Sporadic Brain Arteriovenous Malformations Research Articles

Abstract 52: Prevalence Of Somatic Activating Kras Mutations In Pediatric And Adult Sporadic Brain Arteriovenous Malformations

Introduction: Sporadic brain arteriovenous malformations (bAVMs) are a potentially treatable cause of stroke disproportionately affecting young people. Non-inherited somatic activating mutations in KRAS have been reported in ~50% of bAVM specimens primarily from adults. We hypothesized that KRAS mutations would be associated with an earlier age at diagnosis, larger bAVM size, or earlier time to hemorrhage. Methods: Sporadic bAVM tissue and clinical data were collected from patients seen at our institution. Genotyping was performed by digital droplet polymerase chain reaction to detect KRAS mutations (p.G12D, p.G12V or p.Q61H) in three batches and coded as presence/absence of any KRAS mutation (primary predictor). Age at diagnosis was dichotomized into adults (18 years) or children (<18 years). Regression analyses adjusting for genotyping batch were performed to test association of KRAS mutations between children and adults (logistic), with bAVM size (linear), or with time from diagnosis to hemorrhage (survival), censoring at treatment or last follow-up. Results: We analyzed data from 221 patients: median age at bAVM diagnosis was 20 years; 44% were diagnosed as children; 53% were female; and 56% were ruptured on presentation. Median bAVM diameter was 2.1 cm (IQR: 1.4 - 3.0). KRAS mutations were detected in 53% of samples. Childhood bAVMs were significantly more likely to harbor KRAS mutations than those diagnosed in adulthood (OR=2.20, 95% CI: 1.24 - 3.91, p=0.007). KRAS -mutant bAVMs tended to be larger than KRAS -wildtype bAVMs, but this did not reach significance (+0.29 cm, 95% CI: -0.03 - 0.62, p=0.08). No association was observed for time to hemorrhage (HR=1.31, 95% CI: 0.91 - 1.88, p=0.15). Conclusions: Somatic activating KRAS mutations are more prevalent in bAVMs diagnosed in childhood than adulthood. Further work is required to elucidate mechanisms of mutagenesis and bAVM progression, which may differ in children and adults.

Associations of Reported Genetic Risk Loci with Sporadic Brain Arteriovenous Malformations: Meta-analysis.

An arteriovenous malformation (AVM) is an abnormal nidus of blood vessels that is characterized by a direct connection between arteries and veins without intervening in the capillary network. The exact underlying cause of sporadic AVMs is unknown, but many studies have reported genetic associations between genes that contribute to angiogenesis, vasculogenesis, and inflammation. Eleven studies retrieved from Medline Complete, PubMed, and Google Scholar up to February 2022 were included. Heterogeneity was assessed using I2 and Q-tests. Publication bias was also assessed for the shortlisted CDKN2B-AS1 rs1333040 (T > C), ACVRL1 rs2071219 (A > G), and rs11169953 (C > T) polymorphisms. The rs1333040 polymorphism showed a lower association with sporadic brain AVM for T versus C in an allelic model (OR = 0.59, 95% confidence interval [CI] = 0.41-0.84). In the recessive model, rs2071219 for AA + AG vs. GG was OR = 0.62, 95% CI = 0.43-0.9. In the recessive model, rs11169953 CC + CT vs. TT was OR = 0.56, 95% CI = 0.33-0.95. In summary, the results of this study support the association between CDKN2B-AS1 and ACVRL1 polymorphisms and sporadic brain arteriovenous malformations. This study summarized the existing information and showed the need for more replication studies on the genetic basis of sporadic AVM. In the future, more genome-wide studies should be conducted to validate and fill existing gaps in knowledge about the mechanisms of sporadic AVM development.

Investigating the role of imprinted genes in pediatric sporadic brain arteriovenous malformations.

Investigating the role of imprinted genes in pediatric sporadic brain arteriovenous malformations.

