Editorial
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Feb 15, 2020; 11(2): 33-41
Published online Feb 15, 2020. doi: 10.4239/wjd.v11.i2.33
Epicardial adipose tissue deposition in patients with diabetes and renal impairment: Analysis of the literature
Zoi Kleinaki, Aris P Agouridis, Maria Zafeiri, Theodoros Xanthos, Constantinos Tsioutis
Zoi Kleinaki, Aris P Agouridis, Theodoros Xanthos, Constantinos Tsioutis, School of Medicine, European University Cyprus, Nicosia 2404, Cyprus
Maria Zafeiri, Diabetes and Obesity Center, Konstantopouleio Hospital, Athens 14233, Greece
ORCID number: Zoi Kleinaki (0000-0002-0658-1876); Aris P Agouridis (0000-0002-9749-5075); Maria Zafeiri (0000-0002-5115-7433); Theodoros Xanthos (0000-0003-3670-9305); Constantinos Tsioutis (0000-0002-7865-8529).
Author contributions: Kleinaki Z conceptualized and designed the study, participated in data acquisition, extraction and interpretation, prepared tables, wrote and drafted the initial manuscript and approved the final manuscript as submitted; Agouridis AP participated in data analysis and interpretation, reviewed and revised the manuscript and approved the final manuscript as submitted; Zafeiri M conceptualized the study, participated in data interpretation, reviewed and revised the initial manuscript and approved the final manuscript as submitted; Xanthos T participated in data interpretation, reviewed and revised the initial manuscript and approved the final manuscript as submitted; Tsioutis C conceptualized and designed the study, participated in data acquisition, interpreted the data, wrote and drafted the initial manuscript, reviewed and revised the manuscript and approved the final manuscript as submitted.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Constantinos Tsioutis, MD, PhD, Lecturer, School of Medicine, European University Cyprus, 6 Diogenes Street, Nicosia 2404, Cyprus. kostsioutis@gmail.com
Received: September 3, 2019
Peer-review started: August 28, 2018
First decision: October 9, 2018
Revised: December 11, 2019
Accepted: December 14, 2019
Article in press: December 14, 2019
Published online: February 15, 2020

Abstract

Diabetes mellitus (DM) is defined as a chronic disease of disordered metabolism with an ongoing increase in prevalence and incidence rates. Renal disease in patients with diabetes is associated with increased morbidity and premature mortality, particularly attributed to their very high cardiovascular risk. Since this group of patients frequently lacks specific symptomatology prior to the adverse events, a screening tool for the identification of high-risk patients is necessary. The epicardial adipose tissue (EAT) is a biologically active organ having properties similar to visceral adipose tissue and has been associated with metabolic diseases and coronary artery disease. Superior to conventional cardiovascular risk factors and anthropometric measures, including body mass index and waist circumference, the EAT can early predict the development of coronary artery disease. Assessment of EAT can be performed by two-dimensional echocardiography, magnetic resonance imaging or computer tomography. However, its role and significance in patients with DM and nephropathy has not been thoroughly evaluated. The aim of the current editorial is to evaluate all available evidence regarding EAT in patients with DM and renal impairment. Systematic search of the literature revealed that patients with DM and nephropathy have increased EAT measurements, uncontrolled underlying disease, high body mass index and raised cardiovascular risk markers. Acknowledging the practical implications of this test, EAT assessment could serve as a novel and non-invasive biomarker to identify high-risk patients for cardiovascular adverse events.

Key Words: Epicardial adipose tissue, Epicardial fat, Diabetes mellitus, Renal impairment, Diabetic nephropathy, Cardiovascular risk

Core tip: The epicardial adipose tissue (EAT) is a biologically active organ and has been associated with metabolic diseases and coronary artery disease. EAT is a superior cardiovascular risk factor compared to conventional measures. This editorial evaluates the reported measurements of EAT in patients with diabetes mellitus and renal impairment, along with their clinical and laboratory characteristics. Patients with diabetes mellitus and nephropathy have increased EAT volume, uncontrolled disease, high body mass index and raised cardiovascular risk markers, when compared with healthy population. Based on current literature, EAT assessment could be used as a novel biomarker for the identification of patients at high risk for cardiovascular adverse events.



INTRODUCTION

Diabetes mellitus (DM) consists a chronic multisystem disease of disordered metabolism with a worldwide prevalence reaching approximately 425 million[1]. The major complications of DM can be divided into macrovascular (cardiovascular disease) and microvascular [chronic kidney disease (CKD), diabetic retinopathy, diabetic neuropathy][2-4]. Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetic patients, with a prevalence of 20%-40% in patients with type 1 or type 2 DM[5]. The majority of DM cases with CKD result from DN[6]. In addition, increased albuminuria and diminished renal function indicate unfavorable prognosis in terms of cardiovascular disease[7].

