key: cord-0771990-s2wuw7g5
authors: Iacobellis, Gianluca
title: Epicardial adipose tissue in contemporary cardiology
date: 2022-03-16
journal: Nat Rev Cardiol
DOI: 10.1038/s41569-022-00679-9
sha: c86d904f4f8bd51ec161ad1b059dd513cfd03182
doc_id: 771990
cord_uid: s2wuw7g5

Interest in epicardial adipose tissue (EAT) is growing rapidly, and research in this area appeals to a broad, multidisciplinary audience. EAT is unique in its anatomy and unobstructed proximity to the heart and has a transcriptome and secretome very different from that of other fat depots. EAT has physiological and pathological properties that vary depending on its location. It can be highly protective for the adjacent myocardium through dynamic brown fat-like thermogenic function and harmful via paracrine or vasocrine secretion of pro-inflammatory and profibrotic cytokines. EAT is a modifiable risk factor that can be assessed with traditional and novel imaging techniques. Coronary and left atrial EAT are involved in the pathogenesis of coronary artery disease and atrial fibrillation, respectively, and it also contributes to the development and progression of heart failure. In addition, EAT might have a role in coronavirus disease 2019 (COVID-19)-related cardiac syndrome. EAT is a reliable potential therapeutic target for drugs with cardiovascular benefits such as glucagon-like peptide 1 receptor agonists and sodium–glucose co-transporter 2 inhibitors. This Review provides a comprehensive and up-to-date overview of the role of EAT in cardiovascular disease and highlights the translational nature of EAT research and its applications in contemporary cardiology.

Epicardial adipose tissue (EAT) is a unique fat depot located between the myocardium and the visceral layer of the epicardium, with multiple implications for research and clinical practice in contemporary cardio logy. Since the pioneering work by my research group in the early 2000s 1,2 , interest in EAT has rapidly grown among a multidisciplinary audience ranging from clin ical and research cardiologists to basic scientists and internal medicine practitioners. As research in the field of cardiometabolic diseases has evolved, the focus has narrowed from general obesity to organ specific adipos ity. To date, almost 2,000 original articles describing the multifaceted aspects of EAT have been published.

The unicity of EAT lies not only in its peculiar anat omy and unobstructed proximity to the heart 3 but also in its distinctive transcriptome, which is substantially different from that of other visceral and subcutaneous fat depots 4 . EAT can be highly protective for the adja cent myocardium through its dynamic brown fat like thermogenic function and deeply harmful via paracrine or vasocrine secretion of pro inflammatory and profi brotic cytokines 5 . Owing to its functional proximity to the heart, EAT has been suggested to have a role in the progression and development of leading causes of morbidity and mortality such as coronary artery disease (CAD), atrial fibrillation and heart failure. Of note, EAT is not equally distributed throughout the heart and its regional distribution is not randomly allocated. EAT surrounding the left atrium is not the same as that infil trating the coronary arteries. Each local EAT depot has a distinct transcriptome and proteome and, therefore, has a different effect on the adjacent heart structures.

The proliferative and translational nature of research on EAT makes the subject of this Review very timely. In this Review, I provide a comprehensive and up to date overview of EAT and its role in cardiovascular diseases. I also discuss imaging techniques for the assessment of EAT and the potential for EAT to be a therapeutic target for drugs with cardiovascular benefits such as glucagon-like peptide 1 receptor (GLP1R) agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors 6 . Finally, I explore the hypothesis that EAT amplifies the inflammatory response and cardiac syndrome related to coronavirus disease 2019 (COVID19) 7 .

Anatomy and physiology of EAT EAT is the fat depot located between the myocardium and the epicardium 3, 8 supplied by branches of the coro nary arteries. By contrast, pericardial adipose tissue (PAT) is located externally and is supplied by non coronary arteries. EAT is mostly located in the atrioventricular and interventricular grooves and can be differentiated into pericoronary EAT (located directly around or on the coronary artery adventitia) and myocardial EAT Epicardial adipose tissue (EAT) . The fat depot located between the myocardium and the visceral layer of the epicardium.

Medications indicated for the treatment of type 2 diabetes mellitus, obesity or both, with pleiotropic effects.

(the fat depot just over the myocardium) 9 . Micro scopically, EAT is composed mainly of adipocytes but also contains nerve cells, inflammatory cells (mainly macrophages and mast cells), stromal cells, vascular cells and immune cells. EAT is a white adipose tissue but also has brown fat like and beige fat like features 10 . No muscle fascia is present between EAT and the myo cardium; therefore, the two tissues share the same microcirculation 3 . This feature is unique to EAT; no other visceral fat depot has this contiguity with the target organ. The lack of an anatomical barrier allows crosstalk between EAT and the contiguous myocardium.

The function of EAT in normal conditions is pro tective. Indeed, EAT provides the adjacent myocardium with free fatty acids and functions as a buffer, protecting the heart against high fatty acid levels 11 . Adipocyte fatty acid binding protein (also known as FABP4), which is highly expressed in EAT, participates in the intracellu lar transport of fatty acids from epicardial fat into the myocardium 12 . Fatty acids can reach the myocardium through paracrine or vasocrine pathways, the latter being impaired by coronary atherosclerosis 13 . The EAT transcriptome is rich in genes encoding cardioprotec tive adipokines, such as ADIPOQ and ADM, encod ing adiponectin and adrenomedullin, respectively, both of which have potential anti inflammatory and anti atherogenic properties 14, 15 . Interestingly, ADIPOQ expression in EAT is locally controlled by oxidation fac tors released from the heart in response to myocardial oxidative stress 16 . The paracrine modulation and acti vation of EAT adiponectin can contribute to myocar dial redox homeostasis. Furthermore, when compared with subcutaneous adipose tissue, the EAT transcrip tome contains more genes encoding proteins related to potassium channel activity, mesoderm development, regulation of body fluid levels, wound healing, the endo plasmic reticulum nuclear signalling pathway, plasma membrane organization and biogenesis 4 .

EAT function and morphology change with age and under pathological conditions (FiG. 1) . Interestingly, epi cardial and intra abdominal fat depots both evolve from brown adipose tissue 11 . EAT is thought to provide a direct source of heat to the myocardium and to protect the heart during unfavourable haemodynamic conditions such as ischaemia or hypoxia 17 . The processes implicated in the control of thermogenesis in EAT are complex and yet to be fully understood. In neonates, EAT has brown fat like properties and functions, with limited physical flexibility and responsiveness to external factors 18 . With ageing, epicardial adipocytes become more susceptible to environmental, metabolic and haemodynamic fac tors, which gradually change the function of EAT from thermogenesis to energy storage 18 . Indeed, EAT brown fat like activity decreases substantially with age 18 . The changes are not only functional but also structural. The proportion of brown adipocytes decreases in favour of more unilocular white adipocytes in older indivi duals 10 . This finding suggests that the transition from brown fat to beige fat is a feature of EAT in adults. However, chronic and long term ischaemic conditions, such as the advanced stages of CAD, can also depress brown fat like activity in EAT 18 . In patients with advanced CAD, the expression of genes encoding proteins related to adipo cyte browning and thermogenic activation is downregu lated in EAT, with reciprocal increases in the expression of genes encoding pro inflammatory cytokines 19 . These changes in gene expression could be a consequence of fibrosis and apoptosis that can occur in EAT in end stage organ disease 4 . However, EAT can be induced to resume its brown fat like function and provide beneficial effects to the heart in patients with long term ischaemic condi tions. Pharmacological upregulation of gene expression for proteins involved in brown fat activation and mito chondrial signalling in EAT has been associated with a significant reduction in left ventricular mass and EAT inflammation 20 . Further studies are necessary to evalu ate whether EAT can adapt to various metabolic con ditions and function like a brown fat or beige fat depot as needed.

