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M Pauschinger

Publications and source records attributed to M Pauschinger.

At least 19 recordsLinked to original sources
PubMed2006

Genomic expression profiling of human inflammatory cardiomyopathy (DCMi) suggests novel therapeutic targets.

The clinical phenotype of human dilated cardiomyopathy (DCM) encompasses a broad spectrum of etiologically distinct disorders. As targeting of etiology-related pathogenic pathways may be more efficient than current standard heart failure treatment, we obtained the genomic expression profile of a DCM subtype characterized by cardiac inflammation to identify possible new therapeutic targets in humans. In this inflammatory cardiomyopathy (DCMi), a distinctive cardiac expression pattern not described in any previous study of cardiac disorders was observed. Two significantly altered gene networks of particular interest and possible interdependence centered around the cysteine-rich angiogenic inducer 61 (CYR61) and adiponectin (APN) gene. CYR61 overexpression, as in human DCMi hearts in situ, was similarly induced by inflammatory cytokines in vascular endothelial cells in vitro. APN was strongly downregulated in DCMi hearts and completely abolished cytokine-dependent CYR61 induction in vitro. Dysbalance between the CYR61 and APN networks may play a pathogenic role in DCMi and contain novel therapeutic targets. Multiple immune cell-associated genes were also deregulated (e.g., chemokine ligand 14, interleukin-17D, nuclear factors of activated T cells). In contrast to previous investigations in patients with advanced or end-stage DCM where etiology-related pathomechanisms are overwhelmed by unspecific processes, the deregulations detected in this study occurred at a far less severe and most probably fully reversible disease stage.

Adiponectin↗
PubMed2006

Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus.

AIMS/HYPOTHESIS: We investigated the effect of SB 203580, a pharmacological inhibitor of p38 mitogen-activated protein kinase (MAPK), on cardiac inflammation, cardiac fibrosis, and left ventricular function using an animal model of diabetic cardiomyopathy. MATERIALS AND METHODS: Diabetes mellitus was induced by streptozotocin (50 mg/kg i.p. for 5 days) in 20 C57/BL6J mice. Diabetic mice were treated daily with the p38 MAPK inhibitor SB 203580 (1 mg/kg daily, n=10) or with placebo (n=10) and were compared to non-diabetic controls. Left ventricular function was measured by pressure-volume loops after 8 weeks of diabetes mellitus. The parameters for systolic function were the end systolic pressure-volume relationship (ESPVR) and the left ventricular end systolic pressure. The parameters for diastolic function were the left ventricular end diastolic pressure and the end diastolic pressure-volume relationship (EDPVR). Cardiac tissue was analysed by ELISA for the protein content of the cytokines TNF-alpha, IL6, IL1-beta, and TGF-beta1. Phosphorylation of MAPK p38 was analysed by western blot, and the total cardiac collagen content was analysed by Sirius red staining. RESULTS: Left ventricular dysfunction was documented by impaired ESPVR and EDPVR. Cardiac cytokine levels and cardiac fibrosis were increased in diabetic animals compared to controls. Treatment with the p38 inhibitor normalised cardiac cytokine levels and improved systolic function, but did not change cardiac fibrosis and diastolic dysfunction compared to placebo. CONCLUSIONS/INTERPRETATION: Pharmacological inhibition of p38 MAPK prevents cardiac inflammation and attenuates left ventricular dysfunction in diabetic cardiomyopathy.

Animals↗
PubMed2006

Inflammation, ECG changes and pericardial effusion: whom to biopsy in suspected myocarditis?

The role of endomyocardial biopsies in patients with clinically suspected acute myocarditis, myocarditis in the past, and dilated cardiomyopathy is discussed controversially. In fact, it is still under discussion whether information obtained from endomyocardial biopsies is relevant for further clinical decisions. Therefore this Critical Perspective will deal with the question, which patient should undergo endomyocardial biopsy investigations for an etiopathogenic differentiation of the disease and for the possible choice of immunomodulatory treatment strategies.

