Urinary ketone bodies and stroke recurrence in patient with acute ischemic stroke or TIA.

BACKGROUND: Urine ketone bodies may appear in different states in the acute stage of stroke. We aimed to examine the association between urine ketone bodies and recurrent stroke in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) in this study. METHODS: In Third China National Stroke Registry (CNSR-III), 14,015 patients with AIS or TIA were screened for urine ketone bodies. The outcomes were any stroke, ischemic stroke and combined vascular events within 1 year. The association of urine ketone bodies with recurrent stroke were analyzed by Cox proportional hazards. RESULTS: During 1 year of follow-up, 1,335 (9.53%) participants experienced recurrent stroke. After adjustment for conventional confounding factors, patients with urine ketone bodies test positive had a higher risk of recurrent stroke (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.13-1.82), compared to those were negative. The correlation between positive urine ketone bodies and recurrent stroke were consistent in patient with (HR, 1.45; 95% CI, 1.00-2.12) and without (HR, 1.40; 95% CI, 1.02-1.94) diabetes. No significant interaction between urine ketone bodies and diabetes were observed. CONCLUSIONS: Positive ketone bodies in urine was independently associated with recurrent stroke in patients with AIS or TIA.

Low LDL-C level and intracranial haemorrhage risk after ischaemic stroke: a prospective cohort study.

BACKGROUND AND PURPOSE: The Treat Stroke to Target trial has confirmed the benefit of targeting low-density lipoprotein cholesterol (LDL-C) of <1.8 mmol/L in patients who had an ischaemic stroke (IS). However, haemorrhagic risk brought by this target level (<1.8 mmol/L) or even lower level (<1.4 mmol/L) of LDL-C should also be concerned. In this study, we aimed to demonstrate whether low LDL-C could increase the intracranial haemorrhage risk following IS. METHODS: Patients who had an IS from China Stroke Center Alliance programme with complete baseline information were prospectively enrolled. 793 572 patients who had an IS were categorised into 6 groups according to LDL-C level (<1.40 mmol/L, 1.40-1.79 mmol/L, 1.80-2.59 mmol/L, 2.60-2.99 mmol/L, 3.00-4.89 mmol/L, ≥4.90 mmol/L). The study outcome was defined as intracranial haemorrhage identified during hospitalisation. Logistic regression model was used to examine the association between different LDL-C levels and risk of intracranial haemorrhage. RESULTS: Compared with patients of LDL-C=1.80-2.59 mmol/L, both subgroups of LDL-C<1.40 mmol/L and LDL-C=1.40-1.79 mmol/L showed significantly higher risk of intracranial haemorrhage (OR=1.26, 95% CI=1.18 to 1.35; OR=1.22, 95% CI=1.14 to 1.30, respectively). Interaction effect was found to exist between the subgroups of intravenous thrombolytic therapy (p=0.04), rather than the subgroups of age, sex and body mass index. Moreover, the sensitivity analyses indicated that even patients who had an IS with minor stroke still suffered from the increased intracranial haemorrhage risk related to low LDL-C level. CONCLUSIONS: Among patients who had an IS, the low LDL-C level (<1.4 mmol/L or <1.8 mmol/L) at baseline is associated with increased risk of intracranial haemorrhage during acute stage. While actively lowering LDL-C level for patients who had an IS, clinicians should also concern about the haemorrhagic risk associated with low LDL-C level.

Effects of individual and integrated cumulative burden of blood pressure, glucose, low-density lipoprotein cholesterol, and C-reactive protein on cardiovascular risk.

