The Link Between Obstructive Sleep Apnea and Cardiovascular Disease.

Obstructive sleep apnea (OSA) is common in the general population and highly prevalent in patients with cardiovascular disease. In this paper, we review (1) the pathophysiological mechanisms of OSA that may causally contribute to cardiovascular disease; (2) current evidence regarding the association between OSA and hypertension, stroke, ischemic heart disease, heart failure, atrial fibrillation, and cardiovascular mortality; and (3) the impact of continuous positive airway pressure (CPAP) treatment on cardiovascular risk factors and outcomes. We emphasize the importance of obesity as a comorbidity of OSA and a confounder in the association between OSA and cardiovascular disease. We also discuss the importance of addressing obesity in patients with OSA, as a strategy to reduce the burden of cardiovascular risk factors in this population. Implications for the approach of patients' OSA in clinical practice and future research directions are discussed.

The Role of Patient-Reported Outcomes in Sleep Measurements.

Several questionnaires aka patient-reported outcome measures (PROMs) have been developed for specific use in sleep medicine. Some PROMS are "disease-specific," that is, related to a specific sleep disorder, whereas others are generic. These PROMS constitute a valuable add-on to the conventional history taking. They can be used in the areas of research, clinical practice, and quality of health care appraisal. Still, these instruments have inherent limitations, requiring proficient application in the various areas of interest. Disease-specificity includes a risk for nosologic bias that may confound diagnostic and therapeutic results. Future research should provide solutions for shortcomings of presently available questionnaires.

Adult-onset congenital central hypoventilation syndrome due to PHOX2B mutation.

Central hypoventilation in adult patients is a rare life-threatening condition characterised by the loss of automatic breathing, more pronounced during sleep. In most cases, it is secondary to a brainstem lesion or to a primary pulmonary, cardiac or neuromuscular disease. More rarely, it can be a manifestation of congenital central hypoventilation syndrome (CCHS). We here describe a 25-year-old woman with severe central hypoventilation triggered by analgesics. Genetic analysis confirmed the diagnosis of adult-onset CCHS caused by a heterozygous de novo poly-alanine repeat expansion of the PHOX2B gene. She was treated with nocturnal non-invasive ventilation. We reviewed the literature and found 21 genetically confirmed adult-onset CCHS cases. Because of the risk of deleterious respiratory complications, adult-onset CCHS is an important differential diagnosis in patients with central hypoventilation.

Sex differences in the association between arterial hypertension, blood pressure, and sleep apnea in the general population.

STUDY OBJECTIVES: To assess sex-related differences in the relationship between hypertension (HT), blood pressure (BP), and sleep apnea in the general population. METHODS: We performed home polygraphy in a cohort of 1809 men and women in the general population. Office BP was measured. Presence of HT (drug-treated, physician-diagnosed, or high BP during study visit) was also recorded. HT rate and BP were assessed over a range of 7 sleep apnea severity categories based on the respiratory event index (REI). RESULTS: The age-adjusted HT prevalence rate increased with higher REI in both sexes. After additional adjustment for obesity the association remained significant in women but not in men. In participants not treated with antihypertensive medications, age-adjusted BP increased with REI. Remarkably, the association was already significant within the normal range (REI < 5 events/h). The REI threshold for higher BP was situated at a distinctly lower cutoff point in women compared to men. After additional adjustment for obesity, the associations remained significant for diastolic but not systolic BP. CONCLUSIONS: Significant increases in the age-adjusted BP and HT rate in the general population were present at lower REI cutoffs in women compared to men. Even a very low number of respiratory events was associated with higher BP and HT prevalence. Adjustment for obesity attenuated these associations, especially in men. Sex differences in BP susceptibility across the sleep apnea spectrum may be present.

Sex-specific sleep apnea screening questionnaires: closing the performance gap in women.

BACKGROUND: The availability of poly(somno)graphy [P(S)G] for sleep apnea (SA) diagnosis is limited, making pre-test case evaluation an important challenge. The Neck, Obesity, Snoring, Age, Sex (NoSAS) and STOP-Bang (SBQ) scores are accepted screening tests, but their sex-specific performance in the general population is unknown. OBJECTIVE: To compare the sex-specific diagnostic characteristics of the NoSAS and SBQ scores, and to optimize the performance of these tools for men and women. METHODS: Participants from a population-based cohort (n = 2205) underwent clinical evaluation, including NoSAS, SBQ, and home polygraphy. RESULTS: We obtained successful polygraphy in 1809 participants. Moderate-to-severe SA was present in 11.7%. Diagnostic performance indices of NoSAS and the SBQ calculated on the overall group (men + women) overestimated the performance in both sexes separately. The sensitivity of NoSAS for an apnea/hypopnea index (AHI) ≥15 h-1 was acceptable in men (87.1%), but low in women (55.3%). The reverse was true for the specificity (39.9% in men, 87.4% in women). A similar sex-specific difference in diagnostic performance was seen with the SBQ. Using women-specific cut-offs for the scores (NoSAS ≥6 or SBQ ≥2) and neck circumference (>35 cm) increased the sensitivity in women to levels similar to men (88.5 and 87.2%). Although specificity decreased, it still remained higher than in men. CONCLUSION: In women, the sensitivity of NoSAS and the SBQ is too low for SA screening in the general population. Sex-specific cut-offs reverse this imbalance and achieve test sensitivities in women similar to those in men, whilst still retaining higher specificities than in men. Sleep questionnaires performance reporting should be sex-stratified.

