Hypoxia-sensitive molecules may modulate the development of atherosclerosis in sleep apnoea syndrome. Respirology

First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
Respirology (Impact Factor: 3.35). 02/2006; 11(1):24-31. DOI: 10.1111/j.1440-1843.2006.00780.x
Source: PubMed


Obstructive sleep apnoea hypopnoea syndrome (OSAHS) is associated with increased morbidity and mortality due to cardiovascular disease. In order to examine the association between OSAHS and cardiovascular disease, this study measured hypoxia-inducible and atherosclerosis-associated molecules in the peripheral blood.
In this study peripheral blood was obtained early in the morning from 60 consecutive male patients with OSAHS (AHI > or =10 events/h) and 30 male control subjects without OSAHS (AHI <5 events/h). Serum levels of heat shock protein-70 (Hsp-70), tissue factor (TF), monocyte chemotactic protein-1 (MCP-1), highly sensitive C-reactive protein (hs-CRP), hepatocyte growth factor and plasma vascular endothelial growth factor were measured and their relationship with severity and hypoxaemia in OSAHS examined.
Serum hs-CRP, TF, MCP-1 and Hsp-70 levels were significantly higher in OSAHS compared with control subjects. Categorization of the patients into mild (10 < or = AHI < 30 events/h), moderate (30 < or = AHI < 60 events/h) and severe (AHI > or = 60 events/h) OSAHS subgroups showed that serum levels of hs-CRP, TF and Hsp-70 increased with severity. The hs-CRP, TF, MCP-1 and Hsp-70 levels in the non-obese OSAHS group were also significantly higher than those in the control group whereas there was no difference in BMI between the two groups. Repetitive hypoxaemia significantly correlated with hs-CRP, TF and Hsp-70 levels and appeared to be a significant determinant for these molecules.
These findings suggest that CRP, TF and Hsp-70 may be upregulated by repetitive hypoxaemia in OSAHS and may be involved in the development of the atherogenic process in OSAHS.

