A considerable number of patients with an acute coronary syndrome (ACS) who present with a 0 or low calcium score (CS) still demonstrate coronary artery disease (CAD) and significant stenosis. The aim of the present study was to evaluate the relation between the CS and the degree and character of atherosclerosis in patients with suspected ACS versus patients with stable CAD obtained by computed tomography angiography and virtual histology intravascular ultrasound (VH IVUS). Overall 112 patients were studied, 53 with ACS and 59 with stable CAD. Calcium scoring and computed tomography angiography were performed and followed by VH IVUS. On computed tomography angiography each segment was evaluated for plaque and classified as noncalcified, mixed, or calcified. Vulnerable plaque characteristics on VH IVUS were defined by percent necrotic core and presence of thin-cap fibroatheroma. If the CS was 0, patients with ACS had a higher mean number of plaques (5.0 ± 2.0 vs 2.0 ± 1.9, p <0.05) and noncalcified plaques (4.6 ± 3.5 vs 1.3 ± 1.9, p <0.05) on computed tomography angiography than those with stable CAD. If the CS was 0, VH IVUS demonstrated that patients with ACS had a larger amount of necrotic core area (0.58 ± 0.73 vs 0.22 ± 0.43 mm 2 , p <0.05) and a higher mean number of thin-cap fibroatheromas (0.6 ± 0.7 vs 0.1 ± 0.3, p <0.05) than patients with stable CAD. In conclusion, even in the presence of a 0 CS, patients with ACS have increased plaque burden and increased vulnerability compared to patients with stable CAD. Therefore, absence of coronary calcification does not exclude the presence of clinically relevant and potentially vulnerable atherosclerotic plaque burden in patients with ACS.
The prognostic value of the coronary calcium score (CS) has been extensively investigated, and very low rates of cardiac events have been demonstrated in patients with a 0 CS. However, preliminary data in patients presenting with acute coronary syndrome (ACS) suggest a larger contribution of noncalcified plaque to overall plaque burden compared to patients with stable coronary artery disease (CAD). As a consequence, a 0 or low CS may significantly underestimate overall plaque burden in the setting of ACS. However, current data on how clinical presentation affects the relation between CS and coronary plaque characteristics are still scarce. An important advantage of computed tomography angiography (CTA) over the CS is that additional information on stenosis severity and plaque composition can be obtained. Invasively, virtual histology intravascular ultrasound (VH IVUS) offers detailed information on coronary plaque characteristics. The aim of the present study was to compare the relation between the CS and plaque characteristics in patients with ACS versus patients with stable CAD assessed noninvasively by CTA and invasively by VH IVUS.
Methods
The study population consisted of 112 patients without known CAD (defined as previous myocardial infarction, coronary arterial bypass grafting, and percutaneous coronary intervention) who were referred for CTA for noninvasive evaluation of chest pain. Subsequently patients were referred for invasive coronary angiography in combination with VH IVUS based on a patient’s clinical presentation and/or imaging results. Patient data were prospectively collected in the departmental cardiology information system (EPD-Vision, Leiden University Medical Center, Leiden, The Netherlands) and retrospectively analyzed. Patients with diagnostic computed tomography angiography image quality were selected from an ongoing registry addressing the relative merits of CTA compared to other imaging procedures. Fifty-three patients with suspected ACS were included; ACS was defined according to guidelines of the European Society of Cardiology and the American College of Cardiology/American Heart Association. The remaining 59 patients presented to the outpatient clinic with stable chest pain complaints. Contraindications for CTA were (1) (supra)ventricular arrhythmias, (2) renal insufficiency (glomerular filtration rate <30 ml/min), (3) known allergy to iodine contrast material, (4) severe claustrophobia, and (5) pregnancy.
The CS and CTA were performed using a 64-row or a 320-row scanner (Aquilion 64 or Aquilion One, Toshiba Medical Systems, Otawara, Japan). Beta-blocking medication (metoprolol 50 or 100 mg) was administered if a patient’s heart rate was ≥65 beats/min and no contraindications existed. A noncontrast-enhanced low-dose scan (tube voltage 120 kV, tube current 200 mA) was performed to assess the total CS. A total CS of 0 was defined as no calcium, a CS of 1 to 399 was defined as mild calcium, and a CS of ≥400 was defined as severe calcium. A standard scanning protocol was followed for the 64-row and 320-row contrast-enhanced computed tomography angiography scanning as previously described.
