Jean-Louis Pepin

14 nights of intermittent hypoxia elevate daytime blood pressure and sympathetic activity in healthy humans

Obstructive sleep apnoea syndrome (OSAS) causes nocturnal chronic intermittent hypoxia (IH) that contributes to excess cardiovascular morbidity. To explore the consequences of IH, we used our recently developed model of nocturnal IH in healthy humans to characterise the profile of this blood pressure increase, to determine if it is sustained and to explore potential physiological mechanisms. We performed 24-h ambulatory monitoring of blood pressure in 12 healthy subjects before and after 2 weeks of IH exposure. We also assessed systemic haemodynamics, muscle sympathetic nerve activity (MSNA), ischaemic calf blood flow responses and baroreflex gain. We obtained blood samples for inflammatory markers before, during and after exposure. IH significantly increased daytime ambulatory blood pressure after a single night of exposure (3 mmHg for mean and diastolic) and further increased daytime pressures after 2 weeks of exposure (8 mmHg systolic and 5 mmHg diastolic). Mean±sd MSNA increased across the exposure (17.2±5.1 versus 21.7±7.3 bursts·min−1; p<0.01) and baroreflex control of sympathetic outflow declined from -965.3±375.1 to -598.4±162.6 AIU·min−1·mmHg−1 (p<0.01). There were no evident changes in either vascular reactivity or systemic inflammatory markers. These data are the first to show that the arterial pressure rise is sustained throughout the waking hours beyond the acute phase immediately after exposure. Moreover, they may suggest that sympathoactivation induced by IH likely contributes to blood pressure elevation and may derive from reduced baroreflex inhibition. These mechanisms may reflect those underlying the blood pressure elevation associated with OSAS.

Intermittent hypoxia and sleep-disordered breathing: current concepts and perspectives

There are three major types of sleep-disordered breathing (SDB) with respect to prevalence and health consequences, i.e. obstructive sleep apnoea syndrome (OSAS), Cheyne–Stokes respiration and central sleep apnoea (CSR-CSA) in chronic heart failure, and obesity hypoventilation syndrome (OHS). In all three conditions, hypoxia appears to affect body functioning in different ways. Most of the molecular and cellular mechanisms that occur in response to SDB-related hypoxia remain unknown. In OSAS, an inflammatory cascade mainly dependent upon intermittent hypoxia has been described. There is a strong interaction between haemodynamic and inflammatory changes in promoting vascular remodelling. Moreover, during OSAS, most organ, tissue or functional impairment is related to the severity of nocturnal hypoxia. CSR-CSA occurring during heart failure is primarily a consequence of cardiac impairment. CSR-CSA has deleterious consequences for cardiac prognosis and mortality since it favours sympathetic activation, ventricular ectopy and atrial fibrillation. Although correction of CSR-CSA seems to be critical, there is a need to establish therapy guidelines in large randomised controlled trials. Finally, OHS is a growing health concern, owing to the worldwide obesity epidemic and OHS morbidities. The pathophysiology of OHS remains largely unknown. However, resistance to leptin, obesity and severe nocturnal hypoxia lead to insulin resistance and endothelial dysfunction. In addition, several adipokines may be triggered by hypoxia and explain, at least in part, OHS morbidity and mortality. Overall, chronic intermittent hypoxia appears to have specific genomic effects that differ notably from continuous hypoxia. Further research is required to fully elucidate the molecular and cellular mechanisms.

Relationship between body mass index, age and upper airway measurements in snorers and sleep apnoea patients

