Induction of Nrg1 and ErbB4 Is Specific to Virus Induced Injury of the Myocardium and May be Detected during Pathogenesis of Viral Myocarditis as Blood‐Based Biomarkers for Diagnosis
Notice bibliographique
Résumé
Background Myocarditis, inflammation of the myocardium, globally affects >3 million people annually. Heterogeneous histological findings and clinical presentation ranging from flu‐like illness to acute cardiogenic shock make diagnosis exceedingly difficult. The current gold standard for diagnosis requires histological examination of invasive endomyocardial biopsies, which provides a sensitivity of <30% in independently published studies. Although etiologies are diverse, viruses are the most prominent causes of myocarditis. Our studies demonstrated that the coxsackievirus B3 (CVB3), a common pathogen associated with viral myocarditis, manipulates the expression of Neuregulin 1 (Nrg1) and its ligand, receptor tyrosine‐protein kinase, ErbB4. Moreover, previous studies in other viruses have demonstrated preferential expression of the higher affinity Nrg1 β versus the less potent Nrg1 α isoform. The goal of this research is to determine the specificity of Nrg1 and ErbB4 induction to viral myocarditis as compared to other forms of acute myocardial injury, particularly myocardial infarction (m.i.). Additionally, we aim to analyze expression, tissue and isoform specificity of Nrg1 and ErbB4 in blood and heart tissue during the pathogenesis of viral myocarditis towards developing a non‐invasive blood‐based diagnostic assay via novel biomarkers. Methods 4‐week old male A/J mice were sham or CVB3 infected. Blood and tissue were harvested at time points corresponding to the acute, sub‐acute and chronic phases of disease. Specimens were analyzed for mRNA and protein expression and sub‐cellular localization using RT‐qPCR, Western blotting and confocal microscopy, respectively. Expression of Nrg1 and ErbB4 in viral myocarditis models was compared to murine myocardial infarction models via confocal microscopy. Results Upregulation (p<0.05) of Nrg1 and ErbB4 protein fragments were observed in murine heart tissue at different phases of viral pathogenesis as compared to m.i. and non‐infected controls. The observed upregulation was specific to the heart and not observed in the infected pancreas or lung. In addition, ~35 kDa and ~26 kDa fragments of Nrg1 and ErbB4 respectively were detected in the plasma of infected mice, while absent in the non‐infected controls. Confocal microscopy revealed that Nrg1 localized to the nuclear periphery while a diffuse increase in cellular ErbB4 expression was observed during infection. mRNA levels of Nrg1 β were significantly upregulated (~3‐fold) at the acute phase (6–7 dpi) of viral myocarditis, while the differences in expression of Nrg1 α were not significant. Conclusion Tissue specific upregulation and fragments detected in the plasma of both ErbB4 and Nrg1, with preferential expression of Nrg1 β , were observed as a result of CVB3 infection. Moreover, upregulation was not observed in an ischemic model of acute myocardial injury, indicating a viral specific process. These composite observations support the concept that these biomarkers may ultimately yield a non‐invasive blood‐based diagnostic assay for viral myocarditis. Support or Funding Information This research is supported by the Myocarditis Foundation and the Michael Smith Foundation for Health Research.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».