Rapid antidepressant changes with sleep deprivation in major depressive disorder are associated with changes in vascular endothelial growth factor (VEGF): A pilot study

While conventional antidepressants benefit many patients with major depressive disorder (MDD), as much as eight to 12 weeks can elapse before significant improvements in depressive symptoms are seen. Treatments that act more rapidly in MDD are urgently needed. Sleep deprivation (SD) has been shown to produce a rapid antidepressant response within one day in 50-60% of patients with MDD; thus, identifying its antidepressant mechanism may contribute to the development of antidepressants that act more rapidly. The present study evaluated the effects of 39 h of SD on mood, as well as on plasma levels of brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in patients with MDD. After a drug-free period of at least two weeks, 11 patients (6 males, 5 females; ages 25-62) who met DSM-IV criteria for MDD underwent total SD. Plasma samples for BDNF and VEGF assays were collected on Days 1 (baseline) and 2. The six-item Hamilton Rating Scale for Depression (HAMD-6) was the primary outcome measure. HAMD-6 scores decreased significantly after SD (Day 2). SD was negatively correlated with change in HAMD-6 score and change in VEGF levels, indicating that as depression scores decreased following SD, VEGF plasma levels increased. In contrast, SD did not alter plasma BDNF concentrations, nor was an association found between BDNF levels and clinical improvement on the HAMD-6. These results suggest that SD is associated with mood-related changes in plasma VEGF levels, but not plasma BDNF levels. Further studies using larger sample sizes are needed to confirm these preliminary findings. Published by Elsevier Inc.

Obstructive Sleep Apnea An Emerging Risk Factor for Atherosclerosis

Obstructive sleep apnea (OSA) is independently associated with death from cardiovascular diseases, including myocardial infarction and stroke. Myocardial infarction and stroke are complications of atherosclerosis; therefore, over the last decade investigators have tried to unravel relationships between OSA and atherosclerosis. OSA may accelerate atherosclerosis by exacerbating key atherogenic risk factors. For instance, OSA is a recognized secondary cause of hypertension and may contribute to insulin resistance, diabetes, and dyslipidemia. In addition, clinical data and experimental evidence in animal models suggest that OSA can have direct proatherogenic effects inducing systemic inflammation, oxidative stress, vascular smooth cell activation, increased adhesion molecule expression, monocyte/lymphocyte activation, increased lipid loading in macrophages, lipid peroxidation, and endothelial dysfunction. Several cross-sectional studies have shown consistently that OSA is independently associated with surrogate markers of premature atherosclerosis, most of them in the carotid bed. Moreover, OSA treatment with continuous positive airway pressure may attenuate carotid atherosclerosis, as has been shown in a randomized clinical trial. This review provides an update on the role of OSA in atherogenesis and highlights future perspectives in this important research area. CHEST 2011; 140(2):534-542

Characteristics and Predictors of Obstructive Sleep Apnea in Patients With Systemic Hypertension

Obstructive sleep apnea (OSA) is a secondary cause of hypertension and independently associated with target-organ damage in hypertensive patients. However, OSA remains largely underdiagnosed and undertreated. The aim of the present study was to evaluate the characteristics and clinical predictors of OSA in a consecutive series of patients followed up in a hypertension unit. A total of 99 patients (age 46 +/- 11 years, body mass index 28.8 kg/m(2), range 25.1 to 32.9) underwent polysomnography. The clinical parameters included age, gender, obesity, daytime sleepiness, snoring, Berlin Questionnaire, resistant hypertension, and metabolic syndrome. Of the 99 patients, 55 (56%) had OSA (apnea-hypopnea index >5 events/hour). Patients with OSA were older and more obese, had greater levels of blood pressure, and presented with more diabetes, dyslipidemia, resistant hypenension, and metabolic syndrome than the patients without OSA. Of the patients with OSA, 51% had no excessive daytime sleepiness. The Berlin Questionnaire and patient age revealed a high sensitivity (0.93 and 0.91, respectively) but low specificity (0.59 and 0.48, respectively), and obesity and resistant hypertension revealed a low sensitivity (0.58 and 0.44, respectively) but high specificity (0.75 and 0.91, respectively) for OSA. Metabolic syndrome was associated with high sensitivity and specificity for OSA (0.86 and 0.85, respectively). Multiple regression analysis showed that age of 40 to 70 years (odds ratio 1.09, 95% confidence interval 1.03 to 1.16), a high risk of OSA on the Berlin Questionnaire (odds ratio 8.36, 95% confidence interval 1.67 to 41.85), and metabolic syndrome (odds ratio 19.04, 95% confidence interval 5.25 to 69.03) were independent variables associated with OSA. In conclusion, more important than the typical clinical features that characterize OSA, including snoring and excessive daytime sleepiness, the presence of the metabolic syndrome is as an important marker of OSA among patients with hypertension. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:1135-1139)

