Lipoprotein (a) as a predictor of the possibility of multifocal atherosclerosis in patients with stable CHD in the post-COVID period

Objective. The study aims to investigate the relationship between the severity of COVID-19 and the course of stable coronary heart disease (CHD), as well as to evaluate the role of lipoprotein(a) [LP(a)] as a predictor of multifocal atherosclerosis in patients during the post-COVID period. Material and methods. 431 patients with stable coronary heart disease (CHD) who had confirmed COVID-19 infections lasting between 3 to 18 months were examined. Patients were divided into two groups according to the severity of COVID-19: Group 1 included 203 patients with mild COVID-19 and Group 2 included 228 patients with moderate COVID-19 in the acute period. Clinical, laboratory and instrumental diagnostic methods including lipid profile indices (apolipoprotein A1 (apoA1), B (apoB), lipoprotein (a) (Lp(a)) and coronary angiography to assess the extent of atherosclerosis were used in the study. Logistic regression method was used to identify predictors of multifocal atherosclerosis (MFA) based on comprehensive analysis of clinical data. Results. CHD patients with a moderately severe course of acute COVID-19 in the post-COVID period were characterised by more pronounced altered indices of lipid and carbohydrate metabolism, as well as a higher frequency of hemodynamically significant coronary artery lesions, leading to a worsening of the course of the CHD and an increased risk of complications. They were significantly more likely have uncontrolled arterial hypertension (p < 0.001), atrial fibrillation (p = 0.035) and type 2 diabetes (p = 0.007), and higher levels of such biomarkers as the terminal fragment of brain natriuretic peptide precursor (p < 0.001), glycated haemoglobin (HbA1c) (p = 0.005), apoA1 (p < 0.001), lower apoB/A1 ratio (p = 0.04) and higher Lp(a) concentration (p < 0.001). Construction of multivariate logistic regression model found that in patients with stable CHD in the post-COVID period, Lp(a) level > 317.56 μg/ml increased the risk of MFA by 2.74 times, apoA1 level > 199.4 mg/dl – by 5.27 times, level, HbA1c > 5.85 % – by 8 times, left ventricular mass index > 122.23 in g/m² – by 1.92 times, male sex – by 2.92 times. Conclusions. The obtained data suggest that patients with stable CHD who underwent COVID-19 of medium severity in the acute stage of the infectious process represent a risk group of subsequent more severe course of the underlying disease.

1. Xie Y., Xu E., Bowe B., Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nat. Med., 2022; 28: 583–590.

2. Tsampasian V., Elghazaly H., Chattopadhyay R., Debski M., Naing T.K.P., Garg P., Vassiliou V.S. Risk factors associated with post-COVID-19 condition: a systematic review and meta-analysis. JAMA Intern. Med., 2023; 183 (6): 566–580. doi: 10.1001/jamainternmed.2023.0750

3. Bhatt D.L., Steg P.G., Ohman E.M., Hirsch A.T., Ikeda Y., Mas J.L., REACH Registry Investigators. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA, 2006; 295 (2): 180–189. doi:10.1001/jama.295.2.180

4. Clinical cardiology: diagnosis and treatment. V. 3. Eds. L.A. Bockeria, E.Z. Golukhova. Мoscow: Publishing house Scientific Center for Cardiovascular Surgery named after A. N. Bakulev, 2011. 662 p. (In Russ.)

5. Aboyans V., Ricco J.B., Bartelink M.E.L., Björck M., Brodmann M., Cohnert T., Collet J.P., Czerny M., de Carlo M., Debus S., Espinola-Klein C., Kahan T., Kownator S., Mazzolai L., Naylor A.R., Roffi M., Röther J., Sprynger M., Tendera M., Tepe G., Venermo M., Vlachopoulos C., Desormais I., Widimsky P., Kolh P., Agewall S., Bueno H., Coca A., de Borst G.J., Delgado V., Dick F., Erol C., Ferrini M., Kakkos S., Katus H.A., Knuuti J., Lindholt J., Mattle H., Pieniazek P., Piepoli M.F., Scheinert D., Sievert H., Simpson I., Sulzenko J., Tamargo J., Tokgozoglu L., Torbicki A., Tsakountakis N., Tuсуn J., Vega de Ceniga M., Windecker S., Zamorano J.L. Editor’s Choice — 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS). Eur. J. Vasc. Endovasc. Surg., 2018; 55 (3): 305–368. doi: 10.1016/j.ejvs.2017.07.018