Maternal and Fetal Outcomes in Women with Brain Arteriovenous Malformation Rupture during Pregnancy

Background: Sporadic brain arteriovenous malformations (BAVM) are a major cause of hemorrhagic stroke in younger persons. Prior studies have reported contradictory results regarding the risk of hemorrhage during pregnancy, and there are no standard guidelines for the management of pregnant women who present with BAVM rupture. The purpose of this study is to describe maternal and fetal outcomes and treatment strategies in patients with BAVM hemorrhage during pregnancy. Methods: We performed a retrospective review of the University of California, San Francisco Brain AVM Project database for female patients who were pregnant at the time of BAVM hemorrhage between 2000 and 2017. Clinical and angiographic characteristics at presentation, BAVM treatment, and maternal outcomes using modified Rankin scale (mRS) score at presentation and 2-year follow-up were recorded. Fetal outcomes were abstracted from medical records and maternal reports. Results: Sixteen patients presented with BAVM hemorrhage during pregnancy, 81% (n = 13) of whom were in their second or third trimester. Three patients (19%) who were in their first trimester terminated or miscarried pregnancy prior to BAVM intervention. Of the remaining 13 patients, 77% (n = 10) received emergent BAVM treatment at time of hemorrhage prior to delivery, and 85% of patients achieved BAVM obliteration and good maternal outcomes (mRS 0–2) at 2-year follow-up. All patients had uncomplicated deliveries (69% cesarean and 23% vaginal) with no reports of postnatal cognitive or developmental delays in infants at 2-year follow-up. Conclusions: Our study shows good long-term maternal and fetal outcomes in ruptured BAVM patients presenting during pregnancy, the majority who received BAVM interventional treatment prior to delivery.

Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling.

We previously identified somatic activating mutations in the KRAS (Kirsten rat sarcoma viral oncogene homologue) gene in the endothelium of the majority of human sporadic brain arteriovenous malformations; a disorder characterized by direct connections between arteries and veins. However, whether this genetic abnormality alone is sufficient for lesion formation, as well as how active KRAS signaling contributes to arteriovenous malformations, remains unknown. To establish the first in vivo models of somatic KRAS gain of function in the endothelium in both mice and zebrafish to directly observe the phenotypic consequences of constitutive KRAS activity at a cellular level in vivo, and to test potential therapeutic interventions for arteriovenous malformations. Using both postnatal and adult mice, as well as embryonic zebrafish, we demonstrate that endothelial-specific gain of function mutations in Kras (G12D or G12V) are sufficient to induce brain arteriovenous malformations. Active KRAS signaling leads to altered endothelial cell morphogenesis and increased cell size, ectopic sprouting, expanded vessel lumen diameter, and direct connections between arteries and veins. Furthermore, we show that these lesions are not associated with altered endothelial growth dynamics or a lack of proper arteriovenous identity but instead seem to feature exuberant angiogenic signaling. Finally, we demonstrate that KRAS-dependent arteriovenous malformations in zebrafish are refractory to inhibition of the downstream effector PI3K but instead require active MEK (mitogen-activated protein kinase kinase 1) signaling. We demonstrate that active KRAS expression in the endothelium is sufficient for brain arteriovenous malformations, even in the setting of uninjured adult vasculature. Furthermore, the finding that KRAS-dependent lesions are reversible in zebrafish suggests that MEK inhibition may represent a promising therapeutic treatment for arteriovenous malformation patients. Graphical Abstract: A graphical abstract is available for this article.

Pathogenesis of non-hereditary brain arteriovenous malformation and therapeutic implications.

Brain arteriovenous malformations have a high risk of intracranial hemorrhage, which is a substantial cause of morbidity and mortality in patients with brain arteriovenous malformations. Although a variety of genetic factors leading to hereditary brain arteriovenous malformations have been extensively investigated, their pathogenesis is still not well elucidated, especially in sporadic brain arteriovenous malformations. The authors have reviewed the updated data of not only the genetic aspects of sporadic brain arteriovenous malformations, but also the architecture of microvasculature, the roles of the angiogenic factors, and the signaling pathways. This knowledge may allow us to infer the pathogenesis of sporadic brain arteriovenous malformations and develop pre-emptive treatments for them.

