© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
The Natural Course of Atherosclerosis
Part I: Incidence and Progression
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 |
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Abstract—The natural course of early atherogenesis is not well established. The current prospective survey was designed to monitor 5-year changes in carotid atherosclerosis in a large, stratified random sample of the general population using high-resolution duplex ultrasound (Bruneck Study). Incidence rates of carotid atherosclerosis ranged from near zero to 184 per 1000 person-years. Most atherosclerotic lesions developed at sites with enhanced wall thickness. Incidence of atherosclerosis in premenopausal women was less than half of that observed in men of equal age. The sex difference disappeared within 5 years after menopause and may possibly be attributed to sex variations in body iron stores. Preexisting atherosclerotic lesions may experience 1 of 2 different types of disease progression. 1) The first main type of plaque growth causing nonstenotic or diffuse dilative atherosclerosis was characterized by slow and continuous plaque extension, which usually affected several lesions simultaneously and did not primarily focus on the carotid bifurcation. This step-by-step process relied on a cumulative exposure to well-known risk factors such as hyper-lipidemia. Compensatory enlargement of the artery at the site of active atherosclerosis effectively preserved a (near) normal lumen. 2) The second main type of plaque growth was characterized by occasional prominent increases in lesion size. This process primarily occurred in the internal carotid artery and was mediated by procoagulant risk factors in a way that peak levels were relevant rather than cumulative exposure. As the main underlying pathomechanism, atherothrombosis may be hypothesized. Marked increases in plaque size and insufficient vascular remodeling acted synergistically in producing a significant compromise of the lumen. The current study provides novel insights into the natural course of early carotid atherosclerosis, thereby focusing on disease incidence and various types of spontaneous disease progression. Nonstenotic or diffuse dilating atherosclerosis and focal stenotic disease were found to constitute epidemiologically and etiologically distinct disease entities that develop and proceed independently of each other.
Key Words: carotid arteries • atherosclerosis • atherothrombosis • population study
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Introduction |
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Cardiovascular disease is the leading source of morbidity, disability, and mortality in Western industrialised countries, and atherosclerosis is unquestionably the main underlying pathology. Current knowledge on incidence and course of atherosclerosis mainly originates from patient-based angiographic and Doppler follow-up evaluations, which for methodological reasons are restricted to severe atherosclerosis (stenosis).1 2 3 4 In the late 1980s, advances in technique and resolution of duplex ultrasound scanning afforded the opportunity to noninvasively quantify and monitor atherosclerosis from its precursor lesions to occlusive disease. The carotid arteries are an appropriate target for such evaluations on account of accessibility, size, and limited wall movement. High coincidence of carotid atherosclerosis with vessel pathology in other vascular territories makes it an adequate window for systemic atherosclerosis.5 6 7 8 9 The Bruneck Study ranks among the few large ultrasound-based cohort studies10 11 12 13 14 15 16 aimed at assessing incidence and natural course of early atherogenesis in the general population.
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Methods |
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Population Recruitment
The Bruneck Study is a prospective population-based survey on the epidemiology and etiology of carotid atherosclerosis.16 The baseline examination was performed between July 1990 and November 1990 in the semi-urban mountainous area of Bruneck (Bolzano Province, Italy). Financial and personnel resources allowed us to recruit a random sample of up to 1000 subjects. To best utilize population size in terms of accurate sex- and age-specific rates of atherosclerosis incidence and progression, equal contingents of men and women (n=125) in each the 5th to 8th decade were selected for inclusion.16 In the choice of the follow-up interval, we were mainly guided by the objective of ascertaining a sufficient number of incident carotid stenoses as the ultrasound endpoint with the lowest rate of occurrence. Extrapolation of cross-sectional data suggested that a follow-up period of 5 years suffices for this requirement. Accordingly, the first reevaluation was scheduled for July 1995 to October 1995. Participation and follow-up rates were high at 93.6% (91.9% with complete data assessment) and 96.5%, respectively. Study design, protocol, and characteristics of the survey area have been detailed previously.
