In-Stent Restenosis:

A 3-dimensional model
Carles Bona Casas
with the aid of Joris Borgdoff, Eric Lorenz, Hannan
Tahir, Lampros Mountrakis and Alfons Hoekstra.
Thursday, February 23, 2012
Outline

Illness - Medical intervention - Illness.

That vicious circle.

In-Stent Restenosis (ISR): the model.

Problems found and actions taken to

solve them.

Output and results.

Thursday, February 23, 2012
The Illness part 1:
Atherosclerosis
Thursday, February 23, 2012
Risk factors

Modifyable:

Diabetes.

Cholesterol (LDL:HDL ratios...).

Tobacco smoking.

Hypertension.

C-reactive protein concentrations.

Vitamin B6 deciency.

Nonmodifyable:

Advanced age.

Male sex.

Genetics.
Thursday, February 23, 2012
Atherosclerosis
Thursday, February 23, 2012
Medical intervention:
Percutaneous coronary
intervention
Thursday, February 23, 2012
We have stents!
Thursday, February 23, 2012
Balloon angioplasty
Thursday, February 23, 2012
The Illness part II:
In-Stent Restenosis
Thursday, February 23, 2012
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During balloon angioplasty, which is a procedure performed to open an artery,
an interventional cardiologist places a stent in the artery to support it after the blockage
has been removed. The injury caused by the stent can lead to a maladaptive biological re-
sponse of the cellular tissue (mainly due to smooth muscle cell proliferation). This renewed
narrowing is called in-stent restenosis (SR) or stent reocclusion.
Cardiovascular disease is the main cause of illness and premature death in the EU, ac-
counting for approximately 40% of deaths, with a combined direct and indirect econom-
ic cost of approximately 300 billion C per year. National health systems try to expand or
maintain health provision under fiscal constraints and health funders experience difficulties
in meeting the demands on modern health systems. Device manufacturers face increas-
ing pressure to bring products to market rapidly, whilst minimising costs. Modelling and
simulation will play an increasingly important role in this demanding environment and, as
has already been seen in the aeronautical and car manufacturing industry, are becoming
a standard element in the design process.
7)%8+&9,:./)%*/*
As in many other biological systems, the dynamics of in-stent restenosis span many orders
of magnitude through the scales, from the smallest microscopic scales up to the largest
macroscopic ones. n recent years the computational biology community has developed
extremely powerful methods to model and simulate fundamental processes of a natural
system on a multitude of separate scales. The next challenge is to study, not only funda-
mental processes, on all these separate scales, but also their mutual coupling across the
scales and to determine the emergent structure and function of the resulting system [1].
More citings here. n this context, Complex Automata (CxA) have recently been introduced
as a paradigm to simulate multiscale systems as a collection of single scale models, inter-
acting across the scales [2-4].
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The design and geometry of the stent employed infuences the biological events occur-
ring in the vessel following deployment. Strut thickness, number, cross-sectional shape
and arrangement, and stent length all infuence the haemodynamics and degree of injury
and stretch observed within the stented segment [5] These in turn, are critical determi-
nants of the severity of restenosis observed. Additionally, stents may be coated with active
compounds targeted at the biological processes responsible for driving the progression of
restenosis which, when eluted locally at the stented site, can prevent proliferation of smooth
muscle cells and neointimal growth. Simulations of SR in 2D have recently been able to
reproduce these observations [6] with the help of a MUltiScale Coupling Library and Envi-
ronment (MUSCLE) [7]. A multiscale model for in-stent restenosis that contains four cou-
pled models for blood flow, smooth muscle cell proliferation, drug diffusion, and thrombus
formation as well as a separate simulation to set up initial conditions was developed for that
purpose [8], but running such coupled models in three dimensions under realistic settings
requires the use of high performance computing capabilities. We intend to establish a uni-
versal distributed multiscale simulation environment on large scale European e-nfrastruc-
tures (PRACE, EG), in collaboration with the MAPPER project, resulting in a high-quality
open source tool for the VPH community and beyond. Then have a prototypical three di-
mensional simulation for in-stent restenosis in this environment that will allow us to inves-
tigate new stent designs and test our single scale models under more realistic situations.
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[1] P.M.A. Sloot, A.G. Hoekstra, Multiscale modeling in computational biology, Briefngs
in Bioinformatics 11 (1) (2010) 142152. [2] A.G. Hoekstra, E. Lorenz, J.-L. Falcone, B.
Chopard, Towards a complex automata formalism for multi-scale modeling, nt. J. Mult.
Comp. Eng. 5 (2007) 491502. [3] A.G. Hoekstra, J.-L. Falcone, A. Caiazzo, B. Chopard,
Multi-scale modeling with cellular automata: the complex automata approach, in: Proceed-
ings of ACR 2008, LNCS 5191, Springer-Verlag, Berlin/Heidelberg, 2008, pp. 192199. [4]
A.G. Hoekstra, E. Lorenz, J.L. Falcone & B. Chopard, Towards a complex automata frame-
work for multi-scale modeling: formalism and the scale separation map, in: Proceedings of
7th CCS, LNCS 4487, Springer-Verlag, Berlin/Heidelberg, 2007, pp. 922930. [5] A. Mor-
ton, D. Crossman & J. Gunn, The infuence of physical stent parameters upon restenosis,
Pathologie Biologie 52 (2004) 196205. [6] H. Tahir, A.G. Hoekstra, E. Lorenz, P. Lawford,
R. Hose, J. Gunn & D. Evans [7] Hegewald, J., Krafczyk, M., Tolke, J., Hoekstra, A.G. &
Chopard, B. 2008. An agent-based coupling platform for complex automata. n Computa-
tional ScienceCCS 2008. Lecture Notes in Computer Science, pp. 227233. Heidelberg,
Germany: Springer. [8] A. Caiazzo, D. Evans, J. Falcone, J. Hegewald, E. Lorenz, B. Stahl,
D. Wang, J. Bernsdorf, B. Chopard, J. Gunn, R. Hose, M. Krafczyk, P. Lawford, R. Small-
wood, D. Walker & A.G. Hoekstra, A Complex Automata approach for in-stent restenosis:
Two-dimensional multiscale modelling and simulations, Journal of Computational Science,
Volume 2, ssue 1, March 2011, Pages 9-17.
:0>')<+&#1&%&'/(
This research is funded by European Commission, through MeDDiCA Marie Curie ni-
tial Training Network (www.meddica.eu, EU-FP7/2007-2013 under grant agreement PT-
NGA-2009-238113)
7)'/*0/
Science
Computational
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c.bonacasas@uva.nl (C. Bona-Casas), e.lorenz@uva.nl (E. Lorenz), j.borgdorff@uva.nl
(J. Borgdoff), h.tahir@uva.nl (H. Tahir), a.g.hoekstra@uva.nl (A.G. Hoekstra)
Thursday, February 23, 2012
ISR stats

