Artery-Related Differences in Atherosclerosis Expression

Implications for Atherogenesis and Dynamics in Intima-Media Thickness
Søren Dalager, MD, PhD; William P. Paaske, MD, DrMedSci; Ingrid Bayer Kristensen, MD;
Jacob Marsvin Laurberg, MD, PhD; Erling Falk, MD, DrMedSci

Background and Purpose—Information 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.
Methods—In 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 (n⫽4756) were
analyzed blindly using a modification of the histological classification endorsed by the American Heart Association
Results—We 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.
Conclusions—The 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 䡲 carotid atherosclerosis 䡲 coronary atherosclerosis 䡲 pathology
䡲 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
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
have different impact in different arterial territories. Choles- emphasis on disease severity than composition.9 –12
terol is particularly important in ischemic heart disease, Since then, the American Heart Association (AHA) clas-
hypertension in ischemic stroke, and smoking and diabetes in sification of atherosclerosis has emerged.13–15 Although de-
intermittent claudication.1,2 Moreover, some arteries, eg, the bated16 and subsequently updated17 it provides a useful
internal mammary artery, are relatively spared from athero- framework for atherosclerosis description. Our aims were: (1)
sclerosis.3 Better understanding of the nature and reasons for to characterize and compare the type of atherosclerosis within
these differences are important in prevention and treatment of different arteries using the AHA classification; and (2) to
atherosclerosis and its complications. analyze the relation with age, gender and cause of death.
In spite of the differences, measures of atherosclerosis in
peripheral arteries serve as fast and continuous end points in Materials and Methods
clinical testing of drugs assumed to have antiatherosclerotic
properties,4 and are used in the assessment of the overall Individuals
atherosclerotic burden and cardiovascular risk. Examples of Clinically important atherosclerosis-susceptible segments18,19 were
obtained from 6 locations: the proximal parts of the left anterior
these measures include the carotid artery intima-media thick-
descending (LAD) and the right coronary artery (RCA), both carotid
ness (IMT), and the ankle-brachial blood pressure index.5–7 arteries, and both superficial femoral arteries. The carotid arteries
Comparative and descriptive pathological studies of ath- and the superficial femoral arteries were examined over a large part
erosclerosis in different arteries are numerous but belong to 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.), Århus, Denmark.
Correspondence to Søren Dalager, MD, PhD, Department of Pathology, Aarhus University Hospital, Nørrebrogade 44, DK-8000 Århus C, Denmark.
© 2007 American Heart Association, Inc.
Stroke is available at DOI: 10.1161/STROKEAHA.107.486480