Phenotype and Risk Burden of Sleep Apnea: A Population-Based Cohort Study.

Sleep apnea (SA) prevalence had increased. The socioeconomic burden is significant because of healthcare-related costs and adverse outcome, especially in moderate-to-severe SA. However, the population impact is unclear, particularly for mild SA. We aimed to assess the current prevalence and the cardiovascular risk associates of SA in the general population. We performed home polygraphy and extensive clinical, sociodemographic, and cardiovascular assessment in 2205 eligible subjects from a population-based cohort. Successful polygraphy was obtained in 1809 subjects (mean age, 56.0; SD, 5.9 years; 52.3% women). The prevalence was 41.0%, 11.8%, and 6.5% for mild, moderate, and severe SA in men and 26.6%, 4.4%, and 1.2% in women. Male sex, age, increasing BMI, and snoring were independently associated with SA, whereas sleepiness or tiredness were not. Compared with those without SA, mild SA was associated with (age- and sex-adjusted OR; 95% CI): diabetes mellitus (2.40; 1.52-3.80), hypertension (1.76; 1.42-2.19), left ventricular hypertrophy (1.36; 1.03-1.79), arterial plaques (1.19; 0.94-1.52), and increased IL-6 (interleukin-6) levels (1.37; 1.10-1.72). These associations were more pronounced in moderate-to-severe SA. To conclude, SA is highly prevalent in the middle-aged general population. It is largely undetected and undetectable using a symptom-based strategy. Yet, even the large group with mild SA shows a manifestly higher metabolic, inflammatory, and cardiovascular risk factor burden, with potential public health implications.

Sleep apnea and the impact on cardiovascular risk in patients with Marfan syndrome.

BACKGROUND: Marfan syndrome (MFS) is an inherited connective tissue disorder characterized by ectopia lentis, aortic root dilation and dissection and specific skeletal features. Obstructive sleep apnea (OSA) in MFS has been described earlier but the prevalence and its relation with the cardiovascular risk is still controversial. This study aimed to further investigate these aspects. METHODS: In this prospective longitudinal study, we performed an attended polysomnography in 40 MFS patients (60% women, 37 ± 12.8 years) and evaluated several cardiovascular parameters through echocardiography, resting electrocardiogram, 24 hr-Holter monitoring and serum NT-ProBNP measurements. RESULTS: We found that OSA was present in 42.5% of the patients and that higher body mass index was the most important factor associated with the presence of OSA. We observed that overweight was present in 27.5% of the patients in the whole cohort and in 55.6% if >40 years. Furthermore, when evaluating the impact of OSA on the cardiovascular system, we observed that patients with OSA tended to have higher systolic blood pressure, larger distal aortic diameters and a higher prevalence of ventricular arrhythmia. These differences were, however, not significant after adjusting for confounders. CONCLUSIONS: Our study shows a high prevalence of OSA and a high prevalence of overweight in MFS patients. We found some trends between OSA and cardiovascular features but we could not establish a solid association. Our study, however might be underpowered, and a multicenter collaborative study could be very useful to answer some important open questions.

Titration procedures for nasal CPAP: automatic CPAP or prediction formula?

BACKGROUND: The best method for titration of continuous positive airway pressure (CPAP) therapy in obstructive sleep apnea (OSA) syndrome has not yet been established. The 90th or 95th percentiles of the pressure titrated over time by automatic CPAP (A-CPAP) have been recommended as reference for prescribing therapeutic fixed CPAP (F-CPAP). We compared A-CPAP to F-CPAP, which was determined by a common prediction formula. METHODS: Forty-five patients who were habituated to F-CPAP underwent titration polysomnography. In a double-blind, randomized order, each patient used an A-CPAP device in the autotitration and in the fixed pressure mode during one half of the night. Apnea-hypopnea index (AHI) and pressure profiles were primary outcomes. Bias and precision were additionally assessed for both CPAP modes. RESULTS: No significant differences in various sleep parameters or in subjective sleep quality evaluation were found. The AHI was effectively lowered in both CPAP modes (A-CPAP 7.7 [10.8]events/h versus F-CPAP 5.4 [9.0]events/h, p=0.061). Comparison of group means showed that F-CPAP closely paralleled mean (Pmean) and median (P50), but not the 95th percentile (P95) pressure, of A-CPAP. While bias was lowest for Pmean and P50, there was a lack of precision in all A-CPAP pressure categories. CONCLUSIONS: We confirm that F-CPAP set by prediction formula is not worse in terms of AHI control than A-CPAP. On average, F-CPAP parallels Pmean and P50 but not P95. However, due to imprecise matching, individual F-CPAP values cannot be derived from Pmean or P50.

