The Role of Epicardial Adipose Tissue in the Development of Atrial Fibrillation, Coronary Artery Disease and Chronic Heart Failure in the Context of Obesity and Type 2 Diabetes Mellitus: A Narrative Review

Abstract

Cardiovascular diseases (CVDs) are a significant burden globally and are especially prevalent in obese and/or diabetic populations. Epicardial adipose tissue (EAT) surrounding the heart has been implicated in the development of CVDs as EAT can shift from a protective to a maladaptive phenotype in diseased states. In diabetic and obese patients, an elevated EAT mass both secretes pro-fibrotic/pro-inflammatory adipokines and forms intramyocardial fibrofatty infiltrates. This narrative review considers the proposed pathophysiological roles of EAT in CVDs. Diabetes is associated with a disordered energy utilization in the heart, which promotes intramyocardial fat and structural remodeling. Fibrofatty infiltrates are associated with abnormal cardiomyocyte calcium handling and repolarization, increasing the probability of afterdepolarizations. The inflammatory phenotype also promotes lateralization of connexin (Cx) proteins, undermining unidirectional conduction. These changes are associated with conduction heterogeneity, together creating a substrate for atrial fibrillation (AF). EAT is also strongly implicated in coronary artery disease (CAD); inflammatory adipokines from peri-vascular fat can modulate intra-luminal homeostasis through an "outside-to-inside" mechanism. EAT is also a significant source of sympathetic neurotransmitters, which promote progressive diastolic dysfunction with eventual cardiac failure. Further investigations on the behavior of EAT in diabetic/obese patients with CVD could help elucidate the pathogenesis and uncover potential therapeutic targets.

Keywords: adipokines; fibrofatty infiltrates; inflammatory adipose phenotype; intramyocardial fat.

Figure 1

Layers of tissue surrounding the heart. EAT is situated deep in the pericardial fat, between the layers of visceral pericardium and myocardium. Pericardial fat is situated between the visceral and parietal pericardium. Paracardial fat is the general term referring to fat associated with the heart. Adapted from Newman (left) [13] and Betts et al. (right) [14].

Figure 2

EAT thickness between lean and obese rats in panels (A,B) compared to EAT thickness found on the heart of an 83-year-old overweight female in panel (C). Reproduced from Krishnan et al. [17] under the Creative Commons Attribution License.

Figure 3

Formation of arrhythmogenic substrate as a result of fibrofatty infiltrates increasing conduction heterogeneity across the atrial myocardium. Panel (Aa): Action potential (AP) conduction is linear in healthy myocardium, where the endomysium is comprised of a thin layer of connective tissue with fibroblasts and EAT is predominantly supramyocardial. In contrast, with fibrofatty infiltration of the myocardium, fibrosis, structural remodeling, and production of pro-inflammatory and pro-fibrotic adipokines (Panel (Ab)), AP conduction becomes ‘zigzag’ and the myocardium is at risk of arrhythmias. Examples of specific adipokines associated with arrhythmogenic remodeling are shown in Panel (B); FABP4 = FA binding protein 4, IL = interleukin, TNF = tumor necrosis factor, TGF = transforming growth factor, MMP = matrix metalloproteinases, MCP = monocyte chemoattractant protein. Panel (B) reproduced from Ernault et al. [34] under the Creative Commons CC-BY-NC-ND license.

Figure 4

(A): Oil-red-O-stained RAA sections depicting heterogenous interface between infiltrating adipose tissue (red, globular cells) and myocardium (blue). (B,C): LAA sections stained with HE shows significant EAT infiltration (empty, globular cells) with fibrosis (blue strands) noted along adipocytes. Myocardium is represented as magenta. (A) Reproduced with permission from Nalliah et al. [68]; (B,C) reproduced with permission from Abe et al. [69].

Figure 5

(A): Graphical depiction of myocyte-to-myocyte communication through connexin proteins at intercalated discs located at the ends of the cells. (B): Graphical depiction of structure of connexin protein in relation to plasma membrane. (C): Connexin distribution in normal atrial tissue. (D): Lateralization of Cx proteins away from intercalated discs, leading to aberrant communication between cardiomyocytes. Reproduced from Jennings and Donahue [56] under a Creative Commons Attribution 3.0 Unported License.

Figure 6

Fibrofatty infiltrates highlighted in fat-water separated MRI pre-contrast (left) and late enhancement (right) in a patient with non-ischemic cardiomyopathy. Reproduced from Kellman et al. [46] under the Creative Commons Attribution Noncommercial License.