To test the hypothesis that patients with AoS have a higher prevalence of CHIP driving mutations compared to control subjects. Secondary objectives are to perform extensive phenotyping of circulating monocytes.
ID
Source
Brief title
Condition
- Cardiac valve disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Frequency of CHIP driver mutations in blood cells.
Secondary outcome
Secondary endpoint is cytokine production capacity of isolated innate immunce
cells.
Other explorative endpoints include leukocyte composition,cytokine production
capacity and ROS production of isolated neutrophils, circulating markers of
inflammation, including cytokines and chemokines, circulating metabolome and
proteome, deep transcriptional phenotyping of circulating monocytes and
neutrophils is a subgroup of patients (from all subjects, these cells will be
isolated and stored in liquid nitrogen), detection of epigenetic markers, as a
marker for trained immunity, on a selection of samples, histopathological
examination of (a selection of) sugically removed valvular tissue.
The researcher will call all participants after 2 and 5 year and check medical
files to be able to explore whether the immunological parameters are associated
with incident cardiovascular events and disease progression.
Background summary
Calcific aortic valve stenosis (AoS) is the most common form of valvular heart
disease in the Western world, which can cause heart failure, syncope, and
angina. Due to the fact that the underlying pathophysiology remains
incompletely defined, there are currently no effective medical treatments
capable of altering its course, identifying a major unmet need in this growing
population of patients. AoS resembles atherosclerosis, which is the main cause
of myocardial infarction and stroke, in pathology, and shared risk factors. We
have recently reported pro-inflammatory reprogramming of circulating monocytes
in patients with atherosclerosis of risk factors of atherosclerosis. In
addition, clonal expansion of monocytes with mutations in epigenetic regulators
(clonal hematopoiesis of indeterminate potential; CHIP), which enhance cytokine
production, is associated with atherosclerosis. Based on these findings, we now
propose to test our hypothesis that inflammatory reprogramming of circulating
monocytes contributes to the development of AoS. Proof of this hypothesis will
have huge clinical implications and paves the road for clinical studies with
anti-inflammatory drugs in this patient group.
Study objective
To test the hypothesis that patients with AoS have a higher prevalence of CHIP
driving mutations compared to control subjects. Secondary objectives are to
perform extensive phenotyping of circulating monocytes.
Study design
This study is a single-center observational prospective case-control study.
Between May 2020 and May 2022.
Study burden and risks
There will be no risk, since participation will only include one venous blood
sample. Control subjects will also have a cardiac ultrasound, which is
non-invasive and does not impose any risk. Participants will not have any
direct benefit from participation.
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
- Age > 18 years
- Mild, moderate or Severe degenerative aortic valve stenosis as defined by
transthoracic echocardiography according to the 2017 ESC/EACTS guidelines for
the management of valvular heart disease.
- for the control group:
- 150 healthy subjects without aortic valve stenosis
- 50 subjects with aortic valve stenosis due to congenital biscuspid valve
Exclusion criteria
For patients and controls:
- Active auto-inflammatory or auto-immune diseases
- Anti-inflammatory drugs
- Vaccination less than one month before inclusion
- Bone marrow transplantation
- Active malignancy, except for local basal cell carcinoma or local squamous
cell skin carcinoma, that can be treated curatively by excision.
- History of endocarditis of the aortic valve
- History of radiation therapy aimed at the chest
- Acute ischemic cardiac event less than three months before inclusion
- Systemic inflammation less than one month before inclusion with fever and/or
for which antibiotics have been prescribed, with the exception for the use of
nitrofurantoin for a urinary tract infection without fever.
Extra exclusion for healthy control subjects:
- History of atherosclerotic cardiovascular events
- Current typical complaints of angina pectoris or intermittent claudication.
- Overt heart failure (NYHA class III/IV)
- Aortic valve stenosis on screenings echocardiography, that will be performed
before inclusion. Mild aortic valve sclerosis is allowed.
Extra exclusion for controls with aortic valve stenosis due to a bicuspid
valve:
- History of atherosclerotic cardiovascular events
- Current typical complaints of angina pectoris or intermittent claudication.
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 |
|---|---|
| ClinicalTrials.gov | NCT04717219 |
| CCMO | NL72973.091.20 |