Treatment of cardiac arrhythmias in a mouse model of Rett syndrome with Na+-channel-blocking antiepileptic drugs

Dis Model Mech. 2015 Apr;8(4):363-71. doi: 10.1242/dmm.020131. Epub 2015 Feb 20.

Abstract

One quarter of deaths associated with Rett syndrome (RTT), an X-linked neurodevelopmental disorder, are sudden and unexpected. RTT is associated with prolonged QTc interval (LQT), and LQT-associated cardiac arrhythmias are a potential cause of unexpected death. The standard of care for LQT in RTT is treatment with β-adrenergic antagonists; however, recent work indicates that acute treatment of mice with RTT with a β-antagonist, propranolol, does not prevent lethal arrhythmias. In contrast, acute treatment with the Na(+) channel blocker phenytoin prevented arrhythmias. Chronic dosing of propranolol may be required for efficacy; therefore, we tested the efficacy of chronic treatment with either propranolol or phenytoin on RTT mice. Phenytoin completely abolished arrhythmias, whereas propranolol showed no benefit. Surprisingly, phenytoin also normalized weight and activity, but worsened breathing patterns. To explore the role of Na(+) channel blockers on QT in people with RTT, we performed a retrospective analysis of QT status before and after Na(+) channel blocker antiepileptic therapies. Individuals with RTT and LQT significantly improved their QT interval status after being started on Na(+) channel blocker antiepileptic therapies. Thus, Na(+) channel blockers should be considered for the clinical management of LQT in individuals with RTT.

Keywords: Arrhythmia; Long QT; MECP2; Phenytoin; Propranolol; Rett syndrome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / therapeutic use
  • Animals
  • Anticonvulsants / therapeutic use*
  • Arrhythmias, Cardiac / complications*
  • Arrhythmias, Cardiac / diagnostic imaging
  • Arrhythmias, Cardiac / drug therapy*
  • Disease Models, Animal
  • Female
  • Hyperventilation / complications
  • Hyperventilation / drug therapy
  • Long QT Syndrome / complications
  • Long QT Syndrome / drug therapy
  • Male
  • Methyl-CpG-Binding Protein 2 / deficiency
  • Methyl-CpG-Binding Protein 2 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Obesity / complications
  • Obesity / pathology
  • Phenotype
  • Phenytoin / therapeutic use
  • Propranolol
  • Rett Syndrome / complications*
  • Rett Syndrome / diagnostic imaging
  • Rett Syndrome / drug therapy*
  • Sodium Channel Blockers / therapeutic use*
  • Ultrasonography

Substances

  • Adrenergic beta-Antagonists
  • Anticonvulsants
  • Mecp2 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • Sodium Channel Blockers
  • Phenytoin
  • Propranolol