Downloaded from by guest on December 2, 2015

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 (ⱖ2 layers) III Intermediate lesion (pathological intimal Pools of extracellular lipid with no or only few Minor accumulations of structure.20 22 other natural deaths) whereas 51 “chronic” atherosclerotic plaque (eg. Dalager et al Intima-Media Thickness: a Foam Cell Barometer? 2699 Figure 1. plaque hemorrhage. hematoma. 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. primar.13–15. phate buffered formalin for 24 hours and decalcified (unless ⬍45 years of age) in 10% formic acid for 24 hours. Lesion Table 1. segments were prospectively collected from 100 autopsies at the Institute of Forensic Medicine. The sections were pooled according to localiza- ily from the distal part of the internal carotid arteries). The artery segments were fixed in 4% phos- in that artery segment (range: 0 to 1). Alternative terms proposed by Virmani et al16 are shown in parentheses. Denmark. University of Aarhus. For each artery segment. Fibrosis 2 homicides). Downloaded from http://stroke. mounted on Superfrost⫹glass the proximal part of the internal carotid artery (Figure 1). Statistics ded in paraffin. statistical analysis. Cross-sectioning was performed at 4-mm intervals and the resulting sections were embed. (hyalinization) was detected by the characteristic birefringence of collagen when the HE-stained sections were viewed under polarized Tissue Processing light. hematoma. part of the common carotid artery. Location of artery segments and sections. Only individuals with a postmortem interval ⱕ4 days were included. these lesions were graded according to the underlying natural (27 coronary deaths. not type VI). a type V lesion with rupture individuals had unnatural deaths (7 suicides. no fresh thrombus *Based on the updated17 histological classification of atherosclerotic lesions endorsed by the AHA. In 49 cases the cause of death was Instead. yielding ⬇48 paraffin blocks from each subject Intercooled STATA 9. Cx indicates circumflex.ahajournals.17 The modifications consisted of an mortem risk factors were unavailable. and thrombosis was graded as type V. All tissue tion and further stratified by age. The mean age of the addition of chronic occlusion (type IX lesion) and omission of the 100 individuals was 47. years). range: 20 to 82 “acute” type VI lesion (surface defect.1⫾14. or thrombosis Surface defect. or luminal thrombus VII Calcified plaque (fibrocalcific plaque) ⱖ50% of plaque area calcified ⱖ50% of plaque area calcified. or thrombosis). and stained with hematoxylin and eosin (HE). Modified AHA Classification of Atherosclerotic Lesions* Type Name Characteristics Definition 0 Normal intima or intimal thickening No foam cells No foam cells. 2015 . the plaque burden was calculated as the number of sections The coronary arteries were cut open longitudinally as part of the with plaque (AHA type ⱖIV) divided by the total number of sections forensic examination. the bifurcation (bulb region).org/ by guest on December 2. Data on pre- classification (Table 1). The slides. The individuals eyepiece graticule. gender and cause of death.and colorless thickening) cholesterol crystals material displacing the normal structural components of the intima IV Lipid core plaque (fibrous cap atheroma) Extracellular lipid core. and 30 were women. and sections were cut at 4-␮m thicknesses.2 for Windows (Statacorp LP) was used for (4756 paraffin blocks in total. 42 accidents. Type VI was graded as the underlying lesion without complications. Histological examples are given in Figure 2. 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. Histological evaluation was performed using a light microscope and the study was approved by the Regional Research Ethics (Olympus BX51) equipped with polarization filters and an integrated Committee and The Danish Data Protection Agency. Histological Grading of Arterial Disease The autopsies were performed from February 1996 to March 1999.1 years (mean⫾SD. 44 sections were unavailable. The sections were graded in random order underwent postmortem examination if death occurred unexpectedly blinded to subject data according to a slightly modified AHA outside the hospital or under unclear circumstances.

