Vulnerable Plaque Characteristics at Coronary Computed Tomography Angiography

    Authors

    Abstract

    According to morbidity and mortality indicators, cardiovascular diseases are the leading public health issue in the Republic of Croatia and the European Union. Although mortality rates from ischemic disease have been reduced, Croatia is still categorized among countries with high cardiovascular risk. The guidelines of the European Society of Cardiology from 2020 for acute coronary syndrome (ACS) in patients with low to intermediate risk of coronary atherosclerotic heart disease (CHD) recommend coronary computed tomography angiography (CCTA) as an alternative to invasive coronarography. In most patients with suspicion of CHD, CCTA leads to the diagnosis of non-obstructive diseases, which causes the majority of ACS cases. Multi-slice Computed Tomography scanners of the newest generation employ low doses of radiation and low contrast volume to reliably show the characteristics of vulnerable plaque: (i) positive remodeling, (ii) low attenuation plaque, (iii) spotty calcification, and the (iv) napkin-ring sign. Due to positive remodeling, these plaques are often non-obstructive, and according to the CAD-RADS 2.0 guidelines from 2022 all their characteristics should be specifically emphasized in CCTA findings. Based on the assessment of the prognostic value of vulnerable plaque characteristics for adverse cardiac events, CCTA has been shown to be equally valid as other invasive diagnostic methods. Additionally, it was shown to be useful in indicating the optimal medication therapy and monitoring its effects. The results of large international randomized trials indicate the direction of the treatment approach for vulnerable plaque.

    Keywords

    vulnerabilni plak, koronarna bolest srca, višeslojna kompjutorizirana tomografija koronarnih arterija, akutni koronarni sindrom, vulnerable plaque, coronary artery disease, coronary computed tomography angiography, acute coronary syndrome

