Arginase activity and nitric oxide levels in patients with obstructive sleep apnea syndrome

OBJECTIVE:

Obstructive sleep apnea syndrome is characterized by repetitive obstruction of the upper airways, and it is a risk factor for cardiovascular diseases. There have been several studies demonstrating low levels of nitric oxide in patients with obstructive sleep apnea syndrome compared with healthy controls. In this study, we hypothesized that reduced nitric oxide levels would result in high arginase activity. Arginase reacts with L-arginine and produces urea and L-ornithine, whereas L-arginine is a substrate for nitric oxide synthase, which produces nitric oxide.

METHODS:

The study group consisted of 51 obstructive sleep apnea syndrome patients (M/F: 43/8; mean age 49±10 years of age) and 15 healthy control subjects (M/F: 13/3; mean age 46±14 years of age). Obstructive sleep apnea syndrome patients were divided into two subgroups based on the presence or absence of cardiovascular disease. Nitric oxide levels and arginase activity were measured via an enzyme-linked immunosorbent assay of serum samples.

RESULTS:

Serum nitric oxide levels in the control subjects were higher than in the obstructive sleep apnea patients with and without cardiovascular diseases (p<0.05). Arginase activity was significantly higher (p<0.01) in obstructive sleep apnea syndrome patients without cardiovascular diseases compared with the control group. Obstructive sleep apnea syndrome patients with cardiovascular diseases had higher arginase activity than the controls (p<0.001) and the obstructive sleep apnea syndrome patients without cardiovascular diseases (p<0.05).

CONCLUSION:

Low nitric oxide levels are associated with high arginase activity. The mechanism of nitric oxide depletion in sleep apnea patients suggests that increased arginase activity might reduce the substrate availability of nitric oxide synthase and thus could reduce nitric oxide levels.     

Altered K-complex morphology during sustained inspiratory airflow limitation is associated with next-day lapses in vigilance in obstructive sleep apnea

Study ObjectivesDetermine if changes in K-complexes associated with sustained inspiratory airflow limitation (SIFL) during N2 sleep are associated with next-day vigilance and objective sleepiness.MethodsData from thirty subjects with moderate-to-severe obstructive sleep apnea who completed three in-lab polysomnograms: diagnostic, on therapeutic continuous positive airway pressure (CPAP), and on suboptimal CPAP (4 cmH₂O below optimal titrated CPAP level) were analyzed. Four 20-min psychomotor vigilance tests (PVT) were performed after each PSG, every 2 h. Changes in the proportion of spontaneous K-complexes and spectral characteristics surrounding K-complexes were evaluated for K-complexes associated with both delta (∆SWAK), alpha (∆αK) frequencies.ResultsSuboptimal CPAP induced SIFL (14.7 (20.9) vs 2.9 (9.2); %total sleep time, p < 0.001) with a small increase in apnea–hypopnea index (AHI3A: 6.5 (7.7) vs 1.9 (2.3); p < 0.01) versus optimal CPAP. K-complex density (num./min of stage N2) was higher on suboptimal CPAP (0.97 ± 0.7 vs 0.65±0.5, #/min, mean ± SD, p < 0.01) above and beyond the effect of age, sex, AHI3A, and duration of SIFL. A decrease in ∆SWAK with suboptimal CPAP was associated with increased PVT lapses and explained 17% of additional variance in PVT lapses. Within-night during suboptimal CPAP K-complexes appeared to alternate between promoting sleep and as arousal surrogates. Electroencephalographic changes were not associated with objective sleepiness.ConclusionsSustained inspiratory airflow limitation is associated with altered K-complex morphology including the increased occurrence of K-complexes with bursts of alpha as arousal surrogates. These findings suggest that sustained inspiratory flow limitation may be associated with nonvisible sleep fragmentation and contribute to increased lapses in vigilance.     

Influence of obstructive sleep apnea on serum butyrylcholinesterase activity and ischemia-modified albumin levels

OBJECTIVE:

To investigate the effect of obstructive sleep apnea and continuous positive airway pressure treatment on serum butyrylcholinesterase activity and ischemia-modified albumin levels.

METHODS:

Thirty-two patients with obstructive sleep apnea and 30 age- and sex-matched controls were enrolled and underwent a diagnostic polysomnogram. The serum butyrylcholinesterase activity, ischemia-modified albumin levels, metabolic parameters, and polysomnography scores were detected and evaluated. Nine patients were studied before and after treatment with continuous positive airway pressure.