AIM: This study aimed to demonstrate the impact of cumulative burden of cardiovascular risk factors (CVRFs) on risk of cardiovascular events (CVEs). METHODS AND RESULTS: A total of 34 959 participants were enrolled who participated in the four surveys during 2006-2013. Cumulative CVRF burden was calculated as number of years (2006-2013) multiplied by the values of CVRFs including systolic blood pressure, fasting blood glucose (FBG), low-density lipoprotein cholesterol (LDL-C), and high-sensitive C-reactive protein (hs-CRP). The primary outcome was defined as the CVE during 2012-2017, including ischaemic stroke, myocardial infarction, and all-cause mortality. During 4.62 (±0.71) years follow-up on average, there were 2118 (6.06%) CVE, including 847 (2.42%) ischaemic stroke, 221 (0.63%) myocardial infarction, and 1185 (3.39%) all-cause mortality. Higher cumulative burden of individual CVRF was significantly associated with increased risk of outcomes, except for LDL-C for all-cause mortality, FBG for myocardial infarction, and hs-CRP for ischaemic stroke. In Cox proportional hazards model, compared with the group, of the lower quartile of integrated cumulative burden, the hazard ratio (95% confidence intervals) of the upper quartile was 2.45 (2.03-2.94) for CVE, 3.65 (2.68-4.96) for ischaemic stroke, 4.51 (2.19-9.27) for myocardial infarction, and 1.73 (1.36-2.21) for all-cause mortality. CONCLUSION: We demonstrated the correlation between cumulative burden of CVRFs and cardiovascular risk, except for cumulative burden of hs-CRP and ischaemic stroke. Thus, our study suggests the necessity to extend the observation duration of CVRFs in order to elucidate the life-course cumulative effect.

Application of Age, Body Mass Index, Chronic Kidney Disease, Diabetes, and Genotyping Score for Efficacy of Clopidogrel: Secondary Analysis of the CHANCE Trial.

BACKGROUND AND PURPOSE: The age, body mass index, chronic kidney disease, diabetes, and genotyping (ABCD-GENE) score is a validated risk score integrating CYP2C19 genotypes with clinical risk factors influencing clopidogrel response that would allow the more precise identification of subjects at risk for high platelet reactivity and adverse clinical outcomes. Our objective was to further verify application of the ABCD-GENE score and investigate appropriate cutoff value in patients with minor stroke or transient ischemic attack. METHODS: In this post-analysis of the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events), the ABCD-GENE score was calculated for all patients enrolled in this study. By using the proposed cutoff of 10, patients were stratified as being at high risk for high platelet reactivity or not. We further categorized the ABCD-GENE score to 0 to 5, 6 to 24, and >24 to investigate the cutoff value of this scale in clinical application. Stroke recurrence at 3 months was considered as the primary outcome. RESULTS: Among a total of 2923 patients with minor stroke/transient ischemic attack, there were 2273 (77.76%) with ABCD-GENE score <10 and 650 (22.24%) patients with ABCD-GENE score ≥10. Compared with the aspirin alone, hazard ratios (95% CIs) of the clopidogrel-aspirin therapy for stroke recurrence were 0.70 (0.54-0.91) and 0.76 (0.46-1.24), among patients of ABCD-GENE scores <10 and ABCD-GENE scores ≥10, respectively. Stratified analyses by ABCD-GENE score 0 to 5, 6 to 24, and >24, hazard ratios of the clopidogrel-aspirin therapy for stroke recurrence were 0.57 (95% CI, 0.38-0.85), 0.78 (0.58-1.06), and 1.20 (0.44-3.28) (P value for trend=0.0052). CONCLUSIONS: Among Chinese minor stroke/transient ischemic attack population, the efficacy of clopidogrel-aspirin therapy was decreased in patients with higher ABCD-GENE score. Our study suggests that CYP2C19 genotypes and clinical risk factors can be integrated by ABCD-GENE score to estimate the efficacy of clopidogrel-aspirin therapy.

Trimethylamine N-Oxide and Stroke Recurrence Depends on Ischemic Stroke Subtypes.

BACKGROUND: Trimethylamine N-oxide (TMAO) has been recognized as a risk factor for cardiovascular disease. However, the role of TMAO in ischemic stroke remains unclear. As we know, ischemic stroke is a heterogeneous disease with variable pathogenesis. Hence, we aimed to investigate the association between TMAO and stroke recurrence according to etiology subtypes. METHODS: A total of 10 756 ischemic stroke/transient ischemic attack patients from the Third China National Stroke Registry were enrolled, and 1-year follow-up data for stroke recurrence were analyzed. TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria was used to classify the etiology subtypes. Plasma TMAO levels were quantified by liquid chromatography-mass spectrometry. The association between TMAO and stroke outcomes was analyzed using Cox regression models. We also conducted a meta-analysis on the association of TMAO levels and stroke risk. RESULTS: Elevated TMAO level was independently associated with the risk of stroke recurrence (Q4 versus Q1: adjusted hazard ratio, 1.37 [95% CI, 1.15-1.64]) in multivariate Cox regression model. After stratification by TOAST subtypes, there was a significant association between TMAO and stroke recurrence in small artery occlusion subtype (adjusted hazard ratio, 1.43 [95% CI, 1.03-2.00]) but not in the others subtype (large-artery atherosclerosis, 1.19 [0.95-1.48]; cardioembolism, 1.54 [0.95-2.48]; others, 1.19 [0.98-1.44]). The meta-analysis reported on stroke recurrence for the highest versus lowest TMAO levels with a pooled hazard ratio of 1.66 (95% CI, 0.91-3.01) and similarly found an increased risk of stroke recurrence. CONCLUSIONS: Elevated TMAO level is associated with increased risk of stroke recurrence in patients with small artery occlusion subtype, but this association seems to be attenuated in large-artery atherosclerosis, cardioembolism, and others subtypes.

