The cardiovascular risk in paediatrics: the paradigm of the obstructive sleep apnoea syndrome

Abstract

Background

Obstructive sleep apnoea syndrome (OSAS) describes a spectrum of abnormal breathing patterns during sleep characterised by snoring, increased upper airway resistance and pharyngeal collapsibility, with alteration of normal oxygenation and ventilation. Intermittent desaturations during sleep have multi-organ implications. Adults with OSAS have an increased risk of developing a dysfunctional endothelium that is characterised by greater adherence of inflammatory mediators to endothelial cells and hypercoagulability. There is increasing evidence to show that risk factors for comorbid cardiovascular disease (CVD) can develop during childhood and adolescence and are likely to continue over time. Risk factors for CVD include both modifiable factors and factors that cannot be changed.

Materials and methods

Using the MEDLINE^® electronic database, we reviewed the scientific literature for published studies evaluating the association between sleep-disordered breathing and cardiovascular damage in children.

Results

In this review, we show the role of blood markers in demonstrating the inflammation caused by intermitted oxygen desaturations during sleep in both healthy and obese children. Several instrumental techniques, in addition to serum biomarkers, can be used to assess vascular endothelial damage and its deterioration in the form of a pre-atherosclerotic condition. The confirmation of their role as markers of inflammation and vascular damage is supported by normalisation after resolution or improvement of the sleep-disordered breathing with surgery.

Discussion

Great attention should be given to this condition in infants and children as it will significantly affect their present and future well-being as they grow into adulthood. Healthcare professionals, especially paediatricians, should be trained to recognise the signs and symptoms of the disease in order to send children forward for specialist care in centres dealing with sleep-disordered breathing.

INTRODUCTION

Obstructive sleep apnoea syndrome (OSAS) is a frequent pathology in children. It has been estimated that the frequency of the disease ranges between 1 and 5% in preschool and school children, respectively^1–4. OSAS describes a spectrum of abnormal breathing patterns during sleep characterised by snoring and respiratory effort secondary to increased upper airway resistance and pharyngeal collapsibility⁵, with alterations of normal oxygenation, ventilation and sleep architecture. Polysomnography is the gold standard for OSAS diagnosis. The mean number of apnoea plus hypopnoea episodes per hour of sleep time or apnoea-hypopnoea index (AHI) classifies the OSAS as mild, moderate or severe^6,7. Pulse oximetry measures the blood peripheral SpO₂ and McGill oximetry measures the severity of sleep-disordered breathing (SDB) from 1 to 4⁸. This method is used for screening purposes but is not free from heavy methodological limitations.

Adults with OSAS have an increased risk of developing a dysfunctional endothelium that is characterised by increased adherence of inflammatory mediators to endothelial cells and hypercoagulability⁹. They not only have an increased risk of developing comorbid cardiovascular disease (CVD) but also have worse outcomes related to CVD¹⁰. A growing body of evidence shows that risk factors for CVDs can develop during childhood and adolescence. When risk factors develop at an early age, they are likely to continue over time, maintaining a high-risk status. Risk factors for CVDs include both modifiable factors (e.g., unhealthy diet, amount of physical inactivity) and factors that cannot be changed (e.g., age, heredity, sex)¹¹.

Intermittent desaturations during sleep have multi-organ implications. The link between paediatric OSAS and complications of the cardiovascular system is robust and has been the focus of several studies. Obesity and/or severe OSAS have both been associated with cardiovascular alterations from childhood to adulthood^10,12. The pathogenesis of OSAS-associated CVD is not fully understood. Several factors, such as endothelial dysfunction (ED), arterial stiffening, and systemic inflammation may mediate OSAS-associated CVD^13,14. Specifically, ED makes a substantial contribution to the pathogenesis of cardiovascular disorders, and arterial stiffening is strongly associated with the development of atherosclerosis¹⁵. Furthermore, increasing evidence of selective activation of inflammatory pathways, increased oxidative stress, ED and metabolic dysregulation suggest that inflammation plays an important role in the development of cardiovascular complications in patients with OSAS^16,17.

Growing evidence suggests that OSAS is also associated with cardiovascular consequences in children. The relationship between OSAS and major adverse cardiovascular problems in children and adolescents has recently been emphasised. A study reported that after a 15-year follow up, the incidence rate of major adverse cardiovascular events was higher in children and adolescents with OSAS than in controls without OSAS¹⁸.

The present review aims to describe the current knowledge on inflammation and cardiovascular problems correlated to OSAS in a paediatric setting.

