Altered Cardiac Sodium Channel Function Resulting from Voltage-Sensor Mutation Is a Risk Factor for Dilated Cardiomyopathy

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Mutations in SCN5A, which encodes the cardiac Na+ channel, are known to cause rhythmic and conduction disorders. Recent studies, including ours, indicated that some SCN5A mutations increase susceptibility to dilated cardiomyopathy (DCM), which is a leading cause of heart failure, but the underlying mechanism remains unclear. In a cohort of 90 unrelated patients with idiopathic DCM, we found three non-synonymous SCN5A mutations: R225Q, A226V, and I1448N. R225Q occurred in 3 patients and the others were found in 1 patient each. R225Q and A226V are located within the first voltage sensor of the channel. These two mutations had a combined prevalence of 4.4% in the DCM cohort, but neither was found in 195 healthy subjects nor in a separate cohort of 90 patients with arrhythmias without cardiomyopathy. In vitro, the R225Q and A226V mutant channels behaved similarly, and were characterized as having a slower inactivation with a left-shifted voltage dependence, enhanced rate-dependent Na+ current reduction, and increased late Na+ current. They also caused an outward current. These results suggest that mutations in the first voltage sensor of the cardiac Na+ channel confer an increased risk for DCM, presumably through a mechanism mediated by the Na+ current abnormality that they cause, but the mechanism does not appear to necessarily require a long-standing arrhythmia that would otherwise induce DCM as well.