Najib Ayas

Background: Obstructive Sleep Apnea (OSA) is the most common respiratory disorder during sleep. OSA is an independent risk factor for developing cardiovascular diseases (CVD). Although risk is increased, it is still challenging to identify which patients will develop CVD as standard disease metrics are not that helpful. Circulating biomarkers could be useful to risk stratify OSA patients. However, current evidence in this regard is limited. Oxidative stress biomarkers and cellular adhesion molecules might be particularly useful as these are elevated in OSA patients and in patients with CVD. Thesis Objectives: 1. Identify and summarize the existing evidence on prognostic biomarkers in OSA (Chapters 1-2).2. Evaluate the association between cellular adhesion molecules, oxidative stress markers and OSA (Chapters 3-4).3. Evaluate whether levels of cellular adhesion molecules and oxidative stress markers predict incident CV events in an OSA-cohort (Chapter 5-6).4. Discuss the implications and future directions of the findings (Chapter 7). Methods: Adult patients (>19 years old) referred for suspected OSA to the University of British Columbia Hospital Sleep Disorder Laboratory for inpatient polysomnography (PSG) were studied. Fasting blood (15 ml) was collected on the morning after PSG, and plasma was stored in a -80C freezer. Plasma levels of 8-isoprostane, 8-hydroxydeoxyguanosine (8-OHdG), superoxide dismutase (SOD), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin (endothelial selectin) were assessed. Incidence of CV events was assessed by deterministic linkage through Popdata-BC. Results: OSA severity was independently associated with higher circulating E-selectin and 8-isoprostane levels. In patients with suspected OSA, ICAM-1 was an independent predictor of incident CV events (OR=4.12 95% CI 1.47-11.55). In moderate to severe OSA patients, E-selectin was independently associated with CV events (OR = 4.07 95% CI 1.06 – 15.61), but not in patients without OSA. Oxidative stress markers were not associated with incident CV events. Conclusion: E-selectin and 8-isoprostane were independently associated with OSA. Cellular adhesion molecules such as ICAM-1 and E-selectin were associated with incident CV events and might be promising markers in CV disease prediction in OSA. Oxidative stress markers were not associated with incidence of CV events.

View record

Epidemiological studies demonstrate an association between obstructive sleep apnea (OSA) and accelerated loss of kidney function. OSA is characterized by repetitive episodes of intermittent hypoxia (IH) during sleep, which provokes systemic and renal oxidative stress and inflammation. Here we hypothesized that IH induces structural and functional renal injury by increasing glomerular growth factors, increasing oxidative stress and inflammation, and that α-lipoic acid (LA), an antioxidant, attenuates this injury. To address this hypothesis, the ability of LA to mitigate the structural and functional aspects of renal injury secondary to IH was examined.Ten 8-week old wild-type male CB57BL/6 mice were randomly assigned to receive either IH or intermittent air (IA) for 60 days. The first study involved histological measurements of glomerular area and mesangial matrix expansion (MME), where glomerular growth factors were quantified by immunohistochemistry. Renal cellular apoptosis was investigated by measuring apoptotic proteins in kidney cortex. Finally, measurements of renal function were made by measuring serum creatinine and 24-hour urinary albumin. For the second study, 20 mice were randomized to receive either IH or IA, with regular diet (RD) or 0.2% w/w LA-enriched diet. After 60 days, samples of urine and plasma were collected. Markers for oxidative stress, inflammation, apoptosis, and tubular injury in kidney cortex were quantified. Glomerular area and MME were measured as well.Compared to controls, IH-exposed mice had increased glomerular areas and MME, accompanied by increases in glomerular growth factors and cellular apoptosis markers. IH-exposed mice had increases in albuminuria but not in serum creatinine. The second study demonstrated reduced urinary albumin excretion in the IH-LA group compared to IH-RD. Histological assessment showed significant increases in glomerular area of IH-RD compared to IH-LA. Treatment with LA also normalized systemic and renal oxidative stress and inflammation, and attenuated renal cellular apoptosis and tubular injury secondary to IH.These findings indicate for the first time that IH causes structural and functional kidney injury and increases renal cellular apoptosis, and this injury was attenuated by the antioxidant effect of LA. Treatment with LA may be a potentially promising therapy to reduce renal dysfunction in patients with OSA.

