Sigurdur Juliusson

The interaction of obstructive sleep apnea and obesity on the inflammatory markers C-reactive protein and interleukin-6: the Icelandic Sleep Apnea Cohort.

STUDY OBJECTIVES To assess the relative roles and interaction of obstructive sleep apnea (OSA) severity and obesity on interleukin-6 (IL-6) and C-reactive protein (CRP) levels. DESIGN Cross-sectional cohort. SETTING The Icelandic Sleep Apnea Cohort. PARTICIPANTS 454 untreated OSA patients (380 males and 74 females), mean ± standard deviation age 54.4 ± 10.6 yr. INTERVENTIONS N/A. MEASUREMENTS AND RESULTS Participants underwent a sleep study, abdominal magnetic resonance imaging to measure total abdominal and visceral fat volume, and had fasting morning IL-6 and CRP levels measured in serum. A significantly higher correlation was found for BMI than visceral fat volume with CRP and IL-6 levels. Oxygen desaturation index, hypoxia time, and minimum oxygen saturation (SaO₂) significantly correlated with IL-6 and CRP levels, but apnea-hypopnea index did not. When stratified by body mass index (BMI) category, OSA severity was associated with IL-6 levels in obese participants only (BMI > 30 kg/m²). A multiple linear regression model with interaction terms showed an independent association of OSA severity with IL-6 levels and an interaction between OSA severity and BMI, i.e., degree of obesity altered the relationship between OSA and IL-6 levels. An independent association of OSA severity with CRP levels was found for minimum SaO₂ only. A similar interaction of OSA severity and BMI on CRP levels was found for males and postmenopausal women. CONCLUSIONS OSA severity is an independent predictor of levels of IL-6 and CRP but interacts with obesity such that this association is found only in obese patients.

Symptoms of insomnia among patients with obstructive sleep apnea before and after two years of positive airway pressure treatment.

STUDY OBJECTIVES To assess the changes of insomnia symptoms among patients with obstructive sleep apnea (OSA) from starting treatment with positive airway pressure (PAP) to a 2-y follow-up. DESIGN Longitudinal cohort study. SETTING Landspitali--The National University Hospital of Iceland. PARTICIPANTS There were 705 adults with OSA who were assessed prior to and 2 y after starting PAP treatment. INTERVENTION PAP treatment for OSA. MEASUREMENTS AND RESULTS All patients underwent a medical examination along with a type 3 sleep study and answered questionnaires on health and sleep before and 2 y after starting PAP treatment. The change in prevalence of insomnia symptoms by subtype was assessed by questionnaire and compared between individuals who were using or not using PAP at follow-up. Symptoms of middle insomnia were most common at baseline and improved significantly among patients using PAP (from 59.4% to 30.7%, P < 0.001). Symptoms of initial insomnia tended to persist regardless of PAP treatment, and symptoms of late insomnia were more likely to improve among patients not using PAP. Patients with symptoms of initial and late insomnia at baseline were less likely to adhere to PAP (odds ratio [OR] 0.56, P = 0.007, and OR 0.53, P < 0.001, respectively). CONCLUSION Positive airway pressure treatment significantly reduced symptoms of middle insomnia. Symptoms of initial and late insomnia, however, tended to persist regardless of positive airway pressure treatment and had a negative effect on adherence. Targeted treatment for insomnia may be beneficial for patients with obstructive sleep apnea comorbid with insomnia and has the potential to positively affect adherence to positive airway pressure.

The role of obesity, different fat compartments and sleep apnea severity in circulating leptin levels: the Icelandic Sleep Apnea Cohort study

Objectives:To assess whether sleep apnea severity has an independent relationship with leptin levels in blood after adjusting for different measures of obesity and whether the relationship between obstructive sleep apnea (OSA) severity and leptin levels differs depending on obesity level.Methods:Cross-sectional study of 452 untreated OSA patients (377 males and 75 females), in the Icelandic Sleep Apnea Cohort (ISAC), age 54.3±10.6 (mean±s.d.), body mass index (BMI) 32.7±5.3 kg m−2 and apnea-hypopnea index 40.2±16.1 events per h. A sleep study and magnetic resonance imaging of abdominal visceral and subcutaneous fat volume were performed, as well as fasting serum morning leptin levels were measured.Results:Leptin levels were more highly correlated with BMI, total abdominal and subcutaneous fat volume than visceral fat volume per se. No relationship was found between sleep apnea severity and leptin levels, assessed within three BMI groups (BMI <30, BMI 30–35 and BMI ⩾35 kg m−2). In a multiple linear regression model, adjusted for gender, BMI explained 38.7% of the variance in leptin levels, gender explained 21.2% but OSA severity did not have a significant role and no interaction was found between OSA severity and BMI on leptin levels. However, hypertension had a significant effect on the interaction between OSA severity and obesity (P=0.04). In post-hoc analysis for nonhypertensive OSA subjects (n=249), the association between leptin levels and OSA severity explained a minor but significant variance (3.2%) in leptin levels. This relationship was greatest for nonobese nonhypertensive subjects (significant interaction with obesity level). No relationship of OSA severity and leptin levels was found for hypertensive subjects (n=199).Conclusion:Obesity and gender are the dominant determinants of leptin levels. OSA severity is not related to leptin levels except to a minor degree in nonhypertensive nonobese OSA subjects.

