18 results on '"Heiko Pietsch"'
Search Results
2. Detection of parvovirus mRNAs as markers for viral activity in endomyocardial biopsy-based diagnosis of patients with unexplained heart failure
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Heiko Pietsch, Felicitas Escher, Ganna Aleshcheva, Dirk Lassner, Claus-Thomas Bock, and Heinz-Peter Schultheiss
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Medicine ,Science - Abstract
Abstract Erythroparvovirus (B19V) genomes have been detected in various organs of infected individuals including endothelial cells of the heart muscle. However, the role of B19V as a causative pathogen of myocardial damage is still unknown. The majority of reports focus on the presence of viral DNA ignoring proof of viral RNAs as important markers for viral activity. During this study, we established (RT-) qPCR to characterize expression of B19V RNAs (NS1 and VP1/2) in endomyocardial biopsies (EMBs) of 576 patients with unexplained heart failure. 403/576 (70%) EMBs were positive for B19V DNA. B19V mRNAs NS1 and/or VP1/2, indicating viral activity, could be detected in 38.5% of B19V DNA positive samples using the newly established B19V RT-PCRs. 22.1% of samples were characterized by only NS1 mRNA detection while 6.0% revealed only VP1/2 mRNA expression. Detection of both intermediates was successful in 10.4% of samples. Applying the molecular testing, our study revealed that a high proportion (38.5%) of B19V DNA positive EMBs was characterized by viral transcriptional activity. Further prospective studies will evaluate relevance of viral transcription intermediates as a diagnostic marker to differentiate between latent B19V infection and clinically relevant transcriptionally active B19V-infection of the heart muscle.
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- 2020
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3. Detection of viral SARS‐CoV‐2 genomes and histopathological changes in endomyocardial biopsies
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Felicitas Escher, Heiko Pietsch, Ganna Aleshcheva, Thomas Bock, Christian Baumeier, Albrecht Elsaesser, Philip Wenzel, Christian Hamm, Ralph Westenfeld, Maximilian Schultheiss, Ulrich Gross, Lars Morawietz, and Heinz‐Peter Schultheiss
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SARS‐CoV‐2‐infection ,COVID‐19 ,Endomyocardial biopsy ,Myocarditis ,Heart failure ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Aims Since December 2019, the novel coronavirus SARS‐CoV‐2 has spread rapidly throughout China and keeps the world in suspense. Cardiovascular complications with myocarditis and embolism due to COVID‐19 have been reported. SARS‐CoV‐2 genome detection in the heart muscle has not been demonstrated so far, and the underlying pathophysiological mechanisms remain to be investigated. Methods and results Endomyocardial biopsies (EMBs) of 104 patients (mean age: 57.90 ± 16.37 years; left ventricular ejection fraction: 33.7 ± 14.6%, sex: n = 79 male/25 female) with suspected myocarditis or unexplained heart failure were analysed. EMB analysis included histology, immunohistochemistry, and detection of SARS‐CoV‐2 genomes by real‐time reverse transcription polymerase chain reaction in the IKDT Berlin, Germany. Among 104 EMBs investigated, five were confirmed with SARS‐CoV‐2 infected by reverse real‐time transcriptase polymerase chain reaction. We describe patients of different history of symptoms and time duration. Additionally, we investigated histopathological changes in myocardial tissue showing that the inflammatory process in EMBs seemed to permeate vascular wall leading to small arterial obliteration and damage. Conclusions This is the first report that established the evidence of SARS‐CoV‐2 genomes detection in EMBs. In these patients, myocardial injury ischaemia may play a role, which could explain the ubiquitous troponin increases. EMB‐based identification of the cause of myocardial injury may contribute to explain the different evolution of complicated SARS‐CoV‐2‐infection and to design future specific and personalized treatment strategies.
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- 2020
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4. Proof of SARS-CoV-2 genomes in endomyocardial biopsy with latency after acute infection
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Heiko Pietsch, Felicitas Escher, Ganna Aleshcheva, Christian Baumeier, Lars Morawietz, Albrecht Elsaesser, and Heinz-Peter Schultheiss
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SARS-CoV-2 ,COVID-19 ,Viral myocarditis ,Endomyocardial biopsy ,Infectious and parasitic diseases ,RC109-216 - Abstract
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has reached pandemic levels. Cardiovascular complications in COVID-19 have been reported frequently, however evidence for a causal relationship has not been established. This report describes the detection of SARS-CoV-2 viral genomes in a patient with symptoms of heart failure, in whom endomyocardial biopsy was investigated following a latency period of 4 weeks after the onset of pulmonary symptoms. The viral infection was accompanied by myocardial inflammation indicating an infection of the heart muscle.
