5, which is responsible for the ultra-rapid component of the delayed rectifier potassium current (IKur). The KCNA5 E375X nonsense mutation resulted in a truncated protein lacking the S4-S6 voltage sensor, the pore region, and the C-terminus. Functional studies revealed that this truncated form of KCNA5 was unable to conduct current, which is consistent with a loss-of-function effect.28 In vitro studies using human atrial myocytes and in vivo studies with a murine model found that administration of 4-aminopyridine, a known blocker of IKur, dramatically increased the incidence of early Inhibitors,research,lifescience,medical afterdepolarizations. The authors hypothesized that increased early afterdepolarizations associated with a prolonged

atrial action potential duration could trigger AF akin to that seen in torsade de pointes within the ventricles, which occurs with loss-of-function potassium channels in long QT syndrome. The importance of loss-of-function KCNA5 Inhibitors,research,lifescience,medical mutations in the pathogenesis of AF has been reaffirmed by subsequent reports.29, 30 Loss-of-Function Sodium Channel Mutations The SCN5A gene had been implicated in numerous arrhythmic disorders including the Brugada syndrome, congenital long QT syndrome type 3, and sick sinus syndrome.31-33 A study involving Inhibitors,research,lifescience,medical 375 patients with

a mixture of lone (118) and structural AF (257) identified 8 novel mutations in 10 different subjects that were absent from 360 healthy controls.34 The variants involved highly conserved residues within SCN5A and segregated with disease in all six of the familial cases. This report provided strong evidence that mutations within SCN5A represented an important Inhibitors,research,lifescience,medical cause of AF in patients with and without heart disease. The first SCN5A mutation associated with AF that was selleck inhibitor functionally Inhibitors,research,lifescience,medical characterized was found after screening 57 patients with lone AF or AF with hypertension and a confirmed family history of AF.35 A single novel mutation was found, Asn1986Lys, which was

absent from 300 ethnically matched controls. The affected father of the proband also carried the mutation; however, further genetic profiling of the family was not possible due to lack of consent. Expression of the mutant gene within Xenopus all laevis oocytes suggested a loss-of-function effect as evidenced by a significant hyperpolarizing shift in the midpoint of steady-state inactivation. This alteration was predicted to prolong the atrial action potential duration, and therefore the SCN5A Asn1986Lys was hypothesized to predispose to AF through a manner akin to the aforementioned atrial torsade. Mechanistic Subtype of AF 3: Gap Junction Impairment and Conduction Velocity Heterogeneity Connexins Connexin proteins form specialized channels, termed gap junctions, at the intercellular junction between adjacent cells that permit the flow of charged ions between the cytoplasmic compartments of neighbouring cells.