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Hathcock SF, Mamana J, Keyzer TE, Vollmuth N, Shokri MR, Mauser HD, Correll RN, Lam DW, Kim BJ, Sin J. Transcriptomic analysis of coxsackievirus B3 infection in induced pluripotent stem cell-derived brain-like endothelial cells. J Virol 2025; 99:e0182424. [PMID: 39670741 PMCID: PMC11784093 DOI: 10.1128/jvi.01824-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 10/29/2024] [Indexed: 12/14/2024] Open
Abstract
Viral aseptic meningitis is a neuroinflammatory condition that occurs when viruses gain access to the central nervous system (CNS) and induce inflammation. The blood-brain barrier (BBB) is comprised of brain endothelial cells (BECs) that stringently regulate the passage of molecules, toxins, and pathogens from the circulation into the CNS. Through their unique properties, such as complex tight junctions, reduced rates of endocytosis, expression of efflux transporters, and restricted expression of leukocyte adhesion molecules, the BBB is often able to limit pathogen entry into the brain; however, certain neurotropic pathogens, such as coxsackievirus B3 (CVB3) are able to infect the CNS. We have previously demonstrated that CVB3 can infect and disrupt induced pluripotent stem cell-derived brain-like endothelial cells (iBECs), but the host response to this infection remains unknown. Here, we investigate global host transcriptional changes during CVB3 infection of iBECs using RNA sequencing. We validated our data set by exploring pathways altered by CVB3 using quantitative real-time PCR (qPCR) and enzyme-linked immunosorbent assay of upregulated cytokines and interferon signaling molecules. IMPORTANCE Coxsackievirus B3 (CVB3) is a leading cause of viral aseptic meningitis that can produce severe disease in susceptible individuals. To gain access to the central nervous system, CVB3 must cross central nervous system barriers, such as the blood-brain barrier. Previously, we have shown that CVB3 infects a human stem cell-derived brain-like endothelial cell model. Here, we report the global transcriptome of stem cell-derived brain-like endothelial cells to CVB3 infection and provide proof-of-concept validation of the dataset using molecular biology techniques. These data could inform novel mechanisms of CVB3-mediated blood-brain barrier dysfunction.
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Affiliation(s)
- Sarah F. Hathcock
- Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama, USA
| | - Julia Mamana
- Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama, USA
| | - Taryn E. Keyzer
- Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama, USA
| | - Nadine Vollmuth
- Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama, USA
| | - Mohammad-Reza Shokri
- Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama, USA
| | - Henry D. Mauser
- Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama, USA
| | - Robert N. Correll
- Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama, USA
- Center for Convergent Biosciences and Medicine, The University of Alabama, Tuscaloosa, Alabama, USA
| | - Daryl W. Lam
- Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama, USA
| | - Brandon J. Kim
- Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama, USA
- Center for Convergent Biosciences and Medicine, The University of Alabama, Tuscaloosa, Alabama, USA
- Department of Microbiology, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
- Alabama Life Research Institute, The University of Alabama, Tuscaloosa, Alabama, USA
| | - Jon Sin
- Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama, USA
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Zhao G, Zhang HM, Nasseri AR, Yip F, Telkar N, Chen YT, Aghakeshmiri S, Küper C, Lam W, Yang W, Zhao J, Luo H, McManus BM, Yang D. Heart-specific NFAT5 knockout suppresses type I interferon signaling and aggravates coxsackievirus-induced myocarditis. Basic Res Cardiol 2024; 119:1075-1092. [PMID: 38834767 DOI: 10.1007/s00395-024-01058-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 05/20/2024] [Accepted: 05/23/2024] [Indexed: 06/06/2024]
Abstract
Nuclear factor of activated T cells 5 (NFAT5) is an osmosensitive transcription factor that is well-studied in renal but rarely explored in cardiac diseases. Although the association of Coxsackievirus B3 (CVB3) with viral myocarditis is well-established, the role of NFAT5 in this disease remains largely unexplored. Previous research has demonstrated that NFAT5 restricts CVB3 replication yet is susceptible to cleavage by CVB3 proteases. Using an inducible cardiac-specific Nfat5-knockout mouse model, we uncovered that NFAT5-deficiency exacerbates cardiac pathology, worsens cardiac function, elevates viral load, and reduces survival rates. RNA-seq analysis of CVB3-infected mouse hearts revealed the significant impact of NFAT5-deficiency on gene pathways associated with cytokine signaling and inflammation. Subsequent in vitro and in vivo investigation validated the disruption of the cytokine signaling pathway in response to CVB3 infection, evidenced by reduced expression of key cytokines such as interferon β1 (IFNβ1), C-X-C motif chemokine ligand 10 (CXCL10), interleukin 6 (IL6), among others. Furthermore, NFAT5-deficiency hindered the formation of stress granules, leading to a reduction of important stress granule components, including plakophilin-2, a pivotal protein within the intercalated disc, thereby impacting cardiomyocyte structure and function. These findings unveil a novel mechanism by which NFAT5 inhibits CVB3 replication and pathogenesis through the promotion of antiviral type I interferon signaling and the formation of cytoplasmic stress granules, collectively identifying NFAT5 as a new cardio protective protein.
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Affiliation(s)
- Guangze Zhao
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada
| | - Huifang M Zhang
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada
| | - Ali Reza Nasseri
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada
| | - Fione Yip
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada
| | - Nikita Telkar
- British Columbia Cancer Research Centre, University of British Columbia, Vancouver, Canada
- British Columbia Children's Hospital Research Institute, Vancouver, Canada
| | - Yankuan T Chen
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada
| | - Sana Aghakeshmiri
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada
| | - Christoph Küper
- MSH Medical School Hamburg, IMM Institute for Molecular Medicine, Medical University, Hamburg, Germany
| | - Wan Lam
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
- British Columbia Cancer Research Centre, University of British Columbia, Vancouver, Canada
| | - Wenli Yang
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - James Zhao
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada
| | - Honglin Luo
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada.
| | - Bruce M McManus
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada.
| | - Decheng Yang
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada.
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Machado RS, Tavares FN, Sousa IP. Global landscape of coxsackieviruses in human health. Virus Res 2024; 344:199367. [PMID: 38561065 PMCID: PMC11002681 DOI: 10.1016/j.virusres.2024.199367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 03/28/2024] [Accepted: 03/29/2024] [Indexed: 04/04/2024]
Abstract
Coxsackieviruses-induced infections, particularly in infants and young children, are one of the most important public health issues in low- and middle-income countries, where the surveillance system varies substantially, and these manifestations have been disregarded. They are widespread throughout the world and are responsible for a broad spectrum of human diseases, from mildly symptomatic conditions to severe acute and chronic disorders. Coxsackieviruses (CV) have been found to have 27 identified genotypes, with overlaps in clinical phenotypes between genotypes. In this review, we present a concise overview of the most recent studies and findings of coxsackieviruses-associated disorders, along with epidemiological data that provides comprehensive details on the distribution, variability, and clinical manifestations of different CV types. We also highlight the significant roles that CV infections play in the emergence of neurodegenerative illnesses and their effects on neurocognition. The current role of CVs in oncolytic virotherapy is also mentioned. This review provides readers with a better understanding of coxsackieviruses-associated disorders and pointing the impact that CV infections can have on different organs with variable pathogenicity. A deeper knowledge of these infections could have implications in designing current surveillance and prevention strategies related to severe CVs-caused infections, as well as encourage studies to identify the emergence of more pathogenic types and the etiology of the most common and most severe disorders associated with coxsackievirus infection.
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Affiliation(s)
- Raiana S Machado
- Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Virologia e Parasitologia Molecular, Rio de Janeiro, 21040-900, Brasil; Programa de Pós-Graduação em Medicina Tropical, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, Brasil; Laboratório de Referência Regional em Enteroviroses, Seção de Virologia, Instituto Evandro Chagas, Rodovia BR 316‑ KM 07, S/N Bairro Levilândia, Ananindeua, PA 67030000, Brasil
| | - Fernando N Tavares
- Laboratório de Referência Regional em Enteroviroses, Seção de Virologia, Instituto Evandro Chagas, Rodovia BR 316‑ KM 07, S/N Bairro Levilândia, Ananindeua, PA 67030000, Brasil
| | - Ivanildo P Sousa
- Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Virologia e Parasitologia Molecular, Rio de Janeiro, 21040-900, Brasil.
