Bridging the Gap Between Pediatric Cardiology and Sleep Apnea
Cardiovascular implications in pediatric OSA patients have only been studied recently and more research is needed to more conclusively demonstrate underlying mechanisms and a causal association. It is also crucial to understand that most of the existing evidence has been based on studies conducted on adults.1 Large Cross-Sectional studies like Wisconsin Sleep Cohort have shown that severe OSA in adults can increase the risk of cardiovascular mortality threefold.2 In adults, specific cardiovascular outcomes such as hypertension,3 myocardial ischemia,4 arrhythmias,5 strokes,6 and other events7,8 have been shown to be independently associated. Furthermore, CPAP use in adults has shown to significantly decrease blood pressure during sleep.9 It also suggested by some studies that CPAP reduces both fatal and nonfatal cardiovascular events.10-12 In adults, confounding factors like obesity, diabetes, smoking, alcohol consumption and aging make it particularly challenging to establish causality despite strong evidence. These confounding factors are less likely to influence studies in children with OSA. However, given increasing incidence in children, childhood obesity can also have a confounding effect on such studies. Obesity has resulted in substantial modification of the classical presentation of pediatric OSA, with the typical presentation of OSA in obese children mimicking many of the typical clinical features of adult OSA.13 Even then the severity of cardiovascular complications is less when compared to adults. This is likely owing to higher compensatory vascular capacitance found in children. Furthermore, cardiovascular research in children with OSA has focused primarily on disease mechanisms and has been relatively limited on defining the endpoints that provide unequivocal evidence of cardiovascular morbidity.
Normal sleep is associated with reduction in heart rate, blood pressure (BP) and stroke volume (SV) during non-rapid eye movement (NREM) sleep synchronously with reduced sympathetic nervous system activity.14,15 During rapid eye movement sleep (REM) sympathetic drive increases resulting in increases in vascular resistance, BP and heart rate.16 Increased sympathetic activity during apnea is associated with increased systemic BP, pulmonary arterial pressure and left ventricular (LV) afterload.17-19 Hypoxemia and hypercapnia during SDB events are major contributors for chemoreflex-mediated increases in SNA and cardiovascular changes.18,19 Negative intra-thoracic pressures during upper airway obstruction in SDB events affect intra-thoracic hemodynamics including LV transmural pressure and LV afterload.20 LV relaxation and LV filling might also be affected by the exaggerated negative intra-thoracic pressure swings.21,22 In addition, negative intra-thoracic pressure alters aortic pressure, inducing stretch of the aortic baroreceptors, thus buffering sympathetic activation during obstructive apnea.23,24 Upon resumption of the breathing, increased venous return distends the right ventricle, reduces LV compliance due to leftward shift of the interventricular septum and thus alters LV diastolic filling.25,26 Increased stroke volume upon resumption of breathing, at a time when systemic vascular resistance if highest, elicits further increases of BP.22 Sleep disordered breathing events are commonly associated with arousals from sleep, although such might not be as frequent in young children. Nevertheless, arousal may also contribute to the acute increases in BP at termination of SDB events. Repetitive nocturnal arousals cause sleep fragmentation that might also be associated with daytime cardiovascular dysfunction.27
OSA Elevations in Systemic Blood Pressure and Hypertension Associated With OSA
Unlike adult patients with OSA, hypertension in children is not independently associated with OSA. Multiple studies however have conclusively shown the development of elevated BP compared to healthy children during nighttime sleep and even daytime when awake in resting conditions.28-32 In addition OSA severity, measured by desaturation indices during sleep and the AHI are also associated with increased daytime and nocturnal BP variability. Having said that, severe OSA may be associated with hypertension in children. The BP load is a measure of hypertension and is defined as a percentage of BP measurements that exceed the 95th percentile during 24-hour BP monitoring.29 A recent study in 140 children with AHI>5 events/h, nightly snoring and tonsillar hypertrophy reported increases in BP load and morning surges.29 Significant reductions in 24-hour ambulatory BP are observed after treatment of OSA with adenotosillectomy. The exact mechanism of increased BP in children with OSA is not clear but reduced baroreflex during nighttime and daytime may be a contributory factor.30
