- Email: [email protected]
Intracranial Aneurysm Pathophysiology: To Bleed, or not To Bleed, That Is the Question
Accepted Manuscript Intracranial aneurysm pathophysiology: to bleed, or not to bleed, that is the question Morgan Broggi, M.D., Ph. D., Francesco Acerbi, M.D., Ph.D. PII:
S1878-8750(15)00968-7
DOI:
10.1016/j.wneu.2015.08.001
Reference:
WNEU 3097
To appear in:
World Neurosurgery
Received Date: 31 July 2015 Accepted Date: 1 August 2015
Please cite this article as: Broggi M, Acerbi F, Intracranial aneurysm pathophysiology: to bleed, or not to bleed, that is the question, World Neurosurgery (2015), doi: 10.1016/j.wneu.2015.08.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT INVITED PERSPECTIVE on Manuscript WNS-15-458R1:” Fusiform aneurysms are associated with aortic root dilatation in patients with subarachnoid hemorrhage”
RI PT
Title: Intracranial aneurysm pathophysiology: to bleed, or not to bleed, that is the question.
SC
Short title: Genetic profiles and associations of intracranial aneurysms
Morgan Broggi, M.D., Ph. D. Francesco Acerbi, M.D., Ph.D.
M AN U
Authors:
Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano,
EP
TE D
Italy
AC C
Corresponding author’s details: Morgan Broggi, M.D., Ph.D. Department of Neurosurgery
Fondazione IRCCS Istituto Neurologico Carlo Besta - Address: via Celoria 11, 20133 Milano, Italy - Phone: +39 02 23942411 - Fax: +39 02 70635017 - email: [email protected] 1
Broggi M.
ACCEPTED MANUSCRIPT Highlights: -
Intracranial aneurysms should be considered a multifactorial disease
-
Genetic studies could provide new data on aneurysms pathophysiology
-
The association between congenital aortopathies and intracranial aneurysms indicate a possible common underlying pathophysiology The future hope is to identify on genetic basis those aneurysms that are more
RI PT
-
susceptible to rupture
AC C
EP
TE D
M AN U
single nucleotide polymorphisms; biobank
SC
Keywords: intracranial aneurysm; subarachnoid hemorrhage; aortopathies; genetic;
2
Broggi M.
ACCEPTED MANUSCRIPT Manuscript: At the beginning of neurosurgery, more or less a hundred years ago, intracranial aneurysms (IA) were considered a sporadic disease with unknown etiology. All efforts were directed to promptly recognize their principal clinical manifestation, subarachnoid hemorrhage (SAH), in order to try to save, unfortunately in low percentage of cases,
RI PT
patients’ lives through the only possible treatment, the surgical clipping of the IA neck. However, around seventy years ago, O’Brein first reported a history of SAH in several members of a family (12); in more recent times it has been demonstrated that relatives of IA patients that presented a SAH are at higher risk to develop SAH than the general
SC
population (16); indeed, familial intracranial aneurysm syndrome was discovered (24). Moreover, it has been shown that IA are also associated with some genetic diseases that
M AN U
share connective tissue disorders (autosomal dominant polycystic kidney disease, neurofibromatosis type I, Marfan syndrome, Ehlers-Danlos syndrome types II and IV). Today, the scenario has completely changed: surgical treatment made incredible progress with minimally invasive approaches and with revascularization techniques and endovascular coiling and stenting are now available. Anyway, the exact pathophysiologic mechanism that underlies IA genesis, growth and especially rupture has not been fully
TE D
clarified yet despite many studies performed in the past and many others that are still running worldwide concerning this issue.
The current picture of the problem estimates that 3% of the general population could
EP
develop an IA, while rupture incidence is only 9/100,000/year (5, 22). The consequences of rupture are dramatic even these days: as shown in a recent literature review (20), median case-fatality at one months is 40.4% (range 13.1%-61%) and at one year is 54.7%
AC C
(range 46%-63.6%), and only a minority of patients (approximately 25%) are able to carry out an independent life after SAH. Because of the young age at onset and the poor prognosis, the loss of productive life-years is comparable to that of ischemic stroke. The discrepancy between IA prevalence and rupture rate indicates that some aneurysms are more prone to rupture than others. As a consequence of this, researchers begin to plan their studies with the aim of finding those factors possibly involved in SAH development. Two main fields were under investigation: the joint action of biomedical and behavioral factors and some kind of genetic predisposition.
