Pericoronary inflammation: diagnostic possibilities and clinical perspectives

Introduction

Overview of cardiovascular inflammation

Cardiovascular (CV) inflammation is a critical factor in the progression of atherosclerosis and its complications, including myocardial infarction (MI) and stroke.^1,2 While hyperlipidemia has long been recognized as a primary driver of cardiovascular disease (CVD), recent research underscores the role of vascular inflammation in determining residual CV risk.^1,2 Inflammatory processes contribute to plaque formation, destabilization, and eventual rupture, leading to major adverse CV events (MACEs).^1,2

A large-scale meta-analysis of patients receiving statin therapy demonstrated that high-sensitivity C-reactive protein (hs-CRP), a biomarker of inflammation, was a stronger predictor of CV events and mortality than low-density lipoprotein cholesterol.² This finding has shifted the focus of CV prevention strategies beyond lipid management to include targeted anti-inflammatory interventions as a residual risk contributor to MACEs. Similarly, long-term cohort studies have confirmed that inflammation, as measured by hs-CRP, has played a persistent role in CV risk over decades.¹

The MESA (Multi-Ethnic Study of Atherosclerosis) investigated the association between circulating interleukin-6 (IL-6) levels and CV events in individuals without pre-existing CVD and is representative of both sexes and all racial and ethnic groups.³ The study analyzed 6622 participants from diverse racial and ethnic backgrounds, categorizing them into 3 IL-6 terciles based on their baseline levels.³ The authors found that higher circulating IL-6 levels were strongly associated with an increased risk of all-cause mortality, CV mortality, and non-CV mortality in individuals without pre-existing CVD. Participants in the highest IL-6 tercile had a nearly 2-fold increase in all-cause mortality, compared with those in the lowest tercile, with similar trends observed across all racial and ethnic groups.³ The MESA identified IL-6 as a key inflammatory mediator in atherosclerosis and CVD progression, suggesting its potential as a therapeutic target for risk reduction.³ These findings highlight once again the importance of systemic inflammation in CV health and the potential value of IL-6 measurement in identifying high-risk individuals.

Significance of imaging biomarkers in clinical diagnostics

Given the limitations of conventional risk biomarkers, there is increasing interest in imaging biomarkers that provide direct visualization and quantification of vascular or perivascular inflammation.^4-6 Traditional imaging modalities, such as coronary computed tomography angiography (CCTA) and magnetic resonance imaging, have been essential in assessing atherosclerotic burden.^4-6 However, recent advancements have introduced novel imaging biomarkers. One of the most popular is the fat attenuation index (FAI) which allows for a noninvasive (CT-based) assessment of pericoronary inflammation.^4-6 FAI derived from CCTA quantifies inflammatory changes in pericoronary adipose tissue (PCAT) by detecting shifts in fat composition.^4-6 Several studies have demonstrated that increased pericoronary fat attenuation is strongly associated with the presence of high-risk atherosclerotic plaques and an elevated risk of MACEs.⁷ Moreover, FAI has shown potential in stratifying patients based on their inflammatory burden, independent of traditional risk factors.^4-7

The aim of this review is to present the role of inflammation in PCAT and provide data on the prognostic significance of imaging-derived markers of this condition in patients with suspected CAD.

Fat atteuation index: definition and measurement FAI is an advanced imaging biomarker derived from CCTA that quantifies pericoronary inflammation by analyzing variations in PCAT attenuation. It serves as a noninvasive indicator of vascular inflammation which plays a crucial role in the development and progression of CAD. Inflammatory processes within the coronary arteries trigger changes in the composition of surrounding adipose tissue, leading to alterations in its density, measured in Hounsfield units (HU). This shift occurs as the inflamed vascular environment suppresses lipid accumulation in PCAT, increasing its water content and making the attenuation values less negative. Unlike conventional imaging techniques that primarily detect luminal stenosis and calcified plaques, FAI identifies inflammatory changes before structural damage becomes evident. By providing insights into coronary inflammation, FAI enables early risk assessment and helps predict MACEs, including MI and CV mortality (Figure 1).⁷