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Kordi R, Chang AJ, Hicar MD. Seasonal Testing, Results, and Effect of the Pandemic on Coxsackievirus Serum Studies. Microorganisms 2024; 12:367. [PMID: 38399771 PMCID: PMC10893248 DOI: 10.3390/microorganisms12020367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 01/23/2024] [Accepted: 01/24/2024] [Indexed: 02/25/2024] Open
Abstract
Coxsackieviruses (CVs) are common causes of infections and can be life-threatening. Unfortunately, rigorous studies guiding the clinician in interpreting CV serum antibody titer testing is lacking. To explore the epidemiology of circulating CVs and the serological test utility in aiding diagnosis of CV infections in our community, we obtained results of CV immunologic diagnostic tests between 2018 and 2022 from a regional healthcare database. For CV type A, rare individuals had positive CF (complement fixation) tests whereas all 16 individuals with IFA testing showed at least one positive serotype. For CV type B CF testing, 52.2% of 222 patients had at least one serotype positive, with B5 being most common and also the most common with higher titers (14.8% with ≥1:32). We found a significant reduction in seropositivity rate during the pandemic in 2020 compared to 2018, which continued through 2022 (OR: 0.2, 95% CI: 0.08-0.49, p-value < 0.001). During the pandemic, the seasonal pattern of positive tests varied from the pre-pandemic pattern. Testing for CVs was increased after the first year of the pandemic. Overall, the variability by month and seasonal change in our data support that CF testing can be used to identify recent CVB infection.
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Affiliation(s)
- Ramesh Kordi
- Department of Pediatric Infectious Diseases, State University of New York at Buffalo, Buffalo, NY 14203, USA;
| | - Arthur J. Chang
- Division of Pediatric Infectious Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Mark D. Hicar
- Department of Pediatric Infectious Diseases, State University of New York at Buffalo, Buffalo, NY 14203, USA;
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Kloc A, Campbell KS, Espinoza YAU. Detection of Parvovirus B19 genome in human heart tissue samples. BMC Res Notes 2023; 16:239. [PMID: 37775826 PMCID: PMC10542668 DOI: 10.1186/s13104-023-06527-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 09/21/2023] [Indexed: 10/01/2023] Open
Abstract
OBJECTIVE Identifying viral genomes in human heart tissues is critical for disease diagnosis and assessment of cardiovascular damage. Human heart tissue samples obtained during a biopsy procedure are routinely used to test for the presence of viruses, as guided by clinical manifestations and prognosis. Furthermore, heart tissue samples obtained post-mortem or during a cardiac transplant procedure serve as a valuable research tool, as they allow for an in-depth assessment of cardiac pathology that can aid in our understanding of molecular pathways associated with disease. Because viral nucleic acid constitutes only a small portion of each sample's genetic material, appropriate methods are necessary for positive viral genome identification. RESULTS Snap-frozen heart tissue samples obtained either post-mortem or during a cardiac transplant procedure were used to develop conditions for detection of Parvovirus B19. Briefly, total DNA was isolated from the heart tissue under varying conditions. A PCR-based assay with Parvovirus B19 specific primers was implemented to detect the presence of the viral genome, followed by Sanger Sequencing. The mechanical disruption of the heart tissue, as well as the cardiac tissue processing methods, had a significant effect on the DNA quality and the ability to detect the Parvovirus B19 genome.
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Affiliation(s)
- Anna Kloc
- Department of Biology and Environmental Science, University of New Haven, West Haven, CT, USA.
| | - Kenneth S Campbell
- Saha Cardiovascular Research Center, University of Kentucky College of Medicine, Lexington, KY, USA
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Yip F, Lai B, Yang D. Role of Coxsackievirus B3-Induced Immune Responses in the Transition from Myocarditis to Dilated Cardiomyopathy and Heart Failure. Int J Mol Sci 2023; 24:ijms24097717. [PMID: 37175422 PMCID: PMC10178405 DOI: 10.3390/ijms24097717] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/16/2023] [Accepted: 04/20/2023] [Indexed: 05/15/2023] Open
Abstract
Dilated cardiomyopathy (DCM) is a cardiac disease marked by the stretching and thinning of the heart muscle and impaired left ventricular contractile function. While most patients do not develop significant cardiac diseases from myocarditis, disparate immune responses can affect pathological outcomes, including DCM progression. These altered immune responses, which may be caused by genetic variance, can prolong cytotoxicity, induce direct cleavage of host protein, or encourage atypical wound healing responses that result in tissue scarring and impaired mechanical and electrical heart function. However, it is unclear which alterations within host immune profiles are crucial to dictating the outcomes of myocarditis. Coxsackievirus B3 (CVB3) is a well-studied virus that has been identified as a causal agent of myocarditis in various models, along with other viruses such as adenovirus, parvovirus B19, and SARS-CoV-2. This paper takes CVB3 as a pathogenic example to review the recent advances in understanding virus-induced immune responses and differential gene expression that regulates iron, lipid, and glucose metabolic remodeling, the severity of cardiac tissue damage, and the development of DCM and heart failure.
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Affiliation(s)
- Fione Yip
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada
- The Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC V6Z 1Y6, Canada
| | - Brian Lai
- The Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC V6Z 1Y6, Canada
| | - Decheng Yang
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada
- The Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC V6Z 1Y6, Canada
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Rohrbeck M, Hoerr V, Piccini I, Greber B, Schulte JS, Hübner SS, Jeworutzki E, Theiss C, Matschke V, Stypmann J, Unger A, Ho HT, Disse P, Strutz-Seebohm N, Faber C, Müller FU, Ludwig S, Rescher U, Linke WA, Klingel K, Busch K, Peischard S, Seebohm G. Pathophysiological Mechanisms of Cardiac Dysfunction in Transgenic Mice with Viral Myocarditis. Cells 2023; 12:cells12040550. [PMID: 36831217 PMCID: PMC9954433 DOI: 10.3390/cells12040550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/21/2023] [Accepted: 01/30/2023] [Indexed: 02/11/2023] Open
Abstract
Viral myocarditis is pathologically associated with RNA viruses such as coxsackievirus B3 (CVB3), or more recently, with SARS-CoV-2, but despite intensive research, clinically proven treatment is limited. Here, by use of a transgenic mouse strain (TG) containing a CVB3ΔVP0 genome we unravel virus-mediated cardiac pathophysiological processes in vivo and in vitro. Cardiac function, pathologic ECG alterations, calcium homeostasis, intracellular organization and gene expression were significantly altered in transgenic mice. A marked alteration of mitochondrial structure and gene expression indicates mitochondrial impairment potentially contributing to cardiac contractile dysfunction. An extended picture on viral myocarditis emerges that may help to develop new treatment strategies and to counter cardiac failure.
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Affiliation(s)
- Matthias Rohrbeck
- Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, D-48149 Münster, Germany
| | - Verena Hoerr
- Translational Research Imaging Center, Clinic of Radiology, University Hospital Münster, D-48149 Münster, Germany
| | - Ilaria Piccini
- Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, D-48149 Münster, Germany
| | - Boris Greber
- Human Stem Cell Pluripotency Laboratory, Max Planck Institute for Molecular Biomedicine, D-48149 Münster, Germany
- Chemical Genomics Centre of the Max Planck Society, 44227 Dortmund, Germany
| | - Jan Sebastian Schulte
- Institute of Pharmacology and Toxicology, University Hospital Münster, D-48149 Münster, Germany
| | - Sara-Sophie Hübner
- Translational Research Imaging Center, Clinic of Radiology, University Hospital Münster, D-48149 Münster, Germany
| | - Elena Jeworutzki
- Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, D-48149 Münster, Germany
| | - Carsten Theiss
- Department of Cytology, Institute of Anatomy, Ruhr-University Bochum, D-44780 Bochum, Germany
| | - Veronika Matschke
- Department of Cytology, Institute of Anatomy, Ruhr-University Bochum, D-44780 Bochum, Germany
| | - Jörg Stypmann
- Department of Cardiovascular Medicine, Division of Cardiology, University Clinic Münster, 48149 Münster, Germany
| | - Andreas Unger
- Institute of Physiology II, Faculty of Medicine, University of Münster, D-48149 Münster, Germany
| | - Huyen Tran Ho
- Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, D-48149 Münster, Germany
| | - Paul Disse
- Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, D-48149 Münster, Germany
| | - Nathalie Strutz-Seebohm
- Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, D-48149 Münster, Germany
| | - Cornelius Faber
- Translational Research Imaging Center, Clinic of Radiology, University Hospital Münster, D-48149 Münster, Germany
| | - Frank Ulrich Müller
- Institute of Pharmacology and Toxicology, University Hospital Münster, D-48149 Münster, Germany
| | - Stephan Ludwig
- Institute of Virology Münster (IVM), Centre for Molecular Biology of Inflammation (ZMBE), University of Münster, D-48149 Münster, Germany
| | - Ursula Rescher
- Research Group Regulatory Mechanisms of Inflammation, Institute of Medical Biochemistry, Centre for Molecular Biology of Inflammation, University of Muenster, 48149 Muenster, Germany
| | - Wolfgang A. Linke
- Institute of Physiology II, Faculty of Medicine, University of Münster, D-48149 Münster, Germany
| | - Karin Klingel
- Cardiopathology, Institute for Pathology and Neuropathology, University Hospital of Tübingen, D-72076 Tübingen, Germany
| | - Karin Busch
- Institute of Integrative Cell Biology and Physiology, Faculty of Biology, University of Muenster, Schlossplatz 5, 48149 Muenster, Germany
| | - Stefan Peischard
- Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, D-48149 Münster, Germany
- Correspondence: (S.P.); (G.S.); Tel.: +49-(0)-251/83-58255 (S.P.); +49-(0)-251/83-58251 (G.S.); Fax: +49-(0)-251/83-58257 (S.P. & G.S.)
| | - Guiscard Seebohm
- Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, D-48149 Münster, Germany
- Correspondence: (S.P.); (G.S.); Tel.: +49-(0)-251/83-58255 (S.P.); +49-(0)-251/83-58251 (G.S.); Fax: +49-(0)-251/83-58257 (S.P. & G.S.)
