Biomedical subjects

Axel Linke

Publications and source records attributed to Axel Linke.

At least 37 records · Page 2Linked 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

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

Comparative profile of vasodilation by CVT-3146, a novel A2A receptor agonist, and adenosine in conscious dogs.

The purpose of this study was to determine the magnitude of vasodilation by CVT-3146 in different vascular beds and to compare it with that by adenosine in conscious dogs. Intravenous bolus injections of CVT-3146 (0.1-2.5 microg/kg) or adenosine (10-250 microg/kg) caused a dose-dependent increase in the coronary blood flow (CBF) and a dose-dependent decrease in the late diastolic coronary resistance. Although the maximal increase in CBF response to the two drugs was not significantly different, the ED50 of CVT-3146 and adenosine were 0.45 +/- 0.07 microg/kg and 47 +/- 7.77 microg/kg, respectively. The highest dose of CVT-3146 caused a much longer coronary vasodilation than the highest dose of adenosine. There were no significant differences in increases in cardiac output induced by higher doses of CVT-3146 or adenosine. Most importantly, CVT-3146 resulted in a smaller decrease in total peripheral resistance (TPR) compared to that seen with adenosine. In addition, CVT-3146 yielded a smaller increase in the lower body flow (LBF) than adenosine. Adenosine also caused dose-dependent renal vasoconstriction, whereas CVT-3146 did not affect the renal blood flow. The administration of CVT-3146 or adenosine caused a dose-dependent vasodilation in the mesentery, which was not significantly different from each other. In summary, CVT-3146 is a 100-fold more potent coronary vasodilator than adenosine. CVT-3146 causes smaller decreases in TPR and smaller increases in LBF than those induced by adenosine, indicating that it is more selective for coronary than peripheral vasodilation. Furthermore, CVT-3146 did not cause renal vasoconstriction. These features make CVT-3146 a better candidate for pharmacologic stress testing.

Adenosine↗

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

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

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

Elevated serum levels of leptin and soluble leptin receptor in patients with advanced chronic heart failure.

Patients with chronic heart failure (CHF) have metabolic abnormalities, leading to a catabolic syndrome, with progressive loss of skeletal muscle in advanced stages of the disease. Leptin, the product of an obesity gene, has been associated with energy expenditure and weight regulation. The aim of this study was to assess serum levels of leptin and its soluble receptor in relation to exercise intolerance and neurohumoral activation in patients with CHF. We investigated 53 patients with CHF left ventricular ejection fraction (LVEF) 25+/-1%, age 56.6+/-1.3 years, Maximal oxygen uptake (VO(2) max) 16.3+/-0.6 ml/min.kg) sub-classified according to peak oxygen consumption of > or 14 ml/min.kg and controls). Elevated levels of leptin correlated with an increased serum concentration of TNFalpha (r=0.749, P<0.01) in this subgroup of patients with CHF. We conclude that patients with advanced CHF show elevated serum levels of leptin and its soluble receptor. This finding indicates that leptin may participate in the catabolic state leading to the development of cardiac cachexia in the course of CHF.

Aged↗

PubMed2003

Acute and chronic endothelial dysfunction: implications for the development of heart failure.

Heart failure has been characterized by a reduction in cardiac contractile function resulting in reduced cardiac output. The clinical symptoms including mild tachycardia, reduced arterial pressure, increased venous or filling pressure and exercise intolerance have conceptually, to a large degree, been attributed to cardiac myocyte dysfunction. More recently, a vascular component has been recognized to contribute to heart failure. Among the most studied vascular mechanisms that might contribute to the development of heart failure has been the reduced production of nitric oxide or the reduced bioactivity of NO associated with both basic models of heart failure and disease in patients. The still evolving concept that heart failure is a cytokine activated state has, in addition, focused attention on the possibility that the cytokine driven isoform of NO synthase (NOS), iNOS, may produce sufficient quantities of NO to actually suppress cardiac myocyte function contributing to the reduced inotropic state in the failing heart. Thus, our view of the role of NO in the development of heart failure has evolved from simply a reduction in production of NO in blood vessels, to altered substrate availability (i.e. L-arginine), to increased scavenging of NO by superoxide anion, to increased production of NO from iNOS. As these concepts develop, our approach to the therapeutics of heart failure has also progressed with the recognition of the need to develop treatments directed towards addressing one or more of these etiologies. This review will focus on these aspects of the involvement of NO in the development of heart failure and some of the treatments that have developed from our understanding of the basic biology of NO to address these pathohysiologic states.

