Arterial Stiffness and Oxidized LDL Independently Associated With Post-Acute Sequalae of SARS-CoV-2
Article Sidebar
Main Article Content
Abstract
OBJECTIVE: COVID-19 survivors can experience lingering symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) that appear in different phenotypes, and its etiology remains elusive. We assessed the relationship of endothelial dysfunction with having COVID and PASC.
METHODS: Data was collected from a prospectively enrolled cohort (n=379) of COVID-negative and COVID-positive participants with and without PASC. Primary outcomes, endothelial function (measured by reactive hyperemic index [RHI]), and arterial elasticity (measured by augmentation index standardized at 75 bpm [AI]), were measured using the FDA approved EndoPAT. Patient characteristics, labs, metabolic measures, markers of inflammation, and oxidized LDL (ox-LDL) were collected at each study visit, and PASC symptoms were categorized into 3 non-exclusive phenotypes: cardiopulmonary, neurocognitive, and general. COVID-negative controls were propensity score matched to COVID-negative-infected cases using the greedy nearest neighbor method.
RESULTS: There were 14.3% of participants who were fully recovered COVID positive and 28.5% who were COVID positive with PASC, averaging 8.64 ± 6.26 total number of symptoms. The mean RHI was similar across the cohort and having COVID or PASC was not associated with endothelial function (P=0.33). Age (P<0.0001), female sex (P<0.0001), and CRP P=0.04) were positively associated with arterial stiffness, and COVID positive PASC positive with neurological and/or cardiopulmonary phenotypes had the worst arterial elasticity (highest AI). Values for AI (P=0.002) and ox-LDL (P<0.0001) were independently and positively associated with an increased likelihood of having PASC.
CONCLUSION: There is evidence of an independent association between PASC, ox-LDL, and arterial stiffness with neurological and/or cardiopulmonary phenotypes having the worst arterial elasticity. Future studies should continue investigating the role of oxidative stress in the pathophysiology of PASC.
Downloads
Article Details
This work is licensed under a Creative Commons Attribution 4.0 International License.
Pathogens and Immunity abides by Creative Commons BY 4.0:
http://creativecommons.org/licenses/by/4.0/
This license lets others distribute, remix, tweak, and build upon your work for any lawful purpose, even commercially, as long as they credit you for the original creation. This is the most accommodating of licenses offered. Recommended for maximum dissemination and use of licensed materials. The authors maintain copyright of their materal.
*Due to a template error on our pdfs, articles published from May 20, 2016 to June 24, 2022 incorrectly state the copyright is held by Pathogens and Immunity. Copyright of all articles is held by the authors of each article as noted in the above copyright policy.
References
1. Ambrosino P, Calcaterra I, Molino A, Moretta P, Lupoli R, Spedicato GA, Papa A, Motta A, Maniscalco M, Di Minno MND. Persistent Endothelial Dysfunction in Post-Acute COVID-19 Syndrome: A Case-Control Study. Biomedicines. 2021;9(8). doi: 10.3390/biomedicines9080957. PubMed PMID: 34440161; PMCID: PMC8391623.
2. Xu SW, Ilyas I, Weng JP. Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies. Acta Pharmacol Sin. 2022:1-15. doi: 10.1038/s41401-022-00998-0. PubMed PMID: 36253560; PMCID: PMC9574180.
3. Teuwen LA, Geldhof V, Pasut A, Carmeliet P. COVID-19: the vasculature unleashed. Nat Rev Immunol. 2020;20(7):389-91. doi: 10.1038/s41577-020-0343-0. PubMed PMID: 32439870; PMCID: PMC7240244.
4. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, Mehra MR, Schuepbach RA, Ruschitzka F, Moch H. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417-8. doi: 10.1016/S0140-6736(20)30937-5. PubMed PMID: 32325026; PMCID: PMC7172722.
5. Chioh FW, Fong SW, Young BE, Wu KX, Siau A, Krishnan S, Chan YH, Carissimo G, Teo LL, Gao F, Tan RS, Zhong L, Koh AS, Tan SY, Tambyah PA, Renia L, Ng LF, Lye DC, Cheung C. Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation. Elife. 2021;10. doi: 10.7554/eLife.64909. PubMed PMID: 33752798; PMCID: PMC7987341.