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- 2021
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5. Transcriptional Active Parvovirus B19 Infection Predicts Adverse Long-Term Outcome in Patients with Non-Ischemic Cardiomyopathy
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Felicitas Escher, Ganna Aleshcheva, Heiko Pietsch, Christian Baumeier, Ulrich M. Gross, Benedikt Norbert Schrage, Dirk Westermann, Claus-Thomas Bock, and Heinz-Peter Schultheiss
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parvovirus B19 ,transcriptional activity ,dilated inflammatory cardiomyopathy ,long-term outcome ,Biology (General) ,QH301-705.5 - Abstract
Parvovirus B19 (B19V) is the predominant cardiotropic virus currently found in endomyocardial biopsies (EMBs). However, direct evidence showing a causal relationship between B19V and progression of inflammatory cardiomyopathy are still missing. The aim of this study was to analyze the impact of transcriptionally active cardiotropic B19V infection determined by viral RNA expression upon long-term outcomes in a large cohort of adult patients with non-ischemic cardiomyopathy in a retrospective analysis from a prospective observational cohort. In total, the analyzed study group comprised 871 consecutive B19V-positive patients (mean age 50.0 ± 15.0 years) with non-ischemic cardiomyopathy who underwent EMB. B19V-positivity was ascertained by routine diagnosis of viral genomes in EMBs. Molecular analysis of EMB revealed positive B19V transcriptional activity in n = 165 patients (18.9%). Primary endpoint was all-cause mortality in the overall cohort. The patients were followed up to 60 months. On the Cox regression analysis, B19V transcriptional activity was predictive of a worse prognosis compared to those without actively replicating B19V (p = 0.01). Moreover, multivariable analysis revealed transcriptional active B19V combined with inflammation [hazard ratio 4.013, 95% confidence interval 1.515–10.629 (p = 0.005)] as the strongest predictor of impaired survival even after adjustment for age and baseline LVEF (p = 0.005) and independently of viral load. The study demonstrates for the first time the pathogenic clinical importance of B19V with transcriptional activity in a large cohort of patients. Transcriptionally active B19V infection is an unfavourable prognostic trigger of adverse outcome. Our findings are of high clinical relevance, indicating that advanced diagnostic differentiation of B19V positive patients is of high prognostic importance.
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- 2021
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6. Nucleoside Analogue Reverse Transcriptase Inhibitors Improve Clinical Outcome in Transcriptional Active Human Parvovirus B19-Positive Patients
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Heinz-Peter Schultheiss, Thomas Bock, Heiko Pietsch, Ganna Aleshcheva, Christian Baumeier, Friedrich Fruhwald, and Felicitas Escher
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parvovirus B19 ,dilated inflammatory cardiomyopathy ,telbivudine ,Medicine - Abstract
Human parvovirus B19 (B19V) is the predominant cardiotropic virus associated with dilated inflammatory cardiomyopathy (DCMi). Transcriptionally active cardiotropic B19V infection is clinically relevant and triggers adverse long-term mortality. During the study; we evaluated whether antiviral treatment with the nucleoside analogue telbivudine (LTD) is effective in suppressing transcriptional active B19V in endomyocardial biopsies (EMBs) of B19V positive patients and improving clinical outcomes. Seventeen B19V-positive patients (13 male; mean age 45.7 ± 13.9 years; mean left ventricular ejection fraction (LVEF) 37.7 ± 13.5%) with positive B19V DNA and transcriptional activity (B19V mRNA) in EMBs were treated with 600 mg/d LTD over a period of six months. Patients underwent EMBs before and after termination of the LTD treatment. B19V RNA copy numbers remained unchanged in 3/17 patients (non-responder) and declined or disappeared completely in the remaining 14/17 patients (responder) (p ≤ 0.0001). Notably; LVEF improvement was more significant in patients who reduced or lost B19V RNA (responder; p = 0.02) in contrast to non-responders (p = 0.7). In parallel; responder patients displayed statistically significant improvement in quality of life (QoL) questionnaires (p = 0.03) and dyspnea on exertion (p = 0.0006), reflecting an improvement in New York Heart Association (NYHA) Classification (p = 0.001). Our findings demonstrated for the first time that suppression of B19V transcriptional activity by LTD treatment improved hemodynamic and clinical outcome significantly. Thus; the present study substantiates the clinical relevance of detecting B19V transcriptional activity of the myocardium.
