Andrew Williams Thesis Defense

Quantifying Hemodynamic Changes Caused by Stenting of Coronary Bifurcation Lesions Using Realistic Computational Fluid Dynamics Models November 14, 2008 By Andrew R. Williams, B.S. Committee: John LaDisa, PhD Said Audi, PhD Bon-Kwon Koo, MD PhD Lars Olson, PhD 1 1

Outline • Introduction • Methods • Specific Aim 1 • Specific Aim 2 • Specific Aim 3 • Discussion • Conclusions • Next Steps 2 2

Introduction - Cardiovascular Disease • 1 in 2.8 deaths in the United States is caused by cardiovascular disease (CVD) • 52% of those deaths are caused by coronary artery disease (CAD) in which fatty deposits form and occlude blood ﬂow to the heart • Risk factors manifest globally and include: • High cholesterol • High Blood pressure • Diabetes mellitus • Smoking 3 AHA Heart Disease and Stroke Statistics 2007 update 3

Introduction - Bifurcations • Plaque tends to form locally at • Bends • Branches • Bifurcations Fung Y. Biomechanics: Mech. Properties of Living Tissues. New York: Springer; 1993. 4 4

Introduction - Coronary Anatomy 2 1 Major coronary arteries include the: 3 1. Right Coronary Artery (RCA) 2. Left Circumﬂex (LCX) 3. Left Anterior Descending (LAD) The most common site of bifurcation plaque is the LAD/D1 From Wolf-Heidegger’s Atlas of Human Anatomy. 6th ed. 5 5

Introduction - Bifurcation Flow Profile The flow profile after a bifurcation is skewed towards the carina. 6 Courtesy of Eric Gross MD, PhD 6

Introduction - Important Indices • Wall shear stress (WSS or τ): The tangential stress imparted onto the walls of a blood vessel as a result of moving fluid • Oscillatory shear index (OSI): OSI quantifies the deviation of WSS from the primary flow direction during the cardiac cycle OSI ranges between 0 (no change in direction) and 0.5 (complete reversal of direction) 7 7

Introduction - Coronary Artery Disease Plaque forms at locations of low time averaged wall shear stress (TAWSS) and high oscillatory shear index (OSI) 8 www.nhlbi.nih.gov/health/dci/Diseases/Angioplasty 8

Introduction - Stenting • Stenting is the most common method to treat CAD • Procedure involves: A. Position catheter B. Expand the stent C. Remove the catheter • In 2005 in the US, there were 1,265,000 PCI of which 620,000 were stent implantations 9 www.nhlbi.nih.gov/health/dci/Diseases/Angioplasty 9

Introduction - Restenosis Over the course of months, 15-20% of stented patients have neointimal hyperplasia growth through and around the stent potentially causing: • redevelopment of the stenosis • an increase in resistance • reduced blood ﬂow Stent geometry is an important factor in restenosis 10 Deplano et al. Med Biol Eng Comput. Sep 2004;42(5):650-659. www.nhlbi.nih.gov/health/dci/Diseases/Angioplasty 10

Introduction - Types of Stents Taxus Express2 Taxus Liberte (Boston Scientiﬁc) (Boston Scientiﬁc) Cypher (Cordis, J&J) 11 11

Introduction - Bifurcation Stents MultiLink Frontier (Abbott Vascular) Axxess Plus (Devax) 12 12

Introduction - Bifurcation Stenting There are multiple methods to stent bifurcations with traditional stents. Single Stent Method Two Stent Method Adapted from www.angioscore.com 13 13

Introduction - Difficulties studying blood flow in vivo Blood flow is therefore important, but • WSS measurement is not part of clinical practice • devices do not have required resolution Velocity and shear rate in a human common carotid artery with ultrasound 14 Katritsis et al. Prog Cardiovasc Dis. Mar-Apr 2007;49(5):307-329. 14