3
Broggi M.
ACCEPTED MANUSCRIPT Many prognostic factors for aneurysm rupture have been considered (23). In particular, size and location of the aneurysms have been found to correlate to risk of rupture, with higher risks for larger aneurysms and those located in the posterior circulation (9, 10, 11, 15, 19). Other risk factors for IA rupture include smoking, hypertension, excessive alcohol consumption, non-white ethnicity and female gender (2, 7). Very recently, a predictive
RI PT
model of saccuar IA (sIA) risk of rupture including age, hypertension, geographical region, history of previous SAH, aneurysm size and location, the PHASES-score, was proposed (8). However, it did not consider other possible factors implicated in the mechanisms of sIA rupture and it was not validated in independent series of unruptured sIA. It was also
SC
supposed that the genetic profile could contribute to IA rupture susceptibility; emerging evidence, in fact, suggests that a positive family history represents the strongest known risk factor for SAH from ruptured IA, indicating that heritable DNA variation may influence
M AN U
IA susceptibility (6, 21).
All most relevant studies on genetic predisposition were done through genome-wide association study (GWAS) in order to find single nucleotide polymorphisms (SNPs) associated with IA, independently from the presence of SAH. In 2008, a multicenter collaboration led to complete a multistage GWAS that identified common variants that
TE D
contribute to IA formation in three large cohorts: a Finnish cohort of 920 cases and 985 controls, a Dutch cohort of 781 cases and 6424 controls and a Japanese cohort of 495 cases and 676 controls: common SNPs on chromosomes 2q, 8q and 9p were identified and showed significant association with IA (3). By candidate-gene and GWAS approaches,
EP
a strong association between IA risk and other 7 SNPs at 6 genetic loci encompassing the genes CDKN2B-AS, STARD13-KL, RBBP8, SOX17, CNNM2, and EDNRA were identified
AC C
(1, 21, 26). It was hypothesized that implicated gene products might have a role in cell cycle progression, in the proliferation, senescence and differentiation of progenitor-cell populations, in vascular endothelial maintenance, integrity of the extracellular cellular matrix, and inflammation (18, 26). It should be underlined, anyway, that these two fields of research should not be considered separately, but, on the contrary, there are complex interactions between genetic and environmental/behavioral risk factors. Indeed, given those known non-genetic factors (smoking habits, hypertension, frequent alcohol intake, et cetera) associated with aneurysm formation and subsequent SAH, there is the possibility that these risk factors might hinder the identification of genetic effects. Therefore, studies evaluating genuine 4
Broggi M.
ACCEPTED MANUSCRIPT genetic effects of SNPs contributing to IA must always take in account whether invariable risk factors (e.g. female gender, previous history of SAH) and other modifiable lifestyle factors (e.g. smoking habits, alcohol abuse) could affect an association of each SNP with IA. Nevertheless, no specific loci associated with sIA rupture have been identified yet and very
RI PT
few studies have been performed to compare the genetic of ruptured IA and unruptured IA jointly with an analysis of behavioral risk factors (25); in order to make this possible, large multicenter trials with centralized dedicated biobanks are needed.
SC
Another critical field of interest is represented by the association between IA and other arterial diseases, with aortopathies being by far the more investigated. Specifically, Bicuspid aortic valve (BAV) and coarctation of the aorta (CoA) are congenital conditions
M AN U
that frequently occur with dilated aortic root and aortic or cervical dissection; IA are also more prevalent in patients with BAV or CoA, implying that IA and aortic pathologies share a common developmental defect (13). In recent times there has been a growing interest on an echocardiographic marker, aortic root dimension (ARD)(17), since it seems able to depict a common intrinsic wall defect in IA and aorthopathies (13). Moreover, a recent study evaluated if there was a site-specific relationship between IA and Aortic Aneurysms
TE D
(AA) (14): anterior circulation-IA were found to be most frequent in ascending AA group, while internal carotid artery-IA were found mostly in infrarenal AA group, thus suggesting a site-specific sharing of pathogenical mechanism between the 2 types of aneurysms.
