Cardiovascular Disease In Obstructive Sleep Apnea Research Articles

A novel OSA-related model of intermittent hypoxia in endothelial cells under flow reveals pronounced inflammatory pathway activation.

Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder characterized by recurrent episodes of upper airway obstruction and subsequent hypoxia. In patients with OSA, severity and number of these hypoxic events positively correlate with the extent of associated cardiovascular pathology. The molecular mechanisms underlying intermittent hypoxia (IH)-driven cardiovascular disease in OSA, however, remain poorly understood-partly due to the lack of adequate experimental models. Here, we present a novel experimental approach that utilizes primary human endothelial cells cultivated under shear stress. Oxygen partial pressure dynamics were adopted in our in vitro model according to the desaturation-reoxygenation patterns identified in polysomnographic data of severe OSA patients (n = 10, with 892 severe desaturations, SpO2<80%). Using western blot analysis, we detected a robust activation of the two major inflammatory pathways ERK and NF-κB in endothelial cells, whereas no HIF1α and HIF2α protein stabilization was observed. In line with these findings, mRNA and protein expression of the pro-inflammatory adhesion and signaling molecule ICAM-1 and the chemokine CCL2 were significantly increased. Hence, we established a novel in vitro model for deciphering OSA-elicited effects on the vascular endothelium. First data obtained in this model point to the endothelial activation of pro-inflammatory rather than hypoxia-associated pathways in OSA. Future studies in this model might contribute to the development of targeted strategies against OSA-induced, secondary cardiovascular disease.

The effect of obstructive sleep apnea therapy on cardiovascular autonomic function: a systematic review and meta-analysis.

Autonomic function is impaired in obstructive sleep apnea (OSA) and may mediate the association between OSA and cardiovascular risk. We investigated the effect of OSA therapy on autonomic function through a systematic review and meta-analysis of intervention studies. A systematic search using three databases (Medline, Embase, and Scopus) was performed up to December 9, 2020. Studies of OSA patients ≥ 18 years with autonomic function assessed before and after treatment with positive airway pressure, oral appliance, positional therapy, weight loss, or surgical intervention were included for review. Random effects meta-analysis was carried out for five groups of autonomic function indices. Risk of bias was assessed using the Cochrane Collaboration tool. Forty-three eligible studies were reviewed with 39 included in the meta-analysis. OSA treatment led to large decreases in muscle sympathetic nerve activity (Hedges' g = -1.08; 95% CI -1.50, -0.65, n = 8) and moderate decreases in catecholamines (-0.60; -0.94, -0.27, n = 3) and radio nucleotide imaging (-0.61; -0.99, -0.24, n = 2). OSA therapy had no significant effect on baroreflex function (Hedges' g = 0.15; 95% CI -0.09, 0.39, n = 6) or heart rate variability (0.02; -0.32, 0.36, n = 14). There was a significant risk of bias due to studies being primarily non-randomized trials. OSA therapy selectively improves autonomic function measures. The strongest evidence for the effect of OSA therapy on autonomic function was seen in reduced sympathetic activity as assessed by microneurography, but without increased improvement in parasympathetic function. OSA therapy may reduce the risk of cardiovascular disease in OSA through reduced sympathetic activity.

Stratifying the Risk of Cardiovascular Disease in Obstructive Sleep Apnea Using Machine Learning.

Obstructive sleep apnea (OSA) is associated with higher risk of morbidity and mortality related to cardiovascular disease (CVD). Due to overlapping clinical risk factors, identifying high-risk patients with OSA who are likely to develop CVD remains challenging. We aimed to identify baseline clinical factors associated with the future development of CVD in patients with OSA. Retrospective analysis of prospectively collected data. We performed a retrospective analysis of 967 adults aged 45 to 84 years and enrolled in the Multi-Ethnic Study of Atherosclerosis. Six machine learning models were created using baseline clinical factors initially identified by stepwise variable selection. The performance of these models for the prediction of additional risk of CVD in OSA was calculated. Additionally, these models were evaluated for interpretability using locally interpretable model-agnostic explanations. Of the 967 adults without baseline OSA or CVD, 116 were diagnosed with OSA and CVD and 851 with OSA alone 10 years after enrollment. The best performing models included random forest (sensitivity 84%, specificity 99%, balanced accuracy 91%) and bootstrap aggregation (sensitivity 84%, specificity 100%, balanced accuracy 92%). The strongest predictors of OSA and CVD versus OSA alone were fasting glucose >91 mg/dL, diastolic pressure >73 mm Hg, and age >59 years. In the selected study population of adults without OSA or CVD at baseline, the strongest predictors of CVD in patients with OSA include fasting glucose, diastolic pressure, and age. These results may shape a strategy for cardiovascular risk stratification in patients with OSA and early intervention to mitigate CVD-related morbidity. 3 Laryngoscope, 132:234-241, 2022.