6. Ergul E, Yilmaz AS, Ogutveren MM, Emlek N, Kostakoglu U, Cetin M. COVID 19 disease independently predicted endothelial dysfunction measured by flow-mediated dilatation. Int J Cardiovasc Imaging. 2022;38(1):25-32. doi: 10.1007/s10554-021-02356-3. PubMed PMID: 34286447; PMCID: PMC8294249.
7. Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nat Med. 2022;28(3):583-90. doi: 10.1038/s41591-022-01689-3. PubMed PMID: 35132265; PMCID: PMC8938267.
8. Evans PC, Rainger GE, Mason JC, Guzik TJ, Osto E, Stamataki Z, Neil D, Hoefer IE, Fragiadaki M, Waltenberger J, Weber C, Bochaton-Piallat ML, Back M. Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science. Cardiovasc Res. 2020;116(14):2177-84. doi: 10.1093/cvr/cvaa230. PubMed PMID: 32750108; PMCID: PMC7454368.
9. Rubinshtein R, Kuvin JT, Soffler M, Lennon RJ, Lavi S, Nelson RE, Pumper GM, Lerman LO, Lerman A. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J. 2010;31(9):1142-8. doi: 10.1093/eurheartj/ehq010. PubMed PMID: 20181680.
10. Shah W, Hillman T, Playford ED, Hishmeh L. Managing the long term effects of covid-19: summary of NICE, SIGN, and RCGP rapid guideline. BMJ. 2021;372:n136. doi: 10.1136/bmj.n136. PubMed PMID: 33483331.
11. Axtell AL, Gomari FA, Cooke JP. Assessing endothelial vasodilator function with the Endo-PAT 2000. J Vis Exp. 2010(44). doi: 10.3791/2167. PubMed PMID: 20972417; PMCID: PMC3143035.
12. Newton DJ, Kennedy G, Chan KK, Lang CC, Belch JJ, Khan F. Large and small artery endothelial dysfunction in chronic fatigue syndrome. Int J Cardiol. 2012;154(3):335-6. doi: 10.1016/j.ijcard.2011.10.030. PubMed PMID: 22078396.
13. Mouchati C, Durieux JC, Zisis SN, McComsey GA. HIV and race are independently associated with endothelial dysfunction. AIDS. 2023;37(2):271-7. doi: 10.1097/QAD.0000000000003421. PubMed PMID: 36541639; PMCID: PMC9794140.
14. Charfeddine S, Ibn Hadj Amor H, Jdidi J, Torjmen S, Kraiem S, Hammami R, Bahloul A, Kallel N, Moussa N, Touil I, Ghrab A, Elghoul J, Meddeb Z, Thabet Y, Kammoun S, Bouslama K, Milouchi S, Abdessalem S, Abid L. Long COVID 19 Syndrome: Is It Related to Microcirculation and Endothelial Dysfunction? Insights From TUN-EndCOV Study. Front Cardiovasc Med. 2021;8:745758. doi: 10.3389/fcvm.2021.745758. PubMed PMID: 34917659; PMCID: PMC8670225.
15. Oikonomou E, Souvaliotis N, Lampsas S, Siasos G, Poulakou G, Theofilis P, Papaioannou TG, Haidich AB, Tsaousi G, Ntousopoulos V, Sakka V, Charalambous G, Rapti V, Raftopoulou S, Syrigos K, Tsioufis C, Tousoulis D, Vavuranakis M. Endothelial dysfunction in acute and long standing COVID-19: A prospective cohort study. Vascul Pharmacol. 2022;144:106975. doi: 10.1016/j.vph.2022.106975. PubMed PMID: 35248780; PMCID: PMC8893931.
