R H Schwinger

Universitätsklinikum Düsseldorf, Düsseldorf, North Rhine-Westphalia, Germany

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Publications (268)952.6 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: Aim: The present study investigated whether eNOS-activation may be dysregulated in cardiac tissue of patients suffering from type 2 diabetes (T2D). Main methods: We performed immunohistochemical measurements of translocated eNOS-activation as well as eNOS-phosphorylation at Ser1177, Thr495, Ser 635, Ser114 and of the protein kinase B (Akt) in isolated right atrial trabeculae of patients undergoing cardiac bypass or valve surgery with (n=12, 68.1 ± 2.5 years) and without T2D (n=12, 64.7 ± 2.7 years). In addition, we investigated oxidative (8-isoprostane) and nitrosative stress markers (nitrotyrosine) as well as the effect of pharmacological stimulation of angiotensin (AT)-receptors on eNOS-phosphorylation. Key findings: Translocation-dependent eNOS-activation was similar in both groups. The same holds true for eNOS-phosphorylation at Ser114. eNOS-phosphorylation at Ser635 was significantly increased, whereas eNOS-phosphorylation of Ser1177 was significantly decreased in the diabetic group paralleled by a decrease in phosphorylation of Akt and Thr495. These alterations were accompanied by a significant decrease in nitrotyrosine. After application of angiotensin II (10 µM, 2 min.) for investigation of the AT-receptor-dependent eNOS-stimulation, we did not find differences between the increases in eNOS-Ser1177-phosphorylation in the non-diabetic (+39.7% ± 23.5%) and in the diabetic group (32.22% ± 11.45%). A simultaneous increase in Akt-phosphorylation could not be observed. Significance: The present study indicates that T2D goes along with a decrease in eNOS-phosphorylation at Ser1177 under basal conditions in cardiac tissue. Whether this may be attributed to the insulin resistance of cardiac muscle has to be further investigated. Receptor-stimulated eNOS-activation still works at least for angiotensin II-dependent eNOS-activation.
    Journal of Applied Physiology 12/2012; · 3.48 Impact Factor
  • Hannes Reuter, Robert H G Schwinger
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    ABSTRACT: The fast cycling of calcium between internal stores and the myofilaments with rapid diffusion down steep concentration gradients provides the cellular basis for cardiac contraction and relaxation. In heart failure, the intracellular Ca(2) (+) dynamics are impaired showing reduced systolic peak Ca(2) (+), elevated diastolic Ca(2) (+) levels, and prolonged diastolic Ca(2) (+) decay. The recognition that defects in the function of Ca(2) (+) handling proteins are central to the pathogenesis of heart failure has attracted attention to these proteins as potential targets for therapy. Besides pharmacologic interventions including digitalis, ranolazine, levosimendan and others, cardiac gene therapy holds great promise and the recent clinical studies have proven the feasibility of this therapeutic approach. In this review, the rationale underlying modern therapies that modulate intracellular Ca(2) (+) handling for the treatment of human heart failure are presented and discussed.
    Wiener Medizinische Wochenschrift 06/2012; 162(13-14):297-301.
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    ABSTRACT: The Glasgow-Pittsburgh cerebral performance categories (GP-CPC) and the Glasgow Outcome Score (GOS) have been used to categorize patients according to their neurological outcome for prognostic predictors in patients after cardiac arrest (CA). We postulated that inclusion of deaths without knowing the cerebral status into the group of patients with poor outcome after CA using the GP-CPC and GOS will lead to dilution of the prognostic power of the investigated biochemical marker. The present study was conducted to verify this issue by employing a modified outcome score, which we termed as Modified Glasgow Outcome Score (MGOS). In the present study, 97 patients were enrolled in a prospective manner. Serum NSE and S100B levels were measured daily for 7 days after admission to the intensive care unit. Neurological outcome was assessed by employing the GOS and MGOS after 6 months. By employing the GOS, 46 patients were categorized into the group of patients with poor outcome and 51 patients survived with good neurological outcome. Patients who died without certified brain damage or with unknown cerebral status after CA (n = 20) were separated from patients with poor outcome in the MGOS. The magnitude of NSE (S100B) elevation in patients with poor outcome categorized by the MGOS was approximately 1.7-fold (1.5) higher as compared with patients divided by the GOS. The mean calculated sensitivities and area under the curve values of NSE and S100B predicting poor outcome classified by the MGOS were significantly higher as compared with the GOS. Conclusively, inclusion of deaths without certified brain damage or with unknown cerebral status into the group of patients with poor outcome will lead to underestimation of the prognostic power of investigated biochemical markers such as NSE and S100B. The MGOS will help to avoid this bias.