Anatomical pharyngeal and craniofacial abnormalities have been reported using upper airway imaging in snorers with or without obstructive sleep apnoea (OSA). However, the influences of the age and weight of the patient on these abnormalities remain to be established. The aim of this study was, therefore, to evaluate in a large population of snorers with or without OSA, the relationship between body mass index (BMI), age and upper airway morphology. One hundred and forty patients were referred for assessment of a possible sleep-related breathing disorder and had complete polysomnography, cephalometry and upper airway computed tomography. For the whole population, OSA patients had more upper airway abnormalities than snorers. When subdivided for BMI and age, however, only lean or younger OSA patients were significantly different from snorers as regards their upper airway anatomy. The shape of the oropharynx and hypopharynx changed significantly with BMI both in OSA patients and snorers, being more spherical in the highest BMI group due mainly to a decrease in the transverse axis. On the other hand, older patients (> 63 yrs), whether snorers or apnoeics, had larger upper airways at all pharyngeal levels than the youngest group of patients (< 52 yrs). For the total group of patients, upper airway variables explained 26% of the variance in apnoea/hypopnoea index (AHI), whereas in lean (BMI < 27 kg.m-2) or youngest (age < 52 yrs) subjects upper airway variables explained, respectively 69 and 55% of the variance in AHI. In conclusion, in lean or young subjects, upper airway abnormalities explain a major part of the variance in apnoea/hypopnoea index and are likely to play an important physiopathogenic role. This study also suggests that the shape of the pharyngeal lumen in awake subjects is more dependent on body mass index than on the presence of obstructive sleep apnoea. Further investigation looking at upper airway imaging for surgical selection in obstructive sleep apnoea should focus on lean and young patients.

Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese.

BACKGROUND & AIMS Morbid obesity is frequently associated with low grade systemic inflammation, increased macrophage accumulation in adipose tissue (AT), obstructive sleep apnea (OSA), and nonalcoholic fatty liver disease (NAFLD). It has been suggested that chronic intermittent hypoxia (CIH) resulting from OSA could be an independent factor for early stage of NAFLD in addition to other well-recognized factors (dyslipidemia or insulin resistance). Moreover, macrophage accumulation in AT is associated with local hypoxia in fat tissue. We hypothesized that the association between CIH and morbid obesity could exert additional specific deleterious effects both in the liver and adipose tissues. METHODS One hundred and one morbidly obese subjects were prospectively recruited and underwent bariatric surgery during which a liver needle biopsy as well as surgical subcutaneous and omental AT biopsies were obtained. Oxygen desaturation index (ODI) quantified the severity of nocturnal CIH. RESULTS Histopathologic analysis of liver biopsies demonstrated that NAFLD lesions (ballooning of hepatocytes, lobular inflammation), NAFLD activity score (NAS), and fibrosis were significantly more severe in patients with the highest ODI tertile (p values ≤0.001 for all hepatic lesions). In multivariate analysis, after adjustment for age, obesity, and insulin resistance status, CIH remained independently associated with hepatic fibrosis, fibroinflammation, and NAS. By contrast, no association was found between CIH, macrophage accumulation, and adipocytes size in both subcutaneous and omental adipose tissue. CONCLUSIONS In morbidly obese patients, CIH was strongly associated with more severe liver injuries but did not worsen obesity induced macrophage accumulation in adipose tissue depots.

Most obstructive sleep apnoea patients exhibit vigilance and attention deficits on an extended battery of tests

Excessive daytime sleepiness, fatigue and altered attention are often experienced by obstructive sleep apnoea (OSA) patients. Although attentional problems are presumably responsible for part of the daytime functioning impairment in OSA, thorough investigation is unusual. Clinicians usually attribute these symptoms to somnolence. In clinical practice, only one isolated test is generally used to assess vigilance and attentional defects. It was hypothesised that most OSA patients exhibit a broad range of attentional deficits, beyond impaired maintenance of wakefulness, and a specific battery of tests is needed to correctly assess them. Three attentional tests were performed at 9:00, 11:00 and 13:30 h, measuring maintenance of wakefulness, sustained attention and divided attention. Twenty OSA patients (aged 51±12 yrs, apnoea/hypopnoea index 45±22 h) and 40 control subjects (aged 48.4±9.9 yrs) were tested. OSA patients performed significantly less well on the three tests than the controls at the three sessions. This battery of tests demonstrated that 95% of patients had vigilance and/or attentional impairment. Impairment patterns varied between patients. Vigilance is impaired in obstructive sleep apnoea patients over a wide range of attentional processes. Not only is their ability to remain awake in monotonous situations impaired but their ability to maintain attention in more stimulating conditions is also affected. A single test of vigilance is not sufficient and could underestimate impaired vigilance and attention in some patients.

