Stefan Kiechl and Johann Willeit

The Natural Course of Atherosclerosis : Part I: Incidence and Progression

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doi: 10.1161/01.ATV.19.6.1484
1999;19:1484-1490 Arterioscler Thromb Vasc Biol.
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The Natural Course of Atherosclerosis
Part I: Incidence and Progression
Stefan Kiechl, Johann Willeit, for the Bruneck Study Group
AbstractThe 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.
(Arterioscler Thromb Vasc Biol. 1999;19:1484-1490.)
Key Words: carotid arteries

atherosclerosis

atherothrombosis

population study
C
ardiovascular disease is the leading source of morbidity,
disability, and mortality in Western industrialised coun-
tries, and atherosclerosis is unquestionably the main under-
lying pathology. Current knowledge on incidence and course
of atherosclerosis mainly originates from patient-based an-
giographic and Doppler follow-up evaluations, which for
methodological reasons are restricted to severe atherosclero-
sis (stenosis).
14
In the late 1980s, advances in technique and
resolution of duplex ultrasound scanning afforded the oppor-
tunity 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 pa-
thology in other vascular territories makes it an adequate
window for systemic atherosclerosis.
59
The Bruneck Study
ranks among the few large ultrasound-based cohort stud-
ies
1016
aimed at assessing incidence and natural course of
early atherogenesis in the general population.
Methods
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
(n125) 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 occur-
rence. Extrapolation of cross-sectional data suggested that a
follow-up period of 5 years suffices for this requirement. Accord-
ingly, 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.
Received June 12, 1998; revision accepted November 30, 1998.
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.
1999 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org
1484
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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 pulsedDoppler 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 loca-
tions: 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 arter-
ies). 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 assess-
ment 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 indica-
tive of stenosis 60% and 80%, respectively. Scanning was per-
formed twice, namely in 1990 and 1995, by the same experienced
sonographer, who was unaware of the subjects clinical and labora-
tory 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 (n100). 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
ee
1
2
e
n
2
,
we considered a variety of potential sources of bias: poor scanning
quality, true changes in vascular status in the intervening period,
administration error, attribution of lesions to neighboring segments,
overseeing of hidden plaques, and the measurement error in its
primary sense. Parallel rereading of the scans was performed to
define the source of error responsible for deviations between both
assessments. Poor scanning quality due to anatomical variations
(high bifurcation, n1), real progression of atherosclerosis (1 of 180
plaques), and overseeing of adequately-sized lesions in 1 of the
scannings (1 of 180 plaques) was rare and contributed little to overall
error. At 0.1%, administration and input error were kept low by
multiple checks of the database. Variable attribution of plaques to
neighboring segments requires attention. Pitfalls mainly occurred in
TABLE 1. Incidence and Progression of Carotid Atherosclerosis According to Age, Sex, and
Menopausal Status (n826)
Incidence Men Premenopausal Women Postmenopausal Women
Age
Range (y)
Incidence
Rate
Years of
Follow-Up
Incidence
Rate
Years of
Follow-Up
Incidence
Rate
Years of
Follow-Up
4044 32.8 158.5 5.3 150.0 50.0 4.0
4549 51.1 270.0 13.4 239.0 48.6 53.5
5054 45.7 245.0 15.7 102.1 38.0 163.0
5559 47.1 148.5 13.3 15.0 61.7 181.5
6064 93.2 124.5

62.0 184.0
6569 118.6 72.5

59.9 137.0
7074 183.8 55.5

72.5 69.0
7579 170.5 30.5

74.7 37.5
8084 160.0 5.0

107.1 14.0
Progression Men Premenopausal Women Postmenopausal Women
Age
Range (y)
Progression
Rate
Years of
Follow-Up
Progression
Rate
Years of
Follow-Up
Progression
Rate
Years of
Follow-Up
4044 61.5 6.5 0.0 3.0

4549 50.0 16.0 0.0 4.0 66.7 12.0
5054 87.8 61.5 0.0 7.0 33.3 24.0
5559 90.6 106.0 0.0 7.0 60.9 46.0
6064 118.8 128.0

