Molecular biology and cellular mechanisms of cardiac arrhythmias and sudden death in infants and young children

Abstract

Sudden cardiac death accounts for 19% of sudden deaths in children between 1 and 13 years of age and 30% of sudden deaths that occur between 14 and 1 years of age. The incidence of sudden cardiac death displays 2 peaks: one, between birth and 6 months of age, due to sudden infant death syndrome (SIDS), and the other between 45 and 75 years of age, as a result of coronary artery disease. The role of cardiac arrhythmias in SIDS has long been a matter of debate and the role of cardiac arrhythmias in children in general is not well defined. This presentation focuses on recent molecular biology findings that point to a contribution of primary electrical diseases of the heart to sudden death in infants and children and how these findings have advanced our understanding of mechanisms. The principle focus will be on the Brugada and long QT syndromes. Mutations in SCN5A and HERG and KvLQT1 have recently been shown to be associated with life-threatening arrhythmias and long QT intervals in young infants. These mutations cause changes in sodium and potassium currents that amplify intrinsic electrical heterogeneities within the heart, thus providing a substrate as well as a trigger for the development of reentrant arrhythmias, including Torsade de Pointes (TdP), commonly associated with the long QT syndrome (LQTS). Mutations in SCN5A have also been shown to cause the sodium channel to turn off prematurely and thus to set the stage for the development of a rapid polymorphic VT/VF, similar to that encountered in older patients with the Brugada Syndrome. In LQTS, ion channel mutations cause a preferential prolongation of the M cell action potential that contributes to development of long QT intervals, wide-based or notched T waves, and a large transmural dispersion of repolarization, which provides the substrate for the development of TdP. An early afterdepolarization-induced triggered beat is thought to provide the extrasystole that precipitates TdP. In the Brugada syndrome, mutations in SCN5A reduce sodium current density, causing premature repolarization of the epicardial action potential due to an all or none repolarization at the end of phase 1. The loss of the action potential dome in epicardium but not endocardium, creates a dispersion of repolarization across the ventricular wall, resulting in a transmural voltage gradient that manifests in the ECG as an ST segment elevation and in the development of a vulnerable window during which reentry can be induced. Under these conditions, loss of the action potential dome at some epicardial sites but not others gives rise to phase 2 reentry, which provides an extrasystole capable of precipitating VT/VF (or rapid TdP).