Identification of Macrophage Genotype and Key Biological Pathways in Circulating Angiogenic Cell Transcriptome.

BACKGROUND: Circulating angiogenic cells (CAC) have been identified as important regulators of vascular biology. However, there is still considerable debate about the genotype and function of CAC. METHODS AND RESULTS: Data from publicly available gene expression data sets were used to analyse the transcriptome of in vitro cultured CAC (CACiv). Genes and pathways of interest were further evaluated using qPCR comparing CACiv versus CD14+ monocytic cells. The CACiv transcriptome strongly related to tissue macrophages, and more specifically to regulatory M2c macrophages. The cytokine expression profile of CACiv was predominantly immune modulatory and resembled the cytokine expression of tumor-associated macrophages (TAM). Pathway analysis revealed previously unrecognized biological processes in CACiv, such as riboflavin metabolism and liver X receptor (LXR)/retinoid X receptor (RXR) and farnesoid X receptor (FXR)/retinoid X receptor (RXR) pathways. Analysis of endothelial-specific genes did not show evidence for endothelial transdifferentiation. CONCLUSIONS: CACiv are genotypically similar to regulatory M2c macrophages and lack signs of endothelial differentiation.

Role of oxidative stress, angiogenesis and chemo-attractant cytokines in the pathogenesis of ischaemic protection induced by remote ischaemic conditioning: Study of a human model of ischaemia-reperfusion induced vascular injury.

AIMS: We explored the effect of remote ischaemic conditioning (RIC) on endothelial function and on circulating mediators. METHODS AND RESULTS: In 20 healthy male volunteers (mean age 31 ± 10 years), flow-mediated dilation (FMD) was measured before and after 20 min of arm ischaemia, followed by reperfusion. Remote ischaemic conditioning (RIC) was performed by applying 3 cycles of 5 min of ischaemia of the leg at the onset of index arm ischaemia. Each volunteer underwent the IR-induced vascular injury protocol with and without RIC in a crossover study design. In the control group, IR significantly reduced FMD (5.9 ± 2.9% before IR vs. 2.2 ± 3.7% after IR; p < 0.001). This effect was significantly attenuated by performing RIC (FMD of 5.5 ± 3.1% before IR vs. 4.0 ± 3.4% % after IR; p for interaction = 0.01). Serum levels of SOD and ADMA increased significantly whereas MCP-1 and VEGF levels decreased significantly. Only changes in SOD levels were significantly related to the degree of RIC induced protection (r² = 0.34; p = 0.018). CONCLUSION: RIC has protective effects against endothelial IR injury. Our biomarker study suggests that anti-oxidative stress mediators, such as SOD, seem to be more involved in the pathogenesis of RIC-induced protection in humans than angiogenesis factors or chemo-attractant cytokines.

Failed Downregulation of Circulating MicroRNA-155 in the Early Phase after ST Elevation Myocardial Infarction Is Associated with Adverse Left Ventricular Remodeling.

BACKGROUND: MicroRNA are noncoding RNA that have a significant role in both inflammatory and cardiovascular diseases. AIMS: We aimed to assess whether the inflammation-related microRNA-155 is associated with the development of adverse left ventricular (LV) remodeling following ST elevation myocardial infarction (STEMI). METHODS: Peripheral blood samples were collected in the inflammatory (day 2), proliferative (day 5), and maturation phases (6 months) after STEMI (n = 20). Granulocytes, monocytes, and lymphocytes were enumerated with flow cytometry. The changes in LV volumes were assessed with 3-D echocardiography on day 1 and after 6 months. Adverse remodeling was defined as a >20% increase in end-diastolic volume. Healthy subjects were recruited as controls. RESULTS: MicroRNA-155 measured on day 5 correlated positively with the relative change in end-diastolic volume (ρ = 0.490, p = 0.028). MicroRNA-155 (day 5) was significantly higher in patients with compared to patients without adverse LV remodeling. The expression level was similar in healthy subjects (n = 8) and in patients with LV remodeling. There was a positive correlation between microRNA-155 and the amount of monocytes (day 5, ρ = 0.463, p = 0.046). CONCLUSION: Impaired downregulation of microRNA-155 during the second phase of the post- STEMI inflammatory response is a determinant of the development of adverse LV remodeling.

