Coronary artery disease remains the leading cause of morbidity and mortality worldwide, with most acute coronary syndromes arising not from severe luminal stenosis but from rupture or erosion of vulnerable plaques. Coronary computed tomography angiography (CCTA) has evolved over the past two decades into a powerful non-invasive modality capable of simultaneously assessing luminal narrowing, plaque morphology, and vascular biology. This narrative review summarizes current evidence on the role of CCTA in plaque characterization, highlighting both qualitative and quantitative features. Qualitative high-risk plaque markers such as positive remodeling, low-attenuation plaque, the napkin-ring sign, and spotty calcification have been consistently associated with increased risk of future adverse events. Quantitative plaque analysis, enabled by dedicated software, provides objective measures of total plaque burden and subcomponents, offering incremental prognostic value beyond stenosis severity. Emerging techniques further extend the capabilities of CCTA: perivascular fat attenuation index and epicardial adipose tissue quantification provide insight into vascular inflammation, radiomics and artificial intelligence enable automated risk prediction and more refined tissue characterization, and integration with CT-derived fractional flow reserve enhances the assessment of both anatomic and functional significance of coronary lesions. Clinical trials such as SCOT-HEART and PROMISE have demonstrated that CCTA-guided management leads to greater uptake of preventive therapies and lower rates of myocardial infarction, supporting its role in contemporary practice. Nonetheless, challenges remain, including image artifacts in heavily calcified vessels, radiation and contrast exposure, variability across software platforms, and the need for prospective randomized studies directly testing whether CCTA plaque-guided interventions improve outcomes. Looking ahead, innovations such as photon-counting CT, artificial intelligence integration, and multi-omics approaches are expected to further enhance the precision of CCTA. By moving beyond stenosis detection to comprehensive risk assessment, CCTA is poised to become a cornerstone of precision cardiovascular medicine.

Keywords

coronary CT angiography, coronary plaque characterization, high-risk plaque features, quantitative plaque assessment, precision cardiovascular medicine

CAD, coronary artery disease; ACS, acute coronary syndromes; CCTA, coronary computed tomography angiography; IVUS, intravascular ultrasound; OCT, optical coherence tomography; FFR-CT, fractional flow reserve derived from CT; PR, positive remodeling; LAP, low-attenuation plaque; NRS, napkin-ring sign; HRP, high-risk plaque; QPA, quantitative plaque assessment; MACE, major adverse cardiovascular events; FAI, fat attenuation index; EAT, epicardial adipose tissue; AI, artificial intelligence; SCCT, society of cardiovascular computed tomography; CAD-RADS, coronary artery disease – reporting and data system

Coronary artery disease (CAD) remains the leading cause of morbidity and mortality worldwide, accounting for nearly one-third of all global deaths each year.¹ Despite advances in preventive strategies and therapeutic approaches, the burden of acute coronary events persists, largely driven by the sudden rupture or erosion of vulnerable atherosclerotic plaques rather than by the degree of luminal stenosis alone.² Consequently, modern cardiovascular medicine has increasingly shifted its focus from the detection of obstructive disease to the characterization of plaque morphology and biology, with the ultimate goal of identifying individuals at high risk for future adverse events before clinical manifestation.

Invasive imaging modalities such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT) have provided critical insights into the pathophysiology of vulnerable plaques, revealing features such as thin-cap fibroatheroma, large lipid cores, microcalcifications, and increased inflammatory activity.^3,4 However, these invasive methods are not suitable for routine screening in asymptomatic or broadly at-risk populations. The demand for a non-invasive, widely applicable tool to assess both coronary stenosis and plaque vulnerability has catalyzed the development of coronary computed tomography angiography (CCTA).

