Biomedical subjects

William L Young

Publications and source records attributed to William L Young.

At least 19 recordsLinked to original sources

PubMed2006

Comparison of doxycycline and minocycline in the inhibition of VEGF-induced smooth muscle cell migration.

Smooth muscle cell migration plays an important role during angiogenesis and vascular remodeling. In this study, we examined the effects of doxycycline and minocycline on vascular endothelial growth factor (VEGF)-induced human aortic smooth muscle cell (HASMCs) migration, and explored the mechanisms in which doxycycline or minocycline inhibit HASMC migration. We demonstrated that both doxycycline and minocycline attain consistent anti-angiogenic effects in the inhibition of HASMC migration via a different signal pathway (p<0.05). This effect is through attenuating VEGF-induced matrix metalloproteinase-9 (MMP-9) activity (p<0.05). Doxycycline could increase tissue inhibitors of metalloproteinases-1 (TIMP-1) expression while minocycline down-regulated PI3K/Akt phosphorylation in HASMC. Our study suggests that doxycycline has a stronger ability to inhibit MMP secretion in HASMC by up-regulating endogenous MMPs inhibitor TIMP-1, while minocycline implements anti-angiogenic effect through inhibiting HASMC migration by down-regulating PI3K/Akt pathway.

Base Sequence↗

PubMed2006

MMP-9 expression is associated with leukocytic but not endothelial markers in brain arteriovenous malformations.

Brain arteriovenous malformations (BAVM) have high matrix metalloproteinase-9 (MMP-9) expression, the source of which is unclear. We hypothesized MMP-9 production might be due to inflammation in BAVM. Compared to control brain tissues (n = 5), BAVM tissue (n = 139) had a higher expression (by ELISA) of myeloperoxidase (MPO) (193 +/- 189 vs. 6 +/- 3, ng/mg, P < .001), MMP-9 (28 +/- 32 vs. 0.7 +/- 0.6, ng/mg, P < .001), and IL-6 (102 +/- 218 vs. 0.1 +/- 0.1, pg/mg, P < .001), but not eNOS (114 +/- 87 vs. 65 +/- 9, pg/mg, P = .09). MMP-9 expression in BAVM highly correlated with myeloperoxidase (R2 = .76, P < .001), as well as with IL-6 (R2 = .32, P < .001). In contrast, MMP-9 in BAVM poorly correlated with the endothelial marker, eNOS (R2 = .03, P = .05), and CD31 (R2 = .004, P = .57). Compared to non-embolized patients (n = 46), patients with pre-operative embolization (n = 93) had higher levels of myeloperoxidase (236 +/- 205 vs. 106 +/- 108, ng/mg, P < .001) and MMP-9 (33 +/- 35 vs. 16 +/- 20, ng/mg, P < .001), however the correlation between MMP-9 and myeloperoxidase was equally strong for both groups (R2 = .69, n = 93, P < .001, for both). MMP-9 expression correlated with the lipocalin-MMP-9 complex, suggesting neutrophils as the MMP-9 source. MPO co-localized with majority of MMP-9 signal by immunohistochemistry. Our data suggest that inflammation is a prominent feature of BAVM lesional phenotype, and neutrophils appear to be a major source of MMP-9 in these lesions.

Adult↗

PubMed2006

Recombinant adeno-associated viral vector encoding human VEGF165 induces neomicrovessel formation in the adult mouse brain.

Delivery of therapeutic genes represents a fascinating possibility to accelerate injury-repairing process in tissues that are otherwise difficult to treat, such as cerebral ischemia. Current studies indicate that gene transfer-induced focal angiogenesis in the brain may provide an important therapeutic strategy. In the present study, we reported the efficacy of induction of angiogenesis with an adeno-associated virus (AAV) vector expressing the 165 amino acid isoform of vascular endothelial growth factor (VEGF165). We found AAV serotype 1 has more efficiency in transduction of the brain tissue than AAV serotype 2. Quantitative vessel counting showed that microvessels in AAV-VEGF transduced mice significantly increased from 1 week up to 12 weeks compared to the control groups (AAV-VEGF: 316+/-58 vs. AAV-lacZ: 180+/-34 and saline: 152+/-35 vessels/mm2, at 6 weeks, p<0.05). Proliferating cell nuclear antigen (PCNA) staining confirmed these microvessels were actively proliferating. Double-labeled fluorescence staining demonstrated that neurons, astrocytes, and endothelial cells could express VEGF following AAV-VEGF gene transfer. AAV vectors did not elicit a detectable inflammatory response, cell loss or neuronal damage. Our data underline the importance of angiogenesis in the brain tissue and indicate that VEGF gene transfer might present a valuable approach to treat brain ischemic disorders.