16. Mejia-Renteria H, Travieso A, Sagir A, Martinez-Gomez E, Carrascosa-Granada A, Toya T, Nunez-Gil IJ, Estrada V, Lerman A, Escaned J. In-vivo evidence of systemic endothelial vascular dysfunction in COVID-19. Int J Cardiol. 2021;345:153-5. doi: 10.1016/j.ijcard.2021.10.140. PubMed PMID: 34706286; PMCID: PMC8542397.
17. Centers for Disease Control and Prevention. Post-COVID Conditions: Information for Healthcare Providers 2022 [cited 2023 March 29]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.html#other-tools.
18. Mokhtari T, Hassani F, Ghaffari N, Ebrahimi B, Yarahmadi A, Hassanzadeh G. COVID-19 and multiorgan failure: A narrative review on potential mechanisms. J Mol Histol. 2020;51(6):613-28. doi: 10.1007/s10735-020-09915-3. PubMed PMID: 33011887; PMCID: PMC7533045.
19. Dixit NM, Churchill A, Nsair A, Hsu JJ. Post-Acute COVID-19 Syndrome and the cardiovascular system: What is known? Am Heart J Plus. 2021;5:100025. doi: 10.1016/j.ahjo.2021.100025. PubMed PMID: 34192289; PMCID: PMC8223036.
20. Takahashi T, Ellingson MK, Wong P, Israelow B, Lucas C, Klein J, Silva J, Mao T, Oh JE, Tokuyama M, Lu P, Venkataraman A, Park A, Liu F, Meir A, Sun J, Wang EY, Casanovas-Massana A, Wyllie AL, Vogels CBF, Earnest R, Lapidus S, Ott IM, Moore AJ, Yale IRT, Shaw A, Fournier JB, Odio CD, Farhadian S, Dela Cruz C, Grubaugh ND, Schulz WL, Ring AM, Ko AI, Omer SB, Iwasaki A. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature. 2020;588(7837):315-20. doi: 10.1038/s41586-020-2700-3. PubMed PMID: 32846427; PMCID: PMC7725931.
21. Abbasi J. The COVID Heart-One Year After SARS-CoV-2 Infection, Patients Have an Array of Increased Cardiovascular Risks. JAMA. 2022;327(12):1113-4. doi: 10.1001/jama.2022.2411. PubMed PMID: 35234824.
22. Chung MK, Zidar DA, Bristow MR, Cameron SJ, Chan T, Harding CV, 3rd, Kwon DH, Singh T, Tilton JC, Tsai EJ, Tucker NR, Barnard J, Loscalzo J. COVID-19 and Cardiovascular Disease: From Bench to Bedside. Circ Res. 2021;128(8):1214-36. doi: 10.1161/CIRCRESAHA.121.317997. PubMed PMID: 33856918; PMCID: PMC8048382.
23. Thaweethai T, Jolley SE, Karlson EW, Levitan EB, Levy B, McComsey GA, McCorkell L, Nadkarni GN, Parthasarathy S, Singh U, Walker TA, Selvaggi CA, Shinnick DJ, Schulte CCM, Atchley-Challenner R, Alba GA, Alicic R, Altman N, Anglin K, Argueta U, Ashktorab H, Baslet G, Bassett IV, Bateman L, Bedi B, Bhattacharyya S, Bind MA, Blomkalns AL, Bonilla H, Bush PA, Castro M, Chan J, Charney AW, Chen P, Chibnik LB, Chu HY, Clifton RG, Costantine MM, Cribbs SK, Davila Nieves SI, Deeks SG, Duven A, Emery IF, Erdmann N, Erlandson KM, Ernst KC, Farah-Abraham R, Farner CE, Feuerriegel EM, Fleurimont J, Fonseca V, Franko N, Gainer V, Gander JC, Gardner EM, Geng LN, Gibson KS, Go M, Goldman JD, Grebe H, Greenway FL, Habli M, Hafner J, Han JE, Hanson KA, Heath J, Hernandez C, Hess R, Hodder SL, Hoffman MK, Hoover SE, Huang B, Hughes BL, Jagannathan P, John J, Jordan