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Karin Klingel
Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tuebingen (K.K.).

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Research article
Published: 01 August 2021 in Circulation: Genomic and Precision Medicine
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Background: Myocarditis is one of the most common causes leading to heart failure in children and a possible genetic background has been postulated. We sought to characterize the clinical and genetic characteristics in patients with myocarditis ≤18 years of age to predict outcome. Methods: A cohort of 42 patients (Genetics in Pediatric Myocarditis) with biopsy-proven myocarditis underwent genetic testing with targeted panel sequencing of cardiomyopathy-associated genes. Genetics in Pediatric Myocarditis patients were divided into subgroups according to the phenotype of dilated cardiomyopathy (DCM) at presentation, resulting in 22 patients without DCM (myocarditis without phenotype of DCM) and 20 patients with DCM (myocarditis with phenotype of DCM). Results: Myocarditis with phenotype of DCM patients (median age 1.4 years) were younger than myocarditis without phenotype of DCM patients (median age 16.1 years; P <0.001) and were corresponding to heart failure–like and coronary syndrome–like phenotypes, respectively. At least one likely pathogenic/pathogenic variant was identified in 9 out of 42 patients (22%), 8 of them were heterozygous, and 7 out of 9 were in myocarditis with phenotype of DCM. Likely pathogenic/pathogenic variants were found in genes validated for primary DCM ( BAG3, DSP, LMNA, MYH7, TNNI3, TNNT2 , and TTN ). Rare variant enrichment analysis revealed significant accumulation of high-impact disease variants in myocarditis with phenotype of DCM versus healthy individuals ( P =0.0003). Event-free survival was lower ( P =0.008) in myocarditis with phenotype of DCM patients compared with myocarditis without phenotype of DCM and primary DCM. Conclusions: We report heterozygous likely pathogenic/pathogenic variants in biopsy-proven pediatric myocarditis. Myocarditis patients with DCM phenotype were characterized by early-onset heart failure, significant enrichment of likely pathogenic/pathogenic variants, and poor outcome. These phenotype-specific and age group–specific findings will be useful for personalized management of these patients. Genetic evaluation in children newly diagnosed with myocarditis and DCM phenotype is warranted.

ACS Style

Franziska Seidel; Manuel Holtgrewe; Nadya Al-Wakeel-Marquard; Bernd Opgen-Rhein; Josephine Dartsch; Christopher Herbst; Dieter Beule; Thomas Pickardt; Karin Klingel; Daniel Messroghli; Felix Berger; Stephan Schubert; Jirko Kühnisch; Sabine Klaassen. Pathogenic Variants Associated With Dilated Cardiomyopathy Predict Outcome in Pediatric Myocarditis. Circulation: Genomic and Precision Medicine 2021, 14, 1 .

AMA Style

Franziska Seidel, Manuel Holtgrewe, Nadya Al-Wakeel-Marquard, Bernd Opgen-Rhein, Josephine Dartsch, Christopher Herbst, Dieter Beule, Thomas Pickardt, Karin Klingel, Daniel Messroghli, Felix Berger, Stephan Schubert, Jirko Kühnisch, Sabine Klaassen. Pathogenic Variants Associated With Dilated Cardiomyopathy Predict Outcome in Pediatric Myocarditis. Circulation: Genomic and Precision Medicine. 2021; 14 (4):1.

Chicago/Turabian Style

Franziska Seidel; Manuel Holtgrewe; Nadya Al-Wakeel-Marquard; Bernd Opgen-Rhein; Josephine Dartsch; Christopher Herbst; Dieter Beule; Thomas Pickardt; Karin Klingel; Daniel Messroghli; Felix Berger; Stephan Schubert; Jirko Kühnisch; Sabine Klaassen. 2021. "Pathogenic Variants Associated With Dilated Cardiomyopathy Predict Outcome in Pediatric Myocarditis." Circulation: Genomic and Precision Medicine 14, no. 4: 1.

Journal article
Published: 24 June 2021 in Viruses
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Infection of mice with Coxsackievirus B3 (CVB3) triggers inflammation of the heart and this mouse model is commonly used to investigate underlying mechanisms and therapeutic aspects for viral myocarditis. Virus-triggered cytotoxicity and the activity of infiltrating immune cells contribute to cardiac tissue injury. In addition to cardiac manifestation, CVB3 causes cell death and inflammation in the pancreas. The resulting pancreatitis represents a severe burden and under such experimental conditions, analgesics may be supportive to improve the animals’ well-being. Notably, several known mechanisms exist by which analgesics can interfere with the immune system and thereby compromise the feasibility of the model. We set up a study aiming to improve animal welfare while ensuring model integrity and investigated how tramadol, an opioid, affects virus-induced pathogenicity and immune response in the heart. Tramadol was administered seven days prior to a CVB3 infection in C57BL/6 mice and treatment was continued until the day of analysis. Tramadol had no effect on the virus titer or viral pathogenicity in the heart tissue and the inflammatory response, a hallmark of myocardial injury, was maintained. Our results show that tramadol exerts no disruptive effects on the CVB3 myocarditis mouse model and, therefore, the demonstrated protocol should be considered as a general analgesic strategy for CVB3 infection.

ACS Style

Sandra Pinkert; Meike Kespohl; Nicolas Kelm; Ziya Kaya; Arnd Heuser; Karin Klingel; Antje Beling. Exploration of Analgesia with Tramadol in the Coxsackievirus B3 Myocarditis Mouse Model. Viruses 2021, 13, 1222 .

AMA Style

Sandra Pinkert, Meike Kespohl, Nicolas Kelm, Ziya Kaya, Arnd Heuser, Karin Klingel, Antje Beling. Exploration of Analgesia with Tramadol in the Coxsackievirus B3 Myocarditis Mouse Model. Viruses. 2021; 13 (7):1222.

Chicago/Turabian Style

Sandra Pinkert; Meike Kespohl; Nicolas Kelm; Ziya Kaya; Arnd Heuser; Karin Klingel; Antje Beling. 2021. "Exploration of Analgesia with Tramadol in the Coxsackievirus B3 Myocarditis Mouse Model." Viruses 13, no. 7: 1222.

