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Increased serum adenosine deaminase level is associated with adverse clinical outcomes after ischemic stroke

Year: 2025

Type: article

Abstract: To the Editor: In 2021, there were 4.1 million incident stroke cases, 2.6 million stroke-related deaths, and 53.2 million stroke related disability-adjusted life-years in China.[1] Therefore, a better understanding of the pathogenesis of ischemic stroke and identification of novel biomarkers associated with its prognosis can provide new ideas for the treatment and management of ischemic stroke. Adenosine deaminase (ADA) is essential for energy metabolism and nervous system function. In a prospective cohort study, increased ADA levels were predictive of a large infarct volume, and high National Institutes of Health Stroke Scale (NIHSS) scores and increased modified Rankin Scale (mRS) scores were predictive among patients with large vessel occlusion stroke. However, the significance of serum ADA levels on clinical outcomes among patients with ischemic stroke remains unclear. Therefore, well-designed prospective studies on the association between serum ADA levels and clinical outcomes after ischemic stroke are required. We conducted a large-scale study based on the Minhang Stroke Cohort to prospectively investigate the relationships between serum ADA levels and adverse outcomes at three months among patients with ischemic stroke. The participants in the present study were from the Minhang Stroke Cohort. Briefly, from January 2018 to December 2022, a total of 7323 consecutive patients aged ≥18 years with a clinical diagnosis of ischemic stroke were enrolled from the Department of Neurology at Minhang Hospital. Diagnosis of ischemic stroke was based on the World Health Organization criteria according to computed tomography scan or magnetic resonance imaging.[2] After excluding those with time from onset to admission over seven days (n = 263) or cancer (n = 168), a total of 6892 eligible patients were enrolled in Minhang Stroke Cohort. For the present study, we further excluded 284 patients due to lack of blood samples, and a total of 6608 patients were finally included in the analysis. This study was approved by the Ethics Committee of Minhang Hospital (No. 008-01K). Written consent was obtained from all study participants or their immediate family members. The detailed information on data collection and outcome assessment is available in Supplementary Methods, https://links.lww.com/CM9/C653. Stroke severity was assessed by trained neurologists at baseline using the NIHSS (scores ranged from 0 to 42, with higher scores indicating a more severe neurological deficit). Based on the symptoms and imaging data of the patients, ischemic stroke was classified as large-artery atherosclerosis, cardioembolism, small-vessel occlusion, stroke of other determined etiology, or stroke of undetermined etiology, based on the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria. Diabetes was defined as fasting plasma glucose ≥7.0 mmol/L, history of diabetes, or use of glucose-lowering medications. Dyslipidemia was defined as total cholesterol ≥6.22 mmol/L, triglyceride ≥2.26 mmol/L, low-density lipoprotein cholesterol ≥4.14 mmol/L, high-density lipoprotein cholesterol <1.04 mmol/L, or self-reported history of physician-diagnosed dyslipidemia according to Chinese guidelines on the prevention and treatment of dyslipidemia. Serum ADA concentrations at baseline were measured using a Cobas 8000 automatic analyzer (Roche Diagnostics, Indianapolis, IN, USA). The laboratory technicians who performed these measurements were blinded to the clinical characteristics and outcomes of the study participants. The primary outcome was a composite outcome of death or major disability (mRS score: ≥3 and ≤6) at 3 months after stroke onset. The secondary outcomes were major disability (mRS score: ≥3 and ≤5) and death (mRS score: 6). The baseline characteristics of the study participants are presented according to quartiles of baseline serum ADA levels. Multiple imputations of missing data were performed using the Markov chain Monte Carlo method. A multivariable logistic regression analysis was performed to assess the association between serum ADA levels and adverse outcomes after ischemic stroke. The covariates included in the multivariable models were age, sex, smoking, drinking, time from onset to hospitalization, systolic blood pressure (BP), body mass index, estimated glomerular filtration rate, NIHSS score at