Introduction - CFD Computational Fluid Dynamics (CFD) is an advanced simulation tool ideal for studying the local effects of blood flow. Example Model Geometry Requirements: Inflow • Model Geometry • Computational Mesh Wall properties • Inflow Boundary Conditions • Outflow Boundary Outflow Conditions • Wall Properties 15 15

Introduction - Previous Work - CFD Stents LaDisa et al. simulated blood ﬂow through a stented model to show that WSS correlated with neointimal hyperplasia in rabit illiacs. Deplano et al. simulated blood ﬂow through a stented bifurcation with zero pressure outlet boundary conditions. 16 LaDisa et al. AJP - Heart Circ Physiol 288: H2465-75, 2005 Deplano et al. Med Biol Eng Comput. Sep 2004;42(5):650-659. 16

Introduction - Previous Work (cont.) • CFD bifurcation models with realistic dimensions and physiologic boundary conditions have not been created • Previous CFD studies with stents have used simplified geometries • Treatment-specific changes in coronary bifurcation blood flow have not been studied • Patient-specific models have not included stents previously 17 17

Hypothesis Adverse hemodynamic changes are introduced in bifurcation regions by stenting and are inﬂuenced by implantation technique, stent orientation, and post-implantation geometry 18 18

Specific Aims 1. Create idealized models and simulate blood flow through the LAD/D1 bifurcation pre-stenting, post-stenting, and post-kissing 2. Create patient-specific models and simulate blood flow through the LAD/D1 bifurcation pre- and post-stenting 3. Simulate the expansion of a stent using finite element analysis (FEA) 19 19

Methods • Meshing • Inﬂow Boundary Conditions • Outﬂow Boundary Conditions • Vessel Wall Properties 21 21

Methods - Meshing Meshing discretizes a model into millions of element for which the mass and momentum balance equations are solved 22 22

Methods - Inflow Boundary Conditions • An inflow waveform must be defined for at least one face • LaDisa et al. measured blood flow through a canine coronary artery using an ultrasonic flow probe • Resting and elevated blood flow conditions were applied using a Womersley velocity profile 3.500 1.5 3.000 1.2 2.500 Blood Flow (cc/s) 0.9 2.000 Blood Flow (cc/s) 1.500 0.6 1.000 0.3 0.500 0.0 0.000 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.000 0.100 0.200 0.300 0.400 0.500 0.600 Time (s) Time (s) Rest Elevated Blood Flow 23 LaDisa et al. JAP 2002; 93:1939-1946 23

Methods - Outlet Boundary Conditions • Input impedance represents the contribution of all vessels distal to an outlet • Coronary input impedance increases during systole constituting a non-linear, time-varying system for which standard frequency analysis is invalid • Van Huis et al. measured the impulse response in the canine LAD under resting conditions circumventing this limitation • These methods neglect the time-varying resistance caused by myocardial contraction • The input impedance can be approximated by a three element Windkessel model with limitations 24 From the SimVascular User Manual 24

Outlet Boundary Conditions (cont.) • Rp is the characteristic impedance (Zc): where Cph is wave speed, ρ is density, and r is radius • Rp was calculated for each branch individually 25 Van Huis et al. Am J Physiol. Aug 1987;253(2 Pt 2):H317-324 25

Outlet Boundary Conditions (cont.) • Van Huis et al. calculated Rd: • Capacitance is found by using the pulse pressure method of Stergiopulos et al. which iterates the capacitance until the simulation pulse pressure matches physiologic pulse pressure • The mean ﬂow was calculated as the fraction of the total ﬂow going to each branch, assuming WSS auto- regulation or equal WSS at the outlets 26 Van Huis et al. Am J Physiol. Aug 1987;253(2 Pt 2):H317-324 26

Outlet Boundary Conditions (cont.) • Elevated blood flow conditions (i.e. exercise or hyperemia) representative of those achieved by continuous intracoronary adenosine infusion were applied • Rp was calculated using a representative wave speed for exercise • Elevated blood flow conditions from LaDisa et al. were imposed • Rd and C were calculated with increased flow and the same pressure 27 Koo et al. Circ. Aug. 2005; 69: 908-912 27

