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The role of biomechanics in advanced
atherosclerosis:
data of mice and men
Frank Gijsen
Biomechanics lab
Department of Cardiology
ErasmusMC Rotterdam
Image based biomechanical modelling of the cardiovascular
system to investigate the relationship between
biomechanical parameters and the development and
progression of atherosclerosis
Biomechanics lab
Shear stress and atherosclerosis
in human coronary arteries
D = diameter of the tube
 = viscosity of fluid
V = mean velocity
shear stress: SS =  8V/D
Shear stress (in a straight tube)
Shear stress (in arteries)
Steinman et al. 1999
Poiseuille can be useful, but:
 arteries are not straight tubes
- bend
- stenosis
- bifurcations
 flow in arteries is not steady
 blood is not a Newtonian fluid
Navier-Stokes equations
geometry
viscosity
flow CFD
simulation
local velocity
other …..
shear stress
wall parametersImage analysis
Other (functional) imaging
Image-based hemodynamics
Atherosclerosis
Classification by Stary:
Circulation 1992, 85(1): A definition of the
intima of human arteries and of its
atherosclerosis-prone regions
Circulation 1994, 89(5): A definition of initial,
fatty streak, and intermediate lesions of
atherosclerosis
Circulation 1995, 92(5): A definition of
advanced types of atherosclerotic lesions and a
histological classification of atherosclerosis.
Vulnerable plaques
Histological data provided by Renu Virmani
Shear stress and atherosclerosis
Malek et al.
JAMA 1999
Plaque localization and progression
high shear
stress
low shear
stress
lipid influx
high shear
stress
low shear
stress
lipid influx
Plaque localization and progression
Nakazawa, JACC, 2010
Histological evidence
Progression of atherosclerosis
high shear
stress
low shear
stress
lipid influx
Shear stress and advanced atherosclerosis
high shear stress
cap
blood
flow
lipid core
low shear stress
Dirksen et al., Circulation 98
macrophages
high low
smooth muscle cells
flow
highlow
Slager et al., Nature Clinical Practice, 05
Shear stress and atherosclerosis
Slager et al., Nature Clinical Practice, vol2, #8 and vol2, #9, 2005.
Does shear stress modulate plaque
composition in human coronary
arteries in vivo?
Johannes Schaar, Chris de Korte
geometry
viscosity
flow CFD
simulation
local velocity
other …..
shear stress
wall thicknessImage analysis
Other (functional) imaging
Image-based hemodynamics
MSCT
MSCT: multislice computed
tomography
Contrast-enhanced minimally
invasive imaging technique
High res data of lumen can be
obtained, plaque data less reliable
3D bifurcation reconstruction
generated by combining MSCT and
IVUS
IVUS
ECG gated IVUS
pullback
IVUS catheter
Centerline in MSCT
Fusion of CT and IVUS
Cross sectional images
d≈0.5mm
d=0.2mm
Fusion of CT and IVUS
IVUS contours in 3D
c. d.
Van der Giessen et al., International Journal of Cardiovascular Imaging, 2010
van der Giessen et al., International Journal of Cardiovascular Imaging, 2009
Step 1: fusion of MSCT and IVUS
Step 2: add side branch lumen
data from MSCT only
Gijsen et al., Journal of Biomechanics 2014
3D reconstruction with side branch
geometry
viscosity
flow CFD
simulation
local velocity
other …..
shear stress
plaque compositionImage analysis
IVUS palpography
Image-based hemodynamics
Biomedical Engineering
16/05/2006
27
Plaque composition with palpography
(t1, P1)
(t2, P2)
processing
IVUS at 100 mmHg
Strain map
IVUS at 95 mmHg
Smooth muscle cells
heavymediumminornone
Strain(%)
3.0
2.5
2.0
1.5
1.0
.5
0.0
Macrophages
Strain(%)
3,0
2,5
2,0
1,5
1,0
,5
0,0
heavymediumminornone
Schaar et al., Circulation, vol #8, 2003
Plaque composition with palpography
ANGUS 
3D wall thickness
ANGUS + CFD 
3D shear stress
ANGUS + palpo 
3D strain data
high
low
At index and at 6
months follow up
: wtnorm = 0.2
ANGUS data normalized wall
thickness (wtnorm)
flow
U
U: upstream
S S
S: shoulders
T
T: throat
D
D: downstream
Plaque definition
strain
31 plaques in 13
coronary arteries
were analyzed.
