Arteriovenous Malformation Lesions Research Articles

Differential Gene Expression in Relation to the Clinical Characteristics of Human Brain Arteriovenous Malformations

Arteriovenous malformations (AVMs) of the central nervous system are considered as congenital disorders. They are composed of abnormally developed dilated arteries and veins and are characterized microscopically by the absence of a capillary network. We previously reported DNA fragmentation and increased expression of apoptosis-related factors in AVM lesions. In this article, we used microarray analysis to examine differential gene expression in relation to clinical manifestations in 11 AVM samples from Japanese patients. We categorized the genes with altered expression into four groups: death-related, neuron-related, inflammation-related, and other. The death-related differentially expressed genes were MMP9, LIF, SOD2, BCL2A1, MMP12, and HSPA6. The neuron-related genes were NPY, S100A9, NeuroD2, S100Abeta, CAMK2A, SYNPR, CHRM2, and CAMKV. The inflammation-related genes were PTX3, IL8, IL6, CXCL10, GBP1, CHRM3, CXCL1, IL1R2, CCL18, and CCL13. In addition, we compared gene expression in those with or without clinical characteristics including deep drainer, embolization, and high-flow nidus. We identified a small number of genes. Using these microarray data we are able to generate and test new hypotheses to explore AVM pathophysiology. Microarray analysis is a useful technique to study clinical specimens from patients with brain vascular malformations.

The diagnosis of arteriovenous malformations by 4D-CTA: A clinical study

Digital subtraction angiography (DSA) is the current imaging 'gold standard' for diagnosis of arteriovenous malformation (AVM). The latest technique, four-dimensional computed tomography (4D-CT), offers a new diagnostic method for assessing AVM in real time. This study used a 320-detector-row CT scanner to compare the value of 4D-CT angiography (4D-CTA) with DSA in the diagnosis of untreated AVM patients. Seventeen patients diagnosed with AVM by DSA were included in this study. Two independent readers blind to the results of all examinations evaluated the findings of DSA and 4D-CTA in each patient. All results were then documented using a standardized scoring sheet. The results of 4D-CTA in all 17 cases were fully consistent with DSA for AVM location, size and vascular structures. 4D-CTA had the same ability as DSA to distinguish the main feeding arteries in all cases, although in the identification of smaller and specific arterial branches, there were discrepancies in one patient between the two methods. In the diagnosis of draining veins, however, 4D-CTA successfully displayed all of the vessels found by DSA. 4D-CTA was able to detect all AVM lesions, including their size, location, feeding arteries and draining veins. Thus, 4D-CTA has a value similar to that of DSA in the diagnosis and assessment of AVM.

Commentary on ^|^ldquo;Surgical Treatment with or without Embolotherapy for Arteriovenous Malformations^|^rdquo;

