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Cited by 41Acute Myeloid Leukemia ResearchAcute Ischemic Stroke ManagementMyeloproliferative Neoplasms: Diagnosis and Treatment

Prevalence and Therapeutic Implications of Clonal Hematopoiesis of Indeterminate Potential in Young Patients With Stroke

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Mayerhofer, Ernst, Strecker, Christoph, Becker, Heiko, Georgakis, Marios K., Uddin, Md Mesbah, Hoffmann, Michael M., Nadarajah, Niroshan, Meggendorfer, Manja +6 more·2023·Stroke
DOI 10.1161/strokeaha.122.041416PMC PMC10050122
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Abstract

Background: Undetermined stroke etiology hampers optimal secondary prevention in a large proportion of young patients. We explored whether genetic screening for clonal hematopoiesis of indetermined potential (CHIP), a novel risk factor for stroke, could identify patients with myeloid precursor lesions or covert myeloid neoplasm requiring specific treatment. Methods: We performed targeted sequencing on 56 genes recurrently mutated in hematologic neoplasms in a prospective cohort of patients with acute brain ischemia between 18 and 60 years. CHIP prevalence was compared with age-matched healthy controls from the Nijmegen Biomedical Study (n=1604) and the UK Biobank (n=101 678). Patients with suspicion of high-risk CHIP or myeloid neoplasm were invited for further hematologic evaluation. Results: We included 248 consecutive patients (39% women) of whom 176 (71%) had cryptogenic stroke etiology. Fifty-one (21%) patients had CHIP, 3-fold more than in the general population (7.7% versus 2.6% for the Nijmegen Biomedical Study and 11.9% versus 4.1% for UK Biobank; P <0.001 for both). Patients with CHIP were older (median [interquartile range], 53 [50–59] versus 51 [41–56] years; P <0.001), had higher carotid intima-media thickness (0.68 [0.58–0.80] versus 0.59 [0.51–0.73] mm; P =0.009), and had higher burden of atherosclerosis (29.4% versus 16.7%; P =0.04). We invited 11 patients (4.4%) for further hematologic assessment, which in 7 led to the diagnosis of high-risk CHIP and in 2 to the new diagnosis of a myeloproliferative neoplasm with indication for cytoreductive therapy. Conclusions: Using genetic screening for myeloid disorders in patients with stroke of predominantly undetermined etiology, we found a 3-fold higher CHIP prevalence than in the general population. We identified high-risk CHIP and previously covert myeloproliferative neoplasms as potential stroke etiologies in 4.4% and 1% of patients, respectively. Our findings demonstrate the diagnostic and therapeutic yield of genetic screening in young patients with stroke. Future studies should investigate the role of CHIP for stroke recurrence and optimal secondary prevention.

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  • CHIP is strongly and well-established associated with vascular disease, stroke, and cerebrovascular pathology.

    “A critical yet underappreciated aspect of this emerging literature is the strong and well-established association of CHIP with vascular disease, stroke, and cerebrovascular pathology [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 [16]

    The Introduction reports a higher risk of atherosclerotic cardiovascular disease in CHIP carriers, and the Results find associations with carotid intima-media thickness and aortic plaques in young stroke patients. But the Discussion says the association with stroke etiology was not significant and that CHIP’s role in stroke remains uncertain, so calling the entire association ‘strong and well-established’ overstates this source. Page numbers were not provided in our copy. (LLM, conf=0.85)

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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 [16]

    The Introduction reports a higher risk of atherosclerotic cardiovascular disease in CHIP carriers and cites evidence of increased small-vessel ischemic stroke risk. The Results find more atherosclerotic disease among patients with CHIP, but the Discussion cautions that its causal role in stroke remains uncertain. The paper does not establish increased risk of cerebral small vessel disease as distinct from small-vessel stroke, or address whether these conditions independently contribute to cognitive impairment and dementia (no page numbers provided). (LLM, conf=0.87)

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  • In the cerebral circulation, CHIP-associated processes manifest as increased risk of ischemic stroke, white matter hyperintensities, lacunar infarcts, and microvascular injury, which are hallmarks of cerebral small vessel disease strongly associated with cognitive decline and executive dysfunction.

    “In the cerebral circulation, these processes manifest as increased risk of ischemic stroke, white matter hyperintensities, lacunar infarcts, and microvascular injury, which are hallmarks of cerebral small vessel disease strongly associated with cognitive decline and executive dysfunction [16,17].”

    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 [16]

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Cited by

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Authors
Mayerhofer, E., Strecker, C., Becker, H., Georgakis, M. K., Uddin, M. M., Hoffmann, M. M., Nadarajah, N., Meggendorfer, M., Haferlach, T., Rosand, J., Natarajan, P., Anderson, C. D., Harloff, A., & Hoermann, G.
Affiliations
  • Broad Institute (US)
  • University of Freiburg (DE)
  • Munich Leukemia Laboratory (Germany) (DE)
  • Brigham and Women's Hospital (US)
ORCID
Venue
Stroke
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2023-04
Volume
54
Issue
4
Pages
938-946
ISSN
  • 0039-2499 (ISSN-L)
  • 1524-4628
DOI
10.1161/strokeaha.122.041416
PMC
PMC10050122
OpenAlex
W4320857871
Cited by
41
References
4
Citations by year
2026: 7 · 2025: 16 · 2024: 14 · 2023: 4
FWCI
8.47
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Stroke (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, other-oa)
Funders
  • American Heart Association (18SFRN34250007)
  • Amgen
  • Massachusetts General Hospital
  • Jazz Pharmaceuticals
  • Incyte
  • Deutsche Forschungsgemeinschaft
  • Fondation Leducq
  • Albert-Ludwigs-Universität Freiburg
  • Ludwig-Maximilians-Universität München
  • National Institutes of Health
  • Medizinische Fakultät der Albert-Ludwigs-Universität Freiburg
  • National Heart, Lung, and Blood Institute (R01HL148050)
  • National Institute of Neurological Disorders and Stroke (U01NS069763, R01NS103924)
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 of indeterminate potential, cryptogenic stroke, young stroke patients, myeloproliferative neoplasms, genetic screening, targeted sequencing, stroke etiology, secondary stroke prevention, carotid intima-media thickness, atherosclerosis, cytoreductive therapy
MeSH terms
Clonal Hematopoiesis, Female, Hematopoiesis, Humans, Male, Mutation, Prospective Studies, Prevalence, Hematologic Neoplasms, Stroke, Carotid Intima-Media Thickness

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