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Biomedical subjects

Rainer Hambrecht

Publications and source records attributed to Rainer Hambrecht.

At least 37 records · Page 2Linked to original sources
PubMed2005

Transplantation of blood-derived progenitor cells after recanalization of chronic coronary artery occlusion: first randomized and placebo-controlled study.

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, 63+/-2 years; LV ejection fraction, 53+/-2%) 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 18F deoxyglucose positron emission tomography. CPC application resulted in an increase in coronary flow reserve by 43% from 2.3+/-0.3 to 3.3+/-0.5 (P<0.05 versus beginning and control). At 3 months, the number of hibernating segments in the target region (from 2.9+/-0.6 to 2.0+/-0.6 segments, P<0.05 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 51.7+/-3.7 to 58.9+/-3.2%; P<0.05 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.

Angioplasty, Balloon, Coronary↗
PubMed2005

Molecular mechanisms of vascular adaptations to exercise. Physical activity as an effective antioxidant therapy?

A lack of exercise training and/or regular physical activity is a known risk factor for cardiovascular disease. Exercise training induces marked vascular remodeling by increasing angiogenesis and arteriogenesis. These changes in the architecture of the vascular tree are likely associated with functional changes and improved organ blood flow. Physical forces such as shear stress, transmural pressure and cyclic stretch activate mechanotransduction mechanisms in endothelial and smooth muscle cells that are mediated by integrins and associated RhoA small GTPase. They stimulate various signal transduction pathways involving phosphorylation of kinases such as focal adhesion kinase, c-Src, Akt kinase, phosphatidylinositol 3-kinase, myosin light chain kinase and mitogen-activated protein kinases (MAPK) such as extracellular signal-regulated kinase (ERK). These mechanisms result in upregulation of genes mediating antiatherogenic effects by promoting antiapoptotic and antiproliferative signals, by increasing vascular NO bioavailability and by changing calcium handling and the vascular myogenic response to pressure. Exercise-induced increase of vascular eNOS expression and of eNOS Ser-1177 phosphorylation is most likely an important and potentially vasoprotective effect of exercise training. The underlying mechanisms involve cell membrane proteins such as integrins and products of vascular oxidative stress such as hydrogen peroxide. Exercise-induced eNOS expression is transient and reversible and regulated by factors such as angiogenesis, arteriogenesis and antioxidative effects including upregulation of superoxide dismutases (SOD1, SOD3) and downregulation of NAD(P)H oxidase, which likely blunts the effects of oxidative stress. Based on these observations, it appears reasonable to assume that exercise training can be viewed as an effective antioxidant and antiatherogenic therapy.

Adaptation, Physiological↗
PubMed2005

Effects of exercise and ischemia on mobilization and functional activation of blood-derived progenitor cells in patients with ischemic syndromes: results of 3 randomized studies.

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+/CD34+ 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% (P<0.05 versus control) associated with an increase in CPCs by 440% (P<0.05 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.

Aged↗
PubMed2005

Therapeutical potential of blood-derived progenitor cells in patients with peripheral arterial occlusive disease and critical limb ischaemia.

AIMS: Despite considerable advances in the therapy of patients with peripheral arterial occlusive disease (PAOD) and critical limb ischaemia (CLI), a substantial number remain, in whom amputation has to be considered the only and final option. Recent evidence from animal models of hind limb ischaemia suggests that neovascularization induced by circulating blood-derived progenitor cells (CPCs) may permit limb salvage. It remains unclear, however, whether an intra-arterial application of autologous CPCs in patients with infrapopliteal PAOD and CLI is safe, feasible, and of potentially beneficial effects. METHODS AND RESULTS: Seven patients with critical PAOD were treated with an intra-arterial infusion of autologous CPCs (39+/-24 x 10(6)) isolated from peripheral blood. Pre-interventional stimulation with G-CSF and CPC application was well tolerated. Twelve weeks after CPC administration, the pain-free walking distance increased from 6+/-13 to 195+/-196 m. A significant increase in the ankle-brachial index, transcutaneous O(2), flow-dependent vasodilation, flow reserve in response to adenosine, and endothelium-dependent vasodilation was observed. CONCLUSION: These preliminary data in a small series of patients with CLI without surgical or interventional options indicate that CPC application is safe, feasible, and may improve both functional and clinical indices.

Aged↗
PubMed2005

Antioxidative effects of exercise training in patients with chronic heart failure: increase in radical scavenger enzyme activity in skeletal muscle.