Methods - Vessel Wall Properties • No slip assumed • Rigid walls assumed • Later simulations will include deformable walls with different moduli for vessel and stent surfaces 28 28

Speciﬁc Aim 1 -Idealized models • Motivation • Model generation • Stent Creation • Design parameters • Results • Summary 30 30

Speciﬁc Aim 1- Motivation Carina Shift Intravascular Ultrasound (IVUS) Data Pre-Stent Post-Stent Post-Kiss 31 Images courtesy of Bon-Kwon Koo, MD, PhD 31

Speciﬁc Aim 1- Motivation (cont.) • Finet’s Law Empirically derived formula relating parent vessel radius (rp) to the sum of the daughter vessels radii (rdaughter1, rdaughter2) 32 Courtesy of Bon-Kwon Koo, MD PhD Finet et al. EuroInterv. 2007;3. 32

Speciﬁc Aim 1- Design Parameters 33 Ikeda et al. Jpn Heart J. Sep 1991;32(5):627-633 33

Speciﬁc Aim 1- Design Parameters (cont.) Crimped Stent Sketch 34 34

Speciﬁc Aim 1 - Important Indices • Fractional Flow Reserve (FFR) is clinical method to quantify the severity of a stenosis Where QSmax and QNmax are the maximum ﬂows through the stenosed and normal vessels respectively In practice FFR is approximated, where Pd and Pa are the pressure distal and proximal to the stenosis, respectively, during exercise • % Stenosis is the percent change in area measured by angiography 35 Adapted from Bon-Kwon Koo, MD PhD 35

Speciﬁc Aim 1 - Important Indices (cont.) • Angiographic Severity vs. FFR Severity • FFR Severity does not correlate well with % Why discrepancy???? stenosis. One explanation is that only the minor diameter of the side branch is observed and the major diameter cannot be seen during an angiographic assessment. Why discrepancy???? MB MB MB SB MB SB Major SB SB Diameter Minor Diameter 36 Koo et al. JACC 2005, 46(4) 633-7 Adapted from Bon-Kwon Koo, MD PhD 36

Speciﬁc Aim 1- Model Generation 37 37

Speciﬁc Aim 1- Stent Creation 38 38

Speciﬁc Aim 1- Boolean Subtraction 39 39

Speciﬁc Aim 1- Resulting Models IVUS Data Resulting Idealized Models Pre-Stent Post-Stent Post-Kiss 40 40

Speciﬁc Aim 1- Side Branch Jailing Post-Stent Best Case Post-Stent Worst Case Post-Kiss 41 41

Speciﬁc Aim 1 - Mesh Independence • CFD models were simulated with increasingly reﬁned element density using an adaptive meshing approach • Results were assumed to be mesh independent when TAWSS at 5 locations within the computational domain changed less than 6% (< 0.09 dyn/cm2) between two successive meshes Figure showing faces where WSS was assessed 42 42

Speciﬁc Aim 1 - Mesh Independence (cont.) Number of Elements In Successive Meshes 43 43

Speciﬁc Aim 1- Volume Rendered Velocity Pre-Stent Pre-Stent 0 22.5 0 55 Rest (cm/s) Exercise (cm/s) Post-Stent Worst Post-Kiss 0 20 0 20 Rest (cm/s) Rest (cm/s) 44 44

Speciﬁc Aim 1- TAWSS Resting Post-Stent Post-Stent Pre-Stent Post-Kiss Best Case Worst Case 0 20 Time-averaged WSS (dynes/cm2) 45 45

Speciﬁc Aim 1- TAWSS Exercise Post-Stent Post-Stent Pre-Stent Post-Kiss Best Case Worst Case 0 30 Time-averaged WSS (dynes/cm2) 46 46

