A narrative review of epicardial adipose tissue as a predictor of cardiometabolic risk in rheumatoid arthritis patients

Introduction

Rheumatoid arthritis (RA) is a chronic, systemic, and inflammatory autoimmune disease primarily affecting the synovial joints (1-3). The hallmark of RA is the presence of synovial inflammation that leads to joint destruction and disability (1-3). RA is characterized by the production of rheumatoid factor (RF) and autoantibodies, which contribute to increased functional disability and morbidity (1).

Recent evidence suggests that RA has a broader impact on the body’s systems beyond the joints, particularly on cardiovascular health (4-8). Compared to the general population, individuals with RA have a significantly increased risk of developing cardiovascular conditions, such as heart failure and atherosclerosis (4-8). This is concerning as heart disease remains a significant contributor to the morbidity and mortality of RA patients (4-8).

One emerging factor that has piqued interest in the realm of cardiovascular risk in RA is epicardial adipose tissue (EAT) (4-8). EAT is the layer of fat that surrounds the heart and is actively involved in metabolic processes (4-8). EAT is also crucial in the release of pro-inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-𝛼), and resistin, which are associated with the development of RA and its cardiovascular complications (5-8).

Recent research has indicated that the association between EAT and increased cardiovascular risks in RA patients is becoming a growing concern (4-8). The data suggests that EAT may serve both as a marker and a contributor to cardiovascular conditions associated with RA by potentially promoting a subtle form of atherosclerosis and cardiac muscle dysfunction (4-8). This is concerning because the nature of RA is such that systemic inflammation often coincides with local inflammation in the EAT region (4-8).

The measurement of EAT thickness may facilitate the early detection of cardiovascular issues in patients with RA, potentially allowing for more effective management of the health problems associated with this condition (4-8). Exploring the significance of EAT in RA could unveil innovative treatment approaches aimed at mitigating the risks of heart disease and metabolic disorders; such insights could also pave the way towards improving the overall long-term health and quality of life of patients with RA (4-8). The aim of this review is to identify the role of EAT as a predictive and potential therapeutic tool of cardiovascular complications in RA patients. We present this article in accordance with the Narrative Review reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-25-73/rc).

Methods

This narrative review was conducted by curating data from previously published manuscripts evaluating the role of EAT as a cardiometabolic biomarker guiding diagnostic and therapeutic interventions in the RA patient population. An extensive search of PubMed, Google Scholar, and Embase was performed from July 2024 to June 2025. A search strategy with the following free text search terms (title/abstract) was enlisted: epicardial, rheumatoid arthritis, adipose, fat, cardiovascular risk, cardiovascular morbidity, and cardiometabolic comorbidities. A detailed search strategy can be identified in Table 1. Qualitative and quantitative data were extracted and appraised to determine the significance and clinical utility.

Discussion

EAT and cardiovascular dysfunction in RA

EAT is the adipose tissue between the myocardium and the visceral pericardium. It functions like a neuroendocrine organ that undergoes changes with age and is susceptible to pathological conditions (9). Its location is an important factor in the pathogenesis of cardiovascular diseases (CVDs). The left atrial EAT produces proteins with pro-arrhythmogenic effects that increase the likelihood of atrial fibrillation (AF), the coronary EAT produces pro-inflammatory cytokines that elevate the risk of coronary artery disease (CAD), and the ventricular EAT has fibrotic as well as infiltrative effects on the myocardium causing heart failure with preserved ejection fraction (HFpEF) (9-11). Additionally, studies have shown that patients with AF, CAD, and HF have a greater EAT thickness than the general population (10,11).

Several studies have shown that RA patients exhibit a greater thickness of EAT compared to healthy individuals (12-15). Additionally, Patients with RA are at a 50% to 70% higher risk of CVDs compared to the general population (16). Numerous studies describe a significant association between RA, its disease activity, and CVDs, including CAD, HFpEF, and AF (12,16,17).

