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Stefan Neubauer

Publications and source records attributed to Stefan Neubauer.

At least 91 records · Page 5Linked to original sources
PubMed2003

Cardiac neuronal nitric oxide synthase isoform regulates myocardial contraction and calcium handling.

A neuronal isoform of nitric oxide synthase (nNOS) has recently been located to the cardiac sarcoplasmic reticulum (SR). Subcellular localization of a constitutive NOS in the proximity of an activating source of Ca2+ suggests that cardiac nNOS-derived NO may regulate contraction by exerting a highly specific and localized action on ion channels/transporters involved in Ca2+ cycling. To test this hypothesis, we have investigated myocardial Ca2+ handling and contractility in nNOS knockout mice (nNOS-/-) and in control mice (C) after acute nNOS inhibition with 100 micromol/L L-VNIO. nNOS gene disruption or L-VNIO increased basal contraction both in left ventricular (LV) myocytes (steady-state cell shortening 10.3+/-0.6% in nNOS-/- versus 8.1+/-0.5% in C; P<0.05) and in vivo (LV ejection fraction 53.5+/-2.7 in nNOS-/- versus 44.9+/-1.5% in C; P<0.05). nNOS disruption increased ICa density (in pA/pF, at 0 mV, -11.4+/-0.5 in nNOS-/- versus -9.1+/-0.5 in C; P<0.05) and prolonged the slow time constant of inactivation of ICa by 38% (P<0.05), leading to an increased Ca2+ influx and a greater SR load in nNOS-/- myocytes (in pC/pF, 0.78+/-0.04 in nNOS-/- versus 0.64+/-0.03 in C; P<0.05). Consistent with these data, [Ca2+]i transient (indo-1) peak amplitude was greater in nNOS-/- myocytes (410/495 ratio 0.34+/-0.01 in nNOS-/- versus 0.31+/-0.01 in C; P<0.05). These findings have uncovered a novel mechanism by which intracellular Ca2+ is regulated in LV myocytes and indicate that nNOS is an important determinant of basal contractility in the mammalian myocardium. The full text of this article is available at http://www.circresaha.org.

Animals↗
PubMed2003

Evaluation of sodium T1 relaxation times in human heart.

PURPOSE: To evaluate the sodium longitudinal relaxation (T(1)) characteristics for myocardium and blood in humans. MATERIALS AND METHODS: Eleven healthy volunteers were examined by using a (23)Na heart surface coil at a 1.5 T clinical scanner equipped with a broadband spectroscopy option. (23)Na MR measurements were performed by using a three-dimensional spoiled gradient echo sequence (in-plane resolution, 3.5 mm x 7 mm; slice thickness, 24 mm; TE, 3.1 msec; bandwidth, 65 Hz/pixel; TR, 21 to 150 msec). RESULTS: Longitudinal T(1) relaxation time components were 31.6+/-7.0 msec and 31.1+/-7.5 msec for myocardium and blood, respectively. CONCLUSION: (23)Na T(1) relaxation times of myocardium and blood can be determined in humans. The results are in agreement with values obtained from animal studies.

Adult↗
PubMed2003

Fast, high-resolution in vivo cine magnetic resonance imaging in normal and failing mouse hearts on a vertical 11.7 T system.

PURPOSE: To establish fast, high-resolution in vivo cine magnetic resonance imaging (cine-MRI) on a vertical 11.7-T MR system and to investigate the stability of normal and failing mouse hearts in the vertical position. MATERIALS AND METHODS: To optimize the method on a high-field system, various MR-related parameters, such as relaxation times and the need for respiratory gating, were quantitatively investigated. High-resolution cine-MRI was applied to normal mice and to a murine heart failure model. Cardiac functional parameters were compared to matched mice imaged previously on a horizontal MR system. RESULTS: A T(1) of 1.10 +/- 0.27 seconds and a T(2) of 18.5 +/- 3.9 msec were measured for murine myocardial tissue. A quantitative analysis also proved respiratory gating to be essential for obtaining artifact-free cine images in the vertical position at this field strength. Cardiac functional parameters of mice, obtained within one hour, agreed well with those from previous studies of mice in the horizontal position. CONCLUSION: This work shows that MR systems with a vertical bore design can be used to accurately measure cardiac function in both normal and chronically failing mouse hearts within one hour. The increased signal-to-noise ratio (SNR) due to the higher field strength could be exploited to obtain higher temporal and spatial resolution compared to previous studies that were performed on horizontal systems with lower field strengths.

