Inflammation and endothelial function relevant genetic polymorphisms, carotid atherosclerosis, and vascular events in high-risk stroke population.

Aim: To identify the associations of 19 single nucleotide polymorphisms (SNPs) in genes involved in inflammation and endothelial function and carotid atherosclerosis with subsequent ischemic stroke and other vascular events in the high-risk stroke population. Methods: This was a multicenter community-based sectional survey and prospective cohort study in Sichuan, southwestern China. Eight communities were randomly selected, and the residents in each community were surveyed using a structured face-to-face questionnaire. Carotid ultrasonography and DNA information were obtained from 2,377 out of 2,893 individuals belonging to a high-risk stroke population. Genotypes of the 19 SNPs in genes involved in inflammation and endothelial function were measured. All the 2,377 subjects were followed up for 4.7 years after the face-to-face survey. The primary outcome was ischemic stroke, and the secondary outcome was a composite of vascular events. Results: Among the 2,377 subjects, 2,205 (92.8%) completed a 4.7-year follow-up, 947 (42.9%) had carotid atherosclerosis [372 (16.9%) carotid vulnerable plaque, 405 (18.4%) mean IMT > 0.9 mm, 285 (12.0%) carotid stenosis ≥15%]. Outcomes occurred in 158 (7.2%) subjects [92 (4.2%) ischemic stroke, 17 (0.8%) hemorrhagic stroke, 48 (2.2%) myocardial infarction, and 26 (1.2%) death] during follow-up. There was a significant gene-gene interaction among ITGA2 rs1991013, IL1A rs1609682, and HABP2 rs7923349 in the 19 SNPs. The multivariate logistic regression model revealed that carotid atherosclerosis and the high-risk interactive genotypes among the three SNPs were independent with a higher risk for ischemic stroke (OR = 2.67, 95% CI: 1.52-6.78, p = 0.004; and OR = 3.11, 95% CI: 2.12-9.27, p < 0.001, respectively) and composite vascular events (OR = 3.04, 95% CI: 1.46-6.35, p < 0.001; and OR = 3.23, 95% CI: 1.97-8.52, p < 0.001, respectively). Conclusion: The prevalence of carotid atherosclerosis was shown to be very high in the high-risk stroke population. Specific SNPs, interactions among them, and carotid atherosclerosis were independently associated with a higher risk of ischemic stroke and other vascular events.

The incidence of stroke and contribution of risk factors for stroke in high-risk stroke population in southwestern China.

OBJECTIVE: To estimate the incidence of stroke and determine the role that risk factors play in the high-risk stroke populace in southwest China. METHODS: This research employed a prospective cohort design that focused on the community. Eight communities in southwest China were selected randomly for this study. The residents aged 40 years and older who volunteered to participate were surveyed through face-to-face interviews. Those with a history of stroke or at least three of the eight stroke-related risk factors were categorized as the high-risk stroke population. A total of 2698 high-risk individuals were included in the study after a 4.7-year follow-up period. The incidence of stroke and the association between risk variables and stroke occurrence were estimated. RESULTS: During 4.7-year follow-up, the incidence of total stroke, ischemic stroke, and hemorrhagic stroke in high-risk stroke population were 5.0 %, 4.4 % and 0.9 % respectively. It should be noted that some participants experienced both cerebral infarction and cerebral hemorrhage during the follow-up period. The multivariate analytic model revealed that a personal history of stroke (OR=3.397, 95 % CI 2.365-4.878, p<.001) was substantially linked with an elevated risk of overall stroke. This correlation remained consistent for both ischemic and hemorrhagic stroke. CONCLUSIONS: This study revealed a high prevalence and incidence of stroke among a high-risk group in southwestern China. Furthermore, it demonstrated that individuals with a personal history of stroke are at an elevated risk of future stroke, suggesting the need for additional precautions in this population.

Development and validation of an interpretable machine learning model-Predicting mild cognitive impairment in a high-risk stroke population.

