Abstract 4134967: Pericardial Adipose Tissue Hypertrophy Contributes to Heart Failure via β3 Adrenergic Signaling-Mediated Activation of the TGFβ1 Pathway

Background: The heart is surrounded by pericardial adipose tissue (PeAT). An increase in PeAT volume has been associated with the development of heart failure; however, the precise molecular mechanisms by which hypertrophic PeAT contributes to heart failure remain to be elucidated. Aims: To clarify the involvement of PeAT hypertrophy in the development of heart failure. Methods: Male C57BL/6 mice (8-10 weeks old) were fed a high-fat diet (HFD) for 8 weeks to induce PeAT hypertrophy. Cardiac pressure overload was induced by transverse aortic constriction (TAC) with a 26-gauge needle. Results: PeAT volume significantly increased in HFD-fed mice compared to those on a normal diet (ND) (25.28 ± 4.1 mg vs. 9.35 ± 0.73 mg, p<0.01). Eight weeks after TAC, HFD-fed mice (TAC+HFD) exhibited more pronounced cardiac dysfunction (fractional shortening: 45.21 ± 2.21% vs. 55.99 ± 1.91%, p=0.002, left ventricular mass: 130.3 ± 7.80% vs. 106.8 ± 3.77%, p=0.0154), upregulation of cardiac fibrosis-related genes ( Col1a1 , Col3a1 ), and greater fibrotic area in the left ventricle compared to ND-fed TAC mice (TAC+ND). Simultaneously, the TGFβ/Smad pathway was activated in the left ventricles of TAC+HFD mice. Notably, surgical removal of hypertrophic PeAT improved cardiac function in TAC+HFD mice, while transplantation of PeAT from HFD-fed mice into TAC+ND mice worsened cardiac function. In TAC+HFD mice, local noradrenaline concentration in PeAT decreased, along with reduced activation of hormone-sensitive lipase, a downstream target of β3 adrenergic receptor signaling. Local free fatty acid concentrations also decreased in the PeAT of HFD-fed mice. In the RAW 264.7 macrophage cell line, a decrease in palmitic acid, a major fatty acid, led to increased expression of TGFβ1. Conclusions: These results suggest that HFD-induced PeAT hypertrophy suppresses β3 adrenergic receptor signaling and free fatty acid release, increasing TGFβ1 expression in the macrophages and resulting in cardiac fibrosis and dysfunction. Our findings provide new insights into the pathogenesis of PeAT hypertrophy in heart failure development.