Cardiac autonomic dysfunction in idiopathic REM sleep behavior disorder.

More than 50% of persons with idiopathic REM sleep behavior disorder (RBD) will develop Parkinson's disease or Lewy body dementia. Symptom screens and metaiodobenzylguanine (MIBG)-scintigraphy suggest autonomic abnormalities in idiopathic RBD, but it is unclear whether autonomic abnormalities can predict neurodegenerative disease. From a cohort of 99 patients with idiopathic RBD, we selected those who developed parkinsonism or dementia. These were matched by age, sex, and follow-up duration to patients with RBD who remained disease free and to matched controls. From the polysomnographic trace performed at baseline evaluation, measures of beat-to-beat RR variability including time domains (mean RR-interval and RR-standard deviation) and frequency domains (low and high frequency components) were retrospectively assessed. Twenty-one patients with idiopathic RBD who developed neurodegenerative disease were included (Parkinson's disease-11, multiple system atrophy-1, and dementia-9). Age at PSG was 66 years, and 86% were male. PSG was performed on average 6.7 years before defined neurodegenerative disease. Comparing all patients with idiopathic RBD to controls, there were significant reductions in RR-standard deviation (24.6 ± 2.2 ms vs. 35.2 ± 3.5 ms, P = 0.006), very low frequency components (238.6 ± 99.6 ms(2) vs. 840.1 ± 188.3 ms(2), P < 0.001), and low frequency components (127.8 ± 26.3 ms(2) vs. 288.7 ± 66.2 ms(2), P = 0.032). However, despite clear differences between patients with idiopathic RBD and controls, there were no differences in any measure between those who did or did not develop disease. RR-variability analysis demonstrates substantial autonomic dysfunction in idiopathic RBD. However, this dysfunction is identical in patients who will or will not develop defined neurodegenerative disease. This suggests that autonomic dysfunction is linked with RBD independent of associated Parkinson's disease or Lewy body dementia.

Nighttime blood pressure in normotensive subjects with chronic insomnia: implications for cardiovascular risk.

OBJECTIVE: 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. DESIGN: Prospective case-control study. SETTING: University hospital-based sleep research laboratory. PARTICIPANTS: Thirteen normotensive subjects with chronic primary insomnia (9 women, 42 +/- 7 y) and 13 sex- and age-matched good sleepers. MEASUREMENTS AND RESULTS: 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 < 0.01) in insomniacs than good sleepers. Insomniacs also had higher activity in EEG beta frequency (P < 0.05). Higher nighttime SBP and smaller SBP dipping were independently associated with increased EEG beta activity (P < 0.05). CONCLUSIONS: Higher nighttime SBP and blunted day-to-night SBP dipping are present in normotensive subjects with chronic insomnia and are associated with a hyperactivity of the central nervous system during sleep. An altered BP profile in insomniacs could be one mechanism implicated in the link between insomnia and cardiovascular morbidity and mortality documented in epidemiological studies.

Cardiac autonomic regulation during sleep in idiopathic REM sleep behavior disorder.

OBJECTIVE: To assess cardiac autonomic and respiratory changes from stage 2 non-rapid eye movement sleep (NREM) to rapid eye movement (REM) sleep in subjects with idiopathic REM sleep behavior disorder (RBD) and controls. We tested the hypothesis that REM-related cardiorespiratory activation is altered in subjects with RBD. DESIGN: Retrospective case-control study. SETTING: University hospital-based sleep research laboratory. PATIENTS: Ten subjects with idiopathic RBD (2 women, mean age 63.4 +/- 6.2 years) and 10 sex- and age-matched controls (mean age 63.9 +/- 6.3 years). INTERVENTION: One-night polysomnography was used to assess R-R variability during NREM and REM sleep. MEASUREMENTS AND RESULTS: Spectral analysis of R-R interval and respiration were performed. Mean R-R interval, low-frequency (LF) and high-frequency (HF) components in both absolute and normalized units (LFnu and HFnu), and the LF/HF ratio were obtained from 5-minute electrocardiogram segments selected during NREM and REM sleep under stable conditions (stable breathing pattern, no microarousals or leg movements). Respiratory frequency was also assessed. Values obtained were then averaged for each stage and analyzed by 2 x 2 analysis of variance with group (RBD subjects and controls) as factor and state (NREM and REM) as repeated measures. RR interval, HF, and HFnu components decreased from NREM to REM in controls but did not change in RBD subjects (Interaction P < 0.05). LFnu (interaction P < 0. 001), LF/HF (interaction P < 0. 001), and respiratory frequency (interaction P < 0. 05) increased from NREM to REM sleep in controls but remained stable in RBD subjects. CONCLUSION: REM-related cardiac and respiratory responses are absent in subjects with idiopathic RBD.