Acute Disease↗
PubMed2006

Treatment of coxsackievirus-B3-infected BALB/c mice with the soluble coxsackie adenovirus receptor CAR4/7 aggravates cardiac injury.

Coxsackie adenovirus receptor (CAR) is involved in immunological processes, and its soluble isoforms have antiviral effects on coxsackievirus B3 (CVB3) infection in vitro. We explored in this study the impact of CAR4/7, a soluble CAR isoform, on CVB3-induced myocarditis in BALB/c mice. BALB/c mice were treated daily with recombinant CAR4/7, beta-galactosidase (beta-Gal; as control protein) or buffer for 9 days. Half of each group was infected with CVB3 on day 3, and all mice were killed on day 9. Myocardial CVB3 titer, histology, and serology were analyzed. Treatment with CAR4/7 led to a significant reduction of myocardial CVB3 titer, whereas the application of beta-Gal had no detectable effect on the myocardial virus load. CAR4/7 application, however, resulted in increased myocardial inflammation and tissue damage in CVB3-infected hearts, whereas beta-Gal caused a degree of cardiac inflammation and injury similar to that in buffer-treated CVB3-infected control animals. CAR4/7 and beta-Gal treatment induced the production of antibodies against the respective antigens. CAR4/7-, but not beta-Gal-specific, virus-negative sera reacted against myocardial tissue and cellular membranous CAR, and significantly inhibited CVB3 infection in vitro. Thus, CAR4/7 suppressed CVB3 infection in vivo, supporting the concept of receptor analog in antiviral therapy. However, CAR4/7 treatment also leads to an aggravation of myocardial inflammation and injury most likely secondary to an autoimmune process.

Animals↗
PubMed2006

New therapeutics targets in chronic viral cardiomyopathy.

Dilated cardiomyopathy (DCM) is a prevalent heart muscle disease characterized by impaired contractility and dilation of the ventricles. Recent clinical research suggests that cardiotropic viruses are important environmental pathogenic factors in human DCM, which may therefore be considered as a chronic viral cardiomyopathy. All virus-positive DCM patients thus come into the focus of virological research and should be considered for antiviral strategies. Interferon-beta therapy has been shown to mediate virus elimination in patients with adenovirus or coxsackievirus persistence. We discuss here several possible new molecular targets for patients infected with cardiotropic viruses in (1) the cellular virus uptake system, (2) virus-induced cellular signaling pathways, and (3) interactions between virus-encoded proteins with important cellular target proteins. The potential of these approaches in the setting of a chronic viral infection is significantly different from that in an acute viral infection. Specific problems encountered in a chronic situation and possible solutions are discussed.

Animals↗
PubMed2006

Anti-viral treatment in patients with virus-induced cardiomyopathy.

Ongoing viral persistence in the myocardium is associated with an adverse prognosis of cardiomyopathy eventually resulting in a reduced capacity for work and thus it is associated with enormous social costs. Experimental and clinical data highlight that an imbalance of the cytokine network and a defect in the cytokine-induced immune response may constitute major causes leading to the development of virus persistence and progression of myocardial dysfunction. Reversibility of cardiac impairment during the early stages of the disease and the arising chance of specific treatment options demand early diagnosis and treatment of the disease. Our pilot data on anti-viral treatment using INF-beta showed beneficial clinical effects and suggest that some of the ventricular dysfunction and wall motion abnormalities resolved after elimination of the responsible agents. The data also suggest that elimination of cardiotropic viruses and associated clinical effects may occur even in DCM patients presenting with a long history.

Animals↗
PubMed2006

Frontiers in viral diagnostics.

Dilated cardiomyopathy (DCM) is a fatal myocardial disease with an incidence of 40:100,000. In recent years, viral infection as a causative agent for myocarditis followed by DCM has become a main topic of research. On the one hand, the virus violates the myocardial integrity itself; on the other hand, the virus induces inadequate local humoral and cellular defense reaction resulting in cardiomyocyte death, fibrosis, and overall cardiac dysfunction. Classical virological approaches are no longer sufficient to detect and identify the virus in the heart. The possibility of endomyocardial biopsies, as well as the further development of new high-specific and sensitive molecular approaches including real-time PCR or sequencing, allows us to detect and to identify the patient- specific causal virus and to predict the progression of disease and hopefully, in the future, to develop virus-specific treatment strategies.

