Artery-Related Differences in Atherosclerosis Expression

Implications for Atherogenesis and Dynamics in Intima-Media Thickness

Sren Dalager, MD, PhD; William P. Paaske, MD, DrMedSci; Ingrid Bayer Kristensen, MD;
Jacob Marsvin Laurberg, MD, PhD; Erling Falk, MD, DrMedSci

Background and PurposeInformation about the expression of atherosclerosis in different arteries is important. The
impact of cardiovascular risk factors is artery-related, and the assessment of arterial structure and function in peripheral
arteries are increasingly used as surrogate markers for coronary atherosclerosis and the risk of developing heart attack.
MethodsIn an autopsy study, we analyzed the coronary, carotid and superficial femoral arteries from 100 individuals (70
men; 20 to 82 years of age) of which 27 died from coronary atherosclerosis. Microscopic sections (n4756) were
analyzed blindly using a modification of the histological classification endorsed by the American Heart Association
(AHA).
ResultsWe found distinct artery-dependent patterns of atherosclerosis with a high prevalence of foam cell lesions and
lipid core plaques in the carotid arteries. The femoral arteries were least affected by atherosclerosis, foam cell lesions
were rare, and the development of advanced atherosclerosis was strongly age-dependent and dominated by fibrous
plaques. Plaques were most common in the left anterior descending coronary artery and the carotid bifurcation. In
coronary (versus noncoronary) death, lipid core plaques were more prevalent in all arteries.
ConclusionsThe initiation, speed of development, and phenotypic expression of atherosclerotic plaques are artery-
related. Foam cell lesions are frequent in the carotid arteries, probably explaining the dynamics in carotid intima-media
thickness. Atherosclerosis develops slowly in femoral arteries, and severe atherosclerosis is dominated by fibrous
plaques. The higher prevalence of lipid core plaques in all arteries in coronary death indicates a systemically more
vulnerable expression of atherosclerosis in these individuals. (Stroke. 2007;38:2698-2705.)
Key Words: atherosclerosis carotid atherosclerosis coronary atherosclerosis pathology
peripheral vascular disease

I nformation about the expression of and the relationship

between atherosclerosis in different arteries is important
for several reasons. The classic cardiovascular risk factors
have different impact in different arterial territories. Choles-
terol is particularly important in ischemic heart disease,
hypertension in ischemic stroke, and smoking and diabetes in
intermittent claudication.1,2 Moreover, some arteries, eg, the
internal mammary artery, are relatively spared from athero-
sclerosis.3 Better understanding of the nature and reasons for
these differences are important in prevention and treatment of
atherosclerosis and its complications.
In spite of the differences, measures of atherosclerosis in
peripheral arteries serve as fast and continuous end points in
clinical testing of drugs assumed to have antiatherosclerotic
properties,4 and are used in the assessment of the overall
atherosclerotic burden and cardiovascular risk. Examples of
these measures include the carotid artery intima-media thick-
ness (IMT), and the ankle-brachial blood pressure index.57
Comparative and descriptive pathological studies of ath-
erosclerosis in different arteries are numerous but belong to
an era without any widely accepted histological classification
of atherosclerosis. Many of these studies were not performed
on histological sections, but on gross specimens8 with more
emphasis on disease severity than composition.9 12
Since then, the American Heart Association (AHA) clas-
sification of atherosclerosis has emerged.1315 Although de-
bated16 and subsequently updated17 it provides a useful
framework for atherosclerosis description. Our aims were: (1)
to characterize and compare the type of atherosclerosis within
different arteries using the AHA classification; and (2) to
analyze the relation with age, gender and cause of death.
Materials and Methods
Individuals
Clinically important atherosclerosis-susceptible segments18,19 were
obtained from 6 locations: the proximal parts of the left anterior
descending (LAD) and the right coronary artery (RCA), both carotid
arteries, and both superficial femoral arteries. The carotid arteries
and the superficial femoral arteries were examined over a large part
of their lengths, eg, the carotid artery segments included the distal