Notch signaling pathway is a potential therapeutic target for extracranial vascular malformations

Notch expression has been shown to be aberrant in brain arteriovenous malformations (AVM), and targeting Notch has been suggested as an approach to their treatment. It is unclear whether extracranial vascular malformations follow the same patterning and Notch pathway defects. In this study, we examined human extracranial venous (VM) (n = 3), lymphatic (LM) (n = 10), and AV (n = 6) malformations, as well as sporadic brain AVMs (n = 3). In addition to showing that extracranial AVMs demonstrate interrupted elastin and that AVMs and LMs demonstrate abnormal α-smooth muscle actin just as brain AVMS do, our results demonstrate that NOTCH1, 2, 3 and 4 proteins are overexpressed to varying degrees in both the endothelial and mural lining of the malformed vessels in all types of malformations. We further show that two gamma secretase inhibitors (GSIs), DAPT (GSI-IX) and RO4929097, cause dose-dependent inhibition of Notch target gene expression (Hey1) and rate of migration of monolayer cultures of lymphatic endothelial cells (hLECs) and blood endothelial cells (HUVEC). GSIs also inhibit HUVEC network formation. hLECs are more sensitive to GSIs compared to HUVEC. GSIs have been found to be safe in clinical trials in patients with Alzheimer’s disease or cancer. Our results provide further rationale to support testing of Notch inhibitors in patients with extracranial vascular malformations.

Antithrombotic therapy and intracranial bleeding in subjects with sporadic brain arteriovenous malformations: preliminary results from a retrospective study

Antithrombotic therapy and intracranial bleeding in subjects with sporadic brain arteriovenous malformations: preliminary results from a retrospective study

Antithrombotic therapy and intracranial bleeding in subjects with sporadic brain arteriovenous malformations: preliminary results from a retrospective study.

Whether antithrombotic treatment is safe and/or affects the risk of intracranial bleeding in subjects with sporadic brain arteriovenous malformations (AVMs) is unknown. We conducted a retrospective analysis on the use of antithrombotics among patients affected by brain AVMs in follow-up at our institution. Attention was paid to the type of antithrombotic drug (either antiplatelets or anticoagulants), current or past use, dosage, and duration of treatment. Several clinical and angioarchitectural features of brain AVMs were also taken into consideration. The association between the use of antithrombotics and haemorrhagic onset was analyzed. A total of 77 patients were included in this study. Among them, ten patients were taking antithrombotic drugs at the time of AVM diagnosis. The rate of haemorrhagic onset was not significantly different between subjects who were and were not taking antithrombotic drugs (40 vs 55.2%, p = ns). Among the many clinical and angioarchitectural features analyzed, the only parameter that showed a statistically significant association with haemorrhagic onset was the size of the nidus. Patients who took antithrombotic treatments after being diagnosed with a brain AVM did not show an increased rate of intracranial haemorrhage over time considering a mean follow-up 4years. In our study, antithrombotic treatment was not associated with increased intracranial bleeding among subjects with brain AVMs. In the presence of a strong clinical indication, antiplatelet and anticoagulant medications should not be denied a priori to patients with brain AVMs. Studies on larger populations are necessary to confirm these data.

Association of common candidate variants with vascular malformations and intracranial hemorrhage in hereditary hemorrhagic telangiectasia.

