Paracrine Signals Modulate Atrial Epicardial Progenitor Cells and Development of Subepicardial Adiposity and Fibrosis: Implications for Atrial Fibrillation

Atrial fibrillation is uncommon in healthy young individuals. Diverse pathologies, including hypertension, valvular disease, obesity, excessive alcohol consumption, cancer and aging are associated with increased risk of atrial fibrillation (AF). Why? Recent studies have shown that atrial remodeling in response to hemodynamic and/or metabolic stresses, or as a result of genetic predisposition, contributes the development of atrial dysfunction can increase both the incidence and persistence of AF. A recent global consensus document focused on better understanding the mechanisms and risk factors that contribute to atrial dysfunction – now termed atrial cardiomyopathy, which can be the end result of the disparate mechanisms that promote atrial dysfunction¹. Atrial cardiomyopathy has been defined as “Any complex of structural, architectural, contractile or electrophysiological changes affecting the atria with the potential to produce clinically-relevant manifestations¹.” Atrial cardiomyopathy encompasses a broad range of pathways, some of which are modifiable and some of which may are not (eg., genetic variants, sex, age).

For more than a decade, there has been an appreciation of the role of interstitial fibrosis (collagen deposition) that accumulates between myocytes in response to increased wall stress resulting from hypertension, valvular heart disease or heart failure². Collagen deposition can occur when normally quiescent fibroblasts are transformed into myofibroblasts that secrete collagen into the extracellular matrix (ECM) in response to paracrine signaling molecules (transforming growth factor beta, TGF-β; angiotensin-II, A-II; endothelin-1, ET-1. Interstitial fibrosis especially interferes with lateral myocyte to myocyte connectivity, resulting to slowed and heterogeneous conduction. Heterogenous conduction is a primary cause of cardiac arrhythmogenesis.

In the past decade, a combination of clinical and experimental studies have begun to shed light on the mechanisms linking obesity with risk of atrial fibrillation. In 2008 computed tomography (CT) studies showed an association of metabolic syndrome and obesity with epicardial and peri-coronary fat abundance³. In 2010, using a similar approach, our group showed an association of the thickness of fat on the posterior LAA with AF persistence⁴. Pericardial fat abundance has been associated with AF severity and ablation outcomes⁵, and in experimental studies obesity has been shown to promote structural and electrical remodeling that can promote cardiac lipid accumulation, interstitial fibrosis and form a substrate for AF⁶. An important study from the laboratory of Stephane Hatem demonstrated that secretion of adipo-fibrokines such as activin-A from atrial epicardial adipose tissue promotes to atrial fibrosis by promoting the transition of subepicardial adipocytes to fibroblasts⁷. In a translational study of human right atria and sheep atria from animals with AF of varying persistence, the authors report an inverse association of the abundance of epicardial and subepicardial adipocytes with the persistence of AF⁸. The junction of adipocytes and fibrotic regions was frequently marked by inflammatory cell infiltrates. Thus, while persistent AF is associated with a greater abundance of fibrotically remodeled adipocytes in the subepicardial region than non-AF or paroxysmal AF atria, the mechanisms that underlie subepicardial infiltration of adipocytes or fibroblasts are unclear.

In this issue of Circulation Research, Suffee and colleagues extend their prior work on atrial adipocyte infiltration and fibrosis in the atria⁹. They analyzed the thickness of the epicardium in right atrial appendage samples from 109 cardiac surgery patients. They found that epicardial thickening was positively associated with the development of atrial fibrosis, and inversely associated with the abundance of subepicardial fat. This suggests that distinct pathways underlie the structural remodeling of the atria; this process was impacted by the age of the patients. Older patients, and those with valvular heart disease tended to have a greater shift towards subepicardial fibrosis than adipose deposition. At a more mechanistic level, the authors tested the hypothesis that distinct populations of multipotent adult epicardial progenitor-derived cells (aEPDCs) differentiate into either fibroblasts or adipocytes, and that these cells determine the balance between adipose tissue deposition and accumulation of fibrosis in the atrial subepicardium. Intriguingly, they show that specific components of the atrial secretome can impact the fate of the aEPDCs, resulting in either subepicardial infiltration of the atrial muscle with adipocytes, or of atrial myofibroblasts that promote accumulation of fibrosis. Confirming an earlier study¹⁰, atrial natriuretic peptide (ANP) in the atrial secretome promoted adipogenic differentiation of the progenitor derived cells. Natriuretic peptide release occurs in response to increased wall stress, thus atrial adipose accumulation is in part linked with the hemodynamic stress on the atria. In contrast, angiotensin-II (A-II) promoted differentiation of the aEPDCs to myofibroblasts. Both ANP and A-II upregulated the expression of their own receptors (NPR1 and AGTR1) of epicardial cells, and there was no cross-talk in the signaling. The authors conclude that differentiation of different populations of eEPDCs occurs via a switch, with distinct signaling pathways directing aEPDC differentiation into either fibroblasts or adipocytes. Depending on the stimuli, both pathways may be activated simultaneously, resulting in fibro-fatty subepicardial remodeling.

In vivo activation of the aEPDCs occurs in response to stress or injury. Using a rat model of ischemic heart failure, they show that the atria become vulnerable to AF within two months, with atria that have become hypertrophied, dilated and fibrotic. Epicardial activation occurs more quickly, with evidence of epicardial changes within one week of the onset of the ischemic injury. The abundance of both myofibroblasts and adipocytes increased quickly, and lineage tracking studies using labelled precursor cells showed that the fibroblasts were clearly derived from aEPDCs. Single cell RNA sequencing (scRNAseq) was used to assess the heterogeneity of rat aEPDCs, and eight distinct cell clusters were identified. The cellular distribution depended on the cardiac health of the atria. While many aEPDCs were identified in sham treated atria, the atrial epicardium of heart failure animals contained mostly adipocytes and fibroblasts. These studies in rats show that epicardial changes occur that are similar to those which are present in human right atrial tissues following a myocardial infarction.

This state-of-the-art study provides important new insights into the mechanisms that contribute to the development of atrial cardiomyopathies that create a substrate for atrial arrhythmia. It provides evidence that the regulation of epicardial activation and the balance of subepicardial adipose deposition / fibrosis is aging-dependent, and that risk factors such as hypertension and obesity may have different consequences for the structure and function of the atria. Endocardial-epicardial dissociation has been proposed as a key determinant of atrial arrhythmogenesis¹¹. Modeling studies suggest that epicardial fibrosis may be the primary cause of endocardial-epicardial dissociation¹². Recent clinical guidelines encourage weight loss and aggressive risk factor management to reduce the burden of AF¹³. Whereas weight loss has been shown to reduce AF burden and presumably the extent of atrial adiposity⁶, weight loss associated changes in the extent of fibrosis have not yet been documented clinically. These data suggest that efforts to achieve and maintain a healthy weight by mid-life may have significant long-term benefits. While translation of these complex studies into clinical benefit will require further effort, these efforts are clearly warranted.