When expressed in HL-1 atrial cardiomyocytes, enhanced cellular excitability was observed in the form of spontaneous action potential depolarizations and a lower threshold for action potential firing as compared to wild-type cells. Collectively, these studies suggest that gain-of-function mutations within SCN5A are associated with AF. The existing evidence suggests that SCN5A gain-of-function mutations predispose to AF by enhancing cellular hyperexcitability. The depolarizing shift in steady-state inactivation increases the probability that the channel will be in the open conformation and capable of conducting current.46 This alteration in the gating of the Nav1.5-mediated current #learn more keyword# will

presumably result in

a predisposition for cells to reach threshold potential and fire, consistent with enhanced automaticity. This Inhibitors,research,lifescience,medical increase in focal discharges has the potential to serve as the trigger for AF. In addition, Nav1.5 channels have recently been identified in the autonomic ganglia that surround the pulmonary veins.47 Mutations within SCN5A may therefore result in neuronal hyperexcitability that may trigger AF through a parasympathetic pathway and contribute to the rapidly firing ectopic foci observed in the region of the pulmonary veins in Inhibitors,research,lifescience,medical some patients with the arrhythmia. Mechanistic Subclass of AF 5: ANP Modulation of Atrial Electrophysiology The most recent gene to be associated with AF does not implicate an ion channel but instead involves a circulating hormone, the atrial natriuretic Inhibitors,research,lifescience,medical peptide (ANP). Although known to be important in cardiac physiology, ANP

had been largely viewed as cardioprotective in the setting of heart failure.48 It was known, however, to be capable of modulating the electrical activities of the heart, and there were reports of its effects on specific ion channels.49, 50 However, little work had been done on ANP in the context of AF, and previous studies examining ANP levels as a biomarker in AF had been negative.51 Linkage analysis of a Caucasian family of northern European ancestry with autosomal dominant Inhibitors,research,lifescience,medical AF mapped the causative locus to the small arm of chromosome 1 (1p36-35).52 Review of the genes within this region revealed the presence of NPPA, the gene encoding ANP, and subsequent sequencing revealed a two base-pair deletion in exon 3 that resulted in a frameshift associated with loss Farnesyltransferase of the stop codon. Extension of the reading frame results in an elongated peptide that is 40 amino acids in length relative to the wild-type 28 amino acid length. The deletion was present in all of the affected family members but absent in unaffected family members and 560 control patients. Functional studies involving an isolated rat whole-heart model suggested that the mutant ANP resulted in shortened action potential duration and reduced effective refractory period, although the mechanism was not entirely clear.