A new insight on imaging characteristics of pericoronary adipose tissue for cardiovascular risk

Abstract

Cardiovascular events caused by atherosclerotic plaque are the leading causes of death worldwide. The change in pericoronary adipose tissue (PCAT) and epicardial adipose tissue (EAT) can dynamically reflect the inflammation activity of coronary artery, playing an important role in the development of cardiovascular diseases (CVDs). Recently, PCAT and EAT have been used to assess the atheromatous plaque from its formation and development to rupture, which are of great clinical value in predicting the risk of adverse cardiovascular events, as well as in evaluating the efficacy of cardiovascular drugs. Numerous literature have also reported that evaluating the pathophysiological changes of PCAT and EAT can be performed by non-invasive imaging techniques such as ultrasound, CT, MRI and PET-CT. This review mainly aimed to summarize the PCAT and EAT -related anatomy and physiological function and its correlation with cardiovascular risk by imaging examinations, providing a valuable clinical guidance for early diagnosis and prognostic evaluation of cardiovascular events.

Introduction

Coronary atherosclerosis (AS) is one of the leading causes for cardiovascular events worldwide [1]. Chronic vascular inflammation is not only a critical factor in plaque formation and progression, but also a driving force promoting plaque rupture [2]. Anti-inflammatory therapy has been proven to be effective in preventing plaque progression [3]. For example, in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS), Canakinumab (a monoclonal antibody targeting IL-1β) was first documented to reduce the recurrence rate of cardiovascular events [4, 5]. In studies on colchicine treatment for acute myocardial infarction (AMI), the role of inflammation has been also demonstrated in disease pathogenesis [6]. Therefore, quantifying coronary artery inflammation can help to assess plaque status that is of great significance for preventing the cardiovascular events [7]. Although vascular inflammation can currently be detected through various methods, circulating inflammation biomarkers have insufficient specificity for diagnosing coronary inflammation, and non-invasive imaging examinations such as ultrasound, CT and MRI have limitations such as high cost and significant radiation exposure [8–10]. In recent years, the pericoronary adipose tissue (PCAT) and epicardial adipose tissue (EAT) have been used to quantify coronary artery inflammation [11, 12]. The PCAT and EAT imaging can offer unprecedented capabilities for detecting coronary artery inflammation, making it a non-invasive biomarker that can enhance the predictive value of cardiovascular outcomes [13]. This review mainly summarized the recent studies in the pathophysiology, imaging examinations and clinical applications of PCAT and EAT, providing evidence for risk assessment and clinical decision for patients with coronary heart disease (CAD), as shown in Fig. 1.

Fig. 1.

The pericoronary adipose tissue and epicardial adipose tissue play an important role in the development of cardiovascular events including atherosclerotic plaque and thrombosis formation

Anatomy and physiological function

The both of EAT and PCAT belong to components of visceral fat around the heart [14, 15]. Anatomically, EAT is defined as the fat tissue deposited between the myocardium and the visceral layer of the pericardium, primarily located in the atrioventricular and ventricular groove, directly contacting adjacent myocardium [16]. PCAT is the part of EAT that is closest to the vessel wall, and its close connection with the vascular lumen contributes a specific role on promoting the progression of coronary AS and participating in plaque formation [17–19]. In vessels with different diameters, the anatomical structures of EAT and PCAT were varied. For instance, PCAT is located on the surface of the outer membrane layer in large vessels that direct contacts with the vessel wall, while in small vessels and microvessels, it is part of the vessel wall [20–22].

In fact, pericardial fat (PCAT and EAT) often has a bidirectional communication with the cardiovascular system (Fig. 2). On the one hand, the adipose tissue can act on adjacent vascular walls and myocardium through paracrine mechanisms or influence the cardiovascular system via endocrine mechanisms, which is considered as an "external-to-internal" mechanism [23, 24]. On the other hand, perivascular adipose tissue acts as a sensor, receiving signals from the vascular wall and then altering its own morphology and secretory characteristics [25, 26]. The "internal-to-external" mechanism is considered part of the human body's defense against cardiovascular inflammation and oxidation [26]. The interaction between pericardial fat and cardiovascular system collectively maintains dynamic equilibrium, and the imbalance in this homeostasis is associated with metabolic disorders in the cardiovascular system. Therefore, understanding the pathophysiology, anatomy and function of the pericardial fat is crucial for stratifying, predicting and treating cardiovascular diseases (CVDs) (Figs. 3, 4).

