Abstract
Dilated cardiomyopathy (DCM) is a structural heart disease that causes dilatation of cardiac chambers and impairs cardiac contractility. The SCN5A gene encodes Nav1.5, the predominant cardiac sodium channel alpha subunit. SCN5A mutations have been identified in patients with arrhythmic disorders associated with DCM. The characterization of Nav1.5 mutations located in the voltage sensor domain (VSD) and associated with DCM revealed divergent biophysical defects that do not fully explain the pathologies observed in these patients. The purpose of this study was to characterize the pathological consequences of a gating pore in the heart arising from the Nav1.5/R219H mutation in a patient with complex cardiac arrhythmias and DCM. We report its properties using cardiomyocytes derived from patient-specific human induced pluripotent stem cells. We showed that this mutation generates a proton leak (called gating pore current). We also described disrupted ionic homeostasis, altered cellular morphology, electrical properties, and contractile function, most probably linked to the proton leak. We thus propose a novel link between SCN5A mutation and the complex pathogenesis of cardiac arrhythmias and DCM. Furthermore, we suggest that leaky channels would constitute a common pathological mechanism underlying several neuronal, neuromuscular, and cardiac pathologies.
Highlights
Dilated cardiomyopathy (DCM) is a structural heart disease that causes dilatation of cardiac chambers and impairs cardiac contractility, eventually leading to heart failure
The index patient was diagnosed at age 29 with a clinical phenotype of complex arrhythmias associated with DCM (Table S1)
The last echocardiography in January 2015 revealed the presence of DCM with a mild eccentric dilatation of the left ventricle (LV), a mild decrease in systolic function (LVEF: 49%) associated with general hypokinesia, mild mitral regurgitation, and severe enlargement of the left atrium (LA) (Fig. S1, Table S1)
Summary
Dilated cardiomyopathy (DCM) is a structural heart disease that causes dilatation of cardiac chambers and impairs cardiac contractility, eventually leading to heart failure. The cardiac arrhythmias associated with DCM have been linked to mutations of the SCN5A gene that encodes the Nav1.5 sodium channel, which is responsible for the initiation and propagation of cardiac action potentials[2,6,7,8,9,10,11,12,13,14,15,16]. The underlying causes of DCM in SCN5A-mutated patients are not well understood. We have recently characterized the functional properties of five novel Nav1.5 mutations (Nav1.5/R219H, R222Q, R225W, R225P, and R814W) in familial DCM patients[11,17]. Gating pore currents most probably contributes to the morphological changes, impaired myocardial function, and cardiac arrhythmias observed in patients with DCM
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