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. 2026 Feb 26;21(2):e0343831. doi: 10.1371/journal.pone.0343831

The association between epicardial adipose tissue thickness and diabetes mellitus, hyperlipidemia, hepatosteatosis, pancreatic steatosis and pancreatitis

Ece Zengin 1, Aybuke Ucgun 1, Mehmet Emir Çevik 2, Sehnaz Evrimler 1,*, Ihsaniye Suer Dogan 1
Editor: Eyüp Serhat Çalık3
PMCID: PMC12944748  PMID: 41746929

Abstract

Background

Epicardial adipose tissue (EAT) is associated with cardiometabolic disorders such as diabetes mellitus (DM), hyperlipidemia, and nonalcoholic fatty liver disease. However, its potential relationship with pancreatic steatosis and pancreatitis remains unclear, and existing studies offer inconsistent findings. Therefore, a clearer understanding of whether EAT reflects broader systemic ectopic fat burden or inflammatory processes is needed.This study evaluated the relationships between EAT thickness and DM, hyperlipidemia, hepatosteatosis, pancreatic steatosis, and pancreatitis.

Methods

This retrospective, single-center study included 200 patients who underwent abdominal CT between 2022 and 2024. EAT thickness was measured at the mid-RCA and LAD levels, and subcutaneous fat was measured at the umbilical level. Liver and pancreatic steatosis were assessed with CT or MRI. Demographic and clinical data (age, gender, LDL cholesterol, diabetes, and history of pancreatitis) were collected. Mann-Whitney U, Spearman correlation, and logistic regression were used in analyses; p < 0.05 was considered significant.

Results

Of the 200 patients, 31.4% had diabetes, 42% had hepatosteatosis, and 73.5% had a history of pancreatitis. EAT and subcutaneous fat were significantly higher in women at all levels (p < 0.05). Diabetes was associated with increased EAT in both the RCA (p = 0.002) and the LAD (p = 0.001). In multivariate analysis, RCA-EAT (OR=1.18, p = 0.002) and age (OR=1.03, p = 0.003) were significantly associated with diabetes. High LDL was associated with LAD-EAT (p = 0.030). For pancreatitis, multivariate analysis identified pancreatic steatosis (OR=5.78, p < 0.001) and LAD-EAT (OR=1.52, p = 0.002) as variables significantly associated with a history of pancreatitis.

Conclusions

EAT thickness is significantly associated with DM, LDL cholesterol, pancreatitis history, and age, supporting its role as a potential imaging biomarker of cardiometabolic risk. These findings suggest that EAT may serve as an imaging marker of broader metabolic and inflammatory burden, supporting its relevance for cardiometabolic risk assessment.

Introduction

Epicardial adipose tissue (EAT) represents a metabolically active visceral fat layer located between the myocardium and the visceral layer of the pericardium, mainly in the atrioventricular and interventricular grooves and surrounding the coronary arteries. Increased EAT thickness has emerged as an independent indicator in the development of cardiovascular diseases. In obesity, insulin resistance, diabetes mellitus (DM), and vascular injury, EAT promotes inflammatory cell recruitment to the arterial wall, fostering a proinflammatory environment and chronic vascular remodeling [1]. Growing evidence also links EAT with obesity, hepatosteatosis, DM, and LDL cholesterol [2], highlighting its relevance beyond cardiovascular disease.

Hepatosteatosis (HS), considered a marker of total body fat, is part of the non-alcoholic fatty liver disease (NAFLD) spectrum and can be quantified with high accuracy using multi-detector computed tomography (MDCT). Yet, the association between EAT and HS remains inconclusive [3]. In diabetes, EAT correlates with obesity, fasting glucose, insulin resistance, and adiponectin levels, and is consistently elevated in both Type 1 and Type 2 DM [1]. Furthermore, greater EAT thickness has been associated with higher LDL cholesterol concentrations in hyperlipidemic patients, underscoring its dual impact on cardiovascular pathogenesis and lipid metabolism [4].

Excess fat accumulation in other visceral depots also contributes to metabolic disease. Pancreatic fat deposition impairs insulin secretion and aggravates metabolic dysfunction [5], while visceral adiposity is a known determinant of severity and prognosis in acute pancreatitis [6]. Although EAT is anatomically located around the heart, it functions as an active visceral fat depot that secretes proinflammatory cytokines (IL-6, TNF-α, MCP-1) and strongly correlates with total visceral adipose tissue. This shared inflammatory and metabolic pathway makes it biologically plausible that increased EAT thickness may reflect a broader systemic ectopic fat burden, including liver and pancreatic fat accumulation. However, the relationships between EAT and pancreatic fat or pancreatitis history have not been systematically examined, and existing studies provide inconsistent findings regarding its association with hepatosteatosis. This gap limits our understanding of whether EAT represents only a cardiac fat marker or a more general indicator of metabolic organ involvement. Therefore, we aimed to investigate the associations between EAT thickness and hepatosteatosis, diabetes mellitus, LDL cholesterol, pancreatic fat, pancreatitis history, and subcutaneous abdominal fat. We hypothesized that greater EAT thickness would be positively associated with these metabolic parameters, reflecting its potential role as a marker of systemic ectopic fat accumulation.

Methods

This is a single-center, institutional review board approved study. This retrospective study was approved by the Ankara Etlik City Hospital Scientific Research Evaluation and Ethics Committee. Written informed consent was obtained from all participants for the use of their anonymized medical records for research purposes. All participants were aged over 18 years, and all data were fully anonymized prior to analysis with no access to identifying personal information during or after data collection. Epicardial fat tissue thickness was measured in patients who were admitted to our hospital as outpatients or inpatients and underwent abdominal CT/MRI between 1 December 2022 and 1 December 2024, and the relationship between pancreatic fat, the presence of DM, the presence of high LDL cholesterol, hepatosteatosis, and pancreatitis attacks were evaluated retrospectively. Given that one of the predefined objectives of this study was to evaluate the association between EAT thickness and pancreatitis, patients undergoing abdominal CT/MRI due to a clinical suspicion of pancreatitis were purposefully included in the study cohort. Patients were included if imaging quality was sufficient and if clinical data regarding diabetes mellitus (DM), LDL cholesterol, hepatosteatosis, subcutaneous abdominal fat, and pancreatitis history were available; those with prior cardiac surgery altering pericardial anatomy, malignancy involving the liver or pancreas, severe motion artifacts, or missing clinical or laboratory information were excluded. We accessed the medical records between 01/02/2025 and 06/05/2025 for data extraction.

