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  • 1
    Online Resource
    Online Resource
    Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Stroke Vol. 54, No. 3 ( 2023-03), p. 810-818
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 54, No. 3 ( 2023-03), p. 810-818
    Abstract: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.122.040715
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 1467823-8
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  • 2
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    Role of hemodynamics in initiation/growth of intracranial aneurysms
    Wiley ; 2018
    In:  European Journal of Clinical Investigation Vol. 48, No. 9 ( 2018-09)
    Details
    In: European Journal of Clinical Investigation, Wiley, Vol. 48, No. 9 ( 2018-09)
    Abstract: Intracranial aneurysm (IA) is a disease of the vascular wall resulting in abnormal enlargement of the vessel lumen. It is a common pathology with a prevalence of 2%‐3% in the adult population. IAs are mostly small, quiescent and asymptomatic; yet, upon rupture, severe brain damage or even death is frequently encountered. In addition to clinical factors, hemodynamic forces, mainly wall shear stress (WSS), have been associated with the initiation of IAs and possibly with their risk of rupture. However, the mechanism by which WSS contributes to aneurysm growth and rupture is not completely understood. Design PubMed and Ovid MEDLINE databases were searched. In addition, key review articles were screened for relevant original publications. Results Current knowledge about the relation between WSS and IA has been obtained from both computational fluid dynamic studies in patients and experimental models of IA formation and growth. It is increasingly recognized that a high wall shear stress (gradient) participates to IA formation and that both low and high WSS can drive IA growth. Primary cilia (PC) play an important role as mechanosensors as patients with polycystic kidney disease, which is characterized by the absence or dysfunction of PC, have increased risk to develop IAs as well as increased risk of rupture. Conclusion Wall shear stress is a key player in IA initiation and progression. It is involved in vascular wall remodelling and inflammation, processes underlying aneurysm pathophysiology.
    Type of Medium: Online Resource
    ISSN: 0014-2972 , 1365-2362
    URL: Issue
    URL: Article
    DOI: 10.1111/eci.2018.48.issue-9
    DOI: 10.1111/eci.12992
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2004971-7
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  • 3
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    Sex-related differences in wall remodeling and intraluminal thrombus resolution in a rat saccular aneurysm model
    Journal of Neurosurgery Publishing Group (JNSPG) ; 2019
    In:  Journal of Neurosurgery ( 2019-12), p. 1-14
    Details
    In: Journal of Neurosurgery, Journal of Neurosurgery Publishing Group (JNSPG), ( 2019-12), p. 1-14
    Abstract: Intracranial aneurysms (IAs) are more often diagnosed in women. Hormones and vessel geometry, which influences wall shear stress, may affect pathophysiological processes of the arterial wall. Here, the authors investigated sex-related differences in the remodeling of the aneurysm wall and in intraluminal thrombus resolution. METHODS A well-characterized surgical side-wall aneurysm model was used in female, male, and ovariectomized rats. Decellularized grafts were used to model highly degenerated and decellularized IA walls and native grafts to model healthy IA walls. Aneurysm growth and thrombus composition were analyzed at 1, 7, 14, and 28 days. Sex-related differences in vessel wall remodeling were compared with human IA dome samples of men and pre- and postmenopausal women. RESULTS At 28 days, more aneurysm growth was observed in ovariectomized rats than in males or non-ovariectomized female rats. The parent artery size was larger in male rats than in female or ovariectomized rats, as expected. Wall inflammation increased over time in all groups and was most severe in the decellularized female and ovariectomized groups at 28 days compared with the male group. Likewise, in these groups the most elastin fragmentation was seen at 28 days. In female rats, on days 1, 7, and 14, the intraluminal thrombus was mainly composed of red blood cells and fibrin. On days 14 and 28, macrophage and smooth muscle cell invasion inside the thrombus was shown, leading to the removal of red blood cells and deposition of collagen and elastin. On days 14 and 28, similar profiles of thrombus reorganization were observed in male and ovariectomized female rats. However, collagen content in thrombi and vessel wall macrophage content were higher in aneurysms of male rats at 28 days than in those of female rats. On day 28, thrombus coverage by endothelial cells was lower in ovariectomized than in female or male rats. Finally, analysis of human IA domes showed that endothelial cell coverage was lower in men and postmenopausal women than in younger women. CONCLUSIONS Aneurysm growth and intraluminal thrombus resolution show sex-dependent differences. While certain processes (endothelial cell coverage and collagen deposition) point to a strong hormonal dependence, others (wall inflammation and aneurysm growth) seem to be influenced by both hormones and parent artery size.