Cumulative burden of lipid profiles predict future incidence of ischaemic stroke and residual risk.

OBJECTIVES: Incident ischaemic stroke (IS) risk may increase not only with lipids concentration but also with longer duration of exposure. This study aimed to investigate the impact of cumulative burden of lipid profiles on risk of incident IS. METHODS: A total of 43 836 participants were enrolled who participated in four surveys during 2006-2013. Individual cumulative lipid burden was calculated as number of years (2006-2013) multiplied by the levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-HDL-C and triglyceride (TG), respectively. The primary outcome was defined as the incident IS during 2012-2017. RESULTS: During 4.67 years (±0.70 years) follow-up on average, we identified 1023 (2.33%) incident IS. Compared with respective reference groups, the HRs (95% CIs) of the upper tertile in cumulative TG burden, cumulative LDL-C burden, cumulative TC burden and cumulative non-HDL-C burden were 1.26 mmol/L (1.02-1.55 mmol/L), 1.47 mmol/L (1.25-1.73 mmol/L), 1.33 mmol/L (1.12-1.57 mmol/L) and 1.51 mmol/L (1.28-1.80 mmol/L) for incidence of IS, respectively. However, this association was not significant in cumulative HDL-C burden and IS (HR: 1.09; 95% CI: 0.79 to 1.52), after adjustment for confounding variables. Among 16 600 participants with low cumulative LDL-C burden, HRs (95% CI) for TC, TG, non-HDL-C and HDL-C with IS were 1.63 mmol/L (1.03-2.57 mmol/L), 1.65 mmol/L (1.19-2.31 mmol/L), 1.57 mmol/L (1.06-2.32 mmol/L) and 0.98 mmol/L (0.56-1.72 mmol/L), respectively. CONCLUSIONS: We observed the correlation between cumulative burden of lipid profiles, except for cumulative burden of HDL-C, with the risk of incident IS. Cumulative burden of TC, TG and non-HDL-C may still predict IS in patients with low cumulative LDL-C burden. TRIAL REGISTRATION NUMBER: ChiCTR-TNRC-11001489.

Severity of Nonalcoholic Fatty Liver Disease and Risk of Future Ischemic Stroke Events.

BACKGROUND AND PURPOSE: We assessed prospectively whether nonalcoholic fatty liver disease (NAFLD) and its severity predict future ischemic stroke (IS) events in a community-based cohort. METHODS: From the Kailuan study, participants free of history of stroke, cancer, or myocardial infarction were enrolled after excluding alcohol abuse and other liver diseases. NAFLD was evaluated through ultrasonography. Participants with NAFLD were further stratified into mild, moderate, and severe groups. The outcome was the first occurrence of IS. The secondary outcomes included myocardial infarction and combined vascular events. We used Cox proportional hazards models to estimate hazard ratios and 95% CIs of incident IS according to presence and severity of NAFLD, adjusting for age, sex, physical activity, body mass index, smoker, history of hypertension, diabetes, hypercholesterolemia, lipid-lowering medication, HDL (high-density lipoprotein), triglyceride, hsCRP (high-sensitivity C-reactive protein), and fasting blood glucose. RESULTS: During a median of 10.34 years of follow-up, we documented 3490 incident stroke cases among 79 905 participants. NAFLD was found in 24 874 (31.18%) participants. Relative to participants without NAFLD at the baseline, those with NAFLD had a 16% higher risk (95% CI, 1.07-1.26) of developing ischemic stroke, after adjusted for confounding variables. The hazard ratios for patients with mild, moderate, and severe NAFLD were 1.15 (95% CI, 1.05-1.25), 1.19 (95% CI, 1.06-1.34), and 1.21 (95% CI, 1.08-1.50), respectively. CONCLUSIONS: The severity of NAFLD is associated with a higher risk of future ischemic stroke events.