BackgroundHereditary hemorrhagic telangiectasia (HHT) is caused by mutations in TGFβ/BMP9 pathway genes and characterized by vascular malformations (VM) including arteriovenous malformations (AVM) in lung, liver, and brain, which lead to severe complications including intracranial hemorrhage (ICH) from brain VM. The clinical heterogeneity of HHT suggests a role for genetic modifier effects. Common variants in loci that modify phenotype severity in Tgfb knockout mice were previously reported as associated with lung AVM in HHT. Common variants in candidate genes were reported as associated with sporadic brain AVM and/or ICH. We investigated whether these variants are associated with HHT organ VM or with ICH from brain VM in 752 Caucasian HHT patients enrolled by the Brian Vascular Malformation Consortium.MethodsWe genotyped 11 candidate variants: four variants reported as associated with lung AVM in HHT (PTPN14 rs2936018, USH2A rs700024, ADAM17 rs12474540, rs10495565), and seven variants reported as associated with sporadic BAVM or ICH (APOE ε2, ANGPTL4 rs11672433, EPHB4 rs314308, IL6 rs1800795, IL1B rs1143627, ITGB8 rs10486391, TNFA rs361525). Association of genotype with any VM, lung AVM, liver VM, brain VM or brain VM ICH was evaluated by multivariate logistic regression adjusted for age, gender, and family clustering.ResultsNone of the 11 variants was significantly associated with any phenotype. There was a trend toward association of USH2A rs700024 with ICH (OR = 2.77, 95% CI = 1.13–6.80, p = .026).ConclusionWe did not replicate previously reported associations with HHT lung AVM and variants in Tgfb modifier loci. We also did not find significant associations between variants reported in sporadic brain AVM and VM or ICH in HHT.

Corrigendum to parental age and the occurrence of sporadic brain arteriovenous malformations.

Corrigendum to parental age and the occurrence of sporadic brain arteriovenous malformations.

Abstract WP426: Does Intracerebral Hemorrhage in Brain Arteriovenous Malformation Share Genetic Risk Factors With Primary Intracerebral Hemorrhage?

Introduction: Sporadic brain arteriovenous malformations (BAVMs) are rare vascular lesions that are a major cause of intracerebral hemorrhage (ICH) in younger persons. Genetic risk factors for ICH in BAVM have not been firmly established. Late-onset primary ICH is more common, with several candidate loci reported. It is not known whether genetic variants associated with primary ICH are also associated with BAVM ICH. Methods: We performed a case-control study including 138 Caucasian cases with BAVM ICH and 504 healthy Caucasian controls. We tested 8 candidate variants reported for primary ICH in or near 7 genes ( ACE , APOE , COL4A2 , MTHFR , PMF1 , SLC25A44 , and TRHDE) . Genotypes were extracted from existing Affymetrix genome-wide array data or from PCR-based assays for 3 variants. Logistic regression was used to determine whether candidate variants (or, when unavailable, proxy variants in high linkage disequilibrium) were associated with BAVM ICH, assuming an additive genetic model and adjusting for age and sex. We considered variants statistically significant if P<0.05 and in the same direction of association (risk allele) as reported for primary ICH. Results: No statistically significant associations were observed between BAVM ICH and genetic variants implicated in primary ICH. The strongest finding was for rs9521733 in COL4A2 (OR=1.26, P=0.13). Further evaluation of the COL4A2 +/- 5kb locus revealed nine variants associated with BAVM ICH; the strongest association was with rs9521692 (OR=0.49, P=0.001). Conclusions: Specific candidate variants implicated in primary ICH were not significantly associated with BAVM ICH, suggesting that genetic risk factors may differ between primary and BAVM ICH. The COL4A2 locus may contain additional variants associated with BAVM ICH but will require larger studies to validate findings.

Abstract 50: Evaluation of Candidate Polymorphisms for Association With Brain Arteriovenous Malformations and Intracranial Hemorrhage in Hereditary Hemorrhagic Telangiectasia

