© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
The Natural Course of Atherosclerosis
Part II: Vascular Remodeling
From the Department of Neurology, Innsbruck University Hospital, Innsbruck, Austria
Correspondence to Dr J. Willeit, Department of Neurology, Innsbruck University Hospital, Anichstr. 35, A-6020 Innsbruck, Austria.
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Abstract—Arterial remodelling is a potentially important component in atherogenesis aimed at delaying the development of significant lumen compromise. Current knowledge on this phenomenon is mainly restricted to experimental evaluations and a few postmortem studies. We used high-resolution duplex ultrasound to study 5-year changes (1990 to 1995) in vessel geometry in a large random sample of the general population (Bruneck Study). Carotid arteries free of atherosclerosis and wall thickening preserved a normal size to high ages. In contrast, common and internal carotid arteries with elevated intima-media thickness (
50th percentile) experienced marked age-dependent dilation
that started already in the 5th decade and continuously accelerated
thereafter (structural ageing). Vessel diameters were subject to
complex regulation involving morphometric characteristics, sex, wall
thickness, hypertension, LDL cholesterol levels, and
alcohol consumption. Vascular remodelling secondary to incident or
slowly progressive (mural) atherosclerosis included
local compensation and a generalised dilation response of vascular
segments not primarily affected. Adaptive enlargement at the site of
active atherogenesis effectively preserved a near-normal lumen in most
instances. The current study identified a second main type of plaque
growth, characterized by episodic marked increase in lesion volume
probably on the basis of plaque thrombosis. In this setting, we did not
observe maximum but insufficient compensation but instead usually
observed no compensation at all. Failure of vascular remodelling
and marked expansion in plaque size acted synergistically in producing
significant lumen compromise. The current prospective survey describes
fundamental principles and various facets of arterial
remodelling and vascular biology in the general population (in vivo).
Vessel geometry was subject to marked temporal changes and showed a
correspondingly complex (multifactorial) and dynamic regulation.
Vascular remodelling emerged as an important compensatory process in
human atherogenesis, which crucially contributed to the determination
of lumen obstruction. Efficacy and failure of compensation primarily
depended on the type and pathomechanisms of underlying atherogenesis
and only in second instance on plaque size and location.
Key Words: atherosclerosis • vascular remodelling • vascular biology
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Introduction |
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Traditionally, atherosclerosis research has mainly focused on investigating risk factors for plaque development and thickening of the intima-media tunica. Considerably less is known about compensatory phenomena of the vasculature in atherosclerosis. Contributions from a few experimental studies stimulated the hypothesis that vessels dilate in response to atherogenesis, thereby restoring normal blood flow and delaying the onset of clinically important stenosis.1 2 3 4 5 Vasculature was recognized as a complex organ capable of sensing its environment (eg, shear stress), transducing signals to effector cells or surrounding tissue and responding to various stimuli by releasing local regulatory mediators such as growth factors and vasoactive peptides.3 5 6 7 8 Prospective ultrasound-based surveys may assist in verifying the relevance of these experimental findings in vivo. The Bruneck Study was designed to investigate the natural course of atherosclerosis and accompanying adaptive changes in vessel geometry in a large random sample of men and women 40 to 85 years old.9 10 For the purpose of focus the current report was limited to the following key issues: 1) natural ageing of vasculature, 2) determination of vessel size in vivo and, most importantly, 3) local and systemic arterial remodelling secondary to atherogenesis.
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Methods |
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Population recruitment, ultrasound, and laboratory protocol have been detailed previously.9 10 In brief, a large age- and sex-stratified random population was enrolled in Bruneck and its suburbs (1990; Bolzano Province, Italy) and a first follow-up performed at a 5-year interval (1995). Participation in both assessments was more than 90% complete.
