Assessment of Acute Chest Pain by CT Patrick M. Donnelly, MD, MB, BCh, and Udo Hoffmann, MD, MPH

Corresponding author Patrick M. Donnelly, MD, MB, BCh Cardiac MR/PET/CT Program, Massachusetts General Hospital, 165 Cambridge Street, Suite 400, Boston, MA 02114, USA. E-mail: [email protected] Current Cardiovascular Imaging Reports 2008, 1:87–95 Current Medicine Group LLC ISSN 1941-9066 Copyright © 2008 by Current Medicine Group LLC

Chest pain is one of the most frequent causes of presentation to the emergency department (ED). Often the diagnosis represents a significant challenge to current triage methods. The conventional diagnostic triad of clinical history, electrocardiogram, and biomarker assays has limitations, and consequently patients without significant pathology are often admitted for investigation. This strategy has major implications for the timely delivery of care and effective resource use. CT has developed rapidly over the past 10 years, and the new more robust multidetector CT platforms facilitate rapid noninvasive scans. Emerging indications for CT, coupled with increased availability of ED CT, may make it an attractive option for ED chest pain triage.

Introduction Chest pain accounts for 6 million emergency department (ED) consultations annually [1]. The differential diagnoses are extensive, and life-threatening causes such as acute coronary syndromes (ACS), aortic dissection, and pulmonary embolism must be rapidly identified and treated (Table 1). A strategy that can improve the current triage of chest pain patients is highly desirable, and CT appears to possess some favorable test characteristics. However, for CT to be clinically useful it must accurately identify patients with and without disease, optimize the delivery of patient care, and, most importantly, improve patient outcomes.

CT for Pulmonary Embolism It is estimated that more than 200,000 cases of pulmonary thromboembolism (PE) occur in the United States each year. Additional cases are not diagnosed due to nonspecific symptoms, or subtle or insignificant clinical findings. The Wells decision tool [2] improves the identification of patients with PE. Scores less than 4 represent patients at

low risk of PE, and scores greater than 4 require further investigation. The ventilation/perfusion scan can define an abnormal pattern of regional perfusion, which may be suggestive of PE; however, it requires correlation with other modalities such as ventilation imaging and a recent chest radiograph. These are performed to help differentiate between reduced pulmonary arterial blood flow due to vascular obstruction and secondary reductions due to “shunting” of regional blood flow, which can be associated with airways disease. Recently, CT has emerged as a reliable alternative for the investigation of patients with suspected PE. Data have consistently demonstrated the accuracy of CT pulmonary angiography when compared to ventilation/perfusion imaging and pulmonary angiography for the detection of pulmonary embolism [3]. In a recent meta-analysis of 3500 patients who were enrolled in 15 studies that used CT to rule out acute PE, Quiroz et al. [4] reported that the clinical validity of using a CT scan was similar to that reported for conventional pulmonary angiography. There appears to be an evolving consensus that CT pulmonary angiography is now the primary imaging modality for evaluation of patients suspected to have acute PE [5]. A positive CT result combined with high or intermediate clinical suspicion has a high positive predictive value for the diagnosis of PE. PE can be safely excluded in patients with a low clinical suspicion and a negative CT result (Fig. 1 and Fig. 2).

CT for Acute Aortic Dissection Aortic dissection is rare; however, mortality is high if untreated. An analysis of 963 patients collected from six reported series demonstrated that 50% of patients died within 48 hours, 70% within 1 week, and 90% within 3 months [6]. In the absence of classical symptoms, making a diagnosis can be quite a challenge. Signs and symptoms of aortic dissection can be misleading. An intimal tear can progress along the aortic wall and involve other major vessels, and predominant symptoms may be as diverse as abdominal pain, or neurologic sequelae. Early diagnosis is essential, and the ideal test should provide information on the presence and type of dissection; an assessment of entry and re-entry sites; identification of thrombus in the false lumen; detection of the presence or absence of aortic branch involvement; and the determination of the presence of extravasated blood into mediastinal, pleural, or pericardial space. In addition,

88 Cardiac Computed Tomography

Table 1. Differential diagnosis of life-threatening chest pain Acute coronary syndromes (ST elevation infarction, non-ST elevation infarction, unstable angina) Pulmonary embolism Acute aortic syndromes (Dissection, aneurysm/rupture, intramural hematoma, penetrating ulcer) Esophageal rupture Cardiac tamponade Tension pneumothorax

Figure 2. Full-field view of axial image. Clinical sequelae of multiple pulmonary emboli. Asterisks demonstrate bilateral pleural effusions, arrowhead demonstrates bilateral atelectasis, and arrow demonstrates descending aortic atherosclerosis.