Epicardial fat tissue thickness was measured by calculating the maximum thickness perpendicular to the heart surface from the myocardium to the visceral pericardium, measured in one axial plane, corresponding to the middle portion of the right coronary artery (RCA) and the lateral aspect of the left anterior descending coronary artery (LAD) (Fig 1). HS was calculated based on liver HU values obtained by drawing a region of interest (ROI) in patients undergoing CT. Hepatosteatosis was defined as a liver attenuation of at least 10 HU lower than the spleen attenuation on unenhanced CT, a liver attenuation of less than 40 HU, or a liver attenuation of 15 HU lower than the spleen (Fig 2). On contrast-enhanced CT, a liver-spleen differential attenuation (liver HU–spleen HU) in the portal venous phase of −20 HU to −43 HU, depending on the injection protocol, was considered to be the presence. In patients with available MRI, hepatosteatosis was categorized based on the presence of fat suppression on chemical shift (in-out of phase) sequences. The amount of pancreatic fat was calculated using density measurements from the head, body, and tail of the pancreas on CT scans, and subjective categorization of fat was also performed (Fig 3). Measurements were performed by two radiologists. Because ectopic fat distribution may be influenced by demographic characteristics, age and sex were recorded for all participants to allow appropriate interpretation of potential confounding effects.

Fig 1. a. Epicardial adipose tissue thickness was measured by calculating the maximum thickness perpendicular to the surface of the heart, from the myocardium to the visceral pericardium, at a single axial section level—specifically at the atrioventricular groove at the mid-third of the right coronary artery (RCA) and adjacent to the left anterior descending coronary artery (LAD). B. Umbilical fat tissue thickness was measured at umbilicus level perpendicular to rectus muscle anteriorly.

Fig 1

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Fig 2. a. Hepatic steatosis was assessed by measuring liver attenuation values (in Hounsfield Units, HU) on CT scans using regions of interest (ROIs) drawn within the liver parenchyma. b and c. On dual-echo sequences, the out-of-phase image (c) demonstrates a signal reduction relative to the in-phase image (b).

Fig 2

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Fig 3. Pancreatic fat content was also assessed on CT by measuring attenuation values in the head (a), body (b), and tail (c) regions of the pancreas.

Fig 3

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Statistical analysis

All analyses were conducted using IBM SPSS Statistics, version 26 (IBM Corp., Armonk, NY, USA). Continuous variables were summarized as mean ± standard deviation (SD) and median (range), while categorical variables were expressed as frequency (n) and percentage (%). The Shapiro–Wilk test was applied to assess the normality of data distribution. For comparisons between two independent groups with non-normally distributed data, the Mann–Whitney U test was utilized. Associations between continuous variables were evaluated using Spearman’s rank correlation. To explore factors related to clinical outcomes, both univariate and multivariate binary logistic regression models were performed. Variables with a significance level of p < 0.05 in the univariate analysis were entered into the multivariate model.. All measured variables were included in the univariate regression analyses, and only those that reached statistical significance were subsequently carried forward into the multivariate model to avoid overfitting. Age and sex were retained in the model regardless of univariate significance because they represent established clinical confounders influencing adipose tissue distribution and metabolic outcomes. Logistic regression results were presented as odds ratios (OR) with 95% confidence intervals (CI). A p-value below 0.05 was considered statistically significant in all analyses.

Results

Study population characteristics

The study population consisted of 200 retrospectively evaluated patients. The mean age of the participants was 54.69 ± 16.61 years, and 54.5% were female (n = 109) and 45.5% were male (n = 91). LDL cholesterol levels were found to be high in 59.6% of the participants (n = 84), and normal in 40.4% (n = 57).

Epicardial adipose tissue (EAT) thickness measurements performed on CT scans revealed a median thickness of 3.01 mm (min: 1.03 – max: 10.40 mm) at the LAD level and a median of 9.44 mm (min: 4.06 – max: 27.17 mm) at the RCA level. The median subcutaneous adipose tissue thickness measured at the umbilicus level was 24.44 mm (min: 4.31 – max: 62.12 mm).

The median density values measured from the head, body and tail sections of the pancreatic tissue were found to be 52.5 HU in the head section, 54 HU in the body section and 55 HU in the tail section.

Overall, 31.4% of the participants had a history of diabetes mellitus (DM) (n = 59), 42% had a history of hepatosteatosis (n = 84), and 73.5% (n = 147) had a history of pancreatitis.

EAT thickness and sex differences

In the comparison between genders, epicardial fat thickness was found to be significantly higher in females than in males at all measurement levels. At the RCA level, the median thickness was 8.84 mm in males and 9.92 mm in females (p = 0.001). At the LAD level, these values were 2.91 mm and 3.09 mm, respectively (p = 0.017). At the umbilicus level, the median subcutaneous fat tissue values were found to be 20.61 mm and 29.54 mm, respectively, with statistical significance (p < 0.001; see Table 1).

Table 1. Comparison of EAT and subcutaneous fat thickness across key metabolic and clinical variables.

