Post-COVID-19 Cardiovascular Disorders and the Molecular Mechanism of NET Formation

Abstract

Objective: The post-COVID-19 process is not completely understood, as it affects COVID-19 survivors at all levels of disease severity, not all of whom are hospitalized. One of the long-lasting COVID-19 symptom categories, cardiovascular disorders (including acute heart failure, palpitations, hypotension, venous thromboembolic diseases, arrhythmias, myocarditis, and increased heart rate), may derive from a systemic inflammatory response to the viral infection. NETs (neutrophil extracellular traps) that fight invading viruses in extracellular cardiac spaces accumulate due to COVID-19, hyperinflammation and cytokine storms. Our study focuses on cardiovascular disorders as COVID-19 sequelae. To determine the role of NETs in these disorders, we aimed to measure levels of PAD4, MPO, MMP-9, and H3Cit. Methods: In this study, forty people with long-term cardiac complications associated with a history of COVID-19 were recruited along with forty healthy people. Results: We found significant differences in PAD4, H3Cit, and MPO plasma levels between the post-COVID-19 and control groups (p values < 0.05). The expression levels of PAD4 mRNA were lower and MMP-9 mRNA levels was higher in the post-COVID-19 group compared with the control subjects. Conclusion: These findings suggest that PAD4, MPO, MMP-9, and H3Cit are potential biomarkers of NET dysregulation and may cause post-COVID-19 symptoms, especially cardiovascular disorders.

Keywords

• Cardiovascular abnormalities
• citrullinated Histone H3
• neutrophil extracellular traps
• peptidylarginine deiminases 4
• post-acute COVID-19 syndrome.

Project Number

2021/2-33 M.

COVID-19 Sonrası Kardiyovasküler Bozukluklar ve NET Oluşumunun Moleküler Mekanizması

Abstract

Amaç: COVID-19 sonrası süreç, tamamı hastaneye yatırılmayan, hastalık şiddetinin her seviyesindeki COVID-19 mağdurlarını etkilediği için tam olarak anlaşılamamıştır. Uzun süreli COVID-19 semptom kategorilerinden biri olan kardiyovasküler bozukluklar (akut kalp yetmezliği, çarpıntı, hipotansiyon, venöz tromboembolik hastalıklar, aritmiler, miyokardit ve artmış kalp hızı dahil), viral enfeksiyona sistemik bir inflamatuar yanıttan kaynaklanabilir. Hücre dışı kalp boşluklarında istilacı virüslerle savaşan NET'ler (nötrofil hücre dışı tuzakları), COVID-19, hiperinflamasyon ve sitokin fırtınaları nedeniyle birikir. Çalışmamız, COVID-19 sekeli olarak kardiyovasküler bozukluklara odaklanmaktadır. NET'lerin bu bozukluklardaki rolünü belirlemek için PAD4, MPO, MMP-9 ve H3Cit düzeylerini ölçmeyi amaçladık. Yöntemler: Bu çalışmada, COVID-19 öyküsü ile ilişkili uzun süreli kardiyak komplikasyonları olan kırk sağlıklı insanla birlikte çalışmaya alındı. Bulgular: COVID-19 sonrası ve kontrol grupları arasında PAD4, H3Cit ve MPO plazma seviyelerinde anlamlı farklılıklar bulduk (p değerleri < 0,05). PAD4 mRNA'nın ekspresyon seviyeleri, kontrol deneklerine kıyasla COVID-19 sonrası grupta daha düşük ve MMP-9 mRNA seviyeleri daha yüksekti. Sonuç: Bu bulgular, PAD4, MPO, MMP-9 ve H3Cit'in NET düzensizliğinin potansiyel biyobelirteçleri olduğunu ve özellikle kardiyovasküler bozukluklar olmak üzere COVID-19 sonrası semptomlara neden olabileceğini düşündürmektedir.

Keywords

• Kardiyovasküler anormallikler
• sitrüline Histon H3
• nötrofil hücre dışı tuzakları
• peptidilarjinin deiminazlar 4
• Post akut COVID-19 sendromu

Supporting Institution

Kahramanmaraş Sütçü İmam Üniversitesi Bilimsel Araştırma Projeleri Birimi

Project Number

2021/2-33 M.

