Affected twins in the familial intracranial aneurysm study.

BACKGROUND AND PURPOSE: Very few cases of intracranial aneurysms (IAs) in twins have been reported. Previous work has suggested that vulnerability to IA formation is heritable. Twin studies provide an opportunity to evaluate the impact of genetics on IA characteristics, including IA location. We therefore sought to examine IA location concordance, multiplicity, and rupture status within affected twin-pairs. METHODS: The Familial Intracranial Aneurysm study was a multicenter study whose goal was to identify genetic and other risk factors for formation and rupture of IAs. The study required at least three affected family members or an affected sibling pair for inclusion. Subjects with fusiform aneurysms, an IA associated with an AVM, or a family history of conditions known to predispose to IA formation, such as polycystic kidney disease, Ehlers-Danlos syndrome, Marfan syndrome, fibromuscular dysplasia, or moyamoya syndrome were excluded. Twin-pairs were identified by birth date and were classified as monozygotic (MZ) or dizygotic (DZ) through DNA marker genotypes. In addition to zygosity, we evaluated twin-pairs by smoking status, major arterial territory of IAs, and rupture status. Location concordance was defined as the presence of an IA in the same arterial distribution (ICA, MCA, ACA, and vertebrobasilar), irrespective of laterality, in both members of a twin-pair. The Fisher exact test was used for comparisons between MZ and DZ twin-pairs. RESULTS: A total of 16 affected twin-pairs were identified. Location concordance was observed in 8 of 11 MZ twin-pairs but in only 1 of 5 DZ twin-pairs (p = 0.08). Three MZ subjects had unknown IA locations and comprised the three instances of MZ discordance. Six of the 11 MZ twin-pairs and none of the 5 DZ twin-pairs had IAs in the ICA distribution (p = 0.03). Multiple IAs were observed in 11 of 22 MZ and 5 of 10 DZ twin-pairs. Thirteen (13) of the 32 subjects had an IA rupture, including 10 of 22 MZ twins. CONCLUSIONS: We found that arterial location concordance was greater in MZ than DZ twins, which suggests a genetic influence upon aneurysm location. The 16 twin-pairs in the present study are nearly the total of affected twin-pairs that have been reported in the literature to date. Further studies are needed to determine the impact of genetics in the formation and rupture of IAs.

Genome-wide association study of intracranial aneurysm identifies a new association on chromosome 7.

BACKGROUND AND PURPOSE: Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. METHODS: Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest. RESULTS: Genome-wide evidence of association was detected in the discovery sample on chromosome 9 (CDKN2BAS; rs10733376: P<1.0×10(-11)), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9, was associated with IA (rs10230207; P=4.14×10(-8)). This association replicated in the Dutch sample (P=0.01) but failed to show association in the Finnish sample (P=0.25). Meta-analysis results of the 3 cohorts reached statistical significant (P=9.91×10(-10)). CONCLUSIONS: We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9), suggesting a possible genetic link between this stroke subtype and IA.

Familial intracranial aneurysms: is anatomic vulnerability heritable?

BACKGROUND AND PURPOSE: Previous studies have suggested that family members with intracranial aneurysms (IAs) often harbor IAs in similar anatomic locations. IA location is important because of its association with rupture. We tested the hypothesis that anatomic susceptibility to IA location exists using a family-based IA study. METHODS: We identified all affected probands and first-degree relatives (FDRs) with a definite or probable phenotype in each family. We stratified each IA of the probands by major arterial territory and calculated each family's proband-FDR territory concordance and overall contribution to the concordance analysis. We then matched each family unit to an unrelated family unit selected randomly with replacement and performed 1001 simulations. The median concordance proportions, odds ratios (ORs), and P values from the 1001 logistic regression analyses were used to represent the final results of the analysis. RESULTS: There were 323 family units available for analysis, including 323 probands and 448 FDRs, with a total of 1176 IAs. IA territorial concordance was higher in the internal carotid artery (55.4% versus 45.6%; OR, 1.54 [1.04-2.27]; P=0.032), middle cerebral artery (45.8% versus 30.5%; OR, 1.99 [1.22-3.22]; P=0.006), and vertebrobasilar system (26.6% versus 11.3%; OR, 2.90 [1.05-8.24], P=0.04) distributions in the true family compared with the comparison family. Concordance was also higher when any location was considered (53.0% versus 40.7%; OR, 1.82 [1.34-2.46]; P<0.001). CONCLUSIONS: In a highly enriched sample with familial predisposition to IA development, we found that IA territorial concordance was higher when probands were compared with their own affected FDRs than with comparison FDRs, which suggests that anatomic vulnerability to IA formation exists. Future studies of IA genetics should consider stratifying cases by IA location.

