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Collagen Turnover in Relation to Risk Factors and Hemodynamics in Human Intracranial Aneurysms.

ABSTRACT: Background and Purpose- Determinants for molecular and structural instability, that is, impending growth or rupture, of intracranial aneurysms (IAs) remain uncertain. To elucidate this, we endeavored to estimate the actual turnover rates of the main molecular constituent in human IA (collagen) on the basis of radiocarbon (¹⁴C) birth dating in relation to IA hemodynamics. Methods- Collagen turnover rates in excised human IA samples were calculated using mathematical modeling of ¹⁴C birth dating data of collagen in relation to risk factors and histological markers for collagen maturity/turnover in selected IA. Hemodynamics were simulated using image-based computational fluid dynamics. Correlation, logistic regression, and receiver operating characteristic analyses were performed. Results- Collagen turnover rates were estimated in 46 IA (43 patients); computational fluid dynamics could be performed in 20 IA (20 patients). The mean collagen turnover rate (γ) constituted 126% (±1% error) per year. For patients with arterial hypertension, γ was greater than 2600% annually, whereas γ was distinctly lower with 32% (±1% error) per year for patients without risk factors, such as smoking and hypertension. There was a distinct association between histological presence of rather immature collagen in human IA and the presence of modifiable risk factors. Spatial-temporal averaged wall shear stress predicted rapid collagen turnover (odds ratio, 1.6 [95% CI, 1.0-2.7]). Receiver operating characteristic analysis demonstrated a good test accuracy (area under the curve, 0.798 [95% CI, 0.598-0.998]) for average wall shear stress with a threshold ≥4.9 Pa for rapid collagen turnover. Conclusions- Our data indicate that turnover rates and stability of collagen in human IA are strongly associated with the presence of modifiable risk factors and aneurysmal hemodynamics. These findings underline the importance of strict risk factor modification in patients with unruptured IA. Future should include more detailed risk factor data to establish a more causal understanding of hemodynamics and the rupture risk of individual IA.

SUBMITTER: Hackenberg KAM

PROVIDER: S-EPMC7340076 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and objectiveIntracranial fusiform aneurysms (IFAs) are considered to have a complex pathophysiology process and poor natural history. The purpose of this study was to investigate the pathophysiological mechanisms of IFAs based on the characteristics of aneurysm wall enhancement (AWE), hemodynamics, and morphology.MethodsA total of 21 patients with 21 IFAs (seven fusiform types, seven dolichoectatic types, and seven transitional types) were included in this study. Morphological parameters of IFAs were measured from the vascular model, including the maximum diameter (Dmax), maximum length (Lmax), and centerline curvature and torsion of fusiform aneurysms. The three-dimensional (3D) distribution of AWE in IFAs was obtained based on high-resolution magnetic resonance imaging (HR-MRI). Hemodynamic parameters including time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), gradient oscillatory number (GON), and relative residence time (RRT) were extracted by computational fluid dynamics (CFD) analysis of the vascular model, and the relationship between these parameters and AWE was investigated.ResultsThe results showed that Dmax (p = 0.007), Lmax (p = 0.022), enhancement area (p = 0.002), and proportion of enhancement area (p = 0.006) were significantly different among three IFA types, and the transitional type had the largest Dmax, Lmax, and enhancement area. Compared with the non-enhanced regions of IFAs, the enhanced regions had lower TAWSS but higher OSI, GON, and RRT (p < 0.001). Furthermore, Spearman's correlation analysis showed that AWE was negatively correlated with TAWSS, but positively correlated with OSI, GON, and RRT.ConclusionThere were significant differences in AWE distributions and morphological features among the three IFA types. Additionally, AWE was positively associated with the aneurysm size, OSI, GON, and RRT, while negatively correlated with TAWSS. However, the underlying pathological mechanism of the three fusiform aneurysm types needs to be further studied.

Project description:There is an urgent need to identify risk factors for sporadic intracranial aneurysm (IA) development and rupture. A genetic component has long been recognized, but firm conclusions have been elusive given the generally small sample sizes and lack of replication. Genome-wide association studies have overcome some limitations, but the number of robust genetic risk factors for IA remains uncertain.We conducted a comprehensive systematic review and meta-analysis of all genetic association studies (including genome-wide association studies) of sporadic IA, conducted according to Strengthening the Reporting of Genetic Association Studies and Human Genome Epidemiology Network guidelines. We tested the robustness of associations using random-effects and sensitivity analyses.Sixty-one studies including 32,887 IA cases and 83,683 controls were included. We identified 19 single nucleotide polymorphisms associated with IA. The strongest associations, robust to sensitivity analyses for statistical heterogeneity and ethnicity, were found for the following single nucleotide polymorphisms: on chromosome 9 within the cyclin-dependent kinase inhibitor 2B antisense inhibitor gene (rs10757278: odds ratio [OR] 1.29; 95% confidence interval [CI] 1.21-1.38; and rs1333040: OR 1.24; 95% CI 1.20-1.29), on chromosome 8 near the SOX17 transcription regulator gene (rs9298506: OR 1.21; 95% CI 1.15-1.27; and rs10958409: OR 1.19; 95% CI 1.13-1.26), and on chromosome 4 near the endothelin receptor A gene (rs6841581: OR 1.22; 95% CI 1.14-1.31).Our comprehensive meta-analysis confirms a substantial genetic contribution to sporadic IA, implicating multiple pathophysiologic pathways, mainly relating to vascular endothelial maintenance. However, the limited data for IA compared with other complex diseases necessitates large-scale replication studies in a full spectrum of populations, with investigation of how genetic variants relate to phenotype (e.g., IA size, location, and rupture status).

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Collagen Turnover in Relation to Risk Factors and Hemodynamics in Human Intracranial Aneurysms.

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