Cardiovascular Risk Stratification by Coronary Computed Tomography Angiography Imaging: Current State-Of-The-Art

European Journal of Preventive Cardiology (2022) 29, 608–624 REVIEW
doi:10.1093/eurjpc/zwab067 Risk Prediction/Assessment & Stratification
Cardiovascular risk stratification by coronary

computed tomography angiography imaging:
current state-of-the-art
1,2
Alexios S. Antonopoulos *, Andreas Angelopoulos1, Konstantinos Tsioufis1,
2
, and Dimitris Tousoulis 1
Downloaded from https://academic.oup.com/eurjpc/article/29/4/608/6261148 by guest on 07 July 2022

Charalambos Antoniades
1
1st Department of Cardiology, Hippokration Hospital, National and Kapodistrian University of Athens, 114 Vas. Sofias Avenue, 11527, Athens, Greece; and 2RDM Division of
Cardiovascular Medicine, Oxford Academic CT Programme, University of Oxford, John Radcliffe Hospital, Headley Way, OX3 9DU Oxford, UK
Received 19 January 2021; revised 25 March 2021; accepted 7 April 2021; online publish-ahead-of-print 30 April 2021
Current cardiovascular risk stratification by use of clinical risk score systems or plasma biomarkers is good but less than satisfactory in identifying
patients at residual risk for coronary events. Recent clinical evidence puts now further emphasis on the role of coronary anatomy assessment by
coronary computed tomography angiography (CCTA) for the management of patients with stable ischaemic heart disease. Available computed
tomography (CT) technology allows the quantification of plaque burden, identification of high-risk plaques, or the functional assessment of coronary
lesions for ischaemia detection and revascularization for refractory angina symptoms. The current CT armamentum is also further enhanced by
perivascular Fat Attenuation Index (FAI), a non-invasive metric of coronary inflammation, which allows for the first time the direct quantification of
the residual vascular inflammatory burden. Machine learning and radiomic features’ extraction and spectral CT for tissue characterization are also
expected to maximize the diagnostic and prognostic yield of CCTA. The combination of anatomical, functional, and biological information on cor-
onary circulation by CCTA offers a unique toolkit for the risk stratification of patients, and patient selection for targeted aggressive prevention strat-
egies. We hereby provide a review of the current state-of-the art in the field and discuss how integrating the full capacities of CCTA into clinical
care pathways opens new opportunities for the tailored management of coronary artery disease.
...........................................................................................................................................................................................
Keywords: Coronary computed tomography angiography • Atherosclerosis • Coronary artery disease • Risk stratification •
Fat attenuation index • Fractional flow reserve
.. use of CCTA in patients with stable chest pain resulted in lower num-
Introduction ..
.. bers of myocardial infarction during a follow-up of 3.6 years.5 The
.. value of CCTA in stable CAD is already reflected in the latest NICE
Coronary computed tomography angiography (CCTA) is a non-inva- ..
sive imaging modality with high sensitivity for the detection of coron- .. (National Institute for Health and Care Excellence) guideline update
..
ary artery disease (CAD). The recommendations for the diagnostic .. in the UK,6 where CCTA is recommended for the initial assessment
assessment of stable symptomatic patients at low to intermediate .. of patients with ‘typical’ or ‘atypical’ angina, while additional stress
..
pretest probability for obstructive CAD by CCTA has been recently .. imaging tests are recommended in the case of ambiguity about the
upgraded to class I.1 Compared to functional ischaemia tests, CCTA .. functional significance of identified coronary lesions.7 The results of
..
allows the detection of non-obstructive coronary plaques and the re- .. the ISCHEMIA trial8 also further enforce the role of CCTA over
liable ruling-put of left main disease.2 In recent large randomized clin- .. functional testing in the diagnostic assessment of stable ischaemic
..
ical trials, such as the PROMISE (Prospective Multicenter Imaging .. heart disease patients, to exclude the presence of prognostically sig-
Study for Evaluation of Chest Pain)3 and SCOT-HEART (Scottish
.. nificant left main disease and guide patient management. Recent
..
Computed Tomography of the Heart),4 the use of CCTA was associ- .. advancements in available computed tomography (CT) technology
ated with smaller risks for myocardial infarction compared to con-
.. and the development of novel CT imaging techniques have expanded
..
ventional management. In a Danish registry of >86 000 patients, the .. the use of CCTA beyond the focused assessment of luminal stenosis
* Corresponding author. Tel: þ30 6947607442, Email: alexios.antonopoulos@cardiov.ox.ac.uk; antonopoulosal@yahoo.gr

C The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits
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CCTA and CV risk stratification 609

..
severity. CCTA can now be used for plaque characterization and the .. Anatomical assessment of the
detection of vulnerable, high-risk plaques (HRPs)9 or the functional ..
.. coronary arteries by computed
assessment of coronary lesions by application of computational fluid ..
dynamics10 or stress CT perfusion (CTP) imaging,11 or even to guide .. tomography
..
coronary interventions in chronic total occlusions.12 Recently, novel ..
metrics for the detection of coronary inflammation by pericoronary .. Coronary calcification
..
fat imaging offer the unprecedented capacity to assess underlying vas- .. The extent of coronary calcification is one of the most widely used
cular biological processes from the post-processing of standard .. imaging biomarkers. Coronary calcium relies on the quantification of
..
CCTA images.13 These new applications of CCTA imaging maximize .. calcium depositions on coronary medial arterial wall, typically on
not just the diagnostic yield of the modality, but also its prognostic .. non-contrast-enhanced, low spatial resolution images by using low ef-
..
output.14 .. fective dose of radiation (<1 mSv).15 This permits the estimation of
In this review, we summarize the recent advances in the field of .. coronary calcium volume and the calculation of the Agatston or cor-
..
cardiac CT and provide a comparative assessment of the available .. onary calcium score (CCS), a weighted score of calcium volume and
CT imaging biomarkers. We discuss how the exploitation of the .. density.16 Vascular calcification is present in the early stages of ath-
..
modern, state-of-the-art CT toolset could enhance precision .. erosclerosis in the form of microcalcifications, which is a feature of
medicine pathways for the diagnostic assessment and manage-
.. HRPs and an index of active inflammation.17 Conversely, CCS quanti-
..
ment of CAD, covering unmet needs in clinical care and tailored .. fies the volume of large flakes of coronary calcium, typically seen in
patient management. The presentation of hybrid modalities with
.. the advanced stages of atherosclerosis, and associated with a stable
..
imaging co-registration has purposefully been omitted from this .. plaque phenotype. Although CCS only poorly correlates with the de-
review.
.. gree of luminal stenosis, it serves as a good surrogate marker of
.
610 A.S. Antonopoulos et al.

