Table 4.
Hypothesised mechanisms for myocarditis following mRNA covid-19 vaccination and direct (ie, on myocarditis after covid-19 vaccine) supporting or refuting empirical evidence (question 5)
| Hypothesis | Citations | Direct empirical evidence | ||
|---|---|---|---|---|
| Supporting | Refuting | |||
| 1 | Hyper immune or inflammatory response, via exposure to spike protein, mRNA strand, or unknown trigger | n=99 52 55 58 59 64 65 68 69 | 3 case reports; multiple case series or reports reporting highest incidence in youth who have higher immunogenicity and reactogenicity from vaccines | 2 case reports; 1 case series |
| 2 | Delayed hypersensitivity (serum sickness) | n=59 53 54 58 68 | 1 case report; 1 case series | 6 case reports; 6 case series |
| 3 | Eosinophilic myocarditis | n=49 54 58 66 | 1 case report | 6 case reports; 6 case series |
| 4 | Hypersensitivity to vaccine vehicle components (eg, polyethylene glycol) and tromethamine; lipid nanoparticle sheath) | n=49 61 62 68 | 4 case reports (1 case with biopsy in series); 1 cohort study | 6 several case reports; 6 case series |
| 5 | Response to mRNA vaccine lipid nanoparticles (direct deleterious effect; not delayed—see hypothesis 4 above) | n=260 68 | 1 cohort | None |
| 6 | Autoimmunity triggered by molecular mimicry or other mechanism | n=99 53 54 56 58 59 64 65 68 | Molecular mimicry: 2 case reports, 1 case series, 1 in vitro study; other autoimmune: 1 case report | Molecular mimicry: 3 cohorts or registry, 2 case reports; other autoimmune: direct findings indicated but not cited |
| 7 | Low residual levels of double strand RNA | n=14 | None | None |
| 8 | Dysregulated micro-RNA response | n=151 | None | None |
| 9 | Production of anti-idiotype antibodies against immunogenic regions of antigen-specific antibodies | n=168 | None | None |
| 10 | Trigger of pre-existing dysregulated immune pathways in certain individuals with predispositions (eg, resulting in a polyclonal B cell expansion, immune complex formation, and inflammation9) | n=29 65 | None | For specific predispositions: 1 case report; 1 case series |
| 11 | Antibody-dependent enhancement of immunity or other forms of immune enhancement with re-exposure to virus after vaccine | n=19 | None | Multiple case reports and series reviewed and tabulated, having no evidence of acute covid-19 infections after vaccine when presenting with myocarditis |
| 12 | Direct cell invasion via the spike protein interacting with the angiotensin converting enzyme 2 (ACE2) widely expressed and prevalent in cardiomyocytes53 | n=253 65 | None | 2 cases |
| 13 | Cardiac pericyte expression of ACE2 with immobilized immune complex on the surface of pericytes activation of the complement system | n=160 | None | None |
| 14 | Spike-activated neutrophils (expressing ACE2) augmenting inflammatory response | n=260 87 | 1 case report | None |
| 15 | Hyperviscosity induced cardiac problem | n=170 | None | None |
| 16 | Strenuous exercise induced secretion of proinflammatory interleukin 6 | n=17 | None | None |
| Observation | ||||
| — | Differences in incidence by sex could be due to sex steroid hormones or underdiagnosis of condition in female patients | n=59 53 59 64 68 | Sex hormones: none; underdiagnosis in women: 2 reports (not studies) | Sex hormones: 1 cohort; underdiagnosis in women: none |