Abstract
Aims
Adverse plaque characteristics determined by coronary computed tomography angiography (CTA) have been associated with future cardiac events. Our aim was to investigate whether quantitative global per-patient plaque characteristics from coronary CTA can predict subsequent cardiac death during long-term follow-up.
Methods and results
Out of 2748 patients without prior history of coronary artery disease undergoing CTA with dual-source CT, 32 patients suffered cardiac death (mean follow-up of 5 ± 2 years). These patients were matched to 32 controls by age, gender, risk factors, and symptoms (total 64 patients, 59% male, age 69 ± 10 years). Coronary CTA data sets were analysed by semi-automated software to quantify plaque characteristics over the entire coronary tree, including total plaque volume, volumes of non-calcified plaque (NCP), low-density non-calcified plaque (LD-NCP, attenuation <30 Hounsfield units), calcified plaque (CP), and corresponding burden (plaque volume × 100%/vessel volume), as well as stenosis and contrast density difference (CDD, maximum percent difference in luminal attenuation/cross-sectional area compared to proximal cross-section). In patients who died from cardiac cause, NCP, LD-NCP, CP and total plaque volumes, quantitative stenosis, and CDD were significantly increased compared to controls (P < 0.025 for all). NCP > 146 mm³ [hazards ratio (HR) 2.24; 1.09–4.58; P = 0.027], LD-NCP > 10.6 mm³ (HR 2.26; 1.11–4.63; P = 0.025), total plaque volume > 179 mm³ (HR 2.30; 1.12–4.71; P = 0.022), and CDD > 35% in any vessel (HR 2.85;1.4–5.9; P = 0.005) were associated with increased risk of future cardiac death, when adjusted for segment involvement score.
Conclusion
Among quantitative global plaque characteristics, total, non-calcified, and low-density plaque volumes as well as CDD predict cardiac death in long-term follow-up.
Keywords: cardiac death, coronary plaque, plaque burden, prognosis, coronary computed tomography angiography
Introduction
Cardiac death due to ischaemic heart disease occurs frequently without any pre-monitory symptoms. Acute coronary syndromes are mostly caused by luminal thrombosis following coronary plaque rupture rather than the progressively growth of already obstructive plaques.1 From histology and intravascular imaging studies, distinct features of ‘vulnerable plaques’ at higher risk of rupture have been identified including large plaque volumes, large necrotic core size, attenuated fibrous caps, spotty calcification, and outward arterial remodeling.2,3
Coronary computed tomography angiography (CTA) permits, in addition to luminal stenosis, detailed assessment of lesion characteristics including plaque composition, distribution, and burden, as well as coronary artery remodeling.4–8 Several qualitative high-risk plaque characteristics have been identified. They include positive remodelling, the presence of low-attenuation plaque, spotty calcification, and the ‘napkin-ring’ sign, and they correlate closely with intravascular imaging.9,10 These plaque features have been shown to be independent predictors of major adverse cardiac events.9,11,12 However, a recent study has shown that for mid-term follow-up, the cumulative number of patients suffering acute coronary syndrome is similar for patients both with and without high-risk plaques by CTA13; and this was primarily attributed to the diffuse nature of atherosclerotic coronary artery disease.
The aim of our study, therefore, was to investigate whether global per-patient quantitative plaque characteristics over the entire coronary tree predict future cardiac death after CTA on long-term follow-up. We performed a prognostic case-control study using a semi-automated software for plaque characterization, which included contrast density difference (CDD), a new normalized measure of luminal contrast kinetics shown to predict lesion-specific ischaemia.
Methods
Patient population
For this retrospective, single-centre case-control study, 2748 consecutive patients without prior history of coronary artery disease undergoing coronary CTA at Cedars-Sinai Medical Center, Los Angeles, CA, USA between 2007 and 2013 were screened for cardiac death during follow-up.
