Blood pressure, cardiac structure and severity of obstructive sleep apnea in a sleep clinic population.

OBJECTIVES: We investigated whether the severity of obstructive sleep apnea (OSA) predicts blood pressure or cardiac left ventricular thickness in a clinical population of OSA patients, if adjustments are made for age, gender, use of antihypertensive agents, smoking, body mass index, history of coronary artery disease, hypercholesterolemia and circulating C-peptide concentrations. DESIGN: Relationships in this cross-sectional study were investigated with correlation analysis and multiple regression procedures. PATIENTS AND METHODS: Apnea-hypopnea index (AHI, polysomnography) and office systolic and diastolic blood pressures (SBP and DBP) were measured in 81 subjects referred to a university hospital sleep laboratory. Ambulatory blood pressures were recorded during one 24 h cycle. Left ventricular (LV) muscle size was quantified as two-dimensionally directed M-mode-derived end-diastolic thickness of interventricular septum and posterior chamber wall. RESULTS: After adjustment for separate or the entire set of covariates, AHI predicted office SBP and DBP as well as daytime ambulatory DBP and night-time ambulatory SBP and DBP, but not daytime ambulatory SBP. In contrast, associations between AHI and LV muscle thickness reflected complex inter-relationships with confounding variables. Smoking and age suppressed, whereas body mass index (BMI) and hypertension inflated the relationship between OSA severity and LV muscle thickness in this study. CONCLUSIONS: AHI is an independent predictor of several measures of blood pressure. OSA severity and LV muscle thickness appear to be primarily linked via increased blood pressure.

Impairment of vascular endothelial function and left ventricular filling : association with the severity of apnea-induced hypoxemia during sleep.

STUDY OBJECTIVE: To investigate whether a dose-effect relationship exists between the severity of obstructive sleep apnea (OSA) and subclinical indicators of myocardial or vascular dysfunction. DESIGN: Cross-sectional study using correlation analysis. PARTICIPANTS: Twenty subjects referred to our sleep laboratory for screening or therapy of OSA but without regular medication and without known cardiovascular disease. MEASUREMENTS: Severity of OSA was quantified by polysomnography. Moreover, nocturnal excretion of norepinephrine was determined. Left ventricular (LV) myocardial function was assessed with Doppler echocardiography. Using ultrasonographic measurements, endothelium-dependent and endothelium-independent conduit artery dilation were measured as flow-mediated and glyceryltrinitrate-induced changes in brachial artery diameter. RESULTS: Worsening nocturnal hypoxemia, measured as nocturnal oxygen saturation nadir or percentage of sleep time spent in hypoxemia (< 90% hemoglobin oxygen saturation), predicted increased interventricular septum thickness (corrected for age and body mass index), prolonged isovolumetric relaxation time, decreased ratio between peak early and late mitral flow velocities, as well as reduced endothelium-dependent dilatory capacity of the brachial artery (all relationships corrected for cofactor age and with p < 0.05) were observed. Associations between these cardiovascular function markers and nocturnal excretion of norepinephrine followed the same trend, but relations with interventricular septum thickness and flow-mediated artery dilation missed significance (p = 0.064 and p = 0.061, respectively). LV posterior wall thickness, measures of LV systolic function, early mitral flow deceleration time, and endothelium-independent artery dilation were not significantly related to the degree of nocturnal hypoxemia or norepinephrine excretion. None of the correlations with apnea-hypopnea index were statistically significant. CONCLUSIONS: The severity of apnea-related hypoxemia is associated with a gradual deterioration of LV diastolic function as well as large-artery endothelial function.

Reduced alpha- and beta(2)-adrenergic vascular response in patients with obstructive sleep apnea.

