Circulating endothelial-derived apoptotic microparticles and insulin resistance in non-diabetic patients with chronic heart failure.

BACKGROUND: The objective of this study was to assess the relationship between insulin resistance and apoptotic endothelial-derived microparticles (EMPs) in patients with chronic heart failure (CHF). METHODS: The study involved 300 CHF patients (186 males) aged 48-62 years with angiographically proven coronary artery disease and/or previously defined myocardial infarction. Insulin resistance was assessed by the homeostasis model assessment for insulin resistance (HOMA-IR). EMPs phenotype was determined by flow cytofluorometry. RESULTS: Depending on HOMA-IR cut-off point (over and <2.77 mmol/L×µU/mL) all patients were divided into two cohorts with (n=171) or without (n=129) IR, respectively. Circulating EMPs were higher in CHF patients with IR than in patients without IR. Interestingly, EMPs were directly related to NYHA functional class of CHF, HOMA-IR, NT-pro-BNP, hs-CRP and BMI. There was a significant association between the level of EMPs and HbA1c, gender (r=0.318, p<0.001 for male), age and smoking. On univariate and multivariate regression analysis we found that the NYHA class of CHF,NT-pro-BNP, hs-CRP, and left ventricular ejection fraction (LVEF) appeared to be independent predictors of increased circulatory apoptotic EMPs. The addition of HOMA-IR to the standard model (NYHA class CHF) improved the relative IDI by 19.9% for increased EMPs. For category-free NRI, 10% of events and 24% of non-events were correctly reclassified by the addition of HOMA-IR to the standard model for increased circulating EMPs. CONCLUSIONS: IR may be a contributing factor increasing circulating levels of apoptotic EMPs in non-diabetic CHF patients.

Circulating endothelial progenitor cells as markers for severity of ischemic chronic heart failure.

INTRODUCTION: Despite a high potential of endothelial progenitor cells (EPCs) for diagnostic purposes, the EPC role in developing ischemic chronic heart failure (CHF) has not been determined obviously. The objective of this study was to assess the counts of CD45(+)CD34(+), CD45(-)CD34(+), CD14(+)CD309(+), and CD14(+)CD309(+)Tie2(+) phenotyped circulating EPCs of various subpopulations in patients with ischemic CHF. METHODS AND RESULTS: The study involved 153 patients (86 male), aged 48-62 years, with angiographically proven coronary artery disease (CAD) and 25 healthy volunteers. CHF was diagnosed in 109 patients (71.2%). Mononuclear cell populations were phenotyped by flow cytofluorimetry. Cardiovascular risk factors, such as type 2 diabetes mellitus, hyperlipidemia, arterial hypertension, and adherence to smoking, may have a negative effect on circulating EPC counts in CAD patients regardless of the presence of CHF. The depletion of the CD14(+)CD309(+)- and CD14(+)CD309(+)Tie2(+)-phenotyped circulating EPC counts is associated with the severity of left ventricular dysfunction, whereas the CD45(+)CD34(+)- and CD45(-)CD34(+)-mononuclear cell counts are more representative of the severity of atherosclerotic coronary artery lesions. CONCLUSION: The authors found that New York Heart Association functional class of CHF, left ventricular ejection fraction <42%, the N-terminal pro-B-type natriuretic peptide level >554 pg/mL, and Е/Еm ratio >15 U had the highest predictive value for the depletion of the EPC count in CAD patients.

Altered signature of apoptotic endothelial cell-derived microvesicles predicts chronic heart failure phenotypes.

Aim: to evaluate the associations between signatures of apoptotic endothelial cell-derived microvesicles (MVs) with phenotypes of chronic heart failure (HF). Methods: The study cohort consisted of 388 prospectively involved subjects with HF patients with predominantly reduced left ventricular ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF) and HF with mid-range ejection fraction (HFmrEF). All biomarkers were measured at baseline. Results: The number of circulating CD31+/annexin V+ MVs in HFrEF and HFmrEF patients was similar. The number of circulating CD144+/annexin V+ MVs in HFrEF patients was significantly higher than HFmrEF and HFpEF. We determined that a combination of number of circulating CD31+/annexin V+ MVs and Gal-3 was the best predictor of HFpEF and that number of circulating CD144+/annexin V+ MVs is able to increase predictive capabilities of soluble ST2 (sST2) and Gal-3 for HFrEF. Conclusion: We found that the number of circulating CD31+/annexin V+ MVs may improve a predictive capacity for conventional HF biomarkers.

The pattern of circulating microparticles in patients with diabetes mellitus with asymptomatic atherosclerosis.

