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Role of Epicardial Adipose Tissue in Health and Disease: A Matter of Fat?

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ABSTRACT

Epicardial adipose tissue (EAT) is a small but very biologically active ectopic fat depot that surrounds the heart. Given its rapid metabolism, thermogenic capacity, unique transcriptome, secretory profile, and simply measurability, epicardial fat has drawn increasing attention among researchers attempting to elucidate its putative role in health and cardiovascular diseases. The cellular crosstalk between epicardial adipocytes and cells of the vascular wall or myocytes is high and suggests a local role for this tissue. The balance between protective and proinflammatory/profibrotic cytokines, chemokines, and adipokines released by EAT seem to be a key element in atherogenesis and could represent a future therapeutic target. EAT amount has been found to predict clinical coronary outcomes. EAT can also modulate cardiac structure and function. Its amount has been associated with atrial fibrillation, coronary artery disease, and sleep apnea syndrome. Conversely, a beiging fat profile of EAT has been identified. In this review, we describe the current state of knowledge regarding the anatomy, physiology and pathophysiological role of EAT, and the factors more globally leading to ectopic fat development. We will also highlight the most recent findings on the origin of this ectopic tissue, and its association with cardiac diseases. © 2017 American Physiological Society. Compr Physiol 7:1051‐1082, 2017.

Figure 1. Figure 1. Layers of the heart and pericardium Scheme demonstrating epicardial fat between the visceral pericardium and myocardium, paracardial fat external to the parietal pericardium, and pericardial fat as the combination of epicardial and paracardial fat.
Figure 2. Figure 2. EAT among species—anterior and posterior heart photographic views in a 12‐months‐old rat (A), a 3‐months‐old swine (B), and a 50‐years‐old human (C).
Figure 3. Figure 3. The origin of EAT. Epicardial adipocytes derived from embryonic epicardial progenitors by ETFT. After myocardial infarction in adult animals, reactivation of ETFT enables new epicardial adipocytes formation from epicardium cells.
Figure 4. Figure 4. Main factors leading to ectopic fat deposition in humans. FFA: free fatty acids; ASCs: adipose stem stromal cells; T2D: type 2 diabetes; CAD: coronary artery disease; MHO: metabolically healthy obesity.
Figure 5. Figure 5. Echocardiography parasternal long axis view, thickness of paracardial and epicardial fat were measured on one anatomical point.
Figure 6. Figure 6. CT scans in axial views, without iodine injection and with cardiac synchronization in A and with iodine injection and cardiac synchronization in B, C, and D at different anatomical level. Pericardium was clearly depicted (white arrow) and allows the differentiation between epicardial fat (star in C) and paracardial fat (open arrow in C).
Figure 7. Figure 7. MR short axis cine sequences at the diastolic phase A, with contouring of the heart in B, contouring of the pericardium in C, and contouring of the pericardial fat in D; each surface was multiplicated by slice thickness to obtain volumes. This contouring was repeated on the whole stack of images covering the entire heart to be able to quantify total fat volume. Volume of epicardial fat was measured as = volume in C minus volume B), and paracardial fat (volume D minus volume C).
Figure 8. Figure 8. Atrial EAT and myocardium. (A) Sirius red sections, (B) Oil‐red‐O staining, and (C) Sirius red staining. At high magnification, adipocytes infiltration associated with important fibrosis within myocardium, impairing myocytes network, and (D) haematoxylin and eosin staining.
Figure 9. Figure 9. Role of epicardial fat in AF.
Figure 10. Figure 10. Role of epicardial fat in CAD.


Figure 1. Layers of the heart and pericardium Scheme demonstrating epicardial fat between the visceral pericardium and myocardium, paracardial fat external to the parietal pericardium, and pericardial fat as the combination of epicardial and paracardial fat.


Figure 2. EAT among species—anterior and posterior heart photographic views in a 12‐months‐old rat (A), a 3‐months‐old swine (B), and a 50‐years‐old human (C).


Figure 3. The origin of EAT. Epicardial adipocytes derived from embryonic epicardial progenitors by ETFT. After myocardial infarction in adult animals, reactivation of ETFT enables new epicardial adipocytes formation from epicardium cells.