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- 2021
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7. Evaluation of Myocardial Gene Expression Profiling for Superior Diagnosis of Idiopathic Giant-Cell Myocarditis and Clinical Feasibility in a Large Cohort of Patients with Acute Cardiac Decompensation
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Felicitas Escher, Heiko Pietsch, Ganna Aleshcheva, Philip Wenzel, Friedrich Fruhwald, Christian Stumpf, Dirk Westermann, Johann Bauersachs, Frank Enseleit, Frank Ruschitzka, Herbert Nägele, Karl-Ludwig Laugwitz, Hendrik Haake, Norbert Frey, Johannes Brachmann, Kurt Huber, Rüdiger Christian Braun-Dullaeus, Martin W. Bergmann, Jörg Strotmann, Gerian Grönefeld, Jürgen Krülls-Münch, Ralf Westenfeld, Carsten Skurk, Ulf Landmesser, Burkert Pieske, Ulrich M. Gross, Lars Morawietz, and Heinz-Peter Schultheiss
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idiopathic giant-cell myocarditis ,gene-expression profiling ,endomyocardial biopsy ,Medicine - Abstract
Aims: The diagnostic approach to idiopathic giant-cell myocarditis (IGCM) is based on identifying various patterns of inflammatory cell infiltration and multinucleated giant cells (GCs) in histologic sections taken from endomyocardial biopsies (EMBs). The sampling error for detecting focally located GCs by histopathology is high, however. The aim of this study was to demonstrate the feasibility of gene profiling as a new diagnostic method in clinical practice, namely in a large cohort of patients suffering from acute cardiac decompensation. Methods and Results: In this retrospective multicenter study, EMBs taken from n = 427 patients with clinically acute cardiac decompensation and suspected acute myocarditis were screened (mean age: 47.03 ± 15.69 years). In each patient, the EMBs were analyzed on the basis of histology, immunohistology, molecular virology, and gene-expression profiling. Out of the total of n = 427 patient samples examined, GCs could be detected in 26 cases (6.1%) by histology. An established myocardial gene profile consisting of 27 genes was revealed; this was narrowed down to a specified profile of five genes (CPT1, CCL20, CCR5, CCR6, TLR8) which serve to identify histologically proven IGCM with high specificity in 25 of the 26 patients (96.2%). Once this newly established profiling approach was applied to the remaining patient samples, an additional n = 31 patients (7.3%) could be identified as having IGCM without any histologic proof of myocardial GCs. In a subgroup analysis, patients diagnosed with IGCM using this gene profiling respond in a similar fashion to immunosuppressive therapy as patients diagnosed with IGCM by conventional histology alone. Conclusions: Myocardial gene-expression profiling is a promising new method in clinical practice, one which can predict IGCM even in the absence of any direct histologic proof of GCs in EMB sections. Gene profiling is of great clinical relevance in terms of (a) overcoming the sampling error associated with purely histologic examinations and (b) monitoring the effectiveness of therapy.
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- 2020
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8. Absence of IL-10 production by human PBMCs co-cultivated with human cells expressing or secreting retroviral immunosuppressive domains.
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Daniel Ivanusic, Heiko Pietsch, Jasper König, and Joachim Denner
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Medicine ,Science - Abstract
Immunosuppression by retroviruses including the human immunodeficiency virus-1 (HIV-1) is well known, however the mechanisms how retroviruses induce this immunosuppression is not fully investigated. It was shown that non-infectious retroviral particles as well as retroviral or recombinant retroviral transmembrane envelope (TM) proteins demonstrated immunosuppressive properties. The same was shown for peptides corresponding to a highly conserved domain in the TM protein. This domain is called immunosuppressive (ISU) domain and it induces modulation of the cytokine release of peripheral blood mononuclear cells (PBMCs) from healthy donors. In addition, it changes the gene expression of these cells. Common indications for the immunosuppressive activity were tumour growth in vivo and interleukin-10 (IL-10) release from human PBMCs in vitro. Single mutations in the ISU domain abrogated the immunosuppressive activity. In order to develop a new model system for the expression of the ISU domain and presentation to PBMCs which is not prone to possible endotoxin contaminations, two expression systems were developed. In the first system, designated pOUT, retroviral proteins containing the ISU domain were expressed and released into the cell culture medium, and in the second system, tANCHOR, the ISU domain was presented by a tetraspanin-anchored sequence on the cell surface of human cells. Both systems were exploited to express the wild-type (wt) ISU domains of HIV-1, of the porcine endogenous retrovirus (PERV) and of the murine leukaemia virus (MuLV) as well as to express mutants (mut) of these ISU domains. PERV is of special interest in the context of virus safety of xenotransplantation using pig organs. Expression of the TM proteins was demonstrated by confocal laser scanning microscopy, ELISA and Western blot analyses using specific antibodies. However, when cells expressing and releasing the ISU were co-incubated with human PBMCs, no increased production of IL-10 was observed when compared with the mutants. Similar results were obtained when the released TM proteins were concentrated by immunoprecipitation and added to PBMCs. We suggest that the absence of IL-10 induction can be explained by a low amount of protein, by the lack of a biologically active conformation or the absence of additional factors.
