Medical Adjuvants in the Treatment of Surgically Refractory Arteriovenous Malformations of the Head and Face: Case Report and Review of Literature.

BACKGROUND: Arteriovenous malformations (AVMs) of the brain and face present unique challenges for clinicians. Cerebral AVMs may induce hemorrhage or form aneurysms, while facial AVMs can cause significant disfigurement and pain. Moreover, facial AVMs often draw blood supply from arteries providing critical blood flow to other important structures of the head which may make them impossible to treat curatively. Medical adjuvants may be an important consideration in the management of these patients. SUMMARY: We conducted a systematic review of the literature to identify other instances of molecular target of rapamycin (mTOR) inhibitors used as medical adjuvants for the treatment of cranial and facial AVMs. We also present 2 cases from our own institution where patients were treated with partial embolization, followed by adjuvant therapy with rapamycin. After screening a total of 75 articles, 7 were identified which described use of rapamycin in the treatment of inoperable cranial or facial AVM. In total, 21 cases were reviewed. The median treatment duration was 12 months (3-24.5 months), and the highest recorded dose was 3.5 mg/m2. 76.2% of patients demonstrated at least a partial response to rapamycin therapy. In 2 patients treated at our institution, symptomatic and radiographic improvement were noted 6 months after initiation of therapy. Key Messages: Early results have been encouraging in a small number of patients with inoperable AVM of the head and face treated with mTOR inhibitors. Further study of medical adjuvants such as rapamycin may be worthwhile.

Intramuscular fast-flow vascular anomaly contains somatic MAP2K1 and KRAS mutations.

BACKGROUND: The term "intramuscular hemangioma capillary type" (IHCT) refers to a fast-flow vascular lesion that is classified as a tumor, although its phenotype overlaps with arteriovenous malformation (AVM). The purpose of this study was to identify somatic mutations in IHCT. METHODS: Affected tissue specimens were obtained during a clinically indicated procedure. The diagnosis of IHCT was based on history, physical examination, imaging and histopathology. Because somatic mutations in cancer-associated genes can cause vascular malformations, we sequenced exons from 446 cancer-related genes in DNA from 7 IHCT specimens. We then performed mutation-specific droplet digital PCR (ddPCR) to independently test for the presence of a somatic mutation found by sequencing and to screen one additional IHCT sample. RESULTS: We detected somatic mutations in 6 of 8 IHCT specimens. Four specimens had a mutation in MAP2K1 (p.Q58_E62del, p.P105_I107delinsL, p.Q56P) and 2 specimens had mutations in KRAS (p.K5E and p.G12D, p.G12D and p.Q22R). Mutant allele frequencies detected by sequencing and confirmed by ddPCR ranged from 2 to 15%. CONCLUSIONS: IHCT lesions are phenotypically similar to AVMs and contain the same somatic MAP2K1 or KRAS mutations, suggesting that IHCT is on the AVM spectrum. We propose calling this lesion "intramuscular fast-flow vascular anomaly."

Interaction Between ALK1 Signaling and Connexin40 in the Development of Arteriovenous Malformations.

OBJECTIVE: To determine the role of Gja5 that encodes for the gap junction protein connexin40 in the generation of arteriovenous malformations in the hereditary hemorrhagic telangiectasia type 2 (HHT2) mouse model. APPROACH AND RESULTS: We identified GJA5 as a target gene of the bone morphogenetic protein-9/activin receptor-like kinase 1 signaling pathway in human aortic endothelial cells and importantly found that connexin40 levels were particularly low in a small group of patients with HHT2. We next took advantage of the Acvrl1(+/-) mutant mice that develop lesions similar to those in patients with HHT2 and generated Acvrl1(+/-); Gja5(EGFP/+) mice. Gja5 haploinsufficiency led to vasodilation of the arteries and rarefaction of the capillary bed in Acvrl1(+/-) mice. At the molecular level, we found that reduced Gja5 in Acvrl1(+/-) mice stimulated the production of reactive oxygen species, an important mediator of vessel remodeling. To normalize the altered hemodynamic forces in Acvrl1(+/-); Gja5(EGFP/+) mice, capillaries formed transient arteriovenous shunts that could develop into large malformations when exposed to environmental insults. CONCLUSIONS: We identified GJA5 as a potential modifier gene for HHT2. Our findings demonstrate that Acvrl1 haploinsufficiency combined with the effects of modifier genes that regulate vessel caliber is responsible for the heterogeneity and severity of the disease. The mouse models of HHT have led to the proposal that 3 events-heterozygosity, loss of heterozygosity, and angiogenic stimulation-are necessary for arteriovenous malformation formation. Here, we present a novel 3-step model in which pathological vessel caliber and consequent altered blood flow are necessary events for arteriovenous malformation development.

Circulating Bmp10 acts through endothelial Alk1 to mediate flow-dependent arterial quiescence.