Accelerated cellular senescence as underlying mechanism for functionally impaired bone marrow-derived progenitor cells in ischemic heart disease.

BACKGROUND AND AIMS: Bone marrow (BM)-derived progenitor cells are functionally impaired in patients with ischemic heart disease (IHD), thereby hampering the outcome of autologous stem cell therapy. In search for underlying mechanisms for this BM dysfunction, accelerated cellular senescence was explored. METHODS: We analysed telomere length of BM-derived mononuclear cells (MNC) by MMqPCR in patients with coronary artery disease (n = 12), ischemic heart failure (HF; n = 9), non-ischemic HF (n = 7) and controls (n = 10), and related it to their myeloid differentiation capacity. Expressions of senescence-associated genes p53, p21Cip1 and p16lnk4A; and telomere maintenance genes TERT, TRF1/2, Sirt1 in BM-MNC were evaluated using qPCR. Pro-inflammatory cytokine levels (TNFα, IFNy, IL-6) in BM were measured by MSD. RESULTS: BM-MNC telomere length was shortened in patients with IHD, irrespective of associated cardiomyopathy, and shortened further with increasing angiographic lesions. This telomere shortening was associated with reduced myeloid differentiation capacity of BM-MNC, suggesting accelerated senescence as underlying cause for progenitor cell dysfunction in IHD. Both p16lnk4A and p21Cip1 were activated in IHD and inversely related to myeloid differentiation capacity of BM-MNC; hence, the BM-MNC functional impairment worsens with increasing senescence. While BM-MNC telomere attrition was not related with alterations in TERT, TRF1/2 and Sirt1 expression, IFNy levels were associated with p21Cip1/p16lnk4A upregulation, suggesting a link between inflammation and cellular senescence. Still, the trigger for telomere shortening in IHD needs to be elucidated. CONCLUSIONS: Accelerated replicative senescence is associated with a functional impairment of BM-derived progenitor cells in IHD and could be targeted to improve efficacy of stem cell therapy.

Impact of Lifestyle Intervention on HDL-Induced eNOS Activation and Cholesterol Efflux Capacity in Obese Adolescent.

Background. Endothelial dysfunction occurs in obese children and adolescent and is regarded as a key step in the development of atherosclerosis. Important components for the development of endothelial dysfunction are reduced activity of endothelial nitric oxide synthase (eNOS) and an increase in cholesterol deposition in the vessel wall, due to reduced reverse cholesterol transport (RCT) activity. High density lipoprotein (HDL) exhibits antiatherosclerotic properties including modulation of eNOS activity and cholesterol efflux capacity. Lifestyle intervention programs can modify endothelial dysfunction in obese adolescents, but their impact on HDL-mediated eNOS activation and RCT is unknown so far. Methods. Obese adolescents (15 ± 1 years, BMI > 35 kg/m2) where randomized either to an intervention group (IG, n = 8; restricted diet and exercise) or to a usual care group (UC, n = 8). At the beginning and after 10 months of treatment HDL-mediated eNOS phosphorylation and cholesterol efflux capacity were evaluated. Results. Ten months of treatment resulted in a substantial weight loss (-31%), an improvement of endothelial function, and an increase in HDL-mediated eNOS-Ser1177 phosphorylation and RCT. A correlation between change in eNOS-Ser1177 phosphorylation or RCT and change in endothelial function was noted. Conclusion. A structured lifestyle intervention program improves antiatherosclerotic HDL functions, thereby positively influencing endothelial function.

Impaired vascular function contributes to exercise intolerance in chronic kidney disease.

