Pathogenesis of Lethal Cardiac Arrhythmias in Mecp2 Mutant Mice: Implication for Therapy in Rett Syndrome

Lethal ventricular arrhythmias in a mouse model of Rett syndrome can be prevented by phenytoin, which blocks a persistent sodium current. A Heart-Brain Connection Patients with Rett syndrome, usually girls, have many problems, including impaired brain function and cognition. One of the most unfortunate is the tendency of about 25% of these patients to die suddenly and unexpectedly, likely from cardiac problems. To get to the bottom of this, McCauley et al. examined heart physiology in mice carrying a mutation in methyl-CpG–binding protein 2 (MECP2), the gene that is defective in Rett syndrome. In addition to a Rett-like phenotype, these mice exhibited a long QT interval in their heartbeat tracings and had ventricular tachycardia, and some of the mice died of cardiac causes. Treatment with a common anticonvulsant, phenytoin, normalized these atypical heartbeats, suggesting that this treatment may help to prevent sudden death in patients with Rett syndrome. To determine the underlying cause of the dangerous heartbeats, the authors generated another strain of mice in which MECP2 was only mutated in the nervous system. These mice, which had normal heart MECP2, also showed abnormal heart beating and tachycardia, leading to the conclusion that the heart problems were actually secondary to nervous system deficits. A close look at the cardiac cells showed that even when they were removed from mice and grown in culture, an unusual persistent sodium current was apparent. This current decreased in the presence of phenytoin, consistent with its therapeutic action in the MECP2 mutant mice. The authors hypothesize that nervous system abnormalities cause remodeling of the heart in these patients, including elevation of a persistent sodium current, and suggest that sodium channel blockers such as phenytoin be tested as therapeutic agents. Rett syndrome patients often have recurrent seizures, and a similar situation may occur in patients with epilepsy from other causes. The oddly named SUDEP or “sudden unexpected death in epilepsy” is rare, but is thought also to result from frequent heartbeat abnormalities in these patients, which are similar to those in Rett patients. The connection between seizures and long QT intervals may transcend the exact nature of a patient’s disease. 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.