Associations Between Sleep Apnea and Subclinical Carotid Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis.

Background and Purpose- Many health effects of sleep apnea (SA) may be mediated through accelerated atherosclerosis. We examined the associations of snoring and several measurements of SA with subclinical carotid atherosclerosis in a large multiethnic population sample. Methods- This analysis included 1615 participants (mean age, 68 years) from examination 5 (2010-2013) of the MESA study (Multi-Ethnic Study of Atherosclerosis). Sleep measures including SA (apnea-hypopnea index [4%], ≥15 events/hour) were derived from full in-home polysomnography. Carotid atherosclerosis was measured using high-resolution B-mode ultrasound. Multivariable linear and logistic regression models were used to evaluate the associations between sleep exposures with carotid intima-media thickness and the presence of carotid plaque, respectively. Effect modification by age, sex, and race/ethnicity was examined. Results- In multivariable analysis, SA was associated with an increased odds of carotid plaque presence in individuals aged <68 years (odds ratio, 1.47; 95% CI, 1.05-2.06) but not in older individuals (odds ratio, 0.95; 95% CI, 0.67-1.37; P interaction=0.078). Greater hypoxemia (sleep time <90% saturation) was associated with increasing carotid intima-media thickness in younger (0.028±0.014 mm) but not in older individuals (-0.001±0.013 mm; P interaction=0.106). Self-reported snoring was not associated with carotid atherosclerosis. In assessing race-specific outcomes, greater hypoxemia was associated with increased carotid intima-media thickness in blacks (0.049±0.017 mm; P interaction=0.033). Conclusions- In this large multiethnic population-based sample, sleep disturbances are associated with subclinical carotid atherosclerosis in both men and women, particularly in those <68 years of age. The mechanisms underlying the association between SA and carotid atherosclerosis may differ for carotid plaque and carotid intima-media thickness.

Sleep-disordered breathing and electrocardiographic QRS-T angle: The MESA study.

INTRODUCTION: Sleep-disordered breathing (SDB) has been linked to sudden cardiac death (SCD) but the mechanism is unclear. Abnormal QRS-T angle, a novel electrocardiographic (ECG) marker of ventricular repolarization, has been linked to adverse cardiovascular outcomes including SCD. We hypothesized that individuals with SDB have more pronounced abnormality in QRS-T angle. METHODS: We performed a cross-sectional analysis from the Multi-Ethnic Study of Atherosclerosis (MESA) Exam Sleep ancillary study. We calculated the odds ratio (OR) of abnormal frontal and spatial QRS-T angle (defined as >sex-specific 95th percentile thresholds) related to the apnea-hypopnea index (AHI) using logistic regression, adjusting for demographics, body habitus, cardiovascular risks, and prevalent cardiovascular disease. Linear associations between AHI and frontal and spatial QRS-T angle, separately, were also examined using multiple regression models. RESULTS: A total of 1,804 participants (mean age 67.9 (±9.0) years, 55.3% women and 64.1% non-whites) were included in the study. Sleep-disordered breathing was common among participants (median AHI 8.6 events/hr IQR [3.2-19.5/hr]). Higher AHI was associated with the odds of abnormal frontal (≥81° in men and ≥79° in women) and spatial QRS-T angle (≥129.7° in men and ≥115.9° in women; OR [95%CI]: 1.25 [1.02-1.51], p = 0.03; 1.23 [1.01-1.50], p = 0.04 respectively per 1 SD [16.8 events/hr] increase in AHI). Similarly, linear associations were observed (frontal QRS-T angle: beta coefficient: 2.30° [0.92, 3.66], p = 0.001; spatial QRS-T angle: beta coefficient: 2.16° [0.67, 3.64], p = 0.005). CONCLUSION: In a racially/ethnically diverse community cohort, severity of SDB is associated with abnormal ventricular repolarization as measured by QRS-T angle.

Biomarkers in Sleep Apnea and Heart Failure.

