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Featured researches published by C. Tschoepe.


Circulation | 2003

Induction of coxsackievirus-adenovirus-receptor expression during myocardial tissue formation and remodeling: Identification of a cell-to-cell contact-dependent regulatory mechanism

Henry Fechner; Michel Noutsias; C. Tschoepe; Kerstin Hinze; Xiaomin Wang; Felicitas Escher; Matthias Pauschinger; Dick H. W. Dekkers; Roland Vetter; Martin Paul; Jos M.J. Lamers; Heinz-Peter Schultheiss; Wolfgang Poller

Background—The coxsackievirus-adenovirus receptor (CAR) was cloned as a receptor for both viruses, but its primary biological functions and regulatory mechanisms are unknown. CAR was low in healthy adult myocardium, whereas strong CAR reexpression was observed in human dilated cardiomyopathy. The molecular mechanisms of CAR induction in cardiomyocytes are unknown. Methods and Results—We report on CAR regulation during development, CAR induction after myocardial infarction, and cell-to-cell contact–dependent CAR regulation in the rat. The high CAR expression during development in various organs decreased up to 190-fold after birth. After infarction resulting in severe cardiac dysfunction (dP/dtmax, −53%; dP/dtmin, −58%; left ventricular pressure, −45%), CAR was induced locally in cardiomyocytes of the infarct zone, where it was also expressed by capillary-like CD31+ structures and CD18+ interstitial cells, whereas it remained confined to subendothelial layers of arterioles and venules. In cultured cardiomyocytes, endothelin-1, cardiotrophin-1, leukemia-inhibiting factor, and cyclic stretch had no effect on CAR, whereas at high versus low cell density, CAR was suppressed up to 10-fold (P =0.006). Conditioned media from low- or high-density cardiomyocytes or cardiofibroblasts had no effect. Conclusions—The locally confined CAR upregulation after infarction makes induction by various humoral factors unlikely, because cardiac dysfunction results in high activities of sympathetic and renin-angiotensin systems and cytokines. The cell culture experiments identify a cell-to-cell contact–dependent mechanism of CAR regulation. Further characterization of the signals linking cell-to-cell interactions to CAR gene expression may provide insight into mechanisms and functional consequences of the generalized CAR induction in dilated cardiomyopathy, and of its local induction after myocardial infarction.


Zeitschrift Fur Kardiologie | 2002

Highly variable expression of virus receptors in the human cardiovascular system. Implications for cardiotropic viral infections and gene therapy.

