The effect of sibutramine-assisted weight loss in men with obstructive sleep apnoea.

OBJECTIVE: Obstructive sleep apnoea (OSA) occurs frequently in obese patients and may be reversible with weight loss. Obstructive sleep apnoea and obesity are both independent risk factors for hypertension and increased sympathetic activity. Sibutramine has been increasingly used in the management of obesity, but is relatively contraindicated in patients with hypertension. No studies have investigated the effect of sibutramine on OSA, blood pressure and heart rate. We aimed to assess the changes in OSA and cardiovascular parameters in obese men with OSA enrolled in a sibutramine-assisted weight loss programme (SIB-WL). DESIGN: Open uncontrolled cohort study of obese male subjects with OSA in an SIB-WL. SUBJECTS: Eighty-seven obese (body mass index =34.2+/-2.8 kg/m(2)) middle-aged (46.3+/-9.3 years) male subjects with symptomatic OSA (Epworth score 13.4+/-3.6; respiratory disturbance index (RDI) 46.0+/-23.1 events/h) completed the study. RESULTS: At 6 months, there was significant weight loss (8.3+/-4.7 kg, P<0.0001), as well as a reduction in waist and neck circumference and sagittal height (all P<0.0001). These changes were accompanied by a reduction in OSA severity (RDI fell by 16.3+/-19.4 events/h and Epworth score by 4.5+/-4.6), both P<0.0001). There was no significant change to systolic (P=0.07) or diastolic blood pressure (P=0.87); however, there was a mild rise in resting heart rate (P<0.0001). CONCLUSION: Moderate (approximately 10%) weight loss with SIB-WL results in improvement in OSA severity without increase in blood pressure in closely monitored OSA subjects.

Depressed baroreflex sensitivity in patients with obstructive sleep apnea.

Muscle nerve sympathetic activity (MSA), the interval between two R-waves in the ECG, or the interbeat interval (RR-interval), and blood pressure (BP) were recorded in 10 awake patients with obstructive sleep apnea (OSA) and in nine sex- and age-matched controls. Changes in RR-interval and MSA, evoked by sodium nitroprusside-induced reduction of BP, were used to quantitate baroreflex sensitivity. Both the cardiac (expressed as the RR-interval versus mean arterial BP slope) and the muscle sympathetic (mean MSA area versus diastolic BP slope) baroreflex sensitivity were depressed in patients as compared with controls. Cardiac baroreflex slope sensitivity (expressed as a regression coefficient) was 5.5 +/- 1.2 (mean +/- SEM) in patients and 9.6 +/- 0.96 in controls (p < 0.05). The corresponding figures for the sympathetic slope sensitivity were -4.9 +/- 0.9 and -13.1 +/- 2.3, respectively (p < 0.05). Differences remained after stepwise correction for age, body mass index (BMI), and to some extent BP. Resting MSA correlated with cardiac (r = 0.67, p < 0.003) and sympathetic (r = 0.56, p < 0.025) baroreflex sensitivity in the entire study group. We conclude that OSA patients exhibit an impaired baroreflex sensitivity to a hypotensive stimulus, which may represent an adaptive response to changes in BP or hypoxemia occurring in association with nocturnal apneas. Baroreflex adaptation may also contribute to the augmentation of resting MSA observed in OSA patients in this as well as in a previous study.

Attenuated endothelium-dependent vascular relaxation in patients with sleep apnoea.

OBJECTIVE: To evaluate endothelium-dependent vascular function in obstructive sleep apnoea patients. DESIGN AND METHODS: Forearm blood flow and vascular resistance were studied in eight normotensives and eight obstructive sleep apnoea patients and also in eight normotensive and eight hypertensive controls after graded brachial artery infusion of acetylcholine (10-60 micrograms/min) and sodium nitroprusside (1-6 micrograms/min), respectively. Patients and controls were matched for age, sex and body weight. RESULTS: Forearm blood flow after acetylcholine infusion was reduced in patients compared with that in controls (peak flows were 6.0 +/- 0.7 and 9.8 +/- 1.5 ml/min for 100 g, respectively), but there was no difference between hypertensive and normotensive subjects. However, the hypertensive obstructive sleep apnoea group exhibited a reduced flow response to sodium nitroprusside compared with that of their corresponding hypertensive controls. Minimal forearm vascular resistance after acetylcholine infusion and after sodium nitroprusside infusion was higher in obstructive sleep apnoea patients than it was in controls. CONCLUSIONS: Endothelium-dependent vascular relaxation in patients with obstructive sleep apnoea was reduced independently of hypertension. An additional defect in endothelium-independent vascular relaxation was found in obstructive sleep apnoea patients with hypertension. These findings suggest a vascular pathogenetic link between obstructive sleep apnoea and systemic hypertension.

