Background:
Volume of epicardial adipose tissue (EAT) correlates with severity of heart failure with preserved ejection fraction (HFpEF) in humans while removal of the most equivalent murine adipose tissue (Pericardial adipose tissue, PAT) exerts beneficial effects on post-myocardial infarction remodelling in mice. Yet, the exact role of PAT in heart failure remains elusive. We investigated whether and how PAT removal affects manifestation and extent of HFpEF versus HF with reduced ejection fraction (HFrEF) in mice.

Methods and results:
Progressive remodelling was assessed in male wild-type mice, randomly assigned to transaortic constriction (TAC) for 1 week (early pressure-overload), 8 weeks (HFpEF) or 12 weeks (HFrEF) with or without PAT removal during the surgical intervention. Sham-operated mice served as controls. At early pressure-overload (1 wk TAC) and at HFpEF stage (8 wks), echocardiography, gravimetry and histology confirmed the TAC induced increase in heart weight/tibia length ratio, in left ventricular (LV) wall thickness, in cardomyocyte size and in interstitial fibrosis, which was accompanied by diastolic dysfunction, loss of contractile reserve and a reduced, yet preserved systolic function. This was widely unaffected by the absence of PAT. However, the initial PAT removal prevented a further drastic LV dilation and the simultaneous marked reduction in ejection fraction, thereby the transition from HFpEF to HFrEF at 12 wks post TAC. This protective effect was associated with significant attenuation of LV expression of pro-hypertrophic atrial and brain natriuretic peptide (Nppa, Nppb), pro-inflammatory interleukin-6 (Il-6) and connective tissue growth factor (Ctgf). Subsequent examination of the fibrotic response revealed a significant reduction in microscar formation and perivascular fibrosis, with the latter, at least in part, attributed to reduced accumulation of pro-fibrotic CD206+ macrophages around the coronaries 12 wks post-surgery in the absence of PAT compared to mice with intact PAT. In addition, bulk RNA sequencing analyses of PAT revealed the initiation of an extracellular matrix deposition program in the adipose tissue upon TAC surgery, which might lead to the release of pro-fibrotic factors that in turn act on the underlying myocardium promoting the observed adverse fibrotic responses.

Conclusion:
Our data suggest PAT to play divergent roles in HFpEF versus HFrEF - while widely not affecting the HFpEF phenotype, PAT removal prevents development of HFrEF in mice, at least in part, by counteracting excessive fibrotic responses.