Scanning protocol and definition of ultrasound endpoints were detailed previously (see Part I). Progression of atherosclerosis was coded present when the relative increase in the maximum plaque diameter between 1990 and 1995 exceeded the double measurement error of the method (proximal internal carotid artery [ICA], 30%; common carotid artery ([CCA], 20%). Development of stenosis was assumed when the progression criterion was met and a narrowing of the lumen>40% was achieved in the follow-up examination (for details, see part I).
The interadventitial diameter was defined as the distance between near and far wall media-adventitia interface. Minimum and maximum intima-media thickness (IMT) was measured at the far wall of each segment of both carotid arteries (Part I) with the ultrasound beam directed through the axis of the vessel. It was defined as the distance between the lumen-intima interface and the leading edge of the media-adventitia interface. The lumen diameter was calculated as the interadventitial diameter minus twice the maximum far wall IMT.11 12 All diameters were measured during diastole, which avoids image blurring due to arterial wall motion in the systole and safeguards against spurious associations with blood pressure characteristics. Current analysis focused on the CCA and on the proximal ICA defined as the bulbous and the initial 10 mm of the vessel.9 The vessel diameter in the ICA was measured from the flow divider at a normal angle to the outer wall of the bulbous. We did so for a low measurement variability and the fact that the vast majority of plaques emerged just opposite the flow divider.
Alcohol consumption was assessed in grams per day and LDL
cholesterol calculated with the Friedewald
formula.13 14
Hypercholesterolemia was defined by a
total cholesterol level>6.2 mmol/L or the use of
lipid lowering drugs. Systolic and diastolic blood
pressure were the means of 3 independent measurements each taken with a
standard sphygmomanometer after at least 10 minutes of rest.
Hypertension was defined by a blood pressure 160/95 or the current
use of antihypertensive drugs.
Statistics
Differences in vessel geometry across decades and between sexes
were estimated using ANOVA procedure (SPSS-X statistical software).
Unless otherwise specified, means presented were adjusted for
age, sex, body weight and height, LDL cholesterol,
systolic blood pressure, and daily alcohol consumption (MANOVA,
SPSS-X statistical software). Determinants of vessel diameters were
identified by means of standard linear regression analysis
(forward stepwise selection; probability value for entry and removal,
0.05 and 0.10). We present regression coefficients, which permit us
to estimate expected changes in vessel diameters afforded by a 1-unit
change of given variables, standardized regression coefficients and
R2 as measures of the relative weight
of variables in the prediction model and of the overall explanatory
capacity of the regression models. Because of correlations existing
between independent variables, these calculations were supplemented
using best subset linear regression
analysis15 (BMDP statistical software). The 5
best-fitting models were selected according to Mallows'
Cp.
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Results |
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Assessment of interadventitial diameters was highly reproducible with relative measurement errors amounting to 6.0% (CCA) and 7.5% (ICA). Far wall IMT could be assessed with adequate precision in virtually all CCA segments (relative measurement error, 7.9%) and about two-thirds of ICA segments (n=471; error, 10.5%). Table 1
depicts main age- and sex-specific
features of vessel geometry in the CCA and ICA. Because we did not
observe side-specific differences in vessel and wall diameters, all
data presented are weighted averages of values obtained for the
right and left arteries. Characteristics of vessel geometry are given
for the entire population sample (general healthy population) and
separately for subjects free of carotid
atherosclerosis. The latter data may serve as reference
(normative) values. Marked individual changes in vessel diameters
during follow-up are visualized in Figure 1.
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Determinants of interadventitial and lumen diameters in the
nonatherosclerotic CCA and ICA were assessed by means of linear
regression analysis (Table 2).
