Abstract
BACKGROUND:
Unstable plaque is believed to be responsible for major adverse cardiac events (MACE).
OBJECTIVE:
To determine whether coronary computed tomography angiography (CCTA) could be used to predict future MACE.
METHODS:
Patients undergoing CCTA between January 2008 and February 2010 were consecutively enrolled in the study. The hospital database was screened for patients who later developed acute ST segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI) or cardiac death. Plaque scores were calculated and analyzed using one-way ANOVA to examine the relationship between plaque scores and MACE.
RESULTS:
Of the 8557 patients who underwent CCTA, 1055 had hospital records available for follow-up. During follow-up, 25 patients experienced MACE including death (six patients), heart failure (two patients), STEMI (11 patients) and NSTEMI (six patients). The plaque scores were significantly increased in patients who later died, developed heart failure or experienced STEMI (P<0.05). Calcification, erosion and severe stenosis were responsible for the events (P<0.05). Mild and moderate lesions, positive remodelling, drug-eluting stent placement, occlusion and diffuse lesions were not predictive of MACE (P>0.05).
CONCLUSION:
Severe calcification, erosion and severe stenosis predict death, heart failure and STEMI.
Keywords: Coronary computed tomography angiography, Coronary plaque, Major adverse cardiac events, Risk factor
Cardiac death, acute myocardial infarction, unstable angina and heart failure are coronary artery diseases with the worst prognoses, and are referred to as major adverse cardiac events (MACE) (1–4). Coronary angiography (CAG) was once considered to be the gold standard for the diagnosis of coronary artery disease, due to the advantage that the number of diseased vessels can predict prognosis (5–8). However, CAG is invasive and not ideal for long-term follow-up of cardiac patients. Coronary computed tomography angiography (CCTA) may be a better option for this purpose because it reflects real-world situations and is suitable for long-term monitoring. In addition, CCTA facilitates the visualization of both lumen and plaques within blood vessels and, therefore, may predict MACE more accurately (9–11).
METHODS
Patient population
The study protocol was approved by the Ethics Committee of the PLA General Hospital, Beijing, China. All patients provided written informed consent for CCTA as a part of their participation in the present study. Clinical data for patients who underwent CCTA between January 2008 and February 2010 were collected and recorded in the research database. The risks and benefits of the procedure were explained to all study patients by a dedicated nurse. Any patient who developed acute ST segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI) or cardiac death after CCTA was considered to have experienced a MACE.
CCTA protocol
In the present study, two computed tomography (CT) systems were used: the dual-source CT scanner (Somatom Definition, Siemens Medical Solutions, Germany); and the LightSpeed VCT scanner (GE Healthcare, USA).
Estimation of individual circulation time was based on the test bolus technique, using a 20 mL bolus and dynamic evaluation software (Dyn Eva, Syngo, Siemens, Germany). For contrast-enhanced scans, vessel opacification was achieved through the automated injection of 80 mL iohexol contrast (Ominpaque, GE Healthcare, China) through a power injector at a flow rate of 5 mL/s.
The collimation was 2 mm × 32 mm × 0.6 mm, slice acquisition was 64 mm × 0.6 mm, gantry rotation time was 330 ms, pitch was 0.20 to 0.43 (adapted to the heart rate), tube voltage was 120 kV and maximum tube current was 400 mAs per rotation. Image reconstruction was performed using a B26f kernel and a B46f kernel. Oral metoprolol (25 mg or 50 mg) was administered to patients whose heart rate was >65 beats/min to ensure temporal resolution. Helical scan data were obtained using retrospective electrocardiographic gating. Five 64-slice multidetector CT postprocessing techniques (maximum intensity projection, multiplanar reformat, cross-sectional area, and the diameter and area derived from a semiquantitative coronary software) were used to grade the plaques.
