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

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Item Type:Article
Title:Associations of clonal hematopoiesis with recurrent vascular events and death in patients with incident ischemic stroke
Creators Name:Arends, C.M. and Liman, T.G. and Strzelecka, P.M. and Kufner, A. and Löwe, P. and Huo, S. and Stein, C.M. and Piper, S.K. and Tilgner, M. and Sperber, P.S. and Dimitriou, S. and Heuschmann, P. and Hablesreiter, R. and Harms, C. and Bullinger, L. and Weber, J.E. and Endres, M. and Damm, F.
Abstract:Clonal hematopoiesis (CH) is common among older people and 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 (PROSCIS-B) using error-corrected targeted sequencing. The primary composite endpoint (CEP) consisted of recurrent stroke, myocardial infarction, and all-cause mortality. 348 somatic mutations with a variant allele frequency ≥ 1% were identified in 236/581 patients (41%). CH was associated with large-artery atherosclerosis stroke (P = 0.01) and white matter lesion (P < 0.001). CH-positive patients showed increased levels of pro-inflammatory cytokines such as IL-6, IFN-γ, hsCRP, and VCAM-1. CH-positive patients had a higher risk for the primary CEP (HR: 1.55, 95%-CI 1.04 - 2.31, P = 0.03), 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 = 0.022) in multivariable Cox regression. While 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 pro-inflammatory profile opening new avenues for preventive precision medicine approaches to resolve the self-perpetuating cycle of inflammation and clonal expansion.
Keywords:Atherosclerosis, Clonal Hematopoiesis, Hematopoiesis, Inflammation, Ischemic Stroke, Mutation, Prospective Studies, Stroke
Publisher:American Society of Hematology
Page Range:787-799
Date:16 February 2023
Additional Information:Copyright © 2023 by The American Society of Hematology
Official Publication:https://doi.org/10.1182/blood.2022017661
PubMed:View item in PubMed

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