Cardiac Arrhythmias Related to Sodium Channel Dysfunction

Abstract

The voltage-gated cardiac sodium channel (Na1.5) is a mega-complex comprised of a pore-forming α subunit and 4 ancillary β-subunits together with numerous protein partners. Genetic defects in the form of rare variants in one or more sodium channel-related genes can cause a loss- or gain-of-function of sodium channel current (I) leading to the manifestation of various disease phenotypes, including Brugada syndrome, long QT syndrome, progressive cardiac conduction disease, sick sinus syndrome, multifocal ectopic Purkinje-related premature contractions, and atrial fibrillation. Some sodium channelopathies have also been shown to be responsible for sudden infant death syndrome (SIDS). Although these genetic defects often present as pure electrical diseases, recent studies point to a contribution of structural abnormalities to the electrocardiographic and arrhythmic manifestation in some cases, such as dilated cardiomyopathy. The same rare variants in SCN5A or related genes may present with different clinical phenotypes in different individuals and sometimes in members of the same family. Genetic background and epigenetic and environmental factors contribute to the expression of these overlap syndromes. Our goal in this chapter is to review and discuss what is known about the clinical phenotype and genotype of each cardiac sodium channelopathy, and to briefly discuss the underlying mechanisms.

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“…Loss of function mutations in SCN5A, the gene encoding the Nav1.5 sodium channel account for 30% of all cases in which a gene variant is involved [64]. Nav1.5 dysfunction in the presence of a transmural voltage gradient caused by heterogeneous transmural distribution of the transient outward current (I to ) results in an accentuation of the AP notch, and loss of spike and dome morphology, which leads to the development of phase 2 reentry and polymorphic VT [65,66]. Other mechanisms involve decreased conduction within the right ventricular outflow tract due to reduced I Na [67].…”

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“…In clinical medicine, QT interval prolongation is of concern because it is the defining phenotypic characteristic of a group of inherited long QT syndromes that have been associated with TdP and sudden death . One long QT syndrome, LQT2, is seen when an individual's genetic inheritance includes an abnormal variant of the human ether‐a‐go‐go–related gene ( hERG , or KCNH2 ) that encodes the α‐helix subunit of the cardiac potassium ion channel through which I Kr flows .…”

“…In clinical medicine, QT interval prolongation is of concern because it is the defining phenotypic characteristic of a group of inherited long QT syndromes that have been associated with TdP and sudden death. [11][12][13][14][15][16][17] One long QT syndrome, LQT2, is seen when an individual's genetic inheritance includes an abnormal variant of the human ether-a-go-go-related gene (hERG, or KCNH2) that encodes the α-helix subunit of the cardiac potassium ion channel through which I Kr flows. 18 Abnormal hERG variants lead to a cascade of consequences, including loss of function of the expressed hERG channel (ie, decreased I Kr flow), a less gradual slope in phase 3 of the action potential (ie, delayed repolarization), and manifest QT prolongation on the ECG.…”

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“…Gain-of-function mutations of this channel are associated with many disorders such as the congenital long QT syndrome, multifocal ectopic Purkinje-related premature contractions (MEPPC), and exercise-induced polymorphic ventricular tachycardia [6][7][8][9][10][11]. Whereas the loss-of-function mutations are linked with Brugada syndrome, sick sinus syndrome, and cardiac conduction disease [4,5,12]. In the same line, mutations in genes encoding proteins that regulate, directly or indirectly, Na v 1.5 function are associated with many cardiac arrhythmias [13].…”