Animals↗
PubMed2003

High-resolution MRI with cardiac and respiratory gating allows for accurate in vivo atherosclerotic plaque visualization in the murine aortic arch.

Genetically engineered mouse models provide enormous potential for investigation of the underlying mechanisms of atherosclerotic disease, but noninvasive imaging methods for analysis of atherosclerosis in mice are currently limited. This study aimed to demonstrate the feasibility of MRI to noninvasively visualize atherosclerotic plaques in the thoracic aorta in mice deficient in apolipoprotein-E, who develop atherosclerotic lesions similar to those observed in humans. To freeze motion, MR data acquisition was both ECG- and respiratory-gated. T(1)-weighted MR images were acquired with TR/TE approximately 1000/10 ms. Spatial image resolution was 49 x 98 x 300 micro m(3). MRI revealed a detailed view of the lumen and the vessel wall of the entire thoracic aorta. Comparison of MRI with corresponding cross-sectional histopathology showed excellent agreement of aortic vessel wall area (r = 0.97). Hence, noninvasive MRI should allow new insights into the mechanisms involved in progression and regression of atherosclerotic disease.

Animals↗
PubMed2003

High-resolution, high-throughput magnetic paragraph sign resonance imaging of mouse embryonic paragraph sign anatomy using a fast gradient-echo sequence.

Embryonic development in normal and genetically modified mice is commonly analysed by histological sectioning. This procedure is time-consuming, prone to artefact, and results in the loss of three-dimensional (3D) information. Magnetic resonance imaging (MRI) of embryos has the potential of noninvasively acquiring a complete 3D data set. Published methods have used spin-echo techniques with inherently high signal-to-noise ratio (SNR); however, they required either perfusion of the embryo with a contrast agent, or prolonged acquisition times to improve contrast and resolution. Here, we show that a standard preparation (i.e. paraformaldehyde fixation) of 15.5 days post-coitum embryos followed by MRI using a fast gradient-echo sequence with T(1)-weighting achieves high resolution and high throughput for investigating mouse embryonic anatomy. 3D data sets were acquired in overnight experiments (<9 h) with an experimental resolution of approximately 25 microm(3). This spatial resolution is twofold higher than the values reported previously for comparable paraformaldehyde-fixed embryos, and it was obtained in less than a quarter of the time with sufficient SNR. Our approach combines speed, high resolution and contrast with a simple preparation technique and minimal operator time (<1 h). It allows rapid routine 3D characterisation of normal and abnormal mouse embryonic anatomy.

Anatomy, Cross-Sectional↗
PubMed2003

Cardiac magnetic resonance spectroscopy.

This review describes recent advances in cardiac magnetic resonance spectroscopy (MRS). MRS allows noninvasive characterization of the metabolic state of cardiac muscle, in both animal and human models. Recent experimental MRS studies have allowed new insights into the essential role of energetics in heart failure. Various new studies suggest a rapidly growing role of MRS for phenotyping new genetically modified mouse models, and recent methodologic advances include development of absolute quantification of high-energy phosphates, measurement of ATP turnover rates and thermodynamic parameters (such as free ADP and free energy change of ATP hydrolysis), and improved acquisition sequences. New patient studies demonstrate the potential value of MRS as a clinical diagnostic tool in patients with ischemic heart disease, heart failure, cardiac transplantation, valve disease, and genetic cardiomyopathy.