Variables EAT thickness at RCA level (median(min-max)) p value EAT thickness at LAD level (median(min-max)) p value Subcutaneous fat at umbilical level (median(min-max)) p value
Sex
Male 8.84(4.06-16.49) 0.001 2.91 (1.03-6.71) 0.017 20.61(4.31-57.97) <0.001
Female 9.92(4.29-27.17) 3.09 (1.25-10.40) 29.54(4.46-62.12)
Presence of DM
Absent 9.11(4.06-18.07) 0.002 2.79(1.03-8.90) 0.001 26.23(4.31-62.12) 0.531
Present 10.44(4.24-27.17) 3.21(1.63-10.40) 24.40(9.45-59.06)
Hepatic steatosis
Absent 9.07(4.06-23.53) 0.163 3.05(1.06-7.60) 0.740 25.23(4.31-62.12) 0.849
Present 9.80(4.29-27.17) 2.99(1.03-10.40) 24.26(9.45-55.44)
LDL value
Normal 8.93(5.35-14.59) 0.235 2.59(1.06-4.83) 0.030 23.10(4.31-56.47) 0.290
High 9.43(4.06-15.16) 3.07(1.12-5.36) 26.30(9.45-62.12)
Pancreatic steatosis
Absent 9.00(5.58-21.54) 0.484 3.19(1.06-8.92) 0.134 22.37(4.46-43.99) 0.131
Present 9.44(4.06-27.17) 2.97(1.03-10.40) 25.85(4.31-62.12)
History of pancreatitis
Absent 8.42(4.06-27.17) 0.419 3.21(1.44-10.40) 0.001 21.76(8.24-59.06) 0.024
Present 9.45(5.35-21.54) 2.93(1.03-8.92) 26.50(4.31-62.12)
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Mann-Whitney U test. (EAT: epicardial adipose tissue).

EAT and diabetes mellitus

A significant difference was found between the presence of DM and EAT thickness. EAT thickness measured at the RCA level was greater in those with DM (median: 10.44 mm vs. 9.11 mm; p = 0.002). A similar significant difference was observed at the LAD level (p = 0.001). Subcutaneous adipose tissue thickness at the umbilical level did not differ significantly between patients with and without DM (p = 0.531; Table 1). In univariate and multivariate logistic regression analysis, LAD- and RCA-EAT thickness were significant univariate predictors of DM. In multivariate analysis, only age (OR = 1.03) and RCA-EAT (OR = 1.18) remained significantly associated with diabetes (Table 2).

Table 2. Univariate and multivariate logistic regression analysis for predictors of diabetes mellitus.

Variables Univariate Multivariate
OR (95% CI) p OR (95% CI) p
EAT thickness at LAD level 1.43 (1.14–1.80) 0.002 – –
EAT thickness at RCA level 1.21 (1.08–1.34) 0.001 1.18 (1.06–1.32) 0.002
Subcutaneous fat at umbilical level 0.99 (0.96–1.02) 0.584 – –
Age 1.04 (1.02–1.06) 0.001 1.03 (1.01–1.06) 0.003
Sex 0.62 (0.33–1.17) 0.141 – –
Pancreatic steatosis 0.52 (0.20–1.36) 0.183 – –
LDL elevation 0.49 (0.23–1.05) 0.066 – –
Hepatosteatosis
 0.80 (0.43–1.49) 0.478 – –
History of pancreatitis 1.34 (0.67–2.68) 0.415 – –
Pancreatic head density 0.99 (0.98–1.01) 0.832 – –
Pancreatic body density 1.00 (0.99–1.01) 0.983 – –
Pancreatic tail density 1.00 (0.99–1.01) 0.953 – –
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EAT: Epicardial adipose tissue; OR: Odds ratio; CI: Confidence interval.

EAT and Hepatosteatosis.

There was no statistically significant association between hepatosteatosis and either EAT thickness or subcutaneous fat at the umbilical level (p > 0.05) (Table 1).

EAT and LDL cholesterol

The relationship between LDL values and EAT distributions of LAD levels was statistically significant (p = 0.030). However, there was no significant difference in RCA-EAT thickness and subcutaneous fat thickness between participants with normal or elevated LDL levels (p = 0.235 and 0.290, respectively) (Table 1).

EAT and pancreatic steatosis/pancreatic density

No significant association was observedbetween pancreatic steatosis and EAT thickness at either the RCA or LAD levels (p > 0.05), and subcutaneous adipose tissue measurements at the umbilical level were also comparable between groups (Table 1). Similarly, pancreatic density values (head, body, or tail) were not associated with EAT thickness at either the RCA or LAD levels (p > 0.05) (Table 3). Subcutaneous fat also showed no significant correlation with pancreatic density (Table 3).

Table 3. Correlation of EAT thickness with age and pancreatic density measurements.

Variables EAT thickness at RCA level EAT thickness at LAD level Subcutaneous fat at umbilical level
r p r p r p
Age 0.161 0.022 0.321 <0.001 −0.188 0.008
Pancreatic head density −0.035 0.627 0.005 0.944 −0.128 0.071
Pancreatic body density −0.043 0.547 0.009 0.899 −0.114 0.107
Pancreatic tail density −0.016 0.824 0.036 0.617 −0.076 0.286
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Spearman correlation test. (EAT: Epicardial adipose tissue).

EAT and age

Correlation analysis demonstrated that age showed a weak but statistically significant positive correlation with EAT thickness at both the RCA (r = 0.161, p = 0.022) and LAD levels (r = 0.321, p < 0.001), indicating an age-related increase in epicardial adiposity (Table 3). Age also showed a weak but statistically significant negative correlation with subcutaneous adipose tissue thickness (r = –0.188, p = 0.008) (Table 3).

EAT and pancreatitis history

We then evaluated the relationship between EAT and pancreatitis history, an important exploratory aim of the study. Patients with a history of pancreatitis had significantly higher LAD-EAT thickness (p = 0.001) and greater umbilical subcutaneous fat (p = 0.024), although RCA-EAT thickness was not significantly different (Table 1).

In logistic regression, pancreatic steatosis (OR = 6.91), LAD-EAT thickness (OR = 1.62), and pancreatic density parameters were significant univariate predictors of pancreatitis history. In multivariate analysis, only pancreatic steatosis (OR = 5.78) and LAD-EAT thickness (OR = 1.52) remained significantly associated with diabetes (Table 4).

Table 4. Univariate and multivariate logistic regression analysis of factors associated with pancreatitis history.