EP
The interesting study from Can et al, recently published in World Neurosurgery (4), tried to further deepen the knowledge on possible correlations between IA and aorthopathy, also
AC C
using ARD as a marker. They studied retrospectively a cohort of 151 patients with SAH related to IA rupture, and the analysis performed by multivariate linear regression showed that male gender and the presence of a fusiform aneurysm were correlated with larger ARD (p<0.01 and p=0.041 respectively). They proposed that the association of fusiform aneurysms (and not sIA) with higher ARD could suggest a common pathophysiological mechanism with aortopathy. There are some limitations that the authors honestly recognized, related to the retrospective design of the study, the lack of data about familial history of IA and aortopathy and the bias of selection only patients with available data on echocardiography. In addition, the number of fusiform compared to saccular aneurysms is small and thus a large multicentric study, maybe incorporating other aspects of aortopathy
5
Broggi M.
ACCEPTED MANUSCRIPT and also including and analyzing ruptured and unruptured IA, would be required to confirm this association and possibly exploring causality too. However, even with the results of this future study, we will not have definitive data on “the black hole” of research on sIA, i.e: how to clearly identify the subgroup of patients
AC C
EP
TE D
M AN U
SC
represent the final aim of the future research on IA.
RI PT
that are more prone to rupture? We believe that the answer to this question should
6
Broggi M.
ACCEPTED MANUSCRIPT References: 1. Akiyama K, arita A, Nakaoka H, Cui T, Takahashi T, Yasuno K, Tajima A, Krischek B, Yamamoto K, Kasuya H, Hata A, Inoue I. Genome-wide association study to identify genetic variants present in Japanese patients harboring intracranial aneurysms. J Hum Genet 55(10);656-661, 2010.
RI PT
2. Andreasen TH, Bartek J Jr, Andresen M, Springborg JB, Romner B. Modifiable risk factors for aneurysmal subarachnoid hemorrhage. Stroke 44:3607-3612, 2013. 3. Bilguvar K, Yasuno K, Niemela M, Ruigrok YM, von Und Zu Fraunberg M, van Duijn CM, van den Berg LH, Mane S, Mason CE, Choi M, Gaál E, Bayri Y, Kolb L, Arlier
SC
Z, Ravuri S, Ronkainen A, Tajima A, Laakso A, Hata A, Kasuya H, Koivisto T, Rinne J, Ohman J, Breteler MM, Wijmenga C, State MW, Rinkel GJ, Hernesniemi J,
M AN U
Jääskeläinen JE, Palotie A, Inoue I, Lifton RP, Günel M. Susceptibility loci for intracranial aneurysm in European and Japanese populations. Nat Genet 40:1472– 1477, 2008.
4. Can A, Xu J, Volovici V, Dammers R, Dirven CM, MacRae CA, Du R. Fusiform aneurysms are associated with aortic root dilatation in patients with subarachnoid hemorrhage. World Neurosurg [Epub ahead of print], 2015.
TE D
5. de Rooij NK, Linn FH, van der Plas JA, Algra A, Rinkel GJ. Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry 78:1365-1372, 2007. 6. Farlow JL, Lin H, Sauerbeck L, Lai D, Koller DL, Pugh E, Hetrick K, Ling H,
EP
Kleinloog R, van der Vlies P, Deelen P, Swertz MA, Verweij BH, Regli L, Rinkel GJ, Ruigrok YM, Doheny K, Liu Y, Broderick J, Foroud T; FIA Study Investigators.
AC C
Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm. PLoS One 10(3):e0121104, 2015. 7. Feigin VL, Rinkel GJ, Lawes CM, Algra A, Bennett DA, van Gijn J, Anderson CS. Risk factors for subarachnoid hemorrhage: an updated systematic review of epidemiological studies. Stroke 36:2773-2780, 2005. 8. Greving JP, Wermer MJ, Brown RD Jr, Morita A, Juvela S, Yonekura M, Ishibashi T, Torner JC, Nakayama T, Rinkel GJ, Algra A. Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies. Lancet Neurol 13:59-66, 2014.
7
Broggi M.