A recent study by Wang et al. reported a notable association between EAT thickness and global longitudinal strain (GLS) which is a measure of left ventricular (LV) systolic function (lower GLS values represent weaker ventricular systolic function), in RA patients (13). Expanding on the finding by Wang et al. (13) that greater EAT thickness accompanies a less negative (i.e. worse) GLS in RA cohorts, four complementary, recently described mechanisms explained this anatomical-functional link. First, inflammatory-fibrotic signaling: multi-omics and positron emission tomography and computed tomography (PET/CT) data show that hypertrophic EAT upregulates IL-6, TNF alpha, matrix metallopeptidase-9 (MMP-9), and SERPINE 1, and this cytokine flux diffuses into the subjacent myocardium, driving interstitial collagen deposition that preferentially weakens the longitudinal subendocardial fibers measured by GLS (18,19). Second, Cardio-lipotoxic stress: lipidomic profiling demonstrates that expanded EAT releases ceramides and other toxic intermediates that induce mitochondrial oxidative stress and contractile inefficiency, blunting longitudinal shortening (20). Third, pericardial mechanical restraint: invasive hemodynamic mapping confirms that the bulky EAT clouds the fixed pericardial space, elevates transmural pressures, and independently reduces longitudinal strain, even when ejection fraction is preserved (21). Fourth, coronary microvascular and macrovascular ischemia: Fully automated computed tomography (CT) analysis in asymptomatic aortic stenosis patients shows that larger EAT volumes correlate with higher troponin release, greater LV mass, and less negative GLS despite non-obstructed epicardial arteries, implicating diffuse ischemic injury as an additional contributor (22). Taken together, these inflammatory, metabolic, mechanical and ischemic pathways provide a biological rationale for the EAT-GLS relationship originally reported by Wang.

This also corroborates with the findings of Van Worden et al., who, in their study, explored the relationship between EAT thickness and heart failure (23). Furthermore, Wang et al. and Fatma et al. suggest that a higher EAT volume is linked to CAD risk (13,14), and several studies using CT and PET/CT imaging have strengthened these findings by reporting significant associations between EAT thickness and the risk and severity of CAD (19,24,25). This may be attributed to the pro-inflammatory EAT secretome (13,14).

In addition, studies have suggested that EAT thickness has a strong negative correlation with LV diastolic function (9), with its effect being three-fold: First, it is a source of fatty acids and lipids, which, when excessive, lead to ectopic myocardial lipid accumulation. Second, the large fibrotic fat pad may impede the diastolic relaxation of the myocardium. Third, the inflammatory proteins released by EAT may cause fibrosis and further worsen diastole (9). These pathophysiologic explanations are congruent with the observations by Fatma et al., who reported a positive correlation between EAT thickness and LV wall thickness (or diastolic dysfunction), measured using E/e’ (ratio of early diastolic mitral peak velocity and early diastolic myocardial velocity) and E/A (ratio of early diastolic mitral peak velocity and late diastolic mitral peak velocity) echocardiographic parameters (14). Additionally, Alpaydin et al. indicated that the disease activity score for 28 joints (DAS-28) may further contribute to the EAT thickness in RA patients and the associated LV diastolic dysfunction (15).

EAT as a biomarker in RA

EAT, also referred to as epicardial fat thickness (EFT), has emerged as a critical biomarker in RA. Several studies have emphasized the role of EAT as an early indicator of subclinical atherosclerosis and cardiovascular involvement in RA patients, providing insight into systemic inflammation and associated cardiometabolic risks (26-29).