Review
Published: 27 May 2021 in Viruses
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Myocarditis is an inflammatory disease of the heart with viral infections being the most common aetiology. Its complex biology remains poorly understood and its clinical management is one of the most challenging in the field of cardiology. Toll-like receptors (TLRs), a family of evolutionarily conserved pattern recognition receptors, are increasingly known to be implicated in the pathophysiology of viral myocarditis. Their central role in innate and adaptive immune responses, and in the inflammatory reaction that ensues, indeed makes them prime candidates to profoundly affect every stage of the disease process. This review describes the pathogenesis and pathophysiology of viral myocarditis, and scrutinises the role of TLRs in every phase. We conclude with directions for future research in this field.

ACS Style

Kasper Favere; Matthias Bosman; Karin Klingel; Stephane Heymans; Sophie Van Linthout; Peter Delputte; Johan De Sutter; Hein Heidbuchel; Pieter-Jan Guns. Toll-Like Receptors: Are They Taking a Toll on the Heart in Viral Myocarditis? Viruses 2021, 13, 1003 .

AMA Style

Kasper Favere, Matthias Bosman, Karin Klingel, Stephane Heymans, Sophie Van Linthout, Peter Delputte, Johan De Sutter, Hein Heidbuchel, Pieter-Jan Guns. Toll-Like Receptors: Are They Taking a Toll on the Heart in Viral Myocarditis? Viruses. 2021; 13 (6):1003.

Chicago/Turabian Style

Kasper Favere; Matthias Bosman; Karin Klingel; Stephane Heymans; Sophie Van Linthout; Peter Delputte; Johan De Sutter; Hein Heidbuchel; Pieter-Jan Guns. 2021. "Toll-Like Receptors: Are They Taking a Toll on the Heart in Viral Myocarditis?" Viruses 13, no. 6: 1003.

Journal article
Published: 21 May 2021 in European Heart Journal
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ACS Style

Karin Klingel; Peter Pöml; Johannes Strunk; Martin-Lorenz Werthmann. Lethal enterovirus myocarditis in a patient with granulomatosis with polyangiitis following rituximab and high-dose steroid therapy. European Heart Journal 2021, 42, 2401 -2401.

AMA Style

Karin Klingel, Peter Pöml, Johannes Strunk, Martin-Lorenz Werthmann. Lethal enterovirus myocarditis in a patient with granulomatosis with polyangiitis following rituximab and high-dose steroid therapy. European Heart Journal. 2021; 42 (24):2401-2401.

Chicago/Turabian Style

Karin Klingel; Peter Pöml; Johannes Strunk; Martin-Lorenz Werthmann. 2021. "Lethal enterovirus myocarditis in a patient with granulomatosis with polyangiitis following rituximab and high-dose steroid therapy." European Heart Journal 42, no. 24: 2401-2401.

Journal article
Published: 21 May 2021 in The International Journal of Cardiovascular Imaging
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To provide clinically relevant criteria for differentiation between the athlete’s heart and similar appearing hypertrophic (HCM), dilated (DCM), and arrhythmogenic right-ventricular cardiomyopathy (ARVC) in MRI. 40 top-level athletes were prospectively examined with cardiac MR (CMR) in two university centres and compared to retrospectively recruited patients diagnosed with HCM (n = 14), ARVC (n = 18), and DCM (n = 48). Analysed MR imaging parameters in the whole study cohort included morphology, functional parameters and late gadolinium enhancement (LGE). Mean left-ventricular enddiastolic volume index (LVEDVI) was high in athletes (105 ml/m2) but significantly lower compared to DCM (132 ml/m2; p = 0.001). Mean LV ejection fraction (EF) was 61% in athletes, below normal in 7 (18%) athletes vs. EF 29% in DCM, below normal in 46 (96%) patients (p < 0.0001). Mean RV-EF was 54% in athletes vs. 60% in HCM, 46% in ARVC, and 41% in DCM (p < 0.0001). Mean interventricular myocardial thickness was 10 mm in athletes vs. 12 mm in HCM (p = 0.0005), 9 mm in ARVC, and 9 mm in DCM. LGE was present in 1 (5%) athlete, 8 (57%) HCM, 10 (56%) ARVC, and 21 (44%) DCM patients (p < 0.0001). Healthy athletes’ hearts are characterized by both hypertrophy and dilation, low EF of both ventricles at rest, and increased interventricular septal thickness with a low prevalence of LGE. Differentiation of athlete’s heart from other non-ischemic cardiomyopathies in MRI can be challenging due to a significant overlap of characteristics also seen in HCM, ARVC, and DCM.

ACS Style

J. Kübler; C. Burgstahler; J. M. Brendel; S. Gassenmaier; F. Hagen; K. Klingel; S.-C. Olthof; K. Blume; B. Wolfarth; K. A. L. Mueller; S. Greulich; P. Krumm. Cardiac MRI findings to differentiate athlete's heart from hypertrophic (HCM), arrhythmogenic right ventricular (ARVC) and dilated (DCM) cardiomyopathy. The International Journal of Cardiovascular Imaging 2021, 37, 1 -15.

AMA Style

J. Kübler, C. Burgstahler, J. M. Brendel, S. Gassenmaier, F. Hagen, K. Klingel, S.-C. Olthof, K. Blume, B. Wolfarth, K. A. L. Mueller, S. Greulich, P. Krumm. Cardiac MRI findings to differentiate athlete's heart from hypertrophic (HCM), arrhythmogenic right ventricular (ARVC) and dilated (DCM) cardiomyopathy. The International Journal of Cardiovascular Imaging. 2021; 37 (8):1-15.

Chicago/Turabian Style

J. Kübler; C. Burgstahler; J. M. Brendel; S. Gassenmaier; F. Hagen; K. Klingel; S.-C. Olthof; K. Blume; B. Wolfarth; K. A. L. Mueller; S. Greulich; P. Krumm. 2021. "Cardiac MRI findings to differentiate athlete's heart from hypertrophic (HCM), arrhythmogenic right ventricular (ARVC) and dilated (DCM) cardiomyopathy." The International Journal of Cardiovascular Imaging 37, no. 8: 1-15.

