Association of Mutations Contributing to Clonal Hematopoiesis With Prognosis in Chronic Ischemic Heart Failure
Open accessAbstract
Importance: Somatic mutations causing clonal expansion of hematopoietic cells (clonal hematopoiesis of indeterminate potential [CHIP]) are increased with age and associated with atherosclerosis and inflammation. Age and inflammation are the major risk factors for heart failure, yet the association of CHIP with heart failure in humans is unknown. Objective: To assess the potential prognostic significance of CHIP in patients with chronic heart failure (CHF) owing to ischemic origin. Design, Setting, and Participants: We analyzed bone marrow-derived mononuclear cells from 200 patients with CHF by deep targeted amplicon sequencing to detect the presence of CHIP and associated such with long-term prognosis in patients with CHF at University Hospital Frankfurt, Frankfurt, Germany. Data were analyzed between October 2017 and April 2018. Results: Median age of the patients was 65 years. Forty-seven mutations with a variant allele fraction (VAF) of at least 0.02 were found in 38 of 200 patients with CHF (18.5%). The somatic mutations most commonly occurred in the genes DNMT3A (14 patients), TET2 (9 patients), KDM6A (4 patients), and BCOR (3 patients). Patients with CHIP were older and more frequently had a history of hypertension. During a median follow-up of 4.4 years, a total of 53 patients died, and 23 patients required hospitalization for heart failure. There was a significantly worse long-term clinical outcome for patients with either DNMT3A or TET2 mutations compared with non-CHIP carriers. By multivariable Cox proportional regression analysis, the presence of somatic mutations within TET2 or DNMT3A (HR, 2.1; 95% CI, 1.1-4.0; P = .02, for death combined with heart failure hospitalization) and age (HR, 1.04; 95% CI, 1.01-1.07 per year; P = .005) but not a history of hypertension remained independently associated with adverse outcome. Importantly, there was a significant dose-response association between VAF and clinical outcome. Conclusions and Relevance: Our data suggest that somatic mutations in hematopoietic cells, specifically in the most commonly mutated CHIP driver genes TET2 and DNMT3A, may be significantly associated with the progression and poor prognosis of CHF. Future studies will have to validate our findings in larger cohorts and address whether targeting specific inflammatory pathways may be valuable for precision medicine in patients with CHF carrying specific mutations encoding for CHIP.
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Higher TET2 mutant clone sizes associate with higher mortality from heart failure (VAF > 2%).
“and mortality from heart failure (VAF > 2%).38”
From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [38]
The Results (Prognostic Significance of CHIP in Patients With Heart Failure; page unavailable) report a dose-response association between clone size and survival, including a VAF group of at least 0.02. The Discussion says increased mortality was mainly driven by heart-failure progression. However, the clone-size analysis groups TET2 with DNMT3A; it does not establish the stated association for TET2 alone. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIndividuals with post-MI related congestive heart failure who carry CHIP-associated DNMT3A or TET2 mutations have worse survival outcomes than individuals without CHIP.
“Recent evidence suggests that individuals with post-MI related congestive heart failure who carry CHIP-associated DNMT3A or TET2 mutations have worse survival outcomes than individuals without CHIP 81.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [81]
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- Authors
- Dorsheimer, L., Assmus, B., Rasper, T., Ortmann, C. A., Ecke, A., Abou-El-Ardat, K., Schmid, T., Brüne, B., Wagner, S., Serve, H., Hoffmann, J., Seeger, F., Dimmeler, S., Zeiher, A. M., & Rieger, M. A.
- Affiliations
- University Hospital Frankfurt (DE)
- German Centre for Cardiovascular Research (DE)
- Goethe University Frankfurt (DE)
- Department of Medicine, Hematology/Oncology, Goethe University Hospital, Frankfurt, Germany
- German Cancer Research Center (DE)
- Corresponding author
- Zeiher, Andreas M.
- ORCID
- Venue
- JAMA Cardiology
- Publisher
- American Medical Association (AMA)
- Published
- 2019-01-01
- Volume
- 4
- Issue
- 1
- Pages
- 25
- ISSN
- 2380-6583 (ISSN-L)
- PMC
- PMC6439691
- OpenAlex
- W2904739194
- Cited by
- 470
- References
- 22
- Citations by year
- 2026: 44 · 2025: 63 · 2024: 60 · 2023: 60 · 2022: 87 · 2021: 60 · 2020: 58 · 2019: 36 · 2018: 1 · 2012: 1
- FWCI
- 27.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- JAMA Cardiology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Keywords
- clonal hematopoiesis of indeterminate potential, chronic ischemic heart failure, somatic mutations, DNMT3A, TET2, prognostic factors, variant allele frequency, bone marrow mononuclear cells, heart failure hospitalization, mortality, age, hypertension, clonal expansion, atherosclerosis, inflammation, deep amplicon sequencing, driver genes, KDM6A
- MeSH terms
- DNA Methyltransferase 3A, Aged, Alleles, Bone Marrow Cells, Chronic Disease, DNA (Cytosine-5-)-Methyltransferases, DNA-Binding Proteins, Female, Heart Failure, Hematopoiesis, Hospitalization, Humans, Hypertension, Inflammation, Male, Middle Aged, Monocytes, Mutation, Prognosis, Proto-Oncogene Proteins, Risk Factors, Myocardial Ischemia, Dioxygenases, Atherosclerosis, Clonal Evolution
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