Biomedical subjects

Rainer Hambrecht

Publications and source records attributed to Rainer Hambrecht.

At least 55 records · Page 3Linked to original sources

PubMed2004

Increase of circulating endothelial progenitor cells in patients with coronary artery disease after exercise-induced ischemia.

OBJECTIVE: 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-alpha, 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; DeltaVEGF and DeltaEPC 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.

Aged↗

PubMed2004

[Sports as therapy].

Over the last 2 decades the clinical application of physical exercise as a therapeutic strategy has developed from rehabilitation to prevention and treatment of cardiovascular diseases. This shift in clinical application was accompanied by a more systematic research approach of the involved mechanisms and the objective clinical assessment of sport interventions using prospective randomized clinical trials. This ongoing process established physical exercise as an evidence-based and guideline-oriented treatment option. In stable coronary artery disease (CAD), exercise therapy has long been used for rehabilitation purposes following an acute myocardial infarction. A recent meta-analysis revealed a significant 27% reduction of total mortality among training patients. Four mechanisms are considered important mediators of the reduced cardiac event rate: improvement of endothelial function, reduced progression of coronary lesions, reduced thrombogenic risk, and improved collateralization. The therapeutic benefit of regular physical exercise has also been confirmed in direct comparison with an interventional strategy: a 12-month exercise therapy in stable CAD patients was associated with a higher event-free survival as compared to conventional percutaneous coronary intervention. In stable chronic heart failure (CHF), physical activity was traditionally discouraged-with negative consequences for the patients: exercise intolerance worsened, the progression of disease-related muscular atrophy accelerated. A carefully designed exercise program at 50-70% of the maximal oxygen uptake was effective in improving exercise capacity by 12-32%. In a recent meta-analysis, exercise therapy reduced the relative risk of CHF mortality by 35% and CHF-related hospitalizations by 28%. Considering the growing body of evidence in favor of sport as a therapy, training interventions should be considered additional/alternative therapeutic strategies as compared with established pharmacological/interventional options.

Coronary Artery Disease↗

PubMed2004

The effect of exercise training on endothelial function in cardiovascular disease in humans.

Endothelial dysfunction occurs early in atherosclerosis in response to cardiovascular risk factors. The occurrence of endothelial dysfunction is primarily the result of reduced nitric oxide (NO) bioavailabilty. It represents an independent predictor of cardiovascular events and predicts the prognosis of the patient. Therefore, endothelial function has been identified as a target for therapeutic intervention. Regular exercise training is a nonpharmacological option to improve endothelial dysfunction in patients with cardiovascular disease by increasing NO bioavailability.

Cardiovascular Diseases↗

PubMed2004

Functional and morphological skeletal muscle abnormalities correlate with reduced electromyographic activity in chronic heart failure.

BACKGROUND: Exercise intolerance and early muscle fatigue are key symptoms in patients with chronic heart failure (CHF). In advanced stages of the disease, profound metabolic abnormalities have been described finally leading to a catabolic state with progressive loss of muscle bulk. The aim of this study was to investigate morphological, functional and electromyographical parameters of the skeletal muscle in CHF. METHODS: We included 17 patients with CHF and 12 age-matched healthy controls (left ventricular ejection fraction 25+/-2 versus 68+/-1%, body mass index 26.6+/-0.8 versus 28.0+/-1.0 kg/m2; P=NS) in this study. Cross-sectional area (CSA) of the thigh was assessed by computed tomography. Under electromyographical control, maximal and submaximal (30%) isometric strength as well as the relative decrease of muscle strength of the quadriceps muscle over a period of 20 s were determined. RESULTS: Patients with CHF showed a significant reduction of muscle CSA (134.8+/-5.3 versus 165.2+/-7.4 cm2, P=0.002) as compared with healthy controls. The maximal quadriceps muscle strength was found to be significantly reduced in patients with CHF (226.7+/-22.3 versus 286.9+/-17.1 N, P<0.05) who also exhibited a higher extent of muscular fatigability (-2.18+/-0.33 versus -0.54+/-0.20 N/s, P<0.01). Electromyographic activity at 30% submaximal contraction showed a lower increase in patients with CHF (66+/-22 versus 114+/-36%; P<0.05) indicating impaired muscle fibre recruitment. Furthermore, a significant correlation between muscular fatigability and reduced electromyographic activity was found in CHF (r=0.84; P<0.001). CONCLUSIONS: Our findings demonstrate an impaired electromyographic activity and muscular function in patients with CHF suggesting a new pathomechanism contributing to functional abnormalities of the skeletal muscle in advanced stages of this disease.

