Clinical perspective of obstructive sleep apnea-induced cardiovascular complications

Obstructive sleep apnea (OSA) syndrome is a highly prevalent disorder characterized by recurrent upper airway collapse during sleep, and associated with repetitive episodes of transient oxygen desaturation during sleep. It disrupts normal ventilation and sleep architecture, and is typically associated with excessive daytime sleepiness, snoring, and witnessed apneas. Besides being associated with neurocognitive impairment, mood and behavioral effects, and increased risk for work-related and traffic accidents, OSA has also been implicated in the pathogenesis of various cardiovascular diseases, including systemic hypertension, coronary artery disease, congestive heart failure, pulmonary hypertension, stroke, and cardiac arrhythmias. The mechanisms by which OSA affects the cardiovascular system may involve mechanical effects on intrathoracic pressure, increased sympathetic activation, intermittent hypoxia, and endothelial dysfunction. Therapy with continuous positive airway pressure (CPAP) has been demonstrated to improve cardiopulmonary hemodynamics in patients with OSA and may reverse the endothelial cell dysfunction.     

Is there a link between intermittent hypoxia-induced respiratory plasticity and obstructive sleep apnoea?

Although neuroplasticity is an important property of the respiratory motor control system, its existence has been appreciated only in recent years and, as a result, its functional significance is not completely understood. The most frequently studied models of respiratory plasticity is respiratory long-term facilitation (LTF) following acute intermittent hypoxia and enhanced LTF following chronic intermittent hypoxia. Since intermittent hypoxia is a prominent feature of sleep-disordered breathing, LTF and/or enhanced LTF may compensate for factors that predispose to sleep-disordered breathing, particularly during obstructive sleep apnoea (OSA). Long-term facilitation has been studied most frequently in rats, and exhibits interesting properties consistent with a role in stabilizing breathing during sleep. Specifically, LTF: (1) is prominent in upper airway respiratory motor activity, suggesting that it stabilizes upper airways and maintains airway patency; (2) is most prominent during sleep in unanaesthetized rats; and (3) exhibits sexual dimorphism (greatest in young male and middle-aged female rats; smallest in middle-aged male and young female rats). Although these features are consistent with the hypothesis that upper airway LTF minimizes the prevalence of OSA in humans, there is little direct evidence for such an effect. Here we review advances in our understanding of LTF and its underlying mechanisms and present evidence concerning a potential role for LTF in maintaining upper airway patency, stabilizing breathing and preventing OSA in humans. Regardless of the relationship between LTF and OSA, a detailed understanding of cellular and synaptic mechanisms that underlie LTF may guide the development of new drugs to regulate upper airway tone, thereby offsetting the tendency for upper airway collapse characteristic of heavy snoring and OSA.     

Atherosklerose/Aortenaneurysmen

Patients with obstructive sleep apnea (OSA) show a high prevalence of atherosclerotic disorders. Furthermore, they have evidence for accelerated vascular remodeling which is probably due to intermittent nocturnal hypoxia. Similarly, the prevalence of OSA is increased in patients suffering from aortic dissections and aneurysms. In addition, the presence of OSA is linked with more rapid aneurysm growth. The OSA-associated arterial hypertension with its characteristic non-dipping during sleep is supposed to play a key role within this context. Continuous positive airway pressure therapy may attenuate atherosclerosis, whereas its effects on the development and progression of aortic aneurysms have not yet been investigated.     

Pulmonary artery pressure in sleep apnoea and snoring

SUMMARY  There is a renewed interest in pulmonary hypertension (PH) complicating obstructive sleep apnoea (OSA). The prevalence of PH in populations of patients with less severe OSA was documented to be around 10%. The most recent data from both catheterization and echocardiographic studies indicate that as many as 40% of patients with OSA have PH. It has been shown that non-obese patients with normal respiratory function tests can develop pulmonary hypertension. One of the other possible mechanisms involved may be the presence of heightened pulmonary artery pressure response to hypoxia. There are now data available to indicate that treatment with nasal CPAP can decrease or even normalize pulmonary artery pressure in patients with sleep apnoea.     

