Divergent Biophysical Defects Caused by Mutant Sodium Channels in Dilated Cardiomyopathy With Arrhythmia

Abstract

Abstract-Mutations in SCN5A encoding the principal Na ϩ channel ␣-subunit expressed in human heart (Na V 1.5) have recently been linked to an inherited form of dilated cardiomyopathy with atrial and ventricular arrhythmia. We compared the biophysical properties of 2 novel Na V 1.5 mutations associated with this syndrome (D2/S4 -R814W; D4/S3 -D1595H) with the wild-type (WT) channel using heterologous expression in cultured tsA201 cells and whole-cell patch-clamp recording. Expression levels were similar among WT and mutant channels, and neither mutation affected persistent sodium current. R814W channels exhibited prominent and novel defects in the kinetics and voltage dependence of activation characterized by slower rise times and a hyperpolarized conductance-voltage relationship resulting in an increased "window current." This mutant also displayed enhanced slow inactivation and greater use-dependent reduction in peak current at fast pulsing frequencies. By contrast, D1595H channels exhibited impaired fast inactivation characterized by slower entry into the inactivated state and a hyperpolarized steady-state inactivation curve. Our findings illustrate the divergent biophysical defects caused by 2 different SCN5A mutations associated with familial dilated cardiomyopathy. Retrospective review of the published clinical data suggested that cardiomyopathy was not common in the family with D1595H, but rather sinus bradycardia was the predominant clinical finding. However, for R814W, we speculate that an increased window current coupled with enhanced slow inactivation and rate-dependent loss of channel availability provided a unique substrate predisposing myocytes to disordered Na ϩ and Ca 2ϩ homeostasis leading to myocardial dysfunction. (Circ Res. 2008;102:364-371.) Key Words: arrhythmia Ⅲ ion channels Ⅲ cardiomyopathy Ⅲ genetics M utations in SCN5A, the gene encoding the principle ␣-subunit of the human cardiac voltage-gated sodium channel Na V 1.5, cause inherited susceptibility to ventricular tachyarrhythmia (congenital long-QT syndrome [LQTS], Brugada syndrome [BrS]), 1-3 familial heart block with or without sinus node dysfunction, 4 -6 and other more complex phenotypes with features of both arrhythmia susceptibility and impaired atrioventricular conduction. 7,8 Subclinical expression of SCN5A mutations may also manifest as druginduced arrhythmias, 9,10 sudden infant death syndrome, 11,12 and increased arrhythmia risk in specific populations. 13 Conventional wisdom in the era of molecular cardiology predicts that mutations affecting plasma membrane ion channels will primarily predispose to rhythm disorders, but will not directly affect contractile function. A possible exception to this paradigm was provided by the discovery of SCN5A mutations associated with familial dilated cardiomyopathy associated with atrial and ventricular arrhythmias (DCM-arrhythmia syndrome). In 2004, McNair et al 14 reported that a missense mutation, SCN5A-D1275N, segregated with a phenotype including DCM of variable expression, abnormal ...

Molecular and Functional Changes in Voltage-Gated Na+ Channels in Cardiomyocytes During Mouse Embryogenesis

“…The faster recovery from inactivation combined with similar rate of fast inactivation may promote greater sodium conductance per unit time, and contribute to the increase in Na + current density. 28 Expression Pattern of Na + Channel α-Subunits of Cardiomyocytes In the present study, both the data from single cardiomyocytes and whole ventricles demonstrated developmental changes in the expression of different Na + channel α-subunits. Although the expressions of Nav 1.1, Nav 1.2 and Nav 1.3 mRNA were absent or present at very low levels, Nav 1.4, Nav 1.5 and Nav 1.6 were increased during cardiogenesis.…”

CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice

“…By contrast, neurons isolated from F1.Q54 animals exhibited higher levels of persistent current and a depolarized steady-state inactivation compared with B6.Q54 mice. A consequence of the shift in steady-state inactivation for F1.Q54 animals compared with B6.Q54 animals is a larger window current, which has been shown to be a common feature of cardiac arrhythmias resulting from mutations in SCN5A (27,28). The greater tendency for spontaneous action potential firing observed in F1.Q54 neurons may be a result of both increased persistent current and increased window current.…”

Development of a Patient-Derived Induced Pluripotent Stem Cell Model for the Investigation of <i>SCN5A</i>-D1275N-Related Cardiac Sodium Channelopathy

“…9, 10 The pathogenic mechanisms of SCN5A-associated DCM, arrhythmia-mediated cardiomyopathy, disordered intracellular sodium homeostasis, and the disruption of sodium channel-protein interactions were discussed previously. 33 An investigation into disordered intracellular sodium homeostasis in isolated guinea pig CMs found that sodium currents contributed to the generation of calcium transients by the sarcoplasmic reticulum via the reversemode sodium-calcium exchanger, 34 suggesting that SCN5A loss-of-function mutations might reduce the amplitude of calcium transients, resulting in negative cardiac inotropic effects. Additionally, a sodium channel defect was found to be associated with cardiac fibrosis, causing left ventricular dysfunction, and SCN5A-knockout mice demonstrated cardiomyopathy and cardiac fibrosis.…”