Canadian Journal of Cardiology 29 (2013) 1687e1694

Clinical Research

Early Atherosclerosis Detection in Asymptomatic Patients: A Comparison of Carotid Ultrasound, Coronary Artery Calcium Score, and Coronary Computed Tomography Angiography Benjamin Schroeder, MD,a Gordon Francis, MD,b Jonathon Leipsic, MD,c Brett Heilbron, MD,c G.B. John Mancini, MD,d and Carolyn M. Taylor, MD, MPHc a

Division of Endocrinology and Metabolism, St Paul’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada

b

Department of Medicine, UBC James Hogg Research Centre, St Paul’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada

c

Department of Medical Imaging and Division of Cardiology, St Paul’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada d

Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

ABSTRACT

  RESUM E

Background: Detailed multimodality assessment of subclinical atherosclerosis in asymptomatic subjects referred for risk stratification has not been performed. We analyzed the detection of early atherosclerosis using 3 imaging modalities: coronary artery calcium (CAC) scoring, carotid ultrasound (US), and coronary computed tomography angiography (CCTA). Methods: Asymptomatic subjects free of known vascular disease scheduled to undergo a carotid US for risk stratification were invited to undergo CCTA/CAC. Subjects taking lipid-lowering medication were

valuation de taille e de l’imagerie multimodale de Introduction : L’e roscle rose subclinique chez les sujets asymptomatiques oriente s l’athe  te  re alise e. Nous avons analyse  pour la stratification du risque n’a pas e tection de l’athe roscle rose pre coce en utilisant 3 modalite s la de d’imagerie : le score calcique des artères coronaires (CAC), chographie (EG) carotidienne et la coronarographie par tomodensil’e trie (Coro-TDM). tome thodes : Les sujets asymptomatiques sans maladie vasculaire Me connue inscrits pour subir une EG carotidienne en vue de la stratifi-

Clinical risk assessment tools for the prediction of cardiovascular events exist, however, these tools are imprecise and function best at a population, rather than individual, level.1 Most coronary heart disease deaths occur in individuals classified as low or intermediate risk using traditional risk assessment.2-8 To address this, imaging is endorsed as a consideration for risk refinement, particularly in intermediate, and select low risk patients.5,8-12 The basis of imaging for risk refinement rests in the detection of “subclinical atherosclerosis.” Definitions of “subclinical atherosclerosis” vary widely according to modality used, may reflect different stages in the atherosclerotic process, and, particularly in the early stages, might be demonstrated in 1 vascular bed and not others.13 Accordingly, although the

underlying principle of imaging use for risk refinement might be intuitive, the clinical application can be complex. The purpose of this exploratory study was to correlate the detection of subclinical atherosclerosis using carotid ultrasound (US), coronary artery calcium (CAC) scoring, and coronary computed tomography angiography (CCTA), in an asymptomatic population not using lipid-lowering therapy, in whom further risk stratification was believed to be clinically warranted. A detailed analysis of atherosclerosis detected using these 3 imaging modalities and with respect to multiple, diverse definitions of early atherosclerosis relevant to each method was undertaken.

Methods Patient enrollment Received for publication July 8, 2013. Accepted October 1, 2013. Corresponding author: Dr Carolyn M. Taylor, B476A e 1081 Burrard St, Vancouver, British Columbia V6Z 1Y6, Canada. Tel.: þ1-604-806-8785; fax: þ1-604-806-8137. E-mail: [email protected] See page 1694 for disclosure information.

From July 2010 to August 2011, asymptomatic patients seen at a cardiovascular risk reduction clinic in a quaternary referral centre (the Healthy Heart Program Prevention Clinic, St Paul’s Hospital, Vancouver, British Columbia, Canada) who were scheduled to undergo a carotid US for clinical risk

0828-282X/$ - see front matter Ó 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.10.003

