Autonomic alterations and endothelial dysfunction in pediatric obstructive sleep apnea

Sleep Medicine 11 (2010) 714–720

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Sleep Medicine journal homepage: www.elsevier.com/locate/sleep

Review Article

Autonomic alterations and endothelial dysfunction in pediatric obstructive sleep apnea Leila Kheirandish-Gozal a,*, Rakesh Bhattacharjee b, David Gozal a a b

Department of Pediatrics and Comer Children’s Hospital, Pritzker School of Medicine, The University of Chicago, USA Division of Sleep and Respiratory Medicine, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

a r t i c l e

i n f o

Article history: Received 17 October 2009 Received in revised form 6 December 2009 Accepted 12 December 2009

Keywords: Autonomic nervous system function Cardiovascular disease Endothelium Stem cells Inflammation Pediatric sleep apnea Oxidative stress

a b s t r a c t The cardiovascular consequences of obstructive sleep apnea syndrome (OSAS) in children have started to emerge over the last decade. It is clear that the respiratory and sleep alterations that characterize this relatively prevalent condition induce substantial alterations in autonomic nervous system control, ultimately generating high sympathetic outflow and reactivity that reflect an imbalance between sympatho-excitatory and vagal inhibitory inputs. In addition to these important consequences, the constitutive elements of OSAS also elicit a rather extensive activation of systemic inflammatory pathways that in turn pose substantial risk to the integrity and functional homeostasis of the endothelial network. The complex interactions between the multiple injury-associated pathways recruited by OSAS are further compounded by the potential release of angiogenic factors and by the mobilization and homing of progenitor cells that have the potential to repair and restore the OSAS-disrupted vascular function. Improved characterization of the mechanisms involved in every one of these processes and identification of the determinants of susceptibility in pediatric populations along with the interactions with obesity will clearly modify our approaches to OSAS in the future. Ó 2010 Elsevier B.V. All rights reserved.

1. Introduction Since obstructive sleep apnea syndrome (OSAS) was described by McKenzie in 1880 in adult patients [1], it took almost 100 years before OSAS was recognized in children [2]. Since then, increasing awareness and recognition of OSAS have revealed that OSAS is a highly prevalent disorder, with an estimated frequency of 2–3% in all children, using stringent criteria [3–5], but is also associated with substantial morbidity, primarily involving CNS, cardiovascular and metabolic systems. Over the last several years substantial increments in our understanding of the morbid consequences of OSAS have emerged, and cumulative evidence would implicate processes leading to both injury and to repair and regeneration. In this context, this paper will examine two important aspects of cardiovascular dysfunction that can arise from the presence of OSAS in children, namely, autonomic and endothelial dysfunction. The role of OSAS in blood pressure regulation as well as other cardiovascular consequences of OSA,

* Corresponding author. Address: Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, University of Chicago, 5814 S Maryland Avenue, C-113, Chicago, IL 60637, United States. Tel.: +1 773 704 3815; fax: +1 773 702 4523. E-mail address: [email protected] (L. Kheirandish-Gozal). 1389-9457/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2009.12.013

such as pulmonary vascular hypertension, clearly merit separate attention. 2. Autonomic dysfunction in children with sleep-disordered breathing The recurring episodes of upper airway obstruction that characterize OSAS will lead to intermittent hypoxia and hypercapnia, to disruption of sleep through repetitive arousals, and will also be associated with significant swings of intrathoracic pressures. All of these alterations in the context of OSA could in turn lead to disturbances in autonomic nervous system function and manifest as the occurrence of increased sympathetic nervous system tone, increased sympathetic responsiveness, and presence of sympathetic–parasympathetic imbalance. In adult patients with OSAS, the causal association between intermittent hypoxemia and elevated sympathetic nervous tone has now been conclusively and repeatedly demonstrated [6–8]. Indeed, adult OSAS patients display tonically increased sympathetic tone and also enhanced sympathetic responses to hypoxia when compared to controls [9]. As would be anticipated from such changes, plasma nor-epinephrine levels are elevated in adults with OSAS as well [10]. Furthermore, urinary catecholamine assays (in the context of untreated OSAS elevations in nor-epinephrine) are present and will return to baseline after effective therapy of the underlying OSAS [11]. The