Received March 8, 2007; final revision received April 9, 2007; accepted April 20, 2007.
From the Departments of Cardiothoracic and Vascular Surgery T (S.D., W.P.P.) and Cardiology B (S.D., J.M.L., E.F.), Aarhus University Hospital,
Skejby, Denmark; and the Institute of Forensic Medicine, University of Aarhus (I.B.K., S.D.), rhus, Denmark.
Correspondence to Sren Dalager, MD, PhD, Department of Pathology, Aarhus University Hospital, Nrrebrogade 44, DK-8000 rhus C, Denmark.
E-mail soren@dalager.eu
2007 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.107.486480

2698
Downloaded from http://stroke.ahajournals.org/ by guest on December 2, 2015
 Dalager et al Intima-Media Thickness: a Foam Cell Barometer? 2699

Figure 1. Location of artery segments

and sections. Cx indicates circumflex.

part of the common carotid artery, the bifurcation (bulb region), and
the proximal part of the internal carotid artery (Figure 1). The
segments were prospectively collected from 100 autopsies at the
Institute of Forensic Medicine, University of Aarhus, Denmark.
The autopsies were performed from February 1996 to March 1999,
and the study was approved by the Regional Research Ethics
Committee and The Danish Data Protection Agency. The individuals
underwent postmortem examination if death occurred unexpectedly
outside the hospital or under unclear circumstances. Data on pre-
mortem risk factors were unavailable. Only individuals with a
postmortem interval 4 days were included. The mean age of the
100 individuals was 47.114.1 years (meanSD; range: 20 to 82
years), and 30 were women. In 49 cases the cause of death was
natural (27 coronary deaths,20 22 other natural deaths) whereas 51
individuals had unnatural deaths (7 suicides, 42 accidents,
2 homicides).
Tissue Processing
The coronary arteries were cut open longitudinally as part of the
forensic examination. The artery segments were fixed in 4% phos-
phate buffered formalin for 24 hours and decalcified (unless 45
years of age) in 10% formic acid for 24 hours. Cross-sectioning was
performed at 4-mm intervals and the resulting sections were embed-
ded in paraffin, yielding 48 paraffin blocks from each subject
(4756 paraffin blocks in total; 44 sections were unavailable, primar-
ily from the distal part of the internal carotid arteries). All tissue
sections were cut at 4-m thicknesses, mounted on Superfrostglass
slides, and stained with hematoxylin and eosin (HE).
Histological Grading of Arterial Disease
Histological evaluation was performed using a light microscope
(Olympus BX51) equipped with polarization filters and an integrated
eyepiece graticule. The sections were graded in random order
blinded to subject data according to a slightly modified AHA
classification (Table 1).1315,17 The modifications consisted of an
addition of chronic occlusion (type IX lesion) and omission of the
acute type VI lesion (surface defect, hematoma, or thrombosis).
Instead, these lesions were graded according to the underlying
chronic atherosclerotic plaque (eg, a type V lesion with rupture
and thrombosis was graded as type V, not type VI). Fibrosis
(hyalinization) was detected by the characteristic birefringence of
collagen when the HE-stained sections were viewed under polarized
light. Histological examples are given in Figure 2. For each artery
segment, the plaque burden was calculated as the number of sections
with plaque (AHA type IV) divided by the total number of sections
in that artery segment (range: 0 to 1).
Statistics
Intercooled STATA 9.2 for Windows (Statacorp LP) was used for
statistical analysis. The sections were pooled according to localiza-
tion and further stratified by age, gender and cause of death. Lesion

Table 1. Modified AHA Classification of Atherosclerotic Lesions*

Type Name Characteristics Definition
0 Normal intima or intimal thickening No foam cells No foam cells, may exhibit minor intimal
thickening or lymphocyte infiltration
I Foam cell lesions (intimal xanthoma) Single isolated foam cells Single isolated foam cells
II Foam cell layers Multiple foam cells (2 layers)
III Intermediate lesion (pathological intimal Pools of extracellular lipid with no or only few Minor accumulations of structure- and colorless
thickening) cholesterol crystals material displacing the normal structural
components of the intima
IV Lipid core plaque (fibrous cap atheroma) Extracellular lipid core, also called necrotic core Colorless cavity without extracellular matrix and
containing spindle-shaped empty spaces
(cholesterol crystals)
V fibrosis Hyalinization (birefringent fibres)
VI Complicated plaque Surface defect, hematoma, or thrombosis Surface defect, plaque hemorrhage, or luminal
thrombus
VII Calcified plaque (fibrocalcific plaque) 50% of plaque area calcified 50% of plaque area calcified, with or without
lipid core
VIII Fibrous plaque (fibrocalcific plaque) Fibrous plaque without a lipid core Fibrous plaque with hyalinization without any lipid
core (unless the core has undergone complete
calcification)
IX Chronic occlusion (total occlusion) Chronically occluded artery Artery occluded by plaque and connective tissue,
no fresh thrombus
*Based on the updated17 histological classification of atherosclerotic lesions endorsed by the AHA. Type VI was graded as the underlying lesion without
complications. Alternative terms proposed by Virmani et al16 are shown in parentheses.