Obstructive sleep apnea (OSA) has been associated with increased sympathetic activity. This study tested the hypothesis that the alpha- and beta(2)-receptor-mediated vascular response is altered in patients with OSA. Forearm vascular resistance was evaluated by venous occlusion plethysmography in 10 normotensive OSA patients and 10 normotensive controls (apnea/hypopnea index [mean +/- SD] 29.4 +/- 2.3 and 1.6 +/- 0.3 per hour, respectively) roughly matched for body mass index (BMI) and age. Forearm vascular resistance was measured after intraarterial infusion of norepinephrine (NE) (7.4, 31, 120, 472 and 1421 pmol/100 ml forearm volume [FAV]/min), before and after phentolamine infusion (2 microgram/100 ml FAV/min), and isoproterenol (ISO) (1, 2, 6, and 15 ng/100 ml FAV/min). NE-induced vasoconstriction was significantly attenuated in OSA patients compared with controls (65.0 +/- 36.6% versus 129.4 +/- 81.8%, p = 0.049). The reduction of vascular resistance after phentolamine was similar in patients and control subjects (-50.8 +/- 16.7% versus -43.4 +/- 20.0%, p = 0.38). During ongoing phentolamine infusion NE increased resistance to a similar extent in both groups (0.5 +/- 4.9% versus -0.9 +/- 10.1%, p = 0.96). Vasodilation following ISO was significantly attenuated in OSA patients compared with control subjects (-53.3 +/- 9.0% versus -64.7 +/- 10.3%, p = 0.049). Moreover, the vascular response to NE in OSA patients was negatively correlated with plasma NE concentration (r = -0.76, p < 0.05). The reduced vascular response to alpha- and beta-receptor stimulation suggests a functional downregulation of vascular sympathoadrenergic receptors in patients with sleep apnea.

Three-week neonatal hypoxia reduces blood CGRP and causes persistent pulmonary hypertension in rats.

To increase understanding of persistent pulmonary hypertension, we examined chronic pulmonary effects of hypoxia at birth and their relationships with immunoreactive levels of the potent vasodilator, calcitonin gene-related peptide (CGRP). Rats were born in 10% hypobaric hypoxia, where they remained for 1-2 days, or in 15% hypoxia, where they remained for 21 days. All were then reared in normoxia for 3 mo followed by reexposure to 10% hypoxia for 7 days (H-->H) or continued normoxia (H-->N); age-matched normoxic rats were hypoxic for the last 7 days (N-->H) or normoxic throughout (N-->N). Results are as follows. Pulmonary arterial pressure (P(PA)) in 10% H-->N rats was normal at the end of the experiment (13 wk), but in rats reexposed to hypoxia (H-->H), pressure rose to 19% above N-->H controls. In 15% H-->N rats, P(PA) remained high, similar to that of N-->H rats, and increased further by 40% on reexposure (H-->H). Medial thickness of small pulmonary arteries in 10% H-->H rats also increased by 40% over N-->H controls and was equally high in 15% H-->N and H-->H rats. In N-->H rats from both experiments, right ventricular hypertrophy index (RVH) was increased after hypoxia at 15-16 wk. Also, in the 15% study, RVH remained elevated in H-->N rats and increased in H-->H rats by 19% above N-->H controls. Blood CGRP was reduced by neonate and adult hypoxia, and hypoxic reexposure (H-->H) further lowered blood CGRP in the 15% but not 10% study. Declining left ventricular blood CGRP correlated highly with logarithmically increasing P(PA) in the 15% study (r = -0.81, P = 0.000). In conclusion, 1) short perinatal exposure to 10% O(2) exacerbated pulmonary hypertension with hypoxia later in life, 2) 15% O(2) at birth and for 21 days caused persistent pulmonary hypertension and exacerbation with reexposure, and 3) P(PA) correlated highly with declining blood CGRP levels in the 15% study.

Increased vasoconstrictor sensitivity in obstructive sleep apnea.

We studied vasoconstrictor sensitivity and cholinergic responsiveness of the forearm vasculature in 10 male patients with obstructive sleep apnea (OSA) and 10 healthy controls. Subjects with regular medication, known arterial hypertension, diabetes mellitus, or dyslipidemia were not included in this study. Age, body mass index, blood pressure, blood glucose, serum lipids, and baseline forearm vascular conductance (derived from venous occlusion plethysmography and intra-arterial blood pressure measurement) did not differ significantly between these two groups. With use of three dosage steps each, angiotensin II and acetylcholine were successively infused into the brachial artery. During infusion of angiotensin II, mean conductance was 39.6% lower (P = 0.002) in the OSA patients compared with that in the control subjects. Vascular responsiveness to increasing dosages of acetylcholine was not significantly altered in the OSA group. These findings suggest an enhanced vasoconstrictor sensitivity in the forearm vasculature in OSA. The hypothesis that endothelial function in OSA is impaired independently of other cardiovascular risk factors is not supported by the present results.