Animals↗
PubMed2003

Effect of testosterone on post-myocardial infarction remodeling and function.

BACKGROUND: Men and women are differently affected by coronary artery disease, suggesting an important role of sex steroids. Moreover, testosterone (T) treatment is increasingly used in elderly males. Therefore, we examined effects of chronic anabolic T administration on left ventricular (LV) remodeling after myocardial infarction (MI). METHODS: Adult male rats were treated with intramuscular placebo, testosterone undecanoate (T), or were orchiectomized. After 2 weeks, animals underwent sham-operation (sham) or left coronary artery ligation. Left ventricular remodeling and function was assessed by serial magnetic resonance imaging (MRI) at weeks 2 and 8 and hemodynamic investigation at week 8. RESULTS: In sham operated animals T administration increased serum T levels and led to cardiac hypertrophy, but not to an upregulation of ANP mRNA. The alpha/beta-MHC ratio was significantly higher after T treatment due to an increase in alpha-MHC. As a potential mechanism for this "physiologic" form of hypertrophy, IGF-1 mRNA expression was significantly increased in T treated animals. After coronary artery ligation, infarct size and mortality were similar among the groups. Left ventricular hypertrophy was enhanced by T treatment. However, in vivo LV end-diastolic pressure and wall stress were decreased by T, whereas other hemodynamic parameters (mean arterial pressure, cardiac output, etc.) remained unchanged. CONCLUSION: Chronic anabolic T treatment led to a specific "physiologic" pattern of myocardial hypertrophy with a significant increase in LV weight, but without differences in ANP and with an upregulation in alpha/beta-MHC, possibly mediated by IGF-1. Testosterone treatment had no detrimental effects following MI. Reduced wall stress and LVEDP may even improve long-term outcome.

Animals↗
PubMed2003

Rapid identification and 3D reconstruction of complex cardiac malformations in transgenic mouse embryos using fast gradient echo sequence magnetic resonance imaging.

Developmental malformations of the heart in mouse embryos are commonly studied by histological sectioning. This is slow, labour intensive, and results in the loss of three-dimensional (3D) information. Magnetic resonance studies of embryos typically use spin-echo sequences, using prolonged acquisition times (>36 h) or perfusion with contrast agents to enhance resolution and contrast. This is technically difficult, and requires significant amounts of operator time. We imaged paraformaldehyde fixed embryos using a fast spoiled 3D gradient echo sequence with T(1)-weighting, in unattended overnight runs of less than 9 h. In wild-type embryos, we visualised normal cardiac structures, including cardiac chambers, the ventricular septum, primary and secondary atrial septa, valves, superior and inferior vena cava, aorta, pulmonary artery, and ductus arteriosus. In embryos lacking Cited2 (a transcriptional co-activator required for normal heart development), we identified cardiac malformations including atrial and ventricular septal defects, cono-truncal defects, and aortic arch malformations. We generated 3D reconstructions of normal and mutant hearts using contour identification and surface rendering computer software. The malformations were confirmed by histological sectioning. Our data indicate that fast gradient echo sequence magnetic resonance imaging can be used to rapidly and accurately identify complex cardiovascular malformations in transgenic and mutant mouse embryos.

Animals↗
PubMed2003

Alterations in the myocardial creatine kinase system precede the development of contractile dysfunction in beta(1)-adrenergic receptor transgenic mice.