Cross-sectional studies consistently demonstrate significantly increased EFT in RA patients compared to healthy controls. Delkash et al. reported a mean EFT of 5.22±2.6 mm in RA patients versus 5.22±2.06 mm in healthy controls, with a statistically significant P value (<0.001). In their study, EFT was positively correlated with RF, anti-cyclic citrullinated peptide (anti-CCP), erythrocyte sedimentation rate (ESR), and systolic blood pressure (26). Ekinci et al. observed a strong positive correlation between EFT and serum chemerin levels in RA patients with high disease activity (r=0.73, P=0.046), further linking EAT to systemic inflammation and cardiovascular risk (27). Similarly, Keleşoğlu Dinçer et al. reported an independent association between EFT and disease activity indices such as the DAS28 and the Simple Disease Activity Index (SDAI), with the SDAI showing the strongest association (odds ratio, 13.70; 95% confidence interval: 3.88–48.43; P<0.001). Their study identified a cutoff value of 6.4 mm for EFT, above which patients exhibited significantly higher disease activity and CVD risk (28).

The role of EAT as an inflammatory biomarker is further supported by Saha et al., who demonstrated significant correlations between EFT and RA disease activity markers such as ESR (r=0.62, P<0.01) and C-reactive protein (CRP) (r=0.53, P=0.002). Additionally, DAS28 was positively associated with EFT, underscoring the chronic inflammatory cascade’s role in cardiovascular risk (29).

The clinical utility of EFT lies in its potential to identify subclinical cardiovascular changes early in RA. Echocardiographic studies consistently reveal associations between increased EFT and structural cardiac abnormalities, such as increased LV mass and diastolic dysfunction (29). Low high density lipoprotein (HDL) levels and increased CRP further correlate with elevated EFT, suggesting that EFT serves as a surrogate marker of dyslipidemia and systemic inflammation in RA (26,28,29).

Given its inflammatory and cardiometabolic relevance, routine assessment of EFT via echocardiography in RA patients could provide valuable insights into cardiovascular risk stratification. Early detection of increased EFT might facilitate targeted therapeutic interventions, aiming to mitigate the CVD burden in this vulnerable population.

Inflammatory markers and EAT in RA

Research indicates that excessive visceral adiposity contributes to the pathogenesis of CVD, with RA patients being more likely to accumulate visceral adipose tissue compared to controls of similar body mass index (BMI) (30). A cross-sectional study examining the relationship between EAT and arterial stiffness in RA patients found that an increased arterial stiffness independently correlates with EAT, highlighting EAT’s role in RA-associated cardiovascular risk (30).

EAT also plays a role in the development of atherosclerosis in RA patients (4). A cross-sectional study by Lima-Martinez et al. evaluating EAT thickness in RA patients treated with biological and nonbiological disease-modifying antirheumatic drugs (DMARDs) identified a significant correlation between EAT thickness and plasma levels of high-sensitivity c-reactive protein (hs-CRP) (4). Furthermore, RA patients receiving TNF-𝛼 inhibitors had notably lower EAT thickness compared to those treated with nonbiological DMARDs, underscoring EAT’s role in RA-related inflammation (4).

Adipokines are secretory products of adipose tissue that play a key role in regulating immune and inflammatory responses; elevated levels of these adipokines are observed in chronic diseases such as RA, CVD, and chronic obstructive pulmonary disease (COPD) (31).

Among the adipokines, visfatin, a pro-inflammatory mediator, plays a significant role in immune regulation and inflammation, with high levels reported in conditions like diabetes, asthma, metabolic syndrome (MS), obesity, CVD, and autoimmune diseases (31). In a case-control study of 90 patients by Avesta et al., serum visfatin levels were significantly higher in those with stable angina pectoris (SAP), and especially in those with acute myocardial infarction (AMI) (31). The study also found a positive association between visfatin levels and EFT in both SAP and AMI groups (31).

Beyond EFT, serum biomarkers such as betatrophin, chemerin, and adropin have been explored in RA patients. Ekinci et al. highlighted decreased serum adropin levels (P<0.001) and increased chemerin levels (P=0.016) in RA patients, both of which correlated with higher EFT and disease activity. These findings suggest a potential link between EAT, systemic inflammation, and dysregulated metabolic pathways in RA (27).

