Embed Size (px)
Citation preview
Anatomical Basis for MRI Assessment of Human Atherosclerotic Disease:MRI Dimensions of Post-Mortem
Carotid Artery Pairs from 38 Elderly Individuals
W. Insull Jr., G. J. Adams,C. B. Bordelon Jr., J. D. Morrisett
Baylor College of Medicine, Houston TX
Contact Info: William Insull Jr., M.D. [email protected] D. Morrisett, Ph.D. [email protected]
AbstractCarotid artery atherosclerosis is a significant cause of strokes and can be evaluated non-invasively by MRI. The purpose of this study was to determine by MRI and EBCT the anatomical pathology of atherosclerosis in elderly individuals most likely to have fullest expression of atherosclerosis. Pairs of carotid artery segments around the bifurcation were obtained from 38 individuals in the anatomical laboratory after pressure perfusion fixation. They were examined by high resolution MRI using a 1.5T clinical MR system equipped with a phased array coil and by clinical EBCT. We measured the location of the atherosclerotic plaque along the artery, the volumes of the artery wall and lumen, and estimated the plaque volume. The replicate variation for intra- and interscan volumes (coefficients of variation) measured the minimum variances for the clinical MRI scan procedure excluding patient-dependent sources of variance. Both MRI and EBCT showed close bilateral symmetry of lesions for dimensions and calcium content, respectively. Carotid plaques appeared to be single lesions with maximum development at the bifurcation diminishing progressively to terminate about 15 mm distal and proximal to the bifurcation. We identified the implications of these anatomical observations for the concepts of development of atherosclerosis in single carotid lesions and noted potential clinical applications.
Background• Carotid atherosclerosis provides a potentially fruitful site for the study of
atherosclerosis development, diagnosis, and treatment.• The carotid artery bifurcation is highly susceptible to atherosclerosis. • The growth and development of carotid lesions is unlimited throughout all ages since
lesion size is not restricted by the limits of anatomical geometry of the artery.• Advanced lesions of carotid atherosclerosis occur in populations with high prevalence
of atherosclerosis, stages IV to VII by the AHA classification 1995.• All earlier stages of atherosclerotic lesions occur simultaneously with the most
advanced lesions, generally distributed radially and sequentially directly adjacent to and contiguous to these most advanced lesions.
• The microscopic pathological characteristics of carotid atherosclerosis are similar to atherosclerosis at other clinically significant arterial sites, coronary arteries, peripheral arteries and aorta.
• Inter-individual variation in extent of carotid AS is broad within and among populations, similar to wide variance for coronary and aortic disease.
• The symmetrical pairing of carotid arteries provides an opportunity to evaluate the variance of atherosclerosis lesions between similar sites within each individual.
• Carotid arteries are readily accessible to non-invasive imaging by a variety of techniques, including B mode ultrasound, computed tomography and magnetic resonance imaging.
Purpose
Sample Acquisition:• Cadaveric carotid arteries
were used as the model.• Fifty perfusion-fixed
carotid pairs were excised from human cadavers aged 7413 (48-98) years.
• Of the 50 sample pairs, 38 contained the entire plaque and were suitable for rigorous analysis.
3D Reconstruction of a Carotid Artery from
multiple 3mm thick MRI slices.
Cadaveric Carotid Artery Specimen
To describe the anatomical, pathological, and dimensional characteristics of carotid atherosclerosis in elderly individuals using high resolution MRI 1.5T and EBCT.
Cadaveric Carotid ArteriesUseful properties of the cadaveric carotid artery samples:a) Tissue was pressure perfusion fixed before excision, which
preserves the tissue and maintains in vivo geometry.b) Most of the periadventitial tissue has been removed, which
reduces specimen bulk while retaining essential anatomical features.
CCA BIF
ICA
ECA
Single Cadaveric Carotid Artery Sample
The common carotid artery (CCA), bifurcation (BIF), external carotid artery (ECA), and internal carotid artery (ICA) are clearly seen.
Properties of Cadaveric Carotid ArteriesEssential properties of the cadaveric carotid artery samples:• Contain all three layers of the arterial wall (intima, media,
adventitia), and some perivascular soft tissue.• Contain a range of lesion types.• Give reproducible images over >1 year.• Provide stable reference for:
• intra-laboratory standardization• inter-laboratory standardization for multicenter clinical
trialsOther useful attributes:• Enables comparison of left and right carotids from an
individual.• Can be analyzed using independent techniques other than
MRI (e.g. histology, µCT, FTIR spectroscopy).