    Type of Medium: Online Resource
    ISSN: 0022-3085 , 1933-0693
    URL: Article
    DOI: 10.3171/2019.9.JNS191466
    RVK:
    XA 10000
    RVK:
    XA 55270
    Language: Unknown
    Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
    Publication Date: 2019
    detail.hit.zdb_id: 2026156-1
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  • 4
    Online Resource
    Online Resource
    Unruptured intracranial aneurysm follow-up and treatment after morphological change is safe: observational study and systematic review
    BMJ ; 2016
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 87, No. 12 ( 2016-12), p. 1277-1282
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 87, No. 12 ( 2016-12), p. 1277-1282
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2016-313584
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2016
    detail.hit.zdb_id: 1480429-3
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  • 5
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    Online Resource
    Disturbed flow induces a sustained, stochastic NF-κB activation which may support intracranial aneurysm growth in vivo
    Springer Science and Business Media LLC ; 2019
    In:  Scientific Reports Vol. 9, No. 1 ( 2019-03-18)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2019-03-18)
    Abstract: Intracranial aneurysms are associated with disturbed velocity patterns, and chronic inflammation, but the relevance for these findings are currently unknown. Here, we show that (disturbed) shear stress induced by vortices is a sufficient condition to activate the endothelial NF-kB pathway, possibly through a mechanism of mechanosensor de-activation. We provide evidence for this statement through in-vitro live cell imaging of NF-kB in HUVECs exposed to different flow conditions, stochastic modelling of flow induced NF-kB activation and induction of disturbed flow in mouse carotid arteries. Finally, CFD and immunofluorescence on human intracranial aneurysms showed a correlation similar to the mouse vessels, suggesting that disturbed shear stress may lead to sustained NF-kB activation thereby offering an explanation for the close association between disturbed flow and intracranial aneurysms.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-019-40959-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2615211-3
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  • 6
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    Author Correction: Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors
    Springer Science and Business Media LLC ; 2021
    In:  Nature Genetics Vol. 53, No. 2 ( 2021-02), p. 254-254
    Details
    In: Nature Genetics, Springer Science and Business Media LLC, Vol. 53, No. 2 ( 2021-02), p. 254-254
    Type of Medium: Online Resource
    ISSN: 1061-4036 , 1546-1718
    URL: Article
    DOI: 10.1038/s41588-020-00760-4
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 1494946-5
    SSG: 12
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  • 7
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    Characteristics and Distribution of Intracranial Aneurysms in Patients with Autosomal Dominant Polycystic Kidney Disease Compared with the General Population: A Meta-Analysis
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Kidney360 Vol. 4, No. 4 ( 2023-04), p. e466-e475
    Details
    In: Kidney360, Ovid Technologies (Wolters Kluwer Health), Vol. 4, No. 4 ( 2023-04), p. e466-e475
    Abstract: IAs location distribution in patients with ADPKD differ from the ones in non-ADPKD patients IAs in patients with ADPKD are more commonly located in the anterior circulation and in large caliber arteries Because of IA multiplicity and singular IA distribution, patients with ADPKD represent a special population who need to be closely followed Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic condition associated with intracranial aneurysms (IAs). The associated pathophysiology remains unknown, but an association with wall shear stress is suspected. Cerebral arterial location is the principal factor influencing IA natural history. This study aims to compare IA location-specific distribution between ADPKD and non-ADPKD patients. Methods