Epicardial Fat Thickness and its Association with Cardiovascular Risk in Patients with Type 2 Diabetes Mellitus

Previous studies have clearly shown that epicardial adipose tissue (EAT) mass is associated with increased incidence of coronary artery disease. In the present study, the relationship between the EAT volume measured by cardiac multislice computerized tomography (MSCT) and cardiovascular risk was investigated in patients with type 2 diabetes mellitus. Ninety type 2 diabetic patients and 62 healthy controls were included in the study. We examined metabolic and anthropometric parameters including body mass index (BMI), fasting glucose and serum lipids and EAT volume of patients in comparison to those of control subjects. EAT volume was higher in Type 2 diabetic patients compared to control group (172.75 ± 64.85 cm3 and 68.94 ± 37.74 cm3, respectively) (p<0.001). Type 2 diabetic patients had significantly higher levels of fasting glucose (p=0.014), total cholesterol (p<0.001), triglycerides (p=0,017) and LDL-cholesterol (p=0,022) versus control group. EAT volume was correlated with BMI, glucose, HbA1c, LDL-cholesterol, total cholesterol. In a stepwise regression analysis, Hba1c emerged as a significant predictor of EAT volume (ß= 0.610, p0.001), accounting for 18% of its variability. These results provide additional evidence for the presence of subclinical cardiovascular disease (CVD) in type 2 diabetic patients. It is also important to note that our findings reveal significant relationships between HBA1c and cardiovascular changes and underline the importance of glucose control in predicting CVD.


INTRODUCTION
Cardiovascular diseases (CVD) are a major cause of mortality worldwide (1).Atherosclerotic cardiovascular complications are responsible for increased mortality and morbidity particularly among diabetic patients (2)(3)(4).CVD including coronary artery disease (CAD) and stroke account for 80% of all deaths in diabetic patients (5).There is evidence that abnormal lipid profile of excessive visceral fat tissue is linked with increased systemic inflammation, diabetes mellitus (DM) and CVD (6-8).Epicardial adipose tissue (EAT) is one of the visceral fat depots found in the body (9,10).It shares a common embryogenetic origin with intraabdominal fat and both epicardial and intra-abdominal fat evolve from brown adipose tissue during embryogenesis (11).EAT is located between myocardium and visceral layer of pericardium and shares the same microcirculation with myocardium (10).It is the source of several pro-inflammatory and proatherogenic cytokines as well as anti-inflammatory and antiatherogenic adipokines such as adiponectin and adrenomedulin (12).Studies have shown that EAT mass clearly reflects abdominal visceral fat accumulation as measured by MRI (13,14).EAT may be quantified using MRI, CT and echocardiography, with each method having its advantages and disadvantages (15).
A number of studies demonstrated the relation of visceral adipose tissue and specifically EAT with the risk for metabolic syndrome, CVD and CAD (15-19).EAT thickness has been associated with the extent and severity of CAD in CVD patients (19,20).Since the association between EAT volume and CAD was clearly shown by previous studies, in the present study we retrospectively examined EAT volume and its relation with cardiovascular risk in DM patients who had undergone multislice computed tomography scans (MSCT) for various reasons.

MATERIAL AND METHOD
In this retrospective cohort study, data were reviewed for a total of 90 Type 2 DM patients and control group of 62 patients who had admitted to Mevlana University outpatient clinics and undergone (MSCT) scans for any reason between March 2011 and April 2013.Patients with missing and/or unavailable laboratory data, patients who had undergone percutaneous or surgical revascularization for management of CAD, patients with peripheral artery disease, atrial fibrillation, active chronic obstructive pul-monary disease, heart failure or chronic renal failure and morbidly obese patients were excluded from the study.Control group patients were healthy individuals who did not have chronic renal failure, CAD, vasculitic lesions, DM, hypertension, hepatic parenchymal disease or any current acute infections.Clinical conditions recorded on admission and laboratory results simultaneously obtained during MSCT scans were reviewed for all patients.Body mass index (BMI) was estimated by dividing the body weight (in kilogramme) by height squared (meter) for patients whose height and weight recordings were available.Study procedures were approved by the local ethics committee.
MSCT scans were conducted for all patients (Somatom Sensation 64, Siemens, Forchheim, Germany).A CT attenuation threshold between -≤200 and -≤ 50 HU was used to define the adipose tissue density.EAT volumes were measured using cardiac workstation volume analysis software tool (Siemens, Leonardo) and manual ROI (Region of interest) drawings in cm3.