Imaging techniques are an essential component of con temporary cardiology. EAT can be assessed with tradi tional and novel techniques (TAbLE 1) . The thickness of EAT can be visualized and measured with standard 2D echocardiography as first proposed by my group in 2003 (REF. 1 ). EAT is generally identified as the echo free space between the outer wall of the myocardium and the vis ceral layer of the pericardium, but EAT can also appear as an echo dense space when inflammation or large amounts of EAT are present 21 . EAT thickness is meas ured perpendicularly on the free wall of the right ven tricle at end systole when both walls collapse and allow the widest measurement 21 . However, a much greater EAT thickness can be measured just to the right of the aortic annular plane owing to the steep downward turn of the free wall of the right ventricle as it approaches the proximal ascending aorta.

Echocardiographic measurement of EAT thickness is a marker of visceral adiposity, and EAT thickness variability (ranging from 1 mm to 25 mm) reflects the variation in intra abdominal fat accumulation 2 . However, EAT thickness is primarily a marker of ectopic fat accu mulation. Intramyocardial and intrahepatic lipid content, measured with 1 H magnetic resonance spectroscopy

• Epicardial adipose tissue (EAT) has anatomical and functional interactions with the heart owing to the shared circulation and the absence of muscle fascia separating the two organs. • EAT can be clinically measured with cardiac imaging techniques that can help to predict and stratify cardiovascular risk. • Regional distribution of EAT is important because pericoronary EAT and left atrial EAT differently affect the risk of coronary artery diseases and atrial fibrillation, respectively. • EAT has a role in the development of several cardiovascular diseases through complex mechanisms, including gene expression profile, pro-inflammatory and profibrotic proteome, neuromodulation, and glucose and lipid metabolism. • EAT could be a potential therapeutic target for novel cardiometabolic medications that modulate adipose tissue such as glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter 2 inhibitors. • EAT might be a reservoir of severe acute respiratory syndrome coronavirus 2 and an amplifier of coronavirus disease 2019 (COVID-19)-related cardiac syndrome.

Pericardial adipose tissue (PAT). The fat depot located between the visceral and parietal layers of the epicardium.

brown fat generates heat and non-shivering thermogenesis in response to cold and activation of the autonomic nervous system but is lost before adulthood in humans.

beige fat originates from white adipose tissue but has anatomical features akin to both white and brown fat and can function like brown fat under certain circumstances.

The accumulation or infiltration of lipids in non-adipose tissues such as the heart, liver and muscles.

www.nature.com/nrcardio techniques, are correlated with EAT thickness regard less of BMI 22 . Increased lipid accumulation in the myo cardium has been associated with myocardial disarray, fibrosis and apoptosis, leading to heart failure and atrial fibrillation 23, 24 . Intuitively, the use of echocardiography to measure EAT thickness has several advantages, including its low cost, accessibility and reproducibility but also has several limitations. Even if excellent interobserver and intraobserver agreement is reported, echocardiography is still an operator dependent technique. Cardiac multidetector CT and cardiac MRI can provide volumetric measurement of EAT and additional func tional information by detecting deep regional EAT that is not accessible with transthoracic echocardiography 25, 26 . Visualizing peri atrial and pericoronary EAT is impor tant in understanding, predicting and possibly prevent ing the effects of EAT in atrial fibrillation and CAD 27,28 . Both contrast enhanced and non contrast enhanced, cardiac gated multidetector CT are used to quantify EAT 25 . The combination of high spatial resolution, vol ume coverage of the entire heart and increasing avail ability of software analysis tools makes the use of CT to measure EAT ideal. However, differences exist in the CT attenuation (a measure of EAT density, expressed in Hounsfield units (HU)) characteristics of EAT depend ing on the presence or absence of iodinated contrast and inflammatory status 29 . EAT density is a marker of both EAT and general inflammation 30,31 . EAT attenuation ranges between -45 HU and -195 HU, where a lower negative means higher density 29-31 . Radiographic fat density is determined by adipocyte hypertrophy, hyper plasia and fibrosis that oppositely influence fat CT signal attenuation. Hypertrophic and hyperplastic fat depots usually have low density 29-31 . The increased EAT den sity reported in patients with CAD or severe COVID19 could be caused by inflammation and fibrosis that mit igate the expected effect of hypertrophic or hyperplasic fat cells on fat CT attenuation 32 .

Although 18 F FDG PET-CT can detect EAT inflam matory activity, this modality is not cost effective or readily available. Therefore, the need for imaging biomarkers to directly assess the interaction between adipose tissue and inflammation is compelling. An innovative imaging metric -the CT fat attenuation index (FAI) -has been proposed as a marker of perivascular fat inflammation 33 . FAI reflects transcriptomic, meta bolic and phenotypic changes in perivascular fat. FAI is significantly higher around culprit lesions than around non culprit lesions in individual patients with CAD 34 . FAI can detect the inflammatory burden around vulner able plaques and predict early subclinical CAD in vivo. Further studies evaluating FAI assessment of regional EAT depots, such as peri atrial and pericoronary EAT, are warranted. Artificial intelligence and radiomic analy sis to process and elaborate on images, including those of fat depots obtained by common non invasive imaging methods, could be used to improve the assessment of EAT physiology and pathophysiology 35 .

Coronary artery disease. The pathogenesis of CAD is multifactorial and includes established and novel mech anisms. EAT was first suggested to be a factor in the multifaceted pathways causing coronary atherosclero sis in the early 2000s. Undoubtedly, the anatomical and unobstructed contiguity of EAT with the coronary arter ies supports the argument for a local effect. However, vicinity is not the only factor, because the quantity and activity of EAT have more important roles 27 . The mech anisms through which EAT can cause atherosclerosis are complex and include inflammation, exaggerated innate immunity response, oxidative stress, endothe lial damage, adipocyte stress, lipid accumulation and glucotoxicity 5 (FiGS 2,3).

Inflammation is the major feature of EAT in patients with CAD, with dense infiltrates of macrophages, Under physiological conditions, the brown fat-like properties of EAT rapidly decrease with age, from childhood to adulthood. However, EAT maintains cardioprotective functions such as providing a source of energy and heat to the heart. In pathological conditions, such as coronary artery disease, diabetes mellitus, heart failure and atrial fibrillation, EAT becomes pro-atherogenic and proarrhythmogenic. In patients with advanced or end-stage organ disease, such as cardiac diseases, and in elderly individuals, the thermogenic function of EAT can be further decreased, with reciprocal increases in the expression of genes encoding profibrotic and pro-apoptotic factors.

Multiple-row detector CT that provides greater detail and additional views of the heart and coronary arteries than standard CT.

A measure of tissue density proportionate to the attenuation of X-rays that pass through the tissue; EAT attenuation ranges between -45 and -195 Housefield units.

(FAi). A novel imaging metric that describes adipocyte lipid content and size; FAi correlates with perivascular adipose tissue inflammation.

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mast cells and CD8 + T cells 36 . Pro inflammatory M1 macrophages are significantly more prevalent than anti inflammatory M2 macrophages in EAT from individuals with CAD 37 . The presence of macrophages in EAT has been argued to be reactive to coronary artery plaque rupture and instability rather than the result of intrinsic inflammation 36 . However, a study using microarray analysis demonstrated that EAT has a pro atherogenic transcriptional profile in CAD 4 . The genes encoding many pro inflammatory cytokines (such as IL6, CCL2 (also known as MCP1) and tumour necro sis factor (TNF)), chemokine ligands and receptors as well as several novel pro inflammatory adipokines (such as chemerin, resistin, serglycin and intelectin 1 (also known as omentin 1)) 38-40 are upregulated in EAT of patients with CAD. The level of inflammation is not only greater in EAT than in the subcutaneous adipose tissue in these patients but is also greater than in any other visceral fat depot. For example, levels of CD45 (a marker of haematopoietic cells) have been reported to be signifi cantly higher in EAT than in omental fat depots, indicat ing substantial macrophage infiltration in EAT 41 . Given the proximity of EAT to the coronary arteries, this rich pro inflammatory proteasome surrounds the coronary adventitia and goes directly into the coronary lumen following paracrine or vasocrine pathways. The thicker the layer of EAT and the closer it is to the coronary artery, the greater the inflammatory activity and, conse quently, the more severe the coronary atherosclerosis 36 . The disequilibrium between anti inflammatory and pro inflammatory EAT adipokine secretion has a sig nificant effect on the progression and severity of coro nary atherosclerosis 41, 42 . Whereas the production of EAT pro inflammatory adipokines is significantly higher in patients with CAD than in individuals without CAD, gene and protein expression of adiponectin (a cytokine with anti inflammatory properties) are lower 14 . The peculiar pro atherogenic transcriptome of EAT 4 can influence adipokine production. The proximity of EAT to the coronary arteries makes the defective paracrine secretion of adiponectin an important contributor to coronary atherosclerosis. The adaptive and innate immune responses also con tribute to EAT inflammation in CAD. High concentra tions of adaptive immune cells, particularly CD4 + T cells, in EAT are frequently observed in individuals with obesity or diabetes mellitus [43] [44] [45] . The activation of mediators of the EAT innate response, such as nuclear factor κB (NF κB), JUN N terminal kinase (JNK) and Toll like receptors, in patients with CAD can lead to the upregulation of inflammatory cytokine expression in EAT 41 .

