Intermittent hypoxia and vascular function: implications for obstructive sleep apnoea

Obstructive sleep apnoea (OSA) has been implicated as a risk factor for the development of hypertension, stroke and myocardial infarction. The main cause of cardiovascular and cerebrovascular disease in OSA is thought to be exposure to intermittent hypoxia, which can lead to oxidative stress, inflammation, atherosclerosis, endothelial dysfunction and hypertension. These proposed mechanisms have been drawn from basic research in animal and human models of intermittent hypoxia in addition to clinical investigation of patients with OSA. This review outlines the association between OSA and vascular disease, describes basic mechanisms that may be responsible for this association and compares the results from studies of OSA subjects with those in experimental models of intermittent hypoxia.     

Pulmonary haemodynamics in obstructive sleep apnoea

SUMMARY  The time course of right ventricular output (RVO) and transmural pulmonary artery pressure (PAP) changes, detected beat-by-beat, were analysed in a sample of obstructive sleep apnoea (OSA) episodes recorded in six patients with OSA syndrome. RVO showed a trend to a decrease during apnoeas, due to a decrease in heart rate, and decreased further in the immediate post-apnoeic period, due to a decrease in right ventricular stroke volume [post-apnoeic RVO = 82.6 ± 9.3 (SD) % of the value in the immediate pre-apnoeic period; P <0.01]. Both systolic and diastolic transmural PAP showed a progressive increase throughout apnoeas (from 23.7 ± 7.3 to 29 ± 6.9 and from 9.1 ± 4.4 to 14.3 ± 3.3 mmHg, respectively, from early to late apnoeic period; P <0.01), and similarly high values in the late apnoeic and in the immediate post-apnoeic period. Therefore, cardiac output and arterial pressure in the pulmonary circulation undergo simultaneous inverse changes in OSA, similar to what was previously shown in the systemic circulation. Although these data cannot define accurately the behaviour of pulmonary vascular resistance, they suggest that pulmonary vascular resistance could also undergo continuous oscillations in OSA, with recurring peaks detectable between apnoea termination and the immediate post-apnoeic period.     

Circulating adrenomedullin in obstructive sleep apnoea

Adrenomedullin (AM) is a potent endothelial-derived vasodilator secreted under the influence of various stimuli such as hypoxia, shear stress and cytokines. As all of these stimuli might be active under the conditions of obstructive sleep apnoea (OSA), we hypothesized that vascular AM production is increased in these patients. The study included 41 consecutive OSA patients and 28 control subjects without sleep-disordered breathing who were recruited from a pool of patients hospitalized for other reasons. Both groups were matched for anthropometric and comorbid factors. In all patients, i.e. OSA and controls, peripheral venous blood samples were taken at 07:00 hours after diagnostic polysomnography. In subsets of OSA patients, this was repeated after two nights of continuous positive airway pressure (CPAP) therapy (n = 28) and after several months of constant CPAP use (n = 11). The controls and the untreated OSA patients did not have serial blood sampling. In all blood samples, plasma AM levels were measured by an enzyme immunoassay kit. At baseline, the OSA patients had markedly elevated AM concentrations when compared to the controls. There were no differences between normo- and hypertensive OSA patients. After two nights of CPAP therapy, AM levels significantly decreased. Patients on long-term CPAP treatment showed complete normalization of plasma AM concentrations. In conclusion, this pilot study suggests that circulating AM is increased in untreated OSA irrespective of coexistent arterial hypertension and declines after CPAP therapy. AM upregulation might be considered as an adaptive mechanism to counteract the emergence of OSA-related cardiovascular disease.     

Desbuquois syndrome complicated by obstructive sleep apnoea and cervical kyphosis

We present two children with Desbuquois syndrome and characteristic facial appearance, and musculoskeletal and radiological findings. Two new complications of this syndrome are obstructive sleep apnoea and severe cervical kyphosis. © 1994 Wiley-Liss, Inc.     

