Molecular biology and cellular mechanisms of Brugada and long QT syndromes in infants and young children

J Electrocardiol. 2001:34 Suppl:177-81. doi: 10.1054/jelc.2001.28865.

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 21 years of age. The incidence of sudden cardiac death displays 2 peaks: one between 45 and 75 years of age, as a result of coronary artery disease, and the other between birth and 6 months of age, caused by sudden infant death syndrome. The role of cardiac arrhythmias in sudden infant death syndrome has long been a matter of debate and the role of cardiac arrhythmias in children in general is not well defined. Recent findings point to a contribution of primary electrical diseases of the heart including the Brugada and long QT syndromes to sudden death in infants and children. Mutations in SCN5A and HERG and KvLQT1 have 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 ventricular tachycardia/ventricular fibrillation in patients with the Brugada Syndrome. In LQTS, ion channel mutations cause a preferential prolongation of the M cell action potential that contributes to the 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 electrocardiogram (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 ventricular tachycardia/ventricular fibrillation (or rapid TdP). The practical importance of identifying infants and children with Brugada and LQTS syndromes lies in the fact that most deaths due to these congenital defects can be prevented. A simple ECG is often sufficient to permit diagnosis and thus to prevent the development of life-threatening arrhythmic events. Mass ECG screening of neonates and children however has been the subject of debate focused on issues ranging from the emotional impact of dealing with false positives to those concerning socio-economic and medico-legal factors. These issues are discussed in other articles. These concerns notwithstanding, it is important that we continue to question whether the economic inefficiencies of current screening methodologies supersede the value of a young life.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Cation Transport Proteins*
  • Child
  • Child, Preschool
  • DNA-Binding Proteins*
  • Death, Sudden, Cardiac / etiology*
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • Humans
  • Infant
  • KCNQ Potassium Channels
  • KCNQ1 Potassium Channel
  • Long QT Syndrome / genetics*
  • Mutation
  • NAV1.5 Voltage-Gated Sodium Channel
  • Potassium Channels / genetics
  • Potassium Channels, Voltage-Gated*
  • Sodium Channels / genetics
  • Sudden Infant Death / genetics*
  • Trans-Activators*
  • Transcriptional Regulator ERG
  • Ventricular Fibrillation / genetics*

Substances

  • Cation Transport Proteins
  • DNA-Binding Proteins
  • ERG protein, human
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • KCNH2 protein, human
  • KCNH6 protein, human
  • KCNQ Potassium Channels
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • NAV1.5 Voltage-Gated Sodium Channel
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • SCN5A protein, human
  • Sodium Channels
  • Trans-Activators
  • Transcriptional Regulator ERG