U
D
T
S S
U
D
T
S S
shear stress
average
normalized shear
stress
#
#
0
1
2
3
0
.
5
0
.
2
low medium high
shear stress
#
#
#
strain[%]
0.75
0.50
0.25
average normalized shear stress
U T S D
averageshearstress[Pa]
#
#
U T S D
0
1
2
3
0.5
0.25
averagestrain[%]
U
D
T
S S
strain[%]
U
D
T
S S
shear stress [Pa]
29 out of 31 plaques showed
a positive relationship
between shear stress and
strain
Shear stress vs strain
low medium high
shear stress
#
#
#
strain[%]
0.75
0.50
0.25
Gijsen et al., American journal of Physiology, 2008
Shear stress is low downstream of a plaque, but the complex 3D
shape of human coronary arteries does not allow to predict shear
stress distribution in other plaque regions.
Lower strain values can be observed downstream of a plaque, which
agrees with the observation that at those locations more SMC are
present. Other plaque locations show a heterogenuous strain
distribution.
The plaque regions exposed to the highest shear stress reveal
increased strain values, indicating that shear stress might have an
impact on plaque composition in the more advanced phases of the
disease.
Discussion and conclusions (1)
wall thickness
Final number:
16 plaques in 7 patients
strain index strain fup
∆strain
shear stress
Shear stress vs Δstrain
U T S D
∆strain
Shear stress vs Δstrain
∆strain
#
Gijsen et al., Eurointervention, 2010
Shear stress vs Δstrain
Follow-up studies are difficult!
Changes in strain -and thus plaque composition- over a six month
period are small.
No significant changes in plaque composition can be found if we
look at different plaque regions.
However, those plaque regions exposed to highest shear stress
levels show an increase in strain, confirming our hypothesis that
high shear stress might be involved in destabilizing advanced
atherosclerotic plaques.
Discussion and conclusions (2)
Progression of atherosclerosis
high shear
stress
low shear
stress
lipid influx
Rupture?
Shear stress and the location
of plaque rupture in human
coronary arteries
Alina van der Giessen
IVUS data
 Lumen wall interface after rupture
 Outer vessel wall
 Reconstructed lumen wall
interface before rupture
3D shear stress computations
c. d.
a. b.
c.
low
high
WSS
van der Giessen et al., International Journal of Cardiovascular Imaging, 2009
Data analysis
wall shear stresswall thickness
 14/17 upstream of MLA
 3/17 downstream MLA
 On average 2.7 mm
proximal of MLA
Rupture vs. geometry
0
0. 5
1
1. 5
2
2. 5
3
3. 5
4
4. 5
downstream
upstream
midcap
shouldershoulder
low WSS
high WSS
flow
MLA
Rupture vs. WSS
 13/17 WSS at rupture >
WSS on plaque
 4/17 WSS at rupture <
WSS on plaque
downstream
upstream
midcap
shouldershoulder
MLA
0
0. 5
1
1. 5
2
2. 5
3
3. 5
4
4. 5
low WSS
high WSS
flow
Results
healthy plaque rupture
0.8
1
1.2
1.4
1.6
1.8
shearstressratio
p=0.055
p=0.028
p=0.047
Gijsen et al., Journal of Biomechanics, 2013
Plaques ruptures is induced by blood pressure, and it occurs where the plaque is
weakest.
The weakest plaque locations can be found:
 Mostly proximal of the minimal lumen area (confirms findings from literature)
 Mostly at the shoulder region
 Where shear stress was high
healthy plaque rupture
0.8
1
1.2
1.4
1.6
1.8
shearstressratio
p=0.055
p=0.028
p=0.047
Discussion and conclusions (3)
fusion of cap thickness and shear
stress to assess plaque vulnerability
in human coronary arteries
Jelle Schrauwen, Guillaume Zahnd
geometry
viscosity
flow CFD
simulation
local velocity
other …..
shear stress
cap thicknessImage analysis
OCT
Image-based hemodynamics
Shear stress based on angiography
Schrauwen et al., AJP, 2015
Cap thickness from OCT
Zahnd et al.,MICAI 2014
Zahnd, Schrauwen et al., IJCARS, 2016
Rupture risk map
• A. van der Giessen
• H. Schuurbiers
• A. van der Steen
• J. Wentzel
• J.Schrauwen
• P. Serruys
• E. Regar
• G. Zahnd
• T. van Walsum
• W. Niessen
• F. van de Vosse (TU/e)
• U. Hoffmann (Harvard)
• H. Samady (Emory)
Acknowledgements
Cluster 9: ThoraxcenterCluster 1 to 8
….