MR, Katz SD, Kaufman ES, Kelly JD, Kelly SW, Kemp MM, Kirwan JP, Klein JD, Knox KS, Krishnan JA, Kumar A, Laiyemo AO, Lambert AA, Lanca M, Lee-Iannotti JK, Logarbo BP, Longo MT, Luciano CA, Lutrick K, Maley JH, Marathe JG, Marconi V, Marshall GD, Martin CF, Matusov Y, Mehari A, Mendez-Figueroa H, Mermelstein R, Metz TD, Morse R, Mosier J, Mouchati C, Mullington J, Murphy SN, Neuman RB, Nikolich JZ, Ofotokun I, Ojemakinde E, Palatnik A, Palomares K, Parimon T, Parry S, Patterson JE, Patterson TF, Patzer RE, Peluso MJ, Pemu P, Pettker CM, Plunkett BA, Pogreba-Brown K, Poppas A, Quigley JG, Reddy U, Reece R, Reeder H, Reeves WB, Reiman EM, Rischard F, Rosand J, Rouse DJ, Ruff A, Saade G, Sandoval GJ, Schlater SM, Shepherd F, Sherif ZA, Simhan H, Singer NG, Skupski DW, Sowles A, Sparks JA, Sukhera FI, Taylor BS, Teunis L, Thomas RJ, Thorp JM, Thuluvath P, Ticotsky A, Tita AT, Tuttle KR, Urdaneta AE, Valdivieso D, VanWagoner TM, Vasey A, Verduzco-Gutierrez M, Wallace ZS, Ward HD, Warren DE, Weiner SJ, Welch S, Whiteheart SW, Wiley Z, Wisnivesky JP, Yee LM, Zisis S, Horwitz LI, Foulkes AS. Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection. Jama. 2023;329(22):1934-46. doi: 10.1001/jama.2023.8823. PubMed PMID: 37278994; PMCID: PMC10214179.
24. Mouchati C, Durieux JC, Zisis SN, Labbato D, Rodgers MA, Ailstock K, Reinert BL, Funderburg NT, McComsey GA. Increase in gut permeability and oxidized ldl is associated with post-acute sequelae of SARS-CoV-2. Front Immunol. 2023;14:1182544. doi: 10.3389/fimmu.2023.1182544. PubMed PMID: 37251403; PMCID: PMC10217362.
25. Gameil MA, Marzouk RE, Elsebaie AH, Rozaik SE. Long-term clinical and biochemical residue after COVID-19 recovery. Egypt Liver J. 2021;11(1):74. doi: 10.1186/s43066-021-00144-1. PubMed PMID: 34777873; PMCID: PMC8435147.
26. Prasad M, Leon M, Lerman LO, Lerman A. Viral Endothelial Dysfunction: A Unifying Mechanism for COVID-19. Mayo Clin Proc. 2021;96(12):3099-108. doi: 10.1016/j.mayocp.2021.06.027. PubMed PMID: 34863398; PMCID: PMC8373818.
27. Kohara K, Tabara Y, Oshiumi A, Miyawaki Y, Kobayashi T, Miki T. Radial augmentation index: a useful and easily obtainable parameter for vascular aging. Am J Hypertens. 2005;18(1 Pt 2):11S-4S. doi: 10.1016/j.amjhyper.2004.10.010. PubMed PMID: 15683726.
28. Mitchell GF. Arterial Stiffness and Wave Reflection: Biomarkers of Cardiovascular Risk. Artery Res. 2009;3(2):56-64. doi: 10.1016/j.artres.2009.02.002. PubMed PMID: 20161241; PMCID: PMC2705910.
29. Nichols WW, Singh BM. Augmentation index as a measure of peripheral vascular disease state. 2002;17(5):543-51. doi: 10.1097/00001573-200209000-00016. PubMed PMID: 12357133.
30. Wang X, Keith JC, Jr., Struthers AD, Feuerstein GZ. Assessment of arterial stiffness, a translational medicine biomarker system for evaluation of vascular risk. Cardiovasc Ther. 2008;26(3):214-23. doi: 10.1111/j.1755-5922.2008.00051.x. PubMed PMID: 18786091.