CoChat
Sign Up
Cited by 8COVID-19 Clinical Research StudiesViral Infections and Immunology ResearchSARS-CoV-2 and COVID-19 Research

SARS-CoV-2 infection causes prolonged cardiomyocyte swelling and inhibition of HIF1α translocation in an animal model COVID-19

Open access
Daems, Margo, Liesenborghs, Laurens, Boudewijns, Robbert, Simmonds, Steven J., Kraisin, Sirima, Van Wauwe, Jore, Cuijpers, Ilona, Raman, Jana +10 more·2022·Frontiers in Cardiovascular Medicine
DOI 10.3389/fcvm.2022.964512PMC PMC9618878
Open this paper in CoChat — free accountOpen PDF

Abstract

Recovered COVID-19 patients often display cardiac dysfunction, even after a mild infection. Most current histological results come from patients that are hospitalized and therefore represent more severe outcomes than most COVID-19 patients face. To overcome this limitation, we investigated the cardiac effects of SARS-CoV-2 infection in a hamster model. SARS-CoV-2 infected hamsters developed diastolic dysfunction after recovering from COVID-19. Histologically, increased cardiomyocyte size was present at the peak of viral load and remained at all time points investigated. As this increase is too rapid for hypertrophic remodeling, we found instead that the heart was oedemic. Moreover, cardiomyocyte swelling is associated with the presence of ischemia. Fibrin-rich microthrombi and pericyte loss were observed at the peak of viral load, resulting in increased HIF1α in cardiomyocytes. Surprisingly, SARS-CoV-2 infection inhibited the translocation of HIF1α to the nucleus both in hamster hearts, in cultured cardiomyocytes, as well as in an epithelial cell line. We propose that the observed diastolic dysfunction is the consequence of cardiac oedema, downstream of microvascular cardiac ischemia. Additionally, our data suggest that inhibition of HIF1α translocation could contribute to an exaggerated response upon SARS-CoV-2 infection.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fcvm.2022.964512

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In female Syrian hamsters, cardiomyocyte hypertrophy (at days 4 and 35 after infection) and cardiac fibrosis and diastolic dysfunction were observed at day 35 after SARS-CoV-2 infection using echocardiography.

    “In a separate study using female Syrian hamsters, cardiomyocyte hypertrophy (at days 4 and 35 after infection) and cardiac fibrosis and diastolic dysfunction were observed at day 35 after SARS-CoV-2 infection using echocardiography. 187”

    From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [187]

    The Animal handling section identifies the subjects as female Syrian hamsters, and the cardiac-function results report echocardiographic evidence of diastolic dysfunction at 35 days post-infection. But the cardiac-tissue results report no increase in fibrosis, and the Discussion says the persistent cardiomyocyte enlargement was swelling rather than hypertrophic remodeling. Those findings contradict two of the outcomes attributed to the paper. (LLM, conf=0.90)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 51