Variables Univariate Multivariate
OR (95% CI) p value OR (95% CI) p value
EAT thickness at LAD level 1.62 (1.27–2.07) <0.001 1.52 (1.17–1.97) 0.002
EAT thickness at RCA level 1.04 (0.94–1.14) 0.456 – –
Subcutaneous fat at umbilical level 0.97 (0.94–0.99) 0.040 – –
Age 1.01 (0.99–1.03) 0.378 – –
Sex 0.87 (0.46–1.63) 0.657 – –
Pancreatic steatosis 6.91 (3.00–15.88) <0.001 5.78 (2.39–13.93) <0.001
LDL elevation 0.49 (0.23–1.05) 0.066 – –
Hepatosteatosis 0.86 (0.45–1.62) 0.631 – –
DM presence 1.34 (0.67–2.68) 0.415 – –
Pancreatic head density 1.02 (1.01–1.04) 0.006 – –
Pancreatic body density 1.02 (1.01–1.04) 0.009 – –
Pancreatic tail density 1.02 (1.01–1.04) 0.011 – –
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EAT: Epicardial adipose tissue; OR: Odds ratio; CI: Confidence interval.

Correlation between subcutaneous fat and EAT

We assessed whether abdominal subcutaneous adipose tissue reflected epicardial fat accumulation. Umbilical subcutaneous fat demonstrated a weak yet significant positive correlation with RCA-EAT (r = 0.153, p = 0.031), but not with LAD-EAT thickness (p = 0.779) (Table 5).

Table 5. Correlation analysis between umbilical subcutaneous fat thickness and EAT measurements.

Variables EAT thickness at RCA level EAT thickness at LAD level
r p r p
Subcutaneous fat at umbilical level 0.153 0.031 −0.020 0.779
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Spearman correlation test. (EAT: Epicardial adipose tissue).

Discussion

Our study investigated the relationship between EAT thickness and diabetes, dyslipidemia, hepatosteatosis, pancreatic steatosis, and pancreatitis. EAT and subcutaneous adipose tissue were found to be significantly greater in women, and EAT thickness increased in the presence of diabetes, particularly at the RCA and LAD levels. A distinctive aspect of this study is the evaluation of EAT thickness on CT scans performed for suspected pancreatitis, extending previous research beyond cardiovascular imaging cohorts. Multivariate analysis revealed that age and RCA-EAT were significantly associated with diabetes, Furthermore, high LDL levels were associated with LAD-EAT, and LAD-EAT and pancreatic steatosis were significantly associated with a history of pancreatitis.

EAT represents a dynamic visceral fat compartment positioned adjacent to the myocardium and beneath the visceral pericardium, chiefly surrounding the coronary arteries and occupying the atrioventricular and interventricular regions [1]. EAT consists of smaller adipocytes than other visceral fat depots, yet it shows greater fatty acid uptake and release [7]. Under normal physiological conditions, it serves to protect against elevated free fatty acid levels, provides a local energy source for the myocardium when needed, and serves as a thermogenic barrier through its brown-fat-like activity [8].

Although EAT has beneficial physiological roles, it may also release harmful pro-inflammatory cytokines that negatively affect coronary arteries and the myocardium [9]. Recent evidence has shown that EAT functions as a highly active endocrine organ, producing numerous bioactive adipokines [10].

Among the bioactive mediators secreted by EAT are pro-inflammatory and pro-atherogenic cytokines, including tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), nerve growth factor, resistin, visfatin, omentin, leptin, plasminogen activator inhibitor-1 (PAI-1), and angiotensinogen. In addition, it produces anti-inflammatory and anti-atherogenic factors such as adiponectin and adrenomedullin [11,12]. Increased EAT thickness is a known risk factor for cardiovascular diseases, contributing to chronic vascular remodeling by promoting the migration of pro-inflammatory cells in conditions such as obesity, insulin resistance, diabetes mellitus, and vascular injury [13]. Recent studies have also linked EAT to hepatic steatosis and LDL cholesterol levels, providing new diagnostic and therapeutic insights [1,2–4]. Consistent with these findings, our study also demonstrated a significant association between elevated LDL levels and increased LAD-EAT thickness. However, unlike some previous reports, we did not observe a significant association between hepatic steatosis and EAT thickness; this may reflect differences in patient selection, imaging methodology, or disease severity.

In this study, EAT thickness was found to be significantly higher in female participants across all measurement levels. While Yerramasu et al. reported greater EAT thickness in men, they also emphasized that this may vary depending on age, menopausal status, and hormonal differences [14]. Our findings may be explained by the older age and probable postmenopausal status of our female participants.

Another important finding was the significant association between DM and EAT thickness at both RCA and LAD levels. This supports previous literature highlighting the relationship between EAT, insulin resistance, and glucose metabolism [1–3]. For example, Tarabay et al. reported significantly greater EAT thickness in type 2 diabetes patients in both parasternal echocardiographic views, which aligns with our findings [15]. In our study, both RCA and LAD EAT thickness were significantly associated with diabetes in univariate analysis. However, after adjusting for confounding factors, only age and RCA-EAT thickness remained significantly associated with diabetes, suggesting that increased RCA-EAT may reflect metabolic alterations linked to diabetes rather than indicating a causal relationship.

EAT thickness was also significantly associated with elevated LDL cholesterol levels, especially at the LAD level, corroborating the findings of Dönmez et al. in patients with familial hypercholesterolemia [4]. The relatively weaker correlation observed at the RCA level may reflect local hemodynamic and structural differences in fat distribution around the coronary arteries.

In addition, age was found to be positively related to EAT thickness, supporting previous reports such as Abbara et al., who noted increased EAT in individuals aged ≥65 years [16]. Although the correlations between age, EAT thickness, and subcutaneous adipose tissue were statistically significant, the effect sizes were weak (r = 0.15–0.32). Such small coefficients may have limited clinical relevance and should be interpreted with caution. These associations may reflect unmeasured confounding factors—particularly BMI or overall adiposity—rather than a direct physiological relationship. Since BMI was not available in our dataset, the potential influence of general adiposity cannot be excluded and represents an important limitation of the study.

No significant association was found between EAT thickness and hepatic or pancreatic steatosis in our study. Our results differ from those of Liu et al., who demonstrated a significant association between EAT and non-alcoholic fatty liver disease (NAFLD), as well as Kul et al., who demonstrated significantly increased EAT thickness in patients with non-alcoholic fatty pancreas [3–5]. The discrepancies may be due to our relatively smaller sample size.