Figure 1. Cross-sectional image at level of bifurcation of the pulmonary trunk. Asterisks demonstrate bilateral pulmonary emboli in a patient with prior coronary artery bypass grafts. Arrows demonstrate two patent saphenous vein bypass grafts. Short arrow demonstrates a patent left internal mammary artery graft. AA—ascending aorta; DA—descending aorta; LPA—left pulmonary artery; RPA—right pulmonary artery; SVC—superior vena cava.

imaging should help distinguish classic aortic dissection from other causes of “acute aortic syndrome,” such as acute intramural hematoma and penetrating atherosclerotic ulcer. Transesophageal echocardiography (TEE) is widely available and has a comparable sensitivity to MRI for the detection of aortic dissection. However, TEE has significant limitations—it is invasive, operator dependent, distressing for the patient, and has limited imaging windows. In all, it is most appropriate for patients with a Stanford type A dissection; however, it is of limited value for type B. Contrast-enhanced CT is emerging as a more appropriate initial investigation and was the most common initial diagnostic test performed in the patients enrolled in the International Registry of Acute Aortic Dissection [7]. Numerous studies have evaluated

the efficacy of CT and have demonstrated sensitivities of 90% to 100%, and specificities of 87% to 100%. However, these studies compared conventional CT without ECG-gating, rather than the latest generation of multidetector CT scanners (MDCT). To our knowledge, there is no randomized trial comparing the latest MDCT technology to other imaging modalities for the detection of acute aortic syndromes (Fig. 3 and Fig. 4).

CT for ACS ACS represent the most common and important diagnosis of ED chest pain. Early identification and implementation of treatment is the key to successful management. However, using the current standard of care, only 10% of patients with an ACS can be clearly identified at the time of presentation [8]. The remainder requires further evaluation and risk stratification in the ED, chest pain observation unit, or coronary care unit. Seventy-five percent of these chest pain admissions will not be diagnosed with ACS [9]. The current assessment of patients with suspected ACS involves the evaluation of the clinical history, electrocardiogram (EKG), and the analysis of serum biomarker assays. However, there are limitations with all three triage methods.

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Figure 3. Axial image at level of pulmonary artery bifurcation. Arrow demonstrates true lumen of an aortic dissection in the descending aorta. Asterisk demonstrates extensive hematoma in the false lumen. AA—ascending aorta; PA—pulmonary artery.

There is no single element of a chest pain history that is a powerful enough predictor to rule out ACS. Chest pain is subjective, poorly described, atypical in certain populations, and dependent on the experience of the health care professional eliciting the clinical history [10]. The EKG may be normal or nondiagnostic in one fifth of patients presenting with acute myocardial infarction, and a normal EKG is the most likely predictor for inadvertent discharge of patients with myocardial infarction [11]. Biomarker troponin assays are highly sensitive for the detection of myocardial necrosis. However, they are not specific for the cause of the necrosis, which contributes to a diagnostic dilemma and further testing in patients who are at low risk for ACS. Second, there is a lag of at least 2 to 4 hours from the onset of chest pain symptoms to the detection of biomarker in the serum. It has been recommended that sampling between 6 and 12 hours from the onset of symptoms be performed to provide greatest accuracy [12]. The inadequacies of the current triage system have contributed directly to the clinical practice of patient admission to “rule out myocardial infarction.” Although this strategy is prudent, it contributes to excessive use of resources, bed shortages, and increased health care costs [13]. Health economists argue the need for resource rationalization, but this approach must be considered against the cost of a “missed” ACS to both the patient and the health care system. One study demonstrated that 5% of ACS patients may be discharged inadvertently from the ED, and 20% of these may die within 24 hours [14]. This is an unacceptable statistic for both patient and provider and a major source of malpractice litigation in the

Figure 4. A, Multiplanar reconstruction of nonocclusive proximal left anterior descending lesion (arrow). B, CT demonstrates a mixed plaque. There is a small calcified fleck present, which may represent the site of a recent plaque rupture. Conventional catheter angiography demonstrates an ectatic vessel, but plaque characterization is not possible.