Wolfgang Poller; Henry Fechner; M. Noutsias; C. Tschoepe; H.-P. Schultheiss

Coxsackieviren und Adenoviren sind weitverbreitete Erreger viraler Herzmuskelerkrankungen. Bei der überwiegenden Zahl der Exponierten verursachen sie jedoch keine myokardiale Erkrankung, da sie nicht a priori kardiotrop sind. Die molekularen Grundlagen ihres ungewöhnlichen Tropismus bei Patienten, die eine virale Herzmuskelerkrankung entwickeln, waren bis vor kurzem unbekannt. Ein bedeutender Fortschritt wurde hier erzielt durch die Klonierung eines Rezeptors, der die beiden strukturell unverwandten Viren bindet. Dieser Coxsackievirus-Adenovirus-Rezeptor (CAR) ist eine wesentliche Determinante für die zelluläre Aufnahme beider Viren und für die molekulare Pathogenese von Coxsackievirus- und Adenovirus-Infektionen. Bei der Kartierung der CAR-Expression in menschlichen Herzen fanden wir hochvariable Expressionsmuster. In gesunden Donor-Herzen war die CAR-Expression niedrig, während explantierte Herzen von Patienten mit Dilatativer Cardiomyopathie (DCM) eine hohe CAR-Expression im Myokard aufwiesen. Bemerkenswerterweise war jedoch nicht die Herzinsuffizienz perse mit hoher CAR-Expression assoziiert, da bei non-DCM Herzinsuffizienz keine Induktion gefunden wurde. Zusätzliche Untersuchungen über die molekularen Mechanismen der CAR-Induktion in Kardiomyozyten wiesen auf die Existenz eines Zell-Zell-Kontakt-abhängigen molekularen Regulationsmechanismus für CAR hin, während die zelluläre Aufnahme und eine low level Replikation von Virus keinen Effekt auf die Rezeptor-Expression hatten. Rekombinante Expression von humanem CAR in Kardiomyozyten-Kulturen führte zu einer starken Zunahme der Virus-Aufnahme in diese Zellen. Rezeptor-Induktion in vivo sollte daher die myokardiale Vulnerabilität für Viren wesentlich erhöhen, während gesundes Myokard weitgehend resistent wäre. Sie könnte auch den klinischen Krankheitsverlauf aggravieren, sodass die Blockade der Rezeptor-Expression oder von Rezeptor-Virus Interaktionen neue therapeutische Perspektiven eröffnet. Die Aufklärung des molekularen Mechanismus der CAR-Induktion bei DCM, jedoch nicht bei Herzinsuffizienz perse, könnte möglicherweise zur Identifikation eines spezifischen pathogenetischen Prozesses bei DCM führen. Eine umfassendere Analyse der kardiovaskulären Expression von Rezeptoren auch für andere potentiell kardiotrope Viren (CMV, EBV, HIV, HHV-6, Parvo-B19 etc.) sollte zu einem besseren Verständnis individueller Risikofaktoren für virale Herzmuskelerkrankungen und deren hochvariabler klinischer Verläufe führen, und neue therapeutische Optionen eröffnen. Coxsackieviruses and adenoviruses are common agents of viral heart disease. In the majority of exposed individuals they do not cause myocardial disease, however, since they are not primarily cardiotropic. Until recently the molecular basis of their anomalous tropism in patients who develop viral heart disease was unknown. An important step towards clarification of the molecular basis of cardiotropic viral infections was achieved in 1997, when a common receptor for the two structurally unrelated viruses was cloned. This coxsackievirus-adenovirus receptor (CAR) is a key determinant for the cellular uptake of both viruses and for the molecular pathogenesis of coxsackievirus and adenovirus diseases. We have mapped the CAR expression in human hearts and observed highly variable expression patterns. Healthy donor hearts had low CAR expression levels, whereas explanted hearts of patients with dilated cardiomyopathy (DCM) displayed high CAR expression in the myocardium. Remarkably, however, heart failure per se was not associated with CAR induction, since in heart failure of non-DCM origin no induction was found. Additional studies on the molecular mechanisms of CAR induction in cardiomyocytes indicated the existence of a cell-cell contact-dependent molecular mechanism regulating CAR expression, whereas cellular virus uptake and low level replication had no effect. Recombinant expression of human CAR in cardiomyocytes strongly increased their virus uptake rate suggesting that CAR induction enhances cardiac vulnerability to viral disease, whereas healthy myocardium is rather resistant to CAR-dependent viruses. Receptor induction may significantly aggravate the clinical course of viral heart disease, so that the blockade of receptor expression or receptor-virus interactions opens new therapeutic perspectives. Elucidation of the molecular mechanism of CAR induction in DCM, but not in heart failure per se, may reveal a particular pathogenetic process in this disease. A broader analysis of the cardiovascular expression patterns of receptors for other potentially cardiotropic viruses (CMV, EBV, HIV, HHV-6, Parvo-B19, etc.) should lead to a better understanding of individual risk factors for viral heart diseases and of their highly variable clinical courses, and offer new therapeutic options.


Journal of Molecular Medicine | 2005

Genome–environment interactions in the molecular pathogenesis of dilated cardiomyopathy

Wolfgang Poller; Uwe Kühl; C. Tschoepe; Matthias Pauschinger; Henry Fechner; H.P. Schultheiss

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.


Herz | 2000

Enteroviral and immune mediated myocarditis in SCID mice.

Peter L. Schwimmbeck; Gerhard Rohn; Alexandra Wrusch; Karsten Schulze; Andrea Doerner; Uwe Kuehl; C. Tschoepe; Mathias Pauschinger; Heinz-Peter Schultheiss