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- 2018
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9. FOXO3A acts as immune response modulator in human virus-negative inflammatory cardiomyopathy
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Kamila Makrutzki-Zlotek, Felicitas Escher, Zehra Karadeniz, Ganna Aleshcheva, Heiko Pietsch, Konstanze Küchler, Heinz-Peter Schultheiss, Bettina Heidecker, Wolfgang Poller, Ulf Landmesser, Carmen Scheibenbogen, Tharusan Thevathasan, and Carsten Skurk
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Cardiology and Cardiovascular Medicine - Abstract
ObjectiveInflammatory cardiomyopathy is characterised by inflammatory infiltrates leading to cardiac injury, left ventricular (LV) dilatation and reduced LV ejection fraction (LVEF). Several viral pathogens and autoimmune phenomena may cause cardiac inflammation.The effects of the gain of functionFOXO3Asingle-nucleotide polymorphism (SNP) rs12212067 on inflammation and outcome were studied in a cohort of patients with inflammatory dilated cardiomyopathy (DCMi) in relation to cardiac viral presence.MethodsDistribution of the SNP was determined in virus-positive and virus-negative DCMi patients and in control subjects without myocardial pathology. Baseline and outcome data were compared in 221 virus-negative patients with detection of cardiac inflammation and reduced LVEF according to their carrier status of the SNP.ResultsDistribution of SNP rs12212067 did not differ between virus-positive (n=22, 19.3%), virus-negative (n=45, 20.4 %) and control patients (n=18, 23.4 %), indicating the absence of susceptibility for viral infection or inflammation per se (p=0.199). Patients in the virus-negative DCMi group were characterised by reduced LVEF 35.5% (95% CI) 33.5 to 37.4) and increased LVEDD (LV end-diastolic diameter) 59.8 mm (95% CI 58.5 to 61.2). Within the group, SNP and non-SNP carriers had similarly impaired LVEF 39.2% (95% CI 34.3% to 44.0%) vs 34.5% (95% CI 32.4 to 36.5), p=0.083, and increased LVEDD 58.9 mm (95% CI 56.3 to 61.5) vs 60.1 mm (95% CI 58.6 to 61.6), p=0.702, respectively. The number of inflammatory infiltrates was not different in both SNP groups at baseline. Outcome after 6 months showed a significant improvement in LVEF and clinical symptoms in SNP rs12212067 carriers 50.9% (95% CI 45.4 to 56.3) versus non-SNP carriers 41.7% (95% CI 39.2 to 44.2), p≤0.01. The improvement in clinical symptoms and LVEF was associated with a significant reduction in cardiac inflammation (ΔCD45RO+p≤0.05; ΔMac-1+p≤0.05; ΔLFA-1+p≤0.01; ΔCD54+p≤0.01) in the SNP cohort versus non-SNP cohort, respectively. Subgroup analyses identified ΔMac-1+, ΔLFA-1+, ΔCD3+and Δperforin+as predictors for improvement in cardiac function in SNP-positive patients.ConclusionFOXO3A might act as modulator of the cardiac immune response, diminishing cardiac inflammation and injury in pathogen-negative DCMi.
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- 2023
10. MicroRNA profiling as a novel diagnostic tool for identification of patients with inflammatory and/or virally induced cardiomyopathies
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Heinz-Peter Schultheiss, Felicitas Escher, Ganna Aleshcheva, and Heiko Pietsch
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Cardiomyopathy, Dilated ,Oncology ,lcsh:Diseases of the circulatory (Cardiovascular) system ,medicine.medical_specialty ,Myocarditis ,Inflammation ,030204 cardiovascular system & hematology ,Virus ,Out patients ,03 medical and health sciences ,0302 clinical medicine ,Original Research Articles ,Internal medicine ,microRNA ,medicine ,Humans ,Original Research Article ,030212 general & internal medicine ,DCM ,business.industry ,Dilated cardiomyopathy ,medicine.disease ,MicroRNAs ,lcsh:RC666-701 ,Heart failure ,medicine.symptom ,Cardiomyopathies ,MiRNA ,Cardiology and Cardiovascular Medicine ,Microrna profiling ,business ,Biomarkers - Abstract
Aims MicroRNAs (miRNAs) might be used as prospective biomarkers for the identification of unexplained heart failure caused by a viral and/or inflammatory process. The aim of this study was to identify and to evaluate prognostic miRNAs in serum of patients with inflammatory heart diseases diagnosed by endomyocardial biopsies. Methods and results After TaqMan® OpenArray® screening of 754 unique circulating miRNAs in serum of biopsy‐proven patients [184 patients with inflammatory and/or virally induced myocardial diseases (DCMi), 25 patients with dilated cardiomyopathy (DCM), and 25 healthy donors], we identified seven miRNAs of interest (P
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- 2020
11. Cardiovascular consequences of viral infections: from COVID to other viral diseases
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Heiko Pietsch, C.-Thomas Bock, Felicitas Escher, Heinz-Peter Schultheiss, Wolfgang Poller, and Christian Baumeier
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Cardiomyopathy, Dilated ,Viral Myocarditis ,Myocarditis ,Physiology ,viruses ,Cardiomyopathy ,Disease ,Antiviral Agents ,Parvoviridae Infections ,Physiology (medical) ,Parvovirus B19, Human ,medicine ,Animals ,Humans ,AcademicSubjects/MED00200 ,Invited Review ,biology ,SARS-CoV-2 ,business.industry ,Parvovirus ,COVID-19 ,Dilated cardiomyopathy ,Genetic Therapy ,medicine.disease ,biology.organism_classification ,COVID-19 Drug Treatment ,Host-Pathogen Interactions ,Coxsackieviruses B ,Immunology ,Respiratory virus ,Cardiology and Cardiovascular Medicine ,business - Abstract
Infection of the heart muscle with cardiotropic viruses is one of the major aetiologies of myocarditis and acute and chronic inflammatory cardiomyopathy (DCMi). However, viral myocarditis and subsequent dilated cardiomyopathy is still a challenging disease to diagnose and to treat and is therefore a significant public health issue globally. Advances in clinical examination and thorough molecular genetic analysis of intramyocardial viruses and their activation status have incrementally improved our understanding of molecular pathogenesis and pathophysiology of viral infections of the heart muscle. To date, several cardiotropic viruses have been implicated as causes of myocarditis and DCMi. These include, among others, classical cardiotropic enteroviruses (Coxsackieviruses B), the most commonly detected parvovirus B19, and human herpes virus 6. A newcomer is the respiratory virus that has triggered the worst pandemic in a century, SARS-CoV-2, whose involvement and impact in viral cardiovascular disease is under scrutiny. Despite extensive research into the pathomechanisms of viral infections of the cardiovascular system, our knowledge regarding their treatment and management is still incomplete. Accordingly, in this review, we aim to explore and summarize the current knowledge and available evidence on viral infections of the heart. We focus on diagnostics, clinical relevance and cardiovascular consequences, pathophysiology, and current and novel treatment strategies.