BACKGROUND: Exercise intolerance is an important feature in patients with chronic kidney disease (CKD) and is prognostic for both increased morbidity and mortality. Little is known about the underlying mechanisms in predialysis CKD. This study aimed to gain more insight into the role of vascular dysfunction in the exercise intolerance of predialysis CKD. In addition, vascular-related microRNAs (miRNAs)-as epigenetic regulators of exercise capacity-were analysed. METHODS: Sixty-three patients with CKD stages 1-5 and 18 healthy controls were included. Peak oxygen consumption (VO2peak) was determined by cardiopulmonary exercise testing, endothelial function by flow-mediated dilation (FMD) and arterial stiffness by carotid-femoral pulse wave velocity (PWV). Plasma miRNA levels (miR-21, miR-126, miR-146a, miR-150 and miR-210) were quantified by quantitative RT-PCR. RESULTS: VO2peak was already impaired in mild CKD (stages 1-3A) and significantly correlated with estimated glomerular filtration rate (eGFR; r = 0.525, P < 0.001). Likewise, both FMD and PWV were significantly correlated with eGFR (r = 0.319, P = 0.007 and r = -0.365, P = 0.001, respectively). In multiple regression analysis, PWV remained one of the strongest independent determinants of VO2peak (ß = -0.301, P = 0.01). Of the studied miRNA, circulating levels of miR-146a and miR-150 correlated with eGFR, PWV and VO2peak, but the association with the latter was lost when correcting for PWV. CONCLUSIONS: Arterial stiffness contributes to the observed reduced aerobic capacity in predialysis CKD, independent of age, haemoglobin levels and endothelial function and represents a promising therapeutic target for improving exercise capacity in this population. Future work is required to elucidate why higher circulating levels of miR-146a and miR-150 are associated with impaired renal function and increased arterial stiffness.

The evolving role of adiponectin as an additive biomarker in HFrEF.

Heart failure (HF) is a growing health problem. Despite improved management and outcome, the number of patients with HF is expected to keep rising in the following years. In recent research, adiponectin was shown to exert beneficial effects in the cardiovascular system, but the protein was also implicated in the development and progression of HF. The objective of this review is to provide an overview of current knowledge on the role of adiponectin in HF with reduced ejection fraction. We discuss the cardioprotective and (anti-) inflammatory actions of adiponectin and its potential use in clinical diagnosis and prognosis.

Bone Marrow-Derived Progenitor Cells Are Functionally Impaired in Ischemic Heart Disease.

To determine whether the presence of ischemic heart disease (IHD) per se, or rather the co-presence of heart failure (HF), is the primum movens for less effective stem cell products in autologous stem cell therapy, we assessed numbers and function of bone marrow (BM)-derived progenitor cells in patients with coronary artery disease (n = 17), HF due to ischemic cardiomyopathy (n = 8), non-ischemic HF (n = 7), and control subjects (n = 11). Myeloid and erythroid differentiation capacity of BM-derived mononuclear cells was impaired in patients with underlying IHD but not with non-ischemic HF. Migration capacity decreased with increasing IHD severity. Hence, IHD, with or without associated cardiomyopathy, is an important determinant of progenitor cell function. No depletion of hematopoietic and endothelial progenitor cells (EPC) within the BM was observed, while circulating EPC numbers were increased in the presence of IHD, suggesting active recruitment. The observed myelosuppression was not driven by inflammation and thus other mechanisms are at play.

Improving stem cell therapy in cardiovascular diseases: the potential role of microRNA.