Cardiovascular manifestations in obstructive sleep apnea: current evidence and potential mechanisms.

Obstructive sleep apnea (OSA) is an increasingly prevalent health concern characterized by repeated episodes of pharyngeal collapse during sleep. It is frequently associated with daytime sleepiness and impaired functional capacity, but it is also linked to cardiovascular disease by a growing body of epidemiological, clinical, and translational research. The severity of OSA is traditionally evaluated by the apnea‑hypopnea index (AHI), but the value of this marker as a predictor of cardiovascular outcomes is limited. Thus, there is an increasing focus on alternative classification methods such as the hypoxic burden, other polysomnographic traits, and phenotypic subgroups based on clinical symptoms. There is a need to identify subgroups of patients with OSA who will benefit most from treatment, as recent large randomized controlled trials in selected populations have failed to show benefit in reducing overall cardiovascular mortality. Obstructive sleep apnea adversely affects cardiovascular structure and function by several distinct mechanisms such as intermittent hypoxia, sleep fragmentation, and intrathoracic pressure swings. These mechanisms lead to sympathetic activation, inflammation, and oxidative stress, which may result in the clinical consequences of OSA such as hypertension, coronary artery disease, heart failure, and cerebrovascular disease. This review focuses on the epidemiology and potential mechanisms of cardiovascular diseases in OSA. Furthermore, we will briefly discuss the role of personalized medicine, alternative treatment options, and precise phenotyping to optimize treatment of this complex condition and its associated cardiovascular risk.

Heart rate variability and obstructive sleep apnea: Current perspectives and novel technologies.

Obstructive sleep apnea (OSA) is a highly prevalent condition, resulting in recurrent hypoxic events, sleep arousal, and daytime sleepiness. Patients with OSA are at an increased risk of cardiovascular morbidity and mortality. The mechanisms underlying the development of cardiovascular disease in OSA are multifactorial and cause a cascade of events. The primary contributing factor is sympathetic overactivity. Heart rate variability (HRV) can be used to evaluate shifts in the autonomic nervous system, during sleep and in response to treatment in patients with OSA. Newer technologies are aimed at improving HRV analysis to accelerate processing time, improve the diagnosis of OSA, and detection of cardiovascular risk. The present review will present contemporary understandings and uses for HRV, specifically in the realms of physiology, technology, and clinical management.

Association between Respiratory Sleep Indices and Cardiovascular Disease in Sleep Apnea-A Community-Based Study in Cyprus.