CT image colour coding
Colour coding was performed using a quantitative analysis software package (CREALIFE workstation, China) according to Hounsfield units to better differentiate the plaque characteristics. Hounsfield units 0 to 35 were coded purple, indicating a super soft spot; Hounsfield units 36 to 60 were coded blue, indicating a soft plaque; Hounsfield Units 60 to approximately 150 were coded yellow, indicating a fibre plaque; Hounsfield units 600 to 2000 were coded red, indicating calcification; and Hounsfield units 150 to 600 were coded as no colour, indicating a contrast-filled lumen. The lumen was not colour-coded to visualize the plaque details in grayscale formats (12,13).
The colour coding described above was able to produce the following images: erosive plaque, comprising a mixture of calcified plaque (coded red), lipid plaque (coded yellow), soft plaque (coded blue) and super-soft plaque (coded purple) – this complex ‘geological structure’ was unique (Figure 1); stents – colour-coding with stents showed spiral-shaped red images intertwined with yellow plaques (Figure 2); high-degree localized stenosis, which consisted of fibrous plaque (Figure 3); moderate stenosis (Figure 4); and coronary arterial remodelling, which was defined as a change in the vessel diameter at the plaque site in comparison with the reference segment set proximal to the plaque in a normal-appearing vessel segment (reference segment). Manual inspection, in both cross-sectional and longitudinal reconstructions, was used to define the remodelling index (plaque diameter/reference diameter). The remodelling index was calculated and reported as positive remodelling when the diameter at the plaque site was at least 10% larger than that of the reference segment; and calcification, which was colour-coded red.
Figure 1).
A unique erosive complex plaque, apparent on colour-coded coronary computed tomography angiography. LAD Left anterior descending artery; LCX Left circumflex artery; RCA Right coronary artery
Figure 2).
The strips of the right coronary artery (RCA), left anterior descending artery (LAD) and left circumflex artery (LCX) are shown. The stents were colour-coded as spirally-shaped red images intertwined with yellow plaques.
Figure 3).
High-grade localized stenosis in the left anterior descending artery (LAD). The stenosis consisted of a fibrous plaque. LCX Left circumflex artery; RCA Right coronary artery
Figure 4).
Moderate stenosis in the left anterior descending artery (LAD). LCX Left circumflex artery; RCA Right coronary artery
The strips of right coronary artery (RCA), left anterior descending coronary artery (LAD) and left circumflex coronary artery (LCX) are shown in Figure 2. The plaques consisted of calcified plaques coded as red, fibrous plaques coded as yellow, and super-soft plaques coded as blue and purple, which appeared mottled. The bottom panel of Figure 2 shows a cross-sectional picture of the lumen filled with contrast. However, the filling was uneven, suggesting that plaque was present in the lumen.
Plaque scores
Plaque scores were redefined according to the following (11): minor plaque, one point – plaque is definitely visible as a thin layer, with low-density shadow and estimated stenosis <30%; moderate plaque, two points – a thick layer of low-density plaque is visible, with estimated stenosis 30% to 75%; severe localized stenosis, three points – plaque is highly stenotic (>75%) and is of low density; erosive plaque, five points – plaque is of low density and ultra-low density and shows multiple features including calcification, severe localized stenosis, long lesions of ≥20 mm and involving >2 segments, ulceration and craters; calcification, one point – irrespective of its extensiveness; drug-eluting stent (DES), five points; plaque with positive remodelling, three points; complete occlusion, three points; and diffuse moderate lesions, two points.
Control method
In the present study, a self-controlled method was used. The plaques were divided into event-related plaques and nonevent-related plaques. The nonevent-related plaques served as a control. The culprit lesion was identified using echocardiography (ECG) in cases involving STEMI. In case involving NSTEMI, the culprit lesion was diagnosed by the presence of high-grade stenosis.
Statistical analysis
Statistical analysis was performed using SPSS version 11.5 (IBM Coporation, USA); P<0.05 was considered to be statistically significant. Quantitative variables were expressed as mean ± SD and categorical variables as frequencies or percentages. One-way ANOVA was performed to detect any differences in MACE and plaque characteristics.
RESULTS
Clinical characteristics of MACE
Between February 2008 and February 2010, a total of 8557 patients underwent CCTA at PLA General Hospital. Of the 1055 hospitalized patients, 25 developed MACE (Figure 5), which included six deaths, two heart failures, 11 STEMIs including two stent thromboses, and six NSTEMIs including two stent thromboses. The arteries of the 17 patients without MACE-related lesions served as a control.