    Clinical Research in Cardiology 02/2012; 101(7):533-43. · 3.67 Impact Factor
  • Dennis Ladage, Robert H G Schwinger, Klara Brixius
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    ABSTRACT: SUMMARY  For the past 40 years, beta-blockers have been widely used in cardiovascular medicine, reducing morbidity as well as mortality. Beta-blockers are currently used in a number of cardiovascular conditions such as systolic heart failure, postmyocardial infarction, and in prevention and treatment of arrhythmias. They are not recommended as the first line antihypertensive therapy, particularly in the elderly, unless there are specific indications. Despite the benefits of beta-blockers, tolerability concerns in patients with co-morbidities have limited their use. Some of these problems were overcome with the discovery of cardioselective beta-blockers. The third generation beta-blockers have additional properties of vasodilatation and advantages in terms of minimizing the adverse effects of beta-blockers. Some of the advantages include improvement of insulin resistance, decrease in cholesterol as well as alleviation of erectile dysfunction. Acute treatment with beta-blockers modifies local muscular metabolic properties and impairs endurance exercise capacity whereas the influence of chronic is debated controversially.
    Cardiovascular Therapeutics 01/2012; · 2.85 Impact Factor
  • Eva Rieckeheer, Robert H G Schwinger, Wilhelm Bloch, Klara Brixius
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    ABSTRACT: WS(®) 1442 is a special extract of hawthorn leaves with flowers used for the treatment of mild cardiac failure. The activation of endothelial nitric oxide synthase (eNOS) has been shown to contribute to its vasodilating properties. Quite recently it has been demonstrated that red blood cells (RBCs) express a functional NO-synthase (rbcNOS) and rbcNOS activation has been associated with increased RBC deformability. The aim of the present study was to determine whether WS(®) 1442 is able to activate rbcNOS, to induce NO-formation in RBC and to alter RBC-deformability. Blood from healthy volunteers was incubated with WS(®) 1442 (25-100 μg/ml) for up to 30 min. RbcNOS activation was detected by immunohistochemical staining of phosphorylated rbcNOS and NO-formation was examined by diaminofluorescein (DAF) fluorescence. RBC deformability was measured by a laser assisted optical rotational cell analyzer. Serine 1177 of RbcNOS (rbcNOS Ser(1177)) was time- and concentration-dependently phosphorylated by WS(®) 1442. Rates of rbcNOS Ser(1177) phosphorylation were up to 149% higher in RBCs treated with WS(®) 1442 in comparison to control (DMSO 0.05%). WS(®) 1442 induced a time-dependent increase in NO-formation in RBCs which reached its maximum after 5 min. An increase in shear stress (0.3-50 Pa) caused an increase in RBC deformability. WS(®) 1442 did not change either basal or maximal RBC-deformability or shear stress sensitivity of RBC at normoxia. CONCLUSION: WS(®) 1442 activates rbcNOS and causes NO-formation in RBCs. WS(®) 1442-dependent NO-formation however does not affect RBC-deformability at normoxia.
    Phytomedicine: international journal of phytotherapy and phytopharmacology 09/2011; 19(1):20-4. · 2.97 Impact Factor
  • Christian Brinkmann, Robert H G Schwinger, Klara Brixius
    Wiener Medizinische Wochenschrift 09/2011; 161(17-18):455.