BACKGROUND: Accelerating atherosclerosis in type 2 diabetes mellitus (T2DM) patients may relate to imbalance between pattern of microparticles (MPs), which are frequently involved in repair of vasculature, tissue injury, inflammation and thrombosis. The aim of the study was to investigate the pattern of circulating MPs in T2DM patients with asymptomatic atherosclerosis. METHODS: A total of 103 patients with T2DM (54 subjects without documented coronary atherosclerosis and 49 patients with angiographic evidence of asymptomatic coronary atherosclerosis) who were underwent a contrast-enhanced multispiral computed tomography angiography and 35 healthy volunteers were enrolled in the study. To determine circulating biomarkers, blood samples were collected at baseline. MPs were labelled and characterized by flow cytometry. RESULTS: There were no significant differences between healthy volunteers and T2DM patients in circulating numbers of MPs labelled as CD41a+, CD64+, CD144+, CD144+/CD31+, Annexin V+, CD144+/annexin V+ and CD144+/CD31+/annexin V+. However, lower number of MPs with immune phenotypes CD62E+, CD105E+ and higher numbers of CD31+/annexin V+ MPs were reported in T2DM patients when compared with healthy volunteers. Therefore, we found an increased level of circulating CD41a+ MPs, CD144+/CD31+ MPs, CD31+/annexin V+ MPs, and decreased level of CD62E+ MPs in T2DM patients with asymptomatic coronary atherosclerosis in comparison with those who had no asymptomatic atherosclerosis. Using multivariate log regression analysis, BMI (odds ratio [OR] = 1.04, p = 0.001), LDL-C (OR = 1.05, p = 0.046), hs-CRP (OR = 1.07, p = 0.044), osteoprotegerin (OR = 1.07, p = 0.026), CD62E+ MPs (OR = 1.07, p = 0.001) and CD31+/annexin V+ MPs (OR = 1.12, p = 0.003) were determined independent predictive factors of asymptomatic atherosclerosis in T2DM patients. CONCLUSION: Circulating levels of MP originated from apoptotic endothelial cell-derived were significantly increased in diabetic patients as compared with normal subjects, but level of activated endothelial cell-derived MPs was lower than in healthy volunteers. Among T2DM patients, an increased level of CD31+/annexin V+ MPs and decreased CD62E+ MPs were significantly associated with asymptomatic atherosclerosis.

Pattern of circulating endothelial-derived microparticles among chronic heart failure patients with dysmetabolic comorbidities: The impact of subclinical hypothyroidism.

UNLABELLED: The study aim was to evaluate the impact of dysmetabolic comorbidities including subclinical hypothyroidism (SH) on pattern of circulating endothelial-derived microparticles (EMPs) in chronic heart failure (CHF) patients. METHODS: It was retrospectively involved a cohort of 388 patients with CHF. Fifty three CHF subjects had SH and 335 patients were free from thyroid dysfunction. Circulating levels of NT-pro brain natriuretic peptide (NT-pro-BNP), high-sensitivity C-reactive protein (hs-CRP), thyroid stimulating hormone (TSH), total and free thyroxine (T4) and triiodothyronine (T3) EMPs were measured at baseline. SH was defined per contemporary clinical guideline as state associated with elevated level of serum TSH>10 µU/L and basal normal free T3 and T4 concentration. RESULTS: Circulating CD31+/annexin V+ EMPs were higher in SH patients compared with none SH subjects. In contrast, activated CD62E+ EMP numbers were not significantly different between both patient cohorts. Using C-statistics for Models with TSH, New York Heart Association (NYHA) class, dyslipidemia, and circulating biomarkers (hs-CRP, NT-proBNP, serum uric acid) as Continuous Variables we found that adding of NYHA class alone, NT-proBNP alone or their combination to the based model (TSH) improved the relative integrated discrimination improvement (IDI) for increased CD31+/annexin V+ to CD62E+ ratio by 4.9%; 9.2% and 9.6% respectively. NT-proBNP improves significantly predictive model based on TSH for increased CD31+/annexin V+ to CD62E+ ratio. Among patient study population for category-free net reclassification improvement (NRI), 4% of events (P=0.026) and 6% of non-events (P=0.012) were correctly reclassified by the addition of circulating NT-proBNP to the base model (TSH) for Increased CD31+/annexin V+ to CD62E+ ratio. Therefore, 4% of events (P=0.028) and 5% of non-events (P=0.014) were correctly reclassified using category-free NRI for increased CD31+/annexin V+ to CD62E+ ratio. CONCLUSION: We found that SH state in CHF patients associates with impaired pattern of circulating EMPs with predominantly increased number of apoptotic-derived microparticles.

Pattern of endothelial progenitor cells and apoptotic endothelial cell-derived microparticles in chronic heart failure patients with preserved and reduced left ventricular ejection fraction.

