Abstract
Introduction and aim: Heart failure with preserved ejection fraction (HFpEF) is a significant clinical challenge, often coexisting with atrial fibrillation (AF), which exacerbates patient outcomes by increasing risks of stroke, hospitalizations, and mortality. Recent studies suggest that epicardial adipose tissue (EAT), a metabolically active fat depot, may contribute to AF pathogenesis by promoting atrial remodeling and fibrosis. This study aimed to evaluate the relationship between EAT thickness and AF in HFpEF patients.
Materials and methods: A total of 110 HFpEF patients were included, with 20 (18.2%) having documented AF. EAT thickness was measured using transthoracic echocardiography, and AF was confirmed via electrocardiography.
Results: Patients with AF had significantly greater EAT thickness compared to those without AF (8.3 ± 0.9 mm vs. 7.1 ± 0.8 mm, p < 0.001). Receiver operating characteristic (ROC) analysis demonstrated that EAT thickness was a strong predictor of AF (AUC = 0.87, p < 0.001), with a cut-off value of 7.5 mm achieving 89% sensitivity and 75% specificity.
Conclusion: These findings indicate that increased EAT thickness is independently associated with AF in HFpEF patients, highlighting its potential as a biomarker for AF risk stratification. Future studies should explore whether targeting EAT could improve clinical outcomes in this high-risk population.
Keywords: atrial fibrillation, cardiac remodeling, echocardiography, epicardial adipose tissue, heart failure with preserved ejection fraction
Introduction
Heart failure with preserved ejection fraction (HFpEF) is a common and complex clinical syndrome, accounting for approximately 50% of all heart failure cases. It is characterized by normal left ventricular systolic function but impaired diastolic function, leading to elevated filling pressures and symptoms such as dyspnea and fatigue [1,2]. HFpEF is associated with substantial morbidity, mortality, and frequent hospitalizations, with its prevalence rising due to aging populations and increasing rates of comorbidities such as obesity, diabetes, and hypertension [3].
Atrial fibrillation (AF) is a frequent comorbidity in HFpEF, occurring in up to 40% of patients, and is associated with worse clinical outcomes, including higher risks of stroke, heart failure exacerbations, and mortality [4,5]. Beyond these adverse outcomes, AF is also a significant predictor of coronary artery disease (CAD) and myocardial infarction (MI), as accumulating evidence suggests that AF and CAD share common pathophysiological pathways, including endothelial dysfunction, systemic inflammation, and atrial remodeling [6-10]. Additionally, AF is increasingly recognized as a major risk factor for cognitive impairment and dementia, likely due to cerebral hypoperfusion, microembolization, and systemic inflammation [11]. The intricate interplay between HFpEF and AF is multifactorial; hemodynamic alterations such as left atrial pressure overload and atrial fibrosis in HFpEF predispose patients to AF, while AF exacerbates diastolic dysfunction and left ventricular filling pressures, creating a detrimental cycle [12].
Emerging evidence suggests that epicardial adipose tissue (EAT) may play a pivotal role in atrial remodeling and AF pathogenesis. EAT is a metabolically active fat depot located between the myocardium and visceral pericardium, with both direct anatomic and paracrine effects on the myocardium. It secretes pro-inflammatory cytokines and profibrotic mediators such as interleukin-6 and tumor necrosis factor-α, which contribute to atrial fibrosis, conduction abnormalities, and arrhythmogenesis [13,14]. Increased EAT thickness has been associated with both the development and severity of AF, making it a potential biomarker for risk stratification [15].
In addition to EAT, systemic inflammation is increasingly recognized as a key contributor to AF pathophysiology. High-sensitivity C-reactive protein (hs-CRP), a marker of systemic inflammation, has been linked to both AF incidence and adverse outcomes in AF patients, including thromboembolic events and cardiovascular complications [16,17]. Given the pro-inflammatory state in HFpEF, particularly in the presence of AF, hs-CRP may serve as a critical biomarker for disease progression and therapeutic targeting.