Journal article
Published: 12 May 2021 in Viruses
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Murine models of coxsackievirus B3 (CVB3)-induced myocarditis well represent the different outcomes of this inflammatory heart disease. Previously, we found that CVB3-infected A.BY/SnJ mice, susceptible for severe acute and chronic myocarditis, have lower natural killer (NK) cell levels than C57BL/6 mice, with mild acute myocarditis. There is evidence that myeloid-derived suppressor cells (MDSC) may inhibit NK cells, influencing the course of myocarditis. To investigate the MDSC/NK interrelationship in acute myocarditis, we used CVB3-infected A.BY/SnJ mice. Compared to non-infected mice, we found increased cell numbers of MDSC in the spleen and heart of CVB3-infected A.BY/SnJ mice. In parallel, S100A8 and S100A9 were increased in the heart, spleen, and especially in splenic MDSC cells compared to non-infected mice. In vitro experiments provided evidence that MDSC disrupt cytotoxic NK cell function upon co-culturing with MDSC. MDSC-specific depletion by an anti-Ly6G antibody led to a significant reduction in the virus load and injury in hearts of infected animals. The decreased cardiac damage in MDSC-depleted mice was associated with fewer Mac3+ macrophages and CD3+ T lymphocytes and a reduced cardiac expression of S100A8, S100A9, IL-1β, IL-6, and TNF-α. In conclusion, impairment of functional NK cells by MDSC promotes the development of chronic CVB3 myocarditis in A.BY/SnJ mice.

ACS Style

Irene Müller; Lisa Janson; Martina Sauter; Kathleen Pappritz; Sophie Linthout; Carsten Tschöpe; Karin Klingel. Myeloid-Derived Suppressor Cells Restrain Natural Killer Cell Activity in Acute Coxsackievirus B3-Induced Myocarditis. Viruses 2021, 13, 889 .

AMA Style

Irene Müller, Lisa Janson, Martina Sauter, Kathleen Pappritz, Sophie Linthout, Carsten Tschöpe, Karin Klingel. Myeloid-Derived Suppressor Cells Restrain Natural Killer Cell Activity in Acute Coxsackievirus B3-Induced Myocarditis. Viruses. 2021; 13 (5):889.

Chicago/Turabian Style

Irene Müller; Lisa Janson; Martina Sauter; Kathleen Pappritz; Sophie Linthout; Carsten Tschöpe; Karin Klingel. 2021. "Myeloid-Derived Suppressor Cells Restrain Natural Killer Cell Activity in Acute Coxsackievirus B3-Induced Myocarditis." Viruses 13, no. 5: 889.

Research article
Published: 27 April 2021 in Circulation
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Background: Dilated cardiomyopathy (DCM) is a leading cause of death in children with heart failure. The outcome of pediatric heart failure treatment is inconsistent, and large cohort studies are lacking. Progress may be achieved through personalized therapy that takes age- and disease-related pathophysiology, pathology, and molecular fingerprints into account. We present single nuclei RNA sequencing from pediatric patients with DCM as the next step in identifying cellular signatures. Methods: We performed single nuclei RNA sequencing with heart tissues from 6 children with DCM with an age of 0.5, 0.75, 5, 6, 12, and 13 years. Unsupervised clustering of 18 211 nuclei led to the identification of 14 distinct clusters with 6 major cell types. Results: The number of nuclei in fibroblast clusters increased with age in patients with DCM, a finding that was confirmed by histological analysis and was consistent with an age-related increase in cardiac fibrosis quantified by cardiac magnetic resonance imaging. Fibroblasts of patients with DCM >6 years of age showed a profoundly altered gene expression pattern with enrichment of genes encoding fibrillary collagens, modulation of proteoglycans, switch in thrombospondin isoforms, and signatures of fibroblast activation. In addition, a population of cardiomyocytes with a high proregenerative profile was identified in infant patients with DCM but was absent in children >6 years of age. This cluster showed high expression of cell cycle activators such as cyclin D family members, increased glycolytic metabolism and antioxidative genes, and alterations in ß-adrenergic signaling genes. Conclusions: Novel insights into the cellular transcriptomes of hearts from pediatric patients with DCM provide remarkable age-dependent changes in the expression patterns of fibroblast and cardiomyocyte genes with less fibrotic but enriched proregenerative signatures in infants.

ACS Style

Luka Nicin; Wesley T. Abplanalp; Anne Schänzer; Anke Sprengel; David John; Hannah Mellentin; Lukas Tombor; Matthias Keuper; Evelyn Ullrich; Karin Klingel; Reinhard B. Dettmeyer; Jedrzej Hoffmann; Hakan Akintuerk; Christian Jux; Dietmar Schranz; Andreas M. Zeiher; Stefan Rupp; Stefanie Dimmeler. Single Nuclei Sequencing Reveals Novel Insights Into the Regulation of Cellular Signatures in Children With Dilated Cardiomyopathy. Circulation 2021, 143, 1704 -1719.

AMA Style

Luka Nicin, Wesley T. Abplanalp, Anne Schänzer, Anke Sprengel, David John, Hannah Mellentin, Lukas Tombor, Matthias Keuper, Evelyn Ullrich, Karin Klingel, Reinhard B. Dettmeyer, Jedrzej Hoffmann, Hakan Akintuerk, Christian Jux, Dietmar Schranz, Andreas M. Zeiher, Stefan Rupp, Stefanie Dimmeler. Single Nuclei Sequencing Reveals Novel Insights Into the Regulation of Cellular Signatures in Children With Dilated Cardiomyopathy. Circulation. 2021; 143 (17):1704-1719.

Chicago/Turabian Style

Luka Nicin; Wesley T. Abplanalp; Anne Schänzer; Anke Sprengel; David John; Hannah Mellentin; Lukas Tombor; Matthias Keuper; Evelyn Ullrich; Karin Klingel; Reinhard B. Dettmeyer; Jedrzej Hoffmann; Hakan Akintuerk; Christian Jux; Dietmar Schranz; Andreas M. Zeiher; Stefan Rupp; Stefanie Dimmeler. 2021. "Single Nuclei Sequencing Reveals Novel Insights Into the Regulation of Cellular Signatures in Children With Dilated Cardiomyopathy." Circulation 143, no. 17: 1704-1719.