MATERIAL AND METHODS

Research method

We reviewed the scientific literature for published studies evaluating the association between SDB/OSAS and cardiovascular damage in children. The MEDLINE^® electronic database was searched without temporal limits using only the English Language. The Medical Subject Heading and keywords used were the following: “biochemical marker”, “endothelium”, “inflammation”, “obstructive sleep apnoea syndrome”, “sleep-disordered breathing” and “children.” We also hand-searched the reference lists of the most relevant items to identify further eligible studies not captured in the initial literature search.

Markers of inflammation in paediatric obstructive sleep apnoea syndrome

Biochemical biomarkers in non-obese children

Obstructive sleep apnoea syndrome elicits extensive activation of the inflammatory system, which poses a substantial risk to the integrity of the vascular endothelium^19,20. In clinical practice, one of the most common inflammatory biomarkers is the C-reactive protein (CRP). CRP is a component of the innate immune system produced by the liver in response to interleukin (IL)-1 and IL-6. Plasma CRP levels are increased in children and adolescents with SDB^21–24.

T-helper 17 cells (Th17) are a subset of pro-inflammatory T-helper cells that produce interleukin 17 (IL-17)²⁵. By contrast, regulatory T cells (Tregs) inhibit T-cell proliferation and cytokine production²⁶. Th17 cells cause autoimmunity and inflammation, whereas Treg cells inhibit these complications. A prospective study showed that the peripheral Th17/Treg ratio was positively correlated to OSAS severity, serum CRP, and hypoxia-inducible factor-1α mRNA. Surgery reversed the Th17/Treg imbalance²⁷. This result would confirm normalisation of the inflammatory process following improvement of SDB. Intercellular adhesion molecule 1 (ICAM-1), an inflammatory cytokine-induced by TNFα and IL-6²⁸, contributes to the pathogenesis of atherosclerosis. The levels of ICAM-1 remained stable from evening to morning in children with OSAS²⁹. Both ICAM-1 and CRP returned to normal after adenotonsillectomy (A&T)³⁰. ICAM-1, vascular cell adhesion molecule-1 (sVCAM-1) and other markers of inflammation (IL-6, and high-sensitive CRP) improved after adenoidectomy³¹.

A study investigating the lipid profiles of OSAS children showed increased oxidised LDL-particles (oxLDL)³². Another study showed that obstructive sleep apnoea (OSA) children had significantly elevated plasma levels of lipoprotein-associated phospholipase A2 (Lp-PLA2), a cardiovascular risk marker. Treatment of OSA by A&T resulted in reductions in Lp-PLA2 activity³³.

Another molecule involved in the pathophysiology of atherosclerosis is the myeloid-related protein (MRP) 8/14. Elevated plasma levels of the MRP8/14 heterodimer predict increased risk of cardiovascular events³⁴. In a study involving OSAS children, plasma MRP8/14 levels increased progressively with OSAS severity³⁵.

Low basal levels of vitamin D receptor (VDR) induced a state of endothelial activation with increased leukocyte-endothelial cell interactions that may contribute to atherosclerosis³⁶. Shin et al. reported that children with vitamin D deficiencies had greater adenoidal and/or tonsillar hypertrophy than did those with sufficient vitamin D, pointing to the importance of vitamin D measurement also in children with SDB³⁷. Low vitamin D levels in children with primary snoring (PS) and OSAS has been associated with increased mean platelet volume (MPV) and CRP levels, which both corroborate underlying inflammation²³.

The electronic nose (E-nose) is a device that detects odours or flavours. Exhaled biomarkers of OSAS patients were discriminated from controls with 78% sensitivity and 70% specificity³⁸. Biochemical biomarkers in non-obese children are shown in Table I.

Table I.

Biomarkers of endothelial dysfunction (ED) after adenotonsillectomy (A&T) in non-obese children