Introduction: Brain arteriovenous malformations (AVM) are an important cause of intracranial hemorrhage (ICH) in young adults. Most are sporadic, but also occur in inherited diseases such as hereditary hemorrhagic telangiectasia (HHT). ICH presentation of brain AVM in both sporadic and HHT cases is a marker of high ICH risk. In order to investigate whether the same genetic modifiers influence sporadic and HHT brain AVM, we evaluated candidate genetic polymorphisms reported as associated with sporadic brain AVM, with ICH presentation or ICH during clinical course, in HHT patients. Methods: We genotyped 8 polymorphisms ( APOE E2/3/4 [rs7412, rs429358], ANGPTL rs116724, EPHB4 rs314308, IL6 -174G>C [rs1800795], IL1B -31T>C [rs1143627], ITGB8 rs10486391, TNF -238G>A[rs361525]) in 753 Caucasian HHT patients enrolled by the Brian Vascular Malformation Consortium (BVMC). Genotypes were collapsed into risk allele carriers vs. other for analysis, as published for sporadic AVM. APOE E2/3/4 haplotypes were assigned based on genotypes of the 2 APOE polymorphisms. Association of genotype with phenotype was evaluated by multivariable logistic regression adjusted for age, gender and accounting for family clustering. We used a nominal significance threshold of p=0.05, requiring the same direction of effect as in sporadic brain AVM (odds ratio for risk genotype [OR]>1). Results: Among 753 HHT patients, 155 (21%) had brain AVM, of whom 26 (17%) presented with ICH. Two additional brain AVM patients had ICH during follow-up. None of the 7 variants (6 single nucleotide polymorphisms and APOE haplotype) were significantly associated with brain AVM (OR=0.6-1.3), with ICH presentation of brain AVM (OR=0.4-1.9), or with any brain AVM ICH in HHT patients (OR=0.5-2.1). Conclusions: Common genetic variants previously reported to be associated with sporadic brain AVM were not associated with brain AVM nor with ICH in the BVMC HHT cohort, suggesting different genetic modifiers may influence sporadic and HHT brain AVM. However, the number of ICH cases in the cohort is small, so the confidence intervals are wide and we cannot rule out clinically important associations. The BVMC is enrolling additional HHT patients to expand the cohort and increase power for association analyses.

Genome-wide association study of sporadic brain arteriovenous malformations

BackgroundThe pathogenesis of sporadic brain arteriovenous malformations (BAVMs) remains unknown, but studies suggest a genetic component. We estimated the heritability of sporadic BAVM and performed a genome-wide association study (GWAS)...

Susceptibility loci for sporadic brain arteriovenous malformation; a replication study and meta-analysis

BackgroundCase–control studies have reported multiple genetic loci to be associated with sporadic brain arteriovenous malformations (AVMs) but most of these have not been replicated in independent populations. The aim of...

The ACVRL1 c.314-35A>G polymorphism is associated with organ vascular malformations in hereditary hemorrhagic telangiectasia patients with ENG mutations, but not in patients with ACVRL1 mutations.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by vascular malformations (VMs) and caused by mutations in TGFβ/BMP9 pathway genes, most commonly ENG or ACVRL1. Patients with HHT have diverse manifestations related to skin and mucosal telangiectases and organ VMs, including arteriovenous malformations (AVM). The clinical heterogeneity of HHT suggests a role for genetic modifiers. We hypothesized that the ACVRL1 c.314-35A>G and ENG c.207G>A polymorphisms, previously associated with sporadic brain AVM, are associated with organ VM in HHT. We genotyped these variants in 716 patients with HHT and evaluated association of genotype with presence of any organ VM, and specifically with brain VM, liver VM and pulmonary AVM, by multivariate logistic regression analyses stratified by HHT mutation. Among all patients with HHT, neither polymorphism was significantly associated with presence of any organ VM; ACVRL1 c.314-35A>G showed a trend toward association with pulmonary AVM (OR = 1.48, P = 0.062). ACVRL1 c.314-35A>G was significantly associated with any VM among patients with HHT with ENG (OR = 2.66, P = 0.022), but not ACVRL1 (OR = 0.79, P = 0.52) mutations. ACVRL1 c.314-35A>G was also associated with pulmonary AVM and liver VM among ENG mutation heterozygotes. There were no significant associations between ENG c.207G>A and any VM phenotype. These results suggest that common polymorphisms in HHT genes other than the mutated gene modulate phenotype severity of HHT disease, specifically presence of organ VM.

Association between Venous Angioarchitectural Features of Sporadic Brain Arteriovenous Malformations and Intracranial Hemorrhage.