EAT also secretes factors that regulate endothe lial function, such as resistin, which is associated with increased endothelial cell permeability 46 . EAT is also implicated in oxidative stress. Increased levels of reactive oxygen species and reduced expression of antioxidant enzymes trigger inflammation and atherogenicity in epicardial adipocytes 47 . In patients with CAD, the EAT transcriptome is rich in genes involved in haemostasis and coagulation, including tissue plasminogen activa tor, which links fibrinolysis and inflammation in human adipose tissue 4 . The epicardial adipocytes of individuals with CAD overexpress markers of cellular stress (such as the kinases MAP2K3 and MAP3K5), which are linked to coronary inflammation, as well as multiple pro teases involved in lysosomal degradation and cellular apoptosis 4 .

EAT is also a local source of ectopic lipids. The exces sive secretion and release of fatty acids from epicardial adipocytes infiltrating the adventitia could contribute to lipid accumulation in the coronary arteries. Group II secretory phospholipase A 2 , the rate limiting enzyme in www.nature.com/nrcardio the synthesis of pro inflammatory lipids, is present in high concentrations in EAT of patients with CAD com pared with healthy individuals 48 . FABP4 is expressed in epicardial adipocytes and might act as a local con tributor to ectopic fat accumulation in atherosclerotic plaque 49 . The lipogenic effect of epicardial fat can also be attributed to the high content of conjugated fatty acids in EAT 50 . The innate immune response in EAT mediated by Toll like receptors is upregulated by excessive fatty acid release from EAT 41, 51 . Of note, the expression of genes encoding proteins involved in lipid metabolism, such as endothelial lipase (also known as lipase G) and large neu tral amino acids transporter small subunit 1 (also known as SLC7A5), is upregulated in EAT of patients with CAD and type 2 diabetes compared with patients with CAD without diabetes 52 . Insulin stimulated lipo genesis is greater in EAT than in other visceral fat depots, whereas glucose uptake is extremely low in EAT 11 . Therefore, EAT can contribute to local insulin resistance in the coronary arteries 53, 54 . Interestingly, in patients with CAD, levels of GLUT4 mRNA (which encodes glucose transporter type 4 (GLUT4)) are lower in EAT than in subcutaneous fat 55 . Lower GLUT4 lev els affect insulin mediated glucose uptake into EAT and the adjacent myocardium. Studies suggest that mechanisms underlying coronary atherosclerosis in patients with diabetes include upregulation of signalling between advanced glycation end products (AGEs) and their receptors (RAGEs) in EAT 52 Fig. 2 | role of regional EaT depots on coronary artery disease and atrial fibrillation. The epicardial adipose tissue (EAT) is distributed as localized depots lying between the myocardium and the visceral layer of the pericardium. EAT can infiltrate the left atrium (left atrial EAT) and surround the coronary arteries (coronary EAT). By contrast, pericardial adipose tissue (PAT) is located more externally, within the visceral and parietal layers of the pericardium. EAT contributes to the development and progression of coronary artery disease and atrial fibrillation through complex and multifactorial pathways. The regional distribution of EAT has an important role because each EAT depot is anatomically, genetically and functionally different. a | Left atrial EAT has a high expression of genes encoding pro-arrhythmogenic factors. Left atrial EAT can contribute to atrial fibrillation through the local secretion of profibrotic factors (matrix metalloproteinases (MMPs), transforming growth factor-β1 (TGFβ1) and TGFβ2, connective tissue growth factor (cTGF) and activin A) and inflammatory factors (IL-6 and tumour necrosis factor (TNF)) as well as free fatty acid (FFA) infiltration and increased autonomic control via ganglionated plexi. b | The coronary EAT has a high expression of genes encoding pro-inflammatory adipokines and factors regulating glucose and lipid metabolism. Coronary EAT can influence the development and progression of coronary artery disease through increased infiltration of pro-inflammatory M1 macrophages from EAT into the adjacent myocardium, the paracrine or vasocrine release of several pro-inflammatory cytokines (CCL2, IL-6 and TNF) and adipokines (chemerin, intelectin 1 (also known as omentin 1), resistin and serglycin), and the activation of innate immune response factors such as JUN N-terminal kinase (JNK), nuclear factor-κB (NF-κB) and Toll-like receptors (TLRs). Upregulation of signalling via advanced glycation end products (AGE) binding to their receptor RAGE in EAT can contribute to the oxidative stress and endothelial damage associated with coronary atherosclerosis in patients with diabetes mellitus. The excessive influx of FFAs from EAT into the coronary arteries is mediated by enzymes such as group II secretory phospholipase A 2 (sPLA 2 -II) and adipocyte fatty acid-binding protein (also known as FABP4). GLUT4, glucose transporter type 4. endothelial damage associated with diabetic coronary atherosclerosis. The overexpression of genes related to inflammation in EAT of patients with CAD and dia betes is primarily the result of the increased activity of transcription factors such as those in the NF κB and FOS families 51 . The increased atherogenicity of EAT in patients with diabetes can also be linked to a high con centration of unsaturated fatty acids, sphingolipids and ceramides in EAT 56 .

The complex mechanisms underlying the role of EAT in coronary atherosclerosis can be translated into clinical practice, for example, in early diagnosis and risk stratifi cation. EAT volume and thickness are greater in patients with CAD than in individuals without atherosclerosis 57 . A coronary artery calcium (CAC) score >10 is associated with higher EAT volume, which can predict the risk of atherosclerosis with a sensitivity and specificity of 72% and 70%, respectively 58 . In the EPICHEART study 59 , a high EAT volume was independently associated with a high CAC score in men but not in women. In the Heinz Nixdorf Recall cohort study 56 , a high EAT volume was associated with the progression of coronary artery calcification, particularly in younger (age <55 years) individu als and in those with mild obesity. Other studies seem to confirm the role of EAT volume in predicting the early stages of atherosclerosis in asymptomatic indi viduals, often independent of obesity 60 . This observa tion can be explained by the visceral fat phenotype of EAT and the poor sensitivity of BMI defined obesity in representing body fat distribution 2,23 . The role of EAT volume in predicting early atherosclerosis in individu als at high risk of atherosclerotic cardiovascular disease has also been confirmed in patients with asymptomatic diabetes 61, 62 . Although calcification is a key component of atherosclerotic plaques, EAT volume can predict the risk of CAD independently of the CAC score [63] [64] [65] . An increased EAT volume is associated with the presence of obstructive and vulnerable plaques in patients with symptomatic atherosclerosis and a CAC score of 0 (REF. 66 ). EAT volume is higher in patients with non calcified, vul nerable unstable plaques than in those with stable and calcified lesions [63] [64] [65] . Therefore, EAT might contribute to the development of early and not yet calcified coronary atherosclerotic plaques, which are highly unstable and vulnerable to rupture 67 .

