Introduction

Despite a rapid progress in cardiology, cardiovascular diseases are still the leading cause of morbidity and mortality in developed countries. Therefore, there is an urgent need to introduce effective diagnostic methods that would allow for early, rapid, and noninvasive detection of coronary artery disease (CAD).1 Recently, the European Society of Cardiology (ESC) guidelines improved the position of coronary computed tomography (CCT) and significantly strengthened its role in the diagnosis of chronic coronary syndrome (CCS).2

Coronary computed tomography and the current European Society of Cardiology guidelines

The first and crucial step in the diagnostic process in patients with suspected CCS is to determine the probability of significant CAD. The updated ESC guidelines for the management of CCS2 still recommend the pretest probability (PTP) assessment as the initial evaluation based on the clinical risk factors. The first step is to assess the main symptoms, including chest pain and dyspnea, and the number of cardiovascular risk factors3 (Table 1).

Table 1. Assessment of significant symptoms and risk factors for pretest probability calculation2

Variable

Criterion

Scoring

Assessment of the main symptoms (1 or 2)

Chest pain

Retrosternal discomfort radiating to the neck, jaw, shoulder, or arm

1 point

Aggravated by physical or emotional stress

1 point

Reduction of pain at rest or after nitrates within 5 minutes

1 point

Dyspnea

Dyspnea on exertion or at rest, worsening with physical activity

1 point

CAD risk factors

Family history, smoking, dyslipidemia, hypertension, diabetes

Each factor = 1 point

0–5 points

Abbreviations: CAD, coronary artery disease

Then, the estimated probability (%) of CAD weighted by risk factors according to the age, sex, and symptom score is provided (Table 2). The final result of this calculation influences further diagnostic pathway, including noninvasive or invasive methods.4 The role of CCT in CAD was first emphasized in the 2019 ESC guidelines for the management of CCS.5 According to the 2024 ESC guidelines, CCT is recommended for the diagnosis of CAD and for estimating the risk of major adverse cardiovascular events (MACEs) in individuals with suspected CCS and a low-to-moderate PTP of significant CAD, ranging from below 5% to 50%. In those individuals, CCT is the first-line method to exclude significant CAD. It constitutes a class IA recommendation in the ESC guidelines.2,6

Table 2. Risk ratio–weighted clinical probability model for significant coronary artery disease in women and men

Age, y

CAD risk factor points

Risk for 0–1 symptom points, %

Risk for 2 symptom points, %

Risk for 3 symptom points, %

Women

30–39

0–1

0

0

2

2–3

1

1

2

4–5

2

3

10

40–49

0–1

1

1

4

2–3

1

2

7

4–5

3

5

12

50–59

0–1

1

2

6

2–3

2

3

10

4–5

5

7

15

60–69

0–1

2

3

10

2–3

4

6

14

4–5

7

11

19

70–80

0–1

4

6

16

2–3

7

10

19

4–5

11

16

23

Men

30–39

0–1

1

2

9

2–3

2

4

14

4–5

5

8

22

40–49

0–1

2

3

14

2–3

4

6

20

4–5

8

12

27

50–59

0–1

4

6

21

2–3

7

11

27

4–5

12

17

66

60–69

0–1

8

12

32

2–3

12

17

35

4–5

17

25

39

70–80

0–1

15

22

44

2–3

19

27

44

4–5

24

34

45

Score: 0%–5%, very low probability; 6%–15%, low probability; 16%–50% moderate probability2,60

Abbreviations: see Table 1

Moreover, CCT is recommended for patients with an undetermined result of other noninvasive diagnostic tests, including a functional imaging test.7 As all imaging methods, CCT has its drawbacks and limitations.8 Table 3 lists the most important indications and contraindications for CCT.

