Clonal hematopoiesis of indeterminate potential: A cardiovascular risk factor among others

Clonal hematopoiesis of indeterminate potential (CHIP) are defined by the detection of leukemia-associated somatic mutations in leukocytes of healthy subjects. CHIP are associated with increased risk of cardiovascular event (CVE) related to atherothrombosis (myocardial infarction MI, stroke) independently of traditional cardiovascular risk factors (CVRF). We aim to demonstrate that CHIP increase the risk of occurence of CVE related to atherothrombosis and to determine the mecanisms by which CHIP interact with CVRF to lead to these CVE. The french multi-centric 3 C cohort includes thousands of randomly selected subjects over 65 without history of CVE and who have benefited of cardiological monitoring with 12 years follow-up. We selected 289 subjects (142 suffered from CVE and 147 control without CVE during follow-up) for wich we have biological and clinical data and performed next generation sequencing (NGS) to detect presence of CHIP. We then evaluated global cardiovascular risk using AHA life's simple 7 and defined it as favorable if patient had at least 3 optimum items. Finally, we studied association between presence of CHIP, cardiovascular and inflammatory profile at inclusion, and incidence of CVE (MI or angina). CHIP were detected in 41% of subjects and mainly concerned mutations of DNMT3A (46%) and TET2 (30%) genes. Patients with CHIP were older than ones with no CHIP (P = 0.03) but without increased CRP levels (1.66 vs. 1.75 mg/L respectively). We did not observe any difference between patients with or without CHIP regarding atheroma burden or prevalence of CVRF. However, patients with CHIP had more frequently low cardiovascular risk (68.2% vs. 55.3%, P = 0.042). During follow-up, 79 patients developed a MI and 73 an angina. Presence of CHIP did not impact frequency nor onset time of CVE. Yet, among patients who suffered from CVE, patients with CHIP had more frequently low cardiovascular risk (P = 0.0013 for angina ± MI, P = 0.01 for MI only). In a population without history of CVE, presence of CHIP is not associated with increased inflammation nor increased atheroma burden. CHIP alone do not induce major increase of atherothrombosis-linked CVE incidence. However, CHIP seem to interact with conventional CVRF to induce CVE, either through synergic effect, or by replacing particular factors.