Clinical features and racial/ethnic differences among the 3020 participants in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial.

This study examined the baseline characteristics, racial/ethnic differences, and geographic differences among participants in the Secondary Prevention of Small Subcortical Strokes (SPS3) study. The SPS3 trial enrolled patients who experienced a symptomatic small subcortical stroke (lacunar stroke) within the previous 6 months and an eligible lesion on detected on magnetic resonance imaging. The patients were randomized, in a factorial design, to antiplatelet therapy (aspirin 325 mg daily plus clopidogrel 75 mg daily vs aspirin 325 mg daily plus placebo) and to one of two levels of systolic blood pressure targets ("intensive" [<130 mmHg] or "usual" [130-149 mmHg]). A total of 3020 participants were recruited from 81 clinical sites in 8 countries. In this cohort, the mean age was 63 years, 63% were men, 75% had a history of hypertension, and 37% had diabetes. The racial distribution was 51% white, 30% Hispanic, and 16% black. Compared with white subjects, black subjects were younger (mean age, 58 years vs 64 years; P <.001) and had a higher prevalence of hypertension (87% vs 70%; P <.001). The prevalence of diabetes was higher in the Hispanic and black subjects compared with the white subjects (42% and 40% vs 32%; both P <.001). Tobacco smoking at the time of qualifying stroke was much more frequent in the Spanish participants than in subjects from North America and from Latin America (32%, 22%, and 9%, respectively; P <.001). Mean systolic blood pressure at study entry was 4 mmHg lower in the Spanish subjects compared with the North American subjects (P <.01). The SPS3 cohort is the largest magnetic resonance imaging-defined series of patients with S3. Among the racially/ethnically diverse SPS3 participants, important differences in patient features and vascular risk factors could influence prognosis for recurrent stroke and response to interventions.

Genome-wide association study of intracranial aneurysms confirms role of Anril and SOX17 in disease risk.

BACKGROUND: Genomewide association studies have identified novel genetic factors that contribute to intracranial aneurysm (IA) susceptibility. We sought to confirm previously reported loci, to identify novel risk factors, and to evaluate the contribution of these factors to familial and sporadic IA. METHOD: We utilized 2 complementary samples, one recruited on the basis of a dense family history of IA (discovery sample 1: 388 IA cases and 397 controls) and the other without regard to family history (discovery sample 2: 1095 IA cases and 1286 controls). Imputation was used to generate a common set of single nucleotide polymorphisms (SNP) across samples, and a logistic regression model was used to test for association in each sample. Results from each sample were then combined in a metaanalysis. RESULTS: There was only modest overlap in the association results obtained in the 2 samples. In neither sample did results reach genomewide significance. However, the metaanalysis yielded genomewide significance for SNP on chromosome 9p (CDKN2BAS; rs6475606; P=3.6×10(-8)) and provided further evidence to support the previously reported association of IA with SNP in SOX17 on chromosome 8q (rs1072737; P=8.7×10(-5)). Analyses suggest that the effect of smoking acts multiplicatively with the SNP genotype, and smoking has a greater effect on risk than SNP genotype. CONCLUSIONS: In addition to replicating several previously reported loci, we provide further evidence that the association on chromosome 9p is attributable to variants in CDKN2BAS (also known as ANRIL, an antisense noncoding RNA).

Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture.

BACKGROUND AND PURPOSE: Chronic inflammation is postulated as an important phenomenon in intracranial aneurysm wall pathophysiology. This study was conducted to determine if aspirin use impacts the occurrence of intracranial aneurysm rupture. METHODS: Subjects enrolled in the International Study of Unruptured Intracranial Aneurysms (ISUIA) were selected from the prospective untreated cohort (n=1691) in a nested case-control study. Cases were subjects who subsequently had a proven aneurysmal subarachnoid hemorrhage during a 5-year follow-up period. Four control subjects were matched to each case by site and size of aneurysm (58 cases, 213 control subjects). Frequency of aspirin use was determined at baseline interview. Aspirin frequency groups were analyzed for risk of aneurysmal hemorrhage. Bivariable and multivariable analyses were performed using conditional logistic regression. RESULTS: A trend of a protective effect for risk of unruptured intracranial aneurysm rupture was observed. Patients who used aspirin 3× weekly to daily had an OR for hemorrhage of 0.40 (95% CI, 0.18-0.87); reference group, no use of aspirin), patients in the "< once a month" group had an OR of 0.80 (95% CI, 0.31-2.05), and patients in the "> once a month to 2×/week" group had an OR of 0.87 (95% CI, 0.27-2.81; P=0.025). In multivariable risk factor analyses, patients who used aspirin 3 times weekly to daily had a significantly lower odds of hemorrhage (adjusted OR, 0.27; 95% CI, 0.11-0.67; P=0.03) compared with those who never take aspirin. CONCLUSIONS: Frequent aspirin use may confer a protective effect for risk of intracranial aneurysm rupture. Future investigation in animal models and clinical studies is needed.

The relationship between smoking and replicated sequence variants on chromosomes 8 and 9 with familial intracranial aneurysm.

BACKGROUND AND PURPOSE: The purpose of this study was to replicate the previous association of single nucleotide polymorphisms (SNPs) with risk of intracranial aneurysm (IA) and to examine the relationship of smoking with these variants and the risk of IA. METHODS: White probands with an IA from families with multiple affected members were identified by 26 clinical centers located throughout North America, New Zealand, and Australia. White control subjects free of stroke and IA were selected by random digit dialing from the Greater Cincinnati population. SNPs previously associated with IA on chromosomes 2, 8, and 9 were genotyped using a TaqMan assay or were included in the Affymetrix 6.0 array that was part of a genomewide association study of 406 IA cases and 392 control subjects. Logistic regression modeling tested whether the association of replicated SNPs with IA was modulated by smoking. RESULTS: The strongest evidence of association with IA was found with the 8q SNP rs10958409 (genotypic P=9.2x10(-5); allelic P=1.3x10(-5); OR=1.86, 95% CI: 1.40 to 2.47). We also replicated the association with both SNPs on chromosome 9p, rs1333040 and rs10757278, but were not able to replicate the previously reported association of the 2 SNPs on chromosome 2q. Statistical testing showed a multiplicative relationship between the risk alleles and smoking with regard to the risk of IA. CONCLUSIONS: Our data provide complementary evidence that the variants on chromosomes 8q and 9p are associated with IA and that the risk of IA in patients with these variants is greatly increased with cigarette smoking.

Spontaneous Regression of a Symptomatic Intramedullary Spinal Cord Lesion.