Scanning Protocol
Sonographic assessment of the extracranial carotid arteries was
performed using a duplex ultrasound system (ATL8, Advanced Technology
Laboratories) with 10-MHz scanning frequency in B-mode and 5-MHz
scanning frequency in pulsed–Doppler mode. All subjects were
examined in a supine position. The scanning protocol included imaging
of the right and left common carotid arteries (CCA) and internal
carotid arteries at the following locations: proximal CCA (15 to
30 mm proximal to the carotid bulb), distal CCA (<15 mm
proximal to the carotid bulb), and proximal internal carotid artery
(ICA) (carotid bulb, identified by loss of the parallel wall
present in the CCA and the initial 10 mm of the vessel above
the flow divider between external and internal carotid arteries). For
each segment, the sonographer imaged the vessel in multiple
longitudinal and transversal planes to identify the largest axial
diameter of focal plaques and to adequately visualize the interface
required to measure intima-media thickness (IMT). Pulsed Doppler
was used to provide information on blood flow velocity and to identify
the various arteries.
Atherosclerotic lesions were defined by 2 ultrasound criteria: (1) wall surface (protrusion into the lumen or roughness of the arterial boundary) and (2) wall texture (echogenicity). We did not use an IMT cut-off to discriminate plaques from wall thickening. The maximum axial diameter of each plaque was measured as the distance from the leading edge of the lumen-intima interface to the leading edge of the media-adventitia interface. For the assessment of stenosis, Doppler criteria or, when no hemodynamic disturbances were detectable, the percentage of maximum diameter reduction in the B-mode images was applied.17 Peak systolic velocities exceeding 180cm/s and 250cm/s were considered indicative of stenosis >60% and 80%, respectively. Scanning was performed twice, namely in 1990 and 1995, by the same experienced sonographer, who was unaware of the subjects' clinical and laboratory characteristics. For documentation purposes, short segments of real time ultrasonography and frozen longitudinal and transversal images were recorded for each vessel segment.
Reproducibility, Validity, and Data Quality
To assess the reproducibility of the ultrasound technique
applied in the current evaluation, rescanning was performed in a
representative subsample by the same sonographer
(n=100). To avoid memory effects, we left a waiting period of 6 to 8
weeks between both assessments. In all, 800 vessel segments and 180
plaques served as the basis for computation of intra-observer
variability. Main focus was on the quantification of plaque diameters.
Relative measurement errors that describe the intra-observer error as a
percentage of the pooled mean were low at 10% (CCA) and 15% (ICA),
which enabled us to monitor changes in atherosclerosis
in individuals over time. In an attempt to subdivide the overall error
into various components
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At the lowest end of the plaque size distribution the above relative errors may not fit the data well. As neither surface nor texture criteria used in the definition of plaques are so-called "hard criteria", counting of small lesions may ultimately depend on the investigator's judgment. Diagnostic shifts from wall thickening to atherosclerotic plaques and vice versa represent the main source of error in the quantification of such small lesions. Concordance of classifications markedly increased with lesion size and was near perfect (>95%) for plaques exceeding 0.7 mm (CCA) and 1.1 mm (ICA). These limits were introduced in the definition of incident atherosclerosis as a minimum diameter requirement.
Statistical Analysis
Age-specific incidence/progression rates were assessed for age
strata of 5 years each and expressed as "incidence/progression of
atherosclerosis per 1000 person-years." Rates were
calculated under the assumption of a consistent probability of
incident/progressive atherosclerosis across the 5-year
age intervals. Equal risks were allocated from the first to
fifth year of follow-up; cases contributed, on average, 2.5 years of
follow-up to the denominator of the incidence formula (for details see
Reference 1818 ). Cumulative 
rates were converted into cumulative
risks by means of the formula P=1-exp (-
).18 Standardization of rates was performed
according to the guidelines given by Breslow and Day.18
Strength and type of association between cigarette smoking and various
categories of atherosclerosis progression was assessed
by logistic regression analysis (SPSS-X statistical
software).19
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Results |
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Tables 1
and 2 depict age-, sex-, and site-specific
incidence rates of atherosclerosis. Premenopausal women
showed excellent protection against atherosclerosis,
which was gradually lost within a 5-year period after menopause along
with prominent iron accumulation (Figure 1a). Thereafter, incidence rates were
virtually identical in men and women of equal age (Tables 1 and 2), which results in a convergence of disease manifestation
between sexes with advancing age (Figure 1b). Manifestation of
>1 atherosclerotic lesion during the 5-year follow-up period was as
frequent as the occurrence of a single plaque (percentage of subjects
with 1, 2, 3, and 
4 incident plaques: 57%, 27%, 12%, and 4%).