After a mean follow-up duration of 5 ± 2 years after the index CTA, the occurrence of cardiac death (death due to ischaemic heart disease or sudden death) was obtained through the National Death Index followed by comprehensive review of corresponding medical and death records by independent, experienced cardiologists. One-hundred and one patients were lost to follow-up. There were 109 all-cause death events, of which 35 were identified as cardiac death (Figure 1). In our cohort, cause of cardiac death was classified as acute myocardial infarction in 70%, chronic ischaemic heart disease in 6%, ventricular fibrillation in 3%, and fatal congestive heart failure in 21% of patients. From this group of cardiac deaths, 3 patients were excluded due to non-diagnostic CTA image quality and the remaining 32 patients were matched based on age, gender, risk factors (diabetes, hypertension, dyslipidaemia, smoking history, and family CAD history) and symptoms using a propensity score.14–16 Thus, the final cohort consisted of 64 patients (32 population cohort patients and 32 matched control cases). The leading indication for coronary CTA is presented in Table 1.
Figure 1.
Study enrolment flow chart. From 2748 patients screened for enrolment, 35 patients suffered from cardiac death. Due to non-diagnostic image quality in 3 patients, the final study cohort consisted of 32 patients with future cardiac death and 32 control patients.
Table 1.
Baseline characteristic and outcome
| Variable | Total cohort n = 64 | Control cohort n = 32 | Cardiac death cohort n = 32 | P-value |
|---|---|---|---|---|
| Clinical characteristics | ||||
| Age (years) | 69 ± 10 | 68 ± 10 | 69 ± 11 | 0.788 |
| Male sex (n, %) | 38 (59) | 19 (59) | 19 (59) | 1.000 |
| BMI (kg/m2) | 28.4 ± 7.7 | 27.5 ± 6.1 | 29.3 ± 9.0 | 0.773 |
| Cardiovascular risk factors (n, %) | ||||
| Hypertension | 41 (64) | 21 (66) | 20 (63) | 0.794 |
| Hyperlipidaemia | 31 (48) | 11 (34) | 20 (63) | 0.024* |
| Diabetes mellitus | 12 (19) | 7 (22) | 5 (16) | 0.522 |
| Tobacco use | 13 (20) | 4 (13) | 9 (28) | 0.120 |
| Positive family hx for CAD | 19 (30) | 8 (25) | 11 (34) | 0.412 |
| Number of cardiovascular risk factors | 1.8 ± 1.1 | 1.6 ± 1.2 | 2.1 ± 1.1 | 0.110 |
| Framingham risk score | 13.3 ± 9.0 | 13.3 ± 8.5 | 13.3 + 9.6 | 0.973 |
| Low (n, %) | 21 (33) | 10 (31) | 11 (34) | 0.953 |
| Intermediate (n, %) | 21 (33) | 11 (34) | 10 (31) | |
| High (n, %) | 22 (34) | 11 (34) | 11 (34) | |
| Leading clinical indication for coronary CTA | ||||
| Chest pain and/or dyspnoea | 34 | 17 | 17 | |
| Positive ischaemia testing | 9 | 6 | 3 | |
| Risk assessment in asymptomatic patients | 11 | 5 | 6 | |
| Arrhythmia | 6 | 2 | 4 | |
| Others | 4 | 2 | 2 | |
BMI, body mass index; CAD, coronary artery disease.
P < 0.05.
The study was performed according to guidelines of the institutional review board. All patients provided written consent for use of their data.
Patient characteristics, including cardiac history and risk factors, were obtained by a structured interview when patients presented for CTA examination. The pre-test risk was assessed using the Framingham risk score.17
CT data acquisition and image acquisition
Coronary CTA was performed using a dual-source CT scanner (Somatom Definition, Siemens, Forchheim, Germany) in accordance with societal guidelines. For non-contrast scans, images were acquired by a prospectively electrocardiography (ECG) triggered acquisition mode protocol (120 kVp tube voltage for multi-slice scanning, slice thickness 2.5 mm). The scan range extended from the aortic arch to the diaphragm and was obtained during a single breath-hold. For contrast-enhanced scans, prospective and retrospective gating protocols were applied with a tube voltage of 100 kV in patients with a body weight ≤70 kg and 120 kV otherwise. Beta blockers (orally or intravenously) were administered to achieve a target heart rate <60 beats/min. Sublingual nitrates were administered to all patients. Iodinated contrast (65–130 ml) was power injected, followed by a saline flush.
