Risk Of Incident Ischemic Stroke Research Articles

Predictive role of polymorphisms in interleukin-5 receptor alpha-subunit, lipoprotein lipase, integrin A2 and nitric oxide synthase genes on ischemic stroke in type 2 diabetes—An 8-year prospective cohort analysis of 1327 Chinese patients

ObjectiveIschemic stroke is prevalent in type 2 diabetes and may be due to metabolic, vascular and inflammatory factors. Genetic variants implicated in these pathways may have joint effects on stroke risk. In this proof-of-concept study, we examined gene–gene interactions on risk of incident ischemic stroke in an 8-year prospective cohort of Chinese type 2 diabetic patients. MethodsSeventy-seven single nucleotide polymorphisms (SNPs) of 53 candidate genes for cardiovascular disease and inflammation were genotyped in 1327 patients with no past history of ischemic stroke. The association of SNPs with stroke was tested using Cox proportional hazard regression analysis. Permutation procedure was performed to control for multiple statistical comparisons. ResultsGenetic variants including A/A of IL5RA (interleukin-5 alpha subunit) -5091G>A, X/X of LPL (lipoprotein lipase) S447X, A/A of ITGA2 (integrin A2) G873A and T/T or G/T of NOS3 (endothelial nitric oxide synthase) G894T showed significant correlations with incident ischemic stroke. The hazard ratios (HR) increased with number of genetic risk factors reaching an adjusted HR (confidence interval) of 3.68 (1.78–7.62, P=4.4×10−4) in those with ≥2 genetic risk factors compared to those without. ConclusionPolymorphisms in IL5RA, LPL, ITGA2 and NOS3 genes were independently associated with ischemic stroke in Chinese diabetic population.

Insulin Resistance and Risk of Ischemic Stroke Among Nondiabetic Individuals From the Northern Manhattan Study

Whether insulin resistance predicts ischemic stroke (IS) is still a matter of debate. To determine the association between insulin resistance (IR) and risk of first ischemic stroke in a large, multiethnic, stroke-free cohort without diabetes. Prospective, population-based cohort study. Longitudinal epidemiologic study. A cohort of 1509 nondiabetic participants from the Northern Manhattan Study (mean [SD] age, 11 [10] years; 64.2% women; 58.9% Hispanics). Insulin sensitivity, expressed by the homeostasis model assessment (HOMA) of insulin sensitivity (HOMA index=[fasting insulin×fasting glucose]/22.5). Insulin resistance was defined by a HOMA-IR index in the top quartile (Q4). Cox proportional hazards models were used to determine the effect of HOMA-IR on the risk of incident IS, myocardial infarction (MI), vascular death, and combined outcomes (IS, MI, and vascular death). The mean (SD) HOMA-IR was 2.3 (2.1), and Q4 was at least 2.8. During mean follow-up of 8.5 years, vascular events occurred in 180 participants; 46 had fatal or nonfatal IS, 45 had fatal or nonfatal MI, and 121 died of vascular causes. The HOMA-IR Q4 vs less than Q4 significantly predicted the risk of IS only (adjusted hazard ratio, 2.83; 95% confidence interval, 1.34-5.99) but not other vascular events. This effect was independent of sex, race/ethnicity, traditional vascular risk factors, and metabolic syndrome and its components. Insulin resistance estimated using the HOMA is a marker of increased risk of incident stroke in nondiabetic individuals. These findings emphasize the need to better characterize individuals at increased risk for IS and the potential role of primary preventive therapies targeted at IR.