Impact of disease activity and duration on EAT

RA patients have an increased risk of accelerated atherosclerosis (AS). AS is the most common cause of CVD-related mortality in these individuals. Several markers of AS, including EAT thickness, flow-mediated dilatation (FMD) of the brachial artery, and carotid intima-media thickness (CIMT), have been used to assess the AS risk profile of individuals with RA. Out of the three, EAT is the simplest (32).

Several studies have looked at the association of RA disease activity with EAT volume.

The measures of RA disease activity include DAS28, health assessment questionnaire (HAQ) disability index (DI), anti-CCP, RF, CRP, ESR, and disease duration or duration of treatment (32,33). Temiz et al., in a cross-sectional study, reported a positive correlation between EAT and HAQ score, CRP, ESR, and age of the patient. However, no significant correlation was found with DAS28, anti-CCP, and disease duration (32). These findings align with Ormseth et al.’s study, which reported no significant association of EAT volume with DAS28 score or RF (33). Another study by Karpouzas et al., explored a nuance of the relationship between EAT volume and RA disease activity. It reported that a disease duration of less than 10 years significantly influenced the effect of EAT volume on coronary plaque risk (34).

In the broader context, EAT is directly linked to visceral adiposity (35), which is strongly associated with physical inactivity. Additionally, although EAT is not associated with DAS28, it is positively correlated with HAQ-DI score (32), which is a marker of functional disability and physical inactivity in RA patients (36). This may suggest that physical inactivity may have a confounding effect on the relationship between HAQ-DI score and EAT thickness.

Furthermore, the association of EAT thickness with age and the lack of association between EAT thickness and disease duration may suggest that the higher EAT volume in RA patients may be more correctly attributed to the metabolic abnormalities and visceral obesity that are present at the onset of RA. This also explains why EAT thickness does not significantly increase with disease progression (32).

EAT as a cardiometabolic risk factor

EAT as a significant marker of cardiometabolic risk

In a study by Ormseth et al. where 162 RA patients were compared to 89 healthy controls, EAT volume correlated strongly with visceral adiposity measures, such as weight circumference (ρ=0.52, P<0.001), BMI (ρ=0.34, P<0.001), and waist/hip ratio (ρ=0.45, P<0.001), suggesting its close association with central obesity (33). Notably, EAT was independently associated with elevated triglycerides (ρ=0.25, P=0.004), homocysteine levels (ρ=0.31, P=0.001), and insulin resistance (ρ=0.32, P<0.001), while inversely associated with HDL cholesterol (ρ=−0.27, P=0.005) (33). These correlations persisted after adjustments of the circumference, reinforcing EAT’s role as a marker of metabolic dysfunction beyond traditional visceral fat metrics. RA patients with MS exhibited significantly higher EAT volumes (P<0.001), with each additional MS criterion being associated with a 20% increase in EAT volume (33).

EAT’s contributions appear distinct from systemic inflammation, as it exhibited only weak associations with IL-6 (ρ=0.19, P=0.03) (33). Although EAT is known to express inflammatory mediators like IL-6 and leptin at higher concentrations than subcutaneous fat, Ormseth’s study suggests that EAT’s systemic inflammatory contributions in RA are minimal. Instead, its role in MS and insulin resistance may stem from localized adipokine activity or other direct systemic effects (33).

Current epidemiological evidence confirms that RA inflammation alone raises the risk of myocardial infarction, stroke, and heart failure by almost 50% compared to the general population (5-8). Reflecting this intrinsic inflammatory baseline, the 2022 EULAR guidelines endorse a 1.5-fold multiplier when calculating Framingham-derived scores in patients with active or seropositive RA (37).

An imaging study revealed that an expanded epicardial fat depot confers an additional layer of risk that is not explained by systemic cytokine effects. In 139 RA patients, EAT volume correlated with noncalcified, lipid-rich coronary plaque. It remained an independent predictor of plaque burden after multivariable adjustment for age, sex, hypertension, diabetes, dyslipidemia, smoking, BMI, DAS-28, and CRP (34).