Experimental
echocardiography
Interventoinal
cardiology
Experimental
cardiology
Biomedical
engineering
Contrast
imaging
Intravascular
imaging
Biomechanics lab
The role of TransWSS in the
prediction of plaque progression
and destabilization in human
coronary arteries
Annette Kok, Habib Samady
geometry
viscosity
flow CFD
simulation
local velocity
other …..
TransWSS
plaque compositionImage analysis
IVUS VH
Image-based hemodynamics
TransWSS
Cross-flow index (CFI)
 Values range 0 – 1
TransWSS and athero
In cell culture, TransWSS is associated with increased inflammation
Chong Wang et al., Arterioscler Thromb Vasc Biol., 2013
Flow
OldrabbitsYoungrabbits
* Yumnah Mohamied et al., Annals
of Biomed Eng., 2015
To investigate the role of TransWSS in the prediction
of plaque progression and composition in human
coronary arteries
Aim
MaxP < -25.05
Type: Collagen
#of RO Is : 5
MaxP > -25.05
Type: Collagen
#of RO Is : 26
Int < -28.65
#of RO Is : 31
Int < -14.8
Type: Collagen
#of RO Is : 5
Int > -14.8
Type: Collagen
#of RO Is : 5
F at MaxP < 21.045
#of RO Is : 10
F at MaxP > 21.045
Type: Collagen
#of RO Is : 17
MB F < -65.09
#of RO Is : 27
Int < -4.195
Type: Calcium
#of RO Is : 6
Int > -4.195
Type: Collagen
#of RO Is : 5
MB F > -65.09
#of RO Is : 11
F at MaxP < 30.03
#of RO Is : 38
MaxP < -16.095
Type: Collagen
#of RO Is : 6
F at MaxP < 34.275
Type: Necr otic
#of RO Is : 6
MB F < -66.66
Type: FibroLipidic
#of RO Is : 5
MB F > -66.65
Type: Collagen
#of RO Is : 5
MaxP < -12.145
#of RO Is : 10
MaxP > -12.145
Type: Fibro-Lipidic
#of RO Is : 5
F at MaxP > 34.275
#of RO Is : 15
MaxP < -9.915
#of RO Is : 21
F at MaxP < 35.5
Type: Collagen
#of RO Is : 8
F at MaxP > 35.5
Type: Collagen
#of RO Is : 9
MaxP > -9.915
#of RO Is : 17
MaxP > -16.095
#of RO Is : 38
F at MaxP > 30.03
#of RO Is : 44
Int > -28.65
#of RO Is : 82
MB F < -55.695
#of RO Is : 113
MinP <-17.915
Type: Collagen
#of RO Is : 5
MB F < -53.15
Type: Calcium
#of RO Is : 8
MB F > -53.15
Type: Calcium
#of RO Is : 20
MinP > -17.915
#of RO Is : 28
MB F >-55.695
#of RO Is : 33
146
#of RO Is :


TREE
ROOT













media
fibrous
fibrofatty
calcium
lipid core
CFD and composition
Imaging 3D Shear stress
analysis[Pa]
• Each IVUS image is divided into 8 sectors
• Sector calculations
– Area change of the plaque components
– TAWSS, CFI and TransWSS
Data analyses
*
*
*
#
†
#
†
Low
SS (< 1Pa)
Medium
SS (1 Pa – 2.5 Pa)
High
SS (>2.5 Pa)
TAWSS vs plaque composition
†
Low
transWSS
(< 0.05 Pa )
Medium
transWSS
(0.05 Pa – 0.12 Pa)
High
transWSS
(> 0.12 Pa)
TransWSS vs plaque composition
Low
CFI
Med
CFI
High
CFI
Med TAWSS High TAWSS
Low
CFI
Med
CFI
High
CFI
Low
CFI
Med
CFI
High
CFI
Low TAWSS
*
*
#
†
†
Low
CFI
Med
CFI
High
CFI
Med TAWSS High TAWSS
Low
CFI
Med
CFI
High
CFI
Low
CFI
Med
CFI
High
CFI
Low TAWSS
*
*
#
†
†
#
†
†
* *
• Different results than expected from previous experiments
• Interaction effect of TAWSS and CFI
• Low shear stress + low CFI  plaque progression
• High shear stress + high CFI  characteristics of vulnerability
Discussion and conclusions (4)

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The Role of TransWSS in Predicting Plaque Progression

  • 1. The role of biomechanics in advanced atherosclerosis: data of mice and men Frank Gijsen Biomechanics lab Department of Cardiology ErasmusMC Rotterdam
  • 2. Image based biomechanical modelling of the cardiovascular system to investigate the relationship between biomechanical parameters and the development and progression of atherosclerosis Biomechanics lab
  • 3. Shear stress and atherosclerosis in human coronary arteries
