The Epicardial Adipose Inflammatory Triad: Coronary Atherosclerosis, Atrial Fibrillation, and Heart Failure with a Preserved Ejection Fraction

This article refers to ‘Epicardial fat in heart failure patients with mid-range and preserved ejection fraction’ by G. van Woerden et al., published in this issue on pages 1559–1566. The epicardium plays a critical role in the development of the heart during gestation. Following encapsulation of the helically-wound cardiac loop during embryogenesis, the epicardium directly contributes precursors of numerous cardiac cell types and secretes trophic factors that are critical for the maturation of cardiomyocytes.1 The intimacy of the epicardium with the myocardium allows the epicardium to exert great influence on underlying structures. The epicardium shares an unobstructed microcirculation with adjacent myocardial tissues, allowing for the two-way transit of both pluripotential cells and cytokines.2 After birth, although embryonic gene programmes are suppressed, the epicardium is not quiescent. The multi-potent progenitor cells that gave rise to cardiomyocytes during foetal development undergo a process of epithelial-to-mesenchymal transition in adulthood, producing multi-potent mesenchymal cells that differentiate into adipocytes. In healthy people, the epicardial adipocytes have the features of brown adipose tissue, in that they metabolize fatty acids (thus preventing their local inflammatory action) and nourish adjacent tissues. In addition, healthy epicardial adipocytes secrete adiponectin, which protects cardiomyocytes from hypertrophic stimuli and reduces fibrotic responses in the myocardium.2 Following cardiac injury and under states of low oxidative stress, the epicardium can also assume embryonic-like features and resume its role in cardiac regeneration.1 Therefore, as long as it is metabolically healthy, the epicardium serves an ongoing source of nourishment and renewal. However, systemic inflammation causes a dramatic metamorphosis of the biological and physiological features of the epicardium, so that it shifts away from its nourishing role, and instead, assumes pro-inflammatory characteristics, thereby acting as a transducer through which systemic inflammatory processes can influence underlying cardiac and vascular structures.2 In states of chronic inflammation (e.g. rheumatoid arthritis, AIDS, and psoriasis) or systemic metabolic disorders (e.g. type 2 diabetes and obesity), the cells within the epicardium adopt the characteristics of white adipose tissue, which is inclined to lipolysis, leading to the release of fatty acids and reactive inflammation. Simultaneously, the production of adiponectin diminishes, and the expansion and transformation of the epicardial adipocyte mass promotes the synthesis of pro-inflammatory adipokines (e.g. leptin, tumour necrosis factor-α, interleukin-1β and interleukin-6) that enhance the infiltration of macrophages, cause microvascular injury and stimulate pro-fibrotic mechanisms in underlying tissues.2 The mesenchymal stem cells of the epicardium can also migrate into atrial and ventricular muscle, where they can mature into fibroblasts. The maladaptive expansion of epicardial adipocytes can be assessed noninvasively in human beings by measuring the thickness or volume of epicardial adipose tissue, either by magnetic resonance imaging or computed tomography. Theoretically, the metamorphosis of the epicardium is capable of adversely affecting three underlying structures: (1) the coronary arteries, leading to perivascular inflammation and accelerated coronary atherosclerosis; (2) the atrial myocardium, leading to fibrosis, unstable electrogram fractionation and atrial fibrillation; and (3) the ventricular myocardium, leading to microvascular rarefaction, cardiac fibrosis and decreased ventricular distensibility—the pathological hallmarks of heart failure with a preserved ejection fraction (HFpEF). The specific clinical manifestation may depend on the precise anatomical location of the dysfunctional fat depot within the epicardium. Classically, coronary atherosclerosis has been viewed as an inflammatory response to the transit of lipoproteins from the bloodstream across the endothelium and into the vessel wall. However, accelerated coronary atherosclerosis is also a prominent feature of many systemic inflammatory disorders, in a manner that is independent of circulating lipoproteins. How can systemic inflammation promote the development of obstructive coronary artery disease? Systemic inflammation leads to the accumulation and deranged biology of epicardial adipocytes.2 The resulting transmission of pro-inflammatory cytokines and mesenchymal cells from the perivascular adipose tissue across the vascular adventitia can lead to plaque formation within the coronary vessels. In chronic inflammatory states, the accumulation of epicardial adipose tissue is closely associated with the presence, severity and progression of coronary artery disease, in a manner that is independent of circulating lipids or adiposity. Focal obstructive lesions reside in the coronary arterial segments that are immediately adjacent to areas of epicardial fat with the greatest thickness,3 and experimental resection of the epicardium ameliorates coronary atherosclerosis.4 These observations support the hypothesis that the accumulation of epicardial adipose tissue (and inflammation of perivascular fat) can act in a paracrine manner to adversely influence the structure and function of the coronary arteries. Obesity is associated with structural and functional remodelling of the atria and is an important and reversible