Coronary Endothelial Shear Stress Profiling InVivo to Predict Progression of Atherosclerosis and InS

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Coronary Endothelial Shear Stress
ProfilingIn-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 Womens
Hospital, Harvard Medical School Department of
Mechanical, Industrial and Manufacturing
Engineering, Northeastern University Department
of Electrical and Computer Engineering,
University of Iowa
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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 (lt 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
• (gt 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.

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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.

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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.

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Varying Degrees of CAD Lesion Severity in a
Single Coronary Artery
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Fundamental Nature of the Problem

• Coronary atherosclerotic obstructions behave
  differently based on the degree of luminal
  obstruction and morphology
• Lesions gt 50-75 obstruction Angina
  Pectoris
• Lesions lt 50 obstruction
  Rupture,superimposed
  thrombus, MI, death
• These small, potentially lethal lesions are,
  therefore, clinically silent until they
  rupture.
• It would be of enormous value to identify minor
  obstructions which were progressing and/or
  evolving towards vulnerability since they could
  be treated before rupture occurred, thereby
  averting an acute coronary syndrome.

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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 (lt 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 (gt 30
  dynes/cm2)
• Promotes platelet activation, thrombus formation,
  and probably plaque rupture
• Until now, in vivo determination of intracoronary
  flow velocity and endothelial shear stress has
  not been possible.

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The Detrimental Effect of Low Shear Stress on
Endothelial Structure and Function
Low shear stresses and disturbed local flow (lt
6 dynes/cm2) are atherogenic
Promotes

• Cell proliferation, migration

• Expression of vascular adhesion molecules,
  cytokines, mitogens

• Monocyte recruitment and activation

• Procoagulant and prothrombotic state

• Local oxidation

(Malek, et al. JAMA 1999 2822035)
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The Effect of Physiologic Shear Stress
onEndothelial Structure and Function
Physiologic shear stress (15-50 dynes/cm2)
is vasculoprotective

• Enhances endothelial quiescence
• - decreases proliferation

• Enhances vasodilation

• Enhances anti-oxidant status

• Enhances anti-coagulant and
• anti-thrombotic status

(Malek, et al. JAMA 1999 2822035)
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Overview of Intracoronary Flow Profiling System

• Coronary angiography
• Intracoronary ultrasound
• Coronary flow (TIMI Frame Count)

Patient
Acquire image data
Application of vascular data to patient care
Prediction of restenosis
3D reconstruction of lumen, EEL, Plaque
Prediction of CAD progression
Generation of grid for Computational Fluid
Dynamics
Determination of local velocity vectors and shear
stress
Numerical computation
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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.

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Selected ICUS frames
Total number of frames ? 100-200/arterial segment
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Measurements of Lumen, Outer Vessel Wall, and
Plaque by IVUS

• Lumen
• Outer Vessel Wall
• Area within EEM
• Plaque Intimal-Medial
• Thickness

(DeFranco. AJC 2001 88 Suppl 7M)
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Stacking of ICUS frames
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Reconstructed Lumen
Top half-plane
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Creation of Computational Mesh
3mm
640 Cells per cross-section
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Representative Example of3-D Reconstruction of
Coronary Artery
RAO projection
LAO projection
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Example of 3-D Reconstruction ofCoronary 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
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Example of 3-D Reconstruction of Arterial Segment
Composite reconstruction of portion of the
arterial segment, consisting of outer arterial
wall, plaque, and lumen
Original angiogram of a portion of an
artery studied
Isolated view of reconstructed outer arterial
wall
Isolated view of reconstructed lumen
Isolated view of reconstructed atherosclerotic
plaque
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Velocity Field Presented As ALongitudinal Section

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Coronary Endothelial Shear Stress
dynes/cm2
Artery is displayed as if it were cut and opened
longitudinally, as a pathologist would view it.
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Reproducibility Studies ofIntra-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

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Reproducibility of 3-D Coronary Artery
ReconstructionTest A and Test B Performed
Separately
Arterial Segment Length (mm)
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 lt 0.0001
(Coskun, et al. JACC 2002, 39 44A)
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In-Vivo Determination of the Natural Historyof
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

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Pilot Study of Natural History of Progression of
Coronary Atherosclerosis and In-Stent
RestenosisEffect of Candesartan vs. Felodipine
Candesartan active Felodipine placebo

• Inclusion Criteria
• Hypertension
• CAD requiring stent
• Additional minor CAD

Cath 1
Enter BWH System
Identification of appropriate CAD substrate -PTCA
/stent -obstruction lt 50 in adj artery, not
revascularized
Candesartan placebo Felodipine active
Preliminary identification of hypertensive patient
Consent and Randomize
Cath 2
Titration to BP lt 140/90 mmHg (Outpatient visits)
Time Line Hours Time
0 Mo 1 Mo 2 Mo 3
Mo 6
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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

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Pilot Study of Candesartan to Reduce
CoronaryIn-Stent Restenosis andProgression of
AtherosclerosisPatient 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

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Example of Coronary Atherosclerosis Progression
Over 6-Month Period
Plaque Thickness Increases in Areas of Low ESS
Lumen Radius Decreases in Areas of
Increased Plaque Thickness
ESS Increases in Areas of Plaque Increase and
Decreases in Distal Areas
EEL Radius Increases in Distal Areas
(Stone, et al. JACC 2002, 39 217A)
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Example of Coronary ArteryOutward Remodeling
Over 6-Month Period
Artery Segment Length (mm)
Lumen radius enlarges
Outer vessel radius enlarges
Plaque thickness does not change
ESS returns to normal values
(Stone, et al. JACC 2002, 39 217A)
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Example of Instent RestenosisOver 6-Month Period
Artery Segment Length (mm)
Lumen radius smaller within stent, larger
outside of stent
Endothelial shear stress increases within
stent, normalizes outside stent
Plaque thickens within stent, no change
outside stent
Outer vessel radius enlarges
(Kinlay, et al. JACC 2002, 39 5A)
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Example of No Change in Stented Segment Over
6-Month Period
Artery Segment Length (mm)
(Kinlay, et al. JACC 2002, 39 5A)
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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

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References

• Asakura T, Karino T. Flow patterns and spatial
  distribution of atherosclerotic lesions in human
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• 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.

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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.