Obstructive sleep apnea and dyslipidemia: implications for atherosclerosis

Purpose of review The aim of this review is to summarize current evidence about the impact of obstructive sleep apnea (OSA) and intermittent hypoxia on dyslipidemia and provide future perspectives in this area. Recent findings Intermittent hypoxia, a hallmark of OSA, induces hyperlipidemia in lean mice. Hyperlipidemia of intermittent hypoxia occurs, at least in part, due to activation of the transcription factor sterol regulatory element-binding protein-1 (SREBP-1) and an important downstream enzyme of triglyceride and phospholipid biosynthesis, stearoyl-CoA desaturase-1. Furthermore, intermittent hypoxia may regulate SREBP-1 and stearoyl-CoA desaturase-1 via the transcription factor hypoxia-inducible factor 1. In contrast, key genes involved in cholesterol biosynthesis, SREBP-2 and 3-hydroxy-3-methylglutaryl- CoA (HMG-CoA) reductase, are unaffected by intermittent hypoxia. In humans, there is no definitive evidence regarding the effect of OSA on dyslipidemia. Several cross-sectional studies suggest that OSA is independently associated with increased levels of total cholesterol, low-density lipoprotein and triglycerides, whereas others report no such relationship. Some nonrandomized and randomized studies show that OSA treatment with continuous positive airway pressure may have a beneficial effect on lipid profile. Summary There is increasing evidence that intermittent hypoxia is independently associated with dyslipidemia. However, the role of OSA in causality of dyslipidemia remains to be established.

Obstructive Sleep Apnea, Masked Hypertension, and Arterial Stiffness in Men

BACKGROUND Obstructive sleep apnea (OSA) is an established cause of hypertension However, it is not clear whether the frequency of masked hypertension in patients with OSA and whether OSA have an independent role on arterial stiffness taking into account ambulatory blood pressure (BP) monitoring (ABPM) METHODS We evaluated 61 male normotensive participants as determined by casual clinic BP level <140/90 mm Hg without clinical evidence of cardiovascular disease and on no medications (43 patients with moderate-to-severe OSA (apnea-hypopnea index (AHI) >= 15 events/hour by polysomnography) and 18 age- and body mass index-matched controls without OSA (AHl <5 events/hour)) Pulse wave velocity (PWV), an index of arterial stiffness, and 24-h ABPM were performed in a blinded fashion Masked hypertension was defined when abnormal daytime ABPM was >= 135 or >= 85 mm Hg RESULTS The AHI and lowest oxygen saturation were 26 +/- 16 and 90 +/- 2 vs 528 +/- 210 events/hour and 75 +/- 10% for controls and OSA patients, respectively, P < 0 001. Compared with controls, patients with OSA had higher office systolic BP (113 +/- 9 vs 118 +/- 10 mm Hg, P=0 05) and a higher unadjusted proportion of masked hypertension (2 controls (11.1%)vs 13 patients (30 2%), P < 005) PWV was 87 +/- 0.7, 9.4 +/- 1.0, and 10.6 +/- 1.1 m/s in the control, OSA without and with masked hypertension groups, respectively (P < 0 01 for each comparison) Multiple regression showed that systolic daytime ABPM and the lowest oxygen saturation were independently related to PWV (adjusted R(2) = 0 34, P < 0 01) CONCLUSIONS Patients with OSA presented a higher unadjusted rate of masked hypertension than matched controls. Lowest oxygen saturation has an independent association with arterial stiffness