Obstructive sleep apnea (OSA) is a chronic and prevalent disorder, strongly associated with cardiovascular disease (CVD). The apnea-hypopnea index (AHI), or respiratory event index (REI), and the oxygen desaturation index (ODI) are the clinical metrics of sleep apnea in terms of diagnosis and severity. However, AHI, or REI, does not quantify OSA-related hypoxemia and poorly predicts the consequences of sleep apnea in cardiometabolic diseases. Moreover, it is unclear whether ODI correlates with CVD in OSA. Our study aimed to examine the possible associations between respiratory sleep indices and CVD in OSA, in a non-clinic-based population in Cyprus. We screened 344 subjects of a stratified, total sample of 4118 eligible responders. All participants were adults (age 18+), residing in Cyprus. Each patient answered with a detailed clinical history in terms of CVD. A type III sleep test was performed on 282 subjects (81.97%). OSA (REI ≥ 15) was diagnosed in 92 patients (32.62%, Group A). REI < 15 was observed in the remaining 190 subjects (67.37%, Group B). In OSA group A, 40 individuals (43%) reported hypertension, 17 (18.5%) arrhythmias, 10 (11%) heart failure, 9 (9.8%) ischemic heart disease and 2 (2%) previous stroke, versus 46 (24%), 21 (11%), 7 (3.7%), 12 (6.3%) and 6 (3%), in Group B, respectively. Hypertension correlated with REI (p = 0.001), ODI (p = 0.003) and mean SaO2 (p < 0.001). Arrhythmias correlated with mean SaO2 (p = 0.001) and time spent under 90% oxygen saturation (p = 0.040). Heart failure correlated with REI (p = 0.043), especially in the supine position (0.036). No statistically significant correlations were observed between ischemic heart disease or stroke and REI, ODI and mean SaO2. The pathogenesis underlying CVD in OSA is variable. According to our data, hypertension correlated with REI, ODI and mean SaO2. Arrhythmias correlated only with hypoxemia (mean SaO2), whereas heart failure correlated only with REI, especially in the supine position.

Independent association of severity of obstructive sleep apnea with lipid metabolism of atherogenic index of plasma (AIP) and apoB/apoAI ratio.

Cardiovascular diseases (CVDs) are highly prevalent in obstructive sleep apnea (OSA), and dyslipidemia is an important factor. Atherogenic index of plasma (AIP, log[TG/HDL-C]) and apolipoproteinB to apolipoproteinAI ratio (apoB/apoAI ratio) are considered high quality predictors of cardiovascular risk. However, the associations between OSA severity and AIP and apoB/apoAI ratio remained unclear. A retrospective study was performed in 284 patients. Subjects were assessed with polysomnography (PSG) test, and OSA severity was defined by AHI. Data collected included anthropometric measurements, medical history, sleep parameters, fasting plasma lipids, fasting blood glucose, and insulin. Participants were classified based on AHI into the following groups: control group (n = 28), mild group (n = 52), moderate group (n = 53), and severe group (n = 151). Triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), apoAI, AIP, apoB/apoAI ratio (low-density lipoprotein cholesterol), LDL-C/HDL-C ratio, and HDL-C/apoAI ratio showed statistical significance among AHI subgroups (P < 0.05). The Pearson correlation analysis revealed that AIP (r = 0.32, P < 0.001) and apoB/apoAI ratio (r = 0.24, P < 0.001) were positively related to AHI. By multivariate linear regression analysis, we found that AHI was independently related to AIP (β = 0.24, P = 0.001), apoB/apoAI ratio (β = 0.24, P<0.001). AHI was independently correlated with AIP and apoB/apoAI ratio in OSA. Our findings suggested that AIP and apoB/apoAI ratio increased with OSA severity, which might be partly responsible for the high risk of CVDs in OSA.

The impact of continuous positive airway pressure on heart rate variability in obstructive sleep apnea patients during sleep: A meta-analysis

BackgroundHeart rate variability (HRV), modulated by cardiac autonomic function, is impaired in obstructive sleep apnea (OSA). However, the effect of continuous positive airway pressure (CPAP) on HRV is debated. ObjectivesTo investigate the associations between CPAP and HRV in OSA. MethodsBased on literature from five databases published through August 2017, we performed a meta-analysis of cohort studies of OSA treated with CPAP. The change of low-frequency band (LF), high-frequency band (HF) and the ratio between LF and HF (LHR) were analyzed. ResultsEleven studies were included. Decreased LF (SMD = −0.32, 95%CI: −0.62,−0.01; P = 0.043) and HF (SMD = −0.51, 95%CI: −0.95, −0.08, P = 0.020) were shown while measured on CPAP. When measured off CPAP, HF was increased remarkably (SMD: 0.31, 95%CI: 0.02, 0.60, P = 0.034). ConclusionsCPAP can improve autonomic activity, which might be one mechanism to reduce the risk of cardiovascular diseases in OSA.