Physiological basis for a causal relationship of obstructive sleep apnoea to hypertension

Obstructive sleep apnoea (OSA) is causally related to systemic hypertension through sustained sympathoexcitation. The causes of this sympathoexcitation remain uncertain; however, substantial animal and human data suggest that cyclic intermittent hypoxia (CIH), as is experienced at night by patients with OSA, provides the causal link between upper airway obstruction during sleep and sympathetic activation during waking. Direct and indirect evidence indicates that CIH leads to sympathoexcitation by two mechanisms: (1) augmentation of peripheral chemoreflex sensitivity (hypoxic acclimatization); and (2) direct effects on sites of central sympathetic regulation, such as the subfornical organ and the paraventricular nucleus of the hypothalamus. Initial reports suggest that the molecular mechanisms influencing peripheral chemoreflex sensitivity and central sympathetic activity may be the same, involving such neuromodulators as angiotensin II, endothelin and nitric oxide.     

Obstructive sleep apnea,immuno-inflammation,and atherosclerosis

Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder leading to cardiovascular and metabolic complications. OSA is also a multicomponent disorder, with intermittent hypoxia (IH) as the main trigger for the associated cardiovascular and metabolic alterations. Indeed, recurrent pharyngeal collapses during sleep lead to repetitive sequences of hypoxia–reoxygenation. This IH induces several consequences such as hemodynamic, hormonometabolic, oxidative, and immuno-inflammatory alterations that may interact and aggravate each other, resulting in artery changes, from adaptive to degenerative atherosclerotic remodeling. Atherosclerosis has been found in OSA patients free of other cardiovascular risk factors and is related to the severity of nocturnal hypoxia. Early stages of artery alteration, including functional and structural changes, have been evidenced in both OSA patients and rodents experimentally exposed to IH. Impaired vasoreactivity with endothelial dysfunction and/or increased vasoconstrictive responses due to sympathetic, endothelin, and renin–angiotensin systems have been reported and also contribute to vascular remodeling and inflammation. Oxidative stress, inflammation, and vascular remodeling can be directly triggered by IH, further aggravated by the OSA-associated hormonometabolic alterations, such as insulin resistance, dyslipidemia, and adipokine imbalance. As shown in OSA patients and in the animal model, genetic susceptibility, comorbidities (obesity), and life habits (high fat diet) may aggravate atherosclerosis development or progression. The intimate molecular mechanisms are still largely unknown, and their understanding may contribute to delineate new targets for prevention strategies and/or development of new treatment of OSA-related atherosclerosis, especially in patients at risk for cardiovascular disease.     

Sympathetic nerve activity in obstructive sleep apnoea

The mechanisms underlying the link between obstructive sleep apnoea (OSA) and cardiovascular disease are not completely established. However, there is increasing evidence that autonomic mechanisms are implicated. A number of studies have consistently shown that patients with OSA have high levels of sympathetic nerve traffic. During sleep, repetitive episodes of hypoxia, hypercapnia and obstructive apnoea act through chemoreceptor reflexes and other mechanisms to increase sympathetic drive. Remarkably, the high sympathetic drive is present even during daytime wakefulness when subjects are breathing normally and no evidence of hypoxia or chemoreflex activation is apparent. Several neural and humoral mechanisms may contribute to maintenance of higher sympathetic activity and blood pressure. These mechanisms include chemoreflex and baroreflex dysfunction, altered cardiovascular variability, vasoconstrictor effects of nocturnal endothelin release and endothelial dysfunction. Long-term continuous positive airway pressure treatment decreases muscle sympathetic nerve activity in OSA patients. The vast majority of OSA patients remain undiagnosed. Unrecognized OSA may contribute, in part, to the metabolic and cardiovascular derangements that are thought to be linked to obesity, and to the association between obesity and cardiovascular risk. Furthermore, acting through sympathetic neural mechanisms, OSA may contribute to or augment elevated levels of blood pressure in a large proportion of the hypertensive patient population.     