    DOI

    https://doi.org/10.15836/ccar2023.7

    Full Text

    ## Vulnerable plaque characteristics at
coronary computed tomography angiography The current Coronary Artery Disease-Reporting and Data System 2.0 (CAD-RADS 2.0) guidelines from 2022 replaced the term “vulnerable plaque” with the term “high-risk plaque”. ( 22 ) However, since the original term, “vulnerable plaque”, has become commonplace in the medical community, we retained its use in this article. The following characteristics of this type of plaque are clearly visible at CCTA: (i) positive remodeling, (ii) low attenuation plaque, (iii) spotty calcification, and the (iv) napkin-ring sign. The prevalence of these characteristics is relatively high and estimated at approximately 30%. The current guidelines emphasize the importance of standardized notation in patient charts and recommend describing all of these characteristics of atherosclerotic plaque. ( 22 ) HRP (high risk plaque) should be added as a modifier to written examination findings when two or more of these characteristics are present. ## Positive remodeling Positive remodeling is most commonly seen in clinical practice. It denotes the outward expansion of the blood vessel wall at the location of the atherosclerotic plaque, leading to partial conservation of the lumen at the narrowing site of the coronary artery ( 34 ) ( Figure 1 , Figure 2 ). This characteristic can be quantified using the remodeling index initially suggested in studies with IVUS. Using IVUS, the remodeling index is calculated as the ratio of the area of the cross section at the narrowest spot and the area of the cross section of the vessel proximally and distally from the narrowing ( 35 ) ( Figure 3 ). CCTA often overestimates these values, and those greater than 1.1 are considered clinically significant ( Figure 4 ). Patients with ACS have higher index values than patients with angina and those with culprit plaques. ( 36 , 37 ) The remodeling index calculation for CCTA represents the ratio of the outer diameter of the vessel at the location of the plaque and the average normal diameter of the vessel proximally and distally from the stenosis. Plaques with positive remodeling at CCTA also have larger necroses and are more often described as thin-cap fibroatheroma (TFCA) on IVUS, whereas the positive remodeling index in TFCA measured by MSCT shows higher values than when using optical coherence tomography (OCT). ( 38 , 39 ) Male patient, 58 years old, with previously diagnosed coronary artery disease and a stent in the proximal left anterior descending artery referred to cardiac computed tomography angiography due to atypical chest symptoms and palpitations. Cardiac computed tomography angiography showed a stent in left anterior descending artery and non-obstructive non-calcified plaque in the distal right coronary artery (A, B, C). Detailed plaque analysis in the distal right coronary artery revealed high-risk plaque features – positive remodeling (remodeling index >1.1) with low attenuation values (20 Hounsfield units), and napkin-ring sign (D, E, F). Additionally, non-obstructive fibrous plaque with positive remodeling and attenuation values >30 Hounsfield units was revealed in the proximal circumflex artery (G, H). LAD = left anterior descending artery; RCA = right coronary artery; CX = circumflex artery; HU = Hounsfield units. Male patient, 46 years old, referred to cardiac computed tomography angiography with typical chest symptoms of angina and shortness of breath. Cardiac computed tomography angiography revealed sub-occlusive non-calcified high-risk plaque with positive (and negative) remodeling (remodeling index > 1.1) and low attenuation values (30 Hounsfield units) in the proximal right coronary artery (A, B, C, D). Additionally, non-obstructive non-calcified plaque was revealed in the mid left anterior descending artery with positive remodeling and an attenuation value of 53 Hounsfield units (E, F, G). RCA = right coronary artery; HU = Hounsfield units. Female patient, 64 years old, referred to cardiac computed tomography angiography due to long- standing insufficiently regulated diabetes and multiple cardiovascular disease risk factors. Cardiac computed tomography angiography revealed diffuse non-obstructive coronary artery disease. Curved multiplanar reconstruction and cross-section analysis of the proximal left anterior descending artery showed non-obstructive non-calcified plaque with positive remodeling (remodeling index <1.1) and spotty calcification (A, B). Male patient, 64 years old, with previously diagnosed non-obstructive coronary artery disease and low adherence to optimal medical therapy. Cardiac computed tomography angiography revealed non-obstructive non-calcified plaque in the proximal right coronary artery and proximal and mid left anterior descending artery (A, B, C, D). Detailed plaque analysis in the proximal RCA revealed considerable positive remodeling (remodeling index >1.1) with different attenuation values from 20 to 80 Hounsfield units that was consistent with lipid rich and fibrous components (E, F, G). Proximal left anterior descending cross-section plaque analysis revealed non-calcified fibrous plaque with positive remodeling and an attenuation value of 120 Hounsfield units, and spotty calcification (>300 Hounsfield units) (H, I). In comparison, attenuation values of 600 Hounsfield units are consistent with the contrast agent within the lumen (J). LAD = left anterior descending artery; RCA = right coronary artery; HU = Hounsfield units. ## Low attenuation plaque Low attenuation plaque is defined as non-calcified plaque with a core that has an attenuation value lower than 30 Hounsfield units (HU) in any measurement voxel. ( 22 ) In clinical practice, it is important to differentiate low attenuation plaque from positive remodeling, since the attenuation values in positive remodeling are often higher than 30 HU. It should be emphasized that the 30 HU threshold is generally accepted in clinical practice due to its high sensitivity and specificity in the detection of lipid-rich plaques ( 40 ) ( Figure 4 ). Lower attenuation values, as a rule, match the necrotic contents of the core, while higher diameter values of the core increase risk of ACS ( Figure 1 , Figure 2 ). Plaques with lipid contents on CCTA in comparison with IVUS readings generally have lower attenuation values. ( 40 , 41 ) However, both in studies and in clinical practice, using CCTA to differentiate between soft plaque with lipid contents and fibrous plaque is more challenging due to the density overlap in these two entities ( 40 , 42 ) ( Figure 2 ). Additionally, in comparison with OCT, low attenuation plaques on CCTA are associated with TFCA findings on OCT. ( 43 ) Despite differentiation between lipid plaque and fibrous plaque being challenging, as many as 88% of ruptured plaques in ACS have attenuation values lower than 30 HU, compared with only 18% in stable plaques. Automatized software solutions used for interpreting CCTA enable more reliable quantification of low attenuation plaque. ( 44 , 45 ) ## Spotty calcification In most cases of sudden cardiac