Low Levels of CD4 + CD28 null T Cells at Baseline Are Associated With First-Time Coronary Events in a Prospective Population-Based Case-Control Cohort

Objective: CD4+ CD28null T cells have been shown to be associated with recurrent coronary events and suggested as potential biomarker and therapeutic target. It is unknown whether CD4+ CD28null T cells associate with first-time cardiovascular events. We examined CD4+ CD28null T cells in a prospective population-based cohort and in patients with advanced atherosclerosis.Approach and Results: CD4+ CD28null T cells were quantified in 272 individuals experiencing a first-time coronary event during up to 17 years of follow-up and 272 age- and sex-matched controls in a case-control study, nested within the population-based Malmö Diet and Cancer study. The highest tertile of CD4+ CD28null T cells was associated with a lower incidence of first-time coronary events compared with the lowest tertile (odds ratio, 0.48 [95% CI, 0.29–0.79],P =0.004) when adjusting for Framingham risk factors. This association remained significant for events recorded after >9 years of follow-up, when most coronary events occurred, but not during the first 9 years of follow-up, despite similar odds ratio. Additionally, we analyzed CD4+ CD28null T cells in 201 patients with advanced atherosclerosis undergoing carotid endarterectomy. The adjusted hazard ratio for cardiovascular events in patients with advanced atherosclerosis was 2.11 (95% CI, 1.10–4.05,P =0.024), comparing the highest with the lowest CD4+ CD28null T-cell tertile.Conclusions: Our findings reveal complex associations between CD4+ CD28null T cells and cardiovascular disease. Although we confirm the reported positive associations with an adverse prognosis in patients with already established disease, the opposite associations with first-time coronary events in the population-based cohort may limit the clinical use of CD4+ CD28null T cells.