title: Expansion of CD4+CD28null T-lymphocytes in diabetic patients: exploring new pathogenetic mechanisms of increased cardiovascular risk in diabetes mellitus.
abstract: OBJECTIVE
  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(+)CD28(null)T-lymphocytes, a rare long-lived subset of T-lymphocytes with proatherogenic and plaque-destabilizing properties, in the increased cardiovascular risk associated with DM.
  
  
  RESULTS
  CD4(+)CD28(null)T-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+CD28(null)T-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+CD28(null)T-cell frequency than controls (P= 0.001). Glycosylated haemoglobin A(1c) was the only parameter independently associated with CD4+CD28(null)T-cells in cDM. The 36-month event-free survival was significantly lower in cDM patients with CD4+CD28(null)T-cells ≥4% (90th percentile of normal distribution) than in those with CD4+CD28(null)T-cells <4% (P= 0.039). Among ACS patients, the 36-month event-free survival was the lowest in those with DM and CD4+CD28(null)T-cells ≥4% and highest in those without DM and CD4+CD28(null)T-cells <4% (P< 0.001), being intermediate in those with only one of these features.
  
  
  CONCLUSIONS
  In DM patients, CD4+CD28(null)T-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.
authors.affiliation: Institute of Cardiology, Catholic University, Largo A. Gemelli, Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Giubilato
authors.forename: Giovanna
authors.initials: G
authors.lastname: Liuzzo
authors.forename: Salvatore
authors.initials: S
authors.lastname: Brugaletta
authors.forename: Dario
authors.initials: D
authors.lastname: Pitocco
authors.forename: Francesca
authors.initials: F
authors.lastname: Graziani
authors.forename: Costantino
authors.initials: C
authors.lastname: Smaldone
authors.forename: Rocco Antonio
authors.initials: RA
authors.lastname: Montone
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pazzano
authors.forename: Daniela
authors.initials: D
authors.lastname: Pedicino
authors.forename: Luigi Marzio
authors.initials: LM
authors.lastname: Biasucci
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ghirlanda
authors.forename: Filippo
authors.initials: F
authors.lastname: Crea
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy / Q000276:immunology*; D000367:Age Factors; D000368:Aged; D000704:Analysis of Variance; D018106:CD28 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000276:immunology*; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000276:immunology*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D008215:Lymphocytes, Null / Q000502:physiology; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D016176:T-Lymphocyte Subsets / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D018106:CD28 Antigens; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors