INTRODUCTION — The association between obstructive sleep apnea (OSA) and cardiovascular dysfunction in the pediatric population has been the subject of much investigation [1-3]. Good evidence suggests that the presence of OSA in children is associated with specific adverse consequences to the cardiovascular system. However, the mechanisms and causality have not been completely elucidated. Both cardiac and vascular dysfunction are present in children with OSA, and these abnormalities appear to be mediated, either directly or indirectly, through changes to specific pathways, including the chemoreflex and baroreflex systems and a systemic inflammatory response. As changes in cardiovascular structure and function are not seen in all children with OSA, other genetic and environmental cues likely contribute to disease progression and severity.
This topic review describes changes in cardiovascular health in children with OSA and reviews the neural and inflammatory mechanisms that are implicated in pathophysiologic progression of disease. Other consequences of OSA in children, including effects on behavioral symptoms, daytime sleepiness, and growth, are discussed separately. (See "Management of obstructive sleep apnea in children", section on 'Consequences of untreated obstructive sleep apnea' and "Cognitive and behavioral consequences of sleep disorders in children".)
Cardiovascular disease in adults with OSA is discussed in a separate topic review. (See "Obstructive sleep apnea and cardiovascular disease in adults".)
NORMAL CARDIOVASCULAR FUNCTION DURING SLEEP — During normal sleep, fluctuations in heart rate and blood pressure (BP) are observed and vary with sleep stage . In non-rapid eye movement (NREM) sleep, autonomic changes include a reduction in sympathetic nervous system activity, leading to decreases in both heart rate and BP . By contrast, rapid eye movement (REM) sleep is characterized by fluctuations, with transient increases in heart rate and BP to levels seen during wakefulness . Although REM sleep results in variability and diverse changes in the sympathetic nerve activity, there is an overall activation of the sympathetic system [5,6]. These variations in cardiovascular parameters are altered in the presence of OSA, as detailed in the next section.
CLINICAL CONSEQUENCES OF OSA IN CHILDREN
Overview — OSA is characterized by apneic episodes with varying degrees of hypoxemia and hypercapnia during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. These intermittent episodes of partial or complete cessation of airflow disturb the normal autonomic control of the cardiovascular system [7-10]. Further, oxygen desaturations and elevations in carbon dioxide levels cause surges in sympathetic activity and associated cardiovascular changes [7,10]. Intrathoracic pressure changes during OSA also contribute to the effects on the cardiovascular system. Upper airway obstructions that occur with OSA, with continued diaphragmatic contractions, lead to excessively negative intrathoracic pressures that alter hemodynamics, such as left ventricle (LV) afterload . Expansion of the aorta also occurs in the presence of these intrathoracic pressure changes, movement that activates baroreceptors and prevents further sympathetic input during these apneic events [12,13]. Alternating periods of normal breathing followed by apneas thus lead to episodic changes in LV diastolic filling, stroke volume, and increased vascular resistance . These changes culminate in increased variability of blood pressures (BPs), often in conjunction with each apneic event (waveform 1). Chronic exposure to abnormal sharp fluctuations in BP during and just after the course of each apneic event is thought to eventually lead to loss of normal nocturnal "dipping" in nocturnal BP as compared with daytime BP. Over months to years, this could eventually lead to an increased risk for hypertension.
Changes in heart rate — One of the major consequences of untreated OSA in the pediatric population is increased variability in heart rate and elevated heart rate during both sleep and wake. These abnormalities can be presenting features of OSA in children and indicate subtle, but clinically important, autonomic dysfunction. As an example, in one study, heart rate indices of children with OSA were higher than those obtained from children without OSA . In a separate study, obese children with OSA, in comparison with obese children without OSA, showed elevated mean heart rates . More importantly, increased variability in heart rate was significantly associated with the presence of OSA, independent of age or degree of obesity . Increased heart rate variability has also been previously demonstrated during all sleep stages in children with moderate to severe OSA compared with healthy controls . These changes in heart rate variability in children with OSA are evident even during stable sleep (ie, during periods without respiratory events), demonstrating continued influence of autonomic dysregulation on heart rate even when apneic events are not occurring .