Chronic intermittent hypoxia sensitizes acute hypothalamic-pituitary-adrenal stress reactivity and Fos induction in the rat locus coeruleus in response to subsequent immobilization stress

Obstructive sleep apnea (OSA) is associated with several pathophysiological conditions, including hypertension, obesity, insulin resistance, hypothalamic-pituitary-adrenal (HPA) dysregulation, and other endocrine and metabolic disturbances comprising the "metabolic syndrome." Repeated episodes of hypoxia in OSA may represent a chronic intermittent stress, leading to HPA dysregulation. Alterations in HPA reactivity could then contribute to or exacerbate other pathophysiological processes. We showed previously that another metabolic stressor, chronic intermittent cold stress, enhanced noradrenergic facilitation of acute HPA stress reactivity. In this study, we investigated whether chronic intermittent hypoxia (CIH), a rat model for the arterial hypoxemia that accompanies OSA, similarly sensitizes the HPA response to novel acute stress. Rats were exposed to CIH (alternating cycles of normoxia [3 min at 21% O(2)] and hypoxia [3 min at 10% O(2)], repeated continuously for 8 h/day during the light portion of the cycle for 7 days). On the day after the final CIH exposure, there were no differences in baseline plasma adrenocorticotropic hormone (ACTH), but the peak ACTH response to 30 min acute immobilization stress was greater in CIH-stressed rats than in controls. Induction of Fos expression by acute immobilization stress was comparable following CIH in several HPA-modulatory brain regions, including the paraventricular nucleus, bed nucleus of the stria terminalis, and amygdala. Fos induction was attenuated in lateral hypothalamus, an HPA-inhibitory region. By contrast, acute Fos induction was enhanced in noradrenergic neurons in the locus coeruleus following CIH exposure. Thus, similar to chronic cold stress, CIH sensitized acute HPA and noradrenergic stress reactivity. Plasticity in the acute stress response is important for long-term adaptation, but may also contribute to pathophysiological conditions associated with states of chronic or repeated stress, such as OSA. Determining the neural mechanisms underlying these adaptations may help us better understand the etiology of such disorders, and inform the development of more effective treatments.     

Obstructive sleep apnoea and cardiovascular disease: a literature review

As obesity becomes more common worldwide, the prevalence of obstructive sleep apnoea (OSA) continues to rise. Obstructive sleep apnoea is a well-known disorder that causes chronic intermittent hypoxia (CIH), which is considered a risk factor for atherosclerosis directly and indirectly. Ischaemic heart disease remains the leading cause of death. Most risk factors for atherosclerosis are well understood. However, other factors such as CIH are less well understood. Several studies have investigated the pathophysiology of CIH, attempting to uncover its link to atherosclerosis and to determine whether OSA treatment can be a therapeutic modality to modify the risk for atherosclerosis. In this article, we will review the pathophysiology of OSA as an independent risk factor for cardiovascular disease and discuss the most common markers that have been studied. We will also examine the potential impact of OSA management as a risk factor modifier on the reversibility of atherosclerosis.     

Brain preconditioning and obstructive sleep apnea syndrome

Intermittent hypoxia stimulates the development of adaptive responses, called preconditioning. This process is partially mediated by genetic remodeling, via hypoxia inducible factor (HIF), which induces long-term adaptation processes and is responsible for the increase of levels of vascular endothelial growth factor (VEGF), erythropoietin (Epo), atrial natriuretic peptide (ANP), and nitric oxide (NO). The synthesis of brain-derived neurotrophic factor (BDNF) participates in the control of neural plasticity after hypoxia. The mechanisms of neuroprotection against hypoxia may be related to vascular adjustments and to central neurogenic neuroprotection. Some of the factors known to be involved in the development of the mechanism of neuroprotection are also present in the responses to repetitive apneas that occur during sleep in patients with obstructive sleep apnea (OSA) syndrome, who are frequently exposed to severe sleep hypoxemia. It appears that OSA syndrome represents a clinical example of preconditioning and the development of adaptive responses to intermittent hypoxia.     