Calculation of fat attenuation index using computed tomography angiography

FAI is determined through quantitative analysis of perivascular fat using standard CCTA scans.^5,6 The process begins with coronary vessel segmentation, in which the major coronary arteries, including the right coronary artery, the left anterior descending artery, and the left circumflex artery, are identified and reconstructed in a 3-dimensional model.^4-6 PCAT is then defined as the fat-containing region surrounding these vessels within a predetermined radial distance, typically equivalent to the vessel’s diameter.^4-6 Attenuation values expressed in HU are extracted from this region, with the recognized range for adipose tissue falling between –190 and –30 HU. Higher attenuation values approaching –30 HU indicate increased water content and reduced lipid accumulation, signaling the presence of coronary inflammation.^4-6 This quantitative approach enables clinicians to evaluate the extent of coronary inflammation, providing a functional assessment of disease activity that is independent of traditional risk factors, such as arterial stenosis.^6,7

Advantages over traditional imaging methods

FAI offers several advantages over conventional imaging techniques used in CV diagnostics. Unlike coronary artery calcium scoring (CACS) and invasive coronary angiography, which primarily assess structural abnormalities such as luminal narrowing and calcified plaques, but also thin-cap fibroatheroma−type plaques (TCFA), FAI provides functional information by detecting inflammatory changes in the area surrounding coronary arteries.^5,6 This early detection capability allows for more accurate risk stratification, identifying patients at a high risk for MACEs even before they develop significant arterial stenosis. Additionally, FAI can be obtained using routine good quality CCTA scans (majority of available studies performed on the 128-slice scanners or better), eliminating the need for expensive and less accessible imaging modalities, such as positron emission tomography (PET). PET imaging, which detects vascular inflammation using radiotracers, is often limited due to its cost, radiation exposure, and availability, whereas FAI is derived from commonly performed CCTA without additional contrast or radiation exposure. Furthermore, FAI can be used for monitoring therapeutic response in patients receiving anti-inflammatory treatments, such as colchicine,⁸ providing dynamic insights into the effectiveness of targeted interventions.

It has been demonstrated that higher PCAT attenuation is significantly associated with the presence of TCFA, indicating a link between vascular inflammation and plaque vulnerability.⁹ Moreover, patients with high noncalcified plaque volume not only exhibit greater PCAT attenuation, but also show a higher prevalence of TCFA, suggesting that increased coronary inflammation contributes to plaque instability.⁹ Therefore, the combined assessment of PCAT attenuation and noncalcified plaque volume may serve as a noninvasive method to identify high-risk plaques, as the highest prevalence of TCFA is observed in cases where both markers are elevated.⁹ These findings are especially relevant considering the recently published PREVENT trial ¹⁰ which showed that preventive percutaneous coronary intervention (PCI) in patients with nonflow-limiting but high-risk vulnerable coronary plaques reduced major adverse cardiac events, compared with optimal medical therapy alone. As the first large-scale study to demonstrate the potential benefits of focal treatment for vulnerable plaques, PREVENT provides initial evidence supporting the consideration of expanding PCI indications to include high-risk plaques that do not significantly restrict blood flow.¹⁰

Pericoronary adipose tissue and its role in atherosclerotic plaque formation

Pericoronary fat plays a crucial role in atherosclerosis development and plaque progression through its complex interactions with the coronary vascular wall.^7,11-13 The shift of PCAT from an anti-inflammatory to a pro-inflammatory state enhances vascular inflammation, leading to plaque growth, destabilization, and increased risk of MI.^5,7,12 FAI, derived from CCTA, is a promising tool for early detection and monitoring of pericoronary inflammation, potentially guiding targeted therapeutic interventions to reduce CV risk.

Pericoronary fat as a source of inflammatory mediators

Under physiological conditions, PCAT exerts anti-inflammatory and vasodilatory effects, primarily through the secretion of adipokines, such as adiponectin and omentin, which maintain endothelial homeostasis and suppress oxidative stress.^11,12 However, in the presence of CV risk factors, such as dyslipidemia, hypertension, insulin resistance, and chronic inflammation, the balance of adipokine secretion is disrupted, leading to a pro-inflammatory and pro-oxidant microenvironment.^11-13