Although the relationship between EAT and AF has been well-documented in the general population, limited data exist regarding its role in HFpEF patients specifically. Considering the unique pathophysiological features of HFpEF, including systemic inflammation, atrial remodeling, and heightened cardiovascular risk, understanding the contribution of EAT in this population is of particular importance. This study aims to investigate the association between EAT thickness and the presence of AF in HFpEF patients. By identifying EAT as a potential biomarker and therapeutic target, this research seeks to provide new insights into the underlying mechanisms of AF in HFpEF and inform strategies for risk stratification and intervention.
Materials and methods
This cross-sectional study was conducted at Cumhuriyet University Faculty of Medicine Hospital, Turkey, to investigate the relationship between EAT thickness and the presence of AF in patients diagnosed with HFpEF. A total of 110 patients were included, all of whom met the diagnostic criteria for HFpEF based on current guideline recommendations. The inclusion criteria required patients to have a left ventricular ejection fraction (LVEF) of 50% or higher and clinical symptoms of heart failure such as dyspnea, fatigue, exercise intolerance, and echocardiographic evidence of diastolic dysfunction. Diastolic dysfunction was defined by parameters such as an elevated E/e' ratio greater than 14, left atrial enlargement, or increased left ventricular wall thickness. The diagnosis of HFpEF was confirmed by a cardiologist experienced in heart failure management. Patients were excluded if they had a reduced LVEF (less than 50%), significant valvular heart disease, recent MI, known inflammatory or autoimmune conditions, active malignancy, or a history of cardiac surgery within the past six months. In addition, patients with poor echocardiographic image quality that precluded accurate measurement of EAT were excluded from the analysis. Patients with uncontrolled hypertension or thyroid dysfunction were also excluded to avoid confounding factors that could influence the results.
Baseline demographic and clinical data were collected for all participants through detailed medical record reviews and patient interviews. Variables included age, sex, and the presence of comorbidities such as hypertension and diabetes mellitus. Blood pressure measurements were taken using a validated sphygmomanometer after five minutes of rest in the seated position. The presence of AF was confirmed by a standard 12-lead electrocardiogram (ECG) performed at rest or by a documented history of persistent or paroxysmal AF in the medical record. Persistent AF was defined as AF that required medical or electrical cardioversion, while paroxysmal AF was defined as AF episodes that terminated spontaneously within seven days.
EAT thickness was measured non-invasively using transthoracic echocardiography. Experienced echocardiographers who had no information about the clinical details of each subject undertook transthoracic echocardiographic examinations using the Vivid E95® cardiac ultrasonography system (GE VingMed Ultrasound AS; Horten, Norway) with 2.5- to 5-MHz probes. EAT thickness was measured at the level of the right ventricular free wall in the parasternal long-axis view. Measurements were obtained at end-diastole, as this phase allows for maximal visualization of the epicardial fat layer. The EAT thickness was defined as the distance between the visceral layer of the pericardium and the outer wall of the myocardium. To improve accuracy and minimize variability, three consecutive cardiac cycles were averaged for each measurement. Interobserver and intraobserver variability for EAT measurements were assessed using intraclass correlation coefficients (ICCs) and Bland-Altman analysis, with ICC values of 0.91 and 0.94, respectively, indicating excellent reproducibility. The mean absolute difference between repeated measurements was 0.5 ± 0.2 mm for intraobserver variability and 0.6 ± 0.3 mm for interobserver variability.
The study protocol was approved by the Local Ethics Committee of Cumhuriyet University, and all procedures were conducted in accordance with the Declaration of Helsinki (2010-01/13). Written informed consent was obtained from all participants before enrollment. The study adhered to guidelines for the ethical conduct of research involving human subjects, and patient confidentiality was maintained throughout the study.
