No abstract

Objectives— The concept of neovascularization in response to tissue ischemia has been extended by the finding of postnatal vasculogenesis initiated by endothelial progenitor cells (EPCs). The aim of this study was to analyze whether a maximal stress test in patients with coronary artery disease (CAD) increases the number of circulating EPCs. Methods and Results— Blood concentration of EPCs was analyzed by FACS and cell culture assay in CAD patients with (n=16) or without (n=12) exercise-induced myocardial ischemia and in healthy subjects (n=11) for up to 144 hours after maximal stress test. Plasma concentrations of vascular endothelial growth factor (VEGF), basic fibroblast growth factor, tumor necrosis factor-α, and granulocyte macrophage-colony stimulating factor were determined by ELISA. EPCs increased significantly in ischemic patients, with a maximum after 24 to 48 hours (cell culture: 3.3±0.5-fold increase; FACS: 3.1±0.6-fold increase) and returned to baseline within 72 hour. In nonischemic patients and healthy subjects, no EPC increase was detectable. VEGF levels in ischemic patients increased significantly after 2 to 6 hours (maximum after 2 hours; 4.0±1.1-fold increase) and no change was observed in nonischemic patients and healthy subjects; ΔVEGF and ΔEPC correlated significantly ( r =0.66). Conclusions— Patients with symptomatic CAD respond to a single episode of exercise-induced myocardial ischemia with a time-dependent increase in circulating EPCs. This increase may be related to and preceded by an increase in plasma VEGF.

Background-Exercise training (ET) has been shown to improve regional perfusion in ischemic syndromes. This might be partially related to a regeneration of diseased endothelium by circulating progenitor cells (CPCs) or CPC-derived vasculogenesis. The aim of the present study was to determine whether ischemic stimuli during ET are required to promote CPC mobilization in patients with cardiovascular diseases. Methods and Results-Patients with peripheral arterial occlusive disease (PAOD) were randomized to 4 weeks of daily ischemic ET or control (group A). Successfully revascularized patients with PAOD were randomized to 4 weeks of daily nonischemic ET or control (group B). Patients with stable coronary artery disease were subjected to 4 weeks of subischemic ET or control (group C). At baseline and after 4 weeks, the number of KDR ϩ /CD34 ϩ CPCs was determined by fluorescence-activated cell sorting analysis. Levels of vascular endothelial growth factor (VEGF) were measured by ELISA. A Matrigel assay was used to quantify CPC integration into vascular structures. Expression of the homing factor CXCR4 was determined by reverse transcription-polymerase chain reaction. In group A only, ischemic ET increased VEGF levels by 310% (PϽ0.05 versus control) associated with an increase in CPCs by 440% (PϽ0.05 versus control), increased CXCR4 expression, and enhanced integration of CPCs into endothelial networks. In contrast, subischemic ET in groups B and C increased CXCR4 expression and CPC integration. Conclusions-In training programs, symptomatic tissue ischemia seems to be a prerequisite for CPC mobilization.However, ischemic and subischemic ET programs affect CXCR4 expression of CPCs, which might lead to an improved CPC integration into endothelial networks. (Circulation. 2005;111:3391-3399.)

Skeletal muscle is the most abundant tissue in the human body, and the maintenance of its mass is essential to ensure basic function as locomotion, strength and respiration. The decision to synthesize or to break down skeletal muscle proteins is regulated by a network of signaling pathways that transmit external stimuli to intracellular factors regulating gene transcription. The tightly regulated balance of muscle protein breakdown and synthesis is disturbed in several distinct myopathies, but also in two pathologies: sarcopenia and cachexia. In recent years, it became evident that in these two muscle wasting disorders specific regulating molecules are increased in expression (e.g. members of the ubiquitin–proteasome system, myostatin, apoptosis inducing factors), whereas other factors (e.g. insulin-like growth factor 1) are down-regulated. So far, not many treatment options to fight the muscle loss are available. One of the most promising approaches is exercise training that, due to its multifactorial effects, can act on several signaling pathways. Therefore, this review will concentrate on specific alterations discussed in the current literature that are present in the skeletal muscle of both muscle wasting disorders. In addition, we will focus on exercise training as an intervention strategy.

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Basel Cardiovascular Research Foundation, and B Braun Medical AG.

Objective-Function and availability of circulating progenitor cells (CPC) have been shown to be impaired in patients with diabetes mellitus (DM). Therefore, the aim of the present study was to analyze possible mechanisms leading to the reduction of CPC amount and function. Methods and Results-Peripheral blood mononuclear cells (MNCs) of healthy donors (nϭ15) were cultivated under hyperglycemia (HG) conditions (12 mmol/L D-Glucose) or in osmotic control medium (Con) (5 mmol/L D-Glucose plus 7 mmol/L L-Glucose) for 7 days. CPC amount was determined by uptake of acetylated low-density lipoprotein and lectin binding. On the functional level, cell cycle status, nitric oxide (NO) production, and migrational and integrative capacity of CPCs were assessed. HG conditions caused a significant decrease in CPC amount derived from healthy MNCs. Furthermore, HG conditions led to a functional impairment, reflected in a decreased NO production and matrix metalloproteinase (MMP)-9 activity, as well as an impairment of the migrational and integrative capacities. Conclusion

