Logo of the Cardio Pulmonary Institute (CPI)
Reimer Köster
Paper of the Month: October 2023

Cell-intrinsic effects of clonal hematopoiesis in heart failure

Nat Cardiovasc Res
Abplanalp WT, Schuhmacher B, Cremer S, Merten M, Shumliakivska M, Macinkovic I, Zeiher AM, John D & Dimmeler S

Circulating blood cells are recruited to the heart after myocardial infarction. DNMT3A mutant macrophages promote pro-inflammatory activation of wild-type macrophages (macrophage–macrophage axis) and effector differentiation of CD4+ T cells (macrophage–CD4+ T cell axis). DNMT3Amutant NK cells produce elevated levels of pro-inflammatory cytokines and show increased cytotoxic capacity. Both intrinsic activation of immune cells by DNMT3A mutations and indirect activation of wild-type cells by DNMT3A mutant macrophages promote progression of inflammation causing hypertophy and fibrosis, finally resulting in cardiac dysfunction.

Clonal hematopoiesis of indeterminate potential (CHIP) is caused by somatic mutations in hematopoietic stem cells and associates with worse prognosis in patients with heart failure. Patients harboring CHIP mutations show enhanced inflammation. However, whether these signatures are derived from the relatively low number of cells harboring mutations or are indicators of systemic pro-inflammatory activation that is associated with CHIP is unclear. Here we assess the cell-intrinsic effects of CHIP mutant cells in patients with heart failure. Using an improved single-cell sequencing pipeline (MutDetect-Seq), we show that DNMT3Amutant monocytes, CD4+ T cells and NK cells exhibit altered gene expression profiles. While monocytes showed increased genes associated with inflammation and phagocytosis, T cells and NK cells present increased activation signatures and effector functions. Increased paracrine signaling pathways are predicted and validated between mutant and wild-type monocytes and T cells, which amplify inflammatory circuits. Altogether, these data provide novel insights into how CHIP might promote a worse prognosis in patients with heart failure.

→ Overview "Paper of the Month"
CPI News
Academy News