This document summarizes a study that developed a new methodology for measuring endothelial shear stress (ESS) in coronary arteries in vivo. The methodology uses intravascular ultrasound, biplane angiography, and computational fluid dynamics to reconstruct coronary arteries in 3D and model blood flow/ESS. A pilot study applied this to 8 patients, finding areas of low ESS demonstrated plaque progression over 6 months while areas of normal ESS were stable. The technology may help predict disease progression and response to interventions based on local ESS environments.

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. 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. 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. 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. Varying Degrees of CAD Lesion Severity in a
Single Coronary Artery

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. 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. 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. 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. 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. 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. Selected ICUS frames
Total number of frames ≈ 100-200/arterial segment

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. Stacking of ICUS frames

15. Top half-plane
Reconstructed Lumen

16. Creation of Computational Mesh
640 Cells per
cross-section
3mm

17. Representative Example of
3-D Reconstruction of Coronary Artery
RAO projection LAO projection

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. 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. Velocity Field Presented As A
Longitudinal Section

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.