Single slice vs. volumetric MR assessment of visceral adipose tissue: reliability and validity among the overweight and obese.

Visceral adipose tissue (VAT) is associated with abnormal cardiovascular and metabolic profiles. Total VAT volume of the abdominal compartment by magnetic resonance imaging (MRI) is the gold‐standard measurement for VAT but is costly and time consuming. Prior studies suggest VAT area on a single slice MR image may serve as a surrogate for total VAT volume but it is unknown if this relationship is maintained in overweight and obese men and women. Untreated sleep apnea subjects enrolled into the Icelandic Sleep Apnea Cohort (ISAC) underwent abdominal MRI. VAT area and subcutaneous adipose tissue (SAT) area at the L2‐L3 and L4‐L5 interspaces and total VAT and SAT volumes were determined by manual examination using image analysis software; 539 men and 129 women with mean ages of 54.1 and 58.8 years and mean BMI of 32.2 kg/m2 and 33.7 kg/m2, respectively, were studied. Mean total VAT volume was 40% smaller and mean total SAT was 25% larger among females compared with males. The correlation with VAT volume was significantly larger for L2‐L3 VAT area (r = 0.96) compared to L4‐L5 VAT area (r = 0.83). The difference in correlation coefficients was statistically significant (nonparametric bootstrap P < 0.001 with 95% confidence interval (CI) for the difference from 0.11 to 0.15. VAT area at L2‐L3 was also significantly better correlated with VAT volume than traditional anthropometric variables. Linear regression analyses demonstrated that L2‐L3 area alone was sufficient for predicting total VAT volume and that the nature of the linear association was maintained across all levels of obesity and in both genders.

The effect of reducing levels of cat allergen (Fel d 1) on clinical symptoms in patients with cat allergy

BACKGROUND Treatment of cat allergy normally entails removal of the cat from the household, but cat owners are often unwilling to part with their pets, despite clinically relevant allergies. OBJECTIVE To determine whether levels of Fel d 1 can be reduced without removal of the cat and whether this will affect symptoms of cat allergy. METHODS Cat-allergic patients underwent randomization to either a group instructed in environmental control (EC) and a group with unchanged environment (UE). Dust samples were obtained and settled Fel d 1 measured by enzyme-linked immunosorbent assay. Patients recorded daily nasal inspiratory flow rates. At baseline, 3 months, and 8 months, patients underwent symptom evaluation. RESULTS Eighteen patients were randomized to the EC group and 22 to the UE group; the final number completing the study was 31, 15 in the EC group, and 16 in the UE group. At 8 months, home Fel d 1 levels had diminished to 6.8% of baseline levels in the EC group, whereas no reduction in levels was noted in the UE group. In the EC group, significant improvements were found in nasal inspiratory flow rate and symptoms compared with the UE group. Patients did not have difficulties adhering to EC measures. CONCLUSION A decrease in the allergen load was found in the EC group, which had a significant effect on symptoms of nasal allergy.

Obstructive sleep apnoea treatment and fasting lipids: a comparative effectiveness study

Obstructive sleep apnoea (OSA) is associated with cardiovascular disease. Dyslipidaemia has been implicated as a mechanism linking OSA with atherosclerosis, but no consistent associations with lipids exist for OSA or positive airway pressure treatment. We assessed the relationships between fasting lipid levels and obesity and OSA severity, and explored the impact of positive airway pressure treatment on 2-year fasting lipid level changes. Analyses included moderate-to-severe OSA patients from the Icelandic Sleep Apnoea Cohort. Fasting morning lipids were analysed in 613 untreated participants not on lipid-lowering medications at baseline. Patients were then initiated on positive airway pressure and followed for 2 years. Sub-classification using propensity score quintiles, which aimed to replicate covariate balance associated with randomised trials and, therefore, minimise selection bias and allow causal inference, was used to design the treatment group comparisons. 199 positive airway pressure adherent patients and 118 non-users were identified. At baseline, obesity was positively correlated with triglycerides and negatively correlated with total cholesterol, and low-density and high-density lipoprotein cholesterol. A small correlation was observed between the apnoea/hypopnoea index and high-density lipoprotein cholesterol. No effect of positive airway pressure adherence on 2-year fasting lipid changes was observed. Results do not support the concept of changes in fasting lipids as a primary mechanism for the increased risk of atherosclerotic cardiovascular disease in OSA. Fasting lipid changes are unaffected by positive airway pressure and thus don’t increase cardiovascular risk http://ow.ly/vSEdq

