The location of adipose tissue is important: epicardial fat in patients with chronic kidney disease

In Chinese philosophy, yin and yang are two opposite but complementary and highly inter-related forces that inform many areas including traditional Chinese medicine. Light and dark or water and fire are examples of this duality. Either of the two forces (yin and yang) may be more apparent in a particular context, depending on how they are observed. In modern cardiovascular epidemiology, subcutaneous fat is considered the yang (positive) of the risk of coronary heart disease triggered by obesity. Indeed, fat deposited in peripheral tissues has a lower metabolic activity than central (visceral) fat, the yin (negative) of this duality. Accordingly, the metabolic risk of obesity is more strongly linked to visceral than to subcutaneous fat 1. In visceral adipocytes, increased fat cell volume secondary to accumulation of lipids releases chemotactic factors including monocyte chemoattractant protein-1 (MCP-1), which triggers local accumulation of monocytes 2. Infiltrated monocytes transform into macrophages, activated cells that synthesize pro-inflammatory cytokines including interleukin (IL)-1β, tumour necrosis factor (TNF)-α and IL-6. TNF-α inhibits insulin signalling and entry of glucose and free fatty acids into adipocytes and promotes lipolysis. Failure by visceral adipocytes to store triglycerides favours accumulation of fatty acids (such as ceramide or diacylglycerol) in tissues fundamental for whole-body energy metabolism, including liver, pancreas, striated muscle and the myocardium, eventually leading to systemic insulin resistance 3. The close proximity of inflamed visceral fat to the portal circulation is considered of relevance for the induction of liver steatosis 4. To be seen, the yin and yang of central and peripheral fat demand appropriate observation lenses, that is appropriate metrics. Unfortunately, the most applied anthropometric estimate of body fat, body mass index (BMI), is a much remote measure of visceral adiposity and provides an imperfect estimate of the risk of obesity. Chronic kidney disease (CKD) provides an example of the relevance of body fat metrics for exposing the risk of excessive visceral fat in the development of the disease. BMI is indeed a well-known inverse predictor of mortality in moderate to severe CKD 5 and in kidney failure 6. This apparent paradox depends on the fact that in these conditions, a low BMI mainly underlies protein–energy wasting and associated comorbidities rather than only a low fat mass. Furthermore, visceral fat mass may be high in individuals with a low BMI and, like in those with a high BMI, may cause a high metabolic risk 7. The peripheral versus central fat duality in CKD is evident when better measures of visceral adiposity than BMI, such as waist circumference or waist to hip ratio, are adopted. Indeed, these improved metrics predict an almost linear risk of death and renal disease progression in patients with chronic nephropathies 8 and of death and cardiovascular events in haemodialysis patients with kidney failure 9. Computed tomography (CT) or magnetic resonance imaging allows regional (below and above the diaphragm) and whole-body estimates of subcutaneous and visceral fat. Studies focusing on fat deposits in the thorax using these techniques or echocardiography have revealed that adipose tissue in close proximity to the heart (i.e. epicardial fat) provides prognostic information comparable to that of intra-abdominal visceral fat 10. Epicardial adipose tissue is encased by the visceral pericardium, surrounds the coronary arteries and is in direct contact with the myocardium; in addition, like mesenteric and omental fat, it is derived from the splanchnopleuric mesoderm. It is interesting that epicardial fat and the pericardial fat that envelop the heart (Fig. 1) have features common to both white and brown adipose tissue. The fact that there is direct contact between epicardial fat and the myocardium may be relevant with regard to myocardial steatosis 11. Brown fat is abundant in newborns and in hibernating mammals and serves to generate heat in neonates or mammals that do not shiver. White adipocytes include only a single lipid droplet, whereas brown adipocytes contain numerous smaller droplets and are far richer in mitochondria and capillaries than white fat. Thus, epicardial fat has even subtler elements of yin and yang because brown fat burns energy whilst white fat stores energy. Like visceral abdominal fat, perivascular fat (a fat depot associated with epicardial fat) has a reduced potential to make up adiponectin, a vasculoprotective adipokine, in obese individuals. This effect is fully reversible