Relative Leukocyte Telomere Length and Risk of Incident Ischemic Stroke in Men: A Prospective, Nested Case-Control Approach

Recent data have implicated telomere-length shortening as potential risk predictor for vascular diseases, including stroke. However, to date, prospective epidemiological data are scarce in relation to ischemic stroke risk. Using leukocyte DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we examined the relationship of leukocyte telomere repeat copy number to single gene copy number (TSR), using a quantitative polymerase chain reaction protocol, amongst 259 white males who subsequently developed an ischemic stroke and amongst an equal number of age- and smoking-matched white males who remained free of reported vascular disease during follow up (controls). The observed TSRs were inversely correlated with age in the controls (p < 0.0001). However, the observed TSRs were similar between cases and controls (p = 0.92). In a multivariable adjusted analysis, no evidence was found for an association of the TSRs with ischemic stroke risk (odds ratio [OR] = 1.100, 95% confidence interval [CI], 0.506-2.392, p = 0.811). The present investigation has shown no evidence for an association of relative leukocyte telomere length with risk of incident ischemic stroke. More importantly, our present findings require replication/confirmation in future large, prospective studies.

Hepatocyte Growth Factor and the Risk of Ischemic Stroke Developing Among Postmenopausal Women

Background and Purpose— Hepatocyte growth factor (HGF) is a potent angiogenic factor and may play a role in the development and progression of atherosclerotic lesions, the underlying mechanism of cardiovascular disease. However, there have been no prospective studies examining the relationship between HGF levels and risk of stroke. Methods— We conducted a nested case-control study (972 incident stroke cases and 1:1 age-matched and race-matched controls) to prospectively evaluate the association between plasma HGF and risk of ischemic stroke within the Women’s Health Initiative Observational Study, a cohort of postmenopausal women aged 50 to 79 years. Results— Baseline HGF levels were correlated positively with body mass index, systolic blood pressure, low-density lipoprotein cholesterol, insulin resistance, and inflammatory markers, such as C-reactive protein, and inversely with high-density lipoprotein cholesterol (all P &lt;0.05). Baseline HGF levels were higher among cases than controls (geometric means, 601.8 vs 523.2 pg/mL; P =0.003). Furthermore, the risk of incident ischemic stroke was significantly greater among women in the highest vs lowest quartile of plasma HGF levels (OR, 1.46; 95% CI, 1.12–1.91; P trend =0.003) in a conditional logistic regression model that adjusted for body mass index. These results were only slightly attenuated after further adjustment for additional stroke risk factors (OR, 1.39; 95% CI, 1.04–1.85; P trend =0.023). Conclusions— Circulating levels of HGF are associated with an increased risk of incident ischemic stroke, independent of obesity and other risk factors for cardiovascular disease, among postmenopausal women aged 50 to 79 years.

Homozygosity for the EPHX2 K55R polymorphism increases the long-term risk of ischemic stroke in men: a study in Swedes

The soluble epoxide hydrolase (gene name EPHX2) is responsible for metabolism of 8,9 11,12 and 14,15-epoxyeicosatrienoic acids, vasodilator and anti-inflammatory substances. There are several functional polymorphisms in the EPHX2 gene: two of them, the K55R and R287Q, showing an altered metabolic activity in vitro, were associated with coronary heart disease and ischemic stroke in previous studies. The aim of this study was to evaluate the effect of four polymorphisms in the EPHX2 gene on blood pressure levels, hypertension prevalence, and risk of incident cardiovascular events in a large sample of middle-aged Swedes. The incidence of cardiovascular events (coronary events, n = 274; ischemic stroke, n = 197) was monitored over 10 years of follow-up. In the whole population, all polymorphisms had no effect on the studied parameters but a positive interaction between male sex and three SNPs including the K55R was evident: male, but not female, EPHX2 R55R homozygotes had significantly higher crude and adjusted systolic blood pressure and higher hypertension prevalence with respect to K-carriers. Kaplan-Meier curves showed higher incidence of ischemic strokes in male R55R homozygotes with respect to K-carriers (P = 0.015 by log-rank test). After adjustment for major cardiovascular risk factors, the hazard ratio for incident ischemic stroke in male R55R homozygotes remained significantly higher (hazard ratio: 4.8; 95% confidence interval: 1.2-19.9). The functional K55R polymorphism of the EPHX2 gene confers a higher risk of hypertension prevalence and increases the risk of incident ischemic stroke in male homozygotes. Additional studies are needed to confirm these data and to elucidate the interaction between sex and the EPHX2 K55R polymorphism.

