Clonal hematopoiesis activates pro-calcific pathways in macrophages and promotes aortic valve stenosis.

Summary

Across large biobanks, clonal hematopoiesis, especially with TET2 or ASXL1 mutations, was associated with increased aortic valve stenosis risk. Mechanistically, TET2-deficient macrophages exhibited pro-inflammatory, pro-calcific programs and secreted oncostatin M that drove calcification in vitro; Tet2−/− marrow transfer augmented valve calcification in mice.

Key Findings

• CHIP increased AVS risk across All Of Us, BioVU, and UK Biobank, with stronger associations for TET2/ASXL1 mutations.
• scRNA-seq identified monocyte/macrophage pro-inflammatory, pro-calcific signatures with elevated oncostatin M in TET2-CH AVS patients.
• Conditioned media from TET2-silenced macrophages enhanced in vitro mesenchymal cell calcification, reversed by OSM silencing.
• Ldlr−/− mice receiving Tet2−/− bone marrow exhibited increased aortic valve calcium deposition.

Clinical Implications

Patients with CHIP, particularly TET2/ASXL1 mutations, may merit enhanced surveillance for aortic valve disease; macrophage-OSM axis inhibition could be explored as a disease-modifying strategy.

Limitations

• Observational human associations cannot fully exclude residual confounding.
• Human tissue and cellular experiments may have limited generalizability; precise sample sizes for each mechanistic arm were not detailed.

Future Directions

Prospective studies to evaluate CHIP-informed surveillance for AVS and interventional studies targeting the OSM pathway or CH clones to slow valve calcification.