Changes in blood pressure — Children with OSA, in comparison with healthy children, are more likely to develop higher BPs during both wakefulness and sleep [17-23]. Abnormalities that can be identified by 24-hour ambulatory BP monitoring include elevated mean BPs and increased BP variability during the day and night, with decreased nighttime BP dipping, elevated morning BP surges, and increased BP load [19,21]. In one study, 17 percent of children with OSA had daytime or nighttime hypertension and all of these children had non-dipping BPs during sleep . The elevated nighttime and daytime BPs and BP variability correlate with OSA severity [19,22]. Furthermore, treatment of OSA with adenotonsillectomy modestly reduces mean BP, as measured by 24-hour ambulatory monitoring [24,25]. These findings suggest that OSA has a strong adverse effect on BP in children, and the effect worsens with increasing severity of OSA.
Hypertension is defined as systolic or diastolic BP ≥95th percentile for children 1 to 13 years old, and ≥130/80 for adolescents 13 years and older, on at least three occasions (table 1) . Although children with OSA have a variety of BP abnormalities, as described above, many of these abnormalities do not meet diagnostic criteria for hypertension. Thus, a meta-analysis of pediatric studies was unable to establish a direct relationship between OSA and risk of hypertension . Nonetheless, evidence does suggest that OSA has important effects on the cardiovascular system, as summarized above.
These changes in BP seen in children with OSA could be mediated in part by reduced sensitivity of the baroreflex system (see 'Baroreflex system' below). The mechanisms that allow for these elevations in BP without progression to hypertension in the pediatric population are not understood. These findings could be related to the timing of disease onset, severity of OSA, or length of disease burden. As an example, one study identified differences in diurnal variations of biomarkers in children with OSA compared with healthy controls, a pattern that suggests that the baroreflex system helps to maintain homeostasis of the cardiovascular system, at least in the early stages of OSA . It is possible that, over time, the chronic effects of disease upset this balance, leading to more significant clinical findings.
Despite all the data describing the effects of OSA on BP during childhood, the long-term consequences of OSA in childhood on adult hypertension are not well established. Childhood BPs do appear to predict adult BPs, but with considerable variability , suggesting that BP abnormalities in some children are reversible. However, a population-based cohort study that included 700 children found that OSA that persists through childhood is associated with adolescent hypertension, demonstrating long-term consequences to the cardiovascular system even in young children with OSA . These findings highlight the importance of treating OSA early in this pediatric population.
Pulmonary hypertension — In adults, OSA is clearly associated with pulmonary hypertension. Approximately 20 percent of adults with moderate to severe OSA have pulmonary hypertension, which is typically mild in patients, unless there is coexisting lung disease or obesity hypoventilation syndrome. (See "Obstructive sleep apnea and cardiovascular disease in adults", section on 'Pulmonary hypertension' and "Pulmonary hypertension in children: Classification, evaluation, and diagnosis".)
In children, only limited data exist to suggest an association between OSA and pulmonary hypertension. However, elevation in pulmonary arterial pressures has been seen in the setting of sleep-disordered breathing in children [31-33], and treatment of OSA can effectively reverse pulmonary hypertension . In a study of 318 children with severe OSA, pulmonary hypertension by echocardiogram was detected in 8 percent of patients . Overall, the prevalence of pulmonary hypertension seems to be low among pediatric patients with OSA and is much more likely to occur in children with comorbid cardiac disease . Larger, more sophisticated studies are needed to identify the frequency and mechanisms that lead to the development of pulmonary hypertension in children with OSA.
Structural and functional cardiac changes — Both structural and functional changes of the heart are present in children and adolescents with OSA:
●Brain natriuretic peptide (BNP) levels – BNP is elevated in children and adults with sleep-disordered breathing [36-38]. BNP is released in the setting of cardiac wall distension. The elevations in BNP likely reflect the increased cardiac volume and pressure load due to intermittent upper airway obstruction during sleep and may contribute to the increased prevalence of nocturnal enuresis seen in children and adults with OSA.
●Structural changes – Children with OSA have evidence of structural changes of the LV compared with healthy controls and children with primary snoring [39-41]. In a study that examined echocardiography in nearly 200 children with OSA scheduled for adenotonsillectomy and 174 age- and sex-matched healthy controls, children with OSA had evidence of LV remodeling, with abnormal LV geometry and significantly increased LV mass compared with controls . In another study, LV wall thickness, LV end-diastolic dimension, and interventricular septal thickness were all significantly greater among children with OSA compared with primary snoring controls (table 2) ; importantly, the LV dimension was improved after surgical treatment of the OSA .
