Mouse Models of SCN5A-Related Cardiac Arrhythmias

Abstract

Mutations of SCN5A gene, which encodes the α-subunit of the voltage-gated Na+ channel NaV1.5, underlie hereditary cardiac arrhythmic syndromes such as the type 3 long QT syndrome, cardiac conduction diseases, the Brugada syndrome, the sick sinus syndrome, a trial standstill, and numerous overlap syndromes. Patch-clamp studies in heterologous expression systems have provided important information to understand the genotype-phenotype relationships of these diseases. However, they could not clarify how SCN5A mutations can be responsible for such a large spectrum of diseases, for the late age of onset or the progressiveness of some of these diseases and for the overlapping syndromes. Genetically modified mice rapidly appeared as promising tools for understanding the pathophysiological mechanisms of cardiac SCN5A-related arrhythmic syndromes and several mouse models have been established. This review presents the results obtained on these models that, for most of them, recapitulate the clinical phenotypes of the patients. This includes two models knocked out for Nav1.5 β1 and β3 auxiliary subunits that are also discussed. Despite their own limitations that we point out, the mouse models still appear as powerful tools to elucidate the pathophysiological mechanisms of SCN5A-related diseases and offer the opportunity to investigate the secondary cellular consequences of SCN5A mutations such as the expression remodeling of other genes. This points out the potential role of these genes in the overall human phenotype. Finally, they constitute useful tools for addressing the role of genetic and environmental modifiers on cardiac electrical activity.

Acute heat tolerance of cardiac excitation in the brown trout (Salmo trutta fario)

“…Because the density of I Na is the main determinant for the velocity of impulse conduction, heat inactivation of I Na is expected to compromise the rate of AP propagation over the heart. This is in keeping with the mammalian models, where the loss of cardiac Na + channel function is associated with slowing of sinoatrial conduction and frequent sinoatrial or atrioventricular conduction blocks (Derangeon et al, 2012). Therefore, the large increases in HR variability, missed beats and depression of HR in brown trout at high temperatures could be due to slowed or impaired AP conduction between cardiac compartments rather than caused by heat inactivation of the impulse generation in the pacemaker centre.…”

Cardiac and Autonomic Mechanisms Contributing to SUDEP

“…Most of these patients are young adults. It is caused by a loss of function mutation of SCN5A gene (Derangeon et al, 2012). Characteristic electrocardiogram (ECG) abnormalities include ST segment elevation in derivations V1-V3, syncope, seizures, and sleep abnormalities.…”

Brugada syndrome risk loci seem protective against atrial fibrillation

“…Heterozygote knock-out mice display compromised conduction velocity, impaired AV conduction, and QRS prolongation. 39 An altered SCN5A/SCN10A expression could affect the conduction velocity and thereby the risk for BrS. Of note, both the SCN5A SNP rs11708996 and the SCN10A SNP rs10428132 have previously been associated with PR interval duration in a GWAS, 32 supporting a protective role in AF.…”