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- 2021
12. Nucleoside Analogue Reverse Transcriptase Inhibitors Improve Clinical Outcome in Transcriptional Active Human Parvovirus B19-Positive Patients
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Felicitas Escher, Heiko Pietsch, Friedrich Fruhwald, Christian Baumeier, Thomas Bock, Heinz-Peter Schultheiss, and Ganna Aleshcheva
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medicine.medical_specialty ,viruses ,Cardiomyopathy ,Hemodynamics ,030204 cardiovascular system & hematology ,Gastroenterology ,Article ,Virus ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Telbivudine ,medicine ,dilated inflammatory cardiomyopathy ,Clinical significance ,Exertion ,030304 developmental biology ,0303 health sciences ,Ejection fraction ,Nucleoside analogue ,parvovirus B19 ,business.industry ,virus diseases ,General Medicine ,medicine.disease ,telbivudine ,Medicine ,business ,medicine.drug - Abstract
Human parvovirus B19 (B19V) is the predominant cardiotropic virus associated with dilated inflammatory cardiomyopathy (DCMi). Transcriptionally active cardiotropic B19V infection is clinically relevant and triggers adverse long-term mortality. During the study, we evaluated whether antiviral treatment with the nucleoside analogue telbivudine (LTD) is effective in suppressing transcriptional active B19V in endomyocardial biopsies (EMBs) of B19V positive patients and improving clinical outcomes. Seventeen B19V-positive patients (13 male, mean age 45.7 ± 13.9 years, mean left ventricular ejection fraction (LVEF) 37.7 ± 13.5%) with positive B19V DNA and transcriptional activity (B19V mRNA) in EMBs were treated with 600 mg/d LTD over a period of six months. Patients underwent EMBs before and after termination of the LTD treatment. B19V RNA copy numbers remained unchanged in 3/17 patients (non-responder) and declined or disappeared completely in the remaining 14/17 patients (responder) (p ≤ 0.0001). Notably, LVEF improvement was more significant in patients who reduced or lost B19V RNA (responder, p = 0.02) in contrast to non-responders (p = 0.7). In parallel, responder patients displayed statistically significant improvement in quality of life (QoL) questionnaires (p = 0.03) and dyspnea on exertion (p = 0.0006), reflecting an improvement in New York Heart Association (NYHA) Classification (p = 0.001). Our findings demonstrated for the first time that suppression of B19V transcriptional activity by LTD treatment improved hemodynamic and clinical outcome significantly. Thus, the present study substantiates the clinical relevance of detecting B19V transcriptional activity of the myocardium.
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- 2021
13. Plasminogen activator inhibitor-1 reduces cardiac fibrosis and promotes M2 macrophage polarization in inflammatory cardiomyopathy
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Heiko Pietsch, Felicitas Escher, Heinz-Peter Schultheiss, Christian Baumeier, and Ganna Aleshcheva
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0301 basic medicine ,Male ,Physiology ,Cardiac fibrosis ,Cardiomyopathy ,PAI-1 ,030204 cardiovascular system & hematology ,Monocytes ,chemistry.chemical_compound ,0302 clinical medicine ,Fibrosis ,Inflammatory cardiomyopathy ,Myofibroblasts ,DCM ,Cell Differentiation ,Original Contribution ,Middle Aged ,M2 Macrophage ,Up-Regulation ,Myocarditis ,Phenotype ,Plasminogen activator inhibitor-1 ,Female ,Cardiology and Cardiovascular Medicine ,Myofibroblast ,Signal Transduction ,TGF-β ,Adult ,Cardiomyopathy, Dilated ,Macrophage polarization ,Transforming Growth Factor beta1 ,03 medical and health sciences ,Physiology (medical) ,Plasminogen Activator Inhibitor 1 ,medicine ,Humans ,Aged ,Retrospective Studies ,Alpha-smooth muscle actin ,business.industry ,Macrophages ,Myocardium ,medicine.disease ,030104 developmental biology ,chemistry ,DCMi ,Cancer research ,business ,Plasminogen activator - Abstract
Plasminogen activator inhibitor-1 (PAI-1) has a cardioprotective function in mice by repressing cardiac fibrosis through TGF-β and plasminogen-mediated pathways. In addition it is known to be involved in the recruitment and polarization of monocytes/macrophages towards a M2 phenotype in cancer. Here, we investigated the expression of PAI-1 in human dilated cardiomyopathy (DCM) and inflammatory dilated cardiomyopathy (DCMi) and its effect on cardiac fibrosis and macrophage polarization. We retrospectively analyzed endomyocardial biopsies (EMBs) of patients with DCM or DCMi for PAI-1 expression by immunohistochemistry. Furthermore, EMBs were evaluated for the content of fibrotic tissue, number of activated myofibroblasts, TGF-β expression, as well as for M1 and M2 macrophages. Patients with high-grade DCMi (DCMi-high, CD3+ lymphocytes > 30 cells/mm2) had significantly increased PAI-1 levels compared to DCM and low-grade DCMi patients (DCMi-low, CD3+ lymphocytes = 14–30 cells/mm2) (15.5 ± 0.4% vs. 1.0 ± 0.1% and 4.0 ± 0.1%, p ≤ 0.001). Elevated PAI-1 expression in DCMi-high subjects was associated with a diminished degree of cardiac fibrosis, decreased levels of TGF-β and reduced number of myofibroblasts. In addition, DCMi-high patients revealed an increased proportion of non-classical M2 macrophages towards classical M1 macrophages, indicating M2 macrophage-favoring properties of PAI-1 in inflammatory cardiomyopathies. Our findings give evidence that elevated expression of cardiac PAI-1 in subjects with high-grade DCMi suppresses fibrosis by inhibiting TGF-β and myofibroblast activation. Moreover, our data indicate that PAI-1 is involved in the polarization of M2 macrophages in the heart. Thus, PAI-1 could serve as a potential prognostic biomarker and as a possible therapeutic target in inflammatory cardiomyopathies.