ISR if lumen is >50% occluded (3-6 months

after PCI)

ISR rates:

Without stent (balloon angioplasty

alone): 50% (1980s).

Bare Metal Stents (BMS): 20-30% (1990s).

Drug Eluting Stents (DES): 5-15%

(2000s). But DES have problems too...
Thursday, February 23, 2012
Thursday, February 23, 2012
Thursday, February 23, 2012
ISR: the model
Thursday, February 23, 2012
How to proceed?

Generate initial condition (IC):

Vessel geometry with stent placement.

Atherosclerotic plaque formation.

Then submodels for:

Blood Flow.

SMCs.

Drug Diffusion.

But they happen at different scales! And

submodels after IC need to be coupled!
Thursday, February 23, 2012
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During balloon angioplasty, which is a procedure performed to open an artery,
an interventional cardiologist places a stent in the artery to support it after the blockage
has been removed. The injury caused by the stent can lead to a maladaptive biological re-
sponse of the cellular tissue (mainly due to smooth muscle cell proliferation). This renewed
narrowing is called in-stent restenosis (SR) or stent reocclusion.
Cardiovascular disease is the main cause of illness and premature death in the EU, ac-
counting for approximately 40% of deaths, with a combined direct and indirect econom-
ic cost of approximately 300 billion C per year. National health systems try to expand or
maintain health provision under fiscal constraints and health funders experience difficulties
in meeting the demands on modern health systems. Device manufacturers face increas-
ing pressure to bring products to market rapidly, whilst minimising costs. Modelling and
simulation will play an increasingly important role in this demanding environment and, as
has already been seen in the aeronautical and car manufacturing industry, are becoming
a standard element in the design process.
7)%8+&9,:./)%*/*
As in many other biological systems, the dynamics of in-stent restenosis span many orders
of magnitude through the scales, from the smallest microscopic scales up to the largest
macroscopic ones. n recent years the computational biology community has developed
extremely powerful methods to model and simulate fundamental processes of a natural
system on a multitude of separate scales. The next challenge is to study, not only funda-
mental processes, on all these separate scales, but also their mutual coupling across the
scales and to determine the emergent structure and function of the resulting system [1].
More citings here. n this context, Complex Automata (CxA) have recently been introduced
as a paradigm to simulate multiscale systems as a collection of single scale models, inter-
acting across the scales [2-4].
!"#$%"&"'()*+,%')*'$,-,."/0)#,$)&/-)1!2
;)<*6#(,*,!=,%)#&+,3)6,425
The design and geometry of the stent employed infuences the biological events occur-
ring in the vessel following deployment. Strut thickness, number, cross-sectional shape
and arrangement, and stent length all infuence the haemodynamics and degree of injury
and stretch observed within the stented segment [5] These in turn, are critical determi-
nants of the severity of restenosis observed. Additionally, stents may be coated with active
compounds targeted at the biological processes responsible for driving the progression of
restenosis which, when eluted locally at the stented site, can prevent proliferation of smooth