During the early stages of atherosclerosis, endothelial dysfunction and the infiltration of oxidized low-density lipoprotein into the arterial wall trigger an inflammatory cascade, characterized by the activation of monocytes, macrophages, and T lymphocytes.^11-13 This process results in the release of pro-inflammatory cytokines, such as tumor necrosis factor-α, IL-6, and monocyte chemoattractant protein-1, which diffuse into the surrounding PCAT.^11,12 The inside-out signaling from the vascular wall leads to changes in PCAT phenotype, characterized by reduced lipid accumulation, increased fibrosis, and enhanced production of inflammatory mediators.^11-13

Bidirectional communication between the coronary artery and pericoronary adipose tissue

Inflammatory changes in the vascular wall modify the function of PCAT in a bidirectional manner. As the arterial wall becomes inflamed, the release of oxidative and inflammatory mediators triggers lipolysis and suppresses adipogenesis in PCAT, leading to a loss of lipid-rich adipocytes and an increase in extracellular matrix deposition. This process results in the remodeling of PCAT, shifting its composition from an energy-storing adipose tissue to a fibrotic, pro-inflammatory depot.^4,11-13 PCAT-derived inflammatory cytokines, such as leptin, resistin, and visfatin, stimulate the expression of adhesion molecules on endothelial cells, promoting monocyte recruitment and plaque infiltration.^11,14 The increased secretion of reactive oxygen species from both the vascular wall and PCAT further accelerates oxidative stress and endothelial dysfunction, leading to the progression of atherosclerosis.^4,11-13 Furthermore, altered gene expression in PCAT of CAD patients, characterized by gene upregulation and activation of pathways associated with inflammation and atherosclerosis, is suggested to play a role in the development and progression of CAD.¹⁵

Impact on plaque formation and destabilization

Chronic exposure of the vascular wall to PCAT-derived inflammatory mediators leads to the formation of lipid-rich foam cells which constitute the core of early atherosclerotic plaques.^11,13 Over time, the plaque undergoes expansion, vascular remodeling, and calcification, increasing the risk of lumen narrowing and ischemic events.^4,11-13 Importantly, pericoronary inflammation influences not only plaque growth, but also its stability. Studies have shown that increased pericoronary FAI values, which reflect higher inflammatory activity within PCAT, are associated with the presence of TCFA, low-attenuation plaques, and high-risk plaque features on CCTA.¹⁶ These high-risk plaques are more prone to rupture and thrombosis, leading to acute coronary syndromes. Furthermore, pericoronary inflammation affects the fibrous cap integrity by stimulating matrix metalloproteinase (MMP) activity, which degrades the extracellular matrix and weakens the structural support of the plaque.^17,18 The increased activity of MMPs, combined with persistent inflammation, promotes cap thinning and plaque vulnerability, increasing the likelihood of rupture and subsequent thrombosis.^17,18

Clinical applications of fat attenuation index in cardiovascular disease

Risk stratification for coronary artery disease

Risk stratification for CAD has traditionally relied on clinical risk scores, serum biomarkers, and imaging modalities that assess structural coronary abnormalities— the cornerstone of many recent European Society of Cardiology Guidelines.^19-21 However, these methods often fail to identify patients with nonobstructive, but inflamed, coronary arteries, who remain at an increased risk for future CV events. The assessment of PCAT has emerged as a promising noninvasive imaging biomarker that enhances risk stratification by quantifying coronary inflammation, a key driver of atherosclerosis progression.^4,6,7,22 Unlike conventional assessments focusing on plaque burden and stenosis, FAI provides functional insights into PCAT remodeling, reflecting the inflammatory state of the adjacent coronary arteries.^4-7

In a healthy state, PCAT exhibits low attenuation due to its lipid-rich composition, but in the presence of coronary inflammation, the adipocyte lipid content decreases while water content increases, leading to a shift in HU values. This measurable change provides a quantifiable, noninvasive marker of coronary inflammation, allowing for early identification of patients at a high risk for CAD, even before the development of significant stenosis or calcification.^6,7,11

Compared with traditional methods, such as CACS and invasive angiography, PCAT analysis enables a more comprehensive risk assessment by detecting inflammatory activity in noncalcified plaques, which CACS does not account for despite their potential for rupture and precipitate acute coronary syndromes.¹² Similarly, invasive coronary angiography primarily evaluates luminal narrowing, missing early-stage inflammatory changes that contribute to plaque progression and instability.²¹

FAI provides additional prognostic value by integrating information about vascular inflammation on top of the anatomical findings, including coronary stenosis and anatomical properties of the high-risk plaque (eg, spotty calcifications, low-attenuation plaque, napkin ring sign, or positive remodeling).⁶ In theory, this makes FAI an important tool in risk stratification, as it enables clinicians to identify individuals who may benefit from early preventive interventions, such as intensified lipid-lowering therapy, anti-inflammatory treatments, or lifestyle modifications (Figure 2).

