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Background: Insulin resistance is associated with stroke recurrence and poor functional outcomes of nondiabetic patients with ischemic stroke. The study aimed to investigate whether the association between insulin resistance and the prognosis of nondiabetic patients with ischemic stroke was mediated by systematic inflammation. Methods: Patients with ischemic stroke but without a history of diabetes who were enrolled in CNSR-III (Third China National Stroke Registry) were included in the study and followed up for 1 year after stroke onset. Insulin resistance was determined by using the homeostasis model assessment for insulin resistance (HOMA-IR) method. hs-CRP (high-sensitivity C-reactive protein) and Lp-PLA 2 (lipoprotein-associated phospholipase A 2 ) activity were measured at baseline. The primary outcome was stroke recurrence, and other outcomes included composite vascular events, mortality, and poor functional outcome (modified Rankin Scale score, 3–6). Multivariable Cox or logistic regression analyses were performed to estimate the association between HOMA-IR and the study outcomes. A mediation analysis was performed to examine the relationship between insulin resistance and the study outcomes mediated by systemic inflammation. Results: Among a total of 3808 nondiabetic patients with ischemic stroke who were included in the study, the median HOMA-IR was 1.79 (interquartile range, 1.05–2.97). After adjustments for potential confounders, higher HOMA-IR quartiles were associated with higher risks of stroke recurrence, ischemic stroke, and composite vascular events, especially in the large artery atherosclerosis subtype. hs-CRP partially mediated the association between the HOMA-IR index and the prognosis of ischemic stroke (mediation proportion, 5.9% for stroke recurrence and 7.5% for composite vascular events). No evidence of Lp-PLA 2 activity mediating the association of insulin resistance with stroke outcomes was observed. Conclusions: Our study found that insulin resistance was associated with poor clinical outcomes in nondiabetic patients with ischemic stroke, which was partially mediated by hs-CRP with a modest amount.

Background: The aim of this study was to investigate the relationship between serum cystatin C levels and the presence and severity of cerebral small vessel disease (CSVD). Methods: Community-dwelling residents in the Lishui city in China from the cross-sectional survey of the PRECISE (Poly-Vascular Evaluation for Cognitive Impairment and Vascular Events) cohort study were included in present study from 2017 to 2019. Total CSVD burden and modified total CSVD burden score, as well as the markers of CSVD on magnetic resonance imaging, including white matter hyperintensity, lacunes, cerebral microbleeds, and perivascular spaces, were assessed at baseline survey. Participants were divided into 4 groups according to the quartiles of cystatin C. The association of serum cystatin C with total CSVD burden and imaging markers was analyzed using ordinal or binary logistic regression models. Furthermore, 2-sample Mendelian randomization analysis was performed to investigate the genetically predicted effect of cystatin C on CSVD. Results: A total of 3061 participants were included in this study. The mean age of the participants was 61.2±6.7 years, and 1637 (53.5%) were women. Higher level of cystatin C was associated with an increased total CSVD burden and modified total CSVD burden (Q4 versus Q1: common odds ratio [OR], 1.30 [95% CI, 1.03–1.64] and 1.32 [95% CI, 1.01–1.73]) after adjustment for covariates. Further, compared with the first quartile of cystatin C, subjects in the last quartile had higher risk of lacunes (OR, 1.99 [95% CI, 1.05–3.76]), modified white matter hyperintensity burden (common OR, 1.42 [95% CI, 1.07–1.90]), and moderate-to-severe perivascular spaces (OR, 2.15 [95% CI, 1.29–3.59]) but not cerebral microbleeds. The Mendelian randomization analysis showed that a genetically predicted higher cystatin C level was associated with increased risk of lacunar stroke (OR, 1.16 [95% CI, 1.06–1.27]). Conclusions: In this community-based study, we found a possible association between cystatin C and CSVD, especially for lacunes, that was independent of estimated glomerular filtration rate.