Intramedullary spinal cord tumors and cavernous malformations are rare lesions that can lead to progressive neurologic deficits, impaired quality of life, and even death. Early diagnosis and surgical resection of spinal cord tumors and cavernous malformations are often quoted as essential to optimizing a patient's functional outcome. Unfortunately, these are high-risk operations, with many patients having worse neurological deficits after surgery - sometimes permanent. We present a case of a patient with a cervical intramedullary spinal cord lesion that almost completely resolved spontaneously at short-term follow-up and remained stable at longe-term follow up. Conservative management with careful observation and sequential imaging should be considered in patients with intramedullary spinal cord lesions presenting with acute onset, stable symptoms, especially if the lesion has a hemorrhagic component.

Greater rupture risk for familial as compared to sporadic unruptured intracranial aneurysms.

BACKGROUND AND PURPOSE: The risk of intracranial aneurysm (IA) rupture in asymptomatic members of families who have multiple affected individuals is not known. METHODS: First-degree unaffected relatives of those with a familial history of IA who had a history of smoking or hypertension but no known IA were offered cerebral MR angiography (MRA) and followed yearly as part of a National Institute of Neurological Diseases and Stroke-funded study of familial IA (Familial Intracranial Aneurysm [FIA] Study). RESULTS: A total of 2874 subjects from 542 FIA Study families were enrolled. After study enrollment, MRAs were performed in 548 FIA Study family members with no known history of IA. Of these 548 subjects, 113 subjects (20.6%) had 148 IAs by MRA of whom 5 subjects had IA >or=7 mm. Two subjects with an unruptured IA by MRA/CT angiography (3-mm and 4-mm anterior communicating artery) subsequently had rupture of their IA. This represents an annual rate of 1.2 ruptures per 100 subjects (1.2% per year; 95% CI, 0.14% to 4.3% per year). None of the 435 subjects with a negative MRA have had a ruptured IA. Survival curves between the MRA-positive and -negative cohorts were significantly different (P=0.004). This rupture rate of unruptured IA in the FIA Study cohort of 1.2% per year is approximately 17 times higher than the rupture rate for subjects with an unruptured IA in the International Study of Unruptured Aneurysm Study with a matched distribution of IA size and location 0.069% per year. CONCLUSIONS: Small unruptured IAs in patients from FIA Study families may have a higher risk of rupture than sporadic unruptured IAs of similar size, which should be considered in the management of these patients.

Genome screen in familial intracranial aneurysm.

BACKGROUND: Individuals with 1st degree relatives harboring an intracranial aneurysm (IA) are at an increased risk of IA, suggesting genetic variation is an important risk factor. METHODS: Families with multiple members having ruptured or unruptured IA were recruited and all available medical records and imaging data were reviewed to classify possible IA subjects as definite, probable or possible IA or not a case. A 6 K SNP genome screen was performed in 333 families, representing the largest linkage study of IA reported to date. A 'narrow' (n = 705 definite IA cases) and 'broad' (n = 866 definite or probable IA) disease definition were used in multipoint model-free linkage analysis and parametric linkage analysis, maximizing disease parameters. Ordered subset analysis (OSA) was used to detect gene x smoking interaction. RESULTS: Model-free linkage analyses detected modest evidence of possible linkage (all LOD < 1.5). Parametric analyses yielded an unadjusted LOD score of 2.6 on chromosome 4q (162 cM) and 3.1 on chromosome 12p (50 cM). Significant evidence for a gene x smoking interaction was detected using both disease models on chromosome 7p (60 cM; p

Classification of Strokes in Patients Receiving Intravitreal Anti-Vascular Endothelial Growth Factor.