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    ABSTRACT: Recently, increased cardiac norepinephrine levels were observed in patients who were exposed to irregular stimulation during electrophysiological testing. The molecular mechanisms remain unclear. Intrinsic cardiac adrenergic (ICA) cells are present in mammalian hearts and contain catecholamine-synthesizing enzymes sufficient to produce biologically active norepinephrine levels. Thus, we aimed to investigate the expression of catecholamine-synthesizing enzymes by ICA cells exposed to irregular pacing. Co-cultures of cardiomyocytes and ICA cells were exposed to irregular pacing for 48h (standard deviation (SD)=5%, 25% and 50% of mean cycle length) at a constant rate of 5Hz. The expression of catecholamine-synthesizing enzymes including tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DBH) were analyzed on mRNA and protein levels. First, immunolabeling identified ICA cells presenting TH and DBH staining around the cell nucleus. Irregular pacing with 25% SD at a constant rate of 5Hz significantly increased the expression of TH and DBH enzyme synthesis. Pharmacological approaches have shown that both metoprolol and losartan reversed the irregular pacing induced DBH increase, whereas the expression of TH was only blocked by metoprolol in a significant manner. Blockade of the endothelin-A receptor by BQ123 or the calcineurin-NFAT pathway by cyclosporine-A, 11R-VIVIT or FK506 revealed a potential role of both cascades in irregular pacing induced catecholamine-synthesizing enzyme expression. ICA cells respond to irregular electrical activation with an increase in catecholamine-synthesizing enzymes. Drugs commonly used in clinical routine significantly influence the expression of TH and DBH by ICA cells via different signaling routes.
    Biochemical and Biophysical Research Communications 08/2011; 413(3):432-5. · 2.41 Impact Factor
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    ABSTRACT: An irregular ventricular response during atrial fibrillation (AF) has been shown to mediate an increase in sympathetic nerve activity in human subjects. The molecular mechanisms remain unclear. This study aimed to investigate the impact of rate and irregularity on nerve growth factor (NGF) expression in cardiomyocytes, since NGF is known to be the main contributor to cardiac sympathetic innervation density. Cell cultures of neonatal rat ventricular myocytes were electrically stimulated for 48 h with increasing rates (0, 5 and 50 Hz) and irregularity (standard deviation (SD)=5%, 25% and 50% of mean cycle length). Furthermore, we analyzed the calcineurin-NFAT and the endothelin-1 signalling pathways as possible contributors to NGF regulation during arrhythmic stimulation. We found that the increase of NGF expression reached its maximum at the irregularity of 25% SD by 5 Hz (NGF: 5 Hz 0% SD=1 vs. 5Hz 25% SD=1.57, P<0.05). Specific blockade of the ET-A receptor by BQ123 could abolish this NGF increase (NGF: 5 Hz 25% SD+BQ123=0.66, P<0.05). High frequency electrical field stimulation (HFES) with 50 Hz decreased the NGF expression in a significant manner (NGF: 50Hz=0.55, P<0.05). Inhibition of calcineurin-NFAT signalling with cyclosporine-A or 11R-VIVIT abolished the HFES induced NGF down-regulation (NGF: 50 Hz+CsA=1.14, P<0.05). In summary, this study reveals different signalling routes of NGF expression in cardiomyocytes exposed to increasing rates and irregularity. Whether this translates into different degrees of NGF expression and possibly neural sympathetic growth in various forms of ventricular rate control during AF remains to be elucidated in further studies.
    Cellular signalling 08/2011; 24(1):99-105. · 4.09 Impact Factor
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    ABSTRACT: The molecular background of the Ca(2+)-sensitizing effect of levosimendan relates to its specific interaction with the Ca(2+)-sensor troponin C molecule in the cardiac myofilaments. Over the years, significant preclinical and clinical evidence has accumulated and revealed a variety of beneficial pleiotropic effects of levosimendan and of its long-lived metabolite, OR-1896. First of all, activation of ATP-sensitive sarcolemmal K(+) channels of smooth muscle cells appears as a powerful vasodilator mechanism. Additionally, activation of ATP-sensitive K(+) channels in the mitochondria potentially extends the range of cellular actions towards the modulation of mitochondrial ATP production and implicates a pharmacological mechanism for cardioprotection. Finally, it has become evident, that levosimendan possesses an isoform-selective phosphodiesterase-inhibitory effect. Interpretation of the complex mechanism of levosimendan action requires that all potential pharmacological interactions are analyzed carefully in the framework of the currently available evidence. These data indicate that the cardiovascular effects of levosimendan are exerted via more than an isolated drug-receptor interaction, and involve favorable energetic and neurohormonal changes that are unique in comparison to other types of inodilators.