Background: Mild cognitive impairment (MCI) is considered a preclinical stage of Alzheimer's disease (AD). People with MCI have a higher risk of developing dementia than healthy people. As one of the risk factors for MCI, stroke has been actively treated and intervened. Therefore, selecting the high-risk population of stroke as the research object and discovering the risk factors of MCI as early as possible can prevent the occurrence of MCI more effectively. Methods: The Boruta algorithm was used to screen variables, and eight machine learning models were established and evaluated. The best performing models were used to assess variable importance and build an online risk calculator. Shapley additive explanation is used to explain the model. Results: A total of 199 patients were included in the study, 99 of whom were male. Transient ischemic attack (TIA), homocysteine, education, hematocrit (HCT), diabetes, hemoglobin, red blood cells (RBC), hypertension, prothrombin time (PT) were selected by Boruta algorithm. Logistic regression (AUC = 0.8595) was the best model for predicting MCI in high-risk groups of stroke, followed by elastic network (ENET) (AUC = 0.8312), multilayer perceptron (MLP) (AUC = 0.7908), extreme gradient boosting (XGBoost) (AUC = 0.7691), and support vector machine (SVM) (AUC = 0.7527), random forest (RF) (AUC = 0.7451), K-nearest neighbors (KNN) (AUC = 0.7380), decision tree (DT) (AUC = 0.6972). The importance of variables suggests that TIA, diabetes, education, and hypertension are the top four variables of importance. Conclusion: Transient ischemic attack (TIA), diabetes, education, and hypertension are the most important risk factors for MCI in high-risk groups of stroke, and early intervention should be performed to reduce the occurrence of MCI.

Vulnerable Carotid Plaque is Associated with an Increased Risk of Intracerebral Hemorrhage in Individuals at High Risk of Stroke: A Chinese Population-based Cohort Study.

OBJECTIVES: To assess the association between carotid artery plaques and the risk of incident intracerebral hemorrhage (ICH) event in high-risk individuals for stroke. METHODS: We conducted a population-based cohort study using the longitudinal participant-level data of a multicenter, cross-sectional survey in southwestern China. 2644 high-risk participants for stroke were enrolled in the year 2015. The primary outcome was new-onset ICH events during a five-year follow-up period. Multivariate logistic regression was performed to identify the association between carotid plaque and new-onset ICH. Stratified analyses and interaction tests were conducted to identify variables that might modify the association between vulnerable carotid plaque and ICH. RESULTS: Among 2644 high-risk individuals enrolled, carotid plaques were found in 904 (34.2%) subjects, including 479 (18.1%) with stable plaques and 425 (16.1%) with vulnerable plaques. During a five-year follow-up period, 22 (0.83%) participants developed ICH. Vulnerable carotid plaque was associated with an increased risk of new-onset ICH in multivariable analyses (adjusted RR 3.72, 95 % CI 1.32 to 10.46, p=0.013). Stratified analyses and interaction analyses demonstrated the association between vulnerable carotid plaque and ICH was not changed by age, family history of stroke, hemorrhagic stroke and chronic disease, smoking, drinking, physical activity, BMI, antihypertensives, and antithrombotic drugs (all p for interaction>0.05). However, among the female cohort, participants with vulnerable plaques had a significantly higher risk of ICH compared with participants without vulnerable plaques (crude RR=9.8; 95%CI: 3.1-31.3, p<0.001; adjusted RR=26.3, 95%CI: 5.5-124.5, p<0.001), but not in man (p>0.05). CONCLUSION: In Chinese individuals at high risk of stroke, vulnerable carotid artery plaques are associated with an increased risk of intracerebral hemorrhage independent of classical vascular risk factors, especially in female individuals.

Variants in genes related to inflammation and endothelial function can increase the risk for carotid atherosclerosis in southwestern China.

