Circulating Progenitor Cell Counts Research Articles

Circulating Progenitor Cells and Coronary Collaterals in Chronic Total Occlusion

BackgroundThe role of circulating progenitor cells (CPC) in collateral formation that occurs in the presence of chronic total occlusions (CTO) of a coronary artery is not well established. In stable patients with a CTO, we investigated whether CPC levels are associated with (a) collateral development and (b) ischemic burden, as measured by circulating high sensitivity troponin-I (hsTn-I) levels. MethodsCPCs were enumerated by flow cytometry as CD45med+ blood mononuclear cells expressing CD34 and both CD34 and CD133 epitopes. The association between CPC counts and both Rentrop collateral grade (0, 1, 2, or 3) and hsTn-I levels were evaluated using multivariate regression analysis, after adjusting for demographic and clinical characteristics. ResultsIn 89 patients (age 65.5, 72% male, 27% Black), a higher CPC count was positively associated with a higher Rentrop collateral grade; [CD34+ adjusted odds ratio (OR) 1.49 95% confidence interval (CI) (0.95, 2.34) P = 0.082] and [CD34+/CD133+ OR 1.57 95% CI (1.05, 2.36) P = 0.028]. Every doubling of CPC counts was also associated with lower hsTn-I levels [CD34+ β −0.35 95% CI (−0.49, −0.15) P = 0.002] and [CD34+/CD133+ β −0.27 95% CI (−0.43, −0.08) P = 0.009] after adjustment. ConclusionIndividuals with higher CPC counts have greater collateral development and lower ischemic burden in the presence of a CTO.

Vitamin D Deficiency, Inflammation, and Diminished Endogenous Regenerative Capacity in Coronary Heart Disease

BackgroundVitamin D deficiency (VDD) is associated with coronary heart disease (CHD) and poor outcomes, but supplementation does not improve prognosis. VDD has been implicated in and may promote greater risk through inflammation and impaired progenitor cell function. ObjectivesThe authors examined VDD, high-sensitivity C-reactive protein (hsCRP), circulating progenitor cell (CPC) counts, and outcomes in patients with CHD. They hypothesized that the higher risk with VDD is mediated by inflammation and impaired regenerative capacity. MethodsA total of 5,452 individuals with CHD in the Emory Cardiovascular Biobank had measurement of 25-hydroxyvitamin D, subsets of whom had hsCRP measurements and CPCs estimated as CD34-expressing mononuclear cell counts. Findings were validated in an independent cohort. 25-hydroxyvitamin D <20 ng/mL was considered VDD. Cox and Fine-Gray models determined associations between marker levels and: 1) all-cause mortality; 2) cardiovascular mortality; and 3) major adverse cardiovascular events, a composite of adverse CHD outcomes. ResultsVDD (43.6% of individuals) was associated with higher adjusted cardiovascular mortality (HR: 1.57, 95% CI: 1.09-2.28). There were significant interactions between VDD and hsCRP and CPC counts in predicting cardiovascular mortality. Individuals with both VDD and elevated hsCRP had the greatest risk (HR: 2.82, 95% CI: 2.16-3.67). Only individuals with both VDD and low CPC counts were at high risk (HR: 2.25, 95% CI: 1.46-3.46). These findings were reproduced in the validation cohort. ConclusionsVDD predicts adverse outcomes in CHD. Those with VDD, inflammation and/or diminished regenerative capacity are at a significantly greater risk of cardiovascular mortality. Whether targeted supplementation in these high-risk groups improves risk warrants further study.

