Dataset Information

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.

SUBMITTER: Jacobs W

PROVIDER: S-EPMC7607145 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCoronavirus disease 2019 (COVID-19) has been implicated in a wide spectrum of cardiac manifestations following the acute phase of the disease.ObjectivesTo assess the range of cardiac sequelae after COVID-19 recovery.Data sourcesPubMed, Embase, Scopus (inception through 17 February 2021) and Google scholar (2019 through 17 February 2021).Study eligibility criteriaProspective and retrospective studies, case reports and case series.ParticipantsAdult patients assessed for cardiac manifestations after COVID-19 recovery.ExposureSevere acute respiratory syndrome coronavirus 2 infection diagnosed by PCR.MethodsSystematic review.ResultsThirty-five studies (fifteen prospective cohort, seven case reports, five cross-sectional, four case series, three retrospective cohort and one ambidirectional cohort) evaluating cardiac sequelae in 52 609 patients were included. Twenty-nine studies used objective cardiac assessments, mostly cardiac magnetic resonance imaging (CMR) in 16 studies, echocardiography in 15, electrocardiography (ECG) in 16 and cardiac biomarkers in 18. Most studies had a fair risk of bias. The median time from diagnosis/recovery to cardiac assessment was 48 days (1-180 days). Common short-term cardiac abnormalities (<3 months) included increased T1 (proportion: 30%), T2 (16%), pericardial effusion (15%) and late gadolinium enhancement (11%) on CMR, with symptoms such as chest pain (25%) and dyspnoea (36%). In the medium term (3-6 months), common changes included reduced left ventricular global longitudinal strain (30%) and late gadolinium enhancement (10%) on CMR, diastolic dysfunction (40%) on echocardiography and elevated N-terminal proB-type natriuretic peptide (18%). In addition, COVID-19 survivors had higher risk (risk ratio 3; 95% CI 2.7-3.2) of developing heart failure, arrythmias and myocardial infarction.ConclusionsCOVID-19 appears to be associated with persistent/de novo cardiac injury after recovery, particularly subclinical myocardial injury in the earlier phase and diastolic dysfunction later. Larger well-designed and controlled studies with baseline assessments are needed to better measure the extent of cardiac injury and its clinical impact.