Proliferative Immune Cells Associated With CAD

An exploratory proof-of-concept study in European Heart Journal identified a proliferative immune-cell signature associated with coronary artery disease (CAD) and short- and long-term cardiovascular outcomes independently of high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6).

The investigators performed a nested case-control analysis within the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, a prospective biomarker cohort of 3316 patients enrolled in Germany from 1997 to 2003. After quality-control exclusions, discovery analyses included 44 participants: 15 without CAD and 29 with CAD. The research combined bulk and single-cell RNA sequencing, T-cell receptor sequencing, cytokine testing, mass cytometry, spatial imaging, and clinical data. CAD-associated signals were evaluated in the independent Munich and Groningen cohorts, yielding a joint dataset of 136 patients.

Proliferating leukocytes were more abundant in CAD, whereas naive or intermediate B-cell and naive CD4+ and CD8+ T-cell populations were less abundant. Proliferating-cell abundance provided an area under the receiver operating characteristic curve (AUC) of 0.83 for discrimination of CAD status, compared with 0.63 for hsCRP. In logistic regression, proliferating-cell abundance was associated with CAD (odds ratio, 2.25; 95% confidence interval, 1.35-4.59) and remained consistent in models adjusting for clinical and inflammatory variables.

CAD-associated immune activity included T-cell activation, interferon signaling, memory formation, cytokine secretion, and clonal expansion. Effector-memory T-cell subsets showed greater hyperexpansion, reaching 9.4-fold in CCR6+ CD4+ effector-memory T cells. Mass cytometry and spatial imaging identified proliferating CD4+ T cells, CD8+ T cells, and natural killer cells in human carotid plaques.

The authors described the work as hypothesis-generating and cautioned that the 44-person primary analysis limited power and precision. The external cohorts did not provide comparable 20-year mortality validation. Long-term cryopreservation, residual confounding, and the observational, largely cross-sectional design remained limitations. They said larger prospective studies with long-term outcomes are needed to establish thresholds and incremental predictive value.

Source: Horstmann H, Michel NA, Losert C, et al. Immunological risk identified by single-cell multi-omics and cardiovascular outcomes. Eur Heart J. Published online August 14, 2026. doi:10.1093/eurheartj/ehag553