The European Sleep Apnoea Database (ESADA): report from 22 European sleep laboratories.

The European Sleep Apnoea Database (ESADA) reflects a network of 22 sleep disorder centres in Europe enabled by a COST action B26 programme. This ongoing project aims to describe differences in standard clinical care of patients with obstructive sleep apnoea (OSA) and to establish a resource for genetic research in this disorder. Patients with suspected OSA are consecutively included and followed up according to local clinical standards. Anthropometrics, medical history, medication, daytime symptoms and sleep data (polysomnography or cardiorespiratory polygraphy) are recorded in a structured web-based report form. 5,103 patients (1,426 females, mean±sd age 51.8±12.6 yrs, 79.4% with apnoea/hypopnoea index (AHI) ≥5 events·h(-1)) were included from March 15, 2007 to August 1, 2009. Morbid obesity (body mass index ≥35 kg·m(-2)) was present in 21.1% of males and 28.6% of females. Cardiovascular, metabolic and pulmonary comorbidities were frequent (49.1%, 32.9% and 14.2%, respectively). Patients investigated with a polygraphic method had a lower AHI than those undergoing polysomnography (23.2±23.5 versus 29.1±26.3 events·h(-1), p<0.0001). The ESADA is a rapidly growing multicentre patient cohort that enables unique outcome research opportunities and genotyping. The first cross-sectional analysis reveals a high prevalence of cardiovascular and metabolic morbidity in patients investigated for OSA.

Molecular mechanisms of cardiovascular disease in OSAHS: the oxidative stress link.

Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is a highly prevalent breathing disorder in sleep that is an independent risk factor for cardiovascular morbidity and mortality. A large body of evidence, including clinical studies and cell culture and animal models utilising intermittent hypoxia, delineates the central role of oxidative stress in OSAHS as well as in conditions and comorbidities that aggregate with it. Intermittent hypoxia, the hallmark of OSAHS, is implicated in promoting the formation of reactive oxygen species (ROS) and inducing oxidative stress. The ramifications of increased ROS formation are pivotal. ROS can damage biomolecules, alter cellular functions and function as signalling molecules in physiological as well as in pathophysiological conditions. Consequently, they promote inflammation, endothelial dysfunction and cardiovascular morbidity. Oxidative stress is also a crucial component in obesity, sympathetic activation and metabolic disorders such as hypertension, dyslipidaemia and type 2 diabetes/insulin resistance, which aggregate with OSAHS. These conditions and comorbidities could result directly from the oxidative stress that is characteristic of OSAHS or could develop independently. Hence, oxidative stress represents the common underlying link in OSAHS and the conditions and comorbidities that aggregate with it.

Interindividual heterogeneity in the hypoxic regulation of VEGF: significance for the development of the coronary artery collateral circulation.

BACKGROUND: The coronary artery collateral circulation may be beneficial in protecting against myocardial ischemia and necrosis. However, there is a tremendous interindividual variability in the degree of new collateral formation in patients with coronary artery disease. The basis for this interindividual heterogeneity is not understood. In this study we test the hypothesis that failure to generate collateral vessels is associated with a failure to appropriately induce with hypoxia or ischemia the angiogenic factor, vascular endothelial growth factor (VEGF). METHODS AND RESULTS: We correlated the VEGF response to hypoxia in the monocytes harvested from patients with coronary artery disease with the presence of collaterals visualized during routine angiography. We found that there was a highly significant difference in the hypoxic induction of VEGF in patients with no collaterals compared with patients with some collaterals (mean fold induction 1.9+/-0.2 versus 3.2+/-0.3, P<0.0001). After subjecting the data to ANCOVA, using as covariates a number of factors that might influence the amount of collateral formation (ie, age, sex, diabetes, smoking, hypercholesterolemia), patients with no collaterals still have a significantly lower hypoxic induction of VEGF than patients with collaterals. CONCLUSIONS: This study provides evidence in support of the hypothesis that the ability to respond to progressive coronary artery stenosis is strongly associated with the ability to induce VEGF in response to hypoxia. The observed interindividual heterogeneity in this response may be due to environmental, epigenetic, or genetic causes. This interindividual heterogeneity may also help to explain the variable angiogenic responses seen in other conditions such as diabetic retinopathy and solid tumors.

Nocturnal ischemic events in patients with obstructive sleep apnea syndrome and ischemic heart disease: effects of continuous positive air pressure treatment.