Case-Control Studies↗

PubMed2003

Anti-inflammatory effects of exercise training in the skeletal muscle of patients with chronic heart failure.

OBJECTIVES: The aim of this study was to assess the effects of regular physical exercise on local inflammatory parameters in the skeletal muscle of patients with chronic heart failure (CHF). BACKGROUND: Inflammatory activation with increased serum cytokine levels and expression of inducible nitric oxide synthase (iNOS) in the myocardium and peripheral skeletal muscles has been described in CHF. METHODS: Twenty male patients with stable CHF (left ventricular ejection fraction 25 +/- 2%; age 54 +/- 2 years) were randomized to a training group (n = 10) or a control group (n = 10). At baseline and after six months, serum samples and vastus lateralis muscle biopsies were obtained. Serum tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1-beta levels were measured by enzyme-linked immunosorbent assay, local cytokine, and iNOS expression by real-time polymerase chain reaction. RESULTS: Exercise training improved peak oxygen uptake by 29% in the training group (from 20.3 +/- 1.0 to 26.1 +/- 1.5 ml/kg. min; p < 0.001 vs. control group). While serum levels of TNF-alpha, IL-6, and IL-1-beta remained unaffected by training, local skeletal muscle TNF-alpha decreased from 1.9 +/- 0.4 to 1.2 +/- 0.3 relative U (p < 0.05 for change vs. control group), IL-6 from 71.3 +/- 16.5 to 41.3 +/- 8.8 relative U (p < 0.05 vs. begin), and IL-1-beta from 2.7 +/- 1.1 to 1.4 +/- 0.6 relative U (p = 0.02 vs. control group). Exercise training also reduced local iNOS expression by 52% (from 6.3 +/- 1.2 to 3.0 +/- 1.0 relative U; p = 0.007 vs. control group). CONCLUSIONS: Exercise training significantly reduced the local expression of TNF-alpha, IL-1-beta, IL-6, and iNOS in the skeletal muscle of CHF patients. These local anti-inflammatory effects of exercise may attenuate the catabolic wasting process associated with the progression of CHF.

Biopsy↗

PubMed2003

Short- and long-term hemodynamic effects of intra-aortic balloon support in ventricular septal defect complicating acute myocardial infarction.

In patients with an infarct-related ventricular septal defect, an intra-aortic balloon pump provides immediate and long-term hemodynamic improvement, resulting in an enhanced effective cardiac output and a reduced left-to-right-shunt and shunt flow ration. In patients who can be stabilized or remain stable, there is no habituation to the effects of the intra-aortic balloon pump; thus, later surgical closure of the ventricular septal defect might be possible in some patients.

Aged↗

PubMed2003

Promoter but not exon 7 polymorphism of endothelial nitric oxide synthase affects training-induced correction of endothelial dysfunction.

UNLABELLED: Background- Polymorphisms in the promoter (T-786C) and exon 7 (G894T) of the endothelial nitric oxide synthase (eNOS) gene were shown to be associated with reduced vascular NO production or increased proteolytic cleavage of eNOS. Therefore, we aimed to determine the effects of these polymorphisms on endothelial function and endothelial response to physical exercise in patients with coronary artery disease (CAD). METHODS AND RESULTS: Sixty-seven patients were randomized to either a training or a control group. At the beginning and after 4 weeks, acetylcholine-induced changes in average peak velocity (APV) of a coronary or mammary artery were invasively assessed by Doppler velocimetry. Polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism. At the beginning, in subjects with the wild-type (WT) variant, APV increased by 88+/-7% in response to acetylcholine. This response was significantly blunted in patients who were positive for the promoter (44+/-7%) or the exon 7 (62+/-9%) polymorphism. Four weeks of exercise training resulted in augmentation of an endothelium-dependent increase in APV by +36+/-12% in promoter polymorphism-positive patients but by +81+/-18% and +91+/-15% in WT variant- and exon 7 polymorphism-positive subjects, respectively. CONCLUSIONS: These results suggest that the presence of either one of the polymorphisms attenuates endothelium-dependent vasodilatation in CAD patients. Only the promoter polymorphism might have an adverse effect on training-induced improvement in endothelial function.