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excluded. All images were assessed by experienced core laboratory personnel. Carotid intima media thickness  75th percentile for age and sex, CAC > 0, and detection of either carotid or coronary artery plaque were indicators of atherosclerosis. Results: Fifty patients were included with a median age of 53 years. Atherosclerosis was observed in 28%, 78%, and 90% of subjects using CAC, CCTA, and carotid US, respectively. All subjects showed atherosclerosis on at least 1 modality. In 36 patients with a CAC score ¼ 0, 69% and 86% had atherosclerosis on CCTA and carotid US, respectively. Conclusions: In this detailed analysis, all subjects identified to warrant further risk stratification had subclinical atherosclerosis on at least 1 imaging modality. Concordance between modalities was highly variable, dependent on the specific definition of atherosclerosis used. Carotid US and CCTA detection of plaque were significantly more sensitive than CAC > 0 in this middle-aged population. Considering the prevalence of subclinical disease on carotid US and CCTA, the threshold at which to treat warrants further research.

 te  invite s à subir la Coro-TDM/CAC. Les sujets cation du risque ont e miant ont e  te  exclus. Toutes les images ont e  te  prenant un hypolipide value es par le personnel expe rimente  du laboratoire central. e paisseur de l’intima-me dia de la carotide  75e percentile de l’âge L’e tection de plaque carotidienne ou de et du sexe, le CAC > 0 et la de  te  des indicateurs d’athe roscle rose. plaque de l’artère coronaire ont e sultats : Cinquante (50) patients dont l’âge moyen e tait de 53 ans Re te  inclus. L’athe roscle rose a e te  observe e chez 28 %, 78 % et 90 % ont e des sujets à l’aide de la CAC, la Coro-TDM et l’EG carotidienne,  de l’athe roscle rose dans au respectivement. Tous les sujets ont montre . Chez 36 patients ayant un score de CAC ¼ 0,69 % et moins 1 modalite  de l’athe roscle rose à la Coro-TDM et l’EG carotidienne, 86 % ont montre respectivement. taille e, tous les sujets identifie s Conclusions : Dans cette analyse de e ont montre  de pour justifier une stratification du risque plus pousse roscle rose subclinique dans au moins 1 modalite  d’imagerie. La l’athe s a e  te  très variable, de pendamment concordance entre les modalite finition de l’athe roscle rose utilise e. La de tection de la plaque à de la de  te  significativement plus sensible l’EG carotidienne et à la Coro-TDM a e qu’à la CAC > 0 chez cette population d’âge moyen. Si l’on considère valence de la maladie subclinique à l’EG carotidienne et à la la pre Coro-TDM, le seuil auquel traiter justifie d’autres recherches.

stratification were invited to undergo CCTA/CAC. Only patients aged 20 years or older who provided permission to be contacted for participation in research studies were offered participation. Patients were excluded from the study if they had a diagnosis of vascular disease, diabetes mellitus, chronic kidney disease, past treatment with lipid-lowering therapy greater than 3 months duration or contraindication to CCTA/ CAC (renal dysfunction with estimated glomerular filtration rate < 60 mL/min/m2, pregnancy, contraindication to bblocker use, contraindication to nitroglycerin use, history of intravenous (IV) contrast reaction, or significant arrhythmia). Patients were eligible for study enrollment irrespective of Framingham Risk Score, providing the referring physician believed that carotid US was indicated for clinical risk stratification. The carotid US and CCTA/CAC were performed at a quaternary referral diagnostic imaging centre (St Paul’s Hospital). Studies were performed within 3 months of each other. Each carotid US and CCTA/CAC was anonymized and assigned a unique identifying number. All images were transferred to an experienced imaging core laboratory (Cardiovascular Imaging Research Core Laboratory, University of British Columbia) for detailed analysis. Data were abstracted from patients’ charts and included age, sex, smoking status and duration, presence of hypertension, family history of vascular disease, medication use, and other medical conditions. Physical exam data including height, weight, body mass index, blood pressure, stigmata of dyslipidemia, and evidence of vascular disease was collected. Fasting lipid values and blood sugar, apolipoprotein B100, and high-sensitivity C-reactive protein were recorded. Framingham risk score (FRS) was calculated using the general cardiovascular risk profile.6 Based on results from the Framingham Offspring Study,14 suggesting a 1.7- to 2-fold increased risk, the FRS was doubled in individuals with a history of premature coronary artery disease (men younger than 55 years, women younger than 65 years) in a first-

degree relative. Subjects were classified into low ( 0 CAC > 100x CAC > 75th percentile