Statistical Analysis
For statistical analysis, the SPSS (version 16.0) software package was used.Categorical parameters were presented as percentage.Continuous variables (age, body mass index, body weight, height, lipid panel, blood glucose, EAT) were presented with mean ± standard deviation.Kolmogorov-Smirnov test was applied to ascertain the normality of the variables.Differences between data were studied using the Student's t-test.Statistical correlation was assessed using Pearson's test (r).A multiple linear regression analysis was performed first using the standard method and then forward stepwise selection to identify independent factors affecting EAT, Hba1c, and to estimate the final predictors of their variability.Statistical significance was set at p < 0.05.

RESULTS
One hundred and fifty two patients between 18 to 75 years of age were included in the study.They were divided into two groups: 90 patients in Type 2 DM group and 62 in control groups.Of Type 2 DM patients, 73.2% were male 26.8% were female and 26% were current smokers.64.4% of the control patients were male, 35.6% were female and 31.8% were current smokers.There was no difference between the two groups in age, gender or smoking status.
The HbA1c was 7.69 ± 2.44 % for Type 2 DM patients.EAT volume was 172.75 ± 64.85 cm3 for Type 2 DM patients and 68.94 ± 37.74 cm3 for control group and the difference was statistically significant (p<0.001).Patients in DM group had significantly higher values of FBG (p<0.001),total cholesterol (p<0.001),triglycerides (p=0,017) and LDL-cholesterol (p=0.022)compared to control group.Anthropometric measurements and laboratory data of all participants are shown in Table 1.A gender-based analysis of DM patients divided in two subgroups as females and males showed that there was no significant difference in laboratory values and EAT volume (p=0.264 for EAT volume).Of DM group patients, 63.4% had hypertension and when patients were divided into two groups as normotensives and hypertensives, there was still no significant difference among them with respect to laboratory values  2).In a stepwise regression analysis, Hba1c emerged as a significant predictor of epicardial fat volume (ß= 0.610, p0.001), accounting for 18% of its variability.

DISCUSSION
The results of the current study showed that Type The regression analysis showed that HbA1c was a strong predictor of EAT.This finding lends further support for the prominence of HbA1c value with respect to CVD risk in DM patients.
EAT may be quantified using various techniques (13,24,32).MSCT and three-dimensional MRI were demonstrated to be more sensitive and specific for quantification of epicardial fat mass compared to echocardiography (13).On the other hand, MSCT is a technique that gives the most accurate results for EAT measurement due to its higher resolution (24).It has the advantage to allow for simultaneous assessment of coronary arteries in addition to EAT measurement.However, it has several limitations including exposure to radiation and higher cost.In the present study, EAT volumes were measured for patients previously undergoing MSCT scans due to multiple indications and examined in relation to cardiovascular risk.That way, EAT could be quantified with a high sensitivity and specificity.
In conclusion, EAT which has been previously associated with CVD predicts increased cardiovascular risk in diabetic patients.Our results indicate that patients with diabetes are connoted by higher frequency of dyslipidemia and increased EAT, suggesting an increased cardiovascular risk.Our data underline the importance of glucose monitoring in patients with type 2 diabetes.Measurement of EAT might be considered for early detection and management of potential atherogenic risk factors for complications.In light of these considerations, cardiovascular risk factors should be regularly checked during follow-up of diabetic patients.

Table 2 .
Correlation analysis for EAT volume Pearson's correlation analysis was used for assessment of the relation of EAT volume with other clinical parameters in DM patients.A strong and positive correlation was found between EAT volume and HbA1c, weight, FBG, total cholesterol, LDL cholesterol and BMI.(Table