ACCEPTED MANUSCRIPT 9. International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms--risk of rupture and risks of surgical intervention. N Engl J Med 339(24):1725-1733, 1998. 10. Ishibashi T, Murayama Y, Urashima M, Saguchi T, Ebara M, Arakawa H, Irie K, Takao H, Abe T. Unruptured intracranial aneurysms: incidence of rupture and risk
RI PT
factors. Stroke 40(1):313-316, 2009. 11. Juvela S, Poussa K, Lehto H, Porras M. Natural history of unruptured intracranial aneurysms: a long-term follow-up study. Stroke 44(9):2414-2421, 2013. 12. O’Brien JG. SAH in identical twins. BMJ 1: 607-608, 1942.
SC
13. Shin YW, Jung KH, Kim JM, Cho YD, Lee ST, Chu K, Kim M, Lee SK, Han MH, Roh JK. Echocardiographic evidence of innate aortopathy in the human intracranial aneurysm. PLoS One 25;9(6):e100569, 2014.
M AN U
14. Shin YW, Jung KH, Moon J, Lee ST, Lee SK, Chu K, Roh JK. Site-specific relationship between intracranial aneurysm and aortic aneurysm. Stroke46(7):19931996, 2015.
15. Sonobe M, Yamazaki T, Yonekura M, Kikuchi H. Small unruptured intracranial aneurysm verification study: SUAVe study, Japan. Stroke 41(9):1969-1977, 2010. 16. Teasdale GM, Wardlaw JM, White PM, Murray G, Teasdale EM, Easton V, Davie
TE D
Cooper Scottish Aneurysm Study Group. The familial risk of subarachnoid haemorrhage. Brain 128(Pt 7):1677-1685, 2005. 17. Teixido-Tura G, Almeida AL, Choi EY, Gjesdal O, Jacobs DR Jr, Dietz HC, Liu K,
EP
Sidney S, Lewis CE, Garcia-Dorado D, Evangelista A, Gidding S, Lima JA.Determinants of Aortic Root Dilatation and Reference Values Among Young Adults Over a 20-Year Period: Coronary Artery Risk Development in Young Adults
AC C
Study. Hypertension 66(1):23-29, 2015. 18. Tromp G, Weinsheimer S, Ronkainen A, Kuivaniemi H. Molecular basis and genetic predisposition to intracranial aneurysm. Ann Med 46(8):597-606, 2014. 19. UCAS Japan Investigators, Morita A, Kirino T, Hashi K, Aoki N, Fukuhara S, Hashimoto N, Nakayama T, Sakai M, Teramoto A, Tominari S, Yoshimoto T. The natural course of unruptured cerebral aneurysms in a Japanese cohort. N Engl J Med 366(26):2474-2482, 2012.
8
Broggi M.
ACCEPTED MANUSCRIPT 20. van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol 9:167-176, 2010. 21. van 't Hof FN, Kurki MI, Kleinloog R, de Bakker PI, von und zu Fraunberg M,
RI PT
Jääskeläinen JE, Gaál EI, Lehto H, Kivisaari R, Laakso A, Niemelä M, Hernesniemi J, Brouwer MC, van de Beek D, Rinkel GJ, Ruigrok YM. Genetic risk load according to the site of intracranial aneurysms. Neurology 83(1):34-39, 2014.
22. Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial
SC
aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol 10:626-636, 2011. 23. Wermer MJ, van der Schaaf IC, Algra A, Rinkel GJ. Risk of rupture of unruptured
M AN U
intracranial aneurysms in relation to patient and aneurysm characteristics: an updated meta-analysis. Stroke 38(4):1404-1410, 2007.
24. Wills S, Ronkainen A, van der Voet M, Kuivaniemi H, Helin K, Leinonen E, Frösen J, Niemela M, Jääskeläinen J, Hernesniemi J, Tromp G. Familial intracranial aneurysms: an analysis of 346 multiplex Finnish families. Stroke 34(6):1370-1374, 2003.
TE D
25. Yang S, Wang T, You C, Liu W, Zhao K, Sun H, Mao B, Li X, Xiao A, Mao X, Zhang H. Association of polymorphisms in the elastin gene with sporadic ruptured intracranial aneurysms and unruptured intracranial aneurysms in Chinese patients.
