Association of familial Mediterranean fever and epicardial adipose tissue: A systematic review and meta‐analysis

Abstract Background and Aim Some studies reported a positive link between familial Mediterranean fever (FMF) and epicardial adipose tissue. Our meta‐analysis aimed to evaluate whether there is a significant association between FMF and increased epicardial adipose tissue thickness. Methods We searched the following databases: PUBMED, WOS, OVID, SCOPUS, and EMBASE. Inclusion criteria were any original articles that reported epicardial adipose tissue in FMF patients with no age restriction, excluding reviews, case reports, editorials, animal studies, and non‐English studies. Thirty eligible studies were screened full text but only five studies were suitable. We used RevMan software (5.4) for the meta‐analysis. Results The total number of patients included in the meta‐analysis in the FMF patients group is 256 (mean age = 24.3), and the total number in the control group is 188 (mean age = 24.98). The pooled analysis between FMF patients and controls was [mean difference = 0.82 (95% CI = 0.25–1.39), p‐value = 0.005]. We observed heterogeneity that was not solved by random effects (p > 0.00001). We performed leave one out test by removing the Kozan et al. study, and the heterogeneity was solved (p = 0.07), and the results were (MD = 0.98, 95% CI = 0.52–1.43, p‐value < 0.0001). Conclusion FMF patients are at increased risk of developing epicardial adipose tissue compared to controls. More multicenter studies with higher sample sizes are needed to support our results.


| INTRODUCTION
Familial Mediterranean fever (FMF) is characterized by intermittent attacks of fever, painful inflammation, arthritis, and abdominal pain that last from few hours to days and recur after weeks or months. It is an autosomal recessive illness seen mainly in Turkish, Armenian, and Mediterranean region ethnics and diagnosed by Tel-Hashomer clinical criteria, consisting of two or more significant symptoms (from febrile episodes with serositis or a favorable response to colchicine or amyloidosis) or one major plus two minor symptoms (a first degree relative with FMF, erysipelas like erythema and recurrent febrile episodes). 1 FMF increases the risk of developing coronary artery diseases (CAD), as witnessed in several studies that reported a higher prevalence of CAD in FMF patients. 2,3 The nonsubsiding inflammation that occurs in FMF is a critical player in the pathogenesis of plaque formation and blood vessels thickening, explaining this higher incidence of CAD. 4 Yet abnormal lipid profile that increases atherosclerosis risk due to high Triglycerides/high density lipoprotein (TG/HDL) ratio is not always associated with an increased carotid intima-media thickness. Thus, carotid intima-media thickness can not detect subclinical atherosclerosis. Several studies failed to show any significant difference in carotid intima-media thickness (CIMT) between FMF patients and other patients despite an increase in cholesterol and TG levels. 5,6 On the other hand, some studies have found the Epicardial adipose thickness had a positive correlation with cholesterol and TG levels and thus could be used for early detection of subclinical atherosclerosis. The study aims to find out if there is an association between FMF patients and epicardial adipose tissue and if epicardial adipose tissue could be used as an early predictor of atherosclerosis in FMF patients. 7 2 | METHODS

| *Search and identification of studies
We searched the following databases: PUBMED, WOS, OVID, SCOPUS, and EMBASE through June 2021. We also searched Open Grey, Lilacs, and Proquest databases for relevant literature and dissertations. Search terms used were ("Familial Mediterranean Fever" OR "Familial Paroxysmal Polyserositis" OR "Periodic Disease" OR "Periodic Peritonitis" OR "Recurrent Polyserositis") AND ("epicardial adipose tissue" OR "lipids"). Detailed search strategy for each database and the date, which the database was last consulted are available in Supporting Information.

| *Selection process and inclusion criteria
Yielded results from databases were imported into Covidence. 8 From the searches, initial screening of title and abstract was done along with retrieval of potentially relevant references by four authors. Next, full-text studies were retrieved, if there is a conflict among the authors who screened the studies, a final decision by the first author was taken. The full-text screening was performed for the papers using predetermined inclusion criteria: any controlled clinical trials, case control studies, controlled retrospective or prospective cohort studies that reported epicardial adipose tissue thickness in FMF patients and controls without FMF with no age restriction excluding reviews, case reports, editorials, animal studies, and non-English studies. These controlled studies were included in the analysis if they measured epicardial adipose tissue thickness in FMF patients and controls without FMF.

| Data extraction and quality assessment
Data were extracted from each study by two authors after obtaining the full paper into excel sheets. Each author revised the work of the other one, if there is a conflict between the authors who extracted the data, a final decision by the first author was taken. Quality assessment was done by the New castle Ottawa scale assessment tool. The studies were ranked as good, fair, or poor.

