Abdominal aortic aneurysms (AAAs) are focal, asymmetric dilatations of the infrarenal aorta that are increasingly responsible for significant mortality in our aging society. The primary clinical (global) metrics for deciding intervention remain the maximum diameter and rate of expansion of the lesion. Yet, many smaller lesions rupture whereas many larger ones may not rupture over long periods. Because rupture occurs when wall stress exceeds wall strength, it should not be surprising that calculated (local) wall stress can be a better predictor of rupture-risk than current (geometric) metrics. Our work is motivated, however, by the need to estimate much better both wall stress and strength, that is, to move beyond current stress analyses that are simply """"""""snap shots"""""""" in time based on patient-specific geometric models of lesions that are assumed to have the same uniform, population-averaged material properties regardless of size. In contrast, we will build a novel biochemomechanical computational model to simulate the patient-specific evolution an AAA consistent with the well accepted hypothesis that intramural cells can remodel matrix in response to perturbed mechanical stimuli and thereby generate regional heterogeneities that can offset complexities in geometry and hemodynamics that would otherwise cause marked regional variations in wall stress (and thus perturbed cell function). Complicating this mechano-stimulated evolution, however, is a hemodynamically driven intraluminal thrombus (ILT) that can upset the local balance in matrix production and removal and thereby locally weaken the wall. The primary goal of this Competing Renewal of HL086418 (funded in 2008 at the 6.3 percentile) is to build on a successful first 4 years of funding (22 papers published, plus 6 submitted/in preparation) and extend our current mechano-biological model to include local chemo-biological effects of an evolving ILT on AAA enlargement and rupture-risk. Our three Specific Aims are (i) to build and verify, via parametric studies exploiting idealized geometries, a novel fluid-solid-growth model, (ii) to use a well established rat elastase infusion model to correlate, for the firs time, local effects of thin vs. thick ILT on histological, cell biological, and mechanical propertis of the evolving AAA wall, and (iii) to use serial CT scans retrospectively from 30 patients to trai and test our final model, with the ultimate goal of providing increased confidence in predictions based on standard clinical information of the probable expansion or rupture-risk over the subsequent 6 to 12 months. In summary, the fundamental hypothesis driving this work is - the complexity of AAA pathophysiology and biomechanics results from competing effects of a mechano-stimulated injury response and a chronic inflammatory response, the latter of which depends primarily on spatiotemporal changes in ILT that are driven by the changing hemo- dynamics. We suggest that the only way to understand such complexity is to build and use an appropriate computational model, which we submit will help resolve longstanding controversies regarding the roles of ILT.

Public Health Relevance

Abdominal aortic aneurysms are responsible for increasing morbidity and mortality in our aging population. Mounting evidence suggests that evolving blood flow patterns and associated build-up of intraluminal thrombus within these lesions play important roles in dictating localized changes in wall stress and strength, and thus rupture-risk, via an unbalanced synthesis and degradation of extracellular matrix proteins. This work will build the first computational model to account for these complexities and thus provide unique insight for clinical care.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086418-07
Application #
8649066
Study Section
Special Emphasis Panel (ZRG1-BST-U (02))
Program Officer
Tolunay, Eser
Project Start
2006-10-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
7
Fiscal Year
2014
Total Cost
$382,905
Indirect Cost
$137,905
Name
Yale University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Di Achille, P; Tellides, G; Humphrey, J D (2016) Hemodynamics-driven deposition of intraluminal thrombus in abdominal aortic aneurysms. Int J Numer Method Biomed Eng :
Bersi, Matthew R; Bellini, Chiara; Di Achille, Paolo et al. (2016) Novel Methodology for Characterizing Regional Variations in the Material Properties of Murine Aortas. J Biomech Eng 138:
Rausch, M K; Karniadakis, G E; Humphrey, J D (2016) Modeling Soft Tissue Damage and Failure Using a Combined Particle/Continuum Approach. Biomech Model Mechanobiol :
Rausch, Manuel K; Humphrey, Jay D (2015) A microstructurally inspired damage model for early venous thrombus. J Mech Behav Biomed Mater 55:12-20
Rao, Jayashree; Brown, Bryan N; Weinbaum, Justin S et al. (2015) Distinct macrophage phenotype and collagen organization within the intraluminal thrombus of abdominal aortic aneurysm. J Vasc Surg 62:585-93
Virag, Lana; Wilson, John S; Humphrey, Jay D et al. (2015) A Computational Model of Biochemomechanical Effects of Intraluminal Thrombus on the Enlargement of Abdominal Aortic Aneurysms. Ann Biomed Eng 43:2852-67
Lee, Y-U; Lee, A Y; Humphrey, J D et al. (2015) Histological and biomechanical changes in a mouse model of venous thrombus remodeling. Biorheology 52:235-45
Roccabianca, S; Figueroa, C A; Tellides, G et al. (2014) Quantification of regional differences in aortic stiffness in the aging human. J Mech Behav Biomed Mater 29:618-34
Blose, Kory J; Ennis, Terri L; Arif, Batool et al. (2014) Periadventitial adipose-derived stem cell treatment halts elastase-induced abdominal aortic aneurysm progression. Regen Med 9:733-41
Cyron, C J; Wilson, J S; Humphrey, J D (2014) Mechanobiological stability: a new paradigm to understand the enlargement of aneurysms? J R Soc Interface 11:20140680

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