Expansion of CD4+CD28null T-lymphocytes in diabetic patients: exploring new pathogenetic mechanisms of increased cardiovascular risk in diabetes mellitus

Aims Diabetes mellitus (DM) is associated with high incidence of first and recurrent cardiovascular events, especially acute coronary syndromes (ACSs); however, the mechanisms involved are still unknown. We sought to investigate the role of CD4+CD28nullT-lymphocytes, a rare long-lived subset of T-lymphocytes with proatherogenic and plaque-destabilizing properties, in the increased cardiovascular risk associated with DM. Methods and results CD4+CD28nullT-cell frequency was analysed by flow-cytometry in 60 DM patients without overt cardiovascular disease (cDM), in 166 ACS patients with or without DM (ACS/DM+, n= 51 and ACS/DM−, n= 115), and in 60 healthy individuals. The incidence of cardiovascular events (death, myocardial infarction, unstable angina) was assessed at 36 months follow-up. CD4+CD28nullT-cell frequency (median, range) was higher in ACS/DM+ (12.7%, 0.1–48) vs. ACS/DM− (3.9%, 0.2–35), cDM (3.1%, 0.3–22.4), and controls (1.5%, 0.1–9.1) (P< 0.001 for all comparisons). Notably, cDM patients had significantly higher CD4+CD28nullT-cell frequency than controls (P= 0.001). Glycosylated haemoglobin A1c was the only parameter independently associated with CD4+CD28nullT-cells in cDM. The 36-month event-free survival was significantly lower in cDM patients with CD4+CD28nullT-cells ≥4% (90th percentile of normal distribution) than in those with CD4+CD28nullT-cells <4% (P= 0.039). Among ACS patients, the 36-month event-free survival was the lowest in those with DM and CD4+CD28nullT-cells ≥4% and highest in those without DM and CD4+CD28nullT-cells <4% (P< 0.001), being intermediate in those with only one of these features. Conclusions In DM patients, CD4+CD28nullT-cells are expanded and are associated with poor glycaemic control; they also correlate with the occurrence of a first cardiovascular event and with a worse outcome after an ACS.