overall patency of the bypass grafts and the presence of significant stenosis without exposure to an invasive diagnostic approach.
Assessment of In-Stent Restenosis
The partial volume effect, or imaging artifacts, caused by the metallic stents limits the overall visibility of the inner lumen of a deployed stent and can potentially reduce the diagnostic accuracy of CCTA for the noninvasive evaluation of in-stent restenosis. Stent location, heart rate, and stent diameter are also important determinants of accuracy and feasibility (Fig. 17–11). The feasibility of stent visualization is approximately 95%, with the remaining 5% being unevaluable or uninterpretable because of the aforementioned factors.122 A systematic review of CCTA with 16-slice or more MDCT revealed moderate sensitivity (85%) and high specificity (97%) for the detection of coronary in-stent restenosis when compared with ICA.123 Similarly, a study exclusively comparing 64-slice MDCT with ICA found a sensitivity of 87% and specificity of 98% for the identification of significant in-stent restenosis by CCTA.122 In addition, CCTA has the ability to identify stent gaps, which may represent stent fracture or overlap failure and are often associated with in-stent restenosis.124 A new method of subtraction CCTA with a long breath-hold (25 seconds) using a 320-row scan was recently shown to improve the diagnostic accuracy of CCTA in detecting in-stent restenosis from 62.7% to 89.5% as compared to ICA125 (Fig. 17–12).
Evaluation of coronary stents. (A) Occluded stent in the proximal left anterior descending coronary artery. (B) Multiplanar reconstruction of widely patent stents without evidence of in-stent restenosis.
A 78-year-old woman with multivessel coronary artery disease and multivessel percutaneous coronary intervention. A. Conventional cardiac computed tomography angiography (CCTA) for evaluation of CCTA with no evaluable segment in the left circumflex artery (LCX). B. Subtraction CCTA demonstrating evaluable segments in the left anterior descending coronary artery (LAD), LCX and right coronary artery (RCA). C. Invasive coronary angiography (ICA) confirming the findings of subtraction CCTA in all three vessels.
Evaluation of Coronary Anomalies
Anomalies of the coronary arteries are reported in 0.3% to 1% of the general population.126 Approximately 20% of coronary anomalies can be hemodynamically significant and manifest as arrhythmias, syncope, MI, or sudden death.127,128 An interarterial course between the pulmonary artery and aorta is the coronary anomaly most commonly associated with sudden cardiac death (Fig. 17–13).129
Anomalous right coronary artery. A 37-year-old woman with atypical chest pain who underwent coronary computed tomography angiography to exclude coronary artery disease. Note the right coronary artery (arrowhead) arising to the left of midline from the left sinus of Valsalva taking interarterial course.
The diagnosis of coronary artery anomalies has previously required ICA; however, in up to 50% of patients, the coronary artery anomalies may be incorrectly classified during invasive angiography.130 This misclassification may result from the difficulty in delineating the precise vessel path within a complex 3D geometry using a relatively restricted two-dimensional (2D) view. Coronary CTA has been shown to accurately depict the anomalous vessel origin, its subsequent course, and the relationship to the great vessels.128 Two studies comparing CCTA and ICA found that invasive angiography was able to detect 80% of the anomalous origins, but only 53% of the anomalous coronary courses,131 and resulted in a precise anatomic diagnosis in only 55% of patients.132 In a multicenter coronary artery CT registry, CCTA was able to unequivocally demonstrate the origin and the course of the anomalous artery in all patients with equivocal findings on ICA.133 Demonstrating the precise course of an anomalous coronary artery is crucial for determining proper therapeutic options. Therefore, CCTA may be preferable to invasive angiography for the diagnosis of coronary anomalies given its superior diagnostic accuracy.