EAT is not equally distributed through the heart and, therefore, has regional effects. Pericoronary EAT affects the proximal coronary arteries owing to their anatom ical proximity 27, 68 Fig. 3 | atherogenic effects of coronary EaT on the coronary artery. In patients with coronary artery disease, coronary epicardial adipose tissue (EAT) has a dense inflammatory infiltrate with a high prevalence of pro-inflammatory M1 macrophages. Coronary EAT secretes pro-inflammatory cytokines (such as CCL2, IL-6 and tumour necrosis factor (TNF)) and adipokines (such as chemerin, intelectin 1 (also known as omentin 1), resistin and serglycin) into the coronary lumen, thereby contributing to systemic inflammation. Coronary EAT inflammation also contributes locally to coronary atherosclerotic plaque inflammation. The upregulation in the coronary EAT of innate immune response signalling, such as JUN N-terminal kinase (JNK), nuclear factor-κB (NF-κB) and Toll-like receptor (TLR) signalling, can also induce the secretion of inflammatory mediators from the coronary EAT. The excessive influx of free fatty acids (FFAs) mediated by group II secretory phospholipase A 2 (sPLA 2 -II) and adipocyte fatty acid-binding protein (also known as FABP4) from epicardial adipocytes might infiltrate the adventitia and contribute to the lipid build-up in coronary artery atherosclerotic plaques. The co-occurrence of coronary artery disease with chronic hyperglycaemia can upregulate signalling via advanced glycation end products (AGE) binding to their receptor RAGE and reduce levels of glucose transporter type 4 (GLUT4), thereby contributing to oxidative stress and endothelial cell damage.

A CT-based score that measures calcium content in the coronary arteries.

www.nature.com/nrcardio regional EAT. A greater pericoronary EAT volume is associated with more severe coronary artery stenosis and CAC score in women 27 . The portion of EAT infil trating the left atrioventricular groove has a stronger association with coronary atherosclerosis than the total EAT volume 68 . The inflammatory activity of EAT is also dependent on its location as confirmed by 18 F FDG PET-CT studies 70 . The proteasome derived from pericoronary EAT produces inflammation in the underlying coronary atherosclerotic plaques, and EAT inflammation levels correlate with plaque burden and plaque necrotic core area 69 . EAT volume can also predict major cardiovascular events. In the Heinz Nixdorf Recall cohort study 71 , the incidence of fatal or non fatal coro nary events significantly increased by quartile of EAT volume increase and the association remained signifi cant even after adjustment for CAC score. The MESA study 72 (and other large, population studies) showed the independent association between EAT volume and the incidence of major adverse cardiac events. EAT assessment can, therefore, help to predict the risk of major coronary events before the accumulation of cal cium in the atherosclerotic plaque occurs and in indi viduals with asymptomatic atherosclerosis who are not obese. The use of imaging techniques for the assessment of EAT could be implemented as routine procedures for effective prediction and stratification of CAD.

Atrial fibrillation. Atrial fibrillation increases the risk of heart failure, stroke and all cause death 73 . Obesity is a known risk factor for atrial fibrillation, and weight loss and lifestyle modification can reduce this risk 74 . EAT has emerged as a risk factor and independent predictor of atrial fibrillation development and recurrence after ablation 75, 76 . Importantly, however, EAT has not always been measured in studies as a fat depot separate and distinct from PAT. This issue is not a trivial matter of terminology because EAT is anatomically and function ally different from PAT. Although PAT is a paracardiac visceral fat depot, an excess of which can affect the heart, it is not contiguous to the atrial myocardium 77 . In the Framingham Heart Study cohort, PAT volume was an independent predictor of atrial fibrillation even after adjusting for other risk factors 78 . An association has also been reported between EAT volume or thickness and atrial conduction delays such as prolonged P wave duration, interatrial conduction block and longer P-R interval 76 . CT derived posterior left atria adiposity, including peri atrial EAT thickness, is associated with atrial fibrillation burden independently of left atrium area and BMI 28 . Increased atrial PAT volume was also asso ciated with increased prevalence and severity of atrial fibrillation even after adjusting for body weight 74 . Of note, these studies all showed that the asso ciation between cardiac fat and atrial fibrillation was partially or totally independent of obesity. Several mechanisms for how altered EAT can cause or contribute to atrial fibrillation have been proposed, including genetic and neural factors, inflammation, fibrosis, fatty infiltration, and atrial electrical or struc tural remodelling (FiG. 2) . The pathogenic role of EAT in atrial fibrillation could begin with its embryogenesis and development. Embryonic epicardium can generate coronary smooth muscle cells and cardiac fibroblast or undergo adipogenic differentiation 79 . Atrial EAT adipo cytes originate from the differentiation of progenitor cells resident in the epicardium and from the secretome of atrial myocytes 79 . Interestingly, atrial natriuretic factor secreted by atrial myocytes in response to mechanical stress has adipogenic properties that can contribute to atrial EAT development 80 . Of note, the adipogenic potential of the atrial cell secretome is greater in patients with atrial fibrillation than in those without 80 . Importantly, the epicardium is reactivated during the development of atrial cardiomyopathy and contributes to the fibro fatty infiltration of subepicardium 81 . Under pathological conditions, the atria could be postulated to contribute to peri atrial EAT expansion and myocar dial fibrosis and, therefore, to the development of atrial fibrillation substrate.

As in CAD, the location of EAT is important in atrial fibrillation, and regional EAT distribution has emerged as an important factor in atrial fibrillation. The epicardial fat pad surrounding the left atrium, namely peri atrial EAT, has a unique transcriptome and secretome with potential arrhythmogenic properties that are different from those detected in other EAT depots 82 . Peri atrial EAT has a specific gene expression signature compared with periventricular and pericoronary EAT 82 . EAT infiltrating the atrium has increased expression of genes encoding proteins involved in oxidative phos phorylation, muscular contraction and calcium signal ling compared with periventricular and pericoronary EAT 82 . The absence of a fascia separating peri atrial EAT from the underlying left atrial myocardium and a shared blood supply provide a milieu for bidirectional commu nication. Pro inflammatory and profibrotic cytokines, such as interleukins and TNF, and profibrotic factors, such as matrix metalloproteinases (MMPs) and activin A, can diffuse from EAT into the adjacent atrial myocar dium and promote arrhythmias 82 . Fibrosis also has an important pathogenic role in the development of atrial fibrillation 83 . MMPs, which are abundantly produced in EAT, are regulators of extracellular matrix homeo stasis and their overexpression can cause fibrosis 84 . In rat atria, EAT conditioned medium upregulates the expression of transforming growth factor β1 (TGFβ1) and TGFβ2 and promotes fibrosis in vitro, which is mediated by EAT secretion of activin A 84 . Connective tissue growth factor (cTGF) can also contribute to atrial fibrosis. cTGF expression is significantly higher in EAT than in subcutaneous fat or PAT from patients with atrial fibrillation and in EAT from patients with sinus rhythm 85 . High EAT volume is associated with increased fibrosis, lateralization of connexin 40 and slow conduction in patients with CAD 86 . Interestingly, EAT derived extracellular vesicles collected from EAT from patients with atrial fibrillation contain profibrotic cytokines and microRNAs 87 . This finding supports the paracrine and local interaction between peri atrial EAT and the adjacent left atrium. EAT can serve as a source of lipids infiltrating the contiguous atrium. Free fatty acids can also be transported from EAT to the myocardium and lead to electromechanical changes in atrial tissue.

Free fatty acid infiltration can separate cardiomyocytes, resulting in conduction slowing, loss of side to side cell connections 88 and myocardial disorganization that leads to conduction delay and re entry (FiG. 4) . EAT can also influence the local electrophysiological properties of the atrial and pulmonary veins, such as the refrac tory period, and therefore sustain atrial fibrillation 89 . Investigations with cultured human induced pluripo tent stem cell derived cardiomyocytes indicate that local peri atrial EAT accumulation, rather than global cardiac adiposity, contributes to conduction abnor malities underlying the atrial fibrillation substrate 86 . Peri atrial EAT accumulation can slow conduction and prolong cardiomyocyte field potential duration through two mechanisms: by physical conduction block caused by extensive fibrosis, and by local EAT infiltration of the adjacent atrial myocardium, which causes conduc tion heterogeneity and electrophysiological changes through the paracrine release of cytokines that induce inter cardiomyocyte adhesion disruption and abnor mal cell coupling, alter ionic currents and myocardial metabolism, and promote inflammation 86, 90 .

