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

Abstract

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. 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. 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 (oddsmore » 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. 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. Finally, 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.« less

Authors:
 [1];  [2];  [3];  [4];  [4];  [5];  [1];  [1];  [6];  [7];  [2]; ORCiD logo [1]
  1. Univ. of Heidelberg, Mannheim (Germany)
  2. Univ. at Buffalo, NY (United States)
  3. Westfalian Wilhelms-Univ., Münster (Germany)
  4. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  5. Univ. of California, Davis, CA (United States)
  6. Univ. at Buffalo, NY (United States); Kaleida Health, Buffalo, NY (United States); Jacobs Inst., Buffalo, NY (United States)
  7. Univ. of Toronto, ON (Canada)
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH)
OSTI Identifier:
1618823
Report Number(s):
LLNL-JRNL-787658
Journal ID: ISSN 0039-2499; 985555
Grant/Contract Number:  
AC52-07NA27344; P41GM103483; LLNL LDRD 18-LW-037; R01NS091075
Resource Type:
Accepted Manuscript
Journal Name:
Stroke
Additional Journal Information:
Journal Volume: 51; Journal Issue: 5; Journal ID: ISSN 0039-2499
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; logistic models; humans; intracranial aneurysm; collagen; risk factors; hemodynamics; birth dating; collagen turnover; wall shear stress

Citation Formats

Hackenberg, Katharina A. M., Rajabzadeh-Oghaz, Hamidreza, Dreier, Rita, Buchholz, Bruce A., Navid, Ali, Rocke, David M., Abdulazim, Amr, Hänggi, Daniel, Siddiqui, Adnan, Macdonald, R. Loch, Meng, Hui, and Etminan, Nima. Collagen Turnover in Relation to Risk Factors and Hemodynamics in Human Intracranial Aneurysms. United States: N. p., 2020. Web. doi:10.1161/STROKEAHA.120.029335.
Hackenberg, Katharina A. M., Rajabzadeh-Oghaz, Hamidreza, Dreier, Rita, Buchholz, Bruce A., Navid, Ali, Rocke, David M., Abdulazim, Amr, Hänggi, Daniel, Siddiqui, Adnan, Macdonald, R. Loch, Meng, Hui, & Etminan, Nima. Collagen Turnover in Relation to Risk Factors and Hemodynamics in Human Intracranial Aneurysms. United States. doi:https://doi.org/10.1161/STROKEAHA.120.029335
Hackenberg, Katharina A. M., Rajabzadeh-Oghaz, Hamidreza, Dreier, Rita, Buchholz, Bruce A., Navid, Ali, Rocke, David M., Abdulazim, Amr, Hänggi, Daniel, Siddiqui, Adnan, Macdonald, R. Loch, Meng, Hui, and Etminan, Nima. Wed . "Collagen Turnover in Relation to Risk Factors and Hemodynamics in Human Intracranial Aneurysms". United States. doi:https://doi.org/10.1161/STROKEAHA.120.029335.
@article{osti_1618823,
title = {Collagen Turnover in Relation to Risk Factors and Hemodynamics in Human Intracranial Aneurysms},
author = {Hackenberg, Katharina A. M. and Rajabzadeh-Oghaz, Hamidreza and Dreier, Rita and Buchholz, Bruce A. and Navid, Ali and Rocke, David M. and Abdulazim, Amr and Hänggi, Daniel and Siddiqui, Adnan and Macdonald, R. Loch and Meng, Hui and Etminan, Nima},
abstractNote = {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. 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. 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. 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. Finally, 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.},
doi = {10.1161/STROKEAHA.120.029335},
journal = {Stroke},
number = 5,
volume = 51,
place = {United States},
year = {2020},
month = {5}
}

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Works referenced in this record:

Flow Conditions in the Intracranial Aneurysm Lumen Are Associated with Inflammation and Degenerative Changes of the Aneurysm Wall
journal, September 2016

  • Cebral, J.; Ollikainen, E.; Chung, B. J.
  • American Journal of Neuroradiology, Vol. 38, Issue 1
  • DOI: 10.3174/ajnr.A4951

Age of Collagen in Intracranial Saccular Aneurysms
journal, June 2014


Flow-induced, inflammation-mediated arterial wall remodeling in the formation and progression of intracranial aneurysms
journal, July 2019


High WSS or Low WSS? Complex Interactions of Hemodynamics with Intracranial Aneurysm Initiation, Growth, and Rupture: Toward a Unifying Hypothesis
journal, April 2013

  • Meng, H.; Tutino, V. M.; Xiang, J.
  • American Journal of Neuroradiology, Vol. 35, Issue 7
  • DOI: 10.3174/ajnr.A3558

Impaired Collagen Biosynthesis and Cross‐linking in Aorta of Patients With Bicuspid Aortic Valve
journal, January 2013

  • Wågsäter, Dick; Paloschi, Valentina; Hanemaaijer, Roeland
  • Journal of the American Heart Association, Vol. 2, Issue 1
  • DOI: 10.1161/JAHA.112.000034

Retrospective Birth Dating of Cells in Humans
journal, July 2005


Incidence of subarachnoid hemorrhage is decreasing together with decreasing smoking rates
journal, August 2016


Unruptured intracranial aneurysms: development, rupture and preventive management
journal, November 2016


Effect of Collagen Turnover on the Accumulation of Advanced Glycation End Products
journal, September 2000

  • Verzijl, Nicole; DeGroot, Jeroen; Thorpe, Suzanne R.
  • Journal of Biological Chemistry, Vol. 275, Issue 50
  • DOI: 10.1074/jbc.M006700200

Carbon‐14 bomb pulse dating shows that tendinopathy is preceded by years of abnormally high collagen turnover
journal, March 2018

  • Heinemeier, Katja Maria; Schjerling, Peter; Øhlenschlæger, Tommy F.
  • The FASEB Journal, Vol. 32, Issue 9
  • DOI: 10.1096/fj.201701569R

Regional Mapping of Flow and Wall Characteristics of Intracranial Aneurysms
journal, June 2016

  • Cebral, Juan R.; Duan, Xinjie; Gade, Piyusha S.
  • Annals of Biomedical Engineering, Vol. 44, Issue 12
  • DOI: 10.1007/s10439-016-1682-7