Figure 1 Luminal assessment, plaque burden, and plaque phenotyping for risk stratification by computed tomography angiography. (A) Impact of
non-obstructive coronary artery disease and (B) vessel disease on all-cause mortality of patients undergoing computed tomography angiography
(CCTA) (adapted by Min et al.21). (C) Representative example of curved multiplanar reformatting of coronary dataset with (D) cross-section of a pla-
que in the proximal left anterior descending (LAD) and (E) analysis of plaque components by Hounsfield Units (HU) mapping (reproduced with per-
mission by Maurovich-Horvat et al.22). (F) Imaging appearance of high-risk plaque (HRP) features on CCTA and their prognostic value for an acute
coronary syndrome in the ROMICAT-II study (reproduced with permission by Puchner et al.9). ACS, acute coronary syndromes; Ca, calcium; CI,
confidence interval; HU, Hounsfield units; NRS, napkin-ring sign; PR, positive remodelling.
atherosclerotic plaque burden.18 CCS has incremental prognostic

.. risk-based decisions remain uncertain.25 As a rule of thumb, CCS
..
value on top of classic cardiovascular risk factors for future cardiovas- .. above 100 identifies individuals at elevated risk and CCS >_ 300 flags
cular events in asymptomatic individuals with no known CAD.19 In
.. moderate to severely increased risk,27 although the use of age-, sex-,
..
intermediate-risk individuals improves risk reclassification20 and out- .. and ethnicity adjusted cut-offs (i.e. >_75th percentile) has been pro-
performs other non-invasive biomarkers including carotid intima-
.. posed too (Table 1).
..
media thickness, ankle-brachial index, brachial flow-mediated dilation .. Temporal changes in CCS and its progression rate offer additional
or high-sensitivity C-reactive protein (Figure 1).23
.. prognostic information for cardiovascular events. Budoff et al.24 have
..
CCS is currently recommended for the risk stratification of low .. demonstrated the independent prognostic value of temporal changes in
..
and intermediate-risk asymptomatic individuals; CCS is IIb recom- .. CCS in 4609 asymptomatic patients who underwent serial non-contrast
mendation in the ESC guidelines24 and a IIa recommendation in the .. cardiac CT. A higher progression rate of CCS was independently associ-
..
ACC/AHA guidelines for adults at intermediate risk or selected .. ated with a higher mortality risk.24 Furthermore, beyond calcification
adults at borderline risk (based on the 10-year atherosclerotic car- .. volume, higher calcium density is inversely associated with CAD risk.26
..
diovascular disease risk),25 which also recommend CCS use for the .. The use of CCS has been widely employed thanks to its simplicity in
guidance of risk reduction therapies (e.g. statins or even aspirin26) if .. acquisition using a low radiation dose non-contrast-enhanced CT scan,
.
Table 1 Core syllabus of established and novel computed tomography metrics for the diagnostic assessment of coronary heart disease
Coronary calcium score (CCS)

.................................................................................................................................................................................................................................................................................................
A weighted density score of the area corresponding to coronary calcium (density Appropriate use of CCS
multiplication factor: 130–199 HU: 1; 200–299 HU: 2; 300–399 HU: 3; 400þ HU: 4) • if risk-based treatment decision is uncertaina
• SCORE risk intermediate (5–10%)b
CCS and coronary risk: Pros: easily acquired, independent prognostic and risk-reclassification value in asymptomatic patients
0: very low Cons: does not regress with treatment, inappropriate for use in symptomatic patients/known CAD
CCTA and CV risk stratification
1–99: mildly increased

100–299: moderately increased
>_300: moderate to severely increased
Anatomical extent of coronary artery disease
Grading of luminal stenosis severity (SCCT guidelines) CAD-RADS Score
<25% stenosis: minimal 0: no luminal narrowing
25–49% stenosis: mild 1: 1–24% stenosis
50–69% stenosis: moderate 2: 25–49%
70–99% stenosis: severe 3: 50–69%
100%: occluded 4A: 70–99% in one to two vessels
4B: 70–99% in three vessels or >_50% left main
5: 100%
N: non-diagnostic study
Modified Duke prognostic CAD index Leaman Score: This score uses three sets of weighting factors using a 18-segment coronary model:
1: <50% stenosis (1) Localization of plaques: accounting for dominance [i.e. multiplication factors: left main (right dominance 5,
2: >_2 non-obstructive (<50%) stenoses left dominance6), LAD proximal 3.5, LAD mid 2.5, and LAD distal 1]
3: 50–69% stenosis in two vessels or >_70% in a single vessel (2) Type of plaque: multiplication factor of 1 for calcified plaques and of 1.5 for non-calcified and mixed plaques
4: 50–69% stenosis in three vessels or >_70% in two vessels/proximal LAD (3) Degree of stenosis: multiplication factor of 0.615 for non-obstructive (<50% stenosis) and of 1 for >_50% lesions
5: >_70% stenosis in three vessels or >_70% in 2 vessels including proximal LAD
6: >_50% stenosis in left main
Segment Involvement Score (SIS): The total number of segments involved Segment Stenosis Score (SSS): Each coronary segment is graded based on the degree of stenosis (0: no plaque,
irrespective of the degree of stenosis, ranging from 0 to 16. 1: mild, 2: moderate, 3: severe). Subsequently, the scores of all segments are summed leading to total
score ranging from 0 to 48.
High-risk plaque features
Positive remodelling: outward remodelling of plaque (remodelling index > 1.1) Low attenuation plaque: a plaque area with attenuation <30 HU, marker of a large necrotic nucleus within
the atherosclerotic plaque
Spotty calcification: presence of micro-calcifications < 3 mm. Marker Napkin-ring sign: a cross-section of an artery with luminal narrowing, and presence of a low attenuating
of active calcification process, plaque inflammation necrotic core surrounded by a thin ring-like hyperattenuating rim <130 HU. May represent intraluminal
plaque haemorrhage or neo-vascularization
Pros: independent prognostic value for future events on top of stenosis severity, risk factors
Continued
611

