DNMT3A clonal hematopoiesis — driver mutations in patients with chronic heart failure with mildly reduced ejection fraction of ischemic etiology: an opinion of the problem and the long-term clinical case series

Clonal Hematopoiesis of Indeterminate Potential (CHIP) is a widely studied age-related phenomenon associated with both hematological malignant neoplasms and an unfavorable prognosis of atherosclerotic cardiovascular diseases and chronic heart failure (HF), as well as related to other conditions in the pathogenesis of which low-grade systemic inflammation is involved.

This article outlines current knowledge about the CHIP. Results of a long-term clinical follow-up of two men with cardiometabolic risk factors, coronary artery disease (СAD), post-infarction cardiosclerosis and HF with mildly reduced ejection fraction, who carrying clonal hematopoiesis — driver mutations in DNMT3A gene with high clone sizes (VAF 15.4 % and VAF 8.7 %) are presented. CHIP- DNMT3A mutations in patients were detected at the ages of 47 and 65 years. Genetic testing was performed by next-generation sequencing using a targeted gene panel for CHIP. Over a 7-year period, despite having CHIP, these patients experienced a relatively favorable course of CAD and HF. However, they developed other non-cardiovascular conditions: bilateral coxarthrosis with total hip arthroplasty (in a younger patient) and gastric cancer.

The paper discusses methodological nuances of CHIP detection and unresolved clinical aspects regarding long-term patient management strategies. The authors consider a multidisciplinary approach to managing patients with CHIP appears optimal, potentially within the framework of specialized outpatient clinics as part of preventive personalized medicine.

1. Genovese G, Kähler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood dna sequence. New England Journal of Medicine. 2014;371(26):2477–2487. doi: 10.1056/NEJMOA1409405

2. Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126(1):9–16. doi: 10.1182/BLOOD-2015-03-631747

3. Jaiswal S, Natarajan P, Silver AJ, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. New England Journal of Medicine. 2017;377(2):111–121. doi: 10.1056/NEJMOA1701719

4. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. New England Journal of Medicine. 2014;371(26):2488–2498. doi: 10.1056/NEJMOA1408617

5. Lyasnikova EA, Ivanchenko LY, Kozlova SN, et al. Clonal hematopoiesis of indeterminate potential and heart failure. Russian Journal of Cardiology. 2024;29(11S):6016. (In Russ.) doi: 10.15829/1560-4071-2024-6016

6. Marshall CH, Gondek LP, Luo J, Antonarakis ES. Clonal hematopoiesis of indeterminate potential in patients with solid tumor malignancies. Cancer Res. 2022;82(22):4107–4113. doi: 10.1158/0008-5472.CAN-22-0985

7. Coombs CC, Zehir A, Devlin SM, et al. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell. 2017;21(3):374–382.e4. doi: 10.1016/j.stem.2017.07.010

8. Cacic AM, Schulz FI, Germing U, et al. Molecular and clinical aspects relevant for counseling individuals with clonal hematopoiesis of indeterminate potential. Front Oncol. 2023;13. doi: 10.3389/FONC.2023.1303785

9. Singh J, Li N, Ashrafi E, et al. Clonal hematopoiesis of indeterminate potential as a prognostic factor : a systematic review and meta-analysis. Blood Adv. 2024;8(14):3771–3784. doi: 10.1182/BLOODADVANCES.2024013228

10. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. New England Journal of Medicine. 2014;371(26):2488–2498. doi: 10.1056/NEJMOA1408617

11. Weeks LD, Niroula A, Neuberg D, et al. Prediction of risk for myeloid malignancy in clonal hematopoiesis. NEJM Evidence. 2023;2(5). doi: 10.1056/EVIDOA2200310

12. Gu M, Kovilakam SC, Dunn WG, et al. Multiparameter prediction of myeloid neoplasia risk. Nat Genet. 2023;55(9):1523–1530. doi: 10.1038/S41588-023-01472-1

13. Hecker JS, Hartmann L, Rivière J, et al. CHIP and hips: clonal hematopoiesis is common in patients undergoing hip arthroplasty and is associated with autoimmune disease. Blood. 2021;138(18): 1727–1732. doi: 10.1182/BLOOD.2020010163

14. Tan HSV, Jiang H, Wang SSY. Biomarkers in clonal haematopoiesis of indeterminate potential (CHIP) linking cardiovascular diseases, myeloid neoplasms and inflammation. Ann Hematol. 2025;104(3):1355–1366. doi: 10.1007/S00277-025-06244-X/TABLES/1

15. Tan Y, Zhu X, Huang Y, et al. Clonal hematopoiesis of indeterminate potential is associated with incident abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol. 2025;45(7):1326–1336. doi: 10.1161/ATVBAHA.124.322630

16. Li Z, Huang W, Yin JC, et al. Comprehensive next-generation profiling of clonal hematopoiesis in cancer patients using paired tumor-blood sequencing for guiding personalized therapies. Clin TranslMed. 2020;10(7). doi: 10.1002/CTM2.222

17. Petinati NA, Drize NI. Clonal hematopoiesis and its role in the development of hematological diseases. Russian journal of hematology and transfusiology. 2021;66(4):580–592. (In Russ.) doi: 10.35754/0234-5730-2021-66-4-580-592

18. Hoermann G. Clinical significance of clonal hematopoiesis of indeterminate potential in hematology and cardiovascular disease. Diagnostics. 2022;12(7). doi: 10.3390/DIAGNOSTICS12071613

19. Libby P, Sidlow R, Lin AE, et al. Clonal hematopoiesis: crossroads of aging, cardiovascular disease, and cancer: JACC review topic of the week. J Am Coll Cardiol. 2019;74(4):567–577. doi: 10.1016/J.JACC.2019.06.007