EP
Int J Neurosci 123(7):454-458, 2013.
26. Yasuno K, Bilguvar K, Bijlenga P, Low SK, Krischek B, Auburger G, Simon M, Krex
D, Arlier Z, Nayak N, Ruigrok YM, Niemelä M, Tajima A, von und zu Fraunberg M,
AC C
Dóczi T, Wirjatijasa F, Hata A, Blasco J, Oszvald A, Kasuya H, Zilani G, Schoch B, Singh P, Stüer C, Risselada R, Beck J, Sola T, Ricciardi F, Aromaa A, Illig T, Schreiber S, van Duijn CM, van den Berg LH, Perret C, Proust C, Roder C, Ozturk AK, Gaál E, Berg D, Geisen C, Friedrich CM, Summers P, Frangi AF, State MW, Wichmann HE, Breteler MM, Wijmenga C, Mane S, Peltonen L, Elio V, Sturkenboom MC, Lawford P, Byrne J, Macho J, Sandalcioglu EI, Meyer B, Raabe A, Steinmetz H, Rüfenacht D, Jääskeläinen JE, Hernesniemi J, Rinkel GJ, Zembutsu H, Inoue I, Palotie A, Cambien F, Nakamura Y, Lifton RP, Günel M. Genome-wide association study of intracranial aneurysms identifies three new risk loci. Nat Genet 42(5):420-425, 2010. 9
S1878-8750(15)00968-7
DOI:
10.1016/j.wneu.2015.08.001
Reference:
WNEU 3097
To appear in:
World Neurosurgery
Received Date: 31 July 2015 Accepted Date: 1 August 2015
Please cite this article as: Broggi M, Acerbi F, Intracranial aneurysm pathophysiology: to bleed, or not to bleed, that is the question, World Neurosurgery (2015), doi: 10.1016/j.wneu.2015.08.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT INVITED PERSPECTIVE on Manuscript WNS-15-458R1:” Fusiform aneurysms are associated with aortic root dilatation in patients with subarachnoid hemorrhage”
RI PT
Title: Intracranial aneurysm pathophysiology: to bleed, or not to bleed, that is the question.
SC
Short title: Genetic profiles and associations of intracranial aneurysms
Morgan Broggi, M.D., Ph. D. Francesco Acerbi, M.D., Ph.D.
M AN U
Authors:
Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano,
EP
TE D
Italy
AC C
Corresponding author’s details: Morgan Broggi, M.D., Ph.D. Department of Neurosurgery
Fondazione IRCCS Istituto Neurologico Carlo Besta - Address: via Celoria 11, 20133 Milano, Italy - Phone: +39 02 23942411 - Fax: +39 02 70635017 - email: [email protected] 1
Broggi M.
ACCEPTED MANUSCRIPT Highlights: -
Intracranial aneurysms should be considered a multifactorial disease
-
Genetic studies could provide new data on aneurysms pathophysiology
-
The association between congenital aortopathies and intracranial aneurysms indicate a possible common underlying pathophysiology The future hope is to identify on genetic basis those aneurysms that are more
RI PT
-
susceptible to rupture
AC C
EP
TE D
M AN U
single nucleotide polymorphisms; biobank
SC
Keywords: intracranial aneurysm; subarachnoid hemorrhage; aortopathies; genetic;
2
Broggi M.
ACCEPTED MANUSCRIPT Manuscript: At the beginning of neurosurgery, more or less a hundred years ago, intracranial aneurysms (IA) were considered a sporadic disease with unknown etiology. All efforts were directed to promptly recognize their principal clinical manifestation, subarachnoid hemorrhage (SAH), in order to try to save, unfortunately in low percentage of cases,
RI PT
patients’ lives through the only possible treatment, the surgical clipping of the IA neck. However, around seventy years ago, O’Brein first reported a history of SAH in several members of a family (12); in more recent times it has been demonstrated that relatives of IA patients that presented a SAH are at higher risk to develop SAH than the general
SC
population (16); indeed, familial intracranial aneurysm syndrome was discovered (24). Moreover, it has been shown that IA are also associated with some genetic diseases that
M AN U
share connective tissue disorders (autosomal dominant polycystic kidney disease, neurofibromatosis type I, Marfan syndrome, Ehlers-Danlos syndrome types II and IV). Today, the scenario has completely changed: surgical treatment made incredible progress with minimally invasive approaches and with revascularization techniques and endovascular coiling and stenting are now available. Anyway, the exact pathophysiologic mechanism that underlies IA genesis, growth and especially rupture has not been fully
TE D
clarified yet despite many studies performed in the past and many others that are still running worldwide concerning this issue.