Aerobically trained older adults show impaired resting, but preserved exercise-induced circulating progenitor cell count, which was not improved by sprint interval training

Older adults exhibit a reduced number and function of CD34 + circulating progenitor cells (CPC), a known risk factor for cardiovascular disease. Exercise promotes the mobilisation of CPCs from bone marrow, so whether ageing per se or physical inactivity in older age reduces CPCs is unknown. Thus, this study examined the effect of age on resting and exercise-induced changes in CPCs in aerobically trained adults and the effect of 8 weeks of sprint interval training (SIT) on resting and exercise-induced CPCs in older adults. Twelve young (22–34 years) and nine older (63–70 years) adults participated in the study. Blood was sampled pre and immediately post a graded exercise test to exhaustion in both groups. Older participants repeated the process after 8 weeks of SIT (3 × 20 s ‘all-out’ sprints, 2 × a week). Total CPCs (CD34+) and endothelial progenitor cells (EPCs: CD34+KDR+) were determined by flow cytometry. Older adults exhibited lower basal total CD34+ CPCs (828 ± 314 vs. 1186 ± 272 cells·mL−1, p = 0.0149) and CD34+KDR+ EPCs (177 ± 128 vs. 335 ± 92 cells·mL−1, p = 0.007) than younger adults. The maximal exercise test increased CPCs in young (CD34+: p = 0.004; CD34+KDR+: p = 0.017) and older adults (CD34+: p < 0.001; CD34+KDR+: p = 0.008), without difference between groups (p = 0.211). SIT did not alter resting or exercise-induced changes in CPCs in the older cohort (p > 0.232). This study suggests age per se does not impair exercise-induced CPC counts, but does lower resting CPC counts.

The association between baseline circulating progenitor cells and vascular function: The role of aging and risk factors.

To investigate the cross-sectional and longitudinal relationships between vascular function and circulating progenitor cell (CPC) counts with respect to aging and exposure to risk factors. In 797 adult participants, CPCs were enumerated by flow cytometry as CD45med mononuclear cells expressing CD34 epitope and its subsets co-expressing CD133, and chemokine C-X-C motif receptor 4 (CXCR4+). Arterial stiffness was evaluated by tonometry-derived pulse wave velocity (PWV) and microvascular function was assessed as digital reactive hyperemia index (RHI). In cross-sectional analyses, for every doubling in CD34+ cell counts, PWV was 15% higher and RHI was 9% lower, after adjusting for baseline characteristics and risk factors (p for all < 0.01). There were significant CPC-by-age-by-risk factor interactions (p <0.05) for both vascular measures. Among younger subjects (< 48 years), CPC counts were higher in those with risk factors and vascular function was better in those with higher compared to those with lower CPC counts (p for all < 0.0l). In contrast, in older participants, CPCs were not higher in those with risk factors, and vascular function was worse compared to the younger age group. A lower CPC count at baseline was an independent predictor of worsening vascular function during 2-year follow-up. A higher CPC count in the presence of risk factors is associated with better vascular function among younger individuals. There is no increase in CPC count with risk factors in older individuals who have worse vascular function. Moreover, a higher CPC count is associated with less vascular dysfunction with aging.

Associations Between Inflammation, Cardiovascular Regenerative Capacity, and Cardiovascular Events: A Cohort Study.

Circulating progenitor cells possess immune modulatory properties and might mitigate inflammation that is characteristic of patients with coronary artery disease. We hypothesized that patients with fewer circulating progenitor cells (CPCs) will have higher inflammatory markers and worse outcomes. Patients with stable coronary artery disease were enrolled in a prospective study enumerating CPCs as CD (cluster of differentiation)-34-expressing mononuclear cells (CD34+) and inflammation as levels of IL (interleukin)-6 and high-sensitivity CRP (C-reactive protein) levels. Patients were followed for 5 years for the end points of death and myocardial infarction with repeat inflammatory biomarkers measured after a median of 2 years. In the entire cohort of 392 patients, IL-6 and high-sensitivity CRP levels remained unchanged (0.3+/-2.4 pg/mL and 0.1+/-1.0 mg/L; P=0.45) after 2 years. CPC counts (log-transformed) were inversely correlated with the change in IL-6 levels (r, -0.17; P<0.001). Using linear regression, IL-6 and high-sensitivity CRP levels declined by -0.59 (95% CI, -0.90 to -0.20) pg/mL and -0.13 (-0.28 to 0.01) mg/L per 1 log higher CPC counts after adjustment for the demographic and clinical variables, as well as medications. Using Cox models adjusted for these risk factors, a rise in 1 pg/mL of IL-6 was associated with a 11% (95% CI, 9-13) greater risk of death/myocardial infarction. We found that the change in IL6 level partly (by 40%) mediated the higher risk of adverse events among those with low CPC counts. Reduced cardiovascular regenerative capacity is independently associated with progressive inflammation in patients with coronary artery disease that in turn is associated with poor outcomes.