Different contribution of SBP and DBP variability to vascular events in patients with stroke.

BACKGROUND: High blood pressure variability (BPV) is a novel risk factor for cardiovascular disease. However, the heterogeneity of systolic blood pressure variability (SBPV) and diastolic blood pressure variability (DBPV) for different vascular events remains unclear. This study aims to investigate whether SBPV or DBPV has different contribution to vascular events in patients with acute ischaemic stroke (IS) or transient ischaemic attack (TIA). METHODS: Data from the BOSS (blood pressure and clinical outcome in TIA or IS) study were examined for vascular events at 3-month and 1-year follow-up. BPV was defined as the SD and coefficient of variation (CV) of day-to-day measurements within 3 months after IS/TIA. Vascular events include cardiovascular events (myocardial infarction, unstable angina, cardiac death and congestive heart failure) and cerebrovascular events (ischaemic or haemorrhagic stroke). Logistic regression model was used to test the associations between BPV and vascular events. RESULTS: Of 2325 patients with IS or TIA, 103 (4.43 %) experienced a recurrent stroke and 64 (2.75 %) had cardiovascular events within 3 months. Day-to-day SBPV was only associated with stroke recurrence (BPVSD: OR, 1.72, 95% CI 1.09 to 2.71; BPVCV: 1.86, 95% CI 1.19 to 2.92), but not cardiovascular events (BPVSD: 1.67, 95% CI 0.94 to 2.94; BPVCV: 1.51, 95% CI 0.86 to 2.64). However, DBPV seems to be related to both stroke (BPVSD: 1.60, 95% CI 1.02 to 2.49; BPVCV: 1.53, 95% CI 0.99 to 2.37) and cardiovascular events (BPVSD: 2.48, 95% CI 1.37 to 4.48; BPVCV: 1.92, 95% CI 1.09 to 3.36). Similar results were found at 1 year. CONCLUSIONS: For patients with IS/TIA, stroke recurrence was associated with both SBPV and DBPV; however, cardiovascular events seem to be only related to DBPV.

Effect of Low Diastolic Blood Pressure to Cardiovascular Risk in Patients With Ischemic Stroke or Transient Ischemic Attacks Under Different Systolic Blood Pressure Levels.

Background: In the context of recently updated strategies of pressure management, there is a paucity of evidence on the effect of diastolic blood pressure (DBP) level on adverse events among stroke patients. This study aimed to examine the effect of low DBP (<60 mmHg) under different levels of systolic blood pressure (SBP) on the risk of composite events and stroke recurrence among patients with ischemic stroke (IS) or transient ischemic attack (TIA). Material and Methods: This study was conducted in 2,325 patients with IS or TIA. DBP values were categorized into <60, 60-70, 70-80 (reference), 80-90, and ≥90 mmHg in the main sample and were further categorized as <60 and ≥60 mmHg (reference) when patients were stratified according to SBP levels (<140, <130, and <120 mmHg). The outcomes were defined as recurrent stroke and cumulative composite events (defined as the combination of nonfatal myocardial infarction, nonfatal congestive heart failure, and death) at 1 year. Results: During 1 year of follow-up, a total of 95 composite events and 138 stroke recurrences were identified. The patients with low DBP showed a significantly higher risk of composite events [hazard ratio (HR) = 4.86, 95% confidence interval (CI) = 2.54-8.52], especially the elderly patients (≥60 years); however, this result was not observed for stroke recurrence (HR = 0.90, 95% CI = 0.46-1.74). With the reduction of the SBP levels, the proportion of patients with low DBP increased (6.87, 12.67, and 34.46%), and the risk for composite events persisted. Conclusions: Along with the new target levels of SBP suggested by updated criteria, there is a trend for DBP to be reduced to a harmfully low level, which was associated with an increased risk of composite events among patients with IS or TIA.

Oxidized low-density lipoprotein (LDL) and LDL cholesterol are associated with outcomes of minor stroke and TIA.