Downloaded from http://stroke.ahajournals.org/ by guest on December 2, 2015

2700 Stroke October 2007
types at the different localizations are presented as percentage
distribution. Because of the descriptive and exploratory nature of the
study, the distribution of lesion types is presented without calcula-
tions of statistics. The correlation between plaque burdens in the
different arteries was calculated using Spearman rank correlation
test. Inter- and intraobserver reproducibility of the grading of AHA
lesion types is presented as percentage agreement and kappa
() values.
Results
Sections from all individuals were pooled (n4756), and the
percentage distribution of lesion types at each location is
shown in Figure 3 (tabulated percentages are given in
supplemental Table I, available online at http://stroke.
ahajournals.org). Type I and II lesions were combined as
foam cell lesions, and type IV and V lesions were combined
as lipid core plaques.
Sections from the coronary arteries had the highest preva-
lence of atherosclerotic plaques (LAD 52%; RCA 43%), with
lipid core plaques being more frequent than fibrous plaques.
Plaques were more often fibrous (type VIII) in the RCA (42%
of plaques versus 36% of LAD plaques). Foam cell lesions
and intermediate lesions were rare (9% in both arteries).
Although many of the coronary sections contained intima
without foam cells or plaques, the coronary intima was
diffusely thickened compared with that of other arteries. The
distribution of lesion types was almost similar when compar-
Downloaded from http://stroke.ahajournals.org/ by guest on December 2, 2015
Figure 2. Histological examples of lesion
types. HE staining. A, Normal intima
(type 0), right coronary artery; B, foam
cell lesion (type II), internal carotid artery;
C, intermediate lesion (type III), right cor-
onary artery; D, lipid core plaque (type
V), left anterior descending coronary
artery; E, fibrous plaque (type VIII), femo-
ral artery; F, ruptured plaque with plaque
hemorrhage and luminal thrombosis
(type VI, ie, complicated plaque) which
was graded as the underlying chronic
lesion (type V), femoral artery. IEL indi-
cates internal elastic lamina.
ing right and left sided arteries in the carotid and femoral
beds. Therefore, percentages are presented below as mean
values of right and left. Overall, the carotid arteries had fewer
plaques (30%) and much more foam cell lesions and inter-
mediate lesions (37%) than the coronaries, being diseased in
a distinct pattern. The common carotid arteries were domi-
nated by foam cell lesions (58%) with almost all plaques
(22%) being lipid-rich (90% of plaques).
In the bifurcation region, the fraction of sections with
plaque was actually higher than in the coronary arteries
(55%) and 70% of the plaques were lipid core plaques. The
internal carotid artery was dominated by normal or thickened
intima without foam cells (62%); plaques were rare (17%).
The femoral arteries were dominated by normal or thickened
intima without foam cells (74%) in a binary pattern with
some plaques (20%). Foam cell lesions and intermediate
lesions were few (6%) and more than half (52%) of the
femoral plaques were fibrous type VIII lesions. The proximal
part of the superficial femoral artery immediately after the
bifurcation was most plaque-prone.
Influence of Age
As the carotid arteries were diseased in a distinct pattern, the
common carotid artery, the bifurcation and the internal
carotid artery were treated as separate arteries. The age-
stratified percentage distributions of lesions in the right- and
 Dalager et al
Figure 3. Percentage distribution of AHA lesion types within the different arteries. Types are ordered from bottom (type 0) to the top
