Molecular Genetics of Cardiac Arrhythmias

Abstract

Knowledge derived from human genetics and from studies in animal models has led to the discovery of multiple molecular defects underlying inherited arrhythmias and cardiac conduction system diseases in structurally altered or normal hearts.

Minor disturbances at the molecular and cellular levels can initiate severe rhythm abnormalities. Some congenital heart diseases and cardiomyopathies carry a higher risk for conduction disturbances or arrhythmias. In the structurally normal heart, inherited cardiac arrhythmias or conduction system disease are most often primary electrical diseases. The underlying molecular defect in those disorders, also termed ion channelopathies, typically involves genes that encode ion channels, responsible for maintaining intracellular and extracellular electrolyte balance.

Advances in molecular biology and genetics facilitate the identification of factors that may predispose an individual with or without structural heart disease to arrhythmias or sudden death. Taking those discoveries into clinical practice improves risk stratification and allows potential identification of new therapeutic targets.

Key Concepts:

  • Sudden unexpected cardiac death in the pediatric population is a devastating event with an incidence of approximately 1–6 in 100 000 per year and in some cases is the first presentation of a previously undiagnosed disorder.

  • Inherited arrhythmias and cardiac conduction system disease frequently occur in pediatric patients with congenital heart disease but can also be associated with a structurally normal heart.

  • Mutations in genes encoding for cytoskeletal proteins, sarcomeric proteins and ion channels are responsible for the majority of inherited arrhythmias associated with the structurally normal or abnormal heart.

  • Identifying the molecular basis of congenital arrhythmias optimises patient screening, risk stratification and allows genotype‐directed therapies of patients at risk for sudden cardiac death.

Keywords: arrhythmias; cardiac conduction system disease; congenital heart disease; molecular basis; long QT syndrome; channelopathies; electrophysiology; cardiomyopathy

Figure 1.

Anatomy of the cardiac conduction system. Four chamber view of the heart in a vertical section. The sinoatrial (SA) node is located in the upper right atrium between the venous inflow tract and the crista terminalis. The atrioventricular (AV) node is identified in the crux of the heart, near the anterior component of the tricuspid annulus. The His bundle is the proximal component of the central conduction system leaving the AV node and penetrating through the annulus fibrosis. The bundle branches emanate from the His bundle to provide specialised conduction tracts through both ventricles. SVC, superior vena cava and IVC, inferior vena cava.

Figure 2.

Action potential in myocytes. Shown is the action potential shape of atrial and ventricular myocytes in (a) (Wolf CM and Berul CL (2008) Molecular mechanisms of inherited arrhythmias. Current Genomics9: 160–168.) and of nodal conduction system cells in (b) (upper part), the relevant ion currents crossing the cell membrane (middle part) and the corresponding electrocardiographic ventricular activity (lower part). The action potential of atrial and ventricular myocytes (a) consists of four phases, characteristically of a long plateau phase (3) and a stable resting phase (4). The action potential of nodal conduction system cells (b) differs in phases 4 and 0 in that there is a slow upstroke phase replacing the stable resting phase 4 which allows the cell to spontaneously depolarise. The initial upstroke in phase 0 is caused by calcium instead of sodium influx. The cardiac delayed rectifier current (IK) is a major determinant of phase 3 of the cardiac action potential. It comprises three independent components: Ikur (ultrarapid), Ikr (rapid) and a catecholamine‐sensitive component IKs (slow). Other currents, such as the plateau delayed rectifier K+ current (Ik2p) and the inward rectifier K+ current (IK1), also contribute to repolarisation. The conductance of inward rectifying K+ channels (IK1) is highest near the equilibrium potential for K+. The transient outward potassium current (Ito) is responsible for the initial rapid phase of action potential repolarisation, discernible as a notch preceding the plateau phase. The acetylcholine‐activated current IKACh is mainly found in SA and AV nodal cells and is directly activated by the Gβγ subunit of the G protein, when acetylcholine binds to muscarinic M2 receptors. The adenosine triphosphate‐sensitive current IKATP is inhibited by physiological intracellular ATP levels and thus couples the cell metabolism to the membrane potential. IATP channels function to stabilise resting potential and shorten action potentials. INa, sodium current; ICa,L, L‐type calcium current; INa,Ca, sodium/calcium exchanger; ICa,T, T‐type calcium current; If and pacemaker current. (b) Reproduced from Wolf CM and Berul CI (2006) Inherited conduction system abnormalities – one group of diseases, many genes. Journal of Cardiocascular Electrophysiology17(4): 446–455.

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Wolf, Cordula M, and Berul, Charles I(Apr 2010) Molecular Genetics of Cardiac Arrhythmias. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022491]