Speciﬁc Aim 1 - Area with Low WSS *)%()+,\"-&\"./)'012)/\"3-/)0\"4'00\"51,6\"7-5\"4##\"\" 89\":\"/;+)<=(>?@A\" #!\" '#\" '!\" &#\" &!\" !\"#$%&'()\" %#\" +,2/\"9:;\" %!\" ,<,+=82,9:;\" $#\" $!\" #\" !\" ()\"*+,-./,0/\" ()\"*12/-./,0/\"3,2/\"452,\" ()\"*12/-./,0/\"61+2/\" ()\"*12/-7822\" 452,\" Stenting increases area of low WSS Area of low WSS is reduced during exercise 47 47

Speciﬁc Aim 1- OSI Rest Post-Stent Post-Stent Pre-Stent Post-Kiss Best Case Worst Case 0 0.5 Oscillatory Shear Index 48 48

Speciﬁc Aim 1- OSI Exercise Post-Stent Post-Stent Pre-Stent Post-Kiss Best Case Worst Case 0 0.5 Oscillatory Shear Index 49 49

Specific Aim 1- Summary • Idealized models show the effects of single stent implantation on WSS, OSI and velocity distribution • Stenting causes a shift in the carina towards the side branch, skewing the velocity profile of the main branch • Post-stenting dilation to shift the carina back towards the main branch skews the velocity profile away from the carina 50 50

Specific Aim 1- Summary (cont.) • Velocity profiles near the bifurcation are therefore influenced by the location of the carina • Stenting introduces areas of low WSS near stent struts and opposite the carina that are alleviated by exercise • Stenting introduces areas of high OSI near stent struts and opposite the carina that are pronounced by exercise 51 51

Speciﬁc Aim 2 - Patient Speciﬁc Models • Motivation • Model Generation • Stent Creation • Results • Summary 53 53

Specific Aim 2 - Motivation • Provide increased physiologic realism • Support results from first specific aim • Develop methods for subsequent studies 54 Image courtesy of Jon Freeman MD and Ray Migrino MD 54

Speciﬁc Aim 2 - Model Generation A. 64 slice CT angiographic data taken for a human B. Center paths are drawn through the bifurcated vessel images and cross sections are segmented C. CVSim lofts between the segments to created a geometric model of the bifurcated vessel D. Geometric model is meshed with >1.5 million elements 55 55

Speciﬁc Aim 2- Patient Speciﬁc Stent Creation 56 56

Speciﬁc Aim 2- Velocity Rest Pre-Stent Post-Stent 20 Volume-rendered Velocity (cm/s) 0 57 57

Speciﬁc Aim 2- Velocity Exercise Pre-Stent Post-Stent 55 Volume-rendered Velocity (cm/s) 0 58 58

Speciﬁc Aim 2- Patient Speciﬁc TAWSS Rest Pre-Stent Post-Stent 20 Time-averaged WSS (dynes/cm2) 0 59 59

Speciﬁc Aim 2- Patient Speciﬁc TAWSS Exercise Pre-Stent Post-Stent 30 Time-averaged WSS (dynes/cm2) 0 60 60

Speciﬁc Aim 2- Patient Speciﬁc OSI Rest Pre-Stent Post-Stent Oscillatory Shear Index 0.5 0 61 61

Speciﬁc Aim 2- Patient Speciﬁc OSI Exercise Pre-Stent Post-Stent Oscillatory Shear Index 0.5 0 62 62

Speciﬁc Aim 2 - Summary • Similar to the idealized models, stenting introduces areas of low WSS and high OSI around stent struts that is similarly inﬂuenced by exercise • Regions of high OSI were less pronounced compared to the idealized models • Stent struts protruding into (i.e. jailing) the side branch ostium cause vortices that are pronounced during exercise 63 63

Speciﬁc Aim 3 - Implantation Using FEA • Motivation • Model generation • Results • Summary 65 65

