Frank Gijsen

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

6. Navier-Stokes equations

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

13. Nakazawa, JACC, 2010 Histological evidence

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

20. IVUS ECG gated IVUS pullback IVUS catheter

21. Centerline in MSCT Fusion of CT and IVUS Cross sectional images

22. d≈0.5mm d=0.2mm Fusion of CT and IVUS

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

28. 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

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

47. 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

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

54. Rupture risk map

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

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)

Frank Gijsen

Frank Gijsen

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