  1. Basso C, Leone O, Rizzo S, De Gaspari M, Van Der Wal AC, Aubry M, et al. Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study. Eur Heart J. (2020) 41:3827- 35. doi: 10.1093/eurheartj/ehaa664 · DOI · Paper page
  2. Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol. (2020) 5:802-10. doi: 10.1001/jamacardio.2020.0950 · DOI · Paper page
  3. Shi S, Qin M, Cai Y, Liu T, Shen B, Yang F, et al. Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019. Eur Heart J. (2020) 41:2070-9. doi: 10.1093/eurheartj/ehaa408 · DOI
  4. Puelles VG, Lütgehetmann M, Lindenmeyer MT, Sperhake JP, Wong MN, Allweiss, et al. Multiorgan and renal tropism of SARS-CoV-2. N Engl J Med. (2020) 383:590-2. doi: 10.1056/NEJMc2011400 · DOI · Paper page
  5. Giustino G, Croft LB, Stefanini GG, Bragato R, Silbiger JJ, Vicenzi M, et al. Characterization of myocardial injury in patients with COVID-19. J Am Coll Cardiol. (2020) 76:2043-55. doi: 10.1016/j.jacc.2020.08.069 · DOI
  6. Toraih EA, Elshazli RM, Hussein MH, Elgaml A, Amin M, El-Mowafy M, et al. Association of cardiac biomarkers and comorbidities with increased mortality, severity, and cardiac injury in COVID-19 patients: a meta-regression and decision tree analysis. J Med Virol. (2020) 92:2473-88. doi: 10.1002/jmv.26166 · DOI
  7. Huang L, Zhao P, Tang D, Zhu T, Han R, Zhan C, et al. Cardiac involvement in patients recovered from COVID-2019 identified using magnetic resonance imaging. JACC Cardiovasc Imaging. (2020) 13:2330-9. doi: 10.1016/j.jcmg.2020.05.004 · DOI
  8. Puntmann VO, Carerj ML, Wieters I, Fahim M, Arendt C, Hoffmann J. et al. Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. (2020) 5:1265-73. doi: 10.1001/jamacardio.2020.3557 · DOI
  9. Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nat Med. (2022) 28:583-90. doi: 10.1038/s41591-022-01689-3 · DOI
  10. Abdelnabi R, Boudewijns R, Foo CS, Seldeslachts L, Sanchez-Felipe L, Zhang X, et al. Comparing infectivity and virulence of emerging SARS-CoV-2 variants in Syrian hamsters. EBioMedicine. (2021) 68:1-8. doi: 10.1016/j.ebiom.2021.103403 · DOI
  11. Boudewijns R, Thibaut HJ, Kaptein SJ, Li R, Vergote V, Seldeslachts L. et al. STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2 infected hamsters. Nat Commun. (2020) 11:1- 10. doi: 10.1038/s41467-020-19684-y · DOI
  12. Knight DS, Kotecha T, Razvi Y, Chacko L, Brown JT, Jeetley PS. et al. COVID-19: Myocardial injury in survivors. Circulation. (2020) 1120- 2 doi: 10.1161/CIRCULATIONAHA.120.049252 · DOI
  13. Yuan L, Zhu H, Zhou M, Ma J, Chen R, Chen Y, et al. Gender associates with both susceptibility to infection and pathogenesis of SARS-CoV-2 in Syrian hamster. Signal Transduct Target Ther. (2021) 6:1-8. doi: 10.1038/s41392-021- 00552-0 · DOI
  14. Tanaka DM, Romano MMD, Carvalho EEV, Oliveira LFL, Souza HCD, Maciel BC, et al. Effect of different anesthetic agents on left ventricular systolic function assessed by echocardiography in hamsters Brazilian. J Med Biol Res. (2016) 49. doi: 10.1590/1414-431x20165294 · DOI
  15. Sanchez-Felipe L, Vercruysse T, Sharma S, Ma J, Lemmens V, Van Looveren D, et al. A single-dose live-attenuated YF17D-vectored SARS- CoV-2 vaccine candidate. Nat. (2020) 590:320-5. doi: 10.1038/s41586-020- 3035-9 · DOI
  16. Schepens B, van Schie L, Nerinckx W, Roose K, Van Breedam W, Fijalkowska D, et al. An affinity-enhanced, broadly neutralizing heavy chain-only antibody protects against SARS-CoV-2 infection in animal models. Sci Transl Med. (2021) 13:eabi7826. doi: 10.1126/scitranslmed.abi7826 · DOI
  17. Kaptein SJ, Jacobs S, Langendries L, Seldeslachts L, Ter Horst S, Liesenborghs L, et al. Favipiravir at high doses has potent antiviral activity in SARS-CoV-2- infected hamsters, whereas hydroxychloroquine lacks activity. Proc Natl Acad Sci U S A. (2020) 117:26955-65. doi: 10.1073/pnas.2014441117 · DOI
  18. Abdelnabi R, Foo CS, De Jonghe S, Maes P, Weynand B, Neyts J. Molnupiravir inhibits replication of the emerging SARS-CoV-2 variants of concern in a hamster infection model. J Infect Dis. (2021) 224:749-53. doi: 10.1093/infdis/jiab361 · DOI
  19. Bulfamante GP, Perrucci GL, Falleni M, Sommariva E, Tosi D, Martinelli C, et al. Evidence of SARS-CoV-2 transcriptional activity in cardiomyocytes of COVID-19 patients without clinical signs of cardiac involvement. Biomedicines. (2020) 8:1-13. doi: 10.3390/biomedicines8120626 · DOI
  20. Fox SE Li G, Akmatbekov A, Harbert JL, Lameira FS, Brown JQ, et al. Unexpected features of cardiac pathology in COVID-19 infection. Circulation. (2020) 142:1123-5. doi: 10.1161/CIRCULATIONAHA.120.049465 · DOI
  21. Cuijpers I, Carai P, Mendes-Ferreira P, Simmonds SJ, Mulder P, Miranda- Silva D, et al. The effect of different anaesthetics on echocardiographic evaluation of diastolic dysfunction in a heart failure with preserved ejection fraction model. Sci Rep. (2020) 10:1-12. doi: 10.1038/s41598-020-72924-5 · DOI
  22. Zacchigna S, Paldino A, Falcão-Pires I, Daskalopoulos EP, Dal Ferro M, Vodret S, et al. Towards standardization of echocardiography for the evaluation of left ventricular function in adult rodents: a position paper of the ESC Working Group on Myocardial Function. Cardiovasc Res. (2021) 117:43- 59. doi: 10.1093/cvr/cvaa110 · DOI
  23. Hausenloy DJ, Chilian W, Crea F, Davidson SM, Ferdinandy P, Garcia-Dorado D, et al. The coronary circulation in acute myocardial ischaemia/reperfusion injury: a target for cardioprotection. Cardiovasc Res. (2019) 115:1143-55. doi: 10.1093/cvr/cvy286 · DOI
  24. Bois MC, Boire NA, Layman AJ, Aubry MC, Alexander MP, Roden AC, et al. COVID-19-associated nonocclusive fibrin microthrombi in the heart. Circulation. (2021) 143:230-43 doi: 10.1161/CIRCULATIONAHA.120.050754 · DOI
