Clinical and prognostic significance of detection of enteroviral RNA in the myocardium of patients with myocarditis or dilated cardiomyopathy.

Why, Howard; Meany, Brendan; Richardson, Peter J.; Olsen, E. G. J.; Bowles, Neil E.; Cunningham, Louise; Freeke, C. A.; Archard, L. C.

doi:10.1161/01.cir.89.6.2582

Cited by 243 publications

(141 citation statements)

References 46 publications

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“…These results provide a new basis by which previous detection of enteroviral RNA in cardiomyopathic heart tissue in the absence of infectious virus (4, 60, 92) may be evaluated. Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response, yet long-term persistence in animals and humans has been demonstrated (4,54,60,87,92,95,104,116). The mechanism by which long-term picornavirus persistence occurs in the presence of an intact immune system remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Infectious enteroviruses are frequently isolated from pediatric cases of human myocarditis, but isolation from adult cases of the disease has been exceedingly rare (34,62,88), perhaps because pediatric cases may be more likely to be diagnosed during the acute infection. Despite an apparent absence of infectious enterovirus that can be isolated from adult cardiomyopathies, the detection of positive-and negative-strand enteroviral RNA in approximately 20% of adults with myocarditis or dilated cardiomyopathy by reverse transcription-PCR (RT-PCR) (87,116) as well as the detection of enteroviral protein in cardiomyopathic heart muscle (4,60) provides evidence that enteroviruses can persist and replicate in the heart in the apparent absence of infectious virus. CVB can persist for long periods of time in different strains of mice (22,55,69,95,104).…”

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confidence: 99%

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5′-Terminal Deletions Occur in Coxsackievirus B3 during Replication in Murine Hearts and Cardiac Myocyte Cultures and Correlate with Encapsidation of Negative-Strand Viral RNA

Kim

Tracy

Tapprich

et al. 2005

J Virol

143

251

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Adult human enteroviral heart disease is often associated with the detection of enteroviral RNA in cardiac muscle tissue in the absence of infectious virus. Passage of coxsackievirus B3 (CVB3) in adult murine cardiomyocytes produced CVB3 that was noncytolytic in HeLa cells. Detectable but noncytopathic CVB3 was also isolated from hearts of mice inoculated with CVB3. Sequence analysis revealed five classes of CVB3 genomes with 5 termini containing 7, 12, 17, 30, and 49 nucleotide deletions. Structural changes (assayed by chemical modification) in cloned, terminally deleted 5-nontranslated regions were confined to the cloverleaf domain and localized within the region of the deletion, leaving key functional elements of the RNA intact. Transfection of CVB3 cDNA clones with the 5-terminal deletions into HeLa cells generated noncytolytic virus (CVB3/TD) which was neutralized by anti-CVB3 serum. Encapsidated negative-strand viral RNA was detected using CsCl-purified CVB3/TD virions, although no negative-strand virion RNA was detected in similarly treated parental CVB3 virions. The viral protein VPg was detected on CVB3/TD virion RNA molecules which terminate in 5 CG or 5 AG. Detection of viral RNA in mouse hearts from 1 week to over 5 months postinoculation with CVB3/TD demonstrated that CVB3/TD virus strains replicate and persist in vivo. These studies describe a naturally occurring genomic alteration to an enteroviral genome associated with long-term viral persistence.The six serotypes of the group B coxsackieviruses (CVB1-6) are enteroviruses (Picornaviridae, species HEV-B) (53). The CVB genome is a single-stranded RNA molecule, 7,400 nucleotides (nt) in length, that is encapsidated within an icosahedral shell (74). The 11 viral proteins (83) are encoded by a single open reading frame which is flanked on the 5Ј and 3Ј termini by nontranslated regions (NTRs) (20). The CVB induce numerous human illnesses, including inflammatory heart disease, pancreatitis, and aseptic meningitis and may also trigger the onset of type 1 diabetes (5,31,72,81,82). The CVB were recognized as causes of human heart disease shortly after their description early in the 1950s (26, 27) and remain the enteroviruses most commonly associated with human cardiomyopathies on the grounds of isolation and serology (5,6,34,62,88). Meta-analysis shows an association between enteroviruses and myocarditis in 23% of cases (7), although this association is more variable in cases of dilated cardiomyopathy, a serious disease that often leads to a failing heart (61). Mouse models of CVB-induced pancreatitis (94, 110), myocarditis (45,52,110), myositis (104, 105), and rapid-onset type 1 diabetes (31) which facilitate the study of these diseases have been developed.Enterovirus infections are generally considered to be acute events, with symptoms and virus titers peaking within a few days postinoculation (p.i.) and with virus being cleared by the adaptive immune response (17). However, enterovirus infections can persist under conditions of immunodeficiency (48,51,...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

5′-Terminal Deletions Occur in Coxsackievirus B3 during Replication in Murine Hearts and Cardiac Myocyte Cultures and Correlate with Encapsidation of Negative-Strand Viral RNA

Kim

Tracy

Tapprich

et al. 2005

J Virol

143

251

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“…1,2 It has been demonstrated that the detection of EV RNA in myocardium of DCM patients is associated with adverse prognosis. 3 In particular, the presence of minus-strand EV RNA indicates active viral replication, and plays a role in the development of myocardial injury in DCM. 4 Our previous study has reported that myocardial expression levels of tumor necrosis factor-a (TNF-a) and EV RNA were increased in patients with DCM regardless of etiology of left ventricular (LV) dysfunction.…”