Results are in part different for the CCA and ICA, which are typical
representatives of the elastic and muscular
vasculature, respectively.16 When the variables
hypertension and hypercholesterolemia were
substituted for systolic blood pressure and LDL
cholesterol, the composition of the linear regression
equations was virtually unchanged. Regression coefficients of these
variables were as follows: CCA (interadventitial diameter) 0.137
and –0.169, P<0.05 each; CCA (lumen diameter) 0.144 and
–0.166, P<0.05 each. Ageing predicted (marked) dilation of
the CCA and ICA beyond its well-known effects on IMT. Notably,
structural ageing was confined to subjects with elevated wall thickness
(>50th percentile) (Table 3). Regression
models of 5-year changes in the interadventitial diameter on the
variables given in Table 2 provided a prospective
confirmation of the results obtained. Changes in the levels of these
variables (1990 to 1995) predicted corresponding changes in
vessel size: cessation and initiation of moderate-to-severe alcohol
consumption (
CCA interadventitial diameter, regression coefficients
[95%CI], –0.330 [–0.653 to –0.007] and 0.417 [0.160 to
0.674]), medical lowering of LDL levels by statin therapy (0.226
[0.026 to 0.426]), and incident hypertension (0.214 [0.012 to
0.416]). Vice versa, subjects with wide stiff vessels faced a 2-fold
risk of incident systolic hypertension
(P<0.05).
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Next, we studied vascular remodelling in response to
atherosclerosis progression and incidence. Table 4 depicts age, sex, and risk
factor-adjusted changes in vessel diameters according to 5-year changes
in vascular status. Local dilation response was most pronounced in
incident nonstenotic and slowly progressive
atherosclerosis and mainly determined by the extent of
plaque growth (dose-response relation: CCA and ICA diameters,
0.464 mm [0.262 to 0.666] and 0.297 mm [0.121 to 0.473]
per 1 mm increase in plaque diameter). Local enlargement of vessel
segments with emerging or progressive atherosclerosis
must be viewed in the light of usually increased baseline diameters
(Table 4) and additive effects of structural ageing (see above).
In most instances these processes in concert (vascular remodelling)
effectively preserved a normal or near-normal lumen independently of
plaque size and location (Figure 2).
However, vascular remodelling obviously failed in response to focal
rapid plaque growth (atherothrombosis) (Table 4).
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Table 5 documented significant expansion
of all segments of the carotid vasculature in response to localized
active atherosclerosis, which was at least in part
independent of increased wall thickness and over-representation
of risk factors.
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Discussion |
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Determination of Vessel Geometry
Accumulating experimental data suggest a central (active) role of the vasculature in the control of blood flow.5 6 7 8 Short-term and sustained changes in vascular tone (vessel size) and long-term structural adaptation (growth stimulation17 18 ) are well-known regulatory phenomena in the maintenance of vascular homeostasis.4 5 6 7 8 19 This concept implies that vessel geometry may not be consistent over a long time span but, on the contrary, subject to continuous adaptive changes. In our cohort, vessel diameters of individuals indeed emerged as highly variable (Figure 1
). Regulation and determination of vessel
size were correspondingly complex.
Wall Thickness
Enlargement of vessels in response to wall thickening is
experimentally well founded.2 4 5 20 The current study
documented dilation of carotid arteries secondary to wall thickening in
vivo (Table 2). In the CCA, enlargement was over-compensatory,
whereas in the ICA, compensation did not keep pace with wall growth.
The few previous epidemiologic surveys in this field agreed in that
dilation of the vasculature compensates for wall thickening but
disagreed on the efficacy of this process (over- versus
under-compensation).1 11 21
Hypertension
It has been proposed that elevated blood pressure causes dilation
of exposed arteries.11 21 22 23 24 Vice versa, stiffness of
wide arteries may facilitate manifestation and maintenance of
systolic hypertension.25 Our study yielded
epidemiological support to both components of this bidirectional
association.
Risk Factors
Alcohol consumption and levels of LDL cholesterol
significantly predicted interadventitial and lumen diameters of the CCA
beyond their effects on the IMT. Both associations were similar in
strength but opposite in direction. These findings are in close
agreement with the results of a recent comparable population
survey.11 Notably, enlargement of vessels evoked by
regular alcohol intake appeared to normalize after cessation, as did
the narrowing associated with high LDL cholesterol after
successful medical intervention. Thus, the above associations may
reflect inference of risk factors with vascular
tone5 26 27 28 rather than structural alterations.
