SARS-CoV-2, vaccination or autoimmunity as causes of cardiac inflammation. Which form prevails?

Abstract

The causes of cardiac inflammation during the COVID-19 pandemic are manifold and complex, and may have changed with different virus variants and vaccinations. The underlying viral etiology is self-evident, but its role in the pathogenic process is diverse. The view of many pathologists that myocyte necrosis and cellular infiltrates are indispensable for myocarditis does not suffice and contradicts the clinical criteria of myocarditis, i.e., a combination of serological evidence of necrosis based on troponins or MRI features of necrosis, edema, and inflammation based on prolonged T1 and T2 times and late gadolinium enhancement. The definition of myocarditis is still debated by pathologists and clinicians. We have learned that myocarditis and pericarditis can be induced by the virus via different pathways of action such as direct viral damage to the myocardium through the ACE2 receptor. Indirect damage occurs via immunological effector organs such as the innate immune system by macrophages and cytokines, and then later the acquired immune system via T cells, overactive proinflammatory cytokines, and cardiac autoantibodies. Cardiovascular diseases lead to more severe courses of SARS-CoV‑2 disease. Thus, heart failure patients have a double risk for complicated courses and lethal outcome. So do patients with diabetes, hypertension, and renal insufficiency. Independent of the definition, myocarditis patients benefitted from intensive hospital care, ventilation, if needed, and cortisone treatment. Postvaccination myocarditis and pericarditis affect primarily young male patients after the second RNA vaccine. Both are rare events but severe enough to deserve our full attention, because treatment according to current guidelines is available and necessary.

Keywords: COVID-19; Heart failure; Myocarditis; Pericarditis; Post-vaccination cardiac lesions.

Fig. 1

Epidemiologically relevant mutants and variants of SARS-Cov-2: from the wild type to Omicron

Fig. 2

a Declining number of reported infections. The 7‑day incidence: number of infected persons with SARS-CoV‑2 per 100,000 inhabitants from 2020 to 2023 (© Robert Koch Institute, https://experience.arcgis.com/experience/478220a4c454480e823b17327b2bf1d4). b Occupation of intensive care beds in Germany by number from March 2020 to 2023 (light blue). On top is the occupancy with non-COVID patients with critical illness or postoperative intensive care (© Statista 2023 [23])

Fig. 3

Patterns of myocardial inflammation in patients with SARS-CoV‑2 infection (with permission from [24], modified according to the Word Heart Federation criteria [4, 5])

Fig. 4

Borderline myocarditis in cardiogenic shock in a 69-year-old male patient. a Sparse infiltrate by CD45R0-positive cells (brown spots), no myocytolysis, × 200. b Budding virus from an interstitial cell (red arrow) at electron microscopy. Scale bar: 50 nm (with permission from [30])

Fig. 5

Lymphocytic myocarditis in SARS-CoV-2-positive necropsy cases. a Multifocal lymphocytic myocarditis in a 64-year-old male patient; arrow shows infiltrate + myocytolysis. H&E, × 200. b Focal myocardial lymphocytic infiltration with myocyte injury (arrow) in a 70-year-old man. H&E, × 400. c Biventricular multifocal lymphocytic myocarditis (arrows) with myocyte injury in a 64-year-old man, who developed atrial fibrillation 2 days before death. Double immunostaining CD4 brown/CD8 red, × 400 (with permission from [33])

Fig. 6

Infiltrating cells at the epicardium and the adjacent myocardial tissue. Focal lymphocytic epi- and pericarditis (arrows) in a 66-year-old man with focal myocardial inflammation, but without myocyte injury (arrowheads). a H&E, × 400; b CD8 immunostaining, × 400 (with permission from [33])

Fig. 7

SARS-CoV‑2 cell entry and replication. Medical intervention by drugs. ACE2 angiotensin-converting enzyme 2, TMPRSS2 transmembrane protease serine subtype 2 (with permission from [21])

Fig. 8

PHASES in immunopathology and FACES in clinical presentation. GM-CSF granulocyte–macrophage colony-stimulating factor, IL interleukin, IFN interferon, M‑CSF macrophage colony-stimulating factor, MODS multiple organ dysfunction syndrome, Th T helper, TNF tumor necrosis factor (with permission from [11])

Fig. 9

COVID-19 and perimyocardial inflammation in COVID-19 patients: MRI results. Design: 100 patients after recovery from COVID-19 with previous positive swab test. Inclusion criteria: (1) virus positivity in original swab, (2) clinical myocarditis with elevated troponin. Results: (1) Elevated hs-troponin (> 3 pg/mL in 71 patients). (2) MRI: late gadolinium enhancement (LGE) at epi- (yellow arrowheads) and pericardium (white arrowheads) in 32 patients (a). (3) MRI with prolonged native T1 (edema) in 71 patients (b) and prolonged native T2 (necrosis) in 60 patients (c). (4) Biopsy: sparse infiltrate (CD45R0-positive cells, brown spots, d). No virus found in myocytes (from [35] published under the terms of the CC-BY License. © 2020 Puntmann VO et al. JAMA Cardiology)