OBJECTIVES: To investigate the occurrence of nocturnal ischemic events in patients with obstructive sleep apnea syndrome (OSAS) and ischemic heart disease (IHD). BACKGROUND: Although previous reports documented nocturnal cardiac ischemic events among OSAS patients, the exact association between obstructive apneas and ischemia is not yet clear. It is also not known what differentiates between patients showing nocturnal ischemia and those that do not. METHODS: Fifty-one sleep apnea patients (age 61.3+/-8.3) with IHD participated in the study (after withdrawal of beta-adrenergic blocking agents and anti-anginotic treatment). All patients underwent whole-night polysomnography including ambulatory blood pressure recordings (30 min interval) and continuous Holter monitoring during sleep. A control group of 17 OSAS patients free from IHD were also similarly studied. Fifteen of the 51 patients were also recorded under continuous positive airway pressure (CPAP). RESULTS: Nocturnal ST segment depression occurred in 10 patients (a total of 15 events, 182 min), of whom six also had morning ischemia (06-08 am). Five additional patients had only morning ischemia. No ischemic events occurred in the control group. Age, sleep efficiency, oxygen desaturation, IHD severity and nocturnal-double product (DP) values were the main variables that significantly differentiated between patients who had ischemic events during sleep and those who did not. Nocturnal ischemia predominantly occurred during the rebreathing phase of the obstructive apneas, and it is characterized by increased heart rate (HR) and DP values. Treatment with continuous positive airway pressure significantly ameliorated the nocturnal ST depression time from 78 min to 33 min (p<0.001) as well as the maximal DP values (14,137+/-2,827 vs. 12,083+/-2,933, p<0.001). CONCLUSIONS: Exacerbation of ischemic events during sleep in OSAS may be explained by the combination of increased myocardial oxygen consumption as indicated by increased DP values and decreased oxygen supply due to oxygen desaturation with peak hemodynamic changes during the rebreathing phase of the obstructive apnea. Treatment with CPAP ameliorated the nocturnal ischemia.

Nothing new under the moon. Historical accounts of sleep apnea syndrome.

A systematic review of the 19th-century literature related to sleep disorders revealed that patients with obstructive sleep apnea were vividly described in the second half of the century. Also, there were documented observations on the linkage between airway obstructions and noisy snoring, nocturnal insomnia, and excessive somnolence. The coining of the term "pickwickian" to describe an obese somnolent patient was made in 1889 during a clinical presentation of a patient with sleep apnea. Respiratory failure in sleep because of "failure of the chest and diaphragmatic movements" was defined as a specific sleep disorder by Silas Weir Mitchell in 1890. The two main reasons for overlooking the sleep apnea syndrome for so long have been misdiagnosis of patients with sleep apnea as having narcolepsy and skepticism regarding the validity of excessive somnolence as a clinical sign.

Melatonin: role in gating nocturnal rise in sleep propensity.

The present article reviews the evidence that melatonin possesses sleep-inducing effects and that it gates the increase in nocturnal sleepiness. It is shown that, without exception, all the studies that have investigated daytime administrations of melatonin reported increased sleepiness, even at doses that do not increase plasma levels of melatonin beyond its physiological levels. By contrast, nighttime increase in sleepiness was achieved only after administration of high doses. Based on these findings and on the precise coupling between the endogenous nocturnal increase in melatonin secretion and the opening of the sleep gate, it is suggested that melatonin participates in the regulation of the sleep-wake cycle by inhibiting the central nervous system wakefulness generating system. This inhibition allows a smooth transition from wakefulness to sleep. Clinical findings on decreased levels of nocturnal melatonin in chronic insomniacs, and on the efficacy of exogenous melatonin in improving sleep in melatonin-deficient insomniacs, are congruent with this hypothesis.

The effects of evening bright light on next-day sleep propensity.

The present study investigated the effects of evening bright light (BL) compared to dim light (DL) on next-day sleep propensity as well as the acrophase of oral temperature and mood scores. A total of 12 male subjects (mean age 23.5 +/- 2.6 years) were exposed to 2 h of evening DL or BL 30 min after sunset for 5 consecutive days. The experimental period started after the 5th day of exposure. After light exposure, subjects remained awake in the sleep laboratory until 07:00 h, when they began the 7/13 ultrashort sleep-wake paradigm, which continued for 24 h until 07:00 h the next day. Oral temperature was measured hourly. The results showed that evening exposure to BL, in comparison to DL, significantly delayed the next-day sleep gate as well as the acrophase of the oral temperature curve and the acrophase of negative mood. The effects of BL on the next-day distribution of sleep stages showed an increase of Stage 2 and less REM (rapid eye movement) during the morning. The results indicate that sleep propensity is regulated by a circadian pacemaker that is responsive to evening BL exposure.