6. van Den Berg M.J., Bhatt D.L., Kappelle L.J., de Borst G.J., Cramer M.J., van Der Graaf. SMART study group; REACH Registry investigators. Identification of vascular patients at very high risk for recurrent cardiovascular events: validation of the current ACC/AHA very high risk criteria. Eur. Heart. J., 2017; 38 (43): 3211–3218. doi:10.1093/eurheartj/ehx102

7. Liu Y., Zhang H.G. Vigilance on new-onset atherosclerosis following SARS-CoV-2 infection. Front. Med., 2021; 7: 629413. doi: 10.3389/fmed.2020.629413

8. Ugovšek S., Šebeštjen M. Lipoprotein (a) – the cross-roads of atherosclerosis, atherothrombosis and inflammation. Biomolecules, 2021; 12: 26. doi: 10.3390/biom12010026

9. Li J., Li S., Pan Y., Wang M., Meng X., Wang Y. Relationship between lipoprotein (a) Lp(a)] and cognition in different ischemic stroke subtypes. Front. Neurol., 2021; 12: 1–8. doi: 10.3389/fneur.2021.736365

10. Pawlos A., Gorzelak-Pabiś P., Staciwa M., Broncel M. Elevated Lp(a) and course of COVID-19: is there a relationship? PLoS One, 2022; 17: 1–10. doi: 10.1371/journal.pone.0266814

11. di Maio S., Lamina C., Coassin S., Forer L., Würzner R., Schönherr S., Kronenberg F. Lipoprotein(a) and SARS-CoV-2 infections: susceptibility to infections, ischemic heart disease and thromboembolic events. J. Intern. Med., 2022; 291: 101–107. doi: 10.1111/joim.13338

12. Interim guidelines “Prevention, diagnosis and treatment of novel coronavirus infection (COVID-19)”. Version 16. Available at: https://static0.minzdrav.gov.ru/system/attachments/attaches/000/060/193/original/ВМР_COVID-19_V16.pdf(date of access – 01.02.2024) (In Russ.)

13. Boytsov S.A., Pogosova N.V., Ansheles A.A., Badtieva V.A., Balakhonova T.V., Barbarash O.L., Vasyuk Yu.A., Gambaryan M.G., Gendlin G.E., Golitsyn S.P., Drapkina O.M., Drozdova L.Yu., Yezhov M.V., Ershova A.I., Zhirov I.V., Karpov Yu.A., Kobalava Zh.D., Kontsevaya A.V., Litvin A.Yu., Lukyanov M.M., Martsevich S.Yu., Matskeplishvili S.T., Metelskaya V.A., Meshkov A.N., Mishina I.E., Panchenko E.P., Popova A.B., Sergienko I.V., Smirnova M.D., Smirnova M.I., Sokolova O.Yu., Starodubova A.V., Sukhareva O.Yu., Ternovoy S.K., Tkacheva O.N., Shalnova S.A., Shestakova M.V. Cardiovascular prevention 2022. Russian national guidelines. Russ. J. Cardiol., 2023; 28 (5): 5452. (In Russ.) doi: 10.15829/1560-4071-2023-5452

14. Walldius G., Jungner I. Apolipoprotein B and apolipoprotein A-I: risk indicators of coronary heart disease and targets for lipidmodifying therapy. J. Internal Med., 2004; 255: 188–205. doi: 10.1046/j.1365-2796.2003.01276.x

15. Carnevale Schianca G.P., Pedrazzoli R., Onolfo S., Colli E., Cornetti E., Bergamasco L., Fra G.P., Bartoli E. ApoB/apoA-I ratio is better than LDL-C in detecting cardiovascular risk. Nutr. Metab. Cardiovasc. Dis., 2011; 21: 406–411. doi: 10.1016/j.numecd.2009.11.002

16. Xiang M., Wu X., Jing H., Novakovic V.A., Shi J. The intersection of obesity and (long) COVID-19: hypoxia, thrombotic inflammation, and vascular endothelial injury. Front. Cardiovasc. Med., 2023; 10: 1062491. doi: 10.3389/fcvm.2023.1062491

17. Ayoubkhani D., Khunti K., Nafilyan V., Maddox T., Humberston B., Diamond I., Banerjee A. Post-covid syndrome in individuals admitted to hospital with COVID-19: retrospective cohort study. BMJ, 2021; 372: n693. doi: 10.1136/bmj.n693