Figure 2 describes disease activity as a
function of preexisting atherosclerosis.
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For comparison purposes, rates were adjusted to the age/sex structure of the standard European population,18 thereby obtaining 1 universal estimate of atherosclerosis incidence in the middle-aged and elderly (aged 40 to 84 years), which amounted to 69.9 per 1000 person-years.
Next, we focused on spontaneous progression of atherosclerotic lesions.
Plots of plaque growth against the lesion size ultimately achieved
identified 2 distinct types of growth kinetics.
Atherosclerosis that did not cause lumen obstruction
>40% usually grew slowly and evoked (over)compensatory local dilation
of vessel segments (Figure 3). In
contrast, stenosis >40% usually originated from occasional
marked increases in plaque size and insufficient or even lacking
vascular remodelling (Figure 3). Both types of lesion
progression started from plaques of similar diameters (Figure 3;
1.3 versus 1.6 mm), with the distribution of changes in plaque
size showing only minor overlap (mean [95%CI]: 1.1 mm [0.1 to
2.2 mm] versus 2.4 mm [1.3 to 3.6 mm];
P=0.0001). Progression rates of nonstenotic
atherosclerosis showed age- and sex-trends similar to
those observed for incident atherosclerosis (Tables 1
and 2) and an amplification of disease activity with an
increasing number of preexisting plaques (Figure 2). In
contrast, incidence rates of stenosis in middle-aged and
elderly subjects emerged as independent of sex and age (Table 2). In most instances, nonstenotic atherogenesis
manifested in several plaques simultaneously, whereas
incident stenosis usually occurred only once in the 5-year
follow-up period (Figure 4). Further
differences in the epidemiology of both
processes are opposed in Table 3.
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Vessel diameter, average change in vessel diameter between
1990 and 1995 (in mm).
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The risk profile of nonstenotic atherosclerosis consisted of traditional risk factors (high LDL and low HDL cholesterol, hypertension, and smoking) supplemented by less well-established risk conditions such as prominent body iron stores,20 21 severe alcohol consumption, or chronic infections (unpublished data from the Bruneck Study). Stenotic atherosclerosis emerged as a domain of a procoagulant state involving high fibrinogen and Lp(a), low antithrombin III and APC ratio (factor V mutation), and clinical conditions known to shift hemostasis toward coagulation. As to cigarette smoking, the risk of nonstenotic atherosclerosis was best described by measures of cumulative exposure (pack-years) (OR [95%CI], 1.26 [1.06 to 1.50] for a 1-standard deviation unit change) and did not normalize within a 5- to 10-year period after cessation (1.24 [1.03 to 1.49]). In contrast, peak levels of exposure (number of cigarettes currently smoked) were superior to cumulative measures in predicting the risk of stenotic atherosclerosis (2.57 [1.74 to 3.80]). After secession of smoking, the risk of focal stenotic disease normalized (OR for ex-smokers 1 to 5 years after cessation, 1.29 [0.33 to 5.04]).
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Discussion |
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Initiation of Atherosclerosis
Precursor lesions of atherosclerosis (intima-media thickening) may occur as early as adolescence, but the frequency of definite atherosclerotic lesions remains low until age 40 in men and onset of menopause in women (prevalence <1.0% each). Protection against atherosclerosis in women was gradually lost within a 5-year period after menopause (Figure 1a
). Afterward,
incidence rates were virtually identical to those observed in men of
equal age. In other words, atherogenesis in females usually started at
higher ages than in men but proceeded at a similar pace once a
postmenopausal period of 5 years had elapsed. Plots of cumulative risk
rates in men and women best visualized the convergence in disease
manifestation with advancing age (Figure 1b).