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cumulative findings on changes in sympathetic nervous system activity would support the conceptual framework, whereby disruptions of sleep and gas exchange will lead to alterations in vasomotor tone, promote vascular remodeling, and ultimately induce cardiovascular morbidity [12]. In contrast with the rather extensive work thus far conducted in adults, studies on alterations of autonomic nervous system function in children with OSAS are relatively scarce. One potential reason is the difficulty with any type of invasive tests in children, and in this category, sympathetic nerve fiber recordings are notoriously difficult and require a high level of cooperation, thereby precluding their feasibility in children [13]. However, non-invasive probes of autonomic nervous system tone that are based on heart rate variability analyses using fast Fourier transform (spectral) analyses or Poincare scatterplots have suggested the presence of substantial alterations in sympathetic tone among children with OSAS [14,15]. Similarly, using attenuation of pulse arterial tonometry (PAT) signals as a correlate of sympathetic activity surges, increased reactivity to maneuvers associated with sympathetic responses were found in 14 children with OSAS [16]. Indeed, PAT signal attenuation was significantly exacerbated following sigh and cold pressor tests when compared to control children, suggesting the presence of increased sympathetic nervous system reactivity during wakefulness [16]. Using nonlinear mathematical modeling, evidence of increased sympathetic outflow activity and responsiveness in the absence of apparent disturbances in parasympathetic function were also reported in children with OSAS [17]. Furthermore, as initially suggested [14], the receiver operator curves on the use of heart rate variability derived algorithms for diagnosis of OSAS have shown promising results [18,19]. Other non-invasive approaches for assessment of autonomic nervous system tone are based on the derivation of pulse transit time (PTT). Indeed, PTT has been used as a reliable indicator of sympathetic burst activity by measuring the delay of the pulse wave from the initial left ventricular electrical depolarization in the ECG to the appearance of the corresponding plethysmographic signal of the oximetry waveform at the wrist [20]. When simultaneous recordings of PAT and PTT were conducted in healthy children, it became apparent that arousals were associated with predictable changes in both PAT and PTT, thereby linking the arousal-induced sympathetic discharges to these non-invasive measures in children [21–24]. Another approach to assessment of sympathetic activation would involve measurements of catecholamines in either serum or urine. We are only aware of two studies on children with OSAS, and both of these studies confirmed the presence of OSAS severitydependent increases in urinary catecholamines and, more particularly, nor-epinephrine [25,26]. In addition, up-regulation of catecholamine synthesis genes and reciprocal down-regulation of those genes underlying degradation and removal of catecholamines from the circulation were also found [25]. All of the aforementioned results on different estimates of sympathetic nervous activity and reactivity strongly suggest that autonomic nervous system dysfunction develops in children with OSAS and that systematic identification of those children in whom more pronounced disruption of autonomic function occurs might be necessary and recommended in the future since these children may be at increased risk for cardiovascular morbidity. Nevertheless, the long-term effects of dysregulation of autonomic nervous system control in children with OSAS remain undefined; physicians should clearly be on alert, particularly when considering some of the recent findings in a rodent model of OSAS. Indeed, when intermittent hypoxia mimicing OSAS during sleep was delivered to young developing rats during their early stages of development, persistent attenuations in baroreflex sensitivity and renal sympathetic function occurred, even many months after cessation of hypoxic

