The natural history of CVB3 myocarditis in C57BL/6J mice: an extended in-depth characterization

• Published in: Cardiovascular pathology 2024-09, Vol.72, p.107652, Article 107652
• Main Authors: Favere, Kasper, Van Hecke, Manon, Eens, Sander, Bosman, Matthias, Stobbelaar, Kim, Hotterbeekx, An, Kumar-Singh, Samir, L． Delputte, Peter, Fransen, Erik, De Sutter, Johan, Guns, Pieter-Jan, Roskams, Tania, Heidbuchel, Hein
• Format: Article
• Language: English
• Subjects: Arrhythmogenesis; C57BL/6J; Characterization; Coxsackievirus B3; Cytokine; Electrophysiology study; Fibrogenesis; Gene expression; Histology; Immunohistochemistry; Inflammation; Mice; Myocardial fibrosis; Natural course; Remodeling; Troponin; Viral myocarditis
• ISSN: 1054-8807; 1879-1336; 1879-1336
• DOI: 10.1016/j.carpath.2024.107652

•CVB3 inoculation of C57BL/6J mice induces acute self-limiting viral myocarditis.•Male sex is associated with higher mortality, cardiac inflammation and fibrosis.•A 10-fold increase of the virus inoculation dose does not impact viral myocarditis outcomes in male mice.•Tbet- and iNOS-reactive cells are the dominant inflammatory cells in the subacute phase. Viral infections are the leading cause of myocarditis. Besides acute cardiac complications, late-stage sequelae such as myocardial fibrosis may develop, importantly impacting the prognosis. Coxsackievirus B3 (CVB)-induced myocarditis in mice is the most commonly used translational model to study viral myocarditis and has provided the majority of our current understanding of the disease pathophysiology. Nevertheless, the late stages of disease, encompassing fibrogenesis and arrhythmogenesis, have been underappreciated in viral myocarditis research to date. The present study investigated the natural history of CVB-induced myocarditis in C57BL/6J mice, expanding the focus beyond the acute phase of disease. In addition, we studied the impact of sex and inoculation dose on the disease course. C57BL/6J mice (12 weeks old; n=154) received a single intraperitoneal injection with CVB to induce viral myocarditis, or vehicle (PBS) as control. Male mice (n=92) were injected with 5 × 105 (regular dose) (RD) or 5 × 106 (high dose) (HD) plaque-forming units of CVB, whereas female mice received the RD only. Animals were sacrificed 1, 2, 4, 8, and 11 weeks after CVB or PBS injection. Virally inoculated mice developed viral disease with a temporary decline in general condition and weight loss, which was less pronounced in female animals (P