Friday, March 31, 2023
| Characteristic | CH negative (n = 345) | CH positive (n = 236) | Total (n = 581) | P value* |
|---|---|---|---|---|
| Age, median (IQR), y | 64 (55–73) | 73.5 (66.75–81) | 68 (59–76) | <.001 |
| Sex, no. (%) | .012 | |||
| Female | 227 (65.8) | 130 (55.1) | 357 (61.4) | |
| Male | 118 (34.2) | 106 (44.9) | 224 (38.6) | |
| TOAST classification, no. (%) | .037 | |||
| Large-artery atherosclerosis | 77 (22.3) | 76 (32.2) | 153 (26.3) | |
| Cardiac embolism | 80 (23.2) | 60 (25.4) | 140 (24.1) | |
| Small-artery occlusion | 61 (17.7) | 32 (13.6) | 93 (16.0) | |
| Other determined cause | 12 (3.5) | 4 (1.7) | 16 (2.8) | |
| Undetermined cause | 115 (33.3) | 64 (27.1) | 179 (30.8) | |
| Modified ranking scale, no. (%) | 1 | |||
| ≤1 | 224 (64.9) | 153 (64.8) | 377 (64.9) | |
| ≥2 | 121 (35.1) | 83 (35.2) | 204 (35.1) | |
| NIHSS score, no. (%) | .08 | |||
| ≤4 | 268 (77.7) | 168 (71.2) | 436 (75.0) | |
| >4 | 77 (22.3) | 68 (28.8) | 145 (25.0) | |
| Smoking status, no. (%) | .002 | |||
| Never smoker | 114 (33.4) | 108 (46.8) | 222 (38.8) | |
| Current or former smoker | 227 (66.5) | 123 (53.2) | 350 (61.2) | |
| Arterial hypertension, no. (%) | .01 | |||
| No | 136 (39.4) | 68 (28.8) | 204 (35.1) | |
| Yes | 209 (60.6) | 168 (71.2) | 377 (64.9) | |
| Diabetes mellitus, no. (%) | .066 | |||
| No | 279 (80.9) | 175 (74.2) | 454 (78.1) | |
| Yes | 66 (19.1) | 61 (25.8) | 127 (21.9) | |
| Dyslipidemia, no. (%) | .754 | |||
| No | 272 (79.8) | 183 (78.5) | 455 (79.3) | |
| Yes | 69 (20.2) | 50 (21.5) | 119 (20.7) | |
| Obesity, no. (%) .022 | ||||
| No | 250 (72.7) | 186 (80.9) | 436 (76.0) | |
| Yes | 94 (27.3) | 44 (19.1) | 138 (24.0) | |
| Atrial fibrillation, no. (%) | .01 | |||
| No | 283 (82.0) | 172 (72.9) | 455 (78.3) | |
| Yes | 62 (18.0) | 64 (27.1) | 126 (21.7) | |
| Coronary heart disease, no. (%) | .91 | |||
| No | 287 (83.2) | 198 (83.9) | 485 (83.5) | |
| Yes | 58 (16.8) | 38 (16.1) | 96 (16.5) | |
| Peripheral artery disease, no. (%) | .043 | |||
| No | 328 (95.1) | 214 (90.7) | 542 (93.3) | |
| Yes | 17 (4.9) | 22 (9.3) | 39 (6.7) | |
| History of cancer, no. (%) | .30 | |||
| No | 313 (92.3) | 210 (89.7) | 523 (91.3) | |
| Yes | 26 (7.7) | 24 (10.3) | 50 (8.7) | |
| Statin therapy, no. (%) | .41 | |||
| None | 50 (14.7) | 26 (11.1) | 76 (13.3) | |
| Low dose | 243 (71.7) | 178 (76.1) | 421 (73.5) | |
| High dose† | 46 (13.6) | 30 (12.8) | 76 (13.3) | |
| Antithrombotics, no. (%) | .19 | |||
| None | 0 (0.0) | 1 (0.4) | 1 (0.2) | |
| Antiplatelet | 271 (79.9) | 174 (74.4) | 445 (77.7) | |
| Anticoagulation | 61 (18.0) | 50 (21.4) | 111 (19.4) | |
| Both | 7 (2.1) | 9 (3.8) | 16 (2.8) | |
| IL-6R p.D358A, no. (%) | .069 | |||
| D/D | 148 (42.9) | 91 (38.6) | 239 (41.1) | |
| D/A | 146 (42.3) | 121 (51.3) | 267 (46.0) | |
| A/A | 51 (14.8) | 24 (10.2) | 75 (12.9) |
Table 1. Demographic and clinical characteristics of the PROSCIS-B cohort
Analyses were restricted to patients without missing values in the respective category.
IQR, interquartile range; TOAST, Trial of Org 10172 in Acute Stroke Treatment.
*P value from Wilcoxon rank sum test or Fisher exact test.
†High-dose statin therapy is defined as a dose equivalent to atorvastatin ≥ 40 mg/d.
Table 2: Multivariable Cox regression model for the CEP
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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.
With aging, the risk of cardiovascular disease and cancer is increasing. Clonal hematopoiesis (CH), defined by the acquisition of somatic mutations in hematopoietic stem cells (HSCs), has been identified as a commonality between these 2 age-related conditions. CH occurs in 20% to 30% of individuals aged >60 years and most frequently involves mutations in epigenetic regulatory genes (eg, DNMT3A, TET2, and ASXL1).[1–7] It is associated with a higher all-cause mortality, an increased risk for cardiovascular events, and an approximately 10-fold risk of developing hematologic malignancies.[6,8] A causal relationship between CH and cardiovascular disease is best known for TET2, for which accelerated development of atherosclerosis driven by an altered function of the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3)/interleukin-1β (IL-1β) inflammasome of mutated monocytes/macrophages was reported in preclinical models.[8–10] Moreover, in patients with ischemic and nonischemic heart failure, CH has been reported to be associated with rapid progression and unfavorable overall survival.[11,12] These data point toward multifaceted effects of mutated clones in CH-positive individuals, not only affecting self-renewal and differentiation but also inflammatory signaling of mature blood cells.[13,14] Inflammation plays a crucial role in the pathogenesis of ischemic stroke and its functional consequences after brain injury.[15–17] Compared with the rapidly increasing number of reports in the field of myocardial infarction (MI) and heart failure, little is known with respect to CH and ischemic stroke. In their original 2014 article, Jaiswal and colleagues reported an increased risk of ischemic stroke in individuals with CH, which has recently been confirmed in large patient series.[6,18] To fill the knowledge gap concerning the role of CH in patients with ischemic stroke, we conducted a thorough genetic study investigating secondary cardiovascular risk of patients with ischemic stroke and CH in a large prospective cohort.[19]
