Abnormal Sleep-Cardiovascular System Interaction in Narcolepsy with Cataplexy: Effects of Hypocretin Deficiency in Humans (original) (raw)
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Attenuated Heart Rate Response is Associated with Hypocretin Deficiency in Patients with Narcolepsy
Sleep, 2013
Several studies have suggested that hypocretin-1 may influence the cerebral control of the cardiovascular system. We analyzed whether hypocretin-1 deficiency in narcolepsy patients may result in a reduced heart rate response. Design: We analyzed the heart rate response during various sleep stages from a 1-night polysomnography in patients with narcolepsy and healthy controls. The narcolepsy group was subdivided by the presence of +/-cataplexy and +/-hypocretin-1 deficiency. Setting: Sleep laboratory studies conducted from 2001-2011. Participants: In total 67 narcolepsy patients and 22 control subjects were included in the study. Cataplexy was present in 46 patients and hypocretin-1 deficiency in 38 patients. Interventions: None. Measurements and Results: All patients with narcolepsy had a significantly reduced heart rate response associated with arousals and leg movements (P < 0.05). Heart rate response associated with arousals was significantly lower in the hypocretin-1 deficiency and cataplexy groups compared with patients with normal hypocretin-1 levels (P < 0.04) and patients without cataplexy (P < 0.04). Only hypocretin-1 deficiency significantly predicted the heart rate response associated with arousals in both REM and non-REM in a multivariate linear regression. Conclusions: Our results show that autonomic dysfunction is part of the narcoleptic phenotype, and that hypocretin-1 deficiency is the primary predictor of this dysfunction. This finding suggests that the hypocretin system participates in the modulation of cardiovascular function at rest.
2010
Narcolepsy with cataplexy (NC) is a sleep disorder caused by the loss of the hypothalamic neurons producing hypocretin. The clinical hallmarks of the disease are excessive daytime sleepiness, cataplexy, other rapid eye movement (REM) sleep phenomena, and a fragmented wake-sleep cycle. Experimental data suggest that the hypocretin system is involved primarily in the circadian timing of sleep and wakefulness but also in the control of other biological functions such as thermoregulation. The object of this study was to determine the effects of the hypocretin deficit and of the wake-sleep cycle fragmentation on body core temperature (BcT) modulation in a sample of drug-free NC patients under controlled conditions. Ten adult NC patients with low cerebrospinal fluid (CSF) hypocretin levels (9 men; age: 38 ± 12 yrs) were compared with 10 healthy control subjects (7 men; age: 44.9 ± 12 yrs). BcT and sleep-wake cycle were continuously monitored for 44 h from 12:00 h. During the study, subjects were allowed to sleep ad libitum, living in a temperature-and humidity-controlled room, lying in bed except when eating, in a light-dark schedule (dark [D] period: 23:00-07:00 h). Sleep structure was analyzed over the 24-h period, the light (L) and the D periods. The wake-sleep cycle fragmentation was determined by calculating the frame-shift index (number of 30-s sleep stage shifts occurring every 15 min) throughout the 44-h study. The analysis of BcT circadian rhythmicity was performed according to the single cosinor method. The time-course changes in BcT and in frame-shift index were compared between narcoleptics and controls by testing the time × group (controls versus NC subjects) interaction effect. The state-dependent analysis of BcT during D was performed by fitting a mixed model where the factors were wake-sleep phases (wake, NREM stages 1 and 2, slow-wave sleep, and REM sleep) and group. The results showed that NC patients slept significantly more than controls during the 24 h due to a higher representation of any sleep stage ( p < .