ObjectiveThis study aims to investigate the associations of glymphatic system with the presence, severity and neuroimaging phenotypes of cerebral small vessel disease (CSVD) in a community-based population.MethodThis report included 2219 community-dwelling people aged 50–75 years who participated in the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events cohort. The diffusivity along perivascular spaces based on diffusion tensor imaging (DTI-ALPS index) was measured to assess glymphatic pathway. The presence and severity of CSVD were estimated using a CSVD score (points from 0 to 4) and a modified CSVD score (points from 0 to 4), which were driven by 4 neuroimaging features of CSVD, including white matter hyperintensity (WMH), enlarged perivascular spaces (EPVS), lacunes, cerebral microbleeds. Brain atrophy (BA) was also evaluated. Binary or ordinal logistic regression analyses were carried out to investigate the relationships of DTI-ALPS index with CSVD.ResultThe mean age was 61.3 (SD 6.6) years, and 1019 (45.9%) participants were men. The average DTI-ALPS index was 1.67±0.14. Individuals in the first quartile (Q1) of the DTI-ALPS index had higher risks of the presence of CSVD (OR 1.77, 95% CI 1.33 to 2.35, pConclusionA lower DTI-ALPS index underlay the presence, severity and typical neuroimaging markers of CSVD, implying that glymphatic impairment may interact with CSVD-related pathology in the general ageing population.Trial registration numberNCT03178448.

Background and Purpose Despite administration of evidence-based therapies, residual risk of stroke recurrence persists. This study aimed to evaluate the residual risk of recurrent stroke in acute ischemic stroke or transient ischemic attack (TIA) with adherence to guideline-based secondary stroke prevention and identify the risk factors of the residual risk.Methods Patients with acute ischemic stroke or TIA within 7 hours were enrolled from 169 hospitals in Third China National Stroke Registry (CNSR-III) in China. Adherence to guideline-based secondary stroke prevention was defined as persistently receiving all of the five secondary prevention medications (antithrombotic, antidiabetic and antihypertensive agents, statin and anticoagulants) during hospitalization, at discharge, at 3, 6, and 12 months if eligible. The primary outcome was a new stroke at 12 months.Results Among 9,022 included patients (median age 63.0 years and 31.7% female), 3,146 (34.9%) were identified as adherence to guideline-based secondary prevention. Of all, 864 (9.6%) patients had recurrent stroke at 12 months, and the residual risk in patients with adherence to guidelinebased secondary prevention was 8.3%. Compared with those without adherence, patients with adherence to guideline-based secondary prevention had lower rate of recurrent stroke (hazard ratio, 0.85; 95% confidence interval, 0.74 to 0.99; P=0.04) at 12 months. Female, history of stroke, interleukin-6 ≥5.63 ng/L, and relevant intracranial artery stenosis were independent risk factors of the residual risk.Conclusions There was still a substantial residual risk of 12-month recurrent stroke even in patients with persistent adherence to guideline-based secondary stroke prevention. Future research should focus on efforts to reduce the residual risk.

We aimed to develop a score and validate it in a prospective cohort to identify the patients with ESUS at high risk for stroke recurrence.We assessed the stroke recurrence in ESUS patients of the Third China National Stroke Registry. We performed multivariable logistic regression analysis to identify predictors of stroke recurrence in the derivation cohort. Based on the coefficient of each covariate of the fitted multivariable model, we generated an integer-based point scoring system. We validated the score in the validation cohort assessing its discrimination and calibration.2415 patients were included: 1611 in the derivation and 804 in the validation sample. We developed a scoring system (0-15 points) by assigning 2 points for hypertension, 3 points for diabetes mellitus, 4 points for multiple stage infarction, 2 points for watershed involved infarction, 1 points for left atrial diameter index (per increasing 2.5 mm/m2) and 3 points for without statin at discharge. The rate of stroke recurrence was 5.9% per year (95% CI 4.2-7.6%) in patients with low risk(a score of 0-5), 9.4% (7.3-11.5%) in patients with intermediate risk (6-10), and 26.8% (16.5-37.1%) in patients with high risk (11-15). The AUC (area under curve of receiver operator characteristic curve) of the score in the derivation cohort and validation cohort was, respectively, 0.60 (0.55-0.65) and 0.63 (0.56-0.70). The score was well calibrated both in the derivation cohort (p = 0.36) and validation cohort (p = 0.26) with the Hosmer-Lemeshow test.The developed score can improve risk stratification after ESUS in secondary care settings.