Prolactin secretion during sleep in obstructive sleep apnoea patients

SUMMARY  Plasma prolactin (PRL) concentration exhibits a sleep-dependent pattern, with highest levels during sleep and lowest levels during the waking period. The syndrome of obstructive sleep apnoea (OSA) is associated with severe hypoxaemia and chronic sleep fragmentation, both of which could affect the sleep-entrained PRL rhythm. Treatment with nasal continuous positive airway pressure (CPAP) immediately restores a normal sleep structure by successful abolition of the apnoeas. In the present study, seven OSA patients underwent two night studies, once when no treatment was given and once during the first night of CPAP treatment. Sleep was recorded polygraphically in all experiments. Plasma PRL was measured at 10 min intervals and secretory rates were calculated by a deconvolution procedure. CPAP treatment greatly reduced hypoxaemia and improved sleep quality. The secretory pulse amplitude and the total amount of PRL secreted during the night remained constant regardless of whether patients were treated or not. The only difference found was a lower pulse frequency in untreated OSA patients as compared to treated patients, which may be attributed either to hypoxaemia or to sleep disturbance or to the combined action of both. Treatment may be considered to normalize PRL release by restoring pulse frequency to values similar to those observed for normal subjects.     

Sympathetic nerve activity in obstructive sleep apnoea

The mechanisms underlying the link between obstructive sleep apnoea (OSA) and cardiovascular disease are not completely established. However, there is increasing evidence that autonomic mechanisms are implicated. A number of studies have consistently shown that patients with OSA have high levels of sympathetic nerve traffic. During sleep, repetitive episodes of hypoxia, hypercapnia and obstructive apnoea act through chemoreceptor reflexes and other mechanisms to increase sympathetic drive. Remarkably, the high sympathetic drive is present even during daytime wakefulness when subjects are breathing normally and no evidence of hypoxia or chemoreflex activation is apparent. Several neural and humoral mechanisms may contribute to maintenance of higher sympathetic activity and blood pressure. These mechanisms include chemoreflex and baroreflex dysfunction, altered cardiovascular variability, vasoconstrictor effects of nocturnal endothelin release and endothelial dysfunction. Long-term continuous positive airway pressure treatment decreases muscle sympathetic nerve activity in OSA patients. The vast majority of OSA patients remain undiagnosed. Unrecognized OSA may contribute, in part, to the metabolic and cardiovascular derangements that are thought to be linked to obesity, and to the association between obesity and cardiovascular risk. Furthermore, acting through sympathetic neural mechanisms, OSA may contribute to or augment elevated levels of blood pressure in a large proportion of the hypertensive patient population.     

Ischaemic stroke, snoring and obstructive sleep apnoea

SUMMARY  Ischaemic stroke occurs most often during the morning hours before noon. In recent studies the peak time of onset has been between 10.00 and 12.00 hours. Snoring every night or almost every night (habitual snoring) is in relation with ischaemic stroke. Snoring occasionally, on the contrary, is not significantly related with stroke. Habitual snoring is the most typical sign of obstructive sleep apnoea syndrome and it is strongly associated with being overweight. Other possible pathophysiological factors that are in relation with habitual snoring, obstructive sleep apnoea and stroke include arterial hypertension, changes in fibrinolytic activity, adult onset diabetes and smoking. It remains to be seen whether nightly occurring partial upper airway obstruction (habitual snoring) with intrathoracic pressure changes is an independent risk factor of ischaemic stroke. There is recent evidence that everything cannot be explained by other known risk factors.     

EEG arousal pattern in habitual snorers with and without obstructive sleep apnoea (OSA)

SUMMARY  This study evaluated the arousal pattern and sleep fragmentation in the sleep microstructure of heavy snorers and obstructive sleep apnoea (OSA) patients. Fifteen snorers [Group A, (A + H I) ≤ 10], 15 mild OSA (Group B, A + H I > 10 ≤ 30] and 15 moderate to severe OSA (Group C, A + H I > 30) were studied retrospectively analysing the number, duration and type of arousals according to scoring rules concerning definition (including delta bursts) and length (from 2 to 60 s) of phasic arousal events. The number of arousals per hour of sleep related to respiratory events was higher in Groups B and C, whilst in Group A there was a number of arousals not related to apnoea or hypopnoea. Daytime sleepiness, present in all three groups and measured by a subjective evaluation, correlated with both the number and EEG type of arousal, but not with the duration. Statistical analysis indicated that arousal index related to apnoea or hypopnoea was the best variable for determining the sleepiness risk in OSA and snorers. Sleep microstructure analysis seems a good scoring method for the detection of sleep fragmentation and arousals in relation to abnormal respiratory events.     

