Vaccination-Associated Myocarditis and Myocardial Injury

Abstract

SARS-CoV-2 vaccine-associated myocarditis/myocardial injury should be evaluated in the contexts of COVID-19 infection, other types of viral myocarditis, and other vaccine-associated cardiac disorders. COVID-19 vaccine-associated myocardial injury can be caused by an inflammatory immune cell infiltrate, but other etiologies such as microvascular thrombosis are also possible. The clinical diagnosis is typically based on symptoms and cardiac magnetic resonance imaging. Endomyocardial biopsy is confirmatory for myocarditis, but may not show an inflammatory infiltrate because of rapid resolution or a non-inflammatory etiology. Myocarditis associated with SARS-COVID-19 vaccines occurs primarily with mRNA platform vaccines, which are also the most effective. In persons aged >16 or >12 years the myocarditis estimated crude incidences after the first 2 doses of BNT162b2 and mRNA-1273 are approximately 1.9 and 3.5 per 100 000 individuals, respectively. These rates equate to excess incidences above control populations of approximately 1.2 (BNT162b2) and 1.9 (mRNA-1273) per 100 000 persons, which are lower than the myocarditis rate for smallpox but higher than that for influenza vaccines. In the studies that have included mRNA vaccine and SARS-COVID-19 myocarditis measured by the same methodology, the incidence rate was increased by 3.5-fold over control in COVID-19 compared with 1.5-fold for BNT162b2 and 6.2-fold for mRNA-1273. However, mortality and major morbidity are less and recovery is faster with mRNA vaccine-associated myocarditis compared to COVID-19 infection. The reasons for this include vaccine-associated myocarditis having a higher incidence in young adults and adolescents, typically no involvement of other organs in vaccine-associated myocarditis, and based on comparisons to non-COVID viral myocarditis an inherently more benign clinical course.

Keywords: disorder; infection; inflammatory disease; mRNA vaccine-associated myocarditis.

Figure 1.

Myocarditis appears in different imaging forms as shown in this 4-chamber view of late gadolinium enhanced (LGE) cardiac magnetic resonance imaging (CMR) images. Eosinophillic myocarditis (A) when imaged using LGE has unique subendocardial enhancement of the ventricles (arrows) as a hematologic/immune process. Also common in this type of myocarditis is thrombus formation (smaller arrow, dark within apical chamber). Immune/inflammatory myocarditis (B) tends to be more diffuse affecting the lateral wall, entire septum (arrows), and RV in this case of giant cell myocarditis. Note the focal almost punctate LGE of the lateral and apical walls in a case of vaccine associated myocarditis (C) compared with more diffuse basal and apical linear LGE of lesser intensity of the lateral myocardium in a case of COVID-19 myocarditis (D); this patients’ CMR was performed 8 days after a positive SARS-CoV2-PCR, at a time when the patient was having chest pain.

Figure 2.

Endomyocardial biopsies of myocarditis histotypes (H&E, 200×). A, Lymphocytic myocarditis. B, Giant cell myocarditis, arrows highlight giant cells. C, Eosinophilic myocarditis, arrowheads highlight endocardial involvement by eosinophils. D, COVID-19 myocarditis, from study by Altman et al. Circles highlight areas of myocyte damage.

Figure 3.

Endomyocardial biopsies from clinically diagnosed COVID-19 myocarditis cases. A, COVID-19 myocarditis, histologically confirmed (H&E, 200×). B, CD3 immunostain highlighting T-cells (200×). C, CD68 immunostain highlighting macrophages (200×). D, Possible resolved COVID-19 myocarditis with interstitial fibrosis (H&E, 100×), cardiac magnetic resonance imaging from 40 days earlier exhibited findings of myocarditis (Figure 1D). E, Trichrome stain highlighting fibrosis from likely resolved COVID-19 myocarditis (100×). F, CD45 immunostain demonstrating lack of lymphocytes in resolved COVID-19 myocarditis (100×). G, Microinfarct (circle) in patient clinically diagnosed with COVID-19 myocarditis (100×). H, CD68 immunostain highlighting scattered interstitial macrophages, including in the area of microinfarct (100×). I, Microinfarct (circled) with associated necroinflammatory debris and adjacent capillary (arrow) showing fibrin thrombus (600×). Microinfarct (circled) with associated necroinflammatory debris and adjacent capillary (arrow) showing fibrin thrombus (600×).

Figure 4.

Endomyocardial biopsies from clinically diagnosed postvaccination myocarditis with an mRNA-based vaccine. A, Myocarditis, histologically confirmed (H&E, 400×) from study by Verma et al. B, Myocarditis with associated myocyte damage (H&E, 600×), from study by Verma et al. C, Necrotizing eosinophilic myocarditis following vaccination (H&E, 400×), from study by Kimura et al, circles highlight areas of myocyte damage. D, Microvascular fibrin thrombi (arrows) following mRNA vaccination, without evidence of inflammation (H&E, 600×, from study by Altman et al). E, Trichrome stain highlighting microvascular thrombi (600×). F, Electron micrograph from patient in D and E, demonstrating platelet-rich thrombus partially occluding a capillary (arrowhead). G, Intramyocardial hemorrhage (arrows) following mRNA vaccination, without evidence of inflammation (H&E, 100×). H, Normal appearing myocardium in patient clinically diagnosed with myocarditis following mRNA vaccination (H&E, 200×). I, Electron micrograph from patient H showing extracellular organelles and debris, suggestive of prior myocyte damage/resolving myocardial process.

Figure 5.

Box and Whisker plots for mRNA abundance as 2^-dCt referenced to GAPDH, median (Q1–Q3) for explanted heart nonfailing interventricular septum (IVS; nonfailing [NF], N=20), failing IVS (failing [F], N=25 [15 nonischemic dilated cardiomyopathy, 10 ischemic cardiomyopathy]); 17 endomyocardial biopsy (EmBx) nonfailing controls, 33 EmBx failing nonischemic cardiomyopathy (NDC) controls, 6 EmBx COVID-19 subjects (median [Q1–Q3]), and 4 EmBx postvaccine myocardial injury subjects. ACE2/ACE from BORG study is calculated from microarray fluorescence units (f) that are log2-transformed. Significance levels are given above or below box plots as *P<0.05, **P<0.01, **P<0.001, P≥0.050. Reprinted from Altman et al with permission from Elsevier and JACC: Basic to Translational Science. ACE indicates angiotensin I converting enzyme; AGT, angiotensinogen; AGTRI, angiotensin II receptor type 1; E2, angiotensin converting enzyme 2; ITGA5, integrin alpha 5; F3, factor 3; NS, nonsignificant; NPPB, natriuretic peptide B; and TF, tissue factor.