Value, % (n) 28 (14) 38 (19) 46 (23) 42 (21) 74 (37) 88 (44) 88 (44) 90 (45) 10 (5) 78 (39) 34 (17) 8 (4) 28 (14) 2 (1) 6 (3)

CAC, coronary artery calcium; CCTA, coronary computed tomography angiography; IMT, intima-media thickness. * Any plaque with maximum thickness 1.5 mm. y Any focal structure that encroaches into the arterial lumen of at least 0.5 mm. z Any focal structure with maximum thickness ≥50% of IMT. x CAC ¼ 118.

CAC score CAC scores were derived using validated methodology to allow for extraction of calcium score data from contrast-

enhanced CCTA.16 As previously published, a Hounsfield unit threshold of 320 was used. All other components of the Agatston method were used.17 Definitions of early atherosclerosis A detailed analysis of subclinical atherosclerosis was undertaken using a comprehensive set of definitions including: 1. CAC score > 0 Agatston units 2. CCTA: a. Presence of a plaque b. Presence of a plaque  25% diameter stenosis c. Presence of a plaque  50% diameter stenosis 3. Carotid US: a. Any focal plaque  25% diameter stenosis b. Diffuse IMT  75th percentile for age and sex c. Total area of all plaques  10 mm2 d. Any plaque that meets any of the Mannheim criteria,18 including: i. Plaque with a maximum thickness  1.5mm ii. Focal structure that encroaches into the arterial lumen of at least 0.5mm iii. Focal structure with maximal thickness  50% of surrounding IMT e. Presence of either IMT  75th percentile or presence of any focal plaque Statistical analyses Data are presented as mean  SD or as categorical percentages. Differences between patients were assessed using t tests, c2 test, or Fisher exact test when appropriate. Interand intraobserver reproducibility was assessed using Pearson correlation, k testing, measures of accuracy (mean of paired differences), and measures of precision (SD of paired differences) when appropriate. The relationship between diverse definitions of early atherosclerosis was assessed using c2 tests. A P < 0.05 was considered to be statistically significant. All

Figure 2. Comparison of measures of atherosclerosis. CAC, coronary artery calcium; CTA, computed tomography angiography; DS, diameter stenosis; IMT, intima-media thickness.

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Table 3. Comparison of different measures of disease on carotid ultrasound and plaque on CCTA

Carotid ultrasound Any focal plaque  25% diameter stenosis % Row % Column IMT > 75th percentile % Row % Column Total area of all plaques  10 mm2 % Row % Column Any plaque with max plaque thickness  1.5 mm* % Row % Column Any focal structure that encroaches into the arterial lumen of at least 0.5 mmy % Row % Column Any focal structure with maximum thickness  50% of IMTz % Row % Column Any plaque that meets any Mannheim criteria*,y,z % Row % Column Presence of either IMT  75th percentile or presence of any focal plaque % Row % Column Normal carotid ultrasound (IMT < 75th percentile and no plaques) % Row % Column

CCTA, no plaque, n ¼ 11

CCTA, with plaque, n ¼ 39

14 18

86 31

15 27

84 41

13 27

87 51

10 18

90 49

22 73

78 74

25 100

75 85

25 100

75 85

24 100

76 87

0 0

100 13

Pearson c2 ¼ 1.567, asymptotic significance ¼ 0.211. k ¼ 0.159, approximate significance ¼ 0.211. CCTA, coronary computed tomography angiography; IMT, intimamedia thickness. * Any plaque with maximum thickness 1.5 mm. y Any focal structure that encroaches into the arterial lumen of at least 0.5 mm. z Any focal structure with maximum thickness 50% of IMT.