The effect of 2 sympatholytic medications--propranolol and clonidine--on sleep bruxism: experimental randomized controlled studies.

STUDY OBJECTIVE: To examine whether 2 sympatholytic medications decrease sleep bruxism and prevent the rise in sympathetic activity preceding the onset of sleep bruxism: propranolol, a nonselective adrenergic beta-blocker, and clonidine, a selective alpha2-agonist. DESIGN: Experimental randomized controlled crossover studies with placebo and active treatments (propranolol 120 mg; clonidine 0.3 mg). SETTING: Hospital-based sleep research laboratory. PATIENTS: Twenty-five subjects with a history and diagnosis of SLEEP BRUXISM (11 men, 14 women; age range, 21 to 31 years). INTERVENTION: Polygraphic study. MEASUREMENTS AND RESULTS: Polygraphic sleep laboratory recordings were done for 4 nights: the first night was habituation, the second, sleep bruxism diagnosis; and 3 and 4 were study nights. The sleep bruxism index was estimated using masseter muscle activity. Heart rate variability was estimated with spectral analysis of RR intervals. Sleep and sleep bruxism variables were not significantly influenced by propranolol. A reduction of the mean RR intervals and of the sympathetic dominance (p < .05) was seen. Under clonidine, duration of sleep stage 2 was prolonged, whereas REM sleep was suppressed in 14 of 16 subjects with sleep bruxism. The sleep bruxism index was reduced by 61% (p < .05). Under clonidine, a reduction in heart rate and sympathetic dominance was observed in stable sleep and in the minute preceding the onset of sleep bruxism (p < .05). CONCLUSION: Although propranolol did not affect sleep bruxism, clonidine decreased sympathetic tone in the minute preceding the onset of sleep bruxism, thus reducing sleep bruxism by preventing the sequence of autonomic to motor activation of sleep bruxism. This further supports the role of sympathetic activity in the pathophysiology of sleep bruxism. Because morning hypotension was seen in 19% of patients, further dose-dependant research is required to assess the safety of clonidine for the management of sleep bruxism.

Central sleep apnea in left ventricular dysfunction: prevalence and implications for arrhythmic risk.

BACKGROUND: The prevalence and characteristics of sleep-disordered breathing in patients with asymptomatic left ventricular (LV) dysfunction are unknown. Therefore, we evaluated the prevalence of sleep-disordered breathing in patients with LV dysfunction without overt heart failure and tested the hypothesis that sleep-disordered breathing is linked to greater hemodynamic and autonomic impairment. METHODS AND RESULTS: We studied 47 patients with LV ejection fractions or=15/h, was present in 26 patients (55%), 17 (36%) of whom had severe CSA (apnea-hypopnea index >or=30/h). Obstructive sleep apnea was evident in 5 patients (11%). The prevalence and severity of CSA were higher in patients with ischemic cardiomyopathy than in patients with nonischemic cardiomyopathy (P<0.05). Exercise tolerance and echocardiographic indices of systolic and diastolic function were similar in patients without CSA, with mild CSA, and with severe CSA. Heart rate variability was markedly depressed in patients with CSA (P<0.05). Patients with severe CSA also had a higher incidence of nonsustained ventricular tachycardia (P=0.05). CONCLUSIONS: CSA is highly prevalent in patients with asymptomatic LV dysfunction. The severity of CSA may not be related to the severity of hemodynamic impairment. Severe CSA is associated with impaired cardiac autonomic control and with increased cardiac arrhythmias.

Sex-selective QT prolongation during rapid eye movement sleep.

BACKGROUND: We examined the effects of the various sleep stages on RR and QT intervals in healthy subjects and tested the hypothesis that there is a differential effect of sleep stage on QT interval in women compared with men. METHODS AND RESULTS: Eighteen healthy subjects (9 women, age 22 to 45 years) underwent polysomnography and simultaneous recording of ECG, blood pressure, and respiration. RR interval, RR variability, and QT values were measured in stable conditions (no abrupt changes of heart rate or blood pressure, stable breathing pattern) during inactive wakefulness during stages 2 and 3 to 4 of non-REM sleep and during REM sleep. The absolute QT interval was normalized for variations of RR (QTc). In men, RR interval and RR variability increased through all sleep stages. The QTc remained stable from wakefulness through all sleep stages. In women, however, RR interval increased only during non-REM and was virtually identical in wakefulness and in REM. RR variability remained very stable from wakefulness through all stages of sleep. Also, during REM in women, both absolute QT interval and QTc, regardless of the correction maneuver used, increased compared with wakefulness. CONCLUSIONS: The influence of sleep on RR, RR variability, and QTc is sex-dependent. We speculate that these differential sex effects on cardiac rate and repolarization may have important implications for sleep-selected cardiac arrhythmias in women.