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Badrinath A, Bhatta S, Kloc A. Persistent viral infections and their role in heart disease. Front Microbiol 2022; 13:1030440. [PMID: 36504781 PMCID: PMC9730422 DOI: 10.3389/fmicb.2022.1030440] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 11/02/2022] [Indexed: 11/25/2022] Open
Abstract
Viral infections are the culprit of many diseases, including inflammation of the heart muscle, known as myocarditis. Acute myocarditis cases have been described in scientific literature, and viruses, such as parvovirus B19, coxsackievirus B3, or more recently, SARS-CoV-2, were the direct cause of cardiac inflammation. If not treated, myocarditis could progress to dilated cardiomyopathy, which permanently impairs the heart and limits a person's lifespan. Accumulated evidence suggests that certain viruses may persist in cardiac tissue after the initial infection, which could open up the door to reactivation under favorable conditions. Whether this chronic infection contributes to, or initiates, cardiac damage over time, remains a pressing issue in the field of virus-induced heart pathology, and it is directly tied to patients' treatment. Previously, large case studies found that a few viruses: parvovirus B19, coxsackievirus, adenovirus, human herpesvirus 6, cytomegalovirus and Epstein-Barr virus, are most commonly found in human endomyocardial biopsy samples derived from patients experiencing cardiac inflammation, or dilated cardiomyopathy. SARS-CoV-2 infection has also been shown to have cardiovascular consequences. This review examines the role of viral persistence in cardiac inflammation and heart disease, and discusses its implications for patients' outcomes.
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Dhaduk K, Khosla J, Hussain M, Mangaroliya V, Chauhan S, Ashish K, Gupta R, Pal S. COVID-19 vaccination and myocarditis: A review of current literature. World J Virol 2022; 11:170-175. [PMID: 36159608 PMCID: PMC9372786 DOI: 10.5501/wjv.v11.i4.170] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 03/25/2022] [Accepted: 05/23/2022] [Indexed: 02/06/2023] Open
Abstract
Vaccination for coronavirus disease 2019 (COVID-19) is a critical strategy in controlling the current pandemic of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). After widespread COVID-19 vaccine imple-mentation, isolated case reports about myocarditis as a potential adverse reaction started coming. As of November 12, 2021, Centers for Disease Control and Prevention (CDC) has reported 1793 cases of myocarditis or pericarditis among young people with age 12-29 years, most cases have been reported in the male adolescent age group after the second dose of mRNA COVID-19 vaccines. It is very important to monitor the safety standards and adverse reactions of vaccines to effectively implement the vaccination policies. The CDC and the United States Food and Drug Administration actively monitor vaccine-associated adverse reactions a well-known platform such as Vaccine Adverse Event Reporting System. CDC continues to recommend COVID-19 vaccines and booster doses for eligible individuals (age limit according to the type of vaccine) after careful consideration from risk-benefit assessment and favorable outcomes from vaccination. Mechanisms behind COVID-19 vaccine-induced myocarditis are not clear yet but several possibilities such as molecular mimicry between the spike protein of SARS-CoV-2 and self-antigens, immune response to mRNA, and activation of host immunological system, trigger of the pre-existing dysregulated immunological system have been documented in the literature. Overall, data suggests a good prognosis, especially in young patients. In this review article, we cover currently available data on COVID-19 vaccine-related myocarditis incidence, concerns, possible mechanisms of myocarditis, current treatment, and outcome trends, risk vs benefit assessment of COVID-19 vaccination in this current pandemic.
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Affiliation(s)
- Kartik Dhaduk
- Department of Internal Medicine, Geisinger Wyoming Valley Medical Center, Wilkes-Barre, PA 18702, United States
| | - Jagjit Khosla
- Department of Cardiology, University of Oklahoma, Oklahoma, OK 73019, United States
| | - Muzna Hussain
- Department of Internal Medicine, Geisinger Wyoming Valley Medical Center, Wilkes-Barre, PA 18702, United States
| | - Vrunda Mangaroliya
- Department of Internal Medicine, Geisinger Wyoming Valley Medical Center, Wilkes-Barre, PA 18702, United States
| | - Shaylika Chauhan
- Department of Internal Medicine, Geisinger Wyoming Valley Medical Center, Wilkes-Barre, PA 18702, United States
| | - Kumar Ashish
- Department of Internal Medicine, Carolina East Medical Center, North Carolina, NC 28560, United States
| | - Rahul Gupta
- Department of Medicine, Westchester Medical Center, Valhalla, NY 10595, United States
| | - Suman Pal
- Department of Internal Medicine, University of New Mexico, New Mexico, NM 87106, United States
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Ahmed R, Moaddab A, Hussain SW, Viriya G, Graham-Hill S. A Rare Case of Dilated Cardiomyopathy, Focal Segmental Glomerulosclerosis, and Bell’s Palsy in a 29-Year-Old Male After Coxsackievirus Infection. Cureus 2022; 14:e26285. [PMID: 35898376 PMCID: PMC9308950 DOI: 10.7759/cureus.26285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/24/2022] [Indexed: 11/29/2022] Open
Abstract
Dilated cardiomyopathy (DCM) is a severe myocardial disease with diversified etiologies. Coxsackievirus serotype B (CV-B) is a known cause of infectious myocarditis that leads to DCM. The pathogenesis of CV-B myocarditis is complex and involves a combination of tissue destruction from viral proliferation and host immune response. Diagnosis is based on clinical findings and the presence of post-infection elevated titers of IgM antibodies to CV-B. Echocardiography is an important imaging modality that plays a key role in diagnosing DCM. Rare complications of coxsackievirus infection may include facial paralysis and chronic kidney disease with nephrotic syndrome. Here we present a rare case of a 29-year-old-male with recent Bell’s palsy who presented with new-onset heart failure with left ventricular ejection fraction of 5% and focal segmental glomerulosclerosis nephrotic syndrome in the setting of elevated antibodies to CV-B.
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Razzano D, Fallon JT. Myocarditis: somethings old and something new. Cardiovasc Pathol 2019; 44:107155. [PMID: 31760237 DOI: 10.1016/j.carpath.2019.107155] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 09/16/2019] [Accepted: 09/17/2019] [Indexed: 11/29/2022] Open
Abstract
"Since the pathological conditions take place at the cellular level, viral myocarditis and postinfectious autoimmunity can be suggested but not diagnosed clinically. All clinical methods including imaging techniques are misleading if infectious agents are involved. Accurate diagnosis demands simultaneous histologic, immunohistochemical, and molecular biological workup of the tissue. If the primary infectious or immune-mediated causes of the disease are carefully defined by clinical and biopsy-based tools, specific antiviral treatment options in addition to basic symptomatic therapy are available under certain conditions. These may allow a tailored cause-specific treatment that improves symptoms and prognosis of patients with acute and chronic disease." Uwe Kühl; Heinz-Peter SchultheissViral myocarditis.Swiss Medical Weekly. 144():w14010, JAN 2014 DOI:10.4414/smw.2014.14010.
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Affiliation(s)
- Dana Razzano
- New York Medical College at Westchester Medical Center, Valhalla, NY, 10595, USA.