It remains unclear whether early childhood OSA may predispose to BP dysregulation later in life, however some animal studies do establish this association. In a rat model of OSA, when intermittent hypoxia was applied during early stages of development, persistent reductions in baroreflex sensitivity and renal sympathetic emerged, suggesting altered central and peripheral regulation of sympathetic nervous system function along with a reduction in vagal efferents.34-36 As a result of these complex adaptations and plasticity, both arterial BP responses and HR variability in response to stress were altered in animals, well after cessation of the intermittent hypoxia, thereby illustrating potential long term consequences of OSA if the later develops during critical phases of development. Furthermore, other studies have shown perturbations that intermittent hypoxia during sleep also alters the renin-angiotensin system37 and affects the central expression of the gene early gene c-fos in ressor-related brain regions.38
Ventricular Remodeling With OSA
Left ventricular hypertrophy in children has been described in children with OSA. LV mass and relative wall thickness are significantly greater in normotensive children with OSA compared to children with primary snoring.39 Also, an AHI of 10 is associated with a six fold increase in risk for hypertrophy. In otherwise healthy children, those with more severe OSA (AHI > 5 events/h) had echocardiographic evidence of increased LV wall thickness.40-41 LV end-diastolic dimension and thickness of interventricular septum are significantly greater in children with OSA compared to control children. Adenotonsillectomy was associated with reduction in LV dimension and septal thickness.40,41 Improvement in LV ejection fraction after adenotosillectomy has also recently been described.42 Hypoxic-induced activation of the renin-angiotensin-aldosterone system may be linked to cardiac remodeling in patients with OSA.43 A recent study has also reported impaired right ventricular function in children with adenotonsillar hypertrophy. Brain natriuretic peptide is also known to be increased not only in severe OSA but also in children with snoring.44
Elevated Pulmonary Arterials Pressure and Pulmonary Hypertension Associated With OSA
Only several case reports and studies with small sample sizes have suggested statistically significant increases in pulmonary arterial pressures occurs in children with OSA. Presence of co-morbid conditions like congenital heart diseases might be linked to OSA. They are also further limited by the techniques and procedures utilized in measurements of pulmonary arterial pressures. An echocardiography study looking for cor pulmonale showed increased prevalence in children with adenotosillar hypertrophy and snoring.45 Direct measurements of pulmonary artery pressure by cardiac catheterization reported the presence of pulmonary hypertension in children with OSA who also suffered from underlying genetic disorders and heart failure.46,47 Another recent study demonstrated decreases in pulmonary artery pressure measured by echocardiography after treatment of OSA.
Endothelial Dysfunction Associated With OSA
Several studies have conclusively linked OSA and endothelial dysfunction associated with cardiovascular comorbidity.48-50 In a recent study in children with OSA, both obesity and OSA were shown to be independently and additively increase the risk for endothelial dysfunction.51 Although the mechanisms in children are unclear it is highly likely that both oxidative stress and inflammatory mediators play an important role in vascular injury.51,52 Thus, elevated inflammatory mediators in children with OSA might contribute to endothelial dysfunction and also as reliable reporters of endothelial damage in the context of pediatric OSA.53
Systemic Inflammation, Oxidative Stress and Coagulation in Children With OSA
Evidence of increased inflammatory markers in patients with OSA is accumulating. Chronic low grade inflammation has been linked to the pathophysiology of cardiovascular disease in OSA.54 Patients with OSA have increased levels of interleukin-6, TNF-alpha and C-reactive protein.54 A combination of hypoxemia and sleep deprivation/fragmentation in patients with OSA may lead to increased inflammatory markers.55 Some studies have shown high levels of P-selectin, C-reactive protein, fibrinogen, interleukin-8 and interferon levels were found to be higher in patients with OSA/chronic snoring with possible decrease in their levels after CPAP treatment.56,57 However not all studies demonstrate such a relationship.58,59,60 Oxidative stress and inflammatory markers in the exhaled breath condensate are increased in children with adenotonsillar hypertrophy61 which tends to decrease after adenotosillectomy.
Some studies have also shown, hypoxemia and reperfusion during repetitive nocturnal apnea may generate highly reactive free oxygen radicals which may lead to vascular wall injury and atherosclerosis.62,63 Treatment of OSA reduces production of free radicals. Increased platelet number and aggregatability is also seen in the OSA patient and reduced after treatment of OSA.64 Increased hematocrit, nocturnal and daytime fibrinogen levels and blood viscosity in OSA might also contribute to any predisposition to clot formation and cardiovascular morbidity.65,66 Treatment of OSA has also shown to reduce factor VII clotting activity, hinting causal relationship of OSA with increased coagulability.67
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