Original research article
Published: 08 April 2021 in ESC Heart Failure
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Aims Establishing a diagnosis of inflammatory cardiomyopathy (iCMP) by non‐invasive means remains challenging despite advances in cardiac magnetic resonance imaging. Previous studies suggested the involvement of microRNAs in the pathogenesis of iCMP. We examined the association of a predefined set of circulatory microRNAs with clinical characteristics of iCMP and evaluated their diagnostic performance in suspected iCMP. Methods and results Eighty‐nine patients with clinical suspicion of iCMP were included in the analysis. All patients underwent cardiac catheterization with left ventricular endomyocardial biopsy, echocardiography, and cardiac magnetic resonance imaging applying the Lake Louise criteria (LLC). Plasma levels of miR‐21, miR‐126, miR‐133a, miR‐146b, miR‐155, and miR‐206 were determined using real‐time polymerase chain reaction. Based on immunohistological findings on endomyocardial biopsy, iCMP was diagnosed in 67% of study participants (n = 60). Plasma levels of miR‐155 and miR‐206 were significantly increased in patients with iCMP as compared with patients with dilated cardiomyopathy (P = 0.008 and P = 0.009, respectively). In receiver operating characteristic curve analysis, miR‐155 and miR‐206 demonstrated superior diagnostic performance for iCMP (0.68 and 0.67, respectively) compared with LLC [area under the curve (AUC) 0.60], Troponin T (AUC 0.51), and N‐terminal pro‐brain natriuretic peptide (AUC 0.51). While baseline miR‐155 and miR‐206 plasma levels were predictive for biopsy‐proven iCMP (odds ratio = 2.61, 95% confidence interval = 1.28–5.31, P = 0.008 and odds ratio = 2.65, 95% confidence interval = 1.27–5.52, P = 0.009) on univariate logistic regression analysis, the presence of positive LLC, high baseline C‐reactive protein, or presence of clinical symptoms and signs of viral infection failed to predict iCMP (P > 0.05, respectively). Conclusions The present data suggest that plasma levels of miR‐206 and miR‐155 are potential novel biomarkers for confirming the diagnosis of iCMP.

ACS Style

Danilo Obradovic; Karl‐Philipp Rommel; Stephan Blazek; Karin Klingel; Matthias Gutberlet; Christian Lücke; Petra Büttner; Holger Thiele; Volker Adams; Philipp Lurz; Fabian Emrich; Christian Besler. The potential role of plasma miR‐155 and miR‐206 as circulatory biomarkers in inflammatory cardiomyopathy. ESC Heart Failure 2021, 8, 1850 -1860.

AMA Style

Danilo Obradovic, Karl‐Philipp Rommel, Stephan Blazek, Karin Klingel, Matthias Gutberlet, Christian Lücke, Petra Büttner, Holger Thiele, Volker Adams, Philipp Lurz, Fabian Emrich, Christian Besler. The potential role of plasma miR‐155 and miR‐206 as circulatory biomarkers in inflammatory cardiomyopathy. ESC Heart Failure. 2021; 8 (3):1850-1860.

Chicago/Turabian Style

Danilo Obradovic; Karl‐Philipp Rommel; Stephan Blazek; Karin Klingel; Matthias Gutberlet; Christian Lücke; Petra Büttner; Holger Thiele; Volker Adams; Philipp Lurz; Fabian Emrich; Christian Besler. 2021. "The potential role of plasma miR‐155 and miR‐206 as circulatory biomarkers in inflammatory cardiomyopathy." ESC Heart Failure 8, no. 3: 1850-1860.

Journal article
Published: 06 April 2021 in International Journal of Molecular Sciences
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About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2–c.378+1G>T) in the first patient and a nonsense mutation (DSG2–p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.

ACS Style

Andreas Brodehl; Alexey Meshkov; Roman Myasnikov; Anna Kiseleva; Olga Kulikova; Bärbel Klauke; Evgeniia Sotnikova; Caroline Stanasiuk; Mikhail Divashuk; Greta Pohl; Maria Kudryavtseva; Karin Klingel; Brenda Gerull; Anastasia Zharikova; Jan Gummert; Sergey Koretskiy; Stephan Schubert; Elena Mershina; Anna Gärtner; Polina Pilus; Kai Laser; Valentin Sinitsyn; Sergey Boytsov; Oxana Drapkina; Hendrik Milting. Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset. International Journal of Molecular Sciences 2021, 22, 3786 .

AMA Style

Andreas Brodehl, Alexey Meshkov, Roman Myasnikov, Anna Kiseleva, Olga Kulikova, Bärbel Klauke, Evgeniia Sotnikova, Caroline Stanasiuk, Mikhail Divashuk, Greta Pohl, Maria Kudryavtseva, Karin Klingel, Brenda Gerull, Anastasia Zharikova, Jan Gummert, Sergey Koretskiy, Stephan Schubert, Elena Mershina, Anna Gärtner, Polina Pilus, Kai Laser, Valentin Sinitsyn, Sergey Boytsov, Oxana Drapkina, Hendrik Milting. Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset. International Journal of Molecular Sciences. 2021; 22 (7):3786.

Chicago/Turabian Style

Andreas Brodehl; Alexey Meshkov; Roman Myasnikov; Anna Kiseleva; Olga Kulikova; Bärbel Klauke; Evgeniia Sotnikova; Caroline Stanasiuk; Mikhail Divashuk; Greta Pohl; Maria Kudryavtseva; Karin Klingel; Brenda Gerull; Anastasia Zharikova; Jan Gummert; Sergey Koretskiy; Stephan Schubert; Elena Mershina; Anna Gärtner; Polina Pilus; Kai Laser; Valentin Sinitsyn; Sergey Boytsov; Oxana Drapkina; Hendrik Milting. 2021. "Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset." International Journal of Molecular Sciences 22, no. 7: 3786.

English abstract
Published: 01 March 2021 in Der Pathologe
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Aktuell dauert die Pandemie mit dem neuartigen Coronavirus SARS-CoV‑2 an. Dieses neue Virus gehört zur Familie der Coronaviren, deren erste Vertreter bereits in den 1960er-Jahren entdeckt wurden. Die in Tieren und dem Menschen zirkulierenden Coronaviren weisen dabei teilweise Gemeinsamkeiten, aber auch erhebliche Unterschiede in ihrer Biologie und Pathologie auf. Neben klassischen Erkältungssymptomen und gastroenterologischen Symptomen können das neuartige SARS-CoV‑2 und die vorangegangen Coronaviren SARS-CoV und MERS-CoV auch schwerwiegende Beeinträchtigungen der Lunge und anderer Organe wie dem Herz hervorrufen.

ACS Style

Selina Traxler; Michael Schindler; Hans Bösmüller; Karin Klingel. Biologie und Pathologie von Coronaviren. Der Pathologe 2021, 42, 149 -154.

