The main objective is to compare function and phenotype of bone marrow HSCs of FH patients before and after LDL-c lowering by statins/PCSK9-inhibitors with healthy controls. Secondary objectives are to correlate the function and phenotype of HSPCs…
ID
Source
Brief title
Condition
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main primary outcome is difference in CFU-GM assay (= function) and flow
cytometry (=phenotype) of HSCs of FH patients before versus after treatment
with a statin/PCSK9-inhibitor compared to healthy HSCs
Secondary outcome
Secondary endpoints are difference in lipid accumulation in FH HSCs and
monocytes before and after treatment, flow cytometry (=phenotype) of FH HSCs
compared to flow cytometry of circulating monocytes of FH patients and
epigenetic and metabolic changes in FH HSCs and monocytes before and after
treatment with a statin/PCSK9-inhibitor. This will be compared to healthy HSCs
and monocytes
Background summary
Despite LDL-c optimization with statins, patients with hypercholesterolemia,
and in particular patients with FH, have a high residual CV risk. FH patients
are characterized by high LDL-c plasma levels, monocytosis and premature
development of atherosclerosis. In vivo imaging with 18F-FDG PET/CT scan shows
increased 18F-FDG uptake in bone marrow in patients with atherosclerosis,
suggesting increased hematopoietic activity in these patients. In vitro
co-incubation assays of healthy HSCs with oxLDL showed indeed increased
progenitor capacity, but also a myeloid differentiation bias. Therefore we
hypothesize LDL-c can prime HSPCs, resulting in a chronic monocytosis and
pro-atherogenic monocytes leading to aggravated atherosclerosis in FH patients
despite LDL-c lowering treatment.
Study objective
The main objective is to compare function and phenotype of bone marrow HSCs of
FH patients before and after LDL-c lowering by statins/PCSK9-inhibitors with
healthy controls. Secondary objectives are to correlate the function and
phenotype of HSPCs to lipid accumulation, to compare phenotype of HSPCs with
phenotype of circulating monocytes and to determine epigenetic and metabolic
changes in HSPCs.
Study design
Single center, observational study
Study burden and risks
The results of this study contribute to the understanding why patients are at
risk of cardiovascular events despite optimization of LDL-cholesterol.
Individual subjects will gain no direct benefit from this study. The burden and
risk of participating in this study are estimated to be low. The study requires
a maximum of 2 study visits. Maximum blood withdrawal including clinical
laboratory assessment will be 124 ml. Complications of a sternum biopsy are
rare, a bleeding or an infection may occur.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
Patients:
- Age > 18 years old
- Familial hypercholesterolemia (according to Dutch Lipid network criteria)
- No previous cardiovascular events
- No current lipid lowering treatment
- LDL-cholesterol > 4.9 mmol/L;Healthy controls:
- Age >= 18 years old
- No (previous) clinically significant health problems
- No current medication use
Exclusion criteria
1. Malignant diseases or any clinically significant medical condition that could interfere with the conduct of the study in the opinion of the investigator.
2. Chronic or recent (<1 month) infections and/or clinical signs of acute infection and/or CRP>10
3. Auto-immune diseases
4. Recent or chronic immunosuppressant or antibiotic usage
5. Type I or II diabetes mellitus
6. Inability or unwillingness to comply with the protocol requirements, or deemed by investigator to be unfit for the study.
Design
Recruitment
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 | NL59100.018.16 |