CCTA has evolved remarkably over the past two decades, transitioning from a purely anatomical imaging technique into a powerful modality capable of characterizing plaque composition, quantifying atherosclerotic burden, and providing functional information when combined with computational approaches such as CT-derived fractional flow reserve (FFR-CT).^5,6 Beyond luminal stenosis, CCTA can detect qualitative high-risk plaque features, including low-attenuation plaque, positive remodeling, the napkin-ring sign, and spotty calcification, which are associated with acute coronary syndromes and poor prognosis.⁷ Moreover, advances in quantitative plaque assessment, artificial intelligence, and perivascular fat attenuation index (FAI) analysis further enhance the capacity of CCTA to serve as a comprehensive risk-stratification tool.^8,9

Randomized trials and large-scale registries have consistently demonstrated the clinical utility of CCTA in improving diagnostic accuracy, guiding preventive therapy, and reducing cardiovascular events.^10,11 For instance, the SCOT-HEART and PROMISE trials have shown that the inclusion of CCTA in the diagnostic work-up leads to earlier initiation of evidence-based therapies and improved long-term outcomes, underscoring the importance of plaque assessment in contemporary practice.

The present narrative review aims to summarize the current role of CCTA in the characterization of coronary atherosclerotic plaques. We will first provide a pathophysiological background for plaque vulnerability, then discuss the qualitative and quantitative imaging features available on CCTA, and finally highlight emerging technologies, clinical applications, limitations, and future perspectives. By consolidating the most recent evidence, this review seeks to emphasize the translational value of CCTA in precision cardiovascular medicine.

This narrative review was conducted by systematically searching PubMed and Scopus databases for English-language articles published between January 2000 and September 2025. The search terms included “coronary CT angiography,” “plaque characterization,” “vulnerable plaque,” “quantitative plaque analysis,” “perivascular fat attenuation,” and “artificial intelligence.” Relevant clinical trials, consensus statements, and meta-analyses were prioritized. Additional references were identified through manual screening of bibliographies from key papers. As this was a narrative review, no formal risk-of-bias or quantitative synthesis was performed.

Atherosclerosis is a chronic, progressive disease of the arterial wall, characterized by lipid deposition, inflammatory cell infiltration, and fibrous tissue proliferation. While luminal stenosis has traditionally been regarded as the hallmark of coronary artery disease, it is now well established that most acute coronary syndromes (ACS) arise from the rupture or erosion of so-called “vulnerable plaques,” which may not necessarily cause severe stenosis before the event.^2,12

The vulnerable plaque concept is largely based on histopathological observations. Thin-cap fibroatheroma (TCFA), defined by a fibrous cap thickness of <65 μm covering a large lipid-rich necrotic core, is considered the archetype of rupture-prone lesions.¹³ Cap thinning results from continuous inflammatory activity, particularly macrophage and T-cell infiltration, which produce proteolytic enzymes that degrade collagen and weaken the fibrous cap.¹⁴ In addition, neovascularization of the vasa vasorum and intraplaque hemorrhage contribute to plaque instability and enlargement.¹⁵

Another important mechanism is plaque erosion, which accounts for approximately one-third of ACS cases.¹⁶

Unlike rupture, erosion is characterized by superficial endothelial denudation without disruption of the fibrous cap. Erosive plaques often occur in younger patients, women, and smokers, and may present with different biological pathways involving toll-like receptor signaling and neutrophil extracellular traps.¹⁷

Calcification dynamics also play a dual role in plaque stability. While extensive, sheet-like calcification is generally associated with stable plaques, microcalcifications within the fibrous cap can increase local mechanical stress, predisposing the cap to rupture.¹⁸ Similarly, expansive or positive remodeling, a compensatory vascular response to maintain lumen size, has been linked to high-risk lesions due to its association with large necrotic cores and inflammatory infiltrates.^7,19

Importantly, the clinical significance of vulnerable plaques lies not only in their propensity to cause ACS but also in their systemic and multifocal nature. Autopsy and intravascular imaging studies consistently demonstrate that patients with one vulnerable plaque often harbor multiple high-risk lesions, reflecting the systemic inflammatory burden of atherosclerosis.²⁰ This underlines the need for non-invasive imaging modalities capable of detecting vulnerable features across the entire coronary tree, rather than focusing solely on the most stenotic lesion.

Recent studies have questioned the traditional notion that a single “vulnerable plaque” drives acute coronary events, suggesting instead that plaque instability reflects a diffuse and systemic vascular process. This paradigm shift emphasizes that overall coronary vulnerability and inflammatory burden may be more clinically relevant than the characteristics of an isolated lesion.^21,22 Integrating these perspectives underscores the need for imaging approaches that assess global plaque burden and vascular inflammation rather than focusing solely on focal morphological features.