BACKGROUND: In chronic heart failure (CHF), cross-talk between inflammatory activation and oxidative stress has been anticipated in skeletal muscle (SM). The role of the radical scavenger enzymes superoxide dismutase (SOD), catalase (Cat), and glutathione peroxidase (GPX), which remove oxygen radicals, has never been assessed in the SM in this context. Moreover, it remains unknown whether exercise training augments the activity of these enzymes in CHF. METHODS AND RESULTS: Twenty-three patients with CHF were randomized to either 6 months of exercise training (T) or a sedentary lifestyle (C); 12 age-matched healthy subjects (HS) were studied in parallel. Activity of Cat, SOD, and GPX was assessed in SM biopsies before and after 6 months (6 months). Oxidative stress was determined by measuring nitrotyrosine formation. SOD, Cat, and GPX activity was reduced by 31%, 57%, and 51%, respectively, whereas nitrotyrosine formation was increased by 107% in SM in CHF (P<0.05 versus HS). In CHF, exercise training augmented GPX and Cat activity in SM by 41% (P<0.05 versus before and group C) and 42% (P<0.05 versus before and group C), respectively, and decreased nitrotyrosine production by 35% (from 3.8+/-0.4% tissue area before to 2.5+/-0.3% after 6 months; P<0.05 versus before). CONCLUSIONS: The reduced activity of major antioxidative enzymes in the SM of CHF patients is associated with increased local oxidative stress. Exercise training exerts antioxidative effects in the SM in CHF, in particular, due to an augmentation in activity of radical scavenger enzymes.

Case-Control Studies↗
PubMed2005

Changes in myocardial perfusion due to physical exercise in patients with stable coronary artery disease.

PURPOSE: Percutaneous transluminal coronary angioplasty (PTCA) is one of the main therapy options for patients with coronary artery disease (CAD), resulting in an improvement in myocardial perfusion and exercise capacity. Nevertheless, studies have also demonstrated a positive effect of regular exercise training on myocardial perfusion and maximum exercise capacity. The aim of this study was to evaluate changes in myocardial stress perfusion after 1 year of exercise training in comparison with the effects of PTCA in patients with CAD. METHODS: In 66 male patients with angiographically confirmed significant coronary artery stenosis in one target vessel, myocardial perfusion scintigraphy was performed at baseline and 12 months after randomisation into either a physical exercise group or a PTCA group. Circumferential count rate profiles in 16 wall segments were classified according to their relative count rate and localisation within or outside the area supplied by the stenosed vessel. RESULTS: Ischaemic segments showed a significant improvement in myocardial count rate within the target area after 12 months in both the PTCA and the training group (PTCA group: from 76.8+/-4.9% to 86.6+/-10.9%, p=0.03; training group: from 74.0+/-7.3% to 83.7+/-10.8%, p<0.01). Outside the target area only the training group showed a significant improvement (from 77.7+/-4.4% to 91.7+/-4.8%, p<0.01). CONCLUSION: Our data indicate a significant improvement in stress myocardial perfusion in the training group after 12 months. The ischaemia is reduced not only in the target region of the leading stenosis but also in other ischaemic myocardial areas. In contrast, after PTCA stress perfusion improves only in the initially ischaemic parts of the target area.

Adult↗
PubMed2005

Randomized comparison of intra-aortic balloon support with a percutaneous left ventricular assist device in patients with revascularized acute myocardial infarction complicated by cardiogenic shock.

AIMS: Mortality in cardiogenic shock (CS) following acute myocardial infarction (AMI) remains unacceptably high despite percutaneous coronary intervention (PCI) of the infarcted artery and use of intra-aortic balloon pump (IABP) counterpulsation. A newly developed percutaneous left ventricular assist device (VAD) (Tandem Heart, Cardiac Assist, Pittsburgh, PA, USA) with active circulatory support might have positive haemodynamic effects and decrease mortality. METHODS AND RESULTS: Patients in CS after AMI, with intended PCI of the infarcted artery, were randomized to either IABP (n=20) or percutaneous VAD support (n=21). The primary outcome measure cardiac power index, as well as other haemodynamic and metabolic variables, could be improved more effectively by VAD support from 0.22 [interquartile range (IQR) 0.19-0.30] to 0.37 W/m2 (IQR 0.30-0.47, P<0.001) when compared with IABP from 0.22 (IQR 0.18-0.30) to 0.28 W/m2 (IQR 0.24-0.36, P=0.02; P=0.004 for intergroup comparison). However, complications like severe bleeding (n=19 vs. n=8, P=0.002) or limb ischaemia (n=7 vs. n=0, P=0.009) were encountered more frequently after VAD support, whereas 30 day mortality was similar (IABP 45% vs. VAD 43%, log-rank, P=0.86). CONCLUSION: Haemodynamic and metabolic parameters can be reversed more effectively by VAD than by standard treatment with IABP. However, more complications were encountered by the highly invasive procedure and by the extracorporeal support.

