Abstract 13399: Mecp2 Deficiency Promotes QTc Prolongation and Lethal Arrhythmias in Mice
Background: Mutations in the methyl-CpG-binding protein (MECP2) gene cause Rett Syndrome (RTT), a progressive X-linked disorder characterized by cognitive impairment, autonomic dysfunction, and sudden death. We hypothesized that Mecp2 deficient mice (KO) have an increased propensity to ventricular arrhythmias due to prolonged QTc interval.
Methods: We assessed QTc interval from ECGs of human RTT patients. We then used KO mice to further evaluate the electrical consequences of Mecp2 deficiency. Baseline cardiac function and structure were evaluated with echocardiography and histology, respectively. Electrophysiological studies were performed using ECG telemetry and intracardiac programmed electrical stimulation (PES).
Results: 18% of human RTT patients (n = 379) had long QTc interval (>450 ms). In WT and KO mice, there were no structural or functional differences at baseline, as assessed by histology and echocardiography. 24 hour ECG telemetry studies showed KO mice have a lower HR (468±9 bpm, n=6) versus WT (553±20 bpm, n=6, p=0.003). KO mice had a longer QTc interval (67.6±1.8 ms, n=12) versus WT (53.7±2.2, n=11, p<0.001) on ECG. On PES, there was an increased incidence of pacing-inducible sustained VT in KO mice (66%, n=12) versus WT (0%, n=11, p=0.001). Two KO mice died from pacing-induced ventricular arrhythmias. Propranolol, the standard anti-arrhythmic therapy in RTT, did not rescue mice from long QTc (n=5, p=0.50) or arrhythmias (n=5, p=1.00), however, phenytoin, a sodium channel blocking anti-arrhythmic drug, completely abolished arrhythmias in KO mice (0%, p<0.001).
Conclusion: Long QTc interval is common in human patients with RTT. Mecp2 deficient mice have long QTc interval and are predisposed to ventricular arrhythmias and arrhythmic death. Phenytoin, but not propranolol, rescues KO mice from arrhythmias, suggesting a role for sodium channel blockade in prevention of arrhythmias in RTT.
- © 2011 by American Heart Association, Inc.