Menopause, hormone replacement and RR and QT modulation during sleep.

BACKGROUND AND PURPOSE: Sleep affects the RR interval in electrocardiogram (ECG) recordings and ventricular repolarization differentially in men and women. Compared to men, pre-menopausal women have a more pronounced shortening of RR interval and prolongation of QT and QT corrected (QTc, by Bazett's formula) ECG waves during rapid eye movement (REM) sleep. The aim of the present study was to evaluate sleep-related RR and QT changes: (1) with the physiological decline in female hormones occurring with menopause, and (2) after hormone replacement therapy with estrogen and progesterone (HRT). PATIENTS AND METHODS: We analyzed ECG recordings from 14 post-menopausal women (48-61 years old) who underwent polysomnography before HRT (T1) and after 6 months of HRT (T2) with estrogen and progesterone. Eight of the post-menopausal women (48-54 years) were also compared to eight age-matched pre-menopausal women. In all subjects, mean RR interval, mean QT interval and QTc, were obtained from 1-min recordings selected from wakefulness, stage 2 and REM sleep. RESULTS: Pre-menopausal and post-menopausal women showed similar changes in RR, QT and QTc intervals from wakefulness through sleep. Specifically, in both pre-menopausal and post-menopausal women the RR interval was shorter during REM sleep compared to wakefulness (P=0.009) and stage 2 sleep (P=0.001); the QT interval was more prolonged during stage 2 (P=0.002) and REM (P=0.006); and the QTc interval was significantly prolonged during stage 2 (P=0.01) and REM (P=0.0003) sleep compared to wakefulness. Among post-menopausal women, both before and after HRT (T1 and T2), RR interval shortened significantly during REM compared to wakefulness (P=0.03) and to stage 2 (P=0.002); the absolute QT interval was longer during stage 2, compared to both wakefulness (P<0.001) and REM (P<0.001); the QTc interval was increased during REM sleep compared to wakefulness (P=0.003). CONCLUSIONS: Sleep-related RR and QT changes in women are not altered by menopausal status nor by post-menopausal hormonal replacement with estrogen and progesterone.

Sleep-disordered breathing in heart failure: characteristics and implications.

Sleep-disordered breathing, namely obstructive sleep apnea (OSA) and central sleep apnea (CSA), are both often encountered in the setting of heart failure (HF), and have distinct differences in terms of prevalence, pathophysiology and consequences. OSA is independently associated with an increased risk for cardiovascular disease and for congestive HF in the general population. It is conceivable that this breathing disorder may have particularly deleterious effects in patients with coexisting heart disease, especially in those with a failing heart. There are considerable data addressing the interaction between OSA and the cardiovascular system, which underscore the importance of an early detection of this breathing disorder, especially in patients with HF. CSA is generally considered a consequence rather than a cause of HF, and is correlated with the severity of hemodynamic impairment. However, when present, it is associated with increased arrhythmic risk and higher cardiac mortality. Potential mechanisms implicated in the genesis of this breathing pattern and the possible therapeutic options, which have been proven to be effective in the clinical setting, are discussed.

Blood pressure changes associated with periodic leg movements during sleep in healthy subjects.

BACKGROUND AND OBJECTIVES: Periodic leg movements during sleep (PLMS) are associated with important blood pressure (BP) increases in restless legs syndrome (RLS) patients. These movements also are highly prevalent in the healthy elderly population. The aims of our study were to evaluate if heart rate (HR) and BP changes associated with PLMS are present in healthy subjects with no report of health concerns and to compare the amplitude of cardiovascular changes in healthy subjects to that of RLS subjects. METHODS: Fourteen healthy subjects (six men, eight women; 46.6±9.7 y) and 14 RLS subjects (six men, eight women; 47.6±11.8 y) matched for age and gender participated in our study. Beat-to-beat noninvasive BP was continuously recorded during one night of polysomnography. HR, systolic BP (SBP) and diastolic BP (DBP) were measured for 10 beats before and 15 beats after onset of PLMS with and without microarousals (MA). RESULTS: PLMS were associated with sudden and significant increases of HR, SBP and DBP in both groups; however, cardiovascular increases were more pronounced in RLS subjects than in healthy subjects. CONCLUSIONS: Because PLMS index increases with age in healthy subjects and aging is associated with higher cardiovascular risk, further studies should investigate the impact of PLMS-related BP changes on the development of cardiovascular diseases in healthy elderly populations.