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Lin MS, Tseng YH, Chen MY, Chung CM, Tsai MH, Wang PC, Chang JJ, Chen TH, Lin YS. In-hospital and post-discharge outcomes of pediatric acute myocarditis underwent after high-dose steroid or intravenous immunoglobulin therapy. BMC Cardiovasc Disord 2019; 19:10. [PMID: 30626332 PMCID: PMC6325679 DOI: 10.1186/s12872-018-0981-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 12/17/2018] [Indexed: 12/12/2022] Open
Abstract
Background High-dose steroids and intravenous immunoglobulin (IVIG) are controversial treatments for pediatric patients with acute myocarditis. This study aimed to investigate their efficacies in the Taiwanese pediatric population. Methods This study evaluated 5563 acute myocarditis patients from the Taiwan’s National Health Insurance Research Database and identified 1542 pediatric patients hospitalized for acute myocarditis between January 1, 2001 and December 31, 2011. The exclusion criteria were age of > 11 years, associated cardiovascular comorbidities, autoimmune disease, malignancy before the index hospitalization, extracorporeal membrane oxygenation, intra-aortic balloon pumping, and dual therapy using IVIG and high-dose steroids. Results After 2:1 propensity score matching, we identified 208 subjects without steroid therapy and 104 subjects who received high-dose steroids. The mean age in that cohort was 2.6 ± 2.9 years, and high-dose steroid therapy had no significant effects on major in-hospital complications and post-discharge outcomes. After 2:1 propensity score matching, we identified 178 subjects without IVIG therapy and 89 subjects who received IVIG. The mean age in that cohort was 2.0 ± 2.1 years, and IVIG had no significant effects on the major outcomes. Conclusions The present study revealed that high-dose steroid or IVIG therapy had no significant effects on major in-hospital complications, late heart failure hospitalization, and long-term mortality.
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Affiliation(s)
- Ming-Shyan Lin
- Department of Cardiology, Chiayi Chang Gung Memorial Hospital, No. 6, Sec. West, Chai-Pu Road, Pu-TZ City, Chai Yi Hsien, Taiwan
| | - Yu-Hsiang Tseng
- Department of Cardiology, Chiayi Chang Gung Memorial Hospital, No. 6, Sec. West, Chai-Pu Road, Pu-TZ City, Chai Yi Hsien, Taiwan
| | - Mei-Yen Chen
- Department of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan.,Department of Nursing, Chang Gung University, Taoyuan, Taiwan
| | - Chang-Min Chung
- Department of Cardiology, Chiayi Chang Gung Memorial Hospital, No. 6, Sec. West, Chai-Pu Road, Pu-TZ City, Chai Yi Hsien, Taiwan
| | - Ming-Horng Tsai
- Department of Pediatrics, Chang Gung Memorial Hospital, Yunlin,, Taiwan
| | - Po-Chang Wang
- Department of Cardiology, Chiayi Chang Gung Memorial Hospital, No. 6, Sec. West, Chai-Pu Road, Pu-TZ City, Chai Yi Hsien, Taiwan
| | - Jung-Jung Chang
- Department of Cardiology, Chiayi Chang Gung Memorial Hospital, No. 6, Sec. West, Chai-Pu Road, Pu-TZ City, Chai Yi Hsien, Taiwan
| | - Tien-Hsing Chen
- Department of Cardiology, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Yu-Sheng Lin
- Department of Cardiology, Chiayi Chang Gung Memorial Hospital, No. 6, Sec. West, Chai-Pu Road, Pu-TZ City, Chai Yi Hsien, Taiwan.
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Bejiqi R, Retkoceri R, Maloku A, Mustafa A, Bejiqi H, Bejiqi R. The Diagnostic and Clinical Approach to Pediatric Myocarditis: A Review of the Current Literature. Open Access Maced J Med Sci 2019; 7:162-173. [PMID: 30740183 PMCID: PMC6352488 DOI: 10.3889/oamjms.2019.010] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 12/01/2018] [Accepted: 12/02/2018] [Indexed: 12/25/2022] Open
Abstract
Myocarditis is an inflammatory disease of the myocardium with a broad spectrum of clinical presentations, ranging from mild symptoms to severe heart failure. The course of patients with myocarditis is heterogeneous, varying from partial or full clinical recovery in a few days to advanced low cardiac output syndrome requiring mechanical circulatory support or heart transplantation. Myocarditis is a very heterogeneous disease, especially in the pediatric age group as worldwide disease myocarditis has been defined by the World Health Organization/International Society and Federation of Cardiology as an inflammatory disease of the heart muscle diagnosed by established histological, immunologic, and immunohistological criteria. Pediatric myocarditis remains challenging from the perspectives of diagnosis and management. Multiple etiologies exist, and the majority of cases appear to be related to viral illnesses. Enteroviruses are believed to be the most common cause, although cases related to adenovirus may be more frequent than suspected. The clinical presentation is extremely varied, ranging from asymptomatic to sudden unexpected death. A high index of suspicion is crucial. There is emerging evidence to support investigations such as serum N-terminal B-type natriuretic peptide levels, as well as cardiac magnetic resonance imaging as adjuncts to the clinical diagnosis. In the future, these may reduce the necessity for invasive methods, such as endomyocardial biopsy, which remain the gold standard. Management generally includes supportive care, consisting of cardiac failure medical management, with the potential for mechanical support and cardiac transplantation. Treatments aimed at immunosuppression remain controversial. The paediatrics literature is extremely limited with no conclusive evidence to support or refute these strategies. All these summarised in this article and the listed current literature showed that there is no consensus regarding aetiology, clinical presentation, diagnosis, and management of myocarditis in pediatric patients.
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Affiliation(s)
- Ramush Bejiqi
- Medical School, University of Gjakova, Gjakova, Kosovo.,Pediatric Clinic, University Clinical Center of Kosovo, Prishtina, Kosovo
| | - Ragip Retkoceri
- Pediatric Clinic, University Clinical Center of Kosovo, Prishtina, Kosovo
| | - Arlinda Maloku
- Pediatric Clinic, University Clinical Center of Kosovo, Prishtina, Kosovo
| | - Aferdita Mustafa
- Pediatric Clinic, University Clinical Center of Kosovo, Prishtina, Kosovo
| | - Hana Bejiqi
- Main Center of Family Medicine, Prishtina, Kosovo
| | - Rinor Bejiqi
- Medical School, University of Prishtina, Prishtina, Kosovo
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Dong ZP, Wang Q, Zhang ZJ, Carr MJ, Li D, Shi WF. Murine model of acute myocarditis and cerebral cortical neuron edema induced by coxsackievirus B4. Zool Res 2018; 39:52-57. [PMID: 29511145 PMCID: PMC5869242 DOI: 10.24272/j.issn.2095-8137.2017.056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Globally, coxsackievirus B4 (CV-B4) has been continuously isolated and evidence suggests an association with the development of pancreatitis and type I diabetes. In addition, CV-B4 is also associated with myocarditis and severe central nervous system (CNS) complications, which remain poorly studied and understood. In the present study, we established an Institute for Cancer Research (ICR) mouse model of CV-B4 infection and examined whether CV-B4 infection resulted in a predisposition to myocarditis and CNS infection. We found high survival in both the treatment and control group, with no significant differences in clinical outcomes observed. However, pathological lesions were evident in both brain and heart tissue of the CV-B4-infected mice. In addition, high viral loads were found in the neural and cardiac tissues as early as 2 days post infection. Expressions of IFN-γ and IL-6 in sera were significantly higher in CV-B4-infected mice compared to uninfected negative controls, suggesting the involvement of these cytokines in the development of histopathological lesions. Our murine model successfully reproduced the acute myocarditis and cerebral cortical neuron edema induced by CV-B4, and may be useful for the evaluation of vaccine candidates and potential antivirals against CV-B4 infection.
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Affiliation(s)
- Zhao-Peng Dong
- Key Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong, Taishan Medical University, Taian Shandong 271000, China
- Shanghai Jinshan Center for Disease Control and Prevention, Shanghai 201599, China
| | - Qian Wang
- Key Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong, Taishan Medical University, Taian Shandong 271000, China
- School of Public Health, Taishan Medical University, Taian Shandong 271016, China
| | - Zhen-Jie Zhang
- Key Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong, Taishan Medical University, Taian Shandong 271000, China
| | - Michael J Carr
- Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo 060-8589, Japan
- National Virus Reference Laboratory, School of Medicine, University College Dublin, Dublin 4, Ireland
| | - Dong Li
- School of Public Health, Taishan Medical University, Taian Shandong 271016, China
| | - Wei-Feng Shi
- Key Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong, Taishan Medical University, Taian Shandong 271000, China.