Author, yearRef	Biomarker	ED	Vascular tests	Population study	Main results	After A&T	Comment
Gozal D et al., 201353	Adropin	Yes	Modified hyperemic test after cuff-induced occlusion of the radial and ulnar arteries	OSA+EF+ (n=35) OSA+EF- (n=47) Control (n=35) Age-, sex- and ethnicity-matched children; aged 7.2±1.4 yrs	↓ Adropin levels 2.7±1.1 ng/mL mean morning in OSA+/EF+ vs adropin levels 7.4 ng/mL mean morning in controls p<0.001	N adropin levels only in OSA+/EF+ (n=14) 2.5±1.4 ng/mL to 6.4±1.9 ng/mL p<0.01	Reliable predicted ED
Gozal D et al., 200750	sCD40 ligand ADMA Nitrotyrosine	Yes	2 iterations of 60″ cuff-occlusion tests	OSA (no.=26) Control (no.=8) 6–11 yrs	↑ sCD40 ligand levels in OSA	↓ sCD40 ligand levels in children with normalised hyperemic responses	sCD40 ligand levels reflects the changes in ED function
Apostolidou MT et al., 200830	CRP cICAM-1 Insulin	Yes	Blood pressure	SDB (no.=58), 6.2±2.5 yrs; Controls (no.=17), 6.5±2 yrs	Patients and controls similar regarding outcomes	↓ CRP in SDB patient with >0.3 mg/dL	Absence of biomarker changes

ADMA: Asymmetric dimethylarginine; cICAM-1: Circulating intercellular adhesion molecule-1; EF: endothelial dysfunction; E-selectin: Endothelial leukocyte adhesion molecule; ICAM-1: intercellular cell adhesion molecule-1; N: normal level; T&A: tonsillectomy and adenoidectomy; SDB: obstructive sleep-disordered breathing.

Biochemical biomarkers in obese children

In the context of cardiovascular morbidity associated with OSA, a previous study confirmed the increased frequency of children with abnormal endothelial function, particularly when obesity and OSA are both present at the same time.

Endothelial dysfunction in obese children is one of the major complications³⁹ with or without OSAS³³. To our knowledge, one study has found a link between CRP and high Body Mass Index (BMI) (and fat mass) of patients with OSAS, but not between CRP and OSAS itself⁴⁰.

Circulating MRP8/14 levels have also been associated with the degree of ED in both obese and non-obese children⁴¹. The oxidative stress biomarkers involved in artery dysfunction are serum isoprostanes (8-iso-PGF2α) and soluble NOX2-dp (sNOX2-dp); these were increased in OSAS children but decreased after A&T⁴².

An improvement in uric acid concentration, unlike changes in other inflammatory markers, such as leukocyte differentiation and high sensitivity CRP, were associated with an improvement of both the oxygen desaturation index and OSA, independently of obesity or weight loss⁴³. Biochemical biomarkers in obese children are shown in Table II.

Table II.

Biomarkers of endothelial dysfunction (ED) after adenotonsillectomy (A&T) in obese children

Author, yearRef	Biomarker	ED	Vascular tests	Population study	Main results	After A&T	Comment
Kelishadi R et al., 201131	E-selectin sVCAM-1 IL-6 hsCRP ICAM-1	Yes	None	OSA normal-weight (no.=45) OSA overweight (no.=45) 4–10 yrs	↑ Levels of the ED and inflammation markers	↓ E-Selectin ↓ sVCAM-I ↓ IL-6 ↓ hs-CRP ↓ ICAM-I	Biomarkers of ED reduced in both normal-weight and overweight subjects after 2 weeks and 6 months
Kheirandish-Gozal L et al., 201733	Lp-PLA2	Yes	Post-occlusive reperfusion evaluation	No.=160, age 7.1±2.3 yrs Obese, No OSA (n=40) Obese, OSA (n=40) Nonobese, No OSA (n=40) Nonobese, OSA (n=40)	↑ Plasma Lp-PLA2 in obese and OSA	↓ Lp-PLA2 activity (n=37; p<0.001)	Reliable biomarker for children at risk for atherosclerosis, i.e., when obesity or OSA is present.

E-selectin: leukocyte adhesion molecule; hsCRP: high-sensitive C-reactive protein; ICAM-1: intercellular cell adhesion molecule-1; IL-6: interleukin-6; Lp-PLA2: Lipoprotein-associated phospholipase A2; sVCAM-1: vascular cell adhesion molecule-1.

Tissue biomarkers

Inflammation of the upper airways in children with SDB was found by nasal cytology analysis, which showed inflammation in 88% of children⁴⁴. In addition, various studies have evaluated serum biomarkers in lymphatic tissues (tonsils, adenoids). IL-1α is a non-secreted pro-inflammatory cytokine produced in a variety of cells, including monocytes, tissue macrophages, keratinocytes, and other epithelial cells. High expression of IL-1α and classical NF-kB subunits p65 and p50 is found in adenoid and tonsillar tissues of children with OSAS⁴⁵. Moreover, activated CD4⁺ T cells play a major role in the suppression of immune reaction through secretion of specific cytokines⁴⁶. Tonsillar distribution of CD4⁺ T-lymphocyte subsets proved to be comparable in subjects who underwent tonsillectomy for either OSAS or primary snoring. The inflammation of tonsils of children with snoring and OSAS could be triggered and maintained by recurring upper airway collapse, which promotes soft-tissue damage²⁷.

Endothelial dysfunction

Chronic inflammation can cause acute and/or chronic damage to various organs and tissues, for example, at endothelial level⁴⁷.

Biochemical markers

Biomarkers of endothelial damage/atherosclerosis in patients with SDB have been studied and researched in order to provide indirect monitoring of vascular improvement after adequate treatment. Circulating platelet-derived microparticles (MPs) are increased in children with OSA and vascular dysfunction⁴⁸. Exosomal miRNA-360 in children with ED is reduced in comorbid OSA and/or obesity and normalised after therapy⁴⁹. CD40 ligands, secondary to activation of platelets, are increased in children with OSA and normalised after treatment, suggesting normalisation of endothelial function⁵⁰. Plasma angiopoietins (Ang-2) in children with obesity and OSA are also significantly increased⁵¹. The triggering receptor expressed on myeloid cells-1 (TREM-1) plays an important role in innate immunity and amplifies inflammatory responses. Pentraxin-3 is released from macrophages and vascular endothelial cells, playing a role in atherogenesis. Increased TREM-1 and pentraxin-3 levels in children with OSAS play a role in modulating systemic inflammation⁵². Adropin is significantly lower in children with OSAS and ED but returns to normal levels after A&T^53,54.

Instrumental markers

Post-occlusive hyperaemic test

Post-occlusive reactive hyperaemia is used to investigate microvascular function (endothelial function). The test involves blood perfusion Doppler measurements before, during and after vein occlusion. Post-occlusive hyperaemia is an endothelial nitric oxide synthase (eNOS)-dependent response.

In non-obese OSAS children, cuff-occlusion tests showed blunted perfusion kinetics after the release of the occlusion, which normalised after A&T⁵⁰. Soluble platelet CD40 levels, as markers of cardiovascular risk⁵⁵, were normalised after treatment⁵⁰. In mild, moderate and severe OSA children, a low reactive hyperaemia index was observed that reverted after A&T⁵⁶. Significant delays to peak capillary perfusion after occlusion release occurred in obese compared to non-obese children, and the degree of ED in all groups was associated with increased circulating myeloid-related protein 8/14 (MRP8/14) levels⁵⁷. Low hyperaemic vascular responses in children with OSAS are predictive of neurocognitive status, and in at least 80% of children these co-existed⁵⁸.

A reactive hyperaemia test in children with OSA displayed severity-dependent deterioration of endothelial function⁵⁹. In these children, an altered modified post-occlusive hyperaemic test was correlated with characteristic polymorphisms of the nitric oxide synthase (NOS) and endothelin family gene, showing their contribution in the pathophysiology of cardiovascular morbidity⁶⁰. In addition, a post-occlusive hyperaemia test showed the presence of abnormal eNOS-dependent vascular responses in children with OSA and associated epigenetic modifications in the eNOS gene⁶¹. In addition, monocytes from the OSAS group exhibited overall reduced NO production⁶². Increasing sleep fragmentation reduced T-regulatory lymphocytes (Tregs) and peak occlusive hyperaemia in OSA children⁶³. Stromal cell-derived factor-1 (SDF-1) activates leukocytes, inducing pro-inflammatory stimuli. Endothelial progenitor cells (EPCs) play roles in the regeneration of the endothelial lining of blood vessels. Despite similar OSAS severity, EPC and SDF-1 levels were significantly lower in OSAS children with the longest cuff-induced occlusion but not associated with AHI⁶⁴.

Flow-mediated dilation

Flow-mediated dilatation (FMD) refers to the widening of an artery when the blood flow increases in that artery. The diameter of the brachial artery is recorded by external vascular ultrasound at specific time points during flow occlusion and after the release of the blood pressure (BP) cuff to assess flow-mediated changes in diameter. The primary cause of FMD is the release of nitric oxide by endothelial cells.

A negative correlation between FMD and childhood OSA severity compared to controls was reported⁶⁵. The OSA group had lower FMD than the control group. A significant reduction in OSA severity was documented in the A&T group associated with a significant increase in FMD⁶⁶.