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- 2021
14. Detection of parvovirus mRNAs as markers for viral activity in endomyocardial biopsy-based diagnosis of patients with unexplained heart failure
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Ganna Aleshcheva, Claus-Thomas Bock, Dirk Lassner, Heinz-Peter Schultheiss, Felicitas Escher, and Heiko Pietsch
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Adult ,Male ,0301 basic medicine ,Science ,Biopsy ,viruses ,030204 cardiovascular system & hematology ,Genome ,Article ,Viral Proteins ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Transcription (biology) ,Parvovirus B19, Human ,medicine ,Humans ,RNA, Messenger ,Somatoform Disorders ,Prospective cohort study ,Pathogen ,Heart Failure ,Messenger RNA ,Multidisciplinary ,biology ,business.industry ,Parvovirus ,Heart ,Middle Aged ,medicine.disease ,biology.organism_classification ,Virology ,030104 developmental biology ,chemistry ,Viral infection ,Virus Diseases ,Heart failure ,Medicine ,Female ,Cardiomyopathies ,business ,DNA - Abstract
Erythroparvovirus (B19V) genomes have been detected in various organs of infected individuals including endothelial cells of the heart muscle. However, the role of B19V as a causative pathogen of myocardial damage is still unknown. The majority of reports focus on the presence of viral DNA ignoring proof of viral RNAs as important markers for viral activity. During this study, we established (RT-) qPCR to characterize expression of B19V RNAs (NS1 and VP1/2) in endomyocardial biopsies (EMBs) of 576 patients with unexplained heart failure. 403/576 (70%) EMBs were positive for B19V DNA. B19V mRNAs NS1 and/or VP1/2, indicating viral activity, could be detected in 38.5% of B19V DNA positive samples using the newly established B19V RT-PCRs. 22.1% of samples were characterized by only NS1 mRNA detection while 6.0% revealed only VP1/2 mRNA expression. Detection of both intermediates was successful in 10.4% of samples. Applying the molecular testing, our study revealed that a high proportion (38.5%) of B19V DNA positive EMBs was characterized by viral transcriptional activity. Further prospective studies will evaluate relevance of viral transcription intermediates as a diagnostic marker to differentiate between latent B19V infection and clinically relevant transcriptionally active B19V-infection of the heart muscle.
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- 2020
15. Proof of SARS-CoV-2 Genomes in Endomyocardial Biopsy with Latency After Acute Infection
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Felicitas Escher, Christian Baumeier, Lars Morawietz, Heinz-Peter Schultheiss, Ganna Aleshcheva, Heiko Pietsch, and Albrecht Elsaesser
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0301 basic medicine ,Microbiology (medical) ,Viral Myocarditis ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,viruses ,030106 microbiology ,Case Report ,Genome ,lcsh:Infectious and parasitic diseases ,Endomyocardial biopsy ,03 medical and health sciences ,0302 clinical medicine ,Pandemic ,medicine ,lcsh:RC109-216 ,030212 general & internal medicine ,Latency (engineering) ,business.industry ,SARS-CoV-2 ,COVID-19 ,General Medicine ,medicine.disease ,viral myocarditis ,Infectious Diseases ,Heart failure ,Latency stage ,Immunology ,endomyocardial biopsy ,business - Abstract
Highlights • SARS-CoV-2 viral RNA positivity in the heart is present after a latent period of four weeks after onset of pulmonary symptoms in a COVID-19 patient. • Intramyocardial inflammation is a complication in a patient affected by COVID-19. • Histopathological and clinical improvement of the patient were in accordance with viral clearance on follow-up biopsy investigation., Emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has reached pandemic level. Cardiovascular complications in COVID-19 have been reported frequently, however, evidence for causal relationship has not been established. We describe detection of SARS-CoV-2 viral genomes in a patient with heart failure symptoms investigating endomyocardial biopsy following a latent period of four weeks after onset of pulmonary symptoms. Viral infection was accompanied by myocardial inflammation indicating infection of the heart muscle.