Regulation of plasma volume during obstructive sleep apnoea

SUMMARY  The evidence that plasma volume is altered in obstructive sleep apnoea is an indirect one, based on the observation of a paradoxical elimination of peripheral oedema along with a decrease in water and sodium excretion and of a decrease in haematocrit when apnoeas are eliminated with continuous positive airway pressure (CPAP) treatment. A suggested interpretation of these observations is that in the untreated condition, increased renal sodium excretion and increased vascular membrane permeability lead to increased urine and salt excretion and to a fluid shift from the plasma to the extracellular space, causing nocturnal polyuria, peripheral oedema and haemoconcentration. Treatment with continuous positive airway pressure reverses the increased membrane permeability and urine excretion, allowing the peripheral oedema to resolve and the haematocrit to decrease. Increased atrial natriuretic peptide release and decreased renin-angiotensin-aldosterone activity, along with an increased release of thromboxane and of endothelin (which have been reported in untreated obstructive sleep apnoea), could be the mechanisms of the observed alterations in fluid distribution in obstructive sleep apnoea.     

Cortico-motoneurone excitability in patients with obstructive sleep apnoea

A disordered neuromotor control of pharynx muscles may play a role in the genesis of obstructive sleep apnoea syndrome (OSAS). This raises the possibility of a dysfunction of projections descending from the cortex to segmental nuclei. With single pulse transcranial magnetic stimulation (TMS) we studied the physiology of the corticospinal projection to hand muscles in seven OSAS patients. At first, we compared them with nine age- and sex-matched normal controls in the wake state. The only abnormality was a lengthening of the central silent period (P < 0.001). This supports a steady imbalance of motor cortical interneurone activities towards a state of enhanced inhibition. Then we looked at changes of the motor-evoked potential (MEP) size and latency, according to whether patients were awake, or in a non-rapid eye movement (REM) 2 sleep stage, or during a typical apnoea. During non-REM 2 sleep, the average MEP amplitude was significantly (P < 0.05) smaller than in the awake state. The MEP latency was, in turn, significantly longer (P < 0.05). During apnoeas, the MEP size decreased, and the latency increased further (P < 0.05), indicating an extra depression of the cortico-motoneuronal activity. All TMS changes were detected outside the pharyngeal district, suggesting a widespread dysfunction of the cortico-motoneuronal system in the OSAS, which is more evident during apnoeas.     

Neural drive to human genioglossus in obstructive sleep apnoea

One postulated mechanism for obstructive sleep apnoea (OSA) is insufficient drive to the upper-airway musculature during sleep, with increased (compensatory) drive during wakefulness. This generates more electromyographic activity in upper airway muscles including genioglossus. To understand drives to upper airway muscles, we recorded single motor unit activity from genioglossus in male groups of control ( n = 7, 7 ± 2 events h⁻¹) and severe OSA ( n = 9, 54 ± 4 events h⁻¹) subjects. One hundred and seventy-eight genioglossus units were recorded using monopolar electrodes. Subjects were awake, supine and breathing through a nasal mask. The distribution of the six types of motor unit activity in genioglossus (Inspiratory Phasic, Inspiratory Tonic, Expiratory Phasic, Expiratory Tonic, Tonic and Tonic Other) was identical in both groups. Single unit action potentials in OSA were larger in area (by 34%, P < 0.05) and longer in duration (by 23%, P < 0.05). Inspiratory units were recruited earlier in OSA than control subjects. In control subjects, Inspiratory Tonic units peaked earlier than Inspiratory Phasic units, while in OSA subjects, Inspiratory Tonic and Phasic units peaked simultaneously. Onset frequencies did not differ between groups, but the peak discharge frequency for Inspiratory Phasic units was higher in OSA (22 ± 1 Hz) than control subjects (19 ± 1 Hz, P = 0.003), but conversely, the peak discharge frequency of Inspiratory Tonic units was higher in control subjects (28 ± 1 Hz versus 25 ± 1 Hz, P < 0.05). Increased motor unit action potential area indicates that neurogenic changes have occurred in OSA. In addition, the differences in the timing and firing frequency of the inspiratory classes of genioglossus motor units indicate that the output of the hypoglossal nucleus may have changed.     

