Inflammatory and lipid regulation by cholinergic activity in epicardial stromal cells from patients who underwent open‐heart surgery

Abstract

The modulation of acetylcholine (ACh) release by botulinum toxin injection into epicardial fat diminishes atrial fibrillation (AF) recurrence. These results suggest an interaction between autonomic imbalance and epicardial fat as risk factors of AF. Our aim was to study the inflammatory, lipidic and fibroblastic profile of epicardial stroma from patients who underwent open‐heart surgery, their regulation by cholinergic activity and its association with AF. We performed in vitro and ex vivo assays from paired subcutaneous and epicardial stromal cells or explants from 33 patients. Acute ACh effects in inflammation and lipid‐related genes were analysed by qPCR, in intracellular calcium mobilization were performed by Fluo‐4 AM staining and in neutrophil migration by trans‐well assays. Chronic ACh effects on lipid accumulation were visualized by AdipoRed. Plasma protein regulation by parasympathetic denervation was studied in vagotomized rats. Our results showed a higher pro‐inflammatory profile in epicardial regarding subcutaneous stromal cells. Acute ACh treatment up‐regulated monocyte chemoattractant protein 1 levels. Chronic ACh treatment improved lipid accumulation within epicardial stromal cells (60.50% [22.82‐85.13] vs 13.85% [6.17‐23.16], P < .001). Additionally, patients with AF had higher levels of fatty acid‐binding protein 4 (1.54 ± 0.01 vs 1.47 ± 0.01, P = .005). Its plasma levels were pronouncedly declined in vagotomized rats (2.02 ± 0.21 ng/mL vs 0.65 ± 0.23 ng/mL, P < .001). Our findings support the characterization of acute or chronic cholinergic activity on epicardial stroma and its association with AF.

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

“…31 The ACE2 and ADAM17 arise might counterbalance the proinflammatory profile on epicardial fat stromal cells from patients with cardiovascular disease. 32 After testing MCP-1, IL-6 and TNFa mRNA expression levels on these cells, we observed a similar profile with ACE2 levels. These results might suggest a co-regulation among ACE2 and inflammatory genes (Figure S1).…”

Updates on epicardial adipose tissue mechanisms on atrial fibrillation

“…Chronic ACh treatment enhances lipid accumulation in epicardial stromal cells, which might explain the higher levels of fatty acid binding protein 4 (FABP4), an adipocyte marker, detected in the cells of patients with persistent AF. Thus, modulation of cholinergic activity might decrease adiposity, as circulating FABP4 levels are reduced after vagal nerve denervation 49 . This could reduce the high risk of a free fatty acid (FFA) increment after lipolytic inducers, which can decrease the APD, as demonstrated in ovine LA cardiomyocytes 50 .…”

“…Moreover, its circulating levels have been associated with worse LA substrate, high epicardial fat volume, and high tumor necrosis factor‐α (TNF‐α) levels in AF patients 73 . Because cholinergic activity mobilizes calcium in epicardial fat cells, it might also enhance its secretion 49 and electrical remodeling. These results suggest that the expansion of epicardial fat might induce the secretion of resistin with a paracrine effect on calcium channel expression in cardiomyocytes.…”

“…In one study , the researchers encouraged the performance of individual atrial ganglionated plexus atlas through high‐frequency stimulation (before the ablation procedure) to characterize the loci amenable to targeting during ablation 87 . Epicardial stromal cells were demonstrated to be responsive to catecholaminergic stimulation, which can activate the secretion of proteins from these cells to the neighboring tissue 49 . Adipokines might also affect the cardiac autonomic system and enhance or modulate rapid atrial pacing‐induced AF 88 .…”

“…Specific markers on the epicardium and cell characterization are helpful for determining myofibroblast or adipocyte generation 95 under exposure to specific factors. Our group has contributed to the understanding of how the neurotransmitter, ACh, can improve lipid accumulation, which can explain the interplay between autonomic dysfunction, epicardial fat, and AF 49 . One drawback of this model is the need to purify/isolate specific cells of interest.…”