The beta-adrenergic receptor system not only plays a central role in modulating heart rate and left-ventricular (LV) contractility, but is also involved in the development of heart failure. We have, recently, shown that heart-specific overexpression of the beta(1)-adrenergic receptor in transgenic mice (TG) initially leads to increased contractility, followed by LV hypertrophy and heart failure. Since one feature for all forms of heart failure are characteristic changes in myocardial energy metabolism, we asked whether alterations in energetics are detectable in these mice before signs of LV impairment are present. Myocardial energetics ((31)P NMR spectroscopy) and LV performance were measured simultaneously in isolated perfused hearts at different workloads. LV performance as well as contractile reserve was identical for hearts of 4-month-old TG and wild-type mice. The ratio of phosphocreatine to ATP (1.16 +/- 0.05 vs. 1.46 +/- 0.10) and total creatine content (17.6 +/- 1.2 vs. 22.6 +/- 0.9 mmol/l) were significantly reduced in TG. Furthermore, there was a significant decrease in creatine transporter content (-43%), mitochondrial (-44%) and total creatine kinase (CK) activity (-21%) as well as citrate synthase activity (-25%), indicating impaired oxidative energy generation in TG. In conclusion, these findings of alterations in the CK system, creatine metabolism and mitochondrial proteins in TG hearts prior to the development of LV dysfunction provide further evidence that changes in myocardial energetics play a central role in the deterioration of cardiac function after chronic beta-adrenergic stimulation.

Animals↗
PubMed2003

High-resolution imaging of normal anatomy, and neural and adrenal malformations in mouse embryos using magnetic resonance microscopy.

An efficient investigation of the effects of genetic or environmental manipulation on mouse development relies on the rapid and accurate screening of a substantial number of embryos for congenital malformations. Here we demonstrate that it is possible to examine normal organ development and identify malformations in mouse embryos by magnetic resonance microscopy in a substantially shorter time than by conventional histology. We imaged embryos in overnight runs of under 9 h, with an operator time of less than 1 h. In normal embryos we visualized the brain, spinal cord, ganglia, eyes, inner ear, pituitary, thyroid, thymus, trachea, bronchi, lungs, heart, kidneys, gonads, adrenals, oesophagus, stomach, intestines, spleen, liver and pancreas. Examination of the brain in embryos lacking the transcriptional coactivator Cited2 showed cerebellar and midbrain roof agenesis, in addition to exencephaly. In these embryos we were also able to detect agenesis of the adrenal gland. We confirmed all malformations by histological sectioning. Thus magnetic resonance microscopy can be used to rapidly identify developmental and organ malformations in mutant mouse embryos generated by transgenic techniques, in high-throughput mutagenesis screens, or in screens to identify teratogenic compounds and environmental factors contributing to developmental malformations.

Adrenal Glands↗
PubMed2003

Creatine transporter activity and content in the rat heart supplemented by and depleted of creatine.

The intracellular creatine concentration is an important bioenergetic parameter in cardiac muscle. Although creatine uptake is known to be via a NaCl-dependent creatine transporter (CrT), its localization and regulation are poorly understood. We investigated CrT kinetics in isolated perfused hearts and, by using cardiomyocytes, measured CrT content at the plasma membrane or in total lysates. Rats were fed control diet or diet supplemented with creatine or the creatine analog beta-guanidinopropionic acid (beta-GPA). Creatine transport in control hearts followed saturation kinetics with a K(m) of 70 +/- 13 mM and a V(max) of 3.7 +/- 0.07 nmol x min(-1) x g wet wt(-1). Creatine supplementation significantly decreased the V(max) of the CrT (2.7 +/- 0.17 nmol x min(-1) x g wet wt(-1)). This was matched by an approximately 35% decrease in the plasma membrane CrT; the total CrT pool was unchanged. Rats fed beta-GPA exhibited a >80% decrease in tissue creatine and increase in beta-GPA(total). The V(max) of the CrT was increased (6.0 +/- 0.25 nmol x min(-1) x g wet wt(-1)) and the K(m) decreased (39.8 +/- 3.0 mM). The plasma membrane CrT increased about fivefold, whereas the total CrT pool remained unchanged. We conclude that, in heart, creatine transport is determined by the content of a plasma membrane isoform of the CrT but not by the total cellular CrT pool.

Adenosine Triphosphate↗
PubMed2002

Feedback inhibition of catecholamine release by two different alpha2-adrenoceptor subtypes prevents progression of heart failure.