United States [15]. Cardiac CT (CCT) is a comparatively new application for an established diagnostic imaging modality. Mechanical CT platforms with more than one row of detectors (multi-detector) were introduced in the late 1990s, and Mochizuki et al. [16] were the fi rst to publish a case report on the clinical usefulness of a four-detector scanner in the assessment of a left anterior

90 Cardiac Computed Tomography

Figure 7. Maximum-intensity projection. Long arrow demonstrates an occluded first diagonal branch of the left anterior descending coronary artery (asterisk). Short arrow demonstrates a patent left circumflex coronary artery. AA—ascending aorta; LA—left atrium; PA—pulmonary artery. Figure 5. Angio-emulation three-dimensional view of a normal aorta and coronary arteries. Arrowhead indicates right coronary artery. Arrow indicates left anterior descending coronary artery. Asterisk indicates left circumflex coronary artery. AA—ascending aorta; LV—left ventricle; RV—right ventricle.

Figure 6. Maximum-intensity projection. Arrow demonstrates the C view of normal right coronary artery. AA—ascending aorta; LVOT—left ventricular outflow tract; RV—right ventricle.

descending coronary artery stenosis. Since then, there have been unprecedented advances in CT technology, with new scanners introduced biannually. CCT is unique in that it has the potential to provide both anatomic and functional cardiac information from a single fast scan. There are two principal applications for this technique. Non–contrast-enhanced CCT can be used to detect coronary artery calcification. Parry fi rst linked coronary artery calcification to coronary artery disease in 1799. CCT can accurately detect and quantify coronary calcification burden using calcium mass, volume, and Agatston methods. These measurements are useful surrogate markers of plaque burden, and there is extensive evidence that

they can be used as a risk stratification tool for the prediction of subsequent cardiovascular events. Contrast-enhanced CCT is the principal application for this new technology. Significant numbers of single-center feasibility studies and two multicenter blinded trials have demonstrated the accuracy of contrast-enhanced CCT for the detection of coronary artery stenoses in selected patient populations. A recent metaanalysis assessed the sensitivity and specificity of CCT in studies reported between 1997 and 2006 [17]. A total of 2515 patients had been enrolled, 75% of whom were male with a mean age of 59 years. CCT consistently achieved a high sensitivity and specificity for the detection of coronary artery disease when compared to invasive catheter angiography. A per-segment coronary artery analysis of these studies yielded an overall sensitivity of 95% or 80%, 89%, 86%, and 98% for electron beam CT (EBCT), 4/8-slice, 16-slice, and 64-slice MDCT, respectively, and an overall specificity of 85% or 77%, 84%, 95%, and 91%, respectively. When analysis was limited to assessable segments by CCT, the sensitivity was 96% (86%, 85%, 98%, and 97%, respectively) and specificity was 95% (90%, 96%, 96%, and 96%, respectively). In a per-patient analysis, the sensitivity was 99% (90%, 97%, 99%, and 98%, respectively) and specificity was 76% (59%, 81%, 83%, and 92%, respectively). CCT can also evaluate patients who have undergone prior coronary artery revascularization (Figs. 5–9). CCT can be used to defi ne specific coronary artery plaque characteristics, such as plaque composition, plaque area, and plaque volume [18,19]. Recently, our group demonstrated the feasibility of noninvasive detection and characterization of plaque in patients with ACS. Forty plaques were assessed in 14 patients with ACS and nine patients with stable angina. Culprit lesions

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Figure 8. Significant mid-vessel left anterior descending stenosis (arrow) demonstrated by CT (A) and conventional catheter angiography (B). However, conventional angiography does not convey the extent of the atheroma (calcium is present immediately proximal and distal to the stenosis).

