Association Between Change in Circulating Progenitor Cells During Exercise Stress and Risk of Adverse Cardiovascular Events in Patients With Coronary Artery Disease.

Importance: Stem and progenitor cells mobilize from the bone marrow in response to myocardial ischemia. However, the association between the change in circulating progenitor cell (CPC) counts and disease prognosis among patients with ischemia is unknown. Objective: To investigate the association between the change in CPC counts during stress testing and the risk of adverse cardiovascular events in patients with stable coronary artery disease (CAD). Design, Setting, and Participants: This prospective cohort study included a population-based sample of 454 patients with stable CAD who were recruited between June 1, 2011, and August 15, 2014, at Emory University-affiliated hospitals and followed up for 3 years. Data were analyzed from September 15, 2018, to October 15, 2018. Exposures: Myocardial perfusion imaging with technetium Tc 99m sestamibi at rest and 30 to 60 minutes after conventional stress testing. Main Outcomes and Measures: Circulating progenitor cells were enumerated with flow cytometry as CD34-expressing mononuclear cells (CD45med/CD34+), with additional quantification of subsets coexpressing the chemokine (C-X-C motif) receptor 4 (CD34+/CXCR4+). Changes in CPC counts were calculated as poststress minus resting CPC counts. Cox proportional hazards regression models were used to identify factors associated with the combined end point of cardiovascular death and myocardial infarction after adjusting for clinical covariates, including age, sex, race, smoking history, body mass index, and history of heart failure, hypertension, dyslipidemia, and diabetes.
Results: Of the 454 patients (mean [SD] age, 63 [9] years; 76% men) with stable CAD enrolled in the study, 142 (31.3%) had stress-induced ischemia and 312 (68.7%) did not, as measured by single-photon emission computed tomography. During stress testing, patients with stress-induced ischemia had a mean decrease of 20.2% (interquartile range [IQR], -45.3 to 5.5; P < .001) in their CD34+/CXCR4+ counts, and patients without stress-induced ischemia had a mean increase of 3.2% (IQR, -20.6 to 35.1; P < .001) in their CD34+/CXCR4+ counts. Twenty-four patients (5.2%) experienced adverse events. After adjustment, baseline CPC counts were associated with worse adverse outcomes, but this association was not present after stress-induced ischemia was included in the model. However, the change in CPC counts during exercise remained significantly associated with adverse events (hazard ratio, 2.59; 95% CI, 1.15-5.32, per 50% CD34+/CXCR4+ count decrease), even after adjustment for clinical variables and the presence of ischemia. The discrimination of risk factors associated with incident adverse events improved (increase in C statistic from 0.72 to 0.77; P = .003) with the addition of the change in CD34+/CXCR4+ counts to a model that included clinical characteristics, baseline CPC count, and ischemia. Conclusions and Relevance: In this study of patients with CAD, a decrease in CPC counts during exercise is associated with a worse disease prognosis compared with the presence of stress-induced myocardial ischemia. Further studies are needed to evaluate whether strategies to improve CPC responses during exercise stress will be associated with improvements in the prognosis of patients with CAD.