As detailed previously, differences in prevalence and incidence of
carotid atherosclerosis evident between premenopausal
women and men disappeared when sex variations in body iron stores were
taken into account.20 21 Iron accumulation in
(post)menopause corresponded excellently with the breakdown of female
protection against atherogenesis (Figure 1b). Growing
epidemiological and experimental evidence suggests a crucial role of
prominent iron stores in lipid-induced atherogenesis even though a
general consensus in this field has not yet been
reached.22
As expected, the proximal ICA was the site of predilection for
manifestation of atherosclerosis. In 1 out of 2
subjects with incident atherosclerosis, plaques
occurred simultaneously in 2 or more carotid segments. The
risk of incident atherosclerosis amplified with size
and number of preexisting lesions (Figure 2), which may well
reflect a perpetuation of adverse risk profiles but could,
speculatively, also point to some kind of auto-catalytic propagation of
atherosclerosis. A previous investigation in this
cohort yielded evidence of an (auto)-immune component in human
atherogenesis and identified heat-shock protein 65 as a potential
target antigen.23 Occasionally, plaques evolved as
focal lesions within a normal vasculature. In most instances, however,
atherosclerosis developed at sites with an IMT beyond
the 50th percentile (ICA, 88.8%; CCA, 97.8%). Thus, our survey
supported the view that wall thickening commonly precedes definite
atherosclerosis, possibly in the sense of a precursor
lesion of one and the same disease process.
Progression of Atherosclerosis
From a pathoanatomical perspective, 2 distinct types of
atherosclerosis progression may be distinguished: 1) In
small and medium-sized lesions slow and continuous plaque growth
predominates, which is mediated by a variety of complex biological
step-by-step phenomena such as lipid-induced atherogenesis or smooth
muscle cell proliferation. 2) This type of plaque growth may be
occasionally accelerated by plaque fissuring, thrombosis and fibrous
organization of mural thrombi.24 25 The latter mechanism,
further on referred to as plaque thrombosis, gains increasing weight
with advancing lesion size and may even be the key event in the
development of stenotic lesions. A comprehensive discussion of
the dualism of conventional atherosclerosis and
atherothrombosis in human vessel pathology is given by Fuster et
al26 and Badimon et al.27 The current
prospective survey provides strong in vivo support for this concept and
suggests that a shift in the relevance of both pathomechanisms occurs
when a plaque causes >40% diameter reduction (Figure 3 and
Table 3).
Nonstenotic atherosclerosis expanded slowly
(Figure 3). Such processes usually paralleled in several
atherosclerotic lesions independently of plaque location (Figure 4), ie, they were a continuous and ubiquitous process. In
analogy to the initiation of atherosclerosis, the risk
of disease progression amplified with advancing age and number of
atherosclerotic lesions (Figure 2). Once more than 3 plaques
preexisted in a single subject, further disease extension was an almost
obligatory phenomenon (78%), which reinforces the possibility of an
auto-catalytic component in this type of atherogenesis. Compensatory
enlargement of the vessel at the site of active
atherosclerosis effectively preserved a normal lumen or
was even over-compensatory in the early course of disease (see Part II:
Vascular Remodeling). Diffuse dilative atherosclerosis
may be assumed as a final stage of this type of disease
progression.
In contrast, stenosis >40% usually developed focally at sites
of high hemodynamic stress (ICA) based on occasional
marked increases in plaque size (mean, 2.4 mm). Subjects with
preexisting stenotic disease were at a clearly elevated risk of
developing a further stenosis in a different segment of the
carotid arteries (23 of 55 [41.8%]). On the other hand, such events
appeared to be so rare that manifestation of more than 1
stenosis during the 5-year follow-up period was definitely the
exception and not the rule (Figure 4). Compensatory enlargement
of the vessel as typical for nonstenotic
atherosclerosis did not occur at all or only
insufficiently, which acted synergistically with the rapid growth
pattern in producing significant lumen compromise (Figure 3).
Actually, 95% of stenosis >40% arose from this synergism.