Abstract 466: Obstructive Sleep Apnea And Its Association With Endothelial Function, Oxidative Stress, Inflammation, Metabolic Profile, Blood Pressure And Sympathetic Activity In Obese Individuals

Background: Obstructive sleep apnea (OSA) is associated with an increased risk of cardiovascular disease (CVD). Several of the proposed mechanisms for the development of CVD in OSA are similar to those proposed for the increased risk of CVD in obesity, being difficult to determine the influence of OSA on these pathogenic mechanisms in obese individuals. Objectives: The purpose of this study was to evaluate the relationship of OSA with endothelial function, oxidative stress, inflammatory biomarkers, metabolic profile, sympathetic nervous system activity and blood pressure (BP) in obese individuals. Methods: In this cross-sectional study, were included 53 obese adults (28 women). Sleep study was performed with Watch-PAT200® and the diagnosis of OSA was made when apnea-hipopnea index (AHI) ≥5 events/h (n=33). All participants underwent evaluation of: body adiposity, BP, plasma catecholamines, high sensitivity C-reactive protein (hs-CRP), adiponectin, malondialdehyde, glucose, insulin, lipid profile and endothelial function (Endo-PAT 2000®). Results: Mean age (39.6 ± 1.5 vs. 32.5 ± 2.1y) and percentage of male participants (61% vs. 25%) were significantly higher in participants with OSA than in those without OSA (p=0.01). In univariate analysis participants with OSA compared with those without OSA exhibited higher values of neck circumference (40.98 ± 0.63 vs. 38.65 ± 0.75 cm, p=0.02), glucose (92.54 ± 1.97 vs. 80.2 ± 1.92 mg/dL, p=0.0001), noradrenaline (0.16±0.02 vs. 0.12±0.03 ng/mL, p=0.02) and systolic BP (126.05 ± 1.61 vs. 118.16 ± 1.86 mmHg, p=0.003). After adjustment for confounders, only glucose and hs-CRP were significantly higher in OSA patients. In correlation analysis, after controlling for confounders, AHI was associated with neck circumference (r=0.31,p=0.03) and hs-CRP (r=0.30,p=0.04), while minimum O2 saturation was associated with neck circumference (r=-0.31,p=0.03), insulin (r=-0.29,p=0.04) and HOMA-IR (r=-0.30,p=0.04). Conclusion: The present study suggests that in obese individuals OSA is associated with inflammation and worse glycemia; higher AHI correlates with increased central adiposity and inflammation; and lower oxygen saturation is related with insulin resistance.

Gender difference in protein expression of vascular wall in mice exposed to chronic intermittent hypoxia: a preliminary study.

Obstructive sleep apnea (OSA) is an independent risk factor for cardiovascular diseases such as systemic arterial hypertension, ischemic heart disease, stroke, heart failure, atrial fibrillation, and cardiac sudden death. The pathogenesis of cardiovascular disease in OSA is thought to be induced primarily by chronic intermittent hypoxia (CIH), a specific pattern of change in oxygenation during sleep. However, the underlying mechanisms of CIH-induced vasculature injury and gender differences are not well documented. The iTRAQ Quantitative Proteomic method enables analysis of a number of different proteins among several groups. Thus, we explored gender differences in protein expression in the vascular walls of mice exposed to CIH. C57BL/6J mice of each gender were exposed to CIH with a fractional inspired O2 (FiO2) nadir of 5% or control, with a treatment time of 8 h/day for 28 days. Differential proteins related to CIH-induced vascular injury between genders were identified using iTRAQ proteomic technology. A total of 163 proteins were identified, of which 34 showed significant differences between genders, which may correlate with vascular injury by CIH. Twenty up-regulated proteins and 14 downregulated proteins were observed in female mice compared with male mice. We identified different vascular proteins expressed under CIH between genders, suggesting that these proteins may be biomarkers of vascular injury by CIH.