BACKGROUND: Chronic heart failure (HF) remains a leading cause of cardiovascular (CV) mortality and morbidity worldwide. The aim of the study was to investigate whether the pattern of angiogenic endothelial progenitor cells (EPCs) and apoptotic endothelial cell-derived microparticles (EMPs) would be able to differentiate HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction. METHODS: One hundred sixty four chronic HF subjects met inclusion criteria. Patients with global left ventricular ejection fraction ≥ 50% were categorized as the HFpEF group (n = 79) and those with ≤ 45% as the HFrEF group (n = 85). Therefore, to compare the circulating levels of biological markers 35 control subjects without HF were included in the study. All control individuals were age- and sex-matched chronic HF patients. The serum level of biomarkers was measured at baseline. The flow cytometric technique was used for predictably distinguishing circulating cell subsets depending on expression of CD45, CD34, CD14, Tie-2, and CD309 antigens and determining endothelial cell-derived microparticles. CD31(+)/annexin V(+) was defined as apoptotic endothelial cell-derived MPs, MPs labeled for CD105(+) or CD62E(+) were determined as MPs produced due to activation of endothelial cells. RESULTS: In multivariate logistic regression model T2DM (R(2) = 0.26; P = 0.001), obesity (R(2) = 0.22; P = 0.001), previous MI (R(2) = 0.17; P = 0.012), galectin-3 (R(2) = 0.67; P = 0.012), CD31(+)/annexin V(+) EMPs (R(2) = 0.11; P = 0.001), NT-proBNP (R(2) = 0.11; P = 0.046), CD14(+) CD309(+) cells (R(2) = 0.058; P = 0.001), and CD14(+) СD309(+) Tie-2(+) cells (R(2) = 0.044; P = 0.028) were found as independent predictors of HFpEF. Using multivariate Cox-regression analysis adjusted etiology (previous myocardial infarction), cardiovascular risk factors (obesity, type 2 diabetes mellitus) we found that NT-proBNP (OR 1.08; 95% CI = 1.03-1.12; P = 0.001) and CD31(+)/annexin V(+) EMPs to CD14(+) CD309(+) cell ratio (OR 1.06; 95% CI = 1.02-1.11; P = 0.02) were independent predictors for HFpEF. CONCLUSION: We found that CD31(+)/annexin V(+) EMPs to CD14(+) CD309(+) cell ratio added to NT-proBNP, clinical data, and cardiovascular risk factors has exhibited the best discriminate value and higher reliability to predict HFpEF compared with NT-proBNP and clinical data/cardiovascular risk factors alone.

Data regarding association between serum osteoprotegerin level, numerous of circulating endothelial-derived and mononuclear-derived progenitor cells in patients with metabolic syndrome.

Metabolic syndrome (MetS) is defined as cluster of multiple metabolic and cardiovascular (CV) abnormalities included abdominal obesity, high-normal blood pressure, dyslipidaemia, and impaired fasting glucose tolerance that exhibits has a growing prevalence worldwide. We investigated whether an elevated level of osteoprotegerin (OPG) predicts imbalance between different phenotypes of circulating endothelial (EPCs) and mononuclear (MPCs) progenitor cells in MetS patients. We have analyzed data regarding dysmetabolic disorder subjects without known CV disease), as well as with known type two diabetes mellitus. All patients have given their informed written consent for participation in the study. This article contains data on the independent predictors of depletion in numerous of circulating EPCs and MPCs in MetS patients. The data are supplemental to our original research article describing detailed associations of elevated OPG level in MetS patients with numerous of EPCs and MPCs beyond traditional CV risk factors.

An association of serum vistafin level and number of circulating endothelial progenitor cells in type 2 diabetes mellitus patients.

BACKGROUND: The decreased number and impaired functions of endothelial progenitor cells (EPCs) may associate with cardiovascular disease (CV) including atherosclerosis. However, the role of vistafin in regulation of angiogenic EPC subset maturation in T2DM patients without known atherosclerosis is still not fully understood. THE AIM OF THE STUDY: To investigate an association of serum vistafin level and number of circulating EPCs in T2DM patients beyond known CV disease. METHODS: This case-control observational investigation was evolved 54 subjects with T2DM and 35 healthy volunteers. The flow cytometry was used for predictably distinguishing cell subsets, which depend on expression of CD45, CD34, CD14, Tie-2, and VEGFR2. Biomarkers were measured at baseline of the study. RESULTS: All T2DM patients were divided depending median of vistafin level (5.88ng/mL) in to two cohorts with low vistafin level (<5.88ng/mL; n=29) and high vistafin level (≥5.88ng/mL; n=25) respectively. Logistic regression analysis has shown that visfatin, hs-CRP, age and BMI were the best variables in the prediction of EPC number labeled as CD14+CD309+ and CD14+CD309+Tie2+ cells. After adjustment of the model to age and BMI elevated visfatin level remained the best predictor for both CD14+CD309+ and CD14+CD309+Tie2+ EPCs (OR 0.92, 95% CI: 0.88-0.95; P=0.001 and OR 0.90, 95% CI: 0.87-0.96; P=0.001 respectively). CONCLUSION: We found that elevated level of vistafin was an independent predictor for declined numerous of non-classical EPCs labeled as CD14+CD309+ and CD14+CD309+Tie2+, whereas CD34+ subsets of EPCs did not associate with vistafin level in T2DM individuals.