Carotid stenosis did not develop before age 45 in men and 55 in
women. Thereafter, segment-based incidence rates were constant across
the whole age range and in sexes (Table 2). The higher
prevalence of stenosis in men is thus not a consequence of
enhanced disease activity but simply reflects the higher prevalence of
nonstenotic atherosclerotic lesions at risk of stenotic
transformation. Lack of a significant age trend, which at first glance
may surprise, is explained by peculiarities in the etiology of
stenosis. Consistent with the concept of underlying
plaque thrombosis, this process primarily relied on procoagulant risk
factors, most of which did not show prominent age-dependency.
Both types of disease progression preferentially started from small- to
medium-sized plaques of similar diameter. Stenotic
atherosclerosis should not be viewed as a simple
perpetuation of disease mechanisms relevant to early atherogenesis nor
did it in most instances superimpose on advanced nonstenotic
disease. Actually, both types of atherogenesis develop and proceed
independently of each other (Table 3).
Presentation of detailed risk profiles goes far beyond the scope of this article. Instead, we attempted to clarify main differences in the way risk factors relate to either type of disease progression using the example of cigarette smoking. The risk of nonstenotic atherosclerosis primarily relied on measures of cumulative smoking exposure and did not normalize within a 5- to 10-year period after cessation whereas peak levels of exposure appeared to be of significance for stenotic atherosclerosis. Consistent with a reversible pro-coagulant state, the risk of focal stenotic disease normalized after smoking cessation.
Briefly, the risk profile of nonstenotic atherosclerosis consisted of traditional risk factors and that of stenotic atherosclerosis of markers of enhanced thrombotic activity, attenuated fibrinolysis, and clinical conditions known to interfere with coagulation.
Regression
A variety of angiographic and ultrasound follow-up evaluations
outlined the possibility of spontaneous or drug-induced regression of
increased IMT and atherosclerotic lesions.28 29 30 31 In our
survey, long-lasting regression was quite rare (5.2% of all lesions,
n=45) and confined to lesions with signs of plaque hemorrhage
(19 of 45 [42%]), healing of ulcerated
atherosclerosis (2 of 45 [4%]), and disappearance of
small plaques (18 of 45 [40%]).
Limitations and Merits of the Study Design
1) Accuracy of descriptive epidemiologic data mainly depends on
the choice of an appropriate study population and the sample size. The
current cohort was a random sample of the general population with a
near complete follow-up (96.5%) and an observation period of more than
33 000 segment-years (4000 person-years). 2) The progression model
developed and applied in the current study permitted us to monitor and
characterize changes in vascular status in individuals (person-based
approach), which is a clear advantage over the more commonly used
approach of assessing changes in IMT over time. 3) Ultrasound
evaluations were performed twice, namely in 1990 and 1995. Systematic
interim scanning was not available. Thus, we cannot construct precise
growth curves of atherosclerotic lesions. In particular, it remains to
be elucidated whether slow plaque growth stands for a continuous or
stepwise process or for successive plaque propagation and repair
(regression) with progression overweight.
Conclusions
The current study may well be the first to provide
population-based incidence rates of carotid
atherosclerosis and detailed insights into the course
of early disease progression. These findings contribute to a better
understanding of the nature of atherogenesis and possibly assist in
clinical decision making. Atherogenesis was found to be a
heterogeneous disease that subsumes epidemiologically and
etiologically distinct disease entities. Fighting the same risk
factors in all individuals, as is common clinical practice, ignores the
actual complexity of the disease.