Epicardial adipose tissue (EAT) is a biologically active organ with properties similar to visceral adipose tissue[8,9]. EAT is defined as the adipose tissue located between the visceral pericardium and the myocardium, in the absence of a structure separating it from the myocardium and the epicardial vessels[8]. Assessment of EAT can be performed by the following imaging techniques: Two-dimensional echocardiography, magnetic resonance imaging (MRI), or computer tomography (CT)[10]. CT could concomitantly assess the presence of coronary calcification or stenosis[11]. Increased amounts of EAT have been associated with the presence of metabolic syndrome, DM and coronary artery disease[10]. EAT has also been proposed as a key mediator in the pathogenesis of cardiovascular disease in end-stage renal disease (ESRD) patients, the most common cause of death in this particular group[12,13].

THE NECESSITY OF A NEW SCREENING TOOL

EAT has been currently identified as a marker of cardiovascular risk[8,9]. Patients with DM and renal impairment have a high prevalence of cardiovascular adverse events, frequently lacking warning symptoms such as chest pain, usually due to either diabetic autonomic neuropathy, uremic neuropathy, or impaired exercise capacity[14,15]. This high-risk group of patients requires regular follow-up, since cardiovascular disease consists the single leading cause of morbidity and mortality in patients with CKD in all stages[6]. In light of these considerations, this editorial will focus on the value of EAT assessment in patients with DM and renal disease.

AVAILABLE EVIDENCE

Two online databases (PubMed and Scopus) were systematically searched for articles published from inception up to December 2019. The search term applied consisted of the following key words: (“diabetes mellitus” OR “diabetic” OR “diabetes”) AND (“epicardial fat” OR “epicardial adipose” OR “subepicardial fat” OR “subepicardial adipose”), in order to identify all published articles reporting data on patients with DM and renal impairment who were assessed for EAT measurements. Reference lists of full articles were also reviewed.

Articles with the following requirements were included: (1) Primary research papers (e.g., case reports, case series, observational studies, randomized control trials); (2) Studies describing patients (adults ≥ 18 years) with type 1 or type 2 DM and renal impairment who had undergone measurement of EAT deposition; and (3) Studies published in English.

Studies containing at least one of the following items were excluded: (1) Studies published in other than English language; (2) Experimental studies on animals; (3) Cases not diagnosed with DM; (4) Studies including exclusively patients with gestational DM; (5) Secondary research papers; (6) Editorials and papers not reporting results of primary research; and (7) Studies not referring to patients with DM, renal impairment and epicardial fat deposition measurements.

Study outcomes were to evaluate all available evidence regarding EAT measurements in patients with DM and renal impairment; to record all clinical and laboratory characteristics and comorbid conditions; and to identify possible risk factors that could contribute to epicardial fat tissue deposition in these patients.

ANALYSIS OF CURRENT LITERATURE

A total of eight studies referring to patients with DM and renal impairment with EAT assessment were incorporated in the analysis[16-22]. Table 1 summarizes the characteristics of the 8 included studies and the 452 patients that were analyzed. All were cross-sectional, except one case-report. According to data available in 368 patients, mean age was 59 years of age (range: 49-71) and 140 (31%) patients were female[16,17,19,21,23].

Table 1 Study and patient characteristics.
Ref.Study designAge groupNumber of patients with diabetes and renal impairmentAge, mean in years (range)Gender, female, n (%)
Akbas et al[16], 2014, TurkeyCross-sectionalAdults68Micro-albuminuric patients: 60 ± 1134 (50)
Macro-albuminuric patients: 59 ± 9.6
Christensen et al[17], 2017, DenmarkCross-sectionalAdults20059 (50-68)48 (24)
Darabian et al[18], 2016, United StatesCross-sectionalAdults9NRNR
Do et al[19], 2009, KoreaCase-reportAdult1591 (100)
Kerr et al[20], 2013, CanadaCross-sectionalAdults36NRNR
Tonbul et al[21], 2011, TurkeyCross-sectionalAdults1758 (45-71)8 (47)
Turan et al[22], 2013, TurkeyCross-sectionalAdults39NRNR
Turan et al[23], 2019, TurkeyCross-sectionalAdults8259.4 ± 7.649 (59.7)
Epicardial adipose tissue characteristics

The EAT was quantified in all eight studies. Investigators used either transthoracic echocardiography[16,17] or multi-detector CT (MDCT)[18-22] to assess epicardial fat. Transthoracic echocardiography was used to measure EAT thickness in three studies: mean 3.2 ± 1.6 mm[17], median 4.5 mm (range: 2-9 mm) and 5.3 mm (range: 4.4-9 mm) in the micro- and macro-albuminuric group respectively[16], and mean 6.5 ± 1.4 mm[23]. According to previous studies, the mean thickness value in systole described by Iacobellis et al[24] during the investigation of cardiovascular risk, was 6.8 mm (range: 1.1-22.6). The mean value in diastole introduced by Jeong et al[25] in more than 200 patients admitted for coronary angiography, was 6.4 mm (range: 1.1-16.6). Although there is no consensus for EAT thickness cut-off values, measurements higher than 5 mm indicate increased EAT, especially in low risk populations[8].

