Aortic dissection is a life threatening event;it is responsible for significant morbidity and mortality in individuals ranging in age from children to young and older adults. When a dissection communicates with the true lumen and forms a so-called false lumen within the aortic wall, this false lumen may remain patent or become either partially or completely thrombosed. Increasing clinical evidence suggests that a completely thrombosed false lumen results in an improved prognosis whereas a partially thrombosed false lumen may render the wall more vulnerable to further dissection or rupture. Yet, there is a pressing need to understand better the mechanisms by which, and conditions under which, a false lumen is expected to develop either a partial or a full thrombus and why the latter is beneficial. We hypothesize that the extent of thrombus formation depends primarily on the hemodynamics within the false lumen and that partially thrombosed dissections are dangerous because the continued release of plasmin by an intramural thrombus in contact with flowing blood can activate constitutively produced, latent matrix metalloproteinases within the remnant aortic wall, which in turn weaken the wall. We will develop the first data-driven, multiscale, multiphysics model of the biomechanics of intramural throm- bus in aortic dissection. Specifically, we will extend and then couple a multiscale model of blood flow, platelet kinetics, fibrin organization, and plasmin transport (Karniadakis group) with a multiscale model of aortic wall mechanics and fibrin/collagen remodeling (Humphrey group) that will be informed and validated with extensive new imaging and immuno-histological data from the most widely accepted mouse model of dissecting aortic aneurysms (i.e., 28 day infusion of angiotensin II in the apolipoprotein null mouse). In addition, our model will be designed to simulate the potential benefits of two anti-coagulants in terms of the time(s) of delivery. Realization of our three Specific Aims will significantly increase our understanding of roles of thrombus in aortic dissection, with the promise of eventually leading to an improved prognostic capability and interventional planning. In addition, insight gained in this study will have important implications for a host of other vascular conditions, including dissections of other arteries, treatment of pseudo-aneurysms with thrombin following catheterization, and the different roles of intraluminal thrombus in abdominal aortic aneurysms and intracranial aneurysms. We submit, therefore, that this project has significant promise to increase our basic understanding of a key issue in vascular biology as well as to contribute to treating better a broad class of clinical problems. 1

Public Health Relevance

The initiation, propagation, and either healing or rupture of an aortic dissection all depend strongly on the associated biomechanics, yet aortic dissection has received scant attention from bioengineers. We will develop the first data-driven, multiscale, multiphysics model of the biomechanics of intramural thrombus in aortic dissection. Realization of our three Specific Aims will significantly increase our understanding of dissection, with the promise of eventually leading to an improved prognostic capability and interventional planning for aortic dissection as well as the many other vascular diseases complicated by thrombus.

Agency
National Institute of Health (NIH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL116323-02
Application #
8729005
Study Section
Special Emphasis Panel (ZEB1)
Program Officer
Lee, Albert
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
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
Roccabianca, S; Bellini, C; Humphrey, J D (2014) Computational modelling suggests good, bad and ugly roles of glycosaminoglycans in arterial wall mechanics and mechanobiology. J R Soc Interface 11:20140397