Table 3. Indications and contraindications to coronary computed tomography6-8,61

Indications for CCT

Contraindications to CCT

Cardiovascular risk assessment

Allergy to iodine-based contrast agents

Diagnosis of chest pain of unknown origin in patients with a medium or low risk of CAD

Severe renal failure

Exclusion of significant CAD in patients with symptoms suggestive of angina when other tests are ambiguous

Uncontrolled hyperthyroidism

Assessment of coronary artery anatomy and anomalies

Pregnancy

Assessment of coronary plaque anatomy for revascularization and after percutaneous coronary interventions (eg, stent implantation and patency)

Significant cardiac arrhythmia (image quality)

Evaluation of patency of coronary artery bypass grafts

Uncontrolled tachycardia (target heart rate 55–65 bpm)

Lack of patient cooperation during the examination

Cardiovascular hemodynamic instability

Advanced atherosclerosis with extensive calcifications, which may limit accuracy of the assessment of coronary artery stenosis

Abbreviations: CCT, coronary computed tomography; others, see Table 1

A 64-slice CT scanner using electrocardiogram (ECG)-gated image reconstruction is sufficient for cardiac purposes. However, it is strongly recommended to use modern and more sophisticated scanners (at least 128-slice ones), as the image quality is the cornerstone for further workup.9 A patient is usually exposed to a relatively small radiation dose depending on the scanner, the study protocol, and individual clinical characteristics.10,11

Coronary atherosclerosis on coronary computed tomography: anatomy and plaque characteristics

Routine invasive coronary angiography is focused on assessing the degree of vascular lumen narrowing. It does not provide objective data on the hemodynamic flow or vascular wall and atherosclerosis, unless more sophisticated options are used, for example, intravascular ultrasound or optical coherence tomography. Therefore, it does not provide a complete and comprehensive assessment of CAD and clinical prognosis. It may also not fully reflect the inflammatory component of the disease and the atherosclerotic plaque phenotype.12 There is a need for rapid and minimally-invasive diagnostics of coronary arteries.13 CCT has a potential to fulfill all those expectations.14

CCT angiography is a noninvasive 3-dimensional imaging technique. It uses X-rays and advanced computed reconstructions providing a detailed coronary artery visualization. It allows for quantification of atherosclerotic plaques, identification of high-risk plaques, and functional assessment of the coronary vessels.15 CCT images are used in precise assessment of the degree of arterial stenosis and detailed characterization of the atherosclerotic plaque, including assessment of its composition and morphology. Well-evidenced features of an unstable plaque include a thin fibrous cap, low attenuation coefficient suggesting a lipid-rich core, positive vessel remodeling, spotty calcifications within the plaque, and irregular or ulcerated surface. This phenotype carries a significantly higher risk of MACEs, regardless of the degree of artery stenosis.16 Due to its effectiveness, CCT is increasingly recommended as the first-line imaging test in patients complaining of chest pain. Data from the National Institute for Health and Clinical Excellence and the ESC strongly support this conclusion.17 The position of CCT among other diagnostic methods, depending on the estimated risk, is presented in Table 4.

Table 4. Diagnostic methods depending on coronary artery disease risk2

CAD risk

Diagnostic method

Very high (>85%)

Coronary angiography

High (>50%–85%)

PET/SPECT, stress CMR, stress echocardiography

Moderate (>15%–50%)

CCT, PET/SPECT, stress CMR, stress echocardiography

Low (>5%–15%)

CCT

Very low (0%–5%)

Postponement of diagnostics

Abbreviations: CMR, cardiac magnetic resonance; PET, positron emission tomography; SPECT, single-photon emission computed tomography; others, see Tables 1 and 3

The Coronary Artery Disease Reporting and Data System (CAD-RADS) is a standardized scale for classifying and reporting CCT results. The scale is mainly based on the degree of stenosis and the number of the coronary arteries with atherosclerotic plaque. It provides a structured report with a final clinical conclusion for the referring physician.18 Table 5 presents the levels of the CAD-RADS scale.

Table 5. Coronary Artery Disease Reporting and Data System scale18

CAD-RADS category

Maximal stenosis, %

Description / interpretation

0

0

Complete absence of CAD

1

1–24

Minimal CAD: minimal or no vessel stenosis

2

25–49

Mild CAD

3

50–69

Moderate CAD

4A

70–99

Severe CAD: severe stenosis in 1 or 2 coronary arteries, excluding the left main coronary artery

4B

LMCA >50% or 3-vessel disease with stenoses ≥70%

Severe high-risk CAD: critical left main coronary artery stenosis or severe 3-vessel disease

5

100

Complete occlusion of a coronary artery

Abbreviations: LMCA, left main coronary artery; others, see Table 1

The first step of the examination is usually a noncontrast cardiac CT used to assess and quantify the value of calcium score (SC) and distribution of calcifications within the coronary arteries. It can also be performed as a single procedure and the result is expressed in total coronary CS with separate data on individual arteries. It gives a general overview on the presence and distribution of calcified plaques. The CS index has a very well-evidenced prognostic value and a negative diagnostic value for excluding CAD. CS equal to 0 is an equivalent of 130 or fewer Hounsfield units (HUs).19,20 However, the atherosclerotic plaque may be significant and unstable even in young patients without spotty coronary calcification. The noncalcified plaque is not visible on noncontrast CT images. Therefore, CT-based CS assessment should not be the only diagnostic method in current clinical practice. The test should be supplemented, for example, with complete CCT.21 Sample CCT images are shown in Figure 1.

