Coronary artery disease (CAD) remains the main cause of morbidity and mortality in the world. The American Heart Association 2022 statistical update reported a high prevalence and incidence of CAD [1], which affects 20.1 million Americans ≥20 years of age and is estimated to occur in 720,000 and 335,000 individuals as a new or recurrent (fatal or non-fatal) event, respectively. The same source reports a decreasing trend in morbidity and mortality from CAD, which has occurred despite a worsening in the risk profiles of Americans with atherosclerotic cardiovascular disease (ASCVD), [2] and is likely due to advances in the prediction, detection, and treatment of CAD.

Historically, the prediction of CAD has been based on traditional cardiovascular risk factors and algorithms incorporating them, which provide an estimate of the risk of developing fatal and/or non-fatal coronary and other ASCVD events. Unfortunately, the performance of prediction algorithms is insufficient at the individual level for several reasons, such as a lack of validation in external cohorts or different populations and the lack of regular updates with contemporary epidemiological data [3]. Furthermore, relevant variables may not have been included in these models, prompting the addition of non-traditional cardiovascular risk factors and/or measures of subclinical ASCVD [4].

Instead, the detection of CAD has been based on the presence of symptoms combined with the demonstration of myocardial ischemia/dysfunction and arterial stenosis by stress (functional) testing and invasive coronary angiography (ICA), respectively. However, symptoms, including chest pain and anginal equivalents, such as dyspnea, diaphoresis, fatigue, and non-chest pain, have limited sensitivity and specificity [5], and may even be absent (silent angina) [6], especially in diabetic individuals [7]. Similarly, functional tests, including stress electrocardiography (ECG), echocardiography, and nuclear myocardial perfusion imaging (MPI), yield an insufficient diagnostic accuracy for detecting obstructive CAD in terms of both sensitivity and specificity [8]. Finally, elective ICA, which is considered the gold standard for CAD diagnosis, provides a two-dimensional “lumenogram” of the coronary arteries, but not images of the vessel wall or information on the hemodynamic consequences of stenoses [9], unless it is combined with the assessment of invasive fractional flow reserve (FFR), the use of which is increasing but still limited [10]. Furthermore, the diagnostic yield is low, as only slightly more than one third of patients with suspected CAD were found to have obstructive lesions upon ICA [11].

2. Non-Contrast CT

Non-contrast CT is currently used for the assessment of coronary artery calcium (CAC), which is considered to be the best marker of subclinical CAD/ASCVD ^[12][13]. In addition, it can provide important information with regard to epicardial adipose tissue (EAT), which is a marker of systemic inflammation and ASCVD risk.

