Cardiovascular disease (CVD), diabetes, and chronic kidney disease are recognized to be based on chronic inflammation (Furman et al., 2019). In addition, adipose tissue has recently been shown to not only play a role in energy storage, heat production, and cushioning between tissues, but also as an endocrine organ, secreting inflammatory and anti-inflammatory physiologically active substances that are involved in chronic inflammation (Matsuzawa et al., 2004). Recently, several reports have suggested a relationship between epicardial adipose tissue (EAT) and CVD (Tanaka et al., 2020; Wang et al., 2022). In 2023, the European Society of Cardiology reported a statement on the use of EAT as a therapeutic indicator and biomarker in clinical practice (Antoniades et al., 2023). This article mainly reviews the relationship between CVD and EAT and its potential as a therapeutic target.

A proposal by the European Society of Cardiology defined the names of each adipose tissue in 2023 (Antoniades et al., 2023) (Left side of Figure 1). Thoracic visceral adipose tissue (VAT) includes the EAT, which is enclosed between the cardiac surface and the visceral pericardium, the pericardial adipose tissue (external to the pericardium and surrounding the cardiac silhouette), as well as the non-pericardial thoracic adipose tissue (located anywhere inside the thoracic cavity, but outside the pericardium) (Antonopoulos and Antoniades, 2017). Perivascular adipose tissue (PVAT) around coronary arteries has distinct biological properties compared to the rest of the EAT far from the arterial wall (Antonopoulos et al., 2017; Costa et al., 2018; Antoniades et al., 2020; Turaihi et al., 2020). However, within EAT there is a gradual transition between PVAT and non-PVAT, with no anatomical structures separating the two, and a definition must be agreed upon. Indeed, in recent literature, PVAT has been defined as a layer of adipose tissue located within a distance equal to the luminal diameter of the artery, and this definition was adopted by the working group (Antoniades et al., 2020). This definition applies to PVAT surrounding human arteries with a lumen diameter of up to 2 cm. For arteries with a lumen diameter greater than 2 cm (such as the aorta), PVAT extends up to 2 cm from the external surface of the vessel.

Atherosclerosis is caused when the homeostatic function of vascular endothelial cells is impaired and inflammatory cells infiltrate under the endothelium (Ross, 1999) (Figure 2A). Therefore, it has been thought that inflammation occurs from the luminal side and spreads to the adventitial side. However, more recent findings suggest a pathway through which inflammation on the adventitial side spreads to the lumen side (Figures 2B, C).

Most arteries, except cerebral arteries and microvessels, are surrounded by perivascular adipose tissue (PVAT) (Szasz et al., 2013). Although PVAT has been thought to act as a mechanical cushion for supporting tissues and the vasculature, recent studies have shown that PVAT secretes adipokines, including inflammatory cytokines and chemokines. Under normal circumstances, PVAT induces vasodilation and anti-inflammatory effects through the release of adipokines (such as adiponectin) and vasodilators (such as nitric oxide) (Akoumianakis et al., 2017) (Figure 2A). Under inflammatory conditions such as obesity, PVAT produces adipokines such as leptin, which induces vasoconstriction, SMC migration, and endothelial dysfunction (Kim et al., 2020; Ichikawa et al., 2023). Pro-inflammatory cytokines are produced by PVAT macrophages and other inflammatory cells. Therefore, they cause endothelial dysfunction and atherosclerotic plaque formation (Chen et al., 2010) (Figure 2B). Recent evidence also supports that the relationship between PVAT and vessel walls is bidirectional. This is because the inflammatory condition of vessel wall influences PVAT through paracrine signals that cause changes in the PVAT secretion phenotype (Oikonomou and Antoniades, 2019).

Accumulating evidence highlights the role of adipocytes as secreting cells of exosomes that convey miRNAs with either pro-atherosclerotic or anti-atherosclerotic effects. The expression of MiR-133, miR-21, and miR-143 is significantly decreased in PVAT around segments with occlusive coronary plaques (Marketou et al., 2023). The expression of pro-inflammatory miR-103-3p was higher in coronary PVAT of CAD patients, while PVAT-derived miR-382-5p suppressed foam cell formation (Vacca et al., 2016; Liu et al., 2022).

