While there were two healthy family members that carried the mutation, their unaffected status may have been secondary to incomplete penetrance or their relatively

young ages (33 and 42 years old). Functional analysis of the mutant protein revealed increased current density consistent with a gain-of-function effect. The putative predisposing mechanism of Val93Ile KCNJ2 for AF involves enhanced repolarization and a reduction in refractory period, as hypothesized with KCNQ1 and KCNE2. The final potassium channel gene implicated in the pathogenesis of AF through an acceleration of cardiomyocyte repolarization is KCNE5.26 Investigators Inhibitors,research,lifescience,medical screened 158 AF cases for mutations within the coding region of KCNE5 and identified a Leu65Phe mutation in a 66-year-old female with a persistent form of the arrhythmia. She had no family Z-VAD-FMK datasheet history of AF, unlike the familial forms of AF observed with the previous potassium channel genes, and had risk factors including hypertension and ischemic heart Inhibitors,research,lifescience,medical disease. Although the possibility of a de novo mutation cannot be excluded given that other family members were not screened, the sporadic nature of this case, coupled with the presence of pre-existing risk factors,

suggest that KCNE5 Leu65Phe may actually Inhibitors,research,lifescience,medical reflect a disease-contributing genetic variant as opposed to a disease-causing mutation for AF. The Inhibitors,research,lifescience,medical finding that gain-of-function potassium channel mutations predispose to AF has led to an understanding that enhanced atrial repolarization accounts for a mechanistic subtype of the arrhythmia

(Table 1). This observation leads to reduced atrial tissue refractoriness, providing a substrate capable of supporting multiple self-perpetuating micro-reentrant circuits. Table 1 Mechanistic subclassification of lone atrial fibrillation and putative pharmacogenetic strategy (modified from reference 9). Mechanistic Subtype Inhibitors,research,lifescience,medical of AF 2: Loss-of-Function Potassium and Sodium Channels and Delayed Atrial Action Potential Repolarization Loss-of-Function Potassium Channel Mutations The initial potassium channel gene mutations implicated in the development of AF had been shown to result in gain-of-function effects based on in vitro functional analysis. An alternative form of AF driven by opposing pathophysiology Terminal deoxynucleotidyl transferase had been suggested by previous work, which noted the development of a polymorphic atrial tachycardia that subsequently degenerated into AF after injection of cesium chloride, a potassium channel blocker, into the sinus node artery of dogs.27 These findings led the investigators to coin the term “atrial torsade” and suggested that loss-of-function potassium channel gene mutations may also predispose to AF. Subsequent screening for potassium channel mutations in AF identified a novel nonsense mutation (E375X) within the KCNA5 gene.