Cardiovascular disease (CVD) and its sequelae are the leading cause of premature death, leading not only to significantly increased mortality rates but also to high levels of morbidity . Whilst the causes of CVD are complex there is increasing evidence suggesting an integral role for inflammation in CVD pathogenesis, with recent research examining therapeutics targeting this aspect of the disease [2, 3]. However, the cause of inflammation and its link with CVD is still poorly understood, particularly in humans, due to the difficulty in studying the relevant human tissues.
Previous studies have highlighted the potential importance of adipose tissue in relation to inflammatory burden in CVD, describing the expression and secretion of both pro-inflammatory and protective factors, collectively termed adipocytokines . These factors include tumour necrosis factor alpha (TNF-α), a pluripotent cytokine that is a key mediator of the acute phase response that also affects non-esterified fatty acid (NEFA) metabolism, as well as myocardial contractility . Resistin, a recently identified adipocytokine, has been proposed as a potential link between obesity and inflammation and has been linked to CVD risk [6, 7]. Adiponectin exhibits both insulin sensitising, anti-inflammatory and anti-atherogenic properties with serum levels reduced in both type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) [8, 9]. Kawanami et al have described directly reciprocal effects of resistin and adiponectin with regard to inflammation in vascular endothelial cells . Adipose tissue also produces further pathogenic adipocytokines including plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (ANG II), the active metabolite of angiotensinogen (AGT), both important in the fibrinolytic and thrombotic pathways [11, 12]. Adipose tissue increases the production of these pathogenic adipocytokines in obesity and it is hypothesised that macrophage recruitment into adipose tissue may contribute to this pathogenic response [13, 14].
Studies have further established that adipose tissue distribution has significant impact on disease risk with central abdominal fat increasing both CVD and T2DM risk compared with gluteo-femoral fat [15, 16]. Such differences in risk may be attributable to the depot specific differences in the expression and secretion of adipocytokines [17, 18]. However, whilst many investigations have elucidated the relative pathogenic risk of abdominal and gluteo-femoral adipose tissue, to date, few studies have investigated the adipocytokine profile of epicardial adipose tissue. This depot, situated predominantly on the right-ventricular free wall and the left-ventricular apex , has been shown to have a high capacity for non-esterified fatty acid (NEFA) release and is proposed as a source of this preferred metabolite for the myocardium . Whether adipocytokines are also secreted directly into the cardiac tissue is yet to be established and therefore the potential paracrine effect of epicardial adipocytokines on myocardial metabolism and their role in the pathogenesis of CAD is as yet unknown. However, the lack of any fascia between the adipocytes and the myocardial layer does suggest that factors secreted by the adipocytes would readily interact with the adjacent cardiomyocytes. Clinical studies have noted a strong correlation between the fat mass of epicardial adipose tissue, central abdominal fat and the associated risk of T2DM and CVD . Studies by Mazurek and co-workers comparing expression of pathogenic factors between epicardial and subcutaneous fat from the leg in patients with CAD undergoing coronary artery bypass grafting (CABG), also highlight the potential importance of the inflammatory response of epicardial tissue .
During the CABG operation, systemic metabolic substrate infusions can be administered providing myocardial protection and promotion of post-operative myocardial function. This includes the glucose, insulin and potassium (GIK) infusion. Both insulin and glucose can mediate changes in adipocytokine expression; therefore, due to the epicardial fat's proximity to the myocardium, there may be significant paracrine action upon myocardial metabolism through changes in adipocytokine secretion by this depot. Consequently the aims of this present study were to: 1) characterise the expression profile of adipocytokines in epicardial fat from patients undergoing CABG compared with adipose tissue from central and thigh fat from those without CAD; 2) analyse serum levels of pro- and anti-inflammatory cytokines in patients undergoing CABG and case controls and finally; 3) assess the potential effect of drug treatments and GIK infusion on epicardial mRNA adipocytokine expression.