  25. Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A, Sutherland BA, et al. Capillary pericytes regulate cerebral blood flow in health and disease. Nature. (2014) 508:55-60. doi: 10.1038/nature13165 · DOI · Paper page
  26. Burel-Vandenbos F, Cardot-Leccia N, Passeron T. Apoptosis and pericyte loss in alveolar capillaries in COVID-19 infection: choice of markers matters. Author's reply. Intensive Care Med. (2020) 46:1967-8. doi: 10.1007/s00134-020-06220-1 · DOI
  27. Schimmel L, Chew KY, Stocks CJ, Yordanov TE, Essebier P, Kulasinghe A, et al. Endothelial cells are not productively infected by SARS-CoV-2. Clin Transl Immunol. (2021) 10:1-18. doi: 10.1002/cti2.1350 · DOI
  28. Jahani M, Dokaneheifard S, Mansouri K. Hypoxia: A key feature of COVID- 19 launching activation of HIF-1 and cytokine storm. J Inflamm (Lond). (2020) 17:1-10. doi: 10.1186/s12950-020-00263-3 · DOI
  29. Kopecky-Bromberg SA, Martínez-Sobrido L, Frieman M, Baric RA, Palese P. Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists. J Virol. (2007) 81:548-557. doi: 10.1128/JVI.01782-06 · DOI
  30. Van Linthout S, Klingel K, Tschöpe C. SARS-CoV-2-related myocarditis- like syndromes Shakespeare's question: what's in a name? Eur J Heart Fail. (2020) 22:922-5. doi: 10.1002/ejhf.1899 · DOI
  31. Liu Y, Xie J, Gao P, Tian R, Qian H, Guo F, et al. Swollen heart in COVID-19 patients who progress to critical illness: a perspective from echo-cardiologists. ESC Hear Fail. (2020) 7:3621-32. doi: 10.1002/ehf2.12873 · DOI
  32. Cardot-Leccia N, Hubiche T, Dellamonica J, Burel-Vandenbos F, Passeron T. Pericyte alteration sheds light on micro-vasculopathy in COVID-19 infection. Intensive Care Med. (2020) 46:1. doi: 10.1007/s00134-020-06147-7 · DOI
  33. Berthiaume AA, Grant RI, McDowell KP, Underly RG, Hartmann DA, Levy M, et al. Dynamic remodeling of pericytes in vivo maintains capillary coverage in the adult mouse. Brain Cell Rep. (2018) 22:8-16. doi: 10.1016/j.celrep.2017.12.016 · DOI · Paper page
  34. Hartmann DA, Berthiaume AA, Grant RI, Harrill SA, Koski T, Tieu T, et al. Brain capillary pericytes exert a substantial but slow influence on blood flow. Nat Neurosci. (2021) 24:633-45. doi: 10.1038/s41593-020-00793-2 · DOI
  35. Nikolakopoulou AM, Montagne A, Kisler K, Dai Z, Wang Y, Huuskonen MT, et al. Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss. Nat Neurosci. (2019) 22:1089-98. doi: 10.1038/s41593-019-0434-z · DOI
  36. Reynolds AS, Lee AG, Renz J, DeSantis K, Liang J, Powell CA, et al. Pulmonary vascular dilatation detected by automated transcranial doppler in COVID-19 pneumonia. Am J Respir Crit Care Med. (2020) 202:1037- 9. doi: 10.1164/rccm.202006-2219LE · DOI
  37. Reynolds AS, Lee AG, Renz J, DeSantis K, Liang J, Powell CA, et al. Reply to Cherian et al. Am J Respir Crit Care Med. (2021) 203:265- 6. doi: 10.1164/rccm.202009-3404LE · DOI
  38. Bernard I, Limonta D, Mahal LK, Hobman T. C endothelium infection and dysregulation by SARS-CoV-2: evidence and caveats in COVID-19. Viruses. (2020) 13:1-26. doi: 10.3390/v13010029 · DOI
  39. Avolio E, Carrabba M, Milligan R, Kavanagh Williamson M, Beltrami AP, Gupta K, et al. The SARS-CoV-2 Spike protein disrupts human cardiac pericytes function through CD147 receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease. Clin Sci. (2021) 135:2667- 89. doi: 10.1042/CS20210735 · DOI
  40. Sengillo JD, Winkler EA, Walker CT, Sullivan JS, Johnson M, Zlokovic BV. Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer's disease. Brain Pathol. (2013) 23:303-10. doi: 10.1111/bpa.12004 · DOI · Paper page
  41. Hariyanto TI, Putri C, Situmeang RFV, Kurniawan A. Dementia is a predictor for mortality outcome from coronavirus disease 2019 (COVID-19) infection. Eur Arch Psychiatry Clin Neurosci. (2021) 271:393-5. doi: 10.1007/s00406-020-01205-z · DOI
  42. Wan Y, Wu J, Ni L, Luo Q, Yuan C, Fan F, et al. Prognosis analysis of patients with mental disorders with COVID-19: a single-center retrospective study. Aging (Albany NY). (2020) 12:11238-44. doi: 10.18632/aging.103371 · DOI
  43. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet (London, England). (2020) 395:1054- 62. doi: 10.1016/S0140-6736(20)30566-3 · DOI · Paper page
  44. Serebrovska ZO, Chong EY, Serebrovska TV, Tumanovska LV, Xi L. Hypoxia, HIF-1α, and COVID-19: from pathogenic factors to potential therapeutic targets. Acta Pharmacol Sin. (2020) 41:1539-46. doi: 10.1038/s41401-020- 00554-8 · DOI
  45. Tian M, Liu W, Li X, Zhao P, Shereen MA, Zhu C, et al. HIF-1α promotes SARS-CoV-2 infection and aggravates inflammatory responses to COVID-19. (2021) 6:1-13. doi: 10.1038/s41392-021-00726-w · DOI
  46. Saini Y, Greenwood KK, Merrill C, Kim KY, Patial S, Parameswaran N, et al. Acute cobalt-induced lung injury and the role of hypoxia-inducible factor 1α in modulating. Inflammation Toxicol Sci. (2010) 116:673. doi: 10.1093/toxsci/ kfq155 · DOI
  47. Tan Y, Zhou J, Zhou Q, Hu L, Long Y. Role of eosinophils in the diagnosis and prognostic evaluation of COVID-19. J Med Virol. (2021) 93:1105- 10. doi: 10.1002/jmv.26506 · DOI
  48. Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ, et al. Clinical characteristics of (2020) 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy. 75:1730-41. doi: 10.1111/all.14238 · DOI
  49. Nasserie T, Hittle M, Goodman SN. Assessment of the frequency and variety of persistent symptoms among patients with COVID-19: a systematic review. JAMA Netw Open. (2021) 4:1-19. doi: 10.1001/jamanetworkopen.2021.11417 · DOI · Paper page
  50. Chopoorian AH, Wahba A, Celedonio J, Nwazue V, Smith EC, Garland EM, et al. Impaired endothelial function in patients with postural tachycardia syndrome. Hypertens (Dallas, Tex). (2021) 77:1001-1009. doi: 10.1161/HYPERTENSIONAHA.120.16238 · DOI
  51. Freaney PM, Shah SJ, Khan SS. COVID-19 and heart failure with preserved ejection fraction. JAMA. (2020) 324:1499-500. doi: 10.1001/jama.2020. 17445 · DOI