The ADPKD group comprised data from a systematic review of the literature (2016–2020, N =7) and three cohorts: integrated biomedical informatics for the management of cerebral aneurysms, Novosibirsk, and Unruptured Cerebral Aneurysms Study. The non-ADPKD group was formed from the integrated biomedical informatics for the management of cerebral aneurysms, Unruptured Cerebral Aneurysms Study, International Stroke Genetics Consortium, and the Finnish cohort from the literature. Patients and IAs characteristics were compared between ADPKD and non-ADPKD groups, and a meta-analysis for IA locations was performed. Results A total of 1184 IAs from patients with ADPKD were compared with 21,040 IAs from non-ADPKD patients. In total, 78.6% of patients with ADPKD had hypertension versus 39.2% of non-ADPKD patients. A total of 32.4% of patients with ADPKD were smokers versus 31.5% of non-ADPKD patients. In total, 30.1% of patients with ADPKD had a positive family history for IA versus 15.8% of the non-ADPKD patients. Patients with ADPKD showed a higher rate of IA multiplicity (33.2% versus 23.1%). IAs from patients with ADPKD showed a significant predominance across the internal carotid and middle cerebral arteries. Posterior communicating IAs were more frequently found in the non-ADPKD group. The meta-analysis confirmed a predominance of IAs in the patients with ADPKD across large caliber arteries (odds ratio [95% confidence interval]: internal carotid artery: 1.90 [1.10 to 3.29] ; middle cerebral artery: 1.18 [1.02–1.36]). Small diameter arteries, such as the posterior communicating, were observed more in non-ADPKD patients (0.21 [0.11–0.88] ). Conclusion This analysis shows that IAs diagnosed in patients with ADPKD are more often localized in large caliber arteries from the anterior circulation in comparison with IAs in non-ADPKD patients. It shows that primary cilia driven wall shear stress vessel remodeling to be more critical in cerebral anterior circulation large caliber arteries.
    Type of Medium: Online Resource
    ISSN: 2641-7650
    URL: Article
    DOI: 10.34067/KID.0000000000000092
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
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  • 8
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    Intracranial aneurysm wall (in)stability–current state of knowledge and clinical perspectives
    Springer Science and Business Media LLC ; 2021
    In:  Neurosurgical Review Vol. 45, No. 2 ( 2021-11-06), p. 1233-1253
    Details
    In: Neurosurgical Review, Springer Science and Business Media LLC, Vol. 45, No. 2 ( 2021-11-06), p. 1233-1253
    Abstract: Intracranial aneurysm (IA), a local outpouching of cerebral arteries, is present in 3 to 5% of the population. Once formed, an IA can remain stable, grow, or rupture. Determining the evolution of IAs is almost impossible. Rupture of an IA leads to subarachnoid hemorrhage and affects mostly young people with heavy consequences in terms of death, disabilities, and socioeconomic burden. Even if the large majority of IAs will never rupture, it is critical to determine which IA might be at risk of rupture. IA (in)stability is dependent on the composition of its wall and on its ability to repair. The biology of the IA wall is complex and not completely understood. Nowadays, the risk of rupture of an IA is estimated in clinics by using scores based on the characteristics of the IA itself and on the anamnesis of the patient. Classification and prediction using these scores are not satisfying and decisions whether a patient should be observed or treated need to be better informed by more reliable biomarkers. In the present review, the effects of known risk factors for rupture, as well as the effects of biomechanical forces on the IA wall composition, will be summarized. Moreover, recent advances in high-resolution vessel wall magnetic resonance imaging, which are promising tools to discriminate between stable and unstable IAs, will be described. Common data elements recently defined to improve IA disease knowledge and disease management will be presented. Finally, recent findings in genetics will be introduced and future directions in the field of IA will be exposed.