2.1. Coronary Artery Calcium

Intimal calcification has long been recognized as a typical feature of atherosclerotic lesions, with its extent increasing in parallel with the progression of vascular pathology toward the advanced stage ^[13][14]. It starts as microcalcification nuclei originating from vascular smooth muscle cell (VSMC)-derived apoptotic bodies and macrophage-derived matrix vesicles ^[14][15] in close association with inflammation ^[15][16]. With the progression of atherosclerosis, calcium deposits increase in size and become visible upon imaging as spotty calcification, along with increased plaque instability and risk of rupture ^[16][17][17,18]. Conversely, in more advanced stages, the coalescence of calcium deposits into large, sheet-like plates is related to the blunting of inflammation, which allows for the survival of VSMCs that produce collagen and undergo osteogenic differentiation ^[16][17][17,18]. The transition to uninflamed, fibrocalcific lesions is associated with plaque stabilization ^[17][18], unless calcified plates fracture and form noduli that protrude into the lumen, an event which is, however, uncommon in the coronary arteries ^[18][19]. Thus, the relationship between plaque instability and the extent of calcification appears to be non-linear, since the risk of rupture is low with no calcification, increases progressively with mild and moderate calcification, and decreases with severe calcification ^[14][15]. Non-contrast CT is increasingly used for assessing CAC and quantifying it using scoring systems such as the Agatston score, which is determined by the product of the calcified plaque area and the maximal calcium lesion density (from 1 to 4 based on Hounsfield units) ^[19][20]. Several studies have shown that the CAC score is a powerful predictor of morbidity and mortality from CAD and other ASCVDs. The prognostic value of the CAC score was first demonstrated in asymptomatic individuals ^[20][21]. In the Multi-Ethnic Study of Atherosclerosis (MESA), which included participants 45 to 84 years of age, the overall CAC prevalence ranged from 52.1% to 70.4% in males, and from 34.6% to 44.6%, in females, depending on the ethnicity ^[21][22]. In this cohort, the adjusted risk of a coronary event was increased 7.73-fold in participants with CAC scores between 101 and 300, and 9.67-fold in those with CAC scores >300, as compared with those with no CAC; moreover, a doubling of the CAC score increased the risk of a major coronary event by 15 to 35%, and the risk of any coronary event by 18 to 39% ^[22][23]. The prevalence of CAC was shown to be lower in the younger participants in the Coronary Artery Risk Development in Young Adults (CARDIA), i.e., 5.5% among those aged 33 to 39 years, and 13.3% among those aged 40 to 45 years ^[23][24]. However, even in this younger cohort, the adjusted risk of coronary events was increased five-fold among participants with any CAC and 2.6-, 5.8-, and 9.8-fold among those with CAC scores of 1–19, 20–99, and >100, respectively ^[24][25]. Furthermore, CAC progression was found to correlate with the progression of all types of coronary plaque, including non-calcified plaques, whereas no plaque progression was observed in individuals with no CAC progression ^[25][26]. The prognostic value of the CAC score for CAD events in asymptomatic individuals has recently been confirmed by a systematic review of 45 studies ^[26][27]. Several other studies have subsequently showed that the CAC score improves risk stratification when added to algorithms based on traditional ASCVD risk factors ^[27][28], especially among individuals at intermediate risk, such as those with a Framingham Risk Score of 10–20% or an Adult Treatment Panel score of 6–20%, with reclassification to the high-risk category ^[28][29][29,30]. Moreover, the addition of the CAC score to a cardiovascular risk factor-based algorithm developed in the MESA cohort significantly improved risk prediction and performed well in the external validation cohorts of the Heinz Nixdorf Recall (HNR) Study and the Dallas Heart Study (DHS) ^[30][31]. In women, who were shown to have a lower prevalence of CAC then men, a CAC score >0 was predictive of ASCVD events beyond traditional risk factors, even among those at low risk ^[31][32][32,33], and was associated with a higher relative risk of mortality from ASCVD than in men ^[33][34]. It is worthy of note that, in a prospective follow-up study, a CAC score of 0 conferred a 15-year “warranty period” against mortality in individuals at low-to-intermediate risk, and better survival in those at high risk, as compared to those at low-to-intermediate risk but with any CAC score ^[34][35]. Finally, CAC was found to provide superior discrimination and risk reclassification compared with other markers ^[35][36]. More recently, the CAC score was also found to be of prognostic value in symptomatic individuals. In patients with stable chest pain (or dyspnea) from the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) Study, CAC scoring was in fact shown to be more sensitive, but less specific than functional testing in predicting mortality and CAD events, with similar overall discriminatory ability ^[36][37]. The prognostic value for MACEs of the CAC score in symptomatic individuals was recently confirmed by a meta-analysis of 19 observational studies ^[37][38]. Among symptomatic patients from the Western Denmark Heart Registry, the ASCVD event rate increased stepwise with higher CAC scores, but regardless of whether they have obstructive or non-obstructive CAD ^[38][39]. Conversely, a negative predictive value was demonstrated for a CAC score of 0 among patients with either acute or chronic chest pain, supporting the safe avoidance of additional downstream testing ^[39][40]. However, the absence of CAC does not exclude the presence of a non-calcified plaque causing obstructive CAD and the occurrence of acute events, as shown in symptomatic patients from The Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter (CONFIRM) Registry ^[40][41]. Recent data from the Western Denmark Heart Registry showed that a sizable number of cases of obstructive CAD occurred in patients without CAC who were younger than 60 years ^[41][42]. A main limitation of CAC scoring is that it does not account for the type and pattern of calcium deposition within the vessel wall, which limits its accuracy in predicting obstructive CAD and coronary events in the individual patient ^[17][18]. This concept is supported by studies showing that a high CAC score correlates with plaque stability rather than with plaque instability ^[42][43][44][43,44,45], and that plaque stabilization upon statin treatment is associated with an increase in CAC score ^[45][46][47][46,47,48], indicating that, in patients with heavily calcified coronary arteries, the CAC score is more a marker of overall CAD burden than a predictor of a future coronary event ^[48][49]. This concept is supported by the finding that highly calcified plaques (>1000 HU) were associated with a lower risk of acute coronary syndrome (ACS) in a nested case-control study of patients with no known CAD drawn from the CONFIRM Registry ^[49][50]. Moreover, calcium density was found to be inversely related to CAD and ASCVD for a given calcification volume, which was more predictive of CVD risk when adjusted for calcium density ^[50][51]. An inverse relationship between calcium density and instability features was also observed at the individual plaque level ^[44][45].