References

1. 1. Ambrosino P, Calcaterra IL, Mosella M, Formisano R, D'Anna SE, Bachetti T, et al. Endothelial Dysfunction in COVID-19: A Unifying Mechanism and a Potential Therapeutic Target. Biomedicines. 2022;10(4):812.
2. 2. Allan M, Lièvre M, Laurenson Schaefer H, Barros S, Jinnai Y, Andrews S, et al. The World Health Organization COVID-19 surveillance database International Journal for Equity in Health. 2022;21:167.
3. 3. Ceban F, Ling S, Lui LMW, Lee Y, Gill H, Teopiz KM, et al. Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis. Brain Behav Immun. 2022;101:93-135.
4. 4. Tenforde MW, Kim SS, Lindsell CJ, Rose EB, Shapiro NI. Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network - United States, March-June 2020. MMWR Morb Mortal Wkly Rep. 2020;69(30):993-8.
5. 5. Huang Y, Pinto MD, Borelli JL, Mehrabadi MA, Abrihim H, Dutt N, et al. COVID Symptoms, Symptom Clusters, and Predictors for Becoming a Long-Hauler: Looking for Clarity in the Haze of the Pandemic. medRxiv. Preprint. 2021.
6. 6. Chilosi M, Doglioni C, Ravaglia C, Martignoni G, Salvagno GL, Pizzolo G, et al. Unbalanced IDO1/IDO2 Endothelial Expression and Skewed Keynurenine Pathway in the Pathogenesis of COVID-19 and Post-COVID-19 Pneumonia. Biomedicines. 2022;10(6):1332.
7. 7. Visco V, Vitale C ,Rispoli A, Izzo C, Virtuoso N, Ferruzzi GJ, et al. Post-COVID-19 Syndrome: Involvement and Interactions between Respiratory, Cardiovascular and Nervous Systems. J. Clin. Med. 2022;11:524.
8. 8. Henry BM, Oliveira MHS, Cheruiyot I, Benoit J, Rose J, Favaloro EJ, et al. Cell-Free DNA, Neutrophil extracellular traps (NETs), and Endothelial Injury in Coronavirus Disease 2019- (COVID-19-) Associated Acute Kidney Injury. Mediators Inflamm. 2022;2022:9339411.

9. 9. Zhang R, Sun C, Han Y, Huang L, Sheng H, Wang J, et al. Neutrophil autophagy and NETosis in COVID-19: perspectives. Autophagy. 2022;1-10.
10. 10. Bavishi C, Bonow RO, Trivedi V, Abbott JD, Messerli FH, Bhatt DL. Special Article - Acute myocardial injury in patients hospitalized with COVID-19 infection: A review. Prog Cardiovasc Dis. 2020;63(5):682-9.
11. 11. Rai V, Sharma P, Agrawal S, Agrawal DK. Relevance of mouse models of cardiac fibrosis and hypertrophy in cardiac research. Mol Cell Biochem. 2017;424(1-2):123-45.
12. 12. Thierry AR. Host/genetic factors associated with COVID-19 call for precision medicine. Precis Clin Med. 2020;3(3):228-34.
13. 13. Pollitt KJG, Peccia J, Ko AI, Kaminski N, Cruz CSD. COVID-19 vulnerability: the potential impact of genetic susceptibility and airborne transmission. Hum Genomics. 2020;14(1):17.
14. 14. Li P, Li M, Lindberg MR, Kennett MJ, Xiong N, Wang Y. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med. 2010;207(9):1853-62.
15. 15. Morimont L, Dechamps M, David C, Bouvy C, Gillot C, Haguet H, et al. NETosis and Nucleosome Biomarkers in Septic Shock and Critical COVID-19 Patients: An Observational Study. Biomolecules. 2022;12(8):1038.
16. 16. Carmona-Rivera C, Zhao W, Yalavarthi S, Kaplan MJ. Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2. Ann Rheum Dis. 2015;74(7):1417-24.
17. 17. Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022;22(4):e102-e107.
18. 18. Veras FP, Pontelli MC, Silva CM, Toller-Kawahisa JE, Lima Md, Nascimento DC, et al. SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology. J Exp Med. 2020 Dec 7;217(12):e20201129.
19. 19. Zhu Y, Chen X, Liu X. NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond Front Immunol. 2022;13:838011.
20. 20. Ackermann M, Anders HJ, Bilyy R, Bowlin GL, Daniel C. Patients with COVID-19: in the dark-NETs of neutrophils. Cell Death Differ. 2021;28(11):3125-39.
21. 21. Kessenbrock K, Krumbholz M, Schonermarck U, Back W, Gross WL, Werb Z, et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med. 2009;15(6):623-5
22. 22. Morris G, Bortolasci CC, Puri BK, Olive L, Marx W, O’Neil A, et al. Preventing the development of severe COVID-19 by modifying immunothrombosis. Life Sci. 2021;264:118617.
23. 23. Nicolai L, Leunig A, Brambs S, Kaiser R, Weinberger T, Weigand M, et al. Immunothrombotic dysregulation in covid-19 pneumonia is associated with respiratory failure and coagulopathy. Circulation. 2020;142:1176–89.
24. 24. Borissoff JI, Joosen IA, Versteylen MO, Brill A, Fuchs TA, Savchenko AS, et al. Elevated levels of circulating DNA and chromatin are independently associated with severe coronary atherosclerosis and a pro-thrombotic state. Arterioscler Thromb Vasc Biol. 2013;33:2032–40. 27.
25. 25. Megens RTA, Vijayan S, Lievens D, Döring Y, van Zandvoort MAMJ, Grommes J, et al. Presence of luminal neutrophil extracellular traps in atherosclerosis. Thromb Haemost. 2012;107:597–8.
26. 26. McKenna E, Wubben R, Isaza-Correa JM, Melo AM, Mhaonaigh AU, Conlon N, et al. Neutrophils in COVID-19: Not Innocent Bystanders. Front Immunol. 2022;13:864387.
27. 27. LaSalle TJ, Gonye ALK, Freeman SS, Kaplonek P, Gushterova I, Kays KR, et al. Longitudinal characterization of circulating neutrophils uncovers phenotypes associated with severity in hospitalized COVID-19 patients. Cell Rep Med. 2022;3(10):100779.