Functional Outcomes in Patients with REM-Related Obstructive Sleep Apnea Treated with Positive Airway Pressure Therapy

To evaluate functional outcomes in adults with REM-related obstructive sleep apnea (OSA) treated with positive airway pressure (PAP) therapy. Retrospective observational study. Outpatient sleep clinic. 330 adults (171 males) with OSA receiving PAP therapy, including 130 with REM OSA and 200 with OSA not restricted to REM. REM OSA was defined as a REM apnea-hypopnea index (AHI) / NREM AHI > 2 and NREM AHI < 15. Patients had baseline and post-PAP functional outcomes, including Epworth Sleepiness Scale (ESS), Fatigue Severity Scale (FSS), Patient Health Questionnaire-9 (PHQ-9), and Functional Outcomes Sleep Questionnaire (FOSQ) scores. We compared functional outcomes, demographic, clinical and polysomnographic features, and PAP adherence in patients with REM OSA and OSA not restricted to REM. Female gender was significantly more common in REM OSA. Age, BMI, neck girth, and baseline ESS, FSS, PHQ-9, and FOSQ were similar between groups. Smoking history and comorbid disorders were also similar except for a higher prevalence of depression and cardiovascular disease in OSA not restricted to REM. All functional outcomes improved significantly after PAP therapy in both groups. Change from baseline to post treatment was similar for all functional outcomes between groups. The study is the first addressing clinical outcomes in REM OSA using validated measures. Functional outcomes in patients with REM OSA improve after treatment with PAP therapy comparable to that observed in patients with OSA not restricted to REM. A commentary on this article appears in this issue on page 249.

Effect of mild hyperglycemia on autonomic function in obstructive sleep apnea.

Obstructive sleep apnea (OSA) has been hypothesized to cause a hypersympathetic state, which may be the mechanism for the increased incidence of cardiovascular disease in OSA. However, there is a high prevalence of hyperglycemia in OSA patients, which may also contribute to autonomic dysfunction. Thirty-five patients with OSA and 11 controls with average body mass index (BMI) of 32.0±4.6 underwent polysomnography, glucose tolerance testing, autonomic function tests, lying and standing catecholamines, overnight urine collection, and baseline ECG and continuous blood pressure measurements for spectral analysis. A linear regression model adjusting for age and BMI was used to analyze spectral data, other outcome measures were analyzed with Kruskal-Wallis test. Twenty-three OSA patients and two control patients had hyperglycemia (based on 2001 American Diabetes Association criteria). Apnea-hypopnea index (AHI) correlated with total power and low frequency (LF) power (r=0.138, 0.177, p=0.031; and r=0.013) but not with the LF/high frequency (HF) ratio (p=0.589). Glucose negatively correlated with LF systolic power (r=-0.171, p=0.038) but not AHI (p=0.586) and was marginally associated with pnn50, total power, LF, and HF power (p ranged from 0.07 to 0.08). These data suggest that patients with OSA and mild hyperglycemia have a trend towards lower heart rate variability and sympathetic tone. Hyperglycemia is an important confounder and should be evaluated in studies of OSA and autonomic function.

Obstructive Sleep Apnea, Stroke, and Cardiovascular Diseases

Obstructive sleep apnea (OSA) is gaining recognition as a cardiovascular and cerebrovascular risk factor. Sleep apnea is now implicated in the etiopathogenesis of stroke, coronary artery disease, hypertension, and congestive heart failure. OSA exerts its negative cardiovascular consequences through its unique pattern of intermittent hypoxia and arousals. The putative mechanisms involved in the pathogenesis of cardiovascular disease in OSA include fibrinolytic imbalance, endothelial dysfunction, oxidative stress, and inflammation. This study discusses the known cellular and molecular processes that promote atherogenesis and vascular dysfunction in patients with OSA, and their implications for cardiovascular disease and prevention in that patient population. Neurologists should familiarize themselves with the symptoms and signs of OSA and the pathophysiology of the association between untreated OSA and cardiovascular disease, including stroke. OSA should be ruled out in patients with cardiovascular disease and be regarded as an important modifiable risk factor. Knowledge of this association is of prime public health importance and can result in primary and secondary prevention of cardiovascular events. This study will also help neurologists in providing patient education and treatment.