Gender and Morphometric Characteristics
Male gender, body height, and weight were strong positive
predictors of ICA and CCA diameters. Such morphometric relationships
have been reported previously and appear intuitively
correct.11 12 21
Age
Whether or not normal human vasculature experiences structural
ageing and dilation due to loss of elasticity is a matter of
dispute.1 11 12 21 23 29 For example, it was proposed that
the obvious correlation between arterial size and age
primarily reflects an advance of
atherosclerosis.1 To clarify this
controversial issue, age trends in arterial size were
assessed in subjects who remained free of carotid
atherosclerosis during follow-up. In a subgroup without
focal or diffuse wall thickening (IMT
50th percentile), vessel and
lumen diameters remained unchanged to high ages (Table 3). Once
IMT exceeded the median of 0.75 mm (CCA) or 0.9 mm (ICA),
however, vessels usually showed dilation with advancing age. Such
process already started in the 5th decade and accelerated thereafter.
Age-dependent dilation of the vasculature emerged as independent of
elevated wall thickness and other determinants of vessel size and may
thus reflect direct effects of ageing in terms of attrition or loss of
elastic fibers. In all, structural ageing was not an obligatory
phenomenon in our population but usually occurred once enhanced IMT
indicated incipient wall pathology. Manifestation of definite
atherosclerosis was not at all a precondition for the
ageing process to emerge.
Vascular Remodelling in Atherogenesis
In animal-experimental research, various types of arteries have
been shown to enlarge in response to diet-induced atherogenesis with a
normal lumen preserved early in the course of disease.2 4
Relevancy of such a process in the human vasculature was first proposed
by Glagov et al1 and Zarins et al30 based on
post-mortem evaluations. In the late 1980s, advances in high-resolution
duplex ultrasound provided a basis for a noninvasive and in vivo
investigation of this phenomenon. On applying this technique, Steinke
et al31 revealed a strong relation between plaque growth
and consecutive dilation of carotid arteries in a small patient-based
study (follow-up, 70 segment-years).
In our large ultrasound-based survey, atherogenesis was found to be a
heterogeneous disease and, in analogy, arterial
remodelling was not a uniform response to lesion progression. When
first focusing on incident atherosclerosis and the
progression of nonstenotic plaques (mural
atherosclerosis), adaptive enlargement of affected
vessel segments was a consistent phenomenon (Table 4 and
Figure 2). In the CCA vascular remodelling effectively preserved
a normal lumen even in advanced stages of disease when plaques even
grew to 3 to 4 mm (Figure 2). In the ICA, the lumen
diameter slightly decreased with extending plaque size (Figure 2).
As plaques were mostly eccentric in this location, ie, did
not occupy the whole circumference, compromise of the lumen area may
not occur to the same extent as for the diameter. In this context, it
is worth mentioning that the peak systolic flow velocity, which
is an indirect measure of lumen compromise, did not increase with
plaque size. Dilation of vessels in response to early atherogenesis has
been postulated in previous cross-sectional studies, with the efficacy
of such process varying in relation to given age ranges and types of
arteries.1 12 30 31
Our study identified one further common type of atherogenesis
characterized by occasional marked increases in lesion size followed by
long stable periods. This type of lesion extension primarily occurred
at sites exposed to hemodynamic stress, depended on
procoagulant risk factors, and probably resembles plaque thrombosis
(see Part I). In segments with this type of plaque growth, we did not
observe maximal though overcharged compensation but, on the contrary,
no or only marginal enlargement of the vessel (Table 4). In view
of the fact that we are probably speaking of plaque thrombosis, this
finding may possibly reflect a preserved integrity of the vessel wall.
Failure of vascular remodelling and usually marked expansions in plaque
size act synergistically in producing significant lumen compromise.