death, histopathological plaque samples contain microcalcifications that are not visible at CCTA, as opposed to reliable imaging of spotty calcification. ( 34 ) Spotty calcifications are small calcifications within soft non-calcified plaque. Their attenuation is higher than 130 HU, and they are classified into the following categories: small (<1 mm), medium (1-3 mm), and massive (>3 mm) ( 46 - 48 ) ( Figure 4 ). Spotty calcifications are associated with plaques that cause ACS, and studies performed with CCTA demonstrated that this characteristic of vulnerable plaque is comparable with findings obtained by IVUS ( 37 , 48 , 49 ) ( Figure 3 ). ## Napkin-ring sign The napkin-ring sign is a unique CCTA characteristic of vulnerable plaque that can be seen on cross sections of non-calcified plaque. It comprises a necrotic core zone with low attenuation that borders the lumen and is surrounded by a ring-shaped zone of higher attenuation that matches the fibrous tissue ( 50 , 51 ) ( Figure 1 ). This is a reliable marker for the detection of TFCA and matches pathohistological and OCT findings. ( 39 , 51 , 52 ) The technological development of MSCT scanners at the start of the past decade has enabled us to conduct studies in which the napkin-ring sign was compared with other characteristics present in invasive cardiologic diagnostic methods and pathohistological findings. Diagnostic studies preceded studies focused on the assessment of the prognostic value of vulnerable plaque characteristics for adverse cardiac events. ## Prognostic value of vulnerable plaque
characteristics at coronary computed
tomography angiography The results of studies based on invasive and non-invasive imaging methods of the coronary arteries indicate that ACS was associated with non-obstructive plaque (<50%) in the majority of patients, moreover those with non-obstructive CHD (in comparison with patients without CHD) had significantly higher risk of cardiac death and ACS. ( 9 , 53 , 54 ) Previous studies on pathohistological samples demonstrated an association between vulnerable plaque characteristics and the clinical entity of ACS. Cardiological and radiological diagnostic methods for coronary imaging also allow us to quantify the risk of adverse cardiac events. Most studies focused on the prognostic values of vulnerable plaque characteristics, in addition to differences in study design and study populations, are also marked by different CV outcomes and follow-up times. Despite these differences, almost all studies found increased risk of adverse events to be associated with an increased number of vulnerable plaque characteristics. Additionally, some studies did not take into account the undoubtably positive effect of optimal medication therapy (OMT), which certainly impacted the outcomes. Follow-up time is extremely important, since reliable assessment of the prognostic value of individual characteristics of vulnerable plaque requires long follow-up periods due to potential plaque stabilization. In that sense, CCTA has shown itself to be a reliable tracking method for monitoring the natural course of CHD, and additionally improved prognostic values regarding plaque level are also partially ascribable to more recent software solutions that allow more precise quantification. ( 40 , 55 , 56 ) One of the first prospective studies on the prognostic values of low attenuation plaque, positive remodeling, and spotty calcification for predicting adverse cardiac events after more than two years of follow-up identified low attenuation plaque and positive remodeling as predictors. ( 57 ) Along with positive remodeling and low attenuation plaque, the napkin-ring sign was also shown to be a predictor for ACS and cardiac death after 2.3 years of follow-up. ( 58 ) A meta-analysis demonstrated a significant 12.1 times higher hazard ratio in patients with vulnerable plaque characteristics in comparison with those who had stable plaque, as well as a significantly higher number of low attenuation plaques (<30 HU) in ACS patients compared with the number of plaques detected in patients with stable angina. ( 37 ) Given the nature of positive remodeling from the lumen outwards, vulnerable plaque often causes non-obstructive stenosis, and the benefits of OMT are therefore to be expected. The diagnosis of non-obstructive disease is established in a large proportion of patients referred to CCTA for suspicion of CHD, which is associated with most ACS cases. According to the results of the PARADIGM study, the characteristics of vulnerable plaque did not influence the dynamic of the progression of non-obstructive plaque to obstructive plaque after two years of follow-up, whereas this role was instead demonstrated for initial percentage volume of the atheroma and the stenosis diameter percentage, which were the only significant predictors of the development of obstructive lesions. ( 59 , 60 ) This study also found differences with regard to sex, namely a significantly lower prevalence and slower plaque progression in women. ( 61 ) These results are in contrast with the results of the PROSPECT study, where IVUS was used for the detection of vulnerable plaque in patients with ACS, who were then followed-up for 3.4 years. ( 62 ) In this study, 596 cases of TFCA were found in a sample of 700 patients, and of a total of 74 adverse cardiac events, only six could be ascribed to cardiac death and non-fatal myocardial infarction after somewhat more than three years of follow-up. Other studies, such as for example VIVA, used IVUS and reported similar results. ( 63 , 64 ) These results obtained by imaging of the coronary arteries and plaques partially correspond to the results of pathohistological studies, according to which plaque rupture in 10-20% of non-significant plaques was not accompanied by clinical symptoms. ( 65 ) It is likely that most plaques rupture and heal without causing ACS. Such results bring into question the very concept of risk assessment by detecting vulnerable plaque, as well as the concepts of “vulnerable” and “high-risk” plaque. These results are contrary to the results of MSCT studies where the volume of non-calcified plaque in patients with non-obstructive lesions and NSTEMI was shown to be a significant predictor of adverse cardiac events after 16 months of follow-up. ( 66 ) In patients with acute chest pain, vulnerable plaque characteristics after CCTA were shown to be a significant predictor of ACS, regardless of stenosis stage. ( 49 ) These studies formed a basis for the implementation of CCTA in the clinical practice of emergency services which would be in line with the recommendations from the ESC Guidelines for ACS. ( 5 ) Reliable assessment of the prognostic value of vulnerable plaque for adverse cardiac events regardless of the imaging methods assumes adjustment for other risk factors for ACS. In addition to vulnerable plaque characteristics, simultaneous or asynchronous presence of systemic factors such as prothrombotic milieu, localized or systemic inflammatory state, and environmental proinflammatory factors influences the risk of ACS development. The effect of OMT using statins, aspirin, and