VEGFR2 Expression Correlates with Postnatal Development of Brain Arteriovenous Malformations in a Mouse Model of Type I Hereditary Hemorrhagic Telangiectasia.

Brain arteriovenous malformations (BAVMs) are a critical concern in hereditary hemorrhagic telangiectasia (HHT) patients, carrying the risk of life-threatening intracranial hemorrhage. While traditionally seen as congenital, the debate continues due to documented de novo cases. Our primary goal was to identify the precise postnatal window in which deletion of the HHT gene Endoglin (Eng) triggers BAVM development. We employed SclCreER(+);Eng2f/2f mice, enabling timed Eng gene deletion in endothelial cells via tamoxifen. Tamoxifen was given during four postnatal periods: P1-3, P8-10, P15-17, and P22-24. BAVM development was assessed at 2-3 months using latex dye perfusion. We examined the angiogenic activity by assessing vascular endothelial growth factor receptor 2 (VEGFR2) expression via Western blotting and Flk1-LacZ reporter mice. Longitudinal magnetic resonance angiography (MRA) was conducted up to 9 months. BAVMs emerged in 88% (P1-3), 86% (P8-10), and 55% (P15-17) of cases, with varying localization. Notably, the P22-24 group did not develop BAVMs but exhibited skin AVMs. VEGFR2 expression peaked in the initial 2 postnatal weeks, coinciding with BAVM onset. These findings support the "second hit" theory, highlighting the role of early postnatal angiogenesis in initiating BAVM development in HHT type I mice.

Localized conditional induction of brain arteriovenous malformations in a mouse model of hereditary hemorrhagic telangiectasia.

BACKGROUND: Longitudinal mouse models of brain arteriovenous malformations (AVMs) are crucial for developing novel therapeutics and pathobiological mechanism discovery underlying brain AVM progression and rupture. The sustainability of existing mouse models is limited by ubiquitous Cre activation, which is associated with lethal hemorrhages resulting from AVM formation in visceral organs. To overcome this condition, we developed a novel experimental mouse model of hereditary hemorrhagic telangiectasia (HHT) with CreER-mediated specific, localized induction of brain AVMs. METHODS: Hydroxytamoxifen (4-OHT) was stereotactically delivered into the striatum, parietal cortex, or cerebellum of R26CreER; Alk12f/2f (Alk1-iKO) littermates. Mice were evaluated for vascular malformations with latex dye perfusion and 3D time-of-flight magnetic resonance angiography (MRA). Immunofluorescence and Prussian blue staining were performed for vascular lesion characterization. RESULTS: Our model produced two types of brain vascular malformations, including nidal AVMs (88%, 38/43) and arteriovenous fistulas (12%, 5/43), with an overall frequency of 73% (43/59). By performing stereotaxic injection of 4-OHT targeting different brain regions, Alk1-iKO mice developed vascular malformations in the striatum (73%, 22/30), in the parietal cortex (76%, 13/17), and in the cerebellum (67%, 8/12). Identical application of the stereotaxic injection protocol in reporter mice confirmed localized Cre activity near the injection site. The 4-week mortality was 3% (2/61). Seven mice were studied longitudinally for a mean (SD; range) duration of 7.2 (3; 2.3-9.5) months and demonstrated nidal stability on sequential MRA. The brain AVMs displayed microhemorrhages and diffuse immune cell invasion. CONCLUSIONS: We present the first HHT mouse model of brain AVMs that produces localized AVMs in the brain. The mouse lesions closely resemble the human lesions for complex nidal angioarchitecture, arteriovenous shunts, microhemorrhages, and inflammation. The model's longitudinal robustness is a powerful discovery resource to advance our pathomechanistic understanding of brain AVMs and identify novel therapeutic targets.

Nationwide Readmission Rates and Hospital Charges for Patients With Surgical Evacuation of Nontraumatic Subdural Hematomas: Part 1-Craniotomy.

BACKGROUND: Despite patients experiencing high recurrence and readmission rates after surgical management of nontraumatic subdural hematomas (SDHs), few studies have examined the causes and predictors of unplanned readmissions in this population on a national scale. OBJECTIVE: To analyze independent factors predicting 30-day hospital readmissions after surgical treatment of nontraumatic SDH in patients who survived their index surgery and evaluate hospital readmission rates and charges. METHODS: Using the Nationwide Readmissions Database, we identified patients who underwent craniotomy for nontraumatic SDH evacuation (2010-2015) using a retrospective cohort observational study design. National estimates and variances within the cohort were calculated after stratifying, hospital clustering, and weighting variables. RESULTS: Among 49 013 patients, 10 643 (21.7%) had at least 1 readmission within 30 days of their index treatment and 38 370 (78.3%) were not readmitted. Annual readmission rates did not change during the study period ( P = .74). The most common primary causes of 30-day readmissions were recurrent SDH (n = 3949, 37.1%), venous thromboembolism (n = 1373, 12.9%), and delayed hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (n = 1363, 12.8%). Comorbidities that independently predicted readmission included congestive heart failure, chronic obstructive pulmonary disease, coagulopathy, diabetes mellitus, liver disease, lymphoma, fluid and electrolyte disorders, metastatic cancer, peripheral vascular disease, psychosis, and renal failure ( P ≤ .03). Household income in the 51st to 75th percentile was associated with a decreased risk of readmission. CONCLUSION: National trends in 30-day readmission rates after nontraumatic SDH treatment by craniotomy provide quality benchmarks that can be used to drive quality improvement efforts on a national level.