●Functional changes – Changes in cardiac function have also been demonstrated in children with OSA [40,41,43]. In the same large study that compared nearly 200 children with OSA to 174 controls, those with OSA had dose-dependent reductions in diastolic and systolic LV function preoperatively . Measures of active relaxation, elastic recoil, and lengthening of the LV, all of which contribute to diastolic function, were all worse with increasing OSA severity. Diastolic function improved postoperatively, whereas LV remodeling did not.
Cumulatively, these data emphasize that OSA has important effects on cardiac structure and function, but the mechanisms of these changes are still not well understood. Larger, prospective studies are needed to delineate pathways that lead to end-organ damage in the setting of chronic, untreated OSA. There are no large-scale studies demonstrating an association between OSA in children and heart failure.
Arrhythmias — Adults with OSA have an increased rate of arrhythmias, particularly atrial fibrillation and a bradycardia-tachycardia phenomenon related to respiratory events. Other commonly associated arrhythmias include nonsustained ventricular tachycardia, second-degree atrioventricular conduction block, and sinus arrest . (See "Obstructive sleep apnea and cardiovascular disease in adults", section on 'Atrial fibrillation'.)
Arrhythmias are also observed in children undergoing polysomnography for OSA, but it is unclear if this is increased over the general population, after accounting for comorbidities such as Down syndrome. In one case series, approximately 1 percent (61/5230) of children undergoing polysomnograms had arrhythmias leading to a referral to cardiology . The most common arrhythmia was premature ventricular contractions. Among those referred, 8 percent (5/61) were ultimately diagnosed with significant cardiac disease. P-wave dispersion is more prevalent in children with severe OSA compared with healthy controls and those with mild OSA .
Endothelial dysfunction and vascular resistance — Endothelial dysfunction appears to contribute to cardiovascular consequences in children with OSA . The changes in BP seen during obstructive events result in the release of an array of chemokines and vasoactive mediators that alter the normal physiologic function of the endothelial layer. As an example, endothelin is a peptide that induces vasoconstriction, serves as a marker for endothelial stress, and is elevated in adults with OSA [48,49]. Studies examining genetic variants in children found that several single-nucleotide polymorphisms in the endothelin gene were significantly associated with endothelial dysfunction , and these polymorphisms were more common in children with OSA . Moreover, children with mild OSA, in comparison with non-snoring control subjects, have higher brachial artery flow velocities, suggesting that even mild OSA causes cardiovascular endothelial dysfunction . Obesity and OSA in children are independently associated with endothelial dysfunction, and the risk for endothelial dysfunction increases when the two are present simultaneously . Importantly, endothelial dysfunction, as measured by post-occlusive hyperemia testing, is reversible in children with OSA after adenotonsillectomy .
The processes that lead to endothelial dysfunction in children with OSA have not been fully identified; however, upregulation in a systemic inflammatory response in addition to oxidative stress are thought to underlie the pathophysiologic progression of disease . In one study, vascular stiffness, as measured by pulse transit time, was not significantly different in children with OSA compared with healthy children . However, there were significant differences in both acute phase reactants and proinflammatory cytokines, suggesting that abnormalities in these mediators may appear prior to the other clinical sequelae . More work is needed to determine the significance of such changes and how these surrogates of endothelial dysfunction may serve as diagnostic markers for OSA or persistent OSA.
MECHANISMS UNDERLYING CARDIOVASCULAR DISEASE IN CHILDREN WITH OSA
Overview — The proposed mechanisms for the development of the previously discussed consequences to the cardiovascular system are complex and have not been completely uncovered. These mechanisms likely involve dysregulation of a variety of processes, including neural control, systemic inflammation, and oxidative stress. Some of the major pathways that are involved in cardiovascular dysfunction are reviewed here.
Disruption of neural control — Multiple modulators of the sympathetic system, including the chemoreflex and baroreflex systems, function together to allow appropriate neural control of the cardiovascular and circulatory systems. The interactions of these complex feedback loops result in tight control of the cardiac and vascular function. In the setting of repetitive obstructive events, this control is disturbed, leading to larger variabilities in heart rate, blood pressure (BP), and vascular resistance. In children with OSA, chronic exposure to these intermittent hypoxic and hypercarbic episodes is thought to disrupt these neural control systems, resulting in cardiovascular dysfunction.