..
.. where information on the lumen is not available.16 When interpreting
.................................................................................................................................................................................................................................................................................................
.. coronary calcification several points should be considered. Calcium
Pros: independent prognostic value for future cardiovascular events; not affected by coronary calcifications/stents
..
.. deposition flags irreversible structural changes of the coronary arterial
.. wall, which is a healing process leading to plaque stabilization.25 On the
..
.. opposite soft, non-calcified plaques are at higher risk of rupture13 and
.. while the ‘power of zero’ (i.e. the negative prognostic value of zero
..
.. CCS) is generally acknoweledged30 this may not safely exclude the risk
.. for a coronary event in all cases.27,31 Moreover, implementation of risk
A metric of coronary vascular wall inflammation by measuring of weighted CT attenuation
..
Cons: response to treatment is unknown; not recommended yet by any clinical guidelines
.. reduction strategies, e.g. with statins, does not attenuate the progres-
.. sion of coronary calcification,32 but conversely increases the Agatston
..
.. score despite their pivotal and beneficial effects on the risk of cardio-
.. vascular events.25,33 The effects of statins on coronary calcification
..
gradients in pericoronary fat. A high FAI flags high vascular inflammation
ACS, acute coronary syndromes; CAD-RADS, Coronary Artery Disease Reporting and Data System; CT, computed tomography; SCCT, Society of Cardiovascular Computed Tomography. .. come along with the lowering of the volume of non-calcified plaque34
.. an increase in calcium plaque density, a plaque-stabilizing process.35

..
.. These observations highlight the limitations of CCS as a biomarker in
.. 36
.. patients on statins or known CAD.
..
..
..
.. Luminal assessment for obstructive and
Cons: detection of high-risk plaque features relies on the qualitative assessment of the plaque and is highly dependent on operator’s experience
.. non-obstructive coronary artery disease

..
.. CCTA is currently the modality of choice to exclude disease in symp-
..
Perivascular Fat Attenuation Index (FAI)
.. tomatic patients at low to intermediate-risk pretest probability (15–

.. 50%) for obstructive CAD.37 The updated pretest probabilities tables
..
.. for obstructive CAD (based on sex, age, and symptoms) in the recent
.. ESC guidelines1 means that most symptomatic patients eligible for
..
.. diagnostic testing fall within the range of low to intermediate pretest
.. probabilities, in which range CCTA has the maximum diagnostic
..
.. performance.1
.. According to the guidelines of the Society of Cardiovascular
..
.. Computed Tomography (SCCT), luminal stenosis can be graded as:
.. minimal (<25% stenosis), mild (25–49% stenosis), moderate (50–
..
.. 69% stenosis), severe (70–99% stenosis), and occluded.38 In the two
.. largest multicenter trials on the diagnostic performance of CT,39,40
..
Cons: performed off-site, no operator adjustment, not reliable in small vessels, post-ACS
.. CCTA has a 85–95% sensitivity, 83–90% specificity for obstructive

.. CAD. These measures correspond to the performance of the typical
..
Derived from computational modelling and simulation of hyperaemic conditions;
Pros: clinically recommended to assess the haemodynamic significance of a lesion
.. 64-slice scanners and are even higher with the newer 256-row CT
.. scanners41 (94% sensitivity 94%, specificity 87%, positive predictive
by post-processing of the raw CT dataset without additional tests; guides
..
.. value 83%, negative predictive value 96%).
a cut-off of 0.80 denotes significant flow-limiting disease, associated
.. Obstructive CAD (usually defined as a luminal stenosis of >_50% or

..
.. >_70%) is an independent prognostic factor for clinical outcomes in
2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk.28
..
revascularization; safely defers patients from invasive tests
.. patients with chest pain undergoing CCTA.42 A single or multiple lu-

.. minal stenoses (>50%) are associated with stepwise escalations in
..
.. mortality risk, while absence of any luminal stenosis flags low mortal-
2016 ESC Cardiovascular Disease Prevention Guideline.29
.. ity risk.42 In the multicentre CONFIRM registry involving 23 854

..
.. patients, the severity of anatomical luminal stenosis was independent-
.. ly associated with a higher mortality risk.21 Importantly, not just ob-
..
.. structive but also non-obstructive CAD is associated with increased
Coronary calcium score (CCS)
Fractional flow reserve CT (FFRCT)
.. cardiovascular risk.21 The prognostic importance of non-obstructive

..
.. coronary plaque(s) on CCTA scans has been explored in following
with myocardial ischaemia.
.. studies,43,44 confirming that the presence and extent of non-obstruct-

Table 1 Continued
..
.. ive plaques predicts a poorer clinical outcome even in the absence of
.. concomitant obstructive CAD (Figure 1A and B).
..
.. Such findings are hardly unexpected given the natural history of
.. atherosclerosis and acute coronary syndromes (ACS).45 The major-
..
.. ity of ACS is the result of erosion or rupture of non-obstructive ath-
.. erosclerotic plaques.45 The landmark PROSPECT study45 showed
..
. that in ACS patients treated by percutaneous coronary intervention,
b
a
..
major adverse cardiovascular events (MACEs) were equally attribut- .. Partly for these reasons, most clinical studies adopt the quantifica-
able to the recurrence of culprit lesions and to non-culprit, non-ob- .. tion of calcified vs. non-calcified and total plaque volume. In a recent
..
structive lesions.45 Thus, the detection of non-obstructive disease on .. meta-analysis, non-calcified plaque volume was significantly higher in
CCTA should not be considered as a reassuring finding, given its inde- .. patients with ACS compared with stable angina.54 A higher total plaque
..
pendent associations with an adverse long-term prognosis.43,44 .. volume at baseline in PROSPECT trial was associated with increased
Although current evidence is weak, it is reasonable to argue that such .. risk for cardiac events during the follow-up period.55 In a recent study,
..
patients are eligible for aggressive risk reduction therapies (e.g. sta- .. quantitative plaque analysis in a cohort of 2748 patients without prior
tins). The cost-effectiveness of this strategy has not yet been tested in .. history of CAD undergoing CCTA, total plaque volume and non-calci-
..
randomized clinical trials, but in a multicenter registry of 8372 con- .. fied plaque volume were independent predictors of cardiac death.56
secutive patients with non-obstructive CAD documented by CCTA,
.. The rate of coronary atherosclerosis progression also offers inde-
..
prior use of statins was associated with a lower risk of all-cause mor- .. pendent prognostic information. In a cohort of 449 patients with ser-
tality.46 Recommendations on the clinical management of patients
.. ial CCTA scans and clinical follow-up for cardiovascular events,
..
with non-obstructive coronary plaques detected by CCTA fall within the .. plaque progression was an independent predictor of ACS.57 In a mul-
grey zone, but detection of non-obstructive coronary is likely to prompt
.. ticentre cohort of 1365 patients with serial CCTA scans, both coron-