PURPOSE OF REVIEW: Sleep-disordered breathing (SDB) is highly prevalent in heart failure (HF) and may confer significant stress to the cardiovascular system and increases the risk for future cardiovascular events. The present review will provide updates on the current understanding of the relationship of SDB and common HF biomarkers and the effect of positive airway pressure therapy on these biomarkers, with particular emphasis in patients with coexisting SDB and HF. RECENT FINDINGS: Prior studies have examined the relationship between HF biomarkers and SDB, and the effect of SDB treatment on these biomarkers, with less data available in the context of coexisting SDB and HF. Overall, however, the association of SDB and circulating biomarkers has been inconsistent. Further research is needed to elucidate the relationship between biomarkers and SDB in HF, to evaluate the clinical utility of biomarkers over standard methods in large, prospective studies and also to assess the impact of treatment of SDB on these biomarkers in HF via interventional studies.

Differential Expression of microRNAs and their Regulatory Networks in Skin Tissue of Liaoning Cashmere Goat during Hair Follicle Cycles.

MicroRNAs (miRNAs) are endogenous small noncoding RNA molecules that negatively regulate gene expression. Herein, we investigated a selective number of miRNAs for their expression in skin tissue of Liaoning Cashmere goat during hair follicle cycles, and their intracellular regulatory networks were constructed based on bioinformatics analysis. The relative expression of six miRNAs (mir-103-3p, -15b-5p, 17-5p, -200b, -25-3p, and -30c-5p) at anagen phase is significantly higher than that at catagen and/or telogen phases. In comparison to anagen, the relative expression of seven miRNAs (mir-148a-3p, -199a-3p, -199a-5p, -24-3p, -30a-5p, -30e-5p, and -29a-3p) was revealed to be significantly up-regulated at catagen and/or telogen stages. The network analyses of miRNAs indicated those miRNAs investigated might be directly or indirectly involved in several signaling pathways through their target genes. These results provided a foundation for further insight into the roles of these miRNAs in skin tissue of Liaoning Cashmere goat during hair follicle cycles.

Impact of Continuous Positive Airway Pressure on Cardiovascular Risk Factors in High-Risk Patients.

Cardiovascular disease remains the leading cause of morbidity and mortality in developed countries. Obstructive sleep apnea is a highly prevalent condition characterized by repetitive upper airway collapse during sleep. A large body of evidence suggests that obstructive sleep apnea is associated with the development of cardiovascular disease and increased cardiovascular morbidity and mortality. Continuous positive airway pressure (CPAP) is the current gold standard for the treatment of obstructive sleep apnea. CPAP devices maintain upper airway patency using a pneumatic splint, thereby ameliorating the repetitive deoxygenation and reoxygenation characteristic of sleep in obstructive sleep apnea patients. Accumulating evidence suggests that CPAP treatment may lead to a reduction in blood pressure. Limited evidence also suggests that CPAP therapy may modulate glucose metabolism, serum cholesterol levels, and inflammatory biomarkers. Thus, CPAP treatment may be associated with cardiovascular risk factor modification in patients with obstructive sleep apnea, who are often obese and at an increased risk of developing cardiovascular disease. This review updates the knowledge on the effects of CPAP on cardiovascular risk factors from recently published randomized trials.

New fibrate use and acute renal outcomes in elderly adults: a population-based study.