Overdrive atrial pacing does not improve obstructive sleep apnoea syndrome

The aim of this study was to assess the ability of overdrive atrial pacing to reduce sleep apnoea severity. A total of 17 unselected patients (12 males; mean±sd age 71±10 yrs; body mass index 27±3 kg·m−2) who had received permanent atrial-synchronous ventricular pacemakers for symptomatic bradyarrhythmias and not known to have central or obstructive sleep apnoea syndrome (OSAS) were studied. Using a crossover study design, patients were or were not in pacing mode with atrial overdrive (15 beats·min−1 faster than mean baseline nocturnal cardiac frequency) for 1 month. Patients were paced only during sleep periods, identified by a specific algorithm included in the pacemaker. Patients underwent three overnight polysomnographic evaluations 1 month apart. The first was performed for baseline evaluation. The patients were then randomly assigned to either 1 night in spontaneous rhythm or to 1 night in pacing mode with atrial overdrive. Two patients refused to continue the study after the first polysomnographic evaluation. OSAS was highly prevalent in this population: 10 of the 15 (67%) patients exhibited an apnoea–hypopnoea index of >30 events·h−1. The nocturnal spontaneous rhythm was 59±7 beats·min−1 at baseline, compared to 75±10 beats·min−1 with atrial overdrive pacing. The apnoea–hypopnoea index was 46±29 events·h−1 in spontaneous rhythm, compared to 50±24 events·h−1 with atrial overdrive pacing. Overdrive pacing changed none of the respiratory indices, or sleep fragmentation or sleep structure parameters. In conclusion, atrial overdrive pacing has no significant effect on obstructive sleep apnoea.

Somnofluoroscopy, computed tomography, and cephalometry in the assessment of the airway in obstructive sleep apnoea.

BACKGROUND: Assessments of the upper airways in patients with the obstructive sleep apnoea syndrome are usually carried out on awake patients who are upright. The dynamics of the airway in a patient who is asleep and lying down may be different. METHODS: Somnofluoroscopy, computed tomography of the upper airway, and cephalometry were carried out in 11 patients with the obstructive sleep apnoea syndrome (10 male; mean (SD) age 53 (10) years) to examine the airway while they were awake and asleep. RESULTS: At somnofluoroscopy 10 patients were in stage 2 sleep and only one in REM sleep. At least five obstructive events were visualised by lateral fluoroscopy in each patient. Imaging allowed observation of the dynamics of airway collapse, which began in the oropharynx in all cases, progressing to the hypopharynx in 10 cases and to the laryngopharynx in five. At fluoroscopy the soft palate was seen to hook up during airway occlusion in 10 patients, thereby increasing its cross sectional area. It was then sucked down into the hypopharynx. Somnofluoroscopic and cephalometric findings agreed, eight of the 10 patients with hypopharyngeal collapse shown by somnofluoroscopy having an inferiorly placed hyoid bone according to cephalometry (distance from the mandibular plane to the hyoid bone (MP-H distance) increased); the one patient with no hypopharyngeal collapse had a normal MP-H. By contrast, six of the 11 patients had a normal or supranormal hypopharyngeal cross sectional area of the airway on the computed tomogram. CONCLUSIONS: Somnofluoroscopy allows examination of the dynamics of airway closure in this disorder and shows the important role of the soft palate in acting as a plug in the oropharynx. Dynamic studies are required to determine the pattern of pharyngeal obstruction in obstructive sleep apnoea.

Hypertension and sleep: overview of a tight relationship.