Vascular Regenerative Capacity and the Obesity Paradox in Coronary Artery Disease.

[Figure: see text].

Abstract 12623: Vascular Regenerative Capacity: A Window into the Pathobiology of Obesity Paradox

Introduction: Obese patients (BMI≥30 kg/m 2 ) with CAD have better outcomes as compared with non-obese patients, but the underlying pathobiology is unclear. Hypothesis: Obesity is directly associated with vascular regenerative capacity, measured as circulating progenitor cell (CPC) count, and this association provides insight into obesity paradox pathobiology. Methods: CPCs were enumerated by flow cytometry as CD45 med+ cells expressing CD34+, CD133+, and CXCR4+ epitopes in 672 asymptomatic individuals (50 y, 66% women, 23% Black, 28% obese) and 1,277 patients with CAD (66 y, 39% women, 22% Black, 39% obese). Association of obesity with CPC counts was analyzed using multivariable-adjusted linear regression models. Association of obesity and CPCs with cardiovascular death/myocardial infarction events over 3.5-y follow-up was studied using Kaplan-Meir survival curves and Cox models. Results: Obesity was independently associated with 16-34% higher CPC count (CD34+, CD34+/CD133+, and CD34+/CXCR4+) in asymptomatic individuals. This association was not attenuated after adjusting for measures of systemic inflammation, insulin resistance, or insulin secretion. Cardiorespiratory fitness and android fat only partly attenuated the obesity-CPC relationship. In patients with CAD, obesity was independently associated with 8-12% higher CPC counts, and with 30% lower outcome risk. Lower CPC counts were associated with outcome risk in obese patients. Obese patients with high CD34+ count (≥median) were at a lower risk, while obese participants with low counts (&lt;median) were at a similar risk as compared with non-obese patients with high counts. The highest risk was observed in non-obese patients with low counts. Similar results were observed with CD34+/CD133+ and CD34+/CXCR4+ cells. Conclusions: Obesity is directly associated with vascular regenerative capacity, and the obesity paradox in CAD is observed in obese patients with high, but not low, CPC counts.

Circulating Progenitor Cells and Cognitive Impairment in Men and Women with Coronary Artery Disease.

Circulating progenitor cells (CPC) have been associated with memory function and cognitive impairment in healthy adults. However, it is unclear whether such associations also exist in patients with coronary artery disease (CAD). To assess the association between CPCs and memory performance among individuals with CAD. We assessed cognitive function in 509 patients with CAD using the verbal and visual Memory subtests of the Wechsler memory scale-IV and the Trail Making Test parts A and B. CPCs were enumerated with flow cytometry as CD45med/CD34+ blood mononuclear cells, those co-expressing other epitopes representing populations enriched for hematopoietic and endothelial progenitors. After adjusting for demographic and cardiovascular risk factors, lower number of endothelial progenitor cell counts were independently associated with lower visual and verbal memory scores (p for all < 0.05). There was a significant interaction in the magnitude of this association with race (p < 0.01), such that the association of verbal memory scores with endothelial progenitor subsets was present in Black but not in non-Black participants. No associations were present with the hematopoietic progenitor-enriched cells or with the Trail Making Tests. Lower numbers of circulating endothelial progenitor cells are associated with cognitive impairment in patients with CAD, suggesting a protective effect of repair/regeneration processes in the maintenance of cognitive status. Impairment of verbal memory function was more strongly associated with lower CPC counts in Black compared to non-Black participants with CAD. Whether strategies designed to improve regenerative capacity will improve cognition needs further study.