RESULTS:

The serum ischemia-modified albumin levels were significantly higher and the butyrylcholinesterase activity was significantly lower in patients with obstructive sleep apnea than in the controls (p<0.001). The continuous positive airway pressure treatment decreased the modified albumin levels and elevated the buthrylcholinesterase activity (p = 0.019 and p = 0.023, respectively). The modified albumin levels were positively correlated with the apnea-hypopnea index (r = 0.462, p = 0.008) at baseline. Elevated ischemia-modified albumin levels can be more accurate than butyrylcholinesterase activity at reflecting the presence of obstructive sleep apnea. Receiver operating characteristic curves revealed a significant difference between the areas under the curve 0.916 for ischemia-modified albumin and 0.777 for butyrylcholinesterase (z = 2.154, p = 0.031).

CONCLUSION:

The elevated ischemia-modified albumin level was significantly associated with obstructive sleep apnea and was more sensitive than butyrylcholinesterase activity in reflecting obstructive sleep apnea. The continuous positive airway pressure treatment helped to ameliorate the imbalance.     

Lack of reliable clinical predictors to identify obstructive sleep apnea in patients with hypertrophic cardiomyopathy

OBJECTIVE:

Obstructive sleep apnea is common among patients with hypertrophic cardiomyopathy and may contribute to poor cardiovascular outcomes. However, obstructive sleep apnea is largely unrecognized in this population. We sought to identify the clinical predictors of obstructive sleep apnea among patients with hypertrophic cardiomyopathy.

METHODS:

Consecutive patients with hypertrophic cardiomyopathy were recruited from a tertiary University Hospital and were evaluated using validated sleep questionnaires (Berlin and Epworth) and overnight portable monitoring. Ninety patients (males, 51%; age, 46±15 years; body mass index, 26.6±4.9 kg/m²) were included, and obstructive sleep apnea (respiratory disturbance index ≥15 events/h) was present in 37 patients (41%).

RESULTS:

Compared with the patients without obstructive sleep apnea, patients with obstructive sleep apnea were older and had higher body mass index, larger waist circumference, larger neck circumference, and higher prevalence of atrial fibrillation. Excessive daytime sleepiness (Epworth scale) was low and similar in the patients with and without obstructive sleep apnea, respectively. The only predictors of obstructive sleep apnea (using a logistic regression analysis) were age ≥45 years (odds ratio [OR], 4.46; 95% confidence interval [CI 95%], 1.47–13.54; p = 0.008) and the presence of atrial fibrillation [OR, 5.37; CI 95%, 1.43–20.12; p = 0.013].

CONCLUSION:

Consistent clinical predictors of obstructive sleep apnea are lacking for patients with hypertrophic cardiomyopathy, which suggests that objective sleep evaluations should be considered in this population, particularly among elderly patients with atrial fibrillation.     

Frequency of flow limitation using airflow shape

Study ObjectivesThe presence of flow limitation during sleep is associated with adverse health consequences independent of obstructive sleep apnea (OSA) severity (apnea-hypopnea index, AHI), but remains extremely challenging to quantify. Here we present a unique library and an accompanying automated method that we apply to investigate flow limitation during sleep.MethodsA library of 117,871 breaths (N = 40 participants) were visually classified (certain flow limitation, possible flow limitation, normal) using airflow shape and physiological signals (ventilatory drive per intra-esophageal diaphragm EMG). An ordinal regression model was developed to quantify flow limitation certainty using flow-shape features (e.g. flattening, scooping); breath-by-breath agreement (Cohen’s ƙ); and overnight flow limitation frequency (R², %_breaths in certain or possible categories during sleep) were compared against visual scoring. Subsequent application examined flow limitation frequency during arousals and stable breathing, and associations with ventilatory drive.ResultsThe model (23 features) assessed flow limitation with good agreement (breath-by-breath ƙ = 0.572, p < 0.001) and minimal error (overnight flow limitation frequency R² = 0.86, error = 7.2%). Flow limitation frequency was largely independent of AHI (R² = 0.16) and varied widely within individuals with OSA (74[32–95]%_breaths, mean[range], AHI > 15/h, N = 22). Flow limitation was unexpectedly frequent but variable during arousals (40[5–85]%_breaths) and stable breathing (58[12–91]%_breaths), and was associated with elevated ventilatory drive (R² = 0.26–0.29; R² < 0.01 AHI v. drive).ConclusionsOur method enables quantification of flow limitation frequency, a key aspect of obstructive sleep-disordered breathing that is independent of the AHI and often unavailable. Flow limitation frequency varies widely between individuals, is prevalent during arousals and stable breathing, and reveals elevated ventilatory drive. Clinical trial registration: The current observational physiology study does not qualify as a clinical trial.     