104.6 65.0
6569 157.7 120.5

116.8 113.0
7074 174.1 108.0

121.6 153.0
7579 168.2 107.0

172.8 81.0
8084 160.8 53.5

218.2 55.0
Incidence and progression rates were calculated per 1000 person-years. Incidence rates were assessed in subjects
free of carotid atherosclerosis at the 1990 baseline (n500) and progression rates in those with preexisting
atherosclerosis (n326).
Kiechl and Willeit June 1999 1485
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the correct attribution of plaques to either the ICA or external carotid
artery (4 of 118). In the CCA, lesions that approached or just crossed
the limit between its distal and proximal section were occasionally
counted twice (2 of 62). When this and all aforementioned sources of
variability were eliminated, we arrived at the actual measurement
error caused by physical limitations of the measuring device, lack of
clear-cut interfaces, and the choice of distinct axes through lesions
with complex shape. Rates were 8.5% (CCA) and 12.4% (ICA). To
ensure that increases in plaque size during follow-up did not simply
reflect measurement variability, only changes exceeding the doubled
(overall) measurement error were regarded as true progression.
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 investiga-
tors judgment. Diagnostic shifts from wall thickening to atheroscle-
rotic 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 athero-
sclerosis per 1000 person-years. Rates were calculated under the
assumption of a consistent probability of incident/progressive ath-
erosclerosis across the 5-year age intervals. Equal risks were allo-
cated 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 18). Cumulative rates were
converted into cumulative risks by means of the formula P1-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
Results
Tables 1 and 2 depict age-, sex-, and site-specific incidence
rates of atherosclerosis. Premenopausal women showed ex-
cellent protection against atherosclerosis, which was gradu-
ally lost within a 5-year period after menopause along with
prominent iron accumulation (Figure 1a). Thereafter, inci-
dence 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 dur-
ing 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.
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.
TABLE 2. Segment-Based Incidence and Progression Rates of Atherosclerosis in the CCA and ICA According to Age and Sex
ICA: Age
Range (y)
Incidence of Atherosclerosis:
Rate (Years of Follow-Up)
Incidence of Stenosis 40%:
Rate (Years of Follow-Up)
Progression of Atherosclerosis:
Rate (Years of Follow-Up)
Men Women Men Women Men Women
4044 9.5 (334) 1.9 (311) 33.3 (6) 0.0 (3) 35.7 (4) 0.0 (3)
4549 18.6 (569) 8.3 (601) 40.0 (15) 0.0 (2) 80.0 (15) 0.0 (3)
5054 23.6 (569) 14.0 (571) 25.3 (79) 0.0 (24) 75.1 (79) 24.0 (24)
5559 27.9 (394) 32.7 (447) 35.6 (112) 21.0 (48) 99.6 (112) 54.2 (48)
6064 59.4 (377) 31.5 (458) 37.3 (204) 31.2 (77) 95.9 (207) 98.7 (77)
6569 64.1 (231) 32.5 (388) 26.1 (245) 44.6 (170) 91.9 (215) 109.4 (170)
7074 88.2 (194) 69.7 (264) 31.3 (217) 23.7 (186) 103.5 (217) 104.3 (186)
7579 87.8 (153) 78.4 (171) 57.1 (210) 34.2 (135) 104.4 (210) 139.2 (135)
8084 102.4 (53) 69.0 (87) 34.5 (99) 29.3 (107) 124.9 (99) 115.1 (187)
CCA: Age
Incidence of Atherosclerosis:
Rate (Years of Follow-Up)
Incidence of Stenosis 40%:
Rate (Years of Follow-Up)
Progression of Atherosclerosis:
Rate (Years of Follow-Up)
Range (y) Men Women Men Women Men Women
4044 3.9 (674) 1.3 (628)

4549 7.6 (1160) 3.8 (1203)