Abstract P537: Reduced Cardiovascular Regenerative Capacity is Associated With Enhanced Inflammatory Response to Acute Psychological Stress

Background: Bone marrow-derived progenitor cells (PCs) are involved in vascular regeneration and correlate with vascular function and cumulative cardiovascular risk. Systemic inflammation is associated with increased mobilization and differentiation of circulating PCs (CPCs) which may ultimately lead to exhaustion of vascular regenerative capacity. Individuals with coronary artery disease (CAD) exhibit a pro-inflammatory response to a mental stress challenge that has been associated with an elevated risk of adverse outcomes. We sought to determine whether subjects with reduced numbers of circulating PCs (CPCs) are at higher risk of a pro-inflammatory response to acute mental stress. Methods: 500 outpatients with stable CAD were enrolled into the Mental Stress Ischemia Prognosis study and underwent a laboratory-based mental stress protocol. Mononuclear cells expressing CD45med, CD34 and CXCR4 epitopes, known to be enriched for hematopoietic PCs, were enumerated using flow cytometry. Interleukin-6 (IL6) and C-Reactive Protein (CRP) levels were measured before and after mental stress. Baseline and changes in IL6 levels were compared across CPC tertiles using linear regression after adjusting for patient characteristics. Results: Mean age was 63± 9 years, 77% male, 70% white. Median CD34+ CPC count was 1.64 (1.02-2.43 cells/μL. CPC levels were not associated with either the baseline IL6 level (Beta= 0.071 95%CI, -0.091, 0.23) or CRP levels (Beta, 0.60, 95%CI, -0.25, 0.44). However, independent of demographics, CAD risk factors and baseline IL6 levels, lower CD34+/CXCR4+ CPC counts were associated with a higher inflammatory response during mental stress, measured as a rise in IL6 level (Beta= -0.11, 95%CI, -0.20, -0.028). Conclusions: Patients with reduced CPC levels have a greater pro-inflammatory response to mental stress. Thus, the observed higher risk in subjects with impaired regenerative capacity might be at least partly due to a higher stress-related pro-inflammatory response.

Alterations in the Levels of Circulating and Endothelial Progenitor Cells Levels in Young Adults with Type 1 Diabetes: A 2-Year Follow-Up from the Observational METRO Study.

PurposeType 1 diabetes is associated with high risk of cardiovascular disease (CVD). Reduced levels of circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs) have been indicated as a risk factor for adverse cardiovascular outcomes and death in people at high cardiovascular risk. The aim of the present study was to evaluate the change in CPCs and EPCs levels in a population of young type 1 diabetic patients treated with intensive insulin regimen over a period of 2 years.Patients and MethodsA total of 204 type 1 diabetic patients, of whom 84 treated with insulin pump (CSII) and 120 with multiple daily insulin injections (MDI), completed a 2-year follow-up. Clinical measurements, including the indices of glycemic control and glucose variability, were collected at baseline and after 2 years. Both CPC and EPC cell count were assessed by flow cytometry.ResultsMean age of participants was 24.5 years and mean diabetes duration was 13.6 years. After 2 years, we found a significant reduction of HbA1c (−0.3% versus baseline, P <0.001), associated with decrease in mean amplitude of glucose excursion (MAGE) (−0.5 mmol/L versus baseline, P<0.001), continuous overall net glycemic action (CONGA) (−0.2 mmol/L versus baseline, P=0.006), and blood glucose standard deviation (BGSD) (−0.2 mmol/L versus baseline, P<0.001). The number of all EPCs phenotypes, but not CPC cell count, significantly raised up in the entire population, with higher increase in CSII group. MAGE resulted as an independent predictor for increased levels of both CD34+ (P = 0.020) and CD34+KDR+ (P = 0.004) cell count in the whole population.ConclusionOver a 2-year follow-up, young type 1 diabetic patients showed an increase in circulating EPCs levels, which was higher in patients with CSII. Glucose variability resulted as an independent predictor of the raised levels of EPCs in this selected population.

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

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. 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). 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. Myocardial perfusion imaging with technetium Tc 99m sestamibi at rest and 30 to 60 minutes after conventional stress testing. 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. 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. 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.