Collectively, these pathophysiological insights provide the foundation for the use of coronary CT angiography (CCTA) in plaque characterization. By identifying morphological features such as low attenuation, positive remodeling, and spotty calcification, as well as by quantifying total plaque burden, CCTA offers a non-invasive window into the biological processes that define plaque vulnerability and patient risk.

Coronary computed tomography angiography (CCTA) has become the most widely adopted non-invasive imaging modality for the evaluation of coronary artery disease. Its ability to provide high-resolution, three-dimensional visualization of the coronary arteries, including both the vessel lumen and wall, has transformed the clinical approach to CAD assessment.^5,23

Image acquisition and reconstruction: Modern CCTA relies on multidetector CT scanners, typically with 64 or more detector rows, enabling rapid image acquisition during a single breath-hold.²⁴ Synchronization with the cardiac cycle using prospective or retrospective electrocardiographic (ECG) gating minimizes motion artifacts and improves spatial resolution. Iterative reconstruction algorithms and advanced motion correction software further enhance image quality while reducing noise.²⁵

Spatial and Temporal Resolution: The accuracy of plaque characterization is dependent on both spatial and temporal resolution. Current scanners achieve submillimeter isotropic resolution, allowing detailed visualization of coronary plaque morphology. Temporal resolution, typically in the range of 66–150 ms depending on scanner design, is critical for minimizing motion blur, particularly in patients with higher heart rates.²⁶ Pharmacologic heart rate control with beta-blockers and vasodilation with sublingual nitrates are routinely employed to optimize image quality.²⁷

Advanced CT technologies: Recent advances include dual-energy CT and photon-counting CT, which improve tissue characterization by distinguishing materials based on their attenuation at different energy levels.²⁸ Photon-counting detectors, in particular, offer superior spatial resolution, reduced electronic noise, and the potential for more accurate quantification of plaque composition and calcium burden.²⁹ These emerging technologies are expected to refine non-invasive plaque characterization and may overcome some of the limitations of conventional CCTA.

Contrast and radiation considerations: CCTA requires the administration of iodinated contrast to visualize the coronary lumen and vessel wall. Optimal contrast timing is achieved with bolus tracking or test-bolus techniques. While concerns about radiation exposure have historically limited the use of CCTA, technological advances such as prospective ECG triggering, high-pitch spiral acquisition, and iterative reconstruction have substantially reduced typical effective doses to less than 2 mSv in many protocols, approaching the range of background annual radiation.³⁰

Limitations and artifacts: Despite major improvements, several technical limitations remain. Heavy coronary calcification can cause blooming artifacts, leading to overestimation of stenosis severity and hindering accurate plaque characterization.³¹ Motion artifacts due to irregular heart rhythms or inadequate heart rate control can also impair diagnostic accuracy. Additionally, CCTA performance may be reduced in obese patients due to increased image noise, though iterative reconstruction techniques partially mitigate this issue.

In summary, the technical progress of CCTA over the past decade has laid the foundation for its clinical adoption as both a diagnostic and risk-stratification tool. Understanding these principles is essential for interpreting plaque characteristics reliably and for appreciating the ongoing technological innovations that are driving the field forward.

While coronary CT angiography (CCTA) was initially developed to assess luminal stenosis, one of its most transformative contributions has been the identification of qualitative plaque features associated with future acute coronary syndromes (ACS). These imaging biomarkers, often referred to as high-risk plaque (HRP) features, reflect the underlying histopathological characteristics of vulnerable plaques and provide incremental prognostic information beyond stenosis severity.^7,12

Positive remodeling: Positive remodeling (PR) refers to compensatory outward expansion of the vessel wall at the site of an atherosclerotic lesion, allowing preservation of lumen caliber despite substantial plaque burden.¹⁹ On CCTA, PR is typically defined as a remodeling index >1.1 compared with reference segments. PR is strongly correlated with lipid-rich necrotic cores and inflammatory activity.³² Importantly, lesions with PR have been shown to predict subsequent ACS independent of stenosis severity.⁷