BACKGROUND: Elevated plasma norepinephrine levels are associated with increased mortality in patients and in animal models with chronic heart failure. To test which alpha2-adrenoceptor subtypes operate as presynaptic inhibitory receptors to control norepinephrine release in heart failure, we investigated the response of gene-targeted mice lacking alpha2-adrenoceptor subtypes (alpha2-KO) to chronic left ventricular pressure overload. In addition, we determined the functional consequences of genetic variants of alpha2-adrenoceptors in human patients with chronic heart failure. METHODS AND RESULTS: Cardiac pressure overload was induced by transverse aortic constriction. Three months after aortic banding, survival was dramatically reduced in alpha2A-KO (52%) and alpha2C-KO (47%) mice compared with wild-type and alpha2B-deficient (86%) animals. Excess mortality in alpha2A- and alpha2C-KO strains was attributable to heart failure with enhanced left ventricular hypertrophy and fibrosis and elevated circulating catecholamines. The clinical importance of this finding is emphasized by the fact that heart failure patients with a dysfunctional variant of the alpha2C-adrenoceptor had a worse clinical status and decreased cardiac function as determined by invasive catheterization and by echocardiography. CONCLUSIONS: Our results indicate an essential function of alpha2A- and alpha2C-adrenoceptors in the prevention of heart failure progression in mice and human patients. Identification of heart failure patients with genetic alpha2-adrenoceptor variants as well as new alpha2-receptor subtype-selective drugs may represent novel therapeutic strategies in chronic heart failure and other diseases with enhanced sympathetic activation.

Animals↗
PubMed2002

Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with (31)P-SLOOP magnetic resonance spectroscopy.

OBJECTIVE: The purpose of the present study was to measure absolute concentrations of phosphocreatine (PCr) and adenosine triphosphate (ATP) in normal, hypertrophied, and failing human heart. BACKGROUND: Conflicting evidence exists on the extent of changes of high-energy phosphate metabolites in hypertrophied and failing human heart. Previous reports using phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) have quantified metabolites in relative terms only. However, this analysis cannot detect simultaneous reductions. METHODS: Four groups of subjects (n = 10 each), were studied: volunteers and patients with hypertensive heart disease (HHD), aortic stenosis, and dilated cardiomyopathy (DCM). Left ventricular (LV) function and mass were measured by cine magnetic resonance imaging. Absolute and relative concentrations of PCr and ATP were determined by (31)P-MRS with spatial localization with optimum point spread function. RESULTS: Left ventricular ejection fraction remained normal in HHD and aortic stenosis, but was severely reduced to 18% in DCM; LV mass was increased by 55%, 79%, and 68% respectively. In volunteers, PCr and ATP concentrations were 8.82 +/- 1.30 mmol/kg wet weight and 5.69 +/- 1.02 mmol/kg wet weight, and the PCr/ATP ratio was 1.59 +/- 0.33. High-energy phosphate levels were unaltered in HHD. In aortic stenosis, PCr was decreased by 28%, whereas ATP remained constant. In DCM, PCr was reduced by 51%, ATP by 35%, and reduction of the PCr/ATP ratio by 25% was of borderline significance (p = 0.06). Significant correlations were observed among energetic and functional variables, with the closest relations for PCr. CONCLUSIONS: In human heart failure due to DCM, both PCr and ATP are significantly reduced. Ratios of PCr to ATP underestimate changes of high-energy phosphate levels.

Adenosine Triphosphate↗
PubMed2002

Sodium T2* relaxation times in human heart muscle.