Arteriovenous malformations (AVM) is relatively infrequent congenital vascular malformations (CVMs). But its clinical risk/significance is far exceeding to other CVMs like venous malformation(VM) or lymphatic malformation (LM).1–6) Because, AVMs are the outcome of birth defect involving the vessels of both arterial and venous origins. It maintains direct communications between the different size vessels or a meshwork of primitive reticular networks of dysplastic minute vessels. Such unique condition results in shunting of high velocity, low resistance flow from the arterial vasculature into the venous system so that its hemodynamic consequences is quite serious and often progresses to potentially life or limb threatening condition. Besides, almost all the AVMs are ‘extratruncular’ lsions originated from the early stage of embryogenesis (cf. truncular lesion from the later stage) so that they possess unique mesenchymal cell (angioblast) characteristics to grow when stimulated by various conditions (e.g. female hormone, menarche, pregnancy, trauma, surgery). Ill planned treatment strategy with incomplete excision, for example, often stimulates the residual lesion to grow back. To make the condition more difficult to handle, all these ‘extratruncular’ AVM lesions are diffusely infiltrating into the surrounding tissue by its nature so that the complete excision of such lesion is extremely difficult if not impossible unless risking severe morbidity and complication (e.g. massive bleeding). Therefore, surgically ‘inaccessible’, if not difficult, infiltrating lesions should be considered for the endovascular therapy as the first choice, and only for surgically ‘accessible’ lesions (e.g. localized limited lesion), surgical resection may be the treatment of choice with a chance of optimal control. But the preoperative sclerotherapy or embolization should be considered whenever feasible to supplement to subsequent surgical excision by reducing the morbidity (e.g. operative bleeding) and defining the lesion borders. Such a combined approach may provide an excellent potential for a curative result as the authors claim. Nevertheless, an aggressive control of the nidus of the AVM lesion itself is essential to prevent recurrence and/or fast deterioration of the AVM lesion from much complicated hemodynamic consequences. And previous approach to the AVM only with the strategy to shut off the feeding artery (e.g. ligation, embolization), leaving the nidus of the lesion intact, would make the condition worse, only provoking a more aggressive neovascular recruitment by this primitive lesion without exception. Due to such critical nature of the AVM lesions, all the AVM lesions should be considered for the treatment whenever feasible in earliest possible time. However, right treatment strategy warrants accurate diagnosis of AVM as well as accurate assessment of its extent, severity, and progress, which is critical to avoid/minimize the complication and morbidity by currently available therapies. And the ‘controlled’ aggressiveness has to be exercised for the management of AVM in general within the accepted boundary of the “palliative” concept only when the benefit should exceed the morbidity following the treatment. The temptation to intervene AVM aggressively therefore, must be tempered with realistic assessment of the long-term prospect of the treatment outcome. Critical role of careful assessment of the treatment strategy based on benefit versus risk of morbidity before the commitment cannot be overemphasized, and the ultimate goal of the treatment has to be clearly defined with realistic expectation.

Extravascular Injection of Sclerotic Agents does not Affect Vessels in the Rat: Experimental Implications for Percutaneous Sclerotherapy of Arteriovenous Malformations

ObjectivesSclerotherapy is useful for the treatment of arteriovenous vascular malformations. However, intravascular administration of sclerotic agents into small arteriovenous niduses is often difficult. Extravascular administration of sclerotic agents causes reduction of vascular flow on Doppler echo during clinical sclerotherapy. Therefore, we aimed to investigate whether the extravascular injection of sclerotic agents affects tiny vessels. DesignAnimal study. MaterialsThe effect of extravascular injection of sclerotic agents on vessels was investigated using rat femoral and superficial inferior epigastric vessels. MethodsAfter surgical exposure of vessels, absolute ethanol, 5% ethanolamine oleate and 3% polidocanol were injected into perivascular surrounding tissues, and their effect on vessels was evaluated after 14 days using histology and coloured silicone rubber injection. ResultsThe integrity of the vascular lumen, endothelial cells and vascular patency were not affected by injection of sclerotic agents. ConclusionsAttenuation of vascular flow of an arteriovenous shunt after extravascular injection of sclerotic agents is transient and/or trivial and does not cause disruption of vessels. Therefore, sclerotic agents should be delivered to obtain sufficient destruction of arteriovenous malformation lesions and blood flow.

Age-Dependent Lethality in Novel Transgenic Mouse Models of Central Nervous System Arteriovenous Malformations

The lack of an appropriate animal model has been a limitation in studying hemorrhage from arteriovenous malformations (AVMs) in the central nervous system. Novel mouse central nervous system AVM models were generated by conditionally deleting the activin receptor-like kinase (Alk1; Acvrl1) gene with the SM22-Cre transgene. All mice developed AVMs in their brain and/or spinal cord, and >80% of them showed a paralysis or lethality phenotype due to internal hemorrhages during the first 10 to 15 weeks of life. The mice that survived this early lethal period, however, showed significantly reduced lethality rates even though they carried multiple AVMs. The age-dependent change in hemorrhage rates allowed us to identify molecular factors uniquely upregulated in the rupture-prone AVM lesions. Upregulation of angiopoietin 2 and a few inflammatory genes were identified in the hemorrhage-prone lesions, which may be comparable with human pathology. These models will be an exceptional tool to study pathophysiology of AVM hemorrhage.