Animals↗

PubMed2006

Adeno-associated viral-vector-mediated hypoxia-inducible vascular endothelial growth factor gene expression attenuates ischemic brain injury after focal cerebral ischemia in mice.

BACKGROUND AND PURPOSE: Exogenous delivery of vascular endothelial growth factor gene (VEGF) may provide a useful approach to the treatment of brain ischemia. We investigated the use of a hypoxia-responsive element to control VEGF expression given for neuroprotection. METHODS: Three groups (n=36) of mice received AAVH9-VEGF, AAVH9-lacZ, or saline injection. Five days after gene transfer, the mice underwent 45 minutes of transient middle cerebral artery occlusion (tMCAO) followed by 1 to 7 days of reperfusion. Infarct volume was determined using cresyl violet staining; neuronal injury was examined using TUNEL, cleaved caspase-3, and fluoro-Jade B staining. RESULTS: Hypoxia-inducible factor-1 (HIF-1) was overexpressed after tMCAO in the ischemic hemisphere in the brain. Expression of lacZ, mediated by AAV-lacZ, was seen before and after tMCAO; however, AAVH9-lacZ-mediated lacZ expression was detected only after tMCAO. Infarct volume was smaller in the AAVH9-VEGF-transduced group compared with AAVH9-lacZ and saline groups (55% reduction, P<0.05) with reduced TUNEL (29+/-5% and 30+/-7% versus 12+/-3%, P<0.05), cleaved caspase-3 (20+/-3% and 21+/-5% versus 13+/-4%, P<0.05) and fluoro-Jade B (23+/-3% and 24+/-5% versus 12+/-5%, P<0.05) -positive neurons, respectively. CONCLUSIONS: Exogenous expression of VEGF through AAVH9-VEGF gene transfer 5 days before the onset of ischemia provides neuroprotection. Hypoxia-responsive element is a viable strategy of restricting VEGF expression to areas of ischemia to minimize adverse effects of therapy on adjacent normal parenchyma.

Animals↗

PubMed2006

Interleukin-6 upregulates expression of KDR and stimulates proliferation of human cerebrovascular smooth muscle cells.

Interleukin-6 (IL-6) may play multiple roles in angiogenesis and vascular remodeling. Our previous study showed that a promoter polymorphism (174G>C) in IL-6 is associated with brain arteriovenous malformation hemorrhage; tissue expression is related to genotype. In this study, we investigated the effects of IL-6 on human cerebral smooth muscle cells (HCSMCs) and smooth muscle cells isolated from brain arteriovenous malformation surgical specimens (AVM SMCs) and surgical controls (control HCSMCs--from structurally normal temporal lobe taken during surgical treatment of epilepsy patients). We found that IL-6 (1.1+/-0.27 versus 0.37+/-0.04 pg/mL, n=5, P<0.05) and endogenous vascular endothelial growth factor (VEGF) receptor II (kinase domain-containing receptor (KDR), 15+/-3 versus 1.5+/-3 pg/mL, n=5, P<0.05) were increased in brain AVM SMCs compared with control HCSMCs. Further research revealed that IL-6 could stimulate SMC proliferation, VEGF release, and KDR activation in control HCSMCs. It could also stimulate KDR phosphorylation in control HCSMCs, further confirming a unique role of IL-6 in the triggering of KDR. Interleukin-6 could increase matrix metalloproteinase-9 (MMP-9) secretion through activating KDR in control HCSMCs (P<0.05 versus control). Inhibiting IL-6-induced KDR could reduce MMP-9 activity at least 50% compared with the control group (P<0.05). Increased MMP-9 activity was accompanied by increased control HCSMC proliferation, and blocking MMP-9 activity significantly reduced IL-6-induced control HCSMC proliferation (P<0.05). Collectively, our results show that IL-6 could activate, amplify, and maintain the angiogenic cascade in HCSMCs. A novel role of IL-6 during HCSMC proliferation is upregulating KDR expression and phosphorylation. The results may contribute to the angiogenic phenotype of human brain vascular diseases, such as brain AVM.