Figure 4. Main factors leading to ectopic fat deposition in humans. FFA: free fatty acids; ASCs: adipose stem stromal cells; T2D: type 2 diabetes; CAD: coronary artery disease; MHO: metabolically healthy obesity.


Figure 5. Echocardiography parasternal long axis view, thickness of paracardial and epicardial fat were measured on one anatomical point.


Figure 6. CT scans in axial views, without iodine injection and with cardiac synchronization in A and with iodine injection and cardiac synchronization in B, C, and D at different anatomical level. Pericardium was clearly depicted (white arrow) and allows the differentiation between epicardial fat (star in C) and paracardial fat (open arrow in C).


Figure 7. MR short axis cine sequences at the diastolic phase A, with contouring of the heart in B, contouring of the pericardium in C, and contouring of the pericardial fat in D; each surface was multiplicated by slice thickness to obtain volumes. This contouring was repeated on the whole stack of images covering the entire heart to be able to quantify total fat volume. Volume of epicardial fat was measured as = volume in C minus volume B), and paracardial fat (volume D minus volume C).


Figure 8. Atrial EAT and myocardium. (A) Sirius red sections, (B) Oil‐red‐O staining, and (C) Sirius red staining. At high magnification, adipocytes infiltration associated with important fibrosis within myocardium, impairing myocytes network, and (D) haematoxylin and eosin staining.


Figure 9. Role of epicardial fat in AF.


Figure 10. Role of epicardial fat in CAD.
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Teaching Material

B. Gaborit, C. Sengenes, P. Ancel, A. Jacquier, A. Dutour. Role of Epicardial Adipose Tissue in Health and Disease: A Matter of Fat? Compr Physiol 7 2017, 1051-1082.

Didactic Synopsis

EAT is an ectopic fat depot located between myocardium and the visceral pericardium with no fascia separating the tissues, allowing local interaction and cellular cross-talk between myocytes and adipocytes

  • Given the lack of standard terminology, it is necessary to make a distinction between epicardial and pericardial fat to avoid confusion in the use of terms. The pericardial fat refers to the combination of epicardial fat and paracardial fat (located on the external surface of the parietal pericardium)
  • Imaging techniques such as echocardiography, computed tomography or magnetic resonance imaging are necessary to study EAT distribution in humans
  • Very little amount of EAT is found in rodents compared to humans
  • EAT displays high rate of fatty acids metabolism (lipogenesis and lipolysis), thermogenic (beiging features), and mechanical properties (protective framework for cardiac autonomic nerves and vessels)
  • Compared to visceral fat, EAT is likely to have predominant local effects
  • EAT secretes numerous bioactive factors including adipokines, fibrokines, growth factors, and cytokines that could either be protective or harmful depending on the local microenvironment
  • Human EAT has a unique transcriptome enriched in genes implicated in extracellular matrix remodeling, inflammation, immune signaling, beiging, thrombosis and apoptosis pathways
  • Epicardial adipocytes have a mesothelial origin and derive mainly from epicardium. Cells originating from the Wt1+ mesothelial lineage, can differentiate into EAT and this “epicardium-to-fat transition” fate could be reactivated after myocardial infarction
  • Factors leading to cardiac ectopic fat deposition may include dysfunctional subcutaneous adipose tissue, fibrosis, inflammation, hypoxia, and aging
  • Periatrial EAT has a specific transcriptomic signature and its amount is associated with atrial fibrillation
  • EAT is likely to play a role in the pathogenesis of cardiovascular disease and coronary artery disease
  • EAT amount is a strong independent predictor of future coronary events
  • EAT is increased in obesity, type 2 diabetes, hypertension, metabolic syndrome, nonalcoholic fatty liver disease, and obstructive sleep apnea (OSA)

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: a variety of terms including “epicardial,” “pericardial,” “paracardial,” and “intrathoracic” have been used in the literature to describe ectopic fat depots in proximity to the heart or within mediastinum. The use of these terms appears to be a point of confusion, as there is varied use of definitions. Of particular confusion is the term used to define the adipose tissue located within the pericardial sac, between myocardium and visceral pericardium. This has previously been described in the literature as “pericardial fat,” while other groups have referred it as “epicardial fat.” As illustrated in Figure 1, the most accurate term for the adipose tissue fully enclosed in the pericardial sac that directly surrounds myocardium and coronary arteries is EAT. Pericardial fat (PeriF) refers to paracardial fat (ParaF) plus all adipose tissue located internal to the parietal pericardium. PeriF=ParaF+EAT.

