HEART RATE VARIABILITY ANALYSIS REVEALS ALTERED AUTONOMIC TONE IN A MOUSE MODEL OF DRAVET SYNDROME
Authors: D. S. Auerbach, B. C. Clawson, I. Ogiwara, K. Yamakawa, M. Meisler, J. Parent, L. Isom
Dravet Syndrome (DS) is a very severe and intractable genetic epilepsy with a high incidence of SUDEP: Sudden Unexpected Death in Epilepsy. Cardiac arrhythmias are a proposed cause of SUDEP. We recently demonstrated severe cardiac electrophysiological abnormalities with hallmarks of Long QT Syndrome 3 in a mouse model of DS, which culminated in ventricular fibrillation and sudden cardiac death. Also, mice exhibited idioventricular rhythms and beat to beat sinus variability. DS mice also showed increased persistent INa in ventricular cardiomyocytes providing a substrate for arrhythmia initiation. We sought to determine whether alterations in the autonomic nervous system provide an additional substrate for arrhythmogenesis.
Radiotelemetry ECG recordings were acquired from juvenile mice with a heterozygous knockin DS loss of function mutation in Scn1a (R1407X). To provide enough time for recovery from surgery and the redevelopment of circadian cycling in heart rate, activity, and temperature, all analyses were conducted 18+ days post implantation for a duration of 11-17 days. During sinus rhythm, both time and frequency (fast fourier transformation and autogregressive) domain analyses were performed in WT and DS mice to test for alterated total autonomic tone, as well as changes in sympathetic and parasympathetic tone.
Time and frequency domain analyses revealed no change in total autonomic tone in WT vs. DS mice at periods of either maximum or minimum heart rates. Despite a lack of change in the total frequency power (global autonomic tone), DS mice exhibited reduced contribution of sympathetic tone (low frequency domain, LF), and an increase in parasympathetic tone (high frequency domain, HF), particularly at times of maximum heart rate (p<0.02 WT vs. DS for both LF and HF).
Heart rate variability analysis reveals that DS mice have altered autonomic tone, with an increased contribution of parasympathetic tone. This study highlights the multifaceted DS cardiac pathophysiology, and suggests novel therapeutic strategies for interventions to reduce SUDEP. Supported by grants NIH-NS076752 (to LLI), NIH-NS076916 (to JMP), the University of Michigan Center for Organogenesis (to LLI), Citizens United for Research in Epilepsy Foundation (to JMP) and the Dravet Syndrome Foundation (to JMP and MHM). DSA was supported by NIH T32HL007853 to the University of Michigan Cardiovascular Center and a Postdoctoral Fellowship from the Epilepsy Foundation. No disclosures or conflicts of interest.
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