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INTRODUCTION

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The term cardiac channelopathies refers to a group of genetic diseases in which the primary dysfunction is an abnormal electrophysiologic substrate creating susceptibility to arrhythmias in the context of a substantially normal cardiac structure. Channelopathies are also referred to as inherited arrhythmogenic diseases (IADs).

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IADs typically manifest with peculiar electrocardiographic patterns, syncope, and sudden death in young, otherwise healthy individuals. The common denominator of these disorders is a genetic mutation affecting either directly or indirectly the cardiac excitability.

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It is now evident that the multiplicity of causes and the complex pathogenesis of IADs depict a framework with few “major” well-characterized conditions (ie, long QT syndrome, catecholaminergic polymorphic ventricular tachycardia) and a number of entities that show up as typical Mendelian traits but more inconsistently (eg, lone atrial fibrillation or idiopathic ventricular fibrillation [VF]). In these cases, causative genetic mutations are seldom identified, suggesting a more heterogeneous pathogenesis. In other instances, overlap phenotypes presenting with features of two or more diseases (eg, long QT syndrome type [LQT] 3/Brugada syndrome) are recognized. In this chapter, we will review the clinical and genetic features of the most epidemiologically relevant cardiac channelopathies and will also overview the clinical presentation and genetics of less common disorders and overlap phenotypes that are emerging as a new clinical problem.

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LONG QT SYNDROME

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Definition

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The long QT syndrome (LQTS) encompasses abnormally prolonged QT interval with peculiar morphologic abnormalities of the T wave and syncope and/or cardiac arrest typically occurring in children or teenagers (Fig. 80–1). Two clinical signs (QT prolongation with or without syncope) define the most common LQTS presentation, the so-called Romano-Ward syndrome, which has autosomal dominant inheritance. Other clinical entities have been described, all sharing the presence of QT prolongation and arrhythmic risk but also including other features: Jervell and Lange-Nielsen syndrome (sensorineural deafness, autosomal recessive inheritance), Andersen syndrome (hypokalemic periodic paralysis, facial dimorphism, and autosomal dominant inheritance), and Timothy syndrome (syndactyly, autism spectrum disorders, congenital cardiac defects, and metabolic abnormalities, with sporadic presentation or parental mosaicism). The estimated prevalence of LQTS is between 1:7000 and 1:3000.1,2

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FIGURE 80–1.

Electrocardiogram in long QT syndrome (LQTS). Upper row shows electrocardiogram (ECG) strips from three LQTS patients with marked QT prolongation and typical ST-T morphologic abnormalities: straight ST segment (left), wide T wave with late component (center), and biphasic T wave (right). The ECG shown in the lower row is an example of the typical polymorphic ventricular tachycardia that can lead to syncope and/or sudden cardiac death in LQTS.

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Genetic Basis and Pathophysiology

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Fifteen genes have been associated with LQTS (Table 80–1). Their common consequence is the disruption of one or more ionic currents that contribute to ...

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