baseline, low-density lipoprotein cholesterol, white blood cell count, lipoprotein A, lymphocytes, insulin, diabetes, dyslipidemia, history of hypertension, family history of stroke, ischemic stroke subtypes, use of antihypertensive medication before stroke onset, intravenous thrombolysis, and mechanical thrombectomy. We further used restricted cubic splines to provide more precise estimates and explore the shapes of the associations between serum ADA levels and adverse outcomes after ischemic stroke. Subgroup analyses were performed to investigate the effects of modification of age, sex, smoking, drinking, time from onset to hospitalization, baseline systolic BP, body mass index, estimated glomerular filtration rate, NIHSS score at baseline, history of hypertension, ischemic stroke subtype, intravenous thrombolysis, mechanical thrombectomy, and use of antihypertensive medication before stroke onset on the association between serum ADA and adverse outcomes. Two-tailed P <0.05 was considered to be statistically significant. All analyses were performed using the SAS statistical software (version 9.4; SAS Institute, Inc., Cary, NC, USA). The detailed results on the associations between serum ADA levels and clinical outcomes are available in Supplementary Results, https://links.lww.com/CM9/C653. Most baseline characteristics were well balanced between the participants who were assayed for serum ADA and all participants in the Minhang Stroke Cohort [Supplementary Table 1, https://links.lww.com/CM9/C653]. In total, 6608 patients (4200 males and 2408 females) with an average age of 70 years were included in this study [Supplementary Table 2, https://links.lww.com/CM9/C653]. During 3-month follow-up period, 474 participants (7.17%) were lost to follow-up [Supplementary Table 3, https://links.lww.com/CM9/C653]. After adjusting for important prognostic factors, the adjusted odd ratios or hazard ratios associated with highest quartile of serum ADA were 1.30 (95% confidence interval [CI]: 1.09–1.54; Ptrend = 0.002) for primary outcome, 1.22 (95% CI: 1.02–1.46; Ptrend = 0.029) for major disability, and 1.34 (95% CI: 1.01–1.77; Ptrend = 0.026) for death [Table 1]. Multivariable-adjusted restricted cubic spline analyses further showed linear associations of serum ADA with adverse outcomes (all P for linearity <0.05) [Supplementary Figure 1, https://links.lww.com/CM9/C653]. Table 1 - Associations between ADA level and adverse outcomes at three months after ischemic stroke. Variables ADA (U/L) P trend Each SD (0.1864 U/L) increase in Log-transformed ADA <7.0 7.0–9.1 9.2–11.9 >11.9 Primary outcome: death or major disability (mRS score 3–6) Cases, n 395 529 546 648 Unadjusted OR (95% CI) 1.00 (reference) 1.28 (1.10, 1.49) 1.58 (1.36, 1.84) 1.98 (1.70, 2.30) <0.001 1.28 (1.21, 1.35) Multiple-adjusted OR (95% CI)* 1.00 (reference) 1.14 (0.97, 1.34) 1.23 (1.04, 1.46) 1.30 (1.09, 1.54) 0.002 1.10 (1.04, 1.17) Secondary outcomes Death (mRS score = 6) Cases, n 106 152 180 233 Unadjusted OR (95% CI) 1.00 (reference) 1.31 (1.01, 1.70) 1.79 (1.39, 2.30) 2.32 (1.83, 2.96) <0.001 1.36 (1.25, 1.47) Multiple-adjusted OR (95% CI)* 1.00 (reference) 1.15 (0.86, 1.54) 1.37 (1.03, 1.82) 1.34 (1.01, 1.77) 0.026 1.11 (1.01, 1.21) Major disability (mRS score 3–5) Cases, n 289 377 366 415 Unadjusted OR (95% CI) 1.00 (reference) 1.21 (1.02, 1.44) 1.35 (1.13, 1.60) 1.53 (1.29, 1.81) <0.001 1.16 (1.09, 1.23) Multiple-adjusted OR (95% CI)* 1.00 (reference) 1.12 (0.95, 1.34) 1.16 (0.97, 1.38) 1.22 (1.02, 1.46) 0.029 1.07 (1.01, 1.14) *Adjusted for age, sex, smoking, drinking, time from onset to hospitalization, systolic BP, body mass index, estimated glomerular filtration rate, NIHSS score at baseline, low-density lipoprotein cholesterol, white blood cell count, lipoprotein A, lymphocyte, insulin, diabetes, dyslipidemia, history of hypertension, family history of stroke, ischemic stroke subtypes, using antihypertensive medications drugs before stroke onset, intravenous thrombolysis, and mechanical thrombectomy. ADA: Adenosine deaminase; BP: Blood pressure; CI: Confidence interval; mRS: Modified Rankin Scale; NIHSS: National Institutes of Health Stroke Scale; SD: Standard deviation. Positive associations between serum ADA levels and risk of the primary outcome were observed in almost all subgroups and reached statistical significance in several subgroups [Supplementary Table 4, https://links.lww.com/CM9/C653]. There was no significant interaction between serum ADA levels and these subgroup factors in terms of the