Dilated Cardiomyopathy
2019; Lippincott Williams & Wilkins; Volume: 139; Issue: 20 Linguagem: Inglês
10.1161/circulationaha.119.040037
ISSN1524-4539
Autores Tópico(s)Cardiovascular Effects of Exercise
ResumoHomeCirculationVol. 139, No. 20Dilated Cardiomyopathy Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBDilated CardiomyopathyViral Persistence and a Role for a Viral Proteinase in Human Hearts Kirk U. Knowlton, MD Kirk U. KnowltonKirk U. Knowlton Kirk U. Knowlton, MD, Intermountain Medical Center, Intermountain Heart Institute, 5121 S. Cottonwood St, Murray UT 84107. Email E-mail Address: [email protected] Intermountain Medical Center Heart Institute, Salt Lake City, UT. University of Utah School of Medicine, Salt Lake City. Originally published13 May 2019https://doi.org/10.1161/CIRCULATIONAHA.119.040037Circulation. 2019;139:2339–2341This article is a commentary on the followingEnterovirus Persistence in Cardiac Cells of Patients With Idiopathic Dilated Cardiomyopathy Is Linked to 5' Terminal Genomic RNA-Deleted Viral Populations With Viral-Encoded Proteinase ActivitiesArticle, see p 2326Dilated cardiomyopathy has been linked to genetic abnormalities,1 virus infection, inflammation of the myocardium, and other etiologies.2 Although there is a tendency to ascribe a single etiology to dilated cardiomyopathy, such as either a hereditary or an infectious cause, there is evidence of overlap between genetic and environmental factors that affect the penetrance of the disease. Despite all that has been discovered regarding dilated cardiomyopathy, a clear etiology is identified in only a minority of patients seen in a clinical setting, thus emphasizing the importance of continued investigation into the mechanisms and etiology of this challenging disease.The link between viral infection and cardiomyopathy has been pursued for decades. It is well established that fulminant and acute myocarditis can be caused by viral infection, although the exact incidence is not known. For example, the association between acute myocarditis and coxsackievirus infection dates back to as early as the mid-1950s when advances in viral culture facilitated the isolation of coxsackievirus from individuals with myocarditis.3 Since then, there have been multiple reports of virus being isolated from the myocardium or pericardium of individuals with acute myocarditis.4 With the introduction of polymerase chain reaction, studies have reported the presence of enteroviral RNA in the myocardium of patients with both acute myocarditis and dilated cardiomyopathy.5 However, the prevalence of detectable viral RNA in myocardial tissue varied considerably in different reports,6 leading to speculation as to whether the epidemic nature of infection, the variable rates of infection in different geographic areas, or the varied techniques used to perform the assays accounted for the different detection rates observed. For this reason and others, a cause-effect link between viral infection and dilated cardiomyopathy has been elusive. It is intuitive that acute, viral-mediated myocarditis and the myocardial damage associated with the acute process could ultimately lead to dilated cardiomyopathy. However, when viral genomes were detected in dilated cardiomyopathy, the amount detected was often low. This led to questions regarding whether a very-low-level presence of viral genome could be pathogenic, and if so, through what mechanism.One of the best studied and more consistently identified viruses in myocarditis is coxsackievirus B (CVB). Coxsackieviruses are a serotype of the Enterovirus genus, Picornaviridae family. Enteroviral genomes consist of a single positive-strand RNA that is encapsidated with 4 capsid proteins, including VP1. The viral RNA is ≈7400 nucleotides and includes 5′- and 3′-untranslated regions flanking the monocistronic coding region. The single positive-stranded RNA replicates through a negative-strand intermediate. Efficient generation of the negative-strand RNA is dependent on sequences and RNA 3-dimensional structures that reside in the untranslated regions of the genome. The RNA viral genome is known to mutate more easily than DNA, thus leading to mutated and deleted forms of the viral RNA including the 5′-terminally deleted viral genomes identified in this issue of Circulation.7The viral polyprotein translated from the single reading frame of the viral genome is proteolytically cleaved in cis by viral proteinases 2A and 3C into the respective viral polypeptides. The proteases also cleave a subset of host-cell proteins in trans.4 Of relevance to the article by Bouin et al7 in this issue of Circulation is that proteinase 2A directly cleaves the sarcolemmal protein dystrophin8 and eukaryotic initiation factor-4G. The cleavage of dystrophin disrupts sarcolemmal membrane integrity, and the well-characterized cleavage of eukaryotic initiation factor-4G inhibits cap-dependent translation of host RNA.9 These mechanisms have been thoroughly studied in cell-free systems, in cell culture, and in normal and genetically manipulated mice, but less is known about them in the human heart.10In situ hybridization in mouse models of chronic CVB3 myocarditis have demonstrated that there is a transition from a high positive- to negative-strand RNA ratio in acutely infected mice to predominantly negative-strand RNA in a persistent model of infection.11 In addition, transgenic expression of a replication-defective CVB genome in the cardiac myocyte has been shown to cause cardiomyopathy. This cardiomyopathy is associated with primarily negative-strand RNA in the myocardium without the creation of infectious viruses.12 It has been challenging to detect viral protein expression in these murine models of persistent infection, suggesting that the cardiomyopathy that occurs with viral persistence is related to a low level of virus protein expression that cannot be easily detected, or secondary to potential pathogenic effects from persistence of viral RNA.In the article by Bouin et al,7 the investigators have combined a series of molecular techniques to assess potential mechanisms by which enteroviral infection could contribute to dilated