Computed tomography angiography datasets were evaluated using dedicated software (Vitrea 2.0 or Vitrea FX 1.1 Vital Images, Minnetonka, Minnesota) by 2 experienced readers blinded to baseline patient characteristics, CS, and VH IVUS results. Coronary arteries were divided into 17 segments according to a modified American Heart Association classification. Per segment 1 coronary plaque (if present) was selected at the site of the most severe luminal narrowing. To describe plaque composition, plaques were further classified as (1) noncalcified plaque (plaques with lower density compared to contrast-enhanced lumen without any calcification), (2) mixed plaque (noncalcified and calcified elements in single plaque), or (3) calcified plaque (plaques with high density compared to contrast-enhanced lumen).
VH IVUS examinations were performed during invasive coronary angiography according to standard protocols. A dedicated IVUS console (Volcano Corporation, Rancho Cordova, California) was used for the examination. VH IVUS was performed with a 20-MHz 2.9Fr phased-array IVUS catheter (Eagle Eye, Volcano Corporation). Subsequently, with a speed of 0.5 mm/s, motorized automated IVUS pullback was performed until the IVUS catheter reached the guiding catheter. Images were stored for off-line analysis. VH IVUS analysis was performed by 2 experienced observers blinded to baseline patient characteristics, CS, and computed tomography angiography results. Off-line analysis of VH IVUS images was performed using dedicated software (pcVH 2.1 and VIAS 3.0, Volcano Corporation). The lumen and media–adventitia interface were defined by automatic contour detection, and on all individual frames manual editing was performed. Analysis was performed on a per-plaque basis. Plaque area (square millimeters) was defined as plaque area plus media area and was calculated as vessel area minus lumen area. Four plaque components were differentiated into different color codes (fibrotic tissue displayed in dark green, fibrofatty in light green, necrotic core in red, and dense calcium in white) as validated previously. Vulnerable plaque characteristics on VH IVUS were defined by percent necrotic core and presence of thin-cap fibroatheroma. A thin-cap fibroatheroma was defined as a lesion with a plaque burden ≥40%, presence of confluent necrotic core >10%, and no evidence of an overlying fibrous cap.
Statistical analysis was performed using SPSS 16.0 (SPSS, Inc., Chicago, Illinois). The impact on clinical presentation (ACS vs stable CAD) of coronary plaque characteristics (plaque burden and composition) on computed tomography angiography was explored in all patients and related to the CS score (no, mild, or severe). The impact of clinical presentation on coronary plaque characteristics in relation to the CS score was also evaluated using VH IVUS. Continuous values are expressed as mean ± SD. Continuous values were assessed with Student’s t test if normally distributed or with the Mann–Whitney test if not normally distributed. Categorical values are expressed as number (percentage) and were compared between groups with 2-tailed chi-square test. A p value <0.05 was considered statistically significant.
Results
Overall 112 patients were studied; 53 patients presented with ACS and 59 presented with stable CAD. No differences were observed in the prevalence of risk factors for CAD between the 2 groups ( Table 1 ). In patients with ACS cardiac troponin levels were increased in 11 patients (21%), and in 31 patients (58%) significant CAD was demonstrated on invasive coronary angiography. VH IVUS could be performed in all patients and was obtained in 241 vessels (124 vessels [51%] in ACS and 117 vessels [48%] in stable CAD). Regarding the CS, calcium was absent (CS 0) in 11 patients (21%) with ACS and in 10 patients (17%) with stable CAD. Moreover, mild calcium (CS 1 to 399) was observed in 37 patients (70%) with ACS and in 32 patients (54%) with stable CAD. Severe calcium (CS ≥400) was demonstrated in 5 patients (9%) with ACS and in 17 patients (29%) with stable CAD (p = 0.04).
| Patient Characteristics | Suspected ACS | Stable CAD | p Value |
|---|---|---|---|
| (n = 53) | (n = 59) | ||
| Age (years) | 57 ± 11 | 58 ± 11 | 0.69 |
| Men | 37 (70%) | 35 (59%) | 0.25 |
| Obesity (body mass index ≥30 kg/m 2 ) | 12 (23%) | 8 (14%) | 0.24 |
| Hypertension ⁎ | 28 (53%) | 36 (61%) | 0.38 |
| Hypercholesterolemia † | 32 (60%) | 29 (49%) | 0.23 |
| Positive family history | 25 (47%) | 29 (49%) | 0.83 |
| Smoker | 25 (47%) | 22 (37%) | 0.29 |
| Type 2 diabetes mellitus | 9 (17%) | 17 (29%) | 0.14 |
| Mean calcium score | 149 ± 141 | 530 ± 1258 | <0.001 |
| Presence of significant stenosis (≥50% luminal narrowing) ‡ | 31 (58%) | 35 (59%) | 0.93 |
⁎ Defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg or use of antihypertensive medication.