anti-inflammatory medications further modifies the risk assessment for vulnerable plaque rupture, which should also be considered in the clinical risk assessment. ## The effect of treatment on vulnerable plaque The protective effect of OMT for adverse cardiac events has been confirmed by large international studies. Additionally, the application of CCTA increases OMT prescription, especially in patients with non-obstructive CHD. ( 67 ) After CCTA, medication therapy was changed in more than half of patients, while the indication for invasive coronarography was eliminated in as many as three fourths of patients. ( 68 ) An early study using invasive coronarography demonstrated the positive effects of statins, such as for example moderate regression and stabilization of plaques based on the reduction of the necrotic plaque core and the inflammatory component, with reduced macrophage infiltration and thickening of the fibrous cap. ( 69 ) Stabilization of vulnerable plaques and their characteristics improved treatment outcomes in patients with ACS, which encouraged the introduction of atorvastatin into the therapy. ( 70 ) Similar results were obtained in the PARADIGM study, which aimed to quantify the influence of statin therapy on plaques. ( 71 ) Namely, statins slow down the progression of total atherosclerosis volume, increase plaque calcification, and reduce the development of new vulnerable plaques by up to 35% on follow-up CCTAs in a period longer than two years. However, the proportion of patients with stenosis progressing from non-obstructive to obstructive over two years did not differ significantly. In patients with unstable angina pectoris, high statin doses led to thickening of the fibrous cap in the fibroatheroma, and in combination with ezetimibe it reduced adverse cardiac events in comparison with statin therapy alone. ( 72 , 73 ) These studies confirmed the greater influence of statins on the soft components of the plaque and the reduction of total plaque volume in comparison with coronary artery narrowing, as well as a positive effect on survival due to the reduction of the frequency of adverse cardiac events. In addition to statins, effective reduction of the inflammatory component was also observed with other medications, such as for example lipoprotein-associated phospholipase A2 inhibitors, colchicine, methotrexate, and interleukin-1 antagonists. Lipoprotein-associated phospholipase A2 inhibitors were effective in slowing down the development of the necrotic core in vulnerable plaque, but large randomized trials did not demonstrate benefit in clinical outcomes. ( 74 , 75 ) Compared with placebo, the use of colchicine in small doses (0.5 mg) in patients with recent myocardial infarction significantly reduced future adverse cardiac events, including spontaneous myocardial infarction, after 2.5 years of follow-up. ( 76 ) In contrast to these results, methotrexate at low doses of 15-20 mg per week in comparison with placebo did not show reduction of inflammatory parameters or a reduction in the rate of adverse cardiac events after 2.3 years of follow-up. ( 77 ) Canakinumab, a monoclonal antibody, significantly reduced CV events in comparison with placebo after 3.7 years of follow-up in patients with previous myocardial infarction. ( 78 ) The significant role of inflammatory parameters in the etiology of ACS has been demonstrated in numerous studies, and the negative results of individual medications where the goal was to demonstrate benefits of OMT are ascribable primarily to the inadequately identified biochemical and pathohistological mechanisms of action of these medications in CHD rather than to the questionability of the concept of reducing local and systemic inflammation parameters. As opposed to studies on vulnerable plaque that aimed to demonstrate the benefit of OMT, primarily statins, other studies attempted to identify the benefit of applying percutaneous coronary interventions. Due to their still-superior resolution in comparison with CCTA, many studies used IVUS and OCT for the quantification of individual parameters of the characteristics of vulnerable plaque, but the availability of these invasive imaging methods is relatively poor, requiring more resources and operator experience. We already noted that vulnerable plaques often cause non-obstructive narrowing (<50%) due to positive remodeling, but they are considered high-risk nevertheless. The recent PROSPECT-ABSORB study did not show a significant reduction of adverse cardiac events in patients with vulnerable plaques treated with bioresorbable stents in comparison with OMT after four years of clinical follow-up. ( 79 ) The results of the PECTUS study were similar, in which OCT was used for the detection of non-obstructive vulnerable plaque, but the study was discontinued due the withdrawal of bioresorbable stents from the market. ( 80 ) The low number of patients in that study reduces its scientific usefulness. The current studies, such as PREVENT (NCT02316886) and VULNERABLE (NCT0559906), aim to demonstrate the benefits of PCI for non-obstructive vulnerable plaque, and will surely elucidate the benefits of this approach in patients with ACS. The results of studies performed so far do not indicate a significant benefit from PCI in comparison with OMT with regard to the reduction of adverse cardiac events in patients with vulnerable plaque diagnosed by invasive or non-invasive methods. ## Conclusion Coronary heart disease represents the leading public health issue in the Republic of Croatia, and its diagnosis includes the application of both invasive coronarography and CCTA. Due to its non-invasiveness, CCTA has numerous advantages, especially with regard to its diagnostic performance, which allows clear visualization of qualitative and quantitative characteristics of atherosclerotic plaque. Identification of these characteristics has risen in clinical importance, as the rupture of most stable and vulnerable plaques is not accompanied by clinical symptoms. Thus, current guidelines emphasize that vulnerable plaque characteristics, such as for example positive remodeling, low attenuation plaque, spotty calcification, and the napkin-ring sign should be noted in the examination findings in order to allow risk assessment for rupture and ACS. In the assessment of prognostic value for adverse cardiac events, vulnerable plaque characteristics on CCTA had positive results, but a higher level of scientific evidence is needed to confirm this examination as the sole method of choice for risk assessment. The results of randomized clinical studies without doubt show the positive effect of statins on the stabilization of vulnerable plaque, but also on the reduction of systemic and local inflammation parameters. Optimal medication therapy showed similar therapeutic effectiveness with regard to the reduction of adverse cardiac events at vulnerable plaque, as did the methodologically safe invasive percutaneous approach. However, it should be emphasized that there is currently no unambiguous answer to this therapeutic challenge that is increasingly common in everyday clinical practice.

