Cardiovagal modulation upon postural change is altered in Huntington’s disease

Many patients with Huntington's disease (HD) exhibit disturbances in their daily cycle of sleep and wake as part of their symptoms. These patients have difficulty sleeping at night and staying awake during the day, which has a profound impact on the quality of life of the patients and their care-givers. In the present study, we examined diurnal and circadian rhythms of four models of HD including the BACHD, CAG 140 knock-in and R6/2 CAG 140 and R6/2 CAG 250 lines of mice. The BACHD and both R6/2 lines showed profound circadian phenotypes as measured by wheel-running activity. Focusing on the BACHD line for further analysis, the amplitude of the rhythms in the BACHD mice declined progressively with age. In addition, the circadian regulation of heart rate and body temperature in freely behaving BACHD mice were also disrupted. Furthermore, the distribution of sleep as well as the autonomic regulation of heart rate was disrupted in this HD model. To better understand the mechanistic underpinnings of the circadian disruption, we used electrophysiological tools to record from neurons within the central clock in the suprachiasmatic nucleus (SCN). The BACHD mice exhibit reduced rhythms in spontaneous electrical activity in SCN neurons. Interestingly, the expression of the clock gene PERIOD2 was not altered in the SCN of the BACHD line. Together, this data is consistent with the hypothesis that the HD mutations interfere with the expression of robust circadian rhythms in behavior and physiology. The data raise the possibility that the electrical activity within the central clock itself may be altered in this disease.

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“…Andrich, et al, 2002, Bär, et al, 2008, Kobal, et al, 2004). The telemetry system enabled us to record ECG waveforms ( supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Dysfunctions in circadian behavior and physiology in mouse models of Huntington's disease

Kudo

Schroeder

Loh

et al. 2011

Experimental Neurology

148

164

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“…Nondippers have a higher risk for future cardiovascular events, as well as damage to other organs [23] [24]. Published reports of BP in Huntington’s disease patients do not detect significant differences compared to control groups, however BP measurements were taken during the day when patients are in a more active state, which could mask the higher levels of BP tone [5] [7]. This appears to be the case for HR in BACHD mice, as HR levels are not significantly different between WT and BACHD mice during the active period [16].…”

Section: Discussionmentioning

confidence: 99%

“…In humans, similar studies have been conducted to test the response of the baroreceptor reflex. Results have been mixed, however recent studies report deficits during the Valsalva maneuver, hand-grip test, and the head up tilt test [4] [7] [31] [32]. Furthermore, patients complain of dizziness and light-headedness upon standing, which are symptoms of baroreceptor dysregulation resulting in orthostatic hypotension [6] [8].…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies reported that individuals with Huntington’s disease display aberrant changes in the autonomic nervous system (ANS) that are detected even before the onset of other Huntington’s disease symptoms. Misregulation of both the sympathetic and parasympathetic branches of the ANS have been described, whereby the sympathetic nervous system (SNS) becomes hyperactive in presymptomatic Huntington’s disease patients while the activity of the parasympathetic nervous system (PNS) progressively declines [4] [5] [6] [7] [8] [9]. These types of changes in the ANS are associated with poor prognosis for serious cardiovascular events that many times lead to death [10] [11] [12].…”

Section: Introductionmentioning

confidence: 99%

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Baroreceptor reflex dysfunction in the BACHD mouse model of Huntington’s disease.

et al. 2011

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Huntington’s disease is a progressive, neurodegenerative disorder that presents with a triad of clinical symptoms, which include movement abnormalities, emotional disturbance and cognitive impairment. Recent studies reported dysfunction of the autonomic nervous system in Huntington’s disease patients, which may contribute to the increased incidence of cardiovascular events in this patient population that often leads to death. We measured the baroreceptor reflex, a process dependent on proper autonomic function, in the BACHD mouse model of Huntington’s disease. We found a blunted response of the baroreceptor reflex as well as significantly higher daytime blood pressure in BACHD mice compared to WT controls, which are both indications of autonomic dysfunction. BACHD mice had increased heart weight to tibia length ratios at 7 and 12 mo of age suggesting hypertrophic changes of the heart, which we speculate is a response to the increased blood pressure and aberrant baroreceptor reflex. Despite these structural changes, the hearts of BACHD mice continue to function normally as assessed by echocardiographic analysis. Studies of autonomic and cardiovascular function in BACHD mice may help elucidate the pathophysiology of Huntington’s disease and aid in the development of clinical strategies to offset the incidence of fatal cardiovascular events in the Huntington’s disease patient population.

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“…A further study showed a significant decrease in the parasympathetic heart rate variability values during ‘head-up tilt’ indicating a decreased vagal modulation of heart rate in HD patients. These findings might suggest an over-stimulation of sympathetic activity and might be linked to an increased risk for syncopes and an increased overall cardiovascular risk [17].…”

Section: Introductionmentioning

confidence: 95%

Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease

et al. 2014

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Cardiac remodelling and contractile dysfunction occur during both acute and chronic disease processes including the accumulation of insoluble aggregates of misfolded amyloid proteins that are typical features of Alzheimer's, Parkinson's and Huntington's disease (HD). While HD has been described mainly as a neurological disease, multiple epidemiological studies have shown that HD patients exhibit a high incidence of cardiovascular events leading to heart failure, and that this is the second highest cause of death. Given that huntingtin is ubiquitously expressed, cardiomyocytes may be at risk of an HD-related dysfunction. In mice, the forced expression of an expanded polyQ repeat under the control of a cardiac specific promoter led to severe heart failure followed by reduced lifespan. However the mechanism leading to cardiac dysfunction in the clinical and pre-clinical HD settings remains unknown. To unravel this mechanism, we employed the R6/2 transgenic and HdhQ150 knock-in mouse models of HD. We found that pre-symptomatic animals developed connexin-43 relocation and a significant deregulation of hypertrophic markers and Bdnf transcripts. In the symptomatic animals, pronounced functional changes were visualised by cardiac MRI revealing a contractile dysfunction, which might be a part of dilatated cardiomyopathy (DCM). This was accompanied by the re-expression of foetal genes, apoptotic cardiomyocyte loss and a moderate degree of interstitial fibrosis. To our surprise, we could identify neither mutant HTT aggregates in cardiac tissue nor a HD-specific transcriptional dysregulation, even at the end stage of disease. We postulate that the HD-related cardiomyopathy is caused by altered central autonomic pathways although the pathogenic effects of mutant HTT acting intrinsically in the heart may also be a contributing factor.

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Cardiovagal modulation upon postural change is altered in Huntington’s disease

Cited by 45 publications

References 13 publications

Dysfunctions in circadian behavior and physiology in mouse models of Huntington's disease

Dysfunctions in circadian behavior and physiology in mouse models of Huntington's disease

Baroreceptor reflex dysfunction in the BACHD mouse model of Huntington’s disease.

Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease

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