Imaging Protocol
Samples in EBCT Scanner
Ex Vivo Imaging Apparatus 1.5T GE Clinical MRI Scanner
An Imatron EBCT scanner and AccuImage software were used to obtain calcification scores for each sample.
A 1.5T GE Horizon LX clinical MRI equipped with Pathway phased array coils was used to acquire PDW, T1W, and T2W images with an in-plane spatial resolution of 0.195 mm and a slice thickness of 3mm.
Carotid Artery Volume Quantitation using MRI
Measurement Algorithm:• A semiautomatic active contour algorithm was used
to define the boundaries of the lumen and the outer wall of the artery.
• The generalized gradient vector field force was used as the external force for the active contour algorithm.
• The area of each contour was measured and multiplied by the slice thickness to obtain the volume.
T2W MRI Image
Internal Lumen
External Lumen
Artery Wall
1. Initial Contours 2. Final Contours 3. Measurements
Plaque Volume Estimation and AssumptionsEstimation:• Estimate normal wall thickness as the average minimum wall thickness within
each branch of the carotid tree.• Estimate normal wall volume by sweeping a thickness contour around the
outer wall.• Plaque Volume = Total Wall Volume – Normal Wall Volume.• Percent Stenosis = Plaque Volume / Estimated Normal Lumen.Assumptions:• A normal, non-diseased wall is represented by the wall with the minimal
thickness.• Normal wall thickness remains constant around the artery wall.• Normal wall thickness remains the same within each branch of the carotid.
Internal Lumen
External Lumen
Artery Wall
2. Measurements1. T2W MRI Image
Normal Wall
Plaque
3. Plaque Estimate
Comparison of Volumes within Artery PairsComputation and Comparison of Aggregate Volumes:• For comparison purposes, slices were indexed by their distance from the
bifurcation.• The bifurcation was defined as the first MRI slice in which both the internal
and external lumen were visible as two separate orifices.• Aggregate volumes for nine contiguous slices bounding the bifurcation were
computed for each sample.
1. Locate Bifurcation 2. Align Slices by Offset 3. Compute Volumes
MRI of Left
CarotidArtery
MRI ofRight
CarotidArtery
Slice 10
Slice 11
Offset 0 on Left
Offset 0 on Right
Left Aggregate Volume
Right Aggregate Volume
Multiple Contrast Imaging
PDW
T1W
T2W
Contiguous 3mm thick MRI slices.
I/E2 I/E1 Bifurc. C1 C2
• Tissues were imaged using multiple contrast weightings, including proton density, T1, and T2-weightings.
• The different weightings provide differential contrast among principal tissue components (e.g. necrotic core, fibrous cap, calcification, thrombus) within the atherosclerotic plaque.
• Cai et al. have demonstrated that it is possible to differentiate between different tissue types using multi-contrast MR imaging in vivo.
LuLuHH
RCRC
LiLi
FCFC
SSSS
Correlation of Histology and MR Imaging• Cross-sectional MR images closely match histology slices.
Carotid Volume DistributionsSlice volume averages were computed for slices at the same offset in the left and right carotid arteries for the 38 pairs.
Average LeftSlice Volumes at
Offset 0
Sample 1 Offset 0 Left
+
Sample 2 Offset 0 Left
Average RightSlice Volumes at
Offset 0
Sample 1 Offset 0 Right
+
Sample 2 Offset 0 Right
= =vs.
0
20
40
60
80
100
120
140
160
C10 C8 C6 C4 C2 B I2/E2 I4/E4 I6/E6
Slice
Volu
me
(mm
3 )
CommonInternal
External
Lumen Volume Distributionsin the Left and Right Carotids
Slice volume profiles measured using the semiautomated active contour algorithm. Distance between slices is 3mm.
Dotted lines are left carotid volumes.Solid lines are right carotid volumes.
0
50
100
150
200
250
300
350
400
C10 C8 C6 C4 C2 B I2/E2 I4/E4 I6/E6
Slice
Volu
me
(mm
3 )
Common Internal
External
Total Artery Volume Distributionsin the Left and Right Carotids
Slice volume profiles measured using the semiautomated active contour algorithm. Distance between slices is 3mm.
Dotted lines are left carotid volumes.Solid lines are right carotid volumes.
0
50
100
150
200
250
C10 C8 C6 C4 C2 B I2/E2 I4/E4 I6/E6
Slice
Volu
me
(mm
3 )
CommonInternal
External
Total Wall Volume Distributionsin the Left and Right Carotids
Total wall slice volume profiles calculated as total artery volume minus lumen volume. Distance between slices is 3mm.