Titration efficacy of two auto-adjustable continuous positive airway pressure devices using different flow limitation-based algorithms.

BACKGROUND: Auto-adjustable continuous positive airway pressure devices are widely used in titration procedures to determine therapeutic pressure levels in obstructive sleep apnea patients. However, differences in operational characteristics may influence the effect on the apnea-hypopnea index (AHI). OBJECTIVES: We compared the titration performance of two devices based on detection of inspiratory flow limitation, i.e. the Respironics REMstar Auto (RR) and the ResMed Spirit (RS). METHODS: Fifty obstructive sleep apnea patients were recruited for a double-blind randomized crossover trial. Both devices were employed overnight by means of split-night polysomnography. The primary outcome was the AHI. Secondary outcome measures were the snoring index, pressure profiles and subjective appraisal of sleep quality assessed the morning after the sleep study. The Wilcoxon signed rank test for matched pairs was applied to assess differences between treatment conditions. RESULTS: No significant differences were found in sleep parameters, subjective sleep quality and snoring index. The use of the RR was associated with a significantly lower AHI in comparison with the RS [mean (SD) 6.9 (11.6)/h vs. 9.4 (9.2)/h, p = 0.004]. This result was obtained at significantly lower pressure levels [P95 9.2 (2.3) cm H(2)O vs. 10.2 (1.5) cm H(2)O, p = 0.001]. CONCLUSION: While the RR provided a lower AHI than the RS at lower pressure levels, it could not be assessed whether this difference was relevant for clinical outcomes. However, this face-to-face comparison of Auto-adjustable continuous positive airway pressure devices seems useful for the assessment of titration efficacy.

Efficacy of flow- vs impedance-guided autoadjustable continuous positive airway pressure: a randomized cross-over trial.

STUDY OBJECTIVES: Autoadjustable continuous positive airway pressure (CPAP) devices are increasingly used in the treatment of obstructive sleep apnea (OSA). Since different measurements of upper airway obstruction are applied, it is uncertain whether these devices are equally effective in controlling sleep-disordered breathing. Hypothesizing that differences in therapeutic efficacy were to come out, we compared the performance of the AutoSet device (ResMed; Sydney, Australia), which features autoadjustable positive airway pressure (APAP) guided by detection of flow limitation (APAPfl), with the SOMNOsmart device (Weinmann; Hamburg, Germany), which features APAP guided by the forced oscillation technique (APAPfot). DESIGN: A double-blind, randomized, cross-over trial. SETTING: The sleep disorders center and sleep laboratory of a university hospital. PATIENTS AND INTERVENTIONS: An overnight CPAP autotitration procedure was performed in 30 patients with OSA. A split-night protocol allowed that each patient used both devices. MEASUREMENTS AND RESULTS: Using polysomnography, sleep, indexes of sleep-disordered breathing, snoring, and CPAP levels were recorded. No significant differences were found in conventional sleep variables. While the apnea-hypopnea index (AHI) was lower with APAPfl (3.5 +/- 5.6/h) as compared to APAPfot (9.9 +/- 31.0/h), the difference was not statistically significant (mean +/- SD). The snoring index, however, was significantly lower with APAPfl (35.3 +/- 53.7/h vs 111.6 +/- 175.4/h, respectively; p = 0.01). The median and 95th percentile pressure levels rose from wakefulness to sleep in APAPfl, but decreased in APAPfot. Higher pressure variability was present in the latter method. CONCLUSIONS: These findings suggest that the APAPfl is superior to APAPfot in the control of snoring. While a lower AHI was achieved with APAPfl, at the expense of a higher median pressure but less pressure variability, the difference with APAPfot was not statistically significant.

Comfort and pressure profiles of two auto-adjustable positive airway pressure devices: a technical report.

