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ARTICLE IN PRESS

ELSEVIER

Basic Science Research

Correlation of Intraluminal Thrombus Deposition, Biomechanics, and Hemodynamics with Surface Growth and Rupture in Abdominal Aortic Aneurysm-Application in a Clinical Paradigm

Eleni Metaxa, 1 Konstantinos Tzirakis, 1 Nikolaos Kontopodis, 1'2 Christos V, Ioannou,2

and Yannis Papaharilaou, 1 Heraklion, Crete, Greece

Background: The natural history of abdominal aortic aneurysm (AAA) can be investigated through longitudinal evaluation of localized aneurysm characteristics exploiting clinical images. The major challenge is to identify corresponding regions between follow-ups. We have recently developed an algorithm (VascForm) based on nonrigid registration that can obtain surface cor­respondence and quantify surface growth distribution. Methods: A ruptured AAA with an initial computed tomography scan 2 years ago was studied. Following 3-dimensional reconstruction of outer wall and luminal surfaces, the wall/thrombus thickness was obtained. Wall stress distribution was computed with finite element analysis, and computational fluid dynamics were performed. VascForm was applied and allowed for the ruptured wall site to be traced back to the initial wall surface and be correlated with local initial intraluminal thrombus thickness, wall stress, and hemodynamic parameters. It also allowed for the quantification of wall surface growth based on the surface element growth. Results: Rupture occurred at the posterolateral side. Initial wall surface growth was in most re­gions 40%. However, a large section of the posterior wall presented 110% growth. Initial thrombus deposition was mainly anteriorly accumulated, and there was a posterior thrombus­free isle. Peak wall stress (initial and follow-up) occurred at AAA neck. Nonrigid registration revealed that rupture originated from the vicinity of the initial thrombus-free isle. Furthermore, rupture occurred at the wall region with the largest growth (110%). No clear correlation between hemodynamics and rupture site could be identified. Conclusions: High local surface growth correlates with rupture site and could therefore poten­tially become a marker of rupture risk. The ongoing application of this methodology to a large cohort of AAA patients will focus on identifying characteristic features of AAA regions that pre­sent high surface growth in follow-up evaluations, to assist in improved rupture risk estimation.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

1 Institute of Applied and Computational Mathematics, Foundation

q2 for Research and Technology-He/las, Heraklion, Crete, Greece.

Correspondence to: Yannis Papaharilaou, Nikolaou Plastira 100, VassilikaVouton, Heraklion, Crete GR 700 13, Greece; E-mail: yannisp@iacm.forth.gr

Ann Vase Surg 2017; ■ : 1-10 https:!!doi.org/10.1016/j.avsg.2017.08.007 © 2017 Elsevier Inc. All rights reserved.

2Vascular Surgery Unit, Department of CardioThoracic and Vascular Surgery, University of Crete Medical School, Heraklion, Crete, Greece. Manuscript received: May 23, 2017; manuscript accepted: August 1,

2017; published online: ■ ■ ■

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Volume ■, ■ 2017

Image Processing and Thrombus-Wall

Thickness Quantification

Contrast-enhanced high-resolution spiral CT angi­ography images were processed using ITK-SNAP,as previously described.8• 15 Briefly, from the firstCT scan, a 3-dimensional AAA model of the abdom­inal aorta was reconstructed from the stack of con -tours of the outer wall and lumen surfaces thatwere manually segmented. The reconstructed 3Dsurfaces were processed using the VascularModeling Tool Kit (VMTK). 16 The distance betweenthe outer wall surface and the luminal surface pro­vided the thrombus-wall thickness. Nonrigid Registration

The VascForm algorithm is written in Matlab andis based on nonrigid point cloud registration andspecifically on iterative closest point algorithm.It is adapted to the needs of aneurysm follow-upstudies and has been recently validated. 10 Inshort, it consists of 2 phases. During the firstphase, surfaces are prealigned applying principalcomponent analysis, and a general deformationof the source surface is performed to best matchthe Target using the Procrustes algorithm. Duringthe second phase, surfaces are finely matchedthrough a nonrigid local deformation model.Each point in the source surface is placed closer(with respect to Euclidean distance) to the targetsurface in the following manner: for every pointp on the source surface, the K-nearest neighbors(N

p) are considered, and each neighbor influences

the displacement of p by an amount which is determined via a Gaussian radial basis centered Q3 on p acting as weight function. The input to Vase­Form was the initial and follow-up wall surfaces inSTL format. After registration, surface growthdistribution is the element surface area growthdistribution (triangular elements) and the localsurface growth the element area growth. The rela­tive surface growth was computed as the surfaceelement growth between the 2 follow-ups dividedby the initial element surface. The main uncertainty/error of the method de­pends on the initial surface distance. Specifically, ithas been found to linearly increase with the initialdistance between the surfaces (after pre-align­ment).10 The distance index (DI; mm), is used as aglobal metric for the distance between the surfaces:

DI= µDistance+ <rmstance, (1)

where µDistance and <rmstance the mean and standarddeviation of the distance between source surface

Surface growth and rupture in aneurysm 3

al

nodes and target surface. Based on the DI, the error Q4 index graphin (mm2

Metaxa ) can et al. be 10 The obtained error from index the character­related

izes face the growth± uncertainty error index), window and of when surface divided growth by (sur­the tiveiniti surface element area, it characterizes the rela­surface growth uncertainty window (relativesurface growth ± error index/initial surface elementarea). To identify the corresponding regions betweeninitial and follow-up surfaces, it was first necessaryto mark the rupture site on the follow-up wall sur­face. For this purpose, on 2 consecutive slices ofCT scan where the rupture of the wall was visible,a small mark outside the aorta in front of the rupturewas segmented and saved in the same file of thereconstructed wall surface. Next, VMTK was usedto allow the drawing of the aortic wall region thatwas colocalized with the rupture mark. Thisprovided a surface that had the value of "l" at thenodes of the rupture site and the value of "O" everywhere else. To identify which region of the initial wall surfacehad ruptured, the nodes of rupture site ("l") weretraced back to the initial surface using VascForm. Wall Stress Estimation

Using the outer wall and lumen surfaces and assuminga uniform thickness of 2 mm, the AAA model for finiteelement analysis (FEA) was reconstructed includingboth AAA wall and ILT, as previously described. 17

The 3D mesh was generated using ICEM CFD,v.12.O.1 (ANSYS Inc., Berkeley, CA), and consistedof linear tetrahedral elements with an average meshdensity of 2.4 elements/mm3

, based on previousmesh sensitivity tests. Workbench (ANSYS Inc.) wasused for FEA and estimation of wall stress distributionat peak systole. Hyperelastic material models asdescribed by Raga van and Vorp for wall and VandeGe­est for ILT were adopted.3,

4 A uniform 120 mm Hgsystolic pressure wall loading was applied to the lumenboundary, and the result in maximum principle stressdistribution was evaluated. Computational Flow Dynamics

Flow extensions were added to the luminal surfacesof the first and follow-up scans, and a pure hexahe­dral mesh was constructed using ANSA (BETA CAESystems S.A., Thessaloniki, Greece). The shear thin­ning property of blood was accounted for, byemploying the Herschel-Bulkley model, µ(,y)= (�)-[1 -exp(-m,y)]+K'Yn-1

, (2)

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Volume ■, ■ 2017

Surface growth (%)

117-

-=80

-=40

-34-

Fig. 2. Surface growth distribution of the initial wall sur­face co-mapped with the follow-up surface (semi-trans­parent). Most of the surface grew by 40%. A large part of the posterior region though grew by 110 ± 11.8%.

used to obtain correspondence between initial and

follow-up wall surface meshes. It was found that

most of the initial wall surface (mesh element

area) had grown by 40% (Fig. 2). However, there was a large part of the posterior wall that had grown

by ll0%. The error/uncertainty of surface growth estimation was 11.8% (distance index 5.82 mm,

error index of 0.8 mm2, and mean initial element

area 6.8 mm2).

Projection of rupture site on initial wall surf ace.

Since the posterior wall had been displaced far from its initial position (as seen in Fig. 2), locating

the original location of rupture at the initial wall surface was not straightforward. Therefore, Vase­

Form was used to trace the rupture site back to the

initial wall surface and search for potential colocali­zation with aneurysm characteristics. As seen in

Figure 3, the location of rupture was traced back

to its "region of origin" on the initial wall surface.

