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.

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.

Augmented resting sympathetic activity in awake patients with obstructive sleep apnea.

Muscle nerve sympathetic activity (MSA) was recorded during wakefulness in 11 patients with obstructive sleep apnea (OSA) and in 9 sex- and age-matched healthy control subjects. Plasma levels of norepinephrine (NE) and neuropeptide Y were analyzed. Five patients had established hypertension (resting supine systolic BP/diastolic BP > or = 160/95 mm Hg). The investigation was performed after a minimum of 3 weeks' washout period of antihypertensive medication. Muscle sympathetic activity during supine rest was higher in patients compared with controls (p < 0.01) with no difference between normotensive and hypertensive patients. However, systolic, but not diastolic, BP was positively related to resting MSA (n = 20, p < 0.01). There was no significant correlation between body mass index and MSA. Resting MSA was unrelated to disease severity expressed as apnea frequency or minimum SaO2 during the overnight recording. Both the arterial and venous plasma norepinephrine was higher in patients compared with controls (p < 0.05). Plasma levels of NE correlated to resting MSA (p < 0.01) in the whole study group (patients and controls) but not within the respective subgroups. No significant correlation, however, was found between plasma NE (arterial and venous) and BP. Plasma neuropeptide Y-like immunoreactivity was similar in patients and controls. However, one patient with hypertension had approximately twice this level in repeated samples. It is concluded that neurogenic sympathetic activity as well as circulating plasma NE is increased in patients with OSA. This increased sympathetic activity during awake supine rest may reflect a pathophysiologic adaptation to hypoxia and hemodynamic changes occurring at repetitive apneas during sleep. The correlation between MSA and systolic BP implies that this mechanism may be directly or indirectly involved in the development of cardiovascular complications in OSA.

Secondary polycythaemia associated with nocturnal apnoea--a relationship not mediated by erythropoietin?

A polysomnographic study was undertaken in nine patients with unexplained polycythaemia and nine age- and sex-matched controls. Circulating plasma levels of immunoreactive erythropoietin (IrEPO) were analysed before and after sleep. Seven out of nine polycythaemia patients were found to have sleep-disordered breathing and fulfilled the criteria for the sleep apnoea syndrome. Erythrocyte volume fraction was by definition higher among polycythaemia patients, and showed a weak positive correlation with minimum oxygen saturation during sleep (P less than 0.05). However, plasma IrEPO did not differ between the two groups or between morning and evening samples within the respective groups. In a separate study, IrEPO was repeatedly analysed during sleep in a group of six patients with severe obstructive sleep apnoea and six matched controls. No correlation with severity of sleep-disordered breathing was found. None of these patients had polycythaemia, and there was no obvious diurnal variation in IrEPO levels. A nocturnal sleep study may be warranted in patients with unexplained polycythaemia. Obstructive sleep apnoea does not appear to be related to increased IrEPO levels, although polycythaemia has been reported as a relatively common finding in this disease.

Nuclear transplantation in Bombina orientalis and utilization of the Pale mutation as a nuclear marker.

The discoglossid frog, Bombina orientalis, displays many characteristics that make it desirable as a laboratory animal. We report here the first successful transplantation of embryonic nuclei into enucleated eggs of this organism. The participation of the grafted nucleus in the development of the transplant embryos was confirmed with the use of a genetic marker, the Pale mutation. Frogs homozygous for this recessive gene are much lighter in appearance than the wild-type animals. The use of this trait in appropriate experiments demonstrated that nuclear transplantation in B. orientalis provides embryos whose nuclei may be reliably interpreted as being derived from the injected nucleus.