MDCT was used to assess EAT volume in cm3 or mm3 units. In one study, EAT was expressed as single slice epicardial fat volume or as single slice epicardial fat area[20]. A previous study determined that single slice epicardial fat area measured at the level of left main coronary artery provides a reliable estimate of total epicardial fat volume[26]. Most of the studies using MDCT included the range of -190 to -30 of Hounsfield units regarding determination of fat. The mean EAT volume of the four studies was 258.4 cm3 (range: 0.01-487)[18-20,22]. One study reported the median EAT volume of 17 patients which equaled 215.5 cm3 (range: 126.5-271.2)[21]. The value of 0.01 cm3, reported in one study, could be attributed to the different range of Hounsfield units used for determination of fat density[18]. In comparison, the mean volume of EAT ranged from 68 ± 34 cm3 to 124 ± 50 cm3 in previous population-based studies[27,28]. A cohort study derived from Framingham Heart Study, found a mean EAT volume of 110 ± 41 cm3 in women and 137 ± 53 cm3 in men[11]. Based on current literature, a cut-off EAT volume of more than 125 cm3 can be considered as abnormal[8]. Hence, patients with DM and renal impairment seem to have an increased EAT volume compared to healthy populations.

Diabetes mellitus characteristics

Type of DM was reported in 359 patients[16-18], of which 350 (96.8%) had type 2 DM[16,17,23] and 9 (3.2%) had type 1 DM[18]. Duration of DM was reported in 350 patients and ranged from 0 to 30 years[16,17,23]. The HbA1c levels, reported in 350 patients, ranged from 6% to 14.5%, with an approximate mean value of 8.7%[16,17,23]. Among 291 patients with available data on treatment of diabetes, 223 (76.6%) patients were being treated with oral antidiabetics and/or 180 (80.7%) patients were being treated with either insulin injections or insulin infusion pump[16,17,23]. Average body mass index (BMI), estimated in 368 patients, was 32.3 kg/m2 (range: 28.5-34.4)[16,17,19,21,23]. The characteristics of DM are reported in Table 2.

Table 2 Diabetes and renal disease characteristics.
Ref. (number of patients)Diabetes typeDiabetes duration, median (IQR) or mean ± SD in yearsCriteria for renal impairment diagnosiseGFR,mean ± SD (mL/min/1.73 m2)Albuminuria, median (IQR) (units)Creatinine, median (IQR) or mean ± SD (mg/dL)Other related measurements
Akbas et al[16] (n = 68)Type 2Micro-albuminuric patients: 9 (0-30); Macro-albuminuric patients: 8.5 (1-29)Presence of albuminuria (> 30 mg/g Cr)Micro-albuminuric patients: 94 ± 29; Macro-albuminuric patients: 64 ± 44Micro-albuminuric patients: 74 (33-294) (mg/g Cr); Macro-albuminuric patients: 716 (312-1985) (mg/g Cr)Micro-albuminuric patients: 0.75BMI (kg/m2): 30; Waist circumference (cm): 102; SBP (mmHg): 135 (90-210); DBP (mmHg): 78 (40-110)
(0.5-2); Macro-albuminuric patients: 1.4 (0.4-3.5)
Christensen et al[17] (n = 200)Type 213 ± 7Presence of albuminuria (> 30 mg/g Cr)89 ± 17102 (39-229) (mg/24 h)0.86 ± 0.2BMI (kg/m2): 32.6; SBP (mmHg): 130 ± 16; Cholesterol (mg/dL): 151; LDL (mg/dL): 73.4; HDL (mg/dL): 46.4
Darabian et al[18] (n = 9)Type 1NRPresence of albuminuria (> 30 mg/g Cr) or ESRDNRNRNRNR
Do et al[19] (n = 1)NRNRESRD (peritoneal dialysis)(End-stage renal failure)NR9.13BMI (kg/m2): 29.6
Kerr et al[20] (n = 36)NRNRCKD diagnosis according to National Kidney Foundation CriteriaNRNRNRNR
Tonbul et al[21] (n = 17)NRNRESRD (hemodialysis or peritoneal dialysis)(End-stage renal failure)NRNRBMI (kg/m2): 28.5; SBP (mmHg): 135 ± 27; DBP (mmHg): 80 ± 16; LDL (mg/dL): 120; HDL (mg/dL): 37; Triglycerides (mg/dL): 127
Turan et al[22] (n = 39)NRNRESRD (hemodialysis)(End-stage renal failure)NRNRNR
Turan et al[23] (n = 82)Type 212.7 ± 6.7Presence of micro-albuminuria (30-300 mg/g)80 ± 20134 ± 83 (mg/g)0.91 ± 0.2BMI (kg/m2): 34.4 ± 6.2; SBP (mmHg): 135 ± 16; DBP (mmHg): 80.5 ± 11; LDL (mg/dL): 123 ± 35; HDL (mg/dL): 44 ± 10.6; Triglycerides (mg/dL): 211

BMI is an anthropometric measure widely used to assess visceral adipose tissue deposition[29]. Excess visceral adipose tissue is a marker of patients with high risk for cardiovascular disease[30,31]. This finding is in line with the current literature suggesting that visceral adipose tissue has a strong correlation with EAT[30,32].