(type IX) of bars.
left-sided carotid and femoral arteries were similar and
therefore combined. The age-stratified distribution of athero-
sclerotic lesions is illustrated in Figure 4 (tabulated percent-
ages are given in supplemental Table II, available online at
http://stroke.ahajournals.org). There was an increase in ath-
erosclerosis severity with age in all arterial beds with accel-
eration in severity from the third to the fourth decade.
Coronary and carotid plaques were observed from the third
decade (LAD 22-year-old male, coronary death; RCA and
carotid bifurcation 28-year-old male, noncoronary death)
whereas femoral artery plaques did not occur until 34 years of
age (male, noncoronary death).
Influence of Gender
We included more men (n70) than women (n30); their
mean age did not differ (men 47.815.1 versus women
Downloaded from http://stroke.ahajournals.org/ by guest on December 2, 2015
Intima-Media Thickness: a Foam Cell Barometer? 2701
45.411.5 years; P0.43), and they were equally likely to
have died from coronary causes (18 [26%] men and 9 [30%]
women; P0.66). There were no qualitative difference be-
tween men and women, ie, the pattern was the same, but the
disease was more advanced in men with the exception of the
carotid bifurcation and the internal carotid artery (supplemen-
tal Table II).
Influence of Cause of Death
Twenty-seven individuals died of coronary atherosclerosis.
Their mean age (coronary death: 47.212.0 versus noncoro-
nary death: 47.114.9; P0.97) and gender distribution (see
above) were not different from those dying from noncoronary
causes. Disease was more advanced in all arteries, and
notably lipid core plaques were much more common, espe-
cially in the carotid bifurcation (supplemental Table II).
2702 Stroke October 2007
Figure 4. Percentage distribution of AHA lesion types in the different arteries stratified by age decade. Types are ordered from bottom
(type 0) to the top (type IX) of bars.
Correlations Between Plaque Burden in
Different Arteries
Within individuals, plaque burden in one artery correlated
with plaque burden in another (Table 2; P0.002 for all
correlations). The correlations were strongest when compar-
ing right- and left-sided arteries from the same arterial beds
(0.77 to 0.78).
Reproducibility Studies
A subset of 100 randomly selected sections were graded 1
year later by the same observer (S.D.) and another observer
(J.M.L.) to determine the intra- and interobserver agreement
of the grading. The intraobserver percentage agreement was
83% with a value of 0.77 (95% CI: 0.68 to 0.87) indicating
substantial agreement, whereas the interobserver percentage
agreement was 67% with a value of 0.57 (95% CI: 0.47 to
0.66) indicating moderate agreement.21
Downloaded from http://stroke.ahajournals.org/ by guest on December 2, 2015
Discussion
The most important finding in our study was the artery-
related differences in initiation, speed of development, and
phenotypic expression of atherosclerotic plaques.
Carotid IMT: An Ultrasound Measure of
Foam Cells?
The predominance of foam cell lesions in the common carotid
artery is interesting because this artery is the preferred site for
measurements of intima-media thickness. The reversibility14
of foam cell lesions may explain why the IMT can decrease
in response to treatment, eg, with statins.22 A decrease in
thickness would be difficult to explain if the thickening was
fibrous, but if the bulk of the thickness was accounted for by
foam cells a decrease is much more likely. Numerous clinical
studies have shown that the dynamic changes in IMT follow
favorable changes in risk factors and, therefore, are used as a
 Dalager et al Intima-Media Thickness: a Foam Cell Barometer? 2703