..
clinicians to administer more aggressive measures for cardiovascular dis- .. ary plaque burden and its annual change improved the prognostic
..
ease prevention (and patients to follow such recommendations). .. performance of the model for clinical outcomes over and above con-
.. ventional angiographic assessment.58
..
.. Non-invasive quantification of coronary plaque volume and its rate
Anatomical extent of coronary .. or progression is an attractive alternative to conventional invasive intra-
atherosclerosis ..
.. coronary imaging techniques employed by randomized clinical trials to
Beyond the degree of luminal stenosis and vessel disease, the extent of .. evaluate response to treatments.59,60 For example, it has been shown
..
coronary atherosclerosis also has prognostic significance in patients .. statins induce phenotypic changes in plaque composition by CCTA,
undergoing CCTA.42 A popular score for grading the anatomical ex- .. increasing coronary calcification and slowing plaque progression.61 The
..
tent of coronary atherosclerosis is the Duke CAD Index, which is hier- .. possible drawback of serial CT scans is the high radiation exposure, but
archical and takes into account both stenosis severity and the .. novel acquisition techniques with dose-reduction strategies partly over-
..
anatomical location of plaques, and independently predicts mortality .. come this problem, and could allow for assessment of temporal changes
risk.42 However, the CAD-RADS (Coronary Artery Disease-Reporting .. in plaque burden with minimum cumulative radiation dose.62
..
and Data System), is the officially recommended scoring system by ..
SCCT for the grading the coronary lesions with similar predictive value ..
..
to the Duke Index.47 Other scores for assessing the extent/severity of .. Plaque phenotyping for high-risk features
coronary atherosclerosis are the segment stenosis score and the segment .. The identification of the vulnerable plaque has been the ultimate goal
..
involvement score, which are of prognostic significance for MACEs.48 .. of cardiovascular medicine over the last two decades,63 pursued
These scores assume a linear positive association between coronary
.. mainly via the correlation of intracoronary imaging findings with the
..
plaque burden and clinical outcomes; thus, each plaque has the same .. histological analysis of ruptured atherosclerotic plaques. However,
weight on the calculated risk irrespectively of the number of other dis-
.. intracoronary imaging modalities are of limited use as screening tools
..
eased segments without adjustment for the anatomical location of the .. at population scale. On the contrary non-invasive imaging of coron-
plaques (e.g. a plaque located in the left main stem is assigned the same
.. ary plaques by high spatial resolution CT has emerged as a promising
..
prognostic weight with one located distally in a small diagonal branch). .. screening tool. In clinical studies, characterization of plaques by CT
Other less commonly used scores, such as the Leaman Score,49 are
.. has good agreement with intracoronary imaging by intravascular
..
also prognostic for coronary events.50 A summary of the commonly .. ultrasound or optical coherence tomography.64,65
..
used scores for grading the anatomical extent of coronary atheroscler- .. Further to plaque volume, CCTA can assess the presence of HRP
osis is provided in Table 1. .. features such as low attenuation plaque, positive remodelling, spotty
..
.. calcification and the napkin ring sign (Table 1 and Figure 1F). Low at-
.. tenuation plaque on CCTA flags the presence of large necrotic core,
Plaque volumetrics and rate of ..
.. one of the hallmarks of the vulnerable, rupture-prone coronary pla-
atherosclerosis progression .. ques in histological studies.66 In studies employing computational
..
Further to the scoring of the extent of coronary atherosclerosis, the .. modelling and intravascular ultrasound, the size of the necrotic nu-
direct quantification of non-calcified coronary plaque volume by .. cleus positively correlates with the stress exerted on the fibrous cap-
..
CCTA is currently feasible based on the CT attenuation mapping of .. sule, potentially leading to plaque rupture.67 However, the
the coronary vascular wall.51 Dedicated software52 allows imaging .. establishment of a universal cut-off value in CT attenuation for the
..
post-processing and the automated quantification of plaque volume .. identification of a large necrotic core and unstable plaques has been
(Figure 1C–E). Volumetric analysis of individual plaque components .. an issue of debate. Low attenuation plaque is conventionally defined
..
such as the quantification of the necrotic core, or the low-to-inter- .. as a plaque with CT attenuation <30 HU. Based on this definition,
mediate attenuation fibrous/fibrofatty plaque is feasible.52,53 The ac- .. low attenuation plaque is more often observed in patients with ACS
..
curacy of this analysis is curbed by the considerable overlapping of .. than those with stable angina68 and has been associated with an
the various plaque components in the Hounsfield Units (HU) range
.. eight-fold increased risk for ACS in patients with acute chest pain
..
and contrast attenuation in the lumen.53 . undergoing CCTA.9
..
Positive remodelling is the expansion of the external elastic mem- .. lesion causing intermediate luminal stenosis on CCTA can be fol-
brane area and the compensatory enlargement of the vessel wall at the .. lowed by a stress CTP scan to assess for flow-limiting disease, al-
..
site of atherosclerotic lesions.69 This vascular remodelling (or Glagov .. though the stress scan can be performed first as well.80 Perfusion
phenomenon) dissociates plaque size from the degree of luminal sten- .. imaging using dual-energy or spectral CT (with iodine maps recon-
..
osis during the early stages of plaque growth.70 A positive remodelling .. struction) offers better signal-to-noise ratio for myocardium imaging
in vascular wall is defined as a remodelling index >_1.1 (i.e. the ratio of .. and incremental diagnostic value over CCTA alone for the detection
..
the smallest vessel cross-sectional area of the lesion to the proximal .. of flow-limiting disease.81 CTP has high diagnostic accuracy for myo-
reference luminal area).64 In studies with cross-modality imaging, posi- .. cardial ischaemia, comparable to that of nuclear or CMR stress
..
tive remodelling as assessed by CT is more commonly seen in thin cap .. scans.82 However, most studies on CTP are single-centred, with
fibroatheromas71 and ACS patients compared with stable angina
.. small sample sizes, and different protocols.83 Information on the
..
patients.72,73 In the ROMICAT-II study, the presence of positive .. cost-effectiveness of the technique is also missing, while the issue of
remodelling was associated with 11-fold increased risk for ACS.9
.. the excess radiation dose from the additional perfusion scan remains
..
The most notorious HRP feature is the napkin-ring sign, which is .. the major concern with the method. Despite its diagnostic value,
currently considered to be the CCTA hallmark of the vulnerable
.. CTP remains still underused in the clinical setting.