Chemoreflex system — The chemoreflex system controls respiratory and cardiovascular function during the stress associated with apneic events in the setting of OSA, acting through central chemoreceptors within the central nervous system [55,56]. Episodes of oxygen desaturation and elevations in carbon dioxide levels also trigger peripheral chemoreceptors housed in the carotid bodies, leading to changes in ventilatory rate, heart rate, and vasoconstriction of the peripheral vasculature [57,58]. Obstructive events are characterized by cardiac slowing and decreases in BP during the events, with increases in heart rates and BP at termination of the events (waveform 1) . Compensatory hyperventilation also arises at termination of apneas and hypopneas, from activation of central and peripheral chemoreceptors during periods of hypercapnia . Activation of the peripheral chemoreceptors has also been linked to the longer-term development of hypertension in adults with OSA , emphasizing the significance of repeated acute neural dysregulation in the eventual development of cardiovascular disease in patients with untreated OSA. In children, peripheral chemoreceptors appear to have a greater role in hypoxic conditions compared with adult subjects and the function of the chemoreceptor system appears to attenuate with age and maturation . Taken together, these data suggest that OSA in children, compared with adults, is especially likely to disrupt the physiologic responses of the chemoreceptor system, with consequent effects on cardiovascular risk.
Baroreflex system — Neural control of the cardiovascular system is also mediated through the baroreflex system. This system consists of baroreceptors in the great vessels that respond to fluctuations in arterial pressure . Under normal physiologic conditions, activation of the baroreceptors by increased pressure results in a compensatory reduction in sympathetic activity, increases in parasympathetic activity, and reductions in both heart rate and vascular stiffness . In healthy children without OSA, the baroreflex becomes particularly sensitive at night, and this helps to tightly control heart rate and BP. In children with moderate to severe OSA, nocturnal baroreflex sensitivity is blunted [64,65]. These changes likely contribute to the BP abnormalities seen in children with OSA . Accordingly, gradual improvement in dysregulation of the baroreflex system is seen after adenotonsillectomy in children with OSA, although normalization is not complete six months postoperatively .
As the homeostatic influence of the baroreflex system is disrupted in OSA, there is a heightened response from the central and peripheral chemoreceptors. Thus, disturbances in the chemoreflex and baroreflex systems work additively to produce these changes in the cardiovascular system .
Inflammatory response in obstructive sleep apnea — Some of the adverse consequences of untreated OSA in children have been attributed to the upregulation of a systemic inflammatory process and immune dysregulation, caused by intermittent hypoxic episodes and sleep fragmentation [68,69]. Systemic elevation of a host of inflammatory mediators, including C-reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6), have been demonstrated in children with OSA [70-73]. Meanwhile, IL-10, which is an antiinflammatory cytokine, is lower in children with OSA compared with healthy subjects without disease . In one study, adolescents with moderate to severe OSA, in comparison with those with milder OSA, had higher levels of circulating CRP and these levels were related to the severity of hypoxemia during sleep regardless of body mass index . In another study, systemic levels of acute phase reactants and inflammatory cytokines were compared between healthy children and those with moderate to severe OSA . Differences in the diurnal variation of inflammatory biomarkers were observed, and these biomarkers also had differing effects on vascular stiffness . These data suggest that, however indirectly, a systemic inflammatory response is induced or upregulated by the presence of OSA in children.
Oxidative stress in obstructive sleep apnea — Intermittent hypoxia in the presence of OSA is thought to result in increased oxidative stress. During hypoxic episodes, which can be less extensive and shorter in children than in adults, the tissue adapts to decreased oxygen levels . During the recovery period, the oxygen concentration in the tissue rises sharply. Reactive oxygen species are thought to increase due to this reoxygenation phase, leading to repetitive periods of oxidative stress [77-79]. Under normal physiologic circumstances, reactive oxygen species made by the reduction of oxygen serve a variety of functions, including promoting cell growth and breaking down biologic molecules [76,80]. However, these elevated levels also appear to be detrimental to the tissue.
A few small studies provide evidence of oxidative stress in patients with OSA. OSA was associated with various markers of oxidative stress, including diacron-reactive oxygen metabolites , release of superoxide from neutrophils , hydrogen peroxide in exhaled breath condensate , and increased levels of free radicals and activity of scavenging enzymes . More significantly, these levels were reduced after surgical treatment of OSA by adenotonsillectomy, suggesting that mechanisms to clear free radicals are altered in the setting of airway obstruction .