BACKGROUND AND AIMS: Low-density lipoprotein (LDL) and oxidized low-density lipoprotein (oxLDL) levels are thought to be related to recurrent stroke. However, the joint association of circulating LDL and oxLDL levels with the outcomes of acute minor ischemic stroke and transient ischemic attack (TIA) remains unclear. The goal of the study was to evaluate whether LDL and oxLDL have a combined effect on outcomes of acute minor stroke and TIA. METHODS: In the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) trial, a subgroup of 3019 patients with baseline oxLDL and LDL levels were analyzed. Patients were divided into four groups according to different combinations of LDL (LDL < 3.37 mmol/L, LDL ≥ 3.37 mmol/L) and oxLDL levels (oxLDL <13.96 µg/dL, oxLDL ≥ 13.96 µg/dL). The primary outcome was any stroke within 90 days. The secondary outcomes included any stroke within 1 year and ischemic stroke and combined vascular events within 90 days and 1 year. The poor functional outcome included modified Rankin Scale (mRS) 3-6 at 90-day and 12-month follow-up. The association of LDL and oxLDL with the prognosis of patients was examined using multivariable Cox regression models. RESULTS: Among 3019 patients included in this study, the medians (interquartile range) of oxLDL and LDL were 13.96 (6.65-28.81) µg/dL and 3.1 (2.5-3.8) mmol/L, respectively. The cumulative occurrence of recurrent stroke, ischemic stroke, and combined vascular events was 9.74%, 9.54%, and 9.80% within 90 days of follow-up. Compared with those with low LDL and oxLDL levels (LDL < 3.37 mmol/L with oxLDL <13.96 µg/dL), patients with high levels of LDL and oxLDL (LDL ≥3.37 mmol/L, oxLDL ≥13.96 µg/dL) had significantly increased risk of recurrent stroke at 90 days (HR,1.57; 95% CI, 1.10-2.24) and 1 year (HR,1.49; 95% CI, 1.10-2.04). Patients in groups with LDL ≥3.37 mmol/L, oxLDL <13.96 µg/dL (HR,1.35; 95% CI, 0.94-1.93) or LDL < 3.37 mmol/L with oxLDL ≥13.96 µg/dL (HR,1.11; 95% CI, 0.77-1.59) showed no statistical difference for stroke recurrence. Similar results were found for functional outcomes. CONCLUSIONS: The presence of higher combined serum oxLDL and LDL levels was associated with increased risk of recurrent stroke and poor functional outcomes in minor stroke or high-risk TIA patients.

Efficacy of Clopidogrel-Aspirin Therapy for Stroke Does Not Exist in CYP2C19 Loss-of-Function Allele Noncarriers With Overweight/Obesity.

Background and Purpose- The role of dual-antiplatelet therapy with clopidogrel plus aspirin has been demonstrated to substantially decrease the risk of recurrent stroke among patients with minor stroke and transient ischemic attack. We aimed to determine whether the efficacy of clopidogrel-aspirin therapy among patients with minor stroke / transient ischemic attack was influenced by the stratification of CYP2C19 genotype and body mass index (BMI). Methods- CYP2C19 loss-of-function allele (LoFA) carriers were defined as patients with either LoFA of *2 or *3. Low/normal weight and overweight/obesity was defined as BMI <25 and ≥25 kg/m2, respectively. Primary outcome was defined as stroke recurrence at 3 months. Results- In a total of 2933 patients, there were 1726 (58.8%) LoFA carriers and 1275 (43.5%) patients with overweight/obesity (BMI ≥25 kg/m2). Stratified analyses by LoFA carrying status and BMI, hazard ratios (hazard ratios 95% CIs) of the clopidogrel-aspirin therapy for stroke recurrence were 0.90 (0.60-1.36), 0.87 (0.56-1.35), 0.65 (0.39-1.09), and 0.40 (0.22-0.71) among subgroups of LoFA carriers with overweight/obesity, LoFA carriers with low/normal weight, LoFA noncarriers with overweight/obesity, and LoFA noncarriers with low/normal weight, respectively, with P=0.049 for interaction. Conclusions- Efficacy of clopidogrel-aspirin therapy in reducing the risk of stroke recurrence is not present in CYP2C19 LoFA noncarriers with overweight/obesity. Our study suggests that BMI significantly influences the correlation between CYP2C19 genotype and efficacy of clopidogrel-aspirin therapy. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00979589.

Uric Acid Contributes to Obesity-Paradox of the Outcome of Ischemic Stroke.