BACKGROUND: Fibric acid derivatives (fibrates) have been shown to increase serum creatinine level in randomized trials. OBJECTIVE: To assess renal outcomes in elderly adults within 90 days of a new fibrate prescription. DESIGN: Population-based cohort study. SETTING: Ontario, Canada. PATIENTS: Patients aged 66 years or older with a new outpatient prescription for a fibrate or ezetimibe (comparator drug) between January 2004 and December 2008. MEASUREMENTS: Hospitalization for an increase in serum creatinine level (primary outcome) and consultation with a nephrologist, receipt of dialysis for severe acute kidney injury, all-cause mortality, and increases in serum creatinine level (secondary outcomes). All outcomes were assessed within 90 days of a new prescription for ezetimibe or a fibrate. RESULTS: Compared with ezetimibe users (n = 61,831), fibrate users (n = 19,072) were more likely to be hospitalized for an increase in serum creatinine level (adjusted odds ratio, 2.4 [95% CI, 1.7 to 3.3]) and were more likely to consult a nephrologist (absolute risk difference, 0.15% [CI, 0.01% to 0.29%]; adjusted odds ratio, 1.3 [CI, 1.0 to 1.6]). There were no differences between groups in the risk for all-cause mortality or receiving dialysis for severe acute kidney injury. In a subpopulation of 1110 patients (fibrates, n = 220; ezetimibe, n = 890), 9.1% of fibrate users and 0.3% of ezetimibe users had an increase in serum creatinine level of 50% or more (absolute difference, 8.8% [CI, 4.5% to 13.1%]; odds ratio, 29.6 [CI, 8.7 to 100.5]). Risks were greater among fibrate users with chronic kidney disease. LIMITATIONS: Because hospitalizations for an increase in serum creatinine level were underestimated, absolute differences may be misleading. Most patients (91%) were prescribed fenofibrate. Serum creatinine levels were measured as part of routine care and were not available for everyone or at predefined times. CONCLUSION: New fibrate use in elderly adults was associated with an increase in serum creatinine level and a small 90-day absolute increase in hospitalizations and nephrologist consultations. There was no detectable effect on dialysis for severe acute kidney injury or on mortality. The mechanism and clinical significance of the increase in serum creatinine level with fibrates is unclear. PRIMARY FUNDING SOURCE: Ontario Ministry of Health and Long-Term Care Drug Innovation Fund.

Effect of continuous positive airway pressure treatment on ambulatory blood pressures in high-risk sleep apnea patients: a randomized controlled trial.

STUDY OBJECTIVES: The long-term effect of continuous positive airway pressure (CPAP) on 24-hour blood pressure (BP) in patients at high risk with obstructive sleep apnea (OSA) is uncertain. We aimed to determine the effect of CPAP treatment on ambulatory BP in individuals with moderate or severe OSA and cardiovascular disease or multiple cardiovascular disease risk factors without severe sleepiness. METHODS: In this randomized, controlled, parallel group study, 169 participants were randomly assigned to CPAP treatment or the control group. The primary outcome was the change in mean 24-hour systolic BP between groups from baseline to the average of 6- and 12-month measurements using mixed-effect linear regression models. RESULTS: The 24-hour systolic BP did not significantly differ by group, although there was a trend of decrease in the CPAP group (treatment effect -2.7 mm Hg [95% confidence interval -5.9 to 0.6]; P = .105) compared with control. CPAP had the greatest effect on nighttime systolic BP (treatment effect -5.9 mm Hg [95% confidence interval -9.9 to -1.9]; P = .004). Similar improvements in other nocturnal BP indices were observed. CONCLUSIONS: In patients at high risk with moderate-severe OSA without severe sleepiness, CPAP resulted in modest BP improvements over 6 to 12 months of follow-up, with possibly larger effects for nocturnal BP. Use of office blood pressure may underestimate the effect of CPAP on BP profile in patients with OSA. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: Sleep Apnea Intervention for Cardiovascular Disease Reduction; Identifier: NCT01261390; URL: https://clinicaltrials.gov/ct2/show/NCT01261390. CITATION: Zhao YY, Wang R, Gleason KJ, et al. Effect of continuous positive airway pressure treatment on ambulatory blood pressures in high-risk sleep apnea patients: a randomized controlled trial. J Clin Sleep Med. 2022;18(8):1899-1907.

Slow-Wave Sleep Is Associated With Incident Hypertension: The Sleep Heart Health Study.

We sought to quantify the association between slow-wave (stage N3) sleep and hypertension in a large cohort of middle-aged men and women. Data from 1850 participants free of baseline hypertension from the Sleep Heart Health Study were analyzed. The primary exposure was percentage of N3 sleep on baseline in-home polysomnography and the primary outcome was incident hypertension, defined as systolic blood pressure ≥ 140 mm Hg, diastolic blood pressure ≥ 90 mm Hg, and/or use of any blood pressure lowering medications at follow-up. Multivariable logistic regression models were adjusted for study site, age, sex, race, waist circumference, tobacco use, alcohol use, apnea-hypopnea index, nocturnal oxygen desaturation, sleep duration, sleep efficiency, and arousal index. Mean age was 59.4 ± 10.1 years and 55.5% were female. The mean baseline systolic and diastolic blood pressure was 118.8 and 70.6 mm Hg, respectively. Approximately 30% of the sample developed hypertension during a mean follow-up of 5.3 years. In the multi-adjusted model, participants in quartiles 1 (<9.8%) and 2 (9.8%-17.7%) of N3 sleep had significantly greater odds of incident hypertension compared with those in quartile 3 (17.7%-25.2%) (OR 1.69, 95% CI 1.21-2.36, p = .002 and OR 1.45, 95% CI 1.04-2.00, p = .03, respectively). No significant effect modification by sex on the N3-hypertension association was observed. In conclusion, compared with intermediate levels of N3 sleep (overlapping the "normal" adult range), lower levels of percent N3 sleep are associated with increased odds of incident hypertension in both men and women, independent of potential confounders, including indices of sleep apnea and sleep fragmentation.