cardiomyopathy in humans. These include a sensitive reverse-transcription polymerase chain reaction assay combined with microarray hybridization, a real-time polymerase chain reaction assay to quantify the amount and ratio of positive- to negative-strand RNA, next-generation deep sequencing for enterovirus detection, and molecular characterization of the viral genomes. These analyses demonstrated that 33% of 24 patients with idiopathic dilated cardiomyopathy had evidence of enterovirus B, a serotype that includes coxsackievirus B. Furthermore, they demonstrated that the enteroviral genomes in all samples included a small percentage of full-length viral genomes, but the largest percentage of viral genomes contained terminal deletions in the 5′-untranslated region that omitted various portions of the 3-dimensional RNA clover-leaf structure that is involved in RNA replication. The presence of these terminal-deletion variants is associated with an increase in the percentage of viral RNA that is negative-strand, suggesting that the terminal deletions may contribute to a decrease in the ratio of positive- to negative-strand RNA that has been linked to viral persistence.It is important to note that, in this issue of Circulation, Bouin et al7 identified mechanisms by which viral genomes with terminal deletions or full-length genomes could contribute to cardiomyopathy by studying RNA transfections into primary human cardiomyocytes. RNA transfection of the 5′-terminally deleted viral RNA genomes did not result in viral genome replication at 24 and 48 hours, but replication of the viral genome was facilitated by a mixture of both full-length and terminally deleted viral genomes. Despite limitations on viral genome replication in human cardiac myocytes, both the terminally deleted and full-length viral genomes were able to be translated and produce viral proteins in a cell-free, in vitro translation system at similar efficiencies. This included expression of the viral capsid protein VP1. However, in primary human cardiomyocytes, only the full-length viral genome was able to express detectable levels of the capsid protein, VP1, and generate infectious virus. In contrast, both the full-length and the terminally deleted viral genomes showed evidence of proteinase 2A proteolytic activity.The mechanisms that are defined by Bouin et al7 are important and provide novel insights into a role for viral proteinases in dilated cardiomyopathy, demonstrating that even in the absence of detectable viral structural proteins by immunoblot, there can be evidence of the proteolytic effect of a viral proteinase on host cell proteins. This may be related to the efficient enzymatic activity of proteinase 2A for some host proteins. Over a long period of time, low-level expression of proteinases 2A and 3C could contribute to dilated cardiomyopathy that has been associated with a viral infection. The experiments also highlight the potential therapeutic benefit that could occur with antiviral-specific therapy, including the use of a proteinase inhibitor. Demonstration of proteinase activity in the intact cardiomyocyte from patients with dilated cardiomyopathy strengthens the argument that viral proteinases may have a detrimental effect in dilated cardiomyopathy. This was approached in data by Bouin et al7 in the figures in the online-only Data Supplement that show evidence of dystrophin disruption in cells that were positive for viral RNA and viral capsid protein VP1.It should be noted that the focus of the article in this issue of Circulation was on the terminal deletion of the 5′-untranslated region.7 However, it is also possible that there are deletions or mutations in other regions of the viral genome in the hearts of patients with dilated cardiomyopathy. Theoretically, this could include deletions in the 3′-untranslated region or mutations in capsid or nonstructural viral proteins that may affect the propensity for cardiomyopathy.In the future, mechanistic insight might also be gained by the transfection of mutated viral genomes in human induced pluripotent stem cell–derived cardiomyocytes.13 This could allow for identification of differences in pathogenic effects based on genetic substrate of the patient from whom the cells were derived.14 It might also provide novel insights into the activation of innate immune mechanisms that can be stimulated by the presence of double-stranded viral RNA.10In addition to coxsackievirus B or other enteroviruses, it will be interesting to see if other viruses such as adenovirus, cytomegalovirus, or other previously identified and unidentified viruses might also persist in dilated cardiomyopathy. Improvements in deep sequencing for viral nucleotides in an unbiased manner may lead to additional insights into the role of virus in dilated cardiomyopathy.In summary, Bouin et al7 have provided another building block toward a complete understanding of the mechanisms that cause dilated cardiomyopathy and provide clues for future therapeutic strategies aimed at the etiology of the disease.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circKirk U. Knowlton, MD, Intermountain Medical Center, Intermountain Heart Institute, 5121 S. Cottonwood St, Murray UT 84107. Email Kirk.[email protected]orgReferences1. McNally EM, Mestroni L. Dilated cardiomyopathy: genetic determinants and mechanisms.Circ Res. 2017; 121:731–748. doi: 10.1161/CIRCRESAHA.116.309396LinkGoogle Scholar2. Cooper LT, Knowlton KU. Myocarditis.Mann DL, Zipes DP, Libby P, Bonnow RO, eds. 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Related articlesEnterovirus Persistence in Cardiac Cells of Patients With Idiopathic Dilated Cardiomyopathy Is Linked to 5' Terminal Genomic RNA-Deleted Viral Populations With Viral-Encoded Proteinase ActivitiesAlexis Bouin, et al. Circulation. 2019;139:2326-2338 May 14, 2019Vol 139, Issue 20 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.119.040037PMID: 31082299 Originally publishedMay 13, 2019 Keywordscardiomyopathy, dilatedEditorialsenteroviruscoxsackievirus infectionsmyocarditiseukaryotic initiation factor-4GPDF download Advertisement
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