Inflammation plays a key role in the development and progression of cardiometabolic disease (CMD) and cancer.^1–3 Numerous inflammatory mediators including C-reactive protein (CRP), adiponectin, monocyte chemoattractant protein 1 (MCP-1), and lipoprotein-associated phospholipase A₂ (Lp-PLA₂), as well as alterations of gut microbiota, have been reported to be associated with an increased risk of CMD.^4,5 CRP is the most extensively studied marker of inflammation and is most widely used in daily clinical practice. Yet the precise role of CRP in the assessment of cardiometabolic risk continues to evolve.^1,6,7 However, recent studies have suggested that EAT and carcinoembryonic antigen (CEA) are novel surrogates of inflammation that contribute to the development of CMD.^8,9 EAT is an accumulation of visceral fat that covers 80% of the heart surface. EAT plays a particularly important role in cardiovascular physiology and pathophysiology. Ordinarily, it has cardioprotective mechanical, metabolic, thermogenic, and endocrine/paracrine functions. However, structural and functional changes in EAT have proven to be associated with several CMDs, including insulin resistance and coronary artery disease.^10–13 In pathologic conditions thickened EAT acts as a source of inflammatory mediators and secretes a higher amount of proinflammatory mediators and neuro-hormones so that increased EAT can pathologically influence the cardiovascular system and cause worse outcomes.^10–13

CEA is a serological marker overexpressed in adenocarcinoma of the colon and other organs.⁶ However, serum CEA levels may increase mildly with age and could appear to be high in many nonneoplastic conditions, including smoking, chronic renal failure, hypothyroidism, and chronic hepatitis.^8,11–13 Although its exact function has not been elucidated, the stimulation of monocytes and macrophages by CEA may result in an increased production of proinflammatory cytokines^11–12 and endothelial adhesion molecules,¹⁴ which may subsequently lead to atherosclerotic cardiovascular disorders and the metastasis of malignant cells.^9,14 Other possible underlying mechanisms may include imbalanced oxidative damage and endoplasmic reticulum stress production, which triggers redox imbalance and increasing oxidative damage to proteins, lipids, and DNA.^2,11–14 Furthermore, recent studies have reported CEA to be related to metabolic syndrome and visceral adiposity.⁸ Moreover, Chang et al. has suggested a CEA level of ≥ 3 ng/mL for the early detection and prevention of CMDs through individualized lifestyle modifications.² As mentioned earlier, EAT and CEA both have inflammatory characteristics.^2,10 However, reports linking CEA concentration to the EAT do not exist. Therefore, the present study aimed to investigate the possible association between EAT and CEA.

The study sample consists of Caucasian men and women who visited our hospital for routine health checkups from November 2021 to May 2022. This is a cross-sectional study conducted with 134 individuals (male = 56, female = 78), aged 22 to 83 years. Individuals who were over 18 years of age, and who were willing to participate, were included in the study. Subjects who had a history of cancer, hypothyroidism, active infection, diabetes, coronary/peripheral artery disease, heart failure, chronic renal disease, chronic liver disease, history of current or past smokers, pregnant women, and individuals with evident contraindication to VFR assessment, such as an acute medical condition, patients with an implanted cardioverter defibrillator or pacemaker, unstable weight, inability to assume required positions, and age changes were not included in the study. Demographic, clinical, and laboratory data were obtained from the hospital's electronic database. EAT thickness was assessed by transthoracic echocardiography. Visceral fat rating (VFR) was measured by a bioelectrical impedance analysis (BIA) machine. The present study was conducted in accordance with the guidelines proposed in the Declaration of Helsinki and has been approved by a local clinical research ethics committee. Written informed consent was obtained from all participants included in the study.

Table 1 shows the basal characteristics of the sample-134 subjects (mean age 46.24±11.93 y, 78 female, 56 males) according to serum CEA tertiles. CEA tertiles were categorized separately as follows: T1, 0.5-1.04; T2, 1.06–1.69; and T3, ≥1.7 ng/ml. The mean age, weight, VFR, EAT, and fasting glucose, as well as the median of systolic blood pressure (SBP), creatinine, and aspartate aminotransferase (AST) increased with the increasing CEA tertiles. By contrast, height, BMI, WC, diastolic blood pressure (DBP), heart rate (HR), total cholesterol (TC), LDL-C, high density lipoprotein cholesterol (HDL-C), triglyceride (TG), hemogloin-A1c (HbA1c), GFR, WBC, CRP, RDW, neutrophil to lymphocyte ratio (NLR), alanine aminotransferase (ALT), and thyroid stimulating hormone (TSH) values were not significantly different between CEA categories.

Table 2 demonstrates the pairwise comparison of significantly different variables among the tertiles of Table 1. Participants of tertiles 2 and 3 were significantly older in comparison to the tertile 1 participants. The mean weight, VFR, glucose, SBP, creatinine, and AST were significantly different only between tertiles 1 and 3. The mean EAT and CEA were significantly different among all pairs; as tertile 3>tertile 2>tertile 1.