EAT contains sympathetic and parasympathetic nerve fibres that contribute to overall cardiac autonomic neuronal output. EAT is the site of the ganglionated plexi, which are responsible for the initiation and main tenance of atrial fibrillation 3 . Activation of these ganglia can lead to shortening of action potential duration and to an increase in the calcium transient amplitude in the atrial myocardium 91, 92 . Interestingly, botulinum injection into EAT during cardiac surgery can suppress gangli onated plexi, reduce autonomic nervous activity and have long term beneficial effects on atrial fibrillation 93 . A large peri atrial EAT pad can also mechanically affect the left atrium and cause dilatation 94 . The infiltration of adipocytes into the atrial myocardium disorganizes the depolarization wavefront, inducing micro re entry circuits and local conduction blocks 90 .

EAT thickness and volume are greater in patients with chronic, persistent atrial fibrillation than in those with paroxysmal atrial fibrillation independent of obesity, age, sex, or presence of CAD, diabetes, dys lipidaemia or hypertension 74, 75, 78, 94 . Several studies have highlighted the use of EAT measurement in predict ing outcomes after catheter ablation for paroxysmal or persistent atrial fibrillation 95, 96 . Peri atrial EAT volume is greater in patients with atrial fibrillation and is asso ciated with recurrence after catheter ablation [95] [96] [97] [98] . EAT volume is associated with atrial fibrillation persistence independent of other risk factors or BMI 99 . EAT is, there fore, a potential substrate for the pathogenesis of atrial fibrillation. The ease with which EAT can be measured and its responsiveness to drugs currently under investi gation in the context of atrial fibrillation (such as GLP1R agonists and SGLT2 inhibitors), raises the possibility of novel therapeutic approaches for atrial fibrillation treat ment and prevention of atrial fibrillation recurrence after catheter ablation.

Heart failure. Heart failure is a complex clinical con dition that can result from diastolic or systolic dys function 100 . If left ventricular filling and relaxation are affected but the heart maintains good systolic function, the condition is defined as heart failure with preserved ejection fraction (HFpEF), whereas heart failure with reduced ejection fraction (HFrEF) indicates an impair ment in systolic performance with an ejection fraction <40%. Patients with either HFpEF or HFrEF have a poor quality of life and increased risks of arrhythmias and premature death 100 . Overall, heart failure includes abnor malities in various components of the heart, although the mechanisms are poorly understood. EAT has been suggested to have a role in heart failure, particularly in patients with HFpEF 101-104 . The volume of EAT is significantly higher in patients with HFpEF than in healthy individuals although few studies ruled out potential confounders such as CAD or obesity 101, 102 . The association between EAT thickness or volume and HFrEF is controversial, because they have been shown to be either higher or, more frequently, lower than in healthy individuals 99, 103, 104 . The lower burden of EAT observed in patients with HFrEF is attributed to the left ventricular remodelling that occurs in heart failure [102] [103] [104] .

This variability can be explained by the presence of comorbidities, such as CAD, obesity and diabetes, which can affect the volume of EAT in HFrEF. The overall met abolic and haemodynamic status of patients with HFrEF can also modulate EAT volume [101] [102] [103] [104] [105] . Severely ill patients with HFrEF can present with diffuse systematic fat loss and, therefore, with reduced EAT volume 106 .

EAT can affect cardiac function in the setting of heart failure via several mechanisms, such as increased inflammation, fibrosis and autonomic dysregulation (FiG. 5) , as well as through the mechanical effects of a large, fibrotic fat pad. The EAT proteome can also contribute to the pathogenesis of heart failure [107] [108] [109] . Inflammatory proteins, such as α1 antichymotrypsin (also known as serpin A3), creatine kinase B-type and MMP14, are upregulated in patients with heart failure 107 . α1 Antichymotrypsin could function as a modulator of the inflammatory status, although its role in heart fail ure needs further investigation. TP53 mRNA expression levels have also been shown to be higher in EAT than in subcutaneous fat in patients with heart failure 108 . p53 is a marker of inflammation and its levels are inversely correlated with the levels of adiponectin, specifically in patients with heart failure 109 . The EAT secretome might also affect biochemical processes involved in diastole. Increased EAT volume shows a strong corre lation with worsening left ventricular diastolic relaxa tion and filling 103, 104 . As described earlier, the location of EAT and the lack of fascia enable lipids to infiltrate Fig. 5 | role of EaT in heart failure. Epicardial adipose tissue (EAT) can affect heart function in the setting of heart failure via inflammation, fibrosis and neural dysregulation as observed in coronary artery disease and atrial fibrillation. However, several specific mechanisms link EAT with heart failure. The EAT proteome can contribute to the pathogenesis of heart failure through the paracrine secretion of profibrotic factors, such as α1-antichymotrypsin (ACT; also known as serpin A3) and matrix metalloproteinase 14 (MMP14), inflammatory markers, such as p53, and free fatty acids (FFAs). Large and fibrotic EAT can also exert mechanical effects on both diastolic and systolic function. EAT can also be involved in the pathogenesis of heart failure through neurohormonal mechanisms. The increased catecholamine biosynthetic activity of EAT can increase noradrenaline accumulation in the myocardium and worsen systolic performance. ECM, extracellular matrix. the myocardium. Excessive EAT derived fatty acids can be taken up by cardiomyocytes and lead to ectopic myocardial lipid accumulation 110 , which contributes to the development of heart failure by causing cardiomy ocyte disarray, dysfunction and apoptosis 110 . Patients with HFpEF have significantly more intramyocardial fat than patients with HFrEF or individuals without heart failure 111 . Increased intramyocardial fat content correlates with left ventricular dysfunction parameters in patients with HFpEF 112 .

EAT can also be involved in the pathogenesis of heart failure through neurohormonal mechanisms via the intrinsic adrenergic and cholinergic nerves, which interact with the extrinsic cardiac sympathetic and par asympathetic nervous systems [113] [114] [115] . EAT is, therefore, an important source of catecholamines, both noradrenaline and adrenaline 116 . The production of these molecules is relevant to the heart because EAT secretory abnormal ities are implicated in the development of pathological conditions, including heart failure. In patients with heart failure, noradrenaline levels were increased 5.6 fold in EAT compared with subcutaneous adipose tissue and twofold compared with plasma 116 . In addition, the lev els of the catecholamine biosynthetic enzymes tyros ine hydroxylase and dopamine β hydroxylase were upregulated in EAT compared with subcutaneous fat in patients with heart failure 116 . The increased catechola mine biosynthetic activity of EAT might contribute to the increased prevalence of atrial fibrillation in patients with HFpEF. By contrast, in HFrEF, this increased activ ity might increase total catecholamine accumulation in the myocardium and worsen systolic performance. A biopsy study in patients with heart failure showed that, after treatment with isoprenaline (an agonist of the catecholaminergic β adrenergic receptor), EAT releases molecules involved in the inflammatory response or extracellular matrix 117 . Interestingly, EAT expression of CD5L, a macrophage apoptosis inhibitor stimulated by isoprenaline, was higher in patients with heart failure who developed atrial fibrillation during follow up, although circulating levels of CD5L were not correlated with the risk of atrial fibrillation 118 . Of note, in animal models, lipolysis stimulated by isoprenaline is decreased in EAT compared with subcutaneous fat, leading to lipid storage and inflammation 119 .

