Fatal lymphocytic cardiac damage in coronavirus disease 2019 (COVID‐19): autopsy reveals a ferroptosis signature

Abstract

Aims Cardiovascular complications, including myocarditis, are observed in coronavirus disease 2019 (COVID‐19). Major cardiac involvement is a potentially lethal feature in severe cases. We sought to describe the underlying pathophysiological mechanism in COVID‐19 lethal cardiogenic shock. Methods and results We report on a 48‐year‐old male COVID‐19 patient with cardiogenic shock; despite extracorporeal life support, dialysis, and massive pharmacological support, this rescue therapy was not successful. Severe acute respiratory syndrome coronavirus 2 RNA was detected at autopsy in the lungs and myocardium. Histopathological examination revealed diffuse alveolar damage, proliferation of type II pneumocytes, lymphocytes in the lung interstitium, and pulmonary microemboli. Moreover, patchy muscular, sometimes perivascular, interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, were seen in the cardiac tissue. The lymphocytes ‘interlocked’ the myocytes, resulting in myocyte degeneration and necrosis. Predominantly, T‐cell lymphocytes with a CD4:CD8 ratio of 1.7 infiltrated the interstitial myocardium, reflecting true myocarditis. The myocardial tissue was examined for markers of ferroptosis, an iron‐catalysed form of regulated cell death that occurs through excessive peroxidation of polyunsaturated fatty acids. Immunohistochemical staining with E06, a monoclonal antibody binding to oxidized phosphatidylcholine (reflecting lipid peroxidation during ferroptosis), was positive in morphologically degenerating and necrotic cardiomyocytes adjacent to the infiltrate of lymphocytes, near arteries, in the epicardium and myocardium. A similar ferroptosis signature was present in the myocardium of a COVID‐19 subject without myocarditis. In a case of sudden death due to viral myocarditis of unknown aetiology, however, immunohistochemical staining with E06 was negative. The renal proximal tubuli stained positively for E06 and also hydroxynonenal (4‐HNE), a reactive breakdown product of the lipid peroxides that execute ferroptosis. In the case of myocarditis of other aetiology, the renal tissue displayed no positivity for E06 or 4‐HNE. Conclusions The findings in this case are unique as this is the first report on accumulated oxidized phospholipids (or their breakdown products) in myocardial and renal tissue in COVID‐19. This highlights ferroptosis, proposed to detrimentally contribute to some forms of ischaemia–reperfusion injury, as a detrimental factor in COVID‐19 cardiac damage and multiple organ failure.

Implications of microscale lung damage for COVID-19 pulmonary ventilation dynamics: A narrative review

“…Another large study of 20 patients found 14 with acute DAD and foci of organization [ 28 ]. Studies of smaller cohorts have also found acute DAD with little to no organization [ 26 , 42 , 57 ]. Organizing DAD begins to show up a week to 10 days after symptom onset and rarely within a few days of symptoms which may be due to subclinical phase or rapid disease progression [ 22 , 25 , 36 , 38 ].…”

SARS-CoV-2 infection: can ferroptosis be a potential treatment target for multiple organ involvement?

“…Several evidences also reveal the occurrence of significant lymphopenia in a large proportion of COVID-19 patients [2][3][4]49,62 . Recently, a ferroptosis signature was reported in a case report of COVID-19 patient (48-year-old, male), showing 4-HNE, a reactive breakdown product of the lipid peroxides or oxidized phosphatidylcholine was positive in myocardial tissue staining and in the proximal tubules of acute kidney injury, with decreased lymphocytes in the blood 63 . An in vitro study also showed SARS-CoV-2 suppressed GPX4, the brake of ferroptosis 43 .…”

COVID-19: captures iron and generates reactive oxygen species to damage the human immune system

“…The autopsy report further proves that T-cell lymphocytes with a CD4:CD8 proportion of 1.7 infiltrated the interstitial myocardium. Hypertrophy in the myocardial fibre occurs–-iron-catalysed regulatory cell death induced by extreme peroxidation of fatty acids [ 44 ]. Myocardial interstitial macrophage infiltration spreads, and there is no clear concerning damage to myocardial cells containing the left and right ventricles [ 45 ].…”