Aged↗

PubMed2003

Influence of residual stenosis after percutaneous coronary intervention with stent implantation on development of restenosis and stent thrombosis.

The aim of this study was to assess the effects of residual stenosis after single-stent implantation on the rate of stent thrombosis, as well as restenosis within a 6-month follow-up period. Coronary angiograms of 2,157 patients with 2,523 lesions treated with a single stent were analyzed by quantitative coronary angiography before, immediately after stent implantation, and at a planned 6-month follow-up. Lesions were classified into 4 subgroups according to the degree of residual stenosis after stent implantation: group 1, gross oversizing <-15%; group 2, slight oversizing -15% to <0%; group 3, mild residual 0% to <15%; group 4, moderate residual 15% to <30%. Stent thrombosis rates were not significantly different among the 4 subgroups (group 1: 0 of 60 [0%]; group 2: 2 of 388 [0.5%]; group 3: 8 of 1,370 [0.6%]; group 4: 8 of 705 [1.1%]; p = NS for all). An adequate dosage of ticlopidine (250 mg twice daily) and aspirin (100 mg/day) led to a lower rate of stent thrombosis (6 of 2,189 cases) than inadequate dosages or missing therapy (12 of 343 cases). In 1,882 stenoses with angiographic follow-up (77.7%), gross oversizing of stents lead to a significantly higher increase of percent stenosis (p <0.001) associated with a higher restenosis rate (group 1: 34.7% vs groups 2, 3, and 4: 32.5%, 28.2%, and 29.6%, respectively). A multiple regression analysis was performed. Optimal results with regard to stent thrombosis and restenosis were achieved with mild residual stenoses between 0% and 15% after stent implantation. Oversizing of stents is no longer necessary with an adequate dosage of ticlopidine and aspirin.

Aged↗

PubMed2003

Muscular levels of proinflammatory cytokines correlate with a reduced expression of insulinlike growth factor-I in chronic heart failure.

OBJECTIVE: Chronic heart failure (CHF) is associated with metabolic abnormalities leading to a catabolic syndrome in advanced stages of the disease. To assess the role of proinflammatory cytokines for the local expression of insulin-like growth factor-I (IGF-I) in this process, muscular and systemic levels of interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNFalpha) and IGF-I were analyzed in an animal model of CHF. METHODS: Ligation of the left coronary artery or sham operation was performed in adult Wistar Kyoto rats. After 12 weeks, all animals were assessed by echocardiography and cardiac catheterization. Serum levels of IGF-I, IL-1beta, TNFalpha and IL-6 were determined by ELISA. In the quadriceps muscle, the expression of IGF-I, IGF-I receptor, IL-1beta and TNFalpha were assessed by RT-PCR and quantitative immunohistochemistry. Alterations in muscle fiber morphology were analyzed microscopically. RESULTS: The local expression of IGF-I decreased significantly in animals with CHF (0.47 +/- 0.07 versus 0.77 +/- 0.09; p < 0.01). This reduction correlated with a decreased muscle fiber cross-sectional area (r = 0.62; p < 0.01) and inversely with the local expression of IL-1beta (r = -0.49; p < 0.05). IGF-I serum levels showed no significant differences between the two groups. CONCLUSIONS: In CHF, the local IGF-I expression is reduced in the presence of normal serum levels of IGF-I. Both elevated proinflammatory cytokines and reduced local IGF-I expression contribute to a catabolic metabolism that may finally result in skeletal muscle atrophy and cardiac cachexia.

Animals↗

PubMed2003

Prospective randomized comparison of early and late results of 4 different stent designs.