..
atherosclerotic plaque.22 Studies employing both CCTA and intra- ..
..
coronary imaging have shown that the napkin-ring sign is predomin- ..
antly found in high-risk lesions such as in thin cap fibroatheromas .. Non-invasive CT-derived fractional flow
.. reserve
(44% vs. only 4% in non-thin cap fibroatheromas). Although its exact ..
biological significance is unknown, the napkin-ring sign may repre- .. Fractional flow reserve (FFR) is a method for the functional, haemo-
..
sent intraluminal plaque haemorrhage, neovascularization, microcal- .. dynamic assessment of coronary lesions in the cath lab under condi-
cifications, or pre-existing rupture of the atherosclerotic plaque and .. tions of induced hyperaemic flow to guide coronary
..
it is less common than other HRP features, such as positive remodel- .. revascularization.84 The diagnostic value of FFR is greatest in the case
ling and low attenuation plaque.74 .. of plaques causing moderate luminal stenosis (50–70%),85 where the
..
The combination of HRP features with information on stenosis se- .. functional impact of the lesion on coronary flow cannot be reliably
verity maximizes the prognostic value of CCTA-derived information .. determined. Based on a cut-off value of 0.80 in FFR, it is estimated
..
(Figure 1G). In a cohort of 984 patients undergoing diagnostic CCTA, .. that among lesions causing significant luminal stenosis (>70%) as high
patients with non-calcified plaques and high-risk features (low attenu- .. as 20% are not flow-limiting, while among those causing intermediate
..
ation plaque plus positive remodelling) were at the highest risk for fu- .. luminal stenosis (50–70%) only 35% are haemodynamically signifi-
ture hard clinical events.75 In a meta-analysis of 6 studies with .. cant.86 The technological advancements and increases in computa-
..
prospective follow-up the 3-year risk for ACS was significantly higher .. tional power have recently permitted the accurate modelling of
in patients with any HRP feature (odds ratio = 12.1, 95% confidence
.. coronary flow within short processing times, making it attractive for
..
interval: 5.24–28.1).54 In one of the largest to-date studies on the .. use in the clinical setting. CT-derived FFR (or FFRCT) is calculated by
prognostic value of HRP features in 4415 patients undergoing CCTA,
.. virtually simulating the conditions of coronary hyperaemia, allowing
..
the presence of HRP (i.e. presence of low attenuation plaque, posi- .. for the haemodynamic assessment of coronary stenoses (without
tive remodelling or napkin-ring sign) was an independent predictor of
.. stress conditions or adenosine infusion). FFR measurements are
.. CT
MACEs.76 The risk reclassification provided by HRP features seems .. commercially provided by off-site analysis in mega-computers of the
to be greatest in the lower-risk groups, such as younger patients,
.. entire coronary tree and computation of FFR values for every coron-
..
women and those with non-obstructive CAD.76 .. ary lesion.87 This computationally demanding analysis involves three
.. elements: (i) the anatomical modelling of coronary artery tree, (ii) the
..
.. physiological modelling of blood flow, and (iii) the solution of the gov-
..
Coronary functional assessment .. erning equations of blood flow on a computer using numerical meth-
.. ods.87 Compared to luminal stenosis assessment alone, addition of
..
by computed tomography .. FFRCT measurements improves the diagnostic accuracy of CCTA for
.. detection of flow-limiting disease, overcoming the limitation of the
..
Myocardial CT perfusion .. low positive predictive value of CCTA for obstructive CAD.88 FFRCT
Anatomical information on lumen and plaques has only modestly .. has been validated against invasive FFR in three prospective, multicen-
..
predictive value for myocardial ischaemia.77 Static or dynamic myo- .. ter clinical trials, including more than 600 patients with blinded core-
cardial CTP can be used to assess for myocardial ischaemia by use of .. lab analysis of 1050 vessels. In these trials use of FFRCT significantly
..
pharmacological agents, e.g. adenosine or regadenoson, and myocar- .. improved the diagnostic performance of CCTA-alone.89–91 In a real-
dial imaging at rest and stress in a similar fashion to single-photon .. world multicentre cohort of 5083 patients FFRCT modified treatment
..
emission CT or cardiac magnetic resonance (CMR) perfusion .. recommendation in two-thirds of subjects compared to CCTA
scans.78 Inducible myocardial perfusion defects at stress are identi- .. alone, and was associated with less negative invasive coronary angiog-
..
fied as areas of low attenuation in the myocardium. Fixed perfusion .. raphy tests; importantly, patients with FFRCT>0.80 could be safely
defects corresponding to scar tissue appear as areas of decreased .. deferred from invasive coronary angiography.92 FFRCT measure-
..
myocardial enhancement, while delayed imaging can be used to de- .. ments are technically feasible in >98% of cases, but its diagnostic per-
tect myocardial hyperenhancement analogous to late gadolinium en-
.. formance is reduced in cases with severe calcification and blooming
..
hancement by CMR.79 Typically, the identification of a coronary . artefacts.93 Also, in vessels with small volume-to-mass ratio and in
patients with recent ACS and attenuated vasodilatory responsive-

.. been regarded as the mediator of vascular inflammation by release of
..
ness, FFRCT accuracy is compromised.10 .. pro-atherogenic adipokines,98,99 we have recently shown that a bidir-
Other methods for the calculation of non-invasive FFR by CT have
.. ectional communication exists between the vascular wall and adipose
..
also been developed that use prototype algorithms, under resting .. tissue.100–102 PVAT functions as a sensor of vascular inflammation
conditions to simulate coronary flow without high computational
.. and responds by changing its phenotype (status of adipocyte differen-
..
needs (cFFR).94 The method of cFFR has been validated against inva- .. tiation, adipocyte size and lipid/aqueous balance in adipose). Such
..
sive FFR in small clinical studies, and improved discrimination of .. changes in coronary PVAT are detectable by CT imaging.103 The first
haemodynamically significant stenoses compared to CCTA luminal .. 3D tool to measure appropriately weighted gradients in the CT at-
..
assessment alone.88 In a small validation study against invasive FFR, .. tenuation of PVAT around human vessels (Fat Attenuation Index or
cFFR had good diagnostic accuracy (91% sensitivity, 96% specificity) .. FAI) has been recently developed as a metric of vascular inflammation
..
to detect haemodynamically significant lesions.95 Further validation of .. (Figure 2A).13 Perivascular FAI has been validated against histology
the method is required in large clinical trials before clinical adoption. .. and positron emission tomography (PET) imaging, and correlates
..
.. with the degree of underlying inflammation, as well as plaque burden
.. and disease status.13 Perivascular FAI is a dynamic biomarker that fol-