Endovascular treatment combined with emboloscleorotherapy for pelvic arteriovenous malformations

To describe the clinical features and treatment outcomes after combined endovascular and embolosclerotherapy treatment of pelvic arteriovenous malformations (AVMs). From November 1996 to May 2011, we treated 12 patients (seven males, five females; mean age, 38.1 ±14.6 years; age range, 23-70 years) with pelvic AVMs. Our treatment strategy was coil embolization of a dilated draining vein of the AVM to reduce blood flow velocity in the AVM lesion and sclerotherapy of the residual arteriovenous fistulae with high-concentration ethanol to eradicate potential AVM recurrence. To ensure effective endovascular treatment, we used transarterial, transvenous, percutaneous, or combined access routes. Treatment outcomes were assessed with periodic computed tomography angiograms and clinical examinations. During the follow-up period (mean, 33.2 months; median, 21.3 months; range, 1-96 months) after embolosclerotherapy, we observed complete remission (no residual or recurrent AVM lesion on follow-up computed tomography and complete symptomatic relief) in 10 (83.3%) patients and partial remission in two (16.7%) patients. One major complication of focal bladder necrosis occurred (1/22 sessions, 4.5%, 1/12 patients, 8.3%), but this resolved with conservative treatment. As early procedure-related complications, transient pulmonary hypertension and/or hemoglobinuria developed in 54.5% (12/22 sessions) and 22.7% (5/22 sessions) of patients, respectively. Combined embolosclerotherapy of pelvic AVMs with coils and ethanol was efficacious at achieving complete remission.

Comments regarding ‘Surgical Treatment of Patients with Congenital Vascular Malformation-associated Aneurysms’

Through the last two decades, there has been a significant progress on the understanding of the nature of various congenital vascular malformations (CVMs), and the confusion based on old name-based eponyms and classification is now sufficiently cleared. Further, contemporary concept on the CVMs and its management by a multidisciplinary approach are now fully established. However, current knowledge is not sufficient enough to correct many unfair prejudices with a proper answer, and questions such as the aneurysm of congenital origin as the result of a birth defect remain to be answered. Among the arteriovenous malformations (AVMs), aneurysm formation along the feeding artery and/or draining veins is not rare at all; it is a ‘well anticipated’ haemodynamic reaction/consequence to such ‘high flow’ lesions. Together with a tortuosity, saccular or fusiform dilatation of the vessels is a common complication along the natural course of the progress of such lesion, when left alone. Therefore, all the extratruncular AVM lesions should be considered as candidates for aggressive control ‘before’ they progress to cause such potentially limb-threatening condition (e.g., aneurysmal rupture).

Pial arteriovenous fistula: a review of literature

Pial arteriovenous fistula (AVF) is a rare vascular lesion, with less than 120 reported cases in the English literatures (Hoh et al., Neurosurgery 2001;49(6):1351). The angio-architecture, clinical course and therapeutic options are all different from arteriovenous malformation (AVM), dural AVM or other intracranial vascular lesions. A review of literatures to analyse the clinical course of pial AVF was carried out. The presence of varix dictates the clinical course and presentation. Paediatric type had high percentage of varix, and mass effect as clinical presentation while the adult type usually manifest by haemorrhage. Disconnection of direct shunting, either by endovascular or surgically, is sufficient to achieve successful treatment; therefore, total resection of the lesion is unnecessary.

Acute Pancreatitis Due to Pancreatic Arteriovenous Malformation

Pancreatic arteriovenous malformation (AVM) is a relatively rare disease. Based on our literature search, 51 cases of pancreatic AVM have been reported since 1968. The gastrointestinal bleeding is the most common presenting symptom (24/51 cases [47%]). There were only 6 cases of pancreatitis in these cases. We describe 2 cases of acute pancretitis with pancreatic AVM. The patients who were diagnosed with acute pancreatitis were admitted to our hospital. Pancreatitis was considered to be caused by pancreatic AVM by some modalities of diagnostic imaging. The respective pancreatic AVM lesions of patients were resected to prevent the recurrence of pancreatitis. They are asymptomatic after the surgery. Pancreatic AVM is thought to be the one of the reasons for acute pancreatitis.