Renal impairment characteristics

Patients from all different CKD stages were included. Albuminuria was used as an early and sensitive marker of renal impairment in three studies[16,17,23]. One study included patients with both macroalbuminuria and ESRD[18]. Albuminuria was estimated in 350 patients[16,17,23], among which 274 patients had microalbuminuria (30-299 mg/g Cr) and 76 patients had macroalbuminuria (> 300 mg/g Cr)[16,17,23]. Three studies revealed that albuminuria was a significant predictor of greater EAT[16,18,20]. Mean eGFR and mean creatinine, assessed in 350 patients, were 82 mL/min/1.73/m2 (range: 20-123)[16,17,23] and 1.0 mg/dL (range: 0.4-3.5), respectively[16,17,23]. Patients with ESRD were reported in 57 patients in three studies[19,21,22]. Renal impairment characteristics are depicted in Table 2.

Albuminuria is a marker of diffuse endothelial dysfunction associated with hypertension, smoking, DM, obesity and dyslipidemia[33,34]. Albuminuria consists a risk factor for cardiovascular disease and is associated with increased abdominal adiposity[35]. The ADVANCE Study showed that albuminuria and reduced GFR were independently and additively associated with increased cardiovascular and renal events in patients with type 2 DM[36].

EAT is a biologically active organ having properties similar to the visceral adipose tissue, secreting proatherogenic hormones and cytokines such as leptin and resistin[8]. The absence of a specific fascial layer or aponeurosis between the epicardial vessels and the myocardium surrounding the adventitia of coronary arteries and their branches, allows for a shared micro-circulation and the subsequent development of coronary artery disease[8,37]. The protective effect of adiponectin which acts by increasing insulin sensitivity is found to be reduced in patients with increased deposits of EAT[38,39]. CKD involves chronic inflammation, characterized by the presence of increased inflammatory markers, including C-reactive protein, IL-6, and TNF-α[12]. C-reactive protein is also associated with the prevalence of metabolic syndrome, hypertension and DM in United States adults[40]. Atherosclerosis is greatly enhanced under higher inflammation status or increased oxidative stress[12]. Microvascular complications of DM, including DN, are promoted under the influence of inflammation and oxidative stress by the metabolism of hyperglycemia and dyslipidemia[16,41-46].

Conclusively, the presence of albuminuria along with endothelial dysfunction and increased abdominal adiposity, the secretion of proatherogenic hormones and cytokines by EAT in combination with the loss of protective effect of adiponectin, the pronounced inflammation and oxidative stress in CKD patients, all contribute to the development of coronary artery disease in patients with DM and renal impairment.

Coronary artery calcium score

Total coronary artery calcium score (CACS) was evaluated in 217 patients[17,21]. Left anterior descending coronary artery, circumflex coronary artery and right coronary artery were added to calculate the CACS according to the protocol by Agatston et al[47], for quantification of CACS using ultrafast CT. The mean CACS was 192.5, with a normal range between 1 and 10.

CACS is an index that assesses the severity of atherosclerotic vascular disease and predicts the risk of future adverse cardiovascular events[48]. CACS equal to 192.5 is classified as moderate risk (relative risk: 4.3) of having a cardiovascular event according to Agatston et al[47]. According to previous studies, individuals with DN had a significantly higher prevalence and severity of CACS score when compared to normoalbuminuric diabetic patients[49]. Also, the progression of CACS in patients with DM and CKD is more prevalent in those with albuminuria when compared with normoalbuminuric patient controls[50]. Increased EAT volume was also correlated with CACS in ESRD patients[21]. Two studies included measurements of inflammatory markers[16,17], which were found to be associated with increased albuminuria[16] and with EAT[17,51]. Based on the aforementioned results and according to the literature, EAT volume is associated with the malnutrition, inflammation and atherosclerosis/calcification syndrome in ESRD patients, which is associated with increased morbidity and mortality.

CRITICAL APPRAISAL OF THE LITERATURE

The above findings should be considered in relation to the fact that most available evidence is derived from observational cross-sectional studies with relatively small sample sizes. Several determinants of EAT including obesity, age and ethnicity, which may set different normal ranges, were not reported in all patients[24,52-56]. Additionally, several characteristics of DM and renal disease were not reported in all patients. MDCT protocol and definitions used varied among studies. Although MRI is considered the standard of reference for EAT quantification[57], no studies that utilized MRI were available.

FUTURE DIRECTIONS

According to current literature, EAT can be supported as a superior cardiovascular risk factor compared to conventional anthropometric measures, indicating that localized fat depositions predict more accurately the future adverse coronary events[10]. EAT was particularly increased in non-calcified and mixed plaques, the most commonly implicated in cardiovascular events, in comparison with purely calcified plaques[53,58]. At this point, there is evident need to establish cut-off points for EAT volume and thickness in high-risk patient groups such as patients with DM and DN; to that end, future studies should prefer to opt for EAT volume over thickness assessment, using standardized MDCT or MRI protocols. In addition, future studies should report more detailed data on patients, including DM and DN characteristics and somatometric data. Although not within the scope of the current review, studies have also focused on the reduction of EAT through conservative, pharmacological or surgical means, yielding various results[9,59-65]. Future studies should assess the safety and long-term effects of EAT reduction. This way, EAT could concomitantly be used as a screening tool and as a follow-up marker.