Thrombus and Wall Stress Distribution

To identify potential triggers for wall rupture,

thrombus and wall stress, evaluated at the initial

and follow-up AAA geometries, were investigated. Initial thrombus deposition was not uniformly

distributed in the sac but was mostly accumulated at the anterior region (Fig. 4A). At the posterior

side, there was an isle where lumen and outer wall

had a distance of 2.2 mm (Fig. 4B). If it is assumed

Surface growth and rupture in aneurysm 5

Final wall surface Initial wall surface

VascForm

...

/SZ.

Fig. 3. Projection of rupture site to the initial wall surface.

that the aortic wall has a thickness of 2 mm, this

isle was thrombus-free and could have been the origin of wall rupture, since, after a manual registra­

tion of follow-up to the initial surface (Fig. 4C), there Q5

seemed to be a visual proximity between rupture site and this initial thrombus-free isle. In the follow-up

examination, wall/thrombus thickness was reduced

at the anterior side (Fig. 4D) and not substantially changed at the posterior side (Fig. 4E). Overlay of

the rupture site to the thrombus distribution at the

final examination (Fig. 4F) did not show any

remarkable characteristic of thrombus thickness

that could be associated with rupture. Evaluation of wall stress distribution revealed

that its peak value (0.44 M Pa) occurred distant

from the region of rupture and specifically at the anterior and posterior AAA neck (Fig. 5). At the

follow-up examination, the distribution of wall stress was similar to the initial PWS occurred at

the neck region but with its magnitude reduced to

0.29 M Pa. Robust nonrigid registration revealed that

rupture originated from a region where the wall/

ILT thickness was 3.8 mm (Fig. 6A). Furthermore, rupture occurred at the wall region that grew the

most (Fig. 6B) and specifically ll0%. Having established a correspondence between

initial and follow-up surfaces, it was possible to

also examine the local change in ILT thickness. It was interesting to note that Wall/ILT thickness

increased at the neck region by 5 mm but decreased at the anterior region by 5 mm.

Hemodynamics

Hemodynamic simulation revealed a large spatial

variation of the investigated TAWSS, OSI, and RRT

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ANTERIOR POSTERIOR

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Annals of Vascular Surgery

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Wall/ILT thickness (mm)

10.5-10

I-

z

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0 a..

(.) -st

.c

ca

·;::

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/Sl.

..X.--,,Y

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0...

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.....J

0 LL

Fig. 4. Wall/thrombus thickness distribution at the

initial AAA evaluation (A, B, and C) and final AAA eval­

uation (D, E, and F) at the anterior (A, D) and posterior

(B, E) sides. (A, B) At the initial evaluation, thrombus

was mostly accumulated at the anterior side, whereas

at the posterior side, there was a small isle without

thrombus deposition. (C) Overlay of rupture region

( pointed red disc shape) at final examination (outer semi-

595 (Fig. 8). Interestingly, the thrombus-free isle at the

596 posterior side coincided with low TA WSS and subse-

597 quently with high RRT. The anterior region that was

598 characterized by a substantial decrease in ILT thick-

599 ness presented a marked change in hemodynamics

600 between initial and final examination. Specifically,

601 although at the initial examination, the anterior re-

602 gion experienced low TAWSS, high OSI, and high

603 RRT, as computed to other wall regions, at the final

604 examination, OSI had decreased from 0.49 to 0.1

605 and RRT from 800 (N/m2)-

1 to 20 (N/m2)-

1.

0-

8

transparent surface) on thrombus thickness distribution

at initial AAA surface (inner surface) suggested that

thrombus-free region could potentially coincide with

the origin of rupture. (D, E) At the final evaluation,

thrombus thickness had been increased at the posterior

side but interestingly it had been decreased at the ante­

rior side. (F) Rupture location marked on the final wall

surface with ILT distribution data.

DISCUSSION

In the last 20 years, many research efforts have

been performed to advance patient-specific rupture

risk assessment. However, since AAA growth is a

multifactorial process, many identified risk markers

show a potential for clinical use.5'

6'

13'

22 But how

could such a large body of knowledge reach clinical

practice? The filtering, prioritization, and integra­

tion of suggested rupture risk markers through sta -

tistical modeling could potentially provide a robust

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0 a.. LL

�

·c:c..

Volume ■, ■ 2017

B

Surface growth and rupture in aneurysm 7

Max Principal stress 0.44 l- (MPa)

0.4

�0.3

�0.2

�O. l

0

-0.0496-

Fig. 5. Maximum principle stress distribution at the (A) posterior and (B) anterior side at the initial examination.

