Cell-free nucleic acids as biomarkers of cardiovascular diseases: prospects and limitations
L. O. Korneva,
M. A. Osipova,
M. A. Bortsova,
D. A. Kilina,
A. A. Kostareva,
M. Yu. Sitnikova,
A. S. Golovkin,
O. V. Kalinina,
P. A. Fedotov https://doi.org/10.15829/1560-4071-2025-6235
EDN: JLKDRK
Abstract
One of the urgent tasks is the search for early and specific markers of cardiovascular diseases (CVD) in order to stratify the cardiovascular risk, develop methods for their prevention, early diagnosis and treatment. In recent decades, considerable attention has been paid to plasma cell-free nucleic acids free: circulating cell-free DNA (сfDNA) and circulating non-coding RNA, in particular microRNA, which are considered as promising prognostic and diagnostic biomarkers of many pathological conditions, since they play a key role in the regulation of physiological and pathophysiological processes. This review covers current understanding of the potential of plasma cfDNA and microRNA assessment in cardiovascular patients as specific biomarkers for diagnosis, risk stratification, severity assessment and monitoring of CVD, with a focus on coronary artery disease, heart failure and cardiac allograft rejection, where this area of research is promising.
About the Authors
L. O. Korneva
Almazov National Medical Research Center
Russian Federation
Competing Interests:
Russian Federation
Research Assistant of the Research Laboratory of high-tech treatment of heart failure of the Research Department Heart Failure.
Moscow
Competing Interests:
No conflict of interest declared
M. A. Osipova
Almazov National Medical Research Center
Russian Federation
Competing Interests:
Russian Federation
Research Assistant of the Research Laboratory of high-tech treatment of heart failure of the Research Department Heart Failure.
Moscow
Competing Interests:
No conflict of interest declared
M. A. Bortsova
Almazov National Medical Research Center
Russian Federation
Competing Interests:
Russian Federation
M.D., Ph.D. of Medical Sciences, Department Head of Cardiology № 8.
Moscow
Competing Interests:
No conflict of interest declared
D. A. Kilina
Almazov National Medical Research Center
Russian Federation
Competing Interests:
Russian Federation
Head of HLA laboratory of Central Clinical Laboratory.
Moscow
Competing Interests:
No conflict of interest declared
A. A. Kostareva
Almazov National Medical Research Center
Russian Federation
Competing Interests:
Russian Federation
M.D., D. Sc., Director of Institute of Molecular Biology and Genetics.
Moscow
Competing Interests:
No conflict of interest declared
M. Yu. Sitnikova
Almazov National Medical Research Center
Russian Federation
Competing Interests:
Russian Federation
M.D., Professor, Head of Research Department of Heart Failure.
Moscow
Competing Interests:
No conflict of interest declared
A. S. Golovkin
Almazov National Medical Research Center
Russian Federation
Competing Interests:
Russian Federation
M.D., D. Sc., Head of Research Laboratory of Microvesicular signaling of Institute of Molecular Biology and Genetics.
Moscow
Competing Interests:
No conflict of interest declared
O. V. Kalinina
Almazov National Medical Research Center
Russian Federation
Competing Interests:
Russian Federation
D.Sc., Leading Researcher of Research Laboratory of Microvesicular Signaling of Institute of Molecular Biology and Genetics, Professor of Department of Laboratory Medicine with Clinic, Institute of Medical Education.
Moscow
Competing Interests:
No conflict of interest declared
P. A. Fedotov
Almazov National Medical Research Center
Russian Federation
Competing Interests:
Russian Federation
M.D., Ph.D. of Medical Sciences, Leading Researcher and Head Research Laboratory of high-tech treatment of heart failure, Associate Professor at the Department of Cardiology.
Moscow
Competing Interests:
No conflict of interest declared
References
1. Institute for Health Metrics and Evaluation (IHME). Global Burden of Disease 2021: Findings from the GBD 2021 Study. Seattle, WA: IHME, 2024.
2. Magnussen C, Ojeda FM, Leong DP, et al. Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality. N Engl J Med. 2023;389(14):1273-85. doi:10.1056/NEJMoa2206916.
3. Egorenko SN, Afonin MM, Bobkova NA, et al. Russian Statistical Yearbook: Statistical Handbook. Moscow: Federal State Statistics Service (Rosstat), 2023. p. 701. (In Russ.)