Figure 1. A – correct left anterior descending artery image on coronary computed tomography (CCT); B – calcium score; C – 3-dimensional reconstruction of the CCT image

The fact that CCT provides a detailed information leads to more reliable clinical decisions. This potentially reduces the need for unnecessary, invasive procedures, and may improve patient outcomes.22 According to the latest guidelines, CCT is considered the test of choice to exclude CAD in patients with a low and intermediate risk of this condition.23 Although CCT helps to identify plaque features associated with a high risk of cardiovascular events, it does not always provide sufficient information for optimal risk prediction in selected patients. It is important to be aware that most acute myocardial infarctions are caused by vascular occlusion at noncritical plaques with a rupture or erosion.24 Currently, the role of CCT in assessing inflammation of the atherosclerotic plaque is increasingly described. This opens up new possibilities for understanding and treating the fundamental biological processes in atherosclerosis.17

Fractional flow reserve

CCT is an excellent diagnostic tool to assess the anatomy of coronary arteries and plaques. A nonobstructive plaque (<⁠50% diameter stenosis) and an obviously critical stenosis have their clear treatment pathways: pharmacotherapy or coronary revascularization. However, there is a relatively large group of patients in the gray zone with an intermediate coronary stenosis. Therefore, a noninvasive fractional flow reserve (FFR)-CT has recently been developed and introduced into the clinical practice. FFR-CT is a novel software-based technique to estimate the hemodynamic effects of stenosis on the coronary blood flow. Its basic aim is to provide functional data that complement the anatomical image.25 The FFR-CT values above 0.8 are considered normal, and those below 0.76 indicate a significant flow limitation in the vessel. Values between 0.76 and 0.8 are the gray zone requiring careful clinical interpretation.26

The above-described method is a crucial step forward in the precise evaluation of patients with CCS. It corresponds to FFR measured during invasive coronary angiography. The agreement between invasive and noninvasive measurements is moderate, and it is the strongest for the highest and lowest FFR-CT values. The diagnostic accuracy of FFR-CT against invasive FFR exceeds 90% for FFR-CT values above 0.9 and below 0.49.27

The FFR-CT technique is based on advanced fluid mechanics calculations. It is used to analyze blood flow in the coronary arteries. Currently, most FFR-CT systems combine machine learning algorithms and artificial intelligence, but high-quality CCT images are still necessary to provide a reliable result. The key is the aortic pressure and the resistance in the coronary microcirculation. FFR-CT results are presented as numerical values assigned to individual points along the coronary arteries.28 It is a highly valuable tool with significant clinical potential, although it also has certain limitations. Its use incurs additional costs, and it is not currently reimbursed by the national health system in Poland. At the moment, there are several companies developing their own systems based on artificial intelligence, which should significantly improve the access and reduce the cost in the future.29 However, each of the software systems would need time for validation before the final implementation in the clinical practice.

Stress computed tomography perfusion

Stress CT perfusion (SCTP) is another diagnostic CT-based solution for patients with CCS. This is a stress test performed on the top of the anatomical assessment only in selected cases. It provides additional functional data on regional myocardial blood flow at rest and during pharmacologically-induced stress. The most common methods used to induce stress are vasodilators (adenosine or regadenoson) or dobutamine, which has a positive inotropic effect. Adenosine causes maximal dilation of the coronary arteries, which, in the presence of significant stenosis, leads to a relative flow reduction in the area supplied by the stenotic artery. Dobutamine increases myocardial oxygen demand, thereby unmasking areas with a reduced flow reserve.30,31

