THE ASSOCIATION OF CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL WITH CHRONIC ISCHEMIC HEART FAILURE

Abstract

Cardiovascular diseases (CVD) are one of the leading causes of death. Beside established risk factors, clonal hematopoiesis of indeterminate potential (CHIP) is associated with a higher risk of CVD. CHIP is defined as the expansion of a blood cell clone by somatic mutations in individuals without hematologic diseases. Our studies focused on the questions, whether there is a different disease progression in chronic ischemic heart failure (CHF) patients with CHIP and what the consequences on blood cell lineages and hematopoietic stem and progenitor cells (HSPC) are. Therefore, we investigated a clinically well-characterized cohort of CHF patients and correlated disease progression with CHIP-mutations and investigated alterations of peripheral blood (PB) and bone marrow (BM) cells. The most recurrent mutations occurred in DNMT3A and TET2, which both epigenetically control gene expression and regulate inflammation. We demonstrated a significant association of poor prognosis in CHF and CHIP-mutations in these genes. They may causally contribute to disease progression since there was a striking dose-response between the variant allele fraction and clinical outcome. By analyzing PB and BM in CHF patients, we detected an increase of HSPCs and BM leukocyte numbers without a bias in the distribution of leukocyte lineages in the BM of CHIP carriers. In patients harboring TET2 mutations. Surprisingly, we did not determine any alterations in HSPCs in patients with a DNMT3A mutation, which contrasts the results in knock-out mouse models, showing an increased stem cell self-renewal. Whether non-mutated HSPCs are also affected in individuals with TET2 mutations in a paracrine, cell-extrinsic fashion, caused by an inflammatory milieu due to altered cytokine production, requires further investigation.