..
Quantification of coronary ..
..
lows variations in vascular inflammation following a plaque rupture
.. event (Figure 2B and C).13 These findings have been confirmed by
inflammation by pericoronary fat .. other studies, which by employing a similar approach have demon-
imaging .. strated differences in the attenuation of pericoronary adipose tissue
..
.. around atherosclerotic lesions or unstable plaques of ACS
Perivascular adipose tissue (PVAT) plays a pivotal role in the physi- .. patients.104,105
ology of cardiovascular disease.96,97 Although PVAT has traditionally
..
Figure 2 Assessing coronary inflammation by imaging of pericoronary fat. (A) Attenuation gradients in the perivascular fat (Fat Attenuation Index
or FAI) around the coronaries can be analysed by post-processing of the standard computed tomography angiography (CTA) images as a metric of
vascular inflammation. (B) Perivascular FAI can discriminate between ruptured culprit lesions, and non-culprit or stable atherosclerotic plaques; (C)
relevant representative examples. (D and E) In two prospective clinical cohorts of patients undergoing diagnostic CTA for clinical indications, perivas-
cular FAI was predictive of cardiac mortality both in the derivation cohort (Erlangen, n = 1872, median follow-up 72 months, D) and the validation co-
hort (Cleveland, USA, n = 2040, median follow-up 54 months, E). Reproduced under the terms of Creative Commons Attribution License
(Oikonomou et al.14).
..
Evidence for the prognostic value of perivascular FAI was recently .. artifacts112 as well as high attenuation artefacts caused by coronary
provided by the CRISP-CT (Cardiovascular RISk Prediction using .. stents.113 Noteworthy, it has been shown in a pre-clinical study the
..
Computed Tomography) study which involved analysis of two inde- .. potential of spectral CT in intraplaque inflammation imaging using
pendent cohorts in a total of 3912 patients undergoing diagnostic .. nanoparticle contrast agents targeting activated macrophages.114 The
..
CCTA.14 Perivascular FAI around the three coronaries was strongly .. radiomic phenotyping of coronary plaques is also a novel approach
interrelated and predictive of all-cause and cardiac mortality. The .. to detect HRP by use of machine learning (ML) algorithms and big-
..
prognostic value of perivascular FAI in CRISP-CT was independent of .. data datasets with hundreds of plaque imaging features.115 This is an
traditional risk factors, the extent of coronary atherosclerosis or the .. attractive way to identify vulnerable, rupture-prone plaques, but the
..
presence of HRP features on CCTA. In this large clinical cohort, a ‘J- .. generalizability and transferability of such radiomic biomarkers
shaped’ relationship between perivascular FAI around proximal right
.. remains to be proven.
..
coronary artery or left anterior descending and all-cause or cardiac .. The biological information that can be derived from PVAT imaging
mortality risk. A threshold in perivascular FAI of 70.1HU around
.. can be enriched by extraction of radiomic features. Radiomics are a
..
the proximal right coronary artery was strongly predictive of all- .. rapidly evolving field e.g., in medical oncology that have been success-
cause and cardiac mortality in both the derivation and validation co-
.. fully applied for the phenotyping of tumours.116 Data characterization

..
hort and improved discrimination and risk classification for both all- .. algorithms allow the extraction of hundreds of discrete imaging
..
cause and cardiac mortality beyond traditional risk factors, HRP fea- .. (radiomic) features to assess the inter-relationships between voxels
tures and the extent of CAD (Figure 2D and E).14 CRISP-CT also .. on medical images and can be used to perform texture analysis of a
..
showed that prognostic value of FAI was lost when patients started .. region of interest. Recently, we have demonstrated how such radio-
statin treatment after the CCTA scan, tracking the reduction of their .. mic feature extraction and application of ML algorithms can be used
..
risk. This means that unlike coronary calcium score which reflects ir- .. to extract prognostic information from pericoronary fat analysis on
reversible anatomical changes in vascular wall and cannot be used for .. CCTA images.106 By using a cohort of 167 adipose tissue biopsies
..
risk prognostication in patients under statin treatment. Perivascular .. from patients undergoing cardiac surgery and available coupled
FAI is now a well-validated metric of coronary inflammation,13 dy- .. CCTA scans, ML algorithms were trained to identify adipose tissue
..
namically changes after an acute coronary syndrome13,106 and is re- .. inflammation, fibrosis and vascularity from the radiomic phenotype of
sponsive to anti-inflammatory treatments.107,108 .. fat. Fat Radiomic Profile (FRP) was tested and externally validated in a
..
.. cohort of 5487 participants from the CRISP-CT14 and SCOT-
.. HEART studies4 and shown to independently predict MACEs beyond
..
Implementing FAI analysis in ..
..
traditional risk stratification based on risk factors, coronary calcium
.. score, coronary stenosis, and HRP features on CCTA.106 Such ML/
clinical practice .. radiotranscriptomic approaches are expected to revolutionize our
.. capacity to glimpse into tissue biology by medical imaging and extract
Whilst non-adjusted of PVAT attenuation can be used, we have re- ..
cently shown that the predictive value of such measurements is lower .. diagnostic or prognostic information from medical scans. Still, such
.. ML algorithms remain to be strictly regulated and rigorously validated
to that of FAI, i.e. the fully-adjusted PVAT attenuation index metric, ..
for biological and technical factors.109 Currently, FAI analysis is feas- .. to ascertain their generalizability.
..
ible by artificial intelligence-enhanced algorithms in an automated ..
manner via a cloud service (CaRi-HEART, Caristo Diagnostics Ltd)
..
..
from the post-processing of routine CCTA images acquired from any .. Cardiovascular risk stratification
64-slice scanner type (or higher). When FAI is entered into appropri-
..
.. by coronary CT angiography: a
ate risk prediction models considering the patient risk profile (age, ..
sex, and traditional risk factors) then the personalized risk for cardio-
.. paradigm shift
..
vascular events can be calculated. ..
.. Each of the currently available CT tools has certain strengths and limi-
..
.. tations, and a tailored approach seems appropriate in their clinical
.. use. For example, the use of CCS is appropriate in asymptomatic indi-
Machine learning and future ..
.. viduals without known CAD, while FFRCT is not well-validated in
perspectives in the field of CT ..
.. patients with a recent myocardial infarction. A schematic on the com-
imaging .. parative performance and appropriateness of the available CT met-
.. rics/biomarkers is provided in Figure 3. A growing body of evidence
..
The use of spectral CT may be employed to overcome this problem .. has provided valuable insights on how to maximize the diagnostic
and allow better tissue characterization, but these approaches have .. yield of CCTA and make better use of available tools.
..
not still been widely used in clinical practice. Up to date, there is .. Firstly, the use of CCTA has strongly challenged the binary classifi-
mainly pre-clinical data on coronary plaque imaging using photon .. cation of CAD as an obstructive and non-obstructive entity, by dem-
..
counting CT device, based on phantom models and post-mortem .. onstrating independent associations of coronary plaque burden with
heart samples. Albeit, these novel techniques have the potential to .. clinical outcomes.42,44 Such evidence agrees with basic principles of
..
allow tissue characterization by CT, allowing the separation of con- .. coronary pathophysiology suggesting a continuum of risk with the ex-
trast agents from tissue components,110 obtaining images of better
.. tent of coronary atherosclerosis.44 Whilst obstructive CAD is invari-
..
quality removing calcium from them111 and reducing motion . ably associated with higher cardiovascular risk, the presence of non-