Severe combined immune deficiency (SCID) mice have been used as an animal model to study both the direct cytopathic effect of enteroviruses on the heart in the absence of an effective immune system and to investigate the role of immune mediated processes in the pathogenesis of human myocarditis.The infection of SCID mice with coxsackievirus B3 resulted in severe myocarditis with very high titers of the virus in the myocardium and severe necrosis of myocytes. This direct cytopathic effect caused an impairment of the myocardial function and resulted in a high mortality rate of the infected animals.For the study of the immune mechanisms in human myocarditis, peripheral blood leukocytes of patients with myocarditis, having an impaired left ventricular function without viral persistence in the myocardium, were transferred into SCID mice. As controls peripherals blood leukocytes of normal donors were used. At 60 days after transfer, human immunoglobulines could be demonstrated in the peripheral blood of the SCID mice, however, human autoantibodies against the adenine nucleotide translocator, a myocardial autoantigen, were only present in the animals receiving peripheral blood leukocytes from patients with myocarditis. Cellular infiltrates of human leukocytes in the myocardium and an impaired left ventricular function were also only observed in animals reconstituted with peripheral blood leukocytes from patients. These effects were T cell dependent as shown by differential transfer.These results are of interest for the treatment of human myocarditis, suggesting the avoidance of an immunosuppressive therapy in acute or chronic myocarditis with viral persistence to prevent a direct cytophatic effect in the absence of an effective immune system. However, in the setting of a chronic, (auto-)immunological myocarditis with the proven absence of entero- or adneoviral sequences an immunomodulatory therapy seems to be effective and safe.ZusammenfassungDie Bedeutung einer enteroviralen Infektion sowie einer resultierenden Immunreaktion ist immer noch Gegenstand der Forschung in der Pathogenese der humanen Myokarditis. Mäuse mit einer kombinierten Immundefizienz (“severe combined immundeficiency”, SCID-Mäuse), die keinen eigenen funktionstüchtigen peripheren B- und T-Lymphozyten besitzen, wurden im Tiermodell verwendet, um den direkten zytopathischen Effekt von Enteroviren auf Herzmuskelzellen in der Abwesenheit eines effektiven Immunsystems zu untersuchen. Außerdem kann dieses Tiermodell verwendet werden, um die Rolle von immunologischen und autoimmunologischen Prozessen in der Pathogenese der humanen Myokarditis zu analysieren.Die Infektion von SCID-Mäusen mit Coxsackie-B3-Viren führt zu einer ausgeprägten Myokarditis bei sehr hohen Virustitern im Myokardgewebe und schweren Myokardzellnekrosen. Dieser direkte zytopathische Effekt verursacht eine Einschränkung der myokardialen Pumpfunktion und führte zu einer hohen Mortalitätsrate in den infizierten Tieren, während immunkompetente Mäuse praktisch keine Mortalität aufweisen.Zur Untersuchung der Immunmechanismen bei der humanen Myokarditis wurden periphere Blutleukozyten von Patienten mit Myokarditis, die eine eingeschränkte linksventrikuläre Funktion, jedoch keine Viruspersistenz im Myokard aufwiesen, auf SCID-Mäuse übertragen. Als Kontrollen dienten die peripheren Blutleukozyten von gesunden Personen. 60 Tage nach dem Transfer fanden sich humane Immungloboline im peripheren Blut der SCID-Mäuse. Humane Autoantikörper gegen den Adenin-Nukleotid-Translokator, ein myokardiales Autoantigen, fanden sich hingegen nur bei den Tieren, die periphere Blutleukozyten von Patienten mit Myokarditis erhalten hatten. Zelluläre Infiltrate von humanen Leukozyten im Myokard und eine Einschränkung der linksventrikulären Funktion (verminderte Druckanstiegsgeschwindigkeit) lagen ebenso nur bei den SCID-Mäusen vor, die periphere Blutleukozyten von Patienten mit Myokarditis erhalten hatten. Die Tiere wiesen jedoch keinen Anhalt für eine Graft-versus-Host-Reaktion auf, wie die Untersuchung von verschiedenen anderen Geweben ergab. Der Transfer der humanen Myokarditis in SCID-Mäusen ist ein T-Zell-abhängiger Prozess, wie ein entsprechender differenzieller Transfer von nur CD4-positiven oder CD4-depletierten peripheren Blutleukozyten zeigte.Diese Untersuchungen dürften für die Therapie der humanen Myokarditis von Bedeutung sein. Diese Experimente legen nahe, dass im Rahmen der Myokarditis des Menschen vor allem im Stadium der akuten Erkrankung auf eine immunsuppressive Therapie verzichtet werden sollte, um eine Schwächung des Immunsystems und damit eine erhöhte Virämie und somit auch eine Verstärkung des direkten zytopathischen Effektes auf die Herzmuskelzellen zu verhindern. Aber auch im chronischen Stadium der Erkrankung sollte eine Viruspersistenz durch Entnahme von Myokardbiopsien mit entsprechender molekularbiologischer Analyse (Polymerasekettenreaktion und/oder In-situ-Hybridisierung für Entero- bzw. Adenoviren) untersucht werden, bevor eine immunsuppressive Therapie erwogen wird. In diesem Stadium der Erkrankung sollte bei nachgewiesener Viruspersistenz vielmehr möglicherweise eine Therapie mit subkutanen Gaben von Interferon initiiert werden, wie Untersuchungen unserer eigenen Arbeitsgruppe zwischenzeitlich nahelegen.Zum anderen sprechen die Befunde dieses Tiermodells auch dafür, dass es sich bei der Myokarditis des Menschen im chronischen Stadium der Erkrankung bei Ausschluss einer Viruspersistenz um einen chronischen autoimmunologischen Prozess handelt, der einer immunmodulatorischen Therapie zugeführt werden sollte. Nur durch eine differenzierte histologische, immunhistologische und molekularbiologische Diagnostik ist es jedoch möglich, eine Differenzierung des akuten virologischen Stadiums der Erkrankung von einem chronischen, immunologisch bedingten Stadium vorzunehmen und dementsprechend eine sinnvolle kausale Therapie durchzuführen.


