Mutation of the Cardiac Sodium Channel Nav1.5 Leads to Sex Specific Arrhythmias

Introduction Cardiac Na v 1.5 sodium channels, encoded by the SCN5A gene, are responsible for initiating the electrical action potential in the heart, resulting in coordinated muscular contraction. Channelopathies caused by mutations in Na v 1.5 occur in 1/2500 individuals and lead to arrhythmic diseases, such as long QT syndrome, and cardiomyopathies 1,2 . Males with Na v 1.5 mutations are at a higher risk for sudden cardiac arrest, indicative of an innate protection in females through an unknown mechanism. The gain of function Arg222Gln mutation affects the voltage sensing segment of Na v 1.5, creating an aberrant pore leading to arrhythmia‐inducing membrane ion leaks 3 . We sought to determine the sex‐specific effects of this clinically relevant mutation, attempting to undercover the protective mechanisms present in females. Methods The Arg222Gln mutation was knocked into exon 6 of the mouse SCN5A gene to generate viable animals that phenocopy the human disease. Three‐lead electrocardiograms (ECG) from adult male and female animals were recorded under anesthesia, including wild‐type (WT) controls. Isoproterenol (β‐adrenoreceptor agonist) was injected to examine electrophysiological changes under acute stress. Baseline echocardiograms were collected at four months and after 30 days of transverse aortic constriction (TAC). Differentially expressed genes from whole heart lysate were measured by chip‐based analysis after TAC . Protein levels were quantified using Western blot and ELISA. Results ECG measurements revealed a prolonged QTc (0.064ms±0.006) and QRS interval (0.011ms±0.0003) in mutant males compared to WT males (0.036ms±0.008 and 0.0085ms±0.0004 respectively) (P<0.05). Mutant males had an observable sinus arrhythmia at baseline (RMSSD of beat to beat intervals of 4.60 vs 0.79 in WT males, P<0.05), whereas mutant and wild‐type females had no evidence of adverse changes to the beating rhythm. The ejection fraction (EF) of mutant males decreased by 40%±9.9% 4 weeks post‐TAC, whereas no significant changes in EF were observed in all other groups. We found that transcript and protein levels of pyruvate dehydrogenase kinase‐4, which reduces pyruvate dehydrogenase (PDH) activity through phosphorylation, were 6‐fold higher in mutant males compared to WT males (P<0.05), whereas no differences were observed between females. Despite this, phospho‐PDH levels were lower and PDH activity higher in mutant males compared to WT males (P<0.01), with no differences between the female groups. Conclusion We found functional, electrophysiological, and metabolic enzyme abnormalities in male mice harboring the Arg222Gln Na v 1.5 mutation. These differences did not exist in the female mutant mice. Our data illustrate a strong sex‐specific phenotype, and suggest that metabolic alterations through increased PDH activity provide a protective mechanism against the arrhythmia and heart failure produced by Na v 1.5‐related cation leak. Further experiments will seek to determine if sex hormones alone can induce a protective effect in the context of the Arg222Gln mutation. 1 Priori et al., NEJM, 2003 2 Veerman et al., Gene, 2015 3 Moreau et al., J Gen Physio, 2015

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