Fig. 2.

Mechanism of autocrine and paracrine by pericardial fat with a bidirectional communication with the cardiovascular system

Fig. 3.

The change in pericoronary adipose tissue (PCAT) and epicardial adipose tissue (EAT) can dynamically reflect the inflammation activity of coronary artery, playing an important role in the development of cardiovascular diseases (CVDs)

Fig. 4.

The pericoronary adipose tissue (PCAT) and epicardial adipose tissue (EAT) play an important role in the development of cardiovascular events

In addition to endocrine function, EAT and PCAT can contribute to (1) mechanical protection function [27]: although the pericardial fat account for less than 1% of total body fat and is far from the amount of abdominal fat, it still plays a mechanical role, protecting the coronary artery from torsion caused by arterial pulsation and cardiac contraction; (2) thermogenic function [28]: in newborns or early life, the pericardial fat resembles brown fat tissue in both morphology and function, and it is expressed at the mRNA and protein levels as uncoupling protein 1. This substance disrupts the proton gradient within the mitochondrial inner membrane, hindering ATP synthesis and releasing potential energy as heat, thus EAT and PCAT can serve as a heat source when body temperature is relatively low [29], further protecting the heart and coronary from cold damage; (3) metabolic function [30, 31]: compared to other visceral fat tissues, the pericardial fat has a stronger ability to release and take up free fatty acids, and even lower glucose utilization. As the primary source of free fatty acids, EAT and PCAT can meet the energy needs of cardiac muscle, and also counteract high levels of free fatty acids in the coronary or circulatory system [32, 33], protecting myocardial cells and blood vessels from fat toxicity, thereby maintaining the steady state of fatty acids.

Imaging examination of the pericardial fat

Echocardiography

Echocardiography has been the most economical and simplest method for assessing fat around the heart [34]. It can measure the thickness of pericardial fat in the free wall of the right ventricle by using parasternal long-axis and short-axis views for the left ventricle [34]. Studies have reported that the EAT and PCAT thickness was significantly associated with atrial fibrillation (AF) risk, and patients with AF tend to have more EAT capacity [35–38]. Additionally, another evidence also suggested that the thickness of the PCAT and/or EAT might be an independent predictor for AF recurrence and acute coronary artery syndrome [39–41], supporting for clinical management on stratifying the CVD risk. However, echocardiography often measures the EAT and PCAT in a two-dimensional manner, and its spatial accuracy and inter-operator repeatability are relatively poor, making it difficult to comprehensively and three-dimensionally assess the characteristics of subcutaneous fat around the heart [42]. Furthermore, there are differences in measurement method for different operators, leading to a low reproducibility, which makes it challenging to accurately evaluate the pericardial fat [42]. Therefore, the quantitative study concerning on the fat around heart by using echocardiography is limited in clinical application currently.

Coronary CTA

With the advancement of multi-slice spiral CT technology, the high spatial resolution of coronary computed tomography angiography (CTA) has made it the primary method for quantitative and qualitative measurement of pericardial fat around the heart [43]. It can easily distinguish between myocardial, pericardial and vascular fat tissues, allowing for comprehensive and intuitive evaluation of EAT and PCAT [43]. On CT image, pericardial fat is defined as the tissue with a density between-190 to-30 HU [44, 45]. Morphologically, CT can quantify the thickness, area, mass and volume of PCAT and EAT, and the thickness of pericardial fat measured by CT image has been considered as a risk factor for AF recurrence after catheter ablation [35–38]. Ciuffo et al. found that patients with AF recurrence have a larger pericardial fat area in left atrial [46]. Rosendael et al. proposed that patients with paroxysmal AF have greater fat tissue mass in left atrial posterior than patients with sinus rhythm, reflecting early progression of AF [47]. Additionally, the thickness of EAT and PCAT have been found to be significantly associated with the severity of CAD [48]. Mancio et al. found in patients with moderate to low cardiovascular risk that the volume of EAT could independently predict coronary artery stenosis, myocardial ischemia and other adverse cardiovascular events [49]. Moreover, EAT and PCAT had a predictive power for coronary atherosclerotic cardiomyopathy [50], and the volume of EAT was associated with plaque characteristics, calcification score, degree of vascular stenosis and cardiac function class[51]. In a previous study including 255 patients, univariate analysis showed that EAT volume was also associated with atherosclerotic cardiomyopathy and high-risk plaques. However, in multivariate analysis the significant association was disappeared [52]. This might be related to the diversity of the study population and selection bias, suggesting a more reliable imaging marker was necessary to explore the relationship between the pericardial fat (PCAT and EAT) and cardiovascular events.

