A New Cardiac Channelopathy: From Clinical Phenotypes to Molecular Mechanisms Associated With Nav1.5 Gating Pores.

Adrien Moreau,Mohamed Chahine

doi:10.3389/fcvm.2018.00139

Abstract

Voltage gated sodium channels (NaV) are broadly expressed in the human body. They are responsible for the initiation of action potentials in excitable cells. They also underlie several physiological processes such as cognitive, sensitive, motor, and cardiac functions. The NaV1.5 channel is the main NaV expressed in the heart. A dysfunction of this channel is usually associated with the development of pure electrical disorders such as long QT syndrome, Brugada syndrome, sinus node dysfunction, atrial fibrillation, and cardiac conduction disorders. However, mutations of Nav1.5 have recently been linked to the development of an atypical clinical entity combining complex arrhythmias and dilated cardiomyopathy. Although several Nav1.5 mutations have been linked to dilated cardiomyopathy phenotypes, their pathogenic mechanisms remain to be elucidated. The gating pore may constitute a common biophysical defect for all NaV1.5 mutations located in the channel's VSDs. The creation of such a gating pore may disrupt the ionic homeostasis of cardiomyocytes, affecting electrical signals, cell morphology, and cardiac myocyte function. The main objective of this article is to review the concept of gating pores and their role in structural heart diseases and to discuss potential pharmacological treatments.

Highlights

Cardiovascular diseases are the single most common cause of death worldwide, and sudden deaths due to cardiac arrhythmias account for ∼50% of these deaths [1]
The purpose of this review is to explore the mechanisms involved in SCN5A mutations linked to Dilated cardiomyopathy (DCM), with a focus on their role in generating gating pore currents as a potentially unifying molecular mechanism
It has recently been shown that SCN5A mutations in patients with DCM combined with complex arrhythmias have either gain and/or loss of function biophysical phenotypes when explored in a heterologous expression system [36]

Summary

Introduction

Cardiovascular diseases are the single most common cause of death worldwide, and sudden deaths due to cardiac arrhythmias account for ∼50% of these deaths [1]. Distinct cardiac phenotypes caused by SCN5A mutations have been described, including SND and conduction disorder associated with DCM. It has recently been shown that SCN5A mutations in patients with DCM combined with complex arrhythmias have either gain and/or loss of function biophysical phenotypes when explored in a heterologous expression system [36] (see Figure 1 for a summary of the locations and biophysical properties of these mutants).

Objectives

Results

Conclusion