Improvements in cognitive function and quantitative sleep electroencephalogram in obstructive sleep apnea after six months of continuous positive airway pressure treatment

Study ObjectivesUntreated obstructive sleep apnea (OSA) is associated with cognitive deficits and altered brain electrophysiology. We evaluated the effect of continuous positive airway pressure (CPAP) treatment on quantitative sleep electroencephalogram (EEG) measures and cognitive function.MethodsWe studied 167 patients with OSA (age 50 ± 13, AHI 35.0 ± 26.8) before and after 6 months of CPAP. Cognitive tests assessed working memory, sustained attention, visuospatial scanning, and executive function. All participants underwent overnight polysomnography at baseline and after CPAP. Power spectral analysis was performed on EEG data (C3-M2) in a sub-set of 90 participants. Relative delta EEG power and sigma power in NREM and EEG slowing in REM were calculated. Spindle densities (events/min) in N2 were also derived using automated spindle event detection. All outcomes were analysed as change from baseline.ResultsCognitive function across all cognitive domains improved after six months of CPAP. In our sub-set, increased relative delta power (p < .0001) and reduced sigma power (p = .001) during NREM were observed after the 6-month treatment period. Overall, fast and slow sleep spindle densities during N2 were increased after treatment.ConclusionsCognitive performance was improved and sleep EEG features were enhanced when assessing the effects of CPAP. These findings suggest the reversibility of cognitive deficits and altered brain electrophysiology observed in untreated OSA following six months of treatment.     

Total Surface Area Is Useful for Differentiating between Aggressive and Favorable Multifocal Papillary Thyroid Carcinomas

PurposeThe purpose of the present study was to identify more useful parameters for predicting behaviors of multifocal papillary thyroid carcinoma (PTC).ResultsIn 588 PTCs, tumor multifocality was found in 179 PTCs (30.4%). Multifocal tumors were significantly associated with extrathyroidal extension, lymph node metastasis, and higher tumor stage grouping (p<0.001, p<0.001, and p<0.001, respectively). The rates of nodal metastasis increased with greater TSA and TTD in PTCs. Multifocal papillary thyroid microcarcinomas (mPMCs) with TSA >3.14 cm² had higher rates of nodal metastasis than mPMCs with TSA ≤3.14 cm² (p=0.038); however, there was no significant difference between mPMCs with TTD >1.0 cm and with TTD ≤1.0 cm (p=0.325). In addition, nodal metastasis was more frequent in mPMCs with TSA >3.14 cm² than in unifocal papillary thyroid microcarcinomas (uPMCs) (TD ≤1.0 cm) (p=0.002), but not overt unifocal PTCs (TD >1.0 cm) (p=0.244).ConclusionOur results suggest that mPMCs with TSA >3.14 cm² show more aggressive behavior than uPMCs and mPMCs with TSA ≤3.14 cm². TSA could be useful in distinguishing aggressive mPMCs from favorable cases.     

Oxidative stress and quality of life in elderly patients with obstructive sleep apnea syndrome: are there differences after six months of Continuous Positive Airway Pressure treatment?

OBJECTIVES:

This study evaluated the effect of Continuous Positive Airway Pressure treatment on oxidative stress parameters and the quality of life of elderly patients with obstructive sleep apnea syndrome.

METHODS:

In total, 30 obstructive sleep apnea syndrome patients and 27 subjects without obstructive sleep apnea syndrome were included in this study. Both groups underwent quality of life and oxidative stress evaluations at baseline and after six months. Polysomnography was performed in both groups at baseline and a second time in the obstructive sleep apnea syndrome group after six months of Continuous Positive Airway Pressure treatment. All of the variables were compared between the control and obstructive sleep apnea syndrome groups in this prospective case-control study.

