Effect of Statins on Trained Immunity

Study Overview
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Brief Summary
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In this study, the investigators will determine whether patients with elevated levels of LDL are characterized by specific epigenetic changes in circulating cells of the innate immune system, compared to control subjects with healthy levels of LDL and whether regular statin treatment influences these changes.

Detailed Description
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Rationale: The innate immune system plays a pivotal role in the development and progression of atherosclerosis. Recently, it was reported that monocytes can develop a long-lasting immunological memory after stimulation with various microorganisms, which has been termed 'trained innate immunity'. This memory is induced by epigenetic reprogramming. Here the investigators hypothesize that monocytes of patients with elevated LDL cholesterol levels show epigenetic changes compared to normocholesterolemic subjects and that this can be reversed by treatment with statins. Objective: The main objective is to study whether patients with elevated levels of LDL show increased Histone 3 Lysine 4 trimethylation in the promoter regions of pro-inflammatory cytokines and have an augmented ex vivo Toll-Like Receptor agonist-induced cytokine production in isolated monocytes compared to controls. Subsequently the investigators will study the effect of treatment with statins on these responses. Study design: Observational study Study population: Subjects aged >18 years who have been referred to the out-patient clinic and have LDL levels that require lipid lowering treatment and matched normocholesterolemic control subjects.

Official Title
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Effect of Statins on Epigenetic Reprogramming of Monocytes in Patients With Elevated Levels of LDL

Conditions
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Atherosclerosis

Intervention / Treatment
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* Drug: Statin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients: 18 years or older Elevated LDL levels (>4.9 mmol/l) No previous cardiovascular events Controls: Age > 18 years LDL cholesterol < 3.5 mmol/l No previous cardiovascular events Exclusion Criteria: Current lipid lowering treatment Known malignant disorders, auto-immune disorder, or diabetes Inability or unwillingness to comply with the protocol requirements, or deemed by investigator to be unfit for the study Clinical signs of acute infection Use of anti-inflammatory medication

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients<br>Patients referred to the out-patient clinic with LDL levels >4.9 mmol/l | Drug: Statin<br> <br> |
| Controls<br>Matched normocholesterolemic control subjects | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in histone methylation levels in circulating monocytes | Histone methylation levels on different lysines of histone 3 will be analyzed at baseline and after 3 months of statin treatment | Baseline-3 months follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inflammatory phenotype |  | Baseline-3 months follow up |