Statistical analysis
Statistical analyses were conducted using IBM SPSS Statistics for Windows, Version 25 (Released 2017; IBM Corp., Armonk, New York, United States). Continuous variables were presented as mean ± standard deviation (SD), while categorical variables were expressed as frequencies and percentages. The normality of the continuous data was assessed using the Kolmogorov-Smirnov test. For comparisons between two groups (patients with and without AF), the independent samples t-test was applied for normally distributed continuous variables, and the Mann-Whitney U test was used for non-normally distributed variables. Categorical variables were compared using the chi-square test or Fisher’s exact test, as appropriate. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive value of epicardial adipose tissue (EAT) thickness for AF. The area under the curve (AUC) was calculated to quantify the accuracy of EAT as a diagnostic marker, with an AUC value closer to 1 indicating excellent discriminative ability. Sensitivity, specificity, and the optimal cut-off value for EAT thickness were determined using the Youden Index, which maximizes the sum of sensitivity and specificity. A p-value of less than 0.05 was considered statistically significant for all analyses. Confidence intervals (CIs) were reported at the 95% level to indicate the precision of the estimates. Interobserver and intraobserver variability for EAT thickness measurements were assessed using ICCs, with ICC values above 0.80 indicating excellent reliability. This statistical approach was selected to ensure a robust analysis of the relationship between EAT thickness and AF while accounting for potential differences in baseline characteristics between study groups.
Results
A total of 110 patients with HFpEF were included in the study, among whom 20 (18%) had AF and 90 (81%) did not. The baseline characteristics of the study population are summarized in Table 1. Patients with AF were comparable in age to those without AF (mean age: 66 ± 11 years vs. 69 ± 10 years, p = 0.160). The prevalence of hypertension was higher in the AF group compared to the non-AF group (70% vs. 63%, p = 0.129), and patients with AF were more likely to have diabetes mellitus (65.0% vs. 39%, p = 0.038). There was no significant difference in sex distribution between the two groups. EAT thickness was significantly greater in patients with AF compared to those without AF (8.3 ± 0.9 mm vs. 7.1 ± 0.8 mm, p < 0.001), as shown in Table 1. These findings suggest that increased EAT thickness is associated with the presence of AF in HFpEF patients.
Table 1. Baseline characteristics of study patients.
ALT: alanine aminotransferase; AST: aspartate aminotransferase; HDL: high density lipoprotein; LDL: low density lipoprotein; WBC: white blood count; AF: atrial fibrillation
| AF (+), n = 20 | AF (-), n = 90 | p-value | |
| Age (years) | 66 ± 11 | 69 ± 10 | 0.160 |
| Gender (M/F) | 12/8 | 58/32 | 0.378 |
| Hypertension (%) | 14 (70%) | 57 (63%) | 0.129 |
| Diabetes mellitus (%) | 13 (65%) | 35 (39%) | 0.038 |
| Smoking (%) | 5 (25%) | 26 (29%) | 0.776 |
| Hyperlipidemia (%) | 11 (55%) | 41 (46%) | 0.138 |
| Left ventricular ejection fraction (%) | 57 ± 6 | 59 ± 3 | 0.076 |
| Left atrial diameter (cm) | 4.6 ± 0.3 | 4.2 ± 0.5 | < 0.001 |
| Epicardial adipose tissue | 8.3 ± 0.9 | 7.1 ± 0.8 | < 0.001 |
| Glucose (mg/dL) | 115 (64-450) | 122 (73-342) | 0.333 |
| Creatinine (mg/dL) | 1.2 ± 0.6 | 1.3 ± 0.5 | 0.076 |
| ALT, IU/L | 20 (5-218) | 28 (6-112) | 0.328 |
| AST, IU/L | 22 (2-118) | 29 (11-115) | 0.057 |
| Triglycerides (mg/dL) | 131 (46-693) | 118 (36-205) | 0.061 |
| Total cholesterol (mg/dL) | 160 (96-287) | 148 (49-276) | 0.072 |
| HDL cholesterol (mg/dL) | 42 (23-66) | 36 (12-62) | 0.053 |
| LDL cholesterol (mg/dL) | 115 (58-221) | 104 (39-215) | 0.105 |
| Hemoglobin (g/dL) | 14 ± 2 | 12 ± 3 | 0.065 |
| Platelet (10³/µL) | 215 ± 63 | 224 ± 51 | 0.745 |
| WBC (10³/µL) | 8.1 ± 2 | 8.2 ± 2 | 0.955 |