Aim: To investigate the potential association between polymorphisms in genes involved in endothelial function, inflammation and carotid atherosclerosis. Methods: This was a three-center, population-based sectional survey conducted in Sichuan province of southwestern China. We randomly selected 8 different communities in Sichuan, and the residents in each community volunteered to participate in the survey by face-to-face questionnaire. A total of 2,377 residents with high stroke risk population in the 8 communities were included. Carotid atherosclerosis was evaluated by carotid ultrasound, and the 19 single nucleotide polymorphisms (SNPs) in 10 endothelial function as well as inflammation relevant genes were measured in the high stroke risk population. Carotid atherosclerosis was defined by the presence of carotid plaque or any carotid stenosis ≥15% or mean intima-media thickness (IMT) > 0.9 mm. Generalized multifactor dimensionality reduction (GMDR) approach was used to analyze gene-gene interactions among the 19 SNPs. Results: Among the 2,377 subjects with high stroke risk, 1,028 subjects had carotid atherosclerosis (43.2%), of which 852 (35.8%) cases had carotid plaque, 295 (12.4%) cases had ≥15% carotid stenosis, whereas 445 (18.7%) had mean IMT > 0.9 mm. Multivariate logistic regression revealed that IL1A rs1609682 TT and HABP2 rs7923349 TT served as independent risk factors for carotid atherosclerosis (OR, 1.45, 95% CI: 1.034-2.032, p = 0.031, and OR, 1.829, 95% CI: 1.228-2.723, p = 0.003). GMDR analysis indicated that there was a significant gene-gene interaction found among IL1A rs1609682, ITGA2 rs1991013, and HABP2 rs7923349. After adjusting the covariates, the high-risk interactive genotypes in the 3 variants were significantly associated with a significantly higher risk for carotid atherosclerosis (OR, 2.08, 95% CI: 1.257-5.98, p < 0.001). Conclusion: The prevalence of carotid atherosclerosis was observed to be extremely high in the high-risk stroke population in southwestern China. There were associations observed between the specific variants in inflammation and endothelial function relevant genes and carotid atherosclerosis. The high-risk interactive genotypes among IL1A rs1609682, ITGA2 rs1991013, and HABP2 rs7923349 significantly increased the risk of carotid atherosclerosis. These results are expected to provide novel strategies for the prevention of carotid atherosclerosis. The gene-gene interactive analysis used in this study may be very helpful to elucidate complex genetic risk factors for carotid atherosclerosis.

Inflammation and endothelial function-related gene polymorphisms are associated with carotid atherosclerosis-A study of community population in Southwest China.

OBJECTIVES: To investigate the relationships between 18 single nucleotide polymorphisms with carotid atherosclerosis and whether interactions among these genes were associated with an increased risk of carotid atherosclerosis. METHODS: Face-to-face surveys were conducted with individuals aged 40 or older in eight communities. A total of 2377 individuals were included in the study. Ultrasound was used to detect carotid atherosclerosis in the included population. 18 loci of 10 genes associated with inflammation and endothelial function were detected. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR). RESULTS: Among the 2377 subjects, 445 (18.7%) subjects had increased intima-media thickness in the common carotid artery (CCA-IMT), and 398 (16.7%) subjects were detected with vulnerable plaque. In addition, NOS2A rs2297518 polymorphism was associated with increased CCA-IMT, IL1A rs1609682, and HABP2 rs7923349 polymorphisms were associated with vulnerable plaque. Besides, GMDR analysis showed significant gene-gene interactions among TNFSF4 rs1234313, IL1A rs1609682, TLR4 rs1927911, ITGA2 rs1991013, NOS2A rs2297518, IL6R rs4845625, ITGA2 rs4865756, HABP2 rs7923349, NOS2A rs8081248, HABP2 rs932650. CONCLUSION: The prevalences of increased CCA-IMT and vulnerable plaque were high in Southwestern China's high-risk stroke population. Furthermore, inflammation and endothelial function-related gene polymorphisms were associated with carotid atherosclerosis.

Sex-specific association between inflammation and endothelial function relevant gene and vulnerable carotid plaque.