statistical analyses were performed using SPSS 11.0.1 (IBM, Armonk, NY). Results A total of 50 subjects were included in the study. Subject recruitment is summarized in Figure 1. Baseline demographic characteristics of participants are shown in Table 1. Using carotid US, the percentage of individuals with measures of early atherosclerosis varied from 28% to 90% depending on the measure used (Table 2). Only 10% of individuals had a normal carotid US (IMT < 75th percentile with no plaque present). On CCTA, 78% of individuals were found to have atherosclerosis, defined by the presence of any coronary artery plaque (Table 2). Most plaques (56%) caused minimal luminal narrowing (25%). Of those with coronary atherosclerosis, 46% demonstrated only noncalcified plaque. Four individuals (8%) had obstructive disease (plaque  50%

diameter stenosis), despite their asymptomatic status. The mean radiation exposure from CCTA was 1.82 mSv ( 0.95), which is less than annual background radiation estimates. On CAC scoring, most (72%) subjects had a CAC score of 0 (Table 2). CAC > 75th percentile was seen in 3 subjects (6%) and only 1 individual had CAC > 100. Because CAC scores were extracted from CCTA results, no additional radiation was associated. All 50 subjects had evidence of atherosclerosis on at least 1 imaging modality (Fig. 2). There was no significant correlation between any of the carotid US measures of atherosclerosis and the presence of plaque on CCTA (Table 3). There was a 68% concordance between carotid US and CCTA which was not significant. There was no significant relationship between carotid US measures of early atherosclerosis and the presence or absence of a CAC score > 0. Notably, 25% of subjects with a CAC score ¼ 0 had evidence of a carotid plaque  25% diameter stenosis and 86% had either IMT  75th percentile or focal carotid plaque present (Fig. 3). Table 4 shows a comparison of the CAC definitions of early atherosclerosis to CCTA abnormalities. There were significant associations between the 2 methods of detection of early atherosclerosis. Only 1 patient (3%) had a CAC score ¼ 0 and a plaque  50% diameter stenosis but up to 59% had evidence of some degree of plaque formation in the coronary tree. Maximal concordance (86%, P < 0.0001) was seen between CAC > 0 (vs CAC ¼ 0) and any plaque  25% diameter stenosis or any calcified/partially calcified plaque on CCTA. All subjects, irrespective of FRS, had evidence of subclinical atherosclerosis by at least 1 modality/definition used. Table 5 notes the measures of subclinical atherosclerosis by adjusted and unadjusted FRS. There were very few biological variables that were associated with measures of atherosclerosis. Older age, higher mean fasting blood glucose, and the presence of stigmata of hyperlipidemia including arcus cornealis or xanthomas correlated with at least 1 imaging method on atherosclerosis. Discussion Subclinical atherosclerosis by any definition examined in this study was widely prevalent in this referral population when detailed analysis of 2 vascular beds was performed. The correlation of atherosclerosis detection using carotid US and CCTA was only moderate at best, and a significant proportion of individuals would not have been identified if only 1 modality for atherosclerosis detection was used. A CAC score of 0 was misleading in this young population (mean age, 53 years) with high prevalence of genetic dyslipidemia. These findings are consistent with previous studies which suggest that carotid US might be more sensitive for atherosclerosis detection than CAC in younger individuals.19,20 If atherosclerosis detection for risk stratification is required in a younger population then imaging other than CAC might be of greater benefit. Additionally, studies by Brook et al.21 and Sillesen et al.22 suggest that carotid total plaque area is more sensitive and specific for excluding coronary stenosis than CAC, IMT, or high-sensitivity C-reactive protein, and that carotid plaque burden correlates more strongly with CAC than IMT or other noninvasive measures. Although

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Figure 3. Percentage of patients with carotid US abnormalities and CAC Score ¼ 0. CAC, coronary artery calcium; DS, diameter stenosis; IMT, intima-media thickness; max, maximum; US, ultrasound.