Background: Lp(a) (lipoprotein(a)) contributes to cardiovascular disease mainly through proatherogenic and proinflammatory effects. Here, we aimed to evaluate whether a residual stroke risk of Lp(a) would remain when the LDL-C (low-density lipoprotein cholesterol) and inflammatory levels are maintained low. Methods: This prospective cohort study included 9899 patients with ischemic stroke or transient ischemic attack from the Third China National Stroke Registry who had measurements of plasma Lp(a) and were followed up for 1 year. Cutoffs were set at the 50 mg/dL for Lp(a). LDL-C was corrected for Lp(a)-derived cholesterol (LDL-Cc [LDL-C corrected]) and cutoffs were set at 55 and 70 mg/dL.The threshold values of IL-6 (interleukin 6) and hsCRP (high-sensitive C-reactive protein) were the median 2.65 ng/L and 2 mg/L. Multivariable-adjusted hazard ratio (HR) were calculated using Cox regression models for each category to investigate the associations of Lp(a) with stroke recurrence within 1 year. Results: Among all patients, those with Lp(a) ≥50 mg/dL were at higher stroke recurrence risk than those with Lp(a) Conclusions: Increased Lp(a) was significantly associated with stroke recurrence risk in patients with ischemic stroke/transient ischemic attack. However, at low LDL-Cc or IL-6 levels, the elevated Lp(a) -associated stroke recurrence risk was attenuated in a secondary prevention setting.

Background and purposeCerebral large artery and small vessel diseases are related to different pathogenetic mechanisms and have different risk factor profile. Lipoprotein(a) (Lp(a)) was shown to promote atherosclerosis but data was limited on its association with cerebral small vessel diseases (cSVD). The objective of this study was to assess the associations of Lp(a) level with the two types of cerebrovascular diseases.MethodsCommunity-dwelling subjects aged 50–75 years from the baseline survey of The PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events study were included. Lp(a) concentrations was measured and categorised into three groups according to the tertiles. Eligible participants were scanned by a 3.0T MRI scanner and assessed for intracranial atherosclerosis and cSVD burden based on four imaging markers.ResultsThis study included 3059 subjects. The average age of the participants was 61.2±6.7 years, and 53.5% (1636) were female. Compared with the first tertile, subjects with the second and third tertiles of Lp(a) concentrations were associated with an increased odds of presence of intracranial plaque (18.7% vs 15.4%, adj.OR 1.37, 95% CI 1.08 to 1.75; 18.9% vs 15.4%, adj.OR 1.34, 95% CI 1.05 to 1.72). Similar associations were observed for intracranial atherosclerotic burden. Whereas, subjects with the third tertile of Lp(a) level had a decreased odds of presence of cSVD (25.9% vs 31.7%, adj.OR 0.74, 95% CI 0.60 to 0.92) and lower cSVD burden (adj.cOR 0.76, 95% CI 0.62 to 0.94).ConclusionsIn this study, Lp(a) concentrations were positively associated with presence and burden of intracranial atherosclerosis, but was inversely associated with cSVD.Trial registration numberNCT03178448.

Background and Objectives: The Canadian TIA Score has been verified as a good predictive tool for subsequent stroke risk in Caucasian patients; however, it had insufficient external verification of other races. We aimed to validate the Canadian TIA Score in Chinese patients and compared it with ABCD2 for subsequent stroke risk after transient ischemic attack (TIA). Methods: The Third China National Stroke Registry (CNSR-III) was a nationwide, multicenter prospective registry recruiting consecutive patients with acute ischemic stroke or TIA within 7 days of the onset from August 2015 to March 2018. The Canadian TIA Score was verified in patients diagnosed with TIA from the CNSR-III (N = 1,184). The outcomes were subsequent stroke at 7 days, 14 days/discharge, 3 months, and 1 year. Outcomes were recorded by face-to-face assessment or telephone interview. The prognostic performance of the scoring system was assessed by the area under the receiver operator characteristic curve (AUC). Results: Of 1,184 TIA patients (mean [IQR] age, 61.00 [53.00–69.00] years; 413 women [34.88%]), there were 40 patients (3.38%) having subsequent stroke within 7 days, 45 (3·80%) within 14 days/hospitalization, 66 (5·57%) within 3 months, and 100 (8·45%) within 1 year. The Canadian TIA Score (AUC 0 63–0·68) seemed to be a better prognostic score of stroke risk than the ABCD2 score (AUC 0·61–0·62), although no significant differences were noted. In the subgroup of atypical TIA, the Canadian TIA Score showed significantly stronger predictivity than the ABCD2 score within 7 days (0.80 [0.62–0.98] vs. 0.52 [0.30–0.73]; difference in AUC, 0.28 [0.03–0.53]; p, 0.026), and marginal significantly stronger predictivity within 1 year (0.71 [0.61–0.80] vs. 0.58 [0.48–0.68]; difference in AUC, 0.12 [−0.01 to 0.25]; p, 0.06). Conclusion: The Canadian TIA Score might be a better prognostic score than the ABCD2 score for post-TIA stroke risk, especially in patients with atypical TIA.

