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There is clearly an association between obstructive sleep apnoea (OSA) and vascular disease (Marin et al. 2005; Gottlieb et al. 2010). Much vascular disease remains unexplained even after allowing for well-known risk factors, such as hypertension and dyslipidaemia (Jackson et al. 2009) and, because OSA is common, it certainly could provide a significant extra contribution. In recent years several potential hypotheses have been advanced to link OSA with vascular disease, derived from the complex physiological changes that actually occur during OSA (Kohler these include intermittent hypoxia, intermittent arousal from sleep and increased intrathoracic pressure swings. The link between these consequences of OSA and vascular disease are probably multifactorial, most likely augmented sympathetic activity, with less evidence for oxidative stress, systemic inflammation, and vibration damage to the carotid arteries. However, because of the close association between central obesity and both OSA (Davies et al. 1992) and vascular disease (Yusuf et al. 2005), it has been very difficult to disentangle the inter-relations and demonstrate that OSA is a truly independent risk factor for vascular disease. Although laboratory studies may support plausible hypotheses, this does not prove their relevance to clinical medicine, a painful lesson learnt in other areas of vascular risk (e.g. anti-oxidant treatment and hormone replacement therapy) where plausible hypotheses, based on laboratory experiments and cross-sectional studies, failed to be supported by randomised controlled trials (RCTs; Simon et al. 2001; Lawlor et al. 2004). Therefore, studies of robust design, allowing identification of true causality, are essential in this area. Each of the above-mentioned mechanisms that possibly underpin the association between OSA and vascular disease needs to be proven to be clinically relevant in RCTs. At present such data are most supportive for increased sympathetic nervous system activity, which appears more than adequate as a mechanism to explain the associations observed between OSA and vascular disease. Findings from both animal models and from human studies, have provided ample evidence that OSA is associated with augmented sympathetic activation, ascribed to recurrent arousals from sleep, intermittent hypoxia, and to a lesser extent intrathoracic pressure changes. The exposure of rodents to intermittent hypoxia over 14–30 days increased catecholamines and substantially elevated blood pressure (BP; Lesske et al. 1997; Dematteis et al. 2008). Surgical denervation of peripheral chemoreceptors prevented the observed increase in BP, and adrenal demedullation and chemical denervation of the peripheral sympathetic nervous system prevented the elevation of BP (Lesske et al. 1997). In rats, chronic intermittent hypoxia has also been shown to augment chemoreflex-stimulated sympathetic outflow via the renin–angiotensin system and via modulation of O2-sensing in carotid bodies through activation of HIF-1 and downregulation of HIF-2 (La Rovere et al. 1998; Prabhakar et al. 2009). Furthermore, stimulation of carotid bodies by intermittent hypoxia has been shown to be associated with a reduction in baroreflex sensitivity in cats (Rey et al. 2004). In dogs, arousals from sleep have been shown to be associated with a marked increase in heart rate, which was abolished by sympathetic blockade (Horner et al. 1995). In a RCT including 10 healthy males exposed to intermittent hypoxia or a sham procedure for 6 h per day for 4 days, mean blood pressure increased by 4 mmHg, and nitric oxide derivatives were reduced by 55%. This was associated with an increase in BP and cerebral vascular resistance response to a hypoxic challenge (Foster et al. 2009). In a similar study including 12 healthy subjects, 2 weeks of intermittent hypoxia exposure increased sympathetic outflow associated with an increase in daytime systolic BP of 8 mmHg; however, this was not accompanied by an increase in inflammatory markers (CRP, IL-1Ra, IL-8, TNF-α; Tamisier et al. 2011). In a study including five healthy humans, increasing intensity of experimentally induced arousals caused progressively larger transient increases in BP and heart rate similar in size to those seen with the arousals that usually terminate an obstructive apnoea (Davies et al. 1993). In a larger study involving 14 healthy humans, arousal stimuli during sleep caused bursts of sympathetic nerve activity (as measured by microneurography of the peroneal nerve) and transient increases in BP (Somers et al. 1993). The increasing inspiratory effort against the collapsed pharynx during obstructive apnoeas is also likely to cause increased sympathetic nerve activity; in an experimental study of nine healthy humans, an intrathoracic pressure change induced by a Mueller manoeuvre generated an increase of more than 200% in postganglionic sympathetic nerve activity and a 14% increase in mean BP at the end of the apnoea (Somers et al. 1993). At least five RCTs, with appropriate control subjects, have provided evidence that continuous positive airway pressure (CPAP) therapy in OSA reduces 24 h catecholamine excretion, consistent with a reduction in sympathetic nerve activity (Ziegler et al. 2001; Mills et al. 2006; Drager et al. 2007; Kohler et al. 2008, 2011). A study assessing 38 patients with obstructive sleep apnoea syndrome (OSAS) demonstrated a 26% reduction in 24 h urine norepinephrine (noradrenaline) levels after 7 days of CPAP treatment (Ziegler et al. 2001), and another trial involving 102 patients with moderate-to-severe OSAS reported a 26% reduction in urine normetanephrine levels and augmentation index (a measure of arterial stiffness) after 4 weeks of CPAP therapy; interestingly, however, no reduction in various markers of systemic inflammation (CRP, IL-6, INF-γ) was found (Kohler et al. 2008). In further studies, a reduction in urinary levels of norepinephrine of 38% during daytime, and of 22% during the night, was shown after 14 days of CPAP treatment in 50 patients (Mills et al. 2006), and in 24 patients, 4 months of CPAP therapy was associated with a 44% decrease of plasma norepinephrine levels (Drager et al. 2007). More recently, Kohler et al. 2011 showed in a trial, including 41 patients with OSA, that CPAP therapy withdrawal for 14 days increased urinary norepinephrine levels by 44%, associated with a substantial worsening of endothelial function, BP and heart rate, but no evidence of an increase in inflammatory markers (Fig. 1). Data from a RCT, comparing the effects of 14 days of CPAP with 14 days of overnight supplemental oxygen therapy on urinary norepinephrine levels in patients with OSAS, showed that the oxygen therapy also reduced urinary norepinephrine levels during the daytime (Mills et al. 2006; Norman et al. 2006). Effects of 14 days of CPAP therapy withdrawal from patients with OSA NE, urinary norepinephrine (noradrenaline); FMD, flow mediated dilatation (a measure of endothelial function); HR, heart rate; BP, diastolic blood pressure; LDL, low density lipoprotein; HOMA, homeostatic model assessment (a measure of insulin resistance); CRP, C-reactive protein; IL-6, interleukin 6; TNF, tumour necrosis factor α. Baroreflex sensitivity, an established index of cardiac sympatho-vagal balance, is also depressed and, therefore, contributes to the development of hypertension and cardiovascular disease in patients with OSAS. Two RCTs have provided evidence for an independent link between OSAS and depressed daytime baroreflex sensitivity. In a study of 77 patients with OSA, 4 weeks of CPAP therapy increased baroreflex sensitivity by 24% (Kohler et al. 2008). Similarly, baroreflex sensitivity was increased with CPAP therapy in a trial involving 33 patients (Noda et al. 2007), consistent with a beneficial effect of OSAS treatment on the cardiac sympatho-vagal balance. The findings of these controlled trials provide evidence for a causal relationship between OSA, increased sympathetic nerve activity, and depressed baroreflex sensitivity. There is extensive evidence that the above-described increase in sympathetic activity in patients with OSA, and its effect on heart rate, BP and vascular function, is of considerable clinical importance in determining vascular outcomes (Palatini Fox 590/12/2813 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Kohler et al. (Thu,) studied this question.