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    • "One study found elevated CRP and IL6 levels in OSA patients when compared with controls, however, the patients with OSA were more obese.44 Subsequent studies have shown increased levels of CRP in patients with OSA that were independent of body mass index (BMI).45–47 Conversely, two studies found that obesity per se, rather than OSA, is a better predictor of CRP.48,49 Furthermore, a large community study failed to detect an independent association between CRP and OSA after adjustment for BMI,50 suggesting that the OSA-CRP relationship may be primarily driven by obesity. "
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    ABSTRACT: Obstructive sleep apnea (OSA) is increasingly being recognized as a major health burden with strong focus on the associated cardiovascular risk. Studies from the last two decades have provided strong evidence for a causal role of OSA in the development of systemic hypertension. The acute physiological changes that occur during apnea promote nocturnal hypertension and may lead to the development of sustained daytime hypertension via the pathways of sympathetic activation, inflammation, oxidative stress, and endothelial dysfunction. This review will focus on the acute hemodynamic disturbances and associated intermittent hypoxia that characterize OSA and the potential pathophysiological mechanisms responsible for the development of hypertension in OSA. In addition the epidemiology of OSA and hypertension, as well as the role of treatment of OSA, in improving blood pressure control will be examined.
    Nature and Science of Sleep 05/2013; 5:43-52. DOI:10.2147/NSS.S34841
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    • "However, there are also studies where difference in CRP have been found to be due to obesity (Guilleminault et al., 2004; Sharma et al., 2008). There have been only a few studies that have found an association between mild OSA and elevated levels of CRP (Hayashi et al., 2006). Other studies, which have included a separate group of patients with mild OSA, have detected neither significantly elevated levels of CRP compared with control subjects nor significant correlation of CRP with AHI after statistical adjustments (Guilleminault et al., 2004; Ryan et al., 2007; Saletu et al., 2006; Yokoe et al., 2003). "
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    ABSTRACT: It is widely accepted that obstructive sleep apnoea (OSA) is linked with cardiovascular diseases. The relationship is complex and remains still poorly understood. The presence of chronic systemic inflammation has been connected with pathogenesis of both OSA and cardiovascular diseases. While atherogenesis is believed to be a process of many years, little is known about the potential impact of the largest OSA subgroup, mild OSA, on the development of cardiovascular diseases. The aim of the present study was to assess whether untreated mild OSA is associated with an activation of inflammatory cytokine system. The adult study population consisted of two groups: 84 patients with mild OSA [apnoea-hypopnoea index (AHI) 5-15 h(-1)] and 40 controls (AHI <5 h(-1)). Serum concentrations of pro- and anti-inflammatory cytokines were measured before any interventions. After adjustments for age, sex, body mass index, fat percentage, most important cardiometabolic and inflammatory diseases, and non-steroidal anti-inflammatory medication, the mean level of tumour necrosis factor-alpha was significantly elevated (1.54 versus 1.17 pg mL(-1), P = 0.004), whereas the level of interleukin-1 beta (IL-1 beta) was reduced (0.19 versus 0.23 pg mL(-1), P = 0.004) in patients with mild OSA compared with controls. The concentrations of the protective anti-inflammatory cytokines, interleukin-10 (1.28 versus 0.70 pg mL(-1), P < 0.001) and interleukin-1 receptor antagonist (478 versus 330 pg mL(-1), P = 0.003) were elevated in the OSA group. The concentrations of C-reactive protein increased, but IL-1 beta decreased along with the increase of AHI. Mild OSA was found to be associated not only with the activation of the pro-inflammatory, but also with the anti-inflammatory systems.
    Journal of Sleep Research 06/2010; 19(2):341-8. DOI:10.1111/j.1365-2869.2009.00787.x · 3.35 Impact Factor
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    • "Additionally , in agreement with the present findings, in a preliminary study we reported that basal HSP70 levels were increased in OSA monocytes and, conversely, after HS treatment HSP70 levels were lower than in controls (Ghandour et al., 1999). In addition, plasma and serum levels were also shown to increase in patients with OSA as compared with controls (Hayashi et al., 2006; Lavie, 2003). In accord with these findings and the current study, in rats exposed to intermittent hypoxia, the levels of HSP70 mRNA expression increased progressively in the myocardium along with the duration of intermittent hypoxia. "
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    ABSTRACT: Obstructive sleep apnoea (OSA) is associated with a variety of nightly stresses, including intermittent hypoxaemia, oxidative stress and sleep fragmentation. Heat-shock proteins (HSPs) are upregulated in response to an array of environmental and metabolic stresses. We hypothesized that the OSA-related stresses would affect the expression of HSP70 in monocytes. Basal (30 min, at 37 degrees C), heat stress-induced HSP70 (30 min, at 43 degrees C) and basal tumour necrosis factor-alpha (TNF-alpha) were determined by flow cytometry in monocytes of 10 patients with OSA and 10 controls matched by age, gender and body mass index. Oxidative stress was determined by thiobarbituric acid-reactive substances (TBARS) and antioxidant paraoxonase-1 activity. Basal HSP70 expression was 1.8-fold higher in patients with OSA as compared with controls (P < 0.0005) and was significantly positively correlated with TBARS (r = 0.56, P < 0.009). However, induction of HSP70 in response to heat stress treatment was lower by 40% in OSA monocytes as compared with controls (P < 0.0003). Furthermore, heat stress-induced HSP70 expression was significantly negatively correlated with basal HSP70 expression independently of apnoea severity (r = -0.69, P < 0.0006). Also, basal intracellular TNF-alpha expression was inversely correlated with heat-shock-induced HSP70 (r = -0.78, P < 0.015) in OSA monocytes but not in controls. In conclusion, basal HSP70 overexpression that is a protective mechanism indicative of disease-associated stress was significantly higher in patients with OSA and was correlated with oxidative stress. On the other hand, in response to a defined heat-stress treatment, the induction of HSP70 was lower in patients with OSA, indicative of a possible maladaptive response to an acute stress. Correlations with oxidative stress and TNF-alpha further support this conclusion.
    Journal of Sleep Research 11/2009; 19(1 Pt 2):139-47. DOI:10.1111/j.1365-2869.2009.00789.x · 3.35 Impact Factor
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