Cardiomyopathy, Dilated↗
PubMed2005

Genome-environment interactions in the molecular pathogenesis of dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by impaired contractility and dilation of the ventricles. In a subset of DCM patients, classical inheritance patterns occur (familial DCM), which have led to the identification of specific genomic loci and gene defects causing monogenic DCM subtypes. In the majority of DCM patients, however, there is no evidence for a monogenic etiology of the disorder (sporadic DCM), and in the absence of other recognizable etiological factors, these cases were classified as "idiopathic". Recent research suggests that cardiotropic viruses are important environmental factors in the pathogenesis of "idiopathic" cases and that DCM commonly results from interactions between genetic and environmental factors, whereas "pure" genetic forms are rather rare. Regarding genetics, the clinical cardiomyopathic phenotype associated with single gene defects may be highly variable for unknown reasons. Furthermore, a novel class of genetic defects was identified recently which provide a molecular basis for abnormal reactions of cardiomyocytes to environmental stress. These defects are paradigms of specific molecular links between genome and environment during the pathogenesis of DCM. Regarding environmental factors, a recent molecular virological study based on myocardial biopsies in a large series of sporadic DCM patients has detected cardiac viral infections in the majority of patients, with a broad spectrum of virus species being involved. Apparently, DCM does not only occur as a late sequela of acute viral myocarditis, but also in patients without clinical history of cardiac viral disease. Cardiotropic viruses thus emerge as prevalent environmental factors which may cause or influence the course of DCM in a large fraction of cases. Synopsis of current data suggests that a comprehensive picture of DCM pathogenesis can only be drawn if both genetic and environmental pathogenetic factors are considered. The course of cardiac viral infections depends strongly on genetic host factors and may range from rapid and complete virus elimination or silencing without clinical symptoms, to rapidly progressive or fatal disease. Viruses interact not only with genetically heterogenous host systems of virus uptake, migration, and antiviral immunity, but, due to their prevalence in DCM hearts, are also likely to encounter multiple structural proteins of cardiac cells known to be defective in familial DCM. The combined knowledge on DCM-associated gene defects and viruses therefore suggests in-depth studies on genome-environment interactions in DCM pathogenesis which may underlie the high clinical variability observed both in monogenic and virus-associated DCM and have implications for the clinical management of DCM patients.

Cardiomyopathy, Dilated↗
PubMed2005

High prevalence of cardiac parvovirus B19 infection in patients with isolated left ventricular diastolic dysfunction.

BACKGROUND: The etiology of left ventricular (LV) isolated diastolic dysfunction often remains unclear. In the present study, we report a strong association between parvovirus B19 (PVB19) genomes and isolated LV diastolic dysfunction. METHODS AND RESULTS: In 70 patients (mean+/-SD age, 43+/-11 years) admitted with exertional dyspnea and/or reduced exercise tolerance despite preserved LV systolic contractility (ejection fraction=68%), isolated diastolic dysfunction was clinically suspected. Patients with classic risk factors for diastolic dysfunction such as hypertension, coronary heart disease, diabetes mellitus, or pulmonary disease had been excluded. Diastolic function was assessed by echocardiography and LV and RV catheterization. Endomyocardial biopsies (EMBs) were analyzed for the presence of storage or infiltrative diseases or myocarditis, including molecular screening for cardiotropic virus genomes. In a substudy of 24 patients who reported atypical angina, coronary endothelial function was additionally investigated with a coronary Doppler flow-wire technique. In 37 of 70 patients (53%), isolated diastolic dysfunction was confirmed as the cause of their clinical symptoms. No evidence for cardiac storage or infiltrative diseases was found in these cases, but in 35 of 37 of these patients (95%), cardiotropic virus genomes were detected in EMBs (P<0.001). PVB19 was the most frequent pathogen in 31 of 37 patients (84%). In a subgroup of 10 patients with diastolic dysfunction and coexisting endothelial dysfunction, all 10 (100%) were PVB19 positive. CONCLUSIONS: PVB19 genomes were predominant in patients with unexplained, isolated diastolic dysfunction. A strong association with the incidence of endothelial dysfunction was obvious, consistent with the hypothesis that PVB19-induced endothelial dysfunction may be a possible pathomechanism underlying diastolic dysfunction.

