Our cohort study results show that EAT volume was independently associated with CAC in people with diabetes. This reflects results from another study with a mix of individuals with and without diabetes . Similarly, Yerramasu et al. found that EAT volume was an independent marker of both the presence and severity of CAC burden in 333 asymptomatic patients with T2D . However, the latter finding goes against results from three others studies where no such association was found [12–14]. There are several possible reasons for this. First, these three studies had less statistical power than Yerramasu’s and ours, as they only included between 95 and 200 patients [12–14]. Second, one of the three (Christensen et al.) measured EAT thickness not volume . Third, inclusion criteria differed between the three studies: only patients with T2D and elevated urinary albumin excretion rate were recruited in Christensen et al.’s study , while only young Native Americans with T2D were included in Reinhardt et al.’s study . Our results in diabetic persons are clinically relevant as we were able to show that the association remained significant even after adjustment for numerous confounding factors.
Parameters associated with EAT volume, to be considered as confounders
First, EAT volume was positively correlated with male gender and older age. Elsewhere, EAT volume has been associated with all the components of metabolic syndrome in people with T2D [16,17] and those with T1D [18,19]. Similarly, we found an association between EAT volume and higher BMI, increased triglycerides levels, lower HDL-cholesterol levels and antihypertensive treatment. This result is in line with previous studies which showed a higher EAT volume in individuals with T2D than those with T1D [12,19]. Additionally, cumulative tobacco consumption, which is associated with insulin resistance and metabolic syndrome , was positively correlated with EAT volume in our study. Finally, we also found that EAT volume was higher in individuals of Caucasian ethnicity. Similarly, the difference in EAT thickness between persons with and without metabolic syndrome was more evident in Caucasians [17,21]. Other studies have also found that EAT levels differ according to racial/ethnic group in the general population [22–25].
EAT and subclinical atherosclerosis, including CAC
The association between EAT and CAC in our study suggests that EAT might play a role in subclinical atherosclerosis in diabetes. There are arguments to support this hypothesis. First, increased EAT volume/thickness has been associated with markers of subclinical atherosclerosis other than CAC score, such as coronary artery disease and cardiac dysfunction . Second, prospective studies have shown that high EAT volume/thickness is associated with more cardiovascular events in the general population , in patients with T2D without participant-selection study criteria  and T2D patients with microalbuminuria . Third, EAT identifies individuals at increased risk of CAC progression . Fourth, whereas EAT is physiologically cardioprotective - as it provides mechanical protection and energy to the myocardium and has anti-inflammatory properties -, abnormally increases in EAT volume are proinflammatory [3–6]. Furthermore, EAT secretes vasoactive factors that regulate coronary endothelial function and facilitate free fatty acid influx [3–6]. Therefore, the positive association between EAT and CAC may reflect early pathophysiological effects of EAT on local atherosclerosis. EAT volume could therefore be considered as a surrogate of coronary atherosclerosis. Similarly, EAT volume has been associated with plaque vulnerability, which may contribute to acute coronary syndrome . Finally, EAT might in addition directly promote calcification processes in atheroma .
EAT and diabetic microangiopathic complications
We found that EAT volume was positively associated with albuminuria -without correlation with renal failure- whereas such a correlation was not found previously in the diabetic population [11-12]. Albuminuria is a known marker of poor cardiovascular prognosis in people with diabetes [8,10]. We might hypothesize that the association between EAT and albuminuria only reflects EAT-induced coronary endothelial dysfunction through paracrine effects . On the contrary, EAT volume was lower in case of retinopathy. In the study by Yerramasu et al., the percentage of retinopathy also decreased by increasing EAT tertiles (34, 27 and 23%, respectively) but statistical significance was not reached (p=0.18) . Whether EAT would play a systemic role on eyes need further specific studies. Finally, as previously reported , EAT volume did not differ by presence of neuropathy.
Clinical and therapeutic implications
Our results suggest that measuring EAT volume might improve assessment of cardiovascular prognosis, but whether the prognostic value of EAT is additional to the one of CAC score is unknown [14,26,27]. There are also therapeutic implications of our work. EAT volume can be modified by lifestyle such as diet and/or exercise, bariatric surgery and pharmaceutical interventions [31,32]. For example, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors have all been reported to reduce EAT volume . On the contrary, CAC cannot regress.
Limitations and strengths of the study
Our study has several limitations. Its design was observational, which prevented us from being able to draw conclusions about causal relationships between EAT volume and CAC. Neither were we able to make a conclusion about the role of therapy on EAT volume. Furthermore, in order to evaluate the prognostic value of EAT volume, we used a marker of subclinical atherosclerosis (i.e., CAC) instead of measuring the incidence of cardiovascular events. Moreover, we only included patients who had been admitted to our hospital department and who had their CAC score measured. Therefore, our results may not be representative of all patients with diabetes. Finally, we did not have data on waist circumference, which could have influenced the association between EAT volume and CAC. However, we did adjust for several confounders, including BMI.
The main strength of our study is that we measured EAT and not pericardial (or total cardiac) adipose tissue. EAT lies between the myocardium and the visceral layer of the pericardium and is different from pericardial fat which is located externally to the myocardium. There is no fascia separating EAT and myocardium. Therefore both tissues are in direct contact [3–6,31]. To date, EAT is the only type of cardiac adipose tissue which has been observed to predict incident cardiovascular events in T2D patients . Furthermore, we applied a robust methodology - CT acquisition and assessment following standard methods - as well as cardiac software to automatically quantify EAT. Only 1 EAT measure out of the 410 performed (study population) could not be interpreted. CT scans are considered the gold standard for EAT as, unlike echography, they measure EAT volume not thickness [4,14].