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

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.

Clonal hematopoiesis of indeterminate potential and clonal cytopenias of undetermined significance: 2023 update on clinical associations and management recommendations

“…72,73 CH was also associated with increased white matter lesion load and proinflammatory profile among patients with ischemic stroke, and specifically patients with TET2 and PPM1D CH were associated with a higher risk for secondary vascular events and death after ischemic stroke. 73 DNMT3A CH has been associated with osteoporosis. 11 CH has inconsistently been associated with COVID-19 morbidity and mortality, [74][75][76] with associations existing with regards to increased severity of Clostridium difficile, and Streptococcus/Enterococcus infections.…”

“…CH has been associated with increased of stroke; TET2 CH is associated with both overall and ischemic stroke, while DNMT3A is associated with increased risk of hemorrhagic stroke 72,73 . CH was also associated with increased white matter lesion load and proinflammatory profile among patients with ischemic stroke, and specifically patients with TET2 and PPM1D CH were associated with a higher risk for secondary vascular events and death after ischemic stroke 73 . DNMT3A CH has been associated with osteoporosis 11 .…”

“…Similarly, CH (primarily, DNMT3A and TET2 ) occurrence has been associated with occurrence of severe chronic obstructive pulmonary disease, 12 lung cancer, 70 chronic kidney disease, 71 and gout 13 . CH has been associated with increased of stroke; TET2 CH is associated with both overall and ischemic stroke, while DNMT3A is associated with increased risk of hemorrhagic stroke 72,73 . CH was also associated with increased white matter lesion load and proinflammatory profile among patients with ischemic stroke, and specifically patients with TET2 and PPM1D CH were associated with a higher risk for secondary vascular events and death after ischemic stroke 73 .…”

Soluble Vascular Cell Adhesion Molecule-1 as an Inflammation-Related Biomarker of Coronary Slow Flow

“…It is currently believed that CSF may be related to factors such as inflammation, decreased vascular endothelial function, and abnormal microvascular reserve function [ 4 , 7 , 8 , 9 , 10 , 11 ]. Numerous studies have demonstrated that inflammation plays an important role in the occurrence and development of cardiovascular and microvascular diseases [ 12 , 13 , 14 ]. Nevertheless, the role of inflammation in the occurrence and development of CSF remains unclear.…”

Clonal hematopoiesis in idiopathic cytopenia of undetermined significance

“…CH has been recognized as a premalignant state predisposing to hematological malignancies [5,6]. Moreover, CH also confers risks for non-hematological diseases, such as coronary heart disease and rheumatoid arthritis [7][8][9][10][11].…”