Epicardial adipose tissue as a predictor of adverse prognosis

Introduction

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide. According to estimates, they account for 20.5 million deaths globally, nearly one million of which were recorded in Russia [1]. The World Health Organization (WHO) classifies risk factors into two groups: behavioral and metabolic. The first group includes unhealthy diet, smoking, physical inactivity, and excessive alcohol consumption. Metabolic risk factors comprise arterial hypertension, obesity, elevated blood cholesterol, and hyperglycemia [2]. Notably, obesity, as a modifiable risk factor, was responsible for 2 million deaths in 2021 [3]. It also contributes to the development of dyslipidemia, insulin resistance, arterial hypertension, and atherosclerosis [4, 5]. The number of individuals with modifiable risk factors is rapidly increasing. According to the Federal State Statistics Service, the prevalence of obesity in Russia increased by 12% between 2020 and 2022 [Healthcare in Russia. 2023: Statistical Digest / Rosstat. – Moscow, 2023. – 179 p.]. Currently, obesity has reached pandemic proportions. In the WHO European Region, 60% of adults are overweight or obese, with Russia recording one of the highest proportions of obesity [6].

The aim of this study is to analyze data on the associations between epicardial adipose tissue (EAT) and CVDs and to evaluate the potential of EAT as a predictor of adverse cardiovascular events.

Materials and Methods

To identify relevant literature, the following databases were searched using the keywords “obesity,” “epicardial adipose tissue thickness,” “epicardial adipose tissue,” and “cardiovascular diseases”:

1. PubMed (ncbi.nlm.nih.gov/pubmed).
2. eLIBRARY (eLIBRARY.RU)
3. Google Scholar (https://scholar.google.com/)
4. Web of Science (https://mjl.clarivate.com/search-results)
5. Scopus (https://www.scopus.com/home.uri)

Advantages of Using EAT as a Diagnostic Criterion

Current clinical guidelines recommend body mass index (BMI) and waist circumference (WC) for diagnosing and classifying obesity [7]. While BMI correlates with morbidity and mortality risk, it does not reflect visceral fat accumulation, which has the most detrimental impact on CVD risk [8]. Multiple studies confirmed the association between visceral obesity and increased CVD risk, although the exact mechanisms remain unclear. It is hypothesized that visceral fat, acting as a secretory organ, produces bioactive substances that can directly influence the liver via the portal circulation. Adipocytes secrete adipokines such as TNF-α, leptin, resistin, visfatin, IL-6, and adiponectin. Several adipokines (TNF-α, IL-6, leptin, angiotensin II, visfatin, and resistin) are pro-inflammatory, and their concentrations are higher in overweight individuals. Conversely, individuals with normal body weight secrete anti-inflammatory adipokines such as IL-4, IL-10, IL-13, IL-1 receptor antagonist, and adiponectin [9]. Visceral obesity can be present even in individuals with a normal BMI; one study found it in 17.6% of such cases [10]. Formulas for calculating the visceral adiposity index (VAI) were developed, incorporating BMI, WC, triglyceride levels, and HDL cholesterol [11]. However, studies using computed tomography (CT) and magnetic resonance imaging (MRI) have shown that BMI and WC are limited in their ability to indirectly assess visceral fat in high-risk patients. Direct assessment of visceral fat is therefore preferable [12, 13].

EAT was proposed as a visceral fat marker because its volume strongly correlates with total visceral fat volume [14]. Located between the visceral pericardium and the myocardium, and sharing the same coronary blood supply, EAT can directly influence the heart via bioactive mediators. Under physiological conditions, epicardial adipocytes perform mechanical, thermal, and metabolic functions — serving as an energy source during ischemia and buffering excess free fatty acids [11].

Epicardial adipocytes produce adiponectin and adrenomedullin, which have anti-inflammatory properties, reduce coronary and myocardial fibrosis, exhibit anti-atherogenic and antioxidant effects, and promote vasodilation, natriuresis, and nitric oxide secretion.

In obesity-related chronic inflammation, EAT volume increases, and its secretory profile shifts toward pro-inflammatory and pro-fibrotic factors. Decreased adiponectin mRNA and increased IL-6 mRNA expression in EAT are associated with coronary artery disease (CAD). Additionally, a predominance of pro-inflammatory M1 macrophages over anti-inflammatory M2 macrophages is observed. Excess EAT may also contribute to atherosclerosis, as coronary lesions are often located adjacent to epicardial fat depots, and to left ventricular hypertrophy due to mechanical loading [15–17].