Physiologic Assessment of Coronary Artery Lesions by Cardiac Computed Tomography Angiography
While there is ongoing debate among cardiologists as to whether coronary anatomy or physiology is more important in determining prognosis and impacting treatment decisions, anatomic and functional testing for CAD are often complimentary. Even though the degree of stenosis is one of the factors that partially predicts the presence or absence of ischemia, the association between coronary anatomy and ischemia is poor. For instance, there are lesions causing Ischemia WithOut significant Stenosis (IWOS) and there are lesions that cause significant Stenosis WithOut Ischemia (SWOI).134,135 Therefore, an ideal diagnostic test would possess the technology that not only can give accurate assessment of the burden of atherosclerosis, location and composition of each plaque, but also determine the physiological consequence of each lesion in the form of presence or absence of ischemia. Two such techniques are CTP and CT FFR. They have allowed us to evaluate both coronary anatomy and physiology.
Techniques for Computed Tomography Myocardial Perfusion Imaging
In order to assess both coronary anatomy and myocardial ischemia using CTP, two separate CT acquisitions are required: one for vasodilator induced stress MPI and one for rest MPI and coronary CTA.136 While heart rate is required for the rest acquisition, it is not as stringent for stress MPI because coronary opacification is not necessary or assessed. Typically, a delay ranging from 10 to 30 minutes is currently employed between acquisitions to allow for CT contrast washout and/or reversal of the effects of the pharmacological vasodilator used. For the stress perfusion, peak hyperemia may be achieved with adenosine, dipyridamole, or regadenoson. Regadenoson has can be used with a single injection that results in several minutes of hyperemia. A clinical example of CTP is demonstrated in Fig. 17–14.
Example of stress-induced computed tomography perfusion defect involving the anterior, anteroseptal, and lateral walls (top image). The rest perfusion images demonstrated a small defect in the anterior wall. Collectively, these findings were consistent with severe ischemia and the patient was found to have severe stenosis of the left anterior descending and left circumflex coronary arteries. Reproduced with permission from Hulten E, Ahmadi A, Blankstein R: CT Assessment of Myocardial Perfusion and Fractional Flow Reserve. Prog Cardiovasc Dis. 2015 May-Jun;57(6):623-631.132
Stress-rest perfusion and rest-stress protocols yield similar clinical results. However, rest–stress protocols could lead to more cost effectiveness testing, because the stress portion could be avoided in the rest-stress protocol if no stenosis were identified in the rest images.
Any modern scanner with 64 or more detectors can be used to perform CT MPI, although there are unique considerations for each specific CT platform. Most important is the z-axis coverage. In the 64 MDCT platforms, which require image acquisition over multiple heartbeats, the use of this technique results in nonhomogenous myocardial contrast enhancement resulting from the slight differences in acquisition time of each slab. Even though such heterogeneity does not impact the clinical value of the test, the sufficient z-axis coverage in 320 MDCT eliminates this issue by allowing for a single beat acquisition.
Another important consideration is the estimated effective radiation dose delivered to the patient. Estimated effective dose is significantly dependent on scanner technology and acquisition protocol.137 An axial acquisition with prospected ECG gating, as well as reduction in the tube voltage (kV) in nonobese patients and use of a single data set utilizing either a test bolus or bolus tracking are some of the techniques that could lead to reduction in effective radiation dose.
After raw data acquisition, CTP images should be reconstructed with a smooth filter and beam-hardening correction, when available. For optimal image display of myocardial perfusion, the grayscale window width and level are set at approximately 300/150138 and multiplanar reformat images are viewed using thick slices (6-8 mm) and average intensity projection of each slab.