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Cleavage of osmosensitive transcriptional factor NFAT5 by Coxsackieviral protease 2A promotes viral replication. PLoS Pathog 2017; 13:e1006744. [PMID: 29220410 PMCID: PMC5738146 DOI: 10.1371/journal.ppat.1006744] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 12/20/2017] [Accepted: 11/10/2017] [Indexed: 12/16/2022] Open
Abstract
Nuclear factor of activated T cells 5 (NFAT5)/Tonicity enhancer binding protein (TonEBP) is a transcription factor induced by hypertonic stress in the kidney. However, the function of NFAT5 in other organs has rarely been studied, even though it is ubiquitously expressed. Indeed, although NFAT5 was reported to be critical for heart development and function, its role in infectious heart diseases has remained obscure. In this study, we aimed to understand the mechanism by which NFAT5 interferes with infection of Coxsackievirus B3 (CVB3), a major cause of viral myocarditis. Our initial results demonstrated that although the mRNA level of NFAT5 remained constant during CVB3 infection, NFAT5 protein level decreased because the protein was cleaved. Bioinformatic prediction and verification of the predicted site by site-directed mutagenesis experiments determined that the NFAT5 protein was cleaved by CVB3 protease 2A at Glycine 503. Such cleavage led to the inactivation of NFAT5, and the 70-kDa N-terminal cleavage product (p70-NFAT5) exerted a dominant negative effect on the full-length NFAT5 protein. We further showed that elevated expression of NFAT5 to counteract viral protease cleavage, especially overexpression of a non-cleavable mutant of NFAT5, significantly inhibited CVB3 replication. Ectopic expression of NFAT5 resulted in elevated expression of inducible nitric oxide synthase (iNOS), a factor reported to inhibit CVB3 replication. The necessity of iNOS for the anti-CVB3 effect of NFAT5 was supported by the observation that inhibition of iNOS blocked the anti-CVB3 effect of NFAT5. In a murine model of viral myocarditis, we observed that treatment with hypertonic saline or mannitol solution upregulated NFAT5 and iNOS expression, inhibited CVB3 replication and reduced tissue damage in the heart. Taken together, our data demonstrate that the anti-CVB3 activity of NFAT5 is impaired during CVB3 infection due to 2A-mediated cleavage of NFAT5. Thus induction of NFAT5 by hypertonic agents may be a promising strategy for the development of anti-CVB3 therapeutics.
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Sesti-Costa R, Françozo MCS, Silva GK, Proenca-Modena JL, Silva JS. TLR3 is required for survival following Coxsackievirus B3 infection by driving T lymphocyte activation and polarization: The role of dendritic cells. PLoS One 2017; 12:e0185819. [PMID: 28973047 PMCID: PMC5626506 DOI: 10.1371/journal.pone.0185819] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 09/20/2017] [Indexed: 11/21/2022] Open
Abstract
Type B coxsackievirus (CVB) is a common cause of acute and chronic myocarditis, meningitis and pancreatitis, often leading to heart failure and pancreatic deficiency. The polarization of CD4+ T lymphocytes and their cytokine milieu are key factors in the outcome of CVB-induced diseases. Thus, sensing the virus and driving the adaptive immune response are essential for the establishment of a protective immune response. TLR3 is a crucial virus recognition receptor that confers the host with resistance to CVB infection. In the current study, we found that TLR3 expression in dendritic cells plays a role in their activation upon CVB3 infection in vitro, as TLR3-deficient dendritic cells up-regulate CD80 and CD86 to a less degree than WT cells. Instead, they up-regulated the inhibitory molecule PD-L1 and secreted considerably lower levels of TNF-α and IL-10 and a higher level of IL-23. T lymphocyte proliferation in co-culture with CVB3-infected dendritic cells was increased by TLR3-expressing DCs and other cells. Furthermore, in the absence of TLR3, the T lymphocyte response was shifted toward a Th17 profile, which was previously reported to be deleterious for the host. TLR3-deficient mice were very susceptible to CVB3 infection, with increased pancreatic injury and extensive inflammatory infiltrate in the heart that was associated with uncontrolled viral replication. Adoptive transfer of TLR3+ dendritic cells slightly improved the survival of TLR-deficient mice following CVB3 infection. Therefore, our findings highlight the importance of TLR3 signaling in DCs and in other cells to induce activation and polarization of the CD4+ T lymphocyte response toward a Th1 profile and consequently for a better outcome of CVB3 infection. These data provide new insight into the immune-mediated mechanisms by which CVBs are recognized and cleared in order to prevent the development of myocarditis and pancreatitis and may contribute to the design of therapies for enteroviral infections.
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Affiliation(s)
- Renata Sesti-Costa
- Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Marcela Cristina Santiago Françozo
- Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
- Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research GmbH, Hannover, Germany
| | - Grace Kelly Silva
- Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - José Luiz Proenca-Modena
- Department of Genetics, Evolution and Bioagents, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
| | - João Santana Silva
- Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
- * E-mail:
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Wang F, Qiu Y, Zhang HM, Hanson P, Ye X, Zhao G, Xie R, Tong L, Yang D. Heat shock protein 70 promotes coxsackievirus B3 translation initiation and elongation via Akt-mTORC1 pathway depending on activation of p70S6K and Cdc2. Cell Microbiol 2017; 19. [DOI: 10.1111/cmi.12725] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 12/15/2016] [Accepted: 01/01/2017] [Indexed: 12/19/2022]
Affiliation(s)
- Fengping Wang
- Department of Pathology and Laboratory Medicine; University of British Columbia, Center for Heart Lung Innovation, St. Paul's Hospital; Vancouver British Columbia Canada
| | - Ye Qiu
- Department of Pathology and Laboratory Medicine; University of British Columbia, Center for Heart Lung Innovation, St. Paul's Hospital; Vancouver British Columbia Canada
| | - Huifang M. Zhang
- Department of Pathology and Laboratory Medicine; University of British Columbia, Center for Heart Lung Innovation, St. Paul's Hospital; Vancouver British Columbia Canada
| | - Paul Hanson
- Department of Pathology and Laboratory Medicine; University of British Columbia, Center for Heart Lung Innovation, St. Paul's Hospital; Vancouver British Columbia Canada
| | - Xin Ye
- Department of Pathology and Laboratory Medicine; University of British Columbia, Center for Heart Lung Innovation, St. Paul's Hospital; Vancouver British Columbia Canada
| | - Guangze Zhao
- Department of Pathology and Laboratory Medicine; University of British Columbia, Center for Heart Lung Innovation, St. Paul's Hospital; Vancouver British Columbia Canada
| | - Ronald Xie
- Department of Pathology and Laboratory Medicine; University of British Columbia, Center for Heart Lung Innovation, St. Paul's Hospital; Vancouver British Columbia Canada
| | - Lei Tong
- Department of Pathology and Laboratory Medicine; University of British Columbia, Center for Heart Lung Innovation, St. Paul's Hospital; Vancouver British Columbia Canada
| | - Decheng Yang
- Department of Pathology and Laboratory Medicine; University of British Columbia, Center for Heart Lung Innovation, St. Paul's Hospital; Vancouver British Columbia Canada
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Monocytic myeloid-derived suppressor cells from females, but not males, alleviate CVB3-induced myocarditis by increasing regulatory and CD4(+)IL-10(+) T cells. Sci Rep 2016; 6:22658. [PMID: 26939768 PMCID: PMC4778123 DOI: 10.1038/srep22658] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 02/18/2016] [Indexed: 12/23/2022] Open
Abstract
Coxsackievirus group B type 3 (CVB3) is a common etiologic agent of viral myocarditis and often causes sexually dimorphic myocarditis with increased incidence and mortality in male. So far, the underlying mechanism for the high male prevalence is not well elucidated. In this study, we deciphered the role of myeloid-derived suppressor cells (MDSCs) in the gender bias in murine CVB3-induced myocarditis by comparing their frequencies, subsets as well as immune suppressive functions. We found that much more myocardial MDSCs were enriched in infected females than males, with dramatically higher percentage ratio of CD11b+Ly6G-Ly6Chigh monocytic subset (M-MDSCs) to CD11b+Ly6G+Ly6Clow granulocytic subset (G-MDSCs). Interestingly, more potent suppression on T cell proliferation was also evidenced in female-derived M-MDSCs. Consistently, adoptive transfer of female- but not male-derived M-MDSCs efficiently alleviated CVB3-induced myocarditis in male recipient mice, and this protection could be ascribed to the increased induction of regulatory and CD4+IL-10+ T cells. Our study suggested that myocardial MDSCs were distinctively induced not only in quantities but also in phenotypes and immune suppressive functions in CVB3-infected males and females; and female-derived more suppressive M-MDSCs contributed to their insensitivity to CVB3-induced myocarditis.