Blood flow plays crucial roles in vascular development, remodeling and homeostasis, but the molecular pathways required for transducing flow signals are not well understood. In zebrafish embryos, arterial expression of activin receptor-like kinase 1 (alk1), which encodes a TGFß family type I receptor, is dependent on blood flow, and loss of alk1 mimics lack of blood flow in terms of dysregulation of a subset of flow-responsive arterial genes and increased arterial endothelial cell number. These data suggest that blood flow activates Alk1 signaling to promote a flow-responsive gene expression program that limits nascent arterial caliber. Here, we demonstrate that restoration of endothelial alk1 expression to flow-deprived arteries fails to rescue Alk1 activity or normalize arterial endothelial cell gene expression or number, implying that blood flow may play an additional role in Alk1 signaling independent of alk1 induction. To this end, we define cardiac-derived Bmp10 as the crucial ligand for endothelial Alk1 in embryonic vascular development, and provide evidence that circulating Bmp10 acts through endothelial Alk1 to limit endothelial cell number in and thereby stabilize the caliber of nascent arteries. Thus, blood flow promotes Alk1 activity by concomitantly inducing alk1 expression and distributing Bmp10, thereby reinforcing this signaling pathway, which functions to limit arterial caliber at the onset of flow. Because mutations in ALK1 cause arteriovenous malformations (AVMs), our findings suggest that an impaired flow response initiates AVM development.

ALK1 signaling inhibits angiogenesis by cooperating with the Notch pathway.

Activin receptor-like kinase 1 (ALK1) is an endothelial-specific member of the TGF-ß/BMP receptor family that is inactivated in patients with hereditary hemorrhagic telangiectasia (HHT). How ALK1 signaling regulates angiogenesis remains incompletely understood. Here we show that ALK1 inhibits angiogenesis by cooperating with the Notch pathway. Blocking Alk1 signaling during postnatal development in mice leads to retinal hypervascularization and the appearance of arteriovenous malformations (AVMs). Combined blockade of Alk1 and Notch signaling further exacerbates hypervascularization, whereas activation of Alk1 by its high-affinity ligand BMP9 rescues hypersprouting induced by Notch inhibition. Mechanistically, ALK1-dependent SMAD signaling synergizes with activated Notch in stalk cells to induce expression of the Notch targets HEY1 and HEY2, thereby repressing VEGF signaling, tip cell formation, and endothelial sprouting. Taken together, these results uncover a direct link between ALK1 and Notch signaling during vascular morphogenesis that may be relevant to the pathogenesis of HHT vascular lesions.

Pharmacological treatment of a diffuse arteriovenous malformation of the upper extremity in a child.

A young girl with an arteriovenous malformation involving the right upper extremity developed rapidly progressive bony destruction that did not respond to embolization. Treatment with marimastat, starting at 3 years of age, resulted in rapid resolution of pain and gradual healing of bony destruction, associated with regression of the intraosseous arteriovenous shunts. New arteriovenous shunts with bony destruction developed over the years and responded to an increase in the dose of marimastat. Interruption of therapy resulted in recurrence of pain and formation of new lesions. The patient has been treated in this way for 12 years with no adverse effects from the drug.

Superior cavopulmonary anastomosis suppresses the activity and expression of pulmonary angiotensin-converting enzyme.

BACKGROUND: Superior cavopulmonary anastomosis is widely used for palliation of various forms of univentricular heart defects. However, clinically significant pulmonary arteriovenous malformations develop in 15% to 25% of patients after surgery. OBJECTIVE: To assess altered regulation of pulmonary vascular tone caused by superior cavopulmonary anastomosis in an ovine model. METHODS: Lambs, aged 35 to 45 days, underwent an end-to-end anastomosis of the superior vena cava to the right pulmonary artery. In age-matched controls, a sham operation was performed. Arteriovenous malformations were detectable by contrast echocardiography by 8 weeks after surgery. Animals (n = 24) were studied at various time points after the operations. Expression of angiotensin-converting enzyme messenger RNA, protein levels, and enzyme activity were measured in lung homogenates. Levels of angiotensin II were measured by enzyme-linked immunosorbent assay. RESULTS: Expression of angiotensin-converting enzyme messenger RNA and protein was significantly reduced at 1 to 5 weeks after superior cavopulmonary anastomosis. Angiotensin-converting enzyme activity in the right lung of animals subjected to superior cavopulmonary anastomosis was reduced 86% +/- 1% (standard deviation) compared with control values at 1 week (P =.003) and 77% +/- 8.5% at 2 weeks (P <.001) after surgery. This correlated with a 59% +/- 3.5% (P =.007) reduction in angiotensin II levels up to 5 weeks after cavopulmonary anastomosis. By 15 weeks after the operations, angiotensin II levels were equivalent to control levels (P =.19). CONCLUSIONS: Superior cavopulmonary anastomosis causes an early reversible reduction in activity and expression of angiotensin-converting enzyme, resulting in decreased circulating levels of the vasoconstrictor angiotensin II. These results suggest that the ability of the pulmonary endothelium to regulate vascular tone is inhibited after superior cavopulmonary anastomosis. Dilation of the affected vasculature induced by cavopulmonary anastomosis may contribute to the disordered vascular remodeling observed in this setting.

Hemodynamic and plasma renin responses to treatment of a renal arteriovenous malformation.

We report a case of a right renal arteriovenous malformation with high output cardiac failure and hypertension which was cured by nephrectomy. Hemodynamic findings pre- and post-operatively are presented. Plasma renin activity (PRA), both from peripheral venous and renal vein samples, was assessed. The fall in PRA associated with nephrectomy lends support to the suggestion that the renin-angiotensin system plays a role in the hypertension in these patients.