The concept of high-risk plaque (HRP) criteria has recently emerged as specific indicators for ‘vulnerable plaque’ which may allow an early identification of patients at risk for future major adverse cardiac event. Thus, they could further sharpen risk calculators. However, little prospective outcome data are available to date for enrolling small sample size or collecting short- or mid-term outcomes [8] (Figs. 4, 5, 6, and 7).
Besides, a variety of different HRP criteria have been proposed: the napkin-ring (NR) sign, a pathohistological correlate for advanced/vulnerable atherosclerotic lesions, positive remodeling and spotty calcification (SC), and low-attenuation plaque (LAP) with < 30 Hounsfield units (HU) measured by plaque ‘area ROI’ (region of interest) or by ‘pixel lens’ screening techniques. In contrast, ex vivo studies identified LAP < 60 and < 90 HU as optimal cut-offs for lipid-core plaque [9, 10].
First, our analytic cross-sectional study identified LAP < 60 HU and NR sign are the most powerful high risk criteria. Other applied threshold (LAP < 30 and LAP < 90 were less. Additionally, HRP criteria were at higher strength than SC and stenosis severity which is concordant with Yang et al. [11] stating that there was no significant difference between stable and unstable group concerning degree of stenosis. Contrary, plaque burden exhibited better statistical performance than stenosis severity (P = 0.004) which was in line with study encountered by Nakazato et al. [12]; they assumed that aggregate plaque volume which represent plaque burden improve identification of ischemic lesion.
Currently, our study revealed significant positive relationship between remodeling index and plaque burden (rs = 0.218, P = 0.019). On the other hand, there is a significant negative relationship between remodeling index and degree of stenosis (rs = − 0.229, P = 0.016). As the coronary vessel expands, plaque enlargement occurs with delayed onset of luminal narrowing. These findings agreed with well-designed systematic review established by Kolossváry et al. [13]; they reported that atherosclerotic plaques initially tend to grow outward leaving lumen integrity unchanged. This could explain why plaque burden performed better in our study.
Second, we found increasing non-calcifying plaque component at the unstable patient group compared to the stable group (P ≤ 0.001). However, calcified plaques were more prevailing at the stable. Our findings are in line with study conducted by Feuchtner et al. [14]. They observed increasing non-calcified component in patient who had experienced major adverse cardiac event (MACE).
Third, we identified high-risk plaque criteria as NRS and LAP < 60 HU LAP < 60 (LAP OR 6.015 and 95% CI 2.56–14.12), NRS (OR 11.870 and 95% CI 2.65–53.08) which is in line with the study encountered by Feuchtner et al. [14]; they reported that NRS and LAP < 60 are the most powerful predictors of major adverse cardiac events.
We proposed cutoff value for LAP < 60 as optimal threshold to detect unstable cases; AUC was 0.796 (P = 0.004) and 60 HU (sensitivity 80.5%, specificity 86.3%) which is closely in line with the aforementioned same study. They proposed cutoff 63HU as optimal threshold; AUC was 0.89 (P ≤ 0.001) and 63 HU (sensitivity 89.2%, specificity 82.3%).
In different circumstances, a prospective mid-term outcome study was done by Motoyama et al. [15]. The study was encountered on larger sample size and defined high-risk plaque based on LAP < 30 as an independent predictor of major adverse cardiac event which disagreed with our findings; the criterion LAP < 30 had very low prevalence in unstable patient group. Further, the criterion LAP < 30 is based on only culprit lesion analysis that caused acute coronary syndrome, thus thrombotic apposition on the studied lesion that is characterized by lower CT densities. This may explain why LAP < 60 performed better in our study where all lesions are studied. Liu et al. [16] suggested that both cutoff values < 30 and < 60 were considered to be high-risk plaque features.
Additionally, our findings were in line with an ex vivo study done by Schlett et al. [17], showing LAP < 60 by ROI as valuable marker for lipid core plaque detection.
We observed increasing the number of plaques with increasing CT density indicating more stable fibrous plaque at the stable patient group. Similarly, long-term follow up study done by Feuchtner et al. [14] reported more stable fibrous plaques in patients who remained MACE free. In vivo studies utilizing optical coherence tomography as standard reference demonstrated that high-risk plaques have lower CT numbers as compared to stable lesions (35–45 vs. 62–79 HU; P ≤ 0.001) [12].
Remodeling index was higher in unstable patient group but not significant (P = 0.08 and 0.39 at R.I > 1.1 and 1.4 respectively) due to high prevalence of calcified and mixed plaques with predominate calcified portion that were usually associated with positive remodeling. Those findings agreed with what was suggested by Feuchtner et al. [14]; they stated that remodeling index (R.I) was higher in patients who had experienced major adverse cardiac events but no significant predictive due to inclusion of calcified nodules which appear larger on CTA (positively remodeled).
Our study revealed that NRS has excellent specificity to detect unstable cases (95.4%) which is matched with Liu et al. [16]. They stated that NRS had the best specificity to identify advanced lesions (98.9%, CI 97.6–100%). Notably, its low prevalence limits its sensitivity which is in line with study done by Feuchtner et al. [14]. They stated low prevalence of napkin ring sign in patient with major adverse cardiac event.
Napkin ring sign is caused by difference in CT attenuation between its lipid-rich core corresponding to central low attenuation area and fibrous plaque corresponding to rim of high CT attenuation. The current study showed that the CT number of the inner hypo dense core 43.93 ± 8.39 HU, while the CT number of hyper dense outer rim 141.93 ± 12.58 HU which is matched with the study done by Maurovich-Horvat et al. [9]. They stated that the average CT number of the hypodense core approximately 50–60 HU and higher CT number of the outer rim representing significant amount of fibrous tissue.
Our study was different from those who defined the napkin ring sign as higher CT attenuation of the outer ring than the inner and not more than 130 HU [18, 19].
We set higher threshold for the outer rim (< 150) while lower CT number for inner core (< 60); the outer rim may contain dense fibrous tissue and micro calcification which may lead higher HU than 130 [20].
Additionally, napkin ring sign lesions were usually associated with positive remodeling with high tendency to be non-obstructive as well as special distribution at left anterior descending (LAD). Consistently, these findings are in line with study done by Kashiwagi et al. [19]. They reported that napkin ring sign were more prevalent at left anterior descending (LAD) especially at its proximal segment.
Seifarth et al. [20] investigated the histological correlate of the napkin ring sign and concluded the detection of this specific plaque attenuation linked to lipid core, the size of the plaque, and the vessel area as measured in histology.
As regard spotty calcification (SC) criterion, it was prevalent only at the unstable patient group which hinders assessment of its risk despite being statistically significant (P = 0.001).
Up till now, high-risk plaques criteria are still research point with no standardization or verification. However, intensification of preventive measures is recommended in patients with high-risk criteria. Statins have proven beneficial effect in reducing mortality even in reducing mortality even in patients with non-obstructive CAD on CTA, related to stabilizing effect on lipid-rich fibroatheroma by increasing dense fibro calcified plaque component [21].
Study limitations
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The lack of intravascular ultrasound as reference to assess plaque morphology could be considered a limitation, although previous studies have shown strong correlation between multislice CT and intravascular ultrasound (IVUS) measurements of the composition of coronary atherosclerotic plaques.
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We did not measure intraluminal CT density which influences plaque attenuation and may show minor deviation along individual contrast bolus transient time.
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Spotty calcification was a common finding within outer high attenuation rim of napkin ring sign, so its prevalence may be overestimated.
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Another drawback of this study is the fact that the patient population of both patient groups was still rather small.