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Elucidating Sex Differences in Cerebral Aneurysm Biology and Therapy

2016; Lippincott Williams & Wilkins; Volume: 68; Issue: 2 Linguagem: Inglês

10.1161/hypertensionaha.116.07606

1524-4563

Peter S. Amenta, Ricky Medel, Crissey L. Pascale, Aaron S. Dumont,

Moyamoya disease diagnosis and treatment

HomeHypertensionVol. 68, No. 2Elucidating Sex Differences in Cerebral Aneurysm Biology and Therapy Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBElucidating Sex Differences in Cerebral Aneurysm Biology and TherapyThe Time Is Now Peter S. Amenta, Ricky Medel, Crissey L. Pascale, and Aaron S. Dumont Peter S. AmentaPeter S. Amenta From the Department of Neurosurgery, Tulane Clinical Neurosciences Institute, Tulane University School of Medicine, New Orleans, LA. , Ricky MedelRicky Medel From the Department of Neurosurgery, Tulane Clinical Neurosciences Institute, Tulane University School of Medicine, New Orleans, LA. , Crissey L. PascaleCrissey L. Pascale From the Department of Neurosurgery, Tulane Clinical Neurosciences Institute, Tulane University School of Medicine, New Orleans, LA. , and Aaron S. DumontAaron S. Dumont From the Department of Neurosurgery, Tulane Clinical Neurosciences Institute, Tulane University School of Medicine, New Orleans, LA. Originally published13 Jun 2016https://doi.org/10.1161/HYPERTENSIONAHA.116.07606Hypertension. 2016;68:312–314Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2016: Previous Version 1 See related article, pp 411-417Subarachnoid hemorrhage remains a devastating disease despite improvements in the technology and techniques used in securing and obliterating ruptured aneurysms. As a result, there is evidence to treat unruptured cerebral aneurysms when found incidentally or in the setting of symptoms suggestive of impending rupture. At present, there are no accepted medical therapies that reduce the risk of rupture or lead to aneurysm obliteration. Endovascular and microsurgical treatments continue to be the standards of care but are invasive and not without significant risk. This potential risk is magnified when treating an aneurysm prophylactically, considering it may remain asymptomatic for the entirety of the life of the patient. The widespread availability of highly sensitive noninvasive imaging modalities, such as magnetic resonance angiography and computed tomographic angiography, has greatly increased the number of unruptured aneurysms diagnosed each year. Thus, more now than ever, clinicians are faced with the challenging scenario of managing an unruptured asymptomatic aneurysm. As a result, noninvasive medical therapies that could reduce or eliminate the risk of aneurysm rupture are of great interest.At the heart of developing effective medical therapies is an improved understanding of the mechanisms underlying cerebral aneurysm formation and rupture. The role of inflammation in the development and rupture of cerebral aneurysms has been clearly established based on burgeoning data derived from human and animal studies.1,2 An enhanced understanding of the inflammatory mediators contributing to the pathogenesis of cerebral aneurysms has facilitated the identification of targeted therapies. Hasan et al3 identified aspirin as a therapeutic agent that may reduce the risk of cerebral aneurysm rupture. Aspirin is a particularly attractive therapy because it has well-established anti-inflammatory effects, is inexpensive, is widely available, and has an acceptable safety profile. Furthermore, it is commonly used in the patient population with vascular pathology and is a routine component of treatment for coronary artery disease, stroke, and peripheral vascular disease. As a result, aspirin represents a promising agent for the noninvasive treatment of unruptured cerebral aneurysms.The literature continues to highlight the influence of sex on human disease, particularly the mechanisms, presentation, and management of ischemic heart disease.4 It is well known that cerebral aneurysms have a higher prevalence in women compared with men (prevalence ratio of 1.61 (1.02–2.54) overall and a prevalence ratio of 2.2 (1.3–3.6) in populations with a mean age >50 years).5 The incidence of subarachnoid hemorrhage is also higher in females compared with males.6 Preliminary work has investigated a role for estrogen in mitigating subarachnoid hemorrhage.7 The strength of this article is found