    International journal of cardiology 07/2011; 159(2):82-7. · 7.08 Impact Factor
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    ABSTRACT: Mechanical stretch has been shown to increase vascular endothelial growth factor (VEGF) expression in cultured myocytes. Sympathetic neurons (SN) also possess the ability to express and secrete VEGF, which is mediated by the NGF/TrkA signaling pathway. Recently, we demonstrated that SN respond to stretch with an upregulation of nerve growth factor (NGF) and ciliary neurotrophic factor (CNTF). Whether stretch increases neuronal VEGF expression still remains to be clarified. Therefore, SN from the superior cervical ganglia of neonatal Sprangue Dawley rats were exposed to a gradual increase of stretch from 3% up to 13% within 3days (3%, 7% and 13%). Under these conditions, the expression and secretion of VEGF was analyzed. Mechanical stretch significantly increased VEGF mRNA and protein expression (mRNA: control=1 vs. stretch=3.1; n=3/protein: control=1 vs. stretch=2.7; n=3). ELISA experiments to asses VEGF content in the cell culture supernatant showed a time and dose dependency in VEGF increment due to stretch. NGF and CNTF neutralization decreased stretch-induced VEGF augmentation in a significant manner. This response was mediated in part by TrkA receptor activation. The stretch-induced VEGF upregulation was accompanied by an increase in HIF-1α expression. KDR levels remained unchanged under conditions of stretch, but showed a significant increase due to NGF neutralization. In summary, SN respond to stretch with an upregulation of VEGF, which is mediated by the NGF/CNTF and TrkA signaling pathway paralleled by HIF-1α expression. NGF signaling seems to play an important role in regulating neuronal KDR expression.
    Biochemical and Biophysical Research Communications 06/2011; 410(1):62-7. · 2.41 Impact Factor
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    ABSTRACT: Age has been identified as an independent risk factor for cardiovascular diseases. A shift of the cardiac autonomic nervous system towards an increase in sympathetic tone has been reported in the elderly. Nerve growth factor (NGF) is the main neurotrophic factor that increases the sympathetic activity of the heart. If there is a shift of NGF expression in old compared to young cardiomyocytes and whether there are regional differences in the heart still remain unclear. Therefore, we chose a rat model of different-aged rats (3-4 days = neonatal, 6-8 weeks = young, 20-24 months = old), and isolated cardiomyocytes from the left and the right atrium (LA, RA), as well as from the left and the right ventricle (LV, RV), were used to determine NGF expression on mRNA and protein levels. In neonatal, young, and old rats, NGF amount in LA and RA was significantly lower as compared to LV and RV. In young and old rats, we found significant higher NGF protein levels in LA compared to RA. In addition, both atria showed an increase in NGF expression between age groups neonatal, young, and old. In both ventricles, we observed a significant decrease in NGF expression from neonatal to young rats and a significant increase from young to old rats. The highest NGF amount in LV and RV was observed in neonatal rats. Regarding tyrosine kinase A receptor (TrkA) expression, the main receptor for NGF signaling, both atria showed the largest expression in old rats; while in LV and RV, TrkA was expressed mainly in young rats. These results point to a contribution of nerve growth factors to the change of autonomic tone observed in elderly patients.
    Age 05/2011; 34(3):659-67. · 6.28 Impact Factor
  • Christian Brinkmann, Robert H G Schwinger, Klara Brixius
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    ABSTRACT: Type 2 diabetic patients have an increased level of systemic free radicals, which severely restrict the bioavailability of endothelium-derived nitric oxide (NO) and thus contribute to the development of an endothelial dysfunction. This review analyses the influence of physical training on molecular development mechanisms of the endothelial dysfunction and determines the significance of regular physical exercise for the endothelial function in type 2 diabetic patients. Systematic training reinforces the endogenic antioxidative capacity and results in a reduction in oxidative stress. Training - also combined with a change in diet - furthermore reduces hyperglycaemic blood sugar levels, thus curbing a major source of free radicals in diabetes. Moreover, physical exercise enhances vascular NO synthesis through an increased availability/activity of endothelial NO synthases (eNOS). Endurance, as well as resistance training with submaximal intensity or a combination of both forms of training is suitable to effectively improve the endothelial function in type 2 diabetic patients in the long term.