The association between the nocturnal sleep gate and nocturnal onset of urinary 6-sulfatoxymelatonin.

The present study investigated the relationship between the time of nocturnal onset of urinary 6-sulfatoxymelatonin (aMT6s) secretion, and the timing of the steepest increase in nocturnal sleepiness ("sleep gate"), as determined by an ultrashort sleep-wake cycle test (7 min sleep, 13 min wake). Twenty-nine men (mean age 23.8 +/- 2.7 years) participated. The ultrashort sleep-wake paradigm started at 0700 hr after a night of sleep deprivation and continued for 24 hr until 0700 hr the next day. Electrophysiological recordings were carried out during the 7-min sleep trials, which were then scored conventionally for sleep stages. Urinary aMT6s was measured every 2 hr. The results showed that the timing of the sleep gate was significantly correlated with the onset of aMT6s secretion. These results are discussed in light of the possible role of melatonin in sleep-wake regulation.

Increased nocturnal melatonin secretion in male patients with hypogonadotropic hypogonadism and delayed puberty.

Hypogonadotropic hypogonadism (IGD) and constitutional delayed puberty (DP) share a common pathophysiologic process, i.e. GnRH deficiency. Both conditions are heterogenous and exhibit different grades of GnRH deficiency. To discern whether these disorders of GnRH deficiency are associated with altered melatonin secretion profiles, we compared untreated young males IGD (n = 7) and DP (n = 7) to normal pubertal male controls (n = 6). Serum samples for melatonin, LH, and prolactin concentrations were obtained every 15 min from 1900 h to 0700 h in a controlled light-dark environment with simultaneous sleep recordings. Mean (+/- SD) darktime nocturnal melatonin levels were significantly higher in IGD (259 +/- 73 pmol/L) and DP (217 +/- 29 pmol/L) compared with 182 +/- 69 pmol/L in controls (P < 0.02). So were the mean (+/- SD) peak melatonin levels (410 +/- 117, 327 +/- 97 and 298 +/- 95 pmol/L in IGD, DP, and controls, respectively (P < 0.05). Integrated nocturnal melatonin secretion values (AUC) were also higher in IGD and DP (168 +/- 45 and 134 +/- 28) compared with 119 +/- 45 pmol/min.1 x 10(3) in controls (P < 0.02). The time of melatonin peak and the time of onset of the nocturnal melatonin rise were observed earlier in IGD and DP. Light-time mean (+/- SD) serum melatonin levels were similar in all three groups. No correlations were found between melatonin and LH levels, nor between melatonin and prolactin levels. These data indicate that melatonin secretion is increased in male patients with GnRH deficiency. The lack of correlations between melatonin and LH suggest that circulating sex steroids, rather than LH, modulate melatonin secretion in a reverse fashion.

Testosterone treatment alters melatonin concentrations in male patients with gonadotropin-releasing hormone deficiency.

Recently, we demonstrated that melatonin secretion is increased in untreated male patients with GnRH deficiency. As testosterone (T) can be aromatized to estradiol (E2), and both T and E2 increase during T enanthate treatment, we were interested in determining whether T treatment (when T and E2 levels were well matched with pubertal control values) has an effect on melatonin levels in these patients. We measured nocturnal serum melatonin levels during the administration of 250 mg testosterone enantale/month for 4 months in 12 male patients with idiopathic hypogonadotropic hypogonadism (IGD; n = 6) and delayed puberty (DP; n = 6). Serum samples for melatonin and LH determinations were obtained every 15 min from 1900-0700 h in a controlled light-dark environment. The results of melatonin profiles were compared with the pretreatment values in each group and with values obtained in six normal pubertal male controls. After 4 months of testosterone treatment, all patients attained normal serum testosterone (19.5 +/- 3.7 in IGD vs. 20.8 +/- 4.1 nmol/L in DP) and E2 levels (83 +/- 12 in IGD vs. 84 +/- 9 pmol/L in DP). Serum LH levels were suppressed in all patients during T treatment (0.12 +/- 0.1 in IGD vs. 0.12 +/- 0.2 IU/L in DP). Before T treatment, patient melatonin levels were greater than those in age-matched pubertal controls. Melatonin levels were equal in patients and controls when T and E2 levels were well matched. Mean (+/- SD) dark-time melatonin levels decreased from 286 +/- 23 to 157 +/- 36 pmol/L in IGD and from 217 +/- 32 to 133 +/- 47 pmol/L in DP (vs. 183 +/- 64 pmol/L in controls). The integrated melatonin values decreased to normal (from 184 +/- 16 to 102 +/- 21 in IGD and from 142 +/- 19 to 90 +/- 26 pmol/min.L x 10(3) in DP vs. 119 +/- 61 pmol/min.L x 10(3) in controls). The intraindividual variations in melatonin levels ranged from 7.2-14.5%. These data indicate that male patients with GnRH deficiency have increased nocturnal melatonin secretion. T treatment decreased melatonin secretion to normal levels. The results suggest that in GnRH-deficient male patients, sex steroids, rather than LH, modulate pineal melatonin in a reverse fashion.