Recently, it has been analyzed how FAI values, when combined with CT-derived fractional flow reserve (CT-FFR), improve the assessment of coronary plaque characteristics.²³ It has been demonstrated that patients with higher FAI values have increased inflammatory activity and plaque vulnerability, which correlates with a higher risk of future CV events.²³ It has been shown that FAI is associated with coronary artery stenosis and serves as a novel indicator for identifying myocardial ischemia assessed via CT-FFR.²³

By offering a functional assessment of vascular inflammation, FAI represents a paradigm shift in CAD risk stratification, moving beyond structural assessments towards identifying active disease processes. As a result, FAI is being scientifically tested in CCTA protocols to enhance early detection, personalized risk assessment, and therapeutic decision-making in CV disease prevention.

Use in predicting major adverse cardiovascular events

The ability to predict MACEs, including MI, stroke, and CV death, is critical for improving long-term outcomes in CAD patients. Traditional predictors, such as CACS and high-risk plaque features on CCTA, have provided valuable insights,^24,25 but they do not capture the underlying inflammatory processes that drive plaque destabilization and rupture, which is partly possible for high-risk plaque assessment in CCTA.²⁶ In some clinical studies, PCAT analysis, by quantifying pericoronary inflammation, offers an independent and superior predictor of MACE, helping clinicians identify vulnerable patients before they develop clinical symptoms.^6,18,23,27

Studies have shown that increased FAI values are significantly associated with a higher incidence of fatal and nonfatal CV events, independent of traditional risk factors.^6,18,27 In a large multicenter study, patients with elevated perivascular FAI had a 2- to 3-fold higher risk of cardiac mortality, even in the absence of obstructive CAD.^28,29 These findings suggest that vascular inflammation, rather than the degree of stenosis, may be a stronger predictor of future CV events.^22,28,29

One of the key advantages of FAI in predicting MACEs is its ability to detect high-risk, nonobstructive plaques.²⁸ While traditional imaging focuses on identifying severely narrowed arteries, research indicates that most MIs arise from rupture-prone plaques that do not cause significant stenosis.^18,30 FAI effectively identifies these potentially vulnerable plaques by detecting localized perivascular inflammation, which correlates with plaque vulnerability and the likelihood of rupture.^5,6,28,29

Additionally, FAI has demonstrated potential in monitoring the effects of anti-inflammatory treatments, such as colchicine or anti-interleukin therapies.^8,31 Moreover, FAI also plays a crucial role in longitudinal risk assessment. Unlike static imaging markers such as CACS, which remain relatively stable over time, FAI is a dynamic biomarker that changes along with disease progression or treatment response.^18,28,29,31 This makes it particularly useful for reassessing CV risk in high-risk patients, enabling personalized adjustments to preventive strategies. By offering a noninvasive, highly sensitive measure of coronary inflammation, FAI significantly enhances our ability to predict MACEs, allowing for timely interventions that may prevent life-threatening cardiac events.^27,28 As its clinical utility continues to be validated in large-scale studies, FAI is expected to become an essential component of routine CV risk assessment.

Comparison with traditional imaging markers (eg, coronary artery calcium scoring)

The primary advantage of FAI over traditional imaging markers is its ability to detect inflammatory activity in coronary arteries, rather than simply assess structural changes. CACS, which measures calcified plaque burden, is widely used in CV risk assessment, but has several limitations.²⁵ While a high CACS indicates advanced atherosclerosis and increased CV risk, it does not account for noncalcified, high-risk plaques, which are more likely to rupture and cause acute coronary syndromes.^25,29,32,33 Unlike CACS, FAI provides information about active vascular inflammation, offering a more dynamic assessment of CV risk.^5,6,28 Patients with elevated FAI but low CACS may still be at a high risk for MACEs, as they may have inflammatory, noncalcified plaques that are undetectable by calcium scoring.^34-37 Similarly, FAI can help differentiate high-risk vs low-risk patients among those with similar degrees of calcification, providing additional prognostic value beyond CACS alone.^34,35