Primary snoring children had significantly reduced FMD compared to non-snoring controls in both normal weight and overweight subgroups⁶⁷. There was no difference in maximal FMD response between snoring and non-snoring groups, but the estimated time to reach maximal dilation was significantly delayed in children who snored⁶⁸. OSA and PS children had significantly higher sNOX2-dp and serum 8-iso-PGF2α levels, and lower FMD than healthy controls. FMD was significantly lower in OSA children compared with PS. Finally, A&T significantly decreased sNOX2-dp and serum 8-iso-PGF2α levels, and increased FMD after A&T in OSA children⁴².

Children with severe obesity and SDB showed higher values of the incremental elastic modulus common carotid artery and glyceryl trinitrate-mediated dilation independently of obesity, induced by intermittent hypoxia⁶⁹.

Pulse wave velocity

Pulse wave velocity (PWV) is the velocity at which the BP pulse propagates through the circulatory system. Pulse wave analysis permits the non-invasive assessment of arterial elasticity indices. PWV is considered one of the most important clinical parameters to evaluate cardiovascular risk, vascular adaptation, and therapeutic efficacy. An important part of studies on PWV has focused on the correlation between PWV and BP. The SDB group had increased PWV compared to controls. Overweight/obese children with SDB had higher central systolic blood pressure compared with normal-weight children with SDB and non-snoring controls⁷⁰.

Hypertension or some heart diseases also influence the PWV and result in earlier wave reflections⁷¹. The relationship between nocturnal pulse wave amplitude (PWA) attenuation and office BP is reported. The degree of PWA attenuation during the night is associated with office BP independently of SDB⁷².

Carotid intima-media thickness

Maximal carotid intima-media thickness (cIMTmax) and carotid-femoral pulse wave velocity (CFPWV) are a measure of carotid structural changes and a measure of aortic stiffness. Subjects with OSA demonstrated higher values of aortic stiffness and lower distensibility and FMD than controls⁷³. In another study, the AHI was not associated with cIMTmax and carotid diameter⁷⁴. In a further study, OSAS severity in obese adolescents did not predict carotid structural changes or arterial stiffness; it was not associated with maximal carotid intima-media thickness (cIMTmax), carotid diameter, carotid-femoral pulse wave velocity (CFPWV) or the augmentation index (Aix)⁷⁴.

Thrombosis risks

The epidemiological evidence on adults supports the hypothesis that OSA may be an independent risk factor for venous thromboembolism^75,76. In particular, OSAS was found to be an independent risk factor for either deep-vein thrombosis or pulmonary embolism in adults⁷⁶. Deep venous thromboses and seven pulmonary emboli were observed in children aged 10–18 years and, unexpectedly, in children aged 1–5 years. A central venous line was the main risk factor (55% of venous thromboembolic events); surgery (not cardiac) (25%), concomitant infections (23%), and malignancy (22%) were the clinical conditions most often associated with the onset of venous thromboembolism⁷⁷. The clinical case of a 3-year old boy with severe adenotonsillar hypertrophy and OSAS who developed severe thrombosis (pulmonary arterial microemboli, intracardiac organised thrombus and vein thrombosis of the left sigmoid sinus of the brain), despite tests for inherited thrombophilia being negative, led some authors to study this link⁷⁸. A study performed on 152 children with OSAS tested the association between several haemostatic parameters and sleep breathing-related variables. These children had a significantly higher platelet count, plateletcrit and platelet distribution width compared with those without OSA. However, coagulation indices, prothrombin time and activated partial thromboplastin time correlated with mean SaO₂ and oxygen desaturation index, respectively. Thus, paediatric OSAS may induce measurable coagulation disturbances. The authors believe that different OSA-related effects may contribute to enhanced coagulability in paediatric OSAS⁷⁹.

DISCUSSION

Understanding, preventing, mitigating and treating SDB in children can reduce cardiovascular morbidity and mortality. Moreover, defining appropriate therapeutic targets is cost effective⁸⁰. Surgical treatment for OSA has been shown to be at least partially effective in normalising ED, reducing levels of inflammatory markers, and improving lipid profile and SDB severity⁸¹. The increasing numbers of overweight and obese children play an important role in the development of OSA in this population and the interplay of these two conditions may be an additional risk for cardiovascular morbidities associated with OSA. Indeed, both obesity and OSAS have a common complication in the area of cardiovascular events. Studies have highlighted the pathophysiological mechanisms, including increased oxidative stress, ED, and inflammation, as shown above in this review. It has now been verified that childhood OSAS from adenotonsillar hypertrophy, without any comorbidity, may lead to cardiovascular complications that are based on the degree of severity. In the case of severe OSAS, other conditions that regard the oral cavity (e.g. maxilla development) must be clinically evaluated. It is currently being ascertained whether OSAS may involve a cardiovascular complication independently of obesity, and obesity independently of OSAS. It seems that obesity and OSAS interact with each other to increase cardiovascular morbidity and, consequently, we cannot treat either without the other.