4. Roth GA, Mensah GA, Johnson CO, et al. Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study. J Am Coll Cardiol. 2020;76(25):2982-3021. doi:10.1016/j.jacc.2020.11.010. Erratum in: J Am Coll Cardiol. 2021;77(15):1958-9. doi:10.1016/j.jacc.2021.02.039.5.
5. Bays HE, Agarwala A, German C, et al. Ten things to know about ten cardiovascular disease risk factors — 2022. Am J Prev Cardiol. 2022;10:100342. doi:10.1016/j.ajpc.2022.100342.
6. An J, Zhang Y, Muntner P, et al. Recurrent Atherosclerotic Cardiovascular Event Rates Differ Among Patients Meeting the Very High Risk Definition According to Age, Sex, Race/Ethnicity, and Socioeconomic Status. J Am Heart Assoc. 2020;9(23):e017310. doi:10.1161/JAHA.120.017310.
7. Sun J, Qiao Y, Zhao M, et al. Global, regional, and national burden of cardiovascular diseases in youths and young adults aged 15-39 years in 204 countries/territories, 1990-2019: a systematic analysis of Global Burden of Disease Study 2019. BMC Med. 2023;21(1):222. doi:10.1186/s12916-023-02925-4.
8. Joynt Maddox KE, Elkind MSV, Aparicio HJ, et al. Forecasting the Burden of Cardiovascular Disease and Stroke in the United States Through 2050-Prevalence of Risk Factors and Disease: A Presidential Advisory From the American Heart Association. Circulation. 2024;150(4):e65-e88. doi:10.1161/CIR.0000000000001256.
9. de Miranda FS, Barauna VG, dos Santos L, et al. Properties and Application of Cell-Free DNA as a Clinical Biomarker. Int J Mol Sci. 2021;22(17):9110. doi:10.3390/ijms22179110.
10. Jiapaer Z, Li C, Yang X, et al. Extracellular Non-Coding RNAs in Cardiovascular Diseases. Pharmaceutics. 2023;15(1):155. doi:10.3390/pharmaceutics15010155.
11. Oellerich M, Budde K, Osmanodja B, et al. Donor-derived cell-free DNA as a diagnostic tool in transplantation. Front Genet. 2022;13. doi:10.3389/fgene.2022.1031894.
12. Nuzzo PV, Berchuck JE, Korthauer K, et al. Detection of renal cell carcinoma using plasma and urine cell-free DNA methylomes. Nat Med. 2020;26(7):1041-3. doi:10.1038/s41591-020-0933-1.
13. Han DSC, Ni M, Chan RWY, et al. The Biology of Cell-free DNA Fragmentation and the Roles of DNASE1, DNASE1L3, and DFFB. The American Journal of Human Genetics. 2020;106(2):202-14. doi:10.1016/j.ajhg.2020.01.008.
14. Han DSC, Lo YMD. The Nexus of cfDNA and Nuclease Biology. Trends in Genetics. 2021;37(8):758-70. doi:10.1016/j.tig.2021.04.005.
15. Ranucci R. Cell-Free DNA: Applications in Different Diseases. Methods Mol Biol. 2019; 1909:3-12. doi:10.1007/978-1-4939-8973-7_1.
16. Alborelli I, Generali D, Jermann P, et al. Cell-free DNA analysis in healthy individuals by next-generation sequencing: a proof of concept and technical validation study. Cell Death Dis. 2019;10(7):534. doi:10.1038/s41419-019-1770-3.
17. Aliyeva AM, Teplova NV, Kislyakov VA, et al. Cell-free DNA and cardiovascular diseases. RMJ. 2022;5:26-9. (In Russ.) Алиева А. М., Теплова Н. В., Кисляков В. А. и др. Внеклеточная ДНК и сердечно-сосудистые заболевания. РМЖ. 2022;5:26-9.
18. Polina IA, Ilatovskaya DV, DeLeon-Pennell KY. Cell free DNA as a diagnostic and prognostic marker for cardiovascular diseases. Clin Chim Acta. 2020;503:145-50. doi:10.1016/j.cca.2020.01.013.
19. Kananen L, Hurme M, Bürkle A, et al. Circulating cell-free DNA in health and disease — the relationship to health behaviours, ageing phenotypes and metabolomics. Geroscience. 2023;45(1):85-103. doi:10.1007/s11357-022-00590-8.