The initial promising prospect of autologous bone marrow-derived stem cell therapy in the setting of cardiovascular diseases has been overshadowed by functional shortcomings of the stem cell product. As powerful epigenetic regulators of (stem) cell function, microRNAs are valuable targets for novel therapeutic strategies. Indeed, modulation of specific miRNA expression could contribute to improved therapeutic efficacy of stem cell therapy. First, this review elaborates on the functional relevance of miRNA dysregulation in bone marrow-derived progenitor cells in different cardiovascular diseases. Next, we provide a comprehensive overview of the current evidence on the effect of specific miRNA modulation in several types of progenitor cells on cardiac and/or vascular regeneration. By elaborating on the cardioprotective regulation of progenitor cells on cardiac miRNAs, more insight in the underlying mechanisms of stem cell therapy is provided. Finally, some considerations are made regarding the potential of circulating miRNAs as regulators of the miRNA signature of progenitor cells in cardiovascular diseases.

Primary skeletal muscle myoblasts from chronic heart failure patients exhibit loss of anti-inflammatory and proliferative activity.

BACKGROUND: Peripheral skeletal muscle wasting is a common finding with adverse effects in chronic heart failure (HF). Whereas its clinical relevance is beyond doubt, the underlying pathophysiological mechanisms are not yet fully elucidated. We aimed to introduce and characterize the primary culture of skeletal muscle cells from individual HF patients as a supportive model to study this muscle loss. METHODS AND RESULTS: Primary myoblast and myotubes cultures were successfully propagated from the m. vastus lateralis of 6 HF patients with reduced ejection fraction (HFrEF; LVEF <45 %) and 6 age and gender-matched healthy donors. HFrEF cultures were not different from healthy donors in terms of morphology, such as myoblast size, shape and actin microfilament. Differentiation and fusion indexes were identical between groups. Myoblast proliferation in logarithmic growth phase, however, was attenuated in the HFrEF group (p = 0.032). In addition, HFrEF myoblasts are characterized by a reduced TNFR2 expression and IL-6 secretion (p = 0.017 and p = 0.016; respectively). CONCLUSION: Biopsy derived primary skeletal muscle myoblasts of HFrEF patients produce similar morphological and myogenic differentiation responses as myoblasts of healthy donors, though demonstrate loss of anti-inflammatory and proliferative activity.

Adiponectin resistance in skeletal muscle: pathophysiological implications in chronic heart failure.

Skeletal muscle wasting is a common complication of chronic heart failure (CHF) and linked to poor patient prognosis. In recent years, adiponectin was postulated to be centrally involved in CHF-associated metabolic failure and muscle wasting. This review discusses current knowledge on the role of adiponectin in CHF. Particular emphasis will be given to the complex interaction mechanisms and the intracellular pathways underlying adiponectin resistance in skeletal muscle of CHF patients. In this review, we propose that the resistance process is multifactorial, integrating abnormalities emanating from insulin signalling, mitochondrial biogenesis, and ceramide metabolism.

Childhood obesity-related endothelial dysfunction: an update on pathophysiological mechanisms and diagnostic advancements.

Childhood obesity jeopardizes a healthy future for our society's children as it is associated with increased cardiovascular morbidity and mortality later on in life. Endothelial dysfunction, the first step in the development of atherosclerosis, is already present in obese children and may well represent a targetable risk factor. Technological advancements in recent years have facilitated noninvasive measurements of endothelial homeostasis in children. Thereby this topic ultimately starts to get the attention it deserves. In this paper, we aim to summarize the latest insights on endothelial dysfunction in childhood obesity. We discuss methodological advancements in peripheral endothelial function measurement and newly identified diagnostic markers of vascular homeostasis. Finally, future challenges and perspectives are set forth on how to efficiently tackle the catastrophic rise in cardiovascular morbidity and mortality that will be inflicted on obese children if they are not treated optimally.

Tumor necrosis factor-α impairs adiponectin signalling, mitochondrial biogenesis, and myogenesis in primary human myotubes cultures.