Recently, some scholars have pointed out that pericardial fat attenuation is a more sensitive marker than adipose volume because its relationship with CVDs is closer than that of fat tissue [53]. Under pathological conditions, PCAT can secrete pro-inflammatory cytokines and adipocytes undergo phenotypic changes. The aggravated inflammatory response can lead to the less lipid content and smaller cell size, disrupting the water–lipid phase balance [54]. This pathological change usually displays an increased CT density that is clearly positively correlated with the inflammatory state [54]. Therefore, the fat attenuation index (FAI) from PCAT or EAT has become a biomimetic imaging marker for capturing the density of around the coronary or heart [55, 56]. Antonopoulos found that compared to healthy individuals, patients with AS had a higher FAI value that was associated with an increased levels of inflammatory activity in PCAT, indicating a higher risk of ruptured plaque [54]. In summary, an increased FAI value in EAT or PCAT was associated with a higher risk for adverse cardiovascular events. However, some research has also shown that lower EAT density was associated with more severe coronary calcification and adverse cardiovascular events [51]. The complex pathophysiological mechanisms of EAT and heterogeneity among different populations might be major reasons for these varying outcomes [57]. More exploration are needed to confirm the role of pericardial fat in CVDs.

Cardiac magnetic resonance

Known for its safety and good resolution, cardiac magnetic resonance (CMR) is a non-invasive visualization tool for quantifying adipose tissue [58]. Existing evidence suggested that CMR is considered as the gold standard for measuring EAT or PCAT content [59]. Many studies based on CMR have explored the relationship between the thickness and volume of pericardial fat and risk for cardiovascular events [60, 61]. Since AF is associated with myocardial fibrosis, CMR can not only measure the volume of EAT but also quantitatively assess the degree of myocardial fibrosis [60], providing more information for clinical diagnosis and treatment. Therefore, quantitative assessment of EAT and PCAT based on non-invasive CMR might play a specific significance on the stratification of cardiovascular risk [62–64].

Steady-state free precession (SSFP) can distinguish fat, blood and muscle tissue, making it the most fundamental sequence for cardiac imaging [65]. However, the determination of PCAT and EAT boundary can be affected by pericardial effusion, and current manual marking is predominantly used that has low repeatability and impacts efficiency [66]. In recent years, fully automatic contouring of fat for quantitative analysis has emerged. The DIXON sequence can obtain image of fat–water separation, which is beneficial for delineating fat contour [67]. Continuous update to new technology and post-processing software in CMR can facilitate the exploration of more new indicators for quantitative pericardial fat, potentially reflecting pathophysiological changes in PCAT and EAT. However, its operability has yet to be clinically validated. The MRI imaging of the heart still faces problems such as long acquisition time, susceptibility to artifact and high compliance requirement now. Furthermore, it is relatively expensive so that widespread clinical application might still take some time [68].