Determination of coronary calcium score
From non-contrast scans, coronary calcium was quantified using the Agatston score with a semi-automatic commercially available software (ScImage, Los Altos, CA, USA).18
Plaque analysis from coronary CTA
Coronary artery analysis was performed per segment using the model of the Society of Cardiovascular Computed Tomography.19 Coronary CTA data sets were visually assessed for the presence of plaque in axial images and curved multi-planar reconstructions in at least two orthogonal planes. The extent of coronary atherosclerosis was determined by the segment involvement score (SIS).20
All coronary segments ≥ 2 mm diameter were analysed quantitatively by using semi-automated software (Autoplaque research software, Cedars-Sinai Medical Center, Los Angeles, CA, USA) by an experienced reader blinded to patient characteristics and clinical data. A low intra- and inter-observer variability for plaque assessment using Autoplaque has been demonstrated in earlier work.21 The processing time ranged between 20 and 30 min for complete coronary tree analysis, depending on the number of plaques present. Images were displayed in multi-planar format and the proximal and distal location of each segment was marked. Scan-specific attenuation thresholds were computed by the software for non-calcified and calcified plaque and lumen, as previously described.22,23 Absolute volumes (in mm³) of non-calcified (NCP), low-density NCP, calcified (CP), and total plaque were computed. Low-density NCP was defined as the portion of NCP with density levels ≤ 30 Hounsfield units (HU). Plaque burden was defined as the plaque volume normalized to the vessel volume (plaque volume × 100%/vessel volume), expressed separately for each plaque component. Plaque composition was defined as volume of the plaque component divided by total plaque volume in percentage. Quantitative percent stenosis was calculated as ratio of the narrowest lumen diameter and the mean of two non-diseased reference points and was analysed with ≥ 50% (significant) and ≥ 70% (severe) cut-offs.24 The software computes the luminal contrast density, defined as attenuation per unit area, similar to ‘area gradient’, over 1 mm cross-sections of the arterial segment.25 The contrast density per 1-mm cross-section was defined as the mean lumen attenuation in HU divided by the lumen area. The contrast density difference is the maximum percent difference in measured contrast density with respect to the proximal reference cross section (with no disease, Figure 2).26,27 The CT-Leaman Score was calculated for all patients as previously described.28
Figure 2.
Example of contrast density difference measurement. This panel illustrates contrast density difference, defined as the maximum percent difference in luminal contrast density (at the small green circle, green arrow in the lesion) with respect to the proximal reference cross-section (large blue circle, blue arrow).
Statistical analysis
Statistical analysis was performed using STATA software (version 11 StataCorp LP). Continuous variables were expressed as mean ± standard deviation, categorical variables as frequencies and percentage, unless otherwise specified. Shapiro–Wilk test was used to assess normality for continuous data. Two-sample t-test or Wilcoxon rank-sum test were applied to compare groups for continuous variables, Pearson χ2 or Fisher exact test for small cell counts were used to compare groups for categorical variables. Association of quantitative plaque features with cardiac death during follow-up was assessed using Cox regression models, with shared frailty to take into account matched pairs; Schoenfeld residuals were assessed to verify that assumptions of proportional hazards were met. We examined the continuous measures, as well as for any increase greater than 50% and 60% centile cut-points in the whole cohort. The log-rank test was used to compare the survival across groups and visualized using Kaplan–Meier curves. For normalization to age, parameter was divided by age in years. For multi-variable analysis, stepwise logistic regression models taking into account matched cases and controls were also used to examine independent relationships between quantitative plaque measures and cardiac death. A P-value < 0.05 was considered statistically significant.
Results
In the cohort of 2748 consecutive patients undergoing coronary CTA (mean age 58.4 ± 13.1 years), 62% were male. The prevalence of hypertension, diabetes, hyperlipidaemia, smoking, and family history were 45%, 12%, 57%, 10%, and 40% in this cohort.
Patient characteristics
The patient characteristics of the matched cohort are presented in Table 1. The study cohort included 38 males (59%) with a mean age of 69 ± 10 years. There was no significant difference in age, Framingham risk score, BMI and cardiovascular risk factors except hyperlipidaemia between the cardiac death and control groups at the time of CTA examination (Table 1). In those 32 patients who suffered from cardiac death, mean time to death was 3.2 ± 2.4 years (range 3 days to 7.4 years). Fourteen patients underwent catheterization and out of these 5 patients underwent percutaneous coronary intervention (4 in the cardiac death group). The mean time difference between CTA and catheterization was (398.1 ± 568.1 days).