BACKGROUND: Late results of interventional procedures using coronary stents are largely determined by the rate of restenosis. So far, few data are available addressing the effect of stent design on this crucial variable and on early and late adverse events after stent implantation. METHODS: From 1996 through 1998, a total of 965 lesions in 925 patients with coronary artery disease were randomized to treatment with 1 of 4 different stent designs (Micro stent II [M] AVE, Düsseldorf, Germany; Sito [S] Sitomed, Rangendingen, Germany; Pura Vario [PV], Devon, Hamburg, Germany; Inflow [ID] Inflow Dynamics, München, Germany). The primary end point of the study was the degree of diameter stenosis measured by quantitative coronary angiography 6 months after stent implantation. RESULTS: Diameter stenosis at 6 months follow-up was not different in the 4 study arms (M 40.3 +/- 24.1, S 42.8 +/- 27.0, PV 42.6 +/- 26.9 and ID 42.3 +/- 26.8, P =.7). No significant differences could be detected in net lumen gain and late lumen loss, resulting in comparable restenosis rates (>or=50% diameter stenosis) at follow-up (M 26.0%, S 30.5%, PV 31.3%, and ID 28.7%, P =.7). Early adverse events like stent loss, stent thrombosis, periinterventional acute myocardial infarctions and emergency coronary artery bypass graft also showed no significant differences. Multivariate regression analyses revealed reference vessel diameter <3.0 mm, overall stented length, a history of bypass grafting, localization of the target lesion in the left anterior descending coronary artery, type C lesions, dissection before stent implantation, and diabetes mellitus to be independent predictors for restenosis. CONCLUSION: Stent design does not have significant influence on development of restenosis. Adverse event rates were similar with all stent types used in this trial.

Aged↗

PubMed2003

Improvement of peripheral endothelial dysfunction by acute vitamin C application: different effects in patients with coronary artery disease, ischemic, and dilated cardiomyopathy.

BACKGROUND: Endothelial dysfunction has been described in patients with coronary artery disease (CAD) or chronic heart failure (CHF). Vitamin C administration leads to an improvement of endothelial function by reducing elevated levels of reactive oxygen species. It remains unclear, however, whether the degree of endothelial dysfunction caused by oxidative stress differs between CAD and CHF because of ischemic (ICM) or dilated cardiomyopathy (DCM). METHODS: In patients with CAD (n = 9; left ventricular ejection fraction [LVEF], 64% +/- 3%), ICM (n = 9; LVEF, 25% +/- 4%), DCM (n = 9; LVEF, 25% +/- 3%), and healthy subjects (HS; n = 5; LVEF, 66% +/- 5%) a change in internal radial artery diameter in response to acetylcholine (Ach; 15 and 30 microg/min) was measured with high-resolution ultrasound scanning during a co-infusion of normal saline or vitamin C (25 mg/min). RESULTS: Ach-mediated vasodilation was blunted in patients with CHF (DCM, 90 +/- 20 microm; ICM, 86 +/- 20 microm) and patients with CAD (336 +/- 20 microm) as compared with HS (496 +/- 43 microm; P <.05 vs patients with DCM, ICM, CAD). Vitamin C co-infusion increased Ach-mediated vasodilation by 180 +/- 35 microm (to 270 +/- 30 microm) in DCM (P <.05 vs CAD, HS) and by 294 +/- 40 microm (to 380 +/- 20 microm) in ICM (P <.05 vs DCM, CAD, HS). In patients with CAD, vitamin C increased Ach-mediated vasodilation by 146 +/- 35 microm to normal values, whereas vascular diameter remained unchanged in HS (14 +/- 20 microm; P = not significant). CONCLUSIONS: Acute vitamin C administration restored peripheral endothelial function in patients with CAD to normal values, whereas endothelial function remained attenuated in CHF, in particular in patients with DCM. These results suggest that in patients with CHF, factors other than oxidative stress (eg, cytokines) contribute to the pathologic endothelial function.

Acetylcholine↗

PubMed2003

Home-based versus hospital-based exercise programs in patients with coronary artery disease: effects on coronary vasomotion.