Wall/thrombus Thickness (mm)

10.4- -·-i;;-

�6

�4

Surface Growth (%) 117-

-=80

-=o

716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738

� 2-34-

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LL

0 0.395-

lil.

Fig. 6. Overlay of the rupture's origin (black circle) at the first scan with (A) the initial wall/thrombus thickness distri- 755bution and (B) the surface growth distribution. 756

new methodology for clinical rupture risk assess­ment. 23 In the meantime, the growth rate of AAA, which is 1 of the 2 current basic risk indica­tors, could be substantially improved by exploiting advances in medical image processing. In addition, nonrigid registration techniques in combination with longitudinal AAA images can shed light in a vast amount of so far unexplored data that will improve our understanding of AAA natural his­tory. In the present study, the investigation of a ruptured AAA case with a previous 2-year-old CT scan available demonstrates the potential of

generating valuable information through exploita­tion of nonrigid surface registration, to quantify local surface growth.

The most significant finding of this study is that rupture occurred at a region of high surface growth. This is in line with the current belief that growth in general is a sign of high activity and high rupture risk. This finding alone shows the potentially impor­tant impact that local surface growth information could have on clinical rupture risk assessment. Rupture also occurred at the posterolateral side, a common site of rupture. Although most AAAs

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Volume ■, ■ 2017 Surface growth and rupture in aneurysm 9

POSTERIOR ANTERIOR

_J free isle

<t I-

z

OSI TAWSS(Nim') OSI

2-

1.6

1.2

Fig. 8. Hemodynamics at the posterior and anterior luminal surfaces at initial and follow-up examinations.

section or parts of them where wall calcification is

present or thrombus does not appear to be fully

attached to the wall with an obvious transition or

"gap" in intensity between thrombus and wall. Its

measurement can therefore be highly subjective.

However, there are attempts to estimate wall thick­

ness in AAAs based on intensity histograms and

neural networks involving segmentation of

contrast-enhanced abdominal computed tomogra­

phy images.26 Until a robust methodology for wall

thickness acquisition is established, what is

currently known is that wall thickness can have a

significant impact on PWS estimation, and in the

present case, one could hypothesize that a wall

stress concentration on the posterior thrombus­

free region could have played a role in aneurysm

progression. In addition, wall calcification data

were not included in the estimation of wall stresses

since only few and scattered calcifications were

observed away from the site of rupture, which

would not have affected the current outcome.

When evaluating the results, it should also be

considered that wall stress and hemodynamic com­

putations are based on models that are bound to

many hypotheses and simplifications. For example,

uniform wall thickness, uniform material proper­

ties, and no account for residual stresses are limita­

tions in the FEA analysis. On the other hand, the

computational simulation of blood flow in the

AAA model was not based on patient-specific flow

data and did not extend from the heart to the iliac

arteries. Such limitations are common in similar

studies. One cannot exclude the possibility that

close to the site of rupture, the mechanical proper­

ties of ILT were much different from the ones

assumed, or that the wall was much thinner, or

that the ILT was not fully attached to the wall,

resulting in a higher stress concentration that could

contribute to local growth or rupture. Although no

correlation was found between biomechanics and

rupture, their role cannot be excluded due to

method limitations. However, the main result of

this study (rupture originated from a region with a

thin-wall ILT and a rapid surface growth) is not

affected by these limitations.

In conclusion, with the given data of a single but

rare AAA case, we demonstrate a new tool for longi­

tudinal studies that exploits advancements in image

postprocessing for obtaining a detailed and robust

correlation between characteristics at different

time points of AAA evaluation. This was the first

study of an AAA case with a follow-up, where sur­

face growth distribution is estimated, and its colocal­

ization with rupture was assessed. Furthermore,

with the exploitation of nonrigid registration in

AAA follow-up, and its colocalizations of wall char­

acteristics, biomechanic and hemodynamic forces

between initial and follow-up can be investigated.

Although many aspects of this case were studied,

not all of them could provide adequate suggestions

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to open questions, while others opened new ques­

tions for discussion. The ongoing follow-up study

of surface growth on a large patient cohort will pro­

vide insightful information of growth patterns to­

ward better understanding of AAA evolution and

improved rupture risk assessment.

1003 l004

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