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BackgroundGenome‐wide association studies have implicated variants in SCN10A, which encodes Nav1.8, as modulators of cardiac conduction. Follow‐up work has indicated the SCN10A sequence includes an intronic enhancer for SCN5A. Yet the role of the Nav1.8 protein in the myocardium itself is still unclear. To investigate this, we use homozygous knockout mice (Scn10a−/−) generated by disruption of exons 4 and 5, leaving the Scn5a enhancer intact. Methods and ResultsWe previously reported that pharmacologic blockade of Nav1.8 in wild‐type animals blunts action potential prolongation by ATX‐II at slow drive rates (≤1 Hz). Here we present evidence of the same blunting in Scn10a−/− compared to wild‐type ventricular myocytes, supporting the conclusion that Nav1.8 contributes to late sodium current at slow rates. In contrast to earlier studies, we found no differences in electrocardiographic parameters between genotypes. Low‐dose ATX‐II exposure in lightly anesthetized animals and Langendorff‐perfused hearts prolonged QTc and generated arrhythmias to the same extent in wild‐type and Scn10a−/−. RNA sequencing failed to identify full‐length Scn10a transcripts in wild‐type or knockout isolated ventricular myocytes. However, loss of late current in Scn10a−/− myocytes was replicated independently in a blinded set of experiments. ConclusionsWhile Scn10a transcripts are not detectible in ventricular cardiomyocytes, gene deletion results in reproducible loss of late sodium current under extreme experimental conditions. However, there are no identifiable consequences of this Scn10a deletion in the intact mouse heart at usual rates. These findings argue that common variants in SCN10A that affect ventricular conduction do so by modulating SCN5A.

Background Cardiac involvement is a leading cause of death from sarcoidosis. Because the efficacy of corticosteroid treatment is limited in patients with cardiac manifestation, early diagnosis is important. However, cardiac involvement is difficult to identify at early stages and is often underdiagnosed. Therefore, this study aimed to identify electrocardiographic risk factors for cardiac events in patients with extracardiac sarcoidosis. Methods This prospective observational cohort study included 227 patients with extracardiac sarcoidosis who did not have any cardiac manifestation (age, 49 ± 17 years; women, 63%). We studied the association of electrocardiographic abnormalities with developing cardiac manifestations. Results During a follow-up of 6.3 ± 3.7 years, 11 patients developed cardiac events, including advanced atrioventricular block (4 patients), ventricular tachycardia (4 patients), and systolic dysfunction (3 patients). All patients had electrocardiographic abnormalities prior to the development of cardiac events. In multivariate analyses, the baseline heart rate and PR interval were associated with increased risk of developing cardiac events. The QRS duration and corrected QT interval were not associated with cardiac manifestations. The multivariate analyses also revealed that baseline conduction disorder, ST segment/T wave abnormalities, and fragmented QRS complexes were associated with cardiac events. Conclusions Electrocardiographic abnormalities occurred prior to cardiac events in extracardiac sarcoidosis. Patients with electrocardiographic abnormalities may require further evaluation for cardiac involvement and careful follow-up. [ABSTRACT FROM AUTHOR]