Figure 5).
Major adverse cardiac events (MACE) and plaque characteristics. CCTA Coronary computed tomography angiography; DES Drug-eluting stent; NSTEMI non-ST segment elevation myocardial infarction (STEMI)
Six patients died during the follow-up. Of these, five patients died of heart failure and NSTEMI, and one died of DES thrombosis and STEMI. On the colour-coded CCTA, four patients presented with erosive lesions including chronic occlusion, calcified plaque, soft plaque, fibrous plaque and ulcers. One patient underwent implantation of a DES in 2005. In July 2009, CCTA showed only mild stenosis in this patient. In February 2010, the patient developed acute anterior myocardial infarction. CAG showed a LAD occlusion, which was recanalized by an emergency intervention. One week later, the patient died suddenly. In another patient, CCTA showed only a moderate lesion before the death of the patient. Two patients suffered from heart failure and NSTEMI. The patients had multiple erosive lesions.
Of the 11 patients who suffered from STEMI irrespective of survival, seven patients had severe localized stenosis, three had only moderate lesions, and one had DES. Of the six patients who suffered from NSTEMI irrespective of survival, two had severe localized stenosis, two had DES, and two showed moderate lesions in CCTA findings before developing MACE (Figure 1).
One-way ANOVA showed that advanced age, atrial fibrillation, history of percutaneous transluminal coronary intervention (PCI), low hemoglobin, tachycardia, and a high Grace score contributed to death and heart failure (Table 1). The differences among the groups were significant (P<0.05). Although there was a trend toward increased creatine and brain natriuretic peptide levels, decreased New York Heart Association functional class and ejection fraction, dilated left ventricle, and increased Killip class, the differences were not significant (P>0.05). The time of CT examination to the time of MACE was not different among the five groups.
TABLE 1.
Clinical characteristics
| Variable | Death (n=6) | Heart failure (n=2) | STEMI (n=9) | NSTEMI (n=4) | Stent thrombosis (n=4) | Mean ± SD | P |
|---|---|---|---|---|---|---|---|
| Age, years | 73.17±17.49 | 81.00±3.54 | 58.00±10.14 | 54±6.16 | 60±14.20 | 63.12±14.73 | 0.06 |
| Smoking, % | 2 (33) | 1 (50) | 4(44) | 2 (50) | 2 (50) | 0.98 | |
| Male sex, % | 5 (83) | 2 (100) | 7(78) | 3 (75) | 4 (100) | 0.81 | |
| Atrial fibrillation, % | 3 (50) | 1 (50) | 0(0) | 0 (0) | 0 (0) | 0.034 | |
| History of PCI, % | 3 (50) | 0 (0) | 1(11) | 1 (25) | 4 (100) | 0.022 | |
| Diabetes, % | 1 (17) | 1 (50) | 1(11) | 1 (25) | 2 (50) | 0.52 | |