Predictive value of circulating osteonectin in patients with ischemic symptomatic chronic heart failure.

BACKGROUND: Osteonectin (OSN) plays a pivotal role in cardiac remodeling, but predictive value for OSN in ischemic chronic heart failure (CHF) has not been defined. The aim of the study was to evaluate the prognostic value of OSN for cumulative survival and hospitalization among patients with ischemic-induced CHF. METHODS: A total of 154 patients with ischemic symptomatic moderate-to-severe CHF were enrolled in the study at discharge from the hospital. Observation period was up to 3 years (156 weeks). Blood samples for biomarkers measurements were collected at baseline prior to study entry. ELISA methods for measurements of circulating level of OSN were used. RESULTS: During a median follow-up of 2.18 years, 21 participants died and 106 subjects were re-admitted. Medians of circulating levels of OSN in survival and died patient cohorts were 670.96 ng/mL (95% confidence interval [CI] = 636.53-705.35 ng/mL) and 907.84 ng/mL (95% CI = 878.02-937.60 ng/mL). Receiver operation characteristic curve analysis has shown that cut off point of OSN concentration for cumulative survival function was 845.15 ng/mL. It has been found a significant divergence of Kaplan-Meier survival curves in patients with high (>845.15 ng/mL) and low (<845.15 ng/mL) concentrations of OSN. Circulating OSN independently predicted all-cause mortality (odds ratio [OR] = 1.23; 95% CI = 1.10-1.36; p < 0.001), CHF-related death (OR = 1.46; 95% CI = 1.22-1.80; p < 0.001), and also CHF-related re-admission (OR = 1.92; 95% CI = 1.77-2.45; p < 0.001) within 3 years of observation period. CONCLUSION: Increased circulating secreted protein acidic and rich in cysteine family member OSN associates with increased 3-year CHF-related death, all-cause mortality, and risk for recurrent hospitalization due to CHF.

Impaired phenotype of circulating endothelial microparticles in chronic heart failure patients: Relevance to body mass index.

AIMS: The objective of the study was to investigate the relationship of circulating endothelial-derived microparticls (EMP) pattern with body mass index (BMI) in CHF patients. METHODS: The study retrospectively evolved 153 patients (86 males) who were underwent multispiral contrast-enhanced computed tomography angiography or conventional angiographic examination of coronary arteries. Flowcytometry analysis for quantifying the number of EMPs was used at baseline. RESULTS: Using C-statistics for models with CHF, BMI, and circulating biomarkers (NT-pro-BNP, OPG and adiponectin) as continuous variables we found that adding of BMI to the based model (NYHA class of CHF) improved the relative IDI by 12.5% for increased CD31+/annexin V+ EMPs to CD62E+ EMPs ratio. When we used other model constructed on entering variables IDI appears to be improved up to 5.8% for increased EMPs (available for NT-pro-BNP as continuous variable). Three biomarkers (NYHA class of CHF+NT-pro-BNP+OPG) and four biomarkers (NYHA class of CHF+NT-pro-BNP+OPG+adiponectin) could not significantly improve predictive model based on combination of BMI and NYHA class of CHF for increased CD31+/annexin V+ EMPs to CD62E+ EMPs ratio. CONCLUSION: We suggested that lower BMI is significant predictor for impaired phenotype of circulating EMPs in CHF patients.

Circulating thrombospondine-2 in patients with moderate-to-severe chronic heart failure due to coronary artery disease.

Chronic heart failure (CHF) remains a leading cause of morbidity and mortality. In the current study, we aimed to evaluate the predictive value of circulating thrombospondin-2 (TSP-2) for cumulative survival in patients with ischemic CHF due to coronary artery disease (CAD). The results showed that during a median follow-up of 2.18 years, 21 participants died and 106 subjects were hospitalized repeatedly. The median circulating levels of TSP-2 in patients who survived and those who died were 0.63 ng/mL (95%CI=0.55-0.64 ng/mL) and 1.03 ng/mL (95% CI=0.97-1.07 ng/mL) (P<0.001). Circulating TSP-2 independently predicted all-cause mortality (OR=1.27; 95%CI=1.08-1.59; P=0.002), CHF-related death (OR=1.16; 95%CI=1.02-1.50; P<0.001), and also CHF-related rehospitalization (OR=1.12; 95%CI=1.07-1.25; P<0.001). In conclusion, among CAD patients with symptomatic CHF, increased circulating TSP-2 is correlated with increased 3-year CHF-related death, all-cause mortality, and risk for recurrent hospitalization.