Table 2. Correlation Coefficients (Spearman ) for the Correlation Between Plaque Burdens in Different Arteries (P<0.002 for
all correlations)
LAD RCA Right CCA Right CBif Right ICA Left CCA Left CBif Left ICA Right Femoral Left Femoral
LAD
RCA 0.77
Right CCA 0.52 0.60
Right CBif 0.58 0.67 0.54
Right ICA 0.50 0.52 0.63 0.61
Left CCA 0.55 0.43 0.61 0.45 0.50
Left CBif 0.57 0.64 0.48 0.77 0.50 0.45
Left ICA 0.40 0.52 0.47 0.63 0.65 0.31 0.59
Right femoral 0.63 0.67 0.53 0.57 0.59 0.56 0.52 0.47
Left femoral 0.56 0.67 0.70 0.61 0.60 0.60 0.54 0.55 0.78
CCA indicates common carotid artery; CBif, carotid bifurcation; ICA, internal carotid artery.

surrogate end point in clinical trials.4,5 Foam cell lesions are
not responsible for clinical events, but foam cell lesions are
believed to be precursors of plaques in atherosclerosis-
susceptible arterial segments.6,14 The use of IMT as an
atherosclerosis marker therefore makes more sense if foam
cells are responsible for the dynamics in IMT. The role of
foam cells is supported by our age stratification (Figure 4); in
the third decade of life the carotid bifurcation is dominated by
foam cell lesions which are gradually replaced by lipid core
plaques in the following decades. The same pattern was
observed in the common carotid arteries with a delay of 3
decades.
In spite of methodological differences, there is a remark-
able similarity with findings from the International Athero-
sclerosis Project23 where gross lipid-stained (Sudan IV) artery
specimens were categorized as having either fatty streaks,
fibrous plaques, complicated or calcified lesions in different
segments. If the gross fatty streaks and fibrous plaques in the
article by Solberg23 are interpreted as type III and IVV
lesions respectively, the carotid artery disease pattern is
almost identical with our histological observations using the
AHA classification.
Differential Pathways Toward
Atherosclerotic Plaque?
Unlike the carotid bifurcation and the coronary arteries, the
femoral arteries were not very prone to foam cell lesions and
plaque formation. In addition, femoral plaques were more
often fibrous as noted previously.24 Femoral type VIII lesions
were often so uniformly fibrotic (Figure 2E) that we find it
difficult to believe that they had ever gone through a previous
lipid core phase as assumed in the AHA classification.15,17
Some authors state that pre-existing intimal thickening, not
foam cell lesions, is the precursor of atherosclerotic
plaque.16,25 Our study design does not allow us to elaborate
further on this, but the paucity of foam cell lesions in the
femoral artery indicate that foam cells play a lesser role in
plaque formation in that artery. Atherosclerosis is a multifac-
torial disease resulting in heterogeneous plaques. Different
pathways probably exist, the dominating one being deter-
mined by localization and individual factors. Still, the path-
ways are not exclusive, eg, the femoral arteries may also
Downloaded from http://stroke.ahajournals.org/ by guest on December 2, 2015
exhibit rupture of a lipid core with subsequent thrombosis
(Figure 2F).
The key to the influence of localization may be found in
hemodynamic differences and the underlying arterial wall
structure. The influence of hemodynamics is best understood
and explains some of the propensity for plaque formation in
the carotid bifurcation and the proximal LAD.19,26 A potential
influence of the site-specific arterial wall structure is more
hypothetical. The common carotid artery is an elastic artery,
just as the aorta which is also known to be prone to foam cell
formation.9 The proximal parts of the coronary arteries and
the carotid bifurcation are situated in a transitional zone
between elastic and muscular artery types.27 These artery
segments develop foam cell lesions and lipid core plaque at
an early age. In the coronary arteries foam cell lesions are
common already in childhood and adolescence.28 The internal
carotid artery and superficial femoral arteries are muscular
arteries and exhibit a remarkably similar pattern, albeit foam
cell lesions are more common in the internal carotid artery
which becomes truly muscular at a varying distance (0.5 to 2
cm) from the bifurcation.27 Whatever mechanisms are at play,
the hypothetical influence of arterial wall structure deserves
further study.
More Vulnerable Atherosclerosis in Coronary
Death Individuals?
Plaques were more prevalent in individuals dying from
