Summary
A medRxiv preprint links ASXL1-mutant clonal haematopoiesis with aortic stenosis in human cohorts and reports enhanced calcification in a cultured-cell model. In laboratory experiments, blocking IL-1 or IL-6 reduced calcification.
A medRxiv preprint reports that clonal haematopoiesis involving the gene ASXL1 is associated with aortic stenosis and worse aortic-valve hemodynamics. The researchers also found that ASXL1-mutant macrophage-like cells promoted calcification in cultured human valve cells, and that inhibiting IL-1 or IL-6 reduced that response. The findings combine human cohort analyses with cell experiments; they point to inflammatory pathways for further study, rather than establishing a treatment for patients.
Calcific aortic valve disease (CAVD) involves calcium build-up in the valve and can lead to aortic stenosis, in which the valve narrows. The preprint describes CAVD as having no effective medical therapy. Clonal haematopoiesis of indeterminate potential (CHIP) occurs when a blood-forming stem cell acquires a mutation that gives it a growth advantage, allowing its descendants to form a clone.
What the cohort analyses found
In the UK Biobank, the researchers analysed whole-exome sequencing data from 449,109 people. Large CHIP clones and several CHIP subtypes not driven by DNMT3A—including TET2, ASXL1 and JAK2—were independently associated with the risk of developing aortic stenosis.
A second analysis used CHIP sequencing and echocardiographic data from 1,963 participants in the Atherosclerosis Risk in Communities study. Among the subtypes assessed, ASXL1 CHIP was the one associated with worse aortic-valve hemodynamics. Together, the cohort findings helped the researchers prioritise ASXL1 for laboratory investigation. The different results across the two analyses also make gene-specific effects an important part of the question: CHIP subtypes need not have identical associations with valve disease.
Cell experiments point to inflammatory signals
The researchers generated ASXL1-mutant, human THP-1-derived macrophage-like cells and tested their conditioned media—the mixture of substances released by the cells—on human valvular interstitial cells (VICs), which are cells found in heart valves. The media promoted VIC calcification, and the response was stronger when the macrophage-like cells carried the ASXL1 mutation. The mutant cells also showed increased activation of the AIM2 inflammasome, an inflammatory signalling system.
Proteomic analysis of the cells’ secreted proteins identified inflammatory proteins linked to valve calcification. In the cell model, treatment with anakinra to inhibit IL-1 signalling or tocilizumab to inhibit IL-6 signalling reduced the accelerated calcification. These results connect the cell experiments to candidate inflammatory pathways, but the interventions were tested in cultured cells, not as treatments in people with CAVD.
How to interpret the findings
The study’s central contribution is the combination of gene-specific associations in human cohorts with experiments suggesting a possible mechanism for ASXL1-mutant CHIP. The UK Biobank analysis relates CHIP to incident aortic stenosis, while the cell work tests how mutant macrophage-like cells may influence valve-cell calcification. The cohort evidence is observational; the experiments model cellular processes rather than the course of valve disease in patients.
The report is a medRxiv preprint. Its findings make IL-1 and IL-6 signalling candidates for future investigation in CAVD, but do not establish that inhibiting either pathway prevents or treats aortic-valve disease in people.