SCTP image acquisition techniques can be static or dynamic. With the static techniques, a single acquisition is performed at maximum contrast, while with dynamic ones, a series of scans is performed over time. This allows for the assessment of contrast kinetics. Dynamic SCTP, therefore, allows for the quantitative assessment of perfusion parameters such as blood flow in the myocardium and coronary flow reserve.29 Numerous studies have compared the diagnostic accuracy of SCTP with that of invasive coronary angiography and invasive FFR measurement. One meta-analysis showed high sensitivity and reasonable specificity of this method.32 It is well-evidenced that the presence and the extent of reversible perfusion defects, such as stress-induced ischemia, is associated with an increased risk of MACEs.33

SCTP shows areas of decreased perfusion at the tissue level, and it is a direct indicator of ischemia. It is fundamentally different from FFR-CT, which focuses on assessing the hemodynamic significance of stenoses in the epicardial arteries without assessing the impact of tissue perfusion.34 In clinical practice, SCTP should be used in patients with intermediate coronary stenosis or multivessel CAD to balance the additional exposure and clinical benefit. It is possible to assess coronary artery anatomy and myocardial perfusion simultaneously, and usually it is performed as part of a single, integrated examination. SCTP limitations include exposure to ionizing radiation (modern scanning and image reconstruction protocols allow for a significant dose reduction), the need to administer a contrast agent and a stress-inducing drug (potential adverse effects), and susceptibility to motion artifacts and artifacts related to the presence of extensive calcifications or metal stents. It is worth noting that SCTP exposes a patient to an additional dose of radiation and contrast in comparison with FFR-CT, which involves postprocessing of the CCT examination results.30,35,36

SCTP and FFR-CT represent significant advances in noninvasive CAD diagnostics. Integrated assessment of coronary artery anatomy and its functional consequences allows for more precise clinical decision-making.

Fat attenuation index

CCT was initially a simple tool for excluding stenoses in the coronary arteries. Nowadays, it has a potential for advanced assessment of an atherosclerotic plaque, the degree of stenosis, and the hemodynamic or functional consequences in either distal artery or the cardiac muscle.37 However, the prognostic value of anatomical assessment for cardiac events has some limitations.38 The next step in this evolution is the perivascular fat attenuation index (FAI). It focuses on the inflammatory aspect of CAD. It is a noninvasive and indirect marker of coronary inflammation, which provides novel and direct quantitative assessment of the residual inflammatory burden in the vessels.39 FAI reflects pathological changes in the lipid-to-aqueous phase ratio in pericoronary adipose tissue (PCAT) that result from inflammation.40 This is crucial, as PCAT volume does not necessarily correlate with the severity of proinflammatory changes.41 FAI can be used for both primary and secondary prevention.42 It allows for the prediction of cardiovascular risk and appropriate treatment of patients with CAD without significant vascular stenosis. The FAI score takes into account inflammatory risk beyond current clinical risk stratification and classic CCT interpretation.43

Standard CCT provides images ready for FAI analysis. ECG-gating and image reconstruction techniques are essential for optimal visualization of the coronary arteries and PCAT.44 A huge advantage of this method is that FAI can be obtained from routine CCT scans, which increases its potential for broad clinical application, as it does not require additional imaging procedures or radiation exposure.45 However, special software is necessary for quantitative assessment of PCAT and FAI. Typically, a range of HUs from –190 to –30 indicates the presence of adipose tissue. FAI should be measured at a specific radial distance from the coronary artery wall, usually up to 4 mm outside the vessel.46,47 Physiologically, adipose tissue is characterized by low attenuation, with HU values close to –190. As a response to inflammation in the vessel wall, the previously described changes in PCAT composition coincide with a decrease in lipid content and an increase in water content. In this case, PCAT attenuation increases, and the HU values become higher, closer to –30.48

The level of PCAT attenuation and the FAI values may be influenced by various factors: technical, anatomical, and biological (tube voltage, reconstruction algorithm, body structure, age, or sex).49 Therefore, algorithms and the FAI-score index have been developed. This allows for the standardization of the FAI measurements and improvement of their reliability and repeatability.50 Artificial intelligence–based algorithms automatically determine PCAT and then calculate FAI or plot the adipose tissue distribution around the coronary vessels. Standardized FAI scores are essential for using the values obtained in clinical practice.46