Nocturnal levels of chemerin and progranulin in adolescents: influence of sex, body mass index, glucose metabolism and sleep.

BACKGROUND: Adipokines have been implicated in obesity, insulin resistance and sleep regulation. However, the role of chemerin and progranulin, two recently described adipokines, in the context of sleep remains unclear. The aim of this study was to compare nocturnal serum chemerin and progranulin levels between overweight/obese and normal-weight adolescents and to assess variations by sex, across different sleep stages and in relation to glucose metabolism. METHODS: The study sample included 34 overweight/obese and 32 normal-weight adolescents from secondary schools and the Leipzig Research Center for Civilization Diseases (LIFE) Child study cohort. We obtained longitudinal serum adipokine levels during in-laboratory polysomnography followed by an oral glucose tolerance test. RESULTS: Overweight/obese adolescents had significantly higher mean nocturnal serum chemerin area under the curve (AUC) levels (348.2±133.3 vs. 241.7±67.7 vs. ng/mL×h, p<0.001) compared to normal-weight controls. In detail, higher chemerin AUC levels in obese/overweight subjects were exclusively due to increased levels in females. No overall difference for serum progranulin AUC was found between the groups. However, when assessing sex-specific levels, serum progranulin AUC levels were ~30% higher in overweight/obese males compared to overweight/obese females. Of note, nocturnal serum chemerin and progranulin AUC did not exhibit a correlation with markers of glucose metabolism or sleep stages. CONCLUSIONS: Collectively, we report a sexual dimorphism in nocturnal progranulin and chemerin levels, which may help explain underlying differences in energy balance and body composition between males and females in the context of obesity.

Effect of Manual Editing of Total Recording Time: Implications for Home Sleep Apnea Testing.

STUDY OBJECTIVES: Type 3 home sleep apnea tests may underestimate the apnea-hypopnea index (AHI) due to overestimation of total sleep time (TST). We aimed to evaluate the effect of manual editing of the total recording time (TRT) on the TST and AHI. METHODS: Thirty 15-channel in-home polysomnography studies (AHI 0 to 30 events/h) scored using American Academy of Sleep Medicine criteria were rescored by two blinded polysomnologists after data from electroencephalogram, electrooculogram, and electromyogram were masked. In method 1, periods of probable wakefulness and artifact were manually edited and removed from analysis. Method 2 identified TST as the TRT without manual editing. Paired t-tests were used to compare the TST and AHI between these methods. Sensitivity and specificity of each method were calculated for gold standard AHI cutoffs of ≥ 5 and ≥ 15 events/h. RESULTS: TST (mean [standard deviation, SD]) by polysomnography, method 1, and method 2 was 366.0 (70.1), 447.1 (59.0), and 542 (61.9) min, respectively. The corresponding AHI was 12.5 (8.2), 10.8 (7.0), and 9.1 (6.1) events/h, respectively. Compared to polysomnography, both alternative methods overestimated the TST (method 1: mean difference [SD] 81.1 [56.1] min, method 2: 176.0 [89.7] min; both p < 0.001) and underestimated the AHI (method 1: mean difference [SD] -1.6 [3.3], method 2: -3.3 [3.9]; both p < 0.001). The sensitivity was 100% and 70.0% for method 1, and 91.3% and 40.0% for method 2 for identifying sleep-disordered breathing using AHI cutoffs of ≥ 5 and ≥ 15 events/h, respectively. CONCLUSIONS: Manual editing of TRT reduces the overestimation of TST and improves the sensitivity for identifying studies with sleep-disordered breathing. COMMENTARY: A commentary on this article appears in this issue on page 9.