Short-Term and Long-Term Risk of Incident Ischemic Stroke After Transient Ischemic Attack

The relative risk of ischemic stroke associated with transient ischemic attack (TIA) is not well defined because most studies of stroke after TIA did not include comparison groups. We sought to estimate short-term and long-term relative risks of ischemic stroke associated with clinically diagnosed TIA. We used data from a population-based case-control study. Cases were hypertensive men and women and postmenopausal women, ages 30 to 79, with incident ischemic stroke. Control subjects were sampled within strata of age, sex, hypertension status, and calendar year. The index date was the stroke date for cases and a random date for control subjects. Clinically diagnosed TIA was ascertained from medical records. We used logistic regression to calculate ORs. The study included 1914 stroke cases and 9874 control subjects. Clinically diagnosed TIA was present in 215 (11.2%) cases and 252 (2.5%) control subjects. Analyses focused on the most recent TIA before the index date. For TIA <1 month before the index date, the adjusted OR for stroke was 30.4 (95% CI, 10.4 to 89.4); for TIA 1 to 3 months before the index date, it was 18.9 (8.58 to 41.6); for TIA 4 to 6 months before the index date, it was 3.16 (1.27 to 7.82); and for TIA >5 years before the index date, it was 1.87 (1.22 to 2.85). The relative risk of ischemic stroke was high for TIA diagnosed within the past 3 months and moderately high for TIA diagnosed >5 years in the past compared with no history of clinically diagnosed TIA.

Physical activity and risk of ischemic stroke in the Northern Manhattan Study

It is controversial whether physical activity is protective against first stroke among older persons. We sought to examine whether physical activity, as measured by intensity of exercise and energy expended, is protective against ischemic stroke. The Northern Manhattan Study is a prospective cohort study in older, urban-dwelling, multiethnic, stroke-free individuals. Baseline measures of leisure-time physical activity were collected via in-person questionnaires. Cox proportional hazards models were constructed to examine whether energy expended and intensity of physical activity were associated with the risk of incident ischemic stroke. Physical inactivity was present in 40.5% of the cohort. Over a median follow-up of 9.1 years, there were 238 incident ischemic strokes. Moderate- to heavy-intensity physical activity was associated with a lower risk of ischemic stroke (adjusted hazard ratio [HR] 0.65, 95% confidence interval [0.44-0.98]). Engaging in any physical activity vs none (adjusted HR 1.16, 95% CI 0.88-1.51) and energy expended in kcal/wk (adjusted HR per 500-unit increase 1.01, 95% CI 0.99-1.03) were not associated with ischemic stroke risk. There was an interaction of sex with intensity of physical activity (p = 0.04), such that moderate to heavy activity was protective against ischemic stroke in men (adjusted HR 0.37, 95% CI 0.18-0.78), but not in women (adjusted HR 0.92, 95% CI 0.57-1.50). Moderate- to heavy-intensity physical activity, but not energy expended, is protective against risk of ischemic stroke independent of other stroke risk factors in men in our cohort. Engaging in moderate to heavy physical activities may be an important component of primary prevention strategies aimed at reducing stroke risk.

Relationship of lipoprotein-associated phospholipase A2 and oxidized low density lipoprotein in carotid atherosclerosis

Plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and oxidized low density lipoprotein (oxLDL) have been identified as risk factors for cardiovascular disease. Lp-PLA(2) is the sole enzyme responsible for the hydrolysis of oxidized phospholipids on LDL particles in atherosclerotic plaques. We have studied the relationship between Lp-PLA(2) and oxLDL in carotid endarterectomy (CEA) tissues and in matched plasmas. In extracts from CEA anatomical segments, the levels of oxLDL were significantly associated with the levels of Lp-PLA(2) protein (r = 0.497) and activity (r = 0.615). OxLDL and Lp-PLA(2) mass/activity were most abundant in the carotid bifurcation and internal segments where plaque was most abundant. In extracts from CEA atheroma, the levels of oxLDL and Lp-PLA(2) were significantly correlated (r = 0.634). In matched plasma and atheroma extracts, the levels of Lp-PLA(2) were negatively correlated (r = - 0.578). The ratio of Lp-PLA(2) to oxLDL was higher in atheromatous tissue (277:1) than in normal tissue (135:1) and plasma (13:1). Immunohistochemical experiments indicated that in plaques, oxLDL and Lp-PLA(2) existed in overlapping but distinctly different distribution. Fluorescence microscopy showed both oxLDL and Lp-PLA(2) epitopes on the same LDL particle in plasma but not in plaque. These results suggest that the relationship between Lp-PLA(2) and oxLDL in the atherosclerotic plaque is different from that in the plasma compartment.