randomized controlled trial data to justify the use of imaging methods as an adjunct to or a replacement for traditional risk stratification methods are currently lacking, our analysis suggests that carotid US and CCTA might detect an earlier phase of atherosclerosis than does CAC. Although a CAC score of 0 might portend a good long-term prognosis, this might not be a rational way to identify patients warranting lipid therapy in attempts to slow or arrest the progression of early atherosclerosis. If documentation of subclinical atherosclerosis is believed to be of value, clinicians might need to consider imaging of multiple vascular beds and reserving CAC score use for older individuals. A literature review23 of 34 studies comparing carotid IMT (CIMT) with coronary atherosclerosis reported only modest correlations, which was believed to reflect variability in atherosclerosis development between the vascular beds rather than limitations of CIMT measurements. In contrast to the majority of the studies included in this literature review, our study enrolled asymptomatic, young patients. It is the authors’ hypothesis that especially in the early stages, the detection of Table 4. Relationship between CCTA definitions of early atherosclerosis and the presence or absence of a CAC score > 0 Coronary CTA Any CTA plaque  50% DS % Row % Column Any CTA plaque  25% DS % Row % Column Any CTA plaque % Row % Column

CAC ¼ 0, n ¼ 36

CAC > 0, n ¼ 14

25 3

75 21

0.061

29 14

71 86

< 0.0001

64 69

36 100

0.022

P

CAC, coronary artery calcium; CCTA, coronary computed tomography angiography; DS, diameter stenosis.

atherosclerosis might vary according to vascular bed studied. Additionally, potential measurement variability/error and limited sample size must be considered as potential alternative explanations for the variation seen in the detection of subclinical atherosclerosis using each modality. The imaging modalities used in this study varied widely in technique and measure of atherosclerosis. CIMT uses a 2dimensional assessment of a limited sample (10 mm in the far wall of the common carotid within 2 cm proximal to the bulb) as opposed to CCTA, which offers a 3-D assessment of the medium and large calibre coronary vessels (with more limited assessment of small vessels and branches). The detection of calcium throughout the entire coronary tree is sought through CAC scoring. The significant differences imposed by imaging technique alone must be considered in evaluating the asymmetrical detection of subclinical atherosclerosis. Additionally, the measurement (direct vs indirect) of atherosclerosis differs according to modality used. Although still a subject of some debate, IMT is generally considered a surrogate for atherosclerosis. Similarly, CAC is believed to represent a surrogate marker. CCTA, in contrast, is believed to represent a direct assessment of atherosclerosis. Although each of these assumptions can be challenged, differences in detection are undoubtedly influenced by the target of study and the assumptions used. Study limitations This exploratory analysis of multimodality assessment of subclinical atherosclerosis in 2 vascular beds had a limited sample size and included multiple comparisons. The study population included a high prevalence of individuals with genetic dyslipidemia being referred to a cardiovascular risk reduction clinic at a quaternary referral centre. The high incidence of atherosclerosis seen in this study was most likely

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Table 5. Measures of atherosclerosis and FRS Adjusted FRS Measure of atherosclerosis CAC  0 (n ¼ 14) n, % Row n, % Column Any carotid plaque  25% DS (n ¼ 14) n, % Row n, % Column IMT  75th percentile (n ¼ 19) n, % Row n, % Column Plaque on CCTA (n ¼ 39) n, % Row n, % Column IMT  75th percentile or carotid plaque (n ¼ 45) n, % Row n, % Column

Low (< 10%), n ¼ 23

Moderate (10%-19%), n ¼ 18

High ( 20%), n ¼ 9

6 (43) 6 (26)

6 (43) 6 (33)

2 (14) 2 (22)

6 (43) 6 (26)

7 (50) 7 (39)

1 (7) 1 (11)

9 (47) 9 (39)

8 (42) 8 (44)

2 (11) 2 (22)

17 (44) 17 (74)

16 (41) 16 (89)

6 (15) 6 (67)

22 (49) 22 (96)

16 (36) 16 (89)

7 (15) 7 (78)

Low (< 10%), n ¼ 27

Moderate (10%-19%), n ¼ 18

High ( 20%), n ¼ 5

7 (50) 7 (26)

6 (43) 6 (33)

1 (7) 1 (20)

7 (50) 7 (26)

6 (43) 6 (33)

1 (7) 1 (20)

11 (58) 11 (41)

7 (37) 7 (39)

1 (5) 1 (20)

20 (51) 20 (74)

15 (38) 15 (83)

4 (11) 4 (80)

26 (58) 26 (96)

15 (33) 15 (83)

4 (9) 4 (80)