  • 4. D = diameter of the tube  = viscosity of fluid V = mean velocity shear stress: SS =  8V/D Shear stress (in a straight tube)
  • 5. Shear stress (in arteries) Steinman et al. 1999 Poiseuille can be useful, but:  arteries are not straight tubes - bend - stenosis - bifurcations  flow in arteries is not steady  blood is not a Newtonian fluid
  • 7. geometry viscosity flow CFD simulation local velocity other ….. shear stress wall parametersImage analysis Other (functional) imaging Image-based hemodynamics
  • 8. Atherosclerosis Classification by Stary: Circulation 1992, 85(1): A definition of the intima of human arteries and of its atherosclerosis-prone regions Circulation 1994, 89(5): A definition of initial, fatty streak, and intermediate lesions of atherosclerosis Circulation 1995, 92(5): A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis.
  • 9. Vulnerable plaques Histological data provided by Renu Virmani
  • 10. Shear stress and atherosclerosis Malek et al. JAMA 1999
  • 11. Plaque localization and progression high shear stress low shear stress lipid influx
  • 12. high shear stress low shear stress lipid influx Plaque localization and progression
  • 14. Progression of atherosclerosis high shear stress low shear stress lipid influx
  • 15. Shear stress and advanced atherosclerosis high shear stress cap blood flow lipid core low shear stress Dirksen et al., Circulation 98 macrophages high low smooth muscle cells flow highlow Slager et al., Nature Clinical Practice, 05
  • 16. Shear stress and atherosclerosis Slager et al., Nature Clinical Practice, vol2, #8 and vol2, #9, 2005.
  • 17. Does shear stress modulate plaque composition in human coronary arteries in vivo? Johannes Schaar, Chris de Korte
  • 18. geometry viscosity flow CFD simulation local velocity other ….. shear stress wall thicknessImage analysis Other (functional) imaging Image-based hemodynamics
  • 19. MSCT MSCT: multislice computed tomography Contrast-enhanced minimally invasive imaging technique High res data of lumen can be obtained, plaque data less reliable 3D bifurcation reconstruction generated by combining MSCT and IVUS
  • 21. Centerline in MSCT Fusion of CT and IVUS Cross sectional images
  • 23. IVUS contours in 3D c. d. Van der Giessen et al., International Journal of Cardiovascular Imaging, 2010 van der Giessen et al., International Journal of Cardiovascular Imaging, 2009 Step 1: fusion of MSCT and IVUS
  • 24. Step 2: add side branch lumen data from MSCT only Gijsen et al., Journal of Biomechanics 2014
  • 25. 3D reconstruction with side branch
  • 26. geometry viscosity flow CFD simulation local velocity other ….. shear stress plaque compositionImage analysis IVUS palpography Image-based hemodynamics
  • 27. Biomedical Engineering 16/05/2006 27 Plaque composition with palpography (t1, P1) (t2, P2) processing IVUS at 100 mmHg Strain map IVUS at 95 mmHg
  • 29. ANGUS  3D wall thickness ANGUS + CFD  3D shear stress ANGUS + palpo  3D strain data high low At index and at 6 months follow up
  • 30. : wtnorm = 0.2 ANGUS data normalized wall thickness (wtnorm) flow U U: upstream S S S: shoulders T T: throat D D: downstream Plaque definition
  • 31. strain 31 plaques in 13 coronary arteries were analyzed. U D T S S U D T S S shear stress average normalized shear stress # # 0 1 2 3 0 . 5 0 . 2 low medium high shear stress # # # strain[%] 0.75 0.50 0.25
  • 32. average normalized shear stress U T S D averageshearstress[Pa] # # U T S D 0 1 2 3 0.5 0.25 averagestrain[%]
  • 33. U D T S S strain[%] U D T S S shear stress [Pa] 29 out of 31 plaques showed a positive relationship between shear stress and strain