Adult↗
PubMed2005

[Cardiomyopathies. I: classification of cardiomyopathies--dilated cardiomyopathy].

Cardiomyopathies are common causes of heart failure and sudden cardiac death. According to the WHO classification, "specific" cardiomyopathies are differentiated from "idiopathic" cardiomyopathies. Thus, this classification is primarily based on pathophysiological characteristics. The diagnostic spectrum in cardiomyopathies comprises the entire spectrum of non-invasive and invasive cardiological examination techniques. The exact verification of certain cardiomyopathies necessitates additionally investigations. For example, immunohistological and molecular biological investigations of endomyocardial biopsies may confirm inflammatory cardiomyopathy, which is often induced by viruses. Several studies have shown that specific immunomodulatory treatment options can halt the progressive course of the disease. Several gene mutations have been identified in genetic/familial dilated cardiomyopathy. First-degree relatives should be screened for early stages. Primary prevention of sudden cardiac death shows increasing superiority of the implantable defibrillator compared with pharmacological approaches (i.e. amiodarone).

Cardiomyopathies↗
PubMed2005

[Cardiomyopathies II. Hypertrophic cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy].

This review focuses on hypertrophic (HCM), restrictive (RCM) and arrhythmogenic right ventricular cardiomyopathies (ARVC). The clinical phenotype of HCM depends not only on the gene mutations involved, but also on "modifier genes". It is characterized by an asymmetrical hypertrophy. Investigations of endomyocardial biopsies (EMBs) typically reveal a disarray of the hypertrophied cardiomyocytes. Percutaneous septum ablation has gained relevance as the treatment of choice in hypertrophic obstructive cardiomyopathy. Myocardial and endomyocardial RCM-forms can be differentiated. Enlargement of the atria in concert with normal dimensions of the ventricles and almost normal systolic contractility as well as the dip-plateau phenomenon are characteristic findings in RCM. EMB diagnostics are pivotal to identify the causes underlying secondary RCM types. Treatment is directed at heart failure and specifically at the underlying disease. With ARVC, apoptosis, viral infection/inflammation and genetic dystrophy result in fibrofatty degeneration primarily of the right, and with further progression also of the left ventricle. The primary treatment goal in ARVC is prevention of sudden cardiac death. As for other cardiomyopathies, there is increasing evidence for the superiority of ICD compared with pharmacological approaches.

Cardiomyopathies↗
PubMed2004

Nucleic acid-based modulation of cardiac gene expression for the treatment of cardiac diseases. Approaches and perspectives.

During the past few years major conceptual and technical advances have been made towards the therapeutic modulation of cardiac gene expression for the treatment of cardiac diseases. Among these are 1) the identification of new molecular therapy targets in cardiac disorders, often derived from genetic animal models. 2) A better understanding of the molecular and cellular determinants of cardiac gene transfer in vivo, in animal models and in first clinical trials. 3) The development of novel regulatable and long-term stable vector systems. This review is focused on nucleic acid-based modulation of cardiac calcium homeostasis as a paradigm for the new gene therapeutic approaches, since recent landmark papers have suggested this to be a molecular target of key importance in heart failure. In particular, the development of severe heart failure in the genetic MLP(-/-) animal model could be completely abolished by the targeted ablation of phospholamban (PL), a key regulator of cardiac calcium homeostasis. This impressive effect of permanent germline PL ablation provides-in conjunction with former important work on disturbed calcium handling in the failing human heart-a rationale for the gene therapeutic approach of ad hoc suppression of PL by antisense strategies (antisense RNAs, ribozymes, RNA interference) or PL variants. Based on the broad spectrum of methods employed to characterize this general strategy, PL-targeted approaches may be considered as a paradigm of future genetic treatments of cardiac disorders, although the differences between animal models and humans must be kept in mind. High safety of any such therapy will be a prerequisite for any possible clinical application and therefore novel methods to improve control are being devised: 1) The regulation of gene therapy vectors by biochemical abnormalities associated with the target disease itself (" Induction-by-Disease" gene therapy). 2) External control of vector activity by the employment of drug-sensitive promotors. In addition, the important goal of cardiac long-term stability of the therapeutic vectors has recently been achieved in animal models using vectors derived from adeno-associated viruses (AAVs).