18. Ioannou G.N., Baraff A., Fox A., Shahoumian T., Hickok A., O’Hare A.M., Hynes D.M. Rates and factors associated with documentation of diagnostic codes for long COVID in the National Veterans Affairs Health Care System. JAMA Netw. Open, 2022; 5 (7): e2224359. doi: 10.1001/jamanetworkopen.2022.24359

19. de Vreede J.J., Gorgels A.P., Verstraaten G.M., Vermeer F., Dassen W.R., Wellens H.J. Did prognosis after acute myocardial infarction change during the past 30 years? A meta-analysis. J. Am. Coll. Cardiol., 1991; 18 (3): 698–706. doi: 10.1016/0735-1097(91)90792-8

20. Krempf M., Parhofer K.G., Steg P.G., Bhatt D.L., Ohman E.M., Röther J., Reach Registry Investigators. Cardiovascular event rates in diabetic and nondiabetic individuals with and without established atherothrombosis (from the REduction of Athethrombosis for Continued Health REACH] Registry). Am. J. Cardiol., 2010; 105 (5): 667–671. doi: 1011016/j.amj-card.200910.048

21. Barbarash O.L., Kashtalap V.V. Diagnosis of latent forms of non-coronary atherosclerosis in acute coronary syndrome patients. Is there any practical sense? Complex Issues of Cardiovascular Diseases, 2012; (1): 12–16. (In Russ.) doi: 10.17802/2306-1278-2012-1-12-16

22. Fowkes F.G., Low L.P., Tuta S., Kozak J.; AG-ATHA Investigators. Ankle-brachial index and extent of atherothrombosis in 8891 patients with or at risk of vascular disease: results of the international AGATHA study. Eur. Heart. J., 2006; 27 (15): 1861–1867. doi: 10.1093/eurheartj/ehl114