  • 34. Shear stress vs strain low medium high shear stress # # # strain[%] 0.75 0.50 0.25 Gijsen et al., American journal of Physiology, 2008
  • 35. Shear stress is low downstream of a plaque, but the complex 3D shape of human coronary arteries does not allow to predict shear stress distribution in other plaque regions. Lower strain values can be observed downstream of a plaque, which agrees with the observation that at those locations more SMC are present. Other plaque locations show a heterogenuous strain distribution. The plaque regions exposed to the highest shear stress reveal increased strain values, indicating that shear stress might have an impact on plaque composition in the more advanced phases of the disease. Discussion and conclusions (1)
  • 36. wall thickness Final number: 16 plaques in 7 patients strain index strain fup ∆strain shear stress Shear stress vs Δstrain
  • 37. U T S D ∆strain Shear stress vs Δstrain
  • 38. ∆strain # Gijsen et al., Eurointervention, 2010 Shear stress vs Δstrain
  • 39. Follow-up studies are difficult! Changes in strain -and thus plaque composition- over a six month period are small. No significant changes in plaque composition can be found if we look at different plaque regions. However, those plaque regions exposed to highest shear stress levels show an increase in strain, confirming our hypothesis that high shear stress might be involved in destabilizing advanced atherosclerotic plaques. Discussion and conclusions (2)
  • 40. Progression of atherosclerosis high shear stress low shear stress lipid influx Rupture?
  • 41. Shear stress and the location of plaque rupture in human coronary arteries Alina van der Giessen
  • 42. IVUS data  Lumen wall interface after rupture  Outer vessel wall  Reconstructed lumen wall interface before rupture
  • 43. 3D shear stress computations c. d. a. b. c. low high WSS van der Giessen et al., International Journal of Cardiovascular Imaging, 2009
  • 44. Data analysis wall shear stresswall thickness
  • 45.  14/17 upstream of MLA  3/17 downstream MLA  On average 2.7 mm proximal of MLA Rupture vs. geometry 0 0. 5 1 1. 5 2 2. 5 3 3. 5 4 4. 5 downstream upstream midcap shouldershoulder low WSS high WSS flow MLA
  • 46. Rupture vs. WSS  13/17 WSS at rupture > WSS on plaque  4/17 WSS at rupture < WSS on plaque downstream upstream midcap shouldershoulder MLA 0 0. 5 1 1. 5 2 2. 5 3 3. 5 4 4. 5 low WSS high WSS flow
  • 48. Plaques ruptures is induced by blood pressure, and it occurs where the plaque is weakest. The weakest plaque locations can be found:  Mostly proximal of the minimal lumen area (confirms findings from literature)  Mostly at the shoulder region  Where shear stress was high healthy plaque rupture 0.8 1 1.2 1.4 1.6 1.8 shearstressratio p=0.055 p=0.028 p=0.047 Discussion and conclusions (3)
  • 49. fusion of cap thickness and shear stress to assess plaque vulnerability in human coronary arteries Jelle Schrauwen, Guillaume Zahnd
  • 50. geometry viscosity flow CFD simulation local velocity other ….. shear stress cap thicknessImage analysis OCT Image-based hemodynamics
  • 51. Shear stress based on angiography Schrauwen et al., AJP, 2015
  • 52. Cap thickness from OCT Zahnd et al.,MICAI 2014
  • 53. Zahnd, Schrauwen et al., IJCARS, 2016
  • 55. • A. van der Giessen • H. Schuurbiers • A. van der Steen • J. Wentzel • J.Schrauwen • P. Serruys • E. Regar • G. Zahnd • T. van Walsum • W. Niessen • F. van de Vosse (TU/e) • U. Hoffmann (Harvard) • H. Samady (Emory) Acknowledgements
  • 56.
