title: Migratory activity of circulating mononuclear cells is associated with cardiovascular mortality in type 2 diabetic patients with critical limb ischemia.
abstract: OBJECTIVE
  Prediction of clinical outcome in diabetic patients with critical limb ischemia (CLI) is unsatisfactory. This prospective study investigates if the abundance and migratory activity of a subpopulation of circulating mononuclear cells, namely, CD45(dim)CD34(pos)CXCR4(pos)KDR(pos) cells, predict major amputation and cardiovascular death in type 2 diabetic patients undergoing percutaneous transluminal angioplasty for CLI.
  
  
  METHODS
  A consecutive series of 119 type 2 diabetic patients with CLI was enrolled. CD45(dim)CD34(pos)CXCR4(pos)KDR(pos) cells were assessed by flow cytometry upon isolation and also after spontaneous or stromal cell-derived factor 1α-directed migration in an in vitro assay. The association between basal cell counts and migratory activity and the risk of an event at 18-month follow-up was evaluated in a multivariable regression analysis.
  
  
  RESULTS
  Time-to-event analysis of amputation (n = 13) showed no association with the candidate predictors. Sixteen cardiovascular deaths occurred during 18 months of follow-up. Abundance of CD45(dim)CD34(pos)CXCR4(pos)KDR(pos) cells was not associated with cardiovascular mortality. Interestingly, in vitro migration of CD45(dim)CD34(pos)CXCR4(pos)KDR(pos) cells was higher in patients with cardiovascular death compared with event-free subjects (percentage of migrated cells median value and interquartile range, 0.03 [0.02-0.07] vs. 0.01 [0.01-0.03]; P = 0.0095). Multivariable regression model analysis showed that cell migration forecasts cardiovascular mortality independently of other validated predictors, such as age, diagnosed coronary artery disease, serum C-reactive protein, and estimated glomerular filtration rate. In this model, doubling of migrated cell counts increases the cardiovascular death hazard by 100% (P < 0.0001).
  
  
  CONCLUSIONS
  The new predictor could aid in the identification of high-risk patients with type 2 diabetes requiring special diagnostic and therapeutic care after revascularization.
authors.affiliation: Corresponding author: Paolo Madeddu, paolo.madeddu@bristol.ac.uk.
authors.forename: Gaia
authors.initials: G
authors.lastname: Spinetti
authors.forename: Claudia
authors.initials: C
authors.lastname: Specchia
authors.forename: Orazio
authors.initials: O
authors.lastname: Fortunato
authors.forename: Elena
authors.initials: E
authors.lastname: Sangalli
authors.forename: Giacomo
authors.initials: G
authors.lastname: Clerici
authors.forename: Maurizio
authors.initials: M
authors.lastname: Caminiti
authors.forename: Flavio
authors.initials: F
authors.lastname: Airoldi
authors.forename: Sergio
authors.initials: S
authors.lastname: Losa
authors.forename: Costanza
authors.initials: C
authors.lastname: Emanueli
authors.forename: Ezio
authors.initials: E
authors.lastname: Faglia
authors.forename: Paolo
authors.initials: P
authors.lastname: Madeddu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000671:Amputation, Surgical; D002097:C-Reactive Protein / Q000032:analysis; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000494:pharmacology; D003324:Coronary Artery Disease / Q000209:etiology / Q000401:mortality; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000401:mortality*; D017719:Diabetic Foot / Q000401:mortality* / Q000601:surgery; D005260:Female; D005528:Foot / Q000098:blood supply* / Q000601:surgery; D006801:Humans; D007511:Ischemia / Q000401:mortality* / Q000601:surgery; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D019718:Receptors, CXCR4 / Q000032:analysis
chemical_list: D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D002097:C-Reactive Protein