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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 & 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/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.
Abstract - 2Current 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, These small, potentially lethal lesions are, therefore, “clinically silent” until they rupture.“clinically silent” until they rupture.
• It would be of enormous value to identify minor obstructions It would be of enormous value to identify minor obstructions which were progressing and/or evolving towards which were progressing and/or evolving towards “vulnerability” since they could be treated before rupture “vulnerability” since they could be treated before rupture occurred, thereby averting an acute coronary syndrome.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/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 velocity and determination of intracoronary flow velocity and endothelial shear stress has not been possible.endothelial shear stress has not been possible.
The Detrimental Effect of Low Shear Stress on Endothelial Structure and Function
Low shear stresses and disturbedlocal 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:
The Effect of Physiologic Shear Stress onEndothelial Structure and Function
Physiologic shear stress (~15-50 dynes/cm2) isvasculoprotective:
(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 reconstructionof lumen, EEL, Plaque
Generation of grid for ComputationalFluid Dynamics
Numericalcomputation
Determination oflocal velocity vectorsand shear stress
Application of vascular data to
patient care
Prediction ofrestenosis
Prediction ofCAD 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
3mm
Representative Example of3-D Reconstruction of Coronary Artery
RAO projection LAO projection
Example of 3-D Reconstruction ofCoronary Artery
Solid line passing through the centroid of the lumen defines a pathlinePerpendicular distance between pathline and lumen border defines local lumen radius, perpendicular distance between EEL border and pathline defines the local EEL radiusDifference between local EEL and lumen radii defines local plaque thickness
Original angiogram ofa 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 ALongitudinal Section
Coronary Endothelial Shear Stress
wyuWSS
dynes/cm2
[Artery is displayed as if it were cut and opened longitudinally, as a pathologist would view it.]
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
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)
Arte
rial S
egm
ent L
engt
h (m
m)
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
Pilot Study of Natural History of Progression of Coronary Atherosclerosis and In-Stent Restenosis
Effect of Candesartan vs. Felodipine
Con
sent
and
Ran
dom
ize
Identification ofappropriate CADsubstrate:-PTCA/stent-obstruction < 50% in adj artery, not revascularized
Cath # 1
Cath # 2
EnterBWH System
Candesartan activeFelodipine placebo
Candesartan placeboFelodipine active
Titration to BP < 140/90 mmHg(Outpatient visits)
Time Line: Hours Time 0 Mo 1 Mo 2 Mo 3 Mo 6
Preliminaryidentificationof hypertensivepatient
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 catheterizationOne patient developed acute coronary syndrome
and required urgent cath and restentingSerial Study Cohort: 8 patients
Native CAD Endpoints: 6 patients with serial studies5 Felodipine and 1 patient Candesartan
Restenosis Endpoints: 6 patients with serial studies3 Candesartan and 3 Felodipine
Pilot Study of Candesartan to Reduce CoronaryIn-Stent Restenosis and
Progression of AtherosclerosisPatient Population: 10 patients
9 men; 1 womanMean 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/dlHDL: 36 mg/dlTriglycerides: 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/cm2]
Arte
ry le
ngth
[mm
]
Plaque ThicknessIncreases in Areasof Low ESS
Lumen RadiusDecreases inAreas of IncreasedPlaque Thickness
EEL RadiusIncreases in Distal Areas
ESS Increasesin Areas ofPlaque Increaseand 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/cm2]
Lumen radiusenlarges
Outer vessel radiusenlarges
Plaque thicknessdoes not change
ESS returnsto normal values
(Stone, et al. JACC 2002, 39: 217A)
Arte
ry S
egm
ent L
engt
h (m
m)
Example of Instent RestenosisOver 6-Month Period
Lumen Radius[mm]
EEL Radius[mm]
Plaque Thickness[mm]
Endothelial SS[dynes/cm2]
Lumen radiussmaller withinstent,larger outsideof stent
Outer vesselradiusenlarges
Plaque thickenswithin stent,no change outsidestent
Endothelialshear stress increaseswithin stent,normalizes outsidestent
(Kinlay, et al. JACC 2002, 39: 5A)
Arte
ry S
egm
ent L
engt
h (m
m)
Example of No Change in Stented Segment Over 6-Month Period
Lumen Radius [mm] EEL Radius [mm] Plaque Thickness [mm] ESS [dynes/cm2]
Ar te
r y S
egm
ent L
e ngt
h ( m
m)
(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.