The utility of biomarker risk prediction score in patients with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) has been remained a leading cause of cardiovascular morbidity and mortaluty. The risk stratification of CHF individuals based on clinical criteria and biomarkers' models may improve medical care and probably increase efficacy of treatment strategy. However, various predictive models approved for CHF patients appear to be distinguished in their prognostications. The study aim was to evaluate whether biomarker risk prediction score is powerful tool for risk assessment of three-year fatal and non-fatal cardiovascular events in CHF patients. METHODS: It was studied prospectively the incidence of fatal and non-fatal cardiovascular events in a cohort of 388 patients with ischemic-induced CHF within 3 years. Circulating biomarkers were collected at baseline of the study. RESULTS: Independent predictors of clinical outcomes in patients with CHF were NT-pro-BNP, galectin-3, hs-CRP, osteoprotegerin, CD31(+)/annexin V(+) endothelail-derived microparticles (EMPs) and CD31(+)/annexin V(+) EMPs to CD14(+)CD309(+) monuclear progenitor cells (MPCs) ratio. Index of cardiovascular risk was calculated by mathematical summation of all ranks of independent predictors, which occurred in the patients included in the study. Kaplan-Meier analysis showed that patients with CHF and the magnitude of the risk of less than 4 units have an advantage in survival when compared with patients for whom obtained higher values of cardiovascular risk score ranks. CONCLUSION: Biomarker risk score for cumulative cardiovascular events, constructed by measurement of circulating NT-pro-BNP, galectin-3, hs-CRP, osteoprotegerin, CD31+/annexin V+ EMPs and CD31(+)/annexin V(+) EMPs to CD14(+)CD309(+) MPCs ratio, allowing reliably predict the probability survival of patients with CHF.

The predictive role of circulating microparticles in patients with chronic heart failure.

AIM: The study aim was to evaluate whether circulating microparticles with apoptotic or non-apoptotic phenotypes are useful for risk assessment of 3-year cumulative fatal and non-fatal cardiovascular events in CHF patients. METHODS: The incidence of fatal and non-fatal cardiovascular events, as well as the frequency of occurrence of death from any cause in a cohort of 388 patients with CHF during 3 years of observation was studied prospectively. Circulating levels of NT-pro brain natriuretic peptide (NT-pro-BNP), high-sensitivity C-reactive protein (hs-CRP), and endothelial apoptotic microparticles (EMPs) were measured at baseline. RESULTS: Median follow-up was 2.32 years (IQR = 1.8-3.1). During follow-up, 110 cardiovascular events (including 43 fatal cases) were determined. Additionally, 74 subjects were hospitalized repetitively due to worsening CHF and also 16 subjects were readmitted in the hospital due to other cardiovascular reasons. In the univariate logistic regression analysis, the main factors independently related with cumulative endpoints were creatinine, fasting glucose, HbA1c, total cholesterol, uric acid, various types of EPMs, NT-pro-BNP, hs-CRP, NYHA class, decreased left ventricular ejection fraction (LVEF) less 45%, and type 2 diabetes mellitus. In multivariate model NYHA class, decreased LVEF (less 45%), NT-pro-BNP, hs-CRP, CD144 +/CD31 +/annexin V + EMPs, and CD31 +/annexin V + EMPs remained statistically significant for cumulative endpoint. Adding of CD144 +/CD31 +/annexin V + EMCs and CD31 +/annexin V + EMCs to the standard ABC model may improve the relative IDI for cumulative endpoint by 11.4% and 10.5% respectively. CONCLUSION: Apoptotic phenotype of circulating microparticles may relate 3-year combined clinical outcomes in CHF patients.

The Association of Subclinical Hypothyroidism and Pattern of Circulating Endothelial-Derived Microparticles Among Chronic Heart Failure Patients.