coronary causes, not only in the coronary arteries and the
carotid bifurcation, but also at sites normally spared from
atherosclerosis indicating a generally more aggressive form
of disease. This was particularly evident in the femoral
arteries (supplemental Table II), which is interesting given
the strong epidemiological association between peripheral
arterial disease and coronary death.7,29 It is commonly ac-
cepted that lipid-rich plaques carry a higher risk of compli-
cations.30,31 Lipid core plaques were relatively more common
in all arteries in coronary death, especially in the carotid
arteries. This could point toward a systemically more lipid-rich
plaque phenotype in some atherosclerosis-prone individuals.
The high prevalence of advanced fibrotic atherosclerotic
plaques in the RCA is somewhat conflicting with previous
findings, reporting LAD as the predilection site.32 On the
2704 Stroke October 2007
other hand, it has been shown that proximal culprit lesions in
RCA are more common in sudden cardiac death victims than
among myocardial infarct cases surviving into the hospital.33
RCA culprits may carry a higher risk of brady-asystolic
cardiac arrest because the arterial supply to the sinus node and
atrioventricular node usually comes from RCA. In forensic
materials such as ours, cases of coronary death are almost
invariably sudden out-of-hospital deaths. Thus, the discrep-
ancy may be related to this inherent selection. We found an
almost equal prevalence of mature plaques in the LAD and
the RCA in coronary death individuals. Conversely, the
plaque prevalence was higher in the LAD in individuals
dying from other causes (supplemental Table II).
Plaque Burden Correlations
The correlations between plaque burdens in arteries are well
in line with the findings in other autopsy studies where
correlations are also strongest between bilateral arteries and
different branches within the same arterial territory. The
strongest correlations have been reported between the differ-
ent cerebral artery branches (r0.9),34 whereas the correla-
tions between other arteries, such as between the coronary
arteries, are less strong (r0.7 to 0.8).11,34,35 Spearman is
equivalent with Pearson r, and even though the older data are
primarily based on grading of gross specimens, our correla-
tions are remarkably similar.
The strength of the interarterial correlations appears prom-
ising, but it is important to remember that materials covering
wider age ranges (both including young individuals with
sparse atherosclerosis and older individuals with extensive
atherosclerosis) are more likely to show strong correlations
than materials from narrow age ranges.
Limitations
We illustrated the age, gender, and cause of death related
patterns by pooling of several sections from the same indi-
viduals because our categorical data did not permit calcula-
tion of mean AHA types. Subsequent statistical analyses of
age, gender, and cause of death differences would be inap-
propriate because the sample-size (and subsequently statisti-
cal power) would be artificially increased. Our findings must
therefore be interpreted as descriptive.
We used the AHA classification which has been criticized
by some of the leading atherosclerosis researchers for its
assumption of an orderly, linear pattern of lesion progression,
unclear distinction between lesion types, and for being
difficult to remember with its combination of roman numerals
and letter codes.16 As discussed above, we agree that lesions
do not always follow the same linear progression pattern, and
we did experience problems with distinction between lesion
types (moderate interobserver reproducibility). These prob-
lems were primarily caused by heterogeneous expression of
atherosclerosis. On a group basis, reproducibility was excel-
lent, as shown by the similar lesion distribution in right- and
left-sided arteries.
Conclusions
Our analyses indicate differences in initiation, speed of
progression, and phenotypic expression of atherosclerotic
Downloaded from http://stroke.ahajournals.org/ by guest on December 2, 2015
plaques in different arteries depending on localization and
individual factors. Foam cell lesions play an important role in
progression of carotid atherosclerosis, and they are the most
frequently encountered lesions at the preferred sites for
measurements of carotid IMT. The reversibility of foam cell
lesions, therefore, provides an explanation for the dynamics