| History of stroke, % | 1 (17) | 0 (0) | 0(0) | 0 (0) | 0 (0) | 0.51 | |
| Time from CT to MACE, days | 328.33±470.34 | 486.00±599.63 | 278.44±217.89 | 478.25±371.36 | 127.75±81.78 | 314.89±329.00 | 0.70 |
| Glucose, mmol/L | 6.15±1.089 | 6.70± 0.11 | 5.69±1.02 | 6.42±2.28 | 8.02±3.78 | 6.47±2.17 | 0.603 |
| LDL, mmol/L | 2.47±0.95 | 2.00 ±0.33 | 2.73±0.41 | 2.65±2.00 | 2.48±1.48 | 2.54±1.11 | 0.996 |
| Creatine, mmol/L | 129.77±60.03 | 81.00±14.28 | 87.25±26.21 | 75.03±8.85 | 78.75±21.06 | 95.48±41.54 | 0.202 |
| cTnT, mmol/L | 1.1665±2.42 | 2.00±0.35 | 2.62±3.11 | 1.74±1.30 | 0.33±0.34 | 1.62±2.32 | 0.742 |
| BMI, kg/m2 | 23.08±2.73 | 28.00±7.28 | 26.43±2.76 | 24.03±4.55 | 22.45±3.11 | 24.33±3.88 | 0.353 |
| BNP, mmol/L | 15625.16±15086.83 | 5138.00± 5644.83 | 933.1 | 26.3 | 238.25±180.36 | 8166.97±12178.61 | 0.537 |
| Hemoglobin, g/L | 138±18.38 | 128.00±7.78 | 149.75±7.40 | 149±8.49 | 149±4.02 | 139.22±16.57 | 0.047 |
| NYHA class | 3.5±0.84 | 4.0 ±0.71 | 2.62±1.11 | 2.67±1.15 | 2 | 2.83±1.07 | 0.207 |
| BP, mmHg | 143.83±17.08 | 124.00 ±30.41 | 128±16.21 | 131±17.35 | 138±13.5 | 133.71±17.83 | 0.451 |
| Heart rate, beats/min | 80.5±20.76 | 128.00± 45.25 | 76.56±3.77 | 67.67±9.50 | 68±9.70 | 79.29±21.49 | 0.004 |
| Ejection fraction | 0.45±0.11 | 0.49±0.02 | 0.54±0.06 | 0.52±0.08 | 0.57±0.12 | 0.51±.095 | 0.366 |
| LVEDD, mm | 56.5±9.22 | 57±2.83 | 48.29±4.68 | 45±12.29 | 42.67±10.14 | 50.19±9.50 | 0.139 |
| Killip score | 3.33±0.52 | 3.00±0.00 | 1.78±0.42 | 1.75 ±0.5 | 2±1.22 | 2.28±.93 | 0.603 |
| Grace score | 283.33±43.50 | 318.00±9.19 | 234.11±12.90 | 210±10.10 | 206±50.34 | 244.96±46.39 | 0.001 |
| SYNTAX score | 42.51±24.11 | 49.28 | 15.02±8.93 | 10.99±11.96 | 19.19±9.19 | 22.63±19.55 | 0.001 |
Data presented as mean ± SD unless otherwise indicated. BMI Body mass index; BNP Brain natriuretic peptide; BP Blood pressure; CT Computed tomography; cTnT Cardiac troponin T; LDL Low-density lipoprotein; LVEDD Left ventricular end diastolic diameter; NYHA New York Heart Association; PCI Percutaneouos coronary intervention; STEMI ST segment elevation myocardial infarction
Two-factor ANOVA was used to analyze the factors contributing to MACE (Table 2). Two-factor ANOVA was performed to identify the plaque that was responsible for the MACE. The patients who suffered from death, heart failure and STEMI had increased plaque scores (P<0.05). Patients with erosion plaques, high-degree localized lesions and calcification had a high likelihood of experiencing death, heart failure and STEMI (P<0.05). Mild and moderate lesions, positive remodelling, DES, occlusion and diffuse lesions did not show significant differences (P>0.05).
TABLE 2.
