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057 coronary endothelial shear stress profiling

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057 coronary endothelial shear stress profiling

  1. 1. Coronary Endothelial Shear Stress Profiling In-Vivo to Predict Progression of Atherosclerosis and In-Stent Restenosis in Man Peter H. Stone, M.D. Ahmet U. Coskun, Ph.D. Scott Kinlay, M.D., Ph.D., Maureen E. Clark, M.S. Milan Sonka, Ph.D. Andreas Wahle, Ph.D., Olusegun J. Ilegbusi, Ph.D. Yerem Yeghiazarians, M.D. Jeffrey J. Popma, M.D. Richard E. Kuntz, M.D., M.S. Charles L. Feldman, Sc.D. Cardiovascular Division, Brigham & Women’s Hospital, Harvard Medical School; Department of Mechanical, Industrial and Manufacturing Engineering, Northeastern University; Department of Electrical and Computer Engineering, University of Iowa
  2. 2. Abstract - 1 The focal and eccentric nature of CAD must be related to local hemodynamic factors. The endothelium is uniquely capable of controlling local arterial responses by transduction of hemodynamic shear stress. Low or reversed shear stress (< ~10 dynes/cm2 ) leads to plaque development and progression. Physiologic shear stress (~10 - 30 dynes/cm2 ) is vasculoprotective, maintaining normal vascular morphology. Increased shear stress (> ~ 30 dynes/cm2 ) promotes outward remodeling and platelet aggregation. Characterization of shear stress along the coronary artery may allow for prediction of progression of atherosclerosis and vascular remodeling.
  3. 3. Abstract - 2 Current methodologies cannot provide adequate information concerning the micro-environment of the coronary arteries. We developed a unique system using intravascular ultrasound (IVUS), biplane coronary angiography, and measurements of coronary blood flow, to present the artery in accurate 3-D space, and to produce detailed characteristics of intravascular flow, ESS, and arterial wall and plaque morphology. We observed that over 6 mo followup, areas of low ESS demonstrated plaque progression, areas of physiologic ESS remained quiescent, and areas of increased ESS developed outward remodeling. The technology may be invaluable to study the impact of pharmacologic or device interventions on the natural history of coronary disease.
  4. 4. Fundamental Nature of the Problem • Although all portions of the coronary arterial tree are exposed to the same systemic risk factors, atherosclerosis is focal and eccentric • Each coronary artery has many different obstructions in different “stages” of evolution: – There is not a “wave-front” of vulnerability and consequent rupture.
  5. 5. Varying Degrees of CAD Lesion Severity in a Single Coronary Artery
  6. 6. Fundamental Nature of the Problem • Coronary atherosclerotic obstructions behave differently based on the degree of luminal obstruction and morphology: – Lesions > 50-75% obstruction Angina Pectoris – Lesions < 50% obstruction Rupture,superimposed thrombus, MI, death These small, potentially lethal lesions are,These small, potentially lethal lesions are, therefore, “clinically silent” until they rupture.therefore, “clinically silent” until they rupture. • It would be of enormous value to identify minorIt would be of enormous value to identify minor obstructions which were progressing and/orobstructions which were progressing and/or evolving towards “vulnerability” since they could beevolving towards “vulnerability” since they could be treated before rupture occurred, thereby avertingtreated before rupture occurred, thereby averting an acute coronary syndrome.an acute coronary syndrome.
  7. 7. Nature of Progression of Atherosclerosis • The only truly local phenomena which could lead to varying local vascular responses are endothelial shear stresses (ESS) • Local ESS variations are critical: – Low ESS and disturbed flow (< 6-10 dynes/cm2 ) • Causes atheroma; pro-thrombotic, pro-migration, pro-apoptosis – Physiologic shear stress and laminar flow (10-30 dynes/cm2 ) • Vasculoprotective, anti-thrombotic, anti-migration, pro-survival – High shear stress and turbulent flow (> 30 dynes/cm2 ) • Promotes platelet activation, thrombus formation, and probably plaque rupture • Until now,Until now, in vivoin vivo determination of intracoronary flow velocitydetermination of intracoronary flow velocity and endothelial shear stress has not been possible.and endothelial shear stress has not been possible.