in its examination of the effects of sex on the biochemical processes mitigating aneurysm rupture.The authors used human data from the International Study of Unruptured Intracranial Aneurysms to determine if sexual dimorphism exists in response of human cerebral aneurysms to aspirin.8 The authors found that the proportion of subarachnoid hemorrhage in males using aspirin ≥3 times per week to daily (6%) was significantly lower than the proportion in males using aspirin less frequently (47%; P 0.05).The authors investigated the aspirin effect in mice to elucidate potential protective mechanisms and also to investigate a potential sex difference in aspirin response. The incidence of aneurysm rupture was significantly lower, and survival was significantly higher in the aspirin-treated and cyclooxygenase-2 (COX 2) inhibitor–treated groups. Additionally, expression of matrix metalloproteinase-9, which has been shown to degrade cerebral aneurysm walls, was diminished in the aspirin and COX-2 inhibitor groups. Examination of COX-1 knockout and mPGES-1 (microsomal prostaglandin E synthase-1) knockout mice suggested that the protective effects of aspirin are likely mediated through COX-2 inhibition rather than through COX-1 inhibition. The authors next examined a sex differential response to aspirin in mice. The incidence of cerebral aneurysm rupture was significantly lower in male mice. Furthermore, expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) was significantly higher in male mice, whereas COX-2, CD-68, matrix metalloproteinase-9, MCP-1 (monocyte chemoattractant protein-1), and NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) expression were significantly higher in female mice.Perhaps the most important finding to come from this article is the data on differential expression of 15-PGDH between male and female mice. This enzyme converts prostaglandin E2 to 15-keto-prostaglandin E2, an endogenous peroxisome proliferator–activated receptor γ agonist. Peroxisome proliferator–activated receptor γ agonists have previously been shown to reduce cerebral aneurysm formation and rupture.10 15-PGDH expression was significantly higher in the aspirin, COX-1 inhibitor, and COX-2 inhibitor groups compared with controls. Aneurysm formation and rupture rates were similar, and the sex difference was abolished between male mice treated with aspirin and a 15-PGDH inhibitor and female mice treated with aspirin and a 15-PGDH activator. Female mice treated with aspirin and a 15-PGDH activator had a significantly lower risk of rupture (25%) compared with female mice (75%) receiving aspirin alone. The protective effects of aspirin on rupture may be mediated through its ability to inhibit COX-2 and activate 15-PGDH, thereby increasing an endogenous peroxisome proliferator–activated receptor γ agonist. Thus, the authors have uncovered a sex difference in response to aspirin that seems to be mediated, at least partly, by sex differences in 15-PGDH activation (Figure).There are important limitations to the study that should be discussed. As the authors point out, there remains some question as to whether the murine aneurysm model accurately mimics the human disease. Speaking from experience, intracranial aneurysms are often found to be complex lesions at surgery. The walls may be calcified and atherosclerotic, evidence that these lesions have taken quite some time to develop. Additionally, the great variability between lesions suggests multiple underlying processes leading to development and rupture in humans. It is likely that the cascade of biomechanical and cellular processes at work in the humans are more diverse and long standing when compared with the simplified mechanisms by which these mice develop aneurysms. The aspirin dose required to prevent aneurysm rupture in humans needs to be further explored. In this study, the murine dose of aspirin was disproportionately high compared with the 325 mg dose in humans from in International Study of Unruptured Intracranial Aneurysms. It would also be interesting to determine if varying the dose of aspirin could overcome the sex differences in response. Similarly, determining if COX-2 inhibitors demonstrate a sex difference in response would be interesting.Despite significant clinical data demonstrating the impact of sex on cerebral aneurysm incidence and rupture, this important variable had been largely neglected. This work is indicative of the need