23. Arutyunov G.P., Tarlovskaya E.I., Arutyunov A.G., Belenkov Yu.N., Konradi A.O., Lopatin Yu.M., Rebrov A.P., Tereshchenko S.N., Chesnikova A.I., Hayrapetyan H.G., Babin A.P., Bakulin I.G., Bakulina N.V., Balykova L.A., Blagonravova A.S., Boldina M.V., Vaisberg A.R., Galyavich A.S., Gomonova V.V., Grigorieva N.Yu., Gubareva I.V., Demko I.V., Evzerikhina A.V., Zharkov A.V., Kamilova U.K., Kim Z.F., Kuznetsova T.Yu., Lareva N.V., Makarova E.V., Malchikova S.V., Nedogoda S.V., Petrova M.M., Pochinka I.G., Protasov K.V., Protsenko D.N., Ruzanov D.Yu., Sayganov S.A., Sarybaev A.Sh., Selezneva N.M., Sugraliev A.B., Fomin I.V., Khlynova O.V., Chizhova O.Yu., Shaposhnik I.I., Schukarev D.A., Abdrahmanova A.K., Avetisian S.A., Avoyan H.G., Azarian K.K., Aimakhanova G.T., Ayipova D.A., Akunov A.Ch., Alieva M.K., Aparkina A.V., Aruslanova O.R., Ashina E.Yu., Badina O.Yu., Barisheva O.Yu., Batchayeva A.S., Bikhteyev I.U., Borodulina N.A., Bragin M.V., Budu A.M., Burygina L.A., Bykova G.A., Varlamova D.D., Vezikova N.N., Verbitskaya E.A., Vilkova O.E., Vinnikova E.A., Vustina V.V., Gаlova E.A., Genkel V.V., Gorshenina E.I., Gostishev R.V., Grigorieva E.V., Gubareva E.Yu., Dabylova G.M., Demchenko A.I., Dolgikh O.Yu., Duvanov I.A., Duyshobayev M.Y., Evdokimov D.S., Egorova K.E., Ermilova A.N., Zheldybayeva A.E., Zarechnova N.V., Ivanova S.Yu., Ivanchenko E.Yu., Ilina M.V., Kazakovtseva M.V., Kazymova E.V., Kalinina Yu.S., Kamardina N.A., Karachenova A.M., Karetnikov I.A., Karoli N.A., Karpov O.V., Karsiev M.Kh., Kaskaeva D.S., Kasymova K.F., Kerimbekova Zh.B., Kerimova A.Sh., Kim E.S., Kiseleva N.V., Klimenko D.A., Klimova A.V., Kovalishena O.V., Kolmakova E.V., Kolchinskaya T.P., Kolyadich M.I., Kondriakova O.V., Konoval M.P., Konstantinov D.Yu., Konstantinova E.A., Kordukova V.A., Koroleva E.V., Kraposhina A.Yu., Kriukova T.V., Kuznetsova A.S., Kuzmina T.Yu., Kuzmichev K.V., Kulchoroeva Ch.K., Kuprina T.V., Kouranova I.V., Kurenkova L.V., Kurchugina N.Yu., Kushubakova N.A., Levankova V.I., Levin M.E., Lyubavina N.A., Magdeyeva N.A., Mazalov K.V., Majseenko V.I., Makarova A.S., Maripov A.M., Marusina A.A., Melnikov E.S., Moiseenko N.B., Muradova F.N., Muradyan R.G., Musaelian Sh.N., Nikitina N.M., Ogurlieva B.B., Odegova A.A., Omarova Yu.M., Omurzakova N.A., Ospanova Sh.O., Pahomova E.V., Petrov L.D., Plastinina S.S., Pogrebetskaya V.A., Polyakov D.S., Ponomarenko E.V., Popova L.L., Prokofeva N.A., Pudova I.A., Rakov N.A., Rakhimov A.N., Rozanova N.A., Serikbolkyzy S., Simonov A.A., Skachkova V.V., Smirnova L.A., Soloveva D.V., Soloveva I.A., Sokhova F.M., Subbotin A.K., Sukhomlinova I.M., Sushilova A.G., Tagayeva D.R., Titojkina Yu.V., Tikhonova E.P., Tokmin D.S., Torgunakova M.S., Trenogina K.V., Trostianetckaia N.A., Trofimov D.A., Tulichev A.A., Tupitsin D.I., Tursunova A.T., Ulanova N.D., Fatenkov O.V., Fedorishina O.V., Fil T.S., Fomina I.Yu., Fominova I.S., Frolova I.A., Tsvinger S.M., Tsoma V.V., Cholponbaeva M.B., Chudinovskikh T.I., Shakhgildyan L.D., Shevchenko O.A., Sheshina T.V., Shishkina E.A., Shishkov K.Yu., Sherbakov S.Y., Yausheva E.A. International register “Dynamics analysis of comorbidities in SARS-CoV-2 survivors” (AKTIV SARS-CoV-2): analysis of predictors of short-term adverse outcomes in COVID-19. Russ. J. Cardiol., 2021; 26 (4): 4470. (In Russ.) doi: 10.15829/1560-4071-2021-4470

24. Nurmohamed N.S., Collard D., Reeskamp L.F., Kaiser Y., Kroon J., Tromp T.R.; Amsterdam UMC Covid-19 Biobank; van den Born B.H., Coppens M., Vlaar A.P.J., Beudel M., van de Beek D., van Es N., Moriarty P.M., Tsimikas S., Stroes E.S.G. Lipoprotein(a), venous thromboembolism and COVID-19: a pilot study. Atherosclerosis, 2021; 341: 43– 49. doi: 10.1016/j.atherosclerosis.2021.12.008

25. Dzobo K.E., Kraaijenhof J.M., Stroes E.S., Nurmohamed N.S., Kroon J. Lipoprotein(a): an underestimated inflammatory mastermind. Atherosclerosis, 2022; 349: 101–109. doi: 10.1016/j.atherosclerosis.2022.04.004

26. Kronenberg F. Human genetics and the causal role of lipoprotein(a) for various diseases. Cardiovasc. Drugs. Ther., 2016; 30 (1): 87–100. doi: 10.1007/s10557-016-6648-3

27. Berezhnoy G., Bissinger R., Liu A., Cannet C., Schäfer H., Kienzle K., Bitzer M., Häberle H., Göpel S., Trautwein C., Singh Y. Maintained imbalance of triglycerides, apolipoproteins, energy metabolites and cytokines in long-term COVID-19 syndrome patients. Front. Immunol., 2023; 14: 1144224. doi: 10.3389/fimmu.2023.1144224

28. Hilser J.R., Han Y., Biswas S., Gukasyan J., Cai Z., Zhu R., Allayee H. Association of serum HDL-cholesterol and apolipoprotein A1 levels with risk of severe SARS-CoV-2 infection. J. Lipid Res., 2021: 62: 100061. doi: 10.1016/j.jlr.2021.100061