Acute Disease↗

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↗

PubMed2003

Shift in metabolic substrate uptake by the heart during development of alloxan-induced diabetes.

Inhibition of endothelial nitric oxide (NO) synthase (eNOS) is associated with an increase in glucose uptake by the heart. We have already shown that Type I diabetes also causes a decrease in eNOS protein expression and altered NO control of both coronary vascular resistance and oxygen consumption. Therefore, we predict that the increase in plasma glucose and the reduction in eNOS during diabetes together would result in a large increase in cardiac glucose uptake. Arterial (A) and coronary sinus (C) plasma levels of glucose, free fatty acid (FFA), beta-hydroxybutyric acid (beta-HBA), and lactate were measured, and myocardial uptake was calculated before and at week 1, 2, 3, and 4 of alloxan-induced diabetes. The heart of healthy dogs consumed FFA (19.2 +/- 2.6 microeq/min) and lactate (19.7 +/- 3.4 micromol/min). Dogs in the late stage of diabetes (at week 4) had elevated arterial beta-HBA concentrations (1.6 +/- 0.7 micromol/l) that were accompanied by an increased beta-HBA uptake (0.3 +/- 0.2 micromol/min). In contrast, myocardial lactate (-4.8 +/- 3.0 micromol/min) and FFA uptake (2.5 +/- 1.9 microeq/min) were significantly reduced in diabetic animals. Despite a marked hyperglycemia (449 +/- 25 mg/dl), the heart did not take up glucose (-7.9 +/- 4.1 mg/dl). Our results indicate significant changes in the myocardial substrate utilization in dogs only in the late stage of diabetes, at a time when myocardial NO production is already decreased.

3-Hydroxybutyric Acid↗

PubMed2003

NAD(P)H oxidase-generated superoxide anion accounts for reduced control of myocardial O2 consumption by NO in old Fischer 344 rats.

We investigated the role of nitric oxide (NO) in the control of myocardial O2 consumption in Fischer 344 rats. In Fischer rats at 4, 14, and 23 mo of age, we examined cardiac function using echocardiography, the regulation of cardiac O2 consumption in vitro, endothelial NO synthase (eNOS) protein levels, and potential mechanisms that regulate superoxide. Aging was associated with a reduced ejection fraction [from 75 +/- 2% at 4 mo to 66 +/- 3% (P < 0.05) at 23 mo] and an increased cardiac diastolic volume [from 0.60 +/- 0.04 to 1.00 +/- 0.10 ml (P < 0.01)] and heart weight (from 0.70 +/- 0.02 to 0.90 +/- 0.02 g). The NO-mediated control of cardiac O2 consumption by bradykinin or enalaprilat was not different between 4 mo (36 +/- 2 or 34 +/- 3%) and 14 mo (29 +/- 1 or 25 +/- 3%) but markedly (P < 0.05) reduced in 23-mo-old Fischer rats (15 +/- 3 or 7 +/- 2%). The response to the NO donor S-nitroso-N-acetyl penicillamine was not different across groups (35%, 35%, and 44%). Interestingly, the eNOS protein level was not different at 4, 14, and 23 mo. The addition of tempol (1 mmol/l) to the tissue bath eliminated the depression in the control of cardiac O2 consumption by bradykinin (25 +/- 3%) or enalaprilat (28 +/- 3%) in 23-mo-old Fischer rats. We next examined the levels of enzymes involved in the production and breakdown of superoxide. The expression of Mn SOD, Cu/Zn SOD, extracellular SOD, and p67phox, however, did not differ between 4- and 23-mo-old rats. Importantly, there was a marked increase in gp91phox, and apocynin restored the defect in NO-dependent control of cardiac O2 consumption at 23 mo to that seen in 4-mo-old rats, identifying the role of NADPH oxidase. Thus increased biological activity of superoxide and not decreases in the enzyme that produces NO are responsible for the altered control of cardiac O2 consumption by NO in 23-mo-old Fischer rats. Increased oxidant stress in aging, by decreasing NO bioavailability, may contribute not only to changes in myocardial function but also to altered regulation of vascular tone and the progression of cardiac or vascular disease.

Acetophenones↗

PubMed2002

Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-alpha in pacing-induced heart failure.