Facial phenotyping by quantitative photography reflects craniofacial morphology measured on magnetic resonance imaging in Icelandic sleep apnea patients.

STUDY OBJECTIVES (1) To determine whether facial phenotype, measured by quantitative photography, relates to underlying craniofacial obstructive sleep apnea (OSA) risk factors, measured with magnetic resonance imaging (MRI); (2) To assess whether these associations are independent of body size and obesity. DESIGN Cross-sectional cohort. SETTING Landspitali, The National University Hospital, Iceland. PARTICIPANTS One hundred forty patients (87.1% male) from the Icelandic Sleep Apnea Cohort who had both calibrated frontal and profile craniofacial photographs and upper airway MRI. Mean ± standard deviation age 56.1 ± 10.4 y, body mass index 33.5 ± 5.05 kg/m(2), with on-average severe OSA (apnea-hypopnea index 45.4 ± 19.7 h(-1)). INTERVENTIONS N/A. MEASUREMENTS AND RESULTS Relationships between surface facial dimensions (photos) and facial bony dimensions and upper airway soft-tissue volumes (MRI) was assessed using canonical correlation analysis. Photo and MRI craniofacial datasets related in four significant canonical correlations, primarily driven by measurements of (1) maxillary-mandibular relationship (r = 0.8, P < 0.0001), (2) lower face height (r = 0.76, P < 0.0001), (3) mandibular length (r = 0.67, P < 0.0001), and (4) tongue volume (r = 0.52, P = 0.01). Correlations 1, 2, and 3 were unchanged when controlled for weight and neck and waist circumference. However, tongue volume was no longer significant, suggesting facial dimensions relate to tongue volume as a result of obesity. CONCLUSIONS Significant associations were found between craniofacial variable sets from facial photography and MRI. This study confirms that facial photographic phenotype reflects underlying aspects of craniofacial skeletal abnormalities associated with OSA. Therefore, facial photographic phenotyping may be a useful tool to assess intermediate phenotypes for OSA, particularly in large-scale studies.

Nocturnal sweating—a common symptom of obstructive sleep apnoea: the Icelandic sleep apnoea cohort

Objectives To estimate the prevalence and characteristics of frequent nocturnal sweating in obstructive sleep apnoea (OSA) patients compared with the general population and evaluate the possible changes with positive airway pressure (PAP) treatment. Nocturnal sweating can be very bothersome to the patient and bed partner. Design Case–control and longitudinal cohort study. Setting Landspitali—The National University Hospital, Iceland. Participants The Icelandic Sleep Apnea Cohort consisted of 822 untreated patients with OSA, referred for treatment with PAP. Of these, 700 patients were also assessed at a 2-year follow-up. The control group consisted of 703 randomly selected subjects from the general population. Intervention PAP therapy in the OSA cohort. Main outcome measures Subjective reporting of nocturnal sweating on a frequency scale of 1–5: (1) never or very seldom, (2) less than once a week, (3) once to twice a week, (4) 3–5 times a week and (5) every night or almost every night. Full PAP treatment was defined objectively as the use for ≥4 h/day and ≥5 days/week. Results Frequent nocturnal sweating (≥3× a week) was reported by 30.6% of male and 33.3% of female OSA patients compared with 9.3% of men and 12.4% of women in the general population (p<0.001). This difference remained significant after adjustment for demographic factors. Nocturnal sweating was related to younger age, cardiovascular disease, hypertension, sleepiness and insomnia symptoms. The prevalence of frequent nocturnal sweating decreased with full PAP treatment (from 33.2% to 11.5%, p<0.003 compared with the change in non-users). Conclusions The prevalence of frequent nocturnal sweating was threefold higher in untreated OSA patients than in the general population and decreased to general population levels with successful PAP therapy. Practitioners should consider the possibility of OSA in their patients who complain of nocturnal sweating.

Effects of obesity on the association between long-term sleep apnea treatment and changes in interleukin-6 levels: the Icelandic Sleep Apnea Cohort.