FAI values are significantly higher in CAD patients than in healthy individuals.44 FAI can detect coronary artery inflammation even without overt coronary atherosclerosis. Elevated FAI may be an early indicator of CAD-related vascular inflammation. This suggests that FAI may help to identify individuals at a risk of developing CAD before visible anatomical changes become apparent, potentially allowing for earlier preventive interventions.49

High FAI scores are associated with plaque features promoting plaque rupture, such as low attenuation, positive remodeling, spotty calcifications, and the napkin ring sign. There is an association between FAI and quantitative plaque components, including necrotic core volume, fibrofatty tissue volume, and fibrous volume. Moreover, FAI can also help to differentiate between stable or unstable plaques and identify so-called hot plaques.51 This term usually means an unstable plaque prone to rupture (vulnerable plaque). Such a plaque is characterized by an active inflammatory process, which entails a high risk of causing acute CSs.52 A meta-analysis showed that a mean difference in FAI value around unstable plaques, as compared with stable plaques, was 4.5 HU.53 The strong association with the features of prone-to-rupture plaques underscores the potential of FAI in risk stratification by identifying patients with high-risk plaques that may not be obvious based on the degree of stenosis alone. Researchers examined the relationship between FAI and functional myocardial ischemia assessed by FFR, and found higher FAI values in the lesions causing functional ischemia.51

Another meta-analysis of 12 studies (1500 participants) confirmed the strong predictive value of FAI for future MACEs, emphasizing its role as an effective biomarker for cardiovascular risk stratification. The association was significant in all analyzed studies. The clear risk observed in patients with hyperlipidemia further emphasizes the potential of FAI in identifying high-risk individuals.54 The CRISP-CT (Cardiovascular Risk Prediction using Computed Tomography) and ORFAN (The Oxford Risk Factors And Non-Invasive Imaging Study) studies confirmed a strong association between high FAI values and an increased risk of cardiovascular death.43,55,56 It is worth mentioning that FAI can be used not only as a marker of disease activity but also as a tool to monitor a response to treatment (eg, statins).57,58 Recently, the FAI method showed the association between SARS-CoV-2 infection and an increased risk of coronary artery plaque destabilization. Using FAI as a marker to identify vulnerable patients at a high risk of cardiovascular events may have important implications for implementing targeted preventive strategies.59 Moreover, objective and quantitative data beyond the visual and manual analysis of CT scans (radiomics) were also used to determine the values of PCAT and FAI in logistic regression models. The radiomics phenotype of PCAT was found to outperform the FAI model in distinguishing acute myocardial infarction from unstable angina.40 Table 6 presents the main advantages and disadvantages of FAI. In conclusion, FAI is a promising imaging biomarker that can be successfully used to detect coronary artery inflammation, distinguish stable and unstable plaques, predict future significant cardiovascular events, and assess treatment response. Further studies are needed to establish the utility of this biomarker in clinical practice, improve the detection of high-risk coronary plaques, and predict cardiovascular risk.53

Table 6. Advantages and limitations of fat attenuation index38-40,49,53

Advantages

Limitations

Noninvasive marker of coronary inflammation

Variability of measurements depends on technical, biological, and anatomical factors

Association with CAD and atherosclerotic plaque instability

Lack of standardization hampers comparability and clinical implementation

Significant prognostic value for MACEs and mortality in different populations

High heterogeneity observed in meta-analyses indicates variability of study results

Provides additional risk stratification as compared with traditional factors and some CCT indicators

Susceptibility to artifacts and image quality limitations of CCT (eg, massive calcifications)

Independent of systemic markers of inflammation and degree of arterial stenosis

Clinical use is still in the development phase

Reflects the level of inflammation of adipose tissue, not just its volume

Monitoring disease activity and response to anti-inflammatory therapies

Can be used in routine CCT examinations without additional equipment

Abbreviations: MACEs, major adverse cardiovascular events; other, see Tables 1 and 3

Conclusions

CCT is a modern and comprehensive tool to assess patients with CCS. CCT is a routine, noninvasive, and relatively fast method ready to be used in large patient groups. FFR-CT and SCTP provide functional data based on vessel hemodynamics or myocardial perfusion that complement CCT images. FAI appears as a noninvasive marker of coronary inflammation and residual inflammatory risk. Further research will validate and verify the diagnostic and prognostic value of those techniques in clinical practice. Finally, there are huge expectations for various artificial intelligence algorithms to add more automatic analysis of coronary images and to provide novel data not available for human interpretation.