Risk Of Small Vessel Disease Research Articles

Association between serum triglycerides and stroke type, severity, and prognosis. Analysis in 6558 patients

Background and objectivesHypertriglyceridemia (HT) may increase the risk of stroke. Limited studies have shown that stroke severity and infarction size are smaller in patients with HT. We explored the relationship between triglyceride levels and stroke risk factors, severity and outcome in a large prospective database.DesignProspective Cross-sectional study.SettingWe retrospectively interrogated the Qatar Stroke Database in all patients admitted between 2014-2022 with acute ischemic stroke and evaluated the relationship between triglyceride, diabetes, stroke severity (measured on NIHSS), stroke type (TOAST classification) and the short- (mRS at 90 days) and long-term outcomes (MACE at 1 year) in patients with HT.ParticipantsSix thousand five hundred fifty-eight patients ≥20 years were included in this studyResultsSix thousand five hundred fifty-eight patients with ischemic stroke [mean age 54.6 ± 12. 9; male 82.1%) were included. Triglyceride levels upon admission were low-normal (≤1.1 mmol/L) in 2019 patients, high-normal (1.2-1.7 mmol/L) in 2142 patients, borderline-high (1.8-2.2 mmol/L) in 1072 patients and high (≥2.3 mmol/L) in 1325 patients. Higher triglyceride levels were associated with stroke and increased likelihood of having diabetes, obesity, active smoking, and small vessel/lacunar stroke type. An inverse relationship was noted whereby higher triglyceride levels were associated with lower stroke severity and reduced likelihood of poorer outcome (mRS 3-6) at discharge and 90 days. Long-term MACE events were less frequent in patients with higher triglyceride levels. After adjusting age, gender, diabetes, prior stroke, CAD, and obesity, multivariate analysis showed that hypertension and triglyceride levels were higher in mild ischemic strokes patients.ConclusionsIncreasing triglycerides are associated with higher risk of small vessel disease and requires further prospective cohort studies for confirmation.

Cerebral Small Vessel Disease: Early-Life Antecedents and Long-Term Implications for the Brain, Aging, Stroke, and Dementia.

Cerebral small vessel disease is common in older adults and increases the risk of stroke, cognitive impairment, and dementia. While often attributed to midlife vascular risk factors such as hypertension, factors from earlier in life may contribute to later small vessel disease risk. In this review, we summarize current evidence for early-life effects on small vessel disease, stroke and dementia focusing on prenatal nutrition, and cognitive ability, education, and socioeconomic status in childhood. We discuss possible reasons for these associations, including differences in brain resilience and reserve, access to cognitive, social, and economic resources, and health behaviors, and we consider the extent to which these associations are independent of vascular risk factors. Although early-life factors, particularly education, are major risk factors for Alzheimer disease, they are less established in small vessel disease or vascular cognitive impairment. We discuss current knowledge, gaps in knowledge, targets for future research, clinical practice, and policy change.

Methylenetetrahydrofolate reductase polymorphisms and elevated plasma homocysteine levels in small vessel disease.

Despite its public health importance, the causes of small vessel disease (SVD) are not fully understood. The presence of SVD in monogenic twins indicates the involvement of genetic factors in the pathogenesis of this disease. The purpose of this study was to investigate the association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with SVD risk. Patients with SVD and matched controls were recruited from Tianjin Union Medical Center and Tianjin Huanhu Hospital. Clinical and laboratory data were collected. Plasma total homocysteine (tHcy) and folate levels were measured, and MTHFR rs1801133 (C677T) and rs1801131 (A1298C) single-nucleotide polymorphisms were genotyped. We analyzed potential associations among SVD and MTHFR polymorphisms, tHcy, and folate levels. Patients with SVD displayed significantly decreased plasma folate levels (Z=-3.537, p<.001) and increased tHcy levels (Z=4.910, p<.001) compared with controls. Significantly different plasma tHcy levels were associated with rs1801133 (χ2 =6.664, p=.036), and post hoc analysis indicated higher plasma tHcy levels in individuals carrying the TT allele compared with levels in those carrying the TC allele (Z=2.478, p=.013). No significant differences in tHcy levels were observed for rs1801131 alleles. The genotype and allele frequencies of rs1801133 were different between SVD and control groups (χ2 =9.378, p=.009). There was no significant difference in distributions of rs1801131 genotypes between the two groups, and multivariable logistic regression analysis showed that rs1801131 and rs1801133 were not significantly associated with the risk of SVD. Our study indicates that an elevated plasma tHcy level is independently associated with the development of SVD. Although MTHFR rs1801133 is linked to increased plasma homocysteine (Hcy) levels, it is not a risk factor for SVD. rs1801131 is not related to Hcy levels or SVD risk.