Disruption of the nocturnal testosterone rhythm by sleep fragmentation in normal men.

Recently, we have demonstrated that in normal men the nocturnal testosterone rise antedated the first rapid eye movement (REM) sleep episode by about 90 min and was correlated with REM latency. To further elucidate whether the diurnal testosterone rhythm is a sleep-related phenomenon or controlled by the circadian clock, we determined serum testosterone levels in 10 men during the ultrashort 7/13 sleep-wake cycle paradigm. Using this schedule, subjects experienced partial sleep deprivation and fragmented sleep for a 24-h period. Serum testosterone levels were determined every 20 min between 1900-0700 h with simultaneous sleep recordings during the 7-min sleep attempts. The results were compared with those obtained in men during continuous sleep. Although mean levels and area under the curve of testosterone were similar in both groups, fragmented sleep resulted in a significant delay in testosterone rise (03:24 h +/- 1:13 vs. 22:35 h +/- 0:22). During fragmented sleep, nocturnal testosterone rise was observed only in subjects who showed REM episodes (4/10). Our findings indicate that the sleep-related rise in serum testosterone levels is linked with the appearance of first REM sleep. Fragmented sleep disrupted the testosterone rhythm with a considerable attenuation of the nocturnal rise only in subjects who did not show REM sleep.

Immunohistochemical localization of gonadotropin and gonadal steroid receptors in human pineal glands.

Recently, we demonstrated that melatonin secretion was increased in male patients with GnRH deficiency and decreased to normal levels during testosterone treatment. These data suggested that gonadal steroids modulate melatonin secretion, probably by activating specific receptors in the pineal gland. We used immunohistochemistry to localize gonadotropin (LH and FSH) and gonadal steroid (androgens and estrogens) receptors in human pineal glands. Tissues were obtained at autopsy from 25 males, aged 19-87 yr, and five prepubertal children, aged 0.2-10 yr. Positive staining for all four types of receptors (LH, FSH, androgen, and estrogen) in the pineal parenchymal cells, pinealocytes, was evident in all 30 glands examined. Double staining revealed that nuclear receptors (androgen or estrogen) co-existed with cytoplasmatic receptors (LH or FSH) in the same cells. The results demonstrate the presence of gonadotropin and gonadal steroid receptors in human pinealocytes from infancy to old age.

Plasma parathyroid hormone and calcium are related to sleep stage cycles.

To study dynamic interactions among parathyroid hormone (PTH), plasma calcium, and brain states, seven normal subjects were studied for a total of eight nights in our sleep laboratories. Plasma samples were obtained at 10- to 20-min intervals for PTH and calcium determinations. Electroencephalogram, eye movements, and muscle tone were recorded to determine sleep stages. On each night, several distinct peaks in PTH concentration were seen, which in some cases exceeded the all night mean PTH by as much as 300%. Peaks in plasma PTH were significantly nonrandom and tended to recur about every 100 min. PTH concentration was significantly related to cycles of stages 3 and 4 sleep. Total plasma calcium varied less but was significantly related to cycles of rapid eye movement sleep and to cycles of stage 2 sleep. PTH and calcium were significantly interrelated, especially at high frequencies above 40 cycles/day (1 cycle 36 min). In the 14.4 cycles/day (1 cycle/100 min) frequency range where most PTH and calcium variability was found, however, PTH and calcium were more closely related to sleep stages than to each other. These results suggest that the regulation of PTH and calcium is complex and may involve interactions with neural systems.