D. intermediate lesion (type III). ie. being diseased in lesion types is presented as percentage agreement and kappa a distinct pattern. The proximal lipid core plaques being more frequent than fibrous plaques. Foam cell lesions and intermediate Sections from the coronary arteries had the highest preva. lesions were few (6%) and more than half (52%) of the lence of atherosclerotic plaques (LAD 52%. of plaques versus 36% of LAD plaques). Results In the bifurcation region. Type I and II lesions were combined as The femoral arteries were dominated by normal or thickened foam cell lesions. Influence of Age Although many of the coronary sections contained intima As the carotid arteries were diseased in a distinct pattern. Inter. internal carotid artery. types at the different localizations are presented as percentage ing right and left sided arteries in the carotid and femoral distribution. intima without foam cells (62%). stratified percentage distributions of lesions in the right. the bifurcation and the internal diffusely thickened compared with that of other arteries. right coronary artery. values of right and left. IEL indi- cates internal elastic lamina. fibrous plaque (type VIII). The age- distribution of lesion types was almost similar when compar. ahajournals. available online at http://stroke. the fraction of sections with Sections from all individuals were pooled (n⫽4756).and intraobserver reproducibility of the grading of AHA mediate lesions (37%) than the coronaries. The common carotid arteries were domi- (␬) values. and the plaque was actually higher than in the coronary arteries percentage distribution of lesion types at each location is (55%) and 70% of the plaques were lipid core plaques. C. part of the superficial femoral artery immediately after the Plaques were more often fibrous (type VIII) in the RCA (42% bifurcation was most plaque-prone. Because of the descriptive and exploratory nature of the beds. femo- ral artery.ahajournals. and type IV and V lesions were combined intima without foam cells (74%) in a binary pattern with as lipid core plaques.2700 Stroke October 2007 Figure complicated plaque) which was graded as the underlying “chronic” lesion (type V). F. the distribution of lesion types is presented without calcula. Normal intima (type 0). Therefore. left anterior descending coronary artery. percentages are presented below as mean study. RCA 43%). The carotid artery were treated as separate by guest on December 2. nated by foam cell lesions (58%) with almost all plaques (22%) being lipid-rich (90% of plaques). the carotid arteries had fewer tions of statistics. Overall. plaques were rare (17%). the without foam cells or plaques. with femoral plaques were fibrous type VIII lesions. E. HE staining. some plaques (20%). ruptured plaque with plaque hemorrhage and luminal thrombosis (type VI. B. Histological examples of lesion types. A. The correlation between plaque burdens in the different arteries was calculated using Spearman rank correlation plaques (30%) and much more foam cell lesions and inter- test. 2015 . right cor- onary artery. foam cell lesion (type II). the coronary intima was common carotid artery. lipid core plaque (type V). The shown in Figure 3 (tabulated percentages are given in internal carotid artery was dominated by normal or thickened supplemental Table I.and Downloaded from http://stroke. femoral artery. Foam cell lesions and intermediate lesions were rare (9% in both arteries).

P⫽0. women.43).2⫾12. noncoronary death). noncoronary death) Twenty-seven individuals died of coronary atherosclerosis. whereas femoral artery plaques did not occur until 34 years of Their mean age (coronary death: 47. and they were equally likely to therefore combined. espe- mean age did not differ (men 47. Coronary and carotid plaques were observed from the third decade (LAD 22-year-old male. P⫽0. and We included more men (n⫽70) than women (n⫽30). but the http://stroke. have died from coronary causes (18 [26%] men and 9 [30%] sclerotic lesions is illustrated in Figure 4 (tabulated percent.97) and gender distribution (see above) were not different from those dying from noncoronary Influence of Gender causes.9.0 versus noncoro- age (male. the pattern was the same.5 years. Disease was more advanced in all arteries. RCA and Influence of Cause of Death carotid bifurcation 28-year-old male. available online at tween men and by guest on December 2.1 versus women cially in the carotid bifurcation (supplemental Table II). ie. tal Table II). Percentage distribution of AHA lesion types within the different arteries. There were no qualitative difference be- ages are given in supplemental Table II.66).ahajournals. their notably lipid core plaques were much more common. carotid bifurcation and the internal carotid artery (supplemen- eration in severity from the third to the fourth decade. P⫽0. Types are ordered from bottom (type 0) to the top (type IX) of bars. 2015 . Dalager et al Intima-Media Thickness: a Foam Cell Barometer? 2701 Figure 3. nary death: 47.1⫾14. disease was more advanced in men with the exception of the erosclerosis severity with age in all arterial beds with accel.4⫾ left-sided carotid and femoral arteries were similar and 45. coronary death. Downloaded from http://stroke.8⫾15. There was an increase in ath. The age-stratified distribution of athero.