Impact of self-reported sleep-breathing disturbances on psychosocial performance in the Swedish Obese Subjects (SOS) Study.

Patients with severe obesity commonly have obstructive sleep apnea (OSA). In order to determine the impact of OSA on psychosocial morbidity in severe obesity, subjects enrolled in the Swedish Obese Subjects (SOS) Study were classified into two subgroups based on questionnaire data: one group with a high likelihood and one with a low likelihood of OSA. These groups were contrasted and multivariable analysis was used to examine whether OSA had independent effects on divorce rate, sick leave, work performance, income and self-estimated general health after adjustment for obesity, fat distribution, alcohol, smoking, medications and coexisting medical conditions. A high likelihood of OSA was identified in 338 men and 155 women, compared with 216 men and 481 women who had a low likelihood of OSA. Men with OSA were identical in age to men without OSA and had slightly higher levels of visceral fat (p = 0.01), but were similar in most psychosocial variables except self-perceived general health. Women with OSA were identical in age and visceral fat mass to women without OSA, but were characterized by a higher rate of impaired work performance, sick leave and divorce. When frequent sleepiness was used as an additional discriminator between OSA and non-OSA groups, marked differences in psychosocial morbidity were observed. Multivariable analysis revealed either OSA or frequent sleepiness or both to be independent predictors of amount of sick leave, worse self-rated general health, impaired work performance and divorce rate. Therefore OSA, measured by self report, is an important independent predictor of psychosocial morbidity in subjects with severe obesity.

Platelet function and fibrinolytic activity in hypertensive and normotensive sleep apnea patients.

Platelet function and fibrinolytic activity was studied during rest and after ergometric exercise in 13 hypertensive or normotensive patients with obstructive sleep apnea (OSA) and in 10 sex- and weight-matched controls. All patients had undergone a complete polysomnography for the diagnosis of OSA. The controls did not undergo any sleep investigation but had no history of snoring or witnessed apneas during sleep. On antihypertensive drug wash-out, two of the patients were normotensive, whereas 11 had mild to moderate hypertension. Platelet aggregation measured by adenosine 5'-diphosphate- or adrenaline-induced aggregation, platelet factor-4 or beta-thromboglobulin did not differ between patients and controls. During exercise beta-thromboglobulin decreased significantly in both OSA patients and controls. Plasma tissue plasminogen activator activity was similar in OSA patients and controls and increased significantly in both groups after exercise. Plasminogen activator inhibitor type 1 (PAI-1) was 18.4 +/- 3.6 IU/ml in OSA patients compared with 8.2 +/- 1.7 IU/ml in controls (p < 0.029) during rest, indicating decreased fibrinolytic activity. The difference between groups remained after exercise (p < 0.017). Blood pressure elevation was more common and body mass index (BMI) was higher in patients with OSA, but there was no direct relation between blood pressure level or BMI and PAI-1. Nevertheless, differences between groups were smaller when blood pressure and obesity were accounted for. It is concluded that patients with OSA may exhibit decreased fibrinolytic activity. Low fibrinolytic activity may represent a confounding pathophysiological mechanism behind the high incidence of myocardial infarction and stroke in patients with OSA.

High prevalence of hypertension in sleep apnea patients independent of obesity.

The relative influence of body mass index (BMI) and sleep apnea (SA) on blood pressure and prevalence of hypertension was investigated in 377 consecutive subjects admitted to a sleep laboratory. Among patients, 124 (33%) had SA, 153 (41%) were obese, and 93 (25%) had systemic hypertension. Both oxygen desaturation (OD) and minimal oxygen saturation (SaO2min) were related to BMI (p < 0.001) in patients without antihypertensive medication. Systolic and diastolic blood pressures were related to BMI and disease severity. Moreover, casual blood pressure, frequency of hypertension as well as OD and SaO2min were all significantly related to age. In a multivariate logistic regression analysis, age, BMI, and SA were all identified as independent predictors of hypertension. The relative risk associated with age was 4.3 (40 to 59 yr), with obesity 2.7 (> or = kg/m2) and with SA 2.1 (> 30 desaturation/6 h). The relative risk for hypertension increased with increasing age and BMI. In SA, however, the relative risk was unchanged in patients with a higher number of desaturations (OD > or = 60, 2.2). Combined obesity and SA resulted in a 3.9 times increase in hypertension prevalence. We concluded that age, SA, and overweight represent both independent and additive risk factors for development of systemic hypertension.