Targeting EAT in cardiovascular disease EAT is a modifiable cardiovascular risk factor and a potential novel therapeutic target owing to its respon siveness to drugs with pleiotropic effects such as GLP1R agonists and SGLT2 inhibitors (FiG. 6) . Cardiovascular outcomes trials have shown that GLP1R agonist and SGLT2 inhibitor therapies reduce the incidence of major cardiovascular events, with effect sizes suggesting mech anisms beyond improvements in glycaemic control, although the mechanisms are not fully elucidated [120] [121] [122] [123] [124] [125] .

GLP1R agonists are injectable medications for the treatment of type 2 diabetes and obesity that provide cardiovascular benefits beyond glucose control [120] [121] [122] . Visceral fat reduction has been suggested as one of the non glycaemic effects of the GLP1R agonist liraglutide 126 . In patients with type 2 diabetes and obesity, the GLP1R agonists liraglutide (daily dose), semaglutide (weekly dose) and dulaglutide (weekly dose) reduce EAT thickness to a greater extent than overall weight loss [127] [128] [129] [130] . Notably, EAT expresses GLP1R, whereas sub cutaneous fat does not 131 . Therefore, the presence of GLP1R in EAT supports the hypothesis of a direct effect on the fat depot. Activation of EAT GLP1R can reduce local adipogenesis, improve fat utilization, induce brown fat differentiation and modulate the renin-angiotensinaldosterone system [132] [133] [134] . These metabolic changes might contribute to the beneficial effects of GLP1R agonists on the cardiovascular system 125 . Interestingly, GLP1R is also expressed in human cardiomyocytes 135 .

Selective SGLT2 inhibitors are oral antidiabetic agents that are indicated for the treatment of both HFpEF and HFrEF, irrespective of diabetes status. Potential beneficial cardiometabolic effects of sodiumglucose co-transporter 2 (SGLT2) inhibitor and glucagon-like peptide 1 receptor (GLP1R) agonist therapies beyond their glycaemic and haemodynamic effects. SGLT2 inhibitors and GLP1R agonists can target both left atrial epicardial adipose tissue (EAT) and coronary EAT for the treatment and prevention of atrial fibrillation (part a) and coronary artery disease (part b), respectively. Both SGLT2 inhibitors and GLP1R agonists can reduce EAT inflammation and increase free fatty acid (FFA) oxidation as fuel for the myocardium, and GLP1R agonists induce fat browning (white to brown fat differentiation and pre-adipocyte differentiation, leading to improved myocardial insulin sensitivity), all of which improve myocardial metabolism. SGLT2 inhibitors can induce sympatholytic and lipolytic effects in EAT to increase ketogenesis and reduce oxygen consumption in the setting of heart failure.

www.nature.com/nrcardio Cardiovascular outcomes trials have shown that SGLT2 inhibitor therapy can reduce the risk of major adverse cardiovascular events, cardiovascular death and heart failure 123, 124 . SGLT2 inhibitors, such as dapagliflozin and empagliflozin, reduce EAT thickness or volume [136] [137] [138] [139] [140] [141] to a clinically significant degree, partially independent of weight loss 136 . The cardiovascular benefits of SGLT2 inhibitors can be exerted throughout glycosuric and non glycaemic effects, including targeting EAT. In response to the decreased plasma glucose level caused by glycosuria, SGLT2 inhibitor therapy promotes a shift to fatty acid substrate utilization, leading to increased fatty acid oxidation, lipolysis, ketogenesis and improved myo cardial glucose metabolism 142 . In heart failure, myocar dial insulin mediated glucose uptake and mitochondrial oxidative metabolism are impaired 143 . The failing heart reduces fatty acid and glucose oxidation, with an adaptive increase in myocardial ketone utilization. The oxidation of ketone bodies, such as β hydroxybutyrate, induced by SGLT2 inhibitor therapy becomes the preferential and alternative energy source to both glucose and fatty acid oxidation 144 . This substrate selection improves oxygen consumption, translating to better cardiac performance at the mitochondrial level because the energy cost for β hydroxybutyrate oxidation is reduced compared with oxidation of glucose and pyruvate 144 . EAT might serve as a mediator of the non glycosuric cardiovascular effects of SGLT2 inhibitors. Indeed, SGLT2 inhibitors could induce EAT lipolysis and contribute to the improvement of myocardial metabolism. EAT is a major source of fatty acids and lipids that, if excessive and stored, can infil trate the underlying myocardium and contribute to heart failure 111 . Therefore, SGLT2 inhibitors, such as dapagli flozin and empagliflozin, could reduce intramyocardial lipid content by increasing EAT lipolysis and ketone body oxidation. Although the cardiovascular benefi cial effects of EAT lipolysis induced by SGLT2 inhibitor therapy remain to be demonstrated 145 , some potential mechanisms can be hypothesized on the basis of existing data. The expression of heart fatty acid binding protein (also known as FABP3) is upregulated in EAT of patients with heart failure 146 . FABP3 mobilizes elevated circulat ing fatty acids that are released during EAT lipolysis and transports them to the adjacent myocardium. Fatty acid oxidation is greatly influenced by insulin sensitivity, and dapagliflozin has been shown to improve insulin sensi tivity and glucose uptake 142 . Therefore, the ameliorated myocardial glucose metabolism and insulin sensitivity induced by SGLT2 inhibitors can improve fatty acid utilization 147 . However, if the myocardium becomes over saturated with ectopic fatty acids and is unable to utilize them, the oxidation of ketone bodies induced by SGLT2 inhibitors would become the alternative source of fuel 143 . In addition to these metabolic changes, the mass reduc tion of EAT induced by SGLT2 inhibitors might contrib ute to improved systolic and diastolic function. Further studies are warranted to elucidate the independent effects of SGLT2 inhibitors on EAT.

A reduction in EAT thickness induced by statins has been reported in a few studies [148] [149] [150] , potentially through modulation of peroxisome proliferator activated recep tors (PPARs). Activation of PPARα and PPARγ can improve EAT insulin sensitivity and glucose uptake 150 . However, statins have fewer effects on EAT than GLP1R agonists and SGLT2 inhibitors 126, 136 . Interestingly, in patients with metabolic syndrome, the addition of pio glitazone (an antidiabetic thiazolidinedione) to simvas tatin therapy results in a significant reduction in EAT inflammation 150 . Clinical trials testing the efficacy of drugs used for cardiometabolic disease in reducing EAT volume or thickness are summarized in 

The novel COVID19 caused by severe acute respira tory syndrome coronavirus 2 (SARS CoV2) infection is associated with cardiac involvement, mainly charac terized by myocarditis, pericarditis and thrombosis 151 . Visceral fat, such as EAT, has been suggested to serve as a functional reservoir and amplifier of SARS CoV2 (REF. 7 ). The intrinsic inflammatory milieu of visceral fat depots might amplify the inflammatory response in patients with COVID19, leading to serious cardiovas cular complications. Owing to its contiguity to the myo cardium and high inflammatory secretome, EAT has been suggested to be implicated in the pathophysiology of COVID19 related myocarditis 7 .

Angiotensin converting enzyme 2 (ACE2), which is widely recognized as the entry receptor for SARS CoV2 into host cells 152 , is expressed in human EAT 133 . The downregulation of ACE2 levels increases EAT inflam mation, whereas treatment with angiotensin 1-7 reduced EAT inflammatory cytokines in a mouse model 153 . The modulation of ACE in EAT might, therefore, have a role in COVID19 related myocardial and perivascu lar inflammation. ACE inhibitors could be a potential component of therapy for these sequelae of COVID19, although data are still insufficient and controversial 154 . EAT of patients hospitalized with severe or critical COVID19 shows signs of increased inflammation on CT, irrespective of whether CAD is present 32, [155] [156] [157] . In patients with COVID19, EAT density on CT is mark edly elevated at hospital admission and decreases to normal at discharge, whereas subcutaneous fat shows no signs of inflammation 32 . EAT inflammation decreased in patients with COVID19 who received oral or intra venous dexamethasone, whereas no significant changes in inflammation were observed with other COVID 19 therapies 157 . Therefore, EAT might have a role in COVID19 related cardiac syndrome, and CT measured EAT attenuation could be a marker of inflammation and severity of COVID19.