BACKGROUND: In a randomized study, we recently documented that a vigorous, hospital-based exercise training (ET) program improves coronary endothelial function in coronary artery disease. The aim of this consecutive study was to assess whether a home-based exercise program with reduced average training duration can sustain previously achieved effects on coronary endothelial function. METHODS: Nineteen patients with coronary endothelial dysfunction documented by acetylcholine-induced vasoconstriction were randomly assigned to a training group (n = 10) or a control group (n = 9). After 4 weeks of inhospital training (60 min of bicycle ergometry per day), all training patients were enrolled in a 5-month home-based program of 20 minutes' ergometry training per day and 1 group training session per week. At baseline, after 4 weeks and 6 months, endothelium-mediated vasodilation was assessed by quantitative coronary angiography after intracoronary infusions of acetylcholine. Average peak velocity (APV) was measured with a Doppler wire. Coronary blood flow (CBF) was calculated by multiplying vascular cross-sectional area and APV. RESULTS: CBF increased in response to 7.2 microg/min acetylcholine, from 27% +/- 11% at the beginning of the study to 110% +/- 24% after 4 weeks (P <.01 vs control group). After 6 months, the increase in CBF was lower versus inhospital training (67% +/- 18%, P <.05 vs 4 weeks). Changes in APV between 1 and 6 months correlated with daily training durations (r = 0.65, P =.03). CONCLUSIONS: Home-based ET sustained part of the effects of hospital-based ET on endothelium-dependent vasodilation in coronary artery disease. However, acetylcholine-induced increases in CBF were lower after home-based ET, suggesting a relation between daily training duration and improvement of coronary vasomotion.

Aged↗

PubMed2003

Nuclear factor-kappa B activation in skeletal muscle of patients with chronic heart failure: correlation with the expression of inducible nitric oxide synthase.

BACKGROUND: In the advanced stages of chronic heart failure (CHF) the expression of inducible nitric oxide synthase (iNOS) in skeletal muscle (SM) may contribute to exercise intolerance and early fatigue. Cell culture studies and promoter analysis demonstrated that the transcription factor nuclear factor kappa B (NF-kappaB) is essential for iNOS-expression. The aim of this study was to assess whether NF-kappaB is activated in skeletal muscle of patients with CHF and linked to the expression of iNOS. METHODS: Skeletal muscle biopsies were obtained from seven CHF patients and seven healthy controls (HC). Nuclear proteins were isolated and the content of activated NF-kappaB was analysed by electrophoretic mobility shift assay (EMSA). Inducible nitric oxide synthase expression in SM was determined by real time polymerase chain reaction (PCR). RESULTS: The expression of iNOS (1.4 +/- 0.2 versus 0.5 +/- 0.08 arbitrary units, P=0.001) and the activation of NF-kappaB in the SM (0.5 +/- 0.1 versus 0.1 +/- 0.04 arbitrary units, P=0.009) was significantly increased in CHF patients as compared to healthy controls. Furthermore, a linear correlation was observed between NF-kappaB activation and iNOS expression (r=0.78, P<0.001). CONCLUSIONS: The results of this study indicate for the first time that in the skeletal muscle of patients with chronic heart failure the activation of the transcription factor NF-kappaB is increased and may represent one important regulatory factor for the expression of iNOS in patients. Nevertheless, due to the small sample size this observation has to be confirmed in subsequent studies with more patients.

Aged↗

PubMed2003

Exercise training in patients with severe chronic heart failure: impact on left ventricular performance and cardiac size. A retrospective analysis of the Leipzig Heart Failure Training Trial.

BACKGROUND: Exercise training (ET) has been shown to improve functional work capacity in patients with stable chronic heart failure (CHF) having moderate symptoms (NYHA class II). This analysis was conducted, to evaluate the effects of ET on left ventricular function and haemodynamics in patients with advanced CHF (NYHA class III) fulfilling the inclusion criteria of the COPERNICUS trial. METHODS: Seventy-three patients with moderate and advanced CHF were prospectively randomised to a training (n=36), or to a control group (n=37). At baseline and after six months, patients underwent echocardiography and symptom-limited ergospirometry with measurement of central haemodynamics by thermodilution. RESULTS: Nine out of 37 patients in the control group (C) and 10 out of 36 patients in the training group (T) had symptoms of advanced CHF. Exercise training over a period of six months resulted in an improvement of functional status on average by one NYHA class in patients with advanced CHF. Moreover, oxygen uptake at the ventilatory threshold increased by 49% (from 7.7+/-1.0 to 11.4+/-0.4 mL/min/kg, P<0.01 versus baseline) and at peak exercise by 32% (from 16.3+/-1.6 to 21.5+/-1.2 mL/min/kg, P<0.01 versus baseline) in training patients. The small, but significant reduction in left ventricular end-diastolic diameter by 7% (from 70+/-2 to 66+/-2 mm; P<0.05 versus baseline) was accompanied by an augmentation in stroke volume at rest by 32% (from 45+/-3 to 60+/-6 mL, P<0.05 versus baseline) and at peak exercise by 27% (63+/-9 to 81+/-9 mL, P<0.05 versus baseline) as a result of ET in patients with advanced CHF. CONCLUSIONS: In patients with advanced CHF (NYHA class III), long-term exercise training is associated with an enhanced physical work capacity, an improvement in stroke volume and a reduction in cardiomegaly.

