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Dissections and aneurysms are two of the more common nonatherosclerotic arteriopathies of the cerebrovascular system and a significant contributor to neurovascular complications, particularly in the young. Specifically, ruptured intracranial aneurysms (IA) account for nearly 500,000 cases of subarachnoid hemorrhage annually with a 30-day mortality approaching 40% and survivors suffering often permanent neurologic deficits and disability. Unruptured IAs require dedicated assessment of risk and often warrant serial radiologic monitoring. Cervical artery dissection, affecting the carotid and vertebral arteries, accounts for nearly 20% of strokes in young and middle-aged adults. While approximately 70% of cervical artery dissection (CeAD) cases present with stroke or TIA, additional neurologic complications include severe headache and neck pain, oculosympathetic defect (i.e., partial Horner's syndrome), acute vestibular syndrome, and rarely lower cranial nerve palsies. Both aneurysms and dissections of the cerebrovascular system may occur frequently in patients with syndromic connective tissue disorders; however, the majority of cases are spontaneously occurring or mildly heritable with both polygenic and environmental associations. Fibromuscular dysplasia, in particular, is commonly associated with both risk of CeAD and IA formation. Further research is needed to better understand the pathophysiology of both IA and CeAD to better understand risk, improve treatments, and prevent devastating neurologic complications.

Dissections and aneurysms are two of the more common nonatherosclerotic arteriopathies of the cerebrovascular system and a significant contributor to neurovascular complications, particularly in the young. Specifically, ruptured intracranial aneurysms (IA) account for nearly 500,000 cases of subarachnoid hemorrhage annually with a 30-day mortality approaching 40% and survivors suffering often permanent neurologic deficits and disability. Unruptured IAs require dedicated assessment of risk and often warrant serial radiologic monitoring. Cervical artery dissection, affecting the carotid and vertebral arteries, accounts for nearly 20% of strokes in young and middle-aged adults. While approximately 70% of cervical artery dissection (CeAD) cases present with stroke or TIA, additional neurologic complications include severe headache and neck pain, oculosympathetic defect (i.e., partial Horner's syndrome), acute vestibular syndrome, and rarely lower cranial nerve palsies. Both aneurysms and dissections of the cerebrovascular system may occur frequently in patients with syndromic connective tissue disorders; however, the majority of cases are spontaneously occurring or mildly heritable with both polygenic and environmental associations. Fibromuscular dysplasia, in particular, is commonly associated with both risk of CeAD and IA formation. Further research is needed to better understand the pathophysiology of both IA and CeAD to better understand risk, improve treatments, and prevent devastating neurologic complications.

Background and Purpose: The majority of published data in cervical artery dissection (CeAD), a common cause of stroke in young adults, derive from populations of European ancestry (EA), including a recent genome-wide study identifying an association with the rs9349379 polymorphism of the PHACTR1 gene. Little is known about CeAD in individuals of African ancestry (AA) despite robust epidemiological data showing increased risk of stroke at younger ages. We hypothesize that AA patients with CeAD have different epidemiology and clinical profiles compared to those of EA, and a different genetic architecture related to rs9349379 of the PHACTR1 gene. Methods: We searched a single-center database of CeAD to identify AA and EA patients. We compared differential prevalence of CeAD versus all young stroke between AA and EA patients. We characterized clinical profiles via electronic medical record review. Data include descriptive statistics reported as medians or percentages. We also obtained publicly available allele frequencies of rs9349379 in AA and EA populations. Results: AA patients comprise 7% of CeAD cases and 27% of young stroke cases while EA patients comprise 90% of CeAD cases and 70% of young stroke cases. Prevalence of hypertension, diabetes mellitus, and hyperlipidemia were 74, 30, and 50%, respectively, in AA patients compared to 37, 6, and 25% in EA patients. Allele frequencies for the CeAD risk allele, rs9349379(A), are higher in AA populations compared to EA populations. Conclusion: AA patients represent a smaller proportion of CeAD cases compared to young stroke cases at our center. AA patients suffering CeAD have higher prevalence of both vascular risk factors and frequency of the CeAD risk allele compared to EA patients. These findings suggest a complex interplay between traditional vascular risk factors and genetic predisposition underlying CeAD pathogenesis. Further prospective research is needed to clarify these associations and disparities.

Variation in the phosphatase and actin regulator-1 (PHACTR1) gene, a downstream regulator of the endothelin-1 (EDN1) gene, has been implicated in the pathogenesis of several related vascular phenotypes including atherosclerotic coronary artery disease, non-atherosclerotic coronary artery dissection, and carotid artery dissection, though it has not been studied in carotid atherosclerosis. We analyzed differential expression of PHACTR1 and EDN1 between atheromatous and non-atheromatous carotid artery tissue within the same individual and found lower levels of PHACTR1 expression in the atheromatous carotid tissue.

