Necroptosis is required for atrial fibrillation and involved in aerobic exercise‐conferred cardioprotection

Necroptosis, a novel programmed cell death, plays a critical role in the development of fibrosis, yet its role in atrial fibrillation (AF) remains elusive. Mounting evidence demonstrates that aerobic exercise improves AF‐related symptoms and quality of life. Therefore, we explored the role of necroptosis in AF pathogenesis and exercise‐conferred cardioprotection. A mouse AF model was established either by calcium chloride and acetylcholine (CaCl(2)‐Ach) administration for 3 weeks or high‐fat diet (HFD) feeding for 12 weeks, whereas swim training was conducted 60 min/day, for 3‐week duration. AF susceptibility, heart morphology and function and atrial fibrosis were assessed by electrophysiological examinations, echocardiography and Masson's trichrome staining, respectively. Both CaCl(2)‐Ach administration and HFD feeding significantly enhanced AF susceptibility (including frequency and duration of episodes), left atrial enlargement and fibrosis. Moreover, protein levels of necroptotic signaling (receptor‐interacting protein kinase 1, receptor‐interacting protein kinase 3, mixed lineage kinase domain‐like protein and calcium/calmodulin‐dependent protein kinase II or their phosphorylated forms) were markedly elevated in the atria of AF mice. However, inhibiting necroptosis with necrostatin‐1 partly attenuated CaCl(2)‐Ach (or HFD)‐induced fibrosis and AF susceptibility, implicating necroptosis as contributing to AF pathogenesis. Finally, we found 3‐week swim training inhibited necroptotic signaling, consequently decreasing CaCl(2)‐Ach‐induced AF susceptibility and atrial structural remodeling. Our findings identify necroptosis as a novel mechanism in AF pathogenesis and highlight that aerobic exercise may confer benefits on AF via inhibiting cardiac necroptosis.