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- 2020
16. Evaluation of Myocardial Gene Expression Profiling for Superior Diagnosis of Idiopathic Giant-Cell Myocarditis and Clinical Feasibility in a Large Cohort of Patients with Acute Cardiac Decompensation
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Frank Enseleit, Norbert Frey, Heiko Pietsch, Carsten Skurk, Rüdiger C. Braun-Dullaeus, Kurt Huber, Heinz-Peter Schultheiss, Herbert Nägele, Jürgen Krülls-Münch, Hendrik Haake, Frank Ruschitzka, Jörg Strotmann, Felicitas Escher, Ralf Westenfeld, Ganna Aleshcheva, Ulrich Gross, Lars Morawietz, Christian Stumpf, Martin Bergmann, Burkert Pieske, Dirk Westermann, Karl-Ludwig Laugwitz, Johannes Brachmann, Friedrich Fruhwald, Johann Bauersachs, Gerian Grönefeld, Ulf Landmesser, and Philip Wenzel
- Subjects
medicine.medical_specialty ,Pathology ,Myocarditis ,business.industry ,lcsh:R ,lcsh:Medicine ,Subgroup analysis ,Histology ,General Medicine ,030204 cardiovascular system & hematology ,idiopathic giant-cell myocarditis ,medicine.disease ,Article ,Gene expression profiling ,03 medical and health sciences ,gene-expression profiling ,0302 clinical medicine ,Cardiac decompensation ,Giant cell ,endomyocardial biopsy ,medicine ,Clinical significance ,Histopathology ,business ,030217 neurology & neurosurgery - Abstract
Aims: The diagnostic approach to idiopathic giant-cell myocarditis (IGCM) is based on identifying various patterns of inflammatory cell infiltration and multinucleated giant cells (GCs) in histologic sections taken from endomyocardial biopsies (EMBs). The sampling error for detecting focally located GCs by histopathology is high, however. The aim of this study was to demonstrate the feasibility of gene profiling as a new diagnostic method in clinical practice, namely in a large cohort of patients suffering from acute cardiac decompensation. Methods and Results: In this retrospective multicenter study, EMBs taken from n = 427 patients with clinically acute cardiac decompensation and suspected acute myocarditis were screened (mean age: 47.03 ±, 15.69 years). In each patient, the EMBs were analyzed on the basis of histology, immunohistology, molecular virology, and gene-expression profiling. Out of the total of n = 427 patient samples examined, GCs could be detected in 26 cases (6.1%) by histology. An established myocardial gene profile consisting of 27 genes was revealed, this was narrowed down to a specified profile of five genes (CPT1, CCL20, CCR5, CCR6, TLR8) which serve to identify histologically proven IGCM with high specificity in 25 of the 26 patients (96.2%). Once this newly established profiling approach was applied to the remaining patient samples, an additional n = 31 patients (7.3%) could be identified as having IGCM without any histologic proof of myocardial GCs. In a subgroup analysis, patients diagnosed with IGCM using this gene profiling respond in a similar fashion to immunosuppressive therapy as patients diagnosed with IGCM by conventional histology alone. Conclusions: Myocardial gene-expression profiling is a promising new method in clinical practice, one which can predict IGCM even in the absence of any direct histologic proof of GCs in EMB sections. Gene profiling is of great clinical relevance in terms of a) overcoming the sampling error associated with purely histologic examinations and b) monitoring the effectiveness of therapy.
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- 2020
17. Detection of viral SARS-CoV-2 genomes and histopathological changes in endomyocardial biopsies
- Author
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Christian Baumeier, Thomas Bock, Felicitas Escher, Albrecht Elsaesser, Ralph Westenfeld, Ulrich Gross, Heinz-Peter Schultheiss, Ganna Aleshcheva, Lars Morawietz, Heiko Pietsch, Philip Wenzel, Christian W. Hamm, and Maximilian Schultheiss
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Male ,Pathology ,030204 cardiovascular system & hematology ,Communicable Diseases, Emerging ,Disease Outbreaks ,Cohort Studies ,0302 clinical medicine ,Germany ,Original Research Articles ,030212 general & internal medicine ,Original Research Article ,SARS‐CoV‐2‐infection ,Ejection fraction ,biology ,Incidence ,Biopsy, Needle ,Age Factors ,Genomics ,Middle Aged ,Immunohistochemistry ,Reverse transcription polymerase chain reaction ,Myocarditis ,Severe acute respiratory syndrome-related coronavirus ,Endomyocardial biopsy ,Female ,Cardiology and Cardiovascular Medicine ,Coronavirus Infections ,Adult ,medicine.medical_specialty ,Pneumonia, Viral ,Ischemia ,Heart failure ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,Sex Factors ,COVID‐19 ,medicine ,Diseases of the circulatory (Cardiovascular) system ,Humans ,Pandemics ,Aged ,Retrospective Studies ,business.industry ,COVID-19 ,medicine.disease ,Troponin ,Survival Analysis ,Reverse transcriptase ,Embolism ,Gene Expression Regulation ,RC666-701 ,biology.protein ,business ,Endocardium - Abstract
Aims Since December 2019, the novel coronavirus SARS‐CoV‐2 has spread rapidly throughout China and keeps the world in suspense. Cardiovascular complications with myocarditis and embolism due to COVID‐19 have been reported. SARS‐CoV‐2 genome detection in the heart muscle has not been demonstrated so far, and the underlying pathophysiological mechanisms remain to be investigated. Methods and results Endomyocardial biopsies (EMBs) of 104 patients (mean age: 57.90 ± 16.37 years; left ventricular ejection fraction: 33.7 ± 14.6%, sex: n = 79 male/25 female) with suspected myocarditis or unexplained heart failure were analysed. EMB analysis included histology, immunohistochemistry, and detection of SARS‐CoV‐2 genomes by real‐time reverse transcription polymerase chain reaction in the IKDT Berlin, Germany. Among 104 EMBs investigated, five were confirmed with SARS‐CoV‐2 infected by reverse real‐time transcriptase polymerase chain reaction. We describe patients of different history of symptoms and time duration. Additionally, we investigated histopathological changes in myocardial tissue showing that the inflammatory process in EMBs seemed to permeate vascular wall leading to small arterial obliteration and damage. Conclusions This is the first report that established the evidence of SARS‐CoV‐2 genomes detection in EMBs. In these patients, myocardial injury ischaemia may play a role, which could explain the ubiquitous troponin increases. EMB‐based identification of the cause of myocardial injury may contribute to explain the different evolution of complicated SARS‐CoV‐2‐infection and to design future specific and personalized treatment strategies.