for a comprehensive understanding of sex differences in cerebrovascular disease.Download figureDownload PowerPointFigure. A, Under physiological conditions, 15-hydroxyprostaglandin dehydrogenase (15-PGDH) converts prostaglandin E2 (PGE2) to 15-keto-PGE2, a peroxisome proliferator–activated receptor γ (PPAR γ) agonist. PPAR γ agonists have been previously shown to reduce the incidence of aneurysm formation and rupture. Aspirin may activate 15-PGDH, which increases 15-keto-PGE2 activity and further reduces the incidence of aneurysm rupture. B, The sex difference in aneurysm rupture is abolished when under physiological conditions 15-PGDH converts PGE2 to 15-keto-PGE2, a PPAR γ agonist. PPAR γ agonists have been previously shown to reduce the incidence of aneurysm formation and rupture. Aspirin may activate 15-PGDH, which increases 15-keto-PGE2 activity and further reduces the incidence of aneurysm rupture. C, Female mice treated with aspirin and a 15-PGDH activator demonstrates an increase in 15-keto-PGE2 activity and experiences a significantly lower risk of aneurysm rupture when compared with mice treated with aspirin alone.DisclosuresNone.FootnotesThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Correspondence to Aaron S. Dumont, Department of Neurosurgery, Tulane University School of Medicine, Suite 1300, 131 S Robertson St, New Orleans, LA 70112. E-mail [email protected]References1. Hasan DM, Chalouhi N, Jabbour P, Dumont AS, Kung DK, Magnotta VA, Young WL, Hashimoto T, Richard Winn H, Heistad D. Evidence that acetylsalicylic acid attenuates inflammation in the walls of human cerebral aneurysms: preliminary results.J Am Heart Assoc. 2013; 2:e000019. doi: 10.1161/JAHA.112.000019.LinkGoogle Scholar2. Chalouhi N, Hoh BL, Hasan D. Review of cerebral aneurysm formation, growth, and rupture.Stroke. 2013; 44:3613–3622. doi: 10.1161/STROKEAHA.113.002390.LinkGoogle Scholar3. Hasan DM, Mahaney KB, Brown RD, Meissner I, Piepgras DG, Huston J, Capuano AW, Torner JC; International Study of Unruptured Intracranial Aneurysms Investigators. Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture.Stroke. 2011; 42:3156–3162. doi: 10.1161/STROKEAHA.111.619411.LinkGoogle Scholar4. Crea F, Battipaglia I, Andreotti F. Sex differences in mechanisms, presentation and management of ischaemic heart disease.Atherosclerosis. 2015; 241:157–168. doi: 10.1016/j.atherosclerosis.2015.04.802.CrossrefMedlineGoogle Scholar5. Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis.Lancet Neurol. 2011; 10:626–636. doi: 10.1016/S1474-4422(11)70109-0.CrossrefMedlineGoogle Scholar6. Turan N, Heider RA, Zaharieva D, Ahmad FU, Barrow DL, Pradilla G. Sex differences in the formation of intracranial aneurysms and incidence and outcome of subarachnoid hemorrhage: review of experimental and human studies.Transl Stroke Res. 2016; 7:12–19. doi: 10.1007/s12975-015-0434-6.CrossrefMedlineGoogle Scholar7. Tada Y, Wada K, Shimada K, Makino H, Liang EI, Murakami S, Kudo M, Shikata F, Pena Silva RA, Kitazato KT, Hasan DM, Kanematsu Y, Nagahiro S, Hashimoto T. Estrogen protects against intracranial aneurysm rupture in ovariectomized mice.Hypertension. 2014; 63:1339–1344. doi: 10.1161/HYPERTENSIONAHA.114.03300.LinkGoogle Scholar8. Wiebers DO, Whisnant JP, Huston J, Meissner I, Brown RD, Piepgras DG, Forbes GS, Thielen K, Nichols D, O'Fallon WM, Peacock J, Jaeger L, Kassell NF, Kongable-Beckman GL, Torner JC; International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment.Lancet. 2003; 362:103–110.CrossrefMedlineGoogle Scholar9. Chalouhi N, Starke RM, Correa T, Jabbour PM, Zanaty M, Brown RD, Torner JC, Hasan DM. Differential sex response to aspirin in decreasing aneurysm rupture in humans and mice.Hypertension. 2016; 68:411–417. doi: 10.1161/HYPERTENSIONAHA.116.07515.LinkGoogle Scholar10. Hasan DM, Starke RM, Gu H, Wilson K, Chu Y, Chalouhi N, Heistad DD, Faraci FM, Sigmund CD. Smooth muscle peroxisome proliferator-activated receptor γ plays a critical role in formation and rupture of cerebral aneurysms in mice in vivo.Hypertension. 2015; 66:211–220. doi: 10.1161/HYPERTENSIONAHA.115.05332.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails August 2016Vol 68, Issue 2Article InformationMetrics Download: 255 © 2016 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.116.07606PMID: 27296992 Originally publishedJune 13, 2016 PDF download SubjectsHypertensionBasic Science ResearchVascular DiseaseCerebral Aneurysm