The incremental role of obstructive sleep apnoea on markers of atherosclerosis in patients with metabolic syndrome

Objective: Metabolic syndrome (MS) is associated with subclinical atherosclerosis, but the relative role of obstructive sleep apnoea (OSA) is largely unknown. The main objective of this study is to determine the impact of OSA on markers of atherosclerosis in patients with MS. Methods: Eighty-one consecutive patients with MS according to the Adult Treatment Panel III underwent a clinical evaluation, polysomnography, laboratory and vascular measurements of carotid intima media thickness (IMT), carotid-femoral pulse wave velocity (PWV) and carotid diameter (CD) in a blind fashion. OSA was defined as an apnoea-hypopnoea index (AHI) >= 15 events/hour. Multiple linear regression was performed to determine the variables that were independently associated with the vascular parameters. Results: Fifty-one patients (63%) had OSA. No significant differences existed in age, sex, MS criteria, and cholesterol levels between patients with (MS+OSA) and without OSA (MS-OSA). Compared with MS-OSA patients, MS+OSA patients had higher levels of IMT (661 +/- 117 vs. 767 +/- 140 mu m), PWV (9.6 +/- 1.0 vs. 10.6 +/- 1.6 m/s), and CD (6705 +/- 744 vs. 7811 +/- 862 mu m) (P < 0.001 for each comparison). Among patients with MS+OSA, all vascular parameters were similar in patients with and without daytime sleepiness. The independent parameters associated with IMT, PWV, and CD were AHI, abdominal circumference, and systolic blood pressure (R(2) = 0.42); AHI and systolic blood pressure (R(2) = 0.38); and AHI, age, abdominal circumference and systolic blood pressure (R(2) = 0.45), respectively. The R(2) of AHI for IMT, PWV and CD was 0.12, 0.10 and 0.20, respectively. Conclusions: OSA is very common and has an incremental role in atherosclerotic burden in consecutive patients with MS. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

CPAP and survival in moderate-to-severe obstructive sleep apnoea syndrome and hypoxaemic COPD

Obstructive sleep apnoea syndrome (OSAS) often coexists in patients with chronic obstructive pulmonary disease (COPD). The present prospective cohort study tested the effect of OSAS treatment with continuous positive airway pressure (CPAP) on the survival of hypoxaemic COPD patients. It was hypothesised that CPAP treatment would be associated with higher survival in patients with moderate-to-severe OSAS and hypoxaemic COPD receiving long-term oxygen therapy (LTOT). Prospective study participants attended two outpatient advanced lung disease LTOT clinics in Sao Paulo, Brazil, between January 1996 and July 2006. Of 603 hypoxaemic COPD patients receiving LTOT, 95 were diagnosed with moderate-to-severe OSAS. Of this OSAS group, 61 (64%) patients accepted and were adherent to CPAP treatment, and 34 did not accept or were not adherent and were considered not treated. The 5-yr survival estimate was 71% (95% confidence interval 53-83%) and 26% (12-43%) in the CPAP-treated and nontreated groups, respectively (p<0.01). After adjusting for several confounders, patients treated with CPAP showed a significantly lower risk of death (hazard ratio of death versus nontreated 0.19 (0.08-0.48)). The present study found that CPAP treatment was associated with higher survival in patients with moderate-to-severe OSAS and hypoxaemic COPD receiving LTOT.

Sleep-related changes in hemodynamic and autonomic regulation in human hypertension

