In patients with incident ischemic stroke, the presence of clonal hematopoiesis increased the risk of a second vascular event (e.g., stroke, myocardial infarction) or death, compared with patients without clonal hematopoiesis, according to results of a large prospective study published in Blood. Patients with large clones or TET2- or PPM1D-driven clonal hematopoiesis were particularly at risk.
“Clonal hematopoiesis is a new and independent risk factor for recurrent vascular events and death in patients with incident ischemic stroke,” said co-corresponding author Frederik Damm, DrMed, of the Charité University Medical Center in Berlin.
Clonal hematopoiesis, a condition that is common in older people and is defined by the acquisition of somatic mutations in four hematopoietic cells, is associated with an increased risk of atherosclerosis, inflammation, and shorter overall survival. While age and inflammation are risk factors for ischemic stroke, the association of clonal hematopoiesis with the risk of secondary vascular events and mortality is unknown.
In this study, the researchers used error-corrected targeted sequencing to investigate clonal hematopoiesis in peripheral blood DNA from 581 patients (mean age = 68; 61.4% female) with first-ever ischemic stroke from the Prospective Cohort with Incident Stroke-Berlin study (PROSCIS-B). The primary composite endpoint comprised recurrent stroke, myocardial infarction, and all-cause mortality.
A total of 348 somatic mutations with a variant allele frequency of at least 1% were identified in 236 patients (41%). Clonal hematopoiesis was associated with large-artery atherosclerosis stroke (p=0.01) and white matter lesion (p<0.001).
“Clonal hematopoiesis is very frequent in patients with incident ischemic stroke, in particular in patients with large artery atherosclerosis stroke,” said co-corresponding author Matthias Endres, DrMed, of Charité University Medical Center.
Patients with clonal hematopoiesis showed increased levels of pro-inflammatory cytokines such as interleukin 6 (IL-6), interferon gamma, high-sensitivity C-reactive protein, and vascular cell adhesion molecule 1, suggesting the inflammatory dysregulation caused by clonal hematopoiesis “might mediate this effect,” and “inflammatory pathways might be a potential target for secondary risk prevention strategies,” Dr. Endres said.
“The presence of a common single nucleotide polymorphism, which impairs IL-6 inflammatory signaling, seems to partially mitigate the risk for recurrent vascular events and death in patients with TET2-driven clonal hematopoiesis, but not in TET2 wild-type patients,” Dr. Endres said. “This observation suggests that this group of patients might benefit from anti-inflammatory treatment (e.g., IL-6 inhibition) in terms of secondary prevention. However, studies in larger cohorts and preclinical models are warranted before implications for clinical practice can be derived.”
Patients with clonal hematopoiesis had a higher risk for recurrent stroke, myocardial infarction, and all-cause mortality (hazard ratio [HR] = 1.55, 95% CI 1.04-2.31; p=0.03), which was more pronounced in patients with larger clones, defined as at least 10%. After correction for age and other confounders, clone size remained an independent risk factor (HR=1.30, 95% CI 1.04-1.62; p=0.022).
Aside from clone size, the authors noted several age-independent factors of clonal hematopoiesis on secondary vascular risk, including the number of mutations and the different mutated genes. Mutations in DNMT3A, which occurred most frequently, presented a more benign phenotype, while mutations in TET2 and PPM1D were “strongly associated” with recurrent vascular events and death.
Limitations of the study included that the composite endpoint was primarily driven by mortality. The cause of death is difficult to define in those with ischemic stroke because of comorbidities and is compounded by the link between clonal hematopoiesis and hematologic malignancy. Additionally, the study used sequencing data collected at a single timepoint, while assessing somatic mutations at several timepoints could provide longitudinal data on clonal fitness and clinical outcome.
The results provide new insights into the interplay of clonal hematopoiesis, systemic inflammation, and cardiovascular risk. Further investigations will hopefully lead to improved “personalized risk stratification and secondary prevention strategies” for patients with ischemic stroke, the authors concluded.
Any conflicts of interest declared by the authors can be found in the original article.
Arends CM, Liman TG, Strzelecka PM, et al. Associations of clonal haematopoiesis with recurrent vascular events and death in patients with incident ischemic stroke [published online ahead of print, 2022 Nov 28]. Blood. doi:10.1182/blood.2022017661.