ROC analysis was performed to evaluate the ability of EAT thickness to predict the presence of AF. The analysis revealed an AUC of 0.878 (95% CI: 0.76-0.93, p < 0.001), indicating excellent diagnostic performance. An optimal cut-off value of 7.5 mm for EAT thickness was identified, which provided a sensitivity of 89% and a specificity of 75% (Figure 1). These results highlight the potential of EAT thickness as a robust, non-invasive biomarker for AF in HFpEF patients. To ensure the reliability of EAT thickness measurements, interobserver and intraobserver variability were assessed using ICCs. The ICC for interobserver variability was 0.87, and the ICC for intraobserver variability was 0.89, demonstrating excellent reproducibility of the measurements. These findings suggest that EAT thickness is strongly associated with AF in HFpEF and may serve as a practical tool for identifying patients at higher risk of AF in clinical practice.
Figure 1. Receiver operating characteristic (ROC) analysis demonstrated that EAT thickness was a strong predictor of AF (AUC = 0.878, p < 0.001), with a cut-off value of 7.5 mm achieving 89% sensitivity and 75% specificity.
EAT: epicardial adipose tissue; AF: atrial fibrillation; AUC: area under the curve
Discussion
This study demonstrates a significant association between EAT thickness and the presence of AF in patients with HFpEF. EAT thickness was significantly higher in patients with AF, and ROC analysis confirmed its strong predictive value for AF, with an optimal cut-off value of 7.5 mm achieving excellent sensitivity and specificity. These findings contribute to the growing body of evidence linking EAT, a metabolically active fat depot, to cardiovascular pathophysiology, particularly in the context of AF and HFpEF.
Epicardial adipose tissue and atrial fibrillation
EAT is a visceral fat depot located between the myocardium and the visceral pericardium. Unlike subcutaneous fat, EAT has direct contact with the myocardium, sharing the same microcirculation and lacking a separating fascia. This unique anatomical relationship allows EAT to exert paracrine and vasocrine effects on the myocardium and adjacent cardiac structures [18]. Pro-inflammatory cytokines secreted by EAT, such as interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1, are implicated in promoting atrial fibrosis, structural remodeling, and electrical instability, all of which are key mechanisms underlying AF [19,20]. The findings of this study align with previous research demonstrating a link between increased EAT thickness and the prevalence or severity of AF. Leggio et al. showed that EAT thickness was significantly higher in patients with AF compared to those in sinus rhythm, with a strong correlation between EAT volume and AF burden [21]. Mahajan et al. provided further evidence by demonstrating that EAT contributes to atrial structural remodeling, including increased atrial fibrosis and conduction slowing, which are critical substrates for AF maintenance [22]. In the context of HFpEF, where systemic inflammation and left atrial remodeling are already prominent, the additive effect of EAT may exacerbate the propensity for AF.
Epicardial adipose tissue in heart failure with preserved ejection fraction: a unique pathophysiological context
HFpEF is characterized by systemic inflammation, endothelial dysfunction, and myocardial stiffening, all of which contribute to diastolic dysfunction and elevated left atrial pressures [23,24]. These processes are further amplified by comorbidities such as obesity, diabetes, and hypertension, which are prevalent in HFpEF and contribute to the expansion of EAT [25]. Obesity, in particular, is closely linked to increased EAT deposition, as demonstrated in studies showing that EAT volume correlates strongly with BMI and waist circumference [26,27]. In HFpEF patients with AF, the role of EAT may be even more pronounced. Elevated left atrial pressures and stretching, common in HFpEF, create a substrate for atrial remodeling. The pro-inflammatory cytokines and profibrotic mediators secreted by EAT may amplify these effects, promoting atrial fibrosis and electrical remodeling. Furthermore, the increased EAT thickness observed in this study supports the hypothesis that EAT may serve as both a marker and a mediator of atrial remodeling in HFpEF patients with AF.