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- 2020
18. Absence of IL-10 production by human PBMCs co-cultivated with human cells expressing or secreting retroviral immunosuppressive domains
- Author
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Joachim Denner, Jasper König, Heiko Pietsch, and Daniel Ivanusic
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0301 basic medicine ,RNA viruses ,Swine ,medicine.medical_treatment ,Protein Expression ,Cell Membranes ,Cultured tumor cells ,lcsh:Medicine ,Pathology and Laboratory Medicine ,Biochemistry ,Mice ,Immunodeficiency Viruses ,Medicine and Health Sciences ,Enzyme-Linked Immunoassays ,lcsh:Science ,Expressed Sequence Tags ,Multidisciplinary ,Immune System Proteins ,medicine.diagnostic_test ,Chemistry ,Drugs ,Transfection ,Complementary DNA ,Immunosuppressives ,Interleukin-10 ,Nucleic acids ,Medical Microbiology ,Viral Pathogens ,Viruses ,Cell lines ,Pathogens ,Cellular Structures and Organelles ,Biological cultures ,Research Article ,Forms of DNA ,Xenotransplantation ,Protein domain ,Immunology ,Research and Analysis Methods ,Microbiology ,03 medical and health sciences ,Western blot ,Protein Domains ,Retroviruses ,medicine ,Gene Expression and Vector Techniques ,Genetics ,Immune Tolerance ,Animals ,Humans ,ddc:610 ,HeLa cells ,Molecular Biology Techniques ,Immunoassays ,Microbial Pathogens ,Molecular Biology ,Pharmacology ,Molecular Biology Assays and Analysis Techniques ,HEK 293 cells ,lcsh:R ,Lentivirus ,Organisms ,Biology and Life Sciences ,HIV ,Membrane Proteins ,Proteins ,Gene Products, env ,DNA ,Cell Biology ,Cell cultures ,Molecular biology ,In vitro ,Coculture Techniques ,030104 developmental biology ,HEK293 Cells ,Membrane protein ,Cell culture ,Mutation ,HIV-1 ,Immunologic Techniques ,Leukocytes, Mononuclear ,lcsh:Q ,610 Medizin und Gesundheit - Abstract
Immunosuppression by retroviruses including the human immunodeficiency virus—1 (HIV-1) is well known, however the mechanisms how retroviruses induce this immunosuppression is not fully investigated. It was shown that non-infectious retroviral particles as well as retroviral or recombinant retroviral transmembrane envelope (TM) proteins demonstrated immunosuppressive properties. The same was shown for peptides corresponding to a highly conserved domain in the TM protein. This domain is called immunosuppressive (ISU) domain and it induces modulation of the cytokine release of peripheral blood mononuclear cells (PBMCs) from healthy donors. In addition, it changes the gene expression of these cells. Common indications for the immunosuppressive activity were tumour growth in vivo and interleukin—10 (IL-10) release from human PBMCs in vitro. Single mutations in the ISU domain abrogated the immunosuppressive activity. In order to develop a new model system for the expression of the ISU domain and presentation to PBMCs which is not prone to possible endotoxin contaminations, two expression systems were developed. In the first system, designated pOUT, retroviral proteins containing the ISU domain were expressed and released into the cell culture medium, and in the second system, tANCHOR, the ISU domain was presented by a tetraspanin-anchored sequence on the cell surface of human cells. Both systems were exploited to express the wild-type (wt) ISU domains of HIV-1, of the porcine endogenous retrovirus (PERV) and of the murine leukaemia virus (MuLV) as well as to express mutants (mut) of these ISU domains. PERV is of special interest in the context of virus safety of xenotransplantation using pig organs. Expression of the TM proteins was demonstrated by confocal laser scanning microscopy, ELISA and Western blot analyses using specific antibodies. However, when cells expressing and releasing the ISU were co-incubated with human PBMCs, no increased production of IL-10 was observed when compared with the mutants. Similar results were obtained when the released TM proteins were concentrated by immunoprecipitation and added to PBMCs. We suggest that the absence of IL-10 induction can be explained by a low amount of protein, by the lack of a biologically active conformation or the absence of additional factors.
- Published
- 2018
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