Gene Variation of the Transient Receptor Potential Cation Channel, Subfamily M, Member 7 ( TRPM7 ), and Risk of Incident Ischemic Stroke

Transient receptor potential cation channel, subfamily M, member 7 (TRPM7), has been implicated in ischemic brain damage, a major source of morbidity and mortality in westernized society. We hypothesized that TRPM7 gene variation might play a role in the risk of ischemic stroke. From a group of DNA samples collected at baseline in a prospective cohort of 14 916 initially healthy American men, we assessed 16 TRPM7 tag-single-nucleotide polymorphisms (SNPs) (dbSNP: rs11854949, rs4775899, rs11635825, rs12905120, rs16973487, rs7173321, rs7163283, rs17520378, rs17520350, rs4775892, rs7174839, rs17645523, rs3109894, rs616256, rs11070795, and rs313158) from 245 white men who subsequently had an incident ischemic stroke and from 245 age- and smoking habit-matched white men who remained free of reported vascular disease during follow-up (controls). All SNPs examined were in Hardy-Weinberg equilibrium. Overall allele, genotype, and haplotype distributions were similar between cases and controls. Marker-by-marker conditional logistic-regression analysis, adjusted for potential risk factors, showed no evidence for an association between any of the SNPs tested and ischemic stroke. Further investigation with an Entropy Blocker-defined, haplotype-based approach showed similar null findings. Prespecified analysis limited to participants without baseline diabetes and hypertension (ie, low-risk group) again showed similar null findings. The present prospective investigation provides no evidence of a role for the TRPM7 gene in the risk of incident ischemic stroke.

Dietary Total Fat Intake and Ischemic Stroke Risk: The Northern Manhattan Study

Background: Dietary fat intake is associated with coronary heart disease risk, but the relationship between fat intake and ischemic stroke risk remains unclear. We hypothesized that total dietary fat as part of a Western diet is associated with increased risk of ischemic stroke. Methods: As part of the prospective Northern Manhattan Study, 3,183 stroke-free community residents over 40 years of age underwent evaluation of their medical history and had their diet assessed by a food-frequency survey. Cox proportional hazard models calculated risk of incident ischemic stroke. Results: The mean age of participants was 69 years, 63% were women, 21% were white, 24% black and 52% Hispanic. During a mean of 5.5 years of follow-up, 142 ischemic strokes occurred. After adjusting for potential confounders, risk of ischemic stroke was higher in the upper quintile of total fat intake compared to the lowest quintile (HR 1.6, 95% CI 1.0–2.7). Total fat intake >65 g was associated with increased risk of ischemic stroke (HR 1.6, 95% CI 1.2–2.3). Risk was attenuated after controlling for caloric intake. Conclusions: The results suggest that increased daily total fat intake, especially above 65 g, significantly increases risk of ischemic stroke.

The V433M Variant of the CYP4F2 Is Associated With Ischemic Stroke in Male Swedes Beyond Its Effect on Blood Pressure