Circulation-heart Failure | 2015

Differential Cardiac MicroRNA Expression Predicts the Clinical Course in Human Enterovirus Cardiomyopathy

Uwe Kuehl; Dirk Lassner; Martina Gast; Andrea Stroux; Maria Rohde; Christine Sabine Siegismund; Xiaomin Wang; Felicitas Escher; Michael Gross; Carsten Skurk; C. Tschoepe; Madlen Loebel; Carmen Scheibenbogen; Heinz-Peter Schultheiss; Wolfgang Poller

Background—Investigation of disease pathogenesis confined to protein-coding regions of the genome may be incomplete because many noncoding variants are associated with disease. We aimed to identify novel predictive markers for the course of enterovirus (CVB3) cardiomyopathy by screening for noncoding elements influencing the grossly different antiviral capacity of individual patients. Methods and Results—Transcriptome mapping of CVB3 cardiomyopathy patients revealed distinctive cardiac microRNA (miR) patterns associated with spontaneous virus clearance and recovery (CVB3-ELIM) versus virus persistence and progressive clinical deterioration (CVB3-PERS). Profiling of protein-coding genes and 754 miRs in endomyocardial biopsies of test cohorts was performed at their initial presentation, and those spontaneously eliminating the virus were compared with those with virus persistence on follow-up. miR profiling revealed highly significant differences in cardiac levels of 16 miRs, but not of protein-coding genes. Evaluation of this primary distinctive miR pattern in validation cohorts, and multivariate receiver operating characteristic curve analysis, confirmed this pattern as highly predictive for disease course (area under the curve, 0.897±0.071; 95% confidence interval, 0.758–1.000). Eight miRs were strongly induced in CVB3-PERS (miRs 135b, 155, 190, 422a, 489, 590, 601, 1290), but undetectable in CVB3-ELIM or controls. They are predicted to target multiple immune response genes, and 2 of these were confirmed by antisense-mediated ablation of miRs 135b, 190, and 422a in the monocytic THP-1 cell line. Conclusions—An immediate clinical application of the data is cardiac miR profiling to assess the risk of virus persistence and progressive clinical deterioration in CVB3 cardiomyopathy. Patients at risk are eligible for immediate antiviral therapy to minimize irreversible cardiac damage.