Cardiomegaly↗

PubMed2002

Comparison of stenting with minimally invasive bypass surgery for stenosis of the left anterior descending coronary artery.

BACKGROUND: Minimally invasive bypass surgery and coronary-artery stenting are both accepted treatments for isolated stenosis of the proximal left anterior descending coronary artery. We compared the clinical outcomes after these two procedures. METHODS: A total of 220 symptomatic patients with high-grade lesions in the proximal left anterior descending coronary artery were randomly assigned to treatment--110 to surgery and 110 to stenting. The combined clinical end point was freedom from major adverse cardiac events, such as death from cardiac causes, myocardial infarction, and the need for repeated revascularization of the target lesion within six months. RESULTS: A major adverse cardiac event occurred in 31 percent of patients after stenting, as compared with 15 percent in the surgery group (P=0.02). The difference was predominantly due to a higher rate of repeated revascularization of the target vessel for restenosis after stenting (29 percent vs. 8 percent, P=0.003). The combined rates of death and myocardial infarction did not differ significantly between groups (3 percent in the stenting group and 6 percent in the surgery group, P=0.50). Adverse events occurred more frequently after surgery. The percentage of patients free from angina after six months was 79 percent in the surgery group, as compared with 62 percent in the stenting group (P=0.03). CONCLUSIONS: In patients with isolated high-grade lesions of the proximal left anterior descending artery, both minimally invasive bypass surgery and stenting are effective. Stenting yields excellent short-term results with fewer periprocedural adverse events, but surgery is superior with regard to the need for repeated intervention in the target vessel and freedom from angina at six months of follow-up.

Angioplasty, Balloon, Coronary↗

PubMed2002

Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies.

BACKGROUND: In patients with chronic heart failure (CHF), hyperuricemia is a common finding and is associated with reduced vasodilator capacity and impaired peripheral blood flow. It has been suggested that the causal link of this association is increased xanthine oxidase (XO)-derived oxygen free radical production and endothelial dysfunction. We therefore studied the effects of XO inhibition with allopurinol on endothelial function and peripheral blood flow in CHF patients after intra-arterial infusion and after oral administration in 2 independent placebo-controlled studies. METHODS AND RESULTS: In 10 CHF patients with normal serum uric acid (UA) levels (315+/-42 micromol/L) and 9 patients with elevated UA (535+/-54 micromol/L), endothelium-dependent (acetylcholine infusion) and endothelium-independent (nitroglycerin infusion) vasodilation of the radial artery was determined. Coinfusion of allopurinol (600 microg/min) improved endothelium-dependent but not endothelium-independent vasodilation in hyperuricemic patients (P<0.05). In a double-blind, crossover design, hyperuricemic CHF patients were randomly allocated to allopurinol 300 mg/d or placebo for 1 week. In 14 patients (UA 558+/-21 micromol/L, range 455 to 743 micromol/L), treatment reduced UA by >120 micromol/L in all patients (mean reduction 217+/-15 micromol/L, P<0.0001). Compared with placebo, allopurinol improved peak blood flow (venous occlusion plethysmography) in arms (+24%, P=0.027) and legs (+23%, P=0.029). Flow-dependent flow improved by 58% in arms (P=0.011). Allantoin, a marker of oxygen free radical generation, decreased by 20% after allopurinol treatment (P<0.001). There was a direct relation between change of UA and improvement of flow-dependent flow after allopurinol treatment (r=0.63, P<0.05). CONCLUSIONS: In hyperuricemic CHF patients, XO inhibition with allopurinol improves peripheral vasodilator capacity and blood flow both locally and systemically.

Administration, Oral↗

PubMed2002

Reduction of insulin-like growth factor-I expression in the skeletal muscle of noncachectic patients with chronic heart failure.