  8. 8. The Detrimental Effect of Low Shear Stress on Endothelial Structure and Function Low shear stresses and disturbed local flow (< ~ 6 dynes/cm2 ) are atherogenic: (Malek, et al. JAMA 1999; 282:2035) • Cell proliferation, migration • Expression of vascular adhesion molecules, cytokines, mitogens • Monocyte recruitment and activation • Procoagulant and prothrombotic state • Local oxidation Promotes:
  9. 9. The Effect of Physiologic Shear Stress on Endothelial Structure and Function Physiologic shear stress (~15-50 dynes/cm2 ) is vasculoprotective: (Malek, et al. JAMA 1999; 282:2035) • Enhances endothelial quiescence - decreases proliferation • Enhances vasodilation • Enhances anti-oxidant status • Enhances anti-coagulant and anti-thrombotic status
  10. 10. Overview of Intracoronary Flow Profiling System Patient • Coronary angiography • Intracoronary ultrasound • Coronary flow (TIMI Frame Count) Acquire image data 3D reconstruction of lumen, EEL, Plaque Generation of grid for Computational Fluid Dynamics Numerical computation Determination of local velocity vectors and shear stress Application of vascular data to patient care Prediction of restenosis Prediction of CAD progression
  11. 11. Intracoronary Flow Profiling Methods • The intracoronary ultrasound (ICUS) “core” is positioned in the relevant section of the artery and a biplane angiogram is recorded using dilute contrast. • ICUS is performed with controlled pull-back at 0.5 mm/sec with biplane angiography. ECG is simultaneously recorded for “gating.” • A dynamic programming technique extracts the lumen and EEL outline from the ICUS at end-diastolic frames and re-aligns them. • The ICUS frames are realigned in 3-D space perpendicular to the ICUS core image. • The reconstructed lumen is divided into computational control volumes comprising 0.3 mm thick slices along the segment, 40 equal intervals around the circumference, and 16 intervals in the radial direction. • Dividing the blood into small “cubes” on the grid, the Navier-Stokes equations of fluid flow are solved numerically using an iterative procedure (Computational Fluid Dynamics). • Shear stress at the wall is obtained by multiplying viscosity by the velocity gradient at the wall.
  12. 12. Selected ICUS frames Total number of frames ≈ 100-200/arterial segment
  13. 13. Measurements of Lumen, Outer Vessel Wall, and Plaque by IVUS (DeFranco. AJC 2001; 88 [Suppl]: 7M) • Lumen • Outer Vessel Wall = Area within EEM • Plaque = Intimal-Medial Thickness
  14. 14. Stacking of ICUS frames
  15. 15. Top half-plane Reconstructed Lumen
  16. 16. Creation of Computational Mesh 640 Cells per cross-section 3mm
  17. 17. Representative Example of 3-D Reconstruction of Coronary Artery RAO projection LAO projection
  18. 18. Example of 3-D Reconstruction of Coronary Artery Solid line passing through the centroid of the lumen defines a pathline Perpendicular distance between pathline and lumen border defines local lumen radius, perpendicular distance between EEL border and pathline defines the local EEL radius Difference between local EEL and lumen radii defines local plaque thickness
  19. 19. Original angiogram of a portion of an artery studied Composite reconstruction of portion of the arterial segment, consisting of outer arterial wall, plaque, and lumen: Isolated view of reconstructed outer arterial wall: Isolated view of reconstructed lumen: Isolated view of reconstructed atherosclerotic plaque: Example of 3-D Reconstruction of Arterial Segment
  20. 20. Velocity Field Presented As A Longitudinal Section
  21. 21. Coronary Endothelial Shear Stress w y u WSS ∂ ∂ µ= dynes/cm2 [Artery is displayed as if it were cut and opened longitudinally, as a pathologist would view it.]
  22. 22. Reproducibility Studies of Intra-coronary Flow Profiling Measurements Cardiac catheterization and coronary angiography – Patients studied completely with ICUS pullback and biplane angiography (“Test A”) – All catheters removed, and after a few minutes, entire procedure repeated (“Test B”): • catheters reinserted • angle, skew, table height reproduced to mimic the initial procedure – All calculations performed to measure lumen, outer vessel, plaque morphology, and endothelial shear stress
  23. 23. Reproducibility of 3-D Coronary Artery Reconstruction “Test A” and “Test B” Performed Separately Lumen Radius [mm] EEL Radius [mm] Plaque Thickness [mm] Endothelial SS [dynes/cm2 ] r = 0.96 r = 0.95 r = 0.91 r = 0.88 Grid divided into 2,560-10,640 areas/artery (average 5,900/artery) Each p < 0.0001 (Coskun, et al. JACC 2002, 39; 44A) ArterialSegmentLength(mm)
  24. 24. In-Vivo Determination of the Natural History of Restenosis and Atherosclerosis • First pilot study of its kind in the world • Complete intra-coronary flow profiling at index catheterization and repeated at 6-month followup • 10 patients enrolled: – Followup catheterization completed in 8 patients • one refused recath; one had clinical event prior to recath