Lifestyle Changes Reduced Estimated White Matter Hyperintensities Based on Retinal Image Analysis.

This study evaluates if there is an association between lifestyle changes and the risk of small vessel disease (SVD) as measured by cerebral white matter hyperintensities (WMH) estimated by the automatic retinal image analysis (ARIA) method. We recruited 274 individuals into a community cohort study. Subjects were assessed at baseline and annually with the Health-Promoting Lifestyle Profile II Questionnaire (HPLP-II) and underwent a simple physical assessment. Retinal images were taken using a non-mydriatic digital fundus camera to evaluate the level of WMH estimated by ARIA (ARIA-WMH) to measure the risk of small vessel disease. We calculated the changes from baseline to one year for the six domains of HPLP-II and analysed the relationship with the ARIA-WMH change. A total of 193 (70%) participants completed both the HPLP-II and ARIA-WMH assessments. The mean age was 59.1 ± 9.4 years, and 76.2% (147) were women. HPLP-II was moderate (Baseline, 138.96 ± 20.93; One-year, 141.97 ± 21.85). We observed a significant difference in ARIA-WMH change between diabetes and non-diabetes subjects (0.03 vs. -0.008, respectively, p = 0.03). A multivariate analysis model showed a significant interaction between the health responsibility (HR) domain and diabetes (p = 0.005). For non-diabetes subgroups, those with improvement in the HR domain had significantly decreased in ARIA-WMH than those without HR improvement (-0.04 vs. 0.02, respectively, p = 0.003). The physical activity domain was negatively related to the change in ARIA-WMH (p = 0.02). In conclusion, this study confirms that there is a significant association between lifestyle changes and ARIA-WMH. Furthermore, increasing health responsibility for non-diabetes subjects reduces the risk of having severe white matter hyperintensities.

Left Atrial Function and Arrhythmias in Relation to Small Vessel Disease on Brain MRI: The Multi-Ethnic Study of Atherosclerosis.

Background Atrial fibrillation (AF) is associated with increased stroke risk and accelerated cognitive decline, but the association of early manifestations of left atrial (LA) impairment with subclinical changes in brain structure is unclear. We investigated whether abnormal LA structure and function, greater supraventricular ectopy, and intermittent AF are associated with small vessel disease on magnetic resonance imaging of the brain. Methods and Results In the Multi-Ethnic Study of Atherosclerosis, 967 participants completed 14-day ambulatory electrocardiographic monitoring, speckle tracking echocardiography and, a median 17 months later, magnetic resonance imaging of the brain. We assessed associations of LA volume index and reservoir strain, supraventricular ectopy, and prevalent AF with brain magnetic resonance imaging measures of small vessel disease and atrophy. The mean age of participants was 72 years; 53% were women. In multivariable models, LA enlargement was associated with lower white matter fractional anisotropy and greater prevalence of microbleeds; reduced LA strain, indicating worse LA function, was associated with more microbleeds. More premature atrial contractions were associated with lower total gray matter volume. Compared with no AF, intermittent AF (prevalent AF with <100% AF during electrocardiographic monitoring) was associated with lower white matter fractional anisotropy (-0.25 SDs [95% CI, -0.44 to -0.07]) and greater prevalence of microbleeds (prevalence ratio: 1.42 [95% CI, 1.12-1.79]). Conclusions In individuals without a history of stroke or transient ischemic attack, alterations of LA structure and function, including enlargement, reduced strain, frequent premature atrial contractions, and intermittent AF, were associated with increased markers of small vessel disease. Detailed assessment of LA structure and function and extended ECG monitoring may enable early identification of individuals at greater risk of small vessel disease.