间歇缺氧及睡眠剥夺大鼠血管内皮细胞相关指标的变化

背景：血管内皮功能损坏是睡眠呼吸暂停的病理基础。 目的：观察间歇缺氧、睡眠剥夺对SD大鼠有创动脉收缩压及血浆一氧化氮、内皮素、降钙素基因相关肽水平的影响。 方法：将3月龄雄性SD大鼠16只随机等分为2组,模型组大鼠每天置入睡眠剥夺合并间歇性缺氧条件10 h (22：00-08：00),单纯睡眠剥夺条件12 h(08：00-20：00),剩余时间置大鼠笼饲养。对照组无睡眠剥夺、无缺氧条件饲养。 结果与结论：造模8周后,与对照组比较,模型组大鼠有创动脉压明显升高(P < 0.01),血浆一氧化氮、降钙素基因相关肽水平显著降低(P < 0.01),血浆内皮素水平显著升高(P < 0.01)。说明间歇性缺氧、睡眠剥夺可以引起SD大鼠血压增高,血管内皮功能受损。     

Chronic intermittent hypoxia modulates nNOS mRNA and protein expression in the rat hypothalamus

Exposure to chronic intermittent hypoxia (CIH) as observed in obstructive sleep apnea (OSA) elicits a sustained elevation of sympathetic activity and arterial blood pressure. Our overall hypothesis is that intermittent hypoxia might increase sympathetic activity, in part by altering neuronal nitric oxide synthase (nNOS) expression in the hypothalamus, where nitric oxide is sympathoinhibitory. In this study, we begin investigation of this hypothesis by testing the more specific hypothesis that the CIH alters nNOS expression in regions of the hypothalamus associated with cardiovascular regulation. To test the effect of CIH on NOS expression we subjected male Sprague-Dawley rats to cyclic intermittent hypoxia for 8h/day, for 35 days. Experimental rats showed an increase in systemic blood pressure. In situ hybridization and immunohistochemistry were performed on hypothalamic sections, respectively. The CIH rats displayed significantly lower levels of both nNOS mRNA and protein in the paraventricular hypothalamic nucleus (PVN) with different changes in the subareas of the PVN. There was a decreased level of nNOS mRNA and protein in the subfornical organ and the periventricular hypothalamic nucleus of the CIH rats, but no significant change in the supraoptic nucleus or the lateral hypothalamic area. This work suggests that examination of central regulation of sympathetic activity may help elucidate the mechanisms of hypertension after CIH.     

Mechanisms of sleep-disordered breathing: causes and consequences

Obstructive sleep apnea (OSA) is very common in the general population and is characterized by ineffective inspiratory efforts against a collapsed upper airway during sleep. Collapse occurs mainly at the level of the velopharynx and oropharynx due to a combination of predisposing anatomy and the withdrawal of pharyngeal dilator activity during sleep. Central sleep apnea (CSA) is a manifestation of chemoreflex control instability, leading to periods of inadequate respiratory drive sufficient to trigger breathing, usually alternating with periods of hyperventilation. While both forms of apnea are the result of differing pathophysiology, it has become increasingly clear that OSA and CSA often coexist in the same patient, the existence of one can predispose to the other, and that the two are not as distinct as previously thought. Both OSA and CSA exert a number of acute deleterious effects including intermittent hypoxia, arousals from sleep, and swings in negative intrathoracic pressure, which in turn lead to chronic physiologic consequences such as autonomic dysregulation, endothelial dysfunction, and cardiac remodeling. These underlying pathophysiological mechanisms provide a framework for understanding why OSA and CSA may predispose to cardiovascular diseases like ischemic heart disease and stroke.     