Increased sleep motility and respiration rates in combat neurotic patients.

Noctural rates of body movements and respiratory rates were studied in 11 combat neurosis patients and 9 normal controls. Patients had significantly higher rates of body movements in sleep stage 2, and significantly higher respiratory rates in NONREM sleep and in the second REM period than normals. In patients the rates of body movements were positively correlated with sleep efficiency indices. Since some of these patients were suspected of having non-restorative sleep syndrome, it is suggested that increased sleep motility and autonomic activity might be related to this sleep disorder.

Elevated awakening thresholds in sleep stage 3-4 in war-related post-traumatic stress disorder.

Awakening thresholds from sleep stage 3/4 were investigated in 19 DSM-III-defined, war-related post-traumatic stress disorder (PTSD) patients compared with 6 normal controls. Patients had significantly higher awakening thresholds and significantly longer latencies to an arousal response than controls. These results are interpreted to suggest modifications in the depth of sleep as one of the long-term sequelae of traumatic events.

Elevated awaking thresholds during sleep: characteristics of chronic war-related posttraumatic stress disorder patients.

BACKGROUND: Sleep disturbances are one of the hallmarks of posttraumatic stress disorder (PTSD); however, sleep laboratory studies have provided inconsistent evidence of the existence of objective sleep disturbances in PTSD patients. Reports that awaking thresholds from sleep in war-related PTSD patients were significantly elevated compared to normals are discordant with complaints of insomnia. The present study investigated the relationship between awaking threshold from REM sleep in war-related PTSD patients and their dream recall, dream content, and clinical condition. METHODS: After informed consent was obtained from 12 PTSD patients and 12 controls, they were investigated by polysomnographic recordings for 4 nights. Awaking thresholds to clicks were determined during 1 night, and dreams were collected during 2 nights. Patients' symptoms were assessed by the Zung and Beck depression scales, Impact of Events Scale, State and Trait Anxiety, and Symptom Check List questionnaires. RESULTS: Although there were no significant differences between sleep data of patients and controls, PTSD patients had significantly higher awaking thresholds. Awaking thresholds were significantly positively related to depression and anxiety scores. Patients' dreams were significantly more aggressive and hostile, and in 6 patients they included explicit war-related contents. The severity of the clinical picture was significantly related to the dreams' scores of aggression-hostility, and to sleep quality variables. CONCLUSIONS: Elevated awaking thresholds from sleep are a characteristic finding in chronic war-related PTSD patients, which may help to explain the diverse sleep laboratory findings in this syndrome.

Increased motor activity and recurrent manic episodes: predictors of rapid relapse in remitted bipolar disorder patients after lithium discontinuation.

Ten patients with remitted bipolar illness on lithium maintenance therapy underwent placebo-controlled lithium discontinuation. Clinical ratings and recording of sleep-wake activity using wrist-worn actigraphs were carried out before and after lithium discontinuation. Seven patients experienced relapse into mania or hypomania within the first 3 months after lithium discontinuation. Actigraphic recordings revealed that patients who relapsed had higher baseline levels of daytime motor activity than patients without relapse. This may suggest that motor activity can be a sensitive marker of subclinical manic tendencies and early relapse following lithium discontinuation.

Long-term effects of extreme situational stress on sleep and dreaming.

Sleep data were obtained on 11 patients who had survived traumatic events and who complained of sleep disturbances. Each was awakened from REM and non-REM sleep for dream recall. The patients had lower sleep efficiency indices (because of prolonged sleep latency and larger amounts of "awake" plus "movement" time within sleep periods), shorter REM time, and longer REM latencies than did control subjects. Four of the 11 patients had REM- and non-REM-related nightmares, which, in two sea disaster patients, were associated with REM-related motor activity. The rest of the patients had unusually low dream recall in spite of high eye movement density.

Long-term effects of traumatic war-related events on sleep.

Eleven patients who had combat neuroses resulting from the 1973 Yom Kippur War and complained of sleep disturbances were studied in a sleep laboratory. Sleep-onset insomniacs, dream-interruption insomniacs, and pseudoinsomniacs were differentiated on the basis of electrophysiologic recordings. Compared with normal controls who actively participated in the Yom Kippur War, patients showed significantly longer sleep latencies, lower sleep efficiency indices, lower percentage of REM sleep, and longer REM latencies.