Clonal hematopoiesis activates procalcific pathways in macrophages and promotes aortic valve stenosis.

Abstract

Clonal hematopoiesis (CH) due to Tet methylcytosine dioxygenase 2 (TET2) driver mutations is associated with coronary heart disease and a worse prognosis for patients with aortic valve stenosis (AVS). However, it is unknown what role CH plays in the pathogenesis of AVS. In a meta-analysis of All of Us, BioVU, and the UK Biobank, patients with clonal hematopoiesis of indeterminate potential (CHIP) had an increased risk of AVS, with a higher risk among patients with TET2 or ASXL1 mutations. Single-cell RNA-Seq of immune cells from patients with AVS harboring TET2 CH driver mutations revealed monocytes with heightened proinflammatory signatures and increased expression of procalcific paracrine signaling factors, most notably oncostatin M (OSM). Secreted factors from TET2-silenced macrophages increased in vitro calcium deposition by mesenchymal cells, which was ablated by OSM silencing. Atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr-/-) mice receiving CH-mimicking Tet2-/- bone marrow transplants displayed greater calcium deposition in aortic valves. Together, these results demonstrate that monocytes with CH promote aortic valve calcification and that patients with CH are at increased risk of AVS.