Actually, some 95% of incident stenosis>40% in our study
originated from this synergism. Preferential manifestation of
stenosis in the ICA is explained by the commonplace occurrence
of rapid plaque growth at this site and only in second instance by
peculiarities of vascular remodelling in the ICA.
Systemic Vascular Remodelling
Apart from focal changes in vessel geometry at the site of
progressive atherosclerosis, the whole carotid
vasculature, ie, also unaffected segments, responded to active
atherosclerosis in terms of vasodilation. This as yet
unrecognised component of arterial remodelling involved
segments of the carotid arteries ipsi- and contralateral to the site of
plaque growth to a similar extent, emerged as independent of wall
thickening and other potential confounders (Table 5) and appeared to be reversible when
atherosclerosis entered an inactive stage. These
findings tempt us to speculate that para/endocrine mediators with
relaxing properties are continuously released from active
atherosclerotic tissue or surrounding endothelium. The
biological significance of this finding awaits clarification in future
research.
Methodological Issues and Limitations
1) The lumen diameter was assessed as a surrogate for the
clinically important lumen area. We did so for reasons of
practicability and marked inaccuracies in tracing lumen areas in the
ICA. Implications for data interpretation are given in the text
whenever relevant. 2) As in previous comparable studies, IMT and lumen
of the ICA could not be obtained in all subjects due to poor
visualization of relevant interfaces or lack of nondiseased
segments.12 32 As visualization tends to decrease with
increasing severity of atherosclerosis, the group with
complete data assessment may not be random. This potential source of
bias was addressed in supplementary analyses, in which missing
data were replaced with an estimate calculated with linear regression
equations. On doing so, we obtained results almost identical to those
in the original analysis. Nevertheless, residual confounding
cannot be ruled out and deserves attention when interpreting data on
lumen diameters in the ICA.
Conclusions
So far, advances in the field of vascular biology have mainly
depended on contributions from experimental studies. Our study is among
the first to provide detailed insight into the fundamental principles
and various facets of arterial remodelling from an
epidemiological perspective. The role of carotid vasculature in
atherogenesis is not simply a passive housing of atherosclerotic
lesions. On the contrary, atherosclerosis progression
and arterial remodelling are equivalent components in the
atherogenesis process that crucially interact in determining vessel
obstruction.
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Appendix 1 |
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The Bruneck Study Group
Martin Oberhollenzer, Stefan Brandt, Paula Eder, Klaus Oberlechner, Harald Steiner, Arno Gasperi: Department of Internal Medicine, Bruneck Hospital, Italy; Agnes Mair, Peter Santer: Department of Laboratory Medicine, Bruneck Hospital, Italy; Gregor Rungger, Franz Spögler: Department of Neurology, Innsbruck University Hospital, Austria; Elmar Jarosch, Maria Schober: Department of Laboratory Medicine, Innsbruck University Hospital, Austria; Christian Wiedermann: Department of Internal Medicine, Innsbruck University Hospital, Austria; Enzo Bonora, Michele Muggeo: Department of Endocrinology and Metabolism, Verona University Hospital, Italy.
Received June 12, 1998; accepted November 30, 1998.