    Cardiologia Croatica
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    Vulnerable Plaque Characteristics at Coronary Computed Tomography Angiography

    Review Article
    Issue1-2
    Published
    Pages7-21
    PDF via DOIhttps://doi.org/10.15836/ccar2023.7
    vulnerabilni plak
    koronarna bolest srca
    višeslojna kompjutorizirana tomografija koronarnih arterija
    akutni koronarni sindrom
    vulnerable plaque
    coronary artery disease
    coronary computed tomography angiography
    acute coronary syndrome

    Authors

    Petar Medaković*ORCIDSpecijalna bolnica Agram, Zagreb, Hrvatska
    Mladen JukićORCIDSpecijalna bolnica Agram, Zagreb, Hrvatska
    Zrinka BiloglavORCIDZagreb, Hrvatska

    Abstract

    According to morbidity and mortality indicators, cardiovascular diseases are the leading public health issue in the Republic of Croatia and the European Union. Although mortality rates from ischemic disease have been reduced, Croatia is still categorized among countries with high cardiovascular risk. The guidelines of the European Society of Cardiology from 2020 for acute coronary syndrome (ACS) in patients with low to intermediate risk of coronary atherosclerotic heart disease (CHD) recommend coronary computed tomography angiography (CCTA) as an alternative to invasive coronarography. In most patients with suspicion of CHD, CCTA leads to the diagnosis of non-obstructive diseases, which causes the majority of ACS cases. Multi-slice Computed Tomography scanners of the newest generation employ low doses of radiation and low contrast volume to reliably show the characteristics of vulnerable plaque: (i) positive remodeling, (ii) low attenuation plaque, (iii) spotty calcification, and the (iv) napkin-ring sign. Due to positive remodeling, these plaques are often non-obstructive, and according to the CAD-RADS 2.0 guidelines from 2022 all their characteristics should be specifically emphasized in CCTA findings. Based on the assessment of the prognostic value of vulnerable plaque characteristics for adverse cardiac events, CCTA has been shown to be equally valid as other invasive diagnostic methods. Additionally, it was shown to be useful in indicating the optimal medication therapy and monitoring its effects. The results of large international randomized trials indicate the direction of the treatment approach for vulnerable plaque.