In participants with a history of pancreatitis, subcutaneous fat thickness at the umbilical level was significantly increased, consistent with findings by Bükülmez et al., who associated both visceral and subcutaneous fat with acute pancreatitis and recurrence in pediatric patients [17]. In this study, pancreatitis history was significantly linked to EAT thickness measured at the LAD level, suggesting that pro-inflammatory cytokines released by EAT may contribute to systemic inflammation and increase the frequency of pancreatitis attacks. However, further research with larger patient populations is needed to confirm this finding.

Interestingly, although subcutaneous fat thickness in the umbilical region and pancreatic parenchymal densities (head, body, and tail) were significant in univariate analyses, these associations did not persist after adjustment in multivariate models. This suggests that both subcutaneous fat and pancreatic tissue characteristics may contribute to pancreatitis risk, but their effects are likely overshadowed by the stronger influence of visceral depots such as EAT and pancreatic steatosis. Furthermore, the lack of a significant association between RCA-EAT and a history of pancreatitis suggests a potentially site-specific role for LAD-EAT in reflecting inflammatory and metabolic processes.

This study has several limitations. First, the retrospective, single-center design may introduce selection bias and limits the generalizability of the results to broader populations. In addition, the study population consisted of patients referred with suspected pancreatitis, which may have influenced the clinical and metabolic profile of the cohort and should be considered when interpreting the generalizability of the findings. Another limitation is that, despite the moderate sample size, subgroup analyses such as history of pancreatitis or LDL status may still be insufficient. Another limitation is that EAT was measured at only two CT levels (mid-RCA and mid-LAD), which may not fully reflect total EAT volume or regional variability. Another is that hepatic and pancreatic steatosis were assessed using CT and MRI rather than histopathology, which may lead to diagnostic variability. Finally, the lack of inflammatory biomarkers limited our ability to directly explore the mechanistic pathways between EAT, systemic inflammation, and pancreatitis.

Another important limitation is the absence of key metabolic and clinical confounders such as body mass index (BMI), total body adiposity, hypertension status, and medication use (e.g., statins, antidiabetic agents). Because EAT and subcutaneous adipose tissue are strongly influenced by these factors, the associations observed with diabetes, LDL cholesterol, or pancreatitis may partly reflect unmeasured confounding rather than direct physiological relationships. The lack of these variables limits the ability to fully adjust our multivariate models, and therefore the reported associations should be interpreted cautiously. Future studies incorporating comprehensive metabolic profiling are needed to validate these findings.

Conclusion

Epicardial adipose tissue functions as an active visceral fat store, influencing cardiovascular and metabolic health in both protective and pathological ways. Our study found that EAT thickness is significantly higher in female participants, likely influenced by age and menopausal status. We observed an association of increased EAT thickness with diabetes mellitus and elevated LDL cholesterol levels, suggesting a possible link with insulin resistance and atherogenesis. Age was positively correlated with EAT thickness. No significant relationship was found between EAT and hepatic or pancreatic steatosis, possibly due to sample size. However, increased EAT thickness in participants with a history of pancreatitis suggests a potential inflammatory link. These results highlight the need for prospective, multicenter studies incorporating comprehensive metabolic and inflammatory profiling to clarify the role of EAT in pancreatitis and cardiometabolic risk, and to determine whether EAT may have future value in risk stratification rather than immediate clinical application.

Acknowledgments

The authors have no acknowledgments to declare.

Data Availability

Data cannot be shared publicly because of patient confidentiality. Data are available from the Etlik City Hospital Ethics Committee etliksh.etikkurul@saglik.gov.tr for researchers who meet the criteria for access to confidential data.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Eyüp Serhat Çalık

17 Nov 2025

Dear Dr. EVRİMLER,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Academic Editor

PLOS ONE

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Additional Editor Comments:

I congratulate the esteemed authors for their efforts. The relationship between epicardial adipose tissue and various diseases has been investigated. Your study is generally well planned, and your manuscript is well structured and written. The manuscript was reviewed by two external reviewers, and their comments are below. Please provide point-by-point responses to the comments and make the necessary revisions to your manuscript. We look forward to receiving your revised manuscript. Best of luck.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: I Don't Know

Reviewer #2: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

Reviewer #1: General Comments:

I found your study interesting and relevant, as it addresses the role of epicardial adipose tissue in cardiometabolic health. You clearly put effort into collecting and analyzing the data, and the manuscript is generally well structured. While reading, I paid close attention to how your results link to your study objectives and to the potential limitations of your cohort and methods. I have several comments that I believe could help clarify the interpretation of your findings, improve transparency, and make the manuscript stronger and more convincing for readers

Specific Comments:

Point1: I found the introduction rather weak in terms of focus and logical flow.You mention several conditions (hepatosteatosis, diabetes, pancreatitis, subcutaneous fat), but, there is no clear narrative connecting these elements. It feels as if several conditions were listed without a central rationale explaining why they were all included in the same study... The link between EAT and pancreatitis, in particular, seems weak and needs stronger biological justification. Since EAT is a cardiac fat depot, the biological pathway by which it could influence pancreatic inflammation is not evident. You might consider citing mechanistic or imaging studies, if available, or explaining your hypothesis more clearly. Also, stating that ""the link is not conclusive"" doesn’t clearly define the research gap. Readers need to understand waht exactely is uncertain or conflicting in the literature. I also noticed you didn’t refer to any existing studies with similar objectives or findings. Without that, it’s hard to see how your work differs from what’s already been done or what new aspect it brings. I suggest you restructure this section to highlight one clear gap, explain why these associations are relevant, and end with a precise hypothesis connecting EAT to the selected metabolic factors.

Point2: I think the methods section needs much more detail. While you report sample size and sex in the results section, it’s important to include this information in methods along with how participants were selected and the inclusion//exclusion criteria. Without that, it’s hard to know if your results are reliable or representative. Please consider adding these details so we can understand the conditions of your study and how representative your population is. Also, it would also help to clarify whether potential confounders like age, sex, or BMI were considered, as this is important for interpreting your results.

Point3 : The results section is detailed, but it feels somewhat descriptive and difficult to follow in relation to your study objectives. You report many associations, yet it’s not always clear which ones are most central to your objective. I suggest reorganizing the results according to your main aims (for example, EAT and diabetes, EAT and pancreatitis, etc.) and adding short linking sentences to guide the reader through the key findings. This would make the section clearer and more coherent.

