Objective: The main objective is to evaluate the monocyte phenotype of children with FH compared to normocholesterolemic controls and to explore the effect of statin treatment.
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
In the children with FH, blood will be drawn before start of statins and 3 and
12 months after initiation of statin treatment. In the normocholesterolemic
controls (only in Oslo), blood will only be drawn once. Plasma will be stored
and peripheral blood mononuclear cells will be isolated and viably frozen at
each study site. After inclusion is complete, all samples will be shipped to
Oslo, Norway for analysis of cytokine production capacity upon ex vivo
stimulation with various atherogenic stimuli and flow cytometric analysis.
Monocytes will be isolated for RNA sequencing and epigenetic analyses. The
primary endpoint is LPS-induced IL-1b release in patients with FH compared to
controls. Secondary endpoint is the effect of 3- and 12-month statin treatment
compared to the baseline situation in children with FH.
Secondary outcome
Secondary endpoint is the effect of 3- and 12-month statin treatment compared
to the baseline situation in children with FH.
Background summary
Rationale: Familial hypercholesterolemia (FH) is an autosomal dominant
dyslipoproteinemia, characterized by elevated low density lipoprotein (LDL)
levels, and is an important risk factor for atherosclerotic cardiovascular
disease (ASCVD). Due to genetic defects, patients with FH have elevated plasma
LDL cholesterol from birth onwards, and a variety of markers of atherosclerosis
are observed already in early childhood. In Europe, about 1:250 people have FH
and early treatment is key to lower CVD risk. In the last 10 years, European
guidelines have been published for the identification and management of
children with FH. In Europe, children with genetically diagnosed FH start LDL
lowering treatment with statins from the age of 8 to 10. This treatment is
generally very well tolerated, even better than in adults. Over the last
decades, it has become apparent that atherosclerosis is a chronic inflammatory
disease which benefits from anti-inflammatory treatment. At the same time, it
was discovered that the innate immune system is capable of developing a memory,
which is termed trained immunity. Trained immunity can be induced by
micro-organisms but also by endogenous atherogenic particles, such as
(modified) lipoproteins. We have shown in innate immune cells from adults that
lipoprotein-trained monocytes have a pro-atherogenic phenotype and furthermore
we showed a trained phenotype in monocytes from adults with familial
hypercholesterolemia. Furthermore, 3 months of treatment with statins - in
adults - did not revert the trained immunity phenotype despite lowering the
blood cholesterol levels successfully. It is unknown whether monocytes from
children with FH have a trained immunity phenotype similarly to adults and how
statin treatment affects this.
Study objective
Objective: The main objective is to evaluate the monocyte phenotype of children
with FH compared to normocholesterolemic controls and to explore the effect of
statin treatment.
Study design
Study design: Observational cohort study.
Study burden and risks
Nature and extent of the burden and risks associated with participation,
benefit and group relatedness: There is no risk associated with participation.
After signing for informed consent by the parents and assent by the children if
>12 years old, 20 ml of blood will be drawn at the routine diagnostic
appointments for the ex vivo experiments.
Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Listed location countries
Age
Inclusion criteria
8-18 yrs old FH (by genetics or EASCP criteria) and LDLC levels above 3.5
mmol/L and requiring lipid lowering treatment according to the treating
physician No previous cardiovascular events. Written informed consent from the
parents/legal representatives or patients depending on their age prior to
participation in the study
Exclusion criteria
- Current lipid lowering treatment or treatment with lipid lowering drugs in
the past year
- Parents inability to provide written informed consent (for linguistic,
intellectual or mental reasons)
- Current treatment for malignancy
- Acute or chronic infections with fever at the time of participation
- Medical history of any disease associated with immune deficiency (either
congenital or acquired, including chemotherapy, chronic steroid use, organ
transplant)
- Clinically significant infections within 1 months prior to study entry
(defined as fever above 38.5)
- Previous vaccination within 1 months prior to study entry
- Chronic use of anti-inflammatory drugs such as NSAIDs (acetylsalicylic acid
below 100 mg/day excluded)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL84300.078.23 |