Microvessels present in the adventitia of blood vessels (vasa vasorum; VV) develop in the adventitia of atherosclerotic lesions due to hypoxic stimulation, destroy the tunica media, invade into the plaque, and play a role in inflammatory cell infiltration (Moreno et al., 2004; Phillippi, 2022). These newly proliferated blood vessels within the plaque lack pericytes and are prone to rupture, resulting in intraplaque hemorrhage (Sluimer et al., 2009; Phillippi, 2022). In this way, inflammation from the adventitia side spreads to the luminal side, promoting plaque progression and instability. Adipocytokines secreted by perivascular adipose tissue (PVAT) are thought to infiltrate directly into the vascular wall and also enter the plaque using the VV as a conduit (Sacks and Fain, 2007; Tanaka et al., 2020; Wang et al., 2022) (Right side of Figure 1).

It is reported that EAT in patients undergoing coronary artery bypass graft (CABG) highly expressed several inflammatory cytokines and chemokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α compared with their subcutaneous fat (Mazurek et al., 2003) or compared with EAT in non-CAD patients (Hirata et al., 2011b). Our observational studies revealed that EAT volume, macrophage and inflammatory cytokine content in EAT, and the decrease in adiponectin expression in EAT were risk factors for coronary artery disease requiring CABG (Shimabukuro et al., 2013).

Some clinical studies examining the relationship between EAT levels and blood biomarkers have found that there was an inverse correlation with the blood concentration of apeline, which has a vasodilatory effect (Babapour et al., 2024), and a positive correlation with the blood concentration of branched-chain amino acids (Zhao et al., 2023). Recent clinical research has shown that EAT thickness and/or volume, including those calculated using AI-based deep learning, are predictive factors for increased coronary artery lipid plaque volume (Amangurbanova et al., 2024), the onset of CVD such as coronary artery disease (Mahabadi et al., 2013; Christensen et al., 2019b; Commandeur et al., 2020; Eisenberg et al., 2020; Filtz et al., 2024; Gaborit et al., 2024; Rämö et al., 2024), and MACE (Guglielmo et al., 2024).

In recent basic and translational research on EAT, pan-genomic microarray analysis has shown that EAT have a profile similar to that of beige adipocytes (Doukbi et al., 2024). In mouse models, it has been confirmed that EAT accumulation affects the inflammatory phenotype of cardiac macrophages and induces microvascular occlusion (MVO) (Zhao et al., 2024). Recently, single-cell transcriptome analysis of human normal and pathological EAT tissues was performed, which might provide further detailed mechanisms serve as future therapeutic targets (Liu X. et al., 2024).

Furthermore, our previous studies evaluated the relationship of local inflammation in EAT, intraplaque microluminal structure (determined by optical coherence tomography; OCT) and coronary plaque characteristics (determined by integrated backscatter intravascular ultrasound; IB-IVUS) in fresh cadavers. The results showed that coronary arteries with intraplaque microluminal structure had relatively lipid-rich plaques and increased expression of the inflammatory molecules in EAT compared to coronary arteries without microluminal structure (Ito et al., 2020; Kawabata et al., 2023), suggesting the presence of luminal structures within plaques contribute to plaque instability.

In 2017, anti-inflammatory therapy targeting the IL-1β immune pathway with canakinumab for secondary prevention of myocardial infarction significantly reduced the recurrence rate of cardiovascular events, independent of lower lipid levels (CANTOS study), suggesting the relationship between chronic inflammation and CVD (Ridker et al., 2017). Also in 2017, it was reported that the state of inflammation in coronary artery PVAT can be evaluated using the fatty line attenuation coefficient (FAI), which can be obtained from coronary artery CT images (Antonopoulos et al., 2017). Computed tomography is useful for characterization as morphological changes associated with inflammation can be detected by the gradient of CT signal attenuation in PVAT [-190 to −30 Hounsfield units (HU)] (Antonopoulos et al., 2017; Theofilis et al., 2022). Indeed, lipolysis in PVAT adipocytes and adipocyte dedifferentiation induced by proinflammatory cytokines lead to an increase in the water/lipid ratio in PVAT close to the inflamed vessel wall. Consequently, these morphological changes increase the PVAT mean CT attenuation towards −30 Hounsfield units (HU) (Antonopoulos et al., 2017). The FAI of coronary PVAT in patients with CAD was consciously higher than in patients without CAD. Currently, FAI is considered to be an imaging index that reflects changes in the size of perivascular adipocytes during inflammation, and its clinical application is expected (Antonopoulos et al., 2017).