The current picture of the problem estimates that 3% of the general population could
EP
develop an IA, while rupture incidence is only 9/100,000/year (5, 22). The consequences of rupture are dramatic even these days: as shown in a recent literature review (20), median case-fatality at one months is 40.4% (range 13.1%-61%) and at one year is 54.7%
AC C
(range 46%-63.6%), and only a minority of patients (approximately 25%) are able to carry out an independent life after SAH. Because of the young age at onset and the poor prognosis, the loss of productive life-years is comparable to that of ischemic stroke. The discrepancy between IA prevalence and rupture rate indicates that some aneurysms are more prone to rupture than others. As a consequence of this, researchers begin to plan their studies with the aim of finding those factors possibly involved in SAH development. Two main fields were under investigation: the joint action of biomedical and behavioral factors and some kind of genetic predisposition.
3
Broggi M.
ACCEPTED MANUSCRIPT Many prognostic factors for aneurysm rupture have been considered (23). In particular, size and location of the aneurysms have been found to correlate to risk of rupture, with higher risks for larger aneurysms and those located in the posterior circulation (9, 10, 11, 15, 19). Other risk factors for IA rupture include smoking, hypertension, excessive alcohol consumption, non-white ethnicity and female gender (2, 7). Very recently, a predictive
RI PT
model of saccuar IA (sIA) risk of rupture including age, hypertension, geographical region, history of previous SAH, aneurysm size and location, the PHASES-score, was proposed (8). However, it did not consider other possible factors implicated in the mechanisms of sIA rupture and it was not validated in independent series of unruptured sIA. It was also
SC
supposed that the genetic profile could contribute to IA rupture susceptibility; emerging evidence, in fact, suggests that a positive family history represents the strongest known risk factor for SAH from ruptured IA, indicating that heritable DNA variation may influence
M AN U
IA susceptibility (6, 21).
All most relevant studies on genetic predisposition were done through genome-wide association study (GWAS) in order to find single nucleotide polymorphisms (SNPs) associated with IA, independently from the presence of SAH. In 2008, a multicenter collaboration led to complete a multistage GWAS that identified common variants that
TE D
contribute to IA formation in three large cohorts: a Finnish cohort of 920 cases and 985 controls, a Dutch cohort of 781 cases and 6424 controls and a Japanese cohort of 495 cases and 676 controls: common SNPs on chromosomes 2q, 8q and 9p were identified and showed significant association with IA (3). By candidate-gene and GWAS approaches,
EP
a strong association between IA risk and other 7 SNPs at 6 genetic loci encompassing the genes CDKN2B-AS, STARD13-KL, RBBP8, SOX17, CNNM2, and EDNRA were identified
AC C
(1, 21, 26). It was hypothesized that implicated gene products might have a role in cell cycle progression, in the proliferation, senescence and differentiation of progenitor-cell populations, in vascular endothelial maintenance, integrity of the extracellular cellular matrix, and inflammation (18, 26). It should be underlined, anyway, that these two fields of research should not be considered separately, but, on the contrary, there are complex interactions between genetic and environmental/behavioral risk factors. Indeed, given those known non-genetic factors (smoking habits, hypertension, frequent alcohol intake, et cetera) associated with aneurysm formation and subsequent SAH, there is the possibility that these risk factors might hinder the identification of genetic effects. Therefore, studies evaluating genuine 4
Broggi M.