2.2. Epicardial Adipose Tissue

Epicardial adipose tissue (EAT) is a unique fat depot, as it is anatomically and functionally different from other visceral and subcutaneous fat depots ^[51][52], despite sharing the embryological origin from the splanchnopleuric mesoderm with intra-abdominal fat ^[52][53]. It is located between the myocardium and the visceral pericardium, with no muscle fascia separating the fat depot and the myocardium, which share the same microcirculation ^[51][52]. These anatomical features allow fat infiltration into the myocardium and the coronary arteries, and the direct cross-talk of EAT with muscle and vessels through paracrine and vasocrine mechanisms ^[51][52]. Under physiologic conditions, EAT is protective for the myocardium through its dynamic brown fat-like function that promotes fatty acid uptake, oxidation, and thermogenesis, as well as fatty acid release, thus serving as a source of energy and heat for the myocardium and a buffer for high fatty acid levels ^[53][54]. This brown fat-like activity of EAT decreases substantially with age, with a gradual transition from thermogenesis to energy storage ^[51][52]. As with other visceral fat depots, EAT increases in obese individuals, and becomes harmful for the myocardium by acquiring a functional beige-white phenotype associated with macrophage infiltration, which results in a change in the transcriptome and secretome profile with pro-oxidant, pro-inflammatory, and pro-fibrotic effects on the heart ^[54][55]. For this reason, EAT accumulation and dysfunction is considered to be not only a marker of systemic inflammation in metabolic disorders such as obesity and type 2 diabetes, as with excess intra-abdominal fat, but also a player in the pathogenesis of CAD and other cardiac conditions such as arrhythmias and heart failure ^[51][52]. In this regard, a major role is attributed to the EAT located in close proximity to the coronary arteries, which will be discussed later. Non-contrast CT allows for the measurement of EAT thickness and volume ^[55][56], which represents markers of visceral adiposity and ectopic fat accumulation, as they correlate with intra-abdominal as well as intra-hepatic and intra-muscular (including the myocardium) fat ^[51][52]. While echocardiography only measures EAT thickness, CT (and magnetic resonance) allows also measurement of EAT volume, which can be performed using dedicated software ^[51][52]. In addition, CT can assess EAT attenuation, a measure of EAT density expressed in HU units and ranging between −45 HU and −195 HU, which is decreased (i.e., more negative) in cases of hypertrophic and hyperplastic fat depots, and increased (i.e., less negative) in cases of fibrotic and inflamed fat depots ^[51][52]. Several studies have shown that EAT volume, as assessed by CT, is positively associated with coronary atherosclerosis. In fact, EAT volume was found to be associated with CAC in asymptomatic individuals from the Early Identification of Subclinical Atherosclerosis using Non-invasivE Imaging Research (EISNER) Trial ^[56][57], whereas previous reports from the population-based Rotterdam Study ^[57][58] and the influence of EPICardial adipose tissue in HEART disease (EPICHEART) Study ^[58][59] showed that this relationship was only significant in men. Moreover, the EAT volume was shown to be associated with CAC progression, independent of measures of adiposity, in patients with ^[59][60] and without ^[60][61] diabetes. However, in the HNR Study, the association of EAT volume with CAC progression was found to be stronger in younger individuals with lower CAC scores at baseline ^[61][62], suggesting that EAT expansion is a predictor of early atherosclerosis. Indeed, the EAT volume was shown to be larger in the presence of mixed or non-calcified plaques than with calcified plaques (or no plaques) ^[62][63], and to correlate with plaque instability features independent of measures of adiposity ^[63][64]. In addition, EAT volume was found to correlate with obstructive CAD independently of CAC score in both asymptomatic ^[64][65] and symptomatic ^[61][65][66][62,66,67] individuals undergoing CCTA, and even in patients with a CAC score = 0 ^[67][68]. Finally, a meta-analysis of 70 studies comprising 41,534 subjects, mainly derived from community-based or hospital-based populations with low-to-intermediate pretest CAD probability, showed that EAT volume was independently associated with obstructive CAD (coronary stenosis and myocardial ischemia) and CAD events, whereas the correlation with CAC was only borderline significant ^[68][69].