CHANGE IN CIRCULATING PROGENITOR CELLS DURING STRESS TESTING AND RISK OF ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH CORONARY ARTERY DISEASE

A lower circulating progenitor cell (CPC) count is an independent predictor of adverse cardiovascular outcomes. CPCs are also mobilized in response to ischemia. We investigated the prognostic role of the change in CPC counts with stress testing in stable CAD patients. We hypothesized that impaired

Circulating Progenitor Cells and Racial Differences.

Blacks compared with whites have a greater risk of adverse cardiovascular outcomes. Impaired regenerative capacity, measured as lower levels of circulating progenitor cells (CPCs), is a novel determinant of adverse outcomes; however, little is known about racial differences in CPCs. To investigate the number of CPCs, PC-mobilizing factors, PC mobilization during acute myocardial infarction and the predictive value of CPC counts in blacks compared with whites. CPCs were enumerated by flow cytometry as CD45med+ blood mononuclear cells expressing CD34+, CD133+, VEGF2R+, and CXCR4+ epitopes in 1747 subjects, mean age 58.4±13, 55% male, and 26% self-reported black. Patients presenting with acute myocardial infarction (n=91) were analyzed separately. Models were adjusted for relevant clinical variables. SDF-1α (stromal cell-derived factor-1α), VEGF (vascular endothelial growth factor), and MMP-9 (matrix metallopeptidase-9) levels were measured (n=561), and 623 patients were followed for median of 2.2 years for survival analysis. Blacks were younger, more often female, with a higher burden of cardiovascular risk, and lower CPC counts. Blacks had fewer CD34+ cells (-17.6%; [95% confidence interval (CI), -23.5% to -11.3%]; P<0.001), CD34+/CD133+ cells (-15.5%; [95% CI, -22.4% to -8.1%]; P<0.001), CD34+/CXCR4+ cells (-17.3%; [95% CI, -23.9% to -10.2%]; P<0.001), and CD34+/VEGF2R+ cells (-27.9%; [95% CI, -46.9% to -2.0%]; P=0.04) compared with whites. The association between lower CPC counts and black race was not affected by risk factors or cardiovascular disease. Results were validated in a separate cohort of 411 patients. Blacks with acute myocardial infarction had significantly fewer CPCs compared with whites ( P=0.02). Blacks had significantly lower plasma MMP-9 levels ( P<0.001) which attenuated the association between low CD34+ and black race by 19% (95% CI, 13%-33%). However, VEGF and SDF-1α levels were not significantly different between the races. Lower CD34+ counts were similarly predictive of mortality in blacks (hazard ratio, 2.83; [95% CI, 1.12-7.20]; P=0.03) and whites (hazard ratio, 1.79; [95% CI, 1.09-2.94]; P=0.02) without significant interaction. Black subjects have lower levels of CPCs compared with whites which is partially dependent on lower circulating MMP-9 levels. Impaired regenerative capacity is predictive of adverse outcomes in blacks and may partly account for their increased risk of cardiovascular events.