Pathobiology of Human Cerebrovascular Malformations: Basic Mechanisms and Clinical Relevance

Cerebrovascular malformations affect more than 3% of the population, exposing them to a lifetime risk of hemorrhagic stroke, seizures, and focal neurological deficits. Cerebral cavernous malformations (CCMs) exhibit an immature vessel wall, a brittle hemorrhagic tendency, and epileptogenesis, whereas arteriovenous malformations (AVMs) lack capillary beds and manifest apoplectic bleeding under high-flow conditions. There are also more benign venous anomalies, capillary malformations, and lesions with mixed and transitional features. Advances have been made toward understanding the natural history, radiological and pathological correlates, and clinical management. Yet, mechanisms of lesion genesis and clinical manifestations remain largely unknown, and the clinical behavior in individual patients is highly unpredictable. Lesion pathogenesis likely involves abnormal assembly or maintenance of blood vessels, resulting in dysmorphic vessel phenotypes. Familial CCM disease is in part caused by mutations in a cytoskeletal-related protein that is likely integral to interendothelial cell connectivity and maturation of the vascular wall. Rare familial forms of AVM disease have been correlated with two different transforming growth factor-beta receptor components, possibly causing disturbance in signaling during vascular assembly. Relevance of these mechanisms to the more common and otherwise identical sporadic CCM and AVM lesions is being explored. In this report, basic mechanisms of vasculogenesis and angiogenesis and how they possibly relate to the common cerebrovascular malformation lesions are reviewed. Novel concepts are discussed related to the cellular, molecular, and genetic substrates in CCM and AVM as well as to how this knowledge can be applied to predict, explain, and possibly modify clinical disease manifestations.

Vascular Smooth Muscle Cell Differentiation in Human Cerebral Vascular Malformations

OBJECTIVE The pathogenesis of central nervous system vascular malformations likely involves the abnormal assembly, differentiation of vascular smooth muscle cells (VSMC), or both in association with dysmorphic vessel wall. We hypothesize that intracranial arteriovenous malformations (AVMs) and cerebral cavernous malformations (CCMs) exhibit distinct patterns of expression of molecular markers of differentiation and maturity of VSMCs. We further speculate that the unique VSMC phenotype in the different lesions is not necessarily maintained in cell culture. METHODS Paraffin-embedded sections of five AVMs, CCMs, and control brain tissues were stained immunohistochemically with antibodies to α-smooth muscle actin (α-SMA), myosin heavy chain, and smoothelin, a novel marker for contractile VSMC phenotype. Large (≥100 μm) and small (<100 μm) vessels were counted and assessed for immunoexpression of each protein, then categorized according to expression of one or more of these markers. Cultured nonendothelial cells isolated from four other excised AVM and CCM lesions were assessed for immunoexpression of the same antibodies. RESULTS α-SMA was universally expressed in all vessels in AVMs and in control brains. It was expressed in the subendothelial layer of 97% of large caverns and 85% of small caverns and in scattered intercavernous connective tissue fibrocytes in CCMs. Myosin heavy chain was expressed in the majority of brain and AVM vessels, except for normal veins, and in the subendothelial layer of more than half of the caverns in CCMs. Smoothelin expression was less prevalent in large vessels in AVMs than in control brains and was not found in any caverns in CCMs (large vessels in control brains, 40.9%; AVMs, 21.9%; CCMs, 0%;P < 0.0001). Cultured AVM and CCM nonendothelial cells expressed α-SMA, but myosin heavy chain was expressed weakly in cells from only one CCM. Smoothelin was negative in all cells. CONCLUSION We describe vessels with various stages of VSMC differentiation in AVMs and CCMs. The subendothelial layer of CCMs commonly expresses α-SMA and less commonly expresses myosin heavy chain. Expression of smoothelin was less prevalent in large AVM vessels than in normal brain, which may reflect the loss of contractile property associated with hemodynamic stress. It is difficult to evaluate VSMC differentiation in culture because of phenotypic change.

Vascular smooth muscle cell differentiation in human cerebral vascular malformations.