A 7-year follow-up of 100 RA subjects further demonstrated that high baseline EAT volume more than doubled the odds of developing new vulnerable plaques, even in patients with low traditional risk burden and low cumulative CRP (38).

This data supports a two-tiered model, systemic RA inflammation establishes a heightened starting point for cardiovascular events. In contrast, metabolically active EAT superimposes cardiometabolic and atherogenic insults via local adipokine release (39), lipotoxicity (20), and microvascular impairment (40).

EAT as a central mediator in heart failure

The significant role of EAT and HFpEF in the context of systemic inflammatory and metabolic disorders contributing to morbidity is increasingly being recognized. Studies consistently demonstrate that EAT is a structural entity and an active participant in the cardiac inflammatory milieu. Findings by Haykowsky et al. noted that increased central adiposity relates closely to exercise intolerance in older obese patients with HFpEF; thus, the functional impact of fat distribution and heart failure dynamics is a true phenomenon (41).

On the other side, van Woerden et al. highlighted that heart failure patients, regardless of the ejection fraction status, exhibit significant increases in EAT, which correlates with worsened heart failure symptoms (23). Similarly, Watanabe et al. identified a direct relationship between increased EAT thickness and early impairment of LV systolic function and HfpEF (42). Doesch et al. utilized cardiac MRI to ascertain the presence of EAT in patients with heart failure due to dilated cardiomyopathy, emphasizing broader implications of EAT across different heart failure subtypes, not only limited to HfpEF (43).

EAT in AF

Packer et al. delineated that EAT contributes to atrial structural and functional changes, leading to AF (44). EAT expansion and inflammation cause coronary microvascular dysfunction and fibrosis of the left atrium, causing left atrial myopathy with increased chamber stiffness and blood stasis, which leads to AF, pulmonary venous hypertension, and thromboembolic stroke.

Since the epicardium and myocardium are connected through an unobstructed microcirculation, any biological derangement in epicardial fat is readily transmitted to the underlying myocardial tissue via secretion of pro-inflammatory adipocytokines like TNF-𝛼, IL-1beta and IL-6; Nagashima et al. and Abe et al. also validate the above by linking EAT and pathophysiological substrates for AF in the adjoining atrial myocardium (45,46). Notably, the increase in epicardial fat volume is proportional to the clinical severity of the disease and the intensity of systemic inflammation; Nagashima et al. also stated there is a close association between the severity of electrical abnormalities in the adjacent myocardium and EAT (45).

Bos et al. stated that epicardial fat volume predicts the incidence of AF in the community, even in the absence of prior CVD (47). Oba et al. showed that EAT mass increases as AF involves from paroxysmal to persistent arrhythmia (48). Yao et al. also found that in RA patients, the left atrial diameter correlates with the EAT/BMI ratio and that these patients exhibit larger left atrial-EAT volume and higher left atrial EAT/total EAT ratio (49). The latter also found a higher stroke risk in RA patients with AF compared to non-RA patients with AF.

Specific EAT type assessment and clinical implication

Atrial EAT can be assessed by echocardiography, typically at the right atrioventricular groove, specifically the Rindfleisch fold. The latter shows strong correlation with cardiac magnetic resonance (CMR) and CT, along with high intra- and inter-observer reproducibility (50).

Ventricular EAT is measured as the thickness over the right ventricular free wall using parasternal long and short axis views. This echocardiographic method is reproducible and correlates well with EAT volume on MRI and CT. CT-based measurement is also an alternative (51,52).

Coronary EAT is best evaluated by cardiac CT, which enables 3D assessment of adipose tissue volume and attenuation around the coronary arteries (53,54).