| Statistical analysis
A meta-analysis was carried out evaluating the association between FMF patients and epicardial adipose tissue.
RevMan 5.4 was used for statistical analysis. The continuous outcomes were measured as mean difference (MD) and standard deviation (SD) with a 95% confidence interval. If heterogeneity (Chisquare p-value < 0.05) was observed, a random effect model was used otherwise, a fixed-effect model was performed. The results were considered significant if the p-value was less than 0.05.

| RESULTS
After a search of the literature, 2762 papers resulted and became 2734 eligible for the title and abstract screening after removal of duplicates. Of 2734, 2704 were irrelevant, and 30 were eligible for full-text screening. There were 25 studies that might appear to meet the inclusion criteria, but were excluded as studies [9][10][11][12][13] because of wrong study design and wrong outcomes. Five studies were included in the meta-analysis after performing full-text screening, as shown in (Figure 1). We aimed to pool the data in the five studies to find an association between the increased thickness of epicardial adipose tissue and FMF patients. The quality assessment and summary of the included studies are shown in Tables 1 and 2, respectively. The overall quality was high in the included studies.

| Analyses
The total number of patients included in the meta-analysis in the FMF patients group is 256 (mean age = 24.3), and the total number in the control group is 188 (mean age = 24.98).
The pooled analysis between FMF patients and controls was (MD = 0.82, 95% CI = 0.25-1.39, p-value = 0.005), we observed heterogeneity that was not solved by random effects (p > 0.00001), as shown in Figure 2.

| DISCUSSION
A statistically significant association was found between FMF and increased epicardial adipose tissue thickness compared to controls.
Epicardial adipose tissue (EAT) surrounds the myocardium and is primarily made up of adipocytes. Stromal, nerve, vascular, and even inflammatory cells are also known to exist in EAT. 8 EAT is known to have less adipocyte density than other visceral fat stores, with increased efficiency in fatty acid intake and secretion. 14 EAT is part of the visceral adipose tissue between the heart and pericardium, including both atrioventricular and interventricular sulcus, and is situated around the coronary arteries. 15 Transthoracic echocardiography is typically utilized to visualize the EAT, which is depicted as a thick line above the right ventricles free wall. 16 The EAT is thicker with increased volume in patients with obesity, impaired glucose tolerance, metabolic syndrome, hypertension, diabetes, and atherosclerosis. 17,18 The expression and secretion of multiple interleukins (IL-1, -1β, -6, -8, and -10) are increased from EAT in patients with coronary artery disease versus the healthy control group. 19 Furthermore, EAT is also known to secrete higher levels of reactive oxygen species than subcutaneous fat tissue in those who have coronary artery disease. 20 The utility of epicardial adipose tissue thickness and mean platelet volume are relatively new dimensions used to assess the risk of atherosclerosis. [21][22][23] FMF is thought to predispose patients to atherosclerosis due to its inflammatory process. 24,25 FMF is directly associated with nod-like receptor family pyrin domain-containing three inflammasome (NLRP3) dysfunction, which leads to IL-1β dependent auto-inflammation. 26 The cytokines IL-6 and TNF-α were also increased in FMF patients both during attacks and in the attack-free periods. 27 The inflammation leads to decreased aortic elasticity, increased arterial stiffness, 28 vascular dysfunction, 29 as well as pericarditis, and even rhythm disorders. 30  Regarding the main findings of this current review that determine the existence of significant association between FMF and EAT, these outcomes may need a strict follow-up and the implementation of appropriate preventative measures. It is essential to determine if FMF patients have a higher risk of atherosclerosis, even when they're young. Measurement of mean platelet volume and cholesterol level are easy and inexpensive tests for investigation of thrombosis and atherosclerosis in FMF patients, also echocardiography is an easy and noninvasive way that could be used to measure EAT thickness. 32,35 The results of this study may be interpreted in clinical practice, as epicardial adipose tissue thickness may be used as a marker to assess the risk of atherosclerosis in FMF patients. FMF patients should perform echocardiography regularly to measure EAT, as they are at increased risk of developing increased EAT. Future clinical trials using therapies targeting EAT in FMF patients may be useful in primary prevention of EAT and atherosclerosis in high-risk patients.
Our study is limited by few numbers of studies and patients included, only case control and cohort studies included, as we found no published randomized control trials about the topic and the observed heterogeneity among studies due to different study designs, so further randomized clinical trials with higher numbers of patients are needed to support our findings.

| CONCLUSION
Our meta-analysis revealed that Familial Mediterranean Fever patients are at elevated risk of developing increased epicardial adipose tissue thickness. Epicardial adipose tissue is important in predicting atherosclerosis in FMF patients, as they are at increased risk of developing atherosclerosis. More multicenter studies with higher sample sizes are needed to support our findings.