Autonomic response to periodic leg movements during sleep in narcolepsy-cataplexy.

STUDY OBJECTIVES: To test the hypothesis of autonomic nervous system dysfunction in patients with narcolepsy-cataplexy (NC) by assessing the physiologic activations associated with periodic limb movements during sleep (PLMS). DESIGN: Sleep and heart rate (HR) were recorded during 1 night of polysomnography. SETTING: Data were collected at the Sleep Disorders Center, Sacre-Coeur Hospital, Montreal, Canada. PARTICIPANTS: Data from 14 patients with NC (6 men, 8 women, mean age: 52.5 ± 11.9 years) were compared with data from 14 healthy control subjects matched for age and sex. INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: Analyses included sleep stages, PLMS, microarousals, RR intervals converted into beats per minute on segments lasting 25 heartbeats (10 RR intervals before PLMS and 15 after), and cardiac-activation amplitudes. A Group-by-Heartbeat interaction was noted for PLMS without microarousals; the patients had a tachycardia of lower amplitude and a delayed and lower-amplitude bradycardia, compared with normal control subjects. Similar significant HR modifications were observed for PLMS with microarousals between patients with NC and control subjects. Patients with NC had a reduced magnitude of cardiac activation associated with PLMS with and without microarousals, as compared with control subjects. A negative correlation was noted between cardiac-activation amplitude and age in patients with NC, but no correlation with PLMS index was found in either patients with NC or control subjects. CONCLUSION: A significant reduction in the amplitude of PLMS-related HR responses in both tachycardia and bradycardia was found in patients with NC. These findings favor the physiologic relevance of the action of hypocretin on autonomic function that may be of clinical significance, i.e., increasing the risk of cardiovascular diseases.

Sleep deprivation increases blood pressure in healthy normotensive elderly and attenuates the blood pressure response to orthostatic challenge.

STUDY OBJECTIVES: To determine how aging affects the impact of sleep deprivation on blood pressure at rest and under orthostatic challenge. DESIGN: Subjects underwent a night of sleep and 24.5 h of sleep deprivation in a crossover counterbalanced design. SETTING: Sleep laboratory. PARTICIPANTS: Sixteen healthy normotensive men and women: 8 young adults (mean 24 years [SD 3.1], range 20-28 years) and 8 elderly adults (mean 64.1 years [SD 3.4], range 60-69 years). INTERVENTIONS: Sleep deprivation. MEASUREMENTS AND RESULTS: Brachial cuff arterial blood pressure and heart rate were measured in semi-recumbent and upright positions. These measurements were compared across homeostatic sleep pressure conditions and age groups. Sleep deprivation induced a significant increase in systolic and diastolic blood pressure in elderly but not young adults. Moreover, sleep deprivation attenuated the systolic blood pressure orthostatic response in both age groups. CONCLUSIONS: Our results suggest that sleep deprivation alters the regulatory mechanisms of blood pressure and might increase the risk of hypertension in healthy normotensive elderly.

Gender specificity of the slow wave sleep lost in chronic widespread musculoskeletal pain.

OBJECTIVES: The majority of patients suffering from musculoskeletal chronic widespread pain (CWP) are females, and they tend to report poor sleep. We tested the hypothesis that the poor sleep of female patients reporting CWP is gender specific for changes in (1) electroencephalograph (EEG) features and (2) heart rate variability (HRV). METHODS: Twenty-four normal sleepers were compared to 24 patients with CWP who complained of poor sleep. Patients were referred from general practice and were matched for age (41-47 years) and gender (25 W, 23 M). Sleep variables and spectral EEG activity analyses were performed during 1 night of sleep recording. Time-domain cardiac RR interval and spectral autoregressive analyses were also performed from the same data set. RESULTS: Compared to normal females, female patients with CWP had significantly shorter sleep duration (-68 min), lower sleep efficiency (-9.9%), twice the awakenings and a trend for more periodic limb movements per hour of sleep. Daytime napping was reported by 78% of CWPs. Compared to all controls, females with CWP had significantly less power in the EEG delta band in the first and second non-REM sleep cycle. Although RR interval analysis revealed that CWP patients had a faster heart rate, neither the sympathetic nor sympathovagal analysis reached statistical significance for gender or pain status comparisons. CONCLUSIONS: Female CWP patients have shorter sleep duration with many awakenings and lower sleep EEG delta activity without gender difference in HRV.