Assessment of coronary CTA
Out of 722 possible segments with a diameter > 2mm to be analysed, 17 segments had to be excluded due to non-diagnostic reasons. Seven hundred and five segments were finally included, atherosclerosis was present in 271 segments. The SIS was significantly higher in patients who suffered from cardiac death (5.2 ± 3.4) compared to their controls (3.2 ± 3.7, P = 0.027, Table 2). Figures 3and4 show quantitative plaque analysis examples from our study.
Table 2.
Visual and quantitative coronary CTA plaque variables (updated)
| Variable | Control cohort n = 32 | Cardiac death cohort n = 32 | P-value |
|---|---|---|---|
| Visual assessment | |||
| No CAD | 20 (63) | 26 (81) | 0.096 |
| Segment involvement score | 3.2 ± 3.7 | 5.2 ± 3.4 | 0.027* |
| Coronary calcium score | 283 ± 442 | 970 ± 807 | 0.02*a |
| CT-Leaman score | 5.6 ± 5.3 | 9.4 ± 5.9 | 0.02* |
| Quantitative plaque assessment | |||
| NCP volume (mm3) | 106.0 ± 174.1 | 216.8 ± 184.1 | 0.006* |
| LD-NCP volume (mm3) | 10.6 ± 23.9 | 29.3 ± 37.6 | 0.004* |
| CP volume (mm3) | 44.8 ± 88.2 | 86.0 ± 110.8 | 0.020* |
| Total plaque volume (mm3) | 150.8 ± 244.4 | 302.8 ± 265.9 | 0.007* |
| Diameter stenosis (%) | 42.4 ± 36.8 | 63.7 ± 35.97 | 0.024* |
| Diameter stenosis ≥ 50% | 17 (53) | 22 (69) | 0.200 |
| Diameter stenosis ≥ 70% | 7 (22) | 15 (47) | 0.035* |
| Contrast density difference (%) | 25.9 ± 37.0 | 48.8 ± 40.0 | 0.004* |
| NCP burden (%) | 0.12 ± 0.04 | 0.13 ± 0.02 | 0.093 |
| LD-NCP burden (%) | 0.01 ± 0.00 | 0.02 ± 0.00 | 0.016* |
| CP burden (%) | 0.03 ± 0.01 | 0.05 ± 0.01 | 0.176 |
| Total plaque burden (%) | 0.15 ± 0.04 | 0.18 ± 0.03 | 0.096 |
| NCP composition (%) | 51 ± 40 | 61 ± 34% | 0.420 |
| LD-NCP composition (%) | 3.6 ± 0.0 | 7.0 ± 0.1 | 0.020* |
CAD, coronary artery disease; CP, calcified plaque; NCP, non-calcified plaque; LD-NCP, low-density NCP; CT, computed tomography
aAvailable in 28/64 patients.
P < 0.05.
Figure 3.
Example of semi-automated plaque analysis. Left main and left anterior descending artery (A) and left circumflex artery (B) of a male, 88-year-old patient with shortness of breath and hyperlipidaemia, who suffered subsequent cardiac death. Cross-sectional views are shown at the top and longitudinal straightened views at the bottom. Red overlay shows non-calcified plaque; yellow overlay shows calcified plaque. Total NCP volume was 293 mm3, LD-NCP volume was 20.2 mm3, total plaque volume was 563 mm3, and contrast density difference was 47.1%.
Figure 4.
Three-dimensional rendered view of another example for plaque analysis over the coronary tree for a control patient. The coronary lumen is in blue, non-calcified plaque in red, and calcified plaque in yellow.