Positron emission tomography-CT

Positron emission tomography (PET)-CT is the gold standard for imaging inflammation in body tissues [69]. It can assess the inflammatory state of adipose tissue by using the radiotracer ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) [70]. Kitagawa et al. evaluated myocardial FDG activity through inflammatory uptake of pericardial fat on PET-CT, finding that the FDG uptake in EAT was independently associated with myocardial uptake from left atrial [71]. Moreover, patients with persistent AF had a higher EAT uptake value compared to those with paroxysmal AF, indicating that EAT can serve as an alternative target for assessing myocardial activity [72]. Additionally, ¹⁸F-sodium fluoride (¹⁸F-NaF) can quantitatively assess the degree of inflammation in EAT, and its density is positively correlated with coronary ¹⁸F-NaF activity [73]. Furthermore, an increased PCAT attenuation is associated with ¹⁸F-NaF uptake around and within high-risk plaques, confirming that coronary inflammation around vulnerable plaque can be demonstrated through non-invasive PCAT studies [74]. Thus these results supported that PET/CT can significantly improve the prediction of coronary inflammation. Kiuchi et al. [75] ever combined PET with MRI to simultaneously quantify the volume of myocardial ¹⁸F-FDG uptake and myocardial fibrosis volume after AF ablation, finding a close relationship between the two. However, ¹⁸F-FDG lacks cell specificity that the FDG uptake in myocardium can affect the imaging of adjacent coronary artery, and its clinical application is also limited due to the lack of spatial resolution of PET, ionizing radiation or high cost.

Clinical value of pericardial fat with cardiovascular risk

Coronary heart disease

The evaluation of PCAT can non-invasively quantify the activity of coronary inflammation and plaque vulnerability [76]. Goeller et al. found that the FAI from PCAT around the coronary injury was increased with a reduction of ≥ −68.2 HU, potentially serving as a threshold for identifying coronary lesion [77]. They also discovered that combining high-risk characteristics can be more reliably on identifying vulnerable plaques. In addition to coronary CTA, parameters related to PCAT based on ordinary CT can also be used for assessing risk of plaque rupture [77]. Takahashi et al. found that the PCAT attenuation of right coronary artery based on CT scan was an independent predictor of high-risk plaque [78]. Another study also showed that the combined model of clinical risk factors with PCAT imaging had a good diagnostic efficacy for non-calcified vulnerable plaque, with an area under the receiver operating characteristic curve (AUC) of 0.752 [79]. Recent evidence indicated that PCAT attenuation around atheromatous plaque may be more valuable in assessing plaque vulnerability than proximal FAI attenuation, potentially becoming a standard biomarker for evaluating the severity of coronary AS [80], although further large-sample studies are needed to confirm this conclusion.

In fact the progress of atheromatous plaque is an intermediate step between subclinical AS and coronary events, and the inflammation around the coronary artery can promote the rupture of high-risk plaque, leading to acute coronary syndrome [81]. Researchers analyzed the correlation between the FAI from PCAT and plaque progression, finding that an increase FAI in non-calcified plaque was associated with a high PCAT attenuation, and PCAT attenuation ≥ −75 HU was an independent predictor for an increased risk of plaque disruption [56, 82–84]. Nakajima et al. compared the PCAT attenuation of 107 patients with plaque rupture and 91 patients with plaque erosion, finding that the PCAT attenuation of 3 patients with plaque rupture was significantly higher than that in patients with plaque erosion [85]. Therefore, PCAT-related parameters based on coronary CTA can help identify patients at high risk for plaque progression and/or rupture [85].

Heart failure

Recent studies have shown that parameters related to coronary CTA for PCAT were closely associated with heart failure (HF) with preserved ejection fraction (HFpEF) [86, 87]. Nishihara et al. also found that the FAI value from PCAT in three coronary arteries of HFpEF patients was higher than that in control group, and the PCAT attenuation might be an independent predictor of HFpEF occurrence [86]. This suggested that PCAT inflammation is one of the potential mechanisms of HFpEF that is possibly related to local microvascular dysfunction and the impact of local inflammation on the left ventricle [86]. Liu et al. conducted a follow-up study on 107 non-ischemic HF patients and 129 healthy individuals to investigate the relationship between PCAT and HF rehospitalization [87]. The results showed that the PCAT attenuation in three coronary arteries was higher than in the healthy control group, and it was associated with a increased risk of HF rehospitalization among these patients [87]. However, there are relatively less evidence concerning PCAT in HF study now, and further studies are necessary to elucidate the association of PCAT with HF progression.

