PERSONALIZED APPROACHES TO TREATMENT OF COMPLEX CEREBRAL ARTERIOVENOUS MALFORMATIONS

Background. Cerebral AVMs are not static congenital lesions, but can grow, recur, and appear de novo after complete resection, embolization, or radiosurgery. Understanding the complex molecular biology of AVMs is critical to predicting their behavior during treatment and improving treatment outcomes. Objective. To study the dynamics of angiogenesis factors in the process of cerebral AVM embolization in order to develop a strategy for their personalized treatment. Methods. The study included 314 patients with AVM who received surgical treatment at the Department of Brain Vascular Surgery of the Polenov Neurosurgical Research Institute. Determined the level of vascular endothelial growth factor (VEGF), angiopoietin-2 (ANG-2) and matrix metalloproteinase-9 (MMP-9) in blood serum before and 24 hours after endovascular embolization using enzyme-linked immunosorbent assay (Personal Lab, Adaltis, Italy). Results. 48.4 % of primary patients with AVM showed an increase in VEGF, MMP-9, ANG-2. A high level of VEGF and MMP-9 demonstrated AVM III grades according to SpetzlerMartin, AVM with a hemorrhagic flow type, with a deep drainage pattern, with afferents from the external carotid artery. The return to control values of all elevated growth factors after total embolization confirms the lack of potency for AVM recurrence. The absence of a decrease in aniogenesis factors after radical, according to angiographic criteria, embolization is a sign of subtotal AVM shutdown. A personalized concept of embolization in patients with a high risk of growth and recurrence has been formulated.

1. Novakovic RL, Lazzaro MA, Castonguay AC, Zaidat OO. The diagnosis and management of brain arteriovenous malformations. Neural Clin. 2013; 31:749–763.

2. Amin-Hanjani S: ARUBA results are not applicable to all patients with arteriovenous malformation. Stroke. 2014; 45:1539–1540.

3. Parfenov V, Svistov D, Eliava SH, et al. Clinicheskie pekomendacii po diagnostike i lecheniu arteriovenozni malformaci centralyji nervnoi sistemi. Associacia neurochirurgov Rossii. Moskva. 2014. P. 47. In Russian

4. Goroshchenko SA, Petrov AE, Rozhchenko LV, Samochernykh KA. Endovascular embolization of highflow arteriovenous fistulae with non-adhesive agents in the structure of cerebral arteriovenous malformations on the background of adenosine-induced cardioplegia Zhurnal Voprosy Nejrokhirurgii Imeni N. N. Burdenko. 2020; 84(3): 21–27.

5. Rangel-Castilla L, Russin JJ, Martinez-Del-Campo E. Molecular and cellular biology of cerebral arteriovenous malformations: a review of current concepts and future trends in treatment. Neurosurg Focus. 2014; 37(3):1–17.

6. Zhang R, Zhu W, Su H. Vascular Integrity in the Pathogenesis of Brain Arteriovenous Malformation. // Acta Neurochir Suppl. 2016; 21:29–35.

7. Starke RM, Komotar RJ, Hwang BY. Systemic expression of matrix metallopro-teinase-9 in patients with cerebral arteriovenous malformations. Neurosurgery. 2010; 66: 343–348.

8. Moftakhar P, Hauptman JS, Malkasian D, Martin NA. Cerebral arteriovenous malformations. Part 1: cellular and molecular biology. Neurosurg Focus. 2009; 26(5): 32–39.

9. Karamysheva AF. The Mechanisms of angiogenesis. Biochimia. 2008; 73(7): 751–762. In Russian

10. Chen W, Choi E, McDougall M. Brain Arteriovenous Malformation Modeling, Pathogenesis, and Novel Therapeutic Targets. Translational Stroke Research.2014;5(3): 316–329.

11. Hashimoto T, Lam T, Boudreau NJ, Bollen A, Lawton MT, Young W. Abnormal Balance in the Angiopoietin-Tie2 System in Human Brain Arteriovenous Malformations. Circulation Research. 2011; 89:111–113.

12. Kim H, Marchuk DA, Pawlicowska L. Genetic considerations relevant to intracranial hemorrhage and brain arteriovenous malformation. J. of clinical neurosciens. 2014;21(11):1866–1871.

13. Couquet С, Maizeroi-Eugène F, Bresson D. Development of an angiogenesis animal model featuring brain arteriovenous malformation histological characteristics. J. of NeuroInterventional Surgery. 2017; 9(2):204–210.

14. Murphy PA, Kim TN, Huang L. Constitutively active Notch4 receptor elicits brain arteriovenous malformations through enlargement of capillary-like vessels. Proceedings of the National Academy of Sciences USA. 2014;111(50):18007–18012.

15. Herbert SP, Huisken J, Kim TN. Arterial-venous segregation by selective cell sprouting: an alternative mode of blood vessel formation. Science. 2009; 326(5950):294–298.

16. Bicer A, Guclu B, Ozkan A. Expressions of angiogenesis associated matrix metalloproteinases and extracellular matrix proteins in cerebral vascular malformations. J Clin Neurosci. 2010:17:232–236.

17. Самочерных К.А. Артериовенозные мальформации полушарий большого мозга у детей (вопросы диагностики и результаты хирургического лечения). Автореф. дис. канд. мед. наук/Санкт-Петербург, 2002.