RESULTS:

The baseline concentrations of the antioxidant enzyme catalase were higher in the obstructive sleep apnea syndrome group than the control group. After Continuous Positive Airway Pressure treatment, the obstructive sleep apnea syndrome group exhibited a reduction in the level of oxidative stress, as indicated by a decrease in the level of lipid peroxidation measured by the malondialdehyde (MDA) concentration [pre: 2.7 nmol malondialdehyde/mL (95% 1.6-3.7) vs. post: 1.3 nmol MDA/mL (0.7-1.9), p<0.01]. Additionally, improvements were observed in two domains covered by the SF-36 questionnaire: functional capacity [pre: 77.4 (69.2-85.5) vs. post: 83.4 (76.9-89.9), p = 0.002] and pain [pre: 65.4 (52.8-78.1) vs. post: 77.8 (67.2-88.3), p = 0.004].

CONCLUSION:

Our study demonstrated that the use of Continuous Positive Airway Pressure to treat obstructive sleep apnea syndrome in elderly patients reduced oxidative stress and improved the quality of life.     

Prospective Trial of Efficacy and Safety of Ondansetron and Fluoxetine in Patients with Obstructive Sleep Apnea Syndrome

Study Objective:

Incremental withdrawal of serotonin during wake to sleep transition is postulated as a key mechanism that renders the pharyngeal airway collapsible. While serotonin promotion with reuptake inhibitors have demonstrated modest beneficial effects during NREM sleep on obstructive sleep apnea (OSA), animal studies suggest a potential therapeutic role for selective serotonin receptor antagonists (5-HT₃) in REM sleep. We aimed to test the hypothesis that a combination of ondansetron (Ond) and fluoxetine (Fl) may effectively reduce expression of disordered breathing during REM and NREM sleep in patients with OSA.

Design and Setting:

A prospective, parallel-groups, single-center trial in patients with OSA.

Participants:

35 adults with apnea hypopnea index (AHI) > 10; range 10-98.

Intervention:

Subjects were randomized to placebo, n = 7; Ond (24 mg QD), n = 9; Fl (5 mg QD) + Ond (12 mg QD), n = 9; and Fl (10 mg QD) + Ond (24 mg QD), n = 10.

Measurements and Results:

AHI was measured by in-lab polysomnography after a 7-day no-treatment period (Baseline) and on days 14 and 28 of treatment. The primary endpoint was AHI reduction at days 14 and 28. OND+FL resulted in approximately 40% reduction of baseline AHI at days 14 and 28 (unadjusted P < 0.03 for each) and improved oximetry trends. This treatment-associated relative reduction in AHI was also observed in REM and supine sleep.

Conclusions:

Combined treatment with OND+FL is well-tolerated and reduces AHI, yielding a potentially therapeutic response in some subjects with OSA.

Citation:

Prasad B; Radulovacki M; Olopade C; Herdegen JJ; Logan T; Carley DW. Prospective trial of efficacy and safety of ondansetron and fluoxetine in patients with obstructive sleep apnea syndrome. SLEEP 2010;33(7):982-989.     

Effects of Exercise Training in Patients with Chronic Heart Failure and Sleep Apnea

Study Objectives:

To test the effects of exercise training on sleep and neurovascular control in patients with systolic heart failure with and without sleep disordered breathing.

Design:

Prospective interventional study.

Setting:

Cardiac rehabilitation and exercise physiology unit and sleep laboratory.

Patients:

Twenty-five patients with heart failure, aged 42 to 70 years, and New York Heart Association Functional Class I-III were divided into 1 of 3 groups: obstructive sleep apnea (n = 8), central sleep apnea (n = 9) and no sleep apnea (n = 7).

Interventions:

Four months of no-training (control) followed by 4 months of an exercise training program (three 60-minute, supervised, exercise sessions per week).

Measures and Results:

Sleep (polysomnography), microneurography, forearm blood flow (plethysmography), peak VO_2, and quality of life were evaluated at baseline and at the end of the control and trained periods. No significant changes occurred in the control period. Exercise training reduced muscle sympathetic nerve activity (P < 0.001) and increased forearm blood flow (P < 0.01), peak VO₂(P < 0.01), and quality of life (P < 0.01) in all groups, independent of the presence of sleep apnea. Exercise training improved the apnea-hypopnea index, minimum O₂ saturation, and amount stage 3-4 sleep (P < 0.05) in patients with obstructive sleep apnea but had no significant effects in patients with central sleep apnea.

Conclusions.

The beneficial effects of exercise training on neurovascular function, functional capacity, and quality of life in patients with systolic dysfunction and heart failure occurs independently of sleep disordered breathing. Exercise training lessens the severity of obstructive sleep apnea but does not affect central sleep apnea in patients with heart failure and sleep disordered breathing.