Two-factor ANOVA analysis of plaque characteristics and major adverse cardiovascular events
| Death (n=6) | HF (n=2) | STEMI (n=9) | NSTEMI (n=4) | DES (n=4) | Noninfarct (n=17) | Mean ± SD | P | |
|---|---|---|---|---|---|---|---|---|
| Calcification | 1.00±1.32 | 1.13±1.55 | 0.11±0.46 | 0.06±0.25 | 0.00±0.00 | 0.04±0.28 | 0.38±0.93 | <0.001 |
| Erosion | 2.92±5.50 | 5.63±7.76 | 0.56±1.99 | 0.00±0.00 | 0.00±0.00 | 0.20±1.40 | 1.35±3.95* | 0.02 |
| Mild to moderate | 0.29±0.69 | 0.13±0.35 | 0.14±0.49 | 0.13±0.50 | 0.06±0.25 | 0.06±0.31 | 0.16±0.51 | 0.10 |
| Positive remodeling | 0.00±0.00 | 0.75±2.12 | 0.42±1.27 | 0.56±1.21 | 0.00±0.00 | 0.24±1.01 | 0.3±1.09 | 0.36 |
| Severe stenosis | 2.88±3.90 | 4.88±4.22 | 0.89±1.80 | 0.38±1.02 | 0.19±0.75 | 0.39±1.40 | 1.49±2.86* | 0.00 |
| DES | 0.63±1.69 | 0.00±0.00 | 0.00±0.00 | 0.31±1.25 | 0.94±2.02 | 0.10±0.70 | 0.35±1.28 | 0.10 |
| Occlusion | 0.50±1.14 | 0.00±0.00 | 0.00±0.00 | 0.00±0.00 | 0.00±0.00 | 0.00±0.00 | 0.12±0.59 | 0.07 |
| Diffuse lesions | 0.00±0.00 | 0.00±0.00 | 0.06±0.33 | 0.00±0.00 | 0.00±0.00 | 0.04±0.28 | 0.02±0.20 | 0.31 |
| Mean ± SD | 1.03±2.74* | 1.56±3.78* | 0.27±2.74 | 0.18±0.75 | 0.15±0.80 | 0.13±0.85 | ||
| P | <0.001 | <0.001 | 0.03 | 0.29 | 0.42 | 0.28 |
>3 decimal points are omitted. DES Drug-eluting stent; HF Heart failure; NSTEMI Non-ST segment elevation myocardial infarction (STEMI)
DISCUSSION
The aims of the present study were to explore the possibility of using CCTA to predict MACE. It is well known that MACE can be predicted by traditional risk factors (14) or by invasive imaging techniques (15). The major limitations, however, are that they were either inaccurate compared with CAG or they were invasive and not practical for every patient. In the present study, noninvasive CCTA was used. CCTA had the advantage of being performed in real-life situations and could accurately delineate the coronary anatomy. The CCTA patient population consisted of mainly relatively stable and ambulatory patients, who were different from the patients in the catheter laboratory who were significantly sicker. This was a major difference from other investigations where CAG was used.
During the follow-up, only 25 cases of MACE were reported, which was very low; unfortunately, not every patient had been followed and the missing patients were mainly in the normal population. The patients left hospital after the CCTA and we could not track them; therefore, we included only 1055 patients who were hospitalized.
The advanced age, atrial fibrillation, history of PCI, anemia, tachycardia, high Grace score (16) and SYNTAX score (17) were correlated with the severity of the MACE, and the severity of the MACE was correlated the coronary plaque. Grace score was the most frequently used scoring system to evaluate the severity in acute coronary syndrome (ACS) (Table 1). As could be seen in Table 1, death and heart failure had the highest Grace score followed by survived STEMI, NSTEMI and stent thrombosis. It indicated that the Grace score had a significant capability to stratify the prognoses, as did the SYNTAX score.
However, these were the patients who had already developed MACE. If the MACE could be predicted by a noninvasive test such as the Framingham score (18) before the occurrence of MACE, the morbidity and mortality would be reduced, which would be more meaningful.
To this end we first developed a plaque scoring system modified from that described by Min et al (11). The plaque scoring system was developed to quantify the plaques and their contribution to the MACE. The plaques were classified into erosive lesions (five points), severe localized stenosis (three points), plaque with positive remodelling (three points), mild to moderate lesions (two points), DES (five points), complete occlusion (three points), moderate lesions (two points) and calcification (one point). The score was assigned based on literature reports and our own experience (11). To better delineate the coronary lesions, a colour-coding technique was used to identify the pathological features of the plaques (13). We believed that the erosive plaque and stent thrombosis contributed to poor outcomes while calcification tended to stabilize the plaque.
One may argue that our scoring system was subjective and arbitrary. In fact, our scoring system was a modified version derived from many existing scoring systems (11). For an inter-related scoring system it was impossible to manipulate one datum without affecting the other data. Our scoring system, therefore, was an objective one, although the sample size was small. The system needs to be tested in a larger cohort study in the future.