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exposures [27–29]. Evidence for persistent structural abnormalities in central and peripheral structures underlying autonomic nervous system regulation was also found, such as changes in the number of neurons and their reactivity to neurotransmitters within the nucleus ambiguus along with a reduction in vagal efferents [27–29]. The changes in the configuration of the autonomic system network were life lasting and led to changes in blood pressure and in heart rate variability in response to stress in adult rats, well after cessation of the intermittent hypoxia. These experiments provide initial cues to the potential long-term consequences of OSAS, particularly if the latter occurs during unique phases of maturation. Furthermore, intermittent hypoxia during sleep significantly augments catecholamine synthesis and turnover in the carotid body [30], and such effects could further mediate the induction of hypertension in the context of OSAS [31–33]. Other laboratories demonstrated the presence of perturbations in the renin–angiotensin system [34] and changes in central expression of the early gene c-fos in pressor-related brain regions following intermittent hypoxia during sleep [35]. Therefore, both the acute and prolonged effects of OSAS on the autonomic nervous system (both central and peripheral) may not only translate into transient alteration in the functional regulation of this important system, but may also lead to sustained abnormalities that predispose subsequent cardiovascular and metabolic morbidity later in life, particularly in genetically susceptible individuals. It will be important to gain further insights into the relative contributions of the various sleep measures traditionally collected in nocturnal polysomnography (e.g., arousal index, oxygen desaturation index, AHI, etc.) and measures of autonomic nervous system function in children.

3. Systemic inflammation and atherogenesis in children with OSAS Cumulative evidence gathered over the last several years has explored the underlying hypothesis that pediatric OSAS is in fact a systemic, low-grade, inflammatory disease [36]. Under these assumptions, end-organ morbidity and several of the clinical manifestations and symptoms of pediatric OSAS would result from induction and propagation of inflammatory processes. The induction of systemic inflammatory responses could be either activated directly or linked to the generation of reactive oxidative species secondary to the recurrent hypoxic and arousal episodes that characterize OSAS as well as those associated with the increased intrathoracic pressure swings that develop during upper airway obstructive episodes [37,38]. T cell lymphocyte-dependent inflammatory mechanisms are activated by OSAS, and the specific cytokine secretion that ensues is remarkably analogous to the cytokine networks that have been implicated in atherogenesis. Both CD4 and CD8 T cells are activated in OSAS patients and exhibit increased IL-4 expression and reduced IL-10 expression [39–41]. In addition, CD8 T cells of patients with OSAS show evidence of increased TNF-a activity and induce endothelial cell cytotoxicity. Of note, these inflammatory changes were reversed by treatment of OSAS with CPAP. Additional investigators have also reported increases in circulating TNF-a levels and found significant associations between the morning concentrations of this pro-inflammatory cytokine and the degree of daytime sleepiness and hypoxia [42] and that TNF-a levels are reduced after treatment [43]. In children, the data implicating cytokine induction in OSAS have not been consistent, since the levels of specific pro-inflammatory cytokines have either been in the normal range or found to be increased [44,45]. The likely explanation for such lack of consistency may reside in discrepancies across methodologies (i.e.,

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sampling times and handling, processing delays) and can be modulated by heterogeneities in genetic background and environmental and lifestyle factors. In a recent study from our laboratory, we found that morning TNF-a plasma concentrations were not only elevated in children with OSAS, but were also strongly correlated with the frequency of respiratory-induced arousals [46]. Furthermore, the increases in morning TNF-a levels correlated with the shortening of mean sleep latency and correspondingly improved after adenotonsillectomy [46,47]. As further evidence of the potential role played by genomic variance in the determination of specific phenotypes in pediatric OSAS, we found that the presence or absence of a specific gene polymorphism on the TNF-a gene accounted for a substantial proportion of the variance in TNF-a levels and consequently in phenotypic expression of excessive daytime sleepiness in the context of OSAS [48]. C-reactive protein (CRP), an inflammatory protein intimately associated with atherosclerosis, is synthesized in the liver via stimulation mediated by IL-6 activity. CRP is a firmly established risk factor marker for cardiovascular morbidity and has also been directly implicated in atheroma formation [49–51]. Circulating levels of CRP are increased in both adults [52–59] and children with OSAS [60–64] and can be reduced with effective treatment [54,63,64]. Of note, increased CRP in the presence of OSAS may not always be present, suggesting that the association of OSAS and CRP is not a direct cause and effect and is perhaps dependent on the presence of concurrent risk factors, such as obesity, diabetes, and cigarette smoking [65–70], as well as being dictated by the genetic heterogeneity present among those genes directly implicated in CRP serum concentrations [71,72]. Indeed, CRP levels may or may not be elevated in children with OSAS, but if they are increased end-organ morbidity such as neurocognitive deficits will much more likely be present [73]. OSAS in children also leads to increased expression of adhesion molecules, further lending support to the causal relationship between OSA, inflammation and ultimately vascular injury and dysfunction. Significant correlations between P-selectin and OSAS have emerged in children and have been corroborated by other investigators [74,75]. More recently, we explored the changes in myeloid-related protein (MRP) 8/14, which is known to play an important pathophysiological role in atherosclerosis and whose plasma levels closely correlate with endothelial cell dysfunction. We found dose-dependent increases in this atherogenic biomarker as a function of the severity of OSAS, and the levels were also predictive of endothelial function [76]. Furthermore, there was a strong synergistic interaction between OSA and the degree of obesity and the circulating levels of MRP 8/14. Thus, pro-inflammatory signaling pathways induced by both obesity and OSAS in children will promote amplification of systemic inflammation and expression of pro-atherogenic factors and thus lead to hastened generation of endothelial damage [77].

