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The term channelopathy refers to a genetic cardiac disorder characterized by altered cardiac excitability, in the absence of structural cardiac involvement (with few exceptions). Diseases belonging to this group are also often referred as to inherited arrhythmogenic diseases (IADs). Indeed, growing evidence shows that not only ion channels but also other proteins involved in the control of cardiac excitability are affected.

IADs typically manifest with peculiar electrocardiographic features, syncope, and sudden death in young, otherwise healthy individuals. The common denominator of these disorders is a genetic mutation affecting the genes that control the excitability of myocardial cells (Fig. 36–1).

Figure 36–1

Proteins involved in inherited arrhythmogenic disorders. Diagram showing the intracellular localization of the proteins involved in the pathogenesis of inherited arrhythmogenic syndromes. Each protein can be involved in more than one disease. The figure shows that not only ion channels but also several ion channel interacting proteins are involved in the pathogenesis of inherited arrhythmia syndromes.

The groundbreaking discoveries starting in the 1990s until the beginning of the 2000s gathered the fundamental knowledge on the major genes causing cardiac channelopathies. Stems of such knowledge are the availability of genetic diagnosis, genotype-phenotype correlation, and genotype-based risk stratification schemes that are currently used in clinical practice.

Another interesting area of research that is going to represent an important source of information to link the genetic substrate with the clinics (thus leading to improved risk stratification and clinical management) derives from the evidence of variable expressivity and incomplete penetrance in these disorders. Differential severity of clinical phenotypes is frequently observed not only in patients with mutations on the same gene, but also among patients who harbor exactly the same mutation. Several studies have been recently published that genetic polymorphisms (single nucleotide polymorphisms [SNPs]) may significantly impact cardiac repolarization and the risk of cardiac events. The identification of such modifiers and, even more, the implementation of these findings into clinically applicable tools are in their infancy, but it may be anticipated that this information will be routinely applied for patient management in the near future.

In this chapter, we will review the clinical and genetic features of the most epidemiologically relevant cardiac channelopathies.


The long QT syndrome (LQTS) is an IAD in the structurally normal heart characterized by abnormally prolonged QT interval with peculiar morphologic abnormalities of the T wave. LQTS manifests with syncope and/or cardiac arrest typically occurring in children or teenagers. Two major phenotypic variants have been described in the early 1960s: one autosomal dominant (Romano-Ward syndrome) and one autosomal recessive (Jervell and Lange-Nielsen syndrome) also presenting with sensorineural deafness. Additional rare variants including extracardiac involvement are the Andersen syndrome and the Timothy syndrome. The estimated prevalence of LQTS is between 1:7000 and 1:3000, but these should be considered rough estimates ...

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