Cited by

Sorted by citations

Authors
Daems, M., Liesenborghs, L., Boudewijns, R., Simmonds, S. J., Kraisin, S., Van Wauwe, J., Cuijpers, I., Raman, J., Geuens, N., Buyten, T. V., Lox, M., Verhamme, P., Van Linthout, S., Martinod, K., Heymans, S., Tschöpe, C., Neyts, J., & Jones, E. A. V.
Affiliations
  • KU Leuven (BE)
  • Rega Institute for Medical Research (BE)
  • Maastricht University (NL)
  • Berlin-Brandenburger Centrum für Regenerative Therapien (DE)
Corresponding author
Jones, Elizabeth A. V.
ORCID
Venue
Frontiers in Cardiovascular Medicine
Publisher
Frontiers Media SA
Published
2022-10-17
Volume
9
Pages
964512-964512
ISSN
2297-055X (ISSN-L)
DOI
10.3389/fcvm.2022.964512
PMC
PMC9618878
OpenAlex
W4306385427
Cited by
8
References
4
Citations by year
2024: 3 · 2023: 5
FWCI
0.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cardiovascular Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, cc-by)
  • Lirias (KU Leuven) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
Funders
Bill and Melinda Gates Foundation (101003627, 1107721N, 1160718N, 848109, G091018N, G0B5920N, G0G4820N, INV-00636)
Topics
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Keywords
SARS-CoV-2, COVID-19 pandemic, diastolic dysfunction, myocardial ischemia, microthrombi, pericyte loss, hamster model, cardiomyocyte hypertrophy

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review