Blood Stem Cell Mutations Accelerate Aortic Valve Calcification via Inflammatory Macrophages

Calcific aortic valve disease affects 2–7% of adults over 65 and has no approved medical therapy to halt its progression. Understanding what drives valve calcification is therefore a pressing clinical need. This study investigates whether clonal hematopoiesis (CH) — the age-associated expansion of hematopoietic stem cell clones carrying somatic driver mutations — contributes to aortic valve stenosis (AVS) risk and pathogenesis.

The researchers first performed a meta-analysis across three large biobanks: All of Us (n=275,679), BioVU (n=160,012), and the UK Biobank (n=450,687), together identifying 35,311 CHIP carriers (~3.9% of participants). After full covariate adjustment, CHIP was associated with a 38% increased risk of AVS (HR=1.38, P=1.5×10⁻⁷). Gene-specific analyses showed TET2 mutations conferred a 44% increased risk (HR=1.44) and ASXL1 mutations a 52% increased risk (HR=1.52), while DNMT3A mutations showed a more modest association (HR=1.20).

To explore mechanism, the team performed single-cell RNA sequencing on PBMCs from AVS patients with and without TET2 CH driver mutations. Unsupervised clustering identified six immune cell types with no significant shifts in composition between groups. However, monocytes from TET2-mutant patients showed markedly elevated expression of an osteogenic paracrine signaling module — a composite score of known calcification mediators. TET2-mutant monocytes upregulated 4,320 genes compared with non-CH monocytes, with pathway analyses highlighting inflammatory and procalcific signaling. The most prominent upregulated secreted factor was oncostatin M (OSM), a cytokine in the IL-6 family known to promote osteogenic differentiation.

Functional validation demonstrated that conditioned media from TET2-silenced macrophages significantly increased calcium deposition by mesenchymal cells in vitro. Critically, silencing OSM in these macrophages abolished the procalcific effect, identifying OSM as a key effector. In vivo, atherosclerosis-prone Ldlr−/− mice receiving Tet2−/− bone marrow transplants — a model mimicking CH — showed significantly greater calcium deposition in aortic valves compared with mice receiving wild-type bone marrow, confirming the pathogenic role of CH-mutant immune cells in valve calcification.

Together, these findings establish CH as a novel risk factor for AVS and reveal a mechanistic pathway whereby TET2-mutant monocytes and macrophages secrete procalcific factors, particularly OSM, that drive aortic valve calcification. This positions OSM and downstream inflammatory pathways as potential therapeutic targets in CHIP-positive patients at elevated AVS risk, and suggests that CH screening could help stratify cardiovascular risk beyond existing metrics.