Long-term Prediction of Cardiovascular Outcomes by Circulating CD34+ and CD34+ CD133+ Stem Cells in Patients With Type 2 Diabetes

OBJECTIVE Cardiovascular risk varies substantially in the population with diabetes, and biomarkers can improve risk stratification. Circulating stem cells predict future cardiovascular events and death, but data for the population with diabetes are scant. In this study we evaluated the ability of circulating stem cell levels to predict future cardiovascular outcomes and improve risk discrimination in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A cohort of 187 patients with type 2 diabetes was monitored for a median of 6.1 years. The primary outcome was time to a first cardiovascular event, defined as 3-point major adverse cardiovascular event (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) plus hospitalization for cardiovascular causes. At baseline, we measured six stem/progenitor cell phenotypes in peripheral blood based on expression of CD34, CD133, and KDR. RESULTS The primary outcome occurred in 48 patients (4.5/100 patient-years). Patients with incident cardiovascular events had significantly lower CD34(+) and CD34(+) CD133(+) cells than those without. Higher rates of cardiovascular events occurred in patients with below median levels of CD34(+) and CD34(+) CD133(+). In Cox proportional hazards regression analyses, a reduced CD34(+) (hazard ratio 2.21 [95% CI 1.14-4.29]) and CD34(+) CD133(+) (2.98 [1.46-6.08]) cell count independently predicted future events. Addition of the CD34(+) cell count to the reference model or the UK Prospective Diabetes Study risk engine improved C statistics, continuous net reclassification improvement, and/or integrated discrimination index. CONCLUSIONS In patients with type 2 diabetes, a reduced baseline level of circulating CD34(+) stem cells predicts adverse cardiovascular outcomes up to 6 years later and improves risk stratification.