AMA Style

Selina Traxler, Michael Schindler, Hans Bösmüller, Karin Klingel. Biologie und Pathologie von Coronaviren. Der Pathologe. 2021; 42 (2):149-154.

Chicago/Turabian Style

Selina Traxler; Michael Schindler; Hans Bösmüller; Karin Klingel. 2021. "Biologie und Pathologie von Coronaviren." Der Pathologe 42, no. 2: 149-154.

Journal article
Published: 13 February 2021 in International Journal of Molecular Sciences
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Background: Pathological activation of cardiac fibroblasts is a key step in development and progression of cardiac fibrosis and heart failure. This process has been associated with enhanced autophagocytosis, but molecular mechanisms remain largely unknown. Methods and Results: Immunohistochemical analysis of endomyocardial biopsies showed increased activation of autophagy in fibrotic hearts of patients with inflammatory cardiomyopathy. In vitro experiments using mouse and human cardiac fibroblasts confirmed that blockade of autophagy with Bafilomycin A1 inhibited fibroblast-to-myofibroblast transition induced by transforming growth factor (TGF)-β. Next, we observed that cardiac fibroblasts obtained from mice overexpressing transcription factor Fos-related antigen 2 (Fosl-2tg) expressed elevated protein levels of autophagy markers: the lipid modified form of microtubule-associated protein 1A/1B-light chain 3B (LC3BII), Beclin-1 and autophagy related 5 (Atg5). In complementary experiments, silencing of Fosl-2 with antisense GapmeR oligonucleotides suppressed production of type I collagen, myofibroblast marker alpha smooth muscle actin and autophagy marker Beclin-1 in cardiac fibroblasts. On the other hand, silencing of either LC3B or Beclin-1 reduced Fosl-2 levels in TGF-β-activated, but not in unstimulated cells. Using a cardiac hypertrophy model induced by continuous infusion of angiotensin II with osmotic minipumps, we confirmed that mice lacking either Fosl-2 (Ccl19CreFosl2flox/flox) or Atg5 (Ccl19CreAtg5flox/flox) in stromal cells were protected from cardiac fibrosis. Conclusion: Our findings demonstrate that Fosl-2 regulates autophagocytosis and the TGF-β-Fosl-2-autophagy axis controls differentiation of cardiac fibroblasts. These data provide a new insight for the development of pharmaceutical targets in cardiac fibrosis.

ACS Style

Jemima Seidenberg; Mara Stellato; Amela Hukara; Burkhard Ludewig; Karin Klingel; Oliver Distler; Przemysław Błyszczuk; Gabriela Kania. The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis. International Journal of Molecular Sciences 2021, 22, 1861 .

AMA Style

Jemima Seidenberg, Mara Stellato, Amela Hukara, Burkhard Ludewig, Karin Klingel, Oliver Distler, Przemysław Błyszczuk, Gabriela Kania. The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis. International Journal of Molecular Sciences. 2021; 22 (4):1861.

Chicago/Turabian Style

Jemima Seidenberg; Mara Stellato; Amela Hukara; Burkhard Ludewig; Karin Klingel; Oliver Distler; Przemysław Błyszczuk; Gabriela Kania. 2021. "The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis." International Journal of Molecular Sciences 22, no. 4: 1861.

Journal article
Published: 27 November 2020 in Viruses
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The relationship between the nasopharyngeal virus load, IgA and IgG antibodies to both the S1-RBD-protein and the N-protein, as well as the neutralizing activity (NAbs) against SARS-CoV-2 in the blood of moderately afflicted COVID-19 patients, needs further longitudinal investigation. Several new serological methods to examine these parameters were developed, validated and applied in three patients of a family which underwent an ambulatory course of COVID-19 for six months. The virus load had almost completely disappeared after about four weeks. Serum IgA levels to the S1-RBD-protein and, to a lesser extent, to the N-protein, peaked about three weeks after clinical disease onset but declined soon thereafter. IgG levels rose continuously, reaching a plateau at approximately six weeks, and stayed elevated over the observation period. Virus-neutralizing activity reached a peak about 4 weeks after disease onset but dropped slowly. The longitudinal associations of virus neutralization and the serological immune response suggest immunity in patients even after a mild clinical course of COVID-19.

ACS Style

Bertram Flehmig; Michael Schindler; Natalia Ruetalo; Ramona Businger; Manfred Bayer; Angelika Haage; Thomas Kirchner; Karin Klingel; Andrea Normann; Lutz Pridzun; Despina Tougianidou; Michael B. Ranke. Persisting Neutralizing Activity to SARS-CoV-2 over Months in Sera of COVID-19 Patients. Viruses 2020, 12, 1357 .

AMA Style

Bertram Flehmig, Michael Schindler, Natalia Ruetalo, Ramona Businger, Manfred Bayer, Angelika Haage, Thomas Kirchner, Karin Klingel, Andrea Normann, Lutz Pridzun, Despina Tougianidou, Michael B. Ranke. Persisting Neutralizing Activity to SARS-CoV-2 over Months in Sera of COVID-19 Patients. Viruses. 2020; 12 (12):1357.

Chicago/Turabian Style

Bertram Flehmig; Michael Schindler; Natalia Ruetalo; Ramona Businger; Manfred Bayer; Angelika Haage; Thomas Kirchner; Karin Klingel; Andrea Normann; Lutz Pridzun; Despina Tougianidou; Michael B. Ranke. 2020. "Persisting Neutralizing Activity to SARS-CoV-2 over Months in Sera of COVID-19 Patients." Viruses 12, no. 12: 1357.

