ESC Heart Fail . Fatal lymphocytic cardiac damage in coronavirus disease 2019 (COVID-19): autopsy reveals a ferroptosis signature

[tetano]

ESC Heart Fail


. 2020 Sep 22.
doi: 10.1002/ehf2.12958. Online ahead of print.
Fatal lymphocytic cardiac damage in coronavirus disease 2019 (COVID-19): autopsy reveals a ferroptosis signature


Werner Jacobs ^{1 2} , Martin Lammens ³ , Annelies Kerckhofs ¹ , Evy Voets ⁴ , Emily Van San ^{5 6} , Samya Van Coillie ^{5 6} , C?dric Peleman ^{7 8} , Matthias Mergeay ⁴ , Sabriya Sirimsi ³ , Veerle Matheeussen ⁹ , Hilde Jansens ⁹ , Ingrid Baar ¹⁰ , Tom Vanden Berghe ^{5 6 7 11} , Philippe G Jorens ^{7 8 10}



Affiliations

• PMID: 32959998
• DOI: 10.1002/ehf2.12958

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.

Keywords: Autopsy; COVID-19; Ferroptosis; Lymphocytic myocarditis; Renal failure; SARS-CoV-2-infection.

[kiwibird]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264936/

Title of the above paper - Iron: Innocent bystander or vicious culprit in COVID-19 pathogenesis?

Hepcidin, the key iron regulatory hormone, sequesters iron in the enterocytes and macrophages, leading to increased intracellular ferritin, and preventing iron efflux from enterocytes and macrophages (^{Daher et al., 2017}) (Figure 1 ). Thereby, we speculate that increased serum ferritin levels as a result of COVID-19 related hyper-inflammation signify a vicious cycle of events where increased ferritin levels may lead to further tissue damage (^{Kell and Pretorius, 2014}).
...

Excess intracellular iron interacts with molecular oxygen, generating reactive oxygen species (ROS) (^{Kell and Pretorius, 2014}). This may largely contribute to oxidative damage of cellular components of different organs (lungs, liver, kidney, heart). Mounting evidence links increased ferritin levels to various inflammatory pathologies including cardiovascular events (^{Knovich et al., 2009}).....

Are men at higher risk of myocarditis with Covid-19??? - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397751/ Study includes one very young woman, 21 years old, and one quite young woman of 43. Typical was male of 53years plus. Anecdotally - I seem to have seen a high number of young male athletes flagged with myocarditis.


Does available iron in the blood increase the risk of myocarditis? ???

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567817/ Young women often have lower levels of iron - perhaps this is also a protective attribute.. ???

Excellent article - Thank you Tetano - another treasure. Provokes many questions..

[Vibrant62]

Interesting. I saw a paper that suggested the virus can attack red blood cells but cannot replicate there, but that could account for the raised ferritin levels as infected RBCs are disrupted. Free iron is more harmful that free zinc ions, and so zinc is displaced in metallothionenes when there is excess free Fe+ (which usually store intracellular zinc reserves), and the metallothionenes would then try to mop up the excess Fe. This would displace free zinc into the circulation which then would be excreted, leading potentially to a systemic and intracellular zinc deficiency. Free intracellular zinc has antiviral effects as well as being essential for many aspects of immunity, so perhaps this is part of the mechanism that the virus uses to disable an effective early innate immune response? Just musing.

[kiwibird]

Thank you Vibrant62 - I have read many articles talking about Zinc supplementation to help with a return of lost sense of smell and taste. This would also explain why Zinc supplementation seems to help with severity.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365891/

"Especially, the role of zinc in viral-induced vascular complications has barely been discussed, so far. Interestingly, most of the risk groups described for COVID-19 are at the same time groups that were associated with zinc deficiency. As zinc is essential to preserve natural tissue barriers such as the respiratory epithelium, preventing pathogen entry, for a balanced function of the immune system and the redox system, zinc deficiency can probably be added to the factors predisposing individuals to infection and detrimental progression of COVID-19. Finally, due to its direct antiviral properties, it can be assumed that zinc administration is beneficial for most of the population, especially those with suboptimal zinc status."

[curiosity]

So there could be a use for blood letting after all?
Just kidding, kind of.
What would be a good treatment option for a sudden increase in iron levels in the blood? Certainly it would have to be quick in a COVID case. In hemachromatosis, the treatment is blood removal one pint at a time over a period of time until the iron levels decrease to a normal range, then maintenance blood removal as needed to stay in range.

[kiwibird]

https://www.fox2detroit.com/news/ohio-state-study-30-of-student-athletes-have-heart-damage-linked-to-covid-19

LOS ANGELES - In a study published in September, researchers from Ohio State University found that out of more than two dozen athletes from the university who tested positive for COVID-19, 30% had cellular heart damage and 15% showed signs of heart inflammation caused by a condition known as myocarditis.

After mapping the hearts of 26 Ohio State University athletes using a process known as cardiac magnetic resonance (CMR), researchers found that not only 15% of students exhibited the rare heart condition but 30% showed cellular damage.

[kiwibird]

https://pubmed.ncbi.nlm.nih.gov/11421579/

Metallothionein treatment reduces proinflammatory cytokines IL-6 and TNF-alpha and apoptotic cell death during experimental autoimmune encephalomyelitis (EAE)
...

The Zn-MT-II-induced decrease in proinflammatory cytokines and apoptosis during EAE could contribute to the reported diminution of clinical symptoms and mortality in EAE-immunized rats receiving Zn-MT-II treatment. Our results demonstrate that MT-II reduces the CNS expression of proinflammatory cytokines and the number of apoptotic neurons during EAE in vivo and that MT-II might be a potentially useful factor for treatment of EAE/MS.

https://www.pnas.org/content/103/6/1699

Zinc supplementation of young men alters metallothionein, zinc transporter, and cytokine gene expression in leukocyte populations
....
Supplementation of volunteer subjects with zinc at 15 mg/day produced an increase in MT transcript levels for each of the cell populations

If this is a problem with red blood cells - it sure isn't going to help with oxygen transport. Thanks again Vibrant62.

[kiwibird]

https://www.frontiersin.org/articles/10.3389/fimmu.2020.01712/full

"However, the World Health Organization (WHO) assumes that at least one third of the world population is affected by zinc deficiency (9). The fact that zinc deficiency is responsible for 16% of all deep respiratory infections world-wide (9) provides a first strong hint on a link of zinc deficiency with the risk of infection and severe progression of COVID-19 and suggests potential benefits of zinc supplementation.

The most common symptoms of COVID-19 are impaired smell and taste, fever, cough, sore throat, general weakness, pain as aching limbs, runny nose, and in some cases diarrhea (10). In the subsequent chapters, we will associate most of those symptoms with altered zinc homeostasis and explain how zinc might prevent or attenuate those symptoms, as summarized in Figure 1, and thus should be regarded as promising cost-effective, globally available therapeutic approach for COVID-19 patients, for which minimal to no side effects are known."