Low-attenuation plaque: Low-attenuation plaque (LAP) is a surrogate marker of a lipid-rich necrotic core. On CCTA, LAP is generally defined as a plaque component with attenuation <30 HU, though some studies apply a <60 HU cutoff depending on imaging parameters.³³ Motoyama et al.³³ demonstrated that LAP on baseline CCTA was significantly associated with the development of ACS within a 2-year follow-up, particularly when combined with PR.⁷ Recent large-scale analyses, such as the SCOT-HEART substudy, have confirmed the strong prognostic value of LAP volume for predicting myocardial infarction.³⁴

Napkin-ring sign: The napkin-ring sign (NRS) is a distinct qualitative feature characterized by a central low-attenuation core surrounded by a higher-attenuation rim, resembling the cross-sectional appearance of a napkin ring.³⁵ Pathologically, NRS correlates with thin-cap fibroatheroma.¹³ Although less frequent than PR or LAP, its presence has a high specificity for vulnerable plaque and is independently associated with future events.³⁶

Spotty calcification: Spotty calcifications represent small, punctate calcific deposits (<3 mm in length and occupying <90° of the vessel circumference) embedded within non-calcified plaque. Unlike larger sheet-like calcification, spotty calcification is a marker of active plaque progression and instability.^18,37 Clinical studies demonstrate that plaques with spotty calcifications carry higher risks of ACS and correlate with markers of inflammation on invasive imaging.³⁸

Combined risk of qualitative features: The prognostic value of qualitative features is particularly strong when multiple HRP characteristics are present. In seminal prospective studies, plaques exhibiting ≥2 high-risk features (PR, LAP, NRS, or spotty calcification) were associated with markedly increased incidence of ACS compared to plaques without such features.^7,33 These findings highlight the importance of integrated interpretation rather than isolated assessment.

Clinical Implications: From a clinical perspective, the detection of HRP features on CCTA has implications for risk stratification, preventive therapy initiation, and patient counseling. Patients with non-obstructive CAD but with HRP features often benefit from intensified lipid-lowering therapy, lifestyle modification, and closer follow-up.³⁴ Moreover, these features provide an important rationale for the integration of plaque characterization into structured reporting systems such as CAD-RADS 2.0, which now incorporates HRP modifiers alongside stenosis severity.³²

In summary, qualitative plaque features detectable on CCTA, positive remodeling, low-attenuation plaque, napkin-ring sign, and spotty calcification, represent robust imaging biomarkers of plaque vulnerability. Their identification complements anatomical stenosis assessment, offering a more complete evaluation of patient risk and guiding precision cardiovascular care (Table 1).

Although qualitative features such as positive remodeling and low-attenuation plaque provide important insights into plaque vulnerability, their assessment can be subjective and influenced by inter-observer variability. To overcome these limitations, quantitative plaque assessment (QPA) methods have been developed, enabling standardized and reproducible measurement of plaque burden and composition using CCTA.³⁹

Principles of quantitative plaque analysis: QPA relies on semi-automated software that segments coronary arteries, delineates lumen and vessel wall boundaries, and classifies plaque components according to predefined attenuation thresholds. Plaque volumes are typically categorized as calcified, non-calcified, and low-attenuation components.⁴⁰ This approach provides an objective quantification of total plaque burden and its subtypes across the coronary tree.

Clinical significance of total plaque burden: Several landmark studies have demonstrated that quantitative measures of total plaque burden provide incremental prognostic information beyond stenosis severity. In the CONFIRM registry, non-obstructive but extensive plaque burden was associated with significantly higher risk of major adverse cardiovascular events (MACE).⁴¹ Similarly, the SCOT-HEART trial showed that the extent of non-calcified and low-attenuation plaque volume predicted incident myocardial infarction independently of traditional risk factors and luminal narrowing.³⁴

Low-attenuation plaque volume as a prognostic marker: While qualitative identification of low-attenuation plaque (LAP) is valuable, quantitative measurement of LAP volume provides a more robust and reproducible biomarker. In the PARADIGM study, progression of LAP volume over time was strongly associated with future ACS events.⁴² Quantitative LAP assessment has also been shown to track therapeutic response, for example regression with intensive statin or PCSK9 inhibitor therapy.⁴³