Citation:

Ueno LM; Drager LF; Rodrigues ACT; Rondon MUPB; Braga AMFW; Mathias W; Krieger EM; Barretto ACP; Middlekauff HR; Lorenzi-Filho G; Negrão CE. Effects of exercise training in patients with chronic heart failure and sleep apnea. SLEEP 2009;32(5):637-647.     

Surgical treatment of endometrial cancer in developing countries: reasons to consider systematic two-step surgical treatment

OBJECTIVE:The aim of this study was to determine the lymph node status in a large cohort of women with endometrial cancer from the public health system who were referred to an oncology reference center in Brazil to identify candidates for the omission of lymphadenectomy based on clinicopathological parameters.METHODS:We retrospectively analyzed a cohort of 310 women with endometrial cancer (255 endometrioid, 40 serous, and 15 clear cell tumors) treated between 2009 and 2014. We evaluated the histological type, grade (low vs. high), tumor size (cm), depth of myometrial invasion (≤50%, >50%) and lymphovascular space invasion to determine which factors were correlated with the presence of lymph node metastasis.RESULTS:The factors related to lymph node involvement were tumor size (p=0.03), myometrial invasion (p<0.01), tumor grade (p<0.01), and lymphovascular space invasion (p<0.01). The histological type was not associated with the nodal status (p=0.52). Only twelve of 176 patients (6.8%) had low-grade endometrioid carcinoma, tumor size ≤2 cm and <50% myometrial infiltration.CONCLUSIONS:The omission of lymphadenectomy based on the histological type, grade, tumor size and depth of myometrial invasion is not likely to have a large impact on the surgical treatment of endometrial cancer in our population because most patients present with large and advanced tumors. New strategies are proposed that prioritize hysterectomy performed in a general hospital as soon as possible after diagnosis, followed by an evaluation of the need for lymph node dissection at a reference center.     

Long-Term Safety and Efficacy of Prolonged Dual Antiplatelet Therapy according to Baseline Anemia after Percutaneous Coronary Intervention

PurposeWe aimed to evaluate the outcomes of prolonged dual antiplatelet therapy (DAPT) depending on baseline anemia after percutaneous coronary intervention (PCI).Materials and MethodsAmong the 1470 study participants, 448 (30.5%) were classified as having baseline anemia. We categorized the study population according to baseline anemia and DAPT duration: ≤12-month (m) DAPT (n=226) vs. >12-m DAPT (n=222) in anemic patients, and ≤12-m DAPT (n=521) vs. >12-m DAPT (n=501) in non-anemic patients.ResultsDuring a follow-up of 80.8 (interquartile range 60.6–97.1) months, anemic patients showed a higher incidence of major adverse cardiovascular and cerebrovascular events (MACCEs) (26.9% vs. 17.1%, p<0.001) and major bleeding (9.8% vs. 5.1%, p=0.006). Among the non-anemic patients, prolonged DAPT was associated with a reduced rate of MACCEs [inverse probability of treatment weighting (IPTW) adjusted hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.63–0.96; p=0.019] without an increase in major bleeding (IPTW adjusted HR, 1.12; 95% CI, 0.75–1.68; p=0.574). However, prolonged DAPT was not related to the incidence of MACCEs (IPTW adjusted HR, 1.11; 95% CI, 0.88–1.39; p=0.387), with increased major bleeding (IPTW adjusted HR, 2.01; 95% CI, 1.32–3.06; p=0.001) among anemic patients.ConclusionAlthough extended DAPT led to a reduction in MACCEs in non-anemic patients, it was related to increased major bleeding without reducing MACCEs in anemic patients.     

Correlation of obstructive sleep apnea hypopnea syndrome with metabolic syndrome in snorers

Though obstructive sleep apnea hypopnea syndrome (OSAHS) and metabolic syndrome (MS) are correlated; the contributing factors for the occurrence of MS in Chinese snorers remain largely undefined. We aimed to investigate the associated pathogenesis of coexistence of OSAHS and MS in Chinese snorers. A total of 144 Chinese habitual snorers were divided into 3 groups, the control group (simple snorers) (n  =  36), the mild OSAHS group (n  =  52) and the moderate-to-severe OSAHS group (n  =  56). The incidence of MS in the moderate-to-severe OSAHS group (26.8%) was significantly higher than that in the control group (8.3%), the mild OSAHS group (11.1%) and all the OSAHS patients (19.45%) (all P < 0.05). Homeostatic model assessment (HOMA) index and proinsulin (PI) were negatively correlated with nocturnal meanSpO₂ and miniSpO₂. Meanwhile, nocturnal SpO₂ were negatively correlated with body mass index, waist and neck circumferences and diastolic blood pressure, but positively correlated with total cholesterol and high-density lipoprotein cholesterol. The study indicated that in Chinese snorers, moderate-to-severe OSAHS was closely associated with MS via nocturnal hypoxemia.     