    Wiener Medizinische Wochenschrift 03/2011; 161(11-12):305-14.
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    ABSTRACT: Recently, we have shown that high frequency electrical field stimulation (HFES) of sympathetic neurons (SN) induces nerve sprouting by up-regulation of nerve growth factor (NGF) which targets the tyrosine kinase A receptor (TrkA) in an autocrine/paracrine manner. There is increasing evidence that matrix metalloproteinase-2 (MMP-2) is not only involved in extracellular matrix (ECM) turnover but may also exert beneficial effects during neuronal growth. Therefore, this study aimed to investigate the regulation and function of MMP-2 and its major activator membrane type 1-matrix metalloproteinase (MT1-MMP) as well its inhibitor TIMP-1 in SN under conditions of HFES. Moreover, we analyzed molecular mechanisms of the beneficial effect of losartan, an angiotensin II type I receptor (AT-1)blocker on HFES-induced nerve sprouting. Cell cultures of SN from the superior cervical ganglia (SCG) of neonatal rats were electrically stimulated for 48 h with a frequency of 5 or 50 Hz. HFES increased MMP-2 and MT1-MMP mRNA and protein expression, whereas TIMP-1 expression remained unchanged. Under conditions of HFES, we observed a shift from pro- to active-MMP-2 indicating an increase in MMP-2 enzyme activity. Specific pharmacological MMP-2 inhibition contributed to an increase in pro-NGF amount in the cell culture supernatant and significantly reduced HFES-induced neurite outgrowth. Losartan abolished HFES-induced nerve sprouting in a significant manner by preventing HFES-induced NGF, MMP-2, and MT1-MMP up-regulation. In summary, specific MMP-2 blockade prevents sympathetic nerve sprouting (SNS) by inhibition of pro-NGF conversion while losartan abolishes HFES-induced SNS by reducing total NGF, MMP-2 and MT1-MMP expression.
    Cellular and Molecular Neurobiology 01/2011; 31(1):17-25. · 2.29 Impact Factor
  • Christian Brinkmann, Robert H. G. Schwinger, Klara Brixius
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    ABSTRACT: Typ-2-Diabetiker weisen eine erhöhte Konzentration systemischer freier Radikale auf, welche die Bioverfügbarkeit von Stickstoffmonoxid (NO) im Endothel stark einschränken und damit zur Entstehung einer endothelialen Dysfunktion beitragen. Diese Übersichtsarbeit analysiert den Einfluss von körperlichem Training auf molekulare Entstehungsmechanismen der endothelialen Dysfunktion und eruiert die Bedeutung von regelmäßiger sportlicher Aktivität für die Endothelfunktion bei Typ-2-Diabetikern. Systematisches Training verstärkt die endogene antioxidative Kapazität und bewirkt eine Abnahme von oxidativem Stress. Sportliche Aktivität – auch in Kombination mit einer Ernährungsumstellung – verringert außerdem hyperglykämische Blutzuckerspiegel, wodurch eine Hauptquelle freier Radikale beim Diabetes eingedämmt wird. Zudem steigert körperliches Training die vaskuläre NO-Synthese durch eine erhöhte Verfügbarkeit/Aktivität der endothelialen NO-Synthasen (eNOS). Ein Ausdauer- als auch ein Krafttraining mit submaximalen Intensitäten oder eine Kombination beider Trainingsformen eignet sich langfristig, die Endothelfunktion bei Typ-2-Diabetikern wirksam zu verbessern. Type 2 diabetic patients have an increased level of systemic free radicals, which severely restrict the bioavailability of endothelium-derived nitric oxide (NO) and thus contribute to the development of an endothelial dysfunction. This review analyses the influence of physical training on molecular development mechanisms of the endothelial dysfunction and determines the significance of regular physical exercise for the endothelial function in type 2 diabetic patients. Systematic training reinforces the endogenic antioxidative capacity and results in a reduction in oxidative stress. Training – also combined with a change in diet – furthermore reduces hyperglycaemic blood sugar levels, thus curbing a major source of free radicals in diabetes. Moreover, physical exercise enhances vascular NO synthesis through an increased availability/activity of endothelial NO synthases (eNOS). Endurance, as well as resistance training with submaximal intensity or a combination of both forms of training is suitable to effectively improve the endothelial function in type 2 diabetic patients in the long term. SchlüsselwörterTraining–Typ-2-Diabetes–Kardiovaskuläre Komplikationen–Freie Radikale–Antioxidantien KeywordsTraining–Type 2 diabetes–Cardiovascular complications–Free radicals–Antioxidants
    Wiener Medizinische Wochenschrift 01/2011; 161(11):305-314.