BACKGROUND: The nuclear receptors peroxisome proliferator-activated receptor-alpha (PPARalpha) and retinoid X receptor alpha (RXRalpha) stimulate the expression of key enzymes of free fatty acid (FFA) oxidation. We tested the hypothesis that the altered metabolic phenotype of the failing heart involves changes in the protein expression of PPARalpha and RXRalpha. METHODS AND RESULTS: Cardiac substrate uptake and oxidation were measured in 8 conscious, chronically instrumented dogs with decompensated pacing-induced heart failure and in 8 normal dogs by infusing 3 isotopically labeled substrates: 3H-oleate, 14C-glucose, and 13C-lactate. Although myocardial O2 consumption was not different between the 2 groups, the rate of oxidation of FFA was lower (2.8+/-0.6 versus 4.7+/-0.3 micromol x min(-1) x 100g(-1)) and of glucose was higher (4.6+/-1.0 versus 1.8+/-0.5 micromol x min(-1) x 100g(-1)) in failing compared with normal hearts (P<0.05). The rates of lactate uptake and lactate output were not significantly different between the 2 groups. In left ventricular tissue from failing hearts, the activity of 2 key enzymes of FFA oxidation was significantly reduced: carnitine palmitoyl transferase-I (0.54+/-0.04 versus 0.66+/-0.04 micromol x min(-1) x g(-1)) and medium chain acyl-coenzyme A dehydrogenase (MCAD; 1.8+/-0.1 versus 2.9+/-0.3 micromol x min(-1) x g(-1)). Consistently, the protein expression of MCAD and of RXRalpha were significantly reduced by 38% in failing hearts, but the expression of PPARalpha was not different. Moreover, there were significant correlations between the expression of RXRalpha and the expression and activity of MCAD. CONCLUSIONS: Our results provide the first evidence for a link between the reduced expression of RXRalpha and the switch in metabolic phenotype in severe heart failure.

Acetyl-CoA Carboxylase↗

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

Induction of iNOS expression in skeletal muscle by IL-1beta and NFkappaB activation: an in vitro and in vivo study.

OBJECTIVE: The intracellular pathway and the regulation of inducible nitric oxide synthase (iNOS) expression in skeletal muscle is incompletely understood. In vitro studies, using different cell types, suggest that inflammatory cytokines are potential triggers to induce iNOS expression. METHODS: To analyze intracellular pathways leading to iNOS induction, rat skeletal myoblasts were incubated with inflammatory cytokines and assessed for iNOS expression by Western blot and Griess reaction. To confirm the in vitro findings, local cytokine levels were determined in skeletal muscle biopsies of patients with chronic heart failure (CHF) and correlated with iNOS expression. RESULTS: Nitrite accumulation in the myoblast culture supernatant or iNOS protein in the cell pellet was significantly increased after incubation with IL-1beta in combination with gamma-IFN. Priming experiments revealed that gamma-IFN elevated the expression of IL-1beta receptor mRNA, whereby IL-1beta was able to induce iNOS expression. The cytokine-mediated iNOS induction was significantly reduced by blocking ERK1/ERK2 activation and completely abolished by the inhibition of NFkappaB. In skeletal muscle biopsies of CHF patients the local content of IL-1beta was significantly increased as compared to healthy controls. Furthermore, a linear correlation between IL-1beta content and iNOS expression in the skeletal muscle was detected. CONCLUSIONS: These data demonstrate that IL-1beta, together with the priming effect of gamma-IFN, induces iNOS expression in skeletal muscle via activation of ERK1/ERK2 and NFkappaB.

Aged↗

PubMed2002

Role of cardiac eNOS expression during pregnancy in the coupling of myocardial oxygen consumption to cardiac work.

We assessed whether pregnancy results in enhanced nitric oxide (NO)-mediated control of myocardial oxygen consumption. Rats were studied before (C), at 1 wk (1w) or 2 wk (2w) of pregnancy, and at 4 days after giving birth (-4d). Left ventricular endothelial NO synthase (eNOS) protein expression was determined by immunoblotting. Oxygen consumption of left ventricular tissue samples was measured in vitro in response to increasing doses of bradykinin with or without addition of the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Echocardiography indicated an increased cardiac output during pregnancy. Myocardial eNOS protein expression significantly increased by 46 +/- 9 and 39 +/- 8% at 1w and 2w, respectively, and returned to control levels at -4d. Bradykinin (10(-4) M) decreased cardiac oxygen consumption in a NO-dependent manner by 17 +/- 2% at C, by 21 +/- 2% at 1w, by 24 +/- 2% at 2w (P < 0.05 vs. C and -4d), and by 18 +/- 1% at -4d. Myocardial eNOS protein expression is transiently increased during pregnancy in rats, and this increase is associated with enhanced NO-dependent control of myocardial oxygen consumption at a time when cardiac output is increased.

Amlodipine↗