Journal article
Published: 03 November 2020 in Cardiovascular Research
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Aims To elucidate the prognostic role of monocytes in the immune response of patients with coronary artery disease (CAD) at risk for life-threatening heart and lung injury as major complications of SARS-CoV-2 infection. Methods and results From February to April 2020, we prospectively studied a cohort of 96 participants comprising 47 consecutive patients with CAD and acute SARS-CoV-2 infection (CAD + SARS-CoV-2), 19 CAD patients without infections, and 30 healthy controls. Clinical assessment included blood sampling, echocardiography, and electrocardiography within 12 h of admission. Respiratory failure was stratified by the Horovitz Index (HI) as moderately/severely impaired when HI ≤200 mmHg. The clinical endpoint (EP) was defined as HI ≤200 mmHg with subsequent mechanical ventilation within a follow-up of 30 days. The numbers of CD14dimCD16+ non-classical monocytes in peripheral blood were remarkably low in CAD + SARS-CoV-2 compared with CAD patients without infection and healthy controls (P < 0.0001). Moreover, these CD14dimCD16 monocytes showed decreased expression of established markers of adhesion, migration, and T-cell activation (CD54, CD62L, CX3CR1, CD80, and HLA-DR). Decreased numbers of CD14dimCD16+ monocytes were associated with the occurrence of EP. Kaplan–Meier curves illustrate that CAD + SARS-CoV-2 patients with numbers below the median of CD14dimCD16+ monocytes (median 1443 cells/mL) reached EP significantly more often compared to patients with numbers above the median (log-rank 5.03, P = 0.025). Conclusion Decreased numbers of CD14dimCD16+ monocytes are associated with rapidly progressive respiratory failure in CAD + SARS-CoV-2 patients. Intensified risk assessments comprising monocyte sub- and phenotypes may help to identify patients at risk for respiratory failure.

ACS Style

Karin Anne Lydia Mueller; Carolin Langnau; Manina Günter; Simone Pöschel; Sarah Gekeler; Álvaro Petersen-Uribe; Klaus-Peter Kreisselmeier; Karin Klingel; Hans Bösmüller; Bo Li; Philippa Jaeger; Tatsiana Castor; Dominik Rath; Meinrad Paul Gawaz; Stella E Autenrieth. Numbers and phenotype of non-classical CD14dimCD16+ monocytes are predictors of adverse clinical outcome in patients with coronary artery disease and severe SARS-CoV-2 infection. Cardiovascular Research 2020, 117, 224 -239.

AMA Style

Karin Anne Lydia Mueller, Carolin Langnau, Manina Günter, Simone Pöschel, Sarah Gekeler, Álvaro Petersen-Uribe, Klaus-Peter Kreisselmeier, Karin Klingel, Hans Bösmüller, Bo Li, Philippa Jaeger, Tatsiana Castor, Dominik Rath, Meinrad Paul Gawaz, Stella E Autenrieth. Numbers and phenotype of non-classical CD14dimCD16+ monocytes are predictors of adverse clinical outcome in patients with coronary artery disease and severe SARS-CoV-2 infection. Cardiovascular Research. 2020; 117 (1):224-239.

Chicago/Turabian Style

Karin Anne Lydia Mueller; Carolin Langnau; Manina Günter; Simone Pöschel; Sarah Gekeler; Álvaro Petersen-Uribe; Klaus-Peter Kreisselmeier; Karin Klingel; Hans Bösmüller; Bo Li; Philippa Jaeger; Tatsiana Castor; Dominik Rath; Meinrad Paul Gawaz; Stella E Autenrieth. 2020. "Numbers and phenotype of non-classical CD14dimCD16+ monocytes are predictors of adverse clinical outcome in patients with coronary artery disease and severe SARS-CoV-2 infection." Cardiovascular Research 117, no. 1: 224-239.

Review article
Published: 28 October 2020 in Journal of the American Society of Echocardiography
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Loeffler's endocarditis (LE) is the cardiac manifestation of hypereosinophilic syndrome, a rare systemic disease characterized by the sustained production of eosinophils leading to organ damage. Few data, principally by case reports, are available regarding the diagnostic workup in patients with suspected LE. Thus, we have performed a systematic search of the literature dealing with imaging in LE and propose an integrated multimodality imaging approach in the cardiac diagnostics of LE patients. The aim is to provide an updated state-of-the-art review focused on noninvasive and invasive imaging modalities for this rare and underdiagnosed disease. Standard and advanced echocardiography are typically the first cardiac imaging examinations when LE is suspected and they are also used later in follow-up for prognostic stratification and assessing response to treatment. Cardiac magnetic resonance provides a more detailed anatomical and functional evaluation of cardiac chambers, tissue characterization for the presence and extension of myocardial edema and fibrosis, and ventricular thrombi identification. Computed tomography scan and [18F]-fluoro-deoxy-glucose positron emission tomography may be helpful in selected cases to evaluate the cardiac involvement of LE as well as the other noncardiac manifestations of hypereosinophilic syndrome. Endomyocardial biopsy may be considered in patients with high clinical suspicion of LE if noninvasive imaging findings are confusing or not conclusive. The appropriate use of invasive and noninvasive imaging modalities, combining the available techniques with the patients' clinical features, will hopefully lead to early diagnosis, more accurate staging of disease, and timely treatment of LE that may prevent the irreversible myocardial damage of LE and adverse cardiovascular events.

ACS Style

Maria Vincenza Polito; Andreas Hagendorff; Rodolfo Citro; Costantina Prota; Angelo Silverio; Elena De Angelis; Karin Klingel; Michael Metze; Stephan Stöbe; Karl Titus Hoffmann; Osama Sabri; Federico Piscione; Gennaro Galasso. Loeffler’s Endocarditis: An Integrated Multimodality Approach. Journal of the American Society of Echocardiography 2020, 33, 1427 -1441.

AMA Style

Maria Vincenza Polito, Andreas Hagendorff, Rodolfo Citro, Costantina Prota, Angelo Silverio, Elena De Angelis, Karin Klingel, Michael Metze, Stephan Stöbe, Karl Titus Hoffmann, Osama Sabri, Federico Piscione, Gennaro Galasso. Loeffler’s Endocarditis: An Integrated Multimodality Approach. Journal of the American Society of Echocardiography. 2020; 33 (12):1427-1441.

Chicago/Turabian Style

Maria Vincenza Polito; Andreas Hagendorff; Rodolfo Citro; Costantina Prota; Angelo Silverio; Elena De Angelis; Karin Klingel; Michael Metze; Stephan Stöbe; Karl Titus Hoffmann; Osama Sabri; Federico Piscione; Gennaro Galasso. 2020. "Loeffler’s Endocarditis: An Integrated Multimodality Approach." Journal of the American Society of Echocardiography 33, no. 12: 1427-1441.