Adult↗

PubMed2006

Adrenoceptor polymorphisms and the risk of cardiac injury and dysfunction after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Cardiac abnormalities occur commonly after subarachnoid hemorrhage (SAH) and may be caused by excessive release of catecholamines from the myocardial sympathetic nerves. We hypothesized that adrenoceptor polymorphisms resulting in greater catecholamine sensitivity would be associated with an increased risk of cardiac injury. METHODS: This was a prospective cohort study. The primary outcome variables were the serum level of cardiac troponin I (cTi, abnormal if >1.0 microg/L) and the left ventricular ejection fraction (LVEF, abnormal if <50%). Six adrenoceptor polymorphisms were genotyped: beta1AR Arg389Gly, beta1AR Ser49Gly, beta2AR Gly16Arg, beta2AR Gln27Glu, beta2AR Thr164Ile, and alpha2AR del322-325. The effect of each polymorphism on the risk of developing cardiac abnormalities was quantified using multivariable logistic regression. RESULTS: The study included 182 patients. The CC genotype (Arg/Arg) of beta1AR Arg389Gly (odds ratio [OR] 3.4, P=0.030) and the CC genotype (Gln/Gln) of beta2AR Gln27Glu (OR 3.1, P=0.032) were predictive of cTi release. The presence of the alpha2AR deletion was predictive of reduced LVEF (OR 4.2, P=0.023). The combination of the beta1AR 389 CC and the beta2AR 27 CC genotypes resulted in a marked increase in the odds of cTi release (OR 15.5, P=0.012). The combination of the beta1AR 389 CC and the alpha2AR deletion genotypes resulted in a marked increase in the odds of developing a reduced LVEF (OR 10.3, P=0.033). CONCLUSIONS: Genetic polymorphisms of the adrenoceptors are associated with an increased risk of cardiac abnormalities after SAH. These data support the hypothesis that cardiac dysfunction after SAH is a form of neurocardiogenic injury.

Catecholamines↗

PubMed2006

Interleukin-6 triggers human cerebral endothelial cells proliferation and migration: the role for KDR and MMP-9.

Interleukin-6 (IL-6) is involved in angiogenesis. However, the underlying mechanisms are unknown. Using human cerebral endothelial cell (HCEC), we report for the first time that IL-6 triggers HCEC proliferation and migration in a dose-dependent manner, specifically associated with enhancement of VEGF expression, up-regulated and phosphorylated VEGF receptor-2 (KDR), and stimulated MMP-9 secretion. We investigated the signal pathway of IL-6/IL-6R responsible for KDR's regulation. Pharmacological inhibitor of PI3K failed to inhibit IL-6-mediated VEGF overexpression, while blocking ERK1/2 with PD98059 could abolish IL-6-induced KDR overexpression. Further, neutralizing endogenous VEGF attenuated KDR expression and phosphorylation, suggesting that IL-6-induced KDR activation is independent of VEGF stimulation. MMP-9 inhibitor GM6001 significantly decreases HCEC proliferation and migration (p<0.05), indicating the crucial function of MMP-9 in promoting angiogenic changes in HCECs. We conclude that IL-6 triggers VEGF-induced angiogenic activity through increasing VEGF release, up-regulates KDR expression and phosphorylation through activating ERK1/2 signaling, and stimulates MMP-9 overexpression.

Cell Movement↗

PubMed2006

Dose-response effect of tetracyclines on cerebral matrix metalloproteinase-9 after vascular endothelial growth factor hyperstimulation.