CONCLUSION

Available evidence shows that patients with DM and renal impairment have uncontrolled disease, with raised cardiovascular risk markers, high BMI and increased EAT measurements, when compared with healthy populations. Although specific cut-off limits need to be developed and acknowledging the practical issues concerning this test, EAT assessment could be used as a novel practical and inexpensive biomarker for identification of patients at high risk for cardiovascular adverse events.

Footnotes

Manuscript source: Unsolicited manuscript

Specialty type: Endocrinology and metabolism

Country of origin: Cyprus

Peer-review report classification

Grade A (Excellent): A

Grade B (Very good): B

Grade C (Good): C, C

Grade D (Fair): D

Grade E (Poor): 0

P-Reviewer: Choi MR, Dabla PK, Gonzalez F, Jiang LH, Raghow R S-Editor: Yan JP L-Editor: A E-Editor: Qi LL

References
1.  IDF Diabetes Atlas. IDF diabetes atlas 8th edition [Internet]. 2017 [cited 2019 May 13].  Available from: https://www.diabetesatlas.org/.  [PubMed]  [DOI]
2.  Donaghue KC, Marcovecchio ML, Wadwa RP, Chew EY, Wong TY, Calliari LE, Zabeen B, Salem MA, Craig ME. ISPAD Clinical Practice Consensus Guidelines 2018: Microvascular and macrovascular complications in children and adolescents. Pediatr Diabetes. 2018;19 Suppl 27:262-274.  [PubMed]  [DOI]
3.  Papatheodorou K, Papanas N, Banach M, Papazoglou D, Edmonds M. Complications of Diabetes 2016. J Diabetes Res. 2016;2016:6989453.  [PubMed]  [DOI]
4.  Papatheodorou K, Banach M, Bekiari E, Rizzo M, Edmonds M. Complications of Diabetes 2017. J Diabetes Res. 2018;2018:3086167.  [PubMed]  [DOI]
5.  Rossing P, Persson F, Frimodt-Møller M. Prognosis and treatment of diabetic nephropathy: Recent advances and perspectives. Nephrol Ther. 2018;14 Suppl 1:S31-S37.  [PubMed]  [DOI]
6.  Persson F, Rossing P. Diagnosis of diabetic kidney disease: state of the art and future perspective. Kidney Int Suppl (2011). 2018;8:2-7.  [PubMed]  [DOI]
7.  Levey AS, de Jong PE, Coresh J, El Nahas M, Astor BC, Matsushita K, Gansevoort RT, Kasiske BL, Eckardt KU. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int. 2011;80:17-28.  [PubMed]  [DOI]
8.  Bertaso AG, Bertol D, Duncan BB, Foppa M. Epicardial fat: definition, measurements and systematic review of main outcomes. Arq Bras Cardiol. 2013;101:e18-e28.  [PubMed]  [DOI]
9.  Katsiki N, Mikhailidis DP, Wierzbicki AS. Epicardial fat and vascular risk: a narrative review. Curr Opin Cardiol. 2013;28:458-463.  [PubMed]  [DOI]
10.  Talman AH, Psaltis PJ, Cameron JD, Meredith IT, Seneviratne SK, Wong DT. Epicardial adipose tissue: far more than a fat depot. Cardiovasc Diagn Ther. 2014;4:416-429.  [PubMed]  [DOI]
11.  Rosito GA, Massaro JM, Hoffmann U, Ruberg FL, Mahabadi AA, Vasan RS, O'Donnell CJ, Fox CS. Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community-based sample: the Framingham Heart Study. Circulation. 2008;117:605-613.  [PubMed]  [DOI]
12.  Graham-Brown MP, McCann GP, Burton JO. Epicardial adipose tissue in patients with end-stage renal disease on haemodialysis. Curr Opin Nephrol Hypertens. 2015;24:517-524.  [PubMed]  [DOI]
13.  Russo R, Di Iorio B, Di Lullo L, Russo D. Epicardial adipose tissue: new parameter for cardiovascular risk assessment in high risk populations. J Nephrol. 2018;31:847-853.  [PubMed]  [DOI]
14.  Hakeem A, Bhatti S, Chang SM. Screening and risk stratification of coronary artery disease in end-stage renal disease. JACC Cardiovasc Imaging. 2014;7:715-728.  [PubMed]  [DOI]
15.  Bravo PE, Psaty BM, Di Carli MF, Branch KR. Identification of coronary heart disease in asymptomatic individuals with diabetes mellitus: to screen or not to screen. Colomb Med (Cali). 2015;46:41-46.  [PubMed]  [DOI]
16.  Akbas EM, Demirtas L, Ozcicek A, Timuroglu A, Bakirci EM, Hamur H, Ozcicek F, Turkmen K. Association of epicardial adipose tissue, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio with diabetic nephropathy. Int J Clin Exp Med. 2014;7:1794-1801.  [PubMed]  [DOI]