In univariate analysis, coronary arteries of patients suffering from cardiac death showed significantly higher NCP (P = 0.006), LD-NCP (P = 0.004), CP (P = 0.020) and total plaque volumes (P = 0.007), higher burden of LD-NCP (P = 0.016), higher quantitative percentage stenosis (P = 0.024), more often a diameter stenosis > 70% (P = 0.035), higher composition of LD-NCP (P = 0.020), and an increased contrast density difference (P = 0.004) compared to control patients (see Table 2 and Figure 5). There was no significant difference in NCP, CP, and total plaque burden as well as in NCP composition between the two cohorts.
Figure 5.
Quantitative plaque characteristics in patients with cardiac death and controls. Comparison of quantitative plaque features in patients with future cardiac death (in red) and controls (in grey). CP, calcified plaque; LD-NCP, low-density non-calcified plaque; NCP, non-calcified plaque. *P < 0.05.
When variables were normalized to age, we found a significant increase in all three components of components (NCP P = 0.005; LD-NCP P = 0.005; CP P = 0.022) as well as in total plaque volume (P = 0.006) for the cardiac death cohort. LD-NCP burden normalized to age was significantly increased in the cardiac death cohort (P = 0.023), there was no difference observed for age-adjusted NCP, CP, and total plaque burden (Table 3).
Table 3.
Analysis of quantitative plaque parameters normalized by age
| Variable | Control cohort n = 32 | Cardiac death cohort n = 32 | P-value |
|---|---|---|---|
| NCP volume (mm3/year) | 1.46 ± 2.34 | 3.14 ± 0.51 | 0.005* |
| LD-NCP volume (mm3/year) | 0.14 ± 0.30 | 0.43 ± 0.11 | 0.005* |
| CP volume (mm3/year) | 0.61 ± 1.19 | 1.17 ± 0.27 | 0.022* |
| Total plaque volume (mm3/year) | 2.06 ± 3.33 | 4.32 ± 0.69 | 0.006* |
| NCP burden (%/year) | 0.18 ± 0.03 | 0.18 ± 0.15 | 0.928 |
| LD-NCP burden (%/year) | 0.01 ± 0.02 | 0.03 ± 0.03 | 0.023* |
| CP burden (%/year) | 0.23 ± 0.40 | 0.25 ± 0.21 | 0.078 |
| Total plaque burden (%/year) | 0.05 ± 0.10 | 0.06 ± 0.09 | 0.194 |
CP, calcified plaque; NCP, non-calcified plaque; LD-NCP, low-density NCP.
P < 0.05.
Predictors of cardiac death
Segment involvement score and coronary calcium score as well as NCP volume > 146 mm³, LD-NCP volume > 10.6 mm³, total plaque volume > 179 mm³, LD-NCP burden > 0.8% and CDD > 35% were significant predictors for cardiac death within the 5-year follow-up period (Tables 4 and 5). The receiver operator characteristic area under the curve for the prediction of cardiac death was very similar for low-density NCP, NCP, and total plaque volumes and did not increase significantly with adjustment for age [0.70 (95% confidence interval (CI): 0.58–0.83) for LD-NCP, 0.70 (95% CI: 0.56–0.83) for NCP, 0.69 (95% CI: 0.69 (95% CI: 0.56–0.83) for total plaque volumes, and 0.66 (95% CI: 0.53–0.80) for CP volume]. Survival curves for total plaque volume and CDD are presented in Figure 6. In this cohort of stable patients, stenosis ≥ 50% or stenosis ≥ 70% did not significantly predict cardiac death. From Table 5, NCP, LD-NCP, total plaque volume, and contrast density difference > 35% were associated with significant hazard of cardiac death, even after adjustment with SIS.
Table 4.
Prediction of cardiac death by SIS, coronary calcium score, and CT-Leaman score28
| Hazards ratio | 95% CI | P-value | |
|---|---|---|---|
| Segment involvement score | 1.4 | 1.0;1.9 | 0.03* |
| Coronary calcium score | 1.46 | 1.0;2.1 | 0.04* |
| CT-Leaman score | 1.06 | 1.0;1.12 | 0.05 |
P < 0.05.
Table 5.