Respiratory disturbance index: an independent predictor of mortality in coronary artery disease.

Cardiovascular mortality was prospectively investigated in consecutive coronary artery disease (CAD) patients with versus without obstructive sleep apnea (OSA) during a follow-up period of 5 yr. An overnight sleep/ventilatory study was performed in patients requiring intensive care (n = 62, mean age 67.6 +/- 10.4 yr, range 44 to 86) during a stable condition (New York Heart Association [NYHA] functional class I-II) 4 to 21 mo after discharge from the hospital. OSA, defined as a respiratory disturbance index (RDI) of 10/h or more was found in 19 patients (mean RDI 17.5 +/- 8.3). Three OSA subjects who were successfully treated with continuous positive airway pressure (CPAP) during the observation period were excluded from the final analysis. There was no statistically significant difference (Fisher two-tailed exact test) between the OSA and non-OSA patient groups in terms of number of elderly subjects (age >/= 65 yr), gender, obesity (body mass index [BMI] >/= 30 kg/m(2)), smoking history, presence of hypertension, diabetes mellitus, hypercholesterolemia, or history of myocardial infarction at the study start. During the follow-up period, cardiovascular death occurred in six of 16 OSA patients (37.5%) compared with 4 (9.3%) in the non-OSA group (p = 0.018). The univariate predictors of cardiovascular mortality were RDI (p = 0.007), OSA (p = 0.014), age at baseline (p = 0.028), hypertension at baseline (p = 0.036), history of never-smoking (p = 0.031), and digoxin treatment during the follow-up period (p = 0.013). In a Cox multiple conditional regression model, RDI remained as an independent predictor of cardiovascular mortality (exp beta = 1.13, 95% confidence interval [CI] 1.05 to 1.21, two-sided p < 0.001). We conclude that untreated OSA is associated with an increased risk of cardiovascular mortality in patients with CAD. Furthermore, it appears appropriate that RDI is taken into consideration when evaluating secondary prevention models in CAD.

Comparison of atenolol, amlodipine, enalapril, hydrochlorothiazide, and losartan for antihypertensive treatment in patients with obstructive sleep apnea.

We compared the effects of atenolol (50 mg), amlodipine (5 mg), enalapril (20 mg), hydrochlorothiazide (25 mg), and losartan (50 mg) given in once-daily oral doses on office and ambulatory blood pressures (BPs) in patients with hypertension and obstructive sleep apnea (OSA). Each of 40 randomized patients was treated in sequence with two of the five agents (balanced incomplete block design). Treatment periods lasted 6 wk and were separated by a 3-wk washout period. Changes in BP from baseline with the study substances were compared through analysis of variance. Office diastolic BP, our primary outcome variable, was most effectively lowered by atenolol, with all four post hoc differences between atenolol and the remaining substances being statistically significant. Reductions in office systolic and daytime ambulatory BP were not significantly different among the five compounds. However, atenolol reduced mean nighttime ambulatory diastolic and systolic BP more effectively than did amlodipine, enalapril, or losartan (but not hydrochlorothiazide). Severity of sleep-disordered breathing and well-being during the day were not significantly influenced by any of the study compounds. Our findings are in accordance with the hypothesis that an overactivity of the sympathetic nervous system is an important mechanism behind the development or maintenance of hypertension in patients with OSA.

Therapy with nCPAP: incomplete elimination of Sleep Related Breathing Disorder.