4. Alterations in endothelial function in pediatric OSAS In addition to the autonomic nervous system changes, the systemic inflammatory pathways activated in the presence of OSAS could induce functional and structural disruption of the endothelium (Fig. 1). Indeed, reductions in brachial artery flow-mediated dilation, a surrogate marker of endothelial functional integrity, have been reported in adults with OSAS [78–80] and were improved after treatment with CPAP [81–83]. Similar findings were also communicated in younger adult patients with OSAS who were free of any known cardiovascular involvement, and, as previously shown, CPAP treatment resulted in reversal of endothelial dysfunction [84,85].

Endothelial functional changes have also emerged as a frequent complication of obesity [86] and diabetes [87], and these are important issues considering the increased prevalence of OSAS in obese children [88–93] and the potential interactions between obesity and OSAS to amplify end-organ dysfunction [47,76,77]. We are only aware of a paucity of studies, all of which originated from our laboratory that have thus far explored whether OSAS adversely impacts endothelial function in children. In the initial study we explored endothelial function in 26 non-obese children with OSAS using a novel approach to the post-occlusion hyperemic response test [94]. In this study, endothelial function was significantly impaired when compared to healthy controls [94]. Furthermore, significant improvements or complete normalization of endothelial function occurred 6 months after treatment of OSAS with adenotonsillectomy in the majority of the children. However, the presence of a strong family history of early onset cardiovascular disease in six of the 26 children was associated with no improvements in endothelial function after adenotonsillectomy [94]. This observation, if repeated, would position OSAS not only as a major trigger for disruption of vascular function in genetically predisposed children, but also for initiating a cascade of vascular events in these children that would be more difficult if not impossible to reverse, leading to earlier onset and increased severity of cardiovascular diseases during adulthood. In a subsequent study, we found that obesity and OSAS appear to potentiate the magnitude of endothelial damage possibly via activation of systemic inflammatory pathways, as evidenced by MRP 8/14 and CRP levels [76]. Another potential mechanism of injury to the endothelium that has thus far not been examined in children with OSAS revolves around the induction and formation of circulating microparticles. Microparticles have now been identified for quite some time as a complex, yet intriguing mechanism of cell–cell interactions and both cell dysfunction and protection. Microparticles were first described nearly 30 years ago and named ‘‘platelet dust” and shown to promote coagulation [95]. Microparticles have now been identified as vectors of intercellular exchanges that include induction of endothelial modifications, angiogenesis or differentiation. The unique cell-derived particles are generated after cell activation or apoptosis following alterations in membrane phospholipid asymmetry that modify phosphorylation states and induce restricted cytoskeleton degradation that is then followed by shedding of microparticles [96]. Microparticles have been shown to facilitate the interactions between leukocytes and endothelium and promote the release of cytokines and induction and expression of adhesion molecules, as well as platelet aggregation and adhesive interactions of both platelets and monocytes with endothelial cells [97]. These events could be involved in inflammatory processes and, together with subsequent endothelial dysfunction, may participate to atherosclerosis development. The potential effects of microparticles on the vascular wall include actions on both endothelial cells and smooth muscle cells [98], thereby leading to altered vasomotor reactivity as well as angiogenesis [99,100]. The endothelial responses can be either immediate or delayed via regulation of gene expression, and as such, microparticles can participate in the regulation of the vascular tone through nitric oxide-dependent mechanisms that also play a major role in the survival of endothelial cells [101]. A recent study in adults with OSAS would further lend credence to the potential importance of microparticles in the vascular dysfunction that accompanies sleep-disordered breathing [102], and intense investigation in these directions is currently underway in our laboratory. Preliminary evidence also pointing to potential increases in endothelial cell loss in the context of OSAS has also emerged [103], albeit with some skepticism due to the methodology employed to identify

