RT Journal Article
SR Electronic
T1 Pathogenesis of Lethal Cardiac Arrhythmias in <em>Mecp2</em> Mutant Mice: Implication for Therapy in Rett Syndrome
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 113ra125
OP 113ra125
DO 10.1126/scitranslmed.3002982
VO 3
IS 113
A1 McCauley, Mark D.
A1 Wang, Tiannan
A1 Mike, Elise
A1 Herrera, Jose
A1 Beavers, David L.
A1 Huang, Teng-Wei
A1 Ward, Christopher S.
A1 Skinner, Steven
A1 Percy, Alan K.
A1 Glaze, Daniel G.
A1 Wehrens, Xander H. T.
A1 Neul, Jeffrey L.
YR 2011
UL http://stm.sciencemag.org/content/3/113/113ra125.abstract
AB Rett syndrome is a neurodevelopmental disorder typically caused by mutations in methyl-CpG–binding protein 2 (MECP2) in which 26% of deaths are sudden and of unknown cause. To explore the hypothesis that these deaths may be due to cardiac dysfunction, we characterized the electrocardiograms in 379 people with Rett syndrome and found that 18.5% show prolongation of the corrected QT interval (QTc), an indication of a repolarization abnormality that can predispose to the development of an unstable fatal cardiac rhythm. Male mice lacking MeCP2 function, Mecp2Null/Y, also have prolonged QTc and show increased susceptibility to induced ventricular tachycardia. Female heterozygous null mice, Mecp2Null/+, show an age-dependent prolongation of QTc associated with ventricular tachycardia and cardiac-related death. Genetic deletion of MeCP2 function in only the nervous system was sufficient to cause long QTc and ventricular tachycardia, implicating neuronally mediated changes to cardiac electrical conduction as a potential cause of ventricular tachycardia in Rett syndrome. The standard therapy for prolonged QTc in Rett syndrome, β-adrenergic receptor blockers, did not prevent ventricular tachycardia in Mecp2Null/Y mice. To determine whether an alternative therapy would be more appropriate, we characterized cardiomyocytes from Mecp2Null/Y mice and found increased persistent sodium current, which was normalized when cells were treated with the sodium channel–blocking anti-seizure drug phenytoin. Treatment with phenytoin reduced both QTc and sustained ventricular tachycardia in Mecp2Null/Y mice. These results demonstrate that cardiac abnormalities in Rett syndrome are secondary to abnormal nervous system control, which leads to increased persistent sodium current. Our findings suggest that treatment in people with Rett syndrome would be more effective if it targeted the increased persistent sodium current to prevent lethal cardiac arrhythmias.