Background
Epicardial adipose tissue (EAT) is a specific fat depot between the myocardium and the visceral pericardium, mainly surrounding major epicardial coronary arteries or within the myocardium [
1]. Numerous studies showed that the accumulation of EAT is closely associated with the presence and severity of coronary artery disease (CAD), myocardial ischemia, plaque vulnerability, and major adverse cardiovascular events (MACE) [
2‐
5]. However, not all patients with increased EAT volume develop CAD and vice versa.
To further explain the relation between EAT and CAD, the following two factors are attracting much attention. The first one is peri-coronary EAT, because there is close cross-talk between this focal metabolo-active EAT and its underlying coronary wall via a paracrine pathway [
6]. External administration of interleukin 1β or monocyte chemotactic protein 1 to porcine coronary arteries led to coronary wall inflammation and atherosclerosis formation [
7,
8], while surgical removal of peri-coronary EAT ameliorated the progression of coronary atherosclerosis in the pigs [
9]. The second important factor is EAT quality, shown as fat attenuation on computed tomography (CT), which reveals adipocyte lipid content and size, reflecting a metabolic response to cardiovascular risk factors [
10]. Antonopoulos et al. found that the peri-coronary EAT attenuation index can expose vascular inflammation, subclinical coronary atherosclerosis, and vulnerable plaque [
11] and even independently predict cardiac mortality [
12].
Accordingly, it is theoretically feasible to determine the hemodynamic significance and vulnerability of coronary stenosis by simply measuring peri-coronary EAT quantity or quality via coronary computed tomography angiography (CTA) in high-risk CAD patients before hospitalization. Therefore, in this hypothesis-generating study, we aimed to investigate the association of lesion-specific EAT volume or attenuation with the functional significance of coronary stenosis on a hospital-based Chinese population.
Discussion
We performed a proof-of-concept study to evaluate the associations of EAT volume and density with myocardial ischemia in patient-, vessel-, and lesion-level analyses, in a high-risk Chinese population. First, we found that the total EAT volume index was markedly increased in patients with functionally or anatomically significant stenosis. Second, leEAT volume index was markedly higher for ischemic lesions, furthermore, this index was a lesion-specific predictor of hemodynamic relevance, independent of a variety of lesion-level parameters. Third, the total EAT volume was positively correlated with fat accumulation and glucose metabolism, whereas the leEAT volume was negatively correlated with lesion FFR values. Fourth, we did not observe any significant differences in CT attenuation between non-ischemic and ischemic lesions in both lesion- or vessel-level analyses.
The significant correlations of the total EAT volume with functionally or anatomically significant CAD have been widely observed [
2,
3], although not reported in a recent study by Muthalaly et al. with moderately severe CAD patients [
18] or even in the prospective, large-scale CORE320 multicenter study [
19]. Likewise, Romijn et al. found an independent relation between EAT volume and myocardial ischemia, but the diagnostic performance for identifying hemodynamically significant CAD was not improved when considering coronary artery calcification [
20]. A recent meta-analysis that included more than 40,000 subjects at low to intermediate risk of cardiovascular disorders showed that EAT volume was an independent predictor of obstructive stenosis, significant stenosis, myocardial ischemia, and MACE, irrespective of traditional cardiovascular risk factors [
21]. In line with this meta-analysis, we found that indexed total EAT volume was significantly increased in patients with functionally or anatomically significant stenosis. The above conflicting results might be attributed, at least in part, to a diversity of populations [
21], more importantly illustrate a complex relation between EAT and the pathogenesis of CAD, which is hardly explain by the overall EAT volume alone.
Recent evidence suggests a potentially active role of peri-coronary EAT in the pathogenesis of coronary atherosclerosis [
22]. It was reported that peri-coronary segment EAT quantity was related to plaque size and composition, independent of cardiovascular risk factors and overall EAT volume [
16,
23]. Also, this coronary segment-specific EAT volume was associated with luminal stenosis severity, the presence of reversible perfusion defects, and the culprit lesion [
15,
24,
25]. Unlike the above studies, we performed a lesion-specific analysis and found a close relation between indexed leEAT volume and the presence of lesion ischemia. Furthermore, every 0.1 ml/m
2 increase in the leEAT volume index was independently associated with a 1.6-fold increased risk of lesion ischemia, irrespective of lesion stenosis or plaque features. Although the predicting value was relatively small, our results showed the feasibility to predict lesion-specific ischemia using leEAT volume index, which appeared to have a promising prospective considering a large and increasing number of patients referred to undergo coronary CTA examination for suspected CAD. We did not, however, observe a markedly increased leEAT volume index in significantly luminal stenosis or non-calcified plaque, which has been reported elsewhere [
24]. Mahabadi et al., however, also found no difference between non-calcified and calcified plaque in terms of leEAT volume [
16].
Additionally, a vessel-level analysis showed no associations of veEAT volume and ischemia, which might support the hypothesis that the function of EAT varies depending on its particular depot. In line with this notion, we found the total EAT volume in patient- or vessel-level was significantly associated with fat accumulation and glucose metabolism, while the leEAT volume was associated with FFR values. More specifically, a dysfunctional secretion profile and M2 macrophage accumulation in lesion-level analysis were reported to be higher for peri-coronary EAT near stenotic coronary segments than for those near non-stenotic segments [
26,
27]. Another possible explanation is that the metabolic activities of veEAT and leEAT, shown as EAT CT attenuation, were not consistent or remained unchanged. Markedly increased peri-coronary EAT CT attenuation was observed in stenotic segments, lesions with
18F-sodium fluoride uptake on positron emission tomography and culprit lesions [
28‐
30]. In this study, however, there were no significant differences between ischemic and non-ischemic lesions in terms of peri-coronary EAT and peri-vessel EAT attenuation. In line with our findings, Hell et al. found that EAT volume, but not density, was associated with myocardial ischemia in patients suspected of having CAD [
31]. Also, Balcer et al. reported that the peri-coronary EAT volume, but not attenuation, was independently correlated with culprit lesions [
25].
This study had some limitations. First, the study’s sample size was relatively small, which impeded the performance of more subgroup or exploratory analyses. Second, because of the relatively strict inclusion and exclusion criteria, extrapolating our conclusions to other populations should be cautious. Third, based on the cross-sectional design, no causal relation could be confirmed, although multivariate regression analysis was performed. Fourth, methods for measuring the peri-coronary fat quality varies among studies, which might lead to non-comparable results among them. In addition, ROIs of veEAT and leEAT were manually, not automatically, delineated due to software limitations.
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