ACCEPTED MANUSCRIPT genetic effects of SNPs contributing to IA must always take in account whether invariable risk factors (e.g. female gender, previous history of SAH) and other modifiable lifestyle factors (e.g. smoking habits, alcohol abuse) could affect an association of each SNP with IA. Nevertheless, no specific loci associated with sIA rupture have been identified yet and very
RI PT
few studies have been performed to compare the genetic of ruptured IA and unruptured IA jointly with an analysis of behavioral risk factors (25); in order to make this possible, large multicenter trials with centralized dedicated biobanks are needed.
SC
Another critical field of interest is represented by the association between IA and other arterial diseases, with aortopathies being by far the more investigated. Specifically, Bicuspid aortic valve (BAV) and coarctation of the aorta (CoA) are congenital conditions
M AN U
that frequently occur with dilated aortic root and aortic or cervical dissection; IA are also more prevalent in patients with BAV or CoA, implying that IA and aortic pathologies share a common developmental defect (13). In recent times there has been a growing interest on an echocardiographic marker, aortic root dimension (ARD)(17), since it seems able to depict a common intrinsic wall defect in IA and aorthopathies (13). Moreover, a recent study evaluated if there was a site-specific relationship between IA and Aortic Aneurysms
TE D
(AA) (14): anterior circulation-IA were found to be most frequent in ascending AA group, while internal carotid artery-IA were found mostly in infrarenal AA group, thus suggesting a site-specific sharing of pathogenical mechanism between the 2 types of aneurysms.
EP
The interesting study from Can et al, recently published in World Neurosurgery (4), tried to further deepen the knowledge on possible correlations between IA and aorthopathy, also
AC C
using ARD as a marker. They studied retrospectively a cohort of 151 patients with SAH related to IA rupture, and the analysis performed by multivariate linear regression showed that male gender and the presence of a fusiform aneurysm were correlated with larger ARD (p<0.01 and p=0.041 respectively). They proposed that the association of fusiform aneurysms (and not sIA) with higher ARD could suggest a common pathophysiological mechanism with aortopathy. There are some limitations that the authors honestly recognized, related to the retrospective design of the study, the lack of data about familial history of IA and aortopathy and the bias of selection only patients with available data on echocardiography. In addition, the number of fusiform compared to saccular aneurysms is small and thus a large multicentric study, maybe incorporating other aspects of aortopathy
5
Broggi M.
ACCEPTED MANUSCRIPT and also including and analyzing ruptured and unruptured IA, would be required to confirm this association and possibly exploring causality too. However, even with the results of this future study, we will not have definitive data on “the black hole” of research on sIA, i.e: how to clearly identify the subgroup of patients
AC C
EP
TE D
M AN U
SC
represent the final aim of the future research on IA.
RI PT
that are more prone to rupture? We believe that the answer to this question should
6
Broggi M.
ACCEPTED MANUSCRIPT References: 1. Akiyama K, arita A, Nakaoka H, Cui T, Takahashi T, Yasuno K, Tajima A, Krischek B, Yamamoto K, Kasuya H, Hata A, Inoue I. Genome-wide association study to identify genetic variants present in Japanese patients harboring intracranial aneurysms. J Hum Genet 55(10);656-661, 2010.
RI PT
2. Andreasen TH, Bartek J Jr, Andresen M, Springborg JB, Romner B. Modifiable risk factors for aneurysmal subarachnoid hemorrhage. Stroke 44:3607-3612, 2013. 3. Bilguvar K, Yasuno K, Niemela M, Ruigrok YM, von Und Zu Fraunberg M, van Duijn CM, van den Berg LH, Mane S, Mason CE, Choi M, Gaál E, Bayri Y, Kolb L, Arlier
SC
Z, Ravuri S, Ronkainen A, Tajima A, Laakso A, Hata A, Kasuya H, Koivisto T, Rinne J, Ohman J, Breteler MM, Wijmenga C, State MW, Rinkel GJ, Hernesniemi J,
M AN U
Jääskeläinen JE, Palotie A, Inoue I, Lifton RP, Günel M. Susceptibility loci for intracranial aneurysm in European and Japanese populations. Nat Genet 40:1472– 1477, 2008.
4. Can A, Xu J, Volovici V, Dammers R, Dirven CM, MacRae CA, Du R. Fusiform aneurysms are associated with aortic root dilatation in patients with subarachnoid hemorrhage. World Neurosurg [Epub ahead of print], 2015.
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