77 (95% CI: 0. correlations). Foam Cells? The predominance of foam cell lesions in the common carotid Reproducibility Studies artery is interesting because this artery is the preferred site for A subset of 100 randomly selected sections were graded 1 measurements of intima-media thickness. eg.68 to 0.L. The intraobserver percentage agreement was thickness would be difficult to explain if the thickening was 83% with a ␬ value of 0. plaque burden in one artery correlated related differences in initiation. and with plaque burden in another (Table 2.) to determine the intra.66) indicating moderate agreement.D.77 to 0. P⬍0. Types are ordered from bottom (type 0) to the top (type IX) of bars. 2015 . Correlations Between Plaque Burden in Discussion Different Arteries The most important finding in our study was the artery- Within individuals. but if the bulk of the thickness was accounted for by substantial agreement.002 for all phenotypic expression of atherosclerotic plaques.57 (95% CI: 0. with statins.21 favorable changes in risk factors and.47 to studies have shown that the dynamic changes in IMT follow 0. The reversibility14 year later by the same observer (S.and left-sided arteries from the same arterial beds Carotid IMT: An Ultrasound Measure of (␳⫽ by guest on December 2. Percentage distribution of AHA lesion types in the different arteries stratified by age decade.2702 Stroke October 2007 Figure 4.87) indicating fibrous.ahajournals. Numerous clinical agreement was 67% with a ␬ value of 0.and interobserver agreement in response to treatment.M. The correlations were strongest when compar- ing right. speed of development. whereas the interobserver percentage foam cells a decrease is much more likely.78). are used as a Downloaded from http://stroke.22 A decrease in of the grading.) and another observer of foam cell lesions may explain why the IMT can decrease (J. therefore.

internal carotid artery.55 0.56 0.19.52 0.25 Our study design does not allow us to elaborate cepted that lipid-rich plaques carry a higher risk of compli- further on this. the dominating one being by guest on December 2. the Death Individuals? femoral arteries were not very prone to foam cell lesions and Plaques were more prevalent in individuals dying from plaque formation.78 CCA indicates common carotid artery.31 0. believed to be precursors of plaques in atherosclerosis. plaques in the RCA is somewhat conflicting with previous ways are not exclusive. the carotid bifurcation are situated in a transitional zone In spite of methodological differences.50 0.28 The internal fibrous plaques.67 0.27 These artery able similarity with findings from the International Athero.5 Foam cell lesions are exhibit rupture of a lipid core with subsequent thrombosis not responsible for clinical events.60 Right CBif 0.63 0. not only in the coronary arteries and the often fibrous as noted previously.54 0. the carotid artery disease pattern is which becomes truly muscular at a varying distance (0. especially in the carotid plaque formation in that artery. The role of and explains some of the propensity for plaque formation in foam cells is supported by our age stratification (Figure 4).60 0.17 arteries (supplemental Table II). If the gross fatty streaks and fibrous plaques in the arteries and exhibit a remarkably similar pattern.65 0.59 Right femoral 0. eg.32 On the Downloaded from http://stroke. surrogate end point in clinical trials.40 0.58 0.55 0. but also at sites normally spared from were often so uniformly fibrotic (Figure 2E) that we find it atherosclerosis indicating a generally more aggressive form difficult to believe that they had ever gone through a previous of disease.45 0. the femoral arteries may also findings. ICA.60 0. not the strong epidemiological association between peripheral foam cell lesions.56 0.47 0. 2015 . complicated or calcified lesions in different carotid artery and superficial femoral arteries are muscular segments.30.52 0.52 0.24 Femoral type VIII lesions carotid bifurcation.4. femoral plaques were more coronary causes.6.61 0.64 0. This was particularly evident in the femoral lipid core phase as assumed in the AHA classification.14 The use of IMT as an hemodynamic differences and the underlying arterial wall atherosclerosis marker therefore makes more sense if foam structure. Dalager et al Intima-Media Thickness: a Foam Cell Barometer? 2703 Table 2. the path. Differential Pathways Toward Atherosclerotic Plaque? More Vulnerable Atherosclerosis in Coronary Unlike the carotid bifurcation and the coronary arteries.59 0.7. CBif.61 0.54 Right ICA 0. pathways probably exist.57 0.9 The proximal parts of the coronary arteries and decades. AHA classification.63 0. segments develop foam cell lesions and lipid core plaque at sclerosis Project23 where gross lipid-stained (Sudan IV) artery an early age.50 0. between elastic and muscular artery types. The same pattern was just as the aorta which is also known to be prone to foam cell observed in the common carotid arteries with a delay of ⬇3 formation.43 0. The high prevalence of advanced fibrotic atherosclerotic mined by localization and individual factors.67 0.52 0.77 Right CCA 0.48 0. This could point toward a systemically more lipid-rich torial disease resulting in heterogeneous plaques.70 0.ahajournals.16. in the carotid bifurcation and the proximal LAD.26 A potential the third decade of life the carotid bifurcation is dominated by influence of the site-specific arterial wall structure is more foam cell lesions which are gradually replaced by lipid core hypothetical. but foam cell lesions are (Figure 2F).61 Left CCA 0.45 Left ICA 0. The key to the influence of localization may be found in susceptible arterial segments. which is interesting given Some authors state that pre-existing intimal thickening.47 Left femoral 0. plaques in the following decades.15. In addition.50 Left CBif 0. Different plaque phenotype in some atherosclerosis-prone individuals. is the precursor of atherosclerotic arterial disease and coronary death. reporting LAD as the predilection site. there is a remark.5 to 2 almost identical with our histological observations using the cm) from the bifurcation. but the paucity of foam cell lesions in the cations. Still. Atherosclerosis is a multifac. Correlation Coefficients (Spearman ␳) for the Correlation Between Plaque Burdens in Different Arteries (P<0. The common carotid artery is an elastic artery.77 0.63 0. In the coronary arteries foam cell lesions are specimens were categorized as having either fatty streaks. common already in childhood and adolescence.27 Whatever mechanisms are at play.53 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 0.67 0. carotid bifurcation. albeit foam article by Solberg23 are interpreted as type I–II and IV–V cell lesions are more common in the internal carotid artery lesions respectively.29 It is commonly ac- plaque.31 Lipid core plaques were relatively more common femoral artery indicate that foam cells play a lesser role in in all arteries in coronary death. arteries. The influence of hemodynamics is best understood cells are responsible for the dynamics in IMT. the hypothetical influence of arterial wall structure deserves further study.57 0.