Brain arteriovenous malformations (BAVMs) are a potentially life-threatening disorder. Matrix metalloproteinase (MMP)-9 activity was greatly increased in BAVM tissue specimens. Doxycycline was shown to decrease cerebral MMP-9 activities and angiogenesis induced by vascular endothelial growth factor (VEGF). In the present study, we determined the dose-response effects of doxycycline and minocycline on cerebral MMP-9 using our mouse model with VEGF focal hyperstimulation delivered with adenoviral vector (AdVEGF) in the brain. Mice were treated with doxycycline or minocycline, respectively, at 1, 5, 10, 30, 50, or 100 mg/kg/day through drinking water for 1 week. Our results have shown that MMP-9 messenger ribonucleic acid (mRNA) expression was inhibited by doxycycline starting at 10 mg/kg/day (P<0.02). Minocycline showed more potent inhibition on MMP-9 mRNA expression, starting at 1 (P<0.005) and further at more than 30 (P<0.001) mg/kg/day. At the enzymatic activity level, doxycycline started to suppress MMP-9 activity at 5 mg/kg/day (P<0.001), while minocycline had an effect at a lower dose, 1 mg/kg/day (P<0.02). The inhibition of cerebral MMP-9 mRNA and activity were highly correlated with drug levels in the brain tissue. We also assessed the potential relevant signaling pathway in vitro to elucidate the mechanisms underlying the MMP-9 inhibition by tetracyclines. In vitro, minocycline, but not doxycycline, inhibits MMP-9, at least in part, via the extracellular signaling-related kinase 1/2 (ERK1/2)-mediated pathway. This study provided the evidence that the tetracyclines inhibit stimulated cerebral MMP-9 at multiple levels and are effective at very low doses, offering great potential for therapeutic use.

Animals↗

PubMed2006

Interleukin-6 involvement in brain arteriovenous malformations.

We recently reported that the GG genotype of the interleukin-6 (IL-6)-174G>C promoter polymorphism is associated with clinical presentation of intracranial hemorrhage in brain arteriovenous malformation (AVM) patients. In this study, we investigated whether tissue IL-6 expression was associated with IL-6-174G>C genotype, and whether IL-6 was linked to downstream targets involved in angiogenesis and vascular instability. Our results showed that the highest IL-6 protein levels in brain AVM tissue were associated with IL-6-174GG genotype (GG: 57.7 +/- 20.2; GC: 35.6 +/- 26.6; CC: 13.9 +/- 10.2pg/mg; p = 0.001). IL-6 protein levels were increased in AVM tissue from patients with hemorrhagic presentation compared with patients without hemorrhage (55 +/- 22 vs 40 +/- 27pg/mg; p = 0.038). IL-6 messenger RNA expression strongly correlated with messenger RNA levels of IL-1beta, tumor necrosis factor-alpha, IL-8, matrix metalloproteinase-3 (MMP-3), MMP-9, and MMP-12. We further investigated the plausibility of IL-6 being an upstream cytokine responsible for initiating the angiogenic cascade by cell culture and animal experiments. IL-6 induced MMP-3 and MMP-9 expression and activity in mouse brain and increased proliferation and migration of cerebral endothelial cells. Together, our results suggest that the IL-6 genotype associated with intracranial hemorrhage modulates IL-6 expression in brain AVM tissue, which is consistent with the hypothesis that inflammatory processes induce angiogenic activity possibly contributory to brain AVM intracranial hemorrhage.

Adult↗

PubMed2006

Intracranial aneurysms: links among inflammation, hemodynamics and vascular remodeling.

Abnormal vascular remodeling mediated by inflammatory cells has been identified as a key pathologic component of various vascular diseases, including abdominal aortic aneurysms, brain arteriovenous malformations and atherosclerosis. Based on findings from observational studies that analysed human intracranial aneurysms and experimental studies that utilized animal models, an emerging concept suggests that a key component of the pathophysiology of intracranial aneurysms is sustained abnormal vascular remodeling coupled with inflammation. This concept may provide a new treatment strategy to utilize agents to inhibit inflammation or cytokines produced by inflammatory cells such as matrix metalloproteinases. Such an approach would aim to stabilize these vascular lesions and prevent future expansion or rupture.

Animals↗

PubMed2006

Apolipoprotein E epsilon 2 is associated with new hemorrhage risk in brain arteriovenous malformations.