17.  Christensen RH, von Scholten BJ, Hansen CS, Heywood SE, Rosenmeier JB, Andersen UB, Hovind P, Reinhard H, Parving HH, Pedersen BK, Jørgensen ME, Jacobsen PK, Rossing P. Epicardial, pericardial and total cardiac fat and cardiovascular disease in type 2 diabetic patients with elevated urinary albumin excretion rate. Eur J Prev Cardiol. 2017;24:1517-1524.  [PubMed]  [DOI]
18.  Darabian S, Backlund JY, Cleary PA, Sheidaee N, Bebu I, Lachin JM, Budoff MJ; DCCT/EDIC Research Group. Significance of Epicardial and Intrathoracic Adipose Tissue Volume among Type 1 Diabetes Patients in the DCCT/EDIC: A Pilot Study. PLoS One. 2016;11:e0159958.  [PubMed]  [DOI]
19.  Do GW, Ku BS, Park CS, Kim SJ, Shin ES, Choi SH, Lee SG. A case of constrictive pericarditis associated with huge epicardial fat volume. Korean Circ J. 2009;39:116-120.  [PubMed]  [DOI]
20.  Kerr JD, Holden RM, Morton AR, Nolan RL, Hopman WM, Pruss CM, Garland JS. Associations of epicardial fat with coronary calcification, insulin resistance, inflammation, and fibroblast growth factor-23 in stage 3-5 chronic kidney disease. BMC Nephrol. 2013;14:26.  [PubMed]  [DOI]
21.  Tonbul HZ, Turkmen K, Kayıkcıoglu H, Ozbek O, Kayrak M, Biyik Z. Epicardial adipose tissue and coronary artery calcification in diabetic and nondiabetic end-stage renal disease patients. Ren Fail. 2011;33:770-775.  [PubMed]  [DOI]
22.  Turan MN, Gungor O, Asci G, Kircelli F, Acar T, Yaprak M, Ceylan N, Demirci MS, Bayraktaroglu S, Toz H, Ozkahya M, Ok E. Epicardial adipose tissue volume and cardiovascular disease in hemodialysis patients. Atherosclerosis. 2013;226:129-133.  [PubMed]  [DOI]
23.  Turan Y, Turan E. Aortic Stiffness Index And Carotid Intima-Media Thickness Are Independently Associated With The Presence Of Microalbuminuria In Patients With Type 2 Diabetes Mellitus. Diabetes Metab Syndr Obes. 2019;12:1889-1896.  [PubMed]  [DOI]
24.  Iacobellis G, Willens HJ, Barbaro G, Sharma AM. Threshold values of high-risk echocardiographic epicardial fat thickness. Obesity (Silver Spring). 2008;16:887-892.  [PubMed]  [DOI]
25.  Jeong JW, Jeong MH, Yun KH, Oh SK, Park EM, Kim YK, Rhee SJ, Lee EM, Lee J, Yoo NJ, Kim NH, Park JC. Echocardiographic epicardial fat thickness and coronary artery disease. Circ J. 2007;71:536-539.  [PubMed]  [DOI]
26.  Oyama N, Goto D, Ito YM, Ishimori N, Mimura R, Furumoto T, Kato F, Tsutsui H, Tamaki N, Terae S, Shirato H. Single-slice epicardial fat area measurement: do we need to measure the total epicardial fat volume? Jpn J Radiol. 2011;29:104-109.  [PubMed]  [DOI]
27.  Mahabadi AA, Massaro JM, Rosito GA, Levy D, Murabito JM, Wolf PA, O'Donnell CJ, Fox CS, Hoffmann U. Association of pericardial fat, intrathoracic fat, and visceral abdominal fat with cardiovascular disease burden: the Framingham Heart Study. Eur Heart J. 2009;30:850-856.  [PubMed]  [DOI]
28.  Ding J, Kritchevsky SB, Hsu FC, Harris TB, Burke GL, Detrano RC, Szklo M, Criqui MH, Allison M, Ouyang P, Brown ER, Carr JJ. Association between non-subcutaneous adiposity and calcified coronary plaque: a substudy of the Multi-Ethnic Study of Atherosclerosis. Am J Clin Nutr. 2008;88:645-650.  [PubMed]  [DOI]
29.  Kannel WB, Cupples LA, Ramaswami R, Stokes J, Kreger BE, Higgins M. Regional obesity and risk of cardiovascular disease; the Framingham Study. J Clin Epidemiol. 1991;44:183-190.  [PubMed]  [DOI]
30.  De Larochellière E, Côté J, Gilbert G, Bibeau K, Ross MK, Dion-Roy V, Pibarot P, Després JP, Larose E. Visceral/epicardial adiposity in nonobese and apparently healthy young adults: association with the cardiometabolic profile. Atherosclerosis. 2014;234:23-29.  [PubMed]  [DOI]
31.  Katsiki N, Athyros VG, Mikhailidis DP. Abnormal Peri-Organ or Intra-organ Fat (APIFat) Deposition: An Underestimated Predictor of Vascular Risk? Curr Vasc Pharmacol. 2016;14:432-441.  [PubMed]  [DOI]
