To investigate whether long-term activation of the innate immune system, named *trained innate immunity*, occurs at the level of the bone marrow progenitor cells in patients with significant coronary artery disease and whether this correlates with…
ID
Source
Brief title
Condition
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Comparison of HSPC*s of patients with and without significant coronary artery
disease on epigenetic and phenotypic characteristics, and relate this with
phenotypic appearance of circulating monocytes.
Secondary outcome
Comparison of the pro-inflammatory monocytes and HSPC's phenotype with vascular
wall inflammation, bone marrow and spleen activation by measuring FDG uptake in
PET-CT scanning.
Background summary
Atherosclerosis is increasingly being acknowledged as a chronic, low-grade
inflammatory disorder of the arterial wall. Patients with CVD show increased
FDG uptake in the large arteries and bone marrow, and this strongly predicts
resp. correlates with future cardiovascular events. Previously is shown that
monocytes/macrophages adopt a long-lasting pro-inflammatory phenotype by
epigenetic modulation upon brief exposure to various pro-inflammatory and
pro-atherogenic stimuli such as oxLDL and Lp(a), named *trained innate
immunity*. Recently, our group has proposed that trained immunity contributes
to atherosclerotic vascular inflammation by showing that in patients with
elevated levels of Lp(a) monocytes possessed a pro-atherogenic phenotype
associated with epigenetic changes (H3K4me3 enrichment), and increased vascular
inflammation on PET-CT. Because these pro-inflammatory changes last longer than
the life span of circulating monocytes, up to three months after BCG
vaccination, we shifted our attention to the bone marrow progenitor cells. In
mice, hypercholesterolemia increases the number of monocytes, and skews their
development towards a pro-inflammatory phenotype, via priming of HSPC.
Therefore, we hypothesize that functional, transcriptional en epigenetic
changes at the level of HSPCs are responsible for the long-term trained
immunity phenotype of circulating monocytes, and contributes to the development
of atherosclerosis in the context of traditional CVD risk factors. This is the
first study to address this issue by directly obtaining bone marrow progenitors
from patients with significant coronary artery disease.
Study objective
To investigate whether long-term activation of the innate immune system, named
*trained innate immunity*, occurs at the level of the bone marrow progenitor
cells in patients with significant coronary artery disease and whether this
correlates with the pro-inflammatory phenotype of monocytes.
Study design
An observational pilot proof-of-principle study.
Study burden and risks
There is no direct benefit to the study participants. These results can
potentially lead to new therapeutic options for atherosclerosis. The risks for
participants are negligible, with the only expected risks being unexpected
findings of PET-CT scanning, minor discomfort due to bone marrow aspiration and
venipuncture. This will be minimized by the performance of these procedures by
experienced personnel.
Geert Grooteplein-Zuid 10
Nijmegen 6525 GA
NL
Geert Grooteplein-Zuid 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
Age *18 and *75 years
With or without significant coronary artery disease on CCTA as described earlier
Written informed consent
Exclusion criteria
Chronic infections
Diabetes mellitus
Medical history of any disease associated with immune deficiency (either congenital or acquired, including chemotherapy, chronic steroid use, organ transplant)
Clinically significant infections within 3 months prior to study entry (defined as fever >38.5)
Recent hospital admission or surgery with general anaesthesia (<3 months)
Known chronic kidney (MDRD <45 ml/min) or liver disease (ALAT more than three times upper reference limit or known liver disease)
Previous vaccination within 3 months prior to study entry
Inability to personally provide written informed consent (e.g. for linguistic or mental reasons)
Inability to undergo PET-CT scanning
Chronic use of anti-inflammatory drugs such as NSAIDs (acetylsalicylic acid <100 mg/day excluded)
History of haematological malignant disease
Documented bleeding diathesis or thrombocytopenia <50 *10e9/L
Pregnancy
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 |
|---|---|
| Other | Clinicaltrials.gov nog niet geregistreerd |
| CCMO | NL58806.091.16 |