Journal article
Published: 23 September 2020 in Cardiovascular Research
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Aims Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as a global pandemic. SARS-CoV-2 infection can lead to elevated markers of cardiac injury associated with higher risk of mortality. It is unclear whether cardiac injury is caused by direct infection of cardiomyocytes or is mainly secondary to lung injury and inflammation. Here, we investigate whether cardiomyocytes are permissive for SARS-CoV-2 infection. Methods and results Two strains of SARS-CoV-2 infected human induced pluripotent stem cell-derived cardiomyocytes as demonstrated by detection of intracellular double-stranded viral RNA and viral spike glycoprotein expression. Increasing concentrations of viral RNA are detected in supernatants of infected cardiomyocytes, which induced infections in Caco-2 cell lines, documenting productive infections. SARS-CoV-2 infection and induced cytotoxic and proapoptotic effects associated with it abolished cardiomyocyte beating. RNA sequencing confirmed a transcriptional response to viral infection as demonstrated by the up-regulation of genes associated with pathways related to viral response and interferon signalling, apoptosis, and reactive oxygen stress. SARS-CoV-2 infection and cardiotoxicity was confirmed in a 3D cardiosphere tissue model. Importantly, viral spike protein and viral particles were detected in living human heart slices after infection with SARS-CoV-2. Coronavirus particles were further observed in cardiomyocytes of a patient with coronavirus disease 2019. Infection of induced pluripotent stem cell-derived cardiomyocytes was dependent on cathepsins and angiotensin-converting enzyme 2, and was blocked by remdesivir. Conclusion This study demonstrates that SARS-CoV-2 infects cardiomyocytes in vitro in an angiotensin-converting enzyme 2- and cathepsin-dependent manner. SARS-CoV-2 infection of cardiomyocytes is inhibited by the antiviral drug remdesivir.

ACS Style

Denisa Bojkova; Julian U G Wagner; Mariana Shumliakivska; Galip S Aslan; Umber Saleem; Arne Hansen; Guillermo Luxán; Stefan Günther; Minh Duc Pham; Jaya Krishnan; Patrick N Harter; Utz H Ermel; Achilleas S Frangakis; Hendrik Milting; Andreas M Zeiher; Karin Klingel; Jindrich Cinatl; Andreas Dendorfer; Thomas Eschenhagen; Carsten Tschöpe; Sandra Ciesek; Stefanie Dimmeler. SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes. Cardiovascular Research 2020, 116, 2207 -2215.

AMA Style

Denisa Bojkova, Julian U G Wagner, Mariana Shumliakivska, Galip S Aslan, Umber Saleem, Arne Hansen, Guillermo Luxán, Stefan Günther, Minh Duc Pham, Jaya Krishnan, Patrick N Harter, Utz H Ermel, Achilleas S Frangakis, Hendrik Milting, Andreas M Zeiher, Karin Klingel, Jindrich Cinatl, Andreas Dendorfer, Thomas Eschenhagen, Carsten Tschöpe, Sandra Ciesek, Stefanie Dimmeler. SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes. Cardiovascular Research. 2020; 116 (14):2207-2215.

Chicago/Turabian Style

Denisa Bojkova; Julian U G Wagner; Mariana Shumliakivska; Galip S Aslan; Umber Saleem; Arne Hansen; Guillermo Luxán; Stefan Günther; Minh Duc Pham; Jaya Krishnan; Patrick N Harter; Utz H Ermel; Achilleas S Frangakis; Hendrik Milting; Andreas M Zeiher; Karin Klingel; Jindrich Cinatl; Andreas Dendorfer; Thomas Eschenhagen; Carsten Tschöpe; Sandra Ciesek; Stefanie Dimmeler. 2020. "SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes." Cardiovascular Research 116, no. 14: 2207-2215.

Other
Published: 22 August 2020
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Summary Background Patients infected with SARS-CoV-2 exhibit a highly variable clinical course, varying from barely discernible signs of disease, to moderate flu-like symptoms and, occasionally, with life-threatening pneumonia and/or cytokine storm. The relationship between the nasopharyngeal virus load, IgA and IgG antibodies to both the S1-RBD-protein and the N-protein as well the neutralizing activity (NAbs) against SARS-CoV-2 in the blood of moderately afflicted COVID-19 patients has not been investigated longitudinally so far. Methods Several new serological methods to examine these parameters were developed and validated for the longitudinal investigation in three patients of a family which underwent a mild course of COVID-19. Findings We observed that the virus load had almost completely disappeared after about four weeks, whereas serum antibodies showed a contrasting course. IgA levels to S1-RBD-protein and, to a lesser extent, to the N-protein, peaked about three weeks after clinical disease onset but declined soon thereafter. IgG levels rose continuously, reaching a plateau approximately six weeks after disease onset. NAbs in serum reached a peak about four weeks after disease onset but dropped to a lower level about six weeks later. Interpretation Our data establishes associations of virus neutralization and a serological immune response foremost against Sars-CoV-2 S1-RDB-protein in a longitudinal manner.

ACS Style

Bertram Flehmig; Michael Schindler; Natalia Ruetalo; Ramona Businger; Manfred Bayer; Angelika Haage; Thomas Kirchner; Karin Klingel; Andrea Normann; Lutz Pridzun; Despina Tougianidou; Michael B. Ranke. Longitudinal analysis of virus load, serum antibody levels and virus neutralizing activity in vitro in cases with less severe COVID-19. 2020, 1 .

AMA Style

Bertram Flehmig, Michael Schindler, Natalia Ruetalo, Ramona Businger, Manfred Bayer, Angelika Haage, Thomas Kirchner, Karin Klingel, Andrea Normann, Lutz Pridzun, Despina Tougianidou, Michael B. Ranke. Longitudinal analysis of virus load, serum antibody levels and virus neutralizing activity in vitro in cases with less severe COVID-19. . 2020; ():1.

Chicago/Turabian Style

Bertram Flehmig; Michael Schindler; Natalia Ruetalo; Ramona Businger; Manfred Bayer; Angelika Haage; Thomas Kirchner; Karin Klingel; Andrea Normann; Lutz Pridzun; Despina Tougianidou; Michael B. Ranke. 2020. "Longitudinal analysis of virus load, serum antibody levels and virus neutralizing activity in vitro in cases with less severe COVID-19." , no. : 1.

Journal article
Published: 20 July 2020 in European Heart Journal
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A 57-year-old man presented to our outpatient clinic with worsening angina pectoris and dyspnoea, which he reported to have had during the last 7 years. Transthoracic echocardiography revealed thickened left ventricular walls. Speckle tracking echocardiography was consistent with apical sparing and suggestive of cardiac amyloidosis (Panel A).