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Gaaloul I, Riabi S, Harrath R, Hunter T, Hamda KB, Ghzala AB, Huber S, Aouni M. Coxsackievirus B detection in cases of myocarditis, myopericarditis, pericarditis and dilated cardiomyopathy in hospitalized patients. Mol Med Rep 2014; 10:2811-8. [PMID: 25241846 PMCID: PMC4227425 DOI: 10.3892/mmr.2014.2578] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2013] [Accepted: 05/21/2014] [Indexed: 11/21/2022] Open
Abstract
Coxsackieviruses B (CV-B) are known as the most common viral cause of human heart infections. The aim of the present study was to assess the potential role of CV-B in the etiology of infectious heart disease in hospitalized patients. The present study is based on blood, pericardial fluid and heart biopsies from 102 patients and 100 control subjects. All of the samples were examined for the detection of specific enteroviral genome using the reverse transcription polymerase chain reaction (RT-PCR) and sequence analysis. Immunohistochemical investigations for the detection of the enteroviral capsid protein, VP1, from the biopsies were performed. The samples were cultured on confluent KB monolayer cell line for possible virus isolation. The epidemiological data were also collected. CV-B was detected in 28 of the 102 patients. The sequence analysis demonstrated that 27 strains were identical to CV-B3 and only one strain was identical to CV-B1. Furthermore, VP1 in the heart biopsies was detected in enterovirus-positive cases, as revealed by RT-PCR. Pericarditis infection was more frequent than myocarditis (P<0.05) or myopericarditis (P=0.05). The epidemiological data demonstrate that CV-B heart infections occur mainly during autumn and winter, and young male adults are more susceptible than adolescents or adults (P<0.5). The present findings demonstrate a higher prevalence of viral heart infections, suggesting that CV-B may significantly contribute to heart infections.
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Affiliation(s)
- Imed Gaaloul
- Laboratory of Transmissible Diseases LR99-ES27, Faculty of Pharmacy, Monastir 5000, Tunisia
| | - Samira Riabi
- Laboratory of Transmissible Diseases LR99-ES27, Faculty of Pharmacy, Monastir 5000, Tunisia
| | - Rafik Harrath
- Laboratory of Transmissible Diseases LR99-ES27, Faculty of Pharmacy, Monastir 5000, Tunisia
| | - Timothy Hunter
- DNA Microarray Facility, 305 Health Science Research Facility, University of Vermont, Burlington, VT 05405, USA
| | - Khaldoun B Hamda
- Department of Cardiology, University Hospital Fattouma Bourguiba, Monastir 5000, Tunisia
| | - Assia B Ghzala
- Department of Cardiology, University Hospitals Farhat Hached and Sahloul, Sousse 4054, Tunisia
| | - Sally Huber
- Department of Pathology, University of Vermont, Burlington, VT 05405, USA
| | - Mahjoub Aouni
- Laboratory of Transmissible Diseases LR99-ES27, Faculty of Pharmacy, Monastir 5000, Tunisia
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Mucosal immunization with high-mobility group box 1 in chitosan enhances DNA vaccine-induced protection against coxsackievirus B3-induced myocarditis. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2013; 20:1743-51. [PMID: 24027262 DOI: 10.1128/cvi.00466-13] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Coxsackievirus B3 (CVB3), a small single-stranded RNA virus, belongs to the Picornaviridae family. Its infection is the most common cause of myocarditis, with no vaccine available. Gastrointestinal mucosa is the major entry port for CVB3; therefore, the induction of local immunity in mucosal tissues may help control initial viral infections and alleviate subsequent myocardial injury. Here we evaluated the ability of high-mobility group box 1 (HMGB1) encapsulated in chitosan particles to enhance the mucosal immune responses induced by the CVB3-specific mucosal DNA vaccine chitosan-pVP1. Mice were intranasally coimmunized with 4 doses of chitosan-pHMGB1 and chitosan-pVP1 plasmids, at 2-week intervals, and were challenged with CVB3 4 weeks after the last immunization. Compared with chitosan-pVP1 immunization alone, coimmunization with chitosan-pHMGB1 significantly (P < 0.05) enhanced CVB3-specific fecal secretory IgA levels and promoted mucosal T cell immune responses. In accordance, reduced severity of myocarditis was observed in coimmunized mice, as evidenced by significantly (P < 0.05) reduced viral loads, decreased myocardial injury, and increased survival rates. Flow cytometric analysis indicated that HMGB1 enhanced dendritic cell (DC) recruitment to mesenteric lymph nodes and promoted DC maturation, which might partly account for its mucosal adjuvant effect. This strategy may represent a promising approach to candidate vaccines against CVB3-induced myocarditis.
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Steinke K, Sachse F, Ettischer N, Strutz‐Seebohm N, Henrion U, Rohrbeck M, Klosowski R, Wolters D, Brunner S, Franz W, Pott L, Munoz C, Kandolf R, Schulze‐Bahr E, Lang F, Klingel K, Seebohm G. Coxsackievirus B3 modulates cardiac ion channels. FASEB J 2013; 27:4108-21. [DOI: 10.1096/fj.13-230193] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Katja Steinke
- Institute for Genetics of Heart Diseases (IfGH)Department of Cardiovascular MedicineUniversity Hospital MünsterMünsterGermany
- Department of Biochemistry ICation Channel GroupRuhr University BochumBochumGermany
| | - Frank Sachse
- Nora Eccles Cardiovascular Research and Training InstituteUniversity of UtahSalt Lake CityUtahUSA
- Department of BioengineeringUniversity of UtahSalt Lake CityUtahUSA
| | - Nicole Ettischer
- Department of Molecular PathologyUniversity Hospital of TuebingenTuebingenGermany
| | - Nathalie Strutz‐Seebohm
- Institute for Genetics of Heart Diseases (IfGH)Department of Cardiovascular MedicineUniversity Hospital MünsterMünsterGermany
| | - Ulrike Henrion
- Institute for Genetics of Heart Diseases (IfGH)Department of Cardiovascular MedicineUniversity Hospital MünsterMünsterGermany
- Department of Physiology IUniversity of TuebingenTuebingenGermany
| | - Matthias Rohrbeck
- Institute for Genetics of Heart Diseases (IfGH)Department of Cardiovascular MedicineUniversity Hospital MünsterMünsterGermany
| | - Rafael Klosowski
- Department of Analytical ChemistryRuhr University BochumBochumGermany
| | - Dirk Wolters
- Department of Analytical ChemistryRuhr University BochumBochumGermany
| | - Stefan Brunner
- Department of Biochemistry ICation Channel GroupRuhr University BochumBochumGermany
| | - Wolfgang‐Michael Franz
- Department of Internal Medicine ILudwig Maximilians UniversityCampus GrosshadernMunichGermany
| | - Lutz Pott
- Department of Cellular PhysiologyRuhr University BochumBochumGermany
| | - Carlos Munoz
- Department of Physiology IUniversity of TuebingenTuebingenGermany
| | - Reinhard Kandolf
- Nora Eccles Cardiovascular Research and Training InstituteUniversity of UtahSalt Lake CityUtahUSA
- Department of BioengineeringUniversity of UtahSalt Lake CityUtahUSA
| | - Eric Schulze‐Bahr
- Institute for Genetics of Heart Diseases (IfGH)Department of Cardiovascular MedicineUniversity Hospital MünsterMünsterGermany
| | - Florian Lang
- Department of Physiology IUniversity of TuebingenTuebingenGermany
| | - Karin Klingel
- Department of Molecular PathologyUniversity Hospital of TuebingenTuebingenGermany
| | - Guiscard Seebohm
- Institute for Genetics of Heart Diseases (IfGH)Department of Cardiovascular MedicineUniversity Hospital MünsterMünsterGermany
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Abstract
Apoptosis is a tightly regulated physiologic process of programmed cell death that occurs in both normal and pathologic tissues. Numerous in vitro or in vivo studies have indicated that cardiomyocyte death through apoptosis and necrosis is a primary contributor to the progression of anthracycline-induced cardiomyopathy. There are now several pieces of evidence to suggest that activation of intrinsic and extrinsic apoptotic pathways contribute to anthracycline-induced apoptosis in the heart. Novel strategies were developed to address a wide variety of cardiotoxic mechanisms and apoptotic pathways by which anthracycline influences cardiac structure and function. Anthracycline-induced apoptosis provides a very valid representation of cardiotoxicity in the heart, an argument which has implications for the most appropriate animal models of damaged heart plus diverse pharmacological effects. In this review we describe various aspects of the current understanding of apoptotic cell death triggered by anthracycline. Differences in the sensitivity to anthracycline-induced apoptosis between young and adult hearts are also discussed.