Skeletal muscle metabolic changes are common in patients with chronic heart failure (HF). Previously, we demonstrated a functional skeletal muscle adiponectin resistance in HF patients with reduced left ventricular ejection fraction (HFrEF). We aimed to examine the impact of adiponectin receptor 1 (AdipoR1) deficiency and TNF-α treatment on adiponectin signaling, proliferative capacity, myogenic differentiation, and mitochondrial biogenesis in primary human skeletal muscle cells. Primary cultures of myoblasts and myotubes were initiated from the musculus vastus lateralis of 10 HFrEF patients (left ventricular ejection fraction; 31.30 ± 2.89%) and 10 age- and gender-matched healthy controls. Healthy control cultures were transfected with siAdipoR1 and/or exposed to TNF-α (10 ng/ml; 72 h). Primary cultures from HFrEF patients preserved the features of adiponectin resistance in vivo. AdipoR1 mRNA was negatively correlated with time to reach maximal cell index (r = -0.7319, P = 0.003). SiRNA-mediated AdipoR1 silencing reduced pAMPK (P < 0.01), AMPK activation (P = 0.046), and myoblast proliferation rate (xCELLigence Real-Time Cellular Analysis; P < 0.0001). Moreover, TNF-α decreased the mRNA expression of genes involved in glucose (APPL1, P = 0.0002; AMPK, P = 0.021), lipid (PPARα, P = 0.025; ACADM, P = 0.003), and mitochondrial (FOXO3, P = 0.018) metabolism, impaired myogenesis (MyoD1, P = 0.053; myogenin, P = 0.048) and polarized cytokine secretion toward a growth-promoting phenotype (IL-10, IL-1ß, IFN-γ, P < 0.05 for all; Meso Scale Discovery Technology). Major features of adiponectin resistance are retained in primary cultures from the skeletal muscle of HFrEF patients. In addition, our results suggest that an increased inflammatory constitution contributes to adiponectin resistance and confers alterations in skeletal muscle differentiation, growth, and function.

Adiponectin and ischemia-reperfusion injury in ST segment elevation myocardial infarction.

BACKGROUND: Models of experimental ischemia-reperfusion (IR) in adiponectin knockout animals have shown that adiponectin mediates protection against the development of IR injury. However, the role of adiponectin in IR injury in humans is largely unknown. METHODS: In a total of 234 ST segment elevation myocardial infarction (STEMI) patients, baseline circulating total adiponectin concentration was correlated with IR injury after primary percutaneous coronary intervention (pPCI) and with major adverse cardiac events (MACE, death and cardiac hospitalization) during one year of follow up. IR injury was defined by serial electrocardiography (ECG) as >30% persistent ST segment elevation despite successful restoration of vessel patency and by angiography as thrombolysis in myocardial infarction (TIMI) blush grade<2. RESULTS: IR injury was present in 31% of patients according to ECG criteria and in 28% of patients according to angiographic criteria. The median adiponectin level was 6.8 µg/ml in patients with ECG signs of IR injury and 6.5 µg/ml in patients without ECG signs of IR (p=0.26). When the angiographic criteria of IR were used, the median adiponectin level was 6.9 µg/ml for patients with IR versus 6.3 µg/ml for patients without IR (p=0.06). MACE occurred in 27% of the patients. Median adiponectin levels were similar in patients with MACE and in those without MACE: 6.3 vs. 6.4 µg/ml (p=0.24). In a multivariate model, no significant relation between circulating adiponectin levels and IR injury or MACE was evident. CONCLUSION: In the current era of pPCI, IR injury still occurs in almost one third of STEMI patients. Our findings do not support a major protective role of adiponectin in the prevention or attenuation of IR injury in these patients.

Plasma levels of microRNA in chronic kidney disease: patterns in acute and chronic exercise.