Cerebral hemodynamics during atrial fibrillation: computational fluid dynamics (CFD) analysis of lenticulostriate arteries using 7T high-resolution magnetic resonance imaging

Abstract Background Lenticulostriate arteries (LSAs) are small perforating arteries (0.1–1 mm diameter), perpendicularly departing from middle cerebral artery (MCA) and supplying blood flow to important cerebral subcortical and basal ganglia areas. LSAs are involved in silent strokes and cerebral small vessel disease, potentially leading to cognitive decline and vascular dementia. There is growing evidence that atrial fibrillation (AF), the most common cardiac arrhythmia, increases the risk of dementia even in the absence of clinical strokes. AF also increase the risk of small vessel disease. AF may alter deep cerebral hemodynamics per se, however no data exists regarding a possible impact of AF on MCA-LSA branching sites hemodynamics. Purpose To use computational fluid dynamics (CFD) analysis to study the hemodynamics of LSAs-MCA branching sites. Methods 7T high-resolution magnetic resonance imaging (HR-MRI) brain scans (Figure 1, panel a) were used to derive detailed geometrical models of LSAs-MCA branching sites. CFD analysis was then conducted, simulating AF conditions as well as sinus rhythm (SR), at different ventricular rates (from 50 to 130 bpm). Results Geometrical models were retrieved from HR-MRI scans of 7 patients. By means of the most significant metrics, such as wall shear stress (WSS; Figure 1, panel b), wall shear stress gradient (WSSG), and flow velocity (FV), a comparison between SR and AF was performed. Conclusion CFD analysis of LSAs-MCA branching sites using geometrical models derived from HR-MRI brain scans was feasible and allows to quantify the impact of AF on these critical ramifications of the MCA. Funding Acknowledgement Type of funding sources: None.

Potential key genes for predicting risk of stroke occurrence: A computational approach

To investigate prospective key genes and pathways associated with the pathogenesis and prognosis of stroke types along with subtypes. Human genes using genome assembly build 38 patch release 13 with known gene symbols through NCBI gene database (https://www.ncbi.nlm.nih.gov/gene) were fetched. PubMed advanced queries were constructed using stroke-related keywords and associations were calculated using Normalized pointwise mutual information (nPMI) between each gene symbol and queries. Genes related with stroke risk within their types and subtypes were investigated in order to discover genetic markers to predict individuals who are at the risk of developing stroke with their subtypes. A total of 2,785 (9.4%) genes were found to be linked to the risk of stroke. Based on stroke types, 1,287 (46.2%) and 376 (13.5%) genes were found to be related with ischemic stroke (IS) and hemorrhagic stroke (HS) respectively. Further stratification of IS based on TOAST classification, 86 (6.6%) genes were confined to Large artery atherosclerosis; 131 (10.1%) and 130 (10%) genes were related with the risk of small vessel disease and Cardioembolism subtypes of IS. Evidences reported through published meta-analysis and GWAS studies suggested for the association of nine highly associated genes and therefore, we concluded a prognostic panel of nine genes comprising of CYP4A11, ALOX5P, NOTCH, NINJ2, FGB, MTHFR, PDE4D, HDAC9, and ZHFX3 can be treated as a diagnostic marker to predict individuals who are at the risk of developing stroke. Validation of these nine prognostic markers are further required by conducting case-control studies embedded with large sample size.

Early life predictors of late life cerebral small vessel disease in four prospective cohort studies.

Development of cerebral small vessel disease, a major cause of stroke and dementia, may be influenced by early life factors. It is unclear whether these relationships are independent of each other, of adult socio-economic status or of vascular risk factor exposures.We examined associations between factors from birth (ponderal index, birth weight), childhood (IQ, education, socio-economic status), adult small vessel disease, and brain volumes, using data from four prospective cohort studies: STratifying Resilience And Depression Longitudinally (STRADL) (n = 1080; mean age = 59 years); the Dutch Famine Birth Cohort (n = 118; mean age = 68 years); the Lothian Birth Cohort 1936 (LBC1936; n = 617; mean age = 73 years), and the Simpson’s cohort (n = 110; mean age = 78 years). We analysed each small vessel disease feature individually and summed to give a total small vessel disease score (range 1–4) in each cohort separately, then in meta-analysis, adjusted for vascular risk factors and adult socio-economic status.Higher birth weight was associated with fewer lacunes [odds ratio (OR) per 100 g = 0.93, 95% confidence interval (CI) = 0.88 to 0.99], fewer infarcts (OR = 0.94, 95% CI = 0.89 to 0.99), and fewer perivascular spaces (OR = 0.95, 95% CI = 0.91 to 0.99). Higher childhood IQ was associated with lower white matter hyperintensity burden (OR per IQ point = 0.99, 95% CI 0.98 to 0.998), fewer infarcts (OR = 0.98, 95% CI = 0.97 to 0.998), fewer lacunes (OR = 0.98, 95% CI = 0.97 to 0.999), and lower total small vessel disease burden (OR = 0.98, 95% CI = 0.96 to 0.999). Low education was associated with more microbleeds (OR = 1.90, 95% CI = 1.33 to 2.72) and lower total brain volume (mean difference = −178.86 cm3, 95% CI = −325.07 to −32.66). Low childhood socio-economic status was associated with fewer lacunes (OR = 0.62, 95% CI = 0.40 to 0.95).Early life factors are associated with worse small vessel disease in later life, independent of each other, vascular risk factors and adult socio-economic status. Risk for small vessel disease may originate in early life and provide a mechanistic link between early life factors and risk of stroke and dementia. Policies investing in early child development may improve lifelong brain health and contribute to the prevention of dementia and stroke in older age.