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Affiliation(s)
- Jianjian Shi
- Riley Heart Research Center, Wells Center for Pediatric Research, Department of Pediatrics Indiana University, School of Medicine, Indianapolis, Indiana, USA
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Abstract
Paediatric myocarditis remains challenging from the perspectives of diagnosis and management. Multiple aetiologies exist and the majority of cases appear to be related to viral illnesses. Enteroviruses are believed to be the most common cause, although cases related to adenovirus may be more frequent than suspected. The clinical presentation is extremely varied, ranging from asymptomatic to sudden unexpected death. A high index of suspicion is crucial. There is emerging evidence to support investigations such as serum N-terminal B-type natriuretic peptide levels, as well as cardiac magnetic resonance imaging as adjuncts to the clinical diagnosis. In the future, these may reduce the necessity for invasive methods, such as endomyocardial biopsy, which remain the gold standard. Management generally includes supportive care, consisting of cardiac failure medical management, with the potential for mechanical support and cardiac transplantation. Treatments aimed at immunosuppression remain controversial. The paediatric literature is extremely limited with no conclusive evidence to support or refute these strategies. This article summarises the current literature regarding aetiology, clinical presentation, diagnosis, and management of myocarditis in paediatric patients.
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Hsiao HJ, Hsia SH, Wu CT, Lin JJ, Chung HT, Hwang MS, Su WJ, Chang YS. Clinical presentation of pediatric myocarditis in Taiwan. Pediatr Neonatol 2011; 52:135-9. [PMID: 21703554 DOI: 10.1016/j.pedneo.2011.03.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2010] [Revised: 05/27/2010] [Accepted: 07/13/2010] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND The purposes of this study were to characterize the symptoms and signs of children with myocarditis at the time of presentation to the hospital and to identify the predictors of death. METHODS This was a 5-year retrospective study in a tertiary hospital. We collected demographic data and clinical symptoms and signs when children with myocarditis presented at the hospital. The outcome for patient was classified as either survival or death, and the predictors of death were identified. RESULTS Over the 5-year period, 27 children (14 boys and 13 girls) met the definition of clinical myocarditis. The mean age of the myocarditis patients was 9.1±5.1 years (range, 0.08-17.9 years), and the maximum age was 10-12 years. The most common presentation was gastrointestinal symptoms. We used extracorporeal membrane oxygenation on nine (33%) children, and pacemaker was implanted in eight (30%). Six (22%) children died in this study, and only one of them was younger than 6 years. The poor prognosis predictors were gastrointestinal symptoms, hepatomegaly, and hypotension. CONCLUSIONS Pediatric myocarditis presents primarily with gastrointestinal symptoms in Taiwan. Careful check of heart rhythm may provide a useful objective marker of myocarditis. The predictors of a poor prognosis were gastrointestinal symptoms, hepatomegaly, and hypotension.
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Affiliation(s)
- Hsiang-Ju Hsiao
- Department of Pediatrics, Chang Gung Memorial Hospital at Keelung, Chang Gung University College of Medicine, Taoyuan, Taiwan
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Wei L, Caldwell RL, Payne RM. 2010 Riley Heart Center Symposium on Cardiac Development: cardiomyocyte injury and protection. Pediatr Cardiol 2011; 32:255-7. [PMID: 21327629 PMCID: PMC3198830 DOI: 10.1007/s00246-011-9921-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2011] [Accepted: 02/04/2011] [Indexed: 11/25/2022]
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26
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Riad A, Westermann D, Zietsch C, Savvatis K, Becher PM, Bereswill S, Heimesaat MM, Lettau O, Lassner D, Dörner A, Poller W, Busch M, Felix SB, Schultheiss HP, Tschöpe C. TRIF is a critical survival factor in viral cardiomyopathy. THE JOURNAL OF IMMUNOLOGY 2011; 186:2561-70. [PMID: 21239721 DOI: 10.4049/jimmunol.1002029] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
TRIF is a member of the innate immune system known to be involved in viral recognition and type I IFN activation. Because IFNs are thought to play an important role in viral myocarditis, we investigated the role of TRIF in induced myocarditis in mice. Whereas C57BL/6 (wild-type) mice showed only mild myocarditis, including normal survival postinfection with coxsackievirus group B serotype 3 (CVB3), infection of TRIF(-/-) mice led to the induction of cardiac remodeling, severe heart failure, and 100% mortality (p < 0.0001). These mice showed markedly reduced virus control in cardiac tissues and cardiomyocytes. This was accompained with dynamic cardiac cytokine activation in the heart, including a suppression of the antiviral cytokine IFN-β in the early viremic phase. TRIF(-/-) myocytes displayed a TLR4-dependent suppression of IFN-β, and pharmacological treatment of CVB3-infected TRIF(-/-) mice with murine IFN-β led to improved virus control and reduced cardiac inflammation. Additionally, this treatment within the viremic phase of myocarditis showed a significant long-term outcome indexed by reduced mortality (20 versus 100%; p < 0.001). TRIF is essential toward a cardioprotection against CVB3 infection.
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Affiliation(s)
- Alexander Riad
- Department of Cardiology and Pulmology, University of Griefswald, 17475 Greifswald, Germany.
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27
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Abstract
Children frequently present to a pediatric office or emergency department with the complaint of chest pain. Between 0.3% and 0.6% of visits to a pediatric emergency department are for chest pain. Unlike adult patients with chest pain, most studies have shown that children with chest pain rarely have serious organic pathology. Infrequently, a child with chest pain will present with significant distress and require immediate resuscitation. Most children with chest pain are not in extremis, and for many, the pain is not acute in nature.
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Affiliation(s)
- Steven M Selbst
- Division of Pediatric Emergency Medicine Jefferson Medical College Nemours/A.I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, DE 19803-3607, USA.
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28
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Abstract
Myocarditis and pericarditis are rare but important causes of pediatric chest pain. The diagnostic criteria, clinical course, causes, and treatment of myocarditis is reviewed. There is particular attention to the relationship of myocarditis with dilated cardiomyopathy. Supportive therapy remains the standard of care for pump dysfunction. The identification and treatment of pericarditis with associated large pericardial effusion can be lifesaving. This article reviews the important clinical features that might lead the clinician to diagnose either myocarditis or pericarditis and thus separate the few patients with either of these conditions from the legions of children with noncardiac chest pain.
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29
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Al-Biltagi M, Issa M, Hagar HA, Abdel-Hafez M, Aziz NA. Circulating cardiac troponins levels and cardiac dysfunction in children with acute and fulminant viral myocarditis. Acta Paediatr 2010; 99:1510-6. [PMID: 20491698 DOI: 10.1111/j.1651-2227.2010.01882.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVES To study the correlation between cardiac troponins blood levels and degrees of cardiac dysfunction in children with acute and fulminant viral myocarditis and to study their prognostic role in predicting the outcomes and risk of having dilated cardiomyopathy. METHODOLOGY Troponin I & T blood levels were measured in 65 children with acute or fulminant viral myocarditis. The cardiac functions of RV & LV were assessed by Doppler echocardiography. RESULTS The levels of cTnI & CTnT were significantly higher in patients with fulminant myocarditis than in controls and children with acute myocarditis (p < 0.05 & <0.001* respectively). The cardiac functions were significantly impaired in fulminant myocarditis than in acute myocarditis (p < 0.001*). There were negative correlations between the cardiac troponins levels and the cardiac functions measured by echocardiography in children with acute and fulminant myocarditis. There were 3 deaths (7.5%), and 10 (25%) children developed dilated cardiomyopathy in acute myocarditis while there were eight deaths (32%) and one patient (4%) who developed dilated cardiomyopathy in fulminant myocarditis group. CONCLUSION Cardiac troponins levels can predict the severity of myocarditis and the prognosis on the short-term level. Fulminant myocarditis was associated with higher levels of both cTn I & cTn T than acute myocarditis. Despite that fulminant myocarditis has a more aggressive course, the risk of developing cardiomyopathy was less than in acute myocarditis.
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30
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Durani Y, Egan M, Baffa J, Selbst SM, Nager AL. Pediatric myocarditis: presenting clinical characteristics. Am J Emerg Med 2009; 27:942-7. [PMID: 19857412 DOI: 10.1016/j.ajem.2008.07.032] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2008] [Revised: 07/23/2008] [Accepted: 07/24/2008] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE The objective of the study was to characterize the clinical profiles of pediatric patients with acute myocarditis and dilated cardiomyopathy (DCM) before diagnosis. METHODS A retrospective cross-sectional study was conducted to identify patients with myocarditis and DCM who presented over a 10-year span at 2 tertiary care pediatric hospitals. Patients were identified based on the International Classification of Diseases, Ninth Revision, diagnostic codes. RESULTS A total of 693 charts were reviewed. Sixty-two patients were enrolled in the study. Twenty-four (39%) patients had a final diagnosis of myocarditis, and 38 (61%) had DCM. Of the 62 patients initially evaluated, 10 were diagnosed with myocarditis or DCM immediately, leaving 52 patients who required subsequent evaluation before a diagnosis was determined. Study patients had a mean age of 3.5 years, 47% were male, and 53% were female. Common primary complaints were shortness of breath, vomiting, poor feeding, upper respiratory infection (URI), and fever. Common examination findings were tachypnea, hepatomegaly, respiratory distress, fever, and abnormal lung examination result. Sixty-three percent had cardiomegaly on chest x-ray, and all had an abnormal electrocardiogram results. CONCLUSIONS These data suggest children with acute myocarditis and DCM most commonly present with difficulty breathing. Myocarditis and DCM may mimic other respiratory or viral illnesses, but hepatomegaly or the finding of cardiomegaly and an abnormal electrocardiogram result may help distinguish these diagnoses from other more common pediatric illnesses.