Figure 2. This figure illustrates the relative amount of epicardial adipose tissue among species. Humans and swine have much more EAT than rodents.

Figure 3. This figure illustrates the origin of epicardial adipose tissue. Epicardial adipocytes have a mesothelial origin and derive mainly from epicardium. Cells originating from the (Wilms’ tumor gene Wt1) Wt1+ mesothelial lineage, can differentiate into EAT and this epicardium-to-fat transition (ETFT) fate can be reactivated after myocardial infarction.

Figure 4. This figure illustrates the mechanisms driving the development of ectopic fat deposition and its consequences. In an obesogenic environment and chronic positive energy balance, the ability of subcutaneous adipose tissue (SAT) to expand, and to store the free fatty acids in excess is crucial in preventing the accumulation of fat in ectopic sites, and the development of obesity complications. Healthy SAT and gynoid obesity are associated with a protective phenotype with less ectopic fat and metabolically healthy obesity, while dysfunctional SAT and android obesity are associated with more visceral fat and ectopic fat accumulation with an increased risk of type 2 diabetes, metabolic syndrome and coronary artery disease (CAD). Inflammation or profibrotic processes, hypoxia, and aging could also contribute to ectopic fat development. Mobilization and release of adipose progenitors adipose-derived stem/stromal cells (ASCs) into the circulation and their further infiltration into non adipose tissues leading to ectopic adipocyte formation also cannot be excluded.

Figures 5 to 7. These figures illustrate imaging techniques for EAT quantification. MRI remains the standard reference for adipose tissue quantification. The major advantage of this technique is its excellent spatial resolution and possible distinction between paracardial and epicardial fat. The major limitation of echocardiography is its 2D approach (thickness measurement). The major limitation of computed tomography remains its radiation exposure.

Figure 8. This figure illustrates microscopic images of human atrial epicardial adipose tissue and myocardium. One can observe fatty infiltration of myocardium with EAT, that is, direct adipocytes infiltration into the underlying atrial myocardium, associated with fibrosis. Such direct adipocytes infiltration separating myocytes are supposed to induce remodeled atrial substrate, and lead to conduction defects (conduction slowing or inhomogeneity).

Figure 9. This figure summarizes the possible mechanisms that could link EAT with atrial fibrillation. EAT expansion-induced mechanical stress, direct adipocyte infiltration within atrial myocardium, inflammation, oxidative stress, and EAT producing adipofibrokines are thought to participate in structural and electrical remodeling of the atria, and in cardiac autonomous system activation, hence promoting arrhythmogenesis.

Figure 10. This figures illustrates a transversal and longitudinal view of EAT surrounding a coronary artery. As there is no fascia separating EAT from the vessel wall, free fatty acids or proinflammatory cytokines produced by EAT could diffuse passively or in vasa vasorum through the arterial wall and participate in the early stages of atherosclerosis plaque formation (endothelial dysfunction, ROS production, oxidized LDL uptake, monocyte transmigration, smooth muscle cells proliferation, macrophages transformation into foam cells). An imbalance between antiatherogenic, and harmful adipocytokines secreted by EAT could initiate inflammation in the intima. Innate immunity can be activated via the toll-like receptors (TLRs), which recognize antigens such as lipopolysaccharide (LPS). Activation of TLRs leads to the translocation of NFκB into the adipocyte nucleus to initiate the transcription and the release of proinfammatory molecules such as IL-6, TNF-α, and resistin. NLRP3 inflammasome is a sensor in the nod-like receptor family of the innate immune cell system that activates caspase-1, and mediates the processing and release of IL-1β by the adipocyte, and thereby has a central role in the EAT-induced inflammatory response.

 


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How to Cite

Bénédicte Gaborit, Coralie Sengenes, Patricia Ancel, Alexis Jacquier, Anne Dutour. Role of Epicardial Adipose Tissue in Health and Disease: A Matter of Fat?. Compr Physiol 2017, 7: 1051-1082. doi: 10.1002/cphy.c160034