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Fig. 1. Schematic diagram displaying the activation of inflammatory pathways in the vasculature as related to OSAS, leading to release of microparticles and exosomes. The activation is then effectively mediating endothelial cell interactions with the inflammatory cells and microparticles, leading to reduced nitric oxide bioavailability, endothelial damage and dysfunction, increased adhesion of inflammatory cells and platelets, increased cytokines and other mediators, shedding of apoptotic endothelial cells, and migration of monocytes and macrophages to form foam cells and promote atherosclerosis. As a countermeasure to this cascade of injurious pathways, release of a variety of chemokines and pro-angiogenic agents, such as VEGF, may lead to recruitment, migration and homing of multiple sub-populations of bone marrow resident stem cells that have the potential to repair the injured endothelium and induce a regain of vascular function.

the apoptotic endothelial cells [104]. Of note, a recent study in otherwise healthy adults with OSAS has failed to identify the anticipated increases in circulating endothelial cells, i.e., cells that have been shed from the surface and represent damaged endothelium [105]. 5. Mechanisms for endothelial repair Herein, we have thus far reviewed potential mechanisms associated with vascular end-organ dysfunction (Fig. 1). However, we have not alluded to the flip side of the coin, as it relates to the ability to recruit processes involved in vascular regeneration and repair (Fig. 1). For example, we and others have previously shown that increased circulating levels of VEGF (which may be indicative of a compensatory response to endothelial injury) occur in both adults [106–109] and children [109] with OSAS, and the magnitude of the response may determine cardiovascular risk [106]. The discovery of endothelial progenitor cells (EPCs) has spurred a great deal of interest in the potential to reverse vascular injury [110–113]. In the context of OSAS, adult patients with OSAS who were free of any other known cardiovascular risk factors showed the presence of reduced numbers of circulating EPCs [114]. However, in another small group of adult patients with OSAS who seemed to be free of any cardiovascular risk factors, the investiga-

tor did not find such changes [105]. Furthermore, reduced numbers of circulating EPCs and attenuations in flow-mediated vascular dilation were identified in 32 adult patients with OSAS compared to 15 controls, with CPAP treatment improving both of these measures [115]. Of note, mesenchymal stem cells are released to the peripheral circulation in a rodent model of OSAS [116]. Taken together, and considering that the number of circulating EPCs is greater in children than in adults [19], activation and induction of factors involved in the recruitment and homing of EPCs could account for differences in the magnitude of endothelial dysfunction among children with OSAS (Fig. 1). 6. Summary A causative link between OSAS and autonomic and endothelial dysfunction in children is likely and deserves future exploration, including identification of mechanisms underlying this potential morbidity. Such mechanisms need to account for processes that mediate injury but also for those that promote vascular repair and functional integrity. Although the deleterious effects of OSAS on such systems may be reversed by early diagnosis and treatment, the epidemic of childhood obesity is likely to aggravate this problem, and, therefore, improved techniques aiming to establish the endothelial and autonomic phenotype in the context of clinical

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