OBJECTIVE: Patients with brain arteriovenous malformation (AVM) are at life-threatening risk of intracranial hemorrhage (ICH). Identification of genetic variants associated with increased new ICH risk would facilitate risk stratification and guide therapeutic intervention. METHODS: Brain AVM patients evaluated at University of California, San Francisco or Kaiser Permanente Northern California were followed longitudinally. Primary outcome was new ICH after diagnosis; censoring events were any AVM treatment or last follow-up examination. The association of ApoE epsilon2 and epsilon4 genotype with new ICH was evaluated by Kaplan-Meier survival analysis and further characterized via a Cox proportional hazards model. RESULTS: We genotyped 284 brain AVM patients (50% women; 57% Caucasian; median follow-up time, 0.3 yr) including 18 patients with a history of new ICH). ApoE epsilon2, but not ApoE epsilon4 genotype, was associated with new ICH (P = 0.0052). ApoE epsilon2 carriers had fivefold increased risk of new ICH (hazard ratio, 5.09; 95% confidence interval, 1.46-17.7; P = 0.010; Cox proportional hazards model adjusting for race/ethnicity and clinical presentation). Subset analysis in the largest homogenous ethnic subcohort (Caucasians) confirmed the increased risk of new ICH in ApoE epsilon2 carriers (hazard ratio, 8.71; 95% confidence interval, 1.4-53.9; P = 0.020; multivariate model adjusting for clinical presentation). CONCLUSION: ApoE genotype may influence the risk of ICH in the natural course of brain AVM. The identification of genetic predictors of ICH risk may facilitate estimation of AVM natural history risk and individualize clinical decision-making and therapeutic recommendations.

Adult↗

PubMed2006

Estimating the hemodynamic impact of interventional treatments of aneurysms: numerical simulation with experimental validation: technical case report.

OBJECTIVE: The goal of this study was to use phase-contrast magnetic resonance imaging and computational fluid dynamics to estimate the hemodynamic outcome that might result from different interventional options for treating a patient with a giant fusiform aneurysm. METHODS: We followed a group of patients with giant intracranial aneurysms who have no clear surgical options. One patient demonstrated dramatic aneurysm growth and was selected for further analysis. The aneurysm geometry and input and output flow conditions were measured with contrast-enhanced magnetic resonance angiography and phase-contrast magnetic resonance imaging. The data was imported into a computational fluid dynamics program and the velocity fields and wall shear stress distributions were calculated for the presenting physiological condition and for cases in which the opposing vertebral arteries were either occluded or opened. These models were validated with in vitro flow experiments using a geometrically exact silicone flow phantom. RESULTS: Simulation indicated that altering the flow ratio in the two vertebrals would deflect the main blood jet into the aneurysm belly, and that this would likely reduce the extent of the region of low wall shear stress in the growth zone. CONCLUSIONS: Computational fluid dynamics flow simulations in a complex patient-specific aneurysm geometry were validated by in vivo and in vitro phase-contrast magnetic resonance imaging, and were shown to be useful in modeling the likely hemodynamic impact of interventional treatment of the aneurysm.

Aged↗

PubMed2006

Expression of hypoxia-inducible factor-1 and vascular endothelial growth factor in response to venous hypertension.

OBJECTIVE: Experimentally, a fistula created surgically between the carotid artery and jugular vein, together with occlusion of venous sinuses, generate venous hypertension, which can induce dural arteriovenous fistula formation intracranially in rats. Our aim was to study the effect of nonischemic venous hypertension on the elaboration of the angiogenic signal, hypoxia-inducible factor-1 (HIF-1), and its downstream signal, vascular endothelial growth factor (VEGF). METHODS: Sixty rats were exposed to venous hypertension for periods ranging from 4 hours to 3 weeks. Western blot analysis, transbinding assays, enzyme-linked immunosorbent assays, and immunohistochemistry quantified HIF-1 and VEGF expression in brain. Forty-eight control rats underwent similar surgical procedures without creating venous hypertension. Cerebral blood flow was measured at baseline, after surgery, and before sacrifice. RESULTS: Venous hypertension did not impair cerebral blood flow. Relative to controls, HIF-1 expression increased fivefold in response to venous hypertension (P < 0.005), with peak expression 1 day later localized to endothelial cells in venules next to the sagittal sinus. VEGF expression also increased threefold in response to venous hypertension (P < 0.05), with peak expression 7 days later localized to parasagittal astrocytes. HIF-1 and VEGF were minimally expressed in rat normal venous pressures. CONCLUSION: In this model, venous hypertension stimulates angiogenesis by a mechanism other than ischemia. HIF-1 expression may result from dilation of parasagittal veins and endothelial deformation. HIF-1 and VEGF seem to be molecular agents that convert venous hypertension into intracellular signals and angiogenesis activity.