Serum proteomic changes in adults with obstructive sleep apnoea

To examine whether differentially expressed proteins are present in the serum of patients with obstructive sleep apnoea (OSA), iTRAQ techniques (isobaric tags for relative and absolute quantification) were employed in a prospective study. Individuals were assigned to either a non‐OSA control group (apnoea–hypopnoea index, AHI <5) or an OSA group (AHI ≥5). Blood samples were collected, aliquoted and frozen at ?80 °C. Protein digestion and tagging with iTRAQ4plex^® and mass spectrometry analysis was then performed (MALDI TOF/TOF). Ten male subjects were included in the control group (age = 45 ± 9.7 years) and 30 male patients in the OSA group (age = 45 ± 10.7 years), the latter being then subdivided into three severity groups. A total of 103 proteins were identified with differential levels between patients with OSA and controls. Of these, 11 proteins were underexpressed and 19 were overexpressed in patients with OSA. C4BPA and thrombospondin were underexpressed in all three OSA severity groups. Among the overexpressed proteins, 13 were overexpressed in the mild OSA group, seven in the moderate group and five in the severe group. Analysis of interactions between the identified proteins revealed that protein alterations in OSA are primarily associated with derangements in lipid and vascular metabolic pathways. This study provides initial evidence that differential protein expression occurs in adults with OSA, and that such proteins change according to disease severity, and appear to primarily involve lipid and vascular metabolic pathways.     

Determinants of subjective sleepiness in suspected obstructive sleep apnoea

Although daytime sleepiness is commonly associated with obstructive sleep apnoea (OSA), the relationship between OSA severity and subjective sleepiness has been documented elusive. This study aimed to identify clinical and polysomnographic determinants of subjective sleepiness among patients suspected of having OSA. A sleep clinic-based sample of 915 patients was interviewed with a structured questionnaire and underwent diagnostic overnight polysomnography. Subjective sleepiness was quantified by Epworth Sleepiness Scale (ESS). Excessive daytime sleepiness (defined as ESS score > 10) was present in 38.8% of patients. In multiple linear regression analysis, respiratory disturbance index [RDI; used to define (whenever RDI was >5) and quantify OSA], depression and diabetes were the most important determinants of ESS score accounting for 17%, 11% and 6% of its variability respectively. Chronic obstructive pulmonary disease (COPD), stroke, heart disease, alcohol use and body mass index were less important determinants of ESS score explaining 1-3% of its variability. In conclusion, OSA should not be considered the sole potential cause of increased subjective sleepiness in patients suspected of having OSA. Primarily depression and diabetes, but also COPD, stroke, heart disease, alcohol use and increased body mass index may contribute to increased subjective sleepiness.     

Early online detection of upper airway obstructions in obstructive sleep apnoea syndrome (OSAS) patients

The obstructive sleep apnoea syndrome (OSAS) is a diagnosis related to snoring and caused by a collapse in the upper airway. OSAS patients suffer from desaturated oxygen levels during sleep as well as daytime sleepiness. In this paper, we propose a system able to identify and detect respiratory disorders online based on monitoring the airflow amplitude from a sleeping OSAS patient. By the use of chi(2)-analysis and a Haar wavelet transform on signals performed offline, reference templates indicating the specific apnoea pattern for four different patients are constructed and used for similarity matching against online signals. Detection is performed in the early stages of an upcoming airway dysfunction, thus providing an opportunity to alert the patient at sleep. The system-testing results indicate robust performance and flexibility for the patient. Our proposed solution can in turn operate as an alternative to today's OSAS treatment of choice, the continuous positive airway pressure (CPAP).     