In This Issue

HomeCirculation ResearchVol. 122, No. 11In This Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published25 May 2018https://doi.org/10.1161/RES.0000000000000213Circulation Research. 2018;122:1479NaV1.5 and Kir2.1 Channels’ Common Trafficking Pathway (p 1501)Download figureDownload PowerPointSodium channel NaV1.5 and potassium channel Kir2.1 team up to traverse the cell, report Ponce-Balbuena et al.Kir2.1 is the major potassium channel responsible for the inward potassium current (IK1) of ventricular myocytes, while NaV1.5 generates the fast-inward sodium current (INa). As such, the 2 proteins are crucial for the normal electrical functioning of the heart. Both Kir2.1 and NaV1.5 are parts of a large multiprotein complex, but when and where the channels come together was unknown. Ponce-Balbuena and colleagues have now shown, in cardiomyocytes and other cell types, that expression of a trafficking-deficient version of Kir2.1 not only affected the IK1, but the INa too, suggesting the channels are trafficked together. Indeed, the team found that trafficking-deficient Kir2.1 did not alter NaV1.5 expression levels, but instead interfered with the plasmalemmal localization of the sodium channel. Immunoprecipitation and immunostaining experiments confirmed the 2 channels interact, and showed they also partner with the trafficking factor AP1 (adaptor protein 1). Since both these channels are critical for normal electrophysiological functioning of the heart, these insights into their assembly and trafficking could inform arrhythmia research and the development of antiarrhythmic interventions.S-Nitrosylation Controls GSK3β Function (p 1517)Download figureDownload PowerPointS-Nitrosylation controls glycogen synthase kinase 3β (GSK3β), say Wang and colleagues.Nitric oxide (NO) is a vasodilator, and a critical signaling molecule. And recently, NO has also been found to regulate protein function by S-nitrosylation. In a screen for S-nitrosylated proteins in the heart, Wang et al identified the kinase GSK3β. This enzyme is involved in a wide variety of cellular processes, and its dysregulation has been linked to several pathological conditions, including heart failure. GSK3β is a constitutively active enzyme, but is inhibited via phosphorylation at Ser-9. The researchers now show that S-nitrosylation also inhibits GSK3β, independent of Ser-9 phosphorylation, but that this form of inhibition is specific to GSK3β in the cytosol. S-nitrosylation of GSK3β induced nuclear translocation of the enzyme where the modification drove GSK3β-mediated phosphorylation of nuclear targets with a specific amino acid motif. The team went on to show that the abundance of nitrosylated GSK3β is increased in an animal model of heart failure. They conclude that post-translational modification of GSK3β by NO is a novel regulatory mode that could play an important role in heart failure, as well as other diseases associated with inhibition of GSK3β activity.Progenitor Cells and Outcomes in Acute Coronary Syndrome (p 1565)Download figureDownload PowerPointLevels of circulating progenitor cells predict clinical outcomes of acute coronary syndromes, report Tahhan et al.Acute coronary syndromes (ACS), such as heart attacks and angina, are caused by intravascular thrombosis following rupture of an atherosclerotic plaque. Recent work has shown that circulating progenitor cells (CPCs) and resident stem cells contribute to myocardial recovery after ACS. Indeed, myocardial infarction is associated with both transient and prolonged elevation in CPC levels. Nevertheless, it is unknown whether the magnitude of a CPC response can predict long-term outcomes in ACS patients. Tahhan and colleagues examined CPC levels in more than 2000 patients with stable coronary artery disease (CAD), unstable angina (UA), and acute myocardial infarction (AMI). They found that CPC levels were significantly higher in AMI patients than in either UA or CAD patients, but that in all ACS patients (AMI and UA), subjects with low levels of CPCs had an ≈2.5-fold increased risk of all-cause mortality after 2 years. The team then validated this CPC-mortality link in an additional cohort of 238 ACS patients. These findings suggest that CPC counts could be used to identify high-risk ACS individuals and that novel strategies to boost CPC levels may be a way to improve clinical outcomes in such patients. Previous Back to top Next FiguresReferencesRelatedDetails May 25, 2018Vol 122, Issue 11 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000213 Originally publishedMay 25, 2018 PDF download Advertisement

Progenitor Cells and Clinical Outcomes in Patients With Acute Coronary Syndromes.

