Migratory activity of circulating mononuclear cells is associated with cardiovascular mortality in type 2 diabetic patients with critical limb ischemia

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.

RESEARCH DESIGN AND 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.