Endothelial Dysfunction and Oxidative Stress in Children With Sleep Disordered Breathing.
Condition: Obstructive Sleep Apnea of Child
MeSH terms: Sleep Apnea Syndromes; Sleep Apnea, Obstructive
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Sleep disordered breathing (SDB) is a common disease in both adults and children and is
      caused by the obstruction of the upper airway during sleep. Unlike adults, most cases of
      paediatric SDB are due to the presence of enlarged tonsils and adenoids, thus the main
      treatment option is adenotonsillectomy (AT). It is well known that obstructive sleep apnoea
      (OSA) in adults increases the risk for hypertension, coronary artery disease and stroke, and
      there is now mounting evidence that SDB also has a significant impact on the cardiovascular
      system in children with reports of elevated blood pressure, endothelial dysfunction and
      altered autonomic cardiovascular control.

      Oxidative stress seems to play a pivotal role in impairing flow-mediated dilation (FMD) and
      consequently enhancing cardiovascular risk in SDB patients but the underlying mechanism is
      still undefined.

      Previously, we demonstrated that endothelial dysfunction is directly related to NADPH oxidase
      activation. Furthermore, recently we assessed the association between OSA, endothelial
      dysfunction and oxidative stress in adults showing that increased NADPH oxidase-generated
      oxidative stress and arterial dysfunction are partially reversed by nasal continuous positive
      airway pressure treatment.

      There is evidence in literature that cardiovascular morbidities associated with SDB are
      potentially reversible in children; AT may have a significant role in reversing the
      cardiovascular sequelae of SDB (e.g. children with OSA).

      Nowadays, there aren't studies that analyzed the role of NADPH oxidase-generated oxidative
      stress in SDB children.

      The purpose of the current research project is to examine the role of NADPH oxidase activity,
      oxidative stress, inflammation and endothelial function in SDB children, understanding the
      mechanisms involved in this disease.

      Furthermore we will analyse the effect of a AT on inflammation, oxidative stress, NADPH
      oxidase activity and endothelial function in SDB children.
    

Detailed description: 
      Sleep disordered breathing (SDB) is a spectrum of diseases ranging from primary snoring to
      obstructive sleep apnoea (OSA). Recent studies suggested that the prevalence of SDB childhood
      was 7.4%. In patients with OSA, there are intermittent episodes of complete or partial
      obstruction leading to intermittent desaturations and/or arousals. This would result in
      either stimulation of sympathetic system or suppression of the vagal tone that may persist
      beyond sleep. The disturbance of the autonomic nervous system would result in significant
      changes in the cardiovascular system. The process of intermittent hypoxaemia and subsequent
      re-oxygenation also damages the endothelium because of the generation of free radicals.
      Furthermore, the excessive negative intra-thoracic pressure swing generated during the
      obstruction would also affect cardiac functions. In adults, OSA has been well documented to
      be associated with cardiovascular abnormalities such as hypertension, ischaemic heart
      disease, arrhythmia and heart failure.

      Oxidative stress plays a crucial role in the initiation and progression of atherosclerosis.
      In particular, an imbalance between superoxide and nitric oxide production could be
      responsible for endothelial dysfunction, a key point for atherosclerotic process. Several
      oxidative stress-generating enzymes, including myeloperoxidase, xanthine oxidase and
      nicotinamide adenine dinucleotide phosphate (NADPH) may be implicated in arterial
      dysfunction; NADPH oxidase represents, in human, the most important source of cellular
      superoxide anion production. Experimental studies performed in animal models suggest a
      pivotal role of NADPH oxidase in modulating arterial tone. In particular, overexpression of
      gp91phox (NOX2), potentiates the hemodynamic response to angiotensin II. Furthermore,
      individuals with impaired dilation show an overexpression of the NADPH oxidase subunit
      p47phox in endothelial cells.

      Previously, we demonstrated that endothelial dysfunction is directly related to NADPH oxidase
      activation; in particular we demonstrated that in patients with NADPH oxidase subunits
      deletion, as chronic granulomatous disease, the oxidative stress is lower and flow-mediate
      dilation is higher, compared to controls. Conversely, in other diseases characterized by high
      rate of cardiovascular events (OSAS, Peripheral arterial disease, metabolic syndrome, obesity
      and hypercholesterolemia), we found an endothelial dysfunction and a NOX2 overexpression.

      Recently, we assessed the association between OSAS, endothelial dysfunction and oxidative
      stress in adults. Interestingly, the results of our study indicated that patients with OSAS
      have increased NOX2-generated oxidative stress and arterial dysfunction that are partially
      reversed by nasal continuous positive airway pressure (nCPAP) treatment.

      There is evidence in literature that cardiovascular morbidities associated with SDB are
      potentially reversible in children; AT may have a significant role in reversing the
      cardiovascular sequelae of SDB (e.g. children affected by OSA).

      The purpose of the current research project is to examine NADPH oxidase activity, oxidative
      stress, inflammation and endothelial function in children with SDB.

      Expected outcomes and their interest in advances in the frontier of knowledge and their
      potential impact:

        1. understand the mechanisms mediated by inflammation and oxidative stress involved in SDB

        2. the assessment of NADPH oxidase activity could be a useful tool to identify SDB patients
           at high risk of cardiovascular events in order to prevent their dramatic complications.

        3. Analyse the effect of a surgical correction (e.g. adenotonsillectomy) on inflammation,
           oxidative stress, NADPH oxidase activity and endothelial function in children;
           adenotonsillectomy could represent a potential therapeutic option to reduce the high
           cardiovascular risk of SDB children.

      The study will be divided in 2 phases: a cross-sectional and an interventional study.

        1. In the cross-sectional study we will include at least 100 children (50 SDB children with
           SDB and 50 controls), assessing markers of oxidative stress (serum isoprostanes), NADPH
           oxidase activity, inflammation, endothelial function (by flow-mediated dilation, FMD)
           and the carotid intima media thickness (IMT) measurement.

        2. In the interventional study we will include at least 10 with OSA and adenotonsillar
           hypertrophy that will undergo to adenotonsillectomy, evaluating markers of oxidative
           stress (serum isoprostanes), NADPH oxidase activity, inflammation and endothelial
           function before and after (at least 30 days) the surgical procedure.
    

Intervention name(s): adenotonsillectomy
Intervention type(s): Procedure
Intervention description(s): adenotonsillectomy in children with OSAS and adenotonsillar hypertrophy.
Intervention model: Single Group Assignment
Masking: Single (Investigator)
Primary purpose: Basic Science
Keywords: obstructive sleep apnoea, oxidative stress, FMD