In short, production of free radicals appears to have an important role in the development and progression of cardiovascular disease in children with OSA.
Hypercoagulability in obstructive sleep apnea — Hypercoagulable states, due to changes in coagulation or fibrinolysis, are known to be associated with the development of cardiovascular disease [85,86]. Several findings support the notion that hypercoagulability also contributes to cardiovascular disease in the setting of OSA. In vitro platelet aggregation, a measure of platelet dysfunction, is higher in adult men with OSA as compared with healthy control subjects . Among children with OSA and snoring, compared with healthy children without OSA or snoring, morning fibrinogen levels are elevated . Moreover, nasal continuous positive airway pressure (CPAP) can reduce circulating levels of factor VII clotting activity .
Together, these data suggest that heightened responses in the clotting pathways, along with changes in vascular resistance, could play a major role in the development and progression of the clinical sequelae associated with untreated OSA and emphasize the importance of therapy for OSA.
REFERRAL TO CARDIOLOGY — Although OSA can lead to changes in blood pressure (BP), heart rate, and heart structure and function in children, these changes rarely present in children. However, irregularities noted on electrocardiography (ECG) during polysomnography occasionally warrant further work-up. In one study, approximately 1 percent (61/5230) of children undergoing polysomnograms had arrhythmias that led to referral to cardiology . Common normal variants include isolated premature atrial contractions, ventricular premature beats, sinus arrhythmia, and right ventricular conduction delay (incomplete right bundle branch block). These do not reflect underlying cardiac disease and generally do not require further evaluation.
A referral to cardiology should be considered for all children with any other abnormal findings on ECG such as evidence of left and or right ventricular hypertrophy. Patients with clinician-diagnosed systemic hypertension also warrant further evaluation. For patients with severe OSA (apnea-hypopnea index >10 events/hour) or those with other significant comorbidities that predispose to cardiac disease (such as the presence of Down syndrome), it may be helpful to perform an ECG and echocardiogram prior to a referral to the cardiology team. Echocardiographic evidence of left ventricular hypertrophy or pulmonary hypertension should also be evaluated by a cardiology specialist. (See 'Arrhythmias' above and "Suspected heart disease in infants and children: Criteria for referral".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sleep-related breathing disorders including obstructive sleep apnea in children".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Sleep apnea in children (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Cardiovascular function during sleep
•Physiologic – In healthy individuals without obstructive sleep apnea (OSA), modulators of the autonomic nervous system, including the chemoreflex and baroreflex systems, tightly control cardiovascular and circulatory function during sleep. (See 'Normal cardiovascular function during sleep' above.)
During non-rapid eye movement (NREM) sleep, heart rate and blood pressure (BP) tend to decrease. During rapid eye movement (REM) sleep, heart rate and BP become highly variable. Overall, normal sleep is associated with lower BP (the nocturnal "dipping" phenomenon) compared with wakefulness.
•Changes in patients with OSA – In patients with OSA, episodes of partial or complete airway obstruction cause intermittent hypoxia, hypercarbia, and swings in intrathoracic pressure (waveform 1). These changes disrupt autonomic neural control, mediated through central and peripheral chemoreceptors and a baroreflex system. (See 'Disruption of neural control' above.)
●Clinical consequences – Alterations in cardiovascular function during sleep in patients with OSA have a range of clinical effects.
•Heart rate and blood pressure – Patients with OSA have increased heart rate and heart rate variability, attenuated BP dipping (also called "non-dipping"), and elevated mean BP, compared with healthy individuals. Over time, and with repeated exposure to this complex disease process, these acute changes in heart rate and BP can lead to hypertension that persists into the awake state. (See 'Changes in heart rate' above and 'Changes in blood pressure' above.)
•Inflammatory cascade – Other cardiovascular consequences of OSA are mediated by a cascade of events, including upregulation of a systemic inflammatory response, increases in the production of free oxygen radicals, and changes to coagulation and fibrinolysis. This is made worse by the detrimental consequences to the endothelium as well as the changes in peripheral vascular resistance. (See 'Inflammatory response in obstructive sleep apnea' above and 'Oxidative stress in obstructive sleep apnea' above and 'Hypercoagulability in obstructive sleep apnea' above and 'Endothelial dysfunction and vascular resistance' above.)
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