CHIP in Endothelial Dysfunction Associated With HEpEF

Study Overview
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Brief Summary
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This study aims at identifying processes that are deregulated in blood cells by Clonal Hematopoiesis of Indeterminate Potential (CHIP) which are involved in the development of heart failure with preserved ejection fraction (HEpEF).

Detailed Description
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Heart failure is responsible of 70,000 deaths every year in France. Heart failure can be divided into 2 categories depend on whether the ejection fraction is reduced (HFrEF) or preserved (HFpEF). Most of the treatments efficient in HFrEF are unable to prevent decompensating or reduce mortality associated with HFpEF. HFpEF pathophysiology remains poorly understood, which represents an obstacle to their management and to reduce cardiovascular events they are associated with. Currently, it is admitted that cardiovascular risk factors (CVRF such as aging, female gender, diabetes mellitus, high blood pressure, hypercholesterolemia, obesity) are responsible of a low grade chronic inflammatory state that causes an endothelial dysfunction that contributes to the development of HFpEF. However, not all patients with these CVRF develop HFpEF. Moreover, the mechanisms linking CVRF to inflammation or alteration of cardiomyocyte function by endothelial dysfunction remain unknown. This suggests that it exists a role for another factor that remains to be identified. Clonal Hematopoiesis of Indeterminate Potential (CHIP) result from the acquisition in hematopoietic stem cells of mutations associated with hematological malignancies, in the absence of any hematological disease. This situation initially described with a frequency of <5% before 60 years and >20% after 80 years old appears to be more frequent (>40% of people over 65 years). CHIP are mainly associated with the occurrence of cardiovascular events such as atherothrombosis and heart failure, possibly due to the induction of a chronic inflammation. Because CHIP are very frequent in the elderly and because CHIP are associated with inflammation and cardiovascular events, they could represent the missing link in the pathophysiology sequence that leads to the appearance of endothelial dysfunction and HFpEF development.

Official Title
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Role of Clonal Hematopoiesis of Indeterminate Potential in Endothelial Dysfunction Associated With Heart Failure With Preserved Ejection Fraction

Conditions
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Heart Failure With Preserved Ejection Fraction

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HFpEF group and control group male or female 50 ≤ age ≤ 85 ans Absence of evidence of hematological malignancy (known or obvious by the results of blood counts) Subject registered with a social security scheme Written informed consent obtained HFpEF group patients with a diagnosis of HFpEF according to the criteria defined by the European society of cardiology Control group patients with a neuro-cardiovascular pathology without any link to coronaropathy nor heart failure Exclusion Criteria: Hematological malignancy (known or obvious on the results of blood counts) Chronic inflammatory disease (cancer, vasculitis, rheumatism, hepato-gastro-intestinal diseases) Long term anti-inflammatory treatments: Corticoids Nonsteroidal anti-inflammatory drugs Aspirin (> 325 mg per day) Cyclo-oxygenase II inhibitors Persons under judicial safeguards, trustee or curatorship Person deprived of judicial or administrative freedom Person unable to give her consent Non-cooperative person Exclusion period after another clinical study or participation to another interventional clinical study testing a drug in the 30 days before inclusion

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence of clonal hematopoiesis indeterminate potential (CHIP) | Presence of CHIP defined as the presence of a mutation with an allele frequency greater than 2%. | Inclusion Visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnosis of heart failure with preserved ejection fraction | Diagnosis based on the European Society of Cardiology diagnostic sequence | Inclusion Visit | 
| scRNA-seq analysis | Sixteen patients will be selected for scRNA-seq analysis: 3 patients with HFpEF and TET2 mutation 3 patients with HFpEF and DNMT3A mutation 2 patients with HFpEF but without CHIP 3 patients with TET2 mutation but without HFpEF 3 patients with DNMT3A mutation but without HFpEF 2 patients without HFpEF nor CHIP | 6 months (+/- 3 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clonal Hematopoiesis of Indeterminate Potential (CHIP), Cardiovascular events, Heart Failure, Inflammation, Endothelial dysfunction