For the visualization and quantitative assessment of EAT, CT, MRI, and echocardiography are employed. A comparison of these methods was presented in the study by Jeroen Walpot et al. CT enables the measurement of not only EAT volume but also its density, which has emerged as a focus of research due to the potential prognostic value of this parameter in predicting CVD risk.

Among the advantages of CT, the authors note its ability to produce a clear depiction of the pericardium, which is essential for accurate quantification of EAT. Compared with echocardiography and MRI, CT offers superior spatial resolution and better visualization of this adipose layer. Furthermore, CT-based EAT assessment demonstrates high reproducibility, a characteristic also inherent to MRI. At the same time, MRI does not involve exposure to ionizing radiation, which makes it the preferred modality in terms of patient safety. However, MRI has notable drawbacks, including high cost, longer examination time, and limited availability.

In contrast, echocardiographic assessment of EAT thickness (EATT) is a relatively inexpensive, widely available, and safe imaging technique, owing to the absence of ionizing radiation. Nevertheless, its accuracy is limited by the operator dependency. Importantly, the threshold values for defining increased CVD risk remain undefined for each of the aforementioned methods [18].

Echocardiographic assessment of EAT was first described in 2003 by Iacobellis et al., with the aim of demonstrating the use of transthoracic echocardiography as an accurate, simple, and reliable method for visualizing visceral adipose tissue. EATT was measured on the free wall of the right ventricle in the parasternal long- and short-axis views and identified as an echo-free space. The authors justified the choice of the right ventricle by the fact that epicardial fat is thickest at this location, as well as by the optimal orientation of the ultrasound beam in both views.

The accuracy of this method was confirmed by a strong correlation with anthropometric measures of visceral adiposity (BMI, WC, hip circumference) and with visceral fat volume quantified by MRI [19]. Initially, EATT was measured over ten cardiac cycles; currently, measurement over three cardiac cycles with subsequent averaging is considered sufficient.

However, there is no consensus on the optimal phase of the cardiac cycle for EATT measurement. Some authors recommend measurement at end-systole due to tissue compression and deformation, whereas others consider end-diastole preferable to ensure comparability with CT and MRI measurements [20]. In most published studies, end-systolic measurement is used more frequently.

Atherosclerosis is the most common cause of CVD, which has prompted interest in non-invasive diagnostic methods capable of predicting risk before the onset of clinical symptoms [21]. One such parameter is the coronary calcium score (CCS), designed to quantify coronary artery calcification using CT. A CCS of zero serves as the reference point, indicating the absence of atherosclerotic plaques and a very low risk of coronary events. Increasing CCS values allow the identification of individuals at high risk of cardiovascular events among asymptomatic patients.

For instance, a CCS between 11 and 100 indicates the presence of a small number of atherosclerotic plaques and a moderate risk of CVD [22]. At the same time, a CCS greater than 10 is associated with higher EATT, highlighting the relationship between EATT and atherosclerosis markers, as well as the prognostic value of this parameter [23]. Moreover, longitudinal observations in patients without established CVD but with varying EAT volume demonstrated that the incidence of fatal and non-fatal cardiovascular events increased with greater EAT volume, independently of both traditional risk factors and CCS value [24].

Normal EAT

At present, no definitive reference values for EAT thickness have been established [25]. However, it has been found that under physiological conditions, this layer accounts for approximately 20% of the heart’s mass [26]. According to a 2024 population-based study, the average EATT in the general population is 4.07 mm [27].

As a criterion for epicardial (visceral) obesity (VO), Kuznetsova et al. proposed the following EATT thresholds: ≥5 mm for individuals under 45 years of age, ≥6 mm for those aged 45–55 years, and ≥7 mm for individuals over 55 years of age [28]. Subsequently, Davydova et al. examined EATT in patients with CAD and in asymptomatic individuals. In the CAD group, the mean EATT was 6.4 mm, whereas in the asymptomatic group, it measured 4.7 ± 1.5 mm. The absence of an established reference standard and the inability to use these values as universal cut-off points were attributed by the authors to the insufficient investigation of this issue in large multicenter studies [29].

When performing transthoracic echocardiography in overweight or obese patients, it is recommended not only to quantify EAT but also, in cases where the thickness exceeds 5 mm, to document it in the examination report as excessive visceral fat accumulation [30].

EAT as a Prognostic Predictor

Due to its anatomical characteristics and its location in direct contact with the myocardium, EAT can lead to the mechanical separation of myocardial fibers. Sharing a common microcirculatory network with the myocardium, EAT influences cardiomyocytes directly through the biosynthesis of adipocytokines. Consequently, EAT not only interacts with the myocardium and its vascular bed but may also contribute to the development and progression of CVDs. At present, many questions remain in contemporary cardiology regarding the potential of EAT as a predictor of CVD risk.