Cytochrome (CYP) 4A11 and CYP4F2 are responsible for renal production of 20-hydroxyeicosatetraenoic acid, a vasoconstrictor and natriuretic substance. The CYP4A11 F434S and CYP4F2 V433M polymorphisms reduce 20-hydroxyeicosatetraenoic acid production in vitro. The aim of the present study was to evaluate the effect of these polymorphisms on blood pressure (BP) levels, hypertension prevalence, and risk of incident cardiovascular events in middle-aged Swedes. The polymorphisms were genotyped in the cardiovascular cohort of the Malmö Diet and Cancer Study. The incidence of cardiovascular events (coronary events, n=276; ischemic stroke, n=199) was monitored over 10 years of follow-up. The analysis of BP levels was performed twice: either excluding or including subjects under antihypertensive treatment. In the whole population, CYP4A11 S434S homozygotes had higher systolic BP, both crude and adjusted for the number of antihypertensive drugs, and higher prevalence of hypertension with respect to F434 carriers. Male, but not female, CYP4F2 M433 carriers had significantly higher crude and adjusted systolic and diastolic BPs and a trend toward higher hypertension prevalence (P=0.06) with respect to V433V homozygotes. After adjustment for major cardiovascular risk factors, the hazard ratio for incident ischemic stroke in male CYP4F2 M433 carriers was significantly higher with respect to V433V homozygotes (hazard ratio: 1.69; 95% CI: 1.10 to 2.60) even when baseline BP levels and hypertension prevalence were included in the Cox proportional hazard model. A common CYP4F2 V433M polymorphism might increase the risk of incident ischemic stroke in male subjects only partially through its elevating effect on BP. Additional studies are needed to confirm these data.

Walking Speed and Risk of Incident Ischemic Stroke Among Postmenopausal Women

Walking speed is a simple, reliable, and valid measure of functional status that has been shown to be strongly correlated with age-related outcomes and may be an indicator of subclinical cerebrovascular disease. However, few studies have investigated the association of walking speed with risk of incident ischemic stroke. The present analyses included 13,048 postmenopausal women (mean age 65 years) from the Women's Health Initiative free of stroke at baseline, 264 of whom had incident ischemic strokes on follow-up. Cox proportional hazards regression was used to obtain hazard ratios (HRs) and 95% confidence intervals (CIs) to assess the relationship between performance on a timed walk and risk of incident ischemic stroke. Multivariate adjustment included age, race/ethnicity, body mass index, waist-hip ratio, depression, arthritis, hypertension, smoking, systolic blood pressure, treated diabetes, hormone use, NSAID use, aspirin use, self-reported general health, and history of coronary heart disease. Slower walking speed was a significant predictor of incident ischemic stroke. After multivariate adjustment, the hazard for incident ischemic stroke was increased for the slowest walking speed tertile compared to the fastest walking speed tertile (HR=1.69, 95% CI: 1.21, 2.36). Additional adjustment for other physical function variables (grip strength and chair stands) did not change the association significantly. Slow walking speed was found to be a strong predictor of increased risk of incident ischemic stroke among postmenopausal women independent of other established risk factors for stroke.

Lipoprotein-Associated Phospholipase A 2 , Hormone Use, and the Risk of Ischemic Stroke in Postmenopausal Women

Few studies have investigated the role of elevated lipoprotein-associated phospholipase A2 (Lp-PLA(2)) with stroke risk, and those that have are based on small numbers of strokes. No study has evaluated the effect of hormone therapy use on the association of Lp-PLA(2) and stroke. We assessed the relationship between Lp-PLA(2) and the risk of incident ischemic stroke in 929 stroke patients and 935 control subjects in the Hormones and Biomarkers Predicting Stroke Study, a nested case-control study from the Women's Health Initiative Observational Study. Mean (SD) levels of Lp-PLA(2) were significantly higher among case subjects (309.0 [97.1]) than control subjects (296.3 [87.3]; P<0.01). Odds ratio for ischemic stroke for the highest quartile of Lp-PLA(2), compared with lowest, controlling for multiple covariates, was 1.08 (95% CI: 0.75 to 1.55). However, among 1137 nonusers of hormone therapy at baseline, the corresponding odds ratio was 1.55 (95% CI: 1.05 to 2.28),whereas there was no significant association among 737 hormone users (odds ratio: 0.70; 95% CI: 0.42 to 1.17; P for interaction=0.055). Moreover, among nonhormone users, women with high C-reactive protein and high Lp-PLA2 had more than twice the risk of stroke (odds ratio: 2.26; 95% CI: 1.55 to 3.35) compared with women low levels in both biomarkers. Furthermore, different stroke cases were identified as high risk by Lp-PLA(2) rather than by C-reactive protein. Lp-PLA(2) was associated with incident ischemic stroke independently of C-reactive protein and traditional cardiovascular risk factors among nonusers of hormone therapy with highest risk in those who had both high C-reactive protein and high Lp-PLA(2).