Animals↗

PubMed2006

Cardiovascular predictors of in-patient mortality after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Whether cardiac dysfunction contributes to morbidity and mortality after subarachnoid hemorrhage (SAH) remains controversial. The objective of this study was to test the hypothesis that cardiovascular abnormalities are independently related to in-patient mortality after SAH. METHODS: This was a prospective cohort study of patients with aneurysmal SAH. Heart rate and blood pressure were measured, a blood sample was obtained, and echocardiography was performed on three study days, starting as soon after admission as possible. The cardiovascular predictor variables were heart rate, systolic blood pressure (SBP), cardiac troponin I (cTi) level, B-type natriuretic peptide (BNP) level, and left ventricular ejection fraction. The primary outcome measure was in-patient mortality. The association between each predictor variable and mortality was quantified by multivariate logistic regression, including relevant covariates and reporting odds ratios (OR) and 95% confidence intervals (CI). RESULTS: The study included 300 patients. An initial BNP level greater than 600 pg/mL was markedly associated with death (OR 37.7, p < 0.001). On the third study day (9.1 +/- 4.1 days after SAH symptom onset), a cTi level greater than 0.3 mg/L (OR 7.6, p = 0.002), a heart rate of 100 bpm or greater (OR 4.9, p = 0.009), and a SBP less than 130 mmHg (OR 6.7, p = 0.007) were significantly associated with death. CONCLUSIONS: Cardiovascular abnormalities are independent predictors of in-patient mortality after SAH. Though these effects may be explained by a reduction in cerebral perfusion pressure or other mechanisms, further research is required to determine whether or not they are causal in nature.

Adult↗

PubMed2006

Superior outcomes in children compared with adults after microsurgical resection of brain arteriovenous malformations.

OBJECT: Young age is considered an important factor in determining outcomes after microsurgical resection of arteriovenous malformations (AVMs), but better results in children have not been adequately explained. A consecutive series of pediatric and adult patients was reviewed to determine whether differences in outcomes between these two groups were due to differences in AVM anatomy, rupture rates, neurological condition at presentation, treatment techniques, or other causes. METHODS: As assessed using the modified Rankin Scale (mRS), patient characteristics, clinical presentation, AVM anatomy, treatment techniques, and outcomes were compared between age groups. Thirty-two pediatric and 192 adult patients underwent microsurgical AVM resection during a 6.4-year period; complete resection was achieved in 97% of the children and 98% of adults. Superior outcomes were observed in children, who had better final mRS scores (p = 0.003) and more favorable changes in these scores (the condition of 94% of children improved or remained unchanged, compared with 70% of adults; p = 0.001). The change in the mean mRS scores was 1.31 for children and 0.14 for adults (p = 0.001). There were no significant clinical, anatomical, or therapeutic differences between children and adults. CONCLUSIONS: This analysis confirms the observation that children fare better than adults after microsurgical AVM resection. This discrepancy cannot be explained by differences in AVM anatomy, lesion rupture rates, presenting neurological condition, or treatment techniques, leading the authors to infer that neural plasticity may augment surgical tolerance and recovery in children. These findings bolster the choice of aggressive microsurgical management of AVMs and recalibration of surgical risk assessment in children.

Adult↗

PubMed2005

Tumor necrosis factor-alpha-238G>A promoter polymorphism is associated with increased risk of new hemorrhage in the natural course of patients with brain arteriovenous malformations.