Figure 3 Comparative performance of computed tomography (CT) biomarkers. CCS, coronary calcium score; CTP, CT perfusion; FAI, perivascu-
lar Fat Attenuation Index; FFRCT, CT-derived fractional flow reserve; HRP, high-risk plaques; MI, myocardial infarction.
..
obstructive plaques also raises the risk for future coronary events,44 .. markers of vascular inflammation.123 Other modalities, highly sensi-
and this could probably be taken into account in the evaluation of the .. tive to detect coronary inflammation, such as radiolabelled sodium
..
CCTA scan report. .. fluoride (18NaF) PET/CT,124 suffer from limited clinical availability.
Secondly, the anatomical extent of coronary atherosclerosis (as .. Perivascular FAI overcomes many of the limitations of the existing
..
assessed by score systems) or even the volumetric quantification of .. imaging biomarkers: FAI can be obtained by the post-processing of
coronary plaque burden offers incremental prognostic value for fu- .. the raw CCTA imaging datasets, without the need of extra tests, its
..
ture cardiovascular events.44 The findings of the SCOT-HEART study .. performance is not hampered by the extend of coronary calcification
have played a major role in solidifying the value of CCTA as a diag- .. or the presence of stents and offers incremental prognostic and risk
..
nostic modality in the management of patients with stable chest .. reclassification information on top of traditional risk measures, ana-
pain.4 Additionally, CCTA can provide comprehensive plaque charac- .. tomical extent of disease and HRP features (Table 2 and Figure 4).14
..
terization for the identification of HRP features and the vulnerable .. Integration of perivascular FAI into routine clinical care pathways
patient at risk for plaque rupture and ACS.22,76,117 Whether aggres-
.. could offer new opportunities for the tailored management of
..
sive prevention treatment should be offered to such patients remains .. patients undergoing CCTA. For example, the combination of perivas-
still an open issue.
.. cular FAI and HRP features could be used to detect patients at high
..
Thirdly, full integration of CTP and/or FFRCT into clinical practice .. residual inflammatory burden or rupture-prone plaques,132 eligible
has the potential to make CCTA a one-stop shop for the anatomical ... for aggressive primary prevention strategies, e.g. with antiplatelets or
and functional assessment of the coronaries. First data from the intro-
.. statins. Similarly, high-risk patients at residual inflammatory risk (i.e.
..
duction of these tools into clinical practice suggests that they can .. high FAI) may be eligible for aggressive targeted treatment with high-
serve as gatekeepers to reduce unnecessary referrals for invasive
.. cost secondary prevention strategies, such as canakinumab,133 or
..
tests.92 It should be noted that a normal FFRCT may be prognostically .. PCSK9 inhibitors.134 These concepts (summarized in Figure 5) pro-
..
useful, but there may still be angina due to microvascular dysfunc- .. vide a roadmap for the integration of FAI into clinical care pathways
tion.118 This implies that additional diagnostic information can be .. and highlight some of the questions that could be addressed in rele-
..
offered by myocardial CTP, which is currently underused, and could .. vant, appropriately designed, randomized clinical trials.
be of value.84 ..
..
Importantly, next to these tools, perivascular FAI mapping of ..
human coronaries now offers a unique way to non-invasively quantify ..
.. Conclusion
coronary inflammation.13 Currently, cardiovascular risk stratification ..
of patients relies on risk score systems, which have good but less .. Current risk stratification by use of clinical risk score systems or
..
than satisfactory prognostic performance.119,120 The use of bio- .. plasma biomarkers is good but less than satisfactory for detecting
markers of systemic inflammation has also been proposed as a .. patients at residual risk. The recent advancements in the available CT
..
method to capture residual inflammatory risk and identify the vulner- .. technology offer an elegant way to risk stratify patients by extending
able patients eligible for aggressive secondary prevention.121,122 .. imaging analysis beyond luminal assessment and focusing on plaque
..
However, biomarkers of systemic inflammation are poor surrogate . phenotyping and perivascular tissue to identify the vulnerable patients
Table 2 Large prospective clinical studies on the prognostic value of coronary computed tomography angiography (beyond calcium scoring)
618
Clinical risk models c-index, mean(range)

CCS125–130 0.76 (0.64–0.82)
CCTA4,76,125–131 0.76 (0.64–0.93)
CCTA þ HRP14,76,127,128 0.78 (0.71–0.91)
CCTA þ HRP þ FAI14,106,132 0.90 (0.84–0.96)
Author Sample size Population type Main findings
Kwon et al. 2011125 4338 Low-risk patients underwent CCTA for evaluation of suspected CAD The predictive value of CCTA was superior to CCS for MACEs.
Chow et al. 2011131 14 064 CONFRIM registry CCTA measures of CAD severity presented better prognostic performance for
all-cause mortality over routine clinical predictors and LVEF.
Hou et al. 2012126 5007 Symptomatic patients who underwent CCTA CCS presented prognostic benefit for MACEs when added to clinical risk factors.
Prognostic performance was further improved with CCTA on top of CCS.
Versteylen et al. 2013127 2054 Stable symptomatic patients who underwent CCTA CCS added to FRS had better prognostic performance for ACS prediction.
Semiautomated plaque quantification added to FRS further improved
prognostic performance for ACS.
Hadamitzky et al. 2013128 1584 Patients with suspected CAD Total plaque score had an additive predictive value added to Morise score and
CCS for cardiac events.
SCOT-HEART investigators4 4146 Patients referred for assessment of suspected angina The addition of CCTA to standard clinical care enhanced diagnostic certainty
for angina due to CAD, also reducing the need for further stress testing.
Han et al. 2017129 3145 Patients that underwent diagnostic CCTA CCTA improved prognostic performance for MACEs beyond a model included
FRS and CCS in asymptomatic older adults.
Budoff et al. 2018130 10 003 Symptomatic patients with an intermediate pretest probability CCS had similar prognostic ability with functional testing for MACEs. CCTA
for CAD randomized to functional or anatomic testing with CCTA had significantly higher prognostic value compared to functional testing
and CCS.
Ferencik et al. 201876 4415 Stable symptomatic patients who underwent CCTA HRP was associated with higher risk for MACE and had better prognostic
performance for MACEs when added to a model including ASCVD risk score
and luminal stenosis.
Oikonomou et al. 201814 3912 Patients with an indication for CCTA High perivascular FAI values around proximal right coronary artery and left
anterior descending coronary artery were predictive of all-cause and cardiac
mortality and improved risk discrimination and reclassification on top of
risk factors, CCTA and HRP.
Oikonomou et al. 2019106 5742 167 patients undergoing cardiac surgery, 5487 participants in A machine learning-derived radiotranscriptomic profile of pericoronary fat
the CRISP-CT and SCOT HEART, 44 patients with MI and (Fat Radiomic Profile) significantly improved prediction for MACEs beyond
44 stable CAD controls traditional risk stratification (including risk factors, CCS, coronary stenosis
and HRP features).
A.S. Antonopoulos et al.