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    ABSTRACT: 1. There is evidence that different aetiologies of heart failure, especially ischaemic vs dilated cardiomyopathy (ICM and DCM, respectively), may influence the prognosis of patients with this disease. Patients with ICM have a worse prognosis than those with DCM; the mechanisms underlying this difference have not yet been clarified. The aim of the present study was to investigate whether there are changes in myofibrillar function depending on the aetiology of human heart failure. 2. Ca(2+) -dependent tension (DT) and actomyosin ATPase activity (MYO) in Triton X-skinned fibre preparations of the left ventricular myocardium from patients with heart failure due to ICM (n=5) and DCM (n=5) were measured. Tension-dependent ATP consumption was calculated by the ratio of DT and MYO ('tension cost'). Non-failing myocardium (NF) from donor hearts, which could not be transplanted because of technical reasons, was evaluated as a control. 3. Although DT was reduced, the myofibrillar Ca(2+) sensitivity of DT and MYO, as well as tension cost, were increased in preparations from ICM and DCM myocardium compared with NF. The Ca(2+) sensitivity of DT and MYO was significantly increased in ICM compared with DCM preparations, resulting in more economic cross-bridge cycling in ICM than in DCM. 4. In conclusion, ICM is associated with an increased Ca(2+) sensitivity of myofibrillar tension and ATPase activity accompanied by decreased tension cost compared with DCM. Thus, the worse prognosis associated with ICM does not seem to be due to differences in myofibrillar function.
    Clinical and Experimental Pharmacology and Physiology 12/2010; 37(12):1134-8. · 2.16 Impact Factor
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    ABSTRACT: Cell therapy (CTx) is a strategy to support cardiac regeneration after myocardial infarction (MI). Thus far, clinical studies provided mixed results. Here, we investigated whether transmurality of the infarct may play a relevant role. 18 patients (63 ± 3 years, 15 male) undergoing elective coronary artery bypass graft (CABG) surgery 2.2 ± 0.7 months post MI participated. 10 had transmural and 8 non-transmural infarct scars assessed by Tc-99m-MIBI Single-Photon Emission Computed Tomography (SPECT) and F18-FDG-Positron-Emission-Tomography (PET). During surgery, 10 ml of sternal bone marrow were obtained, mononuclear cells (MNC) were isolated. At the end of surgery MNC were injected into the infarctions' center and border zones (10 injections, 2 ml total, 6.6 ± 1.3 × 10(7) MNC). No major complications attributable to cell therapy were observed. The sizes of non-transmural scars were reduced at 3 and 24 months after treatment (7.7 ± 1.1% and 5.5 ± 1.8 vs. 17.5 ± 4.9%, P=0.05 and P=0.04), while transmural scars remained unchanged (23.5 ± 2.6% and 23.8±3.2 vs. 23.5 ± 2.6%, P>0.99 and P=0.95). A trend towards improved LVEF was seen in patients with non-transmural scars (MRI: 48.8 ± 5.1% vs. 30.6 ± 8.7%, P=0.3; SPECT: 54.1 ± 3.1 vs. 41.0 ± 4.0, P=0.086), but not in patients with transmural scars (MRI: 36.7 ± 3.9 vs. 34.3 ± 5.0, P=0.63, SPECT: 37.8 ± 3.1 vs. 37.9 ± 2.3%, P=0.96). A single hybrid intervention of MNC recovery, purification and injection with CABG-surgery (MNC/CABG) may be an attractive modality for cell therapy. However, no regeneration of avital transmural scar tissue seems to occur, while the contribution of MNC to improved perfusion in non-transmural myocardial infarct scars remains to be determined.