Objectives: We aimed to explore sex-specific association between genes involved in inflammation and endothelial function and vulnerable carotid plaque, a subclinical precursor of ischemic stroke. Methods: Carotid plaque and plaque phenotype were assessed by carotid ultrasound in high-risk participants for stroke drawn from a multicenter, cross-sectional survey in southwestern China. We examined 18 single nucleotide polymorphisms (SNPs) in 10 genes related to inflammation and endothelial function. Sex differences in the genotype of the candidate SNPs and risk of vulnerable carotid plaques were assessed. Interaction tests were performed to identify the SNPs that might modify the association between the sex and vulnerable plaques. For SNPs with suggestive evidence for interaction with sex (p for interaction<0.05), stratification analysis by sex was performed to evaluate the sex-specific association between the SNP and vulnerable plaques. Results: 2,644 high-risk individuals were enrolled, comprising 1,202 (45.5%) men and 1,442 (54.5%) women. Vulnerable carotid plaques were detected in 425 (16.1%) participants. Among candidate SNPs, the genotype frequencies of 5 SNPs (TNFSF4 rs11811788, TNFSF4 rs1234313, IL6R rs4845625, VCAM1 rs2392221, and ITGA2 rs1991013) were significantly different between sex (all p < 0.05). Univariable and multivariable analyses suggested that male individuals had a significantly higher prevalence of vulnerable carotid plaques (20.0% vs. 12.8%, adjusted OR 1.72, 95% CI 1.12-2.66, p = 0.014), while none of the candidate SNPs was significantly associated with vulnerable plaques (all p > 0.05). Interaction tests found the association between sex and vulnerable plaques is affected by the genotype of IL6R rs4845625 (p for interaction = 0.031). Stratification analysis revealed a strong association between IL6R rs4845625 and vulnerable carotid plaque in man (dominant model TT vs. CT + CC: adjusted OR 1.52, 95% CI 1.12-2.07, p = 0.007; codominant model TT vs. CC: adjusted OR 1.50, 95% CI 1.00-2.25, p = 0.048) but not in women (p > 0.05 in all genetic models). Conclusion: The rs4845625 polymorphism in IL6R has sex-specific effects on vulnerable carotid plaque in Chinese Han high-risk individuals for stroke. Our findings provide a plausible genetic basis underlying the sex difference in carotid plaque vulnerability.

Persistence of drug therapy is associated with ischemic stroke and other vascular events in high-risk stroke population.

The high-risk stroke populations are significantly associated with an increased risk of stroke or other vascular events. Although proven primary and secondary stroke prevention medications are available, persistent use is required to be effective. However, the persistence of drug therapy and its association with outcomes in the high-risk stroke population have received limited study in China. Hence, according to the China National Stroke Screening Survey (CNSSS) program in 2015, we performed this multicenter population-based cross-sectional survey and prospective cohort study in Sichuan of southwestern China. The residents aged ≥ 40 years volunteered to participate in a face-to-face survey in 8 communities. Subjects with at least three of eight stroke-related risk factors or a history of stroke were defined as high-risk stroke population. The interviewers recorded individuals' medications at a face-to-face survey, and all the high-risk stroke population was followed up for 4.7 years. The persistence of antihypertensives, hypoglycemics, lipid-lowering medications, and antithrombotics for stroke was evaluated. The primary outcome was new stroke. Secondary outcomes included new composite vascular events of stroke, myocardial infarction, and death during follow-up periods. Among 16,892 participants, 2,893 (17.1%) participants were high-risk stroke population and 2,698 (93.3%) participants completed to follow-up. The 4.7-year persistence of therapy rate of antihypertensives, hypoglycemics, lipid-lowering medications, and antithrombotics was 38.0%, 39.9%, 43.9%, and 59.8%, respectively. The total persistence of therapy rate for antihypertensives, hypoglycemics, lipid-lowering medications, and antithrombotics was 47.6% (136/286) in patients with hypertension, diabetes, dyslipidemia, and stroke at the same time. During the 4.7-year follow-up, there were 118 (4.4%) new ischemic stroke, 24 (0.9%) hemorrhagic stroke, 53 (2.0%) myocardial infarctions, and 33 (1.2%) deaths. After adjusting for the covariates, 4.7-year persistence of antihypertensives, hypoglycemics, lipid-lowering therapy, antithrombotics, and total persistence was independently associated with less new ischemic stroke and less new composite vascular events. Thus, more effective public education and efforts to understand and enhance the persistence of drug therapy are crucial to improve population health and decrease stroke and other vascular events for the high-risk stroke population.