Unadjusted FRS CAC  0 (n ¼ 14) n, % Row n, % Column Any carotid plaque  25% DS (n ¼ 14) n, % Row n, % Column IMT  75th percentile (n ¼ 19) n, % Row n, % Column Plaque on CCTA (n ¼ 39) n, % Row n, % Column IMT  75th percentile or carotid plaque (n ¼ 45) n, % Row n, % Column

CAC, coronary artery calcium; CCTA, coronary computed tomography angiography; DS, diameter stenosis; FRS, Framingham Risk score; IMT, intima-media thickness.

due in part to a high prevalence of genetic dyslipidemia among subjects enrolled and the detailed imaging analyses undertaken. Although an invasive gold standard method was not used, the noninvasive identification of atherosclerosis and its surrogates represents the real world experience. Additionally, asymptomatic atherosclerosis is present even in the more general populations at a young age as shown in autopsy studies.24 Accordingly, we believe that the findings underscore the caution required when restratifying risk using diverse imaging methods with different performance characteristics in differing age groups and with their own unique definitions of early atherosclerosis. CAC scores were derived from the contrast CCTA studies to minimize radiation exposure in this asymptomatic, young population. Although work on extracting CAC scores from contrast enhanced scans has demonstrated significant correlation (r2 ¼ 0.99),16 in this subclinical population using CCTA and carotid US definitions aimed to detect even minimal atherosclerosis, the risk of misclassifying individuals and underestimating CAC score using this extrapolation exists. Patients at high FRS were not excluded from study if the treating physician believed that imaging was clinically indicated. Because these individuals could be considered eligible for secondary prevention strategies irrespective of imaging findings, their inclusion in this study could be questioned.

However, most subjects enrolled were of low to intermediate FRS (FRS mean, 10.8  6.8%) and clinical instances exist in which further justification in support of secondary prevention might be desirable. Finally, randomized data rationalizing treatment with and without imaging for risk stratification and showing optimization of outcome through use of imaging are lacking. Although outcome data based on total plaque area exist,25,26 outcome data are limited for many measures of subclinical atherosclerosis. The outcomes of patients in this study were beyond the scope of this analysis. Despite the paucity of outcome data, imaging to aid in risk stratification, especially in the low (5%-9%) and intermediate (10%-19%) FRS groups, is currently endorsed and frequently practiced. The degree of subclinical atherosclerosis at which pharmacologic intervention is indicated, however, warrants further study. Conclusions Despite these limitations, the potential effect of imaging for the purpose of risk stratification and initiation of intensive treatment is demonstrated strikingly and provides provocative and clinically important insights. Concordance between the modalities was highly variable, and dependent on the specific definition used. Carotid US and CCTA detection of plaque

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were more sensitive than CAC > 0. Considering the strong evidence for low cardiovascular risk in patients with CAC ¼ 0, the threshold of subclinical disease at which to treat using carotid US or CCTA plaque warrants further research.

11. Anderson TJ, Gregoire J, Hegele RA, et al. Supplement to 2012 Update of the Canadian Cardiovascular Society Guidelines for the Diagnosis and Treatment of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. Available at: http://download.journals.elsevierhealth.com/mmcs/journals/ 0828-282X/PIIS0828282X12015103.mmc1.pdf. Accessed October 23, 2013.

Funding Sources Dr C. Taylor received funding from the Providence Health Care Boehringer Ingelheim Heart Centre Physician Scholar Award which helped to support this work.

12. European Association for Cardiovascular Prevention and Rehabilitation, Reiner Z, Catapano AL, et al. ESC/EAS guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818.

Disclosures Dr J. Leipsic has worked on medical advisory boards and is on the speakers bureau for GE Healthcare. All other authors have no conflicts of interest to disclose.

13. Shah PK. Screening asymptomatic subjects for sublinical atherosclerosis can we, does it matter, and should we? J Am Coll Cardiol 2010;56: 98-105.

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Early atherosclerosis detection in asymptomatic patients: a comparison of carotid ultrasound, coronary artery calcium score, and coronary computed tomography angiography.

Detailed multimodality assessment of subclinical atherosclerosis in asymptomatic subjects referred for risk stratification has not been performed. We ...
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