Brianna Cathey

Introduction. Myocarditis is the most frequent manifestation of COVID-19 cardiac involvement, causing up to 7% of COVID related deaths.^1,2 Cardiac injury occurs in approximately 12% of patients and has shown a 51% mortality rate in hospitalized COVID-19 patients.³ While it has been established that COVID-19 particles enter the respiratory tract epithelium to infect the lungs, the mechanism by which it causes myocarditis remains unclear. The leading hypothesis is systemic inflammation caused by cytokine storm that damages the myocardium.⁴ The identification of specific cytokines involved in systemic inflammation will provide a therapeutic target for pharmacological intervention to prevent severe inflammation caused by COVID-19. Methods. Mouse knock-out models of Coxsackie-virus B3 (CVB3) were tested for levels of neutrophils, interleukins (IL-6, -10, -13, -18, -1B), macrophages, T cells, B cells, and other cytokines and then compared to controls in order to investigate the roles of each in the development and maintenance of viral myocarditis (VMC). Clinical trials were conducted using Interferon B-1b for the treatment of VMC. Staining of myocardial slices and echocardiography was also performed. Results. CVB3 infected neutrophils produced toxic pro-inflammatory cytokines  IL-1B, TNFa, and IL-6, while neutrophil depletion showed reduced cardiomyopathy.⁵ Interleukin-1 receptor-associated kinase (IRAK4) contributes to an increase in pro-inflammatory and pro-apoptotic IL-6 and TNFa, and to a decrease in IFN-a and IFN-g, with findings suggesting an early protective effect of macrophage infiltration into the myocardium in acute VMC.⁶ IL-13 KO mice showed a significant increase in chronic VMC in the late phase of infection and 40% survived compared to 100% for WT. Echocardiography showed reduced LVESD, fractional shortening, and EF, and increased IgG autoantibodies. These mice has increased levels of macrophages that produce proinflammatory and profibrotic cytokines IL-1B and IL-18, as illustrated by the presence of significant fibrosis on Day 30 of infection.⁷ Transfer of IL-10 producing B cells demonstrated downregulation of Th1 and Th17, resulting in attenuated inflammatory cell infiltration and cardiomyocyte necrosis in early infection.⁸ The treatment group for Interferon B-1b showed earlier improvement, higher virus elimination, a higher heart failure score, and lower incidence of severe adverse events.⁹ Conclusion. COVID-19 precipitates a cytokine storm that can induce myocarditis, in which multiple cell types play a role. Neutrophils contribute to tissue damage. IRAK4 inhibits migration of protective macrophages in early infection, while macrophages worsen disease later in infection. Treatment for myocarditis centers around targeting the underlying cytokines that induce systemic inflammation and causes myocardial fibrosis.

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