Clinical Evidence for Computed Tomography Myocardial Perfusion Imaging
Single-center studies on 64 MDCT were first reported in 2009139,140 and demonstrated a per-vessel sensitivity and specificity of 86% to 93% and 74% to 91% for CTA-CTP in comparison to ICA-SPECT. These results were followed by other single-center, observational studies evaluating CTP, which demonstrated an accuracy of CTP similar to that of both invasive angiography and functional imaging.141,142,143,144,145,146,147,148
The multicenter, international study Coronary Artery Evaluation using 320-row multidetector computed tomography angiography and myocardial perfusion (CORE 320) followed the previously mentioned single-center studies. This study evaluated 381 patients who underwent CTP and CTA using the 320 MDCT, as well as SPECT MPI and invasive angiography. CTA ≥ 50% demonstrated a sensitivity of 94% and specificity of 64% for detecting obstructive lesions causing defects on myocardial perfusion imaging. There was a modest improvement in specificity with the addition of CTP to CTA.149 The presence of stenosis by CTA had an area under the curve of 0.82 (0.78–0.85), which improved to 0.87 (0.84–0.89) with the addition of CTP. A subsequent multicenter trial has been conducted using regadenoson for CTP in comparison with SPECT incorporating a variety of different vendors' CTA.150,151 This study demonstrated that addition of CTP increased the accuracy of CTA for detecting a reversible perfusion defect on SPECT could be improved from 0.69 to 0.85.
Fractional Flow Reserve Computed Tomography: the Fundamentals
Recent advances in the field of computational fluid dynamics (CFD) and advanced imaging-based modeling have allowed for noninvasive calculation of FFR based on static CT images. As applied to typically acquired coronary CT angiograms, these technologies enable noninvasive calculation of FFR without modification of image acquisition protocols, additional imaging or radiation, or need for vasodilators. The details of methods used in calculation of FFR CT have been described elsewhere.152,153
In general, by using the “Navier-Stokes Equations” of CFD and based on the relationship of mass conservation and momentum balance, coronary artery flow and pressure can be obtained.136,153,154,155 Because blood is an incompressible fluid, it can be treated as a newtonian fluid with a relatively constant viscosity in larger vascular beds such as coronary arteries. Clinical evaluation of a true vascular territory such as coronary arteries requires a numerical method to estimate the principle equations and generate a solution, which must be solved simultaneously over many time intervals in a single cardiac cycle, using CFD methods.153 Definition of flow boundaries is necessary for construction of the 3D model of coronary arteries and aorta and solving flow equations. These boundaries include the vessel lumen, the root of aorta as the inlet, and the thoracic aorta and the coronary arteries as the outlets.156 Myocardial wall volume and mass extracted from the coronary CTA data are used to calculate the overall coronary flow under the resting conditions. Total coronary resistance can be calculated using the coronary flow. Using a simulation model of the effect of adenosine on reducing the peripheral resistance of the coronary microcirculation down-stream to the epicardial coronary arteries, maximum hyperemia state is estimated in the FFR CT model.157 FFR CT can then be obtained by solving the equations of blood flow for velocity and pressure.153 Figure 17–15 demonstrates a clinical example of FFR CT with invasive FFR correlation.
Evaluation of a lesion by fractional flow reserve (FFR) computed tomography (CT). A. Cardiac computed tomography angiography (CTA) finding of heavily calcified left anterior descending coronary artery (LAD) lesion of > 70% stenosis. B. FFR CT of the same lesion demonstrating its clinical significance. C. Invasive angiography and FFR of the same lesion, showing its clinical significance by quantitative coronary angiography (QCA).
Clinical Evidence for Fractional Flow Reserve Computed Tomography to Date
FFR CT technology has been shown to be more accurate than CTA in predicting lesion-specific ischemia, as determined by invasive FFR. To date, three separate multicenter prospective studies have examined the performance of FFR CT using invasive FFR as the gold standard.
The prospective, multicenter international Diagnosis of ISChemia-Causing Stenoses Obtained Via Non-invasivE FRactional FLOW Reserve (DISCOVER-FLOW) trial158 was the first study to evaluate the accuracy of FFR CT in a prospective fashion. In this study, it was demonstrated that in 103 patients who underwent CTA and invasive FFR measurement, FFR CT was superior to CTA as a predictor of lesion-specific ischemia with higher accuracy, specificity, PPV, and NPV in both per-patient and per-vessel analyses.158 Specifically, there was a significant improvement in accuracy of CCTA by FFR CT among the 50% to 69% stenosis group. Moreover, it was shown that in the scans with motion artifact, calcium artifact or low signal-to-noise ratio, FFR CT performed significantly better than CTA.