Software platforms and standardization: Multiple software platforms are available for QPA, but differences in algorithms and attenuation thresholds can lead to variability across studies. Recognizing this, the Society of Cardiovascular Computed Tomography (SCCT) has recently published a consensus statement outlining best practices for quantitative plaque analysis and calling for standardization of methodology and reporting.⁴⁴ Integration of QPA into CAD-RADS 2.0 also reflects its growing clinical importance, as the system now allows plaque burden and high-risk features to be included as modifiers.³²
Strengths and limitations: The strengths of QPA include objectivity, reproducibility, and the ability to quantify plaque progression or regression over time. However, its limitations include the need for high-quality image acquisition, susceptibility to blooming artifacts from calcification, and dependency on proprietary software. Additionally, widespread adoption in daily practice is hampered by cost, analysis time, and lack of universal standardization.⁴⁵
In summary, quantitative plaque assessment enhances the diagnostic and prognostic value of CCTA by providing objective measurements of plaque burden and composition. As methods become standardized and integrated into clinical workflows, QPA has the potential to play a central role in precision cardiovascular risk stratification and monitoring of therapeutic interventions (Table 2).

Beyond conventional qualitative and quantitative analysis, recent innovations have expanded the role of CCTA in coronary plaque characterization. These novel approaches aim to capture biological activity, microstructural detail, and systemic risk that traditional imaging cannot fully assess.

Perivascular Fat Attenuation Index (FAI): The perivascular fat attenuation index (FAI) is an emerging biomarker derived from the attenuation of pericoronary adipose tissue on CT. FAI reflects local coronary inflammation, as inflamed vessels release cytokines that alter the composition of surrounding fat, increasing its CT attenuation (8,46). Large-scale clinical studies have demonstrated that abnormal FAI values independently predict cardiac mortality and can reclassify patient risk beyond traditional measures (47). This metric represents a promising bridge between structural imaging and vascular biology.

Epicardial adipose tissue (EAT) quantification: Closely related to FAI, epicardial adipose tissue (EAT) volume and density measured by CCTA are increasingly recognized as markers of metabolic and cardiovascular risk. High EAT burden has been associated with accelerated atherosclerosis, high-risk plaque features, and adverse outcomes.⁴⁸ While not yet routinely integrated into clinical workflows, EAT quantification may provide additional insight into the systemic-inflammatory environment contributing to plaque vulnerability.

Radiomics and Texture Analysis: Radiomics extracts large numbers of quantitative features from imaging data, analyzing texture, shape, and intensity beyond what the human eye can perceive. Applied to CCTA, radiomics can characterize plaque heterogeneity, detect subtle differences in tissue composition, and predict lesion vulnerability.⁴⁹ Early studies suggest that radiomic signatures can identify culprit lesions with higher accuracy than conventional metrics, but external validation and standardization are needed before widespread adoption.⁵⁰

Artificial Intelligence and Machine Learning: Artificial intelligence (AI) and machine learning algorithms have shown significant potential in automating plaque quantification, risk stratification, and event prediction. AI models trained on large multicenter CCTA datasets can integrate plaque characteristics, clinical variables, and hemodynamic information to generate individualized risk scores.^9,51 Such approaches may eventually enable real-time, automated decision support in clinical practice, reducing observer variability and enhancing prognostic accuracy.

Despite rapid progress, several important challenges currently limit the clinical translation of AI- and radiomics-based CCTA tools. Many algorithms have been trained and validated in single-center or retrospective datasets, raising concerns about generalizability and external validity. The risk of algorithmic overfitting and the lack of transparent, explainable models remain significant barriers to clinical trust and regulatory approval. Furthermore, standardized frameworks for regulatory oversight and quality assurance are still evolving, underscoring the need for prospective multicenter validation before these technologies can be routinely adopted in cardiovascular practice.⁵¹

Integration with FFR-CT and Other Functional Metrics: CCTA-derived fractional flow reserve (FFR-CT) provides non-invasive functional assessment of coronary lesions by computational modeling of blood flow.⁶ While FFR-CT primarily evaluates ischemia, its integration with plaque characterization offers a more comprehensive assessment of both anatomical and physiological risk. Recent studies demonstrate that lesions with both high-risk plaque features and abnormal FFR-CT are associated with the greatest risk of events.⁵²

Future experimental metrics: Novel parameters under investigation include CT-based biomechanical stress analysis, which estimates local stress distributions on the fibrous cap, and dual-energy or photon-counting CT–derived tissue signatures, which may provide more accurate delineation of lipid, fibrous, and calcific components.^28,29,53 These technologies aim to bridge the gap between invasive histopathological insight and non-invasive imaging.