View record

Background: Obstructive Sleep Apnea (OSA) is a common but under diagnosed respiratory disorder characterized by recurrent upper airway obstruction during sleep. OSA results in sleep fragmentation and hypoxemia and is associated with neurocognitive impairments. OSA negatively affects vigilance and work performance, yet there is limited evidence on the relationship between OSA and the risk of occupational injuries (OI). It is hypothesized that individuals with OSA would have an increased risk of OI, and that OSA treatment may reduce this risk. Dissertation Objectives:1. Summarize the existing evidence on the relationship between OSA and OI (Chapter 1).2. Evaluate the association between the presence and severity of OSA and the risk of OI, both before and after diagnosis (Chapters 2-4). 3. Evaluate the impact of Continuous Positive Airway Pressure (CPAP) treatment on the risk of OI (Chapter 5).Methods: Patients referred to the UBC Sleep Disorders Clinic (SDC) for suspected OSA (2003-2011) were recruited to participate and diagnosed with OSA using polysomnography (PSG). Rates and risk of OI in the five years pre and post-PSG were calculated and compared by OSA status by linking to workers claims data. In addition, a matched sample of residents linked to claims data was drawn from the provincial health registry and compared to the OSA group. CPAP adherence data was collected from all OSA patients whose charts were available, and the impact of CPAP on the risk of OI was assessed using a pre/post treatment design.

View record

Obstructive sleep apnea (OSA) is a chronic condition characterized by recurring upper airway collapse during sleep, leading to chronic intermittent hypoxia (CIH) that can evoke oxidative stress and inflammation leading to cardiovascular disease (CVD). Current treatments for OSA are relatively ineffective in preventing CVD. Moreover, the effects of gestational OSA on the health of the offspring are unknown. We hypothesized that 1) antioxidant treatment can improve vascular outcomes in mice exposed to CIH and that 2) gestational intermittent hypoxia (GIH) can adversely impact fetoplacental outcomes and lead to cardiometabolic disease in the adult offspring. The first chapter of this thesis examines the effects of CIH on vascular function, oxidative stress and inflammatory markers in CB57BL/6 male mice with or without treatment with the dietary antioxidant, alpha lipoic acid (ALA). CIH impaired aortic relaxation and basal nitric oxide (NO) production. Furthermore, CIH increased systemic oxidative stress, inflammation and proinflammatory gene expression in the aorta. Treatment with ALA improved endothelial function and reduced oxidative stress and inflammation.In the second chapter, the impact of 14.5 days of GIH on vascular function of pregnant mice is reported. The following were evaluated: uterine artery function, plasma oxidative stress and inflammatory markers, spiral artery remodeling, placental morphology, hypoxia, oxidative stress, and fetal weights. GIH increased placental weights and decreased fetal weights, impaired uterine artery function, increased systemic oxidative stress and inflammation, increased placental hypoxia, and oxidative stress with no effect on spiral artery remodeling. In the third chapter, aortic endothelial and perivascular adipose tissue (PVAT) function were evaluated in sixteen-week-old offspring of dams exposed to GIH only in utero. GIH male offspring had increased body weights and developed metabolic syndrome. Furthermore, aortic relaxation was impaired in offspring with a loss of PVAT anti-contractile effects, which was facilitated by adiponectin. Levels of adiponectin were lower in the PVAT and in plasma. Pyrosequencing of adiponectin promoter in PVAT indicated increased DNA methylation in male GIH offspring. These data suggest that treatment of OSA patients with ALA could be a strategy to improve cardiovascular outcomes. Furthermore, maternal OSA may lead to adverse metabolic and vascular outcomes during adulthood.

View record