The Determination of Fractional Flow Reserve from Anatomic Computed Tomographic Angiography (DEFACTO) trial159 was a multicenter study of 252 patients and 407 vessels were investigated by both FFR CT and invasive FFR. The primary end point was to assess the diagnostic accuracy of FFR CT compared to that of invasive FFR. The primary end point of the study was set as having the lower bound of the confidence interval for diagnostic accuracy to be more than 70%, because this represents a 15% increase in diagnostic accuracy over stress echocardiography or MPI when compared to invasive FFR. The per-patient diagnostic accuracy for FFR CT plus CT was 73% (95% CI, 67%-78%), which did not meet the prespecified primary end point. Although the performance of FFR CT did not meet the criteria for the prespecified primary end point, DEFACTO confirmed the superiority of FFR CT over CT alone for the determination of lesion-specific ischemia. The diagnostic accuracy of CTA alone was 64% (95% CI, 58%-70%), and FFR CT showed 9% absolute improvement in the diagnostic accuracy. Importantly, there was a significant improvement in the evaluation of intermediate severity lesions causing 30% to 70% luminal narrowing. DEFACTO also represents the first large-scale demonstration of patient-specific computational models to assess for lesion-specific ischemia from CT images.
The Analysis of Coronary Blood Flow Using CT Angiography: Next Steps (NXT) trial is the third multicenter prospective study that has evaluated the diagnostic performance of FFR CT using invasive FFR as a gold standard.160 This study evaluated the diagnostic accuracy of an updated iteration of FFR CT and for the first time compared the FFR CT accuracy to ICA in predicting invasive FFR. Two hundred fifty-four patients had a clinically indicated CCTA before ICA. Diagnostic accuracy of FFR CT, CTA, and ICA were compared to invasive FFR. This study compared FFR CT with CCTA and ICA against the reference standard of invasive FFR in patients with CCTA stenosis of 30% to 90%. The area under the receiver-operating characteristic curve of FFR CT was 0.90 (95% CI, 0.87-0.94) versus 0.81 (95% CI, 0.76-0.87) for coronary CTA (P = .0008). The per-patient and per-vessel sensitivity, specificity, PPV, and NPV of FFR CT were superior to CTA for detecting lesion-specific ischemia. FFR CT was also superior in diagnostic accuracy for lesion-specific ischemia compared to diameter stenosis by ICA.
Following the validation of the diagnostic accuracy of FFR CT, it was then necessary to assess the potential impact FFR CT may have on clinical practice and patient outcomes. The Prospective LongitudinAl Trial of FFR CT: Outcome and Resource IMpacts study (PLATFORM) trial was published in the European Heart Journal in 2015. PLATFORM is a multicenter, prospective consecutive cohort study conducted in 11 European sites with a total of 584 patients. The aim of the PLATFORM trial was to compare the accuracy and clinical outcomes of a CCTA/FFR CT–guided approach to assessing stable patients at intermediate risk (20%-80%) of obstructive CAD. Importantly, there were two separate arms of the trial. One arm aimed to evaluate the potential role of CTA/FFR CT as a gatekeeper to the coronary angiography by comparing the rate of nonobstructive disease at the time of ICA in those who simply underwent ICA when referred as compared to those who only underwent ICA following an abnormal CT/FFR CT assessment. The second, noninvasive arm, compared a noninvasive strategy of CTA/FFR CT to a traditional noninvasive assessment, with any chosen ischemia test. The primary end point was the rate of nonobstructive CAD (< 50%) at ICA in the cohort planned for ICA, where CCTA/FFR CT was used as a gatekeeper compared to the arm of direct ICA. The secondary accuracy end point was the rate of nonobstructive CAD at ICA in the noninvasive cohort with standard noninvasive testing as gatekeeper to ICA compared to CCTA/FFR CT as gatekeeper. The clinical outcomes' end point was the rate of MACE and vascular complications as well as resource utilization, change in quality of life, and cumulative radiation exposure. MACE was defined as all-cause mortality, nonfatal MI, and unplanned urgent revascularization.161
With respect to the primary end point, the rate of nonobstructive CAD in the standard-of-care invasive cohort was 73.3% compared to only 12.4% in the CCTA/FFR CT arm (P < .0001). An impressive 61% of CCTA/FFR CT patients had ICA canceled with no resultant adverse events; however, the reported follow-up period was short, at 90 days.161
The comparison of radiation exposure between the groups in PLATFORM was suboptimal. The CCTA radiation exposure was calculated for each individual case or inferred using the median measured value. For all other modalities, predetermined standard values were used; 7 mSv for ICA, 15 mSv for percutaneous coronary intervention, and 14 mSv for MPI.161 The use of standardized values instead of measured values reduces the robustness of the radiation dose comparison, which showed a significantly lower dose in the usual care arm (5.8 mSv) versus the FFR CT arm (8.8 mSv) in the noninvasive cohort. No difference was shown in the invasive cohort with respect to radiation dose.
