PB0042 - Clonal hematopoiesis of indeterminate potential is associated with increased NETosis in patients with myocardial infarction

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

MD

Mélody Dufossée

PhD student
INSERM U1034 Biology of cardiovascular diseases
Pessac, Aquitaine, France

Co-Author(s)

SM

Séverine Marti

PharmD
Bordeaux University Hospital, Hematology Laboratory
Pessac, Aquitaine, France
SC

Sylvie Colomer-Labrouche

PharmD, PhD
Bordeaux University Hospital, Hematology Laboratory
Pessac, Aquitaine, France
SF

Sami Fawaz

MD
Bordeaux University Hospital, Coronary Diseases Service
Pessac, Aquitaine, France
GG

Geoffrey Garcia

PharmD
Bordeaux University, Inserm, UMR1034, Biology of Cardiovascular Diseases
Pessac, Aquitaine, France
YP

Yann Pucheu

MD
Bordeaux University Hospital, Coronary Diseases Service
Pessac, Aquitaine, France
David-Alexandre Trégouët

Senior Investigator
Bordeaux Population Health research Center, Inserm U1219, Bordeaux University
Bordeaux, Aquitaine, France
TC

Thierry Couffinhal

MD, PhD
Bordeaux University, Inserm, UMR1034, Biology of Cardiovascular Diseases
Pessac, Aquitaine, France
Chloe James, MD PhD

Professor
University of Bordeaux, France
OM

Olivier Mansier

PharmD, PhD
Bordeaux University, Inserm, UMR1034, Biology of Cardiovascular Diseases
Pessac, Aquitaine, France

Background: In recent years, Clonal Hematopoiesis of Indeterminate Potential (CHIP) has been associated with increased mortality, particularly consecutive to cardiovascular events (CVE). Most studies focused on the role of pro-inflammatory mutated monocytes/macrophages. However, CHIP mutations are also found in neutrophils which can infiltrate atherosclerotic plaques and contribute to thrombo-inflammatory processes, via release of Neutrophil Extracellular Traps (NETs).

Aims: To investigate whether mutated neutrophils contribute to the pathophysiology of CVE through NETs emission.

Methods: Examining 81 patients with myocardial infarction (MI) from the CHAth study (NCT04581057), the presence of CHIP was determined by sequencing 56 leukemia-associated genes and detecting at least one mutation with a variant allele frequency ≥2%. Inflammation was assessed by hsCRP levels, and atheromatous burden was evaluated through detection of carotid stenosis >50%, multi-truncal lesions, and global atheroma volume measured by 3D ultrasonography. Plasmatic NETs markers (myeloperoxidase-DNA complex (MPO-DNA) and citrullinated histone H3 (H3-Cit)) were measured by ELISA.

Results: CHIP prevalence was 54%, with DNMT3A (50%) and TET2 (39%) being the most frequently mutated genes. CHIP presence was associated with increased MPO-DNA (3.1 vs 2.5%, p=0.004) and H3-Cit (0.19 vs 0.15, p=0.038) levels. Neither CHIP presence nor increased NETs biomarkers, alone or combined, showed associations with increased inflammation, atheromatous burden, or post-MI complications.

Conclusion(s): This study reveals, for the first time, a connection between CHIP and increased plasmatic NETs levels in MI patients, suggesting a potential role of CHIP in favoring NETosis. Nevertheless, in the context of recent MI, CHIP and NETs do not appear to be linked to systemic inflammation, increased atherosclerosis, or an increased risk of post-MI complications. Further analysis on larger cohort is necessary to confirm the involvement of NETs in CVE occurrence in the presence of CHIP. Ongoing investigations in DNMT3A-flox and TET2-flox CHIP mouse models will provide additional insights about the causal role of CHIP in inducing NETosis.