The group above mentioned conducted two independent prospective cohort studies of symptomatic patients who underwent coronary artery CT examination to investigate the association between FAI at the root of the right coronary artery, which was most strongly associated with event onset, and all-cause mortality and cardiac death (CRISP-CT study) (Oikonomou et al., 2018). In both cohorts, FAI at the root of the right coronary artery was associated with all-cause and cardiac death, independent of conventional risk factors such as age, sex, and cardiovascular risk factors; The cutoff value was −70.1 Hounsfield units (HU), which was confirmed in the validation cohort. This group also proposed a new method using artificial intelligence (AI) to predict cardiovascular risk by analyzing the radiomic profile obtained from radiographic images of coronary artery PVAT (Oikonomou et al., 2019).

Accumulating recent clinical research have suggested a correlation between coronary artery FAI and control level of diabetes (Liu Y. et al., 2024), control level of dyslipidemia (Feng et al., 2024), coronary flow reserve (CFR) (Chen et al., 2024), plaque instability (Sagris et al., 2022; Antonopoulos and Simantiris, 2023; Kuneman et al., 2023; Wang et al., 2024), future percutaneous coronary intervention (He et al., 2024), incidence of coronary restenosis (Qin et al., 2022), and coronary bypass graft occlusion (Han et al., 2024; Huang et al., 2024). It should be noted that there may be differences between men and women regarding the characteristics of FAI (Kinoshita et al., 2024). Although many retrospective and prospective observational studies have suggested a correlation between coronary FAI and future incidence of MACE (Ichikawa et al., 2022; Kato et al., 2022; Chan et al., 2024; Choi et al., 2024; Zhan et al., 2024), there are also negative reports (van Rosendael et al., 2024; Yang et al., 2024). Alternatively, there is also literature showing that lesion-specific pericoronary FAI is a predictive factor for MACE (Liu M. et al., 2024). Currently, a large-scale prospective cohort study is underway in a multiethnic and multinational country in Asia, and will evaluate the association between AI-based coronary artery FAI and clinical endpoints such as cardiovascular events, hospitalization, and mortality (Baskaran et al., 2024). The 2023 European Society of Cardiology Recommendation document summarizes imaging methods for EAT and coronary PVAT, including FAI (Antoniades et al., 2023).

If accumulation of EAT, coronary PVAT, is associated with cardiovascular events, treatment targeting PVAT resuction may potentially suppress the onset of CVD. We summarize treatments in which EAT, including coronary PVAT, is described as the potential therapeutic target.

In this review, we have summarized recent findings regarding the role of EAT and PVAT in the pathogenesis of atherosclerosis. Adipose tissue serves not only as an energy storage or mechanical cushion, but also as an endocrine organ. Recent evidence has revealed that perivascular adipose tissue is involved in vascular homeostasis and adjacent arterial pathophysiology by producing various adipokines (Soltis and Cassis, 1991; Löhn et al., 2002). EAT is located between the surface of the heart and the visceral layer of the pericardium and surrounds the coronary arteries. Many clinical studies suggest that an increase in EAT volume is associated with CAD (Dagvasumberel et al., 2012; Shimabukuro et al., 2013; Hirata et al., 2015; Yamada and Sata, 2015). We also reported that inflammation is enhanced in the EAT of patients with CAD (Hirata et al., 2011a; Hirata et al., 2011b), suggesting that EAT plays a crucial role in the pathogenesis of coronary atherosclerosis (Tanaka and Sata, 2018). It has been reported that exercise and some antidiabetic drugs can reduce EAT volume. Although this article mainly discussed coronary artery disease, EAT has also been reported to be associated with atrial fibrillation and heart failure (Tanaka and Sata, 2018; Elsanhoury et al., 2021). EAT and coronary PVAT may become new therapeutic targets or part of existing therapeutic targets. In particular, the CVD suppressing effects of anti-inflammatory drugs are attracting attention, and elucidation of the relationship between EAT and inflammation is expected in the future.

Accumulating evidence suggests that EAT, coronary PVAT, may represent new prognostic factors, new therapeutic targets, or part of existing therapeutic targets. In particular, the CVD suppressing effects of anti-inflammatory drugs are attracting attention, and elucidation of the relationship between EAT and inflammation is expected in the future.