Eur Heart J. 2026 Oct 20:ehag810. doi: 10.1093/eurheartj/ehag810. Online ahead of print.
ABSTRACT
BACKGROUND AND AIMS: Lifelong exposure to elevated low-density lipoprotein cholesterol in familial hypercholesterolaemia (FH) patients not only increases the risk of atherosclerotic cardiovascular disease, but also affects other organs beyond the cardiovascular system. In a large FH cohort, this study investigated the effects of hypercholesterolaemia on the thymic output and explored whether lipid-lowering therapy can reverse these effects.
METHODS: According to the Dutch Lipid Clinic Network criteria, 562 heterozygous FH patients (236 treatment-naïve, 326 on lipid-lowering therapy) and 295 age-matched healthy controls (HCs) were enrolled. Thymic output was measured by circulating CD4+ recent thymic emigrants (RTEs) with flow cytometry, and T-cell receptor excision circles in sorted naïve CD4+ and CD8+ T cells. Repertoire diversity and clonal expansion were evaluated by T-cell receptor beta sequencing.
RESULTS: Compared with HCs, treatment-naïve FH patients displayed a significantly reduced percentage of CD4+ RTE among naïve CD4+ T cells, particularly in those aged 18-30 years or carrying highly pathogenic LDLR variants. T-cell receptor excision circle analysis supported reduced thymic output in both CD4+ and CD8+ naïve T cells. Quantified thymic ageing further showed that FH patients reached the median CD4+ RTE percentage of HCs ∼6 years earlier (males: 19.12 vs 25.51 years; females: 19.18 vs 25.58 years). Consistent with reduced thymic output, FH patients showed skewing towards high-frequency T-cell receptor beta clones. Statin-treated FH patients, particularly females, showed higher circulating CD4+ RTE levels than statin-naïve FH patients.
CONCLUSIONS: Hypercholesterolaemia was associated with reduced thymic output, while statin-treated patients showed partially preserved circulating CD4+ RTE levels, supporting integrated metabolic and immunologic strategies for FH management.
PMID:42900678 | DOI:10.1093/eurheartj/ehag810