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inflammatory process appears to possess multiple REFERENCES
targets ideally suited for such pharmacological
treatment. 1. Schievink WI. Intracranial aneurysms. N Engl J Med 1997;336:28‑40.
2. Jayaraman T, Paget A, Shin YS, Li X, Mayer J, Chaudhry H,
Niimi Y, Silane M, Berenstein A. TNF‑alpha‑mediated inflammation
The wide range of pro-inflammatory pathways induced in cerebral aneurysms: a potential link to growth and rupture. Vasc
by TNF-α makes this cytokine an attractive target Health Risk Manag 2008;4:805‑17.
for blockade. Preservation of endothelial function, 3. Stegmayr B, Eriksson M, Asplund K. Declining mortality from
[2]
maintenance of the VSMC contractile phenotype, and subarachnoid hemorrhage: changes in incidence and case fatality
inhibition of inflammatory cell migration are all potential 4. from 1985 through 2000. Stroke 2004;35:2059‑63.
Nieuwkamp DJ, Setz LE, Algra A, Linn FH, de Rooij NK, Rinkel GJ.
benefits of TNF-α antagonism. MMP-2 and MMP-9 Changes in case fatality of aneurysmal subarachnoid haemorrhage
blockade has proven to limit aneurysm development over time, according to age, sex, and region: a meta‑analysis. Lancet
in animal models, possibly identifying an additional Neurol 2009;8:635‑42.
mechanism with clinical relevance. [51] Modification of 5. Frösen J, Tulamo R, Paetau A, Laaksamo E, Korja M, Laakso A,
Niemela M, Hernesniemi J. Saccular intracranial aneurysm:
VSMC phenotype continues to be an area of interest, pathology and mechanisms. Acta Neuropathol 2012;123:773‑86.
with both cytokine and transcription factor-mediated 6. Ronkainen A, Hernesniemi J, Ryynänen M. Familial subarachnoid
changes representing possible therapeutic targets. [102] hemorrhage in east Finland, 1977‑1990. Neurosurgery
Macrophages represent an additional cellular target 7. 1993;33:787‑96.
Schievink WI, Schaid DJ, Michels VV, Piepgras DG. Familial
for pharmacologic intervention. Hasan et al. [113] has aneurysmal subarachnoid hemorrhage: a community‑based study.
already shown aspirin to potentially decrease the J Neurosurg 1995;83:426‑9.
risk of aneurysm rupture, a clinical benefit possibly 8. Juvela S, Porras M, Poussa K. Natural history of unruptured
derived from diminished macrophage infiltration of intracranial aneurysms: probability of and risk factors for aneurysm
rupture. J Neurosurg 2000;93:379‑87.
the aneurysm wall. Nakakoa et al. [115] has demonstrated 9. Yasui N, Suzuki A, Nishimura H, Suzuki K, Abe T. Long‑term

gene expression profiles in ruptured aneurysms that follow‑up study of unruptured intracranial aneurysms. Neurosurgery
indicate the macrophage-mediated inflammation as 1997;40:1155‑9.
a key contributor to aneurysm rupture. Future studies 10. Isaksen J, Egge A, Waterloo K, Romner B, Ingebrigtsen T. Risk

factors for aneurysmal subarachnoid haemorrhage: the Tromsø
may determine these identified genes as diagnostic study. J Neurol Neurosurg Psychiatry 2002;73:185‑7.
markers for aneurysms prone to rupture or potential 11. Sandvei MS, Romundstad PR, Müller TB, Vatten L, Vik A. Risk factors
therapeutic targets. Importantly, in all of these areas for aneurysmal subarachnoid hemorrhage in a prospective population
study: the HUNT study in Norway. Stroke 2009;40:1958‑62.
the therapeutic benefit must be weighed against the 12. Lijnen HR. Metalloproteinases in development and progression of
risks of altering what, in many instances, is a natural vascular disease. Pathophysiol Haemost Thromb 2003;33:275‑81.
and protective biological response. [2] 13. Juvela S, Hillbom M, Numminen H, Koskinen P. Cigarette
smoking and alcohol consumption as risk factors for aneurysmal
CONCLUSION subarachnoid hemorrhage. Stroke 1993;24:639‑46.
14. Hashimoto N, Handa H, Hazama F. Experimentally induced cerebral
aneurysms in rats. Surg Neurol 1978;10:3‑8.
Cerebral aneurysms remain a significant health and 15. Hashimoto N, Kim C, Kikuchi H, Kojima M, Kang Y, Hazama F.
socioeconomic problem, with the majority of ruptures Experimental induction of cerebral aneurysms in monkeys.
leading to death or severe disability. Microsurgical J Neurosurg 1987;67:903‑5.
and endovascular interventions represent the two 16. Morimoto M, Miyamoto S, Mizoguchi A, Kume N, Kita T,
Hashimoto N. Mouse model of cerebral aneurysm: experimental
modalities of treatment; however, both are associated induction by renal hypertension and local hemodynamic changes.
with risk. An understanding of the mechanisms leading Stroke 2002;33:1911‑5.
to aneurysm development is necessary to identify 17. Turjman AS, Turjman F, Edelman ER. Role of fluid dynamics and
markers predictive of growth and rupture, as well inflammation in intracranial aneurysm formation. Circulation
2014;129:373‑82.
as targets for pharmacologic intervention. Through 18. Penn DL, Komotar RJ, Sander Connolly E. Hemodynamic
multiple pathways, the inflammatory response appears mechanisms underlying cerebral aneurysm pathogenesis. J Clin
to drive the initiation of aneurysm formation, potentiate Neurosci 2011;18:1435‑8.
continued growth, and contribute to eventual rupture. 19. Chalouhi N, Ali MS, Starke RM, Jabbour PM, Tjoumakaris SI,
Gonzalez LF, Rosenwasser RH, Koch WJ, Dumont AS. Cigarette
Animal and human studies highlight the complex smoke and inflammation: role in cerebral aneurysm formation and
interaction between the endothelium, VSMCs, and rupture. Mediators Inflamm 2012;2012:271582.
inflammatory cells. Phenotypic change, cytokine 20. Chiu JJ, Wang DL, Chien S, Skalak R, Usami S. Effects of disturbed
flow on endothelial cells. J Biomech Eng 1998;120:2‑8.
production, apoptosis, and cellular migration all 21. Nagel T, Resnick N, Dewey CF Jr, Gimbrone MA Jr. Vascular
partake in aneurysm evolution. Delineation of those endothelial cells respond to spatial gradients in fluid shear stress by
at greatest risk for rupture would afford improved enhanced activation of transcription factors. Arterioscler Thromb
patient selection with regards to aneurysm obliteration. Vasc Biol 1999;19:1825‑34.
Furthermore, the definition of these various processes 22. Tardy Y, Resnick N, Nagel T, Gimbrone MA Jr, Dewey CF Jr. Shear
stress gradients remodel endothelial monolayers in vitro via a cell
may hold promising pharmacological therapeutic proliferation‑migration‑loss cycle. Arterioscler Thromb Vasc Biol
implications in the future. 1997;17:3102‑6.

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