Prediction of cardiac death adjusted by segment involvement score
| Hazards ratio | 95% CI | P-value | |
|---|---|---|---|
| NCP volume > 146 mm³ | 2.24 | 1.09;4.58 | 0.027*a |
| LD-NCP volume > 10.6 mm³ | 2.26 | 1.11;4.63 | 0.025*a |
| CP volume > 32 mm³ | 1.99 | 0.98;4.04 | 0.056 |
| Total plaque volume > 179 mm³ | 2.30 | 1.12;4.71 | 0.022*a |
| Contrast density difference > 35% | 2.85 | 1.38;5.88 | 0.005*a |
| NCP burden > 12.7% | 1.46 | 0.71;3.02 | 0.299 |
| LD-NCP burden > 0.8% | 2.54 | 1.21;5.38 | 0.014*a |
| CP burden > 3.3% | 1.53 | 0.76;3.11 | 0.235 |
| Total plaque burden > 17% | 1.10 | 1.0;1.22 | 0.04*a |
| Diameter stenosis ≥ 50% | 1.99 | 0.89;4.48 | 0.096 |
| Diameter stenosis ≥ 70% | 1.84 | 0.89;3.77 | 0.096 |
| Normalized by age | |||
| NCP volume > 2.2 mm³/year | 2.70 | 1.31;5.58 | 0.007*a |
| LD-NCP volume > 0.2 mm³/year | 2.45 | 1.20;5.01 | 0.014*a |
| CP volume > 0.4 mm³/year | 2.11 | 1.03;4.29 | 0.47 |
| Total plaque volume > 2.5 mm³/year | 2.55 | 1.24;5.25 | 0.011*a |
| NCP burden > 0.19%/year | 1.42 | 0.69;2.92 | 0.340 |
| LD-NCP burden > 0.01%/year | 1.75 | 0.8;3.9 | 0.17 |
| CP burden > 0.05%/year | 2.00 | 0.86;3.55 | 0.6 |
| Total plaque burden > 0.26%/year | 1.53 | 0.74;3.14 | 0.7 |
Thresholds in this table except for stenosis ≥ 50% and ≥ 70% correspond to the 60th centile values in the whole cohort for the quantitative features. Test of proportional-hazards assumption > 0.05 in all parameters presented in this table.
CI, confidence interval; CP, calcified plaque; NCP, non-calcified plaque; LD-NCP, low-density NCP.
aFor segment involvement score, P > 0.4 (non-significant) for all.
P < 0.05.
Figure 6.
Five-year Kaplan–Meier cardiac-death-free survival by quantitative plaque features. (A) Five-year Kaplan–Meier cardiac-death-free survival by non-calcified plaque volume (60th percentile level). (B) Five-year Kaplan–Meier cardiac-death-free survival by low-density non-calcified plaque volume (60th percentile level). (C) Five-year Kaplan–Meier cardiac-death-free survival by total plaque volume (60th percentile level). (D) Five-year Kaplan–Meier cardiac-death-free survival by contrast density difference (60th percentile level).
In multi-variable analysis of the plaque parameters in Table 2 by stepwise logistic regression, only LD-NCP volume > 10.6 mm³ and contrast density difference > 35% were predictive of cardiac death [odds ratios 3.3 (1.1–10.4), P = 0.039 and 4.1 (95% CI 1.22–13.3), P =0.022, respectively], even when adjusted for SIS (P = 0.45, non-significant). When adjusted by the CT-Leaman score, LD-NCP volume > 10.6 mm³ was predictive of cardiac death (odds ratio 3.6 (95% CI: 1.0–12.3), P = 0.04); with P = 0.8 (non-significant) for the CT-Leaman score.
Discussion
In this case-control study with quantitative plaque analysis, we show that per-patient NCP, LD-NCP and total plaque volumes, and CDD are associated with increased risk of cardiac death. We evaluated quantitative plaque burden variables per-patient which accounts for the fact that atherosclerosis is a diffuse disease. We found that contrast density difference, a new normalized measure of luminal contrast kinetics shown to predict lesion-specific ischaemia, is an independent predictor of cardiac death.