To investigate potential association between collateral arterial supply and stroke in patients with isolated internal carotid artery dissection (iCeAD). We hypothesized a lower risk of stroke in patients with more robust collateral supply. This is a single-center, retrospective review of iCeAD patients between 1994 and 2018. iCeAD patients with sufficient neuroimaging data were included. Patients were categorized based on cerebral infarction (stroke) on neuroimaging. The collaterals score, ranging from 0 to 8 with higher scores indicating more robust collaterals, was assessed based on contributions from leptomeningeal arteries (0-2 points), anterior communicating artery (0-2 points) and anterior cerebral artery A1 segment (0-2 points), and posterior communicating artery (0-2 points). The study included 62 iCeAD patients, comprising 33 and 29 patients in the stroke and no stroke groups, respectively. Neurological motor deficit (p 0.001) and internal carotid artery occlusion (p = 0.033) were independent predictors of stroke. More robust collaterals was associated with lower stroke risk (p = 0.032) in univariable analysis, but not after adjustment for baseline differences. The collaterals score performed poorly in receiver-operating characteristics (ROC) curve analysis, with area under the ROC (AUROC) curve of 0.640. A collaterals score of4 had a sensitivity and specificity of 89.7% and 36.4% for no stroke, respectively. The covariate-adjusted AUROC curve was 0.514. Collateral circulation appeared to be a poor predictor of cerebral infarction in patients with isolated iCeAD. Future studies in larger, independent cohorts are needed to better understand the interaction of collaterals with stroke in cervical artery dissection.

Introduction: Several related neurovascular phenotypes, including cervical artery dissection, fibromuscular dysplasia, large artery stroke, hypertension, and migraine headache are associated with a single nucleotide polymorphism (rs9349378) in the phosphatase and actin regulator-1 ( PHACTR1 ) gene recently identified as a distal regulator of the endothelin-1 ( EDN1 ) gene. Vascular endothelial cells release EDN1, a potent vasoconstrictor. We hypothesize that atheromatous and normal carotid tissue will differentially express PHACTR1 and EDN1 . Methods: We obtained gene expression data from the publically available Gene Expression Omnibus Carotid Atheroma Dataset (GSE43292). This resource contains 32 paired samples of carotid atheroma and distant macroscopically intact carotid tissue from the same individual and gene expression data from the Affymetrix Human Gene 1.0 ST Array. We compared log transformed count of signal intensity of PHACTR1 and EDN1 expression in the 32 paired samples using a two-sample t-test assuming equal variance with SPSS (IBM, Armonk, NY). Results: PHACTR1 expression was lower in atheromatous compared to normal carotid tissue (7.152 vs. 7.399, delta 0.248, 95%CI 0.180 - 0.315, p=1.9 E -8 ). EDN1 expression did not differ (6.514 and 6.339, delta 0.176, 95%CI -0.004 - 0.356, p = 0.055). with genetic data associating the rs9349378[G] allele with lower levels of expression and atherosclerotic vascular diseases. The lack of differential EDN1 expression may reflect the small sample size or may challenge the assertion that EDNI is the mediator of the PHACTR1 association. Our data support the hypothesis that this pathway may play an important and potentially variable role in neurovascular phenotypes including large artery atherosclerotic stroke and non-atherosclerotic arteriopathies.

Introduction: The pathogenesis of spontaneous cervical artery dissection (sCeAD), a common cause of stroke in young adults, is poorly understood. The majority of published data in sCeAD derive from populations of European ancestry, including a recent genome-wide study identifying an association with the rs9349379 polymorphism of the PHACTR1 gene. Little is known about sCeAD in individuals of African ancestry despite robust epidemiological data showing increased risk of stroke at younger ages, partially explained by higher prevalence of traditional vascular risk factors. We hypothesize that people of African ancestry with sCeAD have different epidemiology and clinical profiles compared to those of European ancestry, and a different genetic architecture related to rs9349379 of the PHACTR1 gene. Methods: We searched a single-center database of sCeAD (n=278) to identify individuals of African and European ancestry. We compared differential prevalence of sCeAD versus all young stroke (≤ 60) between patients of African and European ancestry at our center. We characterized clinical profiles, confirmed by electronic medical record review. Data include descriptive statistics reported as medians or percentages as appropriate. We also used the publicly available HapMap Project to obtain allele frequencies of rs9349379 in different ancestral populations. Results: Conclusion: Individuals of African Ancestry account for a relatively smaller proportion of sCeAD cases compared to the proportion of all young stroke cases. Despite similar ages at time of event, individuals of African ancestry suffering sCeAD have higher prevalence of vascular risk factors compared to individuals of European Ancestry. Reviewing HapMap data demonstrates striking differences in allele frequencies for rs9349379 in the PHACTR1 gene between ancestral populations. Further prospective research is needed to clarify these associations and disparities in the pathogenesis of sCeAD.