    International journal of cardiology 12/2010; 156(3):303-8. · 7.08 Impact Factor
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    ABSTRACT: In patients with diabetes mellitus type 2 and arterial hypertension, the control of systolic and diastolic blood pressure is essential to reduce the risk of adverse events. The present study investigates the effect of treatment with the third-generation beta-blocker nebivolol, in female and male patients of different ages. Five thousand thirty-one male and female patients with mild to moderate hypertension and type 2 diabetes were treated with a daily dose of 5-mg nebivolol for 12 weeks. Before and after therapy, each patient's blood pressure, heart rate, and body weight were measured and blood samples were obtained to study metabolic parameters. Nebivolol reduced systolic blood pressure, in both sexes, to a similar extent. In regard to age, the most significant reduction in blood pressure over the 12-week treatment period was observed in the group of patients below the age of 40. With advancing age, there was a decline in the reduction of systolic blood pressure induced by nebivolol. This effect was more evident among the decennial age groups in respect to diastolic blood pressure. In addition, we found weight reduction to be age dependent. Body weight was significantly more reduced in men compared with women. Nebivolol is effective in treating patients with diabetes suffering from high blood pressure and metabolic syndrome. The significantly decreased effect on blood pressure found in elderly patients may be attributed to increased endothelial dysfunction with advancing age.
    Journal of cardiovascular pharmacology 09/2010; 56(3):275-81. · 2.83 Impact Factor
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    ABSTRACT: Sympathetic nerve sprouting (SNS) has been shown to occur after myocardial infarction (MI) and heart failure (HF) and is known to be responsible for the development of lethal arrhythmias. During MI or HF intracardiac cells are exposed to increased mechanical stretch. Molecular mechanisms which trigger sympathetic neural growth are largely unknown. Therefore, this study aimed to investigate the impact of mechanical stretch on rat neonatal sympathetic neurocytes of the superior cervical ganglion (SCG). Mechanical stretch resulted in an increased growth of sympathetic neurocytes. Furthermore, we could demonstrate that SCG neurocytes express nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), neurotrophin-3 (NT-3) and glial derived neurotrophic factor (GDNF) on mRNA and protein level. An increased NGF and CNTF expression, a down-regulated GDNF expression and an unchanged NT-3 expression were identified in the neurocyte cell culture supernatant of neurocytes exposed to mechanical stretch. However, neither brain derived neurotrophic factor (BDNF) mRNA and protein was expressed in SCG neurocytes, nor BDNF could be detected in the cell culture supernatant of SCG neurons. By anti-neurotrophin neutralizing experiments NGF and CNTF were identified as important stretch-induced growth-inducing factors. Losartan, an angiotensin-II type 1 receptor inhibitor, abolished the stretch-induced increase of NGF and CNTF expression and thereby prevented the stretch-induced neural growth. This study provides new molecular mechanisms by which the inhibitory effect of angiotensin-II type 1 receptor blockers on the neural/arrhythmogenic remodeling can be explained. However, further in-vivo studies are required to address this important issue.
    Autonomic neuroscience: basic & clinical 06/2010; 155(1-2):25-32. · 1.82 Impact Factor
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    ABSTRACT: Little is known about sex-dependent physiological and pathophysiological differences in cardiac endothelial nitric oxide synthase (eNOS) expression and activation. Therefore, we investigated cardiac morphology and eNOS protein expression, including its translocation-dependent activation and phosphorylation, in cardiac tissue of male and female wild-type mice and transgenic heart-failure mice having a cardiac-specific, 5-fold overexpression of the Galphaq protein. In addition, we measured calcineurin protein expression. Heart-to-body weight ratio was increased in Galphaq mice. Female wild-type mice showed higher eNOS protein expression and activation (translocation and phosphorylation) than did wild-type males. In cardiac tissue of Galphaq mice, these sex-dependent differences remained or were enhanced. Protein expression of the catalytic subunit calcineurin A, which has been shown to dephosphorylate eNOS, was higher in wild-type males than in wild-type females. These differences were increased in the Galphaq mice model. We conclude that sex differences exist in cardiac eNOS protein expression and phosphorylation. Increased activation of the Galphaq protein appears to alter eNOS protein expression and phosphorylation only in males.