20. Dutta A, Das M, Ghosh A, Rana S. Molecular and cellular pathophysiology of circulating cardiomyocyte-specific cell free DNA (cfDNA): Biomarkers of heart failure and potential therapeutic targets. Genes Dis. 2023;10(3):948-59. doi:10.1016/j.gendis.2022.08.008.
21. Cui M, Fan M, Jing R, et al. Cell-Free Circulating DNA: A New Biomarker for the Acute Coronary Syndrome. Cardiology. 2013;124(2):76-84. doi:10.1159/000345855.
22. Ren J, Jiang L, Liu X, et al. Heart-specific DNA methylation analysis in plasma for the investigation of myocardial damage. J Transl Med. 2022;20(1):36. doi:10.1186/s12967-022-03234-9.
23. Wang L, Xie L, Zhang Q, et al. Plasma nuclear and mitochondrial DNA levels in acute myocardial infarction patients. Coron Artery Dis. 2015;26(4):296-300. doi:10.1097/MCA.0000000000000231.
24. Cuadrat RRC, Kratzer A, Arnal HG, et al. Cardiovascular disease biomarkers derived from circulating cell-free DNA methylation. NAR Genom Bioinform. 2023;5(2):lqad061. doi:10.1093/nargab/lqad061.
25. Zhang Q, He X, Ling J, Xiang Q, et al. Association Between Circulating Cell-Free DNA Level at Admission and the Risk of Heart Failure Incidence in Acute Myocardial Infarction Patients. DNA Cell Biol. 2022;41(8):742-9. doi:10.1089/dna.2022.0238.
26. Tan E, Liu D, Perry L, et al. Cell-free DNA as a potential biomarker for acute myocardial infarction: A systematic review and meta-analysis. Int J Cardiol Heart Vasc. 2023;47: 101246. doi:10.1016/j.ijcha.2023.101246.
27. Zaigraev IA, Fomenko AN, Krotenko NP, et al. Association of cell-free DNA with the length of ulcerated plaque in the infarct-related artery and the myocardial infarct size among patients with ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention. Russian Journal of Cardiology. 2024;29(8):5957. (In Russ.) doi:10.15829/1560-4071-2024-5957.
28. Trofimova EA, Kireeva VV, Usoltsev YuK, et al. Circulating free DNA in hypertensive patients with high cardiovascular risk. Russian Journal of Cardiology. 2022;27(4):4709. (In Russ.) doi:10.15829/1560-4071-2022-4709.
29. Salzano A, Israr MZ, Garcia DF, et al. Circulating cell-free DNA levels are associated with adverse outcomes in heart failure: testing liquid biopsy in heart failure. Eur J Prev Cardiol. 2021;28(9):e28-e31. doi:10.1177/2047487320912375.
30. Kolesnikova EV, Myachina OV, Pashkov AN. Relationship between free circulating DNA levels, ejection fraction and brain natriuretic peptide levels in patients with chronic heart failure: prospective observational study. Cardiosomatics. 2023;14(3):167-75. (In Russ.) doi:10.17816/CS456434.
31. Khush KK, Patel J, Pinney S, et al. Noninvasive detection of graft injury after heart transplant using donor-derived cell-free DNA: A prospective multicenter study. American Journal of Transplantation. 2019;19(10):2889-99. doi:10.1111/ajt.15339.
32. Agbor-Enoh S, Shah P, Tunc I, et al. Cell-Free DNA to Detect Heart Allograft Acute Rejection. Circulation. 2021;143(12):1184-97. doi:10.1161/CIRCULATIONAHA.120.049098.
33. Diener C, Keller A, Meese E. Emerging concepts of miRNA therapeutics: from cells to clinic. Trends Genet. 2022;38(6):613-26. doi:10.1016/j.tig.2022.02.006.
34. Searles CD. MicroRNAs and Cardiovascular Disease Risk. Curr Cardiol Rep. 2024; 26(2):51-60. doi:10.1007/s11886-023-02014-1.
35. Wang B, Li Y, Hao X, et al. Comparison of the Clinical Value of miRNAs and Conventional Biomarkers in AMI: A Systematic Review. Front Genet. 2021;12:668324. doi:10.3389/fgene.2021.668324.
36. Torres-Paz YE, Gamboa R, Fuentevilla-Álvarez G, et al. Overexpression of microRNA-21-5p and microRNA-221-5p in Monocytes Increases the Risk of Developing Coronary Artery Disease. Int J Mol Sci. 2023;24(10). doi:10.3390/ijms24108641.
