PHYSIOLOGICAL TRIGGERS EXACERBATE THE ARRHYTHMOGENICITY OF THE NAV1.5 MUTANT, E1784K

Abstract

Sudden cardiac death (SCD) from inherited channelopathies disproportionately affects those under the age of 40. The E1784K mutant in the cardiac sodium channel causes two diseases: long QT syndrome type 3 (LQT3) and Brugada syndrome type 1 (BrS1). Cardiac voltage-gated sodium channels pass a transient inward sodium current responsible for depolarizing ventricular cardiomyocytes. Mutant channels have either decreased transient current amplitude or an increased fraction of persistent current, the underlying mechanisms of BrS1 and LQT3, respectively, and both of which may cause ventricular arrhythmia. Despite carrying mutant channels from birth, patients may live for many years and millions of heart beats without incident, suggesting the presence of external triggers. We investigated whether physiological perturbations during exercise can exacerbate the effects of sodium channel mutants and trigger SCD. We studied the effects of increased temperature, decreased extracellular pH, and increased cytosolic calcium on wildtype and mutant sodium channels. We find that decreased peak sodium currents in the E1784K mutant are exacerbated by low extracellular pH. Mutant-induced increases in the persistent sodium current are further increased both by low pH and by high temperature. In some LQT3 mutants, such as ΔKPQ and 1795insD, increases in intracellular calcium provide a protective role by decreasing the persistent current. In contrast, the persistent sodium current in E1784K is insensitive to changes in intracellular calcium. Also, when intracellular calcium is elevated, persistent current in the E1784K mutant is not sensitive to Ranolazine, a selective persistent sodium current blocker. Our results suggest the pro-arrhythmic effects of the E1784K mutant in cardiac sodium channels are exacerbated by physiological changes associated with exercise. Increases in temperature and blood acidosis further decrease peak sodium currents and increase persistent sodium currents; both these changes are potentially arrhythmogenic. Additionally, E1784K persistent currents are not sensitive to exercise-induced increases in intracellular calcium, which mitigates the arrhythmogenicity of other sodium channel mutants. Overall our results suggest that factors associated with exercise may act as mutant-specific arrhythmogenic triggers underlying SCD.