BACKGROUND AND OBJECTIVE: The purpose of this study was to identify the differences in the types of strokes seen in patients receiving intravitreal anti-vascular endothelial growth factor (VEGF) compared with normal control populations. PATIENTS AND METHODS: We performed a retrospective consecutive review of all patients receiving intravitreal anti-VEGF injections in Olmsted County, Minnesota, from January 1, 2004, to December 31, 2013, for exudative age-related macular degeneration (AMD), diabetic macular edema (DME), proliferative diabetic retinopathy (PDR), or retinal vein occlusion (RVO). A 2-year follow-up period was required for study inclusion. Three age- and sex-matched cohorts were identified. RESULTS: A total of 2,541 patients were examined. There were 690 patients identified during the study period as receiving an intravitreal injection for AMD, DME, PDR, or RVO. Of these patients, 38 (5.8%) suffered a stroke after starting intravitreal injection therapy. Of these strokes, 27 (71.1%) were ischemic, six (15.8%) were embolic, and five (13.2%) were hemorrhagic. There were no differences in the types of strokes identified among the patients receiving intravitreal injections between the case cohort and the control cohorts (P > .05 for all). CONCLUSION: The authors' data suggest there is no predilection to the development of ischemic infarcts or hemorrhagic strokes in those patients receiving intravitreal anti-VEGF compared with control populations. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e140-e157.].

Association of Intravitreal Anti-Vascular Endothelial Growth Factor Therapy With Risk of Stroke, Myocardial Infarction, and Death in Patients With Exudative Age-Related Macular Degeneration.

Importance: Current studies assessing the risk of stroke, myocardial infarction (MI), and death in patients undergoing intravitreal anti-vascular endothelial growth factor (VEGF) therapy are inconclusive. To our knowledge, no population-based studies have been performed to examine these potential risks. Objective: To examine whether patients with exudative age-related macular degeneration (AMD) receiving intravitreal anti-VEGF injections have a higher incidence of MI, stroke, or death compared with control populations. Design, Setting, and Participants: This population-based, retrospective cohort study included 504 patients from Olmsted County, Minnesota, identified through the Rochester Epidemiology Project (REP) database as receiving at least 1 intravitreal anti-VEGF injection for exudative AMD from January 1, 2004, to December 31, 2013. Three age- and sex-matched control groups of individuals who did not receive anti-VEGF treatment and were derived from the REP database were also studied: control individuals with exudative AMD in the era before anti-VEGF (January 1, 1990, to December 31, 2003), controls with dry AMD, and controls without AMD. Data analysis was performed from September 1, 2016, to September 1, 2017. Main Outcomes and Measures: Five-year risk of stroke, MI, and death were assessed in patients compared with controls using Kaplan-Meier and multivariate analysis with Cox proportional hazards regression models. Results: The study included 504 patients (321 female [63.7%]; mean [SD] age, 76.5 [10.0] years) who received at least 1 intravitreal anti-VEGF injection for exudative AMD during the study period. Kaplan-Meier analysis revealed a 5-year risk of 7.2% for stroke, 6.1% for MI, and 30.0% for death. Patients who received anti-VEGF had no increased risk of stroke or MI compared with controls with dry AMD (n = 504), controls with exudative AMD (n = 473), or controls without AMD (n = 504). There was an increased risk of mortality compared with controls with exudative AMD in the era prior to anti-VEGF therapy but not the other control groups on multivariate analysis (hazard ratio, 1.63; 95% CI, 1.30-2.04; P < .001). Conclusions and Relevance: This population-based study revealed that intravitreal anti-VEGF therapy for exudative AMD was not associated with consistent increases in the risk of stroke, MI, or death compared with no therapy in patients with or without AMD. It appears to be likely the cardiac events these patients experience are not attributable to their anti-VEGF therapy.

Genome screen to detect linkage to intracranial aneurysm susceptibility genes: the Familial Intracranial Aneurysm (FIA) study.

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 x 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 x smoking interaction with 3 of the loci.

Screening for brain aneurysm in the Familial Intracranial Aneurysm study: frequency and predictors of lesion detection.

