Serum biomarkers of cardiovascular complications in COVID-19

The coronavirus disease 2019 (COVID-19) affects not only the respiratory system, but also the cardiovascular system in 20-28% of cases, causing endothelial dysfunction, vasculitis, hyper- and hypocoagulation, myocarditis, endothelial dysfunction and other adverse effects. The presence of cardiovascular risk factors and diseases has been shown to worsen the disease severity and increase mortality from COVID-19. Recent studies have also found that elevations in some serum cardiovascular biomarkers can stratify the disease severity, in particular rates of hospitalizations to an internal medicine or intensive care unit, intubation, and mortality. They can be divided into markers of damage (TnT/I, creatine phosphokinase (CPK) and CPK-MB, myoglobin, NT-proBNP), coagulation (prothrombin time, fibrinogen and D-dimer), as well as prospective biomarkers for which the available evidence base is limited but there is a pathophysiological rationale (homocysteine and sST2). This review presents studies on the use of above serum biomarkers to stratify the risk of death in patients with COVID-19.

1. Zagidullin NS, Gareeva DF, Ishmetov VS, et al. Renin-angiotensin-aldosterone system in new coronavirus infection 2019. “Arterial'nayaGipertenziya” (“Arterial Hypertension”). 2020;26(3):240-7 (In Russ.) doi:10.18705/1607-419X-2020-26-3-240-247.

2. Lu R, Zhao X, Li J, et al. Genomic characterization and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395:565-74. doi:10.1016/S0140-6736(20)30251-8.

3. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet. 2020;395:1054-62. doi:10.1016/S0140-6736(20)30566-3.

4. Shi S, Qin M, Shen B, et al. Association of Cardiac Injury with Mortality in Hospitalized Patients with COVID-19 in Wuhan, China. JAMA Cardiol. 2020;5(7):802-10. doi:10.1001/jamacardio.2020.0950.

5. Guo T, Fan Y, Chen M, et al. Cardiovascular Implications of Fatal Outcomes of Patients with Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020;5(7):811-8. doi:10.1001/jamacardio.2020.1017.

6. Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities in the novel Wuhan corona-virus (COVID-19) infection: A systematic review and meta-analysis. Int. J. Infect. Dis. 2020;94:91-5. doi:10.1016/j.ijid.2020.03.017.

7. Gohar A, Chong JPC, Liew OW, et al. The prognostic value of highly sensitive cardiac troponin assays for adverse events in men and women with stable heart failure and a preserved vs. reduced ejection fraction. Eur. J. Heart Fail. 2017;19:1638-47. doi:101002/ejhf.911.

8. Khamitova AF, Dozhdev SS, Zagidullin SZ, et al. Serum biomarkers in heart failure and cardiovascular mortality prediction. “Arterial'nayaGipertenziya” (“Arterial Hypertension”). 2018;24(1):101-7 (In Russ.) doi:10.18705/1607-419X-2018-24-1-101-107.

9. Zagidullin N, Motloch LJ, Gareeva D, et al. Combining Novel Biomarkers for Risk Stratification of Two-Year Cardiovascular Mortality in Patients with ST-Elevation Myocardial Infarction. J Clin Med. 2020;9(2):550. doi:10.3390/jcm9020550.

10. Ciaccio M, Agnello L. Biochemical biomarkers alterations in Coronavirus Disease 2019 (COVID-19). Diagnosis (Berl). 2020;7(4):365-72. doi:10.1515/dx-2020-0057.

11. Yang C, Jin Z. An Acute Respiratory Infection Runs Into the Most Common Noncommunicable Epidemic-COVID-19 and Cardiovascular Diseases. JAMA Cardiol. 2020;5(7):743-4. doi:10.1001/jamacardio.2020.0934.

12. Santoso A, Pranata R, Wibowo A, et al. Cardiac injury is associated with mortality and critically ill pneumonia in COVID-19: a meta-analysis. Am J Emerg Med. 2021;44:352-7. doi:10.1016/j.ajem.2020.04.052.

13. Boytsov SA, Pogosova NV, Paleev FN, et al. Clinical Characteristics and Factors Associated with Poor Outcomes in Hospitalized Patients with Novel Coronavirus Infection COVID-19. Kardiologiia. 2021;61(2):4-14. (In Russ.) doi:10.18087/cardio.2021.2.n1532.

14. Lippi G, Lavie CJ, Sanchis-Gomar F. Cardiac troponin I in patients with coronavirus disease 2019, (COVID-19): Evidence from a meta-analysis. ProgCardiovasc Dis. 2020;63(3):390-1. doi:10.1016/j.pcad.2020.03.001.

15. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-9. doi:10.1001/jama.2020.1585.

16. Dawson D, Dominic P, Sheth A, Modi M. Prognostic value of Cardiac Biomarkers in COVID-19 Infection: A Meta-analysis. Res Sq [Preprint]. 2020:rs.3.rs-34729. doi:10.21203/rs.3.rs-34729/v1. Update in: Sci Rep. 2021;11(1):4930.

17. Wan S, Xiang Y, Fang W, et al. Clinical Features and Treatment of COVID-19 Patients in Northeast Chongqing. J Med Virol. 2020;92(7):797-806. doi:10.1002/jmv.25783.

18. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coro-navirus in Wuhan, China. Lancet. 2020;395:497-506. doi:10.1016/S0140-6736(20)30183-5.

19. Qin JJ, Cheng X, Zhou F, et al. Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19. Hypertension. 2020;76(4):1104-12. doi:10.1161/HYPERTENSIONAHA.120.15528.

20. Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417-8. doi:10.1016/S0140-6736(20)30937-5.

21. Spiezia L, Boscolo A, Poletto F, et al. COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure. Thromb Haemost. 2020;120(6):998-1000. doi:10.1055/s-0040-1710018.

22. Panigada M, Bottino N, Tagliabue P, et al. Hypercoagulability of COVID-19 patients in intensive care unit. A report of thromboelastography findings and other parameters of hemostasis. J ThrombHaemost. 2020;18(7):1738-42. doi:10.1111/jth.14850.

23. Zatroch I, Smudla A, Babik B, et al. Procoagulation, hypercoagulation and fibrinolytic “shut down” detected with ClotPro viscoelastic tests in COVID-19 patients. [In Hu.]. ORV Hetil. 2020;161(22):899-907 doi:10.1556/650.2020.31870.

24. Tang N, Li D, Wang X, et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J. Thromb. Haemost. 2020;18:844-7. doi:10.1111/jth.14768.

25. Wang K, Zuo P, Liu Y, et al. Clinical and laboratory predictors of in-hospital mortality in patients with COVID-19: a cohort study in Wuhan, China. Clin Infect Dis. 2020;71(16):2079-88. doi:10.1093/cid/ciaa538.

26. Qin L, Li X, Shi J, et al. Gendered effects on inflammation reaction and outcome of COVID-19 patients in Wuhan. J Med Virol. 2020;92(11):2684-92. doi:10.1002/jmv.26137.

27. Ciccone MM, Cortese F, Gesualdo M, et al. A novel cardiac bio-marker: ST2: A review. Molecules. 2013;18:15314-28. doi:10.3390/molecules181215314.

28. Miftode RS, Petris AO, Onofrei AV, et al. The Novel Perspectives Opened by ST2 in the Pandemic: A Review of Its Role in the Diagnosis and Prognosis of Patients with Heart Failure and COVID-19. Diagnostics (Basel). 2021;11(2):175. doi:10.3390/diagnostics11020175.

29. Junyi G, Zheng H, Li L, et al. Coronavirus Disease 2019 (COVID-19) and Cardiovascular Disease: A Viewpoint on the Potential Influence of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on Onset and Severity of Severe Acute Respiratory Syndrome Coronavirus 2 Infec. J. Am. Heart Assoc. 2020;9:e016219. doi:10.1161/JAHA.120.016219.

30. Bavishi C, Maddox TM, Messerli FH. Coronavirus Disease 2019 (COVID-19) Infection and Renin Angiotensin System Blockers. JAMA Cardiol. 2020;5(7):745-7. doi:10.1001/jamacardio.2020.1282.

31. Wen H. Oxidative stress-mediated effects of angiotensin II in the cardiovascular system. World J. Hypertens. 2012;2:34-44. doi:10.5494/wjh.v2.i4.34.

32. Zou Z, Yan Y, Shu Y, et al. Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections. Nat Commun. 2014;5:3594. doi:10.1038/ncomms4594.

33. Gomolak JR, Didion SP. Angiotensin II-induced endothelial dysfunction is temporally linked with increases in interleukin-6 and vascular macrophage accumulation. Front Physiol. 2014;5:396. doi:10.3389/fphys.2014.00396.

34. Mendoza-Torres E, Oyarzun A, Mondaca-Ruff D, et al. ACE2 and vasoactive peptides: novel players in cardiovascular renal remodeling and hypertension. Ther Adv Cardiovasc Dis. 2015;9(4):217-37 doi:10.1177/1753944715597623.

35. Arendse LB, Danser AHJ, Poglitsch M, et al. Novel therapeutic approaches targeting the renin — angiotensin system and associated peptides in hypertension and heart failure. Pharmacol Rev. 2019;71(4):539-70. doi:10.1124/pr.118.017129.

36. Qaradakhi T, Apostolopoulos V, Zulli A. Angiotensin (1-7) and alamandine: similarities and differences. Pharmacol Res. 2016;111:820-6. doi:10.1016/j.phrs.2016.07.025.

37. Hrenak J, Paulis L, Simko F. Angiotensin A/alamandine/MrgD axis: another clue to understanding cardiovascular pathophysiology. Int J Mol Sci. 2016; 17. doi: 10.3390/ijms17071098.

38. Liu Y, Yang Y, Zhang C, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci. China Life Sci. 2020;63:364-74. doi:10.1007/s11427-020-1643-8.

39. Balint B, Jepchumba VK, Gueant JL, et al. Mechanisms of homocysteine-induced damage to the endothelial, medial and adventitial layers of the arterial wall. Biochimie. 2020;173:100-6. doi:10.1016/j.biochi.2020.02.012.

40. Graham IM, Daly LE, Refsum HM, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA. 1997;277(22):1775-81. doi:10.1001/jama.1997.03540460039030.

41. Guo H, Chi J, Xing Y, et al. Influence of folic acid on plasma homocysteine levels & arterial endothelial function in patients with unstable angina. Indian J Med Res. 2009;129:279-84.

42. Yang Z, Shi J, He Z, et al. Predictors for imaging progression on chest CT from coronavirus disease 2019 (COVID-19) patients. Aging. 2020;12:6037-48. doi:10.18632/aging.102999.

43. Inciardi RM, Adamo M, Lupi L, et al. Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy. Eur Heart J. 2020;41(19):1821-9. doi:10.1093/eurheartj/ehaa388.

44. Terpos E, Ntanasis-Stathopoulos I, Elalamy I, et al. Hematological findings and complications of COVID-19. Am J Hematol. 2020;95(7):834-47 doi:10.1002/ajh.25829.