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Appendix 1 |
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The Bruneck Study Group
Georg Egger, Martin Oberhollenzer, Friedrich 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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A. R. Afzal, S. Kiechl, Y. P. Daryani, A. Weerasinghe, Y. Zhang, M. Reindl, A. Mayr, S. Weger, Q. Xu, and J. Willeit Common CCR5-del32 Frameshift Mutation Associated With Serum Levels of Inflammatory Markers and Cardiovascular Disease Risk in the Bruneck Population Stroke, July 1, 2008; 39(7): 1972 - 1978. [Abstract] [Full Text] [PDF]
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 S. Kiechl, J. Willeit, M. Mayr, B. Viehweider, M. Oberhollenzer, F. Kronenberg, C. J. Wiedermann, S. Oberthaler, Q. Xu, J. L. Witztum, et al. Oxidized Phospholipids, Lipoprotein(a), Lipoprotein-Associated Phospholipase A2 Activity, and 10-Year Cardiovascular Outcomes: Prospective Results From the Bruneck Study Arterioscler Thromb Vasc Biol, August 1, 2007; 27(8): 1788 - 1795. [Abstract] [Full Text] [PDF]
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 S. Kiechl, G. Schett, J. Schwaiger, K. Seppi, P. Eder, G. Egger, P. Santer, A. Mayr, Q. Xu, and J. Willeit Soluble Receptor Activator of Nuclear Factor-{kappa}B Ligand and Risk for Cardiovascular Disease Circulation, July 24, 2007; 116(4): 385 - 391. [Abstract] [Full Text] [PDF]
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 L. R. Zacharski, B. K. Chow, P. S. Howes, G. Shamayeva, J. A. Baron, R. L. Dalman, D. J. Malenka, C. K. Ozaki, and P. W. Lavori Reduction of Iron Stores and Cardiovascular Outcomes in Patients With Peripheral Arterial Disease: A Randomized Controlled Trial JAMA, February 14, 2007; 297(6): 603 - 610. [Abstract] [Full Text] [PDF]
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H. S. Markus, R. Labrum, S. Bevan, M. Reindl, G. Egger, C. J. Wiedermann, Q. Xu, S. Kiechl, and J. Willeit Genetic and Acquired Inflammatory Conditions Are Synergistically Associated With Early Carotid Atherosclerosis Stroke, September 1, 2006; 37(9): 2253 - 2259. [Abstract] [Full Text] [PDF]
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M. Mayr, S. Kiechl, S. Tsimikas, E. Miller, J. Sheldon, J. Willeit, J. L. Witztum, and Q. Xu Oxidized Low-Density Lipoprotein Autoantibodies, Chronic Infections, and Carotid Atherosclerosis in a Population-Based Study J. Am. Coll. Cardiol., June 20, 2006; 47(12): 2436 - 2443. [Abstract] [Full Text] [PDF]
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S. Tsimikas, S. Kiechl, J. Willeit, M. Mayr, E. R. Miller, F. Kronenberg, Q. Xu, C. Bergmark, S. Weger, F. Oberhollenzer, et al. Oxidized Phospholipids Predict the Presence and Progression of Carotid and Femoral Atherosclerosis and Symptomatic Cardiovascular Disease: Five-Year Prospective Results From the Bruneck Study J. Am. Coll. Cardiol., June 6, 2006; 47(11): 2219 - 2228. [Abstract] [Full Text] [PDF]
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J. Rodenburg, M. N. Vissers, A. Wiegman, E. R. Miller, P. M. Ridker, J. L. Witztum, J. J.P. Kastelein, and S. Tsimikas Oxidized Low-Density Lipoprotein in Children With Familial Hypercholesterolemia and Unaffected Siblings: Effect of Pravastatin J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1803 - 1810. [Abstract] [Full Text] [PDF]
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R. Sztajzel, I. Momjian-Mayor, M. Comelli, and S. Momjian Correlation of Cerebrovascular Symptoms and Microembolic Signals With the Stratified Gray-Scale Median Analysis and Color Mapping of the Carotid Plaque Stroke, March 1, 2006; 37(3): 824 - 829. [Abstract] [Full Text] [PDF]
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 M. Hassinen, P. Komulainen, T. A. Lakka, S. B. Vaisanen, I. Haapala, H. Gylling, M. Alen, A. Schmidt-Trucksass, A. Nissinen, and R. Rauramaa Metabolic syndrome and the progression of carotid intima-media thickness in elderly women. Arch Intern Med, February 27, 2006; 166(4): 444 - 449. [Abstract] [Full Text] [PDF]