Dotted lines are left carotid volumes.Solid lines are right carotid volumes.
0
20
40
60
80
100
120
140
C10 C8 C6 C4 C2 B I2/E2 I4/E4 I6/E6
Slice
Volu
me
(mm
3 )
Common
Internal
External
Normal Wall Volume Distributionsin the Left and Right Carotids
Slice volume profiles estimated using the automated plaque estimation algorithm. Distance between slices is 3mm.
Dotted lines are left carotid volumes.Solid lines are right carotid volumes.
0
10
20
30
40
50
60
70
80
C10 C8 C6 C4 C2 B I2/E2 I4/E4 I6/E6
Slice
Volu
me
(mm
3 )
Common
Internal
External
Dotted lines are left carotid volumes.Solid lines are right carotid volumes.
Plaque Volume Distributionsin the Left and Right Carotids
Slice volume profiles estimated using the automated plaque estimation algorithm. Distance between slices is 3mm. Plaque volume is concentrated near the bifurcation, with 80% of the plaque within 9mm of the bifurcation in the internal carotid, 12 mm within the external carotid, and 18mm in the common carotid.
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
C10 C8 C6 C4 C2 B I2/E2 I4/E4 I6/E6
Slice
Volu
me
(mm
3 )
Common
Internal(Circles)
External(Triangles)
Percent Stenosis Distributionsin the Left and Right Carotids
Slice volume profiles estimated using the automated plaque estimation algorithm. Distance between slices is 3mm. Percent stenosis was calculated by dividing the estimated plaque volume by the estimated original lumen.
Dotted lines are left carotid volumes.Solid lines are right carotid volumes.
Wall Thickness Distributions• Wall thickness distributions were calculated for each MR slice
in the carotid artery. • Averages for each branch were computed by taking the mean
of the average wall thickness of each slice within that branch.• Maximums for each branch were computed by finding the
largest maximum wall thickness for each slice within that branch.
MaximumWall
Thickness
Scatter Plots of the Average and Max Wall Thicknessin mm. of the Internal, External and Common
Carotid Artery Branches from MRI
0 1 2 30
1
2
3
Left Internal
Rig
ht In
tern
al
0 1 2 30
1
2
3
Left External
Rig
ht E
xter
nal
0 1 2 30
1
2
3
Left Common
Rig
ht C
omm
on
r=0.63r=0.75r=0.48
0.0 2.5 5.0 7.5 10.00.0
2.5
5.0
7.5
10.0
Left Common
Rig
ht C
omm
on
0.0 2.5 5.0 7.50.0
2.5
5.0
7.5
Left Internal
Rig
ht In
tern
al
0.0 2.5 5.0 7.50.0
2.5
5.0
7.5
Left External
Rig
ht E
xter
nal
r=0.57r=0.23 r=0.52
Average Wall Thicknesses
Maximum Wall Thicknesses
Scatter Plots of the Average Wall Thickness v. the Maximum Wall Thickness
in mm. of the Internal, External and Common Carotid Artery Branches from MRI
0 1 2 30.0
2.5
5.0
7.5
Left Internal Avg
Left
Inte
rnal
Max
0 1 2 30.0
2.5
5.0
7.5
Right Internal Avg
Rig
ht In
tern
al M
ax
0 1 2 30
1
2
3
4
5
Left External Avg
Left
Exte
rnal
Max
0 1 2 30.0
2.5
5.0
7.5
Right External Avg
Rig
ht E
xter
nal M
ax
0 1 2 30.0
2.5
5.0
7.5
10.0
Left Common Avg
Left
Com
mon
Max
0 1 2 30.0
2.5
5.0
7.5
10.0
Right Common Avg
Rig
ht C
omm
on M
ax
r=0.73
r=0.85
r=0.74
r=0.71
r=0.79
r=0.53
Aggregate Volumes StatisticsAggregate volumes were computed for nine contiguous slices
bounding the bifurcation for each sample in the 38 pairs.
vs.