The integration of EAT assessment into routine imaging is supported by strong clinical evidence (9,53). Elevated atrial EAT is linked to increased AF risk and supports improved AF risk stratification in the clinical setting (55,56). Ventricular EAT is associated with LV hypertrophy, remodeling, and diastolic dysfunction, making it relevant for MS and heart failure risk assessment (51,57). Coronary EAT reflects coronary inflammation and plaque vulnerability, offering a non-invasive prognostic value for major cardiovascular events and guiding preventive strategies in high-risk patients (58,59).

Therapeutic implications of EAT in RA

In RA, EAT contributes to enhanced risk by promoting atherosclerosis through additional mechanisms. Temiz et al. demonstrated that RA patients have significantly thicker EAT, which correlates with increased CIMT (r=0.52, P<0.001), suggesting its utility in the early identification of subclinical atherosclerosis (32).

FMD is a noninvasive technique that measures the dilation of an artery, particularly the brachial artery, as blood flow increases. Dilation results primarily from the release of nitric oxide by the endothelium, the inner lining of blood vessels (60). FMD is widely used to assess endothelial function, providing insights into the health of the vascular system, especially regarding endothelial integrity and its response to stressors like ischemia. The assessment involves temporarily restricting blood flow with the cuff and then measuring the artery’s dilation response when the cuff is released, which induces reactive hyperemia–a rapid increase in blood flow. Kocaman et al. demonstrated that EAT is an independent factor associated with adverse changes in FMD, indicating that increased EAT thickness correlates with impaired endothelial function, which is crucial for vascular health (61). This aligns with the assertion that reduced FMD is indicative of endothelial dysfunction, potentially leading to atherosclerosis. Thus, it is important to monitor EAT and cardiovascular risk assessments, particularly in high-risk populations such as RA, and there is a need for targeted therapies to mitigate vascular complications.

Studies by Chang et al. and McKenney-Drake et al., where the removal of EAT post-myocardial infarction led to improved cardiac function and arrested coronary atherogenesis, suggest that reducing EAT could mitigate the inflammatory impact on the myocardium and improve overall cardiac outcomes (62,63).

EAT acts as a source of inflammatory cytokines that contribute to the pathogenesis of atherosclerosis and is supported by broader research. For instance, Bachar et al. showed EAT thickness associated with the presence and severity of CAD (64).

Therapeutic implications

• Anti-inflammatory therapies: Temiz et al. found that EAT correlates with systemic inflammatory markers like CRP (r=0.32, P<0.001) and ESR (r=0.21, P=0.007), further strengthening the premise that controlling systemic inflammation may indirectly reduce EAT (32). In a study by Szeremeta et al., a beneficial effect of anti-TNF alpha therapy on cell surface heparin sulfate proteoglycan’s (HSPGs) to heparan sulfate (HS) turnover and endothelial dysfunction was observed, manifested by a decrease in blood HSPG/HS levels and other markers of endothelial activation such as circulating vascular adhesion molecule-1 (sVCAM-1), monocyte chemoattractant-1 (MCP-1), MMP-9 (65). Thus, anti-inflammatory treatments already used in RA could reduce EAT thickness and cardiovascular impact by mitigating inflammation, and further research is needed to clarify the direct effects.
• Lifestyle modifications: encouraging physical activity and dietary restrictions could help reduce EAT. Physical inactivity, as reflected in the correlation between EAT and HAQ scores (r=0.17, P=0.009), further implicates lifestyle interventions as adjunctive therapies. Even Giles et al. showed physical inactivity associated with increased EAT leads to worse outcomes (66).
• Metabolic interventions: Gunes et al. found that metformin could decrease EAT in obese children, suggesting potential application in adults with RA, especially in those with MS features (67).
• Direct targeting of EAT: this includes localized therapeutic interventions, anti-adiposity therapies, and novel pharmacological agents. A meta-analysis including five studies confirmed that exercise training reduced epicardial fat deposition (68). Several studies have reported that bariatric surgery substantially reduces the accumulation of EAT in patients (69,70). Bao et al. showed that sodium-glucose cotransporter 2 inhibitor (SGLT2i) have a distinct advantage over both placebo and other therapies in lowering EAT thickness (71).
• Future research and clinical implications: the strong correlation between EAT, CIMT, and FMD in Temiz’s study (32) of RA patients relays that EAT is a therapeutic target. A study by Cetin et al. showed that increased EAT may be associated with diastolic dysfunction and left atrial dilatation due to local or systemic effects in untreated hypertensive patients (72). A different study by Temiz et al. found that RA patients with hypertension exhibited significantly increased EAT and CIMT, alongside impaired diastolic dysfunction compared to those without hypertension. Thus, hypertension may amplify the inflammatory and atherosclerotic process mediated by EAT (73). Mice studies done by Mitchell et al. showed that inhibition of the renin-angiotensin system reduces gene expression of inflammatory mediators in adipose tissue (74). Thus, ACE inhibitors and ARBs could reduce EAT and CIMT, mitigating atherosclerosis risk. Further human-based data is needed, but this explores the possibility of adequate blood pressure control in RA to improve prognosis. Based on these findings, clinicians should consider echocardiographic evaluation of EAT in RA patients as part of comprehensive risk management. Longitudinal studies are required to see if interventions or reducing EAT can improve outcomes in this high-risk population.