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References |
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Q. Xiao, K. Mandal, G. Schett, M. Mayr, G. Wick, F. Oberhollenzer, J. Willeit, S. Kiechl, and Q. Xu Association of Serum-Soluble Heat Shock Protein 60 With Carotid Atherosclerosis: Clinical Significance Determined in a Follow-Up Study Stroke, December 1, 2005; 36(12): 2571 - 2576. [Abstract] [Full Text] [PDF]
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 S. Pilz, R. Horejsi, R. Moller, G. Almer, H. Scharnagl, T. Stojakovic, R. Dimitrova, G. Weihrauch, M. Borkenstein, W. Maerz, et al. Early Atherosclerosis in Obese Juveniles Is Associated with Low Serum Levels of Adiponectin J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4792 - 4796. [Abstract] [Full Text] [PDF]
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 K. Yamamoto, K. Takeshita, T. Kojima, J. Takamatsu, and H. Saito Aging and plasminogen activator inhibitor-1 (PAI-1) regulation: implication in the pathogenesis of thrombotic disorders in the elderly Cardiovasc Res, May 1, 2005; 66(2): 276 - 285. [Abstract] [Full Text] [PDF]
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M. L. Bots, D. E. Grobbee, A. Hofman, and J. C.M. Witteman Common Carotid Intima-Media Thickness and Risk of Acute Myocardial Infarction: The Role of Lumen Diameter Stroke, April 1, 2005; 36(4): 762 - 767. [Abstract] [Full Text] [PDF]
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 M. Furtner, S. Kiechl, A. Mair, K. Seppi, S. Weger, F. Oberhollenzer, W. Poewe, and J. Willeit Urinary albumin excretion is independently associated with carotid and femoral artery atherosclerosis in the general population Eur. Heart J., February 1, 2005; 26(3): 279 - 287. [Abstract] [Full Text] [PDF]
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 R. P. Wildman, V. Mehta, T. Thompson, S. Brockwell, and K. Sutton-Tyrrell Obesity Is Associated With Larger Arterial Diameters in Caucasian and African-American Young Adults Diabetes Care, December 1, 2004; 27(12): 2997 - 2999. [Full Text] [PDF]
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 M.L. Eigenbrodt, Z. Bursac, E.P. Eigenbrodt, D.J. Couper, R.E. Tracy, and J.L. Mehta Mathematical estimation of the potential effect of vascular remodelling/dilatation on B-mode ultrasound intima-medial thickness QJM, November 1, 2004; 97(11): 729 - 737. [Abstract] [Full Text] [PDF]
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G. Pasterkamp, Z. S. Galis, and D. P.V. de Kleijn Expansive Arterial Remodeling: Location, Location, Location Arterioscler Thromb Vasc Biol, April 1, 2004; 24(4): 650 - 657. [Abstract] [Full Text] [PDF]
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M. Ogami, Y. Ikura, M. Ohsawa, T. Matsuo, S. Kayo, N. Yoshimi, E. Hai, N. Shirai, S. Ehara, R. Komatsu, et al. Telomere Shortening in Human Coronary Artery Diseases Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 546 - 550. [Abstract] [Full Text]
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R. M.A. Henry, P. J. Kostense, J. M. Dekker, G. Nijpels, R. J. Heine, O. Kamp, L. M. Bouter, and C. D.A. Stehouwer Carotid Arterial Remodeling: A Maladaptive Phenomenon in Type 2 Diabetes but Not in Impaired Glucose Metabolism: The Hoorn Study Stroke, March 1, 2004; 35(3): 671 - 676. [Abstract] [Full Text] [PDF]
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M. L. Bots, G. W. Evans, W. A. Riley, and D. E. Grobbee Carotid Intima-Media Thickness Measurements in Intervention Studies: Design Options, Progression Rates, and Sample Size Considerations: A Point of View Stroke, December 1, 2003; 34(12): 2985 - 2994. [Abstract] [Full Text] [PDF]
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 C. Foerch, A. Buehler, S. von Kegler, and M. Sitzer Intima-Media Thickness Side Differences Are Limited to the Common Carotid Artery Hypertension, December 1, 2003; 42 (6): e17 - e17. [Full Text] [PDF]