Point4: I see that several of your results are statistically significant, but when I look at the actual correlation values. For example, between age, EAT, and subcutaneous fat (r = 0.15–0.32). These relationships appear quite weak. Even with low p values, such small effect sizes may not have much clinical meaning. I think it would really strengthen your paper if you could comment on whether these findings are meaningful in practice, or if they might simply reflect confounding factors like BMI or general adiposity.

point5: I noticed that some important potential confounders, such as BMI, overall body fat, hypertension, or medication use, don’t seem to have been accounted for in your analyses. Since EAT and subcutaneous fat are strongly influenced by these factors, the associations you report with diabetes, pancreatitis, or LDL cholesterol could be affected. Could you clarify whether these variables were available, and if so, consider including them in your multivariate models??? If not, a discussion of the possible impact of unmeasured confounding would help strengthen the study.

point6: In the regression analyses, it’s not clear how you decided which variables to include in the multivariate models. Were variables selected based on univariate significance (e.g.,, p < 0.1), or were all measured variables considered???

Point7: I see that you mention the retrospective design as a limitation, which is good. However, some of the language in the results and discussion, such as "independent predictors"" implies causality. Since causality cannot be established in a retrospective study, I suggest clarifying this in the text and using more neutral language (e.g.. "variables significantly associated with…") to avoid overinterpretation.

Point8: The prevalence of pancreatitis (73.5%%) and diabetes (31.4%) in your cohort seems unusually high compared with the general population. Could this reflect a selection bias; for example, if the sample mainly includes patients undergoing CT for pancreatic evaluation?? Could you clarify your sampling source and whether this distribution is representative of the broader population you aim to study..

Reviewer #2: The manuscript has potential but would require major revision before it could be suitable for publication. Please address the following comments in the manuscript:

The abstract lacks a clear problem statement as it lists results but does not sufficiently justify why this research matters or what specific knowledge gap it addresses. The final sentence should highlight the broader relevance rather than repeat outcomes.

The research gap is weakly articulated in the introduction. While prior work is mentioned, the authors do not convincingly explain what was missing in existing literature that this study uniquely addresses.

The rationale for selecting the study design is limited. The manuscript does not explain why the chosen population, tools, and parameters are most appropriate to answer the stated research question.

Methodology lacks detail and reproducibility in some areas. Key procedural specifics (e.g., selection criteria, sample handling, or validation of measurement tools) are missing or insufficiently described. This may prevent replication.

The study seems observational/descriptive, yet some statements imply causal relationships. These need to be toned down or reframed as associations only.

Sample size justification is not clearly provided. A power analysis or rationale for participant numbers would strengthen the manuscript.

The statistical analysis section is too brief. The authors should clarify corrections for multiple testing, how missing data were handled, and whether data met normality assumptions before applying parametric tests.

Results presentation feels fragmented. While data are provided, there is limited integration of findings into a coherent narrative. Tables/figures could be better linked in the text with clearer interpretation rather than simple reporting.

Tables and figures appear overly descriptive. Several contain too much raw numerical detail without clear summaries or take-home messages. They also need clearer captions that explain what readers should focus on.

Discussion largely restates results rather than interpreting them. There is little critical reflection on why certain outcomes emerged, how they compare to similar studies, or what mechanisms may be involved.

Limitations are acknowledged but underdeveloped. Key issues such as potential confounders, selection bias, and measurement limitations deserve a more honest discussion.

The manuscript overextends its conclusions. The findings support limited association but not practical recommendations. The authors should temper claims to match the strength of their data.

The implications for policy, clinical relevance, or future research are not clearly drawn. The conclusion could be more forward-looking, stating how these results should guide subsequent work.

Language is generally understandable, but certain paragraphs feel stiff and overly technical, reducing flow. Some grammatical issues remain; the manuscript would benefit from careful editing for clarity and conciseness.

Overall novelty appears modest. The study adds incremental information rather than a fundamentally new insight. The authors should emphasize what is genuinely new i.e., population studied, new analytical approach, or unique findings if applicable.

**********

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Reviewer #1: No

Reviewer #2: No

**********

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PLoS One. 2026 Feb 26;21(2):e0343831. doi: 10.1371/journal.pone.0343831.r002

Author response to Decision Letter 1

8 Jan 2026

We would like to thank the Editor and the reviewers for their careful evaluation of our manuscript and for their constructive and insightful comments. We have revised the manuscript thoroughly in response to all suggestions, which have helped improve the clarity, methodological transparency, and overall quality of the study. Below, we provide a point-by-point response to each comment, and all changes made to the manuscript are indicated with corresponding line numbers.

RESPONSE TO REVIEWERS

Reviewer 1.

Point 1. I found the introduction rather weak in terms of focus and logical flow. You mention several conditions (hepatosteatosis, diabetes, pancreatitis, subcutaneous fat), but, there is no clear narrative connecting these elements. It feels as if several conditions were listed without a central rationale explaining why they were all included in the same study... The link between EAT and pancreatitis, in particular, seems weak and needs stronger biological justification. Since EAT is a cardiac fat depot, the biological pathway by which it could influence pancreatic inflammation is not evident. You might consider citing mechanistic or imaging studies, if available, or explaining your hypothesis more clearly. Also, stating that ""the link is not conclusive"" doesn’t clearly define the research gap. Readers need to understand waht exactely is uncertain or conflicting in the literature. I also noticed you didn’t refer to any existing studies with similar objectives or findings. Without that, it’s hard to see how your work differs from what’s already been done or what new aspect it brings. I suggest you restructure this section to highlight one clear gap, explain why these associations are relevant, and end with a precise hypothesis connecting EAT to the selected metabolic factors.

