Neurocardiac dysregulation and neurogenic arrhythmias in a transgenic mouse model of Huntington's disease

Huntington's disease (HD) is a heritable neurodegenerative disorder, with heart disease implicated as one major cause of death. While the responsible mechanism remains unknown, autonomic nervous system (ANS) dysfunction may play a role. We studied the cardiac phenotype in R6/1 transgenic mice at early (3 months old) and advanced (7 months old) stages of HD. While exhibiting a modest reduction in cardiomyocyte diameter, R6/1 mice had preserved baseline cardiac function. Conscious ECG telemetry revealed the absence of 24-h variation of heart rate (HR), and higher HR levels than wild-type littermates in young but not older R6/1 mice. Older R6/1 mice had increased plasma level of noradrenaline (NA), which was associated with reduced cardiac NA content. R6/1 mice also had unstable R-R intervals that were reversed following atropine treatment, suggesting parasympathetic nervous activation, and developed brady- and tachyarrhythmias, including paroxysmal atrial fibrillation and sudden death. c-Fos immunohistochemistry revealed greater numbers of active neurons in ANS-regulatory regions of R6/1 brains. Collectively, R6/1 mice exhibit profound ANS-cardiac dysfunction involving both sympathetic and parasympathetic limbs, that may be related to altered central autonomic pathways and lead to cardiac arrhythmias and sudden death.