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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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M. Knoflach, S. Kiechl, A. Mayr, J. Willeit, W. Poewe, and G. Wick Allergic Rhinitis, Asthma, and Atherosclerosis in the Bruneck and ARMY Studies Arch Intern Med, November 28, 2005; 165(21): 2521 - 2526. [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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 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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 J. F. Arenillas, C. A. Molina, P. Chacon, A. Rovira, J. Montaner, P. Coscojuela, E. Sanchez, M. Quintana, and J. Alvarez-Sabin High lipoprotein (a), diabetes, and the extent of symptomatic intracranial atherosclerosis Neurology, July 13, 2004; 63(1): 27 - 32. [Abstract] [Full Text] [PDF]
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S. Kiechl, G. Schett, G. Wenning, K. Redlich, M. Oberhollenzer, A. Mayr, P. Santer, J. Smolen, W. Poewe, and J. Willeit Osteoprotegerin Is a Risk Factor for Progressive Atherosclerosis and Cardiovascular Disease Circulation, May 11, 2004; 109(18): 2175 - 2180. [Abstract] [Full Text] [PDF]
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 V. P. Korovkina, A. M. Brainard, P. Ismail, T. J. Schmidt, and S. K. England Estradiol Binding to Maxi-K Channels Induces Their Down-regulation via Proteasomal Degradation J. Biol. Chem., January 9, 2004; 279(2): 1217 - 1223. [Abstract] [Full Text] [PDF]
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 M. Tatsumi, C. Cohade, Y. Nakamoto, and R. L. Wahl Fluorodeoxyglucose Uptake in the Aortic Wall at PET/CT: Possible Finding for Active Atherosclerosis Radiology, December 1, 2003; 229(3): 831 - 837. [Abstract] [Full Text] [PDF]
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T. J. Wang, B.-H. Nam, R. B. D'Agostino, P. A. Wolf, D. M. Lloyd-Jones, C. A. MacRae, P. W. Wilson, J. F. Polak, and C. J. O'Donnell Carotid Intima-Media Thickness Is Associated With Premature Parental Coronary Heart Disease: The Framingham Heart Study Circulation, August 5, 2003; 108(5): 572 - 576. [Abstract] [Full Text] [PDF]
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A. R. Moody, R. E. Murphy, P. S. Morgan, A. L. Martel, G.S. Delay, S. Allder, S. T. MacSweeney, W. G. Tennant, J. Gladman, J. Lowe, et al. Characterization of Complicated Carotid Plaque With Magnetic Resonance Direct Thrombus Imaging in Patients With Cerebral Ischemia Circulation, June 24, 2003; 107(24): 3047 - 3052. [Abstract] [Full Text] [PDF]
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L. E. Wagenknecht, D. Zaccaro, M. A. Espeland, A. J. Karter, D. H. O'Leary, and S. M. Haffner Diabetes and Progression of Carotid Atherosclerosis: The Insulin Resistance Atherosclerosis Study Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 1035 - 1041. [Abstract] [Full Text] [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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 G. S. Cooke, S. Segal, A. V.S. Hill, the Tuberculosis, Genetics, and Environment (TBGEN, B. Beutler, E. Beutler, S. Kiechl, J. Willeit, and D. A. Schwartz Toll-like Receptor 4 Polymorphisms and Atherogenesis N. Engl. J. Med., December 12, 2002; 347(24): 1978 - 1980. [Full Text] [PDF]
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T. J. Wang, B.-H. Nam, P. W.F. Wilson, P. A. Wolf, D. Levy, J. F. Polak, R. B. D'Agostino, and C. J. O'Donnell Association of C-Reactive Protein With Carotid Atherosclerosis in Men and Women: The Framingham Heart Study Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1662 - 1667. [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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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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S. Kiechl, J. Willeit, A. Ascherio, E. B. Rimm, E. Giovannucci, W. C. Willett, and M. J. Stampfer Ongoing Controversies Surrounding the Vascular Benefits of Blood Donation Response Circulation, October 30, 2001; 104 (18): e99 - e99. [Full Text] [PDF]
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M. Zureik, F. Kauffmann, P.-J. Touboul, D. Courbon, and P. Ducimetiere Association Between Peak Expiratory Flow and the Development of Carotid Atherosclerotic Plaques Arch Intern Med, July 9, 2001; 161(13): 1669 - 1676. [Abstract] [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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