Ion Channel and Structural Remodeling in Obesity: Mediated Atrial Fibrillation

Mark D McCauley, Liang Hong, Arvind Sridhar, Ambili Menon, Srikanth Perike, Meihong Zhang, Ivson Bezerra da Silva, JiaJie Yan, Marcelo G Bonini, Xun Ai, Jalees Rehman, Dawood Darbar
Circulation. Arrhythmia and Electrophysiology 2020 July 12
Background - Epidemiological studies have established obesity as an independent risk factor for atrial fibrillation (AF) but the underlying pathophysiological mechanisms remain unclear. Reduced cardiac sodium channel expression is a known causal mechanism in AF. We hypothesized that obesity decreases Nav1.5 expression via enhanced oxidative stress, thus reducing INa , and enhancing susceptibility to AF. Methods - To elucidate the underlying electrophysiologic (EP) mechanisms a diet-induced obese (DIO) mouse model was used. Weight, BP, glucose, F2 -isoprostanes (F2 -IsoPs), NADPH oxidase 2 (NOX2), and protein kinase C (PKC) were measured in obese mice and compared to lean controls. Invasive EP, immunohistochemistry, Western blotting and patch clamping of membrane potentials was performed to evaluate the molecular and EP phenotype of atrial myocytes. Results - Pacing induced AF in 100% of DIO mice versus 25% in controls ( P < 0.01) with increased AF burden. Cardiac sodium channel expression, INa and atrial action potential duration (APD) were reduced and potassium channel expression (Kv1.5) and current ( IKur ) and F2 -IsoPs, NOX2, and PKC-α/δ expression and atrial fibrosis were significantly increased in DIO mice as compared to controls. A mitochondrial antioxidant reduced AF burden, restored INa , ICa,L , IKur , APD and reversed atrial fibrosis in DIO mice as compared with controls. Conclusions - Inducible AF in obese mice is mediated in part by a combined effect of sodium, potassium and calcium channel remodeling and atrial fibrosis. Mitochondrial antioxidant therapy abrogated the ion channel and structural remodeling and reversed the obesity-induced AF burden. Our findings have important implications for the management of obesity-mediated AF in patients.

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