in carotid IMT. Femoral atherosclerosis was less advanced;
more fibrous and foam cell lesions were rare. These pheno-
typic differences may relate to underlying differences in
hemodynamics and arterial wall structure. Plaques in all
analyzed arteries were more lipid-rich in coronary (versus
noncoronary) death, indicating a systemically more vulnera-
ble expression of atherosclerosis in persons dying of coronary
atherosclerosis.
Sources of Funding
The Danish Heart Foundation (grant no. 02-2-3-67-22018); Jrgen
Mllers Fond; Aase og Ejnar Danielsens Fond; Kbmand Sven
Hansen og hustru Ina Hansens Fond; Direktr Jacob Madsen og
hustru Olga Madsens Fond; Kirsten Anthonius Mindelegat;
Snedkermester Sophus Jacobsen og hustru Astrid Jacobsens
Fond; Forskningsfonden for Lgekredsforeningen for rhus
Amt; Beckett-fonden.
Disclosures
Dr Falk is on the Scientific Advisory board of the High-Risk Plaque
Initiative, BG Medicine, Waltham, Mass.
References
1. Kannel WB. Risk factors for atherosclerotic cardiovascular outcomes in
different arterial territories. J Cardiovasc Risk. 1994;1:333339.
2. Kannel WB, Wolf PA. Peripheral and cerebral atherothrombosis and
cardiovascular events in different vascular territories: insights from the
Framingham Study. Curr Atheroscler Rep. 2006;8:317323.
3. Sims FH. A comparison of coronary and internal mammary arteries and
implications of the results in the etiology of arteriosclerosis. Am Heart J.
1983;105:560 566.
4. Mazzone T, Meyer PM, Feinstein SB, Davidson MH, Kondos GT,
DAgostino RB Sr, Perez A, Provost JC, Haffner SM. Effect of piogli-
tazone compared with glimepiride on carotid intima-media thickness in
type 2 diabetes: a randomized trial. JAMA. 2006;296:25722581.
5. OLeary DH, Polak JF. Intima-media thickness: a tool for atherosclerosis
imaging and event prediction. Am J Cardiol. 2002;90:18L21L.
6. Crouse JR, III, Grobbee DE, OLeary DH, Bots ML, Evans GW, Palmer
MK, Riley WA, Raichlen JS. Measuring Effects on intima media
Thickness: an Evaluation Of Rosuvastatin in subclinical atherosclero-
sisthe rationale and methodology of the METEOR study. Cardiovasc
Drugs Ther. 2004;18:231238.
7. Beckman JA, Jaff MR, Creager MA. The United States preventive
services task force recommendation statement on screening for peripheral
arterial disease: more harm than benefit? Circulation. 2006;114:861 866.
8. Gore I, Tejada C. The Quantitative Appraisal of Atherosclerosis. Am J
Pathol. 1957;33:875 885.
9. General findings of the International Atherosclerosis Project. Lab Invest.
1968;18:498 502.
10. Kagan AR, Sternby NH, Uemura K, Vanecek R, Vihert AM, Lifsic AM,
Matova EE, Zahor Z, Zdanov VS. Atherosclerosis of the aorta and
coronary arteries in five towns. Bull World Health Organ. 1976;53:
485 645.
11. Sternby NH. Atherosclerosis in a defined population: an autopsy survey
in Malmo, Sweden. Acta Pathol Microbiol Immunol Scand. 1968;
194(Suppl):1216.
12. McGill HC Jr, McMahan CA; Pathobiological Determinants of Athero-
sclerosis in Youth (PDAY) Research Group. Determinants of atheroscle-
rosis in the young. Am J Cardiol. 1998;82:30T36T.
13. Stary HC, Blankenhorn DH, Chandler AB, Glagov S, Insull W Jr, Rich-
ardson M, Rosenfeld ME, Schaffer SA, Schwartz CJ, Wagner WD. A
definition of the intima of human arteries and of its atherosclerosis- prone
regions: a report from the Committee on Vascular Lesions of the Council
 Dalager et al
on Arteriosclerosis, American Heart Association. Circulation. 1992;85:
391 405.
14. Stary HC, Chandler AB, Glagov S, Guyton JR, Insull W Jr, Rosenfeld
ME, Schaffer SA, Schwartz CJ, Wagner WD, Wissler RW. A definition
of initial, fatty streak, and intermediate lesions of atherosclerosis: a report
from the Committee on Vascular Lesions of the Council on Arterioscle-
rosis, American Heart Association. Circulation. 1994;89:24622478.
15. Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr,
Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW. A definition of
advanced types of atherosclerotic lesions and a histological classification
of atherosclerosis: a report from the Committee on Vascular Lesions of
the Council on Arteriosclerosis, American Heart Association. Circulation.
1995;92:13551374.
16. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from
sudden coronary death: a comprehensive morphological classification
scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000;
20:12621275.