Objectives The present study investigates the hemodynamic and autonomic regulation during sleep-awake transitions and across different sleep cycles in patients with essential hypertension. Methods Nineteen individuals free of sleep apnea (10 normotensive and nine hypertensive matched for age, sex, and body mass index) underwent a standard polysomnography, with simultaneous electrocardiography and beat-to-beat blood pressure monitoring (Portapres). All measurements were determined while awake (before and after sleep), as well as in the beginning and at end of the sleep cycle (first/last cycle of nonrapid and rapid eye movement stages). Results Systolic blood pressure was higher in hypertensives and exhibited a similar reduction to the normotensives ones in initial nonrapid eye movement sleep. This reduction was because of different mechanisms: a significant fall in cardiac output in normotensives, whereas in hypertensives was also dependent of a decrease in peripheral vascular resistance. Hypertensive patients presented lower heart rate variation and attenuated baroreflex sensitivity during sleep but not immediately before and after sleep. Spectral analysis suggested a higher sympathetic activity in the sleep stages in hypertension. Additionally, a progressive sympathetic predominance (final rapid eye movement> initial rapid eye movement and awake period postsleep> awake period presleep) was observed in both groups. Conclusion Hypertension is associated with depressed baroreflex sensitivity and increased sympathetic activation during sleep. The greater sympathetic predominance at the end of night (preceding the morning surge of sympathetic activity) could be implicated in the occurrence of cardiovascular events. J Hypertens 27: 1655-1663 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Effects of Oropharyngeal Exercises on Patients with Moderate Obstructive Sleep Apnea Syndrome

Rationale: Upper airway muscle function plays a major role in maintenance of the upper airway patency and contributes to the genesis of obstructive sleep apnea syndrome (OSAS). Preliminary results suggested that oropharyngeal exercises derived from speech therapy may be an effective treatment option for patients with moderate OSAS. Objectives: To determine the impact of oropharyngeal exercises in patients with moderate OSAS. Methods: Thirty-one patients with moderate OSAS were randomized to 3 months of daily (similar to 30 min) sham therapy (n = 15, control) or a set of oropharyngeal exercises (n = 16), consisting of exercises involving the tongue, soft palate, and lateral pharyngeal wall. Measurements and Main Results: Anthropometric measurements, snoring frequency (range 0-4), intensity (1-3), Epworth daytime sleepiness (0-24) and Pittsburgh sleep quality (0-21) questionnaires, and full polysomnography were performed at baseline and at study conclusion. Body mass index and abdominal circumference of the entire group were 30.3 +/- 3.4 kg/m(2) and 101.4 +/- 9.0 cm, respectively, and did not change significantly over the study period. No significant change occurred in the control group in all variables. In contrast, patients randomized to oropharyngeal exercises had a significant decrease (P < 0.05) in neck circumference (39.6 +/- 3.6 vs. 38.5 +/- 4.0 cm), snoring frequency (4 [4-4] vs. 3 [1.5-3.5]), snoring intensity (3 [3-4] vs. 1 [1-2]), daytime sleepiness (14 +/- 5 vs. 8 +/- 6), sleep quality score (10.2 +/- 3.7vs. 6.9 +/- 2.5), and OSAS severity (apnea-hypopnea index, 22.4 +/- 4.8 vs. 13.7 +/- 8.5 events/h). Changes in neck circumference correlated inversely with changes in apnea-hypopnea index (r = 0.59; P < 0.001). Conclusions: Oropharyngeal exercises significantly reduce OSAS severity and symptoms and represent a promising treatment for moderate OSAS. Clinical trial registered with www.clinicaltrials.gov (NCT 00660777).

Treatment of obstructive sleep apnea syndrome in patients from a teaching hospital in Brazil: is it possible?

The aim of this study was to evaluate the efficacy of a cost-effective intra-oral appliance for obstructive sleep apnea syndrome built into a large teaching hospital. Out of 20 evaluated and treated patients, 14 concluded the study: eight men and six women, with a mean age of 42-46 (mean + SD) years and mean body mass index of 27.66. Inclusion criteria were mild or moderate apnea-hypopnea index (AHI) according to a polysomnographic study. All patients were treated with the monobloco intra-oral appliance. They were then submitted to a follow-up polysomnographic study after 60 days using the appliance. An orofacial clinical evaluation was carried out with the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) questionnaire and with clinical evaluation questionnaire devised by the Orofacial Pain Team before and 60 days after fitting the intra-oral appliance. The AHI showed a statistically meaningful (p = 0.002) reduction from 15.53 to 7.82 events per hour, a non-statistically significant oxygen saturation increase from 83.36 to 84.86 (p = 0.09), and Epworth`s sleepiness scale reduction from 9.14 to 6.36 (p = 0.001). Three patients did not show any improvement. The most common side effect during the use of the appliance/device was pain and facial discomfort (28.57%), without myofascial or temporomandibular joint pain as evaluated by the RDC/TMD questionnaire. The intra-oral device produced a significant reduction of the apnea-hypopnea index during the study period with the use of the monobloco intra-oral appliance. Patients did not show prior myofascial pain or 60 days after use of the intra-oral appliance.