A number of studies were conducted to investigate the associations between EATT and the development of CVDs in patients with obesity but no previously diagnosed cardiopathology, as well as to determine the advantages of epicardial obesity as a prognostic criterion.

In an original study by Blinova et al., the contribution of EAT to the risk of left ventricular diastolic dysfunction (LVDD) was evaluated. The study observed 104 male and female patients with diagnosed abdominal obesity and no CVD. EATT was assessed using multislice computed tomography (MSCT) and echocardiography. Measurements were taken in both systole and diastole over three cardiac cycles, with the average value considered as final. A statistically significant correlation was found between EATT measured by echocardiography and EAT volume measured by MSCT. Further analysis identified EAT volume as an independent and stronger predictor of LVDD risk than BMI or mean arterial pressure. As threshold values for CVD risk assessment, the authors proposed the following EATT cut-offs: >7.5 mm in systole and >4.0 mm in diastole. Thus, EAT may be used to identify patients at risk for LV diastolic dysfunction [31].

Chumakova et al. assessed the primary and additional risk factors for the development of left ventricular diastolic dysfunction (LVDD) in 149 asymptomatic men with grade I–III obesity. EATT was measured using transthoracic echocardiography (TTE) at end-systole over three cardiac cycles. Based on the TTE results, participants were divided into two groups: those with EATT ≥7 mm, indicative of epicardial (visceral) obesity, and those with EATT <7 mm. A follow-up TTE was performed after 4.7 years. Among all patients who developed LVDD, 90% belonged to the first group, which allowed the authors to classify EATT as one of the most significant predictors of LVDD development, with a predictive ability of 95.3% [32].

In a recent study by Chin et al., the role of EAT as an early marker of cardiac dysfunction in patients without cardiopathology was investigated. The study included 186 men and women with grade II obesity (BMI ≥35 kg/m²). EAT was assessed using both standard and speckle-tracking echocardiography, with thickness measured at end-systole. Additional parameters included global longitudinal strain (GLS) and left ventricular strain, both considered early markers of cardiac dysfunction. Participants were divided into three groups: Group I with EAT <3.8 mm, Group II with EAT 3.8–5.4 mm, and Group III with EAT >5.4 mm. There were no significant differences in clinical characteristics, including BMI and diabetes mellitus, among the groups. However, participants in Group III (EAT >5.4 mm) exhibited lower GLS and LV strain values. Thus, EATT >5.4 mm was found to independently predict cardiac dysfunction, with the added advantage over comparable parameters due to the speed and simplicity of its assessment [33].

Druzhilov and Kuznetsova conducted a four-year follow-up study involving 224 men with abdominal obesity, classified as low cardiovascular risk according to the SCORE scale (<5%) and with no extracranial atherosclerotic plaques in the carotid arteries, in order to evaluate EATT as a predictor of subclinical carotid atherosclerosis. Echocardiographic assessment of EATT was performed at end-systole, with a mean value of 5 mm across all participants. Additionally, a subgroup with epicardial visceral obesity, defined as EATT >5.9 mm, was identified. By the end of the study, atherosclerotic plaques in the carotid arteries were detected in 31% of patients, with 86.5% of these belonging to the group with epicardial visceral obesity (EATT >5.9 mm). It was determined that an EATT value of 5.9 mm could predict the risk of atherosclerosis with a sensitivity of 71.5% and a specificity of 92.3%. The authors proposed using these results for the implementation of early preventive measures [34].

The study by Fernandes-Cardoso et al. included 20 individuals with morbid obesity (BMI 46.97 ± 6.45 kg/m²) and no CVD. The follow-up was divided into two stages — before and after bariatric surgery. Echocardiography was used to assess EATT, measured over three cardiac cycles at end-systole, while ECG was used to determine P-wave duration. Prior to bariatric surgery, the mean EATT was 7.72 ± 1.60 mm, and the mean P-wave duration was 109.55 ± 11.52 ms. After surgery, these values decreased to 4.56 ± 1.40 mm and 98.00 ± 10.49 ms, respectively. Thus, a reduction in epicardial fat thickness associated with weight loss following bariatric surgery was accompanied by a significant shortening of P-wave duration, indicating the role of epicardial obesity in atrial remodeling [35].