Clinical implications
The findings of this study highlight the potential utility of EAT thickness as a non-invasive biomarker for identifying HFpEF patients at higher risk of developing AF. Transthoracic echocardiography, a widely available imaging modality, can be used to measure EAT thickness, making it a practical tool in routine clinical practice. The optimal cut-off value of 6.5 mm identified in this study provides a threshold that may guide clinicians in risk stratification and early intervention. From a therapeutic perspective, interventions targeting EAT may hold promise for reducing AF risk in HFpEF. Lifestyle modifications, such as weight loss and exercise, have been shown to reduce EAT volume and improve atrial remodeling, as evidenced by the LEGACY trial, which demonstrated significant reductions in AF burden with weight management [28]. Pharmacological approaches targeting inflammation, such as the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists, may also reduce EAT volume and its adverse effects on the myocardium [29]. Further research is warranted to explore the impact of these interventions on clinical outcomes in HFpEF patients with AF.
Strengths and limitations
This study has several strengths, including its focus on HFpEF, a population with limited data on the role of EAT, and the use of transthoracic echocardiography, a non-invasive and widely accessible imaging method, for EAT thickness measurement. The strong statistical significance of the findings and the excellent reproducibility of EAT measurements further enhance the reliability of the results. However, the study also has limitations. The cross-sectional design precludes conclusions about causality between increased EAT thickness and AF. Additionally, the study was conducted at a single center with a relatively small sample size, which may limit the generalizability of the findings. The lack of a volumetric EAT assessment, which could provide more comprehensive insights into the relationship between EAT and AF, is another limitation. Despite these limitations, the study provides important insights into the pathophysiological role of EAT in HFpEF patients with AF and sets the stage for future prospective and interventional studies.
Future directions
Future research should focus on longitudinal studies to establish causal relationships between EAT and AF in HFpEF. Interventional trials exploring the impact of targeted therapies, such as anti-inflammatory agents or weight loss programs, on EAT thickness and clinical outcomes in HFpEF patients with AF, are also needed. Advanced imaging modalities, such as cardiac magnetic resonance imaging or computed tomography, could be used to assess EAT volume and distribution more precisely, providing additional insights into its pathophysiological role.
Conclusions
In conclusion, this study demonstrates that increased EAT thickness is strongly associated with the presence of AF in patients with HFpEF. EAT thickness measured by transthoracic echocardiography is a practical, non-invasive biomarker that may aid in risk stratification and guide therapeutic interventions in this population. The findings underscore the need for further research to explore the role of EAT as a modifiable risk factor and a therapeutic target in HFpEF patients with AF.
Disclosures
Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. The Local Ethics Committee of Cumhuriyet University issued approval 2010-01/13.
Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:
Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.
Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.
Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
Author Contributions
Concept and design: Oguzhan Yucel
Acquisition, analysis, or interpretation of data: Oguzhan Yucel
Drafting of the manuscript: Oguzhan Yucel
Critical review of the manuscript for important intellectual content: Oguzhan Yucel
References
- 1.Trends in prevalence and outcome of heart failure with preserved ejection fraction. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. N Engl J Med. 2006;355:251–259. doi: 10.1056/NEJMoa052256. [DOI] [PubMed] [Google Scholar]
- 2.Heart failure with preserved ejection fraction: new approaches to diagnosis and management. Upadhya B, Kitzman DW. Clin Cardiol. 2020;43:145–155. doi: 10.1002/clc.23321. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Heart failure with preserved ejection fraction in the elderly: scope of the problem. Upadhya B, Taffet GE, Cheng CP, Kitzman DW. J Mol Cell Cardiol. 2015;83:73–87. doi: 10.1016/j.yjmcc.2015.02.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Atrial fibrillation begets heart failure and vice versa: temporal associations and differences in preserved versus reduced ejection fraction. Santhanakrishnan R, Wang N, Larson MG, et al. Circulation. 2016;133:484–492. doi: 10.1161/CIRCULATIONAHA.115.018614. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Temporal relationship and prognostic significance of atrial fibrillation in heart failure patients with preserved ejection fraction: a community-based study. Zakeri R, Chamberlain AM, Roger VL, Redfield MM. Circulation. 2013;128:1085–1093. doi: 10.1161/CIRCULATIONAHA.113.001475. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Assessment of coronary artery disease in non-valvular atrial fibrillation: is this light at the end of the tunnel? Batta A, Hatwal J, Sharma YP. Vasc Health Risk Manag. 2024;20:493–499. doi: 10.2147/VHRM.S484638. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.The relationship between atrial fibrillation and coronary artery disease: understanding common denominators. Mekhael M, Marrouche N, Hajjar AH, Donnellan E. Trends Cardiovasc Med. 2024;34:91–98. doi: 10.1016/j.tcm.2022.09.006. [DOI] [PubMed] [Google Scholar]
- 8.Atrial fibrillation and coronary artery disease: an integrative review focusing on therapeutic implications of this relationship. Batta A, Hatwal J, Batta A, Verma S, Sharma YP. World J Cardiol. 2023;15:229–243. doi: 10.4330/wjc.v15.i5.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Pathophysiology, diagnosis, and management of coronary artery disease in the setting of atrial fibrillation. Pintea Bentea G, Berdaoui B, Morissens M, van de Borne P, Castro Rodriguez J. J Am Heart Assoc. 2024;13:0. doi: 10.1161/JAHA.124.037552. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Angiographic profile and outcomes in persistent non-valvular atrial fibrillation: a study from tertiary care center in North India. Sharma YP, Batta A, Makkar K, et al. Indian Heart J. 2022;74:7–12. doi: 10.1016/j.ihj.2021.12.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Predictors of dementia amongst newly diagnosed non-valvular atrial fibrillation patients. Batta A, Sharma YP, Hatwal J, Panda P, Kumar BG, Bhogal S. Indian Heart J. 2022;74:505–509. doi: 10.1016/j.ihj.2022.11.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Heart failure with preserved ejection fraction and atrial fibrillation: vicious twins. Kotecha D, Lam CS, Van Veldhuisen DJ, Van Gelder IC, Voors AA, Rienstra M. J Am Coll Cardiol. 2016;68:2217–2228. doi: 10.1016/j.jacc.2016.08.048. [DOI] [PubMed] [Google Scholar]
- 13.Epicardial adipose tissue: emerging physiological, pathophysiological and clinical features. Iacobellis G, Bianco AC. Trends Endocrinol Metab. 2011;22:450–457. doi: 10.1016/j.tem.2011.07.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Obesity results in progressive atrial structural and electrical remodeling: implications for atrial fibrillation. Abed HS, Samuel CS, Lau DH, et al. Heart Rhythm. 2013;10:90–100. doi: 10.1016/j.hrthm.2012.08.043. [DOI] [PubMed] [Google Scholar]
