Prothrombotic gene variants and mortality after cerebral ischemia of arterial origin.

BACKGROUND: Several functional prothrombotic gene variants have been associated with cerebral ischemia and myocardial infarction. We hypothesized that such gene variants may also be associated with mortality after cerebral ischemia of arterial origin because of an increased risk of fatal vascular events. METHODS: We performed a case-control study in 316 long-term survivors and 887 patients with recent cerebral ischemia of arterial origin. False discovery rate q values were calculated to account for multiple testing. The mean duration between occurrence of cerebral ischemia and DNA collection was 16.8 years in long-term survivors and 3.2 months in recent patients. RESULTS: Two of 23 variants were associated with mortality: the 95Arg allele of the coagulation factor XIII subunit B (F13B) His95Arg variant (OR, 1.5 for Arg/Arg and His/Arg vs. His/His genotype; 95% CI, 1.1-2.2, q = 0.29) and the 4G allele of the plasminogen activator inhibitor-1 (PAI-1) 4G/5G variant (OR, 1.5 for 4G/4G and 5G/4G vs. 5G/5G genotype; 95% CI, 1.1-2.0, q = 0.29). Both associations disappeared after accounting for multiple testing. Data analysis restricted to recently deceased patients (n = 133) yielded similar results. CONCLUSIONS: In this hospital-based study none of 23 prothrombotic gene variants were associated with long-term mortality after cerebral ischemia of arterial origin. Prothrombotic gene variants do not appear to play an important role in long-term mortality after cerebral ischemia.

Genetic association studies in ischaemic stroke: replication failure and prospects.

Although hundreds of genetic association studies of ischaemic stroke have been published, the failure to replicate associations has led to scepticism about their findings. Possible explanations for this failure are: (1) a false-positive association in the initial study; (2) a false-negative association in a replication study; (3) methodological differences (e.g. study populations or study designs). We review underlying causes for replication failure, such as small sample size, multiple testing and publication bias, and methods to deal with these problems. We also make suggestions about the design of genetic association studies in ischaemic stroke with regard to stroke subtype classification, candidate pathways, subgroups, intermediate phenotypes and potential clinical impact.

Prothrombotic gene variation in patients with large and small vessel disease.

The classification of ischemic stroke into different subtypes is supported in genetic association studies. While several gene variants have been identified as being associated with ischemia subtypes, most studies have not been powered to study subtypes separately. We investigated 887 patients with nondisabling cerebral ischemia of arterial origin and classified ischemia as being caused by large or small vessel disease (LVD or SVD), primarily based on neuroimaging findings. In total, 621 patients had LVD and 266 SVD. The coagulation factor XIII subunit B gene (F13B) His95Arg variant was more common in patients with LVD (mean prevalence difference 9.9%; 95% CI 4.7-15). None of 21 other prothrombotic gene variants was associated with LVD or SVD. Many gene variants may not be specific for one subtype. We could not replicate the genetic associations identified in previous smaller previous studies. Thus claims about genetic associations with specific subtypes of ischemia should be interpreted with caution. The association between F13B His95Arg and LVD requires replication.

Carotid intima-media thickness is different in large- and small-vessel ischemic stroke: the SMART study.

BACKGROUND AND PURPOSE: The role of athersclerosis in the difference between the pathogenesis of large-vessel disease (LVD) and small-vessel disease (SVD) is a matter of debate. Common carotid artery intima-media thickness (CCA IMT) is a marker of atherosclerosis. Our aim was to compare CCA IMT between SVD and LVD patients. METHODS: Two independent observers classified ischemic stroke or transient ischemic attack as caused by SVD or LVD, primarily based on imaging and in addition on clinical features. Mean CCA IMT was calculated based on 6 measurements for each patient. RESULTS: Four hundred and seventeen patients were classified LVD and 115 SVD. Mean CCA IMT was higher in patients with LVD (1.08 mm) than in patients with SVD (0.92 mm). The crude mean difference was 0.16 mm (95% CI, 0.09 to 0.23). After adjustment for age, sex and hypertension, the mean difference was 0.11 mm (95% CI, 0.05 to 0.18). CONCLUSIONS: CCA IMT is higher in LVD patients than in SVD patients supporting the hypothesis that LVD and SVD have a different pathogenesis.

CT within 6 hours of headache onset to rule out subarachnoid hemorrhage in nonacademic hospitals.

OBJECTIVE: To investigate whether staff radiologists working in nonacademic hospitals can adequately rule out subarachnoid hemorrhage (SAH) on head CT <6 hours after headache onset. METHODS: In a multicenter, retrospective study, we studied a consecutive series of patients presenting with acute headache to 11 nonacademic hospitals. Inclusion criteria were (1) normal level of consciousness without focal deficits, (2) head CT <6 hours after headache onset and reported negative for the presence of SAH by a staff radiologist, and (3) subsequent CSF spectrophotometry. Two neuroradiologists and one stroke neurologist from 2 academic tertiary care centers independently reviewed admission CTs of patients with CSF results that were considered positive for presence of bilirubin according to local criteria. We investigated the negative predictive value for detection of SAH by staff radiologists in nonacademic hospitals on head CT in patients scanned <6 hours after onset of acute headache. RESULTS: Of 760 included patients, CSF analysis was considered positive for bilirubin in 52 patients (7%). Independent review of these patients' CTs identified one patient (1/52; 2%) with a perimesencephalic nonaneurysmal SAH. Negative predictive value for detection of subarachnoid blood by staff radiologists working in a nonacademic hospital was 99.9% (95% confidence interval 99.3%-100.0%). CONCLUSIONS: Our results support a change of practice wherein a lumbar puncture can be withheld in patients with a head CT scan performed <6 hours after headache onset and reported negative for the presence of SAH by a staff radiologist in the described nonacademic setting.

Coagulation factor XIII gene variation, oral contraceptives, and risk of ischemic stroke.

Prothrombotic conditions are associated with ischemic stroke in young women. In particular, the combination of oral contraceptive use and prothrombotic genetic variants appears to increase the risk of ischemic stroke. We performed a population-based case-control study in 190 women aged 20 to 49 years with ischemic stroke and 767 women without cardiovascular disease stratified for age, calendar year of the index event, and residence. A total of 4 variants of coagulation factor XIII subunit A and B genes (F13A1 and F13B) were investigated. The Phe allele of the F13A1 Tyr204Phe variant was present in 59 (31%) patients and 43 (6%) controls; the odds ratio for ischemic stroke was 9.1 for Phe/Phe and Phe/Tyr versus Tyr/Tyr genotype; the 95% confidence interval was 5.5 to 15. Homozygous genotypes (Phe/Phe) conferred a higher risk (odds ratio, 77; 95% confidence interval, 7.0-848) than heterozygous (Tyr/Phe) genotypes (odds ratio, 8.2; 95% confidence interval, 4.9-14). The risk of ischemic stroke was further increased in carriers of the 204Phe allele using oral contraceptives (odds ratio, 20; 95% confidence interval, 9-46) compared with nonusers with Tyr/Tyr genotype. In conclusion, the F13A1 204Phe allele was strongly associated with ischemic stroke in young women. Oral contraceptive use further increased the risk of ischemic stroke.