A cost-effectiveness analysis of the PLATFORM trial demonstrated that among patients in the invasive strategy arm the use of CCTA/FFR CT as a gatekeeper to ICA was considerably less expensive than the usual care arm ($7,343 vs $10,734; P < .0001). By trial design, 100% of patients in the ICA usual care arm proceeded to coronary angiography compared with 61% in the FFR CT arm. Importantly, despite the lower rate of ICA, the rate of coronary revascularization was comparable between the two strategies (28% vs 32%). This important cost analysis seems to suggest that FFR CT is not only more accurate than traditional stress testing for lesion-specific ischemia by FFR but that it is also a cost effective method to determine which patients will benefit from ICA and revascularization.
In the noninvasive arm of the trial, despite the higher rates of ICA (18% vs 12%) and revascularization (10% vs 5%) in the FFR CT cohort, the 90-day cost of care was not significantly different than that in the usual care group ($2,679 vs $2,137; P = .26). Interestingly, there was a greater improvement in quality of life scores in the FFR CT group (19.5 vs 11.4; P = .04), which one could hypothesize may reflect more appropriate physiologically guided revascularization.162
Association of Plaque Morphology on Computed Tomography Angiography and Invasive Fractional Flow Reserve: An Emerging Concept in Coronary Atherosclerosis
As mentioned above, the relationship between FFR and luminal stenosis is not perfect,163 because there are numerous examples of IWOS and SWOI seen in day-to-day clinical practice and have been reported in various studies.134,135 Features other than the degree of luminal stenosis, such as lesion length, entrance angle, exit angle, size of the reference vessel, and absolute flow relative to the territory supplied, were originally thought to explain the lesions with IWOS and SWOI.164 Recently, it has been shown that the presence of high-risk plaque features, especially large LAP, a CTA surrogate for necrotic core, is a strong predictor of FFR-verified ischemia independent of degree of luminal stenosis.165,166 Local impairment of the vessel to dilate at the site of a large necrotic core may contribute to ischemia independent of the degree of luminal narrowing. A once nonsignificant stenosis with impaired local vasodilatory ability could cause significant functional stenosis when the adjacent segments dilate at the time of maximal hyperemia. The reason for such local inability of vessel to dilate at the site of large necrotic core could be related to reaching the Glagovian limit caused by the presence of significant positive remodeling, presence of significant local endothelial dysfunction at the site of large necrotic core,134,167,168,169 or disruption of the local signaling mechanism between intima and smooth muscle cells that is essential for vasodilatation resulting from the presence of large necrotic core.135 As a result, FFR-negative lesions are more likely to be devoid of both large necrotic core and severe stenosis. Therefore, FFR may indirectly be a sensitive (but not specific) detector of stenotic plaques with large volume necrotic core.135 This might also explain the favorable prognosis associated with negative FFR, given the excellent prognosis of lesions without large necrotic core on CTA.135