Secondary Manifestations of ARTerial diseases in the Young with a chronic condition

The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study
established that atherogenesis starts in childhood, initiating in the iliac
arteries and abdominal aorta and subsequently develops in higher regions of the
arterial tree. Childhood and adolescence thereby provide a unique window of
opportunity to prevent atherosclerotic cardiovascular disease (ASCVD) later in
life, especially for pediatric groups at risk. The growing list of pediatric
groups at risk includes chronic inflammatory disorders, organ transplant
recipients, familial hypercholesterolemia, endocrine disorders, childhood
cancer survivors, chronic kidney diseases, congenital heart diseases, fetal
growth restriction, and premature birth, next to increasing numbers of children
and adolescents with traditional risk factors such as obesity, hypertension,
hyperlipidemia, and hyperglycemia. The best way to assess cardiovascular health
in the pediatric population is relatively uncharted territory. Multisite and
multimodal assessment of early atherosclerosis emerged as the best way to
capture the complexity of atherosclerosis as a systemic disease. Next to
conventional carotid intima-media thickness measurements, implementation of
aortic pulse wave velocity and endothelial function measurements can advance
the assessment of early atherosclerosis in pediatrics.

Substudy: SMART-CF

In this substudy, we aim to expand the study to include adults within a
specific subset of this cohort, namely cystic fibrosis (CF). Although the
original study focuses on pediatric patients, we believe it is valuable to
conduct the same measurements in adults with CF to fulfill the life course
medicine perspective. By mapping cardiovascular health in both children and
adults with cystic fibrosis, we aim to gain unique insights into the long-term
effects of this chronic disease on the cardiovascular system. These insights
become increasingly important in CF since the disease has undergone a
remarkable transformation from being considered a life-threatening condition in
childhood to a chronic disease due to high-quality care. More recently, through
new therapeutics, known as CFTR modulators, outcomes in CF can significantly
improve even more. As the life expectancy continues to increase, naturally it
brings forth new challenges, one pressing population of which one is the
cardiovascular health. A recent study has shown an increased risk of
cardiovascular disease in pwCF making it ideal to study the atherosclerosis and
the factors influencing cardiovascular risk in this group as they could also be
useful for developing targeted strategies for risk stratification, allowing for
more personalized and proactive management of cardiovascular health in
individuals with risk factors growing into older ages.

Due to vascular impairment it may be related to the ovarian reserve. The
ovarian reserve is related to fertility decline and menopausal age. The ovarian
reserve can be measured via a surrogate marker which is anti-Mullerian hormone
in serum. AMH declines alongside ovarian reserve during the reproductive
lifespan and is associated with cardiovascular disease in young women. Female
infertility and hormone levels are linked to increased risk of cardiovascular
disease and outcomes later in life. However, it remains unknown if a poor
cardiovascular health is the origin or consequence of diminished ovarian
reserve, reduced fertility and early menopause.

Therefore, in adult women with CF ovarian reserve markers will be assessed and
a questionnaire about their menstrual cycle and reproductive outcome will be
inventoried to study a possible association with cardiovascular markers. It is
of importance to note that since the ovarian reserve marker in the general
adult population does not carry strong predictive values for reproductive
outcomes. Therefore these test are currently not used to identify women at risk
for infertility in the general population.

The primary objective of this study is to establish the effect of
cardiovascular risk factors on preclinical atherosclerosis in children with a
chronic condition, and follow this up over time.

The SMART-Youth study will be a prospective, longitudinal cohort study
including children with various chronic conditions followed up in the
Wilhelmina Children*s Hospital. In order to determine the development over
time, cardiovascular risk factors and preclinical atherosclerosis measurements
will be assessed every two years. For now, the study duration entails 5 years,
with future plans of possible extension after this time.

Furthermore, we set up a substudy into adults with CF who are followed up in
the UMC Utrecht.

The burden and associated risks with participation are low. In most patients,
routine lipid blood sampling is already included in outpatient follow-up. For
some patient groups, such as children with congenital heart disease, routine
blood sampling is included in outpatient follow-up in the course of the
SMART-Youth study. Given the atherosclerotic cardiovascular disease risk of
these children, and after consultation with the treating physicians, lipid
sampling will be viewed as clinical care and not solely from a research
perspective for all children. We will combine the check-up visit at the
outpatient clinic of the Wilhelmina Children*s Hospital with the SMART-Youth
visit, to minimize the burden of traveling to the hospital. Both visits will
take approximately 1 hour. There are no direct benefits for the subject when
participating in this study. Participation will be completely voluntary.