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

Abstract

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 PARTICIPANTSThis 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 MEASURESCirculating progenitor cells were enumerated with flow cytometry as CD34-expressing mononuclear cells (CD45 med /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. RESULTSOf 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 RELEVANCEIn this study of patients with CAD, a decrease in CPC counts during exercise is associated with a worse disease prognosis compared with the ...

Crucial role of hematopoietic <i>JAK2</i> V617F in the development of aortic aneurysms

“… 13 , 14 In this term, inflammatory AAA which characterizes an unusually thickened aneurysm wall and dense adhesions of adjacent intra-abdominal structures represent different features from atherosclerotic AAA. 9 Although bone marrow (BM) progenitor cells contribute to the tissue inflammation and pathogenesis of cardiovascular diseases such as atherosclerotic diseases, 15 , 16 the causal role of BM-derived cells on the onset and progression of AA has not yet been fully explored. Moreover, the prevalence of AA has not been studied in MPN patients with JAK2 V617F, who are more prone to vascular disorders than both the general population and MPN patients with driver mutations other than JAK2 V617F.…”

Type 1 diabetes patients increase CXCR4+ and CXCR7+ haematopoietic and endothelial progenitor cells with exercise, but the response is attenuated

“…Our primary finding that individuals with type 1 diabetes can mobilize HPCs and EPCs in response to exercise is of interest, as exercise-induced mobilization has been shown to be a more powerful predictor of complications and mortality than basal circulating count in thoracic surgery and coronary artery disease patients 27 , 28 , and contrasts previous research which found no mobilisation of EPCs in type 1 35 , 36 or 2 diabetes 26 . Differences between our study and those previously exploring exercise-induced mobilisation in people with type 1 diabetes likely arose due to alternative ways of quantifying circulating angiogenic cell numbers.…”

“…However, exercise-induced increases of EPCs appears attenuated in those with chronic diseases 25 , 26 , which may partially explain the increased CVD risk in these populations. Indeed, increased pre-operative exercise-induced mobilization of EPCs is correlated with reduced post-operative complications after major thoracic surgery 27 , while HPCs response to exercise was a stronger predictor of myocardial ischemia and mortality than resting circulating count in patients with coronary artery disease over a subsequent 3 year period 28 . Insight into the ability of these cells to respond to a stimulus, such as exercise, migrating into circulation and homing to ischemic tissue can be measured by the surface expression of chemokine (C-X-C motif) receptor 4 (CXCR4) and 7 (CXCR7) 29 , 30 , although evidence on the influence of type 1 diabetes is lacking.…”

Circulating CD34+ Progenitor Cells are Predictive of All-Cause and Cardiovascular Mortality and are Influenced by Physical Activity.

“…In addition given the reduced number and function of these cells in CVD 5 , and the predictive association with mortality, it is pertinent to find therapies to augment production, mobilization and function of these cells. Exercise and physical activity has the potential to mobilize these cells into the circulation as evident from acute exercise studies showing transient increases in CPCs in both healthy 11, 24 and diseased populations 25 , although the response to acute exercise is somewhat diminished in CVD patients 26 . Long-term physical exercise and physical activity shows promise in increasing number and/or function of these CPCs 27 , potentially through promoting bone marrow production of progenitor cell subsets (although the origin of EPCs has been a topic of debate recently 28 ) or via reducing inflammatory or pro-apoptotic stimuli in the circulation 29 , thus enhancing survival of these cells in our body.…”