Background: The mechanism of obesity paradox in stroke is not clear. This study aimed to investigate whether uric acid (UA) contributes to obesity-stroke outcome paradox. Material and Methods: The study cohort consisted of 1,984 IS patients recruited in the ACROSS-China study. Serum UA and BMI were measured at admission. Low and high BMI groups were defined by the threshold of 24, and low and high UA by the age- and sex-specific median. Poor outcomes were defined as modified Rankin scale score ≥3 in 1 year after onset. Results: UA was significantly and positively correlated with BMI. Lower levels of UA and BMI were significantly associated with higher risk of poor outcomes. Incidence of the poor outcome was 34.5, 29.4, 27.7, and 23.5% in the BMI/UA groups of low/low, high/low, low/high and high/high, respectively, with p = 0.001 for trend. The association between low UA and poor outcome was significant in lower BMI groups (odds ratio = 1.36, p = 0.006 in quartile 1 and 1.28, p = 0.021 in quartile 2), but the odds ratios were not significant in the BMI quartile 3 and 4 groups, with p = 0.038 for trend. The adverse effect of lower UA was significant in males, but not in females, with p = 0.006 for sex difference. Conclusions: These findings suggest that low UA and low BMI have a joint effect on poor outcomes in IS patients. Across BMI categories, uric acid is differentially associated with functional outcome after stroke. This effect of low UA in the low BMI groups may be one of the mechanisms underlying the obesity-stroke paradox of the outcome in IS patients.

Acute-phase blood pressure trajectories and clinical outcomes in ischemic stroke.

High blood pressure (BP) is frequent in acute ischemic stroke (IS). However, the impact of BP change patterns during acute phase on clinical outcomes is not conclusive. This study aims to investigate the association between the acute-phase BP trajectories and clinical outcomes in IS patients with high admission BP. The cohort consisted of 316 IS patients with admission systolic BP (SBP) ≥160 mm Hg. SBP trajectories during the first 7 days after onset were characterized using a random effects model. The patients were classified into three groups based on the SBP trajectory curve parameters: sustained high SBP (T1), moderate decrease (T2), and rapid decrease in SBP (T3). Poor outcomes were defined as modified Rankin scale score ≥3 in 3 months after onset. The relationship between SBP trajectory groups and the outcome was examined in multivariable logistic regression models. The decreasing trend was greater in the favorable than in the poor outcome group (P = 0.028 for difference in linear slopes). The incidence of poor outcomes was 25.9%, 13.5%, and 9.8% in T1 (n = 54), T2 (n = 170), and T3 (n = 92) groups, respectively. Compared with T1 group, the decrease in SBP in T2 and T3 groups was significantly associated with lower risk of the poor outcome (odds ratio = 0.25, 95% confidence interval = 0.10-0.67, P = 0.006). These findings suggest that a decrease in BP in the acute phase is predictive of favorable outcomes in IS patients. BP trajectories have a greater power to detect the association than individual BP values at one time-point.

Efficacy of clopidogrel for stroke depends on CYP2C19 genotype and risk profile.

OBJECTIVE: Dual antiplatelet therapy (DAT) with clopidogrel plus aspirin has been suggested by American Heart Association/American Stroke Association guidelines for minor stroke (MS) and transient ischemic attack (TIA) patients. The purpose of this study was to find the potential subgroups that benefit from DAT. We aimed to compare the efficacy of clopidogrel-aspirin therapy with that of aspirin therapy in MS/TIA patients stratified by CYP2C19 genotype and risk profiles. METHODS: CYP2C19 loss-of-function allele (LoFA) carriers were defined as patients with LoFA of either *2 or *3. Low- and high-risk profile was defined as Essen Stroke Risk Score (ESRS) <3 and ≥3, respectively. Stroke recurrence at 1 year was considered primary outcome. RESULTS: Of a total 2,933 MS/TIA patients, there were 1,726 (58.8%) LoFA carriers and 1,068 (36.4%) patients at high risk (ESRS ≥3). No significant difference for stroke recurrence between the clopidogrel-aspirin group and aspirin alone group was found in LoFA carriers (11.2% vs 13.3%, hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.64~1.09). In stratified analyses by CYP2C19 genotype and ESRS, HRs (95% CIs) of the clopidogrel-aspirin therapy for stroke recurrence were 1.00 (0.70~1.42), 0.63 (0.41~0.97), 0.62 (0.40~0.96), and 0.52 (0.31~0.88) among subgroups of LoFA carriers at low risk, LoFA carriers at high risk, LoFA noncarriers at low risk, and LoFA noncarriers at high risk, respectively, with p = 0.021 for interaction. INTERPRETATION: Overall, LoFA carriers do not benefit from DAT, but there is significant benefit for LoFA carriers who are at high risk. The benefit of clopidogrel in Chinese MS/TIA patients depends on CYP2C19 genotype and risk profile. ANN NEUROL 2019;86:419-426.