OBJECT: Approximately 20% of patients with an intracranial saccular aneurysm report a family history of intracranial aneurysm (IA) or subarachnoid hemorrhage. A better understanding of predictors of aneurysm detection in familial IA may allow more targeted aneurysm screening strategies. METHODS: The Familial Intracranial Aneurysm (FIA) study is a multicenter study, in which the primary objective is to define the susceptibility genes related to the formation of IA. First-degree relatives (FDRs) of those affected with IA are offered screening with magnetic resonance (MR) angiography if they were previously unaffected, are > or = 30 years of age, and have a history of smoking and/or hypertension. Independent predictors of aneurysm detection on MR angiography were determined using the generalized estimating equation version of logistic regression. RESULTS: Among the first 303 patients screened with MR angiography, 58 (19.1%) had at least 1 IA, including 24% of women and 11.7% of men. Ten (17.2%) of 58 affected patients had multiple aneurysms. Independent predictors of aneurysm detection included female sex (odds ratio [OR] 2.46, p = 0.001), pack-years of cigarette smoking (OR 3.24 for 20 pack-years of cigarette smoking compared with never having smoked, p < 0.001), and duration of hypertension (OR 1.26 comparing those with 10 years of hypertension to those with no hypertension, p = 0.006). CONCLUSIONS: In the FIA study, among the affected patients' FDRs who are > 30 years of age, those who are women or who have a history of smoking or hypertension are at increased risk of suffering an IA and should be strongly considered for screening.

Aneurysm Morphology and Prediction of Rupture: An International Study of Unruptured Intracranial Aneurysms Analysis.

BACKGROUND: There are conflicting data between natural history studies suggesting a very low risk of rupture for small, unruptured intracranial aneurysms and retrospective studies that have identified a much higher frequency of small, ruptured aneurysms than expected. OBJECTIVE: To use the prospective International Study of Unruptured Intracranial Aneurysms cohort to identify morphological characteristics predictive of unruptured intracranial aneurysm rupture. METHODS: A case-control design was used to analyze morphological characteristics associated with aneurysm rupture in the International Study of Unruptured Intracranial Aneurysms database. Fifty-seven patients with ruptured aneurysms during follow-up were matched (by size and location) with 198 patients with unruptured intracranial aneurysms without rupture during follow-up. Twelve morphological metrics were measured from cerebral angiograms in a blinded fashion. RESULTS: Perpendicular height (P = .008) and size ratio (ratio of maximum diameter to the parent vessel diameter; P = .01) were predictors of aneurysm rupture on univariate analysis. Aspect ratio, daughter sacs, multiple lobes, aneurysm angle, neck diameter, parent vessel diameter, and calculated aneurysm volume were not statistically significant predictors of rupture. On multivariate analysis, perpendicular height was the only significant predictor of rupture (Chi-square 7.1, P-value .008). CONCLUSION: This study underscores the importance of other morphological factors, such as perpendicular height and size ratio, that may influence unruptured intracranial aneurysm rupture risk in addition to greatest diameter and anterior vs posterior location.

Population-based study of the relationship between patent foramen ovale and cerebrovascular ischemic events.

OBJECTIVE: To determine whether patent foramen ovale (PFO) is a risk factor for a cryptogenic cerebrovascular ischemic event (CIE). METHODS: This case-control study of 1072 residents of Olmsted County, Minnesota, who underwent contrast transesophageal echocardiography between 1993 and 1997 included 519 controls without CIE randomly selected from the population, 262 controls without CIE referred for transesophageal echocardiography because of cardiac disease, 158 cases with incident CIE of obvious cause (noncryptogenic), and 133 cases with incident CIE of uncertain cause (cryptogenic). RESULTS: Large PFOs were detected in 108 randomly selected controls (20.8%), 22 referred controls (8.4%), 17 noncryptogenic CIE cases (10.8%), and 22 cryptogenic CIE cases (16.5%). After adjustment for age, sex, hypertension, smoking, atrial fibrillation, ischemic heart disease, and number of contrast injections, the presence of a large PFO was not significantly associated with group status (P=.07). Using the odds of the presence of large PFO in the randomly selected controls as the reference, the odds ratio (95% confidence interval) of the presence of large PFO was 0.47 (0.26-0.87) for referred controls, 0.69 (0.37-1.29) for noncryptogenic CIE cases, and 1.10 (0.63-1.90) for cryptogenic CIE cases. CONCLUSIONS: Patent foramen ovale is not a risk factor for cryptogenic ischemic stroke or transient ischemic attack in the general population. The PFO's importance in the genesis of cryptogenic CIE may have been overestimated in previous studies because of selective referral of cases and underascertainment of PFO among comparison groups of patients referred for echocardiography for clinical indications other than cryptogenic CIE.