A similar study involving individuals with obesity but without CVD was conducted using MRI. In this prospective study by Ng et al., 40 patients were included, with a mean BMI of 25.0 ± 4.1 kg/m², indicating the presence of excess body weight. According to MRI data, the mean EAT volume was 30.0 ± 19.6 cm³/m². Similar to the previously described study, an increase in the indexed EAT volume was associated with a decrease in global longitudinal strain, as assessed by speckle-tracking echocardiography, previously identified as a marker of cardiac dysfunction [36].

Alongside this, several studies were conducted to determine the amount of EAT associated with the development of major adverse cardiac events (MACE) in asymptomatic patients. Choy et al. evaluated the relationship between EATT and circulating biomarkers of atherosclerosis, as well as parameters such as left ventricular diastolic volume, left atrial internal diameter, left ventricular wall thickness, left ventricular ejection fraction measured by MRI, and global longitudinal strain assessed by echocardiography. The mean EATT according to MRI data was 9.8 mm. Patients with EATT greater than 9 mm, compared to those with EATT less than 9 mm, exhibited higher systolic blood pressure, heart rate, and triglyceride levels, while showing lower high-density lipoprotein cholesterol (HDL) levels and poorer global longitudinal strain values. During a 12.7-year follow-up period, among 206 recorded MACE cases, 59% of events occurred in participants with EATT greater than 9.8 mm [37].

Goeller et al. included 456 participants with a mean BMI of 27.2 kg/m² in the study group. EAT volume was measured by CT, with additional assessment of tissue density; the mean values in the population were 83.9 cm³ and −76.2 Hounsfield units (HU), respectively. As a result, 64% of participants experienced adverse cardiac events. Notably, in addition to a statistically significant increase in volume, a marked decrease in EAT density was observed in these individuals. Specifically, in the healthy subgroup, the mean EAT volume was 79.3 cm³ and density was −81.3 HU, whereas in those who developed MACE, the values were 135 cm³ and −75.8 HU, respectively [38].

Subsequently, Eisenberg et al. investigated EAT volume and density to evaluate its prognostic potential. The study included 2,068 asymptomatic individuals with mean EAT volume and density values of 78.5 cm³ and −73.8 HU, respectively, followed over a 14-year period. MACE occurred in 11% of participants, of which 65% underwent late revascularization, 19% suffered myocardial infarction, and 16% experienced cardiac arrest. In this group, the mean EAT volume was 90.6 cm³, and density was −75.4 HU [39].

At the same time, the authors expressed interest in determining the specific EATT associated with the occurrence of MACE in patients already diagnosed with CVD.

In a recent study by Islas et al., investigating the role of EATT in the development of major adverse cardiac events (MACE), 41 patients with a history of acute myocardial infarction were enrolled. All participants underwent transthoracic echocardiography with EATT measurement at end-diastole, after which they were divided into two groups: EATT < 4 mm and EATT ≥ 4 mm. Over a five-year follow-up, 22% of patients in the EATT ≥ 4 mm group experienced adverse cardiac events, 60% of which were recurrent myocardial infarctions, compared to 0% in the lower-thickness group. Based on these results, the authors identified 4 mm as the optimal threshold for prognostic prediction [40].

Morales-Portano et al. studied 107 patients with CAD. EATT was measured using echocardiography over ten cardiac cycles at end-systole, yielding a mean value of 4.6 mm. The development of adverse cardiac events — including cardiovascular death, myocardial infarction, unstable angina, in-stent restenosis, and episodes of decompensated heart failure — was subsequently monitored. Patients who developed complications demonstrated significantly higher EATT values: 5.3 mm versus 4.4 mm in those without events [41].

Similarly, Gruzdeva et al. evaluated EATT in CAD patients, dividing them into groups according to the presence of visceral obesity (VO), as assessed by MSCT. In the VO group, left ventricular EATT exceeded that of the non-VO group (4.9 mm vs. 2.8 mm), with a similar pattern for right ventricular EATT (5.9 mm vs. 4.1 mm). Increased EATT was associated with left ventricular hypertrophy, HOMA-IR index, and elevated free fatty acid levels [42].

Later, the CTA VISION Substudy addressed this question using CT. A total of 995 patients were followed, and after one month, MACE occurred in 7.9% of cases. In this group, EAT volume indexed to BMI was 5.4 cm³/kg/m², compared to 4.7 cm³/kg/m² in patients without MACE [43].

EAT is a unique fat depot, whose anatomical location and secretory function make it an important parameter in the evaluation of cardiac patients. Elevated quantitative measures of EAT may serve as a predictor of poor cardiovascular prognosis. However, there is still no consensus on the optimal measurement method, nor have definitive threshold values for cardiovascular risk assessment been established. Thus, EAT remains a subject of ongoing research interest.