Metabolic disorders

Patients with type 2 diabetes mellitus (T2DM) are highly susceptible to CVDs, with CAD being the primary cause of death [88, 89]. Thus evaluating inflammation and coronary dysfunction through PCAT parameters before CAD symptoms occur can help identify high risk from general populations. A previous study showed that in coronary CTA, regardless of whether there was obstructive stenosis or high-risk plaque, the PCAT attenuation in the right coronary artery among diabetic patients was significantly higher than that in non-diabetic individuals [90]. Even after adjusting for confounding factors, significant difference in PCAT attenuation remained between the two groups. Studies have also shown that combining imaging features based on CT with the imaging score calculated from PCAT attenuation was an independent predictor for obstructive CAD [91]. These studies indicated that parameters related to PCAT can help patients with T2DM to identify and monitor CAD progress in the early subclinical stage [92]. A previous study on drug therapy for T2DM even found that FAI on the right coronary artery in the drug group was significantly lower than in the control group [93]. Liu et al. evaluated diabetic patients after drug therapy and found that the PCAT attenuation in all three coronary arteries decreased, indicating reduced coronary artery inflammation in T2DM patients after drug therapy [94]. Therefore, PCAT attenuation might be a more sensitive and useful biomarker than traditional indicators for monitoring the effectiveness of T2DM treatment and assessing cardiovascular risk in T2DM patients.

Furthermore, non-alcoholic fatty liver disease (NAFLD) is a risk factor for cardiac death [95]. Ichikawa et al. analyzed the PCAT-related indicators by CTA, and showed that FAI value in NAFLD patients was significantly higher than that in non-NAFLD patients [96, 97]. This indicated that a high PCAT attenuation is a new predictor for adverse cardiovascular events for NAFLD patients. Another study also showed that FAI on left anterior descending artery in NAFLD patients was a significant independent predictor of cardiovascular events such as cardiac death, non-fatal acute coronary syndrome and hospitalization for HF [96].

Coronary vascular dysfunction

Recent studies have shown that PCAT attenuation was associated with coronary hemodynamics dysfunction [98–100]. Duncker et al. found that compared to control group, patients suffered from myocardial ischemia had a significantly higher PCAT attenuation on right coronary artery, suggesting that an increased FAI on right coronary artery may be an important predictor of myocardial ischemia [101]. Yu et al. studied 167 patients with stable angina and found that FAI around the coronary arteries was a significant predictor of lesion-specific ischemia [102]. The accuracy of predicting coronary stenosis and ischemia by using FAI combined with vessel diameter stenosis and plaque volume can match the diagnostic efficacy of CT -fractional flow reserve (FFR), which is similar to the results of Ma et al. [103]. Another study also found that adding FAI ≥ −71.9 HU for plaque assessment can improve the ability to identify ischemia [104]. In recent years, some models by combining PCAT imaging and CT-FFR have shown a high value in distinguishing between blood flow limited lesions and non-blood flow limited lesions, and the diagnostic value of coronary stenosis is significantly higher than that of CT-FFR and PCAT imaging models alone [104].

Summary

EAT and PCAT has garnered significant attention on its application for predicting cardiovascular outcomes. By quantifying the vascular inflammation, the pericardiac fat can offer a novel method for plaque assessment. PCAT and EAT can even monitor plaque change and then offer an objective quantitative indicator for observing and tracking the disease progression for patients with CAD. Furthermore, the clinical value of PCAT and EAT is very important and promising for targeting therapy on appropriate patients, possibly bringing revolutionary change for the prevention of CVDs. However, the pericardiac fat still have some limitations in plaque assessment such as clinical application and popularization. In the future, with the continuous advancement of technology and deeper research in PCAT and EAT, its confounding factors might gradually decrease, and the standardization of imaging histology can be achieved. The pericardiac tissue is expected to be widely applied in the early screening and treatment of CVDs.

Authors’ contributions

Jiacheng Zhu and Dongxue Wu wrote the main manuscript text, and Bo Han revised it. All authors reviewed the manuscript.

Funding

The work was not supported by any fund.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.