cause of atrial fibrillation.5 The mechanisms that underlie this relationship are not related to sodium retention and volume overload of the cardiac chambers. Instead, there is a strong association between obesity, the accumulation and inflammation of epicardial fat, and the development of atrial arrhythmias. The strength of the association of atrial fibrillation with epicardial fat is greater than for measures of abdominal adiposity (i.e. waist circumference) or overall obesity (i.e. body mass index).6 There is a particularly strong relationship between the size of the depot of posterior left atrial adipose tissue and the onset, persistence and recurrence of atrial fibrillation.7 Additionally, periatrial fat in patients with atrial fibrillation demonstrates genomic signatures that reflect activation of pro-inflammatory and pro-fibrotic pathways. Of note, epicardial adipose tissue with the most severe structural and functional derangements resides in close proximity to myocardial foci with the greatest electrophysiological abnormalities.8 The accumulation of epicardial fat in obesity is accompanied by impairment of the myocardial microcirculation, derangements of diastolic filling and left atrial dilatation. Obese patients have increased circulating levels of pro-inflammatory cytokines and cardiac filling abnormalities long before their clinical presentation with heart failure.9 Patients with chronic systemic inflammatory disorders other than obesity (e.g. rheumatoid arthritis, AIDS and psoriasis) also demonstrate an accumulation of epicardial adipose tissue, along with the microcirculatory derangements, myocardial fibrosis and impairments of diastolic filling that are typically seen in HFpEF.2 However, previous studies have not directly characterized the quantity of epicardial fat in patients with an established diagnosis of HFpEF, when compared with appropriate controls, and thus, the potential pathophysiological role of the epicardium in patients with clinically overt HFpEF has remained speculative. Given this perspective, the paper by van Woerden et al.10 in this issue of the Journal provides important and novel findings. The investigators utilized cardiac magnetic resonance imaging to quantify total epicardial fat and, in particular, ventricular epicardial fat. They found that the volume of ventricular (but not atrial) epicardial adipose tissue was increased by 50% in patients with HFpEF, when compared to well-matched controls. The accumulation of epicardial fat was particularly striking in the HFpEF patients with type 2 diabetes and atrial fibrillation; previous studies have shown increases in the volume of epicardial adipose tissue in these two disorders in the absence of heart failure.6, 11 Interestingly, van Woerden et al. also noted that epicardial fat was associated with biomarkers of myocardial injury, a finding that is consistent with reports suggesting that the mild systolic dysfunction that is often seen in patients with HFpEF may be related to the quantity of epicardial fat.12 These novel observations lend strong support to the hypothesis that HFpEF represents the ventricular consequence of epicardial adipose tissue expansion and inflammation, in a manner similar to the premise that the accumulation of periatrial fat depots contributes to atrial fibrillation. Further studies are needed to characterize the secretion of pro-inflammatory adipocytokines in these patients and to determine if changes in epicardial adipose tissue volume are predictably accompanied by changes in cardiac filling dynamics and left atrial size. If additional studies confirm that dysfunctional expansion of epicardial adipocytes contribute to structural and functional derangements of the underlying ventricular myocardium, then epicardial adipose tissue may become an important therapeutic target in the management of patients with HFpEF. Aldosterone can promote the accumulation and inflammation of epicardial fat,13 and mineralocorticoid receptor antagonists reduce obesity-related adipose tissue inflammation and may have benefits in obesity-related HFpEF.2, 14 Natriuretic peptide receptor signalling has anti-adipogenic effects and ameliorates adipocyte inflammation, and levels of natriuretic peptides are inversely related to epicardial fat thickness.15 These relationships may explain the favourable effects of neprilysin inhibition on cardiac remodelling in HFpEF.2 Finally, sodium–glucose co-transporter 2 (SGLT2) inhibitors reduce the quantity of epicardial fat and its secretion of pro-inflammatory adipokines, and thereby, may ameliorate cardiac fibrosis and ventricular filling abnormalities.2, 16 An adipocytolytic effect may explain why SGLT2 inhibitors reduce the likelihood of heart failure events in patients with type 2 diabetes who are highly prone to HFpEF.2 Therefore, the potential benefits of three classes of therapeutic agents in the treatment of HFpEF may be related to their ability to calm the deranged biological excesses of epicardial adipocytes in states of systemic inflammation, thereby restoring the epicardium to its role as a source of nourishment and regeneration. The nexus of the epicardium and myocardium has played a special role in cardiac and vascular health for millions of years. It is now time to understand that it may not only be a fountain for rejuvenation, but also a source of grief. Conflict of interest: M.P. has recently consulted for Actavis, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Celyad, Daiichi Sankyo, Gilead, NovoNordisk, Novartis, Relypsa, Sanofi, Takeda and ZS Pharma. None of these activities are related to the topic of this manuscript.