BACKGROUND: Subclinical hypothyroidism (SH) is diagnosed biochemically by the presence of normal serum free thyroxine concentration, in conjunction with an elevated serum thyroid-stimulating hormone level. Recent studies have demonstrated the frequent association between SH and cardiovascular diseases and risk factors. OBJECTIVES: To evaluate the impact of SH on patterns of circulating endothelial-derived microparticles, (EMPs) among chronic heart failure (CHF) patients. PATIENTS AND METHODS: This is a retrospective study involving a cohort of 388 patients with CHF. Fifty-three CHF subjects had SH and 335 patients were free from thyroid dysfunction. Circulating levels of N-terminal-pro brain natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), thyroid-stimulating hormone (TSH), total and free thyroxine (T4), and triiodothyronine (T3), and endothelial apoptotic microparticles (EMPs), were measured at baseline. SH was defined, according to contemporary clinical guidelines, as a biochemical state associated with an elevated serum TSH level of greater 10 µU/L and normal basal free T3 and T4 concentrations. RESULTS: Circulating CD31+/annexin V+ EMPs were higher in patients with SH compared to those without SH. In contrast, activated CD62E+ EMP numbers were not significantly different between both patient cohorts. Using uni (bi) variate and multivariate age- and gender-adjusted regression analysis, we found several predictors that affected the increase of the CD31+/annexin V+ to CD62E+ ratio in the patient study population. The independent impact of TSH per 6.5 µU/L (odds ratio [OR] = 1.23, P = 0.001), SH (OR = 1.22, P = 0.001), NT-proBNP (OR = 1.19, P = 0.001), NYHA class (OR = 1.09, P = 0.001), hs-CRP per 4.50 mg/L (OR = 1.05, P = 0.001), dyslipidemia (OR = 1.06, P = 0.001), serum uric acid per 9.5 mmol/L (OR = 1.04, P = 0.022) on the increase in the CD31+/annexin V+ to CD62E+ ratio, was determined. CONCLUSIONS: We believe that the SH state in CHF patients may be associated with the impaired pattern of circulating EMPs, with the predominantly increased number of apoptotic-derived microparticles.

The effect of angiotensin-2 receptor blocker valsartan on circulating level of endothelial progenitor cells in diabetic patients with asymptomatic coronary artery disease.

BACKGROUND: Decreased circulating endothelial progenitor cells (EPCs) are considered as strong and robust biomarkers for the prediction of cardiovascular outcomes in diabetic populations. The perspectives for modulating EPCs levels in T2DM with known coronary artery disease (CAD) with different drugs, affected mechanisms of improving mobilization of EPCs from tissue, are not still understood. AIMS: To evaluate an effect of angiotensin-2 receptor blocker valsartan on circulating level of EPCs in diabetic patients with asymptomatic CAD. METHODS: The study population was structured retrospectively after determining the CAD by contrast-enhanced spiral computed tomography angiography in 126 asymptomatic subjects. All subjects were distributed into two cohorts depending on daily doses of valsartan given. Low (80-160 mg daily orally) and high doses (240-320 mg daily orally) of valsartan were used and they were adjusted depending on achieving BP level less than 140/80 mmHg. RESULTS: The change from baseline in CD34(+) subset cells (frequencies and absolute values) was not significantly different between treatment cohorts. We found a significant increase of circulating level of CD14(+)CD309(+) cells in two patient cohorts. But more prominent change of CD14(+)CD309(+) cells was verified in subjects who were given valsartan in high daily doses when compared with persons who were included into cohort with low daily doses of the drug (1.96% versus 2.59%, respectively; P<0.05). Therefore, both frequencies and absolute values in CD14(+)CD309(+)Tie(2+) were increased significantly in patients who were treated with high doses of valsartan only. CONCLUSION: We found positive influence of angiotensin-2 receptor blocker valsartan in escalation doses on bone marrow-derived EPCs phenotyped as CD14(+)CD309(+) and CD14(+)CD309(+)Tie(2+) in T2DM patients with known asymptomatic CAD.

The utility of biomarker risk prediction score in patients with chronic heart failure.

UNLABELLED: Chronic heart failure (CHF) remains a leading cause of cardiovascular death worldwide. Current risk models allow better prognosis, however further tools for assessing risk are needed. Thus, this study was aimed to evaluate whether biomarker risk prediction score is powerful tool for risk assessment of three-year fatal and non-fatal cardiovascular events in CHF patients. METHODS: A prospective study on the incidence of fatal and non-fatal cardiovascular events, as well as the frequency of occurrence of death from any cause in a cohort of 388 patients with CHF during 3 years of observation was performed. Circulating levels of NT-pro brain natriuretic peptide (NT-pro-BNP), galectin-3, high-sensitivity C-reactive protein (hs-CRP), osteoprotegerin and its soluble receptor sRANKL, osteopontin, osteonectin, adiponectin, endothelial apoptotic microparticles (EMPs) and mononuclear progenitor cells (MPCs) were measured at baseline. RESULTS: Median follow-up of patients included in the study was 2.76 years. There were 285 cardiovascular events determined, including 43 deaths and 242 readmissions. Independent predictors of clinical outcomes in patients with CHF were NT-pro-BNP, galectin-3, hs-CRP, osteoprotegerin, CD31(+)/annexin V(+) EMPs and EMPs/CD14(+)CD309(+) MPCs ratio. Index of cardiovascular risk was calculated by mathematical summation of all ranks of independent predictors, which occurred in the patients included in the study. The findings showed that the average value of the index of cardiovascular risk in patients with CHF was 3.17 points (95% CI = 1.65-5.10 points). Kaplan-Meier analysis showed that patients with CHF and the magnitude of the risk of less than 4 units have an advantage in survival when compared with patients for whom obtained higher values of ranks cardiovascular risk score. CONCLUSION: Biomarker risk score for cumulative cardiovascular events, constructed by measurement of circulating NT-pro-BNP, galectin-3, hs-CRP, osteoprotegerin, CD31(+)/annexin V(+) EMPs and EMPs/CD14(+)CD309(+) MPCs ratio, reliably predicts the probability survival of patients with CHF, regardless of age, gender, state of the contractile function of the left ventricle and the number of comorbidities.