Cardiovascular variability as a function of sleep-wake behaviour in narcolepsy with cataplexy
Journal of Sleep Research, 2013
Hypocretin/orexin signalling varies among sleep-wake behaviours, impacts upon cardiovascular autonomic control and is impaired in patients with narcolepsy with cataplexy (NC). However, evidence concerning disturbed cardiovascular autonomic control in NC patients is contrasting, and limited mainly to waking behaviour. We thus investigated whether control of cardiovascular variability is altered in NC patients during wakefulness preceding sleep, light (1-2) and deep (3 -4) stages of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. Polysomnographic recordings and finger blood pressure measurements were performed on nine drug-free male NC patients and nine matched healthy control subjects during spontaneous sleep-wake behaviour in a standardized laboratory environment. Indices of autonomic function were computed based on spontaneous fluctuations of systolic blood pressure (SBP) and heart period (HP). During wakefulness before sleep, NC patients showed significant decreases in indices of vagal HP modulation, cardiac baroreflex sensitivity and amplitude of central autonomic (feed-forward) cardiac control compared with control subjects. During NREM sleep, the negative correlation between HP and subsequent SBP values was greater in NC patients than in control subjects, suggesting a greater contribution of central autonomic commands to cardiac control. Collectively, these results provide preliminary evidence that autonomic control of cardiac variability by baroreflex and central autonomic (feed-forward) mechanisms is altered in NC patients during spontaneous sleep-wake behaviour, and particularly during wakefulness before sleep.
Cardiovascular regulation and cardiovascular diseases: what can sleep teach us?
Journal of Hypertension, 2009
Sleep has always fascinated mankind, influencing arts and literatures. This is not surprising because we spend about one-third of our lives sleeping. For the same reason, sleep has drawn the attention of clinicians and researchers, working in different fields such as psychoanalysis, neurology and lung disease, since many years. More recently, this has occurred also in the field of cardiovascular diseases, with a progressively growing interest in those aspects of cardiovascular physiology and pathology related to sleep, which has led to the defining of sleep as 'a new cardiovascular frontier' [1].
Non-Dipping Blood Pressure Profile in Narcolepsy with Cataplexy
PLoS ONE, 2012
Background: Patients with narcolepsy-cataplexy (NC) mostly exhibit undetectable hypocretin levels. Hypocretin system is one of the key players in the complex interaction between sleep and the cardiovascular system. We tested the hypothesis that hypocretin deficiency affects cardiovascular risk factors by measuring nighttime and daytime ambulatory blood pressure (BP) and the night-today BP ratio as well as endothelial dysfunction by the digital pulse amplitude response in drug-free patients with NC compared to controls. Methodology: Sleep, clinical and biological cardiovascular risk factors, fingertip peripheral arterial tonometry, and 24-hour ambulatory BP monitoring were recorded in 50 drug-free patients with NC and 42 healthy control subjects, except for BP monitoring available in all controls but in 36 patients with NC.
Medical statistics dating to the late 1800s indicate that human mortality does rise rapidly from a low at midnight to 2:00 A.M. to a peak at 6:00 to 8:00 A.M. The neural processes controlling alertness and sleep produce an increased sleep tendency and diminished capacity to function during certain early morning hours (circa 2:00 to 7:00 A..M.) and to a lesser degree during a period in the midaftemoon (circa 2:00 to 5:00 P.M.). Sleep and sleep-related processes can be linked to the timing of drops in human functioning ranging from automobile-driver error to disease-related mortality. The role of sleep-related processes in upper airways resistance, hypertension, and myocardial infarction is discussed. Given the evidence that as many as 189'6 of people over the age of 65 have sleep apnea, sleep-related cardiopulmonary abnormalities may contribute significantly to the early morning peak in cardiac deaths. A syndrome of nocturnal periodic breathing with apnea (NPBA) is described in patients with severe cardiomyopathy. illustrative cases are presented.