Figure 9. Maximum-intensity projection. Arrow demonstrates the proximal course of a patent left internal mammary artery (LIMA) graft. Arrowhead demonstrates LIMA distal anastomosis site with the left anterior descending coronary artery. AA—ascending aorta; LV—left ventricle; PA—pulmonary artery; RVOT—right ventricular outflow tract.

in patients with ACS had a signifi cantly greater plaque area and a higher remodeling index than both stable lesions in patients with ACS and lesions in patients with

Figure 10. Axial four-chamber image. Asterisk demonstrates a pericardial effusion adjacent to the right ventricular free wall. LA—left atrium; LV—left ventricle; RA—right atrium; RV—right ventricle.

stable angina (17.5 ± 5.9 mm 2 vs 9.1 ± 4.8 mm 2 vs 13.5 ± 10.7 mm 2 , P = 0.02; and 1.4 ± 0.3 vs 1.0 ± 0.4 vs 1.2 ± 0.3, P = 0.04, respectively) [20]. First pass perfusion and functional imaging may also be feasible with CCT [21–24]. Nikolaou et al [25]. evaluated the diagnostic accuracy of the arterial rule out phase of CCT in the assessment of myocardial infarction in 106

92 Cardiac Computed Tomography

Table 2. Overview of emergency department ACS CT studies (all numbers are absolute values) Study, year

Study design

CT platform

Patients

CAD

Follow-up

Event rate*

Observational blinded

EBCT

105

46†

4 months

0‡

McLaughlin et al. [28], 1999 Observational blinded

EBCT

134

86†

30 days

8

Georgiou et al. [26], 2001

EBCT

192

NA

50 months

58

Observational blinded

64-MDCT

103

62§

Index hospitalization

14

Case series

64-MDCT

58

43§

Index hospitalization

20

Observational randomized unblinded

64-MDCT

197 (99)

24§

6 months

0

16-MDCT

69

10†

NA

NA

NA

NA

NA

NA

Coronary calcium Laudon et al. [27], 1999

Observational blinded

Contrast-enhanced coronary CT Hoffmann et al. [29•], 2006 Rubinshtein et al. [30•], 2007 Goldstein et al. [32•], 2007

Comprehensive EKG-gated chest CT White et al. [33], 2005 Schertler et al. [36], 2007 Johnson et al. [34], 2007

Case series Case series Case series

DSCT 64-MDCT

60 55

§

3

§

24

*Event rates defined as patients diagnosed with ACS or death. † CAD defined as the presence of calcium. ‡ Zero calcium score only. § CAD defined as the presence of plaque and/or stenosis. ACS—acute coronary syndrome; CAD—coronary artery disease; DSCT—dual source CT; EBCT—electron beam CT; MDCT—multi-detector CT; NA—not available/applicable.

patients. Evidence of myocardial infarction was found in 27 subjects, and the accuracy of this protocol was 90%.

ED CT Chest Pain Assessment As a consequence of this growing evidence base, expert consensus opinion, and deficiencies in the current standard of care, there has been enthusiasm to use CT more effectively in the ED. Three CT imaging strategies have been investigated for the assessment of chest pain (Table 2).

ED coronary calcium assessment Evidence for the clinical use of coronary artery calcium assessment in ED chest pain evaluation is limited to three major single-center observational studies [26–28]. All were performed using EBCT in patients presenting with chest pain and nonspecific EKG. In the fi rst publication on ED calcium assessment, Laudon et al. [27] assessed 105 patients with possible ACS. Inclusion criteria were normal cardiac enzymes and a nondiagnostic EKG result. All patients underwent EBCT, and a positive calcium score was considered positive for ACS. No patient with a negative calcium score using EBCT had a cardiac event at 4-month follow-up. McLaughlin et al. [28] and Georgiou et al. [26] also demonstrated the high negative predictive value of the absence of coronary artery calcium for the exclusion of ACS. In a 7-year follow-up study, Georgiou et al. [26] demonstrated that patients with no coronary artery calcium could be discharged safely with an annualized future event rate of 0.6%.

