WHeezing Illnesses Study Leidsche Rijn / Childhood adiposity and Arterial Disease Onset 2

Cardiovascular diseases (CVD) belong to the major causes of morbidity and
mortality in adults. Since the process of atherosclerosis is known to begin in
early childhood, CVDs become a major threat for children*s health.
Overweight and obese subjects more often develop dyslipidemia, insulin
resistance leading to diabetes mellitus, and atherosclerosis. One of the causes
of this association is thought to be dysfunctional adipose tissue, which leads
to secretion of hormones, so called adipokines, and pro-inflammatory cytokines.
In adults, adipocytokines are associated with hypertension, insulin resistance
and thereby increased cardiovascular risk. However, in children it remains
unclear whether these adipocytokines are associated with fat distribution.
Moreover, the exact impact of adipocytokines on the cardiovascular system in
childhood remains uncertain.
Besides the role of dysfunctional adipose tissue on early atherosclerotic
changes, other determinants of early atherosclerosis are of interest. In the
ongoing WHISTLER study and in the follow-up at the age of 5 year, the
WHISTLER/Cardio study, relationships between both smoking and overweight and
early functional and structural changes of the carotid arterial wall were
already detected at the age of 5 year. However, the effect of changes in fat
distribution on the vascular properties remains unknown. Moreover, the
persistence of changes of the arterial wall to later childhood is unknown.

This research theme consists of two related studies with the primary aim to
investigate determinants of the pathogenesis of atherosclerosis in early
childhood. The first part is performed to determine the association of
adipocytokines with fat distribution and the arterial wall in children.
Although adipocytokines are produced by adipose tissue, it is not known whether
weight itself is associated to the adipokine profile, or if the secretion of
adipocytokines is more dependent on the distribution of fat, for example the
waist circumference. Furthermore, dysfunctional adipose tissue, and therefore a
changed adipokine profile, might be present in non-obese children. One of the
research questions in this first study will therefore be *Are adipocytokines
related to anthropometric parameters in childhood?* The second research
question is conducted to learn about the effect of different adipocytokines and
the adipocytokine profile on the arterial wall, since arterial wall properties
like IMT and vascular stiffness are known to change in the early stages of
atherosclerosis. This will be studied by the following research question: *Are
adipocytokines related to properties of the arterial walls, namely the carotid
IMT and vascular stiffness, in childhood?*
The second part of this study is performed to investigate the effect of growth
and relative weight changes on the vascular system in childhood. It is unknown
whether changes in the vascular system present at the age of 5 year persist
over time. Moreover, the effects of growth and changes in weight, blood
pressure and other cardiovascular risk factors on the persistence of vascular
changes from the age of 5 years to the age of 7-9 years are unknown. Research
questions belonging to this objective are: Do vascular changes in IMT and
stiffness persist over time in childhood? To what extent is the vascular system
influenced by the process of growth in childhood?

The WHISTLER study is a cohort study. This study is a follow-up measurement of
children who participated in WHISTLER, an ongoing birth cohort study, and who
already were followed at the age of 5 years (WHISTLER/Cardio).
Due to a different nature of the different research questions, this study
contains a cross-sectional and a longitudinal component. The relation between
adipocytokines and both anthropometrics and vascular properties will be studied
cross-sectional, at the age of approximately eight years. In the
cross-sectional part of this study, the relation between the adipocytokine
profile and the vascular system, the assessment of the determinant and outcome
will not per se be performed on the same day, since the adipocytokine profile
has to be assessed in the morning, after an overnight fasting period. However,
we do not consider both outcome measurements as highly changeable variables and
therefore it is very unlikely that this small period between the two visits
will have consequences for the validity of this study.
By (re)measurement of the carotid IMT and distension at the age of 8 years,
longitudinal data on ultrasonographic measures of the carotid artery will be
obtained. In this longitudinal component, the persistence of vascular changes
over time and the effect of growth and differences in fat distribution over
time on the vascular system can be studied.

Since the pathogenesis of CVDs is known to start early in life and symptoms of
cardiovascular disease become present later in life, early factors associated
with the pathogenesis of CVDs have to be studies in children and is therefore
group-related.
Subjects will have no benefit form participating to this study. The risks
associated with participating to this study are very small and the possible
complications non-severe. The only procedure in this study which implies a
health risk, although it is a very small risk, is the venous puncture. There
are no risks associated with the other measurements in this study.
The risks associated with the venous puncture include the sensation of pain for
a short period during and after the venous puncture and the risk on a vasovagal
collaps. Moreover, there is a risk on the development of a haematoma after the
venous puncture. These risks have a short duration and are non-severe. The
study related burden for the subjects will be minimized by using local
anaesthetics before the venous puncture will be conducted and by using a small
needle. Moreover, the venous puncture will be only performed once. If after one
venous puncture, the blood sample is not collected, only if the subject and the
parents agree a second venous puncture will be performed.