    Type of Medium: Online Resource
    ISSN: 1437-2320
    URL: Article
    DOI: 10.1007/s10143-021-01672-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 1474861-7
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  • 9
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    Primary cilia control endothelial permeability by regulating expression and location of junction proteins
    Oxford University Press (OUP) ; 2022
    In:  Cardiovascular Research Vol. 118, No. 6 ( 2022-05-06), p. 1583-1596
    Details
    In: Cardiovascular Research, Oxford University Press (OUP), Vol. 118, No. 6 ( 2022-05-06), p. 1583-1596
    Abstract: Wall shear stress (WSS) determines intracranial aneurysm (IA) development. Polycystic kidney disease (PKD) patients have a high IA incidence and risk of rupture. Dysfunction/absence of primary cilia in PKD endothelial cells (ECs) may impair mechano-transduction of WSS and favour vascular disorders. The molecular links between primary cilia dysfunction and IAs are unknown. Methods and results Wild-type and primary cilia-deficient Tg737orpk/orpk arterial ECs were submitted to physiological (30 dynes/cm2) or aneurysmal (2 dynes/cm2) WSS, and unbiased transcriptomics were performed. Tg737orpk/orpk ECs displayed a fivefold increase in the number of WSS-responsive genes compared to wild-type cells. Moreover, we observed a lower trans-endothelial resistance and a higher endothelial permeability, which correlated with disorganized intercellular junctions in Tg737orpk/orpk cells. We identified ZO-1 as a central regulator of primary cilia-dependent endothelial junction integrity. Finally, clinical and histological characteristics of IAs from non-PKD and PKD patients were analysed. IAs in PKD patients were more frequently located in the middle cerebral artery (MCA) territory than in non-PKD patients. IA domes from the MCA of PKD patients appeared thinner with less collagen and reduced endothelial ZO-1 compared with IA domes from non-PKD patients. Conclusion Primary cilia dampen the endothelial response to aneurysmal low WSS. In absence of primary cilia, ZO-1 expression levels are reduced, which disorganizes intercellular junctions resulting in increased endothelial permeability. This altered endothelial function may not only contribute to the severity of IA disease observed in PKD patients, but may also serve as a potential diagnostic tool to determine the vulnerability of IAs.
    Type of Medium: Online Resource
    ISSN: 0008-6363 , 1755-3245
    URL: Article
    DOI: 10.1093/cvr/cvab165
    RVK:
    WA 15000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 1499917-1
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  • 10
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    Data_Sheet_1.xlsx
    Frontiers Media SA ; 2021
    In:  Frontiers in Cardiovascular Medicine Vol. 8 ( 2021-12-8)
    Details
    In: Frontiers in Cardiovascular Medicine, Frontiers Media SA, Vol. 8 ( 2021-12-8)
    Abstract: Background: The circle of Willis is a network of arteries allowing blood supply to the brain. Bulging of these arteries leads to formation of intracranial aneurysm (IA). Subarachnoid hemorrhage (SAH) due to IA rupture is among the leading causes of disability in the western world. The formation and rupture of IAs is a complex pathological process not completely understood. In the present study, we have precisely measured aneurysmal wall thickness and its uniformity on histological sections and investigated for associations between IA wall thickness/uniformity and commonly admitted risk factors for IA rupture. Methods: Fifty-five aneurysm domes were obtained at the Geneva University Hospitals during microsurgery after clipping of the IA neck. Samples were embedded in paraffin, sectioned and stained with hematoxylin-eosin to measure IA wall thickness. The mean, minimum, and maximum wall thickness as well as thickness uniformity was measured for each IA. Clinical data related to IA characteristics (ruptured or unruptured, vascular location, maximum dome diameter, neck size, bottleneck factor, aspect and morphology), and patient characteristics [age, smoking, hypertension, sex, ethnicity, previous SAH, positive family history for IA/SAH, presence of multiple IAs and diagnosis of polycystic kidney disease (PKD)] were collected. Results: We found positive correlations between maximum dome diameter or neck size and IA wall thickness and thickness uniformity. PKD patients had thinner IA walls. No associations were found between smoking, hypertension, sex, IA multiplicity, rupture status or vascular location, and IA wall thickness. No correlation was found between patient age and IA wall thickness. The group of IAs with non-uniform wall thickness contained more ruptured IAs, women and patients harboring multiple IAs. Finally, PHASES and ELAPSS scores were positively correlated with higher IA wall heterogeneity. Conclusion: Among our patient and aneurysm characteristics of interest, maximum dome diameter, neck size and PKD were the three factors having the most significant impact on IA wall thickness and thickness uniformity. Moreover, wall thickness heterogeneity was more observed in ruptured IAs, in women and in patients with multiple IAs. Advanced medical imaging allowing in vivo measurement of IA wall thickness would certainly improve personalized management of the disease and patient care.
    Type of Medium: Online Resource
    ISSN: 2297-055X
    URL: Article
    URL: Article
    DOI: 10.3389/fcvm.2021.775307
    DOI: 10.3389/fcvm.2021.775307.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2781496-8
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