Apo\u03b54 disrupts neurovascular regulation and undermines white matter integrity and cognitive function

The ApoE4 allele is associated with increased risk of small vessel disease, which is a cause of vascular cognitive impairment. Here, we report that mice with targeted replacement (TR) of the ApoE gene with human ApoE4 have reduced neocortical cerebral blood flow compared to ApoE3-TR mice, an effect due to reduced vascular density rather than slowing of microvascular red blood cell flow. Furthermore, homeostatic mechanisms matching local delivery of blood flow to brain activity are impaired in ApoE4-TR mice. In a model of cerebral hypoperfusion, these cerebrovascular alterations exacerbate damage to the white matter of the corpus callosum and worsen cognitive dysfunction. Using 3-photon microscopy we found that the increased white matter damage is linked to an enhanced reduction of microvascular flow resulting in local hypoxia. Such alterations may be responsible for the increased susceptibility to hypoxic-ischemic lesions in the subcortical white matter of individuals carrying the ApoE4 allele.

Abstract P277: Mineralocorticoid Receptor Signaling Regulates TRPV4-mediated Vasodilation of Parenchymal Arterioles

Hypertension impairs endothelium-dependent dilation of the parenchymal arterioles (PA) that regulate white matter perfusion. In the periphery, mineralocorticoid receptor (MR) activation facilitates hypertension-associated artery dysfunction; the role of MR signaling in PA dysfunction has not been defined. We hypothesized that Angiotensin II (AngII)-hypertension impairs TRPV4-mediated dilation in an MR-dependent manner. 16 week old male C57bl/6 mice were treated with AngII (800ng/kg/min) ± the MR antagonist, eplerenone (EPL; 100mg/kg/day) for 4 weeks; Sham mice served as control. PAs were isolated and studied by pressure myography. Data are presented as mean ± SEM; n=4-6 per group. AngII increased systolic blood pressure, an effect not blunted by EPL (Sham:147 ± 3; AngII: 177* ± 3; AngII+EPL: 182* ± 6mmHg; *=p&lt;0.05 vs. Sham). However, EPL prevented the increased myogenic tone (31±1 vs 48*±4 vs 35±3 % tone; *=p&lt;0.05 vs. Sham) and the impaired carbachol (CbCh)-induced dilation (51±3 vs 24*±2 vs 49±3 %dilation; Sham vs. AngII vs. AngII+EPL; *=p&lt;0.05 vs. Sham) caused by AngII infusion. CbCh-induced dilation was unaltered by L-NAME (10 -5 M) and indomethacin (10 -4 M) in all groups (Sham: 51±3 vs. 53±2; AngII:24±2 vs. 28±2; AngII+EPL 49±3 vs. 47±3% dilation; CbCh vs. CbCh+L-NAME+Indomethacin) implicating endothelium-derived hyperpolarization (EDH). In contrast, the TRPV4 antagonist, GSK2193874 (GSK2, 10 -7 M) blunted the CbCh-induced dilation in all groups (Sham: 51±3 vs 13*±8; AngII: 24±2 vs 7*±2; AngII+EPL: 49±3 vs 16*±4 % dilation; CbCh vs CbCh+GSK2 ;*=p&lt;0.05). In the AngII and AngII+EPL mice, TRPV4 inhibition reduced myogenic tone (AngII: 16±3; AngII+EPL: 17±6 %tone loss; p&lt;0.05), an effect that was not observed in the Sham mice (2±3 %tone loss). AngII infusion decreased cerebral perfusion; EPL prevented this decrease (Sham: 938±32; AngII:596*±53; AngII+EPL:793±36 perfusion units; *=p&lt;0.05 vs. Sham). MR activation regulates TRPV4 signaling in PAs during AngII-infusion, independent of hypertension. Impaired TRPV4 function plays a critical role in AngII-hypertension-associated changes in PA reactivity and may increase the risk of small vessel disease.