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G. Chironi, J. Gariepy, N. Denarie, M. Balice, J.-L. Megnien, J. Levenson, and A. Simon Influence of Hypertension on Early Carotid Artery Remodeling Arterioscler Thromb Vasc Biol, August 1, 2003; 23(8): 1460 - 1464. [Abstract] [Full Text] [PDF]
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 E. F. Steinmetz, C. Buckley, and R. W. Thompson Prospects for the Medical Management of Abdominal Aortic Aneurysms Vascular and Endovascular Surgery, May 1, 2003; 37(3): 151 - 163. [Abstract] [PDF]
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E. Bonora, S. Kiechl, J. Willeit, F. Oberhollenzer, G. Egger, R. C. Bonadonna, and M. Muggeo Carotid Atherosclerosis and Coronary Heart Disease in the Metabolic Syndrome: Prospective data from the Bruneck Study Diabetes Care, April 1, 2003; 26(4): 1251 - 1257. [Abstract] [Full Text] [PDF]
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J. G. Terry, R. Tang, M. A. Espeland, D. H. Davis, J. L.C. Vieira, M. F. Mercuri, and J. R. Crouse III Carotid Arterial Structure in Patients With Documented Coronary Artery Disease and Disease-Free Control Subjects Circulation, March 4, 2003; 107(8): 1146 - 1151. [Abstract] [Full Text] [PDF]
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M. Mayr, S. Kiechl, M. A. Mendall, J. Willeit, G. Wick, and Q. Xu Increased Risk of Atherosclerosis Is Confined to CagA-Positive Helicobacter pylori Strains: Prospective Results From the Bruneck Study Stroke, March 1, 2003; 34(3): 610 - 615. [Abstract] [Full Text] [PDF]
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J. Willeit, S. Kiechl, T. Weimer, A. Mair, P. Santer, C. J. Wiedermann, and J. Roemisch Marburg I Polymorphism of Factor VII-Activating Protease: A Prominent Risk Predictor of Carotid Stenosis Circulation, February 11, 2003; 107(5): 667 - 670. [Abstract] [Full Text] [PDF]
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 K. L. Moreau, A. J. Donato, D. R. Seals, F. A. Dinenno, S. D. Blackett, G. L. Hoetzer, C. A. Desouza, and H. Tanaka Arterial intima-media thickness: site-specific associations with HRT and habitual exercise Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1409 - H1417. [Abstract] [Full Text] [PDF]
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S. Kiechl, P. Werner, G. Egger, F. Oberhollenzer, M. Mayr, Q. Xu, W. Poewe, and J. Willeit Active and Passive Smoking, Chronic Infections, and the Risk of Carotid Atherosclerosis: Prospective Results From the Bruneck Study Stroke, September 1, 2002; 33(9): 2170 - 2176. [Abstract] [Full Text] [PDF]
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 S. Kiechl, E. Lorenz, M. Reindl, C. J. Wiedermann, F. Oberhollenzer, E. Bonora, J. Willeit, and D. A. Schwartz Toll-like Receptor 4 Polymorphisms and Atherogenesis N. Engl. J. Med., July 18, 2002; 347(3): 185 - 192. [Abstract] [Full Text] [PDF]
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D. G. Kuhel, B. Zhu, D. P. Witte, and D. Y. Hui Distinction in Genetic Determinants for Injury-Induced Neointimal Hyperplasia and Diet-Induced Atherosclerosis in Inbred Mice Arterioscler Thromb Vasc Biol, June 1, 2002; 22(6): 955 - 960. [Abstract] [Full Text] [PDF]
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 D Saito, T Oka, A Kajiyama, N Ohnishi, and T Shiraki Factors predicting compensatory vascular remodelling of the carotid artery affected by atherosclerosis Heart, February 1, 2002; 87(2): 136 - 139. [Abstract] [Full Text] [PDF]
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R. Blackburn, P. Giral, E. Bruckert, J.-M. Andre, S. Gonbert, M. Bernard, M. J. Chapman, and G. Turpin Elevated C-Reactive Protein Constitutes an Independent Predictor of Advanced Carotid Plaques in Dyslipidemic Subjects Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1962 - 1968. [Abstract] [Full Text] [PDF]