BACKGROUND AND PURPOSE: Identification of single-nucleotide polymorphisms (SNPs) associated with increased risk of new intracranial hemorrhage (ICH) after brain arteriovenous malformation (BAVM) diagnosis would facilitate risk stratification and identify potential targets for therapeutic intervention. METHODS: Patients with BAVM were longitudinally followed. Primary outcome was new ICH after diagnosis; censoring events were last follow-up or any BAVM treatment. We genotyped 4 promoter SNPs in 2 inflammatory cytokine genes: interleukin-6 (IL-6-174G>C; IL-6-572G>C) and tumor necrosis factor-alpha (TNF-alpha-238G>A; TNF-alpha-308G>A). Association of genotype with risk of new ICH was screened using chi2; SNPs associated with new ICH were further characterized using Cox proportional hazards. RESULTS: We genotyped 280 patients (50% female; 59% white, mean+/-SD age at diagnosis 37+/-17 years; 40% presenting with ICH). TNF-alpha-238G>A was associated with increased risk of new ICH after diagnosis (chi2; P=0.003). After adjusting for age, race/ethnicity, and clinical presentation, the risk of new ICH was increased for patients with TNF-alpha-238 AG genotype (hazard ratio, 4.01; P=0.015). No other SNP was found to be associated with new ICH. CONCLUSIONS: A TNF-alpha SNP was associated with increased risk of new ICH in the natural course of BAVMs. The role of inflammatory cytokines in the pathogenesis of BAVM hemorrhage merits further study.

Adult↗

PubMed2005

Polymorphisms in transforming growth factor-beta-related genes ALK1 and ENG are associated with sporadic brain arteriovenous malformations.

BACKGROUND AND PURPOSE: Mutations in endoglin (ENG) and activin-like kinase (ALK1) cause hereditary hemorrhagic telangiectasias, disorders characterized by pulmonary and brain arteriovenous malformations (BAVMs). We investigated whether polymorphisms in these genes are also associated with sporadic BAVM. METHODS: A total of 177 sporadic BAVM patients and 129 controls (all subjects white) were genotyped for 2 variants in ALK1 and 7 variants in ENG. RESULTS: The ALK1 IVS3-35A>G polymorphism was associated with BAVM: (AnyA [AA+AG] genotype: odds ratio, 2.47; 95% CI, 1.38 to 4.44; P=0.002). Two ENG polymorphisms, ENG -1742A>G and ENG 207G>A, showed a trend toward association with BAVM that did not reach statistical significance. CONCLUSIONS: A common polymorphism in ALK1 is associated with sporadic BAVM, suggesting that genetic variation in genes mutated in familial BAVM syndromes may play a role in sporadic BAVMs.

Activin Receptors, Type I↗

PubMed2005

Long-term hemorrhage risk in children versus adults with brain arteriovenous malformations.

BACKGROUND AND PURPOSE: Children with brain arteriovenous malformations (BAVMs) are said to be at higher risk for intracranial hemorrhage (ICH) than adults. Although this notion affects treatment decisions, the evidence to support this claim is limited. METHODS: To compare the risk of ICH in children versus adults with BAVM, we studied all cases of BAVM evaluated at the University of California, San Francisco (January 2000 to December 2004; n=400) and Kaiser Permanente Northern California (January 1993 to December 2004; n=819). In Kaplan-Meier survival analyses, the index date was the date of initial BAVM detection; cases were censored at time of subsequent ICH (the primary outcome, defined as ICH after initial presentation), first BAVM treatment, or loss to follow-up. Cox proportional hazards models included childhood presentation (<20 years old), hemorrhagic presentation, and other potential confounders. RESULTS: Our study included 996 person-years of follow-up in the childhood presentation group and 3260 in the adult presentation group. In the unadjusted survival analysis, the subsequent ICH rates were similar for the 2 age groups (average annual rate 2.0% for children; 2.2% for adults; P=0.82 by log-rank test). BAVMs in childhood were more likely to present initially with ICH (P<0.001). After adjustment for presentation in the multivariate model, subsequent ICH rates were lower in children (hazard ratio, 0.10; 95% CI, 0.01 to 0.86; P=0.036). CONCLUSIONS: Children with BAVMs do not appear to be at increased risk for a subsequent ICH compared with adults, and may even be relatively protected. Confounding by hemorrhagic presentation should be considered in any study comparing BAVM hemorrhage rates in children versus adults.

Adolescent↗