First, univariate analysis was performed, which identified age, gender, BMI, WC, SBD, DBS, AST, LDL-C, TG, FG, HBA1C, VFR, and EAT as possible predictors of CEA. As seen in Table 2 and Figure 1, EAT has a stronger correlation with CEA than other variables. All of these variables were then included in a multivariate linear regression analysis for a truly adjusted result. Multivariate linear regression analysis confirmed that gender, age, and EAT were the significant independent variables associated with CEA, accounting for a combined 42.9% of the variance in serum CEA. However, the contribution of BMI, WC, SBD, DBS, AST, LDL-C, TG, FG, HBA1C, and VFR to the model proved to be insignificant, as shown in Tables 3 and 4.

An excellent interobserver agreement regarding EAT measurement was observed; the intraclass correlation coefficient was (İCC; 0.966 %Cİ; 0.824-0.987).

Our analysis revealed a significant relationship between EATs and serum CEA levels (Central illustration). Moreover, the multivariate linear regression analysis confirmed that EAT was among the significant explanatory variables for CEA. This clearly indicates that EAT thickness is closely related to, as well as a good predictor of, CEA.

CEA, is an oncofetal glycoprotein (180- to 200-kDa), expressed in normal mucosal cells, and is overexpressed in adenocarcinoma, particularly in colorectal malignancies. In addition, elevated CEA levels are also associated with several non-cancerous conditions, including cigarette smoking, older age, chronic renal and hepatic failure, and metabolic disorders.^11–14 Furthermore, recent studies have reported a positive relationship between CEA and carotid atherosclerosis, arterial stiffness, metabolic syndrome, and low-grade chronic inflammation.^8,15,16 Similar to the oxidized LDL-C,^9,14 CEA stimulates monocytes and macrophages and may cause an increase in the production of proinflammatory cytokines,¹⁴ which may subsequently induce endothelial cell expression of adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and E-selectin that bind monocytes and T lymphocytes, allowing them to penetrate the intima. These processes play a key role in facilitating the metastasis of cancer cells as well as in the early stage of atherosclerosis, which involves the recruitment of inflammatory cells and their trans-intimal migration.

Low-grade chronic inflammation is also promoted by EAT, a very active secreting visceral adipose tissue.⁹ Structurally and functionally altered EAT is associated with a greater inflammatory response, which appears to be one of its mechanisms of developing cardiovascular diseases, including coronary artery disease, aortic stenosis, and heart failure. As previously mentioned, CEA levels are associated with various chronic inflammatory diseases. Therefore, increased inflammatory cytokines and adipokines secreting from EAT may stimulate CEA expression. In addition, it is also conceivable that pathologically thickened EAT can directly express and release CEA.

CEA and EAT are closely associated with aging. In this regard, our findings were in excellent agreement with the literature.^8,9,15 Our results demonstrated a positive correlation between the subject's age and EAT (r = 0.59 P<0.001), as well as age and CEA (r = 0.42, P<0.001). These findings support the concept of increasing inflammatory burden with increasing age. Similarly, our findings were consistent with previously published papers in the context of mean weight, adiposity index, SBP, and fasting glucose, which were gradually increased with a rising CEA concentration.^15,17 These data suggest the possible association of CEA with CMDs. However, findings from the present study regarding the relationship between CEA and simple markers of inflammation are not consistent with those of other recently published studies.^15,17 In the current study, leucocyte count, NLR, RDW, and CRP values did not significantly differ among CEA tertiles. An explanation for this paradox may be the absence of certain inflammation-promoting confounders, such as smoking, diabetes, and cardiovascular disease in our sample.

Jee-Yon Lee et al. reported CEA to be associated with abdominal visceral fat accumulation assessed by computed tomography in the female gender, and they suggested CEA as a mediator of metabolic disturbance.⁸ In addition to the visceral adiposity index, in our analysis, CEA recorded a better association both with the VFR as well as with EAT. Thus, this analysis not only complements the aforementioned report, but it also linked CEA with EAT – a more pathological visceral adipose tissue.

Understanding the role of inflammation in atherosclerosis and CMDs has resulted in the prevention of CV events through the development of anti-inflammatory therapies.³ In this context, CEA's inflammatory characteristics and its association with EAT may enhance the knowledge of the role of different inflammatory actions in the pathophysiology of CMD. Therefore, agents targeting CEA, such as the “CEA-related cell adhesion molecule”, may provide additional advantages in CV prevention.

In general terms, our results were consistent with previous studies. In addition, our study counted on the participation of both genders, simultaneously analyzed EAT and VFR, and did not use any ionizing method in the evaluation of visceral adiposity. Moreover, to achieve a purer relationship between CEA and EAT, our study excluded individuals with diabetes and smokers in whom EAT and CEA could be increased. However, the current study does have some limitations. Our sample was small, included only the Caucasian ethnicity, and performed a cross-sectional study that was unable to confirm casualty between CEA and EAT. Furthermore, the method used for EAT assessment has many limitations and is not currently the gold-standard. The use of bioelectrical impedance to assess visceral fat is also an indirect measurement.

The present study showed that EAT is independently associated with CEAs. Our results propose that CEA could be a metabolic marker. Supplemental investigations are required to improve the present work and comprehend the clinical and pathophysiological importance of our results.