Predicve performance of commonly used biomarkers for

cardiovascular risk straﬁcaon
clinical risk models +
Plasma inﬂammatory biomarkers ++
Arterial FDG ++
Myocardial injury ++
CCS ++
CCTA +++
CCTA+HRP +++
CCTA+HRP+FAI +++
0.5 0.6 0.7 0.8 0.9 1.0

Predicve performance Level of
(c-index) adjustment
Figure 4 Predictive performance of commonly used biomarkers for cardiovascular risk stratification in stable patients. CCS, coronary calcium
score; CCTA, coronary computed tomography angiography; FAI, fat attenuation index; FDG, fluorodeoxyglucose uptake; HRP, high-risk plaque fea-
tures; myocardial injury biomarkers; high sensitivity cardiac troponin I/T; systemic inflammation: plasma levels of C-reactive protein and interleukin-6;
bar graphs represent low-high (and mean) value for predictive performance of each biomarker (i.e. c-index). Reproduced under the terms of Creative
Commons Attribution License (Antoniades et al. European Heart Journal 2019; European Heart Journal, 2020: 41(6), 748–758).
Figure 5 Proposed workflow for the integration of Fat Attenuation Index (FAI) into clinical care pathways and cardiovascular risk stratification by
coronary computed tomography angiography (CCTA). The suggested workflow demonstrates the potential of CCTA to be used as a ‘one-stop shop’
in the evaluation of both symptomatic patients with stable chest pain and patients with acute chest pain. The workflow is used for the risk stratification
of patients undergoing CCTA and generates hypotheses that could be tested in future randomized clinical trials to tackle residual risk of both low-
and high-risk populations. ACS, acute coronary syndrome; CAD, coronary artery disease; CTP, CT perfusion; ECG, electrocardiography; FFRCT, CT-
derived fractional flow reserve; HRP, high-risk plaques; hscTnI, high sensitivity cardiac troponin I; MR, myocardial revascularization; OMT, optimal
medical treatment; PCSK9i, Proprotein convertase subtilisin/kexin type 9 inhibitors.
..
at risk for coronary events. The combination of anatomical, morpho- .. significant stenosis in acute chest pain: results from the ROMICAT-II trial. J
logical and biological metrics of the coronary tree together with non- .. Am Coll Cardiol 2014;64:684–692.
.. 10. Gaur S, Taylor CA, Jensen JM, Botker HE, Christiansen EH, Kaltoft AK, Holm
invasive functional tests offers a unique CT toolkit for the risk stratifi- .. NR, Leipsic J, Zarins CK, Achenbach S, Khem S, Wilk A, Bezerra HG, Lassen
cation of patients, patient selection for targeted aggressive preven- .. JF, Norgaard BL. FFR derived from coronary CT angiography in nonculprit
.. lesions of patients with recent STEMI. JACC Cardiovasc Imaging 2017;10:
tion strategies and for guiding revascularization procedures or safely .. 424–433.
deferring patients from invasive tests (Figure 5). Future clinical studies ..
.. 11. Coenen A, Rossi A, Lubbers MM, Kurata A, Kono AK, Chelu RG, Segreto S,
in the field are expected to provide suggestions on how to make .. Dijkshoorn ML, Wragg A, van Geuns RM, Pugliese F, Nieman K. Integrating
cost-effective use of these newer CT metrics, and incorporate them .. CT myocardial perfusion and CT-FFR in the work-up of coronary artery dis-
.. ease. JACC Cardiovasc Imaging 2017;10:760–770.
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..
Conflict of interest: A.A. and C.A. are inventors of intellectual .. 2016;117:1868–1876.
property relevant to CT imaging (AA/CA: GB2015/052359, GR2018/ .. 13. Antonopoulos AS, Sanna F, Sabharwal N, Thomas S, Oikonomou EK,
.. Herdman L, Margaritis M, Shirodaria C, Kampoli AM, Akoumianakis I, Petrou
0100490, GR2018/0100510; CA: GB2015/052359, GB2016/ .. M, Sayeed R, Krasopoulos G, Psarros C, Ciccone P, Brophy CM, Digby J,

1620494.3, GB2018/1818049.9). C.A. is founder, shareholder, and .. Kelion A, Uberoi R, Anthony S, Alexopoulos N, Tousoulis D, Achenbach S,
.. Neubauer S, Channon KM, Antoniades C. Detecting human coronary inflam-
director of Caristo Diagnostics Ltd, a spin-out company of the .. mation by imaging perivascular fat. Sci Transl Med 2017;9:eaal2658.
University of Oxford; he is also head of Oxford Academic .. 14. Oikonomou EK, Marwan M, Desai MY, Mancio J, Alashi A, Hutt Centeno E,
..
Cardiovascular CT Core lab. .. Thomas S, Herdman L, Kotanidis CP, Thomas KE, Griffin BP, Flamm SD,
.. Antonopoulos AS, Shirodaria C, Sabharwal N, Deanfield J, Neubauer S,
.. Hopewell JC, Channon KM, Achenbach S, Antoniades C. Non-invasive detec-
.. tion of coronary inflammation using computed tomography and prediction of
.. residual cardiovascular risk (the CRISP CT study): a post-hoc analysis of pro-
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Cardiovascular Risk Stratification by Coronary Computed Tomography Angiography Imaging: Current State-Of-The-Art

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European Journal of Preventive Cardiology (2022) 29, 608–624 REVIEW

doi:10.1093/eurjpc/zwab067 Risk Prediction/Assessment & Stratification

Cardiovascular risk stratification by coronary

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* Corresponding author. Tel: þ30 6947607442, Email: alexios.antonopoulos@cardiov.ox.ac.uk; antonopoulosal@yahoo.gr

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atherosclerotic plaque burden.18 CCS has incremental prognostic

Coronary calcium score (CCS)

1–99: mildly increased

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.. non-obstructive coronary artery disease

.. tomatic patients at low to intermediate-risk pretest probability (15–

.. CCTA has a 85–95% sensitivity, 83–90% specificity for obstructive

Pros: clinically recommended to assess the haemodynamic significance of a lesion

.. Obstructive CAD (usually defined as a luminal stenosis of >_50% or

.. patients with chest pain undergoing CCTA.42 A single or multiple lu-

.. ity risk.42 In the multicentre CONFIRM registry involving 23 854

Fractional flow reserve CT (FFRCT)

.. cardiovascular risk.21 The prognostic importance of non-obstructive

.. studies,43,44 confirming that the presence and extent of non-obstruct-

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patients with recent ACS and attenuated vasodilatory responsive-

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Clinical risk models c-index, mean(range)

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Predicve performance of commonly used biomarkers for

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