ACS Style

Phillip Suwalski; Karin Klingel; Ulf Landmesser; Bettina Heidecker. Apical sparing on speckle tracking in Morbus Fabry. European Heart Journal 2020, 41, 3486 -3486.

AMA Style

Phillip Suwalski, Karin Klingel, Ulf Landmesser, Bettina Heidecker. Apical sparing on speckle tracking in Morbus Fabry. European Heart Journal. 2020; 41 (36):3486-3486.

Chicago/Turabian Style

Phillip Suwalski; Karin Klingel; Ulf Landmesser; Bettina Heidecker. 2020. "Apical sparing on speckle tracking in Morbus Fabry." European Heart Journal 41, no. 36: 3486-3486.

Case reports
Published: 17 June 2020 in European Heart Journal - Case Reports
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Background Eosinophilic myocarditis (EM) is rare but accounts for 12–22% of histologically proven acute myocarditis cases. Acute necrotizing EM is considered an aggressive, life-threatening disease which is usually treated by high-dose corticosteroid therapy. Case summary We report the case of a 27-year-old man with acute severe pericarditic chest pain, moderately reduced left ventricular (LV) ejection fraction, and a small pericardial effusion. Troponin I level was highly elevated in the absence of coronary artery disease, leading to the diagnosis of acute myopericarditis. In the absence of blood eosinophilia and despite a negative cardiac magnetic resonance study, LV endomyocardial biopsy revealed an acute necrotizing EM. With conventional antiphlogistic and heart failure therapy, the patient became symptom-free and inflammatory and cardiac necrosis markers as well as LV ejection fraction normalized within days. Thus, in the absence of a systemic hypereosinophilic disorder, there was no need for steroid therapy. Long-term follow-up over 12 months showed sustained normalization of cardiac structure and function. Discussion Acute necrotizing eosinophilic myopericarditis is not always a dreadful cardiac disease. There are idiopathic cases which may quickly resolve without immunosuppression. There seems to be a publication bias towards critical cases.

ACS Style

Michael Kindermann; Nitin Sood; Peter Ehrlich; Karin Klingel. Fast spontaneous recovery from acute necrotizing eosinophilic myopericarditis without need for immunosuppressive therapy: a case report of a 27-year-old male. European Heart Journal - Case Reports 2020, 4, 1 -5.

AMA Style

Michael Kindermann, Nitin Sood, Peter Ehrlich, Karin Klingel. Fast spontaneous recovery from acute necrotizing eosinophilic myopericarditis without need for immunosuppressive therapy: a case report of a 27-year-old male. European Heart Journal - Case Reports. 2020; 4 (4):1-5.

Chicago/Turabian Style

Michael Kindermann; Nitin Sood; Peter Ehrlich; Karin Klingel. 2020. "Fast spontaneous recovery from acute necrotizing eosinophilic myopericarditis without need for immunosuppressive therapy: a case report of a 27-year-old male." European Heart Journal - Case Reports 4, no. 4: 1-5.

Journal article
Published: 20 May 2020 in European Heart Journal
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Philipp Schellhorn; Karin Klingel; Christof Burgstahler. Return to sports after COVID-19 infection. European Heart Journal 2020, 41, 4382 -4384.

AMA Style

Philipp Schellhorn, Karin Klingel, Christof Burgstahler. Return to sports after COVID-19 infection. European Heart Journal. 2020; 41 (46):4382-4384.

Chicago/Turabian Style

Philipp Schellhorn; Karin Klingel; Christof Burgstahler. 2020. "Return to sports after COVID-19 infection." European Heart Journal 41, no. 46: 4382-4384.

Journal article
Published: 28 April 2020 in Cells
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Inhibition of proteasome function by small molecules is highly efficacious in cancer treatment. Other than non-selective proteasome inhibitors, immunoproteasome-specific inhibitors allow for specific targeting of the proteasome in immune cells and the profound anti-inflammatory potential of such compounds revealed implications for inflammatory scenarios. For pathogen-triggered inflammation, however, the efficacy of immunoproteasome inhibitors is controversial. In this study, we investigated how ONX 0914, an immunoproteasome-selective inhibitor, influences CoxsackievirusB3 infection in NMRI mice, resulting in the development of acute and chronic myocarditis, which is accompanied by formation of the immunoproteasome in heart tissue. In groups in which ONX 0914 treatment was initiated once viral cytotoxicity had emerged in the heart, ONX 0914 had no anti-inflammatory effect in the acute or chronic stages. ONX 0914 treatment initiated prior to infection, however, increased viral cytotoxicity in cardiomyocytes, promoting infiltration of myeloid immune cells into the heart. At this stage, ONX 0914 completely inhibited the β5 subunit of the standard cardiac proteasome and less efficiently blocked its immunoproteasome counterpart LMP7. In conclusion, ONX 0914 unselectively perturbs cardiac proteasome function in viral myocarditis of NMRI mice, reduces the capacity of the host to control the viral burden and promotes cardiac inflammation.

ACS Style

Hannah Louise Neumaier; Shelly Harel; Karin Klingel; Ziya Kaya; Arnd Heuser; Meike Kespohl; Antje Beling. ONX 0914 Lacks Selectivity for the Cardiac Immunoproteasome in CoxsackievirusB3 Myocarditis of NMRI Mice and Promotes Virus-Mediated Tissue Damage. Cells 2020, 9, 1093 .

AMA Style

Hannah Louise Neumaier, Shelly Harel, Karin Klingel, Ziya Kaya, Arnd Heuser, Meike Kespohl, Antje Beling. ONX 0914 Lacks Selectivity for the Cardiac Immunoproteasome in CoxsackievirusB3 Myocarditis of NMRI Mice and Promotes Virus-Mediated Tissue Damage. Cells. 2020; 9 (5):1093.

Chicago/Turabian Style

Hannah Louise Neumaier; Shelly Harel; Karin Klingel; Ziya Kaya; Arnd Heuser; Meike Kespohl; Antje Beling. 2020. "ONX 0914 Lacks Selectivity for the Cardiac Immunoproteasome in CoxsackievirusB3 Myocarditis of NMRI Mice and Promotes Virus-Mediated Tissue Damage." Cells 9, no. 5: 1093.