Epicardial adipose tissue in the pathogenesis and progression of coronary artery disease| JOURNAL OF GERONTOLOGY AND GERIATRICS

Abstract

Coronary artery disease (CAD) represents one of the most important causes of morbility, hospitalization and
death, and its incidence greatly increases in the elderly population. In the last decades, several pieces of evidence have suggested a pathogenetic role of systemic and visceral fat inflammation in the development and
progression of CAD. The epicardial adipose tissue (EAT), the visceral fat depot of heart, produces and secretes
numerous pro-inflammatory mediators that could be involved in the pathogenesis of coronary atherosclerosis.
Furthermore, age-related low-grade inflammation leads to the accumulation and inflammation of EAT. Therefore, this review aims to explore the potential implication of EAT in the pathogenesis of CAD, the link between systemic inflammation and an EAT pro-inflammatory phenotype, and, finally the perspectives for novel therapeutic strategies targeting the cardiac visceral fat.

INTRODUCTION

Coronary artery disease (CAD) represents one of the most important causes of morbility, hospitalization and death worldwide. In the elders, the incidence of cardiovascular disease is greatly increased. In particular, advanced age is associated with higher incidence of myocardial infarction, cardiovascular and extracardiac comorbidities ^1-5. Furthermore, elderly subjects form the largest and fastest growing part of the population, accounting for one-third of hospitalization for acute cardiovascular events and for most of all cardiac deaths ^6-8. Age has been reported as an important risk predictor in patients admitted in hospital with non-ST elevation myocardial infarction (NSTE-ACS) ⁹ and some studies have shown poor outcomes and high age-related mortality rates, after primary percutaneous coronary interventions in the elderly ^{10 11}.

The causes of cardiovascular diseases are complex, but increasing evidence suggests a pathogenetic role of inflammation in the development and progression of CAD. The epicardial adipose tissue (EAT), the visceral fat depot of heart, produces and secretes numerous inflammatory mediators that could be involved in the pathogenesis of coronary atherosclerosis.

Inflammation and CAD

A correlation between inflammation and CAD has been initially hypothesized since autopsy studies, conducted in patients died for acute coronary syndrome, showed the presence of rich inflammatory infiltrates, consisting of lymphocytes, monocytes, and macrophages, in the adventitia of coronary arteries. In these studies, the degree of coronary narrowing correlated with the number of inflammatory cells in the coronary adventitia ¹².

In the last decades, several pieces of evidence have supported the association between inflammation and CAD, identifying many inflammatory mediators involved in the atherosclerotic process. In particular, it has been demonstrated that, following an atherogenic stimulus, vascular cells adhesion molecule-1 binds monocytes and T lymphocytes ¹³. Once adherent to the endothelium, the leukocytes penetrate the intima. Some chemoattractant molecules, such as monocyte chemoattractant protein-1 (MCP-1), are responsible for this transmigration at sites of lesion formation ^{14 15}. The recruited macrophages ingest lipids and become foam cells ¹⁶. Afterwards, blood-derived inflammatory cells trigger and perpetuate a local inflammatory response, also through the release of numerous inflammatory and fibrogenic mediators, as tumor necrosis factor-α (TNF-α) and interleukins (IL) ¹⁷. Interestingly, in the atherosclerotic plaque, activated macrophages and T cells can release hydrolytic enzymes, cytokines, chemokines and growth factors, leading to a focal necrosis of the fibrous cap, that becomes thin, weak, and susceptible to rupture ^{18 19}. Macrophages also produce tissue factor, the major procoagulant mediator, triggering thrombosis found in the plaques ²⁰. Thus, inflammation is responsible for the onset and progression of atherosclerotic process and plaques rupture.

The pathogenetic role of inflammation in the atherosclerotic process is also confirmed by high circulating levels of acute phase proteins. In clinical studies, elevated serum levels of C-reactive protein (CRP), IL-6 and TNF-α represent an important prognostic factor of atherosclerosis development both in patients with known CAD and in healthy population ^{21 22}. There is also a direct correlation between the level of CRP in the serum and the severity of atherosclerosis in patients with stable CAD ²³. In apparently healthy men, elevated levels of IL-6 are associated with increased risk of future myocardial infarction ²⁴.