The pathogenesis of central nervous system vascular malformations likely involves the abnormal assembly, differentiation of vascular smooth muscle cells (VSMC), or both in association with dysmorphic vessel wall. We hypothesize that intracranial arteriovenous malformations (AVMs) and cerebral cavernous malformations (CCMs) exhibit distinct patterns of expression of molecular markers of differentiation and maturity of VSMCs. We further speculate that the unique VSMC phenotype in the different lesions is not necessarily maintained in cell culture. Paraffin-embedded sections of five AVMs, CCMs, and control brain tissues were stained immunohistochemically with antibodies to alpha-smooth muscle actin (alpha-SMA), myosin heavy chain, and smoothelin, a novel marker for contractile VSMC phenotype. Large (> or =100 microm) and small (<100 microm) vessels were counted and assessed for immunoexpression of each protein, then categorized according to expression of one or more of these markers. Cultured nonendothelial cells isolated from four other excised AVM and CCM lesions were assessed for immunoexpression of the same antibodies. Alpha-SMA was universally expressed in all vessels in AVMs and in control brains. It was expressed in the subendothelial layer of 97% of large caverns and 85% of small caverns and in scattered intercavernous connective tissue fibrocytes in CCMs. Myosin heavy chain was expressed in the majority of brain and AVM vessels, except for normal veins, and in the subendothelial layer of more than half of the caverns in CCMs. Smoothelin expression was less prevalent in large vessels in AVMs than in control brains and was not found in any caverns in CCMs (large vessels in control brains, 40.9%; AVMs, 21.9%; CCMs, 0%; P < 0.0001). Cultured AVM and CCM nonendothelial cells expressed alpha-SMA, but myosin heavy chain was expressed weakly in cells from only one CCM. Smoothelin was negative in all cells. We describe vessels with various stages of VSMC differentiation in AVMs and CCMs. The subendothelial layer of CCMs commonly expresses alpha-SMA and less commonly expresses myosin heavy chain. Expression of smoothelin was less prevalent in large AVM vessels than in normal brain, which may reflect the loss of contractile property associated with hemodynamic stress. It is difficult to evaluate VSMC differentiation in culture because of phenotypic change.

Multiple cranial arteriovenous malformations in a child with eventual blindness in the affected eye

PURPOSE: To report a case of multiple cranial arteriovenous malformations involving the orbit and retina. METHOD: Case report. We treated a 7-year-old girl who was diagnosed with a left submaxillary, a left retinal, a left orbital, and a middle subdural arteriovenous malformation. RESULTS: Enlargement of the arteriovenous malformations, except for the retinal arteriovenous malformation, was observed. After external carotid artery embolizations and radiation therapy for uncontrolled oral cavity bleeding, loss of light perception in the affected eye occurred, but no marked changes occurred in the retinal arteriovenous malformation. CONCLUSION: This rare case suggests that the clinical finding of a stable retinal arteriovenous malformation may be associated with enlargement of arteriovenous malformation lesions at other sites.

Specific repression of the preproendothelin-1 gene in intracranial arteriovenous malformations.

Cerebrovascular arteriovenous malformations (AVMs) display abnormal vascular development and dysautoregulation of blood flow. Genetic mechanisms that contribute to the pathogenesis and phenotype of cerebral AVMs are unknown. As a first step in understanding the pathophysiology of AVMs, the authors investigated the hypothesis that endothelial dysfunction-specifically, deregulation of endothelin-1 (ET-1) secretion-contributes to the abnormal vascular phenotype and the lack of hemodynamic autoregulation elaborated by these lesions. Endothelin-1 peptide and preproendothelin-1 (ppET1) messenger RNA were not detected in the intranidal vasculature of all 17 patients with AVMs studied, but were prominently expressed in human control subjects with normal cerebrovasculature (p < 0.01). Although AVM vasculature lacked ET-1, its expression was prominent in vasculature distant from these lesions, suggesting local repression of the ppET-1 gene. Local repression of ET-1 was specific to AVMs; ET-1 in vascular malformations of patients with Sturge-Weber disease was actually elevated compared to normal controls (p < 0.01). Repression of the ppET-1 gene was an intrinsic phenotype of AVM endothelial cells and was not due to factors in the AVM microenvironment. The authors also showed that ETA receptor expression was low in AVM vasculature compared to normal controls. Together, these results demonstrate that the ppET-1 gene is locally repressed in AVM lesions and suggest a role for abnormal ppET-1 gene regulation in the pathogenesis and clinical sequelae of cerebral AVMs.