CHiEF: CHIP in Endothelial Dysfunction Associated With HEpEF

Sponsor

University Hospital, Bordeaux (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05828888

Collaborator

INSERM - UMR 1219 (Other)

Enrollment

33.1

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Heart Failure With Preserved Ejection Fraction

Detailed Description

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.

Study Design

Study Type:

Observational

Anticipated Enrollment :

80 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

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

Anticipated Study Start Date :

May 1, 2023

Anticipated Primary Completion Date :

May 1, 2025

Anticipated Study Completion Date :

Feb 1, 2026

Outcome Measures

Primary Outcome Measures

Presence of clonal hematopoiesis indeterminate potential (CHIP) [Inclusion Visit]
Presence of CHIP defined as the presence of a mutation with an allele frequency greater than 2%.

Secondary Outcome Measures

Diagnosis of heart failure with preserved ejection fraction [Inclusion Visit]
Diagnosis based on the European Society of Cardiology diagnostic sequence
scRNA-seq analysis [6 months (+/- 3 months)]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

50 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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