Left Aggregate Volume Right Aggregate Volume
0 500 1000 1500 20000
500
1000
1500
2000
Left Lumen
Rig
ht L
umen
Scatter Plots of Carotid Artery Aggregate Volumes from MRI
0 1000 2000 3000 40000
1000
2000
3000
4000
5000
Left Total ArteryR
ight
Tot
al A
rter
y0 1000 2000 3000
0
1000
2000
3000
Left Total Wall
Rig
ht T
otal
Wal
l0 500 1000 1500 2000
0
500
1000
1500
2000
Left Normal Wall
Rig
ht N
orm
al W
all
0 500 1000 15000
500
1000
1500
Left Plaque
Rig
ht P
laqu
e
0 25 50 750
25
50
75
Left Percent StenosisR
ight
Per
cent
Ste
nosi
s
Average Carotid Artery Aggregate Volumes from MRI
0
500
1000
1500
2000
2500
3000
3500
LeftLumenVolume
RightLumenVolume
Left TotalArtery
Volume
Right TotalArtery
Volume
Left TotalWall
Volume
Right TotalWall
Volume
LeftNormal
WallVolume
RightNormal
WallVolume
LeftPlaqueVolume
RightPlaqueVolume
• Average volumes in mm3 for left and right carotid volumes from MRI.• None of the left v. right volumes were significantly different.• Error bars are standard deviations.
Scatter Plots of Carotid Artery Calcium Volume Scores from EBCT
0 500 1000 1500 20000
500
1000
1500
2000
Left Calcium Volume Score
Rig
ht C
alci
um V
olum
e Sc
ore
0 1000 2000 30000
1000
2000
3000
Left Agatston Score
Rig
ht A
gats
ton
Scor
e
• Two separate scores were computed from the same images. • The Agatston Score is calculated based on calcification area times a scale factor. • The Volume Score uses the isotropic interpolation to calculate the volume of
calcification.• The two calcification scores are highly correlated with one another (r=0.997).• The scores are not normally distributed within the population of individuals.
Average Carotid Artery Calcification Scores from EBCTTwo separate scores were computed from the same images. The Agatston Score is calculated based on calcification area times a scale factor, whereas the Volume Score uses the isotropic interpolation to calculate the volume of calcification.
Left and Right Carotid Artery EBCT Calcification Scores from 38 Sample Pairs
Error Bars are Standard Deviations Agatston Score Volume Score
-200
0
200
400
600
800
1000
Left AgatstonScore
Right AgatstonScore
Left CalciumVolume Score
Right CalciumVolume Score
Left v. Right Carotid Volume (MRI) and Agatston Score (EBCT) Concordance Correlations
• Lin’s concordance correlation coefficients of left and right carotid volumes from MR and left and right calcification scores from EBCT.
• Lin’s concordance correlation coefficient measures the agreement between a pair of variables.
• Error bars are 95% confidence intervals.
0.54
0.630.71
0.640.58
0.51
0.95 0.94
0.0
0.2
0.4
0.6
0.8
1.0
LumenVolume
Total ArteryVolume
Total WallVolume
NormalWall
Volume
PlaqueVolume
PercentStenosis
AgatstonScore
VolumeScore
Conc
orda
nce
Corr
elat
ion
Coef
ficie
nt
Correlations between Agatston Score (EBCT) and Aggregate Volumes (MRI)
Correlations of Agatston Score vs Aggregate Volumes (N=76)Error Bars are 95% Confidence Intervals
-0.17
0.27
0.50 0.46 0.44 0.53
-0.60
-0.40
-0.20
0.00
0.20
0.40
0.60
0.80
1.00
LumenVolume
Total ArteryVolume
Total WallVolume
Normal WallVolume
PlaqueVolume
PercentStenosis
Aggregate Volume
Corr
elat
ion
Coef
ficie
nt
Reproducibility Statistics• To test the reproducibility of MRI imaging of the models, two image sets,
consisting of two full acquisitions (PDW, T1W, T2W) on four models, were acquired.
• Between the two sets the holder was removed from the magnet, the coils were removed from the holder, and the temperature of the water bath was re-equilibrated.
• Arterial volumes of each model were quantified using the semiautomated algorithm.
• The reproducibility of the measured volumes from the different models is quantified using the coefficient of variation (mean±SD), which is expressed as a percentage.
Lumen Total Wall Normal Wall PlaqueWithin Sets COV (N=8)
0.33±0.24 0.70±0.30 1.01±1.11 2.48±2.14
Between Sets COV (N=4)
2.19±2.00 2.63±1.75 3.96±2.16 4.47±1.56
Summary of Results
The anatomical characteristics of the carotid plaques have been described by the average values of the study subjects:
• Carotid plaque is a single continuous lesion extending from the common carotid into the internal and external branches, without evidence of discontinuities of structure that indicate multiple plaques at the carotid site.