Correct assessment of the overall treatment effectiveness requires knowledge about therapy compliance and efficacy. This study aimed to determine overall long-term apnoea alleviation after continuous positive airway pressure (CPAP) in a complete sleep laboratory cohort. Out of 209 consecutive CPAP candidates (mean age 57+/-12 yrs, body mass index (BMI) 30.0+/-5.1 kg x m2, respiratory disturbance index (RDI) 32.9+/-29 h), follow-up treatment was performed in 149 of them at 9, 18 and 30 months after CPAP prescription. Compliance with CPAP (machine run time/days CPAP available) was adjusted for the individual subjective sleep-time. Apnoea alleviation was defined as adjusted compliance multiplied by the CPAP effect (RDI with CPAP applied), remaining RDI was calculated. The baseline RDI, age or BMI in 75 patients, who did not tolerate nasal continuous positive airway pressure (nCPAP), did not differ from those accepting CPAP (acceptors, n=74). In acceptors at 9 months follow-up RDI with CPAP applied was 1.4+/-2.6 (CPAP effect, n=66), mean CPAP use was 3.6+/-2.5 x 24 h(-1) (n=68), mean apnoea alleviation was 52.4+/-32.0% (range 1-100%, n=47), the average remaining whole-night RDI was 17.8+/-26. At 9, 18 and 30 months (n=47), the mean daily CPAP use increased from 3.6+/-2.5 h to 4.1+/-2.5 h and 4.4+/-2.4 h (p<0.01). Effectiveness of continuous positive airway pressure is potentially high but acceptance was low. When accounting for sleep-time, its actual effect and use, only 50% adjusted continuous positive airway pressure effectiveness was observed.

Hypoxic pressor response, cardiac size, and natriuretic peptides are modified by long-term intermittent hypoxia.

We investigated whether the effect of long-term intermittent hypoxia (LTIH) on cardiovascular function may be modified by preexisting genetic traits. To induce LTIH experimentally, cycles of 90-s hypoxia (nadir 6%) followed by 90-s normoxia were applied to six Wistar-Kyoto and six spontaneously hypertensive rats during 8 h daily. Comparison with the same number of control animals after 70 days revealed no alteration of intra-arterial blood pressure or heart rate. Blood pressure responsiveness to a brief hypoxic stimulus was enhanced in the LTIH animals, regardless of strain, whereas the hypoxia-induced increase in heart rate was abolished. In the spontaneously hypertensive but not the Wistar-Kyoto rats, LTIH increased left ventricular weight-to-body weight ratio and content of atrial natriuretic peptide mRNA. Expression of B-type natriuretic peptide was unchanged (Northern blot). Slightly increased right ventricular weight-to-body weight ratios in the LTIH animals were associated with higher right ventricular atrial natriuretic peptide and B-type natriuretic peptide mRNA amounts. Consequently, the effects of LTIH on different components of cardiovascular function appear incompletely related to each other and differentially influenced by constitutional traits.

An independent association between obstructive sleep apnoea and coronary artery disease.

Previous studies of sleep and breathing suggest an independent association between coronary artery disease (CAD) and obstructive sleep apnoea (OSA) in middle-aged males and females. These studies, however, were criticized because they did not properly adjust for all important confounding factors. In order to better control for the impact of these confounders, a case-control study was performed, matching for age, sex and body mass index (BMI), and additionally adjusting for hypertension, hypercholesterolemia, diabetes mellitus and current smoking. A consecutive selection of 62 patients (44 males and 18 females, mean age 69 yrs, range 44-88 yrs) requiring intensive care for angina pectoris or myocardial infarction at the County Hospital of Skaraborg, Skövde, Sweden, as well as 62 age-, sex- and BMI- matched control subjects without history or signs of heart disease underwent an overnight sleep/ventilatory monitoring study. The time interval between discharge from the intensive care unit and the overnight study ranged between 4 and 21 months. OSA, defined as a Respiratory Disturbance Index (RDI) of > or =10 x h(-1), was present in 19 CAD patients but only in eight control subjects (p=0.017). Using a univariate logistic regression analysis, current smoking (odds ratio (OR) 8.1, 95% confidence interval (CI) 2.2-29.0), diabetes mellitus (OR 4.2, 95% CI 1.1-16.1) and OSA (OR 3.0, 95% CI 1.2-7.5), but not hypertension (OR 1.5, 95% CI 0.7-3.2) and hypercholesterolaemia (OR 1.8, 95% CI 0.7-4.1) were significantly correlated with CAD. In a multiple logistic regression model, current smoking (OR 9.8, 95% CI 2.6-36.5), diabetes mellitus (OR 4.2, 95% CI 1.1-17.1) and OSA (OR 3.1, 95% CI 1.2-8.3) all remained independently associated with CAD. In summary, these data suggest a high occurrence of obstructive sleep apnoea in middle-aged and elderly patients with coronary artery disease requiring intensive care, which should be taken into account when considering risk factors for coronary artery disease.