PLOS ONE | 2017

CX3CR1 knockout aggravates Coxsackievirus B3-induced myocarditis

Irene Mueller; Kathleen Pappritz; Konstantinos Savvatis; Kerstin Puhl; Fengquan Dong; Muhammad El-Shafeey; Nazha Hamdani; Isabell Hamann; Michel Noutsias; Carmen Infante-Duarte; Wolfgang A. Linke; Sophie Van Linthout; C. Tschoepe

Studies on inflammatory disorders elucidated the pivotal role of the CX3CL1/CX3CR1 axis with respect to the pathophysiology and diseases progression. Coxsackievirus B3 (CVB3)-induced myocarditis is associated with severe cardiac inflammation, which may progress to heart failure. We therefore investigated the influence of CX3CR1 ablation in the model of acute myocarditis, which was induced by inoculation with 5x105 plaque forming units of CVB3 (Nancy strain) in either CX3CR1-/- or C57BL6/j (WT) mice. Seven days after infection, myocardial inflammation, remodeling, and titin expression and phosphorylation were examined by immunohistochemistry, real-time PCR and Pro-Q diamond stain. Cardiac function was assessed by tip catheter. Compared to WT CVB3 mice, CX3CR1-/- CVB3 mice exhibited enhanced left ventricular expression of inflammatory cytokines and chemokines, which was associated with an increase of immune cell infiltration/presence. This shift towards a pro-inflammatory immune response further resulted in increased cardiac fibrosis and cardiomyocyte apoptosis, which was reflected by an impaired cardiac function in CX3CR1-/- CVB3 compared to WT CVB3 mice. These findings demonstrate a cardioprotective role of CX3CR1 in CVB3-infected mice and indicate the relevance of the CX3CL1/CX3CR1 system in CVB3-induced myocarditis.


Pacing and Clinical Electrophysiology | 2008

Cardiac resynchronization therapy in a patient with a mitral annuloplasty device.

Dirk Mueller; C. Tschoepe; Sebastian Spencker

We present a case of a 58‐year‐old man. Due to high‐degree mitral regurgitation an anuloplasty device (MONARC™) was inserted. During continuous pacing, inter‐ and intraventricular asynchrony occurred and heart failure worsened. The indication for cardiac resynchronization was established. A biventricular ICD was successfully inserted with the left ventricular approach via the coronary sinus over the MONARC™ device (Edward Lifescience, Irvine, CA, USA). Biventricular pacing significantly shortened the QRS duration and improved the clinical status as well as the 6‐minute walking test.


Türk Kardiyoloji Derneği arşivi : Türk Kardiyoloji Derneğinin yayın organıdır | 2015

Myocarditis and inflammatory cardiomyopathy: from diagnosis to treatment.

Felicitas Escher; C. Tschoepe; Dirk Lassner; Heinz-Peter Schultheiss

Based on the definition in the European Society of Cardiology statement, myocarditis is an inflammatory disease of the myocardium diagnosed by established histological, immunological, and immunohistochemical criteria, whereas inflammatory cardiomyopathy is myocarditis in association with cardiac dysfunction. Actual incidences of myocarditis and CMi are difficult to determine. Studies addressing the issue of sudden cardiac death in young people report a highly variable autopsy prevalence of myocarditis, ranging from 2-42% of cases. Similarly, biopsy-proven myocarditis has been reported in 9-16% of adult patients with unexplained nonischemic dilated cardiomyopathy (DCM). In up to 30% of cases, biopsy-proven myocarditis can progress to DCM and is associated with a poor prognosis. Prognosis in myocarditis patients also varies according to underlying etiology.


Journal of the American College of Cardiology | 2016

ROLE OF S100A8 AND S100A9 ALARMINS IN COXSACKIEVIRUS B3-INDUCED MYOCARDITIS

C. Tschoepe; Irene Müller; Thomas Vogl; Burkert Pieske; Sophie Van Linthout

The alarmins S100A8 and S100A9, which preferentially form the S100A8/S100A9 heterodimer, are danger-associated molecular pattern molecules and have been shown to be of importance in several cardiovascular disorders. Their role in myocarditis has not been explored yet. The aim of the present study


Journal of the American College of Cardiology | 2014

ANALYSIS OF ENDOMYOCARDIAL BIOPSIES IN CARDIOMYOPATHIES: DIAGNOSTIC VALUE ON LEFT VERSUS RIGHT VENTRICULAR BIOPSY

Felicitas Escher; Uwe Kühl; Dirk Lassner; Dirk Westermann; Wolfgang Poller; C. Tschoepe; Heinz-Peter Schultheiss

Endomyocardial biopsies (EMBs) are the gold standard to identify causative factors in structural heart disease. However, no clear recommendations on diagnostic value of left ventricular (LV-) versus right ventricular (RV-) EMB with regard to detecting inflammation, virus persistence, and

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