• Lesions are located at the region of the bifurcation, presumably in the area of the carotid bulb, within 15mm proximally and distally from the flow divider. Lesions’ longitudinal development within the artery wall appears to be equal along the common carotid and the internal and external branches.
• Lesion bulk is greater in the internal carotid that in the internal carotid. Volumes within the external carotid are 30 to 50% smaller per slice.
• The sum of the plaque volumes in the internal and external carotid in the slice most proximal to the bifurcation is equal to the plaque volume in the common carotid slice most proximal to the bifurcation.
• The maximum volume of plaque is at the region of the bifurcation. This is probably the region with the most advanced plaque.
• Proximal and distal to the region of maximal development, the volume per slice decreases rapidly in a curvilinear fashion.
Discussion of Results
1. Studying elderly patients has the inherent advantage of studying individuals with the fullest development of atherosclerosis due to prolonged exposure to all risk factors. The development of carotid atherosclerosis, raised lesions to the naked eye, is progressive with age and in high risk populations is a companied by increasing occurrence of complicated and calcified lesions. Solberg et al
2. The analysis of variance of MRI measurements of a single cadaveric carotid artery provides an estimate of the minimum variance achievable with the MRI scan procedure alone. This procedure excludes all sources of variance related to patients, as within scan movements, and interscan differences of positioning and movement. This provides as basis for systematic analysis of variance of MRI clinical scans that are essential for estimating sample sizes for studies of treatment effects on the dimensions of the plaque volume.
3. The comparison of pairs of carotids within individual patients shows the strong bilateral symmetry of the disease. This supports the use of analysis of a single artery as an estimate of the burden of atherosclerosis among similar arteries. It also starts to define the inter-arterial variance of atherosclerosis within an individual, the least difference as it occurs between bilaterally symmetrical arteries.
Discussion of Results
The analysis provides measurements on the development of atherosclerosis within a single plaque. The results support the following statements:
• The plaque region with the greatest volume, at the carotid bifurcation, probably has the plaques most advanced stage of development, and are probably the oldest region of the plaque.
• The plaque regions with the smallest detectable volumes, at the proximal and distal edges of the plaque, probably have the earliest stage of development, and are the youngest region of the plaque.
• Since plaques appear to grow centrifugally along radial vectors, similar young regions probably occur at the lateral edges of the plaque.
• These observations support the concept of the plaques’ centrifugal growth and development along radii from the initial site.
• Whether the grades of lesions described by the AHA classification are arranged along the radial vectors of growth requires further study.
Discussion of Results
The analysis of the anatomical dimensions of carotid plaques from MRI images has substantial implications for clinical use of MRI:
• Diagnosis of atherosclerosis by detection of arterial lesions.• Staging of the development of carotid atherosclerosis. Staging procedures require
initially the quantitative measurements of the lesion location and the lesions’ physical dimensions. While plaques’ degree of surface involvement surface, and compositional heterogeneity have been used customarily for staging plaque development, the volume of the plaque can now be used to further define the stage of development.
• Rationale for selection of therapy based on the characteristics of the plaque, it’s location, dimensions and composition.
• Monitoring therapy developing criteria for significant therapeutic effect, as reduction in plaque volume.
• Adjusting therapy if treatment effects are not satisfactory• Guidance to endarterectomy surgeon for dissection to excise lesions.
References and Acknowledgements
References• Adams GJ, Simoni DM, Bordelon
CB, et al. Stroke. 2002;33:2575-2580.
• Cai J-M, Hatsukami TS, Ferguson MS, et al. Circulation. 2002;106:1368-1373.
• Karmonik C, Eldrige C, Vick GW, et al. Am J Cardiol. 2001;88:78E.
• Solberg LA, McGarry PA, Moossy J, et al. Ann N Y Acad Sci. 1968;149:956-973.
• Stary HC, Chandler AB, Dinsmore RE, et al. Circulation. 1995;92:1355-1374.
• Zarins CK, Giddens DP, Bharadvaj BK, et al. Circ. Res. 1983;53:502-514.
Acknowledgements• Funding was provided by grants to Dr.
Morrisett from the Welch Foundation (Q1325) and the National Heart, Lung and Blood Institute of the NIH (HL07812 and HL63090.
• Gareth Adams was supported in part by a training fellowship from the Keck Center for Computational and Structural Biology of the Gulf Coast Consortia (NLM 5T5LM07093).
• EBCT calcification scoring was performed by Darlene Simoni, RT.