Of note, aging is characterized by the presence of chronic low-grade inflammation. This condition can contribute to the recruitment of inflammatory cells, damage and impairment of endothelial function, migration and proliferation of smooth muscle cells to the site of injury, resulting in the formation of early atherosclerotic lesions and higher susceptibility to CAD ¹⁹.

VISCERAL ADIPOSE TISSUE AND CAD

In the literature, visceral adipose tissue (VAT) is usually defined as an intra-abdominal accumulation of adiposity, predominantly localized at the omental and mesenteric level. The adipose tissue is composed of 50% of adipocytes and 50% of other cells, such as stromal vasculature fraction of fibroblasts, endothelial cells, macrophages and preadipocytes ²⁵. It has been demonstrated that persistent positive caloric balance, as occurs in obesity, induces excessive fat cell enlargement with consequent adipocyte metabolic and immune dysfunction ^26-29. These alterations lead to the activation of lipolysis, increased formation of free fatty acids (FFA), oxidative stress, hypoxia, and increased apoptosis of adipocytes ³⁰. Moreover, infiltrated monocytes generate M1 macrophages, increasing the total secretion of pro-inflammatory cytokines, such as TNF-a, IL-1β, and IL-6. Through these mediators, the increase of VAT mass can also contribute to systemic inflammation ^{31 32}. Several studies have confirmed the central role of this pro-inflammatory state in endothelial dysfunction and cardiovascular disease ^33-35. Of note, clinical data initially suggested the association between VAT and CAD. In one of the first observations, non-obese men with CAD showed larger VAT deposits than age- and BMI-matched controls ³⁶. The association with CAD remained significant even after adjustment for risk factors ³⁷. In a small study population with known CAD, it has been reported that increased VAT volume correlates with the presence of multivessel rather than single vessel disease ³⁸. In a recent study, VAT was associated with the risk of progression of non-calcified coronary artery plaques in patients with CAD ³⁹. Interestingly, in obese people, cardiovascular risk is predominantly associated with visceral than with subcutaneous adiposity ^{40 41}.

EPICARDIAL ADIPOSE TISSUE AND CORONARY ARTERY DISEASE (FIG. 1)

EAT is the visceral fat depot of the heart, principally distributed in atrio-ventricular and interventricular grooves, between the myocardium and the visceral layer of pericardium. The absence of fascial boundaries permits a direct influence of EAT on surrounding tissues and coronary arterial vessels ^{42 43}. The increase of EAT mass is associated to production of several pro-inflammatory and pro-atherogenic mediators ^44-47. Interestingly, subjects with angiographically significant CAD show higher EAT thickness than patients without CAD. EAT thickness increases as the number of vessels with > 50% stenosis increase. On multiple logistic analysis including various CAD risk factors, EAT results an independent predictor of CAD ^{48 49}.

A prospective study, exploring the metabolic activity of EAT measured by positron emission tomography (PET)/CT, has demonstrated that patients with NSTE-ACS show maximum fludeoxyglucose uptake (SUV) in fat surrounding coronary arteries. Additionally, the inflammatory activity of EAT was greater than in subcutaneous, visceral or thoracic adipose tissue, and correlated with plaque burden and with the necrotic core component, assessed by virtual histology intravascular ultrasound ^{50 51}. These clinical observations have been also supported by a positive correlation between density of macrophage infiltrates and SUV, in an experimental model of atherosclerosis ⁵².

Other studies, conducted in patients with established CAD, have demonstrated a pathological increase of EAT-derived inflammatory mediators and their messenger RNA, with a dense infiltration of inflammatory cells observed in EAT but not in the subcutaneous adipose tissue ⁴⁵. The inflammatory proatherogenic stimulus results more evident in patients with acute coronary syndromes than in patients with stable CAD ⁵³.