after weight loss. Epicardial fat attracts increasing attention in current cardiovascular literature. A PubMed search on 4 January 2015 using the terms ‘Epicardial fat’ and ‘Risk’ yielded 177 references, of which as many as 48 were published in 2014. Although only three cohort studies have investigated the predictive power of this depot, it has already been shown that epicardial fat predicts the progression of coronary disease in intermediate-risk patients 12. Given the exceedingly high risk of coronary heart disease events in patients with CKD 13 and the complex relationship between metrics of body adiposity and cardiovascular disease risk in these patients 5, studies focusing on epicardial fat in CKD appear to be highly relevant. So far, five studies have been conducted in patients with this disease: four studies in patients with kidney failure 14-17 and one in predialysis stage G3–5 patients 18. However, all these studies were cross-sectional and relatively small (ranging from 16 to 93 patients). Furthermore, the outcome measure was the coronary calcium score with simultaneous epicardial fat measurement (or a weaker surrogate). The cohort study by Antonio Carlos Cordeiro et al. 19 in a large cohort (n =277) of predialysis stage G3–5 patients with CKD published in the current issue of the Journal of Internal Medicine comes as fresh air in the field. In this study, the relationships between both epicardial (as assessed by CT) and abdominal visceral adipose tissue and cardiovascular disease risk were investigated cross-sectionally and prospectively and compared. In an analysis categorizing patients with CKD on the basis of epicardial fat quintiles, this variable was associated not only with a high coronary calcium score but also with an increased prevalence of left ventricular hypertrophy and myocardial ischaemia. More importantly, epicardial fat was associated with an increased risk of cardiovascular events independently of visceral (abdominal) fat and other potential confounders. In aetiological terms, this association supports the notion that, due to its proximity to the heart and to its direct contact with the myocardium, epicardial fat may be more relevant for the pathogenesis of cardiac events than distant visceral abdominal tissue. This finding in patients with CKD is in contrast to the lack of an independent association between epicardial fat and the incidence of cardiovascular events in the general population of the Framingham Heart Study 10. This discrepancy may imply that the risk associated with epicardial fat is more relevant in patients with CKD than in the general population. The study by Cordeiro et al. is based on only 57 cardiovascular events. Therefore, larger studies in the same population are needed to confirm such an intriguing hypothesis. Furthermore, even though independently associated with cardiovascular events, epicardial fat in patients with CKD failed to add discriminant power for these events to a prediction model formed by other risk factors and visceral fat. The findings of the study by Cordeiro et al. clearly indicate that epicardial fat mass per se is unlikely to add any meaningful, independent prognostic power beyond visceral (abdominal) fat and classical and CKD-related risk factors. However, the aetiological hypothesis generated by the findings of this study implicating epicardial fat in cardiovascular disease risk in CKD is interesting. A case–control study comparing the gene expression of cytokines in adipose tissue in predialysis patients with CKD and in age- and sex-matched individuals demonstrated a threefold increase in interleukin 6 gene expression in patients with CKD 20, supporting the idea that the risk of inflammation driven by adipose tissue may be of greater relevance in patients with CKD than in the general population. If a similar upregulation of IL-6 and other pro-inflammatory cytokines exists in the epicardial fat of patients with CKD, this depot may be regarded as a potential therapeutic target. Dietary interventions, exercise programmes and bariatric surgery all reduce visceral and epicardial fat mass along with metabolic risk in obese individuals 21. Experimental treatments that inhibit inflammation in epicardial fat, or epicardial fat removal, are intriguing possibilities to further investigate the role of this adipose tissue in patients with CKD. In a pilot study, it has already been shown that physical exercise reduces epicardial fat in kidney failure patients on dialysis 22. Obesity has now become the leading risk factor implicated in the current epidemic of CKD 23. The focus on obesity and fat depots in patients with CKD is not an academic curiosity but a public health priority. No conflicts of interest to declare.