This study demonstrated, for the first time, that children with oSDB have augmented arterial stiffness, evidenced by the increase in AIx@75, measured non-invasively by brachial artery oscillometry with a portable device. emale gender, age, SV, and RC were independent determinants of AIx@75 response in oSDB children. There was no difference in PWV between groups. However, it had an inverse relationship with the total score of the PedsQLquestionnaire. These data suggest that children with oSDB have subclinical changes in vascular parameters that could lead to the development of cardiovascular diseases in adulthood.
There are few validation studies that compare invasive and non-invasive measures of arterial stiffness in children. Shiraishi et al (2020) demonstrated that central pressure measures performed by Mobil-o-graph® in children and adolescents are accurate and promising for future studies and research.[15] Furthermore, there are already standardized values of arterial stiffness indices for children, which allow the evaluation of these indicators in this age group. [16][17] Other studies have described arterial stiffness are present in childhood and AIx@75 reference equations have been proposed for children in different health conditions. [17] Walter et al (2018) reported changes in arterial stiffness in children with oSDB through increased PWV. [18] Similarly, Montero Lopez et al (2019), described a positive correlation of PWV with BMI in a multicenter study involving children aged 9 to 10 years. [19]
In addition to the increased AIx@75 in children with oSDB, it was observed in our results that AIx@75 in females was 31.64% higher than in males. However, the difference was not significant. Despite this, the sex variable was introduced in the multiple regression model, as well as all other variables with p < 0.2. Ayer et al. (2010) described that healthy girls, assessed in the first decade of life, had higher AIx compared to boys, regardless of the individual's height or arterial diameter.[20] This change is also described in female adults.[21] As discussed by Ayer et al, this finding suggests that factors responsible for higher AIx in women in adulthood would already be determined in the first decade of life and, in part, unrelated to height. These authors also reported that such data could justify different cardiovascular responses in men and women in adulthood for the same disease. Thus, such a result would be expected in the sample of this study.
Hidvégi et al [22] described in healthy children that AIx@75 tends to decrease in both sexes with age, occurring at different times due to puberty. This phenomenon is explained by the short stature, which leads to an early return of the reflection wave. In the present study, data related to puberty were not evaluated. However, the influence of this factor would not be expected, since the average age of the children evaluated was 5 years, lower than the beginning of puberty. In addition, height was similar in both groups and higher levels of AIx@75 in the oSDB group could not be attributed to it.
The magnitude of the reflection wave is assessed by the RC, which is defined by the relationship between the amplitude of the reflection wave and the ejection wave. Thus, the concomitant increase in AIx@75 is expected since the greater the amplitude of the reflection wave, the greater the RC, the greater the AP and the greater the AIx@75. The last predictor of AIx@75 in children with oSDB is SV. Increase in SV reduces AIx@75. Similar results were described by Santos et al in healthy children.[23]
Obesity is an independent risk factor for cardiovascular morbidity.[24] In this study, 16.7% of the children were classified as overweight and 18.8% as obese in the oSDB group compared to 1.5% of overweight and no obese children in the control group. Walter et al showed that overweight and obese children with oSDB had higher PWV than normal weight children with oSDB, which suggests obesity as an exacerbation factor of arterial stiffness in this age group. [18] Obesity can aggravate the effects of oSDB because the macrophages present in adipose tissue are the target of the effects of intermittent hypoxemia, leading to an increase in inflammatory markers. The study Icelandic Sleep Apnea Cohort suggested that oSDB could result in a progressive inflammatory state, which would justify the mechanism of vascular damage and that such consequences could vary with the degree of obesity.[25] There were no differences in BMI between the oSDB and control groups in the hereby investigated cohort. Similarly to the existing literature, BMI correlated positively with the PWV arterial stiffness indices (r= 0.359, p=0.012) and cSBP.
Guilleminault et al (1976) were the first to describe children with oSDB and high blood pressure (BP). [1] Walter et al. (2018) were the first to describe that both during wakefulness and during sleep, children with oSDB, regardless of their weight or sex, had higher PWV values when compared to non-snoring children in the control group. [18] In contrast, our study revealed similar PWV between control and oSDB groups. However, it was observed that it correlated negatively with the social, physical, and total scores of the PEDSQL 4.0questionnaire in the oSDB group. These results suggest that a low quality of life and therefore a high disease burden in children with oSDB may be a risk factor for arterial stiffness. To the best of our knowledge, this study was the first to demonstrate an association between PWV and quality of life in children with oSDB. Tap et al. (2020) demonstrated an association between arterial stiffness and low quality of life in Dutch elderly people over 75 years old, regardless of age, blood pressure levels and comorbidities. [26] The authors suggested that the findings could be explained by poor physical or mental health. Other authors [27, 28] demonstrated a relationship between low quality of life and arterial stiffness. However, these studies were performed in an adult population with specific comorbidities.
Arterial stiffness is a predictor of cardiovascular diseases [29], and therefore its investigation is important. In a meta-analysis, Li et al described that a 10% increase in AIx in adults is related to an 1.18 relative risk of increased chance of cardiovascular events. [30] In order to evaluate the prognostic impact of increased AIx on the future cardiovascular risk in this sample, children would have to be followed up to adulthood and should not be treated for oSDB, which would be ethically objectionable. However, the hereby-presented observations indicate the importance of diagnosis and appropriate treatment of oSDB in children. It is well-known in the literature that treatment of apnea in the adult population leads to significant improvements in cardiovascular function, which includes a reduction in pulmonary artery pressure, MAP and endothelial dysfunction.[5] Changes in PWV are more marked in older individuals (50 years), suggesting that AIx might be a more sensitive marker of arterial aging in younger individuals, and PWV more sensitive in those over 50 years of age. [31]
The implications of treating oSDB in children and their cardiovascular outcomes are still poorly explored. Existing studies vary in terms of methods and evaluation of results. Since the main cause of oSDB in children is adenotonsillar hypertrophy, T&A would be the first line of treatment for this disease. [6] Although Apostolidou et al [7] and NG et al [8] have shown a decrease in diastolic blood pressure in children undergoing this surgical procedure, these authors have not been able to conclude about its medium and long term effects on the cardiovascular system. Furthermore, it is already discussed that surgery does not always lead to complete resolution of oSDB symptoms.[1] Bhattacharjee R et al., in a retrospective study, concluded that residual disease is present in a large proportion of children after T&A.[32] Comparably, Yu-Shu Huang and coworkers, in a prospective study, described that T&A leads to significant improvement in PSG findings, though generally with incomplete resolution and a worsening over time.[33] Thus, one must also question T&A´s role in resolving arterial stiffness, which would be the subject of a new study.
Study limitation
In adults, arterial stiffness is associated with both the presence and severity of oSDB. PSG is necessary to stratify the severity of oSDB.[2] AAO-HNS produced clinical guidelines or practice parameters regarding indications for PSG in children. [10] Currently in Brazil, PSG is not required for T&A indication since it is a costly and time-consuming test, and not all sleep laboratories evaluate children. Moreover, its use for scientific purposes is even more limited in our country. Thus, PSG was not performed in our sample. Another limitation of this study is its cross-sectional character, which prevents causal associations and reduces the generalizability of regression analyzes. Furthermore, it was carried out in a single center, which reduces the external validity of the data.