    Full Text

    ## Vulnerable plaque characteristics at
coronary computed tomography angiography The current Coronary Artery Disease-Reporting and Data System 2.0 (CAD-RADS 2.0) guidelines from 2022 replaced the term “vulnerable plaque” with the term “high-risk plaque”. ( 22 ) However, since the original term, “vulnerable plaque”, has become commonplace in the medical community, we retained its use in this article. The following characteristics of this type of plaque are clearly visible at CCTA: (i) positive remodeling, (ii) low attenuation plaque, (iii) spotty calcification, and the (iv) napkin-ring sign. The prevalence of these characteristics is relatively high and estimated at approximately 30%. The current guidelines emphasize the importance of standardized notation in patient charts and recommend describing all of these characteristics of atherosclerotic plaque. ( 22 ) HRP (high risk plaque) should be added as a modifier to written examination findings when two or more of these characteristics are present. ## Positive remodeling Positive remodeling is most commonly seen in clinical practice. It denotes the outward expansion of the blood vessel wall at the location of the atherosclerotic plaque, leading to partial conservation of the lumen at the narrowing site of the coronary artery ( 34 ) ( Figure 1 , Figure 2 ). This characteristic can be quantified using the remodeling index initially suggested in studies with IVUS. Using IVUS, the remodeling index is calculated as the ratio of the area of the cross section at the narrowest spot and the area of the cross section of the vessel proximally and distally from the narrowing ( 35 ) ( Figure 3 ). CCTA often overestimates these values, and those greater than 1.1 are considered clinically significant ( Figure 4 ). Patients with ACS have higher index values than patients with angina and those with culprit plaques. ( 36 , 37 ) The remodeling index calculation for CCTA represents the ratio of the outer diameter of the vessel at the location of the plaque and the average normal diameter of the vessel proximally and distally from the stenosis. Plaques with positive remodeling at CCTA also have larger necroses and are more often described as thin-cap fibroatheroma (TFCA) on IVUS, whereas the positive remodeling index in TFCA measured by MSCT shows higher values than when using optical coherence tomography (OCT). ( 38 , 39 ) Male patient, 58 years old, with previously diagnosed coronary artery disease and a stent in the proximal left anterior descending artery referred to cardiac computed tomography angiography due to atypical chest symptoms and palpitations. Cardiac computed tomography angiography showed a stent in left anterior descending artery and non-obstructive non-calcified plaque in the distal right coronary artery (A, B, C). Detailed plaque analysis in the distal right coronary artery revealed high-risk plaque features – positive remodeling (remodeling index >1.1) with low attenuation values (20 Hounsfield units), and napkin-ring sign (D, E, F). Additionally, non-obstructive fibrous plaque with positive remodeling and attenuation values >30 Hounsfield units was revealed in the proximal circumflex artery (G, H). LAD = left anterior descending artery; RCA = right coronary artery; CX = circumflex artery; HU = Hounsfield units. Male patient, 46 years old, referred to cardiac computed tomography angiography with typical chest symptoms of angina and shortness of breath. Cardiac computed tomography angiography revealed sub-occlusive non-calcified high-risk plaque with positive (and negative) remodeling (remodeling index > 1.1) and low attenuation values (30 Hounsfield units) in the proximal right coronary artery (A, B, C, D). Additionally, non-obstructive non-calcified plaque was revealed in the mid left anterior descending artery with positive remodeling and an attenuation value of 53 Hounsfield units (E, F, G). RCA = right coronary artery; HU = Hounsfield units. Female patient, 64 years old, referred to cardiac computed tomography angiography due to long- standing insufficiently regulated diabetes and multiple cardiovascular disease risk factors. Cardiac computed tomography angiography revealed diffuse non-obstructive coronary artery disease. Curved multiplanar reconstruction and cross-section analysis of the proximal left anterior descending artery showed non-obstructive non-calcified plaque with positive remodeling (remodeling index <1.1) and spotty calcification (A, B). Male patient, 64 years old, with previously diagnosed non-obstructive coronary artery disease and low adherence to optimal medical therapy. Cardiac computed tomography angiography revealed non-obstructive non-calcified plaque in the proximal right coronary artery and proximal and mid left anterior descending artery (A, B, C, D). Detailed plaque analysis in the proximal RCA revealed considerable positive remodeling (remodeling index >1.1) with different attenuation values from 20 to 80 Hounsfield units that was consistent with lipid rich and fibrous components (E, F, G). Proximal left anterior descending cross-section plaque analysis revealed non-calcified fibrous plaque with positive remodeling and an attenuation value of 120 Hounsfield units, and spotty calcification (>300 Hounsfield units) (H, I). In comparison, attenuation values of 600 Hounsfield units are consistent with the contrast agent within the lumen (J). LAD = left anterior descending artery; RCA = right coronary artery; HU = Hounsfield units. ## Low attenuation plaque Low attenuation plaque is defined as non-calcified plaque with a core that has an attenuation value lower than 30 Hounsfield units (HU) in any measurement voxel. ( 22 ) In clinical practice, it is important to differentiate low attenuation plaque from positive remodeling, since the attenuation values in positive remodeling are often higher than 30 HU. It should be emphasized that the 30 HU threshold is generally accepted in clinical practice due to its high sensitivity and specificity in the detection of lipid-rich plaques ( 40 ) ( Figure 4 ). Lower attenuation values, as a rule, match the necrotic contents of the core, while higher diameter values of the core increase risk of ACS ( Figure 1 , Figure 2 ). Plaques with lipid contents on CCTA in comparison with IVUS readings generally have lower attenuation values. ( 40 , 41 ) However, both in studies and in clinical practice, using CCTA to differentiate between soft plaque with lipid contents and fibrous plaque is more challenging due to the density overlap in these two entities ( 40 , 42 ) ( Figure 2 ). Additionally, in comparison with OCT, low attenuation plaques on CCTA are associated with TFCA findings on OCT. ( 43 ) Despite differentiation between lipid plaque and fibrous plaque being challenging, as many as 88% of ruptured plaques in ACS have attenuation values lower than 30 HU, compared with only 18% in stable plaques. Automatized software solutions used for interpreting CCTA enable more reliable quantification of low attenuation plaque. ( 44 , 45 ) ## Spotty calcification In most cases of sudden cardiac death, histopathological plaque