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

Circulating CD34 + /KDR + endothelial progenitor cells are reduced in chronic heart failure patients as a function of Type D personality

A B S T R A C T The aim of the present study was to assess whether EPC (endothelial progenitor cell) number/function might be an explanatory factor for the observed relationship between Type D personality (a joint tendency towards negative affectivity and social inhibition) and poor cardiovascular prognosis. We also assessed whether the effect of a single exercise bout on EPC number/function was affected by Type D personality. A total of 35 sedentary men with CHF (chronic heart failure; left ventricular ejection fraction 45 %) underwent CPET (cardiopulmonary exercise testing) and personality assessment with the 14-item Type D scale. CD34 + /KDR (kinase insert domain-containing receptor) + cells were quantified by flow cytometry before and immediately after CPET. Migration of early EPC towards VEGF (vascular endothelial growth factor) and SDF-1α (stromal-cell-derived factor-1α) was investigated. Type D (n = 10) and non-Type D (n = 25) patients were comparable with regards to demographics, disease severity and Framingham risk factor score. Circulating EPC numbers were reduced by 54 % in Type D compared with non-Type D patients (0.084 + − 0.055 and 0.183 + − 0.029 % of lymphocytes respectively; P = 0.006). Exercise led to a 60 % increase in EPC in Type D patients, whereas the EPC number remained unchanged in the non-Type D group (P = 0.049). Baseline migratory capacity was related to disease severity, but was not different between Type D and non-Type D patients. Exercise induced a highly significant enhancement of migratory capacity in both groups. In conclusion, reduced EPC numbers might explain the impaired cardiovascular outcome in Type D patients. The larger increase in circulating EPCs observed in these patients suggests that acute exercise elicits a more pronounced stimulus for endothelial repair

Acute Exercise-Induced Response of Monocyte Subtypes in Chronic Heart and Renal Failure

Purpose. Monocytes (Mon1-2-3) play a substantial role in low-grade inflammation associated with high cardiovascular morbidity and mortality of patients with chronic kidney disease (CKD) and chronic heart failure (CHF). The effect of an acute exercise bout on monocyte subsets in the setting of systemic inflammation is currently unknown. This study aims (1) to evaluate baseline distribution of monocyte subsets in CHF and CKD versus healthy subjects (HS) and (2) to evaluate the effect of an acute exercise bout. Exercise-induced IL-6 and MCP-1 release are related to the Mon1-2-3 response. Methods. Twenty CHF patients, 20 CKD patients, and 15 HS were included. Before and after a maximal cardiopulmonary exercise test, monocyte subsets were quantified by flow cytometry: CD14++CD16−CCR2+ (Mon1), CD14++CD16+CCR2+ (Mon2), and CD14+CD16++CCR2− (Mon3). Serum levels of IL-6 and MCP-1 were determined by ELISA. Results. Baseline distribution of Mon1-2-3 was comparable between the 3 groups. Following acute exercise, %Mon2 and %Mon3 increased significantly at the expense of a decrease in %Mon1 in HS and in CKD. This response was significantly attenuated in CHF (P<0.05). In HS only, MCP-1 levels increased following exercise; IL-6 levels were unchanged. Circulatory power was a strong and independent predictor of the changes in Mon1 (β=-0.461, P<0.001) and Mon3 (β=0.449, P<0.001); and baseline LVEF of the change in Mon2 (β=0.441, P<0.001). Conclusion. The response of monocytes to acute exercise is characterized by an increase in proangiogenic and proinflammatory Mon2 and Mon3 at the expense of phagocytic Mon1. This exercise-induced monocyte subset response is mainly driven by hemodynamic changes and not by preexistent low-grade inflammation

Endothelial Microparticles (EMP) for the Assessment of Endothelial Function: An In Vitro and In Vivo Study on Possible Interference of Plasma Lipids

BACKGROUND: Circulating endothelial microparticles (EMP) reflect the condition of the endothelium and are of increasing interest in cardiovascular and inflammatory diseases. Recently, increased numbers of EMP following oral fat intake, possibly due to acute endothelial injury, have been reported. On the other hand, the direct interference of lipids with the detection of EMP has been suggested. This study aimed to investigate the effect of lipid-rich solutions, commonly administered in clinical practice, on the detection, both in vitro and in vivo, of EMP. METHODS: For the in vitro assessment, several lipid-rich solutions were added to whole blood of healthy subjects (n = 8) and patients with coronary heart disease (n = 5). EMP (CD31+/CD42b-) were detected in platelet poor plasma by flow cytometry. For the in vivo study, healthy volunteers were evaluated on 3 different study-days: baseline evaluation, following lipid infusion and after a NaCl infusion. EMP quantification, lipid measurements and peripheral arterial tonometry were performed on each day. RESULTS: Both in vitro addition and in vivo administration of lipids significantly decreased EMP (from 198.6 to 53.0 and from 272.6 to 90.6/µl PPP, respectively, p = 0.001 and p = 0.012). The EMP number correlated inversely with the concentration of triglycerides, both in vitro and in vivo (r = -0.707 and -0.589, p<0.001 and p = 0.021, respectively). The validity of EMP as a marker of endothelial function is supported by their inverse relationship with the reactive hyperemia index (r = -0.758, p = 0.011). This inverse relation was confounded by the intravenous administration of lipids. CONCLUSION: The confounding effect of high circulating levels of lipids, commonly found in patients that receive intravenous lipid-based solutions, should be taken into account when flow cytometry is used to quantify EMP

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 Deficiency Blunts Hypoxia-Induced Mobilization and Homing of Circulating Angiogenic Cells

Aim. We investigated the effects of adiponectin deficiency on circulating angiogenic cell (CAC) mobilization, homing, and neovascularization in the setting of acute myocardial infarction (AMI). Methods &amp; Results. AMI was induced in wild-type (WT) ( = 10) and adiponectin knockout (Adipoq −/− ) mice ( = 7). One week after AMI, bone marrow (BM) concentration and mobilization of Sca-1 + and Lin − Sca-1 + progenitor cells (PCs) were markedly attenuated under Adipoq −/− conditions, as assessed by flow cytometry. The mRNA expression of HIF-1-dependent chemotactic factors, such as Cxcl12 ( = 0.005) and Ccl5 ( = 0.025), and vascular adhesion molecules, such as Icam1 ( = 0.010), and Vcam1 ( = 0.014), was significantly lower in the infarction border zone of Adipoq −/− mice. Histologically, Adipoq −/− mice evidenced a decrease in neovascularization capacity in the infarction border zone ( &lt; 0.001). Overall, capillary density was positively correlated with Sca-1 + PC numbers in BM ( = 0.01) and peripheral blood (PB) ( = 0.005) and with the expression of the homing factors Cxcl12 ( = 0.013), Icam1 ( = 0.034) and Vcam1 ( = 0.014). Conclusions. Adiponectin deficiency reduced the BM reserve and mobilization capacity of CACs, attenuated the expression of hypoxia-induced chemokines and vascular adhesion molecules, and impaired the neovascularization capacity one week after AMI