Effect of serotonin uptake inhibition on breathing during sleep and daytime symptoms in obstructive sleep apnea.

Pharmacologic enhancement of serotonergic transmission by serotonin uptake inhibition has been suggested as one approach to improve upper-airway patency and thus nocturnal breathing in patients with obstructive sleep apnea (OSA). To test this hypothesis, we performed a double-blind, randomized, placebo-controlled crossover study testing the effect of paroxetine (20 mg od) on polysomnographic and psychopathologic outcomes in 20 male OSA patients (mean age 52.1 years, mean BMI 28.7 kg/m2, mean oxygen desaturation index on a previous screening 25.4/hour). The two treatment periods of 6 weeks and the separating washout period of 4 weeks were completed by 17 patients. Paroxetine reduced the apnea index during NREM sleep (-35%, p = 0.003), but not during REM sleep. No significant effect on hypopnea indices was found. With the exception of a previously described REM-postponing effect (p = 0.05), sleep architecture was not significantly influenced by paroxetine. Similarly, the effect of paroxetine on apnea was not associated with a significant overall alleviation of psychopathologic symptoms as rated on the Comprehensive Psychopathological Rating Scale or OSA-related daytime complaints assessed by visual analog scales. We conclude that enhanced serotonergic transmission improves breathing during NREM sleep in OSA. This effect is poorly related to effects on sleep architecture or daytime symptoms.

Sensory CGRP depletion by capsaicin exacerbates hypoxia-induced pulmonary hypertension in rats.

Pulmonary hypertension is a debilitating disease that occurs among infants and adults. One of many etiologies is airway hypoxia. We previously demonstrated a role of endogenous calcitonin gene-related peptide (CGRP), a potent vasodilator, in ameliorating the pulmonary vascular pressor response to chronic hypoxia and related changes in the lungs and heart. This study evaluates the role of endogenous sensory CGRP in hypoxic pulmonary hypertension and examines the intrinsic neural microcircuitry. Rats were pretreated with capsaicin i.p. to deplete pulmonary sensory C-fiber stores of CGRP and substance P and placed in hypobaric hypoxia (10% O2, 16 days) or normoxia together with sham controls. Hypoxia increased pulmonary artery pressure, right-ventricular weight, arterial medial thickness, elasticized capillaries, endothelial cell density, lung water and hematocrit in control rats. Capsaicin augmented pulmonary artery pressure and right-ventricular hypertrophy in hypoxia, and medial thickness and endothelial cell density both in normoxia and hypoxia. Because of the limited effects on these parameters by substance P and other capsaicin-sensitive lung agents, our results suggest that sensory CGRP deficit severely exacerbates pathological signs of hypoxic pulmonary hypertension. A neural microcircuitry consistent with an axon reflex pathway is outlined histochemically. We conclude that endogenous CGRP modulates pulmonary vascular tone in hypoxic pulmonary hypertension which requires intact primary sensory fibers.

Analytical extraction of regulatory peptides from rat lung tissue.

We evaluated protocols for the extraction of calcitonin gene-related peptide, neuropeptide Y, substance P, peptide YY and beta-endorphin from rat lung tissue for subsequent radioimmunoassay. The effects of varying acidity of the extraction solution and repeating extraction on the recovery of peptide immunoreactivity and non-specific tracer-binding were compared by analysis of variance. Moreover, variability of immunoreactivity was quantified for comparison. Considering all three criteria, the optimal acidity for extraction was: 0.1 M or 1 M acetic acid for CGRP and beta-endorphin, 0.1 M acetic acid for NPY, 1 M acetic acid for substance P and phosphate buffer for peptide YY. Double or combined extraction unambiguously improved assay results only for substance P. Reversed-phase high-performance liquid chromatography of CGRP-, NPY- and SP-immunoreactivity obtained from selected extracts suggested that differences in recovery of these peptides are not explainable by differential peptide fragmentation during extraction.