Circulating progenitor cells (CPCs) mobilize in response to ischemic injury, but their predictive value remains unknown in acute coronary syndrome (ACS). We aimed to investigate the number of CPCs in ACS compared with those with stable coronary artery disease (CAD), relationship between bone marrow PCs and CPCs, and whether CPC counts predict mortality in patients with ACS. In 2028 patients, 346 had unstable angina, 183 had an acute myocardial infarction (AMI), and the remaining 1499 patients had stable CAD. Patients with ACS were followed for the primary end point of all-cause death. CPCs were enumerated by flow cytometry as mononuclear cells expressing a combination of CD34+, CD133+, vascular endothelial growth factor receptor 2+, or chemokine (C-X-C motif) receptor 4+. CPC counts were higher in subjects with AMI compared those with stable CAD even after adjustment for age, sex, race, body mass index, renal function, hypertension, diabetes mellitus, hyperlipidemia, and smoking; CD34+, CD34+/CD133+, CD34+/CXCR4+, and CD34+/VEGFR2+ CPC counts were 19%, 25%, 28%, and 142% higher in those with AMI, respectively, compared with stable CAD. There were strong correlations between the concentrations of CPCs and the PC counts in bone marrow aspirates in 20 patients with AMI. During a 2 (interquartile range, 1.31-2.86)-year follow-up period of 529 patients with ACS, 12.4% died. In Cox regression models adjusted for age, sex, body mass index, heart failure history, estimated glomerular filtration rate, and AMI, subjects with low CD34+ cell counts had a 2.46-fold (95% confidence interval, 1.18-5.13) increase in all-cause mortality, P=0.01. CD34+/CD133+ and CD34+/CXCR4+, but not CD34+/VEGFR2+ PC counts, had similar associations with mortality. Results were validated in a separate cohort of 238 patients with ACS. CPC levels are significantly higher in patients after an AMI compared with those with stable CAD and reflect bone marrow PC content. Among patients with ACS, a lower number of hematopoietic-enriched CPCs are associated with a higher mortality.

Circulating progenitor cells in patients with familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a genetic disease with very high levels of circulating low density lipoprotein cholesterol (LDL-C) levels that leads to accelerated atherosclerosis. Lipoprotein apheresis is an effective treatment option for patients with FH and results in reduced cardiovascular morbidity and mortality. Circulating progenitor cells (CPCs) are markers of overall vascular health and diminished levels have been associated with decreased reparative potential and worse outcomes. We assessed the short-term change in CPC levels following a single lipoprotein apheresis session in FH patients who are already on stable lipoprotein apheresis therapy. We hypothesized that in addition to a reduction in atherogenic lipids, the cardiovascular benefit from lipoprotein apheresis therapy is mediated by enhanced vascular reparative capacity through mobilization of CPCs. Eight FH patients (1 homozygous and 7 heterozygous) on stable lipoprotein apheresis therapy for at least three months had CPCs measured at baseline (prior to apheresis) and two hours after apheresis. Results were compared with data from age-matched hyperlipidemic (HLP) patients on statin therapy and healthy volunteers. FH patients had higher baseline circulating levels of CD34+/CD133+ and CD34+/CD133+/CXCR4+ cells compared to HLP and healthy subjects. There was no significant change in CPCs after apheresis in FH patients. FH patients had higher CPC counts at baseline compared to age-matched HLP and healthy controls, suggesting activation of reparative mechanism in this high risk population. Larger studies are needed to better characterize differences in CPC counts between FH subjects and HLP patients over time.

Abstract P326: Myocardial Ischemia and Mobilization of Circulating Progenitor Cells

Background: Circulating progenitor cells (CPCs) are involved in vascular repair and regeneration. Low levels of CPCs in patients with CAD have been linked to adverse cardiovascular outcomes. The response of CPCs to transient myocardial ischemia in patients with CAD has not been studied before. We aimed to investigate the CPC response to exercise provoked myocardial ischemia (demand ischemia), and compare it to myocardial ischemia detected during pharmacological stress test (flow mismatch). Methods: 570 patients with stable CAD underwent 99mTc sestamibi myocardial perfusion imaging during exercise (69%), or pharmacological stress (31%). myocardial ischemia was defined as a new or worsening impairment in myocardial perfusion using a 17-segment model. CD34+ CPCs were enumerated by flow cytometry at rest and 30 min after stress testing. The change in CPC count was compared between patients with and without myocardial ischemia using mixed linear models. Results: Mean age was 63±9 years, 76% males, 36% with previous myocardial infarction. The incidence of myocardial ischemia was 31% and 41% during exercise and pharmacological stress test, respectively. No difference was observed in resting CPC between patients undergoing exercise vs pharmacological stress test, nor between patients with or without myocardial ischemia. However, patients who developed myocardial ischemia during exercise stress had a significant decrease in CPC with stress in comparison to those without myocardial ischemia (-12% vs 4%, respectively, p=0.006). Furthermore, the change in CPCs was inversely correlated with the magnitude of myocardial ischemia (R=-0.13, p=0.023), suggesting a greater CPC reduction with larger ischemic burden. These findings remained significant even after adjustment for age, gender, race, BMI, previous myocardial infarction, resting levels of CPCs and hematocrit change with stress. No difference was observed in CPC response to pharmacological stress test (change of -1% vs 3%, for patients with and without myocardial ischemia, respectively, p=0.96). Conclusion: Exercise stress-induced myocardial ischemia is associated with a decrease in CPC counts, likely due to increased homing of stem cells to the ischemic myocardium. Whether the extent of CPC uptake has prognostic implication, or whether the CPC response can be altered with intervention needs further investigation.