Speciﬁc Aim 3 - Motivation Wu et al. simulated the expansion of a stent in a straight vessel (SV) and curved vessel (CV) model. (Displacement (top) and stress (bottom)) Applying these methods would allow simulation of two stent bifurcation approaches 66 Wu et al. J Biomech. 2007;40(11):2580-2585. 66

Speciﬁc Aim 3 - Model Generation 67 67

Speciﬁc Aim 3 - Simulation Parameters Number of Elements 24,000 Element Type 8-node Solid 185 Stent Material 316L annealed stainless steal Modulus 201 GPa Poisons Ratio 0.3 Simulation Time 100 seconds Number of Substeps 50 Pressure Applied to Inner 2.01*104 Pa Surface of the Ring 68 68

Speciﬁc Aim 3 - Results 69 69

Speciﬁc Aim 3 - Results (cont.) 70 70

Speciﬁc Aim 3 - Summary • Simulated expansion of one macro ring element of the Taxus Express2 stent with FEA demonstrates feasibility of these methods • Expansion caused stress concentration in regions of curvature within the macro ring element • Expansion introduced modest “S” curve in straight regions of the macro ring elements • This progress reveals the geometric limitations of the stent models used in speciﬁc aims 1 and 2 71 71

Discussion • Clinical Application to FFR • Area of Low TAWSS and High OSI • Limitations of Models • Novelty of Current Work 73 73

Discussion - FFR !\"#$%&'#()!(&*)+,-,\".,)/$\"&--)01,)234,)5\"#'$1) 6-%78) ,% !\"##% !\"#+% !\"#*% !\"#)% !\"#(% !\"#'% !\"#&% !\"#$% 0% 0% % 3% 3% % 43 <66 04 04 96 96 30 ; 23 23 %8 3%8 631 312 63 1 01 /0 06 .5 56 5/ ./ \"%. %7 -\"% \"%. 3%: -\"% 43 .\"2 .\"2 30 04 2 23 631 631 .5 .5 -\"% -\"% Stenting reduces FFR but not to a clinically signiﬁcant level (0.75) The worst case orientation decreased FFR most 74 74

Discussion - TAWSS and OSI • Low TAWSS and high OSI have been correlated with restenosis • Stenting introduces areas of low WSS and high OSI near stent struts and near the carina • Therefore, we might expect restenosis to occur in those areas 75 75

Discussion - Limitations • Straight Vessels - Coronary arteries are located on the curved surface of the heart • Sharp Transitions - Sharp vascular transitions add artifact to idealized models • Simpliﬁed Stent Implantation - Some distortion of strut length • RCR Boundary Conditions - Time varying resistor not included • Rigid Walls - Future simulations will include deformable walls 76 76

Discussion - Novelty of Current Work • Idealized models reproduced clinical observations with improved realism allowing for measurement of hemodynamic and clinical parameters • Results of patient-specific models built upon findings of idealized models by adding increased physiologic realism • FEA simulations of stent expansion helped evaluate geometric limitations of the stented models and developed tools for future work with patient- specific models 77 77

Conclusions • Stenting causes geometric changes to the lumen of the vessel which cause increased areas of low TAWSS and high OSI • Low TAWSS and high OSI have been shown to correlate with restenosis • Idealized and patient-speciﬁc CFD models of the LAD/D1 bifurcation site were developed with virtual implantation of a common stent used in clinical practice • Implantation technique, stent orientation in the side branch ostium, and carina location affect WSS and OSI • Methods were also developed to simulate the virtual implantation of a stent with FEA 78 78

Next Steps • Simulate with deformable walls • Investigate different stent types and multiple stent strategies • Investigate the effect of strut orientation in the ostium • Apply current and future developments to next generation bifurcation stent designs 79 79

Acknowledgements John LaDisa, PhD Bon-Kwon Koo, MD, PhD Lars Olson, PhD Said Audi, PhD John Freeman, MD Ray Migrino, MD 80 80

Questions? • Thank You 81

Andrew Williams Thesis Defense

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