Increased Susceptibility of Atrial Fibrillation Induced by Hyperuricemia in Rats: Mechanisms and Implications

High levels of serum uric acid is closely associated with atrial fibrillation (AF); nonetheless, the detailed mechanisms remain unknown. Therefore, this work examined the intricate mechanisms of AF triggered by hyperuricemia and the impact of the uricosuric agent benzbromarone on atrial remodeling in hyperuricemic rats. After adjusting baseline serum uric acid levels, a total of 28 healthy male adult Sprague Dawley rats were randomly divided into 4 groups, namely, control (CTR), hyperuricemia (oxonic acid potassium salt, OXO) and benzbromarone (+ BBR), and OXO withdrawal groups. Primary rat cardiomyocytes were cultured with uric acid for 24 h to investigate the direct influence of uric acid on cardiomyocytes. Results revealed that AF vulnerability and AF duration were dramatically greater in hyperuricemic rats (OXO group), while the atrial effective refractory periods (AERPs) were significantly shorter. Meanwhile, BBR treatment and withdrawal of 2% OXO administration remarkably reduced AF inducibility and shortened AF duration. Moreover, abnormal morphology of atrial myocytes, atrial fibrosis, apoptosis, and substantial sympathetic nerve sprouting were observed in hyperuricemic rats. Apoptosis and fibrosis of atria were partly mediated by caspase-3, BAX, TGF-β1, and α-smooth muscle actin. Uric acid significantly induced primary rat cardiomyocyte apoptosis and fibrosis in vitro. Also, we found that sympathetic nerve sprouting was markedly upregulated in the atria of hyperuricemia rats, and was restored by BRB or absence of OXO administration. In summary, our study confirmed that AF induced by hyperuricemic rats occurred primarily via induction of atrial remodeling, thereby providing a novel potential treatment approach for hyperuricemia-related AF.