† Serum total cholesterol ≥230 mg/dl or serum triglycerides ≥200 mg/dl, or treatment with lipid-lowering drugs.
In total 662 coronary plaques were identified on computed tomography angiography. Overall 327 coronary plaques (49% of total amount of plaques) were observed in patients with ACS, whereas 335 coronary plaques (51% of total amount of plaques) were observed in patients with stable CAD (p = 0.14). No difference in total plaque burden on computed tomography angiography, reflected by the mean number of total plaques per patient, was observed between patients with ACS (6.3 ± 3.1) and those with stable CAD (5.7 ± 3.7, p = 0.30). Subsequently, the mean number of plaques per patient was compared between patients with ACS and those with stable CAD within the various CS categories ( Figure 1 ). If coronary calcium was absent, significantly more plaques were present in patients with ACS (5.0 ± 3.2) than in patients with stable CAD (2.0 ± 1.9, p = 0.04). Similarly, if coronary calcium was mild, significantly more plaques were still detected in patients with ACS (6.6 ± 3.0) than in patients with stable CAD (5.0 ± 2.9, p = 0.02). However, if coronary calcium was severe, no differences were observed.
Differences in plaque composition were evaluated within the various CS categories between patients with ACS and those with stable CAD. Regarding noncalcified plaques, if coronary calcium was absent, significantly more noncalcified plaques were observed in patients with ACS (4.6 ± 3.5) than patients with stable CAD (1.3 ± 1.9, p = 0.03). Similarly, if coronary calcium was mild, significantly more noncalcified plaques were observed in patients with ACS (2.9 ± 2.5) than in patients with stable CAD (1.9 ± 2.4, p = 0.03). However, for severe coronary calcium, no significant differences were identified in the mean number of noncalcified plaques between patients with ACS (0.8 ± 1.1) and those with stable CAD (1.5 ± 1.5, p = 0.36). For mixed plaques, if coronary calcium was mild, more mixed plaques were observed in patients with ACS than in patients with stable CAD (3.0 ± 2.1 vs 1.6 ± 1.9, p = 0.002). In contrast, for calcified plaques, in patients with mild or severe calcium, calcified lesions were more prominent in patients with stable CAD compared to patients with ACS for each CS category.
VH IVUS images were available for 429 coronary plaques; 219 plaques were present in patients with ACS (49% of total amount of plaques) and 210 plaques were present in patients with stable CAD (51% of total amount of plaques). No difference in total plaque burden on VH IVUS images, reflected by the mean plaque area per patient, was observed between patients with ACS (7.55 ± 3.09 mm 2 ) and those with stable CAD (7.68 ± 3.14 mm 2 , p = 0.66). In addition, difference in plaque area between patients with ACS and those with stable CAD within the various CS categories was assessed as presented in Figure 2 . If coronary calcium was absent, plaque area (square millimeters) was significantly larger in coronary plaques of patients with ACS compared to patients with stable CAD. However, for mild or severe coronary calcium, plaque area (square millimeters) was not significantly different between patients with ACS and those with stable CAD.
Plaque composition on VH IVUS images was compared between patients with ACS and those with stable CAD within the different CS categories as illustrated in Figure 3 . Interestingly, if coronary calcium was absent, necrotic core area (square millimeters) was significantly larger in coronary plaques of patients with ACS than in those with stable CAD. This difference was preserved when coronary calcium was mild. However, for severe coronary calcium, no differences in necrotic core area between coronary plaques of patients with ACS and patients with stable CAD were identified. For the mean number of thin-cap fibroatheromas within different CS categories, the number of thin-cap fibroatheromas was significantly larger in patients with ACS in all CS categories compared to patients with stable CAD ( Figure 4 ). An example of a patient with ACS without coronary calcium but with considerable atherosclerosis is provided in Figure 5 .
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