- 15.Pericardial fat is associated with atrial fibrillation severity and ablation outcome. Wong CX, Abed HS, Molaee P, et al. J Am Coll Cardiol. 2011;57:1745–1751. doi: 10.1016/j.jacc.2010.11.045. [DOI] [PubMed] [Google Scholar]
- 16.Impact of initial high sensitivity C-reactive protein on outcomes in nonvalvular atrial fibrillation: an observational study. Batta A, Hatwal J, Panda P, Sharma Y, Wander GS, Mohan B. Future Cardiol. 2024;20:295–303. doi: 10.1080/14796678.2024.2354110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Association of estimated glomerular filtration rate (EGFR) and high-sensitivity C-reactive protein (hs-CRP) with the risk of new-onset atrial fibrillation in patients with diabetes. Liu Y, Liu H, Sun D, et al. J Inflamm Res. 2025;18:91–103. doi: 10.2147/JIR.S493068. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Epicardial fat and atrial fibrillation: current evidence, potential mechanisms, clinical implications, and future directions. Wong CX, Ganesan AN, Selvanayagam JB. Eur Heart J. 2017;38:1294–1302. doi: 10.1093/eurheartj/ehw045. [DOI] [PubMed] [Google Scholar]
- 19.Echocardiographic epicardial fat: a review of research and clinical applications. Iacobellis G, Willens HJ. J Am Soc Echocardiogr. 2009;12:1311–1319. doi: 10.1016/j.echo.2009.10.013. [DOI] [PubMed] [Google Scholar]
- 20.Epicardial adipose tissue and cardiac lipotoxicity: a review. Mukherjee AG, Renu K, Gopalakrishnan AV, Jayaraj R, Dey A, Vellingiri B, Ganesan R. Life Sci. 2023;328:121913. doi: 10.1016/j.lfs.2023.121913. [DOI] [PubMed] [Google Scholar]
- 21.Epicardial adipose tissue and atrial fibrillation: the other side of the coin. Leggio M, Severi P, D'Emidio S, Mazza A. Anatol J Cardiol. 2017;17:415–416. doi: 10.14744/AnatolJCardiol.2017.7752. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Electrophysiological, electroanatomical, and structural remodeling of the atria as consequences of sustained obesity. Mahajan R, Lau DH, Brooks AG, et al. J Am Coll Cardiol. 2015;66:1–11. doi: 10.1016/j.jacc.2015.04.058. [DOI] [PubMed] [Google Scholar]
- 23.Importance of epicardial adipose tissue localization using cardiac magnetic resonance imaging in patients with heart failure with mid-range and preserved ejection fraction. van Woerden G, van Veldhuisen DJ, Gorter TM, et al. Clin Cardiol. 2021;44:987–993. doi: 10.1002/clc.23644. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Heart failure with preserved ejection fraction: insights from recent clinical researches. Kim MN, Park SM. Korean J Intern Med. 2020;35:514–534. doi: 10.3904/kjim.2020.104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Amplified P-wave duration predicts new-onset atrial fibrillation in patients with heart failure with preserved ejection fraction. Müller-Edenborn B, Minners J, Kocher S, et al. Clin Res Cardiol. 2020;109:978–987. doi: 10.1007/s00392-019-01590-z. [DOI] [PubMed] [Google Scholar]
- 26.Epicardial adipose tissue may mediate deleterious effects of obesity and inflammation on the myocardium. Packer M. J Am Coll Cardiol. 2018;71:2360–2372. doi: 10.1016/j.jacc.2018.03.509. [DOI] [PubMed] [Google Scholar]
- 27.A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. Paulus WJ, Tschöpe C. J Am Coll Cardiol. 2013;23:263–271. doi: 10.1016/j.jacc.2013.02.092. [DOI] [PubMed] [Google Scholar]
- 28.Long-term effect of goal-directed weight management in an atrial fibrillation cohort: a long-term follow-up study (LEGACY) Pathak RK, Middeldorp ME, Meredith M, et al. J Am Coll Cardiol. 2015;26:2159–2169. doi: 10.1016/j.jacc.2015.03.002. [DOI] [PubMed] [Google Scholar]
- 29.SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Verma S, McMurray JJ. Diabetologia. 2018;61:2108–2117. doi: 10.1007/s00125-018-4670-7. [DOI] [PubMed] [Google Scholar]