ED rule out of myocardial infarction The high negative predictive value of contrast-enhanced CCT for the detection of coronary artery disease makes it an attractive tool to rule out myocardial infarction. The utility of contrast-enhanced CCT has been reported in three single-center studies. Hoffmann et al. [29•], in a prospective double-blind observational cohort study, demonstrated the feasibility of CCT in 103 consecutive patients awaiting hospital admission to rule out myocardial infarction. All patients were low risk. Forty percent of patients had no CT evidence of atherosclerotic plaque. None of these patients was determined to have ACS. Sixty percent of patients had demonstrable atheroma, including all 14 patients with ACS. The presence of a significant stenosis (> 50%) was excluded in 71% of these patients, none of whom had ACS. A significant stenosis was detected in 13 patients, eight of whom had ACS. In 17 patients, a significant stenosis could not be excluded. Six of these patients were determined to have ACS. The overall positive and negative predictive value of CCT for the detection of ACS was 47% and 100%, respectively. In a registry-based observational study, Rubinshtein et al. [30•,31] assessed the impact of CCT on clinical decision making in 58 intermediate-risk patients. This represented one half of the potential intermediate-risk population presenting to their ED with chest pain. Forty-one patients were considered by two physicians to have ACS. Nineteen of these patients had established coronary heart disease. Only 10 of the 22 patients with no prior diagnosis of coronary heart disease were considered to have ACS after

Assessment of Acute Chest Pain by CT

CCT. CCT detected ACS with a sensitivity of 100% and a specificity of 92%. The initial diagnosis of ACS was revised in 44%, and after diagnostic revision, hospitalization was considered unnecessary in 45% of the ACS cohort. Goldstein et al. [32•] performed a randomized trial in 197 low-risk patients to compare the efficiency of CCT with single photon emission CT (SPECT). Ninetynine patients underwent CCT; 67 were considered normal and discharged. Twenty-four patients were considered to have moderate plaque (> 25%, < 70%) or were nondiagnostic. This cohort underwent SPECT evaluation. Three studies were considered functionally abnormal. The remaining eight patients were considered to have severe stenoses (> 70%) at CCT, and all were found to have severe stenoses at invasive catheter angiography. In the population assessed with CCT, an immediate diagnosis and discharge was achieved in 68% of patients. Eightyseven percent of the patients with moderate plaque or nondiagnostic scans were discharged after SPECT imaging. There were no events in the entire population. Interestingly, the rate of discharge was greater in the standard of care group. In both diagnostic studies, CCT increased the demand for invasive coronary angiography.

ED comprehensive thoracic evaluation A comprehensive thoracic CT evaluation to diagnose ACS, pulmonary embolism, and acute aortic syndromes (triple rule out) is desirable. A single study performed rapidly to exclude the major causes of life-threatening chest pain could make a significant impact on ED chest pain triage. White et al. [33], in an observational case series of 69 stable patients with chest pain, demonstrated the feasibility of a comprehensive cardiothoracic CT protocol. An initial CT assessment was made of noncardiac disease and for the contrast-enhanced presence of coronary artery calcification using the extended field of view images (ECG-gated 75% R-R interval). Further postprocessing and analysis of the CCT dataset for coronary artery anatomy, cardiac function, and myocardial perfusion abnormalities was performed. The consensus group reviewed the discharge diagnoses, clinical records, and all relevant standard care test results. The CT result was normal in 75% of the cases; coronary heart disease was found in 14%, and there were noncardiac fi ndings in 4%. The sensitivity and specificity for a diagnosis of a cardiac cause of chest pain were 83% and 96%, respectively. Johnson et al. [34] demonstrated the feasibility of 64-slice CCT in 55 patients. Adequate contrast enhancement of the pulmonary vessels, coronary arteries, and aorta was achieved in all cases. Regarding image quality of the coronary arteries, there was minor blurring in seven patients, and in one examination the images did not provide enough information for diagnosis. The average image quality rating was 1.2 on a scale in which 1 indicated no artifacts, 2 indicated minor motion artifacts, and 3 indicated image insufficient for diagnosis. The cause of chest pain was correctly

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identified with MDCT in 37 patients. Savino et al. [35], in an observational study of 23 patients, found 11 scans were completely normal, 10 indicated coronary artery disease (two of which were not considered significant), and two showed pulmonary embolism. Confi rmation of a significant coronary stenosis was made using invasive coronary angiography. Schertler et al. [36] demonstrated the feasibility of a comprehensive evaluation of the thorax using dual-source CT (DSCT). Unique to this study is the fact that no pre-scan β-blockade was administered. Vessel attenuation of different thoracic vascular territories was measured, and two independent readers semi-quantitatively analyzed image quality. With a mean scan time of 12 seconds and diagnostic image quality for the aorta and coronary and pulmonary arteries in 58 of the 60 patients enrolled, at last there may be a realistic possibility of ED triple rule out. Johnson et al. [37] examined 109 patients with DSCT using a body-weight-adapted contrast material injection regimen. Images were evaluated for the cause of chest pain, and the coronary fi ndings were correlated to invasive coronary angiography in 29 patients (27%). Overall sensitivity for the identification of the cause of chest pain was 98%. Correlation to invasive coronary angiography showed 100% sensitivity and negative predictive value for coronary stenoses.