Effect of Continuous Positive Airway Pressure Treatment on Health-Related Quality of Life and Sleepiness in High Cardiovascular Risk Individuals With Sleep Apnea: Best Apnea Interventions for Research (BestAIR) Trial.

Study Objectives: The long-term effect of continuous positive airway pressure (CPAP) on health-related quality of life (HRQOL) in patients with high cardiovascular disease risk and obstructive sleep apnea (OSA) without severe sleepiness is uncertain. We aimed to determine the effect of CPAP treatment on HRQOL in individuals with moderate or severe OSA and cardiovascular disease (CVD) or multiple CVD risk factors without severe sleepiness. Methods: In this randomized, controlled, parallel group study, 169 participants were assigned to treatment with CPAP or the control group (conservative medical therapy [CMT] or CMT with sham CPAP). Analyses were based on an intention-to-treat approach. Linear mixed effect models were fitted to compare the changes in the Medical Outcomes Study Short Form-36 (SF-36) and in subjective sleepiness (Epworth Sleepiness Scale [ESS]) between groups from baseline to the average of 6- and 12-month measurements. Results: CPAP improved several domains of HRQOL including bodily pain (treatment effect 9.7 [95% confidence interval, CI 3.9 to 15.4]; p = .001), vitality (5.7 [95% CI 1.5 to 9.9]; p = .008), general health (8.2 [95% CI 3.7 to 12.7]; p < .001), physical functioning (5.5 [95% CI 1.1 to 10.0]; p = .016), and the physical health summary score (3.3 [95% CI 1.4 to 5.3]; p = .001). CPAP also resulted in less daytime sleepiness (mean change in ESS -1.0 point [95% CI -2.0 to -0.0]; p = .040). Conclusions: In patients with moderate-severe OSA at high risk of cardiovascular events and without severe sleepiness, CPAP improved daytime sleepiness and multiple domains of HRQOL over 6 to 12 months of follow-up, with the largest improvement observed for bodily pain.

Sleep Apnea and Obstructive Airway Disease in Older Men: Outcomes of Sleep Disorders in Older Men Study.

STUDY OBJECTIVES: To evaluate the association between obstructive airway disease (OAD) and sleep apnea in older men. METHODS: A community-based cross-sectional study of 853 community-dwelling older men (mean age 80.7 ± 4.1 years [range 73 to 90]) across 6 centers in the United States from the Outcomes of Sleep Disorders in Older Men Study. Sleep was objectively measured using full in-home polysomnography and lung function was objectively measured using spirometry. The association of OAD (pre-bronchodilator FEV1/FVC ratio < 0.7 and FEV1 < 80% predicted) and sleep apnea (apnea-hypopnea index [AHI] ≥ 15 events/hour) was assessed using logistic regression. RESULTS: OAD and sleep apnea were identified in 111 (13.0%) and 247 (29.0%) men, respectively. In univariate analysis, participants with OAD had a lower AHI (mean ± SD; 8.7 ± 11.7 vs. 12.7 ± 13.8, P = 0.0009) and a lower prevalence of sleep apnea (14.4 vs. 31.1%, P = 0.0003) compared to participants without OAD. OAD remained independently associated with a lower odds of sleep apnea (odds ratio 0.30, 95% CI 0.16 to 0.55, P = 0.0001) after adjustment for demographics, body composition, smoking, and potential mediators (arousal index, time spent in rapid eye movement sleep). Individuals with OAD and sleep apnea (n = 16) had an increased arousal index and lower oxygen saturation level as compared to individuals with OAD alone (P values < 0.05). CONCLUSIONS: Obstructive airway disease was associated with a lower prevalence of sleep apnea in a cohort of community-dwelling elderly men, and unexplained by differences in adiposity or sleep architecture. Although uncommon in this cohort, coexisting sleep apnea and OAD was associated with increased sleep fragmentation and nocturnal oxygen desaturation compared to OAD alone.