Autonomic cardiovascular control changes across sleep stages. Thus, blood pressure (BP), heart rate and peripheral vascular resistance progressively decrease in non-rapid eye movement sleep. Any deterioration in sleep quality or quantity may be associated with an increase in nocturnal BP which could participate in the development or poor control of hypertension. In the present report, sleep problems/disorders, which impact either the quality or quantity of sleep, are reviewed for their interaction with BP regulation and their potential association with prevalent or incident hypertension. Obstructive sleep apnea syndrome, sleep duration/deprivation, insomnia, restless legs syndrome and narcolepsy are successively reviewed. Obstructive sleep apnea is clearly associated with the development of hypertension that is only slightly reduced by continuous positive airway pressure treatment. Shorter and longer sleep durations are associated with prevalent or incident hypertension but age, gender, environmental exposures and ethnic differences are clear confounders. Insomnia with objective short sleep duration, restless legs syndrome and narcolepsy may impact BP control, needing additional studies to establish their impact in the development of permanent hypertension. Addressing sleep disorders or sleep habits seems a relevant issue when considering the risk of developing hypertension or the control of pre-existent hypertension. Combined sleep problems may have potential synergistic deleterious effects.

Simultaneous laboratory-based comparison of ResMed Autoset with polysomnography in the diagnosis of sleep apnoea/hypopnoea syndrome

ResMed Autoset (AS) is a simplified diagnosis system for obstructive sleep apnoea/hypopnoea syndrome (OSAS) based on the respiratory flow/time relationship by pressure variation measured through simple nasal prongs. A multicentre prospective trial was used to compare AS and polysomnography (PSG) for diagnosing 95 patients, with suspected OSAS. Physicians gave a pretest probability of the patient having OSAS. The apnoea/hypopnoea index (AHI) was compared between the two methods of diagnosis for the whole population and for subgroups according to the pretest probability. Twenty-four patients had AHI < 15 events x h(-1) on PSG and 19 AHI 15-30, and 52 patients had AHI > or = 30. Correlation between AHI assessed by AS and PSG was r=0.87 for total sleep time (TST), p<0.0001. A Bland and Altman plot gave an agreement between the two methods of +/-40%. For a threshold of AHI > or = 15 events x h(-1) to diagnose OSAS, AS has a sensitivity of 92%, specificity of 79%, positive predictive value of 93% and negative predictive value of 76%. With a pretest probability > or = 80%, sensitivity and positive predictive value were 98 and 100% respectively. Of six false negative, four had a high pretest probability (> 80%) or Epworth score > or = 10. Using these parameters as a criterion for proceeding to PSG after a negative AS study would mean that two apnoeic patients (AHI 20 and 17 events x h(-1) by PSG) would escape detection. The Autoset is useful for the detection of obstructive sleep apnoea but with high pretest probability and a negative Autoset result polysomnography should be performed.

Impairment of serum albumin antioxidant properties in obstructive sleep apnoea syndrome.

Antioxidant counteraction of oxidative stress has been poorly explored in obstructive sleep apnoea (OSA). Serum albumin is a major antioxidant agent and structural modifications induced by glucose or free radicals impair its antioxidant properties. The aim of the present study was to compare antioxidant capacities and structural changes of albumin in nonobese OSA patients and healthy volunteers. Albumin structural changes were studied by quenching of fluorescence in the presence of acrylamide. Albumin thiols and fructosamines, reflecting oxidation- and glycation-induced changes in serum albumin, respectively, were assessed. Albumin structural changes were demonstrated by a significant decrease in quenching of fluorescence in OSA patients. Oxidation, resulting in a significant decrease in thiol groups (3.7±0.7 versus 2.3±0.4 μmol·g−1 protein), and glycation, associated with a significant increase in fructosamines (226.6±27 versus 286±44.4 μmol·L−1), were found when comparing healthy volunteers with OSA patients. There was a significant relationship between both parameters and sleep apnoea severity. After continuous positive airway pressure intervention, albumin thiol groups were reassessed in seven of the 16 OSA patients and increased significantly from 2.25±0.39 to 2.79±0.31 µmol·g−1 protein. Obstructive sleep apnoea patients demonstrated a reduction in serum albumin antioxidant properties that may aggravate oxidative stress and, thus, contribute to cardiovascular and metabolic morbidities.