Associations between sleep apnea and advanced brain aging in a large-scale population study

Advanced brain aging is commonly regarded as a risk factor for neurodegenerative diseases, for example, Alzheimer’s dementia, and it was suggested that sleep disorders such as obstructive sleep apnea (OSA) are significantly contributing factors to these neurodegenerative processes. To determine the association between OSA and advanced brain aging, we investigated the specific effect of two indices quantifying OSA, namely the apnea–hypopnea index (AHI) and the oxygen desaturation index (ODI), on brain age, a score quantifying age-related brain patterns in 169 brain regions, using magnetic resonance imaging and overnight polysomnography data from 690 participants (48.8% women, mean age 52.5 ± 13.4 years) of the Study of Health in Pomerania. We additionally investigated the mediating effect of subclinical inflammation parameters on these associations via a causal mediation analysis. AHI and ODI were both positively associated with brain age (AHI std. effect [95% CI]: 0.07 [0.03; 0.12], p-value: 0.002; ODI std. effect [95% CI]: 0.09 [0.04; 0.13], p-value: < 0.0003). The effects remained stable in the presence of various confounders such as diabetes and were partially mediated by the white blood cell count, indicating a subclinical inflammation process. Our results reveal an association between OSA and brain age, indicating subtle but widespread age-related changes in regional brain structures, in one of the largest general population studies to date, warranting further examination of OSA in the prevention of neurodegenerative diseases.     

Neck fat and obstructive sleep apnea in obese adolescents

Study ObjectivesIncreased neck circumference, a surrogate for the neck fat that can narrow the upper airway in obese individuals, is a risk factor for obstructive sleep apnea syndrome (OSAS) in adults, but the association between neck fat and OSAS in adolescent males and females is unknown. We hypothesized that obese adolescents with OSAS have more neck fat than controls, females more neck fat than males, and that neck fat correlates with obesity and OSAS severity.MethodsObese adolescents with OSAS and obese and normal-weight controls underwent upper airway magnetic resonance imaging, polysomnography, and anthropometrics, including neck circumference measurement. Intra-neck and subcutaneous neck fat measurements were manually segmented and compared among the three groups using ANOVA and between males and females using t-tests. The relationship between polysomnographic parameters and neck fat measurements was assessed in adolescents with OSAS using Pearson correlations.ResultsOne-hundred nineteen adolescents (38 females) were studied: 39 obese with OSAS, 34 obese controls, and 46 normal-weight controls. Neck fat was not greater in adolescents with OSAS compared to obese controls (p=0.35), and neck fat volume was not related to OSAS severity (p = 0.36). However, obese adolescents had more neck fat than normal-weight controls (p < 0.001), and neck fat volume correlated with neck circumference (r = 0.53, p < 0.001). Females had significantly greater cross-sectional neck fat than males (p < 0.001).ConclusionsWhile neck fat is associated with obesity and neck circumference in adolescents and is greater in females versus males, it does not appear to correlate with presence and severity of OSAS.     

Heart rate variability during wakefulness as a marker of obstructive sleep apnea severity

