Epicardial Adipose Tissue—Metabolic Memory of the Heart?

Objectives: Epicardial adipose tissue (EAT), consisting mainly of adipocytes, preadipocytes, stromavascular and immune cells, regulates contractile properties of cardiomyocytes, and progression of cardiac fibrosis or atherosclerosis. EAT volume is associated with an increased for atrial fibrillation, which may be induced or maintained via secretion of profibrotic adipokines form EAT. Here, we investigated, the differential impact of EAT secretome, depending on patients age and body mass index on cardiac fibroblasts and followed the question whether epicardial adipocytes retain their metabolic memory.

Methods: Serum and epicardial adipose tissue from CABG patients (n = 136, all-comers; exclusion criteria: diabetes, female gender) were obtained. Patients were grouped according to age (54.8 ± 1.1 vs. 73.8 ± 1.5 years) and BMI (22.8 ± 0.8 vs. 33.4 ± 1.1 kg/m²). Human epicardial preadipocytes were isolated and in vitro differentiated to mature adipocytes. Serum, tissue samples and adipocytes were analyzed for their adipokine release or expression (mRNA and protein). Conditioned adipocyte-medium was utilized to treat human cardiac fibroblasts.

Results: Adiponectin plasma levels were significantly decreased in young obese (YO), old obese (OO), and old normal-weight (ON) patients compared to young normal-weight (ON) patients while serum leptin demonstrated the opposite changes. Insulin was, however, only increased in YO and OO patients. Comparable changes in adiponectin and leptin gene expression (mRNA and protein) were observed in EAT. Furthermore, mature epicardial adipocytes, in vitro differentiated for of up to 4 weeks, demonstrated a lower expression and release of adiponectin but increased leptin with increasing patient’s age and BMI, suggesting a robust cellular memory. In addition, adipocytes from older patients showed signs of reduced differentiation. Treatment of human cardiac fibroblasts with conditioned medium from obese patients (YO, OO), which was rich in activin A, TGF?β1 and leptin, induced their transdifferentiation into myofibroblasts, and increased expression of profibrotic genes (e.g., TGF-beta1, CTGF, and collagen) and microRNAs (e.g., miR-21-5p). These effects could be directly mimicked by leptin treatment.

Conclusion: Epicardial adipocytes demonstrate a robust cellular memory for patient’s age and nutritional status. The secretome of epicardial adipocytes from obese patients is rich in various profibrotic mediators. Epicardial adipocytes may mediate significant direct effects on cardiac fibroblasts which is potentially important for induction and progression of atrial fibrillation.