3. Contrast-Enhanced CT

During the last decade, coronary CT angiography (CCTA) has emerged as a useful tool in CAD detection by allowing for the non-invasive assessment of the presence and extent of coronary artery stenosis, eventually combined with the evaluation of its functional significance through the measurement of FFR derived from CT (FFR_CT), or CT perfusion imaging (CTPI). Moreover, and possibly more importantly, by also imaging the vessel wall, CCTA has been found to provide information on the biological processes driving coronary atherosclerosis which are not fully reflected by the severity of lumen narrowing and/or myocardial ischemia, and allow a more accurate diagnostic and prognostic assessment. It is in fact known that a significant proportion of acute CAD events result from originally non-obstructive, unstable plaques which subsequently progress and undergo fibrous cap rupture and thrombus formation with consequent lumen occlusion ^[69][70][70,71]. This points to the importance of assessing the plaque burden, composition, and features of instability, as well as changes in perivascular adipose tissue (PVAT), indicating an active process of vascular inflammation.

3.1. Lumen Stenosis

Coronary stenosis is the hallmark of CAD, as it is associated with reduced coronary blood flow and myocardial ischemia at a threshold of ~50% and ~80%, respectively ^[71][72]. Conventionally, a stenosis of 70% or more is considered to be hemodynamically significant and worthy of therapeutic intervention with invasive procedures and, hence, assessing the extent of lumen narrowing is of pivotal importance for evaluating CAD severity ^[72][73]. This is the reason why ICA is the gold standard for detecting obstructive CAD, and why CCTA has been proposed as a safe, non-invasive gatekeeper for identifying patients who warrant subsequent ICA, as an alternative to functional testing ^[72][73]. In fact, CCTA provides a three-dimensional imaging of the arterial lumen that allows for the quantification of stenosis and the classification of patients according to the degree of maximal stenosis based on the CAD Reporting and Data System (CAD-RADS) ^[73][74]. A meta-analysis including small-size single-center studies first showed that the diagnostic performance of CCTA was approximately similar to that of ICA ^[74][75]. This was subsequently confirmed by larger single-center or multi-center studies in patients referred for ICA, which demonstrated that CCTA was effective in detecting, and especially ruling out, obstructive CAD ^{[75][76][77][78]}[76,77,78,79], although it was found to somewhat overestimate its severity ^[78][79]. In addition, a number of studies comparing CCTA with ICA as an initial imaging approach in patients with suspected CAD showed that CCTA resulted in less invasive procedures and a higher diagnostic yield than ICA, with similar clinical outcomes in terms of major adverse cardiovascular events (MACEs) ^[79][80][81][80,81,82]. Finally, CCTA was found to have the potential for guiding the decision-making between percutaneous coronary intervention (PCI) and coronary artery by-pass grafting in patients with complex CAD ^[82][83]. In particular, CCTA was shown to be as accurate as ICA in the assessment of CAD anatomical complexity for calculating the SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery (SYNTAX) scores ^[83][84][84,85], or the SYNTAX-II score ^[85][86], which integrates anatomical and clinical features ^[86][87]. As compared with functional tests, CCTA was shown to have a higher specificity and sensitivity with ICA >50% diameter stenosis as the reference standard ^[87][88][88,89], and the highest sensitivity but the lowest specificity with invasive FFR <0.80 as the reference standard ^[89][90]. In low- and/or intermediate-risk individuals with acute chest pain and normal ECG and troponin values, CCTA resulted in similar outcomes and resource use as functional testing, as shown in the American College of Radiology Imaging Network-Pennsylvania (ACRIN-PA) Multicenter Trial ^[90][91], the Prospective Randomized Outcome trial comparing radionuclide Stress myocardial Perfusion imaging, the ECG-gated coronary CT angiography (PROSPECT) Study ^[91][92], and the Prospective First Evaluation in Chest Pain (PERFECT) Trial ^[92][93]. However, improved outcomes with CCTA compared with functional tests were reported in the Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography (ROMICAT)-II Study ^[93][94] and the CArdiac cT in the treatment of acute CHest pain (CATCH) Trial ^[94][95], whereas the CT Coronary Angiography Compared to Exercise ECG (CT-COMPARE) Study showed a better performance with lower costs with CCTA ^[95][96]. Studies in low- and/or intermediate-risk individuals with stable chest pain also showed similar, if not better, outcomes with CCTA compared with functional tests. No difference was found in the PROMISE Study ^[96][97], and in an earlier small-size study comparing CCTA and MPI with single-proton emission computed tomography (PET) scanning ^[97][98]. Conversely, the superiority of CCTA in terms of CAD morbidity and mortality over a 4.8-year follow-up was observed in the Scottish Computed Tomography of the Heart (SCOT-HEART) Trial, which was associated with no increase in the rate of ICA or coronary revascularization ^[98][99], whereas less symptoms with CCTA than with functional tests were reported in the Computed Tomography vs. Exercise Testing in Suspected Coronary Artery Disease (CRESCENT) ^[99][100] and the Cardiac CT for the Assessment of Pain and Plaque (CAPP) ^[100][101]. A meta-analysis including most of the above studies in patients with either acute or stable chest pain showed that anatomical testing with CCTA as the initial non-invasive diagnostic modality resulted in a lower risk of non-fatal myocardial infarction, but not MACEs or all-cause mortality, as compared with the usual care with functional testing at the expense of a more frequent use of invasive procedures ^[101][102]. Moreover, a systematic review in patients with acute or stable chest pain showed that CCTA is cost-effective when compared with the standard of care, including functional testing ^[102][103].