Purinergic receptor P2Y, G-protein coupled, 12 gene variants and risk of incident ischemic stroke, myocardial infarction, and venous thromboembolism

Recent data have implicated a haplotype of the purinergic receptor P2Y, G-protein coupled, 12 gene (P2RY12), as potential risk determinant for atherothrombosis. However, to date, no prospective, genetic-epidemiological data are available. Using DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we examined the possible association of P2RY12 genetic variants, in particular a haplotype H2 (constituted by dbSNP rs10935838, rs2046934, rs5853517, and rs6809699) amongst 708 white males who subsequently developed a thromboembolic event (incident myocardial infarction (MI), ischemic stroke, or deep venous thromboembolism/pulmonary embolism (DVT/PE)) and amongst an equal number of age- and smoking-matched white males who remained free of reported vascular disease during follow-up (controls). The P2RY12 gene variants tested were in linkage disequilibrium. The haplotype H2 distribution was significantly different between the DVT/PE cases (12%) and their matched controls (21%), p-permuted=0.02. In an adjusted conditional logistic regression analysis, the haplotype H2 was significantly associated with a lower risk of incident DVT/PE as compared to the reference haplotype H1 (odds ratio=0.50, 95% CI=0.27–0.93, p=0.028). However, we found no evidence for an association of the P2RY12 variants or the haplotype H2 with incident MI or ischemic stroke. The present investigation provides evidence for an association of the P2RY12 haplotype H2 with lower risk of DVT/PE; however these findings require replication in other well-designed studies.

Renal dysfunction and risk of ischemic stroke or TIA in patients with cardiovascular disease

Mild renal insufficiency is increasingly recognized as an independent risk factor for cardiovascular disease. However, few data exist regarding its relation to risk of ischemic stroke. Patients with chronic coronary heart disease and measured serum creatinine levels (n = 6,685) were followed up for incident ischemic stroke or TIA over 4.8 to 8.1 years. Glomerular filtration rate was estimated by the Cockroft-Gault equation and by the four-component Modification of Diet in Renal Disease (MDRD) equation and a rate < or =60 mL/minute/1.73 m2 defined chronic kidney disease (CKD). Among 6,685 patients, a quarter of patients had CKD. Adjusting for conventional risk factors and related medications, patients with CKD exhibited 1.54-fold hazard ratios (95% CI 1.13 to 2.09) of incident ischemic stroke or TIA by the Cockroft-Gault equation (1.53; 95% CI 1.16 to 2.01 by the MDRD equation). The corresponding adjusted hazard ratio associated with an increment of 1 SD in GFR was 0.71 (95% CI 0.57 to 0.88) when estimated by the Cockroft-Gault equation (0.84; 95% CI 0.75 to 0.95 estimated by the MDRD equation). Mild degrees of renal dysfunction are associated with increased risk of incident ischemic stroke or TIA in patients with pre-existing atherothrombotic disease. These findings expand the recommendation that patients with renal dysfunction should be considered as a high-risk group for cardiovascular disease and for ischemic stroke.

Polymorphisms of the Phosphodiesterase 4D, cAMP-Specific ( PDE4D ) Gene and Risk of Ischemic Stroke

