Abstract

Venous anastomotic intimal hyperplasia (VAIH) is the most prevalent cause of hemodialysis arteriovenous (AV) graft failure. The economic impact of AV access and its related morbidity approaches one billion dollars annually in the US. Previously, this laboratory has demonstrated that hemodynamic forces regulate key in vivo molecular and structural events in artery wall intimal hyperplasia. We will apply and extend this expertise to investigate the independent role(s) of turbulence-induced solid and fluid dynamic forces in inducing VAIH following AV graft implantation. The investigators have established a realistic experimental in vivo model of the human AV circuit and VAIH to test the following hypotheses: 1) VAIH is modulated by turbulence-induced vein wall vibration levels, with elevated vein wall vibration enhancing, and reduced vein wall vibration attenuating, VAIH; 2) This relationship is independent of regional variations in wall shear stress magnitude within venous anastomoses subjected to turbulent flow conditions; 3) Elevated vein wall vibration upregulates the level and activity of the extra-cellular regulatory kinase (ERK1/2) and the stress activated protein kinase (JNK and p38) required for transcriptional activation of the immediate early genes (IEGs) Egr-1, c-jun and c-fos involved in VSMC differentiation, proliferation, apoptosis and VAIH. To verify the proposed hypotheses we will correlate the degree and localization (transmural, circumferential, and axial) of the above-mentioned molecular and cellular events with the corresponding magnitude and spatial distribution of the venous anastomotic biomechanical variables under conditions of elevated and reduced levels of vein wall vibration. It is anticipated that the results of these novel investigations will provide seminal information regarding the pathogenesis and detection of AV grafts at risk for accelerated VAIH, and for the design of interventions to inhibit VAIH and extend patency of hemodialysis AV grafts.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055296-07
Application #
6922942
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Wassef, Momtaz K
Project Start
1996-09-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2007-07-31
Support Year
7
Fiscal Year
2005
Total Cost
$367,658
Indirect Cost

  Institution

Name
University of Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637

  Publications

Lee, Seung E; Lee, Sang-Wook; Fischer, Paul F et al. (2008) Direct numerical simulation of transitional flow in a stenosed carotid bifurcation. J Biomech 41:2551-61
Lee, Sang-Wook; Smith, David S; Loth, Francis et al. (2007) Importance of flow division on transition to turbulence within an arteriovenous graft. J Biomech 40:981-92
Yazicioglu, Yigit; Royston, Thomas J; Spohnholtz, Todd et al. (2005) Acoustic radiation from a fluid-filled, subsurface vascular tube with internal turbulent flow due to a constriction. J Acoust Soc Am 118:1193-209
Loth, Francis; Jones, Steven A; Zarins, Christopher K et al. (2002) Relative contribution of wall shear stress and injury in experimental intimal thickening at PTFE end-to-side arterial anastomoses. J Biomech Eng 124:44-51
Lei, M; Giddens, D P; Jones, S A et al. (2001) Pulsatile flow in an end-to-side vascular graft model: comparison of computations with experimental data. J Biomech Eng 123:80-7
Fortunato, J E; Mauceri, H J; Kocharyan, H et al. (2000) Gene therapy enhances the antiproliferative effect of radiation in intimal hyperplasia. J Surg Res 89:155-62
Fortunato, J E; Bassiouny, H S; Song, R H et al. (2000) Apolipoprotein (a) fragments in relation to human carotid plaque instability. J Vasc Surg 32:555-63
Fortunato, J E; Glagov, S; Bassiouny, H S (1999) Biomechanical factors as regulators of biological responses to vascular grafts. Semin Vasc Surg 12:27-37
Fortunato, J E; Glagov, S; Bassiouny, H S (1998) Irradiation for the treatment of intimal hyperplasia. Ann Vasc Surg 12:495-503
Bassiouny, H S; Song, R H; Kocharyan, H et al. (1998) Low flow enhances platelet activation after acute experimental arterial injury. J Vasc Surg 27:910-8

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