STUDY OBJECTIVES: The purpose of this study was to compare comfort parameters and pressure profiles of the AutoSet (Resmed) and the SOMNOsmart (Weinmann), two auto-adjustable positive airway pressure (APAP) devices. SETTING: The sleep disorders center of a university hospital. DESIGN: A single-blind randomized trial protocol was applied. A split night procedure allowed each patient to be treated in a crossover fashion with both APAP devices during one overnight study. PATIENTS AND METHODS: Fifty consecutive obstructive sleep apnea (OSA) patients were recruited. Each patient filled out an evaluation form for both devices after the study night. Visual analogue scales were used to score four comfort measures. Three CPAP outcomes generated by the devices (P50, P95 and Pmax) were assessed, compared with each other and correlated with the individually predicted CPAP (Ppred). RESULTS: Forty-five males and 5 females, mean age 53.0 years, body mass index 31.0, were included. The mean apnea-hypopnea index was 58.7, the mean arousal index was 54.3. Mean CPAP-compliance before the titration study was 4.9 h per night. Comparison of the two devices regarding the effect on the subjective sleep quality parameters showed no differences. The AutoSet pressure outcomes correlated significantly better with Ppred in comparison with the SOMNOsmart. The P50 and P95 but not the Pmax values were significantly lower in the SOMNOsmart as compared with the AutoSet (P50: 5.1+/-1.3 vs 7.1 +/- 1.9 mbar, P<0.0001; P95: 7.8+/-3.0 vs 9.6+/-1.9 mbar, P<0.0005; Pmax: 10.0+/-3.4 vs 10.8+/-1.8 mbar, NS). CONCLUSION: While the subjective tolerance of the two APAP machines was comparable, these devices were characterized by different pressure profiles. The pressure parameters of the AutoSet correlated better with Ppred than those of the SOMNOsmart.

Feasibility of following up gamma-hydroxybutyric acid concentrations in sodium oxybate (Xyrem®)-treated narcoleptic patients using dried blood spot sampling at home: an exploratory study.

BACKGROUND: Gamma-hydroxybutyric acid (GHB), well known as a party drug, especially in Europe, is also legally used (sodium oxybate, Xyrem(®)) to treat a rare sleep disorder, narcolepsy with cataplexy. This exploratory study was set up to measure GHB concentrations in dried blood spots (DBS) collected by narcoleptic patients treated with sodium oxybate. Intra- and inter-individual variation in clinical effects following sodium oxybate administration has been reported. The use of DBS as a sampling technique, which is stated to be easy and convenient, may provide a better insight into GHB concentrations following sodium oxybate intake in a real-life setting. OBJECTIVE: The aim was twofold: evaluation of the applicability of a recently developed DBS-based gas chromatography-mass spectrometry (GC-MS) method, and of the feasibility of the sampling technique in an ambulant setting. METHODS: Seven narcoleptic patients being treated with sodium oxybate at the Department for Respiratory Diseases of Ghent University Hospital were asked to collect DBS approximately 20 min after the first sodium oxybate (Xyrem(®); UCB Pharma Ltd, Brussels, Belgium) intake on a maximum of 7 consecutive days. Using an automatic lancet, patients pricked their fingertip and, after wiping off the first drop of blood, subsequent drops were collected on a DBS card. The DBS cards were sent to the laboratory by regular mail and, before analysis, were visually inspected to record DBS quality (large enough, symmetrically spread on the filter paper with even colouration on both sides of the filter paper). RESULTS: Of the seven patients, three patients succeeded to collect five series of DBS, one patient decided to cease participation because of nausea, one was lost during follow-up and two patients started falling asleep almost immediately after the intake of sodium oxybate. Analysing the DBS in duplicate resulted in acceptable within-DBS card precision. DBS with acceptable quality were obtained by patients without supervision. CONCLUSION: Our results demonstrate the acceptable precision of the complete procedure, from sampling at home to quantitative analysis in the laboratory. Given the intra- and inter-individual variability in clinical effects seen with sodium oxybate, the easy adaptation of DBS sampling opens the possibility of following up GHB concentrations in patients in real-life settings in future studies.

The value of auto-adjustable CPAP devices in pressure titration and treatment of patients with obstructive sleep apnea syndrome.

In moderate to severe obstructive sleep apnea syndrome (OSAS), the use of Continuous Positive Airway Pressure (CPAP) is the gold standard therapy. In the last decade, new technologies such as auto-adjustable CPAP (APAP) have been promoted as having an added advantage over CPAP, because of their ability to adapt the pressure level to the patient's need at all times. This could logically result in the deliverance of lower pressures, which was hypothesized to improve patient acceptance and compliance for therapy. Several clinical trials have been performed with APAP in different modalities, as a titration tool in attended or unattended conditions, or as a treatment device for chronic use. Comparison of these trials is challenging, since APAP technology is evolving promptly and devices differ not only in how sleep-disordered breathing is detected, but also in how the operational algorithm responds accordingly. Although the question remains whether proof has yet been delivered of the superiority of this technology over CPAP, there is a tendency to accept it as common standard practice in OSAS titration and treatment. This review will bring available evidence on this subject into perspective.