Pathophysiologische Grundlagen der OSA-assoziierten Herz-Kreislauf-Erkrankungen

Obstructive sleep apnea (OSA) is an independent risk factor for a wide spectrum of cardio- and cerebrovascular diseases such as hypertension, heart failure, and stroke. The pathophysiological basis for this causal relationship is a specific disturbance of the “vascular micromilieu” by intermittent nocturnal hypoxia with the main features being sympathetic activation, oxidative stress, and inflammation. These changes lead to endothelial dysfunction, i.e., a reduction of endothelial-dependent vasodilation, which finally gives rise to the clinical manifestations of OSA within the cardiovascular system. Importantly, effective continuous positive airway pressure (CPAP) therapy reverses these abnormalities and thereby exerts its well known cardioprotective effects.     

A bioreactor for subjecting cultured cells to fast-rate intermittent hypoxia

High frequency intermittent hypoxia is one of the most relevant injurious stimuli experienced by patients with obstructive sleep apnea (OSA). Given that the conventional setting for culturing cells under intermittent hypoxia conditions is limited by long equilibration times, we designed a simple bioreactor capable of effectively subjecting cultured cells to controlled high-frequency hypoxic/normoxic stimuli. The bioreactor's operation is based on exposing cells to a medium that is bubbled with the appropriate mixture of gases into two separate containers, and from there it is directed to the cell culture dish with the aid of two bidirectional peristaltic pumps. The device was tested on human alveolar epithelial cells (A549) and mouse melanoma cells (B16-F10), subjecting them to patterns of intermittent hypoxia (20s at 5% O(2) and 50s at 20% O(2)), which realistically mimic OSA of up to severe intensity as defined by the apnea hypopnea index. The proposed bioreactor can be easily and inexpensively assembled and is of practical use for investigating the effects of high-rate changes in oxygen concentration in the cell culture medium.     

Chronic intermittent hypoxia induces cardiac inflammation and dysfunction in a rat obstructive sleep apnea model

Chronic intermittent hypoxia is considered to play an important role in cardiovascular pathogenesis during the development of obstructive sleep apnea (OSA). We used a well-described OSA rat model induced with simultaneous intermittent hypoxia. Male Sprague Dawley rats were individually placed into plexiglass chambers with air pressure and components were electronically controlled. The rats were exposed to intermittent hypoxia 8 hours daily for 5 weeks. The changes of cardiac structure and function were examined by ultrasound. The cardiac pathology, apoptosis, and fibrosis were analyzed by H&E staining, TUNNEL assay, and picosirius staining, respectively. The expression of inflammation and fibrosis marker genes was analyzed by quantitative real-time PCR and Western blot. Chronic intermittent hypoxia/low pressure resulted in significant increase of left ventricular internal diameters (LVIDs), endsystolic volume (ESV), end-diastolic volume (EDV), and blood lactate level and marked reduction in ejection fraction and fractional shortening. Chronic intermittent hypoxia increased TUNNEL-positive myocytes, disrupted normal arrangement of cardiac fibers, and increased Sirius stained collagen fibers. The expression levels of hypoxia induced factor (HIF)-1α, NF-kB, IL-6, and matrix metallopeptidase 2 (MMP-2) were significantly increased in the heart of rats exposed to chronic intermittent hypoxia. In conclusion, the left ventricular function was adversely affected by chronic intermittent hypoxia, which is associated with increased expression of HIF-1α and NF-kB signaling molecules and development of cardiac inflammation, apoptosis and fibrosis.     

Effects of continuous positive airway pressure on cognitition and neuroimaging data in sleep apnea

Obstructive sleep apnea (OSA) has been associated with a broad range of neurocognitive difficulties. The current view is that the neurocognitive impairment in OSA is due to the adverse effects of sleep fragmentation and/or intermittent hypoxia. The overall picture of cognitive deficits in OSA is complex. On balance, there appears to be negative effects of OSA on cognition, most likely in the domains of attention/vigilance, verbal and visual delayed long-term memory, visuospatial/constructional abilities, and executive dysfunction. Continuous positive airway pressure (CPAP) is the most effective and widely used treatment of OSA. In the majority of studies of OSA patients treated with CPAP, attention/vigilance improved, but changes in global functioning, executive functioning, and memory improved in about half of the studies. This may be due, in part, to variability in study design and sampling methodology across studies.