Epicardial adipose tissue has an increased thickness and is a source of inflammatory mediators in patients with calcific aortic stenosis

It is widely recognized that biological processes leading to calcific aortic stenosis (AS) include chronic inflammation, lipoprotein deposition and activation of specific osteogenic and apoptotic signaling pathways [1]. These phenomena resemble those observed in the early stages of coronary artery disease (CAD). Further, AS and CAD share common risk factors, early pathogenesis, and clinical coexistence with a high percentage (40% to 75%) of patients with severe AS and concomitant CAD [2]. Thus, it is reasonable to hypothesize that the pathogenesis and progression of AS and CAD might be induced by similar stimuli, largely represented by the inflammatory activity intrinsic to the atherogenic process. Epicardial adipose tissue (EAT) represents a visceral fat depot which plays several protective functions for the heart in physiologic conditions [3]. However, it is known that EAT may also play an unfavorable activity for the heart. In fact, it is a source of several pro-inflammatory and pro-atherogenic cytokines, which can biologically influence the myocardium and epicardial coronary arteries through paracrine or vasocrine actions [3]. It has been reported that EAT thickness represents a specific marker of visceral adiposity which is strongly associated with the presence and severity of atherosclerotic coronary artery disease (CAD) [4]. In this study, we sought to investigate whether EAT could also contribute to the inflammatory burden of AS. To this aim, we analyzed echocardiographic EAT thickness and EAT secretory profile obtained from patients with calcific AS. We enrolled 95 patients with severe, isolated, calcific AS, referred to cardiac surgery for aortic valve (AV) replacement. Exclusion criteria were: 1) pathologic conditions already known to be associated with increased echocardiographic EAT thickness and/or altered inflammatory EAT status (CAD, metabolic syndrome, atrial fibrillation) [3,5]; and 2) chronic inflammatory diseases which could affect EAT thickness and/or systemic and local inflammatory profiles. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by our institution's human research committee. All patients provided written informed consent. We measured EAT thickness by echocardiography in AS patients and in a control group of 44 healthy subjects matched for age, gender and body mass index (BMI). Intra and inter-observer reproducibility for echocardiographic EAT thickness assessment was excellent (0.962 and 0.951, respectively). In patients referred to aortic valve replacement, plasma and EAT were collected and analyzed by human cytokine 27 multiplex immunoassay for the assessment of systemic and local inflammatory status. Table 1 illustrates demographic and clinical characteristics of the study population. EAT thickness was markedly increased in patients with AS with respect to controls (9.85 ± 2.78 vs 4.91 ± 1.27 mm; p < 0.0001). Demographic and clinical variables were also evaluated after study population stratification above and below EAT thickness median value (10 mm). There were no differences between the two groups for age, BMI, glomerular filtration rate, and atherosclerotic risk factors. Interestingly, as regard to cardiovascular therapy, only statin use was significantly higher (p < 0.04) in patients below the EAT thickness median value. No differences were found between the two groups in plasma inflammatory mediator levels, except for PDGF and VEGF. Contrarily, in EAT secretome, 22 of 27 measured inflammatory mediator levels were significantly higher in patients above the EAT thickness median value (Table 2). Further, EAT levels of several inflammatory cytokines, such as IL-6, IL-8, IL-1?, and TNF-? showed a highly significant increase (p < 0.0001) compared to systemic levels (Table 2). We also tested the relationship between EAT echocardiographic thickness and its inflammatory profile. Interestingly, we found a close direct correlation between EAT thickness and levels of secreted inflammatory mediators. In particular, EAT thickness significantly correlated with levels of IL-1?, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-17, basic FGF, eotaxin, G-CSF, IFN-?, IP-10, MCP-1, MIP-1?, MIP-1?, PDGF and TNF-?.