Limitations It remains unclear which CCT imaging strategy should be implemented. Coronary calcium scoring as a “stand alone” test is not sufficient. Beyond the fi fth decade, calcium is the major constituent of coronary atherosclerotic plaque and may be of value in this patient cohort; however, in younger patients calcium scores are of limited value [38,39]. Secondly, the presence of coronary artery calcium cannot be considered pathognomonic for ACS or significant obstructive coronary artery disease. Finally, it must also be considered that ruling out coronary artery calcium is not equivalent to excluding ACS. Coronary calcium represents just 20% of the total coronary atherosclerotic plaque burden, and evidence suggests that noncalcified plaque rupture accounts for half of all ACS [40]. A recent publication observed that as many as 33% of patients who had presented with suspected ACS had no coronary calcium detected on CCT [41]. However, CCTdefi ned “soft and mixed plaque” represented 86% of all plaque detected in this patient cohort. Contrast-enhanced CCT also has limitations. Many patients who present at the ED with chest pain are distressed, breathing rapidly, and have high heart rates. The temporal resolution of existing systems may be inadequate to ensure high diagnostic image quality in all patients. The accuracy of contrast-enhanced CCT for the detection of the total coronary plaque burden remains unclear. Interobserver variability for the detection of noncalcified (fibroatheroma with predominantly lipid core) is fair at best. CCT is also unable to determine the hemodynamic

94 Cardiac Computed Tomography

significance of a coronary artery stenosis. Many of the CT studies performed have determined a significant coronary artery stenosis to be a greater than 50% occlusion of the vessel lumen due to the spatial limitation of the current technology. However many lesions that encroach on the vessel lumen by 50% to 70% are not of functional significance. Lesions defi ned as significant by CT (> 50% stenosis) may contribute to an increased number of investigations to establish the hemodynamic relevance of the stenosis, with a corresponding loss in the efficiency of an ED CT triage protocol and increased health care costs. Finally, a rule out coronary atheroma application for ED CT may be inappropriate for some patient groups in whom nonatherosclerotic sources of myocardial necrosis can occur (coronary artery spasm, embolism, dissection, cardiomyopathy, myopericarditis, and vasculitis) [40]. The comprehensive thoracic assessment poses significant challenges. The protocol differs from a dedicated coronary CT in several important respects. A large field of view is used to encompass the entire thorax, which facilitates assessment of the pulmonary vessels to a subsegmental level, ascending and descending thoracic aorta, and the pericardium (Fig. 10). A second important difference is the protocol for contrast administration. Unlike dedicated coronary CT, in which washout of contrast in the right heart is desirable, a triple rule out protocol must provide optimal enhancement of both the right and left heart for simultaneous visualization of the pulmonary arteries, the aorta, and the coronary arteries. Finally, this strategy is likely to expose patients to a higher radiation dose and is more prone to motion artifact particularly due to inadequate breath-hold.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

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Conclusions ED CT chest pain evaluation is feasible, and the noninvasive assessment of coronary artery disease, specifically the absence of coronary artery disease, appears to facilitate the early discharge of low-risk patients. Although coronary calcium imaging has good test characteristics, it may not be suitable for triage. It also remains to be determined whether additional information on regional wall motion abnormalities and perfusion defects may further improve the triage of patients with suspected ACS. Although the initial data are promising, the validation of a safe and cost-effective algorithm based on randomized, observational, multicenter trials is required before the application of clinical CCT in the ED. In addition, CT platforms with higher temporal and spatial resolution are essential to facilitate more robust imaging and enable widespread clinical use in this unique patient cohort.

Disclosures No potential confl icts of interest relevant to this article were reported.

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