In patients undergoing coronary artery bypass graft (CABG) surgery, it has been reported an increased EAT expression of interleukin (IL)-1β, IL-6, TNF-α, and MCP-1 compared to that observed in the subcutaneous adipose tissue ^{45 46}. In order to investigate the underlying mechanism of pro-inflammatory cytokines levels in EAT of CAD patients, Bourlier et al., performed immunohistochemistry against CD68, marker for all types of macrophages, CD11c, marker for inflammatory M1 macrophages, and CD206, marker for anti-inflammatory M2 macrophage. CD68 positive macrophages were significantly increased in the EAT of the CAD group. The ratio of CD11c/CD68-positive cells was significantly increased, while the ratio of CD206/CD68-positive cells was significantly decreased in the EAT of the CAD group ⁵⁴. This result demonstrates a relative increase of M1 macrophages and a relative decrease of M2 macrophages in the EAT of the CAD group. Furthermore, the ratio of M1/M2 macrophages showed a positive correlation with the severity of CAD. Overall, these results suggest that the macrophage polarization in EAT would play a central pathological role in the coronary atherosclerotic process ^55-57.

Other studies have demonstrated that patients with acute coronary syndrome present with a higher expression and secretion of resistin in the EAT, compared to patients with stable CAD or subjects without CAD 58. The exact role of resistin is currently unclear. It is probably involved in the processes of inflammation and atherogenesis through increasing expression of adhesion molecules on endothelial cells and impairing vasodilation ^{59 60}. Resistin has been recently linked to the incidence of acute coronary syndromes and stroke ⁶¹. In humans, resistin is produced by macrophages ⁶² and correlates with markers of inflammation, as well as with coronary atherosclerosis ⁶³. Plasma resistin levels have been also recently shown to be predictive of mortality in patients with acute myocardial infarction ⁶⁴. Similar clinical evidence has been reported for Leptin ⁶⁵.

Several studies have identified adiponectin as the principal antiatherogenic protein detected in EAT in physiologic conditions. Adiponectin inhibits the expression of IL-8 by endothelial cells, increases the production of anti-inflammatory IL-10 and tissue inhibitor of metalloproteinase-1 in macrophages. Finally, this cytokine exerts vasodilatory properties on small arteries ⁶⁶. The observation of lower levels of adiponectin in the EAT of CAD patients ⁶⁷ suggests that the pro-atherogenic properties of EAT in CAD are determined by both an increase of pro-inflammatory mediators and a decrease of anti-inflammatory cytokines.

Of note, the definitive demonstration of the causative role of EAT in the development and progression of CAD derives from animal studies. In fact, surgical resection of EAT depot in pigs arrests coronary atherogenesis ^68-70.

As regards the intercorrelation between EAT and systemic inflammation, it is plausible to hypothesize a bidirectional continuum. The release of proinflammatory adipocytokines from EAT into the blood may contribute to the systemic inflammatory state; systemic inflammation in turn promotes the accumulation of EAT, which induces local and systemic inflammation and end-organ dysfunction ^70-72.

PREVENTION AND THERAPEUTIC INTERVENTIONS

Given the recognized role of EAT in the development and progression of CAD, this adipose depot could represent a novel therapeutic target. First of all, dietary and lifestyle changes can affect the EAT volume and its inflammatory profile. Some studies have demonstrated that a marked wheight loss can lead to a reduction or stabilization of EAT volume ^{73 74}. Furthermore, in obese patients, Kim et al. ⁷⁵ have shown that aerobic exercise is associated with lowering EAT mass. However, these data remain controversial and are only partially confirmed by studies conducted on patients underwent bariatric surgery, showing a greater decrease in VAT compared to EAT ^{76 77}. Interestingly, in experimental animals, Walker et al. ⁷⁸ have tested EAT fatty acid composition and inflammatory gene expression after exposure to two different dietary patterns, containing respectively high levels of saturated or polyunsaturated fatty acids. High saturated fatty acids diet modulates EAT composition, increasing percentage of saturated fatty acid, and results positively associated with the expression of pro-inflammatory genes, providing a link between diet and EAT inflammation. Thus, changes in dietary quality could represent a nutritional strategy to reduce EAT inflammation and development of CAD.