muscle cells and neointimal growth. Simulations of SR in 2D have recently been able to
reproduce these observations [6] with the help of a MUltiScale Coupling Library and Envi-
ronment (MUSCLE) [7]. A multiscale model for in-stent restenosis that contains four cou-
pled models for blood flow, smooth muscle cell proliferation, drug diffusion, and thrombus
formation as well as a separate simulation to set up initial conditions was developed for that
purpose [8], but running such coupled models in three dimensions under realistic settings
requires the use of high performance computing capabilities. We intend to establish a uni-
versal distributed multiscale simulation environment on large scale European e-nfrastruc-
tures (PRACE, EG), in collaboration with the MAPPER project, resulting in a high-quality
open source tool for the VPH community and beyond. Then have a prototypical three di-
mensional simulation for in-stent restenosis in this environment that will allow us to inves-
tigate new stent designs and test our single scale models under more realistic situations.
2"34.5)$-'%"#"0,-6)-'*7%.*)&/-)89
*"#7%,."/0*)/&)1!2:)!.'0.)"*)-'(
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+/0+'0.-,."/0),0()4/<)".)"*)4"34'-
+%/*'-)./).4')+/,.'()*.'0.:
5&3&6&'0&(
[1] P.M.A. Sloot, A.G. Hoekstra, Multiscale modeling in computational biology, Briefngs
in Bioinformatics 11 (1) (2010) 142152. [2] A.G. Hoekstra, E. Lorenz, J.-L. Falcone, B.
Chopard, Towards a complex automata formalism for multi-scale modeling, nt. J. Mult.
Comp. Eng. 5 (2007) 491502. [3] A.G. Hoekstra, J.-L. Falcone, A. Caiazzo, B. Chopard,
Multi-scale modeling with cellular automata: the complex automata approach, in: Proceed-
ings of ACR 2008, LNCS 5191, Springer-Verlag, Berlin/Heidelberg, 2008, pp. 192199. [4]
A.G. Hoekstra, E. Lorenz, J.L. Falcone & B. Chopard, Towards a complex automata frame-
work for multi-scale modeling: formalism and the scale separation map, in: Proceedings of
7th CCS, LNCS 4487, Springer-Verlag, Berlin/Heidelberg, 2007, pp. 922930. [5] A. Mor-
ton, D. Crossman & J. Gunn, The infuence of physical stent parameters upon restenosis,
Pathologie Biologie 52 (2004) 196205. [6] H. Tahir, A.G. Hoekstra, E. Lorenz, P. Lawford,
R. Hose, J. Gunn & D. Evans [7] Hegewald, J., Krafczyk, M., Tolke, J., Hoekstra, A.G. &
Chopard, B. 2008. An agent-based coupling platform for complex automata. n Computa-
tional ScienceCCS 2008. Lecture Notes in Computer Science, pp. 227233. Heidelberg,
Germany: Springer. [8] A. Caiazzo, D. Evans, J. Falcone, J. Hegewald, E. Lorenz, B. Stahl,
D. Wang, J. Bernsdorf, B. Chopard, J. Gunn, R. Hose, M. Krafczyk, P. Lawford, R. Small-
wood, D. Walker & A.G. Hoekstra, A Complex Automata approach for in-stent restenosis:
Two-dimensional multiscale modelling and simulations, Journal of Computational Science,
Volume 2, ssue 1, March 2011, Pages 9-17.
:0>')<+&#1&%&'/(
This research is funded by European Commission, through MeDDiCA Marie Curie ni-
tial Training Network (www.meddica.eu, EU-FP7/2007-2013 under grant agreement PT-
NGA-2009-238113)
7)'/*0/
Science
Computational
?//8@AA.B*C0)%8./*/$)'*+(0$&'0&C'+A !"#$%&'(!')')*#+"#,%-.&/*#0"#$%-12%33*#4"#5'67-*#8"9"#4%.:);-'
c.bonacasas@uva.nl (C. Bona-Casas), e.lorenz@uva.nl (E. Lorenz), j.borgdorff@uva.nl
(J. Borgdoff), h.tahir@uva.nl (H. Tahir), a.g.hoekstra@uva.nl (A.G. Hoekstra)
Thursday, February 23, 2012
In need of strength?
Use MUSCLE.