3.2. Myocardial Ischemia

The extent of myocardial ischemia is certainly dependent on the severity of lumen stenosis. However, the 70% threshold for hemodynamically significant coronary stenosis does not necessarily imply the presence of myocardial ischemia which requires invasive therapeutic interventions, thus suggesting the need for assessing the functional significance of lumen narrowing ^[72][73]. The accuracy of ICA to indicate the need for coronary revascularization is greatly increased by combining it with invasive FFR assessment, which allows for the more precise assessment of the hemodynamic consequences of the coronary stenoses compared to non-invasive functional tests ^[103][117]. In fact, ischemia assessed by functional testing was not associated with outcomes after adjusting for CAD severity in the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) Trial ^[104][118]. Conversely, the use of invasive FFR to guide coronary revascularization resulted in improved clinical outcomes compared with ICA in the Percutaneous Coronary Intervention of Functionally Non-significant Stenosis (DEFER) Trial ^[105][119] and the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) Study ^[106][120]. Coupling CCTA with either FFR_CT or CTPI represents a suitable non-invasive alternative to invasive FFR. While computational flow dynamic or machine learning techniques are applied to derive FFR_CT, static or dynamic imaging acquisitions under rest and stress conditions (or vice versa) are required for CTPI ^[107][121]. Several meta-analyses have provided evidence that both FFR_CT ^{[89][108][109][110]}[90,122,123,124] and CTPI ^{[108][109][111]}[122,123,125] are valuable tools for detecting hemodynamically significant coronary stenosis compared with invasive FFR. In particular, two of these meta-analyses reported similar sensitivity and specificity for FFR_CT and/or CTPI compared to other functional imaging modalities ^[108][111][122,125], whereas the others showed that FFR_CT and/or CTPI improved the diagnostic accuracy of CCTA by increasing the specificity ^{[89][109][110]}[90,123,124]. For FFR_CT, this was confirmed in the large cohort of the Assessing Diagnostic Value of Non-invasive FFR_CT in Coronary Care (ADVANCE) registry ^[112][126], and in participants in the NXT ^[113][127] and Prospective Comparison of Cardiac PET/CT, SPECT/CT Perfusion Imaging and CT Coronary Angiography with Invasive Coronary Angiography (PACIFIC) ^[114][128] trials. In addition, the 90-day ^[112][126] and 1-year ^[115][129] outcome data from the ADVANCE registry showed that FFR_CT significantly modified patients’ management with the safe deferral of invasive evaluation in those with negative values (i.e., >0.80). Similarly, in the NXT Trial, FFR_CT significantly ameliorated the ability of CCTA to predict long-term outcomes driven by planned and unplanned revascularization ^[116][130]. Moreover, the FFR_CT Planner is a novel tool that allows for the virtual stenting of coronary stenoses and the prediction of post-PCI FFR ^[117][131]. This might be useful in patient selection and procedural planning because of the important prognostic implications of post-PCI FFR ^[118][132], which remains suboptimal in a substantial proportion of individuals ^[119][133]. Post-PCI FFR was also shown to correlate with vessel/lesion-specific myocardial mass, in addition to the coronary volume to mass ratio ^[120][134], which can be quantified on CCTA using dedicated algorithms ^[121][135]. However, costs increase substantially when using FFR_CT, which should be reserved for patients with an intermediate-to-high pre-test probability of CAD with significant or uncertain stenosis at CCTA, who showed the highest post-test probability in a recent meta-analysis ^[122][136].