risk of the primary outcome (all P for interaction >0.05). We found that high baseline serum ADA levels were independently associated with an increased risk of adverse outcomes after ischemic stroke. These findings indicated that serum ADA levels may be involved in the development of ischemic stroke. A case-control study involving 30 patients with ischemic stroke found that reduced ADA activity was an adaptive mechanism for protecting the brain from ischemic injury, while a single-center prospective study found that ADA levels were predictors of stroke in patients with tuberculous meningitis. In addition, in a cohort of 61 patients with emergent large-vessel occlusion stroke, elevated ADA levels were associated with more serious stroke and greater stroke-related disability. It is noteworthy that all these studies were limited by small sample sizes. Therefore, the association between serum ADA levels and the clinical outcomes in patients with ischemic stroke remains unclear. This study was based on the Minhang Stroke Cohort, with a large sample size and high statistical power. We found that elevated serum ADA levels were independently associated with an increased risk of adverse outcomes at three months after ischemic stroke, and subgroup analyses confirmed these positive associations. Therefore, our findings would provide critical population-based evidence for the adverse role of serum ADA in the development of ischemic stroke. Atherosclerosis is a well-known mechanism underlying ischemic stroke. Experimental evidence has shown that ADA activity of ADA was elevated together with plaque formation and contributes to the progression of atherosclerosis. It had been reported that ADA modulates the immune response associated with atherosclerosis by inducing T-helper cell-dependent differentiation of monocytes into macrophages.[3] In addition, inflammatory responses may impact long-term neurological outcomes after stroke, whereas ADA can promote the release of adhesion molecules and proinflammatory cytokines from endothelial cells. The inhibition of ADA can result in decreased levels of interleukin-6, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 by restoring the extracellular adenosine pool and adenosine receptor-dependent pathways.[3] Furthermore, inhibition of ADA blocks endothelial activation, suggesting that ADA plays a crucial role in regulating vascular inflammation. This study had several important clinical and public health implications. It has been reported that inhibiting ADA activity can suppress the development of atherosclerosis in apolipoprotein E−/− mice.[4] In addition, several cardiovascular drugs (e.g., statins, acetylsalicylic acid, and diclofenac) have the potential to inhibit ADA.[5] Therefore, it is of clinical interest to investigate whether serum ADA level reduction using specific antagonists can improve the prognosis of patients with ischemic stroke. In the subgroup analyses, there were no significant modified effects of subgroup factors on the associations between serum ADA levels and adverse outcomes, suggesting that the positive associations between serum ADA levels and prognosis of ischemic stroke were consistent across different patients. This study has several limitations. First, we only collected data on death status, and detailed reasons for death were not collected. Therefore, we were unable to focus specifically on ischemic stroke-related deaths. Second, we did not assess the prognosis at one or two months after ischemic stroke, and further studies are needed to investigate the association between serum ADA levels and outcomes at one or two months after ischemic stroke. Last, all patients in the current study were Chinese; therefore, our findings should be generalized to other populations with caution. In conclusion, elevated serum ADA levels at admission were associated with increased risks of adverse clinical outcomes at three months among patients with ischemic stroke. Acknowledgements We thank the study participants and their relatives and the clinical staff at all participating hospitals for their support and contribution to this project. Funding This study was supported by grants from the National Natural Science Foundation of China (Nos. 81973157 and 82173646); Public Health Discipline Construction project of Shanghai Minhang District Health Commission (No. MGWXK2023-04); and a Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions. Conflicts of interest None.

Source: Chinese Medical Journal

DOI: 10.1097/cm9.0000000000003863