Looking beyond ectopic fat amount: A SMART method to quantify epicardial adipose tissue density

Epicardial adipose tissue (EAT) is a visceral fat deposit located between the visceral pericardium and myocardium.1 However, in contrast to visceral abdominal adipose tissue, it has predominantly local effects as it represents less than 1% of total fat mass.2 Indeed, EAT has a unique anatomical proximity to the heart. As there is no dividing fascia plane between EAT, coronary arteries adventitia and myocardium, it allows cellular cross-talk and a functional relationship between ectopic adipocytes, myocytes and cells of the vascular wall.3,4 Free fatty acids, proinflammatory cytokines (IL-6, IL-1β, IL-8, sPLA2-IIA), vasoactive molecules (angiotensin), adipofibrokines (activin-A) and growth factors (TNF-α, VEGF) are likely to diffuse paracrinally, or through microcirculation from EAT to the lumen of coronary arteries.5,6 The EAT secretome of coronary artery disease (CAD) patients has been shown to induce inflammation and M1 polarisation of macrophages, adhesion of monocytic to endothelial cells, proliferation of smooth muscle cells, oxidative stress, fibrosis and neovascularization.7–9 On the other hand, EAT can secrete cardioprotective adipokines such as adiponectin, omentin or adrenomedullin and has ‘brown like’ properties.10,11 This brite phenotype seems to decrease with age, diabetes mellitus and the severity of CAD.12,13 There has been growing interest in the past decade in the non-invasive imaging of EAT volume as a predictor of future coronary events.14 In the Heinz Nixdorf recall study, which included more than 4000 middle-aged participants, EAT volume measured by computed tomography (CT), was significantly associated with coronary events over the following 8 years.15 This effect remained unchanged after adjustment for traditional cardiovascular risk factors, including waist circumference, systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein, diabetes, smoking and coronary artery calcium score.15 The amount of EAT has been associated with plaque vulnerability, myocardial infarction, unstable angina, coronary flow reserve and stent restenosis.16–18 Evaluating the volume of EAT is important. Nevertheless, because of the dual beneficial and harmful effect of EAT on myocardium and coronary arteries, better evaluating epicardial adipose tissue characteristics is therefore crucial. In this substudy of the SMART cohort (n=140), Franssens et al. investigated the possible relationship between cardiovascular risk factors and CT measured radiodensity of EAT in patients at high risk of cardiovascular disease.19 EAT radiodensity in this setting is of particular interest as it allows for the ‘quality’ or lipids and water composition of the tissue to be imaged.20 Lower CT attenuation (more negative Hounsfield units; HU) is thought to represent increased lipid content, and possibly greater metabolic risk, whereas higher CT attenuation, corresponding to higher HU values, relates to higher water content and increased thermogenic activity. The Secondary Manifestations of ARTerial disease study (SMART) study is a single-centre cohort study that included well phenotyped patients with clinically manifest atherosclerotic vessel disease, or marked risk factors for atherosclerosis such as hypertension or type 2 diabetes.21 Remarkably, the authors showed that low EAT CT attenuation was associated with an adverse cardiovascular risk profile.19 Interestingly, this association was independent of adiposity measures such as waist circumference, and also epicardial fat volume. This highly suggests that epicardial fat density could be a more sensitive marker than epicardial fat volume to evaluate CAD-related risk. Unfortunately, no histological confirmation of the molecular and cellular characteristics of EAT has been made in this study, for evident ethical reasons. The mechanisms underlying EAT attenuation in this study thus remain unknown. Although many studies have emphasised the associations of epicardial fat volume with CAD risk factors, these relations are more complex than initially assessed, or fall out after multivariate adjustment for abdominal visceral fat.22,23 Other studies in patients with subclinical atherosclerosis or high-risk plaque fail to show an independent association between epicardial fat density and cardiovascular risk factors.24,25 Many experimental studies point to a local effect of EAT on coronary arteries and myocardium and transcriptomic studies indicate that periatrial, periventricular and peri-coronary artery EAT could have distinct transcriptomic signatures.26 In evaluating the cellular characteristics of EAT with imaging, the presence of inflammation in EAT has been shown to be associated with a higher density in CT images and has been correlated with culprit lesions in patients with CAD.27,28 This is not consistent with the hypothesis that higher CT EAT attenuation would represent exclusively metabolic activity of the adipose tissue. Much work is thus needed to complete our understanding of the characteristics of EAT as well as its implications with atherosclerosis and CAD. Non-invasive tools such as EAT density need to be developed, in order to find relevant biomarkers of EAT function and cardiovascular risk. In the next few years, prospective imaging studies with biopsy validation will help to decipher the link between EAT density and cellular phenotype. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article.