Prevalence and Risk Factors of High-Risk Population for Stroke: A Population-Based Cross-Sectional Survey in Southwestern China.

With the aging of the population and the change of lifestyle in China, the prevalence and risk factors of the high-risk population for stroke may change. However, few studies performed community-based high-risk stroke population surveys in China. Hence, we performed this multicenter, cross-sectional, and community-based survey in Sichuan of southwestern China, according to the China National Stroke Screening Survey (CNSSS) program in 2015. The residents aged ≥ 40 years volunteered to participate in the face-to-face survey in 8 communities in Sichuan. The 8 communities were selected using the cluster randomization method. Subjects with at least three of the eight stroke-related risk factors were classified as a high-risk population for stroke. Otherwise were classified as a low-risk population for stroke. Furthermore, 1,011 individuals were randomly selected among the low-risk population for stroke as controls. Among 16,892 participants, 2,369 (14.0%) were high-risk population for stroke. After full adjustments, all eight risk factors for stroke were significantly associated with the high-risk population for stroke (P < 0.001). The largest contributor was hypertension [population-attributable risk (PAR) 28.4%], followed by physical inactivity (PAR 14.2%), dyslipidemia (PAR 11.2%), overweight/obesity (PAR 9.4%), diabetes (PAR 7.2%), family history (PAR 6.8%), smoking (PAR 5.9%), and atrial fibrillation (PAR 3.5%). Carotid atherosclerosis was more serious in the high-risk population for stroke than in controls (P < 0.05). The prevalence of the high-risk population for stroke was high in southwestern China. Hypertension, physical inactivity, and dyslipidemia were stronger contributors for the high-risk population for stroke. Individual-level and population-level interventions for these leading risk factors are very important for the primary prevention of stroke.

Blood homocysteine level in Shanghai rural residents with high risk of stroke / 上海预防医学

Objective:To determine the blood level of homocysteine （Hcy） and its influencing factors among Shanghai rural residents with high risk of stroke and to verify if hyperhomocysteinemia （HHcy） is a main biomarker of stroke. Methods:With a clustered random sampling method， questionnaire survey and physical examination were conducted among 4 073 rural residents， aged 55 years and above， in Luojing community， Shanghai， in 2018. A total of 470 residents were at high-risk for stroke based on screening of plasma Hcy and other blood indicators. Multivariate logistic regression method was performed for data analysis. Results:The overall level of Hcy was （18.92±6.37）μmol/L， with （20.40±5.89）μmol/L for men and （17.87±2.12）μmol/L for women （t=5.431，P<0.001）. HHcy was detected in 78.94%（371/470） of the participants， in which 85.77%（235/274） were men and 69.39%（136/196） were women （χ2=12.400，P=0.001）. In the high-risk male group， subjects with smoking history， overweight or obesity， exercise frequency <1 h/d， and hypertension has a higher detection rate of HHcy than those without smoking history， normal body mass index， exercise frequency ≥1 h/d and without hypertension （χ2=11.340，8.170，8.200， and 12.400， respectively， all P<0.01）. However， there was no significant difference in HHcy detection rate in different age groups and between the patients with or without diabetes， and dyslipidemia（χ2=3.120，2.311， and 0.984， respectively， all P>0.05）. In the high-risk women group， HHcy detection rate increased with age （χ2=13.874，P<0.01）， and it was higher in participants with overweight or obesity， exercise frequency < 1 h/d， hypertension， and dyslipidemia（χ2=10.278， 13.840， 14.100， and 12.330， respectively， all P<0.01）. Unconditional logistic regression analysis showed that the factors affecting HHcy in the high-risk population of stroke include being male， smoking， hypertension， overweight and obesity. Conclusion:Screening of high-risk populations for stroke should include blood level of Hcy.

Inflammation and Endothelial Function Relevant Genetic Polymorphisms and Carotid Plaque in Chinese Population.