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confidence: 99%

Toll-like receptor 4 is expressed with enteroviral replication in myocardium from patients with dilated cardiomyopathy

Satoh

Nakamura

Akatsu

et al. 2004

Laboratory Investigation

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Expressions of innate immune response proteins, most notably proinflammatory cytokines, against enteroviral (EV) infection have been documented in the heart of human dilated cardiomyopathy (DCM). Toll-like receptor 4 (TLR4) activates signaling pathways leading to the expression of proinflammatory cytokines implicated the etiology of DCM. We sought to determine whether EV replication activates TLR4-dependent immune response in myocardium obtained from patients with DCM. Endomyocardial biopsy tissues were obtained from 56 patients with DCM and 10 controls. Levels of plus-and minus-strand EV RNA and TLR4 mRNA were measured by real-time RT-PCR. Immunohistochemical analysis was performed to identify the cellular source of EV capsid protein VP1 and TLR4. Both plus-and minus-strand EV RNA were detected in 19 DCM patients (34%). Neither strand of EV RNA was detected in controls. TLR4 mRNA levels were higher in DCM patients than in controls (Po0.001). A positive correlation was found between TLR4 levels and each strand type of EV RNA in EV RNApositive patients (plus-strand vs TLR4: r ¼ 0.69, Po0.001; minus-strand vs TLR4: r ¼ 0.65, P ¼ 0.002). VP1/TLR4 double staining showed extensive colocalization of VP1 and TLR4 proteins in cytoplasm of cardiac myocytes in myocardium obtained from DCM patients. EV RNA-positive patients showed lower systolic function and larger ventricular volume compared with EV RNA-negative patients left ventricular ejection fraction (LVEF): P ¼ 0.002; left ventricular end-systolic diameter (LVESD): P ¼ 0.004). The DCM subgroup with high TLR4 levels showed lower LVEF and larger LVESD than the subgroup with TLR4 levels (both Po0.001). This study suggests that myocardial expression of TLR4 associates with EV replication in human DCM. EV RNA and TLR4 mRNA levels may correlate with LV dysfunction in DCM. The expression of TLR4 against EV replication may be involved in the pathogenesis of DCM.

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“…Among them, coxsackievirus B3 (CVB3)-a member of the picornavirus family-is one of the most important causes of virus-induced acute or chronic myocarditis in humans (37). The presence of CVB3 in heart tissue of patients with acute myocarditis or dilated cardiomyopathy has been demonstrated, e.g., by detection of virus genome (18) and virus protein (23).…”

mentioning

confidence: 99%

Expression of Immunoregulatory Cytokines by Recombinant Coxsackievirus B3 Variants Confers Protection against Virus-Caused Myocarditis

Henke

Zell

Ehrlich

et al. 2001

J Virol

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Clinical and laboratory investigations have demonstrated the involvement of viruses and bacteria as potential causative agents in cardiovascular disease and have specifically found coxsackievirus B3 (CVB3) to be a leading cause. Experimental data indicate that cytokines are involved in controlling CVB3 replication. Therefore, recombinant CVB3 (CVB3rec) variants expressing the T-helper-1 (T H 1)-specific gamma interferon (IFN-␥) or the T H 2-specific interleukin-10 (IL-10) as well as the control virus CVB3(muIL-10), which produce only biologically inactive IL-10, were established. Coding regions of murine cytokines were cloned into the 5 end of the CVB3 wild type (CVB3wt) open reading frame and were supplied with an artificial viral 3Cpro-specific Q-G cleavage site. Correct processing releases active cytokines, and the concentration of IFN-␥ and IL-10 was analyzed by enzyme-linked immunosorbent assay and bioassays. In mice, CVB3wt was detectable in pancreas and heart tissue, causing massive destruction of the exocrine pancreas as well as myocardial inflammation and heart cell lysis. Most of the CVB3wt-infected mice revealed virus-associated symptoms, and some died within 28 days postinfection. In contrast, CVB3rec variants were present only in the pancreas of infected mice, causing local inflammation with subsequent healing. Four weeks after the first infection, surviving mice were challenged with the lethal CVB3H3 variant, causing casualties in the CVB3wt-and CVB3(muIL-10)-infected groups, whereas almost none of the CVB3(IFN-␥)-and CVB3(IL-10)-infected mice died and no pathological disorders were detectable. This study demonstrates that expression of immunoregulatory cytokines during CVB3 replication simultaneously protects mice against a lethal disease and prevents virus-caused tissue destruction.

show abstract

Clinical and prognostic significance of detection of enteroviral RNA in the myocardium of patients with myocarditis or dilated cardiomyopathy.

Abstract: These data demonstrate that the detection of enterovirus RNA in the myocardium of patients with heart muscle disease at the time of initial investigation is associated with an adverse prognosis and that the presence of enterovirus RNA is an independent predictor of clinical outcome.

Cited by 243 publications

References 46 publications

5′-Terminal Deletions Occur in Coxsackievirus B3 during Replication in Murine Hearts and Cardiac Myocyte Cultures and Correlate with Encapsidation of Negative-Strand Viral RNA

5′-Terminal Deletions Occur in Coxsackievirus B3 during Replication in Murine Hearts and Cardiac Myocyte Cultures and Correlate with Encapsidation of Negative-Strand Viral RNA

Toll-like receptor 4 is expressed with enteroviral replication in myocardium from patients with dilated cardiomyopathy

Expression of Immunoregulatory Cytokines by Recombinant Coxsackievirus B3 Variants Confers Protection against Virus-Caused Myocarditis

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