Intramyocardial Inflammation after COVID-19 Vaccination: An Endomyocardial Biopsy-Proven Case Series

Abstract

Myocarditis in response to COVID-19 vaccination has been reported since early 2021. In particular, young male individuals have been identified to exhibit an increased risk of myocardial inflammation following the administration of mRNA-based vaccines. Even though the first epidemiological analyses and numerous case reports investigated potential relationships, endomyocardial biopsy (EMB)-proven cases are limited. Here, we present a comprehensive histopathological analysis of EMBs from 15 patients with reduced ejection fraction (LVEF = 30 (14-39)%) and the clinical suspicion of myocarditis following vaccination with Comirnaty^® (Pfizer-BioNTech) (n = 11), Vaxzevria^® (AstraZenica) (n = 2) and Janssen^® (Johnson & Johnson) (n = 2). Immunohistochemical EMB analyses reveal myocardial inflammation in 14 of 15 patients, with the histopathological diagnosis of active myocarditis according the Dallas criteria (n = 2), severe giant cell myocarditis (n = 2) and inflammatory cardiomyopathy (n = 10). Importantly, infectious causes have been excluded in all patients. The SARS-CoV-2 spike protein has been detected sparsely on cardiomyocytes of nine patients, and differential analysis of inflammatory markers such as CD4⁺ and CD8⁺ T cells suggests that the inflammatory response triggered by the vaccine may be of autoimmunological origin. Although a definitive causal relationship between COVID-19 vaccination and the occurrence of myocardial inflammation cannot be demonstrated in this study, data suggest a temporal connection. The expression of SARS-CoV-2 spike protein within the heart and the dominance of CD4⁺ lymphocytic infiltrates indicate an autoimmunological response to the vaccination.

Keywords: COVID-19; Comirnaty; Janssen; SARS-CoV-2; Vaxzevria; giant cell myocarditis; inflammatory cardiomyopathy; myocarditis; vaccination.

Figure 1

Representative images of haematoxylin and eosin (H & E) staining, and immunohistochemical stainings for the assessment of inflammation in endomyocardial biopsies from patients with the suspicion of myocarditis after COVID-19 vaccination. Immunohistochemical detection of CD3⁺ T cells, CD45R0⁺ T-memory cells, LFA-1⁺ lymphocytes, MAC-1⁺ macrophages, perforin⁺ cytotoxic cells and HLA-DR⁺ activated T cells in patients diagnosed for (A) inflammatory cardiomyopathy (DCMi, patient 4, Comirnaty^® vaccine), (B) acute myocarditis (AMC, patient 2, Comirnaty^® vaccine) and (C,D) giant cell myocarditis (GCMC, patient 14, Janssen^® vaccine; patient 3, Cormirnaty^® vaccine; giant cells are marked by arrows in H & E staining). Immunohistochemical staining was quantified by digital image analysis and is depicted for each patient in Table 2. Magnification 200×. Scale bars 50 μm.

Figure 2

Evidence of SARS-CoV-2 spike protein in cardiac tissue after COVID-19 vaccination. (A–C) Representative immunohistochemical stainings of SARS-CoV-2 spike protein in EMBs from patients diagnosed with DCMi after receiving Comirnaty^® (panel A and B, patients 5 and 10) or Vaxzevria^® (panel C, patient 13). (D) SARS-CoV-2-positive cardiac tissue served as positive control. Magnification 400×. Scale bars 20 μm.

Figure 3

Inflammatory cardiomyopathy in response to COVID-19 vaccination is dominated by CD4⁺ T cells. (A–C) Representative immunohistochemical stainings of CD4⁺ and CD8⁺ T cells in endomyocardial biopsies from patients diagnosed for inflammatory cardiomyopathy (DCMi) after receiving Comirnaty^® (panel A and B, patients 6 and 10) or Vaxzevria^® (panel C, patient 13) vaccines, respectively. Immunohistochemical staining was quantified by digital image analysis and CD4-to-CD8 ratio is depicted for each patient in Table 2. Magnification 400×. Scale bars 20 μm.