Future directions

Our study aimed to draw significant conclusions from various studies. Initially, Lima Martinez et al. revealed significant findings regarding the health of patients with RA (4). It was discovered that these individuals exhibit thicker EAT when compared to those without the disease, a difference that persisted regardless of BMI or waist circumference (WC). This suggests that traditional factors such as obesity and MS do not play a role in influencing the relationship between EAT and RA. The observed increase in EAT likely points to a higher presence of visceral fat that is not connected to MS or obesity and may be associated with the use of glucocorticoids among RA patients (4).

According to Ormseth et al., the connection between EAT and WC was more pronounced than that with BMI in RA patients (33). It became clear that the increased EAT volume stems largely from higher levels of visceral fat, which correlates with larger waist measurements in these individuals. The relationship between EAT volume and hypertension, along with triglycerides, solidified an inverse link with HDL levels, corroborating similar findings in both RA and the broader population concerning visceral obesity. Notably, a significant association was identified between EAT volume and smoking, suggesting that smoking habits may exacerbate the accumulation of visceral fat, specifically EAT. Moreover, greater EAT volumes were associated with elevated Homeostasis Model Assessment (HOMA) scores, indicating increased insulin resistance among these individuals (33).

In a related exploration, Senolt et al. conducted research that highlighted the effects of etanercept, a TNF-𝛼 inhibitor, used in the treatment of RA (75). Their findings showed that etanercept not only raised levels of leptin, a hormone involved in regulating energy balance, but also decreased adiponectin levels in the subcutaneous fat of RA patients, further complicating the picture of adipose tissue in this population (75). Additionally, Renzo et al. observed that patients suffering from psoriasis and who were treated with TNF-𝛼 inhibitors experienced notable increases in fat mass, reported as 8.6% and 8.9% (76). However, this study did not differentiate between subcutaneous and visceral adipose tissue, which differ in their embryologic origin and metabolic functions. Interestingly, it has also demonstrated that inflammation and heightened immune cell activity are more pronounced in EAT compared to subcutaneous fat, establishing a strong association between elevated plasma TNF-𝛼 levels and immune cell activity in EAT (76).

Furthermore, Goldfine et al. showcased that utilizing a nuclear factor kappa-light-chain-enhancer of activated B cells inhibitor (NF-𝜅Bi) could effectively lower blood sugar levels in individuals diagnosed with type 2 diabetes, implying a potential pathway for TNF-𝛼 inhibitors to reduce EAT thickness by alleviating inflammation and enhancing insulin sensitivity in adipose tissues (77).