Oxidized Low-Density Lipoprotein to High-Density Lipoprotein Ratio Predicts Recurrent Stroke in Minor Stroke or Transient Ischemic Attack.

Background and Purpose- Oxidized low-density lipoprotein (oxLDL) level is thought to be associated with recurrent stroke. We aimed to investigate the association between oxLDL to high-density lipoprotein (HDL) ratio and recurrent stroke in patients with minor stroke or transient ischemic attack. Methods- The study included 3019 patients with minor ischemic stroke or high-risk transient ischemic attack from the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events). Baseline oxLDL and HDL levels were measured. The primary outcome was any stroke within 90 days. The secondary outcomes included any stroke within 1 year and ischemic stroke and combined vascular events within 90 days and 1 year. The association between oxLDL/HDL and recurrent stroke was analyzed by using Cox proportional hazards. Results- Patients in the highest oxLDL/HDL quartile had a higher risk of recurrent stroke within 90 days (hazards ratio, 1.50; 95% CI, 1.08-2.08) compared with the lowest quartile after adjusting relevant confounding factors ( P=0.02). Similar results were found for secondary outcomes ( P<0.05 for all). There were no significant interaction between oxLDL/HDL and use of statins agents. Conclusions- Higher serum oxLDL/HDL level in minor stroke or transient ischemic attack was associated with increased risk of recurrent stroke in 90 days and 1 year. OxLDL/HDL may act as a powerful indicator of recurrent stroke in patients with minor stroke or transient ischemic attack. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00979589.

Oxidized low-density lipoprotein predicts recurrent stroke in patients with minor stroke or TIA.

OBJECTIVE: To investigate the association between oxidized low-density lipoprotein (oxLDL) and recurrent stroke in patients with minor stroke or TIA. METHODS: In the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) trial, baseline oxLDL levels were blindly measured in plasma with the 4E6 antibody in the core laboratory. The primary outcome was any stroke within 90 days. The secondary outcomes included any stroke within 1 year and ischemic stroke and combined vascular events within 90 days and 1 year. The associations of oxLDL with recurrent stroke were analyzed by Cox proportional hazards. RESULTS: Among 3,019 patients included in this study, the median (interquartile range) of oxLDL was 13.96 (6.65-28.81) µg/dL. After adjustment for conventional confounding factors, patients in the highest oxLDL quartile (≥28.81 µg/dL) had a higher risk of recurrent stroke within 90 days (hazard ratio 1.43, 95% confidence interval 1.03-1.98) compared to those in the lowest oxLDL quartile (<6.65 µg/dL). Similar results were found for secondary outcomes. We also found a J-shaped association between oxLDL and risk of each outcome. There were no significant interactions between oxLDL and low-density lipoprotein and use of dual antiplatelet, antihypertensive, antidiabetic, and statins agents. CONCLUSIONS: Elevated oxLDL levels can independently predict recurrent stroke in patients with minor stroke or TIA. CLINICALTRIALSGOV IDENTIFIER: NCT00979589.

Proteinuria and risk of stroke in patients with hypertension: The Kailuan cohort study.

Proteinuria is associated with stroke, but the effects of changes in proteinuria on stroke risk are not well understood in the hypertensive population. This study examined whether proteinuria changes across 2-year assessments were associated with incident stroke in individuals with hypertension. We used visit data from 24 300 participants with hypertension of the Kailuan study who were stroke free at baseline. Based on the baseline and 2-year dipstick screening results, participants were classified as having no, remittent, incident, or persistent proteinuria. The relationship between proteinuria and stroke was analyzed using Cox proportional-hazards models after adjusting for potential variables. During a median of 6.89-year follow-up, we identified 1197 people with stroke. Compared to those with no proteinuria, stroke risk was significantly increased in participants with incident (hazard ratio [HR] 1.41, 95% CI, 1.05-1.77) and persistent proteinuria (HR 1.49, 95% CI, 1.25-1.89) after adjustment for other factors, which was consistent in ischemic stroke and intracerebral hemorrhage. No interaction was found between changes of proteinuria and diabetes mellitus in the hypertensive population. Changes in proteinuria exposure, particularly persistent proteinuria, play a role in reflecting the risk of stroke in patients with hypertension.

