Pericardial adipose tissue promotes transition to heart failure with reduced ejection fraction upon pressure-overload in mice.

In patients, severity of pressure-induced heart failure (HF) due to aortic stenosis and metabolic disorder correlates with thickness and mass of epicardial adipose tissue (EAT). We examined the role of the less studied pericardial adipose tissue (PAT) during manifestation and progression of pressure-induced HF in mice. Progressive remodeling was assessed in C57BL/6 J males, aged 9 weeks, following sham surgery or transverse aortic constriction (TAC) for 1 week (early pressure-overload), 8 (chronic pressure-overload), or 12 weeks (HF with reduced ejection fraction, HFrEF) with or without concomitant PAT excision. PAT removal did not affect early (1-week TAC) or chronic (8 weeks) pressure-overload-induced concentric remodeling. However, initial PAT excision prevented lung congestion, progressive LV dilation and systolic dysfunction and thereby protected against transition to HFrEF. This protection was associated with alleviation of early TAC-induced pro-inflammatory monocyte and macrophage expansion, attenuation of persistent pro-hypertrophic, pro-inflammatory and pro-fibrotic LV gene expression and the reduction of microscar and perivascular fibrosis in the long term. The latter was reflected by reduced peri-coronary accumulation of pro-fibrotic CD206 macrophages, and prevention of periostin upregulation. Moreover, PAT protein directly activated naïve cardiac fibroblasts in vitro while bulk RNAsequencing revealed the initiation of an extracellular matrix deposition, monocyte recruiting, and macrophage activation program in the PAT early upon TAC. Our data suggest that PAT does not exert crucial impact on pressure-induced hypertrophy, while its removal counteracts HFrEF manifestation in mice, at least in part, by preventing excessive fibrotic responses suggested to derive from reciprocal fibroblast-macrophage interactions.