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 N. M. Caplice, C. Panetta, T. E. Peterson, L. S. Kleppe, C. S. Mueske, G. M. Kostner, G. J. Broze Jr, and R. D. Simari Lipoprotein (a) binds and inactivates tissue factor pathway inhibitor: a novel link between lipoproteins and thrombosis Blood, November 15, 2001; 98(10): 2980 - 2987. [Abstract] [Full Text] [PDF]
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E. Lutgens, E. D. de Muinck, S. Heeneman, and M. J.A.P. Daemen Compensatory Enlargement and Stenosis Develop in ApoE-/- and ApoE*3-Leiden Transgenic Mice Arterioscler Thromb Vasc Biol, August 1, 2001; 21(8): 1359 - 1365. [Abstract] [Full Text] [PDF]
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M. R. Ward, P. Smits, N. A. Herity, A. Jeremias, P. J. Fitzgerald, A. C. Yeung, P. de Jaegere, P. W. Serruys, and G. Pasterkamp Letter to the Editor: No Relationship Between Compensatory Arterial Remodeling of Focal Stenotic Atherosclerotic Lesions and Tortuosity of the Arterial Segment Involved Arterioscler Thromb Vasc Biol, August 1, 2001; 21(8): 1383 - 1383. [Full Text] [PDF]
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S. Kiechl, G. Egger, M. Mayr, C. J. Wiedermann, E. Bonora, F. Oberhollenzer, M. Muggeo, Q. Xu, G. Wick, W. Poewe, et al. Chronic Infections and the Risk of Carotid Atherosclerosis : Prospective Results From a Large Population Study Circulation, February 27, 2001; 103(8): 1064 - 1070. [Abstract] [Full Text] [PDF]
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H. Tanaka, F. A. Dinenno, K. D. Monahan, C. A. DeSouza, and D. R. Seals Carotid Artery Wall Hypertrophy With Age Is Related to Local Systolic Blood Pressure in Healthy Men Arterioscler Thromb Vasc Biol, January 1, 2001; 21(1): 82 - 87. [Abstract] [Full Text] [PDF]
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M. Mayr, S. Kiechl, J. Willeit, G. Wick, and Q. Xu Infections, Immunity, and Atherosclerosis : Associations of Antibodies to Chlamydia pneumoniae, Helicobacter pylori, and Cytomegalovirus With Immune Reactions to Heat-Shock Protein 60 and Carotid or Femoral Atherosclerosis Circulation, August 22, 2000; 102(8): 833 - 839. [Abstract] [Full Text] [PDF]
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Q. Xu, G. Schett, H. Perschinka, M. Mayr, G. Egger, F. Oberhollenzer, J. Willeit, S. Kiechl, and G. Wick Serum Soluble Heat Shock Protein 60 Is Elevated in Subjects With Atherosclerosis in a General Population Circulation, July 4, 2000; 102(1): 14 - 20. [Abstract] [Full Text] [PDF]
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S. Kiechl, J. Willeit, E. Bonora, S. Schwarz, and Q. Xu No Association Between Dehydroepiandrosterone Sulfate and Development of Atherosclerosis in a Prospective Population Study (Bruneck Study) Arterioscler Thromb Vasc Biol, April 1, 2000; 20(4): 1094 - 1100. [Abstract] [Full Text] [PDF]
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J. Willeit, S. Kiechl, F. Oberhollenzer, G. Rungger, G. Egger, E. Bonora, M. Mitterer, and M. Muggeo Distinct Risk Profiles of Early and Advanced Atherosclerosis : Prospective Results From the Bruneck Study Arterioscler Thromb Vasc Biol, February 1, 2000; 20(2): 529 - 537. [Abstract] [Full Text] [PDF]
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F. Kronenberg, M. F. Kronenberg, S. Kiechl, E. Trenkwalder, P. Santer, F. Oberhollenzer, G. Egger, G. Utermann, and J. Willeit Role of Lipoprotein(a) and Apolipoprotein(a) Phenotype in Atherogenesis : Prospective Results From the Bruneck Study Circulation, September 14, 1999; 100(11): 1154 - 1160. [Abstract] [Full Text] [PDF]
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