American Journal of Hypertension, 2015
BACKGROUND Many cardiovascular disease events occur before morning awaking and are more severe in hypertensive patients. Sleep-related cardiovascular regulation has been suggested to play an important role in the pathogenesis. In this study, we explored whether such impairments are exaggerated during late sleep (before the active phase) in spontaneously hypertensive rats (SHRs). METHODS Polysomnographic recording was performed through wireless transmission in freely moving SHRs and Wistar-Kyoto rats (WKYs) over 24 hours. The SHRs were injected with saline and an α1-adrenergic antagonist (prazosin: 5 mg/kg) on 2 separate days. Cardiovascular and autonomic functions were assessed by cardiovascular variability and spontaneous baroreflex analysis. RESULTS Compared with the early-light period (Zeitgeber time (ZT) 0-6 hours), both the WKYs and SHRs during the late-light period (ZT 6-12 hours) showed sleep fragmentation, sympathovagal imbalance, and baroreflex impairment, which were exaggerated and more advanced in the SHRs. Like the morning blood pressure (BP) surge in humans, we found that there was a wake-related blood pressure surge (WBPS) during the late-light period in both groups of rats. The WBPS was also greater and occurred earlier in the SHRs, and was accompanied by a surge in vascular sympathetic index. Under α1-adrenergic antagonism, the late-light periodrelated sleep fragmentation and BP surge in the SHRs were partially reversed. CONCLUSIONS Our results reveal that sleep-related sympathetic overactivity, baroreflex sensitivity impairment, WBPS, and sleep fragmentation in SHRs deteriorates during the late-light period can be partially alleviated by treatment with an α1-adrenoceptor antagonist.
Sleep, 2009
To assess as whether insomniacs have higher nighttime blood pressure (BP) and a blunted day-to-night BP reduction, recognized markers of increased risk of cardiovascular morbidity and mortality. Prospective case-control study. University hospital-based sleep research laboratory. Thirteen normotensive subjects with chronic primary insomnia (9 women, 42 +/- 7 y) and 13 sex- and age-matched good sleepers. Subjects underwent 2-week sleep diary and 3 sleep studies to provide subjective and objective sleep variables, and 24-h beat-to-beat BP recording to provide daytime, night-time and day-to-night BP changes ([nighttime-daytime]/daytime)*100) (BP dipping). Spectral analysis of the electroencephalogram (EEG) was also performed during sleep of night 3 to assess EEG activity in the beta frequency (16-32 Hz), a measure of brain cortical activation. Nighttime SBP was higher (111 +/- 15 vs 102 +/- 12 mm Hg, P < 0.01) and day-to-night SBP dipping was lower (-8% +/- 6% vs -15% +/- 5%, P < ...
Blood Pressure Rhythms in Sleep Disorders and Dysautonomia
Annals of the New York Academy of Sciences, 1996
With the developments in polysomnographic techniques, sleep can be monitored during the night or throughout the whole nycthemeral cycle. This has led to remarkable advances in our understanding of mechanisms controlling blood pressure (BP), heart rate (HR), breathing, temperature, and the motor system. This paper summarizes the pattern of BP changes during wakefulness and sleep in normal subjects, in sleep-related breathing disorders, and in neurodegenerative diseases with dysautonomia.
Hypocretins: the timing of sleep and waking
Chronobiology International, 2006
The appropriate time and place for sleep and waking are important factors for survival. Sleep and waking, rest and activity, flight and fight, feeding, and reproduction are all organized in relation to the day and night. A biological clock, the suprachiasmatic nucleus (SCN), synchronized by photic influences and other environmental cues, provides an endogenous timing signal that entrains circadian body rhythms and is complemented by a homeostatic sleep pressure factor. Cholinergic, catecholaminergic, serotonergic, and histaminergic nuclei control wakefulness and mutually interact with the SCN as well as sleep-and wake-promoting neurons in the hypothalamus to form a bistable switch that controlls the timing of behavioral state transitions. Hypocretin neurons integrate circadian-photic and nutritional-metabolic influences and act as a conductor in the aminergic orchestra. Their loss causes narcolepsy, a disease conferring the inability to separate sleep and waking. Their role in appetitive behavior, stress, and memory functions is important to our understanding of addiction and compulsion.