Thank you very much for this insightful and constructive feedback. In line with your suggestions, we substantially revised the final paragraph of the Introduction to improve coherence, strengthen the biological rationale, and clearly articulate the research gap. First, we clarified that although EAT is anatomically a cardiac fat depot, it acts as an active visceral adipose tissue with systemic inflammatory effects and a strong correlation with total visceral fat, making its potential association with hepatic and pancreatic fat biologically plausible. We also added mechanistic justification by referencing the proinflammatory cytokines secreted by EAT and explaining how ectopic fat depots—including hepatic and pancreatic fat—share common metabolic and inflammatory pathways. Second, we specified that the relationships between EAT and pancreatic fat or pancreatitis history have not been systematically examined, and that existing literature on EAT and hepatosteatosis provides inconsistent results, thereby defining the precise gap our study addresses. Finally, we added a clearer rationale for why these metabolic factors were included together and concluded the Introduction with a precise, hypothesis-driven statement. All revisions have been incorporated into the manuscript and marked accordingly (Lines 61-73).

Point 2: I think the methods section needs much more detail. While you report sample size and sex in the results section, it’s important to include this information in methods along with how participants were selected and the inclusion//exclusion criteria. Without that, it’s hard to know if your results are reliable or representative. Please consider adding these details so we can understand the conditions of your study and how representative your population is. Also, it would also help to clarify whether potential confounders like age, sex, or BMI were considered, as this is important for interpreting your results.

Thank you very much for this valuable comment. We have substantially revised the Methods section to address your concerns and improve clarity and reproducibility. Specifically, we added detailed descriptions of the study population, including how patients were selected, the time frame of imaging, and the inclusion of abdominal CT/MRI examinations performed for suspected pancreatitis. We also incorporated explicit inclusion and exclusion criteria and clarified that age, sex, and BMI were collected as potential confounders relevant to ectopic fat distribution. In addition, we expanded the descriptions of the imaging measurements for EAT thickness, hepatosteatosis, and pancreatic fat, and clarified that all assessments were performed independently by two radiologists. These revisions ensure a complete and transparent methodological framework. All changes have been incorporated into the manuscript and marked accordingly (Lines 83-90 and 104-106).

Point 3 : The results section is detailed, but it feels somewhat descriptive and difficult to follow in relation to your study objectives. You report many associations, yet it’s not always clear which ones are most central to your objective. I suggest reorganizing the results according to your main aims (for example, EAT and diabetes, EAT and pancreatitis, etc.) and adding short linking sentences to guide the reader through the key findings. This would make the section clearer and more coherent.

Thank you for this valuable comment. We have substantially reorganized the Results section to improve clarity and alignment with our study aims. The findings are now presented under clear thematic subsections (e.g., EAT and Diabetes Mellitus, EAT and Hepatic Steatosis, EAT and Pancreatitis History), and brief linking sentences were added to guide the reader through the key results. These revisions improve the overall readability and coherence of the Results section. All changes have been incorporated into the revised manuscript (Lines 134-204).

Point 4: I see that several of your results are statistically significant, but when I look at the actual correlation values. For example, between age, EAT, and subcutaneous fat (r = 0.15–0.32). These relationships appear quite weak. Even with low p values, such small effect sizes may not have much clinical meaning. I think it would really strengthen your paper if you could comment on whether these findings are meaningful in practice, or if they might simply reflect confounding factors like BMI or general adiposity.

Thank you for this insightful observation. We agree that although several correlations reached statistical significance, their effect sizes were small (r = 0.15–0.32). To address this, we expanded the Discussion to clarify that these weak associations may have limited clinical relevance. We also added commentary noting that unmeasured confounders—particularly BMI and overall adiposity—may partially explain these relationships. The revised text now emphasizes the need for cautious interpretation and highlights this as an important limitation. These additions have been incorporated into the updated manuscript (Lines 257-263).

Point 5: I noticed that some important potential confounders, such as BMI, overall body fat, hypertension, or medication use, don’t seem to have been accounted for in your analyses. Since EAT and subcutaneous fat are strongly influenced by these factors, the associations you report with diabetes, pancreatitis, or LDL cholesterol could be affected. Could you clarify whether these variables were available, and if so, consider including them in your multivariate models??? If not, a discussion of the possible impact of unmeasured confounding would help strengthen the study.

Thank you for this insightful comment. Unfortunately, BMI, total body fat, hypertension status, and detailed medication history were not available in the retrospective dataset. We fully agree that these variables are important determinants of EAT and subcutaneous adiposity, and their absence may have introduced unmeasured confounding. To address this concern, we added a paragraph in the Discussion acknowledging this limitation and clarifying that the associations observed—particularly with diabetes, LDL cholesterol, and pancreatitis—should be interpreted with caution. We also highlighted the need for future prospective studies including comprehensive metabolic data (Lines 283- 287 and 293-301).

Point 6: In the regression analyses, it’s not clear how you decided which variables to include in the multivariate models. Were variables selected based on univariate significance (e.g.,, p < 0.1), or were all measured variables considered???

Thank you for this important comment. In our analysis, all measured variables were first entered into the univariate logistic regression. Only variables that showed statistical significance in the univariate analysis (p < 0.05) were subsequently included in the multivariate model. This stepwise approach was chosen to avoid overfitting and to ensure that only meaningful predictors were retained. Age and sex were kept in the model as clinically essential covariates. We have clarified this procedure in the Methods section (Lines 127-131).

Point 7: I see that you mention the retrospective design as a limitation, which is good. However, some of the language in the results and discussion, such as "independent predictors"" implies causality. Since causality cannot be established in a retrospective study, I suggest clarifying this in the text and using more neutral language (e.g.. "variables significantly associated with…") to avoid overinterpretation.

Thank you for this important comment. We fully agree that causal interpretations cannot be made in a retrospective study. In accordance with your suggestion, we carefully reviewed the Results and Discussion sections and revised the wording to avoid causal language. Terms such as “independent predictor” were replaced with neutral expressions including “significantly associated with” reflecting statistical relationships rather than causality. These revisions ensure that the findings are interpreted appropriately within the limitations of the study design (Lines 32-39, 162, 213-217).

Point8: The prevalence of pancreatitis (73.5%%) and diabetes (31.4%) in your cohort seems unusually high compared with the general population. Could this reflect a selection bias; for example, if the sample mainly includes patients undergoing CT for pancreatic evaluation?? Could you clarify your sampling source and whether this distribution is representative of the broader population you aim to study..