In summary, advanced CCTA-derived metrics, such as FAI, radiomics, AI applications, and integration with FFR-CT, represent the next frontier in non-invasive coronary imaging. By moving beyond morphology to capture inflammation, tissue biology, and functional impact, these approaches hold the promise of transforming CCTA into a comprehensive, precision-medicine tool for cardiovascular risk assessment (Table 3).

The ultimate value of coronary CT angiography (CCTA) plaque characterization lies in its translation from imaging findings to clinical outcomes. A growing body of evidence demonstrates that both qualitative and quantitative plaque features identified on CCTA provide significant prognostic information and influence clinical management.

Prediction of major adverse cardiovascular events (MACE): Multiple prospective studies have shown that CCTA-derived plaque characteristics predict future MACE independently of traditional risk factors and stenosis severity. In the ROMICAT II trial, the presence of high-risk plaque (HRP) features, such as low-attenuation plaque and positive remodeling, was associated with a substantially higher risk of ACS within 2 years.³⁹ Similarly, analyses from the SCOT-HEART trial confirmed that quantitative low-attenuation plaque burden was the strongest imaging predictor of myocardial infarction over long-term follow-up.³⁴

Role in acute chest pain evaluation: CCTA is increasingly utilized in the emergency department for the evaluation of acute chest pain. The ROMICAT and ROMICAT II studies established its safety and efficiency in ruling out obstructive CAD, reducing unnecessary hospitalizations, and enabling early discharge.⁵⁴ Importantly, the ability of CCTA to detect HRP provides incremental value over stenosis assessment in identifying patients at imminent risk of ACS.^7,33

Impact on Preventive Therapy: Evidence suggests that identification of HRP on CCTA prompts clinicians to initiate or intensify preventive therapies. In the SCOT-HEART trial, patients undergoing CCTA were more likely to receive statins and antiplatelet therapy, which translated into reduced rates of myocardial infarction at 5 years.^10,34 Moreover, serial CCTA imaging in the PARADIGM study demonstrated that statins reduced progression of low-attenuation plaque volume, providing mechanistic support for treatment efficacy.⁴²

Monitoring of therapeutic ınterventions: Beyond guiding therapy initiation, CCTA allows non-invasive monitoring of plaque regression or stabilization under pharmacological interventions. Trials such as GLAGOV have shown regression of plaque burden with PCSK9 inhibitors, while PARADIGM highlighted the beneficial effects of statins^.42,43 These findings underscore the utility of CCTA as a surrogate endpoint in drug development and personalized therapy monitoring.

Although multiple studies have established robust prognostic associations between CCTA-derived plaque characteristics and cardiovascular outcomes, randomized controlled trials directly evaluating whether plaque-guided management strategies improve clinical endpoints remain scarce. Further prospective investigations are required to confirm the clinical benefit of CCTA-based risk stratification in therapeutic decision-making.

Integrating CCTA into risk models: Traditional risk scores (e.g., Framingham, ASCVD) are limited in their ability to predict individual outcomes. Integration of CCTA findings, particularly total plaque burden and HRP features, significantly improves risk reclassification (55). Studies demonstrate that patients with non-obstructive but high-burden or high-risk plaque have a prognosis similar to or worse than those with moderate stenosis, emphasizing the clinical importance of plaque characterization beyond lumen narrowing.^41,45

Cost-effectiveness and healthcare impact: Economic analyses indicate that incorporating CCTA into diagnostic strategies is cost-effective, particularly when plaque assessment guides targeted therapy and reduces downstream testing.^24,56 By enabling earlier intervention, CCTA may lower long-term healthcare costs through the prevention of myocardial infarction and avoidance of unnecessary invasive angiography.

