Primary Electrical Heart Disease-Principles of Pathophysiology and Genetics

Abstract

Primary electrical heart diseases, often considered channelopathies, are inherited genetic abnormalities of cardiomyocyte electrical behavior carrying the risk of malignant arrhythmias leading to sudden cardiac death (SCD). Approximately 54% of sudden, unexpected deaths in individuals under the age of 35 do not exhibit signs of structural heart disease during autopsy, suggesting the potential significance of channelopathies in this group of age. Channelopathies constitute a highly heterogenous group comprising various diseases such as long QT syndrome (LQTS), short QT syndrome (SQTS), idiopathic ventricular fibrillation (IVF), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and early repolarization syndromes (ERS). Although new advances in the diagnostic process of channelopathies have been made, the link between a disease and sudden cardiac death remains not fully explained. Evolving data in electrophysiology and genetic testing suggest previously described diseases as complex with multiple underlying genes and a high variety of factors associated with SCD in channelopathies. This review summarizes available, well-established information about channelopathy pathogenesis, genetic basics, and molecular aspects relative to principles of the pathophysiology of arrhythmia. In addition, general information about diagnostic approaches and management is presented. Analyzing principles of channelopathies and their underlying causes improves the understanding of genetic and molecular basics that may assist general research and improve SCD prevention.

Keywords: Brugada syndrome; CPVT; arrhythmia; channelopathy; early repolarization syndrome; long QT syndrome; sudden cardiac death.

Figure 1

Pathophysiological mechanisms leading to arrhythmia. DAD—delayed afterdepolarization; EAD—early afterdepolarization.

Figure 2

EAD and DAD formation. Phases of action potential are presented in boxes. AP—action potential; DAD—delayed afterdepolarization; EAD—early afterdepolarization.

Figure 3

Cardiac conditions besides BrS are associated with SCN5A mutations [112,117].

Figure 4

Electrocardiographic types of Brugada syndrome [122,123]. ECG—electrocardiography.

Figure 5

Genes of idiopathic VF [61].

Figure 6

ECG patterns in channelopathies. BrS—Brugada syndrome; CA—cardiac arrest; CPVT—catecholaminergic polymorphic ventricular tachycardia; ECG—electrocardiography; ERS—early repolarization syndrome; IVF—idiopathic ventricular fibrillation; LQTS—long QT syndrome; PVC—premature ventricular complex; SCA—sudden cardiac arrest; SHD—structural heart disease; SQTS—short QT syndrome; QTc—corrected QT; VF—ventricular fibrillation; VT—ventricular tachycardia.