Intracranial hemorrhage is the most serious outcome for brain arteriovenous malformations. This study examines associations between venous characteristics of these lesions and intracranial hemorrhage. Statistical analysis was performed on a prospectively maintained data base of brain AVMs evaluated at an academic medical center. DSA, CT, and MR imaging studies were evaluated to classify lesion side, drainage pattern, venous stenosis, number of draining veins, venous ectasia, and venous reflux. Logistic regression analyses were performed to identify the association of these angiographic features with intracranial hemorrhage of any age at initial presentation. Exclusively deep drainage (OR, 3.42; 95% CI, 1.87-6.26; P < .001) and a single draining vein (OR, 1.98; 95% CI, 1.26-3.08; P = .002) were associated with hemorrhage, whereas venous ectasia (OR, 0.52; 95% CI, 0.34-0.78; P = .002) was inversely associated with hemorrhage. Analysis of venous characteristics of brain AVMs may help determine their prognosis and thereby identify lesions most appropriate for treatment.

Evaluation of genetic risk loci for intracranial aneurysms in sporadic arteriovenous malformations of the brain

BackgroundIn genome-wide association studies (GWAS) five putative risk loci are associated with intracranial aneurysm. As brain arteriovenous malformations (AVM) and intracranial aneurysms are both intracranial vascular diseases and AVMs often...

Hemorrhage rates and risk factors in the natural history course of brain arteriovenous malformations.

Brain arteriovenous malformations (AVMs) are abnormal connections of arteries and veins, resulting in arteriovenous shunting of blood. Primary medical therapy is lacking; treatment options include surgery, radiosurgery, and embolization, often in combination. Judicious selection of AVM patients for treatment requires balancing risk of treatment complications against the risk of hemorrhage in the natural history course. This review focuses on the epidemiology, hemorrhage risk, and factors influencing risk of hemorrhage in the untreated natural course associated with sporadic brain AVM.

Association between Polymorphisms rs1333040 and rs7865618 of Chromosome 9p21 and Sporadic Brain Arteriovenous Malformations

Background: The chromosomal locus 9p21 is a novel genetic marker for a variety of cardiovascular and cerebrovascular diseases. In a recent study, we have demonstrated an association between the single nucleotide polymorphism (SNP) rs1333040C>T on chromosome 9p21 and sporadic brain arteriovenous malformations (BAVMs). Here, we extended our analysis to an additional SNP on chromosome 9p21 (rs7865618A>G) and increased our sample size including BAVMs from two different Italian neurosurgical centers. Methods: We studied 206 patients with sporadic BAVMs and 171 unaffected controls. Genomic DNA was isolated from peripheral blood and the rs1333040C>T and rs7865618A>G polymorphisms were assessed by PCR-RFLP using the BsmI and MspI restriction endonucleases, respectively. For each SNP, we performed dominant, recessive, and additive genetic models. Results: The distribution of the three possible genotypes of rs1333040 (TT, TC and CC) was statistically different between cases and controls (p = 0.0008). The TT genotype was significantly associated with BAVMs both in the dominant (p = 0.013) and recessive (p = 0.012) models. The T allele was significantly associated with BAVMs in the additive model (p = 0.002). Also the distribution of the three possible genotypes of rs7865618 (GG, AG and AA) was statistically different between cases and controls (p = 0.005), and the GG genotype and G allele were significantly associated with BAVMs in the dominant (p = 0.032), recessive (p = 0.007), and additive models (p = 0.009). We also detected a significant association between BAVMs with large nidus size and the GG genotype and G allele of rs7865618 and the TT genotype of rs1333040. A deep venous drainage was instead associated with the TT genotype of the rs1333040 and the GG genotype of the rs7865618. The occurrence of bleeding was associated with the TT genotype and T allele of rs1333040, while the presence of seizures appeared associated with the GG genotype of rs7865618. Conclusions: SNPs of the 9p21 region, in addition to be genetic markers for coronary artery disease, stroke, and intracranial aneurysms, are associated with sporadic BAVMs. These results extend and strengthen the role of the 9p21 chromosomal region as a common risk factor for cerebrovascular diseases.