The physiology and pathophysiology of EAT and their clinical implications form a fast moving and productive field of research. EAT is a measurable and modifiable cardiovascular risk factor that adds qualitative value to the stratification of cardiovascular risk. Assessment of EAT, with commonly used imaging techniques, such as echocardiography, CT and MRI, should be readily accessible to contemporary cardiologists.

EAT provides a novel and unconventional perspective on the pathophysiology of major cardiovascular diseases. EAT directly contributes to the development and pro gression of CAD, mainly by causing inflammation but also by endothelial damage and oxidative stress as well as the accumulation of glucose and lipids in the proxi mal coronary arteries. In the context of atrial fibrillation, EAT represents a new pathogenic substrate through the regional secretion of factors that induce fibrosis and neurohormonal disarray of the atrial myocytes. The role of EAT in heart failure is mediated through several pathways, including the excessive release of fatty acids leading to intracardiac cell ectopic lipid accumulation, overexpression of local pro inflammatory and profi brotic cytokines with pro arrhythmogenic properties, and increased β adrenergic receptor activation.

Pharmacological modulation of EAT induces previ ously unexpected beneficial cardiometabolic effects. The potential to restore the cardioprotective function of EAT with targeted agents, such as GLP1R agonists and SGLT2 inhibitors, can open new avenues in pharmacotherapy for cardiovascular diseases. Several challenges remain for research on EAT. Further investigations are needed to determine whether reducing the mass of EAT can help to improve or eliminate atherosclerosis or prevent the development of atrial fibrillation and heart failure. The potential for pharmacological manipulation of the EAT transcriptome to restore its physiological and pro tective properties is a fascinating concept but is yet to be demonstrated. www.nature.com/nrcardio

Epicardial fat from echocardiography: a new method for visceral adipose tissue prediction

Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk

Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart

Epicardial adipose tissue has a unique transcriptome modified in severe coronary artery disease

Local and systemic effects of the multifaceted epicardial adipose tissue depot

Epicardial fat: a new cardiovascular therapeutic target

Does epicardial fat contribute to COVID-19 myocardial inflammation?

The ventricular epicardial fat is related to the myocardial mass in normal, ischemic and hypertrophic hearts

Epicardial fat gene expression after aerobic exercise training in pigs with coronary atherosclerosis: relationship to visceral and subcutaneous fat

Human epicardial fat exhibits beige features

Site-specific properties of pericardial and epicardial adipose tissue: the effects of insulin and high-fat feeding on lipogenesis and the incorporation of fatty acids in vitro

Presence of fatty-acid-binding protein 4 expression in human epicardial adipose tissue in metabolic syndrome

Vasocrine signalling" from perivascular fat: a mechanism linking insulin resistance to vascular disease

Adiponectin expression in human epicardial adipose tissue in vivo is lower in patients with CAD

Epicardial adipose tissue and intracoronary adrenomedullin levels in coronary artery disease

Mutual regulation of epicardial adipose tissue and myocardial redox state by PPAR-γ/adiponectin signaling

Uncoupling protein-1 and related mRNAs in human epicardial and other adipose tissues: epicardial fat functioning as brown fat

Transcriptional analysis of adipose tissue during development reveals depot-specific responsiveness to maternal dietary supplementation

Depot-specific overexpression of proinflammatory, redox, endothelial cell, and angiogenic genes in epicardial fat adjacent to severe stable coronary atherosclerosis

Cardioprotective heme oxygenase 1-PGC1α signaling in epicardial fat attenuates cardiovascular risk in humans as in obese mice

Echocardiographic epicardial fat: a review of research and clinical applications

Relation of echocardiographic epicardial fat thickness and myocardial fat

Cardiovascular and metabolic heterogeneity of obesity: clinical challenges and implications for management

The role of adipose tissue in cardiovascular health and disease

Prognostic value of epicardial fat volume measurements by computed tomography: a systematic review of the literature

Association of chemerin mRNA expression in human epicardial adipose tissue with coronary atherosclerosis

Serglycin is a novel adipocytokine highly expressed in epicardial adipose tissue

Epicardial adipose tissue as a source of nuclear factor-kappaB and c-Jun N-terminal kinase mediated inflammation in patients with coronary artery disease

Association between omentin-1 expression in human epicardial adipose tissue and coronary atherosclerosis

Epicardial adipokines in obesity and coronary artery disease induce atherogenic changes in monocytes and endothelial cells

Increased subcutaneous and epicardial adipose tissue production of proinflammatory cytokines in cardiac surgery patients: possible role in postoperative insulin resistance

Adipocytokines and proinflammatory mediators from abdominal and epicardial adipose tissue in patients with coronary artery disease

Vasodilator-stimulated phosphoprotein: regulators of adipokines resistin and phenotype conversion of epicardial adipocytes

Proteomic analysis of epicardial and subcutaneous adipose tissue reveals differences in proteins involved in oxidative stress

Secretory type II phospholipase A2 is produced and secreted by epicardial adipose tissue and overexpressed in patients with CAD

Local production of fatty acidbinding protein 4 in epicardial/perivascular fat and macrophages is linked to coronary atherosclerosis

Epicardial and subcutaneous adipose tissue fatty acids profiles in diabetic and non-diabetic patients candidate for coronary artery bypass graft

Role of the Toll-like receptor 4/NF-κB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages

Novel atherogenic pathways from the differential transcriptome analysis of diabetic epicardial adipose tissue

Expression of the receptor for advanced glycation end products in epicardial fat: link with tissue thickness and local insulin resistance in coronary artery disease

Obesity and diabetes are major risk factors for epicardial adipose tissue inflammation

Coronary artery disease is associated with higher epicardial retinol-binding protein 4 (RBP4) and lower glucose transporter (GLUT) 4 levels in epicardial and subcutaneous adipose tissue

Epicardial adipose tissue lipid content/ceramide

Association of epicardial adipose tissue with progression of coronary artery calcification is more pronounced in the early phase of atherosclerosis: results from the Heinz Nixdorf Recall Study

Relation of epicardial and pericoronary fat to coronary atherosclerosis and coronary artery calcium in patients undergoing coronary angiography

Relation of epicardial adipose tissue to coronary atherosclerosis

Gender differences in the association of epicardial adipose tissue and coronary artery calcification: EPICHEART study: EAT and coronary calcification by gender

Epicardial fat thickness and CAD correlate independently of obesity

Increased volume of epicardial fat is an independent risk factor for accelerated progression of sub-clinical coronary atherosclerosis

Epicardial adipose tissue as a predictor of coronary artery disease in asymptomatic subjects

Association between epicardial adipose tissue volume and characteristics of non-calcified plaques assessed by coronary computed tomographic angiography

Epicardial adipose tissue and coronary artery plaque characteristics

Persistent epicardial adipose tissue accumulation is associated with coronary plaque vulnerability and future acute coronary syndrome in non-obese subjects with coronary artery disease

Impact of epicardial fat volume on coronary artery disease in symptomatic patients with a zero calcium score

Epicardial adipose tissue thickness as a predictor of impaired microvascular function in patients with non-obstructive coronary artery disease

Association of epicardial adipose tissue with coronary atherosclerosis is region-specific and independent of conventional risk factors and intraabdominal adiposity

PET/CT evaluation of 18F-FDG uptake in pericoronary adipose tissue in patients with stable coronary artery disease: independent predictor of atherosclerotic lesions' formation?