Aged↗
PubMed2005

Impact of regular physical activity on the NAD(P)H oxidase and angiotensin receptor system in patients with coronary artery disease.

BACKGROUND: In patients with stable coronary artery disease, physical exercise training (ET) improves endothelial dysfunction. A potential mechanism mediating the enhanced vasomotor function is a reduced breakdown of endothelium-derived nitric oxide by reactive oxygen species (ROS). The aim of the present study was to analyze the impact of ET on sources of ROS generation in the left internal mammary artery of patients with symptomatic coronary artery disease. METHODS AND RESULTS: In left internal mammary artery rings sampled during bypass surgery from 45 patients randomized to either a training (n=22) or an inactive control (n=23) group, the mRNA expression of NAD(P)H oxidase subunits, NAD(P)H oxidase activity, and ROS production were assessed. In addition, endothelial function, expression of angiotensin II (Ang II) receptor type 1 and 2 (AT1-R and AT2-R), and Ang II-mediated vasoconstriction were determined. ET resulted in a significant lower expression of gp91phox (23.1+/-0.5 versus 69.1+/-18.1 arbitrary units, training versus control), p22phox (0.7+/-0.3 versus 2.0+/-0.5 arbitrary units), and Nox4 (2.7+/-1.2 versus 5.4+/-1.0 arbitrary units). Enzymatic activity (2.1+/-0.3 versus 4.9+/-0.4 mU/mg) and ROS generation (0.02+/-0.01 versus 0.06+/-0.02 arbitrary units) were significantly lower in the training compared with the control group. On a functional level, ET resulted in improved acetylcholine-mediated vasodilatation and a 49% reduction in Ang II-induced vasoconstriction, accompanied by lower AT1-R (3.7+/-0.8 versus 16.6+/-5.7 arbitrary units, training versus control) and higher AT2-R (7.8+/-2.5 versus 1.6+/-0.7 arbitrary units) mRNA expression. CONCLUSIONS: ET reduces vascular expression of NAD(P)H oxidase and AT1-R, resulting in decreased local ROS generation. These molecular effects converge in a reduced Ang II-mediated vasoconstriction.

Aged↗
PubMed2005

Hyperglycemia reduces survival and impairs function of circulating blood-derived progenitor cells.

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 (n=15) 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. CONCLUSIONS: HG, a main feature of DM, affects important functional characteristics of CPCs. These results may provide further insight into the pathomechanism of endothelial dysfunction in HG.

Adolescent↗
PubMed2005

Effects of exercise training on insulin-like growth factor-I expression in the skeletal muscle of non-cachectic patients with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) is associated with progressive muscle atrophy and reduced local expression of insulin-like growth factor I (IGF-I). DESIGN: The present study was designed to test the hypothesis that the local deficiency of IGF-I in the skeletal muscle of patients with CHF would respond to a 6-months aerobic training intervention. Therefore, 18 patients [mean age 52.4 (SD 4.8) years, left ventricular ejection function (LVEF) 27 (SD 6)%] were prospectively randomized to either 6 months of training or sedentary lifestyle. METHODS: Serum levels of growth hormone (GH) were measured by immunofluorometric assay, IGF-I by competitive solid phase immunoassay. IGF-I expression was assessed in vastus lateralis biopsies by real-time PCR. RESULTS: Exercise training led to a significant increase in peak oxygen uptake by 26% [from 20.3 (SD 3.3) ml/kg per min to 25.5 (SD 5.7) ml/kg per min, P=0.003 versus control]. Local expression of IGF-I increased significantly after exercise training by 81% [from 6.3 (SE 0.8) to 11.4 (SE 1.4) relative units, P=0.007 versus control] while IGF-I receptor expression was reduced by 33% [from 20.0 (SE 2.1) to 13.8 (SE 1.7) relative units, P=0.008 versus control]. Serum growth hormone (GH) rose modestly from 0.12 (SE 0.07) to 0.65 (SE 0.37) ng/ml in the training group (P=0.043 versus baseline), however, this change was not significant compared to the control group (P=0.848). IGF-I serum levels remained virtually unchanged. CONCLUSIONS: Exercise training improves local IGF-I expression without significant changes of systemic parameters of the GH/IGF-I axis. These findings indicate that exercise training has the therapeutic potential to attenuate peripheral skeletal muscle alterations in particular with respect to local IGF-I expression in patients with moderate CHF.

Adult↗
PubMed2005

Exercise training in chronic heart failure: correlation between reduced local inflammation and improved oxidative capacity in the skeletal muscle.