In summary, CCTA plaque characterization has demonstrated robust prognostic value in predicting adverse outcomes, guiding preventive strategies, and monitoring therapeutic efficacy. By providing actionable information beyond stenosis severity, it represents a cornerstone of modern cardiovascular precision medicine (Table 4).

Despite remarkable progress, several limitations constrain the widespread use of coronary CT angiography (CCTA) plaque characterization in daily practice. These challenges span technical, biological, and clinical domains, and must be carefully considered when interpreting results.

Image quality and artifacts: Accurate plaque assessment depends on high-quality image acquisition. Motion artifacts, especially in patients with atrial fibrillation or inadequate heart rate control, can degrade spatial resolution and obscure plaque features.²⁷ Blooming artifacts caused by heavy coronary calcification remain a major limitation, leading to overestimation of stenosis severity and hampering accurate quantification of non-calcified components.³¹ Similarly, obesity and poor breath-hold compliance can increase image noise despite iterative reconstruction techniques.²⁵

Radiation and contrast exposure: Although radiation doses have decreased substantially with advances such as prospective ECG-gating and iterative reconstruction, CCTA still exposes patients to ionizing radiation, raising concerns about cumulative dose, particularly in younger populations.³⁰ Iodinated contrast agents also pose a risk of contrast-induced nephropathy and allergic reactions, limiting applicability in patients with chronic kidney disease or severe allergy.⁵⁷

Variability and standardization ıssues: One of the most significant challenges in plaque characterization is inter-observer variability, especially for qualitative features such as the napkin-ring sign. Quantitative plaque analysis, while more objective, suffers from a lack of standardization across vendors and software platforms.⁴⁴ Differences in attenuation thresholds, segmentation algorithms, and reconstruction parameters can lead to inconsistent results between centers.⁵⁸

Considerable heterogeneity persists across quantitative plaque analysis software platforms, including differences in attenuation thresholds, segmentation algorithms, and reconstruction techniques. This variability can lead to significant discrepancies in measured plaque volumes and component classification. Harmonization efforts such as the 2024 SCCT consensus statement on quantitative plaque analysis are critical to enhance reproducibility, facilitate multicenter comparisons, and support broader clinical adoption of CCTA-based plaque characterization.⁴⁵

Limited validation against histopathology: While invasive imaging modalities such as IVUS and OCT have validated several CCTA-derived plaque features, direct histopathological correlation remains limited due to the difficulty of obtaining ex vivo specimens. Consequently, certain features, especially novel metrics like radiomics signatures or perivascular fat attenuation index (FAI), require further validation before routine clinical adoption.^46,49

Clinical translation and cost: Although trials such as SCOT-HEART and PROMISE have demonstrated improved outcomes with CCTA-guided management,^10,11 the cost-effectiveness of plaque characterization specifically remains to be established across diverse healthcare systems. Analysis times for quantitative plaque assessment are still relatively long, requiring specialized expertise and expensive proprietary software, which hinders integration into routine workflows.^45,56

Unresolved prognostic questions: A final challenge lies in the translation of imaging biomarkers into actionable therapeutic strategies. While features such as low-attenuation plaque volume clearly predict risk, it remains uncertain which interventions most effectively reduce event rates once these high-risk plaques are identified. Randomized trials directly testing whether intensified therapy guided by CCTA plaque findings improves outcomes are still scarce.⁵⁹

In summary, although CCTA plaque characterization offers powerful insights into atherosclerosis biology and risk, significant limitations, including artifacts, contrast and radiation concerns, lack of standardization, and uncertain therapeutic implications, must be addressed. Overcoming these challenges will be crucial for the broad adoption of CCTA as a routine precision-medicine tool.

The role of coronary CT angiography (CCTA) in plaque characterization is expected to expand considerably in the coming years, driven by rapid advances in scanner technology, computational methods, and integration into clinical practice. Several key directions can be anticipated.

Photon-counting CT and ultra-high resolution imaging: The introduction of photon-counting CT (PCCT) offers unprecedented opportunities for plaque imaging. With improved spatial resolution, lower electronic noise, and superior contrast-to-noise ratios compared with conventional energy-integrating detectors, PCCT may enable precise differentiation of lipid, fibrous, and calcified components.^29,53,60 Early human studies already demonstrate clearer delineation of coronary lumen and plaque substructures, suggesting a future where CCTA approaches the resolution of invasive modalities such as IVUS and OCT.