Invasive coronary angiography, including intravascular imaging (eg, optical coherent tomography), is another widely used diagnostic tool, effective in identifying luminal stenosis, but it does not capture early inflammatory changes in or around the vessel wall.^24,29,34,35 Many patients with acute coronary syndromes have nonobstructive but highly inflamed plaques, which angiography fails to detect.^34,38,39 FAI, by contrast, identifies vascular inflammation before plaques reach the stenotic threshold, making it a valuable tool for early detection.^28,30

Other imaging techniques, such as PET, can assess vascular inflammation using radiotracers, but they are expensive, require high radiation exposure, and are not widely available.⁶ Derived from standard CCTA, FAI offers a cost-effective and widely accessible alternative without the need for additional imaging modalities.^4-7

Overall, FAI surpasses traditional imaging markers by offering a real-time, inflammation-based assessment of CV risk, rather than relying solely on structural changes. By integrating FAI into routine CV imaging, clinicians can achieve a more comprehensive risk assessment, improving early detection, personalized treatment, and long-term patient outcomes.

Future directions and potential research areas

Given the strong association between PCAT inflammation and atherosclerotic plaque progression, targeting pericoronary inflammation has emerged as a potential strategy for CV risk reduction. Imaging biomarkers such as FAI provide a noninvasive method to assess the extent of pericoronary inflammation and identify high-risk patients who may benefit from early anti-inflammatory interventions. Several pharmacological strategies, including colchicine, interleukin-1β or IL-6 inhibitors (eg, canakinumab or ziltivekimab), and statins, have shown promise in reducing systemic inflammation and stabilizing plaques.^40-43 The use of FAI in longitudinal monitoring may help determine whether these therapies effectively suppress pericoronary inflammation and improve CV outcomes. Nevertheless, currently, there is a lack of data on other subgroups of patients at higher CV risk, such as those who have recently experienced de novo acute coronary syndrome or with recurrent MI. Another group includes patients with conditions, such as type 2 diabetes, where widespread atherosclerotic changes frequently lead to MIs and revascularization procedures, including coronary artery bypass grafting. Ultimately, there is still no randomized clinical trial that, based on a specific measure of pericoronary inflammation (eg, FAI), would allocate patients to a group receiving more intensive (or interventional) treatment versus those receiving standard therapy.

Conclusions

The role of PCAT in CAD has gained significant attention, with research emphasizing its contribution to detecting vascular inflammation, plaque formation, and overall CV risk. FAI, an imaging biomarker derived from CCTA, quantifies pericoronary inflammation by assessing HU changes within PCAT. Studies indicate that the assessment of PCAT inflammation via FAI provides superior risk stratification, compared with traditional imaging techniques, enabling early detection of inflammation-driven atherosclerosis, even in the absence of significant luminal stenosis. The bidirectional interaction between PCAT and the vascular wall plays a crucial role in plaque instability, making rupture more likely and increasing the risk of MACE, including MI and CV mortality. As mentioned above, chronic exposure to pro-inflammatory cytokines and oxidative stress from PCAT might lead to plaque remodeling and enhanced thrombotic potential.^18,38,44,45 Additionally, elevated FAI values have been linked to high-risk plaque features, such as TCFA and low-attenuation plaques, further validating its importance as a prognostic tool in CV risk assessment.^18,44,45

Call for further research

Despite the promising applications of FAI in CV imaging, several key questions remain unanswered, necessitating further research to optimize its clinical use. Large-scale, multicenter prospective studies are needed to validate the predictive accuracy of FAI across diverse populations and determine optimal cutoff values for CV risk assessment. Additionally, comparative studies evaluating FAI alongside other inflammatory biomarkers, such as hs-CRP and PET-based inflammation markers, could enhance understanding of its clinical relevance in different patient subsets. Research should also assess whether FAI-guided treatment adjustments can improve long-term CV outcomes, particularly in patients with residual inflammatory risk despite optimal statin therapy. Finally, further studies on the cost-effectiveness of implementing FAI in routine CV screening are needed to support its widespread adoption in clinical practice and preventive cardiology.