AIM: To examine the association between carotid plaque and variants in genes involved in inflammation and endothelial function. METHODS: This was a multicenter, cross-sectional survey in southwestern China. The residents aged ≥ 40 years volunteered to participate in the face-to-face survey in eight communities. A total of 2,377 subjects with high stroke risk were enrolled. Carotid plaque and plaque phenotype were assessed by carotid ultrasound. Genotypes of 19 variants in 10 genes related to inflammation and endothelial function were examined. Gene-gene interaction was analyzed by generalized multifactor dimensionality reduction (GMDR). RESULTS: Carotid plaques were found in 852 (35.8%) subjects, and 454 (53.3%) had stable plaques, whereas 398 (46.7%) had vulnerable plaques. PPARA rs4253655, HABP2 rs7923349, and IL1A rs1609682 were associated with the presence of carotid plaque, and NOS2A rs2297518 and PPARA rs4253655 were associated with vulnerable plaque in univariate analysis. The GMDR analysis revealed that there was a significant gene-gene interaction among HABP2 rs7923349, ITGA2 rs1991013, IL1A rs1609682, and NOS2A rs8081248, and the high-risk interactive genotype among the four variants was independently associated with a higher risk of carotid vulnerable plaque after adjusting the covariates (OR, 2.86, 95% CI: 1.32-7.13, P=0.003). CONCLUSION: The prevalence of carotid plaque was very high in the high-risk stroke population in southwestern China. Variants in genes involved in the endothelial function and inflammation were associated with the carotid plaque. The high-risk interactive genotype among rs7923349, rs1991013, rs1609682, and rs8081248 was independently associated with a higher risk of vulnerable plaque.

Telomere length associated with the risks of high-risk and ischemic stroke in southern Chinese Han population.

Some previous studies suggested telomere length was associated with the risk of ischemic stroke (IS). The aim of this study was to further confirm the association between relative telomere length (RTL) and risk of IS and to especially explore its correlation with the risk of high-risk stroke population in southern Chinese Han. RTL was determined by using real-time quantitative polymerase chain reaction from 400 ischemic stroke patients, 409 high-risk stroke populations and 399 healthy controls. The correlations between the controls and the risk of high-risk and ischemic stroke were evaluated by using an unconditional logistic regression. IS patients have shown longer RTL than controls (median1.52vs1.11, p60 years) and gender suggested that the first and second tertile of RTL were correlated with the risk of IS in each group when the second tertile was used as a reference. However, the increased risk for high-risk stroke populations were only presented in the first tertile of RTL in the age≤60 years and female groups. the RTL was associated with an increased risk of ischemic stroke, while it elevated the risk of high-risk stroke in some specific subpopulations.

Effect of a comprehensive health education program on pre-hospital delay intentions in high-risk stroke population and caregivers.

OBJECTIVE: Many factors influence pre-hospital delays in the event of stroke. This study aimed to develop and evaluate a comprehensive educational program for decreasing pre-hospital delays in high-risk stroke population. METHODS: We enrolled 220 high-risk stroke population and caregivers from six urban communities in Harbin from May 2013 to May 2015, and randomly divided them into intervention and control groups. We implemented a comprehensive educational program (intervention group), comprising public lectures, instructional brochures, case videos, simulations, and role-playing from May 2013 to May 2015. We delivered conventional oral education in the control group. We compared stroke pre-hospital delay behavioral intention (SPDBI), pre-hospital stroke symptom coping test (PSSCT), and stroke pre-symptoms alert test (SPSAT) results between the groups before and 6, 12, and 18 months after health intervention. RESULTS: There were significant differences between before and after intervention (P < 0.01). SPDBI, PSSCT, and SPSAT scores were significantly different between the groups (P < 0.01). The interaction between time and intervention method was significant (P < 0.01). According to multivariate repeated measures analysis of variance, SPDBI, PSSCT, and SPSAT scores were significantly different at each time after intervention (P < 0.05). CONCLUSION: The comprehensive educational program was significantly effective in decreasing SPDBI, improving knowledge, enhancing stroke pre-symptoms alert, and reducing the possibility of pre-hospital delays.