Thank you for this important observation. The high prevalence of pancreatitis and diabetes in our cohort indeed reflects a targeted sampling strategy rather than the general population distribution. As one of the predefined aims of the study was to examine the relationship between EAT and pancreatitis, patients who underwent abdominal CT/MRI due to clinical suspicion of pancreatitis were intentionally included. Therefore, the sample is enriched with individuals evaluated for possible pancreatitis, which explains the higher prevalence. We have clarified this point in the Methods section to avoid misinterpretation (Lines 83-86).

Reviewer 2.

Point 1. The abstract lacks a clear problem statement as it lists results but does not sufficiently justify why this research matters or what specific knowledge gap it addresses. The final sentence should highlight the broader relevance rather than repeat outcomes.

Thank you for your comment. We revised the abstract to clearly state the knowledge gap regarding the unclear relationship between EAT, pancreatic steatosis, and pancreatitis, and to justify the clinical relevance of the study. We also adjusted the final sentence to emphasize the broader significance rather than repeating results. We believe these changes enhance clarity and focus (Lines 18-21, 32-33, 35-39).

Point 2. The research gap is weakly articulated in the introduction. While prior work is mentioned, the authors do not convincingly explain what was missing in existing literature that this study uniquely addresses.

Thank you for this insightful comment. We revised the Introduction to more clearly define the research gap. The updated text now explicitly highlights: the lack of studies examining the relationship between EAT and pancreatic fat or pancreatitis, inconsistent evidence regarding the association between EAT and hepatosteatosis, and the uncertainty about whether EAT reflects only cardiac adiposity or broader systemic ectopic fat accumulation. These revisions strengthen the rationale and clarify the unmet need addressed by our study (Lines 61-73).

Point 3. The rationale for selecting the study design is limited. The manuscript does not explain why the chosen population, tools, and parameters are most appropriate to answer the stated research question.

Thank you for the comment. We clarified in the Methods why this study population and imaging parameters were appropriate. Abdominal CT/MRI enabled simultaneous evaluation of EAT, hepatic steatosis, pancreatic fat, and pancreatitis, directly aligning with our research aims. We also specified that patients imaged for suspected pancreatitis were intentionally included because assessing the EAT–pancreatitis relationship was one of the study objectives (Lines 83-86).

Point 4. Methodology lacks detail and reproducibility in some areas. Key procedural specifics (e.g., selection criteria, sample handling, or validation of measurement tools) are missing or insufficiently described. This may prevent replication.

Thank you for your constructive comment. We expanded the Methods section to provide full reproducibility, including detailed inclusion/exclusion criteria, rationale for the study population, CT/MRI measurement protocols and HU-based definitions (Lines 86-90).

Point 5. The study seems observational/descriptive, yet some statements imply causal relationships. These need to be toned down or reframed as associations only.

Thank you for this important remark. We carefully revised the manuscript to remove any causal wording. All expressions suggesting prediction or causality were replaced with neutral, association-based terminology (e.g., “significantly associated with”). The revised text now accurately reflects the observational nature of the study (Lines 163, 194-195, 216-217, 248-252).

Point 6. Sample size justification is not clearly provided. A power analysis or rationale for participant numbers would strengthen the manuscript.

Thank you for your constructive comment. Because this was an exploratory, retrospective study, no formal a priori sample size calculation was performed. The sample size was determined by the number of consecutive patients who met the inclusion criteria during the study period, which we considered sufficient to explore the hypothesized associations; however, future prospective studies with formal power calculations are warranted.

Point 7. The statistical analysis section is too brief. The authors should clarify corrections for multiple testing, how missing data were handled, and whether data met normality assumptions before applying parametric tests.

We thank the reviewer for this comment. There were no missing data in the dataset. Normality assumptions were assessed prior to applying parametric tests, and the relevant details have now been clarified and explicitly stated in the statistical analysis section (Lines 118-132).

Point 8. Results presentation feels fragmented. While data are provided, there is limited integration of findings into a coherent narrative. Tables/figures could be better linked in the text with clearer interpretation rather than simple reporting.

Thank you for this valuable comment. We have revised the Results section to create a more coherent and integrated narrative. Data are now presented with clearer transitions, and tables are referenced at points directly relevant to their findings. Each table is accompanied by brief interpretative statements rather than simple numerical reporting (Lines 133-204).

Point 9. Tables and figures appear overly descriptive. Several contain too much raw numerical detail without clear summaries or take-home messages. They also need clearer captions that explain what readers should focus on.

Thank you for this helpful comment. In line with your suggestion, we revised the caption of Table 1 to clearly highlight its key findings. Additionally, the captions of all other tables were rewritten to be more explanat

Attachment

Submitted filename: Response to Reviewers.docx

pone.0343831.s001.docx (22.8KB, docx)

Decision Letter 1

Eyüp Serhat Çalık

12 Feb 2026

<p>THE ASSOCIATION BETWEEN EPICARDIAL ADIPOSE TISSUE THICKNESS AND DIABETES MELLITUS, HYPERLIPIDEMIA, HEPATOSTEATOSIS, PANCREATIC STEATOSIS AND PANCREATITIS

PONE-D-25-52339R1

Dear Dr. Evrimler,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager®  and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support .

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Eyüp Serhat Çalık

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: I Don't Know

Reviewer #2: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

Reviewer #1: I appreciate the author's thorough and thoughtful responses to my previous comments. The revisions have significantly improved the focus of the introduction, the transparency of the Methods, and the organization of the results, and the limitaion are now appropriately discussed. I have no further comments. Only minor editorial ajustements, if any, may be handeled at at the discretion of the editor.

Reviewer #2: (No Response)

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

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Reviewer #1: No

Reviewer #2: Yes: Zargham Faisal

**********

Acceptance letter

Eyüp Serhat Çalık

PONE-D-25-52339R1

PLOS One

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PLOS One

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    Attachment

    Submitted filename: Response to Reviewers.docx

    pone.0343831.s001.docx (22.8KB, docx)

    Data Availability Statement

    Data cannot be shared publicly because of patient confidentiality. Data are available from the Etlik City Hospital Ethics Committee etliksh.etikkurul@saglik.gov.tr for researchers who meet the criteria for access to confidential data.

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