Effect of nasal continuous positive airway pressure during sleep on 24-hour blood pressure in obstructive sleep apnea.

Ambulatory blood pressure (BP) was measured noninvasively (Oxford Medilog ABP) at 15-minute intervals for 24 hours before and after 8 weeks of treatment with nasal continuous positive airway pressure (nCPAP) in 19 men with obstructive sleep apnea (OSA). We included both normotensive and hypertensive patients, but hypertensives were studied after withdrawal of antihypertensive drugs. Ambulatory BP before and after treatment was compared using patients as their own controls. Treatment with nCPAP was successfully established in 14 of the 19 patients (74%). Blood pressure fell significantly in patients who were successfully treated: 24-hour mean BP (systolic/diastolic) decreased from 141 +/- 18/89 +/- 11 mm Hg to 134 +/- 19/85 +/- 13 mm Hg (p < 0.05). The reduction in 24-hour mean systolic BP occurred during both day and night, but a significant fall in mean diastolic BP was only observed during the day. The mean blood pressure fell in both normotensive and hypertensive patients. Patients who were inadequately treated with nCPAP had no reduction in mean 24-hour BP. Effective treatment of sleep apnea with nCPAP was associated with a significant fall in both systolic and diastolic BP independent of changes in body weight or alcohol consumption, suggesting that sleep apnea was an independent factor contributing to elevated nighttime and daytime BP in these patients.

A specific and potent pressor effect of hypoxia in patients with sleep apnea.

A hypoxic ramp test (to 75% arterial oxygen saturation) during the awake state was performed in 17 patients with obstructive sleep apnea (OSA). Blood pressure was monitored with an indwelling arterial line (radial artery), and the ventilatory response to eucapnic hypoxia was determined. Eight of the patients were normotensive. The remaining nine hypertensive patients were studied after a 3-wk washout of antihypertensive medication. Compared with a nonmatched group of normotensive nonsnoring control subjects in whom hypoxemia did not affect blood pressure, all OSA patients showed various degrees of pressor responses during hypoxia. The pressor response was of similar magnitude in normotensive and hypertensive patients with OSA. There was a significant relationship between the ventilatory and the pressor responses to hypoxia (p = 0.03) that was similar in both normotensive and hypertensive patients. Although disease severity expressed as apnea index (number of apneas per hour of sleep) or minimum arterial oxygen saturation reached during the overnight recording correlated with the magnitude of the pressor response (p = 0.03 and 0.045, respectively), the ventilatory response to hypoxia was unrelated to disease severity. Hypoxemia induced a similar increase in heart rate in controls and in normotensive patients, but an attenuated heart rate response was seen at the nadir of oxygen saturation in hypertensive subjects (p < 0.05). These data demonstrate that patients with obstructive sleep apneas have a pressor response to hypoxia. This response is likely to be involved in the blood pressure swings seen during apnea in patients with OSA.(ABSTRACT TRUNCATED AT 250 WORDS)

Brainstem localization of a thyrotropin-releasing hormone-induced change in respiratory function.

When rats received microinjections of 100 ng thyrotropin-releasing hormone (TRH) into the medial portions of the nucleus tractus solitarius and 12th nucleus or raphe obscurus, at the level of the obex, a significant decrease in the inspiratory time was found. Examination of TRH immunocytochemistry revealed a high density of TRH-positive nerve terminals in these regions, especially the more caudal aspects. If serotonin was depleted by neonatal 5,7-dihydroxytryptamine treatment, the respiratory response of the adults to TRH appeared potentiated. Even though the neonatal 5,7-dihydroxytryptamine reduces the occurrence of TRH-positive cell bodies, TRH-positive fibers were not appreciably altered. These results are discussed with regard to a possible role of endogenous TRH in the brainstem on rhythmic respiratory activity.