32.  Karayiannakis AJ, Makri GG, Mantzioka A, Karousos D, Karatzas G. Systemic stress response after laparoscopic or open cholecystectomy: a randomized trial. Br J Surg. 1997;84:467-471.  [PubMed]  [DOI]
33.  Karagiannis A, Mikhailidis DP, Tziomalos K, Kakafika AI, Athyros VG. Has the time come for a new definition of microalbuminuria? Curr Vasc Pharmacol. 2008;6:81-83.  [PubMed]  [DOI]
34.  Futrakul N, Sridama V, Futrakul P. Microalbuminuria--a biomarker of renal microvascular disease. Ren Fail. 2009;31:140-143.  [PubMed]  [DOI]
35.  Tamba S, Nakatsuji H, Kishida K, Noguchi M, Ogawa T, Okauchi Y, Nishizawa H, Imagawa A, Nakamura T, Matsuzawa Y, Funahashi T, Shimomura I. Relationship between visceral fat accumulation and urinary albumin-creatinine ratio in middle-aged Japanese men. Atherosclerosis. 2010;211:601-605.  [PubMed]  [DOI]
36.  Rifkin DE, Katz R, Chonchol M, Fried LF, Cao J, de Boer IH, Siscovick DS, Shlipak MG, Sarnak MJ. Albuminuria, impaired kidney function and cardiovascular outcomes or mortality in the elderly. Nephrol Dial Transplant. 2010;25:1560-1567.  [PubMed]  [DOI]
37.  Company JM, Booth FW, Laughlin MH, Arce-Esquivel AA, Sacks HS, Bahouth SW, Fain JN. Epicardial fat gene expression after aerobic exercise training in pigs with coronary atherosclerosis: relationship to visceral and subcutaneous fat. J Appl Physiol (1985). 2010;109:1904-1912.  [PubMed]  [DOI]
38.  Jain SH, Massaro JM, Hoffmann U, Rosito GA, Vasan RS, Raji A, O'Donnell CJ, Meigs JB, Fox CS. Cross-sectional associations between abdominal and thoracic adipose tissue compartments and adiponectin and resistin in the Framingham Heart Study. Diabetes Care. 2009;32:903-908.  [PubMed]  [DOI]
39.  Katsiki N, Mantzoros C, Mikhailidis DP. Adiponectin, lipids and atherosclerosis. Curr Opin Lipidol. 2017;28:347-354.  [PubMed]  [DOI]
40.  Mazidi M, Toth PP, Banach M. C-reactive Protein Is Associated With Prevalence of the Metabolic Syndrome, Hypertension, and Diabetes Mellitus in US Adults. Angiology. 2018;69:438-442.  [PubMed]  [DOI]
41.  Goldberg RB. Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. J Clin Endocrinol Metab. 2009;94:3171-3182.  [PubMed]  [DOI]
42.  Lim AK, Tesch GH. Inflammation in diabetic nephropathy. Mediators Inflamm. 2012;2012:146154.  [PubMed]  [DOI]
43.  Astrup AS, Tarnow L, Pietraszek L, Schalkwijk CG, Stehouwer CD, Parving HH, Rossing P. Markers of endothelial dysfunction and inflammation in type 1 diabetic patients with or without diabetic nephropathy followed for 10 years: association with mortality and decline of glomerular filtration rate. Diabetes Care. 2008;31:1170-1176.  [PubMed]  [DOI]
44.  Sun YM, Su Y, Li J, Wang LF. Recent advances in understanding the biochemical and molecular mechanism of diabetic nephropathy. Biochem Biophys Res Commun. 2013;433:359-361.  [PubMed]  [DOI]
45.  Mima A. Inflammation and oxidative stress in diabetic nephropathy: new insights on its inhibition as new therapeutic targets. J Diabetes Res. 2013;2013:248563.  [PubMed]  [DOI]
46.  Luis-Rodríguez D, Martínez-Castelao A, Górriz JL, De-Álvaro F, Navarro-González JF. Pathophysiological role and therapeutic implications of inflammation in diabetic nephropathy. World J Diabetes. 2012;3:7-18.  [PubMed]  [DOI]
47.  Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15:827-832.  [PubMed]  [DOI]
48.  Neves PO, Andrade J, Monção H. Coronary artery calcium score: current status. Radiol Bras. 2017;50:182-189.  [PubMed]  [DOI]
49.  Mehrotra R, Budoff M, Christenson P, Ipp E, Takasu J, Gupta A, Norris K, Adler S. Determinants of coronary artery calcification in diabetics with and without nephropathy. Kidney Int. 2004;66:2022-2031.  [PubMed]  [DOI]
50.  Mehrotra R, Budoff M, Hokanson JE, Ipp E, Takasu J, Adler S. Progression of coronary artery calcification in diabetics with and without chronic kidney disease. Kidney Int. 2005;68:1258-1266.  [PubMed]  [DOI]
