COVID-19, Myocarditis and Pericarditis

Abstract

Viral infections are a leading cause of myocarditis and pericarditis worldwide, conditions that frequently coexist. Myocarditis and pericarditis were some of the early comorbidities associated with SARS-CoV-2 infection and COVID-19. Many epidemiologic studies have been conducted since that time concluding that SARS-CoV-2 increased the incidence of myocarditis/pericarditis at least 15× over pre-COVID levels although the condition remains rare. The incidence of myocarditis pre-COVID was reported at 1 to 10 cases/100 000 individuals and with COVID ranging from 150 to 4000 cases/100 000 individuals. Before COVID-19, some vaccines were reported to cause myocarditis and pericarditis in rare cases, but the use of novel mRNA platforms led to a higher number of reported cases than with previous platforms providing new insight into potential pathogenic mechanisms. The incidence of COVID-19 vaccine-associated myocarditis/pericarditis covers a large range depending on the vaccine platform, age, and sex examined. Importantly, the findings highlight that myocarditis occurs predominantly in male patients aged 12 to 40 years regardless of whether the cause was due to a virus-like SARS-CoV-2 or associated with a vaccine-a demographic that has been reported before COVID-19. This review discusses findings from COVID-19 and COVID-19 vaccine-associated myocarditis and pericarditis considering the known symptoms, diagnosis, management, treatment, and pathogenesis of disease that has been gleaned from clinical research and animal models. Sex differences in the immune response to COVID-19 are discussed, and theories for how mRNA vaccines could lead to myocarditis/pericarditis are proposed. Additionally, gaps in our understanding that need further research are raised.

Keywords: COVID-19 vaccines; mRNA vaccines; models, animal; sex characteristics; vaccines.

Figure 1.

Potential mechanisms leading to myocarditis/pericarditis following SARS-CoV-2 infection or vaccination. SARS-CoV-2 initially infects the lungs generating a cytokine storm including TNFα (tumor necrosis factor-alpha), IL (interleukin)-1β, and IL-6 and releasing extracellular vesicles (EVs) that contain virus or virus particles. 2. EVs may traffic through the blood or lymph to the heart where they infect cardiac cells that express the necessary receptors (ACE2 [angiotensin-converting enzyme 2], TMPRSS2 [transmembrane serine protease-2], and NRP1 [neuropilin-1 receptor]) such as cardiomyocytes, pericytes, mast cells, and macrophages. Additionally, resident antigen-presenting cells like mast cells, dendritic cells, and macrophages respond to virus and damaged cardiac tissue by activating an adaptive autoimmune response leading to myocarditis. 3. COVID-19 vaccines may activate resident mast cells or macrophages at the injection site that in susceptible individuals who have cardiac injury may promote an autoimmune response leading to myocarditis. Illustration credit: Sceyence Studios.

Figure 2.

Similarity in histological staining ratio for macrophages and T cells during COVID-19 myocarditis and vaccination versus pre-COVID myocarditis in humans and mice. Representative immunohistochemistry staining of myocardium in both human and mouse samples. Hematoxylin and eosin (H&E) staining shows inflammatory foci. Species-specific markers for macrophages (CD63+ human, CD11b+ mouse) and T cells (CD3+) show immune cell composition of the inflammatory infiltrate. Human scale bars, 100 µm; mouse scale bars, 200 µm.

Figure 3.

Myocarditis and pericarditis/perimyocarditis in the autoimmune CVB3 model. Male BALB/c mice received 10³ plaque-forming units of CVB3 with damaged heart protein on day 0 and myocarditis and pericarditis assessed histologically at day 10 after infection. Hematoxylin and eosin staining. Scale bars, 200 µm.

Figure 4.

Mast cell signaling contributes to myocarditis and may contribute to SARS-CoV-2 or vaccine-associated myocarditis. ACE2 indicates angiotensin-converting enzyme 2; cKit, receptor tyrosine kinase; IL, interleukin; MHC, major histocompatibility complex; serpin A3n, serpin family A member 3n (α1-antichymotrypsin); ST2, interleukin-1 receptor-like 1/IL-1RL1; TLR, Toll-like receptor; TMPRSS2, transmembrane protease serine-2; and TNFα, tumor necrosis factor-alpha. Illustration credit: Sceyence Studios.