Animals↗
PubMed2004

Cardiac safety of trastuzumab in combination with epirubicin and cyclophosphamide in women with metastatic breast cancer: results of a phase I trial.

This prospective, parallel-group, dose-escalation study evaluated the cardiac safety of trastuzumab (Herceptin) plus epirubicin/cyclophosphamide (EC) in women with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC) and determined an epirubicin dose for further evaluation. HER2-positive patients received standard-dose trastuzumab plus epirubicin (60 or 90 mg/m(2))/cyclophosphamide (600 mg/m(2)) 3-weekly (EC60+H, n=26; EC90+H, n=25), for four to six cycles; 23 HER2-negative patients received EC alone (90/600 mg/m(2)) 3-weekly for six cycles (EC90). All patients underwent thorough cardiac evaluation. Two EC90+H-treated patients experienced symptomatic congestive heart failure 4.5 and 6 months after the end of chemotherapy. One EC60+H-treated patient experienced an asymptomatic decrease in left ventricular ejection fraction (LVEF) to <50% 6 months after the end of chemotherapy. No such events occurred in control patients. Asymptomatic LVEF decreases of >10% points were detected in 12 (48%), 14 (56%) and 5 (24%) patients treated with EC60+H, EC90+H, and EC90. Objective response rates with EC60+H and EC90+H were >60%, and 26% for EC90 alone. These results indicate that trastuzumab may be combined with EC with manageable cardiotoxicity and promising efficacy.

Adult↗
PubMed2004

Catheter based intracoronary brachytherapy leads to increased platelet activation.

BACKGROUND: Vascular brachytherapy (VBT) after percutaneous coronary intervention (PCI) is associated with a higher risk of stent thrombosis than conventional treatment. OBJECTIVE: To investigate in vivo periprocedural platelet activation with and without VBT, and to assess a possible direct effect of radiation on platelet activation. DESIGN: Of 50 patients with stable angina, 23 received VBT after PCI, while 27 had PCI only. The 23 patients who received VBT after PCI were pretreated for one month with aspirin and clopidogrel. Platelet activation was assessed by flow cytometry. RESULTS: The two patient groups did not differ in their platelet activation before the intervention. There was a significant increase in activation immediately after VBT, with 21.2% (interquartile range 13.0% to 37.6%) thrombospondin positive and 54.0% (42.3% to 63.6%) CD 63 positive platelets compared with 12.7% (9.8% to 14.9%) thrombospondin positive and 37.9% (33.2% to 45.2%) CD 63 positive platelets before the intervention (p < 0.001 and p < 0.01, respectively). Patients without VBT had no periprocedural difference in platelet activation immediately after PCI. No increase in platelet activation was found after ex vivo irradiation of blood samples obtained from healthy controls. CONCLUSIONS: Catheter based intracoronary VBT carried out according to current standards is highly thrombogenic. The current antithrombotic treatment with aspirin and clopidogrel is not sufficient to suppress platelet activation during the procedure. From in vitro experiments, it appears that platelet activation during brachytherapy is not caused by irradiation but by the procedure of catheter based VBT.

Angina Pectoris↗
PubMed2004

Anthracycline and trastuzumab in breast cancer treatment.

