In silico investigation of the mechanisms underlying atrial fibrillation due to impaired Pitx2
Fig 6
Mechanisms underlying Pitx2 deficiency-induced AF and ionic mechanisms of anti-arrhythmic effects of flecainide in AF patients with Pitx2 down-regulation.
a, Pitx2 regulates calcium handling genes Atp2a2, Ryr2 and Sln, electrical remodelling genes Scn5a, Kcnj2, Kcnj4, Kcnj11, Kcnj12, Kcnq1 Cacna1d, Cacna2d2, and Cav1, and structural remodelling genes Gja1, Gja5 and Dsp. Pitx2 down-regulation in the LA leads calcium handling abnormities, electrical remodelling and structural remodelling, contributing to APD abbreviation, slowed atrial conduction and DAD, leading to AF triggers and substrates. b, Flecainide has block effects on RyR, INa and IKr. Flecainide can reduce spontaneous calcium waves and triggered activity, and prolong the APD, thereby suppressing Pitx2 deficiency-induced AF. Abbreviations: AF–atrial fibrillation; LA–left atrium; DAD–delayed afterdepolarization; APD–action potential duration; RyR–ryanodine receptor.