In this review, we show the role of blood markers in demonstrating inflammation caused by intermittent oxygen desaturation during sleep, which poses a substantial risk to the integrity of the vascular endothelium in healthy and obese children^19,20. Confirmation of their role as markers of the condition is supported by the different concentration in a control population and normalisation after surgery (Tables I and II)^{27,30,31,33,42}. For this reason, physicians should recognise and treat SDB disorders because of the potential consequences for children in the short and long term. Unfortunately, in most cases, these markers cannot be used in clinical practice and therefore have an exclusively research orientated role.

Tissue markers of inflammation limited to the lymphatic tissue of the neck were also detected in children with SDB^45,46. The role of these markers could be a predisposing SDB condition or an independent inflammatory situation; both are valid assumptions. To our knowledge, there have been no studies to show that resolution of lymphatic tissue inflammation of the neck, through appropriate therapy and with the normalisation of these markers, confirms the positive contribution of improving SDBs; though this is plausible in mild or moderate cases, it cannot be the case in severe disorders.

Vascular ED is one of the consequences of systemic inflammation. This condition was indirectly investigated by measuring blood markers in subjects suffering from vascular dysfunction who normalise after treatment^49,50,53,54. In a few cases, some markers are known to be related to atherosclerosis. It is, however, difficult to demonstrate with the single measurement of blood markers that vascular dysfunction presents an improvement in such a short study period. Therefore, some authors have studied vascular damage using direct techniques (post-occlusive hyperaemic test, FMD, PWV and carotid intima-media thickness). All these studies evaluate vascular changes with these techniques and some markers at the same time. Few studies evaluate the improvement of vascular damage^42,50,56,66. In addition, the normalisation of these markers could itself testify its future improvement. Even in these studies, it would be easy to presume that SDB resolution^42,55,57 can lead to long-term vascular improvement, particularly in obese children^57,69,70,74.

The study of thrombotic risk in children with SDB has received much attention^78,79. However, one study in particular was well executed and appears quite convincing⁷⁹. However, the incidence of this complication in the paediatric age is not known. Thus, it seems that it is either extremely rare or inconsistent at this age but could become significant in adulthood. Further studies are needed to confirm this relationship.

Unexplored and unmet needs in the assessment of cardiovascular disease associated to obstructive sleep apnoea syndrome in children.

Sleep-disordered breathing is a multifaceted disease both in terms of pathogenesis and complications. There is a large bibliography and related keywords which testify a growing interest in the paediatric setting.

Although OSAS-associated CVD assessment is relevant for a more comprehensive description of the disease and its treatment, some evidence has been found in previous studies. The following areas, which have as yet remained unexplored or not explored in sufficient depth, should be further investigated:

• extensive assessment of the interaction between OSAS and obesity;

• development of integrated tools evaluating obesity and OSAS interaction in the short and long term;

• comprehensive assessment of ED markers in clinical practice;

• advanced assessment of tissue markers of inflammation to evaluate whether their normalisation is linked to SDB improvement in severe disorders;

• broad assessment of the relationship between blood markers and vascular dysfunction;

• thorough assessment of future long-term vascular damage improvement after SDB resolution;

• far-reaching assessment of thrombotic risk in children with SDB.

CONCLUSIONS

Nowadays there is a large amount of data showing that, through activation of a state of systemic inflammation, paediatric SDBs cause significant but likely reversible cardiovascular damage. Great attention should be given to this condition in infants and children as it can significantly affect their present and future well-being as they grow into adulthood. In the current global condition of economic hardship, particularly in health, the prompt treatment of this pathology would have important economic advantages. Healthcare professionals, especially paediatricians, should be trained to recognise the signs and symptoms of the disease in order to send children forward for specialist care. In this context, early diagnosis of OSAS is very important for encouraging primary prevention interventions to correct the risk factors responsible for disease progression and the occurrence of CVDs. Future studies should be aimed at unravelling other reliable and specific biomarker panels as well as instrumental and easy-to-apply clinical methods that can identify those children at higher risk for OSAS-induced morbidities. This would also facilitate the implementation of precision medicine interventions among OSAS patients.