Exercise training is an effective way to improve exercise capacity in chronic kidney disease (CKD), but the underlying mechanisms are only partly understood. In healthy subjects (HS), microRNA (miRNA or miR) are dynamically regulated following exercise and have, therefore, been suggested as regulators of cardiovascular adaptation to exercise. However, these effects were not studied in CKD before. The effect of acute exercise (i.e., an acute exercise bout) was assessed in 32 patients with CKD and 12 age- and sex-matched HS (study 1). miRNA expression in response to chronic exercise (i.e., a 3-mo exercise training program) was evaluated in 40 CKD patients (study 2). In a subgroup of study 2, the acute-exercise induced effect was evaluated at baseline and at follow-up. Plasma levels of a preselected panel miRNA, involved in exercise adaptation processes such as angiogenesis (miR-126, miR-210), inflammation (miR-21, miR-146a), hypoxia/ischemia (miR-21, miR-210), and progenitor cells (miR-150), were quantified by RT-PCR. Additionally, seven miRNA involved in similar biological processes were quantified in the subgroup of study 2. Baseline, studied miRNA were comparable in CKD and HS. Following acute exercise, miR-150 levels increased in both CKD (fold change 2.12 ± 0.39, P = 0.002; and HS: fold change 2.41 ± 0.48 P = 0.018, P for interaction > 0.05). miR-146a acutely decreased in CKD (fold change 0.92 ± 0.13, P = 0.024), whereas it remained unchanged in HS. Levels of miR-21, miR-126, and miR-210 remained unaltered. Chronic exercise did not elicit a significant change in the studied miRNA levels. However, an acute exercise-induced decrease in miR-210 was observed in CKD patients, only after training (fold change 0.76 ± 0.15). The differential expression in circulating miRNA in response to acute and chronic exercise may point toward a physiological role in cardiovascular adaptation to exercise, also in CKD.

Effects of aerobic interval training and continuous training on cellular markers of endothelial integrity in coronary artery disease: a SAINTEX-CAD substudy.

In this large multicenter trial, we aimed to assess the effect of aerobic exercise training in stable coronary artery disease (CAD) patients on cellular markers of endothelial integrity and to examine their relation with improvement of endothelial function. Two-hundred CAD patients (left ventricular ejection fraction > 40%, 90% male, mean age 58.4 ± 9.1 yr) were randomized on a 1:1 base to a supervised 12-wk rehabilitation program of either aerobic interval training or aerobic continuous training on a bicycle. At baseline and after 12 wk, numbers of circulating CD34(+)/KDR(+)/CD45dim endothelial progenitor cells (EPCs), CD31(+)/CD3(+)/CXCR4(+) angiogenic T cells, and CD31(+)/CD42b(-) endothelial microparticles (EMPs) were analyzed by flow cytometry. Endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery. After 12 wk of aerobic interval training or aerobic continuous training, numbers of circulating EPCs, angiogenic T cells, and EMPs were comparable with baseline levels. Whereas improvement in peak oxygen consumption was correlated to improvement in FMD (Pearson r = 0.17, P = 0.035), a direct correlation of baseline or posttraining EPCs, angiogenic T cells, and EMP levels with FMD was absent. Baseline EMPs related inversely to the magnitude of the increases in peak oxygen consumption (Spearman rho = -0.245, P = 0.027) and FMD (Spearman rho = -0.374, P = 0.001) following exercise training. In conclusion, endothelial function improvement in response to exercise training in patients with CAD did not relate to altered levels of EPCs and angiogenic T cells and/or a diminished shedding of EMPs into the circulation. EMP flow cytometry may be predictive of the increase in aerobic capacity and endothelial function.

Altered expression of monocyte and dendritic cell membrane-associated antigens following coronary angiography.