Population-based study of the relationship between atherosclerotic aortic debris and cerebrovascular ischemic events.

OBJECTIVE: To assess the validity of the suggestion that protruding atheromatous material in the thoracic aorta is an important cause of cerebrovascular ischemic events (CIEs) (ie, transient ischemic attack or ischemic stroke). METHODS: This case-control study of Olmsted County, Minnesota, residents who underwent transesophageal echocardiography (TEE) from 1993 to 1997 included controls without CIE randomly selected from the population, controls without CIE referred for TEE because of cardiac disease, cases with incident CIE of obvious cause (noncryptogenic), and cases with incident CIE of uncertain cause (cryptogenic). RESULTS: Of the 1135 subjects, 520 were randomly selected controls without CIE, 329 were controls without CIE referred for TEE, 159 were noncryptogenic CIE cases, and 127 were cryptogenic CIE cases. Complex atherosclerotic aortic debris in ascending and transverse segments of the arch was detected in 8 randomly selected controls (1.5%), 13 referred controls (4.0%), and 15 noncryptogenic (9.4%) and 4 cryptogenic (3.1%) CIE cases. After adjusting for age, sex, hypertension, smoking, atrial fibrillation, valvular heart disease, congestive heart failure, and atherosclerosis other than in the thoracic aorta, complex atherosclerotic aortic debris was not significantly associated with group status. With randomly selected controls as the referent group, odds ratios (95% confidence intervals) were 1.72 (0.61-4.87) for referred controls, 3.16 (1.18-8.51) for noncryptogenic CIE cases, and 1.39 (0.39-4.88) for cryptogenic CIE cases. CONCLUSIONS: Complex atherosclerotic aortic debris is not a risk factor for cryptogenic ischemic stroke or transient ischemic attack but is a marker for generalized atherosclerosis and well-established atherosclerotic and cardioembolic mechanisms of cerebral ischemia. Embolization from the aorta is not a common mechanism of ischemic stroke or transient ischemic attack.

Update on evidence for a genetic predisposition to cerebral vasospasm.

Considerable evidence links cerebral vasospasm to the decreased bioavailability of endothelial nitric oxide synthase (eNOS) after aneurysmal subarachnoid hemorrhage (SAH). In recent studies from the cardiology literature, researchers have suggested that a genetic predisposition to coronary vasospasm might develop as the result of a T-786C single nucleotide polymorphism (SNP) in the eNOS gene. The authors of this study attempted to determine if there may be a similar genetic predisposition toward cerebral vasospasm. The authors prospectively identified 28 patients with Fisher Grade 3 SAH from a group of 51 consecutive patients with ruptured intracranial saccular aneurysms. Genomic DNA was isolated from a peripheral blood sample obtained with permission from each patient. Gene microarray technology was used to assay the samples for the presence and distribution of certain key eNOS gene polymorphisms. Clinical, radiological, and genomic data were analyzed. The finding of eNOS T-786C SNP could be used to significantly differentiate between the presence and severity of cerebral vasospasm (p = 0.04). The findings from this preliminary study support similar findings in the coronary vasospasm literature as well as the hypothesis that a predisposition toward cerebral vasospasm may be related partially to genetic factors, which needs to be confirmed in a larger study. Such gene-based information may be important in rapidly identifying patients at increased risk of vasospasm after SAH, independent of their Fisher grade. In this article, the authors review key studies in this area.