OBJECTIVES: We sought to assess the role of insulin-like growth factor-I (IGF-I) in muscle wasting in chronic heart failure (CHF), serum concentrations and local muscular IGF-I expression were determined in patients with severe CHF. BACKGROUND: Chronic heart failure is associated with progressive muscle atrophy, leading to cardiac cachexia. Skeletal muscle disuse and inflammatory activation with elevated cytokine levels have been implicated; however, the pathomechanism involved remains largely unknown. METHODS: Serum levels of IGF-I were measured by competitive solid phase immunoassay in 47 patients with severe CHF (left ventricular ejection fraction < or =30%) and 15 age-matched healthy subjects (HS). Insulin-like growth factor-I and IGF-I receptor expression were assessed in vastus lateralis biopsies by real-time PCR and Western blot analysis. RESULTS: Although serum IGF-I was not significantly different (175 +/- 10 ng/ml in CHF vs. 170 +/- 12 ng/ml in HS, p = NS), local muscle IGF-I mRNA expression was reduced by 52% in CHF (6.7 +/- 0.4 vs. 14.0 +/- 0.9 arbitrary units in HS, p < 0.001). This was accompanied by an increase in IGF-I receptor mRNA expression (86.8 +/- 5.4 in CHF vs. 23.1 +/- 1.8 arbitrary units in HS, p < 0.001). Local IGF-I expression was significantly correlated with muscle cross-sectional area (R = 0.75, p = 0.01). Chronic heart failure patients with a body mass index of < 25 kg/m(2) showed signs of peripheral growth hormone (GH) resistance, as indicated by elevated serum GH, and reduced IGF-I levels. CONCLUSIONS: In CHF patients, muscle IGF-I expression is considerably reduced in the presence of normal serum IGF-I levels, possibly contributing to early loss of muscle mass. These findings are consistent with a potential role of IGF-I for skeletal muscle atrophy in CHF.

Body Mass Index↗

PubMed2002

[Stress and stress tolerance in chronic heart failure].

BACKGROUND: Exercise intolerance in patients with chronic heart failure (CHF) shows no correlation to the degree of left ventricular dysfunction. This surprising finding has directed attention to peripheral changes in CHF. During the last years several different peripheral factors as determinants of exercise intolerance have been defined, i.e. abnormalities in ventilation, reduced endothelium-dependent vasodilatation of peripheral conduit and resistance vessels, and altered skeletal muscle metabolism. Skeletal muscle alterations are characterized by a reduced oxidative capacity, a catabolic state with reduced local IGF-I expression and muscle atrophy, chronic inflammation with local expression of the inducible isoform of nitric oxide synthase (iNOS) and an accelerated rate of programmed cell death (apoptosis). EFFECTS OF PHYSICAL EXERCISE: Physical exercise training has evolved as an important therapeutic approach to influence these non-cardiac causes of exercise intolerance. After the first studies documenting the effect of aerobic training on the peripheral causes of exercise intolerance in CHF the question was asked: Should we treat the heart or the periphery to improve exercise intolerance in CHF? Today, we have come closer to the answer: It is now clear that these two systems are not mutually exclusive. Exercise training in CHF has been shown to improve skeletal muscle metabolism and function, to avert muscle catabolism, to reduce neurohumoral overactivation, to reverse endothelial dysfunction and to contribute to the prevention of pathologic left ventricular remodeling. After 6 months of regular exercise training oxidative capacity of the working skeletal muscle increases by approximately 40%. Regular exercise training leads to a significant improvement of endothelium-dependent vasodilatory capacity of peripheral resistance vessels, thereby reducting peripheral resistance in particular during exercise. These beneficial training effects result in a small, but significant improvement of stroke volume and reduction in cardiomegaly. CONCLUSION: Although several questions regarding patient selection, optimal training protocol and training intensity remain unanswered, exercise training can been seen as an established adjunct to pharmacotherapy in CHF. We may soon reach the conclusion that by treating the periphery with exercise programs we are in fact treating the heart, as well. All exercise-induced adaptations converge to increase peak oxygen uptake by up to 2 ml/kg.min. For patients in stable CHF on optimal cardiac medication a combination of in-hospital and home-based aerobic endurance training in combination with local muscle strength training seems most promising. Although exercise training offers no causal treatment of CHF, it has great potentials as an adjunct therapy directed at improving exercise tolerance and expanding the physical limits of CHF patients.

Chronic Disease↗