Background Whether chronic
obstructive sleep apnea ( OSA ) could promote epicardial adipose tissue ( EAT ) secretion of profibrotic
adipokines, and thereby contribute to atrial
fibrosis, and the potential
therapeutic effects of
metoprolol remain unknown. Methods and Results A chronic OSA canine model was established by repeatedly clamping the endotracheal tube for and then reopening it for 4 hours every other day for 12 weeks. In a
metoprolol treatment group,
metoprolol succinate was administered daily for 12 weeks. The EAT infiltration and left atrial
fibrosis were examined. The expressions of
adipokines secreted by EAT and hypoxic 3T3-L1 adipocytes were detected. The changes in
collagen synthesis, transforming growth factor-β1 expression, and cell differentiation and proliferation in cardiac fibroblasts induced by hypoxic 3T3-L1 adipocyte-derived
conditioned medium were further analyzed. Chronic OSA induced infiltration of EAT into the left atrium. OSA enhanced the profibrotic effect of EAT on the adjacent atrial myocardium. Moreover, OSA induced profibrotic
cytokine secretion from EAT . We also found that
hypoxia induced
adipokine secretion in cultured adipocytes, and the
medium conditioned by the hypoxic adipocytes increased
collagen and transforming growth factor-β1
protein expression and cell proliferation of cardiac fibroblasts. More importantly,
metoprolol attenuated infiltration of EAT and alleviated the profibrotic effect of EAT by inhibiting
adipokine secretion.
Metoprolol also inhibited
hypoxia-induced
adipokine secretion in adipocytes and thereby blocked the hypoxic adipocyte-derived
conditioned medium-induced fibrotic response of cardiac fibroblasts. Conclusions Chronic OSA enhanced the profibrotic effect of EAT on the neighboring atrial myocardium by stimulating the secretion of profibrotic
adipokines from EAT , which was significantly attenuated by
metoprolol. This study gives insights into mechanisms underlying OSA -induced
atrial fibrillation and also provides experimental evidence for the protective effects of
metoprolol.