Coronary Endothelial Shear Stress Profiling

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16 Νοε 2013 (πριν από 3 χρόνια και 8 μήνες)

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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

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/cm
2
) leads to plaque
development and progression. Physiologic shear stress
(~10
-

30 dynes/cm
2
) is vasculoprotective, maintaining
normal vascular morphology. Increased shear stress

(> ~ 30 dynes/cm
2
) 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.

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.

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.


Varying Degrees of CAD Lesion Severity in a
Single Coronary Artery

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,
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.


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/cm
2
)


Causes atheroma; pro
-
thrombotic, pro
-
migration, pro
-
apoptosis


Physiologic shear stress and laminar flow

(10
-
30
dynes/cm
2
)


Vasculoprotective, anti
-
thrombotic, anti
-
migration, pro
-
survival


High shear stress and turbulent flow (> 30 dynes/cm
2
)


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.

The Detrimental Effect of
Low
Shear Stress on
Endothelial Structure and Function



Low shear stresses and disturbed

local flow (< ~ 6 dynes/cm
2
)

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
:

The Effect of
Physiologic

Shear Stress on

Endothelial Structure and Function



Physiologic shear stress


(~15
-
50 dynes/cm
2
) 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

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

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.


Selected ICUS frames

Total number of frames


100
-
200/arterial segment

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

Stacking of ICUS frames

Top half
-
plane

Reconstructed Lumen

Creation of Computational Mesh

640 Cells per
cross
-
section

Representative Example of

3
-
D Reconstruction of Coronary Artery

RAO projection

LAO projection

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

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

Velocity Field Presented As A

Longitudinal Section



Coronary Endothelial Shear Stress

w
y
u
WSS




dynes/cm
2

[Artery is displayed as if it were cut and opened longitudinally, as a

pathologist would view it.]

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

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/cm
2
]
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)

Arterial Segment Length (mm)

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


Pilot Study of Natural History of Progression of
Coronary Atherosclerosis and In
-
Stent Restenosis

Effect of Candesartan vs. Felodipine

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

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

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


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
]
Artery length [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

Example of Coronary Artery

“Outward Remodeling” Over 6
-
Month Period

Lumen Radius
[mm]
EEL Radius
[mm]
Plaque Thickness
[mm]
Endothelial SS
[dynes/cm
2
]
Lumen radius

enlarges

Outer vessel radius

enlarges

Plaque thickness

does not change

ESS returns

to normal values

(Stone, et al. JACC 2002, 39: 217A)

Artery Segment Length (mm)

Example of Instent Restenosis

Over 6
-
Month Period

Lumen Radius
[mm]
EEL Radius
[mm]
Plaque Thickness
[mm]
Endothelial SS
[dynes/cm
2
]
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)

Artery Segment Length (mm)

Example of No Change in Stented Segment
Over 6
-
Month Period

Lumen Radius [mm]
EEL Radius [mm]
Plaque Thickness [mm]
ESS [dynes/cm
2
]
(Kinlay, et al. JACC 2002, 39: 5A)

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

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.

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.