51.  Gerszten RE, Garcia-Zepeda EA, Lim YC, Yoshida M, Ding HA, Gimbrone MA, Luster AD, Luscinskas FW, Rosenzweig A. MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature. 1999;398:718-723.  [PubMed]  [DOI]
52.  Iacobellis G, Singh N, Wharton S, Sharma AM. Substantial changes in epicardial fat thickness after weight loss in severely obese subjects. Obesity (Silver Spring). 2008;16:1693-1697.  [PubMed]  [DOI]
53.  Alexopoulos N, McLean DS, Janik M, Arepalli CD, Stillman AE, Raggi P. Epicardial adipose tissue and coronary artery plaque characteristics. Atherosclerosis. 2010;210:150-154.  [PubMed]  [DOI]
54.  Silaghi A, Piercecchi-Marti MD, Grino M, Leonetti G, Alessi MC, Clement K, Dadoun F, Dutour A. Epicardial adipose tissue extent: relationship with age, body fat distribution, and coronaropathy. Obesity (Silver Spring). 2008;16:2424-2430.  [PubMed]  [DOI]
55.  Katsiki N, Mikhailidis DP. Epicardial fat: a novel marker of subclinical atherosclerosis in clinical practice? Anatol J Cardiol. 2017;17:64-65.  [PubMed]  [DOI]
56.  Duncan BB, Chambless LE, Schmidt MI, Szklo M, Folsom AR, Carpenter MA, Crouse JR. Correlates of body fat distribution. Variation across categories of race, sex, and body mass in the atherosclerosis risk in communities study. The Atherosclerosis Risk in communities (ARIC) Study Investigators. Ann Epidemiol. 1995;5:192-200.  [PubMed]  [DOI]
57.  Iacobellis G, Ribaudo MC, Assael F, Vecci E, Tiberti C, Zappaterreno A, Di Mario U, Leonetti F. Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk. J Clin Endocrinol Metab. 2003;88:5163-5168.  [PubMed]  [DOI]
58.  Blankstein R, Ferencik M. The vulnerable plaque: Can it be detected with Cardiac CT? Atherosclerosis. 2010;211:386-389.  [PubMed]  [DOI]
59.  Athyros VG, Katsiki N, Karagiannis A, Mikhailidis DP. Statins can improve proteinuria and glomerular filtration rate loss in chronic kidney disease patients, further reducing cardiovascular risk. Fact or fiction? Expert Opin Pharmacother. 2015;16:1449-1461.  [PubMed]  [DOI]
60.  Gaborit B, Jacquier A, Kober F, Abdesselam I, Cuisset T, Boullu-Ciocca S, Emungania O, Alessi MC, Clément K, Bernard M, Dutour A. Effects of bariatric surgery on cardiac ectopic fat: lesser decrease in epicardial fat compared to visceral fat loss and no change in myocardial triglyceride content. J Am Coll Cardiol. 2012;60:1381-1389.  [PubMed]  [DOI]
61.  Liang KW, Tsai IC, Lee WJ, Lin SY, Lee WL, Lee IT, Fu CP, Wang JS, Sheu WH. Correlation between reduction of superior interventricular groove epicardial fat thickness and improvement of insulin resistance after weight loss in obese men. Diabetol Metab Syndr. 2014;6:115.  [PubMed]  [DOI]
62.  Parisi V, Petraglia L, D'Esposito V, Cabaro S, Rengo G, Caruso A, Grimaldi MG, Baldascino F, De Bellis A, Vitale D, Formisano R, Ferro A, Paolillo S, Davin L, Lancellotti P, Formisano P, Perrone Filardi P, Ferrara N, Leosco D. Statin therapy modulates thickness and inflammatory profile of human epicardial adipose tissue. Int J Cardiol. 2019;274:326-330.  [PubMed]  [DOI]
63.  Díaz-Rodríguez E, Agra RM, Fernández ÁL, Adrio B, García-Caballero T, González-Juanatey JR, Eiras S. Effects of dapagliflozin on human epicardial adipose tissue: modulation of insulin resistance, inflammatory chemokine production, and differentiation ability. Cardiovasc Res. 2018;114:336-346.  [PubMed]  [DOI]
64.  Sacks HS, Fain JN, Cheema P, Bahouth SW, Garrett E, Wolf RY, Wolford D, Samaha J. Inflammatory genes in epicardial fat contiguous with coronary atherosclerosis in the metabolic syndrome and type 2 diabetes: changes associated with pioglitazone. Diabetes Care. 2011;34:730-733.  [PubMed]  [DOI]
65.  Grosso AF, de Oliveira SF, Higuchi Mde L, Favarato D, Dallan LA, da Luz PL. Synergistic anti-inflammatory effect: simvastatin and pioglitazone reduce inflammatory markers of plasma and epicardial adipose tissue of coronary patients with metabolic syndrome. Diabetol Metab Syndr. 2014;6:47.  [PubMed]  [DOI]