Obstructive Sleep Apnea and Aging Effects on Macrovascular and Microcirculatory Function

Many patients with obstructive sleep apnea (OSA) are obese, and whether obesity itself explains the increased prevalence of cardiovascular disease in OSA is unknown. We hypothesize that OSA, independent of obesity, contributes to abnormal vascular function. Physiology study. Academic medical centers. Obese subjects, free of known comorbidities, were enrolled. Vascular function was assessed with brachial artery ultrasound for flow-mediated dilation (FMD) and in skin microcirculation by laser Doppler flowmetry. Arterial stiffness was measured by arterial tonometry. Seventy-two subjects (43/72 women, 38/72 with OSA) were studied. FMD was impaired in patients with OSA, compared with control subjects (5.7% +/- 3.8% vs 8.3% +/- 4.1%, P = 0.005). In step-forward regression analysis inclusive of age, sex, and body mass index, age (P = 0.013) was a significant independent predictor of FMD. In a subgroup of subjects younger than 50 years of age (n = 59), however, OSA was the only independent predictor of FMD (P = 0.04), adjusted for known covariates. OSA did not significantly influence vascular function in the skin microcirculation. The augmentation index, a measure of arterial stiffness, was similar between the OSA and control groups (16.2% +/- 11.4% vs 20.4% +/- 10.1%, respectively, P = 0.10). In step-forward regression analysis of younger men (< or = 50 years old, 23 subjects), OSA independently predicted the augmentation index in men only (P = 0.001). In obesity, both OSA and aging impair endothelial function and increase arterial stiffness. The influence of OSA on vascular function is most pronounced in young subjects. OSA, therefore, may be associated with functional impairment ("a premature aging effect") on the endothelium and on arterial stiffness (in men), although skin microcirculatory function appears preserved.

The Effect of Acute Intermittent Hypercapnic Hypoxia Treatment on IL-6, TNF-α, and CRP Levels in Piglets

Obstructive sleep apnea (OSA) is characterized by repeated episodes of upper-airway obstruction during sleep leading to significant hypercapnic hypoxic conditions. These conditions are associated with increased levels of proinflammatory cytokines (including interleukin [IL]-6, tumor necrosis factor [TNF]-alpha, and C-reactive protein [CRP]) and subsequent increased cardiovascular risk. It is unclear whether hypercapnic hypoxia itself causes inflammatory perturbations. We evaluated circulating IL-6, TNF- a and CRP in a piglet model of infant OSA, following exposure to acute intermittent hypercapnic hypoxia (IHH). Study groups comprised of treatment (n = 8) and control (n = 8) groups. Treatment was two 90-minute sessions of IHH with arterial blood sampled before and after each IHH session. IL-6, TNF-alpha and CRP levels were measured before and after IHH treatment sessions. Results showed an increase in IL-6 following the first session of IHH that was neither sustained, nor repeated, during a subsequent exposure. Using mixed-modelling, TNF-alpha changed between time points and groups. There were no changes in CRP over the duration of the study. These results suggest that acute hypoxia causes a transient increase in IL-6 levels and has implications for the pathogenesis of increased cardiovascular disease in OSA, especially in childhood.

Antioxidant nutrient intake and supplements as potential moderators of cognitive decline and cardiovascular disease in obstructive sleep apnea

Cognitive deficits and cardiovascular disease (CVD) are comorbid conditions frequently associated with obstructive sleep apnea (OSA). Oxygen free radical release and its differential regulation of cytokine synthesis and immune modulation resulting from OSA-related hypoxic events have been hypothesized as the underlying mechanism(s) for the cognitive deficits and CVD in OSA. A number of studies have suggested that increased levels of oxidative stress and/or antioxidant deficiencies may also be risk factors in cognitive decline and CVD. The influence of antioxidant nutrients and supplements, such as Vitamins B6, B12, C, E, folic acid, alpha-lipoic acid and Coenzyme Q(10) on cognitive decline and CVD have been investigated. The influence of antioxidant nutrients or supplements on OSA remains to be investigated. Even if dietary or supplemental antioxidants do not prove to be effective therapies for OSA, dietary assessment and prescription to increase dietary intake of neuro- and cardio-protective nutrients may make it possible to reduce some of the cognitive and cardiovascular sequelae associated with OSA.