Association between methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and risk of ischemic stroke in North Indian population: A hospital based case–control study

ObjectiveThe aim of the present case–control study was to determine the association between methylene tetrahydrofolate reductase (MTHFR) C677T (rs1801133) gene polymorphism and risk of ischemic stroke (IS) in North Indian population. MethodsPatients with IS and age-sex matched controls were recruited from Neurology Outpatient Department and Ward of All India Institute of Medical Sciences, New Delhi, India. Genotyping was performed by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) method. PCR–RFLP results of nine randomly selected samples were confirmed by DNA sequencing. Genotypic and allelic distributions were compared between cases and controls. Statistical analysis was done by STATA, version 13.0 software. ResultsHypertension, diabetes, dyslipidemia, low socioeconomic status and family history of stroke were found to have an independent association with the risk of IS after adjusting for potential confounding factors. Mean age of cases and controls were 52.83±12.59 and 50.97±12.70years. Multivariate logistic regression analysis showed an independent association between MTHFR C677T gene polymorphism and risk of IS (OR 1.91; 95% CI 1.07–3.41; p=0.028) under dominant model [CT+TT vs. CC]. MTHFR C677T gene polymorphism was found to be independently associated with risk of small vessel disease (SVD) after adjustment for potential confounding factors [OR 2.51; 95% CI 1.30–4.85; p=0.006] under the dominant model. ConclusionFindings of the present study suggest that MTHFR C677T gene polymorphism might be a risk factor of IS mainly for SVD subtypes of IS in North Indian population. Further large prospective studies are required to confirm these findings.

Correlation of matrix metalloproteinase-2 single nucleotide polymorphisms with the risk of small vessel disease (SVD)

BackgroundMaladjustment of matrix metalloproteinases (MMPs) results in cerebral vasculature and blood–brain barrier dysfunction, which is associated with small vessel disease (SVD). This study was to aim at evaluating correlations between matrix metalloproteinase-2 and 9 single nucleotide polymorphisms and the risk of SVD. MethodsA total of 178 patients with SVD were enrolled into this study via Nanjing Stroke Registry Program (NSRP) from January 2010 to November 2011. SVD patients were further subtyped as isolated lacunar infarction (ILI, absent or with mild leukoaraiosis) and ischemic leukoaraiosis (ILA, with moderate or severe leukoaraiosis) according to the Fazekas scale. 100 age- and gender-matched individuals from outpatient medical examination were recruited as the control group. The genotypes of MMP-2-1306 T/C and MMP-9-1562 C/T were determined by the TaqMan method. ResultsOf 178 SVD patients, 86 and 92 patients were classified as ILI and ILA, respectively. Comparison analysis between SVD patients and controls revealed a significant correlation between SVD and hypertension, as well as a prevalence of hypertension in ILA. Further genotype analysis showed that the frequency of MMP-2-1306 CC genotype was higher in ILA patients than in controls (P=0.009, χ2 test; P=0.027, the multiple test with Bonferroni correction). Finally, logistic regression analysis with adjustment of age, sex and vascular risk factors showed that the MMP-2-1306 T/C polymorphism was an independent predictor for ILA (OR: 2.605; 95% confidence interval [CI], 1.067–6.364; P=0.036). ConclusionOur findings suggest that the MMP-2-1306 T/C polymorphism is a direct risk factor for ILA.

Association between angiotensin converting enzyme gene insertion/deletion polymorphism and ischemic stroke in north Indian population: a case–control study and meta-analysis