This study was designed to evaluate the cardiac safety of the combined treatment of HER2-positive metastatic breast cancer patients with trastuzumab (Herceptin) plus epirubicin and cyclophosphamide (EC) in comparison with EC alone in HER2-negative metastatic breast cancer patients. Patients included those with metastatic breast cancer without any prior anti-HER2 treatment, anthracycline therapy, or any other chemotherapy for metastatic disease. This was a nonrandomized, prospective, dose-escalating, multicenter, open-label, phase I study in Germany. A control group of 23 patients received EC 90/600 mg/m2 3-weekly for six cycles (EC90 alone). A total of 26 HER2-positive patients were treated with trastuzumab, or H (2 mg/kg weekly after an initial loading dose of 4 mg/kg), and EC 60/600 mg/m2 3-weekly for six cycles (EC60+H); another 25 HER2-positive patients received H and EC 90/600 mg/m2 3-weekly for six cycles. Asymptomatic reductions in left ventricular ejection fraction (LVEF) of more than 10% points were detected in 12 patients (48%) treated with EC60+H and in 14 patients (56%) treated with EC90+H vs 6 patients (26%) in the EC90 alone cohort. LVEF decreases to <50% occurred in one patient in the EC60+H cohort and in two patients in the EC90+H cohort during the H monotherapy. No cardiac event occurred in the cohort with EC90 alone. The overall response rates for EC60+H and EC90+H were >60%, vs 26% for EC90 alone. The interim results of this study approve the cardiac safety of the combination of H with EC, with low risk of cardiac toxicity. The combination regimen revealed promising efficacy.

Adult↗
PubMed2002

[Myocarditis and dilated cardiomyopathy. New methods in diagnosis and therapy].

In 20% of cases, acute myocarditis can progress to dilated cardiomyopathy as a result of persistence of intramyocardial inflammation or of a virus genome. Both acute myocarditis (10-year survival rate 45%) and dilated cardiomyopathy (leading indication for cardiac transplantation) have a grave prognosis. Etiopathogenic differentiation of dilated cardiomyopathy was made possible for the first time by the use of immunohistochemical and molecular-biological diagnostic procedures applied to endomyocardial biopsy material. In addition to conventional treatment of heart failure, initial randomized studies have shown immunosuppression and antiviral immunomodulation to be effective measures and harbingers of a new era of rational therapeutic concepts in the treatment of dilated cardiomyopathy.

Biopsy↗
PubMed2002

[Increased thrombocyte activation in dilated cardiomyopathy: a risk factor for development of ventricular thrombosis despite anticoagulant therapy?].

HISTORY AND CLINICAL FINDINGS: A 48-year-old patient with dilated cardiomyopathy complained of dyspnea at rest, severe sleeplessness and a slight pain in the stomach. The clinical examination was normal except for a murmur at the apex of the heart. There was no evidence of edema or congestion of the jugular veins. INVESTIGATION: The echocardiography demonstrated a dilated left ventricle with severely compromised function. No ventricular thrombi were present at this time. Coronary artery disease was excluded by coronary angiography. Endomyocardial biopsies were obtained from the right ventricular septum. The immunohistological analysis of the endomyocardial biopsy specimens revealed pathologically increased lymphocytic infiltrates and increased expression of interstitial and endothelial MHC I and II antigens. Flow cytometric analysis of platelets surface antigens (P-selectin, GP53, thrombospondin) was performed as a measure for intravasal platelet activation. Our patient compared to a healthy control group (> 4 SD) and to other patients with dilated cardiomyopathy (> 2 SD). A high grade increase of platelet activation was found. TREATMENT AND COURSE: ACE inhibitor, diuretics, spironolactone and digitalis were used to treat the heart insufficiency. Due to the severe left ventricular dysfunction phenprocoumone and aspirin were also prescribed. A follow-up echocardiography was performed 6 months later. Comparable to the first examination left ventricular contractility was found to be severely reduced. In addition, a marginal thrombus was now present in the left ventricle despite antithrombotic therapy. DISCUSSION: An increased platelet activation was found in the peripheral circulation of our patient with dilated cardiomyopathy. After 6 months, ventricular thrombi were found in the dilated ventricle, although aspirin and phenprocoumone had been administred. We speculate that an additional thrombotic treatment with clopidogrel is necessary in patients with dilated cardiomyopathy and increased platelet activation.

Anticoagulants↗