37. Zhelankin AV, Stonogina DA, Vasiliev SV, et al. Circulating Extracellular miRNA Analysis in Patients with Stable CAD and Acute Coronary Syndromes. Biomolecules. 2021;11(7): 962. doi:10.3390/biom11070962.
38. Iusupova AO, Pakhtusov NN, Slepova OA, et al. MiRNA-21a, miRNA-145, and miRNA-221 Expression and Their Correlations with WNT Proteins in Patients with Obstructive and Non-Obstructive Coronary Artery Disease. Int J Mol Sci. 2023;24(24):17613. doi:10.3390/ijms242417613.
39. Wang X, Dong Y, Fang T, et al. Circulating MicroRNA-423-3p Improves the Prediction of Coronary Artery Disease in a General Population- Six-Year Follow-up Results From the China-Cardiovascular Disease Study. Circ J. 2020;84(7):1155-62. doi:10.1253/circj.CJ-19-1181.
40. Yu H, Tu YF, Liu HM, et al. Diagnostic utility of circulating plasma microRNA-101a in severity of coronary heart disease. Ir J Med Sci. 2021;190:1391-6. doi:10.1007/s11845-021-02512-7.
41. Polyakova EA, Zaraiskii MI, Mikhaylov EN, et al. Association of myocardial and serum miRNA expression patterns with the presence and extent of coronary artery disease: A cross-sectional study. Int J Cardiol. 2021;322:9-15. doi:10.1016/j.ijcard.2020.08.043.
42. Van Aelst LNL, Summer G, Li S, et al. RNA Profiling in Human and Murine Transplanted Hearts: Identification and Validation of Therapeutic Targets for Acute Cardiac and Renal Allograft Rejection. Am J Transplant. 2016;16(1):99-110. doi:10.1111/ajt.13421.
43. Kong G, Chen Y, Liu Z, et al. Adenovirus-IL-10 relieves chronic rejection after mouse heart transplantation by inhibiting miR-155 and activating SOCS5. Int J Med Sci. 2023; 20(2):172-85. doi:10.7150/ijms.77093.
44. Duong Van Huyen JP, Tible M, Gay A, et al. MicroRNAs as non-invasive biomarkers of heart transplant rejection. Eur Heart J. 2014;35(45):3194-202. doi:10.1093/eurheartj/ehu346.
45. Velikiy DA, Gichkun OE, Sharapchenko SO, et al. MicroRNA expression levels in early and long-term period following heart transplantation. Russian Journal of Transplantology and Artificial Organs. 2020;22(1):26-34. (In Russ.) doi:10.15825/1995-1191-2020-1-26-34.
46. Pérez-Carrillo L, Sánchez-Lázaro I, Triviño JC, et al. Combining Serum miR-144-3p and miR-652-3p as Potential Biomarkers for the Early Diagnosis and Stratification of Acute Cellular Rejection in Heart Transplantation Patients. Transplantation. 2023;107(9):2064-72. doi:10.1097/TP.0000000000004622.
47. Shah P, Agbor-Enoh S, Bagchi P, et al. Circulating microRNAs in cellular and antibody-mediated heart transplant rejection. J Heart Lung Transplant. 2022;41(10):1401-13. doi:10.1016/j.healun.2022.06.019.
Supplementary files
- In recent years, evidence has been obtained on the potential of circulating cell-free nucleic acids as early and specific biomarkers of cardiovascular diseases (CVD) in order to develop methods for early diagnosis, risk stratification and prognosis of the disease.
- The level of cell-free DNA is elevated in patients with CVD, but there are conflicting data regarding its relationship with other myocardial damage markers and its significance as markers of various pathological conditions.
- Assessment of plasma level and profile of circulating microRNAs is a promising approach for the development of methods for early diagnosis, monitoring and prognosis of the outcome of various pathological conditions in CVD.
- Levels of cell-free DNA and microRNA may be a specific marker of heart transplant rejection, which requires further study.
Review
For citations:
Korneva L.O., Osipova M.A., Bortsova M.A., Kilina D.A., Kostareva A.A., Sitnikova M.Yu., Golovkin A.S., Kalinina O.V., Fedotov P.A. Cell-free nucleic acids as biomarkers of cardiovascular diseases: prospects and limitations. Russian Journal of Cardiology. 2025;30(6S):6235. (In Russ.) https://doi.org/10.15829/1560-4071-2025-6235. EDN: JLKDRK
Views:
385
Email this article 