Study into the use of continuous positive airway pressure in obstructive sleep apnoea-hypopnoea syndrome patients with daytime drowsiness

Background: Obstructive sleep apnoea-hypopnoea syndrome (OSAHS) is a respiratory disorder with high morbidity and mortality. Continuous positive airway pressure (CPAP) is the most commonly prescribed conservative treatment for adults with OSAHS. CPAP therapy normalises or decreases OSAHS symptoms and can reduce and prevent OSAHS complications. Aims: To evaluate adherence to nasal CPAP treatment and CPAP impact on daytime drowsiness. Method: A sample of 20 patients evaluated for daytime drowsiness using the Epworth sleepiness scale and interviewed for adherence to nasal CPAP use. Results: There was a significant decrease in the level of daytime sleepiness of the patients users of nasal CPAP (p=0.017); patients not using nasal CPAP experienced a decrease without statistical significance (p=0.162). 100% of CPAP users reported benefits and 50% of these reported related discomforts. Conclusions: Patients with OSAHS that use CPAP have a greater reduced level of sleepiness than those who do not use it.

Additive Effects of Obstructive Sleep Apnea and Hypertension on Early Markers of Carotid Atherosclerosis

Obstructive sleep apnea (OSA) has emerged as an independent risk factor for atherosclerosis. However, OSA is frequently associated with several risk factors for atherosclerosis, including hypertension (HTN). The impact of OSA and HTN alone compared with the association of both conditions on carotid atherosclerosis is not understood. We studied 94 middle-aged participants free of smoking and diabetes mellitus who were divided into 4 groups: controls (n = 22), OSA (n = 25), HTN (n = 20), and OSA + HTN (n = 27). All of the participants underwent polysomnography and carotid measurements of intima-media thickness, diameter, and distensibility with an echo-tracking device. Compared with controls, intima-media thickness and carotid diameter were similarly higher in OSA (713 +/- 117 and 7117 +/- 805 mu m), and HTN groups (713 +/- 182 and 7191 +/- 818 mu m), with a further significant increase in OSA + HTN patients (837 +/- 181 and 7927 +/- 821 mu m, respectively; P < 0.01). Carotid distensibility was significantly lower in HTN (P < 0.05) and OSA + HTN subjects (P < 0.001) compared with controls. In the OSA + HTN group, carotid distensibility was significantly lower than in the OSA group and controls (P < 0.05 for each comparison). Multivariate analysis showed that intima-media thickness was positively related to systolic blood pressure and apnea-hypopnea index. Apnea-hypopnea index was the only factor related to carotid diameter. Age and systolic blood pressure were independently related to carotid distensibility. In conclusion, the association of OSA and HTN has additive effects on markers of carotid atherosclerosis. Because early markers of carotid atherosclerosis predict future cardiovascular events, including not only stroke but also myocardial infarction, these findings may help to explain the increased risk of cardiovascular disease in patients with OSA. (Hypertension. 2009; 53: 64-69.)

Obstructive Sleep Apnea in Patients on Conventional and Short Daily Hemodialysis

Obstructive sleep apnea (OSA) is common among patients on maintenance hemodialysis. However, the factors associated with the origin of OSA as well as the cardiovascular consequences in this population are not completely understood. We evaluated, by standard overnight polysomnography, 24-hour ambulatory blood pressure (BP) monitoring and echocardiography in 30 patients (14 males, age 34 +/- 11 years, BMI 23.2 +/- 5.2) - 15 on short daily hemodialysis (SDH) and 15 matched patients on conventional hemodialysis (CHD). The hemodialysis dose (standard Kt/V) was higher in patients on SDH than on CHD (p = 0.001). OSA (apnea-hypopnea index 1 5 events/h) was present in 13 patients (43%). Patients with OSA were predominantly males (77 vs. 44%), presented a higher BMI (25.5 +/- 6.2 vs. 21.5 +/- 3.6), a larger neck circumference (38 +/- 1 vs. 34 +/- 1 cm) and a lower Kt/V (2.6 +/- 0.3 vs. 2.2 +/- 0.1) than patients with no OSA (p < 0.05). Neck circumference and lower Kt/V were independently associated with OSA on multivariate analysis. No patient with Kt/V > 2.5 (n = 10) presented OSA. On the other hand, hypertensive patients with OSA needed more BP control pills (p = 0.03). Despite similar BP control, patients with OSA presented a higher interventricular septum thickness (11.5 +/- 0.5 vs. 9.9 +/- 0.3 mm; p = 0.011). In conclusion, among patients on maintenance hemodialysis, the traditional risk factors for OSA are present and interact with hemodialysis efficiency. Among these patients, OSA is associated with difficult BP control and heart remodeling suggesting that OSA may contribute to poor cardiovascular outcome. Copyright (c) 2008 S. Karger AG, Basel