Early online detection of upper airway obstructions in obstructive sleep apnoea syndrome (OSAS) patients

The obstructive sleep apnoea syndrome (OSAS) is a diagnosis related to snoring and caused by a collapse in the upper airway. OSAS patients suffer from desaturated oxygen levels during sleep as well as daytime sleepiness. In this paper, we propose a system able to identify and detect respiratory disorders online based on monitoring the airflow amplitude from a sleeping OSAS patient. By the use of &#104 2 -analysis and a Haar wavelet transform on signals performed offline, reference templates indicating the specific apnoea pattern for four different patients are constructed and used for similarity matching against online signals. Detection is performed in the early stages of an upcoming airway dysfunction, thus providing an opportunity to alert the patient at sleep. The system-testing results indicate robust performance and flexibility for the patient. Our proposed solution can in turn operate as an alternative to today's OSAS treatment of choice, the continuous positive airway pressure (CPAP).     

Daytime variability of baroreflex function in patients with obstructive sleep apnoea: implications for hypertension

Obstructive events during sleep in patients with obstructive sleep apnoea (OSA) cause large alterations in blood pressure, and this may lead to changes in baroreflex function with implications for long-term blood pressure control. This study examined the daytime variations in the responses to carotid baroreceptor stimulation in OSA patients. We determined the cardiac and vascular responses every 3 h between 09.00 and 21.00 h in 20 patients with OSA, using graded suctions and pressures applied to a neck collar. These responses were plotted against estimated carotid sinus pressures and, from these plots, baroreflex sensitivities and operating points were taken as the maximal slopes and the corresponding carotid sinus pressures, respectively. We found that at 09.00 h, sensitivity for the control of vascular resistance was at its lowest (--1.2 +/- 0.2% mmHg(-1), compared with --1.9 +/- 0.3% mmHg(-1) at 12.00 h, P < 0.02) and operating point for control of mean arterial pressure was at its highest (101.1 +/- 5.8 mmHg, compared with 94.1 +/- 5.8 mmHg at 12.00 h, P < 0.05). This is in contrast to previous data from normal subjects, in whom sensitivity was highest and operating point lowest at 09.00 h. We suggest that the higher baroreflex sensitivity and lower operating point seen in the mornings in normal subjects may provide a protective mechanism against hypertension and that this protection is absent in patients with OSA. It is possible that the reduced reflex sensitivity and increased operating point in the mornings may actually promote hypertension.     

Sleep-related sweating in obstructive sleep apnoea: association with sleep stages and blood pressure

The aim of this study was to investigate sleep-related sweating as a symptom of obstructive sleep apnoea (OSA). Fifteen otherwise healthy male non-smoking patients with untreated moderate-to-severe OSA underwent polysomnography, including measurements of skin and core body temperature and electrodermal activity (EDA) as an objective indicator of sweating. Evening and morning blood pressure was measured as well as catecholamines in nocturnal urine. All measurements were repeated after 3 months on successful continuous positive airway pressure (CPAP) treatment. The untreated OSA subjects had a mean (±SD) apnoea–hypopnoea index of 45.3 ± 3.9 and a mean EDA index during sleep of 131.9 ± 22.4 events per hour. Patients with higher EDA indices had higher systolic blood pressure in the evening and morning ( P  = 0.001 and 0.006) and lower rapid eye movement (REM) sleep percentage ( P  = 0.003). The EDA index decreased significantly to 78.5 ± 17.7 in the patients on CPAP treatment ( P  = 0.04). The decrease correlated with lower evening systolic and diastolic blood pressure ( P  = 0.05 and 0.006) and an increase in REM% ( P  = 0.02). No relationship was observed between EDA and skin or core body temperature, or to catecholamine levels in urine. OSA patients who experience sleep-related sweating may have increased blood pressure and decreased REM sleep compared with other OSA patients. CPAP treatment appears to lower blood pressure and increase REM sleep to a higher extent in these patients compared with other OSA patients.