Background-Muscle wasting occurs in both chronic heart failure (CHF) and normal aging and contributes to exercise intolerance and increased morbidity/mortality. However, the molecular mechanisms of muscle atrophy in CHF and their interaction with aging are still largely unknown. We therefore measured the activation of the ubiquitin-proteasome system and the lysosomal pathway of intracellular proteolysis in muscle biopsies of CHF patients and healthy controls in two age strata and assessed the age-dependent effects of a 4-week endurance training program on the catabolic-anabolic balance. Methods and Results-Sixty CHF patients (30 patients aged Յ55 years, mean age 46Ϯ5 years; 30 patients aged Ն65 years, mean age 72Ϯ5 years) and 60 healthy controls (30 subjects aged Յ55 years, mean age 50Ϯ5 years; 30 subjects aged Ն65 years, mean age 72Ϯ4 years) were randomized to 4 weeks of supervised endurance training or to a control group. Before and after the intervention, vastus lateralis muscle biopsies were obtained. The expressions of cathepsin-L and the muscle-specific E3 ligases MuRF-1 and MAFbx were measured by real-time polymerase chain reaction and confirmed by Western blot. At baseline, MuRF-1 expression was significantly higher in CHF patients versus healthy controls (mRNA: 624Ϯ59 versus 401Ϯ25 relative units; Pϭ0.007). After 4 weeks of exercise training, MuRF-1 mRNA expression was reduced by Ϫ32.8% (Pϭ0.02) in CHF patients aged Յ55 years and by Ϫ37.0% (PϽ0.05) in CHF patients aged Ն65 years. Conclusions-MuRF-1, a component of the ubiquitin-proteasome system involved in muscle proteolysis, is increased in the skeletal muscle of patients with heart failure. Exercise training results in reduced MuRF-1 levels, suggesting that it blocks ubiquitin-proteasome system activation and does so in both younger and older CHF patients. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00176319.

Abstract-Transplantation of blood-derived circulating progenitor cells (CPC) has been shown to improve myocardial regeneration after myocardial infarction. It remains unclear whether CPC transplantation exerts beneficial effects also in patients with chronic myocardial ischemia. We initiated a randomized, double-blind, placebo-controlled study evaluating the impact of intracoronary infusion of CPCs on coronary vasomotion and left ventricular (LV) function in patients after recanalization of chronic coronary total occlusion (CTO). After recanalization of CTO, 26 patients (age, 63Ϯ2 years; LV ejection fraction, 53Ϯ2%) were randomly assigned to the treatment (intracoronary transplantation of CPCs) or control group. Coronary flow reserve in response to adenosine (2.4 mg/min) was measured in the target vessel at the beginning of the study and after 3 months. LV function and infarct size were assessed by MRI and metabolism by 18 F deoxyglucose positron emission tomography. CPC application resulted in an increase in coronary flow reserve by 43% from 2.3Ϯ0.3 to 3.3Ϯ0.5 (PϽ0.05 versus beginning and control). At 3 months, the number of hibernating segments in the target region (from 2.9Ϯ0.6 to 2.0Ϯ0.6 segments, PϽ0.05 versus beginning and control) had declined in the treatment group, whereas no significant changes were observed in the control group. MRI revealed a reduction in infarct size by 16% and an increase in LV ejection fraction by 14% in the treatment group (from 51.7Ϯ3.7 to 58.9Ϯ3.2%; PϽ0.05 versus beginning and control) because of an augmented wall motion in the target region. Hence, intracoronary transplantation of CPCs after recanalization of CTO results in an improvement of macro-and microvascular function and contributes to the recruitment of hibernating myocardium. Key Words: ischemic heart disease Ⅲ endothelial dysfunction Ⅲ progenitor cells Ⅲ hibernating myocardium Ⅲ reperfusion R ecently, bone marrow-derived circulating progenitor cells (CPCs) have been shown to promote formation of entirely new vessels into ischemic tissues by a process termed vasculogenesis. 1-3 The CPC-mediated augmentation in myocardial neoangiogenesis in animal experiments prompted researchers to conduct pioneer clinical trials. [3][4][5][6][7][8][9][10] In the TOPCARE-AMI (Transplantation Of Progenitor Cells And Regeneration Enhancement in Acute Myocardial Infarction) study, bone marrow-derived and progenitor cells from peripheral blood administered after successful recanalization in acute myocardial infarction were shown to improve myocardial perfusion, increase left ventricular (LV) contractility, and attenuate LV remodeling equally effective. 9 Perin et al were able to extend the knowledge with regard to bone marrowderived stem cell therapy in patients with severe ischemic heart failure: intramyocardial injection of these cells at the site of ischemia was elucidated to increase blood flow and improve regional and global ventricular function. 5 Additional evidence is emerging from the first randomized study, BOOST (BOne marrOw tr...