Association of visit-to-visit blood pressure variability with the risk of all-cause mortality and cardiovascular events in general population.

The association between blood pressure variability (BPV) and the risk of all-cause mortality and cardiovascular diseases (CVD) is not well understood. The Kailuan study is a prospective longitudinal cohort study on cerebrovascular events and cardiovascular factors. In this study, resting blood pressure was measured at baseline and every 2 years from 2006 to 2007. BPV is mainly defined as the coefficient of variation (CV). Hazard ratio (HR), with 95% confidence intervals (CI) was calculated using Cox regression model. Among 52 387 participants, we identified 1817 who ended up with all-cause death and 1198 with CVD. Each 4.68% increase in BPV was associated with a 13% increase in the risk of mortality (HR = 1.13, 95% CI = 1.09-1.18) and a 7% increase in CVD (HR = 1.07, 95% CI = 1.02-1.13), respectively. After adjustment of confounding factors, the HR of comparing participants in the highest versus lowest quartile of CV of systolic blood pressure (SBP) was 1.37 (1.19, 1.57) for all-cause death, 1.18 (1.01, 1.39) for CVD. Similar results were also observed when BPV was measured by different parameters. We concluded that visit-to-visit BPV was associated with all-cause death and cardiovascular and cerebrovascular events in Chinese general population.

The relationship between oxidized low-density lipoprotein and the NIHSS score among patients with acute ischemic stroke: The SOS-Stroke Study.

BACKGROUND AND AIMS: Oxidized low-density lipoprotein (oxLDL) has a defined role in the genesis and development of atherosclerosis, however, whether it is related to severity of neurological deficits is rarely reported. The aim of our study was to investigate the potential association between oxLDL and the National Institutes of Health Stroke Scale (NIHSS) score among patients with acute ischemic stroke. METHODS: Between January 2014 and October 2014, we recruited 4111 patients with acute ischemic stroke (AIS), who were admitted within 7 days-43 hospitals in China, and participated in the SOS-Stroke Study. We collected detailed clinical data and then tested the relationship between oxLDL and the NIHSS score using a multivariate linear regression analysis. RESULTS: After adjusting for age, gender, ethnicity, marriage and other confounding variables, the elevated NIHSS score was significantly associated with increased oxLDL levels, and each 1-µg/dL elevation in oxLDL concentration resulted in an increase of 0.027 in the NIHSS score. CONCLUSIONS: A positive correlation was found between plasma levels of oxLDL and the NIHSS score in patients with acute ischemic stroke. Higher plasma levels of oxLDL potentially suggest a worse prognosis in AIS patients.

Association of Cumulative Exposure to Resting Heart Rate with Risk of Stroke in General Population: The Kailuan Cohort Study.

BACKGROUND AND PURPOSE: It remains unclear whether resting heart rate (RHR), particularly cumulative exposure to resting heart rate (cumRHR), is associated with stroke. The aim of our study was to prospectively explore the relationship between cumRHR and stroke morbidity. MATERIALS AND METHODS: The Kailuan study is a prospective longitudinal cohort study on cerebrovascular events and cardiovascular factors. Hazard ratios (HRs) with 95% confidence interval (CI) were calculated using a Cox competing risk model. RESULTS: A total of 46,568 participants were included in the final analysis. In the observation population, we identified 851 stroke events and 1012 incident death cases in the 4.98 ± .51 year followed-up. Each 46.74 (beats/min) × year increase in heart rate was associated with a 12% increase in the risk of stroke (HR = 1.12, 95% CI = 1.05-1.20). In the categorical model, the highest quartile had an increased risk of stroke (HR = 1.43, 95% CI = 1.13-1.81), compared with the bottom quartile. Gender and age had no interaction with cumRHR for the risk of stroke. CONCLUSION: Increase of exposure to cumulative heart rate is independently associated with a higher risk of stroke in the general population.