  25. 25. Pilot Study of Natural History of Progression of Coronary Atherosclerosis and In-Stent Restenosis Effect of Candesartan vs. Felodipine ConsentandRandomize Identification of appropriate CAD substrate: -PTCA/stent -obstruction < 50% in adj artery, not revascularized Cath # 1 Cath # 2 Enter BWH System Candesartan active Felodipine placebo Candesartan placebo Felodipine active Titration to BP < 140/90 mmHg (Outpatient visits) Time Line: Hours Time 0 Mo 1 Mo 2 Mo 3 Mo 6 Preliminary identification of hypertensive patient Inclusion Criteria: • Hypertension • CAD requiring stent • Additional minor CAD
  26. 26. Pilot Study of Natural History of Progression of Coronary Atherosclerosis and In-Stent Restenosis Followup Status: One patient refused repeat catheterization One patient developed acute coronary syndrome and required urgent cath and restenting Serial Study Cohort: 8 patients Native CAD Endpoints: 6 patients with serial studies 5 Felodipine and 1 patient Candesartan Restenosis Endpoints: 6 patients with serial studies 3 Candesartan and 3 Felodipine
  27. 27. Pilot Study of Candesartan to Reduce Coronary In-Stent Restenosis and Progression of Atherosclerosis Patient Population: 10 patients 9 men; 1 woman Mean age: 60.8 years (range 37-83 years) Concomitant medications: B-blockers, statins, and aspirin (all patients) Mean fasting lipids: Total cholesterol: 156 mg/dl LDL cholesterol: 95 mg/dl HDL: 36 mg/dl Triglycerides: 150 mg/dl Blood Pressure:Baseline: 156/89 mmHg Followup: 137/78 mmHg
  28. 28. Example of Coronary Atherosclerosis Progression Over 6-Month Period (Stone, et al. JACC 2002, 39: 217A) Plaque Thickness [mm] Lumen Radius [mm] EEL Radius [mm] ESS [dynes/cm 2 ] Arterylength[mm] Plaque Thickness Increases in Areas of Low ESS Lumen Radius Decreases in Areas of Increased Plaque Thickness EEL Radius Increases in Distal Areas ESS Increases in Areas of Plaque Increase and Decreases in Distal Areas
  29. 29. Example of Coronary Artery “Outward Remodeling” Over 6-Month Period Lumen Radius [mm] EEL Radius [mm] Plaque Thickness [mm] Endothelial SS [dynes/cm2 ] Lumen radius enlarges Outer vessel radius enlarges Plaque thickness does not change ESS returns to normal values (Stone, et al. JACC 2002, 39: 217A) ArterySegmentLength(mm)
  30. 30. Example of Instent Restenosis Over 6-Month Period Lumen Radius [mm] EEL Radius [mm] Plaque Thickness [mm] Endothelial SS [dynes/cm2 ] Lumen radius smaller within stent, larger outside of stent Outer vessel radius enlarges Plaque thickens within stent, no change outside stent Endothelial shear stress increases within stent, normalizes outside stent (Kinlay, et al. JACC 2002, 39: 5A) ArterySegmentLength(mm)
  31. 31. Example of No Change in Stented Segment Over 6-Month Period Lumen Radius [mm] EEL Radius [mm] Plaque Thickness [mm] ESS [dynes/cm 2 ] ArterySegmentLength(mm) (Kinlay, et al. JACC 2002, 39: 5A)
  32. 32. Conclusions • This methodology allows for the first time in man the systematic and serial in vivo investigation of the natural history of CAD and consequent vascular responses. • There are different and rapidly changing behaviors of different areas within a coronary artery in response to different ESS environments. • The methodology can evaluate in detail the ESS that are responsible for the development and progression of CAD, as well as the remodeling that occurs in response to CAD. • The technology may be invaluable to study the impact of pharmacologic or device interventions on these natural histories
  33. 33. References • Asakura T, Karino T. Flow patterns and spatial distribution of atherosclerotic lesions in human coronary arteries. Circ 1990; 66: 1045-66. • Nosovitsky VA, et al. Effects of curvature and stenosis-like narrowing on wall shear stress in a coronary artery model with phasic flow. Computer and Biomed Res 1997; 9: 575-580. • Malek A, et al. Hemodynamic shear stress and its role in atherosclerosis. JAMA 1999; 282: 2035-42. • Ward M, et al. Arterial remodeling. Mechanisms and clinical implications. Circ 2000; 102: 1186-91. • Ilegbusi O, et al. Determination of blood flow and endothelial shear stress in human coronary artery in vivo. J Invas Cardiol 1999; 11: 667-74. • Feldman CL, et al. Determination of in vivo velocity and endothelial shear stress patterns with phasic flow in human coronary arteries: A methodology to predict progression of coronary atherosclerosis. Am Heart J 2002; 143: (in press). • Feldman CL, Stone PH. Intravascular hemodynamic factors responsible for progression of coronary atherosclerosis and development of vulnerable plaque. Curr Opin in Cardiol 2000; 15: 430-40.
  34. 34. References • Coskun AU, et al. Reproducibility of 3-D lumen, plaque and outer vessel reconstructions and of endothelial shear stress measurements in vivo to determine progression of atherosclerosis. JACC 2002; 39: 44A. • Stone PH, et al. Prediction of sites of progression of native coronary disease in vivo based on identification of sites of low endothelial shear stress. JACC 2002; 39: 217A. • Kinlay S, et al. Endothelial shear stress identified in vivo within the stent is related to in-stent restenosis and remodeling of stented coronary arteries. JACC 2002; 39: 5A. • Feldman CL, et al. In-vivo prediction of outward remodeling in native portions of stented coronary arteries associated with sites of high endothelial shear stress at the time of deployment. JACC 2002; 39: 247A.

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