Two-factor ANOVA was used to analyze the factors contributing to MACE. The advantage of the analysis was that it pinpointed the responsible lesions in the table. For example, in the column ‘death’, the highest plaque score was found for erosive plaques. We speculated that the higher the score the higher the risk for MACE. The erosion plaque were associated with increased risk for death, heart failure and STEMI. On CCTA, the erosive plaque was a mixture of various colours instead of only one or two colours, and thus helped in forming a unique picture of an erosive plaque. It meant that various components of the plaque existed in one segment of the artery at the same time, without any sharp distinction. This represented a complex structure of the lesions, consisting of the ultra-soft plaque, soft plaque, thrombus and calcification mixed together. In our previous study, we compared discrete plaque and diffuse plaque in patients with ACS using CCTA. Follow-up data showed that MACE occurred more frequently in the diffuse plaque group than in the discrete plaque group (29.41% versus 11.48%; P=0.0288) (19). In ACS, the diffuse plaque was nearly synonymous with erosive plaque. The technology of colour coding helped us to further stratify the plaque. We found that erosion plaque indicated extremely poor clinical prognosis.
Severe stenosis was associated with an increased risk of death, heart failure and STEMI. There has been increasing dispute over the optimal medical treatment versus PCI (20). In stable coronary artery disease in which stenosis was not so severe, it was appropriate to treat the patient medically. However, if the stenosis was severe and the patient was symptomatic, medical treatment alone was not safe (21). There had been many prognostic studies using CCTA to date (22,23). During a median follow-up of 24 months, all-cause mortality occurred in 136 individuals. Individuals with obstructive two- and three-vessel disease or left main coronary artery disease experienced higher rates of death and composite outcome. It almost never occurred in patients with normal CCTA. Our study reaffirmed the fact that high-degree coronary stenosis should be dealt with more aggressively.
The most difficult challenge was encountered in moderate lesions. Fractional flow reserve (FFR) results have been widely accepted in the evaluation of stenosis (21). Patients in whom at least one stenosis was functionally significant (FFR ≤0.80) were randomly assigned to FFR-guided PCI. There were increased events in the medical therapy group (primary endpoint events: 4.3% in the PCI group and 12.7% in the medical therapy group). According to our own and others’ experience, stenosis is correlated closely with FFR (21). The moderate stenosis on CCTA would never exhibit FFR ≤0.80. Therefore, it was difficult to determine the prognostic significance of moderate lesions using present technology. Angiographically mild, thin-cap fibroatheromas, or a large plaque burden or small luminal area may be predisposing factors for MACE (15). The presence of noncalcified or mixed plaques was the strongest predictor of events. One of our patients had a moderate lesion 435 days before his death. Although the diagnosis of NSTEMI was confirmed in this patient, the prediction of MACE using CCTA was again difficult because during this period many unexpected events may have occured, which may not be related to the MACE.
One patient developed stent thrombosis and died although the initial CCTA only showed a moderate stenosis. This suggested that prediction of stent thrombosis using CCTA was difficult, due to the fact that stent thrombosis occurs suddenly without warning. Due to the noninvasive nature, CCTA has become the most popular post-PCI follow-up. Because of the artifact of the stent it was difficult to evaluate the images; however, restenosis or stent fracture has been detected. Complete or incomplete stent thrombosis has also been found on occasion. Although it was a catastrophic event, the incidence remained low. In our study, we did not detect significant difference among the five groups in terms of stent thrombosis.
The value of coronary calcification in diagnosis of coronary artery disease had long been recognized (25). In the present study, we once again showed that the higher the calcium score, the more severe the MACE, even though we assigned only one point for calcification.
In a controlled, prospective, randomized trial, a comparison is usually made between events and a suitable control. However, randomized trials require a large sample size to identify only a dozen cases of MACE. In the present study, a self-controlled method was used to increase the accuracy of plaque identification and reduced the costs. The plaques were divided into event-related plaques and non-event-related plaques, which served as a control (15).
CONCLUSION
The plaque characteristics revealed by CCTA are predictive of MACE. Erosion plaques and severe localized stenosis are powerful predictors of severe MACE. Use of clinical indexes significantly improves the prediction of MACE.
Footnotes
DISCLOSURES: The authors have no financial disclosures or conflicts of interest to declare.
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