BACKGROUND: Chronic heart failure (CHF) is accompanied by an inflammatory activation which occurs both systemically and in the skeletal muscle. Exercise training has been shown to reduce the local expression of cytokines and inducible nitric oxide synthase (iNOS) in muscle biopsies of CHF patients. INOS-derived NO can inhibit oxidative phosphorylation and contribute to skeletal muscle dysfunction in CHF. DESIGN: To investigate the correlation between changes in local iNOS expression associated with regular exercise and changes in aerobic enzyme activities in the skeletal muscle of patients with CHF. Twenty male CHF patients [ejection fraction 25% (SE 2), age 54 (SE 2) years] were randomized to a training (n=10) or a control group (C, n=10). METHODS: At baseline and after 6 months skeletal muscle iNOS expression was measured by real-time polymerase chain reaction. INOS protein and protein nitrosylation were assessed by immunohistochemistry. Cytochrome c oxidase (COX) activity was quantified electrochemically using the Clark oxygen electrode. RESULTS: Exercise training led to a 27% increase in cytochrome c oxidase activity [from 21.8 (SE 3.2) to 27.7 (SE 3.5) nmol O2/mg per min, P=0.02 versus baseline]. Changes in iNOS expression and iNOS protein content were inversely correlated with changes in COX-activity (r=-0.60, P=0.01; r=-0.71, P<0.001). CONCLUSIONS: The inverse correlation between iNOS expression/iNOS protein content and COX-activity indicates that local anti-inflammatory effects may contribute to improved muscular oxidative metabolism.

Aged↗
PubMed2005

Aging and heart failure--similar syndromes of exercise intolerance? Implications for exercise-based interventions.

A classic hallmark of chronic heart failure (CHF) is exercise intolerance; however, the extent of exercise limitation is not correlated with the degree of left ventricular dysfunction. Over the past 2 decades it has become more and more evident that peripheral factors, such as skeletal muscle dysfunction, ventilatory abnormalities, and endothelial dysfunction, contribute the greater part to the limitation of exercise capacity. The molecular and pathophysiological changes observed in these organ systems are not always specific to the underlying CHF but rather represent a common pathway that is activated in several chronic disease processes, including severe chronic obstructive pulmonary disease, cancer, and in the normal aging process. A major contributing factor for skeletal muscle catabolism (i.e. elevated cytokine expression in the skeletal muscle) can be found in both normal healthy aging and in heart failure patients. It is reasonable to assume that the overlap of aging and CHF-associated changes in the skeletal muscle partially explains the disabling consequences of the CHF syndrome among elderly patients (nearly 80% of all patients hospitalized for CHF are >65 years old). Peripheral alterations in CHF are often not adequately treated in routine clinical care since standard pharmacological therapy is still focused on the cardiac function and neurohormonal alteration. Exercise training is a guideline-oriented adjuvant therapy with well-documented beneficial effects on exercise tolerance, skeletal muscle function, endothelial function, and respiration. In this review, the effects of exercise in aging and in CHF are compared and the parallel mechanisms are explored.

Aged↗
PubMed2004

Percutaneous coronary angioplasty compared with exercise training in patients with stable coronary artery disease: a randomized trial.

BACKGROUND: Regular exercise in patients with stable coronary artery disease has been shown to improve myocardial perfusion and to retard disease progression. We therefore conducted a randomized study to compare the effects of exercise training versus standard percutaneous coronary intervention (PCI) with stenting on clinical symptoms, angina-free exercise capacity, myocardial perfusion, cost-effectiveness, and frequency of a combined clinical end point (death of cardiac cause, stroke, CABG, angioplasty, acute myocardial infarction, and worsening angina with objective evidence resulting in hospitalization). METHODS AND RESULTS: A total of 101 male patients aged < or =70 years were recruited after routine coronary angiography and randomized to 12 months of exercise training (20 minutes of bicycle ergometry per day) or to PCI. Cost efficiency was calculated as the average expense (in US dollars) needed to improve the Canadian Cardiovascular Society class by 1 class. Exercise training was associated with a higher event-free survival (88% versus 70% in the PCI group, P=0.023) and increased maximal oxygen uptake (+16%, from 22.7+/-0.7 to 26.2+/-0.8 mL O2/kg, P<0.001 versus baseline, P<0.001 versus PCI group after 12 months). To gain 1 Canadian Cardiovascular Society class, 6956 dollars was spent in the PCI group versus 3429 dollars in the training group (P<0.001). CONCLUSIONS: Compared with PCI, a 12-month program of regular physical exercise in selected patients with stable coronary artery disease resulted in superior event-free survival and exercise capacity at lower costs, notably owing to reduced rehospitalizations and repeat revascularizations.

Aged↗