Bioactive Lipids and Circulating Progenitor Cells in Patients with Cardiovascular Disease.

Bone marrow‐derived progenitor cells are mobilized into the peripheral blood after acute myocardial injury and in chronic ischemic heart disease. However, the mechanisms responsible for this mobilization are poorly understood. We examined the relationship between plasma levels of bioactive lipids and number of circulating progenitor cells (CPCs) in patients (N = 437) undergoing elective or emergent cardiac catheterization. Plasma levels of sphingosine‐1 phosphate (S1P) and ceramide‐1 phosphate (C1P) were quantified using mass spectrometry. CPCs were assessed using flow cytometry. S1P levels correlated with the numbers of CD34+, CD34+/CD133+, and CD34+/CXCR4+ CPCs even after adjustment for potential confounding factors. However, no significant correlation was observed between C1P levels and CPC count. Plasma levels of S1P correlated with the number of CPCs in patients with coronary artery disease, suggesting an important mechanistic role for S1P in stem cell mobilization. The therapeutic effects of adjunctive S1P therapy to mobilize endogenous stem cells need to be investigated. Stem Cells Translational Medicine 2017;6:731–735

SHORTER TELOMERE LENGTH IS ASSOCIATED WITH LOWER LEVELS OF CIRCULATING PROGENITOR CELLS

Leucocyte telomere length (LTL) is a biological marker of aging which has been associated with decreased survival. Bone marrow-derived circulating progenitor cells (CPC) are involved in vascular repair and regeneration, and reduced CPC counts are associated with poor outcomes. We sought to determine

Circulating Progenitor Cell Count Predicts Microvascular Outcomes in Type 2 Diabetic Patients.

Diabetes reduces the levels of circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs), which promote vascular repair and are inversely correlated with cardiovascular risk. The objective of the study was to test whether CPC/EPC levels predict onset/progression of microangiopathy in a cohort of type 2 diabetic (T2D) patients. This was a pseudoprospective study with a 3.9-year follow-up. The study was conducted at a tertial referral diabetes outpatient clinic. A total of 187 T2D patients having a baseline determination of CPCs/EPCs participated in the study. Baseline data on demographics, anthropometrics, concomitant risk factors, diabetic complications, and medications were collected. Onset or progression of microangiopathy was assessed at follow-up compared with baseline. New onset or progression of microalbuminuria, chronic kidney disease, retinopathy, and neuropathy occurred in 70 patients (9.5%/y). After controlling the false discovery rate, baseline CD34(+) CPCs and EPCs were significantly lower in patients with onset/progression of microalbuminuria and any microangiopathy. Patients with baseline CD34(+) CPC or CD133(+)/kinase insert domain-containing receptor(+)/EPC levels below the median were more likely to experience worsening microangiopathy than those with high cell levels. Independently from confounders, including age, sex, glycated hemoglobin, and diabetes duration, CD34(+) cells predicted onset/progression of microalbuminuria, retinopathy, and any microangiopathy in false discovery rate-adjusted analyses. A low CD34(+) cell count limited the beneficial effects of renin-angiotensin system blockers on microalbuminuria progression. Levels of circulating (endothelial) progenitor cells predict microvascular outcomes in T2D. Together with previous studies showing an association with cardiovascular events, these data indicate that CPCs/EPCs represent biomarkers of the global complication burden in diabetes.