Meissner, Irene

Background and Purpose— Evidence supports a substantial genetic contribution to the risk of intracranial aneurysm (IA). The purpose of this study was to identify chromosomal regions likely to harbor genes that contribute to the risk of IA. Methods— Multiplex families having at least 2 individuals with “definite” or “probable” IA were ascertained through an international consortium. First-degree relatives of individuals with IA who were at increased risk of an IA because of a history of hypertension or present smoking were offered cerebral magnetic resonance angiography. A genome screen was completed using the Illumina 6K SNP system, and the resulting data from 192 families, containing 1155 genotyped individuals, were analyzed. Narrow and broad disease definitions were used when testing for linkage using multipoint model-independent methods. Ordered subset analysis was performed to test for a gene×smoking (pack-years) interaction. Results— The greatest evidence of linkage was found on chromosomes 4 (LOD=2.5; 156 cM), 7 (LOD=1.7; 183 cM), 8 (LOD=1.9; 70 cM), and 12 (LOD=1.6; 102 cM) using the broad disease definition. Using the average pack-years for the affected individuals in each family, the genes on chromosomes 4 (LOD=3.5; P =0.03), 7 (LOD=4.1; P =0.01) and 12 (LOD=3.6; P =0.02) all appear to be modulated by the degree of smoking in the affected members of the family. On chromosome 8, inclusion of smoking as a covariate did not significantly strengthen the linkage evidence, suggesting no interaction between the loci in this region and smoking. Conclusions— We have detected possible evidence of linkage to 4 chromosomal regions. There is potential evidence for a gene×smoking interaction with 3 of the loci.

Rupture of an intracranial aneurysm (subarachnoid hemorrhage) is a potentially devastating condition frequently complicated by delayed cerebral ischemia from sustained contraction of intracranial arteries (cerebral vasospasm). There is mounting evidence linking the formation of intracranial aneurysms and the pathogenesis of post-subarachnoid hemorrhage vasospasm to aberrant bioavailability and action of the vasodilator molecule nitric oxide generated by isoforms of nitric oxide synthase. In humans, the gene encoding the endothelial isoform of nitric oxide synthase (eNOS) is known to be polymorphic, with certain polymorphisms associated with increased cardiovascular disease susceptibility. In this prospective clinical study involving 141 participants, we used gene microarray technology to demonstrate that the eNOS gene intron-4 27-base pair variable number tandem repeat polymorphism (eNOS 27 VNTR) predicts susceptibility to intracranial aneurysm rupture, while the eNOS gene promoter T-786C single nucleotide polymorphism (eNOS T-786C SNP) predicts susceptibility to post-subarachnoid hemorrhage vasospasm. We believe that genetic information such as this, which can be obtained expeditiously at the time of diagnosis, may be used as a helpful adjunct to other clinical information aimed at predicting and favorably modifying the clinical course of persons with intracranial aneurysms.

Background and Purpose—We sought to determine the incidence of recurrent stenosis after carotid endarterectomy.Methods—One thousand consecutive carotid endarterectomy patients were followed prospectively. The surgery was performed in a standard fashion. Cerebral protection was provided with intraoperative electroencephalographic monitoring and selective shunting. All arteriotomies were repaired with a patch graft. Each patient was seen 3 months after surgery and then yearly, with a duplex ultrasound obtained at each visit. Evidence for new ischemic events or recurrent stenosis of ≥70% was recorded.Results—The 30-day combined minor and major stroke and death rate was 1.9%. At 7.1-year follow-up, 0.1% of patients had recurrent stenosis ≥70%, the majority of which were asymptomatic.Conclusions—Carotid endarterectomy is a low-risk procedure for the treatment of carotid occlusive disease, with excellent long-term durability. Although less invasive, carotid angioplasty must demonstrate equal robustness in long-term follow-up before it is considered a routine alternative to surgery.

Background and Purpose— Anecdotal evidence exists for at least 2 subpopulations of intracranial saccular aneurysms, namely, those that may form rapidly and rupture when small versus those that enlarge slowly and may rupture particularly when ≥10 mm in diameter. We sought to determine whether the endothelial nitric oxide synthase (eNOS) T-786C single nucleotide polymorphism (SNP), implicated in cardiovascular disease susceptibility, could facilitate differentiation between small (≤5 mm) versus large (≥10 mm) ruptured aneurysms. Methods— In accordance with institutional guidelines, clinical data were recorded prospectively and genomic DNA was isolated from blood samples obtained from 52 aneurysmal subarachnoid hemorrhage (SAH) patients (cases) and 90 randomly selected controls. Samples were assayed for eNOS gene promoter T-786C SNP with the use of gene microarray technology. Statistical analyses included multiple logistic regression. Results— Although there was no difference in genotype distributions between cases and controls, all 13 patients with large aneurysms were ( T / C ) heterozygous for the polymorphism, while 9 of 22 patients (41%) with small aneurysms were ( T / T or C / C ) homozygous ( P =0.01). The mean (±SD) ruptured aneurysm diameter among all heterozygotes (8.5±5.2 mm) was significantly greater than that for C / C (6.0±2.3 mm) or T / T (4.7±1.8 mm) homozygotes ( P =0.04). With the use of multivariate analysis, heterozygosity remained significantly associated with aneurysm size ≥10 mm ( P =0.03). Conclusions— The eNOS T-786C SNP distinguishes genetically between small and large ruptured aneurysms. Although not predictive of SAH in the population at large, our data suggest that among persons with known intracranial aneurysms, eNOS T-786C genotype may be a factor influencing the size at which an aneurysm ruptures, a finding that should be taken into consideration along with other anatomic features of the aneurysm.