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Affiliation(s)
- Yamini Durani
- Division of Emergency Medicine, Department of Pediatrics, Alfred I. duPont Hospital for Children, Thomas Jefferson University, Wilmington, DE 19899, USA.
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31
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Field LJ, Shou W, Caldwell RL. 2008 Riley Heart Center Symposium on cardiac development: growth and morphogenesis of the ventricular wall. Pediatr Cardiol 2009; 30:577-9. [PMID: 19340479 DOI: 10.1007/s00246-009-9407-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2009] [Accepted: 02/26/2009] [Indexed: 11/30/2022]
Affiliation(s)
- Loren J Field
- The Riley Heart Center, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
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32
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Savón C, Acosta B, Valdés O, Goyenechea A, Gonzalez G, Piñón A, Más P, Rosario D, Capó V, Kourí V, Martínez PA, Marchena JJ, González G, Rodriguez H, Guzmán MG. A myocarditis outbreak with fatal cases associated with adenovirus subgenera C among children from Havana City in 2005. J Clin Virol 2008; 43:152-7. [PMID: 18657472 DOI: 10.1016/j.jcv.2008.05.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2008] [Revised: 04/01/2008] [Accepted: 05/09/2008] [Indexed: 11/19/2022]
Abstract
BACKGROUND Among multiple causes of acute myocarditis, viral infection, especially that due to enteroviruses and adenoviruses, is the leading cause. In the summer 2005 an outbreak of a febrile syndrome accompanied by acute cardiac decompensation occurred in infants and young children in Havana City. Eleven patients had a rapid evolution of disease and there were 8 fatalities from cardiac failure secondary to myocarditis. OBJECTIVE The aim of the present study was to determine the etiological agent responsible for this outbreak. STUDY DESIGN Children admitted to the pediatric hospitals of Havana City from July 3 to August 2 with this clinical presentation were studied. Forty samples of necropsy tissue, cerebrospinal fluid, stools and serum were tested by molecular methods for 14 respiratory viruses, 6 herpesviruses and generic enteroviruses and flavirus and alfaviruses. Viral isolation was performed in A-549 cells. Isolated viruses were typed by sequence analysis. RESULTS Adenovirus genome was detected in 6 of the 8 fatal cases-the lungs in 5 (63%) and the myocardium in 3 (37%). In two fatal cases, viral genome was detected in both lung and myocardium. Adenovirus was isolated in five fatal cases. In all three non-fatal cases, adenovirus genome was detected and adenovirus was isolated into two. Sequence analysis showed that adenovirus type 5 was the only isolate from fatal cases and adenovirus 1 the only isolate in non-fatal cases. No other viruses were found by PCR or isolation techniques. CONCLUSION Adenovirus was the etiologic agent implicated in this myocarditis outbreak and adenovirus type 5 was associated with fatal outcome.
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Affiliation(s)
- Clara Savón
- Tropical Medicine Institute Pedro Kourí, Havana, Cuba.
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Affiliation(s)
- Tammy L. Uhl
- Tammy L. Uhl is a pediatric critical care clinical nurse specialist at Brenner Children’s Hospital, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina
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Brunetti L, DeSantis ERH. Treatment of viral myocarditis caused by coxsackievirus B. Am J Health Syst Pharm 2008; 65:132-7. [DOI: 10.2146/ajhp060586] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Affiliation(s)
- Luigi Brunetti
- Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ; at the time of writing he was Specialized Resident, Drug Information Service, Ernest Mario School of Pharmacy, Rutgers University
| | - Evelyn R. Hermes DeSantis
- Drug Information Service, Robert Wood Johnson University Hospital, New Brunswick, NJ, and Clinical Associate Professor, Ernest Mario School of Pharmacy, Rutgers University
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Liu Z, Yuan J, Yanagawa B, Qiu D, McManus BM, Yang D. Coxsackievirus-induced myocarditis: new trends in treatment. Expert Rev Anti Infect Ther 2007; 3:641-50. [PMID: 16107202 DOI: 10.1586/14787210.3.4.641] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Myocarditis is a common inflammatory heart disease in children and young adults that may result in chronically dilated cardiomyopathy. Coxsackievirus B3 is the major etiologic agent of this disease. Current treatments for patients with viral myocarditis are almost entirely supportive. In recent years, some promising therapeutic candidates have emerged, including novel treatments and improvements of existing drugs. Among these are molecules that specially target virus entry, such as pleconaril, WIN 54954 and CAR-Fc; nucleic acid-based antiviral agents that inhibit viral translation and/or transcription, such as antisense oligodeoxynucleotide and short interfering RNA; and immunomodulatory agents that augment the host-protective immune responses to effectively clear viruses from target tissues, including interferons and immunoglobulins. In addition, certain new antiviral strategies, still in the early stages, include modulation of signal transduction pathways responsible for viral replication using enzyme inhibitors, which have revealed potential therapeutic targets for viral myocarditis. Finally, the progress in cellular cardiomyoplasty for end-stage therapy, in particular the preliminary clinical trials, is also discussed with respect to its potential future application.
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Affiliation(s)
- Zhen Liu
- Department of Pathology & Laboratory Medicine, James Hogg iCAPTURE Centre for Cardiovascular & Pulmonary Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada
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Roberts SS, Leeborg N, Loriaux M, Johnson FL, Huang ML, Stenzel P, Thiede C, Godder KT. Acute graft-versus-host disease of the heart. Pediatr Blood Cancer 2006; 47:624-8. [PMID: 16206193 DOI: 10.1002/pbc.20621] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Graft-versus-host disease (GVHD) is a frequent cause of morbidity and mortality after bone marrow transplantation. Acute GVHD most commonly involves the skin, gastrointestinal tract, and liver. Involvement of other organ systems is rare and remains controversial. We report a patient with GVHD who suffered a fatal ventricular arrhythmia shortly after bone marrow transplantation. Autopsy of the heart showed lymphocyte infiltration. Investigations for cardiotrophic viruses were negative, and chimerism analysis of the heart showed both donor and recipient DNA. We conclude that the cause of death was possibly graft-versus-host disease of the heart. A review of the literature revealed a total of 14 cases of possible cardiac GVHD. All but one of the reported cases have occurred in pediatric patients and six of those patients died, suggesting that this may be a rare but frequently fatal complication of pediatric allogeneic stem cell transplant.
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Affiliation(s)
- Stephen S Roberts
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, USA.
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37
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Esfandiarei M, Suarez A, Amaral A, Si X, Rahmani M, Dedhar S, McManus BM. Novel role for integrin-linked kinase in modulation of coxsackievirus B3 replication and virus-induced cardiomyocyte injury. Circ Res 2006; 99:354-61. [PMID: 16840719 DOI: 10.1161/01.res.0000237022.72726.01] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Viral myocarditis is a major cause of sudden cardiac death in children and young adults. Among viruses, coxsackievirus B3 (CVB3) is the most common agent for myocarditis. Recently, more consideration has been given to the role of signaling pathways in pathogenesis of enteroviral myocarditis, providing new platform for identifying a new potential therapeutic target for this, so far, incurable disease. Previously, we reported on the role of the protein kinase-B/Akt in CVB3 replication and virus-induced cell injury. Here, we report on regulation of virus-induced Akt activation by the integrin-linked kinase in infected mouse cardiomyocytes and HeLa cells. This study also presents the first observation that inhibition of ILK in CVB3-infected cells significantly improves the viability of infected cells, while blocking viral replication and virus release. Complementary experiments using a constitutively active form of Akt1 revealed that the observed protective effect of ILK inhibition is dependent on the associated downregulation of virus-induced Akt activation. To our knowledge, this is the first report of such beneficial effects of ILK inhibition in a viral infection model and conveys new insights in our efforts to characterize a novel therapeutic target for treatment of enteroviral myocarditis.
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Affiliation(s)
- Mitra Esfandiarei
- The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research/Providence Health Care Research Institute, Vancouver, British Columbia, Canada
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