As regards pharmacological interventions, new interesting perspectives could result from oral statin therapy. As known, this class of drug, in addition to lipid levels control, exerts relevant pleiotropic effects, such as modulation of cell signalling, differentiation and proliferation ⁷⁹. A recent study has reported a statin-induced decrease in EAT attenuation on computed tomography, independent of low-density lipoprotein cholesterol lowering, thus demonstrating a decrement in the metabolic activity of EAT by reduction in cellularity, vascularity and inflammation ⁸⁰. As reported by Parisi et al., the EAT thickness correlates with its inflammatory profile, thus the EAT volume reduction corresponds to a lower secretion of pro-inflammatory cytokines ^{44 81 82}.

Furthermore, in the obese and diabetic populations, some studies have demonstrated that the use of glucagon-like-protein-1 receptor agonists (GLP-1R), in particular of liraglutide, induces a significant reduction of EAT (13%) after 12 weeks of treatment ^83-85. Moreover, liraglutide, but not metformin, reduces EAT by 29% and 36% at 3 and 6 months, respectively ⁸⁴. In an animal model, liraglutide also promotes browning and thermogenesis independently of nutrient intake ⁸⁶.

Accordingly, sitagliptin, a DPP-4 inhibitor that prevents GLP-1 degradation, reduces EAT (15%) and VAT in diabetic individuals ⁸⁷. The thiazolidinediones, acting mainly through the PPAR-γ, regulate the expression of numerous factors secreted from adipose tissue that greatly influence insulin sensitivity ⁸⁸.

Finally, novel opportunities could result from genetic manipulation using oligonucleotide inhibitors or microRNA mimics. MicroRNAs are short noncoding RNA molecules, that permit the fine-tuning of protein expression in vivo ⁸⁹ and the modulation of important biological pathways, such as vascular proliferation (miR-21), remodeling (miR-143/miR145), and atherosclerosis (miR-126) ⁹⁰. It has been demonstrated that some microRNAs, involved in regulation of adiponectin, glucose and fatty acids, are upregulated in abdominal adipose tissue of obese patients ^{91 92}. Further studies are needed to demonstrate the same effect in EAT.

Unfortunately, outcome studies reporting the predictive value of diet and/or drug related EAT reduction in CAD patients are not yet available. These studies are dramatically needed given the emergent role of EAT in the pathogenesis of several cardiovascular diseases.

CONCLUSIONS

Several studies have demonstrated the participating role of pro-inflammatory mediators in the atherogenic process. Because of the intimacy with myocardium and coronary vessels, the EAT seems to be the main source of pro-atherogenic molecules, involved in the development and progression of CAD. Realistically, the causative role of EAT in CAD is determined by both an increase of pro-inflammatory mediators and a decrease of anti-inflammatory molecules. Furthermore, chronic inflammatory disorders and age-related low-grade inflammation lead to the accumulation and inflammation of EAT, promoting in turn local and systemic inflammation with unavoidable implications in the pathogenesis of CAD. Finally, dietary/life-style changes and/or drug therapies can modify volume and secretory profile of EAT, thus suggesting that cardial visceral fat might represent, in the next future, a novel therapeutic target for CAD patients.

Figures and tables

Figure 1.Involvement of epicardial adipose tissue in the pathogenesis of atherosclerotic plaque. The figure illustrates the intercorrelation between Epicardial Adipose Tissue (EAT) and systemic inflammation through a bidirectional continuum. Inflammatory cells from systemic circulation and from EAT penetrate the lipid core of the atherosclerotic plaque. The imbalance between production of pro-inflammatory and anti-inflammatory molecules promotes plaque progression and contributes to plaque instability and rupture.

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