5054 13.3 (1231) 3.1 (1183) 5.6 (72) 0.0 (7) 69.9 (72) 22.2 (7)
5559 11.1 (905) 11.5 (973) 8.3 (120) 0.0 (20) 66.7 (120) 60.0 (20)
6064 16.0 (974) 10.3 (1010) 15.8 (203) 0.0 (77) 52.2 (207) 65.3 (77)
6569 21.8 (735) 16.2 (963) 15.2 (222) 9.5 (126) 79.3 (222) 68.9 (126)
7074 21.8 (614) 27.8 (755) 15.5 (220) 12.3 (162) 97.4 (220) 89.1 (162)
7579 33.3 (450) 25.9 (455) 14.1 (262) 10.9 (164) 87.8 (262) 94.9 (164)
8084 42.6 (159) 39.2 (250) 14.1 (146) 14.5 (153) 100.0 (149) 106.2 (153)
Incidence and progression rates were calculated per 1000 segment years. Incidence of atherosclerosis was assessed in segments free of atherosclerosis at the
1990 baseline. Progression rates of nonstenotic atherosclerosis and incidence rates of stenosis focused on segments with preexisting atherosclerosis (segment-based
approach).
The ICA was defined as the carotid bulbous and the initial 10 mm of the vessel.
1486 Natural Course of Atherosclerosis: Part I
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Next, we focused on spontaneous progression of athero-
sclerotic 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 pro-
gression 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]; P0.0001).
Progression rates of nonstenotic atherosclerosis showed age-
and sex-trends similar to those observed for incident athero-
sclerosis (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 inci-
dent stenosis usually occurred only once in the 5-year
follow-up period (Figure 4). Further differences in the epide-
miology of both processes are opposed in Table 3.
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 athero-
sclerosis 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 smok-
ing, 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 su-
perior 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]).
Discussion
Initiation of Atherosclerosis
Precursor lesions of atherosclerosis (intima-media thicken-
ing) 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 grad-
ually 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 manifes-
tation with advancing age (Figure 1b).
Figure 1. a, Iron accumulation and incidence rates of carotid
atherosclerosis before and 1 to 5, 5 to 10, and 10 years after
menopause. The gure visualizes the temporal loss of female
protection against atherosclerosis. Incidence rates were stan-
dardized to the age-distribution of men in our population (40 to
59 years). b, Cumulative risk of carotid atherosclerosis in men
and women.
Figure 2. Age- and sex-standardized incidence and progression
rates of carotid atherosclerosis according to the number of pre-
existing plaques.
Kiechl and Willeit June 1999 1487
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As detailed previously, differences in prevalence and
incidence of carotid atherosclerosis evident between pre-
menopausal women and men disappeared when sex varia-
tions in body iron stores were taken into account.
20,21
Iron
accumulation in (post)menopause corresponded excellently
with the breakdown of female protection against atherogen-
esis (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 simulta-
neously 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 iden-
tified heat-shock protein 65 as a potential target antigen.
23
Occasionally, plaques evolved as focal lesions within a
normal vasculature. In most instances, however, atheroscle-
rosis 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 advanc-
ing 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 athero-
thrombosis in human vessel pathology is given by Fuster et
al
26
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 possibil-
ity of an auto-catalytic component in this type of atherogen-
esis. 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 athero-
Figure 3. Growth kinetics of plaques
and vascular remodelling (compensatory
dilation of vessels) according to the
degree of lumen obstruction (% diameter
stenosis). Diameters were adjusted for
age and sex. This graph shows a marked
increase in plaque growth and a
decrease in compensatory vessel dilation
at a cut-off of 40%. Vessel diameter,
average change in vessel diameter
between 1990 and 1995 (in mm).
Figure 4. Number of preexisting plaques involved in nonstenot-
ic and stenotic atherogenesis. This graph shows that nonstenot-
ic atherogenesis usually manifested in more than 1 plaque of
given subjects whereas stenotic atherogenesis was a focal dis-
ease which usually occurred only once in the 5-year follow-up
period.
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sclerosis 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). Compen-
satory 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). Actu-
ally, 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 pri-
marily 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 athero-
genesis 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 signifi-
cance for stenotic atherosclerosis. Consistent with a revers-
ible 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 evalua-
tions outlined the possibility of spontaneous or drug-induced
regression of increased IMT and atherosclerotic lesions.
2831
In our survey, long-lasting regression was quite rare (5.2% of
all lesions, n45) 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 de-
pends 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 advan-
tage 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 con-
struct 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.
TABLE 3. Distinct Epidemiology and Etiology of Nonstenotic and Stenotic Carotid
Atherosclerosis in the Bruneck Study Cohort (1990 to 1995) (n826)
Nonstenotic Atherosclerosis
Diffuse Dilative Atherosclerosis
Stenotic Atherosclerosis
Focal Stenotic Disease
Site of predilection Ubiquitous Internal carotid artery
(bulbous)
Plaque growth Slow, continuous and diffuse
growth
Focal rapid plaque extension
with long interictal periods
Vascular remodeling Prominent or even
over-compensatory
Insufficient or even lacking
Risk profile Hyperlipidemia (cofactor body iron
stores), hypertension, smoking
Procoagulant state
Association with risk factors Cumulative Peak levels
Suspected pathological sequela Conventional atherogenesis
(step-by-step mechanisms)
Plaque thrombosis
Both types of atherosclerosis develop and proceed independently of each other. Of subjects with 1 atherosclerotic
lesion at the 1990 baseline (n219) 131 showed nonstenotic plaque growth and 88 did not. In both groups, the
percentage of subjects with incident stenosis 40% was strikingly similar at 38.6% and 37.4% (
2
0.03, P0.85;
coefficient 0.01, P0.91).
Kiechl and Willeit June 1999 1489
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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.
Appendix
The Bruneck Study Group
Georg Egger, Martin Oberhollenzer, Friedrich Oberhollenzer, Stefan
Brandt, Paula Eder, Klaus Oberlechner, Harald Steiner, Arno Gas-
peri: Department of Internal Medicine, Bruneck Hospital, Italy;
Agnes Mair, Peter Santer: Department of Laboratory Medicine,
Bruneck Hospital, Italy; Gregor Rungger, Franz Spogler: Depart-
ment of Neurology, Innsbruck University Hospital, Austria; Elmar
Jarosch, Maria Schober: Department of Laboratory Medicine, Inns-
bruck University Hospital, Austria; Christian Wiedermann: Depart-
ment of Internal Medicine, Innsbruck University Hospital, Austria;
Enzo Bonora, Michele Muggeo: Department of Endocrinology and
Metabolism, Verona University Hospital, Italy.
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