O’Leary DH. JAMA. Sims FH. Foam cell lesions play an important role in among myocardial infarct cases surviving into the hospital. Dr Falk is on the Scientific Advisory board of the High-Risk Plaque Initiative. In forensic lesions. arterial disease: more harm than benefit? Circulation. gender. MK. ble expression of atherosclerosis in persons dying of coronary atherosclerosis. lent. Chandler AB.16 As discussed above.34.8). Sternby NH. gender. and they are the most RCA culprits may carry a higher risk of brady-asystolic frequently encountered lesions at the preferred sites for cardiac arrest because the arterial supply to the sinus node and measurements of carotid IMT. we agree that lesions 1968. 2006. Atherosclerosis of the aorta and we did experience problems with distinction between lesion coronary arteries in five towns. 1998.35 Spearman ␳ is equivalent with Pearson r. Jaff MR. 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A Our analyses indicate differences in initiation. difficult to remember with its combination of roman numerals 9. and even though the older data are Disclosures primarily based on grading of gross specimens. reproducibility was excel. Plaques in all the RCA in coronary death individuals. J Cardiovasc Risk. strongest correlations have been reported between the differ. Rich- Conclusions ardson M. Vihert AM. Kannel WB.9). Effect of piogli- patterns by pooling of several sections from the same indi. Zahor by guest on December 2. Stary HC. Grobbee DE. Peripheral and cerebral atherothrombosis and cardiovascular events in different vascular territories: insights from the atherosclerosis) are more likely to show strong correlations Framingham Study. Pathobiological Determinants of Athero- left-sided arteries. 02-2-3-67-22018). The Quantitative Appraisal of Atherosclerosis. do not always follow the same linear progression pattern. Conversely.34 whereas the correla. 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