17. Stary HC. Natural history and histological classification of atherosclerotic
lesions: an update. Arterioscler Thromb Vasc Biol. 2000;20:11771178.
18. Wang JC, Normand SL, Mauri L, Kuntz RE. Coronary artery spatial
distribution of acute myocardial infarction occlusions. Circulation. 2004;
110:278 284.
19. Zarins CK, Giddens DP, Bharadvaj BK, Sottiurai VS, Mabon RF, Glagov
S. Carotid bifurcation atherosclerosis: quantitative correlation of plaque
localization with flow velocity profiles and wall shear stress. Circ Res.
1983;53:502514.
20. Burke AP, Farb A, Malcom GT, Liang YH, Smialek J, Virmani R.
Coronary risk factors and plaque morphology in men with coronary
disease who died suddenly. N Engl J Med. 1997;336:1276 1282.
21. Landis JR, Koch GG. The measurement of observer agreement for cate-
gorical data. Biometrics. 1977;33:159 174.
22. Hodis HN, Mack WJ, LaBree L, Selzer RH, Liu C, Liu C, Alaupovic P,
Kwong-Fu H, Azen SP. Reduction in carotid arterial wall thickness using
lovastatin and dietary therapy: a randomized controlled clinical trial. Ann
Intern Med. 1996;124:548 556.
Downloaded from http://stroke.ahajournals.org/ by guest on December 2, 2015
Intima-Media Thickness: a Foam Cell Barometer? 2705
23. Solberg LA, Eggen DA. Localization and sequence of development of
atherosclerotic lesions in the carotid and vertebral arteries. Circulation.
1971;43:711724.
24. Ross R, Wight TN, Strandness E, Thiele B. Human atherosclerosis. I. Cell
constitution and characteristics of advanced lesions of the superficial
femoral artery. Am J Pathol. 1984;114:79 93.
25. Schwartz SM, Virmani R, Rosenfeld ME. The good smooth muscle cells
in atherosclerosis. Curr Atheroscler Rep. 2000;2:422 429.
26. Glagov S, Zarins C, Giddens DP, Ku DN. Hemodynamics and athero-
sclerosis: insights and perspectives gained from studies of human arteries.
Arch Pathol Lab Med. 1988;112:1018 1031.
27. Janzen J. The microscopic transitional zone between elastic and muscular
arteries. Arch Mal Coeur Vaiss. 2004;97:909 914.
28. Stary HC. Evolution and progression of atherosclerotic lesions in coronary
arteries of children and young adults. Arteriosclerosis. 1989;9:I19I32.
29. Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann
TJ, Browner D. Mortality over a period of 10 years in patients with
peripheral arterial disease. N Engl J Med. 1992;326:381386.
30. Davies MJ, Richardson PD, Woolf N, Katz DR, Mann J. Risk of
thrombosis in human atherosclerotic plaques: role of extracellular lipid,
macrophage, and smooth muscle cell content. Br Heart J. 1993;69:
377381.
31. Falk E. Pathogenesis of atherosclerosis. J Am Coll Cardiol. 2006;47:C712.
32. Montenegro MR, Eggen DA. Topography of atherosclerosis in the
coronary arteries. Lab Invest. 1968;18:586 593.
33. Mikkelsson J, Eskola M, Nikus K, Pietila, K, Karhunen PJ, Niemela K.
Fatality of myocardial infarction in relation to the coronary anatomy: role
of culprit lesion location. Annals of Medicine. 2004;36:474 479.
34. Young W, Gofman JW, Tandy R, Malamud N, Waters ESG. The quan-
titation of atherosclerosis: III. The extent of correlation of degrees of
atherosclerosis within and between the coronary and cerebral vascular
beds. The Am J Cardiol. 1960;6:300 308.
35. Mathur KS, Patney NL, Kumar V. Atherosclerosis in India: An autopsy
study of the aorta and the coronary, cerebral, renal, and pulmonary
arteries. Circulation. 1961;24:68 75.
Artery-Related Differences in Atherosclerosis Expression: Implications for Atherogenesis
and Dynamics in Intima-Media Thickness
Sren Dalager, William P. Paaske, Ingrid Bayer Kristensen, Jacob Marsvin Laurberg and Erling
Falk

Stroke. 2007;38:2698-2705; originally published online August 30, 2007;

doi: 10.1161/STROKEAHA.107.486480
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2007 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/38/10/2698

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.
Once the online version of the published article for which permission is being requested is located, click
Request Permissions in the middle column of the Web page under Services. Further information about this
process is available in the Permissions and Rights Question and Answer document.

Reprints: Information about reprints can be found online at:

http://www.lww.com/reprints

Subscriptions: Information about subscribing to Stroke is online at:

http://stroke.ahajournals.org//subscriptions/

Downloaded from http://stroke.ahajournals.org/ by guest on December 2, 2015