Objective:The purpose of this case–control study was to determine the relationship between angiotensin converting enzyme (ACE) insertion/deletion polymorphism and serum ACE level in north Indian patients with ischemic stroke.Methods:In the present study, 224 ischemic stroke patients and 224 age- and sex-matched control participants were recruited. Genotyping was performed using polymerase chain reaction (PCR) method. Serum ACE levels were measured by colorimetric method. Our results were integrated with other reported studies from India for a meta-analysis.Results:We observed that DD genotypes were more frequently distributed in cases (32·6%) compared with controls (26·8%). Borderline significance was observed between DD genotype and risk of small vessel disease (SVD) stroke as compared to controls (OR, 1·9; 95% CI, 0·88-4·4; P value 0·09) assuming dominant model of inheritance. The mean ACE serum level in IU/l for II, ID, and DD genotypes were 17·1 ± 7·7, 26 ± 12·4, and 51·3 ± 21 (P value < 0·001) in cases and 16·5 ± 9·4, 26·8 ± 13, and 45·19 ± 18·3 (P value < 0·001) in controls, respectively.Discussion:The results of the study show lack of significant association between ACE insertion/deletion polymorphism and ischemic stroke, however, higher risk was observed with DD genotype in small vessel disease stroke, but with borderline significance. Meta-analysis of studies from India showed that DD genotype is associated with risk of ischemic stroke.

Carotid Flow Augmentation as a Risk for Small Vessel Disease of the Brain

Carotid Flow Augmentation as a Risk for Small Vessel Disease of the Brain

Response to "Carotid Flow Augmentation as a Risk for Small Vessel Disease of the Brain"

Response to "Carotid Flow Augmentation as a Risk for Small Vessel Disease of the Brain"

Increased brachial–ankle pulse wave velocity is independently associated with risk of cerebral ischemic small vessel disease in elderly hypertensive patients

Objective Increased arterial stiffness is an independent predictor of cardiovascular diseases in hypertensive patients. Hypertension and aging can cause similar damage to small vessel walls. The objective of this study was to determine relationship between arterial stiffness measured by brachial–ankle pulse wave velocity (baPWV) and the risk of cerebral small vessel disease (SVD) in elderly people with hypertension. Methods We studied 196 elderly subjects with hypertension (≥50 years of age) who had neither large vessel stroke nor cardiac embolism. These patients were divided into three groups based on the results of brain MRI: (1) those with first-ever small vessel stroke; (2) those with asymptomatic subcortical ischemia; and (3) a control group with hypertension. Results The baPWV was significantly increased in the patients with first-ever small vessel stroke or asymptomatic subcortical infarction when compared to the control group, after adjusting for systolic blood pressure (SBP), pulse pressure (PP), and hs-CRP ( p = 0.005). Among subjects with SVD on MRI, the number of lacunar infarcts (LIs) ≥ 5 was significantly related to a higher baPWV ( p = 0.02). The relationship between the severity of periventricular white matter hyperintensities (PWMH) and the degree of baPWV became insignificant after adjustment for age. Conclusion Increased baPWV was significantly associated with the risk of SVD in elderly persons with hypertension. Therefore, the measurement of baPWV could be used to predict SVD.

Genetic Variation in Members of the Leukotriene Biosynthesis Pathway Confer an Increased Risk of Ischemic Stroke

The recent finding that genetic variants in 5-lipoxygenase activating protein and leukotriene A4 hydrolase may confer an increased risk of ischemic stroke has implicated the leukotriene family as potential mediators of cardiovascular disease. Using a case control replication methodology, all members of the leukotriene synthesis pathway and their receptors were examined for genetic variants, which may act as risk factors for all ischemic stroke and stroke subtypes. A case control methodology using a UK stroke cohort (872 cases, 933 controls) was adopted, with additional 5-lipoxygenase activating protein genotyping and replication of positive findings undertaken in an independent stroke population from Germany (601 cases, 736 controls). Association was identified with variants in 5-lipoxygenase activating protein, leukotriene C4 synthase (leukotriene A4 hydrolase),and the leukotriene B4 receptor complex. Differing risks were identified for ischemic stroke subtypes. A variant in leukotriene C4 synthase was found to confer a 1.5-fold increase in risk of small vessel disease (RR, 1.515; 1.041 to 2.262; P=0.043) with replication in an independent cohort showing a similar risk (RR, 1.687; 1.065 to 2.675; P=0.026). A haplotype in the leukotriene B4 receptor complex was found to confer a 2.3-fold increase in risk of cardioembolic stroke (RR, 2.118; 1.194 to 3.760; P=0.01) and replication in a German cohort revealed a similar risk with a second distinct haplotype (RR, 2.060; 1.162 to 3.665; P=0.013). Genetic variation in leukotriene pathway members and their receptors confer an increased risk of ischemic stroke in 2 independent populations. These risks show different magnitudes depending on ischemic stroke subtype.