Association of epicardial fat with cardiovascular risk factors and incident myocardial infarction in the general population: the Heinz Nixdorf recall study

The association of pericardial fat with incident coronary heart disease: the multi-ethnic study of atherosclerosis (MESA)

Atrial fibrillation: current knowledge and future directions in epidemiology and genomics

Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study

Epicardial fat and atrial fibrillation: current evidence, potential mechanisms, clinical implications, and future directions

The association of the amounts of epicardial fat, P wave duration, and PR interval in electrocardiogram

Epicardial and pericardial fat: close, but very different

Pericardial fat is associated with prevalent atrial fibrillation: the Framingham heart study

Adipogenesis and epicardial adipose tissue: a novel fate of the epicardium induced by mesenchymal transformation and PPARγ activation

Atrial natriuretic peptide regulates adipose tissue accumulation in adult atria

Reactivation of the epicardium at the origin of myocardial fibro-fatty infiltration during the atrial cardiomyopathy

Human epicardial adipose tissue has a specific transcriptomic signature depending on its anatomical peri-atrial, peri-ventricular, or pericoronary location

Evaluating the atrial myopathy underlying atrial fibrillation: identifying the arrhythmogenic and thrombogenic substrate

Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipo-fibrokines

Human epicardial adipose tissue cTGF expression is an independent risk factor for atrial fibrillation and highly associated with atrial fibrosis

Epicardial adipose tissue accumulation confers atrial conduction abnormality

Extracellular vesicles from epicardial fat facilitate atrial fibrillation

Direction-dependent conduction in lone atrial fibrillation

Electrophysiological and hemodynamic characteristics associated with obesity in patients with atrial fibrillation

Adipocytes modulate the electrophysiology of atrial myocytes: implications in obesity-induced atrial fibrillation

Localization of left atrial ganglionated plexi in patients with atrial fibrillation

Arrhythmogenic evidence for epicardial adipose tissue: heart rate variability and turbulence are influenced by epicardial fat thickness

Long-term suppression of atrial fibrillation by botulinum toxin injection into epicardial fat pads in patients undergoing cardiac surgery: one-year follow-up of a randomized pilot study

Association between epicardial adipose tissue volumes on 3-dimensional reconstructed CT images and recurrence of atrial fibrillation after catheter ablation

Quantitative analysis of quantity and distribution of epicardial adipose tissue surrounding the left atrium in patients with atrial fibrillation and effect of recurrence after ablation

Epicardial adipose tissue thickness and ablation outcome of atrial fibrillation

Periatrial epicardial adipose tissue thickness is an independent predictor of atrial fibrillation recurrence after cryoballoon-based pulmonary vein isolation

Abundant epicardial adipose tissue surrounding the left atrium predicts early rather than late recurrence of atrial fibrillation after catheter ablation

Epicardial fat in atrial fibrillation and heart failure

ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America

Epicardial fat in heart failure patients with mid-range and preserved ejection fraction

Influence of epicardial and visceral fat on left ventricular diastolic and systolic functions in patients after myocardial infarction

Epicardial adipose tissue in patients with heart failure

Epicardial adipose tissue assessed by cardiac magnetic resonance imaging in patients with heart failure due to dilated cardiomyopathy

Epicardial fat volume in patients with left ventricular systolic dysfunction

Weight loss and mortality risk in patients with chronic heart failure in the candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM) programme

Proteomics of epicardial adipose tissue in patients with heart failure

Adiponectin and p53 mRNA in epicardial and subcutaneous fat from heart failure patients

p53 functions in adipose tissue metabolism and homeostasis

Evolutional change in epicardial fat and its correlation with myocardial diffuse fibrosis in heart failure patients

Myocardial triglyceride content and epicardial fat mass in human obesity: relationship to left ventricular function and serum free fatty acid levels

Myocardial adipose deposition and the development of heart failure with preserved ejection fraction

Cardiac sympathetic denervation in the failing heart: a role for epicardial adipose tissue

Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure

Reduction of sympathetic activity via adrenal-targeted GRK2 gene deletion attenuates heart failure progression and improves cardiac function after myocardial infarction

Increased epicardial adipose tissue volume correlates with cardiac sympathetic denervation in patients with heart failure

CD5L, macrophage apoptosis inhibitor, was identified in epicardial fat-secretome and regulated by isoproterenol from patients with heart failure

Linking arrhythmias and adipocytes: insights, mechanisms, and future directions

Glucose uptake and lipid metabolism are impaired in epicardial adipose tissue from heart failure patients with or without diabetes

Liraglutide and cardiovascular outcomes in type 2 diabetes

Semaglutide and cardiovascular outcomes in patients with type 2 diabetes

Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a doubleblind, randomised placebo-controlled trial

Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes

Dapagliflozin and cardiovascular outcomes in type 2 diabetes

Effects of liraglutide on visceral and ectopic fat in adults with overweight and obesity at high cardiovascular risk: a randomised, doubleblind, placebo-controlled, clinical trial

Liraglutide causes large and rapid epicardial fat reduction

Effects of semaglutide versus dulaglutide on epicardial fat thickness in subjects with type 2 diabetes and obesity

Short-term effects of glucagon-like peptide 1 (GLP-1) receptor agonists on fat distribution in patients with type 2 diabetes mellitus: an ultrasonography study

Effect of liraglutide on epicardial adipose tissue thickness with echocardiography in patients with obese type 2 diabetes mellitus

Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: a prospective randomized clinical trial using magnetic resonance imaging and spectroscopy

Human epicardial fat expresses glucagon-like peptide 1 and 2 receptors genes

Epicardial adipose tissue GLP-1 receptor is associated with genes involved in fatty acid oxidation and white-to-brown fat differentiation: a target to modulate cardiovascular risk?

Higher ACE2 expression levels in epicardial cells than subcutaneous stromal cells from patients with cardiovascular disease: diabetes and obesity as possible enhancer

GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK

GLP-1 receptor expression within the human heart

Effects of dapagliflozin on epicardial fat thickness in patients with type 2 diabetes and obesity

Mechanistic insights of empagliflozin in nondiabetic patients with HFrEF: from the EMPA-TROPISM Study

The effect of dapagliflozin treatment on epicardial adipose tissue volume

Canagliflozin reduces epicardial fat in patients with type 2 diabetes mellitus

Ipragliflozin reduces epicardial fat accumulation in nonobese type 2 diabetic patients with visceral obesity: a pilot study

Luseogliflozin reduces epicardial fat accumulation in patients with type 2 diabetes: a pilot study

Effects of dapagliflozin on human epicardial adipose tissue: modulation of insulin resistance, inflammatory chemokine production, and differentiation ability

CV protection in the EMPA-REG OUTCOME trial: a "thrifty substrate" hypothesis

Myocardial fatty acid metabolism in health and disease

Empagliflozin increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors

Altered levels of fatty acids and inflammatory and metabolic mediators in epicardial adipose tissue in patients with systolic heart failure

Effect of dapagliflozin on myocardial insulin sensitivity and perfusion: rationale and design of the DAPAHEART trial

Effects of statins on the epicardial fat thickness in patients with coronary artery stenosis underwent percutaneous coronary intervention: comparison of, atorvastatin with simvastatin/ ezetimibe

Effect of intensive versus moderate lipid-lowering therapy on epicardial adipose tissue in hyperlipidemic post-menopausal women: a substudy of the BELLES trial (Beyond Endorsed Lipid Lowering with EBT Scanning)

Synergistic anti-inflammatory effect: simvastatin and pioglitazone reduce inflammatory markers of plasma and epicardial adipose tissue of coronary patients with metabolic syndrome

COVID-19 and the cardiovascular system

Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor

ACE2 deficiency worsens epicardial adipose tissue inflammation and cardiac dysfunction in response to diet-induced obesity

Renin-angiotensinaldosterone system inhibitors in patients with COVID-19

Obesity as a potential predictor of disease severity in young COVID-19 patients: a retrospective study

Epicardial adipose tissue is associated with extent of pneumonia and adverse outcomes in patients with COVID-19

Epicardial fat inflammation response to COVID-19 therapies

The author declares no competing interests.

Nature Reviews Cardiology thanks Charalambos Antoniades, Sonia Eiras and Stephane Hatem for their contribution to the peer review of this work.

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A search for original articles published between 1984 and 2021 with a focus on the past 10 years was performed in MEDLINE and PubMed. The search terms used were "epicardial fat" and "epicardial adipose tissue". A total of 1,903 articles were found. The articles identified for this Review were restricted to English language, full-text papers. The reference lists of identified articles were searched for additional relevant papers.