PURPOSE: To determine sodium transverse relaxation (T2*) characteristics for myocardium, blood and cartilage in humans. METHODS: T2* measurements were performed using a 3D ECG-gated spoiled gradient echo sequence. A 1.5 Tesla clinical scanner and a 23Na heart surface coil were used to examine eight healthy volunteers. In biological tissue, the sodium 23 nucleus exhibits a two-component T2 relaxation due to the spin 3/2 and its quadrupolar nature. The long T2* components of normal myocardium, blood, and cartilage were quantified. For myocardium, the T2* was determined separately for the septum, anterior wall, lateral wall, and posterior wall. RESULTS: The long T2* relaxation time components of 13.3 +/- 4.3 msec (septum 13.9 +/- 3.2 msec, anterior wall 13.8 +/- 5.4 msec, lateral wall 11.4 +/- 4.1 msec, posterior wall 14.1 +/- 3.7 msec), 19.3 +/- 3.3 msec, and 10.2 +/- 1.6 msec, were significantly different for myocardium, blood, and cartilage, respectively (P < 0.00001, Friedman's ANOVA). CONCLUSION: Measurement of 23Na T2* relaxation times is feasible for different regions of the human heart muscle, which might be useful for the evaluation of cardiac pathologies.

Adult↗
PubMed2002

Imaging of intracellular sodium with shift reagent aided (23)Na CSI in isolated rat hearts.

23Na chemical shift imaging (CSI) in conjunction with shift reagents was used to obtain images of intracellular (Na(i)) and extracellular sodium (Na(e)) in isolated rat hearts. It was demonstrated that the increase of Na(i) concentration in ischemic myocardium can be detected with this technique. 3D acquisition-weighted (23)Na CSI datasets with a nominal spatial resolution of 1.7 x 1.7 x 2.9 mm were acquired in 30 min in normoxic hearts and in globally or locally ischemic hearts. The shift reagent Tm(DOTP)(5-) was used to discriminate Na(i) and Na(e) signals. Na(i) maps could be generated in ischemic hearts, but not in normoxic hearts as the signal-to-noise ratio is too low. The Na(i) signal increased by more than 100% and the Na(e) signal decreased by more than 50% in myocardium of globally ischemic hearts (n = 3) compared to normoxic hearts (n = 3). In hearts with an acute occlusion of the left anterior descending coronary artery (n = 3), there was a local Na(i) signal increase in the anterior wall in the range of 60-110% compared to remote, normoxic tissue.

Animals↗
PubMed2002

Susceptibility to cardiac ischemia/reperfusion injury is modulated by chronic estrogen status.

The purpose of this study was to test whether the susceptibility of the heart to ischemia/reperfusion injury is modulated by the chronic estrogen status, i.e., increased with estrogen deficiency and attenuated by pharmacologic estrogen supplementation. In addition, the study tested whether estrogen-dependent changes in mechanical function are associated with alterations of cardiac high-energy phosphate metabolism. Rats were ovariectomized, not ovariectomized, or ovariectomized and treated with subcutaneous estrogen pellets (1.5 mg/21 d) (n = 8-11 per group). Three weeks later, hearts were isolated and perfused isovolumically under constant perfusion pressure conditions. Hearts were subjected to 15 min of total global ischemia (37 degrees C) and 30 min of reperfusion. Simultaneous [31P] nuclear magnetic resonance spectra were recorded throughout this protocol to monitor changes in ATP, phosphocreatine, and inorganic phosphate content. Whereas preischemic values for heart rate, end-diastolic pressure, and coronary flow were not different among groups, left ventricular developed pressure was slightly but significantly decreased in the estrogen-treated group (p < 0.05). However, treated hearts showed improved recovery of left ventricular developed pressure on reperfusion (89 +/- 4% in control rats, 70 +/- 8% in ovariectomized hearts, and 114 +/- 9% of preischemic values in estrogen-treated rats). However, changes in ATP, phosphocreatine, and inorganic phosphate during ischemia were as previously described and were unaffected by chronic estrogen status. In conclusion, in the isolated buffer-perfused rat heart, estradiol treatment caused improved functional recovery after ischemia/reperfusion injury. This improvement, however, did not include preservation of high-energy phosphate metabolism. Other potential mechanisms include an anti-oxidant activity of 17beta-estradiol-and estrogen-induced alterations in glucose metabolism.

Animals↗