Gene-specific paradoxical QT responses during rapid eye movement sleep in women with congenital long QT syndrome.

BACKGROUND: Patients with congenital long QT syndrome (LQTS) type 2 (LQT2) may develop arrhythmias during emotional stress, acoustic stimuli, or sleep. Women with LQT2 are more susceptible to fatal arrhythmias than are men. OBJECTIVE: The purpose of this study was to examine the effects of sleep on RR and QT intervals in patients with LQT1, in those with LQT2, and in controls and to test the hypothesis that there is a gene-specific effect of sleep on the QT interval in LQT2 that may be especially evident in women with LQT2. METHODS: Thirty-four subjects with genotyped LQTS and 18 healthy controls were studied. Among the 34 subjects with LQTS, 16 (10 women, age 32 +/- 3 years) had LQT1 and 18 (11 women, age 38 +/- 3 years) had LQT2. Subjects underwent standard polysomnography including ECG recordings. RR, QT, and QTc (Bazett and Fridericia formulas) were measured over recordings obtained during stable conditions during wakefulness, during stage 2 and stages 3-4 of non-rapid eye movement (NREM), and during rapid eye movement (REM) sleep. RESULTS: LQT2 women showed a marked RR decrease and marked QT and QTc increase from NREM to REM sleep, changes that were not observed in either women or men with LQT1 or in men with LQT2. CONCLUSION: Pronounced cardiac activation during REM and substantial QTc prolongation is noted in a sex- and gene-specific fashion among women with LQT2. REM-related changes in cardiac activation and ventricular repolarization may be implicated in sleep-related malignant arrhythmias in women with the LQT2 genotype.

Autonomic cardiovascular regulation in subjects with acute mountain sickness.

The aims of this study were 1) to evaluate whether subjects suffering from acute mountain sickness (AMS) during exposure to high altitude have signs of autonomic dysfunction and 2) to verify whether autonomic variables at low altitude may identify subjects who are prone to develop AMS. Forty-one mountaineers were studied at 4,559-m altitude. AMS was diagnosed using the Lake Louise score, and autonomic cardiovascular function was explored using spectral analysis of R-R interval and blood pressure (BP) variability on 10-min resting recordings. Seventeen subjects (41%) had AMS. Subjects with AMS were older than those without AMS (P < 0.01). At high altitude, the low-frequency (LF) component of systolic BP variability (LF(SBP)) was higher (P = 0.02) and the LF component of R-R variability in normalized units (LF(RR)NU) was lower (P = 0.001) in subjects with AMS. After 3 mo, 21 subjects (43% with AMS) repeated the evaluation at low altitude at rest and in response to a hypoxic gas mixture. LF(RR)NU was similar in the two groups at baseline and during hypoxia at low altitude but increased only in subjects without AMS at high altitude (P < 0.001) and did not change between low and high altitude in subjects with AMS. Conversely, LF(SBP) increased significantly during short-term hypoxia only in subjects with AMS, who also had higher resting BP (P < 0.05) than those without AMS. Autonomic cardiovascular dysfunction accompanies AMS. Marked LF(SBP) response to short-term hypoxia identifies AMS-prone subjects, supporting the potential role of an exaggerated individual chemoreflex vasoconstrictive response to hypoxia in the genesis of AMS.

Arterial baroreflex function and cardiovascular variability: interactions and implications.

The arterial baroreflex contributes importantly to the short-term regulation of blood pressure and cardiovascular variability. A number of factors (including reflex, humoral, behavioral, and environmental) may influence gain and effectiveness of the baroreflex, as well as cardiovascular variability. Many central neural structures are also involved in the regulation of the cardiovascular system and contribute to the integrity of the baroreflex. Consequently, brain injuries or ischemia may induce baroreflex impairment and deranged cardiovascular variability. Baroreflex dysfunction and deranged cardiovascular variability are also common findings in cardiovascular disease. A blunted baroreflex gain and impaired heart rate variability are predictive of poor outcome in patients with heart failure and myocardial infarction and may represent an early index of autonomic activation in left ventricular dysfunction. The mechanisms mediating these relationships are not well understood and may in part be the result of cardiac structural changes and/or altered central neural processing of baroreflex signals.