Predictive value of apoptotic microparticles to mononuclear progenitor cells ratio in advanced chronic heart failure patients.

BACKGROUND: Acutely decompensated chronic heart failure (ADHF) is considered a life-threatening event. Despite contemporary treatment strategies of ADHF, frequent recurrent hospitalizations due to other cardiovascular reasons after discharge of patients from hospital occur. The objective of the study was to examine the prognostic value of circulating endothelial-derived apoptotic microparticles (EMPs) to mononuclear progenitor cells (MPCs) ratio for post-discharge patients with clinical stabilization after ischemic ADHF. METHODS: We consecutively enrolled 136 patients (62 male) with coronary artery disease (CAD) admitted with a primary diagnosis of ADHF. All patients gave written informed consent for participation in the study. At baseline, all enrolled patients were hemodynamically stable and they had New York Heart Association (NYHA) III/IV classes of ischemic chronic heart failure (CHF). Observation period started at discharge from the hospital and was up to 3 years. Flow cytometry analysis for quantifying the number of EMPs and angiogenic MPCs was used. RESULTS: Calculated EMP to MPC ratios in survivor and dead patient cohort were 8.4 (95% CI=7.6-9.2) and 78.9 (95% CI=53.0-116.6), respectively (p=0.001). MPCs, EMPs, NYHA class, N-terminal pro-brain natriuretic peptide (NT-proBNP) and increased NT-proBNP>30% within 24-84h of admission period remained statistically significant for all-cause mortality, CHF-related death, and CHF-related rehospitalization, whereas left ventricular ejection fraction and high-sensitivity C-reactive protein for all variables did not. We found that the addition of EPMs to MPCs ratio to the ABC model (NT-pro-BNP, increased NT-pro-BNP>30%) improved the relative integrated discrimination indices by 19.6% for all-cause mortality, by 21.7% for CHF-related death, and by 19.5% for CHF-related rehospitalization. CONCLUSION: We demonstrated that EMP to MPC ratio is considered an important indicator of an imbalance between angiogenic and apoptotic responses with possible relation to cardiovascular outcomes in post-discharge patients with clinical stabilization after ischemic ADHF.

Relationship between circulating endothelial progenitor cells and insulin resistance in non-diabetic patients with ischemic chronic heart failure.

AIM: The objective of this study was to assess a relationship between insulin resistance (IR) and counts of CD45(-)CD34(+), CD14(+)CD309(+), and CD14(+)CD309(+)Tie2(+) phenotyped circulating endothelial progenitor cells (EPCs) in patients with ischemic chronic heart failure (CHF). METHODS: The study involved 300 CHF patients (186 males) aged 48-62 years with angiografically proven coronary artery disease and/or previously defined myocardial infarction. Insulin resistance was assessed by the homeostasis model assessment for insulin resistance (HOMA-IR). EPC populations were phenotyped by flow cytofluorimetry. RESULTS: Circulating EPCs counts were statistically significantly lower in CHF patients with IR than in patients without IR. We found that the most valuable multivariable predictors of the depletion of the CD45(+)CD34(+) EPCs were NT-pro-brain natriuretic peptide (BNP) (1.32; 95% CI=1.19-2.77; P=0.001), left ventricular ejection fraction (OR=1.30; 95% CI=1.09-1.60; P=0.002), NYHA class (OR=1.12; 95% CI=1.02-1.19; P=0.001). NT-pro-BNP (OR=1.45; 95% CI=1.15-2.90; P=0.003), left ventricular ejection fraction (OR=1.32; 95% CI=1.11-1.65; P=0.001) were found as powerful predictors for depletion in CD45(-)CD34(+) EPCs. We also identified six independent variables with high predictive value for depletion of CD14(+)CD309(+) EPCs: NT-pro-BNP (OR=1.41; 95% CI=1.15-2.90; P=0.003), left ventricular ejection fraction (OR=1.18; 95% CI=1.10-1.76; P=0.036), NYHA class (OR=1.15; 95% CI=1.07-1.22; P=0.001), hs-C reactive protein (OR=1.02; 95% CI=1.01-1.05; P=0.012). As independent multivariable predictors for depletion in CD14(+)CD309(+)Tie2(+) EPCs were selected five variables: NT-pro-BNP (OR=1.65; 95% CI=1.44-4.70; P=0.006), left ventricular ejection fraction (OR=1.07; 95% CI=1.02-1.12; P=0.018), NYHA class (OR=1.13; 95% CI=1.06-1.21; P=0.001), hs-C-reactive protein (OR=1.08; 95% CI=1.03-1.16; P=0.002). CONCLUSION: IR may be an additional factor contributing decreased circulating level of proangiogenic EPCs in non-diabetic CHF patients.