    Canadian Journal of Physiology and Pharmacology 02/2010; 88(2):121-9. · 1.56 Impact Factor
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    ABSTRACT: Neuronal remodeling with increased sympathetic innervation density has been implicated in the pathogenesis of atrial fibrillation (AF). Recently, increased transcardiac nerve growth factor (NGF) levels were observed in a canine model of AF. Whether atrial myocytes or cardiac sympathetic neurons are the source of neurotrophins, and whether NGF is the main neurotrophic factor contributing to sympathetic nerve sprouting (SNS) in AF still remains unclear. Therefore, neonatal rat atrial myocytes were cultured under conditions of high frequency electrical field stimulation (HFES) to mimic rapid atrial depolarization. Likewise, sympathetic neurons from the superior cervical ganglia of neonatal rats were exposed to HFES to simulate the physiological effect of sympathetic stimulation. Real-time PCR, ELISA and Western blots were performed to analyze the expression pattern of NGF and neurotrophin-3 (NT-3). Baseline NGF and NT-3 content was 3-fold higher in sympathetic neurons than in atrial myocytes (relative NGF protein expression: 1+/-0.0 vs. 0.37+/-0.11, all n=5, p<0.05). HFES of sympathetic neurons induced a frequency dependent NGF and NT-3 gene and protein up-regulation (relative NGF protein expression: 0Hz=1+/-0.0 vs. 5Hz=1.13+/-0.19 vs. 50Hz=1.77+/-0.08, all n=5, 0Hz/5Hz vs. 50Hz p<0.05), with a subsequent increase of growth associated protein 43 (GAP-43) expression and morphological SNS. Moreover, HFES of sympathetic neurons increased the tyrosine kinase A (TrkA) receptor expression. HFES induced neurotrophic effects could be abolished by lidocaine, TrkA blockade or NGF neutralizing antibodies, while NT-3 neutralizing antibodies had no significant effect on SNS. In neonatal rat atrial myocytes, HFES resulted in myocyte hypertrophy accompanied by an increase in NT-3 and a decrease in NGF expression. In summary, this study provides evidence that high-rate electrical stimulation of sympathetic neurons mediates nerve sprouting by an increase in NGF expression that targets the TrkA receptor in an autocrine/paracrine manner.
    Journal of Molecular and Cellular Cardiology 02/2010; 49(1):79-87. · 5.15 Impact Factor

Publication Stats

3k Citations
952.60 Total Impact Points


  • 2012
    • Universitätsklinikum Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
    • University Hospital Regensburg
      • Klinik und Poliklinik für Innere Medizin II
      Ratisbon, Bavaria, Germany
  • 2007–2012
    • Klinikum Weiden
      Weyden, Bavaria, Germany
  • 2006–2012
    • Deutsche Sporthochschule Köln
      • Abteilung molekulare und zelluläre Sportmedizin
      Köln, North Rhine-Westphalia, Germany
    • Ruhr-Universität Bochum
      Bochum, North Rhine-Westphalia, Germany
  • 1993–2012
    • University of Cologne
      • • Department of Internal Medicine
      • • Institute of Anatomy I
      • • Division of Cardiology, Pneumology, Angiology and Intensive Care
      Köln, North Rhine-Westphalia, Germany
  • 2009–2011
    • RWTH Aachen University
      • Klinik für Kardiologie, Pneumologie, Angiologie und Internistische Intensivmedizin (Medizinische Klinik I)
      Aachen, North Rhine-Westphalia, Germany
  • 2008
    • University of Duisburg-Essen
      Essen, North Rhine-Westphalia, Germany
    • University Hospital RWTH Aachen
      Aachen, North Rhine-Westphalia, Germany
  • 2006–2008
    • Universitätsklinikum Münster
      Muenster, North Rhine-Westphalia, Germany
  • 1989–1993
    • Technische Universität München
      • Medizinische Klinik und Poliklinik I
      München, Bavaria, Germany
  • 1990–1991
    • University Hospital München
      München, Bavaria, Germany