The aim of this study was to evaluate changes in interleukin (IL)‐6 and soluble IL‐6 receptor levels in obstructive sleep apnea patients and assess the role of positive airway pressure treatment and obesity on these changes. A total of 309 newly diagnosed subjects with sleep apnea from the Icelandic Sleep Apnea Cohort were referred for treatment and reassessed at a 2‐year follow‐up. Full treatment was defined objectively as use ≥4 h day−1 and ≥20 days month−1. At the 2‐year follow‐up, there were 177 full users, 44 partial users and 88 non‐users. The mean change in biomarker levels from baseline to the 2‐year follow‐up was assessed in a primary model that included adjustment for baseline biomarker levels, baseline body mass index and change in body mass index, as well as after adjustment for numerous relevant covariates. No significant overall difference in IL‐6 level change was found among full, partial and non‐users. However, in severely obese patients (body mass index ≥35), a significant increase in IL‐6 levels during the 2‐year period was found in partial and non‐users, compared to no change in full users. Results were attenuated in a smaller propensity score matched subsample, although similar trends were observed. No differences were found in soluble IL‐6 receptor levels between full users and non‐users, after adjustment for confounders. In conclusion, among untreated obese sleep apnea patients, IL‐6 levels increase substantially during 2 years, while adherence to positive airway pressure treatment may prevent further increases in this inflammatory biomarker.

Fiix-prothrombin time versus standard prothrombin time for monitoring of warfarin anticoagulation: a single centre, double-blind, randomised, non-inferiority trial

BACKGROUND Rapid fluctuations in factor VII during warfarin anticoagulation change the international normalised ratio (INR) but contribute little to the antithrombotic effect. We aimed to assess non-inferiority of anticoagulation stabilisation with a warfarin monitoring method affected only by factors II and X (Fiix-prothrombin time [Fiix-PT]) compared with standard PT-INR monitoring that includes factor VII measurement as well. METHODS The Fiix trial was a single centre, double-blind, prospective, non-inferiority, randomised controlled clinical trial. Ambulatory adults on warfarin with an INR target of 2-3 managed by an anticoagulation dosing service using software-assisted dosing at the National University Hospital of Iceland, Reykjavik, Iceland, were eligible for inclusion in this study. We excluded patients undergoing electroconversion and nursing home residents. Patients were randomly assigned (1:1) to either the Fiix-PT monitoring group or the PT monitoring group by block randomisation. A blinded research INR (R-INR) based on results of the respective test was reported to the dosing staff. Participants were contacted by a study nurse at 4-week intervals to elicit information about thromboembolism or bleeding otherwise unknown to the anticoagulation management centre. The primary efficacy outcome was a composite of objectively diagnosed non-fatal and fatal arterial or venous thromboembolism, including myocardial infarction and transient ischaemic attacks, assessed in all eligible patients who were randomised (intention-to-monitor population). The safety endpoint was major bleeding or other clinically relevant bleeding, assessed in the per-protocol population. We assumed a 3% annual thromboembolism incidence and a non-inferiority margin of 2·5%. This trial is registered with ClinicalTrials.gov, number NCT01565239. FINDINGS Between March 1, 2012, and Feb 28, 2014, we enrolled 1156 patients. 573 patients were assigned to Fiix-PT and 575 to PT-INR monitoring after exclusion of four patients from each group for various reasons. Median follow-up was 1·7 years (IQR 1·1-1·9). During days 1-720, ten (1·2% per patient year) thromboembolic events occurred in the Fiix-PT group versus 19 (2·3% per patient year) in the PT group (relative risk [RR] 0·52, 95% CI 0·25-1·13; pnon-inferiority<0·0001). Major bleeding occurred in 17 of 571 patients in the Fiix group (2·2% per patient year) versus 20 of 573 patients in the PT group (2·5% per patient year; RR 0·85, 0·45-1·61; pnon-inferiority=0·0034). Anticoagulation stability was improved with Fiix-PT monitoring as manifested by fewer tests, fewer dose adjustments, increased time in range and less INR variability than reported with standard PT monitoring. INTERPRETATION Monitoring of warfarin with Fiix-PT improved anticoagulation and dosing stability and was clinically non-inferior to PT monitoring. Results from this trial suggest that during vitamin K antagonist treatment INR monitoring could be replaced by Fiix-PT and that this would lead to at least a non-inferior clinical outcome compared with monitoring with PT-INR. FUNDING Innovation Center Iceland, University of Iceland Science Fund, Landspitali Science Fund and Actavis.