Introduction: Cervical artery dissection (CeAD) of the carotid and vertebral arteries is a prevalent cause of stroke in young adults. While the pathogenesis of incident CeAD remains poorly understood, clinical and genetic associations suggest a systemic arteriopathy at time of event. Hypothesis: Individuals suffering CeAD express a distinct gene expression profile at time of event compared to (1) age and sex-matched controls and (2) convalescent profiles within the same individual at a later time point. Methods: We enrolled 37 consecutive patients with carotid or vertebral artery dissection (with and without ischemic stroke) from 2013-2016, excluding concurrence of major trauma. Cases were age and sex matched to non-CeAD ischemic stroke controls (n=16) and healthy controls (n=11). Whole blood samples were collected within four weeks from time of event, and again at 3 and 6-month follow-up. We used IlluminaHT-12 microarrays to assess differential gene expression at time of CeAD relative to controls, and relative to gene expression at >3 month follow-up within CeAD cases. Mixed effects regression models included relevant covariates of age, sex, race/ethnicity, time of enrollment, and occurrence of stroke. We used a False Discovery Rate (FDR) cutoff of 5% to account for multiple testing as well as a 1.5 fold change cutoff to identify robust, differential gene expression. Results: We identified 538 differentially expressed genes between CeAD patients and healthy controls with 30 of these genes reaching our predetermined 1.5x fold change limit. Within CeAD cases, 1,238 genes showed differential expression at a 5% FDR compared to time points at 3-6 month follow-up, with 31 genes showing at least a 1.5 fold change. Compared to controls and convalescent profiles, 12 genes were significant using the 5% FDR and 1.5 fold change cutoffs. Preliminary gene-ontology analysis indicate the largest differential expression for genes associated with oxygen and gas transport. Conclusion: In this consecutive cohort of individuals with CeAD, we identified a distinct gene expression profile associated with incident dissection. These data are limited by small sample size and results are hypothesis generating. Replication in larger, independent cohorts is warranted.

Introduction: Abdominal aortic aneurysm (AAA) rupture has a mortality rate of 64% and intracranial aneurysm (IA) rupture has a mortality rate of 50%. Despite the high mortality rates, early detection and treatment of these vascular lesions prior to rupture can prevent devastating clinical outcomes, underscoring the need to identify high-risk populations for screening. Current evidence demonstrates shared genetic and environmental risk factors for both AAA and IA. Methods: The BAAS study sought to establish the co-prevalence of AAA and IA. In one arm of BAAS, we recruited patients presenting with AAA and screened them for IA. All participants underwent a detailed interview to collect demographic, radiographic, and clinical data and also had genetic counseling. Results: Of the 126 individuals with an AAA enrolled, 65% (82/126) completed the MRA. Difficulty with logistics of obtaining the research MRA with long distance travel to clinic was the principal reason for failure to obtain MRA. We identified 20.7% (17/82) with one or more IA, including 21 aneurysms found during systematic screening. IA ranged in size from 1.5-14 mm (height) x 1.4-7 mm (width) and varied in location. 9.5% (2/21) had a maximum diameter of 7 mm or more. One participant with a positive MRA underwent early coil embolization with the remainder undergoing continued clinical surveillance. Of the 15 individuals completing the genetic counseling screening, two underwent recommended clinical genetic testing, revealing one negative screen and one variant of unknown significance in the MYH11 gene. Conclusion: Consistent with our prior cost effectiveness models, these prospective data support the clinical utility of routine screening for IA in patients presenting with AAA.

Introduction: Aneurysm rupture is associated with high mortality and morbidity, including both intracranial aneurysms (IA) and abdominal aortic aneurysms (AAA). Despite potential preemptive treatment in those identified prior to IA or AAA rupture, the evidence for whom to screen remains limited. IA and AAA share both environmental and genetic risk, and prior cost-effectiveness models suggest the potential efficacy of screening in these high-risk individuals. We hypothesized that reciprocal screening in those presenting with IA for AAA would yield positive results. Methods: The BAAS study sought to establish the co-prevalence of IA and AAA. In this arm of BAAS, we recruited patients presenting with IA and screened them for AAA using abdominal ultrasound (aU/S) at two sites: Mayo Clinic and the University of Virginia (UVA). All participants underwent a detailed interview to collect demographic, radiographic, and clinical data. At UVA, participants also received genetic counseling. Results: At Mayo Clinic, we enrolled and screened 81 consecutive patients with aSAH (3 patients with known AAA were excluded) with 3 (3.7%) positive aU/S for AAA. At UVA, we recruited 195 consecutive patients presenting with ruptured or unruptured IA and completed screening aU/S in 178 (93%). Only one (0.6%) had an AAA. Conclusion: The lower positive screening at UVA (0.6%) which enrolled both ruptured and unruptured IA compared to the 3.7% positive results at Mayo suggests that future efforts to identify who with IA might benefit from AAA screening should focus on those with aneurysmal subarachnoid hemorrhage (aSAH).