samples contain microcalcifications that are not visible at CCTA, as opposed to reliable imaging of spotty calcification. ( 34 ) Spotty calcifications are small calcifications within soft non-calcified plaque. Their attenuation is higher than 130 HU, and they are classified into the following categories: small (<1 mm), medium (1-3 mm), and massive (>3 mm) ( 46 - 48 ) ( Figure 4 ). Spotty calcifications are associated with plaques that cause ACS, and studies performed with CCTA demonstrated that this characteristic of vulnerable plaque is comparable with findings obtained by IVUS ( 37 , 48 , 49 ) ( Figure 3 ). ## Napkin-ring sign The napkin-ring sign is a unique CCTA characteristic of vulnerable plaque that can be seen on cross sections of non-calcified plaque. It comprises a necrotic core zone with low attenuation that borders the lumen and is surrounded by a ring-shaped zone of higher attenuation that matches the fibrous tissue ( 50 , 51 ) ( Figure 1 ). This is a reliable marker for the detection of TFCA and matches pathohistological and OCT findings. ( 39 , 51 , 52 ) The technological development of MSCT scanners at the start of the past decade has enabled us to conduct studies in which the napkin-ring sign was compared with other characteristics present in invasive cardiologic diagnostic methods and pathohistological findings. Diagnostic studies preceded studies focused on the assessment of the prognostic value of vulnerable plaque characteristics for adverse cardiac events. ## Prognostic value of vulnerable plaque
characteristics at coronary computed
tomography angiography The results of studies based on invasive and non-invasive imaging methods of the coronary arteries indicate that ACS was associated with non-obstructive plaque (<50%) in the majority of patients, moreover those with non-obstructive CHD (in comparison with patients without CHD) had significantly higher risk of cardiac death and ACS. ( 9 , 53 , 54 ) Previous studies on pathohistological samples demonstrated an association between vulnerable plaque characteristics and the clinical entity of ACS. Cardiological and radiological diagnostic methods for coronary imaging also allow us to quantify the risk of adverse cardiac events. Most studies focused on the prognostic values of vulnerable plaque characteristics, in addition to differences in study design and study populations, are also marked by different CV outcomes and follow-up times. Despite these differences, almost all studies found increased risk of adverse events to be associated with an increased number of vulnerable plaque characteristics. Additionally, some studies did not take into account the undoubtably positive effect of optimal medication therapy (OMT), which certainly impacted the outcomes. Follow-up time is extremely important, since reliable assessment of the prognostic value of individual characteristics of vulnerable plaque requires long follow-up periods due to potential plaque stabilization. In that sense, CCTA has shown itself to be a reliable tracking method for monitoring the natural course of CHD, and additionally improved prognostic values regarding plaque level are also partially ascribable to more recent software solutions that allow more precise quantification. ( 40 , 55 , 56 ) One of the first prospective studies on the prognostic values of low attenuation plaque, positive remodeling, and spotty calcification for predicting adverse cardiac events after more than two years of follow-up identified low attenuation plaque and positive remodeling as predictors. ( 57 ) Along with positive remodeling and low attenuation plaque, the napkin-ring sign was also shown to be a predictor for ACS and cardiac death after 2.3 years of follow-up. ( 58 ) A meta-analysis demonstrated a significant 12.1 times higher hazard ratio in patients with vulnerable plaque characteristics in comparison with those who had stable plaque, as well as a significantly higher number of low attenuation plaques (<30 HU) in ACS patients compared with the number of plaques detected in patients with stable angina. ( 37 ) Given the nature of positive remodeling from the lumen outwards, vulnerable plaque often causes non-obstructive stenosis, and the benefits of OMT are therefore to be expected. The diagnosis of non-obstructive disease is established in a large proportion of patients referred to CCTA for suspicion of CHD, which is associated with most ACS cases. According to the results of the PARADIGM study, the characteristics of vulnerable plaque did not influence the dynamic of the progression of non-obstructive plaque to obstructive plaque after two years of follow-up, whereas this role was instead demonstrated for initial percentage volume of the atheroma and the stenosis diameter percentage, which were the only significant predictors of the development of obstructive lesions. ( 59 , 60 ) This study also found differences with regard to sex, namely a significantly lower prevalence and slower plaque progression in women. ( 61 ) These results are in contrast with the results of the PROSPECT study, where IVUS was used for the detection of vulnerable plaque in patients with ACS, who were then followed-up for 3.4 years. ( 62 ) In this study, 596 cases of TFCA were found in a sample of 700 patients, and of a total of 74 adverse cardiac events, only six could be ascribed to cardiac death and non-fatal myocardial infarction after somewhat more than three years of follow-up. Other studies, such as for example VIVA, used IVUS and reported similar results. ( 63 , 64 ) These results obtained by imaging of the coronary arteries and plaques partially correspond to the results of pathohistological studies, according to which plaque rupture in 10-20% of non-significant plaques was not accompanied by clinical symptoms. ( 65 ) It is likely that most plaques rupture and heal without causing ACS. Such results bring into question the very concept of risk assessment by detecting vulnerable plaque, as well as the concepts of “vulnerable” and “high-risk” plaque. These results are contrary to the results of MSCT studies where the volume of non-calcified plaque in patients with non-obstructive lesions and NSTEMI was shown to be a significant predictor of adverse cardiac events after 16 months of follow-up. ( 66 ) In patients with acute chest pain, vulnerable plaque characteristics after CCTA were shown to be a significant predictor of ACS, regardless of stenosis stage. ( 49 ) These studies formed a basis for the implementation of CCTA in the clinical practice of emergency services which would be in line with the recommendations from the ESC Guidelines for ACS. ( 5 ) Reliable assessment of the prognostic value of vulnerable plaque for adverse cardiac events regardless of the imaging methods assumes adjustment for other risk factors for ACS. In addition to vulnerable plaque characteristics, simultaneous or asynchronous presence of systemic factors such as prothrombotic milieu, localized or systemic inflammatory state, and environmental proinflammatory factors influences the risk of ACS development. The effect of OMT using statins, aspirin, and anti-inflammatory