  • 57.
  • 58. Cluster 9: ThoraxcenterCluster 1 to 8 …. Experimental echocardiography Interventoinal cardiology Experimental cardiology Biomedical engineering Contrast imaging Intravascular imaging Biomechanics lab
  • 59. The role of TransWSS in the prediction of plaque progression and destabilization in human coronary arteries Annette Kok, Habib Samady
  • 60. geometry viscosity flow CFD simulation local velocity other ….. TransWSS plaque compositionImage analysis IVUS VH Image-based hemodynamics
  • 61. TransWSS Cross-flow index (CFI)  Values range 0 – 1
  • 62. TransWSS and athero In cell culture, TransWSS is associated with increased inflammation Chong Wang et al., Arterioscler Thromb Vasc Biol., 2013 Flow OldrabbitsYoungrabbits * Yumnah Mohamied et al., Annals of Biomed Eng., 2015
  • 63. To investigate the role of TransWSS in the prediction of plaque progression and composition in human coronary arteries Aim MaxP < -25.05 Type: Collagen #of RO Is : 5 MaxP > -25.05 Type: Collagen #of RO Is : 26 Int < -28.65 #of RO Is : 31 Int < -14.8 Type: Collagen #of RO Is : 5 Int > -14.8 Type: Collagen #of RO Is : 5 F at MaxP < 21.045 #of RO Is : 10 F at MaxP > 21.045 Type: Collagen #of RO Is : 17 MB F < -65.09 #of RO Is : 27 Int < -4.195 Type: Calcium #of RO Is : 6 Int > -4.195 Type: Collagen #of RO Is : 5 MB F > -65.09 #of RO Is : 11 F at MaxP < 30.03 #of RO Is : 38 MaxP < -16.095 Type: Collagen #of RO Is : 6 F at MaxP < 34.275 Type: Necr otic #of RO Is : 6 MB F < -66.66 Type: FibroLipidic #of RO Is : 5 MB F > -66.65 Type: Collagen #of RO Is : 5 MaxP < -12.145 #of RO Is : 10 MaxP > -12.145 Type: Fibro-Lipidic #of RO Is : 5 F at MaxP > 34.275 #of RO Is : 15 MaxP < -9.915 #of RO Is : 21 F at MaxP < 35.5 Type: Collagen #of RO Is : 8 F at MaxP > 35.5 Type: Collagen #of RO Is : 9 MaxP > -9.915 #of RO Is : 17 MaxP > -16.095 #of RO Is : 38 F at MaxP > 30.03 #of RO Is : 44 Int > -28.65 #of RO Is : 82 MB F < -55.695 #of RO Is : 113 MinP <-17.915 Type: Collagen #of RO Is : 5 MB F < -53.15 Type: Calcium #of RO Is : 8 MB F > -53.15 Type: Calcium #of RO Is : 20 MinP > -17.915 #of RO Is : 28 MB F >-55.695 #of RO Is : 33 146 #of RO Is :   TREE ROOT              media fibrous fibrofatty calcium lipid core
  • 64. CFD and composition Imaging 3D Shear stress analysis[Pa]
  • 65. • Each IVUS image is divided into 8 sectors • Sector calculations – Area change of the plaque components – TAWSS, CFI and TransWSS Data analyses
  • 66. * * * # † # † Low SS (< 1Pa) Medium SS (1 Pa – 2.5 Pa) High SS (>2.5 Pa) TAWSS vs plaque composition
  • 67. † Low transWSS (< 0.05 Pa ) Medium transWSS (0.05 Pa – 0.12 Pa) High transWSS (> 0.12 Pa) TransWSS vs plaque composition
  • 68. Low CFI Med CFI High CFI Med TAWSS High TAWSS Low CFI Med CFI High CFI Low CFI Med CFI High CFI Low TAWSS * * # † †
  • 69. Low CFI Med CFI High CFI Med TAWSS High TAWSS Low CFI Med CFI High CFI Low CFI Med CFI High CFI Low TAWSS * * # † † # † † * *
  • 70. • Different results than expected from previous experiments • Interaction effect of TAWSS and CFI • Low shear stress + low CFI  plaque progression • High shear stress + high CFI  characteristics of vulnerability Discussion and conclusions (4)