MUltiScale Coupling Library and

Environment (MUSCLE).

Build mappers to translate information

between submodels.

Done! But wait... this is very slow... 3D

takes a lot of computing resources...
Thursday, February 23, 2012
Too slow? Go parallel.

Existant BF code: not open source,

undocumented and had only shared
memory parallelism. We switched to
Palabos. Still Lattice-Boltzmann solver.

SMC code not parallel. Still thinking what is

best to do with it.

Drug difussion code. We parallelized it.

Thursday, February 23, 2012
Submodels are so
different...

MUSCLE allows different submodels to run

on different machines (supercomputers,
small clusters, PCs...).

But supercomputers need reservation and

have queues!
Thursday, February 23, 2012
MAPPER Tools

Multiscale APPlications on European e-

infrastRuctures (MAPPER).

Set of tools to aid scientists involved in

multiscale computing (MaMe, MAD,
Gridspace).

Need to teach your application to speak

Multiscale Modeling Language (MML).

Allows running in Huygens (NL), Mavrino

(UK), Grass (PL), Zeus (PL), Reef (PL).
Thursday, February 23, 2012
Thursday, February 23, 2012
Thursday, February 23, 2012
Thursday, February 23, 2012
Output and results
Thursday, February 23, 2012
Future work

Role of endothelium.

Decisions on SMC code.

Dive in the literature for parameter values

and experimental results for validation.

Blood ow pulsatility.
Thursday, February 23, 2012