Atrial fibrillation (AF) is an important and poorly understood condition whose incidence increases with age and certain ion channel mutations. We compare evidence concerning mechanisms for its initiation, from genetically modified murine hearts. Arrhythmic substrate has been attributed to abnormal action potential (AP) recovery altering AP duration (APD) and effective refractory period (AERP), and compromised AP propagation reducing conduction velocity (θ). These abnormalities increase the APD/AERP ratio and decrease AP wavelength (λ). Triggering is attributed to early and/or delayed after-depolarisations produced by abnormal Ca2+ homeostasis. Scn5a+/− atria with loss of cardiac Na+ channel (Nav1.5) function show reduced θ. Young but not aged Scn5a+/− atria additionally show atrial arrhythmias accompanied by prolonged APDs despite normal AERPs. In contrast, aged but not young atria from gain of Nav1.5 function, Scn5a+/ΔKPQ, hearts show atrial arrhythmias accompanied by prolonged APDs, shortened AERPs, reduced θ, and reduced Nav1.5 expression. Young Scn5a+/− and aged Scn5a+/ΔKPQ thus shared arrhythmic phenotypes resulting from substrate produced by shortened λ and increased APD/AERP ratio. Finally, both heterozygotic and homozygotic ryanodine receptor type 2 (RyR2)-P2328S atria with gain of Ca2+-release channel-RyR2 function show normal APD and AERP, but reduced θ and therefore reduced λ but unchanged APD/AERP ratio, and arrhythmic substrate following extrasystolic and isoproterenol challenge. Homozygotic but not heterozygotic RyR2-P2328S show spontaneous DADs triggering arrhythmia. These comparisons lead to a simple scheme for the initiation and perpetuation of AF. Once established, chronic AF leads to the subsequent, previously established, electrophysiological and anatomical remodelling further exacerbating arrhythmic tendency.
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