Artificial intelligence integration: Artificial intelligence is likely to play an increasingly central role in the analysis and interpretation of CCTA. Fully automated platforms could provide real-time plaque quantification, integrate hemodynamic metrics such as FFR-CT, and generate individualized risk predictions at the point of care.^51,61 As AI models become more transparent and regulatory frameworks mature, these systems may transition from research tools to standard clinical decision-support systems.

Precision prevention and therapy guidance: The future of plaque imaging is closely tied to precision cardiovascular prevention. By identifying high-risk, non-obstructive lesions, CCTA has the potential to guide more personalized interventions, whether intensification of lipid-lowering therapy, anti-inflammatory treatment, or lifestyle modification.^42,43 Prospective trials specifically testing whether CCTA-guided therapy improves outcomes will be critical to translating imaging biomarkers into routine therapeutic strategies.^59,62

Multi-omics and systems medicine integration: Another promising avenue is the integration of imaging with genomic, proteomic, and metabolomic data. Combining CCTA-derived plaque features with systemic biomarkers of inflammation and lipid metabolism could provide a comprehensive risk profile that better captures the multifactorial nature of atherosclerosis.⁶³ Such integration may pave the way for precision-medicine approaches in which imaging serves as one component of a multimodal risk algorithm.

Widespread adoption and standardization: For these advances to translate into everyday practice, standardization of acquisition, analysis, and reporting will be essential. Consensus statements such as the 2024 SCCT guidelines represent a first step,⁴⁴ but harmonization across vendors, software, and healthcare systems will be required. In parallel, cost-effectiveness analyses and health policy initiatives must support reimbursement models that recognize the long-term value of plaque characterization.^56,64

In summary, the future of CCTA plaque characterization is bright. Emerging technologies such as photon-counting CT, AI-driven analysis, and integration with systemic risk markers hold the promise of transforming CCTA into a cornerstone of precision cardiovascular medicine. Achieving this vision will depend on technological maturation, rigorous clinical validation, and broad implementation across healthcare systems.

Over the past two decades, coronary CT angiography (CCTA) has evolved from a purely anatomical tool for detecting stenosis into a comprehensive modality capable of characterizing atherosclerotic plaque. Both qualitative features, such as positive remodeling, low-attenuation plaque, napkin-ring sign, and spotty calcification, and quantitative metrics of plaque burden and composition provide powerful prognostic information that extends well beyond luminal narrowing.

Advanced approaches, including perivascular fat attenuation index (FAI), epicardial adipose tissue quantification, radiomics, and artificial intelligence, have opened new avenues for capturing the biological activity and systemic risk underlying atherosclerosis. Meanwhile, the integration of CCTA findings with functional data such as FFR-CT has moved the field closer to a holistic, non-invasive assessment of both anatomical and physiological disease burden.

Clinical trials and registry studies have consistently demonstrated that CCTA plaque characterization improves risk stratification, informs preventive therapy, and enables monitoring of therapeutic efficacy. Nonetheless, important limitations remain, including technical artifacts, standardization issues, radiation and contrast exposure, and the need for randomized trials directly testing whether therapy guided by plaque features improves outcomes.

Looking forward, innovations such as photon-counting CT, AI-driven analysis, and multi-omics integration promise to further enhance the precision and clinical value of CCTA. To achieve widespread adoption, standardization across vendors and validation through large prospective studies will be critical.

In conclusion, CCTA plaque characterization represents a paradigm shift in cardiovascular imaging, transforming the focus from stenosis detection to comprehensive risk assessment. By bridging structural, functional, and biological insights, CCTA holds strong potential to become a cornerstone of precision cardiovascular medicine. However, further randomized controlled trials and long-term outcome studies are required to confirm whether plaque-guided strategies can meaningfully improve clinical endpoints and justify widespread clinical integration.

Contributorship: All of the authors contributed planning, conduct, and reporting of the work. All authors had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Funding: No financial funding was received for this study.

Competing interests: All of the authors have no conflict of interest.

None.

None.

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