Study ObjectivesPatients with obstructive sleep apnea (OSA) exhibit heterogeneous heart rate variability (HRV) during wakefulness and sleep. We investigated the influence of OSA severity on HRV parameters during wakefulness in a large international clinical sample.Methods1247 subjects (426 without OSA and 821 patients with OSA) were enrolled from the Sleep Apnea Global Interdisciplinary Consortium. HRV parameters were calculated during a 5-minute wakefulness period with spontaneous breathing prior to the sleep study, using time-domain, frequency-domain and nonlinear methods. Differences in HRV were evaluated among groups using analysis of covariance, controlling for relevant covariates.ResultsPatients with OSA showed significantly lower time-domain variations and less complexity of heartbeats compared to individuals without OSA. Those with severe OSA had remarkably reduced HRV compared to all other groups. Compared to non-OSA patients, those with severe OSA had lower HRV based on SDNN (adjusted mean: 37.4 vs. 46.2 ms; p < 0.0001), RMSSD (21.5 vs. 27.9 ms; p < 0.0001), ShanEn (1.83 vs. 2.01; p < 0.0001), and Forbword (36.7 vs. 33.0; p = 0.0001). While no differences were found in frequency-domain measures overall, among obese patients there was a shift to sympathetic dominance in severe OSA, with a higher LF/HF ratio compared to obese non-OSA patients (4.2 vs. 2.7; p = 0.009).ConclusionsTime-domain and nonlinear HRV measures during wakefulness are associated with OSA severity, with severe patients having remarkably reduced and less complex HRV. Frequency-domain measures show a shift to sympathetic dominance only in obese OSA patients. Thus, HRV during wakefulness could provide additional information about cardiovascular physiology in OSA patients.Clinical Trial Information: A Prospective Observational Cohort to Study the Genetics of Obstructive Sleep Apnea and Associated Co-Morbidities (German Clinical Trials Register - DKRS, DRKS00003966) https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00003966     

Obstructive sleep apnea is associated with increased arterial stiffness in severe obesity

Obstructive sleep apnea is associated with obesity and metabolic syndrome, leading to greater cardiovascular risk. Severely obese patients with obstructive sleep apnea may still be at risk of adverse health outcomes, even without previous cardiovascular disease. Pulse wave analysis non‐invasively measures peripheral pulse waveforms and derives measures of haemodynamic status, including arterial stiffness, augmentation pressure and subendocardial viability ratio. We hypothesized that the presence of obstructive sleep apnea in severe obesity, even in the absence of an antecedent history of cardiovascular disease, would affect measurements derived from pulse wave analysis. Seventy‐two severely obese adult subjects [obstructive sleep apnea 47 (body mass index 42 ± 7 kg m^?2), without obstructive sleep apnea (non‐OSA) 25 (body mass index 40 ± 5 kg m^?2)] were characterised using anthropometric, respiratory and cardio‐metabolic parameters. Groups were similar in age, body mass index and gender. More subjects with obstructive sleep apnea had metabolic syndrome [obstructive sleep apnea 60%, without obstructive sleep apnea (non‐OSA) 12%]. Those with obstructive sleep apnea had greater arterial stiffness, augmentation pressure and decreased subendocardial viability ratio (all P < 0.001), with significantly higher systolic (P = 0.003), diastolic (P = 0.04) and mean arterial pressures (P = 0.004) than patients without obstructive sleep apnea (non‐OSA). Arterial stiffness correlated with mean arterial blood pressure (P = 0.003) and obstructive sleep apnea severity (apnea–hypopnea index; P < 0.001). apnea–hypopnea index significantly predicted arterial stiffness in multiple regression analysis, but components of the metabolic syndrome did not. Thus, patients with obstructive sleep apnea with severe obesity have increased arterial stiffness that may potentially influence cardiovascular risk independently of metabolic abnormalities. The presence of obstructive sleep apnea in severe obesity identifies a group at high cardiovascular risk; clinicians should ensure that risk factors are managed appropriately in this group whether or not treatment of obstructive sleep apnea is offered or accepted by patients.     

Characterization of obstructive sleep apnea–hypopnea syndrome (OSA) population by means of cluster analysis

Obstructive sleep apnea–hypopnea syndrome (OSA) is being identified increasingly as an important health issue. It is typified by repeated episodes of upper airway collapse during sleep leading to occasional hypoxaemia, sleep fragmentation and poor sleep quality. OSA is also being considered as an independent risk factor for hypertension, diabetes and cardiovascular diseases, leading to increased multi‐morbidity and mortality. Cluster analysis, a powerful statistical set of techniques, may help in investigating and classifying homogeneous groups of patients with similar OSA characteristics. This study aims to investigate the (possible) different groups of patients in an OSA population, and to analyse the relationships among the main clinical variables in each group to better understand the impact of OSA on patients. Starting from a well‐characterized OSA population of 198 subjects afferent to our sleep centre, we identified three different communities of OSA patients. The first has a very severe disease [apnea–hypopnea index (AHI) = 65.91 ± 22.47] and sleep disorder has a strong impact on daily life: a low level of diurnal partial pressure of oxygen (PaO₂) (77.39 ± 11.64 mmHg) and a high prevalence of hypertension (64%); the second, with less severe disease (AHI = 28.88 ± 17.13), in which sleep disorders seem to be less important for diurnal PaO₂ and have a minimum impact on comorbidity; and the last with very severe OSA (AHI = 57.26 ± 15.09) but with a low risk of nocturnal hypoxaemia (T90 = 11.58 ± 8.54) and less sleepy (Epworth Sleepiness Scale 10.00 ± 4.77).     