Effects of sinoaortic Denervation on Hemodynamic parameters during natural sleep in rats

Study Objectives: To analyze the role of arterial baroreflex on hemodynamic changes during synchronized and desynchronized sleep phases of natural sleep in rats. Design: Experimental study. Setting: Laboratory. Participants: Seventeen male Wistar rats. Interventions: No intervention (control, n = 8) or sinoaortic denervation (SAD, n = 9). Measurements and Results: Sleep phases were monitored by electrocorticogram, and blood pressure was measured directly by a catheter in the carotid artery. Cardiac output, as well as total and regional vascular resistances, were determined by measuring the subdiaphragmatic aorta and iliac artery flows with Doppler flow probes, respectively. In contrast to the control group, the SAD group had a strong reduction in blood pressure (-19.9% +/- 2.6% vs -0.7% +/- 2.1%) during desynchronized sleep, and cardiac output showed an exacerbated reduction (-10.4% +/- 3.5% vs 1.1% +/- 1.7%). In SAD rats, total vascular resistance decreased during desynchronized sleep (-10.1% +/- 3.5% vs -1.0% +/- 1.7%), and the increase in regional vascular resistance observed in the control group was abolished (27.5% +/- 8.3% vs -0.8% +/- 9.4%). Conclusions: SAD caused profound changes in blood pressure, cardiac output, and total vascular resistance, with a significant increase in muscle vascular resistance during synchronized sleep. Our results suggest that baroreflex plays an important role in maintaining the normal balance of cardiac output and total vascular resistance during sleep.

Calcium channel blockers are independently associated with short sleep duration in hypertensive patients with obstructive sleep apnea

Objective Obstructive sleep apnea (OSA) and hypertension (HYP) frequently coexist and have additive harmful effects on the cardiovascular system. There is also growing evidence that short sleep duration may contribute independently to poor cardiovascular outcome. The aim of this study was to evaluate the potential influence of antihypertensive medication on sleep parameters objectively measured by standard polysomnography in hypertensive patients with OSA. Methods We evaluated consecutive patients with a recent diagnosis of OSA by full polysomnography (apnea hypopnea index >= 5 events/h) and HYP. Smokers, patients with diabetes mellitus, heart failure, or using hypnotics and benzodiazepines were excluded. Results We evaluated 186 hypertensive patients with OSA, 64% men. All patients were on at least one antihypertensive medication, including angiotensin-converting enzyme inhibitors (37%), beta-blockers (35%), angiotensin receptor blockers (32%), diuretics (29%) and calcium channel blockers (21%). Backward multiple regression analysis showed that age (P <= 0.001) and the use of calcium channel blockers (P=0.037) were the only factors inversely associated with lower total sleep time. Sleep efficiency was inversely associated only with age (P <= 0.001), whereas the use of calcium channel blockers had a nonsignificant trend (P=0.092). Use of calcium channel blockers was associated with significant reduction in total sleep time (-41 min, P=0.005) and 8% lower sleep efficiency (P=0.004). No other antihypertensive medication, including diuretics and beta-blockers, was associated with sleep impairment. Conclusion Calcium channel blockers may impact negatively on sleep duration in hypertensive patients with OSA. The mechanisms and significance of this novel finding warrants further investigation. J Hypertens 29: 1236-1241 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.