Background and purposeDyslipidaemia is a major risk factor for ischaemic stroke and transient ischaemic attack (TIA). This study aimed to investigate the association between baseline low-density lipoprotein cholesterol (LDL-C) level, lipid-lowering treatment and short-term risk of new stroke in patients with a minor ischaemic stroke or TIA.MethodsWe derived data from the Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events trial. Patients with a minor stroke or TIA were categorised by LDL-C level at baseline (ResultsAmong 3027 patients, 2154 (71.2%) patients had an initial LDL-C ≥2.6 mmol/L, of which 1267 (41.9%) received lipid-lowering treatment. Elevated LDL-C level was associated with a higher risk of new ischaemic stroke at 3 months in patients without lipid-lowering treatment (adj.HR=1.35, 95% CI: 1.19 to 1.53), but not in those with lipid-lowering treatment (adj.HR=0.99, 95% CI: 0.82 to 1.19) (p for interaction=0.007). Patients with LDL-C ≥2.6 mmol/L had a numerically higher risk of ischaemic stroke (11.8% vs 8.0%, adj.HR=1.37, 95% CI: 0.96 to 1.96) in those without lipid-lowering treatment. For patients with LDL-C ≥2.6 mmol/L, lipid-lowering treatment was associated with reduced risk of ischaemic stroke at 3 months (7.9% vs 11.8%; adj.HR=0.54, 95% CI: 0.39 to 0.75).ConclusionsElevated untreated baseline LDL-C level was associated with an increased short-term risk of ischaemic stroke among patients presenting with minor ischaemic stroke or TIA. There was potential benefit of lipid-lowering treatment in minor stroke or TIA patients with LDL-C ≥2.6 mmol/L.Trial registration numberNCT00979589.

Dual antiplatelet therapy (DAPT) with ticagrelor and aspirin has been found to be effective for secondary prevention after minor ischemic stroke or transient ischemic attack (TIA) in individuals who carry CYP2C19 loss-of-function (LOF) alleles; however, uncertainties remain about the time course of benefit and risk with ticagrelor and aspirin in these patients.To obtain time-course estimates of efficacy and risk with ticagrelor and aspirin after minor stroke or TIA in individuals with CYP2C19 LOF alleles.The Ticagrelor or Clopidogrel With Aspirin in High-risk Patients With Acute Nondisabling Cerebrovascular Events II (CHANCE-2) randomized clinical trial enrolled patients 40 years and older from 202 hospitals in China with acute minor stroke or TIA who carried CYP2C19 LOF alleles between September 23, 2019, and March 22, 2021, and were followed up for 90 days. All 6412 patients enrolled in the CHANCE-2 trial were included in this secondary analysis. Data were analyzed in October 2021.Ticagrelor (180 mg on day 1 followed by 90 mg twice daily on days 2-90) or clopidogrel (300 mg on day 1 followed by 75 mg daily on days 2-90). All patients received aspirin (75-300 mg on day 1 followed by 75 mg daily for 21 days).The efficacy outcome was major ischemic event, defined as the composite of ischemic stroke or nonhemorrhagic death. Safety outcomes included moderate to severe bleeding and any bleeding.A total of 6412 patients were included (3205 in the ticagrelor and aspirin group and 3207 in the clopidogrel and aspirin group). The median (IQR) age was 65 (57-71) years, and 4242 patients (66%) were men. The reduction of major ischemic events with ticagrelor and aspirin predominately occurred in the first week (absolute risk reduction, 1.34%; 95% CI, 0.29 to 2.39) and attenuated but remained in the next 3 weeks (absolute risk reduction in the second week, 0.11%; 95% CI, -0.24 to 0.45; absolute risk reduction in the third week, 0.14%; 95% CI, -0.11 to 0.38; absolute risk reduction in the fourth week, 0.04%; 95% CI, -0.18 to 0.25). The risk of moderate to severe bleeding was consistently low in the ticagrelor and aspirin group. The absolute increase in any bleeding seen in the first week (0.87%; 95% CI, 0.25 to 1.50) remained in the next 3 weeks (absolute increase in the second week, 1.21%; 95% CI, 0.75 to 1.68; absolute increase in the third week, 0.33%; 95% CI, -0.05 to 0.72; absolute increase in the fourth week, 0.23%; 95% CI, -0.03 to 0.49).Among patients with minor stroke or TIA who carried CYP2C19 LOF alleles, benefit with ticagrelor and aspirin was present predominately in the first week, with additional small benefit accruing in the next 2 weeks.