Hypoadiponectinemia is Related to Sympathetic Activation and Severity of Obstructive Sleep Apnea

Study Objectives:

Hypoadiponectinemia is associated with cardiovascular morbidity and diabetes mellitus. We hypothesize that adiponectin may be downregulated in sleep apnea through various mechanisms, contributing to cardiometabolic risks. This study investigated the relationship between serum adiponectin and sleep disordered breathing and its potential determinants.

Design:

Cross-sectional study.

Subjects and setting:

Adult men without prevailing medical comorbidity from the sleep clinic in a teaching hospital.

Measurements & Results:

One hundred thirty-four men underwent polysomnography, with mean age of 43.9 (9.8) years, and median apnea-hypopnea index (AHI) of 17.1 (5.7, 46.6). Overnight urine samples for catecholamines and blood samples for analyses of insulin, glucose and adiponectin levels from fasting subjects were taken. Insulin resistance was estimated by homeostasis model assessment (HOMA-IR). Magnetic resonance imaging was performed to quantify the amount of abdominal visceral fat. Serum adiponectin level, adjusted for age, body mass index, and visceral fat volume, was significantly lower in subjects with severe obstructive sleep apnea (AHI ≥ 30) compared with those with an AHI of less than 30: 4.0 (3.1, 5.4) versus 5.4 (3.6, 7.9) μg/mL, P = 0.039. After we adjusted for adiposity, adiponectin levels remained negatively correlated with AHI (P = 0.037), arousal index (P = 0.022), HOMA-IR/fasting insulin (P < 0.001), and urinary norepinephrine and normetanephrine (P < 0.008). In a multiple stepwise regression model, the independent determinants of adiponectin after adjustment for adiposity were HOMA-IR (P < 0.001) and urinary norepinephrine and normetanephrine (P = 0.037).

Conclusions:

Adiponectin was suppressed in subjects with severe obstructive sleep apnea, independent of obesity. Adiponectin levels were determined by insulin resistance and sympathetic activation, factors that may be totally or partially attributed to sleep disordered breathing.

Citation:

Lam JCM; Xu A; Tam S; Khong PL; Yao TJ; Lam DCL; Lai AYK; Lam B; Lam KSL; Ip MSM. Hypoadiponectinemia is related to sympathetic activation and severity of obstructive sleep apnea. SLEEP 2008;31(12):1721–1727.     

Brachial-Ankle Pulse Wave Velocity Predicts Decline in Renal Function and Cardiovascular Events in Early Stages of Chronic Kidney Disease

Objective: In this study, we investigated the predictive capacity of the brachial-ankle aortic pulse wave velocity (baPWV), a marker of arterial stiffness, for the decline in renal function and for cardiovascular events in the early stages of chronic kidney disease (CKD).Method: Two hundred forty-one patients who underwent a comprehensive check-up were included and were divided into two groups according to their estimated glomerular filtration rates (eGFR): patients with CKD categories G2, G3a and G3b (30 ≤ eGFR < 90 ml/min/1.73m², eGFR < 90 group; n=117) and those with eGFR ≥ 90 ml/min/1.73 m² (eGFR ≥ 90 group; n=124). The change in renal function, the eGFR change, was determined by the slope of eGFR against time. We analysed whether baPWV was associated with eGFR change or predicted cardiovascular events.Results: baPWV was independently associated with eGFR change in a multivariate analysis of the total patients (β=-0.011, p=0.011) and remained significantly associated with eGFR change in a subgroup analysis of the eGFR < 90 group (β=-0.015, p=0.035). baPWV was independently associated with cardiovascular events (odds ratio=1.002, p=0.048) in the eGFR < 90 group, but not in the eGFR ≥ 90 group. The receiver operative characteristic curve analysis showed that 1,568 cm/sec was the cut-off value of baPWV for predicting CV events in the eGFR < 90 group (area under curve=0.691, p=0.03)Conclusions: In patients with early stages of CKD, baPWV was independently associated with the decline in renal function and short-term cardiovascular events.