In an Icelandic population, gene variants of the phosphodiesterase 4D, cAMP-specific (PDE4D) gene were reported to be risk predictors for ischemic stroke. Case-control studies in other populations have yielded mixed evidence for association. A recent analysis in a prospective, non-Icelandic study found an association with stroke after stratification by hypertension. We evaluated nine PDE4D single nucleotide polymorphisms (SNPs) among 259 incident ischemic stroke cases and 259 controls were matched on age and smoking status and length of follow up since randomization, all drawn from initially healthy white males within the Physicians' Health Study cohort who were prospectively followed for first-ever stroke events. Genotype and allele distributions were similar between cases and controls. Results from single-marker conditional logistic regression analysis adjusting for traditional stroke risk factors showed significant association of SNP56 with risk of ischemic stroke (recessive odds ratio [OR], 2.26; 95% confidence interval [CI], 1.11 to 4.61; P=0.03). Among the participants without baseline hypertension, SNP42 (additive OR, 1.68; 95% CI, 0.99 to 2.86, P=0.06), SNP45 (dominant odds ratio, 2.24; 95% CI, 1.00 to 5.00, P=0.05), and SNP56 (additive odds ratio, 1.77; 95% CI, 1.02 to 3.10, P=0.04) showed modest association with increased risk of ischemic stroke. We found modest associations between several PDE4D gene polymorphisms and risk of incident ischemic stroke in men without baseline hypertension in this prospective, non-Icelandic study. Although of borderline statistical significance, the direction and magnitude of the effect for SNP42 parallels that observed in a recent study evaluating women from an independent, nested case-control study.

C-Reactive Protein as a Predictor of Incident Ischemic Stroke Among Patients With Preexisting Cardiovascular Disease

C-reactive protein (CRP) has emerged as an important predictor of cardiovascular disease, but there are few prospective data on its association with risk of ischemic stroke in patients at high risk. We examined the association between CRP levels and subsequent risk of incident ischemic stroke among 2979 patients with stable coronary heart disease included in a controlled clinical trial (Bezafibrate Infarction Prevention) that assessed the efficacy of bezafibrate, a fibric acid derivative, versus placebo for secondary prevention. CRP was measured by a high-sensitivity assay in plasma samples collected before randomization and again at the second follow-up year of an overall mean follow-up of 6.2 years. Risk of ischemic stroke per 1000 person-years increased from 4.1% for baseline CRP in the lowest tertile (<2.3 mg/L; n=982) to 5.9% for levels at the middle tertile (2.3 to 5.4 mg/L; n=1013) and 10.5% for CRP levels at the upper tertile (>5.4 mg/L; n=984; P<0.001). With adjustment for potential confounders, baseline CRP levels in the top versus bottom tertile were associated with a 2.16-fold increased hazard (95% CI, 1.32 to 3.53) for ischemic stroke, and CRP levels measured after 2 years were associated with a hazard ratio of 2.43 (95% CI, 1.30 to 4.57). The risk of an incident ischemic stroke did not differ between the bezafibrate group compared with the placebo group regardless of baseline CRP levels. These findings, based on a large prospective study, demonstrate the risk prediction for incident ischemic stroke conferred by CRP levels in patients at high risk.

Lipoprotein-Associated Phospholipase A2, High-Sensitivity C-Reactive Protein, and Risk for Incident Ischemic Stroke in Middle-aged Men and Women in the Atherosclerosis Risk in Communities (ARIC) Study

Measurement of inflammatory markers has been reported to identify individuals at increased risk for ischemic stroke. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a proinflammatory enzyme secreted by macrophages. We assessed Lp-PLA2 and C-reactive protein (CRP) levels along with traditional risk factors to examine their relation to ischemic stroke. A proportional hazards model was used in a prospective case-cohort study of 12,762 apparently healthy middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study who were observed for about 6 years. Mean Lp-PLA2 and CRP levels adjusted for sex, race, and age were higher in the 194 stroke cases than the 766 noncases, whereas low-density lipoprotein cholesterol (LDL-C) level was not significantly different. Both Lp-PLA2 and CRP levels were associated with ischemic stroke after adjustment for age, sex, and race: hazard ratios were 2.23 for the highest vs the lowest tertile of Lp-PLA2 and 2.70 for CRP level higher than 3 vs lower than 1 mg/L. In a model that included smoking, systolic hypertension, lipid levels, and diabetes, Lp-PLA2 and CRP levels in the highest category were associated with hazard ratios of 1.91 (95% confidence interval, 1.15-3.18; P = .01) and 1.87 (95% confidence interval, 1.13-3.10; P = .02), respectively. Individuals with high levels of both CRP and Lp-PLA2 were at the highest risk after adjusting for traditional risk factors compared with individuals with low levels of both, whereas others were at intermediate risk. Levels of Lp-PLA2 and CRP may be complementary beyond traditional risk factors in identifying middle-aged individuals at increased risk for ischemic stroke.