Serum uric Acid predicts declining of circulating proangiogenic mononuclear progenitor cells in chronic heart failure patients.

INTRODUCTION: Serum uric acid (SUA) is considered a marker for natural progression of chronic heart failure (CHF) mediated cardiovascular remodelling. CHF associates with declining of circulating mononuclear progenitor cells (MPCs). The objective of this study was to evaluate the interrelationship between SUA concentrations and proangiogenic MPCs in ischemic CHF patients. METHODS: The study population was structured retrospectively after determining the coronary artery disease (CAD) by contrast-enhanced spiral computed tomography angiography in 126 subjects with symptomatic ischemic mild-to-severe CHF and 128 CAD subjects without CHF. Baseline biomarkers were measured in all patients. Cox proportional multivariate hazard ratio was calculated for predictors of MPCs declining in both CHF and non-CHF patient population predictors of MPCs declining in CHF subjects were examined in stepwise logistic regression. C-statistics, integrated discrimination indices (IDI) and net-reclassification improvement were utilized for prediction performance analyses. RESULTS: Cox proportional adjusted hazard ratio analyses for CD14(+)CD309(+) and CD14(+)CD309(+)Tie2(+) MPCs by SUA has shown that the higher quartiles (Q3 and Q4) of SUA compared to the lower quartiles (Q1 and Q2) are associated with increased risks of depletion of both CD14(+)CD309(+) and CD14(+)CD309(+)Tie2(+) MPCs. The addition of Q4 SUA to the ABC model improved the relative IDI by 13.8% for depletion of CD14(+)CD309(+) MPCs and by 14.5% for depletion of CD14(+)CD309(+)Tie2(+) MPCs. CONCLUSION: Circulating levels of proangiogenic MPCs are declined progressively depending on the levels of SUA in the HF subjects with CHF. We suggest that even mild elevations of SUA might be used to predict of relative depletion of proangiogenic MPCs among chronic HF patients.

Circulating endothelial-derived apoptotic microparticles in the patients with ischemic symptomatic chronic heart failure: relevance of pro-inflammatory activation and outcomes.

BACKGROUND: Endothelial-derived apoptotic microparticles (EMPs) play a pivotal role in endothelial dysfunction in hronic Heart Failure (CHF). OBJECTIVES: The present study aimed to evaluate the association between EMPs and pro-inflammatory biomarkers, clinical status, and outcomes in the patients with ischemic CHF. PATIENTS AND METHODS: This study was conducted on 154 patients with ischemic symptomatic moderate-to-severe CHF on discharge from hospital. The observation period was up to 3 years. Circulating NT-pro-BNP, TNF-alpha, sFas, and sFas ligand were determined at baseline. Flow cytometry analysis was used for quantifying the number of EMPs. All-cause mortality, CHF-related death, and CHD-re-hospitalization rate were examined. The data were analyzed using descriptive statistics, Receive Operation Characteristic Curve (ROC), and logistic regression analysis. Besides, P < 0.05 was considered as statistically significant. RESULTS: During a median follow-up of 2.18 years, 21 participants died and 106 subjects were hospitalized repetitively. The results showed a significant difference between the patients with a large number of EMPs (> 0.514 n/mL) and those with a low level of the biomarker (< 0.514 n/mL) regarding their survival. The number of circulating EPMs independently predicted all-cause mortality (OR = 1.58; 95% CI = 1.20 - 1.88; P = 0.001), CHF-related death (OR = 1.22; 95% CI: 1.12 - 1.36; P < 0.001), and CHF-related re-hospitalization (OR = 1.20; 95% CI: 1.11 - 1.32; P < 0.001). CONCLUSIONS: Among the patients with symptoms of CHF, increased number of circulating EMPs was associated with increased 3-year CHF-related death, all-cause mortality, and risk of recurrent hospitalization due to CHF.