Abstract 19072: Cardiac Autonomic Dysfunction in Mice Lacking Methyl CpG Binding Protein 2

Abstract

Background: Rett Syndrome (RTT) is an X-linked dominant neurodevelopmental disorder primarily caused by mutations in Methyl-CpG-binding protein ( MECP2 ), a transcriptional regulator. Twenty-five percent of all deaths in RTT are sudden and unexpected, and autonomic nervous system (ANS) dysfunction is hypothesized to be the cause of sudden deaths in RTT. However, the role of MeCP2 in cardiac autonomic function has not been investigated in depth. Design/Methods: Male (2 months) and female (9 months) Mecp2 deficient and wildtype mice were implanted with ETA-F10 telemeters and 24h recordings were taken to calculate heart rate, heart rate variability, and incidence of arrhythmic events. Effects of pharmacological stimulants or inhibitors on heart rate were normalized to saline injection response. Results: Male Mecp2 deficient mice (NULL) have a decreased heart rate (WT = 634 ±3, NULL = 518 ±8, p<0.001), while female deficient mice (NULL/+) do not present with a decreased heart rate. Interestingly, NULL and NULL/+ mice both have a high incidence of sinus pauses and AV block (WT 1/5, NULL 6/6, NULL /+ 4/4, p<0.05). Additionally, both NULL and NULL/+ mice have increased bradycardia events defined as a heart rate below 200 bpm, (WT = 17 ±6, NULL = 307 ±94, NULL/+ = 198 ±67, p<0.05) and an increased heart rate variability. The normalized heart rate response to atropine, a parasympathetic blocker, of NULL mice was above wildtype levels (p<0.05) Chemical denervation by combined antagonism of parasympathetic (atropine) and sympathetic (propranolol) resulted in NULL mice having an increased normalized heart rate response compared to wildtype (p<0.05). Finally, the incidence of AVB/sinus pauses counts per 30 minutes post-acute treatment with atropine and chemical denervation (NULL saline 49 ±10, NULL atropine 8 ±5, NULL atropine/propranolol 0.5 ±0.5 p<0.05) decreased the severity of the cardiac phenotype in NULL mice. Conclusions: In summary, Mecp2 is required for a normal heart rhythm. Loss of Mecp2 causes bradycardia, sinus pauses, AV block, and increased heart rate variability that may be attributed by aberrant innervation. Acute atropine and chemical denervation was therapeutic and ameliorated the cardiac phenotype observed in Mecp2 deficient mice.