medications further modifies the risk assessment for vulnerable plaque rupture, which should also be considered in the clinical risk assessment. ## The effect of treatment on vulnerable plaque The protective effect of OMT for adverse cardiac events has been confirmed by large international studies. Additionally, the application of CCTA increases OMT prescription, especially in patients with non-obstructive CHD. ( 67 ) After CCTA, medication therapy was changed in more than half of patients, while the indication for invasive coronarography was eliminated in as many as three fourths of patients. ( 68 ) An early study using invasive coronarography demonstrated the positive effects of statins, such as for example moderate regression and stabilization of plaques based on the reduction of the necrotic plaque core and the inflammatory component, with reduced macrophage infiltration and thickening of the fibrous cap. ( 69 ) Stabilization of vulnerable plaques and their characteristics improved treatment outcomes in patients with ACS, which encouraged the introduction of atorvastatin into the therapy. ( 70 ) Similar results were obtained in the PARADIGM study, which aimed to quantify the influence of statin therapy on plaques. ( 71 ) Namely, statins slow down the progression of total atherosclerosis volume, increase plaque calcification, and reduce the development of new vulnerable plaques by up to 35% on follow-up CCTAs in a period longer than two years. However, the proportion of patients with stenosis progressing from non-obstructive to obstructive over two years did not differ significantly. In patients with unstable angina pectoris, high statin doses led to thickening of the fibrous cap in the fibroatheroma, and in combination with ezetimibe it reduced adverse cardiac events in comparison with statin therapy alone. ( 72 , 73 ) These studies confirmed the greater influence of statins on the soft components of the plaque and the reduction of total plaque volume in comparison with coronary artery narrowing, as well as a positive effect on survival due to the reduction of the frequency of adverse cardiac events. In addition to statins, effective reduction of the inflammatory component was also observed with other medications, such as for example lipoprotein-associated phospholipase A2 inhibitors, colchicine, methotrexate, and interleukin-1 antagonists. Lipoprotein-associated phospholipase A2 inhibitors were effective in slowing down the development of the necrotic core in vulnerable plaque, but large randomized trials did not demonstrate benefit in clinical outcomes. ( 74 , 75 ) Compared with placebo, the use of colchicine in small doses (0.5 mg) in patients with recent myocardial infarction significantly reduced future adverse cardiac events, including spontaneous myocardial infarction, after 2.5 years of follow-up. ( 76 ) In contrast to these results, methotrexate at low doses of 15-20 mg per week in comparison with placebo did not show reduction of inflammatory parameters or a reduction in the rate of adverse cardiac events after 2.3 years of follow-up. ( 77 ) Canakinumab, a monoclonal antibody, significantly reduced CV events in comparison with placebo after 3.7 years of follow-up in patients with previous myocardial infarction. ( 78 ) The significant role of inflammatory parameters in the etiology of ACS has been demonstrated in numerous studies, and the negative results of individual medications where the goal was to demonstrate benefits of OMT are ascribable primarily to the inadequately identified biochemical and pathohistological mechanisms of action of these medications in CHD rather than to the questionability of the concept of reducing local and systemic inflammation parameters. As opposed to studies on vulnerable plaque that aimed to demonstrate the benefit of OMT, primarily statins, other studies attempted to identify the benefit of applying percutaneous coronary interventions. Due to their still-superior resolution in comparison with CCTA, many studies used IVUS and OCT for the quantification of individual parameters of the characteristics of vulnerable plaque, but the availability of these invasive imaging methods is relatively poor, requiring more resources and operator experience. We already noted that vulnerable plaques often cause non-obstructive narrowing (<50%) due to positive remodeling, but they are considered high-risk nevertheless. The recent PROSPECT-ABSORB study did not show a significant reduction of adverse cardiac events in patients with vulnerable plaques treated with bioresorbable stents in comparison with OMT after four years of clinical follow-up. ( 79 ) The results of the PECTUS study were similar, in which OCT was used for the detection of non-obstructive vulnerable plaque, but the study was discontinued due the withdrawal of bioresorbable stents from the market. ( 80 ) The low number of patients in that study reduces its scientific usefulness. The current studies, such as PREVENT (NCT02316886) and VULNERABLE (NCT0559906), aim to demonstrate the benefits of PCI for non-obstructive vulnerable plaque, and will surely elucidate the benefits of this approach in patients with ACS. The results of studies performed so far do not indicate a significant benefit from PCI in comparison with OMT with regard to the reduction of adverse cardiac events in patients with vulnerable plaque diagnosed by invasive or non-invasive methods. ## Conclusion Coronary heart disease represents the leading public health issue in the Republic of Croatia, and its diagnosis includes the application of both invasive coronarography and CCTA. Due to its non-invasiveness, CCTA has numerous advantages, especially with regard to its diagnostic performance, which allows clear visualization of qualitative and quantitative characteristics of atherosclerotic plaque. Identification of these characteristics has risen in clinical importance, as the rupture of most stable and vulnerable plaques is not accompanied by clinical symptoms. Thus, current guidelines emphasize that vulnerable plaque characteristics, such as for example positive remodeling, low attenuation plaque, spotty calcification, and the napkin-ring sign should be noted in the examination findings in order to allow risk assessment for rupture and ACS. In the assessment of prognostic value for adverse cardiac events, vulnerable plaque characteristics on CCTA had positive results, but a higher level of scientific evidence is needed to confirm this examination as the sole method of choice for risk assessment. The results of randomized clinical studies without doubt show the positive effect of statins on the stabilization of vulnerable plaque, but also on the reduction of systemic and local inflammation parameters. Optimal medication therapy showed similar therapeutic effectiveness with regard to the reduction of adverse cardiac events at vulnerable plaque, as did the methodologically safe invasive percutaneous approach. However, it should be emphasized that there is currently no unambiguous answer to this therapeutic challenge that is increasingly common in everyday clinical practice.