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Associations of clonal hematopoiesis with recurrent vascular events and death in patients with incident ischemic stroke

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Arends, Christopher M., Liman, Thomas G., Strzelecka, Paulina M., Kufner, Anna, Löwe, Pelle, Huo, Shufan, Stein, Catarina M., Piper, Sophie K. +10 more·2023·Blood
DOI 10.1182/blood.2022017661
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Abstract

Clonal hematopoiesis (CH) is common among older people and is associated with an increased risk of atherosclerosis, inflammation, and shorter overall survival. Age and inflammation are major risk factors for ischemic stroke, yet the association of CH with risk of secondary vascular events and death is unknown. We investigated CH in peripheral blood DNA from 581 patients with first-ever ischemic stroke from the Prospective Cohort With Incident Stroke–Berlin study using error-corrected targeted sequencing. The primary composite end point (CEP) consisted of recurrent stroke, myocardial infarction, and all-cause mortality. A total of 348 somatic mutations with a variant allele frequency ≥1% were identified in 236 of 581 patients (41%). CH was associated with large-artery atherosclerosis stroke (P = .01) and white matter lesion (P < .001). CH-positive patients showed increased levels of proinflammatory cytokines, such as interleukin-6 (IL-6), interferon gamma, high-sensitivity C-reactive protein, and vascular cell adhesion molecule 1. CH-positive patients had a higher risk for the primary CEP (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.04-2.31; P = .03), which was more pronounced in patients with larger clones. CH clone size remained an independent risk factor (HR, 1.30; 95% CI, 1.04-1.62; P = .022) in multivariable Cox regression. Although our data show that, in particular, larger and TET2- or PPM1D-mutated clones are associated with increased risk of recurrent vascular events and death, this risk is partially mitigated by a common germline variant of the IL-6 receptor (IL-6R p.D358A). The CH mutation profile is accompanied by a proinflammatory profile, opening new avenues for preventive precision medicine approaches to resolve the self-perpetuating cycle of inflammation and clonal expansion.

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  • CHIP robustly increases the risk of atherosclerotic cardiovascular disease, ischemic stroke, and cerebral small vessel disease, conditions that independently contribute to cognitive impairment and dementia.

    “CHIP robustly increases the risk of atherosclerotic cardiovascular disease, ischemic stroke, and cerebral small vessel disease, conditions that independently contribute to cognitive impairment and dementia [4,5,15,16].”

    From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [5]

    The Introduction reports an increased ischemic-stroke risk in people with clonal hematopoiesis, and the baseline-characteristics and white-matter-lesion sections find associations with large-artery atherosclerosis and lesions considered a marker of small-vessel disease. But this stroke-patient study does not establish that CHIP causally increases the risk of all three conditions; the white-matter-lesion section only links those lesions to neurodegenerative conditions, not that all three independently contribute to cognitive impairment and dementia. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • CHIP is associated with increased all-cause mortality and a broad spectrum of non-malignant diseases, most prominently atherosclerotic cardiovascular disease and stroke.

    “CHIP has emerged as a clinically relevant state associated with increased all-cause mortality and a broad spectrum of non-malignant diseases, most prominently atherosclerotic cardiovascular disease and stroke [1,4,5].”

    From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [5]

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Authors
Arends, C. M., Liman, T. G., Strzelecka, P. M., Kufner, A., Löwe, P., Huo, S., Stein, C. M., Piper, S. K., Tilgner, M., Sperber, P. S., Dimitriou, S., Heuschmann, P. U., Hablesreiter, R., Harms, C., Bullinger, L., Weber, J. E., Endres, M., & Damm, F.
Affiliations
  • Humboldt-Universität zu Berlin (DE)
  • Carl von Ossietzky Universität Oldenburg (DE)
  • Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
  • Max Delbrück Center (DE)
  • University of Würzburg (DE)
  • German Cancer Research Center (DE)
  • German Center for Neurodegenerative Diseases (DE)
  • 1Department of Hematology, Oncology, and Cancer Immunology, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2023-02-16
Volume
141
Issue
7
Pages
787-799
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood.2022017661
OpenAlex
W4310109023
Cited by
99
References
10
Citations by year
2026: 23 · 2025: 28 · 2024: 32 · 2023: 16
FWCI
13.81
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
Funders
American Society of Hematology
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
  • Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
Keywords
clonal hematopoiesis, ischemic stroke, recurrent vascular events, all-cause mortality, somatic mutations, clone size, TET2 mutation, PPM1D mutation, interleukin-6, inflammatory cytokines, white matter lesions, inflammation, cardiovascular risk
MeSH terms
Clonal Hematopoiesis, Ischemic Stroke, Aged, Hematopoiesis, Humans, Inflammation, Mutation, Prospective Studies, Stroke, Atherosclerosis

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