Coronary CTA-assessed features of individual plaques associated with a major adverse cardiac event have been extensively studied. Plaques featuring high-risk characteristics including positive remodelling and low-attenuation plaque are predictors of high event-risk.9,10,13,29,30 However, even plaques initially lacking high-risk plaque features may portend risk for a future adverse event since they may progress over time and evolve to higher risk lesions.13 Therefore, identifying characteristics of coronary artery disease in early stages may help identifying patients suffering from later events. In the present case-control study, we investigated quantitative plaque parameters for the prediction of future cardiac death during a long-term follow-up with a mean duration of 5 years. Most previous studies have considered shorter follow-up periods of 2–4 years.9,13,30 Plaque volume, separately for the per-patient non-calcified and the low-density non-calcified plaque components as well as for total plaque, was identified as a strong predictor for future death. This is in line with previous follow-up reports on plaque risk characterization for major adverse cardiovascular events.30,31 Versteylen et al.30 assessed a cohort of 25 cases with 101 randomly selected controls with stable chest pain with a mean follow-up of 26 months. In semi-automated plaque analysis, they found a significant per-patient increase in NCP and total plaque volume but did not analyse LD-NCP volume as a separate analysis parameter.
The plaque characteristics of individual plaques have been investigated regarding their prediction of subsequent cardiac events.13 It is widely recognized, however, that the overall plaque burden, as opposed to individual coronary lesions, are important predictors of events.20,31,32 In univariate analysis, we observed that the segmental involvement score, taking into account the visual extent of plaque, was higher in the patients with cardiac events. The SIS, however, is subjective, and takes into account only the number of segments with plaque, rather than the global plaque burden. The software-based quantitation of plaque burden used in our analysis allows objective assessment of the total plaque burden and the burden of individual plaque components that is not possible by visual analysis. In our study, quantitative plaque characteristics (LD-NCP, NCP, total plaque volume as well as contrast density difference, as seen in Table 5) significantly predicted future cardiac death, over visually assessed SIS. In multi-variable analysis, LD-NCP volume > 10.6 mm³ and contrast density difference > 35% showed significant incremental value for the prediction of cardiac death, over SIS. Previous studies have also reported that quantitative parameters described in this study—in particular, total plaque volume, low-density plaque volume, and contrast density difference—are associated with lesion-specific ischaemia by fractional flow reserve (FFR),26,33 as well as myocardial ischaemia by single-photon-emission computed tomography (SPECT) perfusion imaging.34
Contrast density difference, a normalized measure of luminal contrast kinetics, a variable that cannot be assessed visually, has been reported to be significantly increased in culprit lesions compared to non-culprit lesions in a cohort of patients with a first acute coronary syndrome.35 This luminal measurement parameter is associated with ischaemia by myocardial perfusion SPECT imaging and has been shown to effectively predict lesion-specific ischaemia by FFR in a cohort of patients with moderate- to high-grade stenosis.26,34 For the first time in this study, we could show a prognostic significance of contrast density difference for the prediction of a future cardiac death.
Limitations
Several limitations in this study need to be acknowledged. This was a single-centre study. Extensive or multi-variable subgroup analysis on the prediction of cardiac death, e.g. gender, was not feasible due to the small study size. Furthermore, we focused on future cardiac death events rather than overall major adverse cardiac events. Since follow-up for major adverse cardiovascular events (particularly myocardial infarction and late revascularization) for all the 2748 patients is ongoing, this prognostic outcome could not be considered in our current study. Plaque analysis and prediction of cardiac death were examined in a matched case-control cohort. However, while ours was a matched study, matching was performed with an overall propensity score to compare cases and controls with similar clinical cardiovascular risk profiles. Further larger studies are needed to confirm our findings.
Conclusions
Among quantitative global plaque characteristics, total plaque volume, non-calcified plaque and low-density non-calcified plaque volumes as well as contrast density difference are independent predictors of future cardiac death in long-term follow-up.
Funding
This work was supported in part by the Bundesministerium für Bildung und Forschung (01EX1012B, Spitzencluster Medical Valley); National Heart, Lung, and Blood Institute grant 1R01HL133616; and the Cardiac Imaging Research Initiative (Adelson Medical Research Foundation).
Conflict of interest: P.J.S., D.S.B., and D.D. received software royalties from Cedars-Sinai Medical Center and have a patent. M.M.H., M.M., Y.O., S.C., H.G., R.M.P., J.V., V.Y.C., A.R., B.K.T., S.H., and S.A. have nothing to declare.
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