Fasting plasma glucose and risk of incident ischemic stroke or transient ischemic attacks: a prospective cohort study.

Diabetes and impaired fasting glucose are diagnosed based on an elevated plasma glucose level after an overnight fast. The diagnostic cutpoint of diabetes arises from the threshold for development of microvascular complications. Our aim was to examine the associations between clinical relevant categories of fasting glucose levels and the risk of incident ischemic stroke. Patients with documented coronary heart disease who were screened for inclusion in a secondary prevention clinical trial (n=13,999) were followed-up. At baseline, medical histories were obtained and plasma glucose and lipids assessed at a central study laboratory. During a 6- to 8-year follow-up period 1037 cases were identified with ischemic cerebrovascular disease, of which, after reviewing hospital records with diagnoses of cerebrovascular disease, 576 cases were verified to have had ischemic stroke or transient ischemic attacks. Increasing fasting glucose level categories were positively associated with increasing age, male gender, body mass index, hypertension, total cholesterol, and triglycerides, and were inversely associated with high-density lipoprotein cholesterol and percent high-density lipoprotein of total cholesterol. In comparison with patients with fasting glucose levels of 90 to 99 mg/dL (n=3706) who constitute the largest category, the odds ratios of ischemic cerebrovascular disease, adjusting for potential confounders, were 1.47 (95% CI, 1.07 to 2.02) for fasting glucose <80, 1.22 (0.98 to 1.52) for 80 to 89, 1.27 (1.02 to 1.60) for 100 to 109, 1.60 (1.26 to 2.03) for 110 to 125, 1.82 (1.33 to 2.49) for 126 to 140, and 2.82 (2.32 to 3.43) for >140 mg/dL. Similar J-shaped associations were observed in analysis excluding patients with known diagnosis of diabetes mellitus. The association between fasting plasma glucose and incident ischemic cerebrovascular events in patients with pre-existing atherothrombotic disease is J-shaped. Rates increase for fasting plasma glucose levels >100 mg/dL and also for those with low fasting glucose levels. These findings may carry important implications for prevention strategies.

Prospective Study of Chlamydia pneumoniae IgG and IgA Seropositivity and Risk of Incident Ischemic Stroke

Background and Purpose:Chlamydia pneumoniae infection or exposure to C. pneumoniae was implicated as a risk factor for ischemic stroke. Our aim was to evaluate prospectively the association between the presence of antibodies to C. pneumoniae (IgG and IgA) and the risk of incident ischemic stroke among patients with pre-existing vascular disease. Methods: Sera were collected from 3,090 coronary heart disease patients enrolled in a secondary prevention trial. We measured baseline antibodies (IgG and IgA) in the sera of patients who developed subsequent ischemic strokes (cases, n = 134) during follow-up (mean 8.2 years), and in 134 age- and gender-matched pairs without subsequent stroke or myocardial infarction. Results: The crude relative odds (95%CI) of incident ischemic strokes in seropositive patients at baseline (>1.1 relative value units) were 1.29 (95%CI, 0.69–2.47) for IgG and 1.31 (95% CI, 0.69–2.55) for IgA by matched-pair analyses, and 1.42 (95%CI, 0.69–2.98) for IgG and 1.57 (95%CI, 0.76–3.35) for IgA after adjustments for conventional risk factors and the inflammatory marker, soluble intercellular adhesion molecule-1. We explored the possibility that the risk of ischemic stroke may increase in parallel to increasing antibody titers, but did not demonstrate any significant association. Conclusions: Serological evidence for prior infection with C. pneumoniae did not emerge as an independent risk factor for incident ischemic stroke among patients at high risk due to pre-existing vascular disease.