INTRODUCTION: Coronary angiography is able to induce a systemic inflammatory response. We hypothesised that this procedure may affect monocyte and dendritic cell count and membrane-associated antigen expression. METHODS: Blood samples were obtained before and immediately after coronary angiography in twenty patients with stable angina pectoris. Cell enumeration and antigen expression levels were evaluated by flow cytometry. Plasma levels of soluble CD14 and interleukin-6 were quantified by ELISA. RESULTS: The absolute and relative numbers of circulating monocytes (Mon1, Mon2 and Mon3 subsets) and dendritic cells (myeloid and plasmacytoid subsets) were not significantly different pre-versus post-angiography. Expression of CD14 on Mon1 and Mon2 decreased significantly by 12.01% (P = 0.002) and 13.01% (P=0.012), respectively. CD16 expression on Mon2 (+10.53%; P=0.017) and Mon3 (+12.58%; P<0.001) increased. CD45 expressed by monocytic and dendritic cells was lowered (-5.80% and P = 0.001, -11.49% and P < 0.001, respectively). The level of plasma IL-6 decreased significantly (P = 0.002). The reduction in sCD14 was not significant (P = 0.054). CONCLUSION: Coronary angiography leads to changes in surface expression of CD14, CD16 and CD45. These findings underline the importance of blood collection prior to the angiographic procedure when aiming to study the functional analysis of monocyte and dendritic cell numbers by flow cytometry.

Diet, exercise, and endothelial function in obese adolescents.

BACKGROUND AND OBJECTIVES: Endothelial dysfunction is the first, although reversible, sign of atherosclerosis and is present in obese adolescents. The primary end point of this study was to investigate the influence of a multicomponent treatment on microvascular function. Additional objectives and end points were a reduced BMI SD score, improvements in body composition, exercise capacity, and cardiovascular risk factors, an increase in endothelial progenitor cells (EPCs), and a decrease in endothelial microparticles (EMPs). METHODS: We used a quasi-randomized study with 2 cohorts of obese adolescents: an intervention group (n = 33; 15.4 ± 1.5 years, 24 girls and 9 boys) treated residentially with supervised diet and exercise and a usual care group (n = 28; 15.1 ± 1.2 years, 22 girls and 6 boys), treated ambulantly. Changes in body mass, body composition, cardiorespiratory fitness, microvascular endothelial function, and circulating EPCs and EMPs were evaluated after 5 months and at the end of the 10-month program. RESULTS: Residential intervention decreased BMI and body fat percentage, whereas it increased exercise capacity (P < .001 after 5 and 10 months). Microvascular endothelial function also improved in the intervention group (P = .04 at 10 months; + 0.59 ± 0.20 compared with + 0.01 ± 0.12 arbitrary units). Furthermore, intervention produced a significant reduction in traditional cardiovascular risk factors, including high-sensitivity C-reactive protein (P = .012 at 10 months). EPCs were increased after 5 months (P = .01), and EMPs decreased after 10 months (P = .004). CONCLUSIONS: A treatment regimen consisting of supervised diet and exercise training was effective in improving multiple adolescent obesity-related end points.

Endothelial dysfunction in acute brain injury and the development of cerebral ischemia.

Cerebral ischemia (CeI) is a major complicating event after acute brain injury (ABI) in which endothelial dysfunction is a key player. This study evaluates cellular markers of endothelial function and in vivo reactive hyperemia in patients with ABI and their relationship to the development of cerebral ischemia. We studied cellular markers of endothelial dysfunction and the peripheral reactive hyperemia index (RHI) in 26 patients with ABI at admission and after 6 and 12 days, and compared these with those of healthy volunteers (n = 15). CeI was determined clinically or by computer tomography. In patients with ABI, RHI at admission was significantly reduced compared with healthy subjects (P = 0.003), coinciding with a decrease in circulating endothelial progenitor cells (EPC; P = 0.002). The RHI recovered in eight patients without development of CeI, but failed to fully recover by day 12 in three of four patients who developed CeI. Despite recovery of the RHI within 12 days in these patients (P = 0.003), EPC count remained significantly lower after 12 days in patients with ABI (P = 0.022). CD31(+) T cells and endothelial microparticles were not different between controls and patients. No differences were noted in cellular markers of endothelial dysfunction in patients developing CeI and those not. In conclusion, patients with ABI exhibit impaired microvascular endothelial function measured as RHI and a decreased circulating level of EPC.