Is aortic dilatation an atherosclerosis-related process? Clinical, laboratory, and transesophageal echocardiographic correlates of thoracic aortic dimensions in the population with implications for thoracic aortic aneurysm formation.

OBJECTIVES: The study determined, in a population-based setting, whether dilatation of the thoracic aorta is an atherosclerosis-related process. BACKGROUND: The role of atherosclerosis in thoracic aortic dilatation and aneurysm formation is poorly defined. METHODS: The dimensions of the thoracic aorta were measured with transesophageal echocardiography in 373 subjects participating in a population-based study (median age 66 years; 52% men). The associations between clinical and laboratory atherosclerosis risk factors, aortic atherosclerotic plaques, and aortic dimensions were examined. RESULTS: Age, male gender, and body surface area (BSA) jointly accounted for 41%, 31%, 38%, and 47% of the variability in diameters of the sinuses of Valsalva, ascending aorta, aortic arch, and descending aorta, respectively. Adjusting for age, gender, and BSA: 1) smoking was associated with a greater aortic arch diameter, and diastolic blood pressure and diabetes were each associated with a greater descending aorta diameter (p < 0.05); 2) atherosclerotic plaques in the descending aorta were associated with a greater descending aorta diameter (0.18 +/- 0.08-mm increase in diameter per 1-mm increase in plaque thickness; p = 0.02); and 3) minor negative associations were noted between atherosclerotic plaques and risk factors for atherosclerosis and the dimensions of the proximal thoracic aorta. Notably, atherosclerosis risk factors and plaque variables each accounted for <2% of the variability in aortic dimensions, adjusting for age, gender, and BSA. CONCLUSIONS: Age, gender, and BSA are major determinants of thoracic aortic dimensions. Atherosclerosis risk factors and aortic atherosclerotic plaques are weakly associated with distal aortic dilatation, suggesting that atherosclerosis plays a minor role in aortic dilatation in the population.

Lack of association between Chlamydia pneumoniae seropositivity and aortic atherosclerotic plaques: a population-based transesophageal echocardiographic study.

OBJECTIVES: The objective of this study was to examine the relationship between Chlamydia pneumoniae seropositivity and aortic atherosclerotic plaques in the general population. BACKGROUND: Seroepidemiologic studies suggest that C pneumoniae infection plays a role in the pathogenesis of atherosclerosis. METHODS: Transesophageal echocardiography was performed in 385 subjects (median age 66 years, range 51 to 101 years; 53% men), a sample of the Olmsted County (Minnesota) population. The association between C pneumoniae immunoglobulin (Ig) G antibody titers and aortic atherosclerotic plaques was examined. RESULTS: Chlamydia pneumoniae IgG antibodies (titers >or=1:16) were detected in 287 subjects (74.5%): low titers (1:16 to 1:32) in 58 (15.1%), intermediate titers (1:64 to 1:128) in 144 (37.4%), and high titers (>or=1:256) in 85 subjects (22.1%). Antibody titers were not associated with the presence of aortic plaques after adjustment for age, gender, and smoking status (p = 0.64). Compared with titers <1:16, the adjusted odds ratios for aortic plaques were 1.46 (95% confidence interval [CI] 0.63 to 3.42) for low titers, 1.32 (95% CI 0.68 to 2.55) for intermediate titers, and 0.94 (95% CI 0.42 to 2.07) for high titers. Among the subgroup with plaques, antibody titers were not associated with the presence of plaques >or=4 mm thick (p = 0.99), plaques >or=6 mm (p = 0.49), or mobile debris (p = 0.71), after adjustment for age and smoking. CONCLUSIONS: Chlamydia pneumoniae IgG antibody titers are not associated with the presence or severity of aortic atherosclerosis in the general population. These observations do not support a role for C pneumoniae infection in the initiation or progression of atherosclerosis.