When it comes to the potential implication of EAT in cardiovascular dysfunction, Delkash et al. delved into the relationship between EFT and its link with age, lipid profiles, and the presence of specific markers such as RF and anti-CCP antibodies in RA patients (26). It became evident that elevated EFT is linked to increased systolic blood pressure and a heightened cardiovascular risk, positioning positive antibody status as a potential indicator of early-stage atherosclerosis. The chronic inflammation associated with RA may contribute to an increase in fat cell formation within epicardial tissues. Overall, the study highlighted that higher EFT serves as a predictive measure for cardiovascular events, emphasizing the urgent need for thorough cardiovascular assessments among RA patients (26). This necessitates further exploration into whether autoimmune factors may underpin cardiac health in this demographic.

Karpouzas et al. expanded on these themes, revealing that the EAT volume (EATV) is distinctly higher in RA patients who also have coronary atherosclerosis compared to their counterparts without the disease (34). The interaction between RA and EATV significantly influences various plaque outcomes, showcasing a unique relationship intimately linked to RA. Adjustments for confounding variables indicated that a higher EATV correlated with an increased likelihood of multivessel or obstructive disease, as well as a greater number of plaque segments in RA patients, contrasting sharply with observations made in control groups. This suggests a more profound dysfunction of EAT in RA, which could contribute to the development of atherosclerosis within coronary arteries. Notably, EATV was associated specifically with noncalcified and high-risk plaques in RA patients, further complicating the picture of cardiometabolic risk. Additionally, expressions of TNF-𝛼 and IL-1β in EAT were correlated with noncalcified, mixed, and vulnerable plaques, but not with calcified plaques, indicating the need for further investigation regarding the role of EAT in active atherosclerosis and whether it serves as a catalyst for the disease or merely a resultant factor (34).

In another significant study conducted by Avesta et al., researchers explored the expression of visfatin within the epicardial and abdominal adipose tissue of patients diagnosed with CAD (31). They discovered that visfatin levels were substantially higher in these patients compared to control subjects, and this elevation was correlated with the severity of CAD. The study uncovered an independent relationship between visfatin levels and key biomarkers such as white blood cell (WBC) counts and creatine kinase-MB (CK-MB) levels in patients facing AMI and SAP. Additionally, the research established connections between visfatin levels and various important markers, including EFT, IL-6 levels, troponin-T levels, the Gensini score, and left ventricular ejection fraction (LVEF). While no direct causal link between visfatin and CAD in AMI patients was confirmed, the findings imply that visfatin could play a role in the underlying mechanisms of CAD, suggesting that adipokines should be evaluated from both systemic and local perspectives in CAD pathophysiology (31).

Given the heightened risk of CVD in RA patients, elevated chemerin and reduced adropin levels may play a substantial role in this concerning health trend, warranting further exploration into these biomarkers to inform prevention and treatment strategies, as highlighted by Ekinci et al. (27).

The intricacies of how RA impacts the left ventricle remain partially obscured, yet it is also linked with elevated levels of inflammatory cytokines, particularly TNF-𝛼, which are known to induce alterations in heart structure over time. This underscores the necessity for further studies to determine how echocardiographic EAT thickness could enhance our understanding of cardiometabolic risk stratification in patients with RA. Monitoring EFT in RA patients can provide critical insights into cardiovascular risk, potentially facilitating early intervention strategies.

Conclusions

In conclusion, EAT is emerging as a crucial marker of cardiometabolic risk in patients with RA. Multiple studies underscore its association with inflammation, disease activity, cardiovascular dysfunction, and atherosclerosis. As EAT is modifiable with treatment, it represents both a predictor of risk and a potential therapeutic target for reducing cardiovascular complications in RA patients. Further research is necessary to understand its pathophysiological role better and to refine therapeutic strategies targeting EAT. Long-term prospective trials are needed to establish causal relationships between EAT, inflammatory markers, and RA.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-25-73/rc

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Funding: None.

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