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(Circulation. 1999;100:1154-1160.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Role of Lipoprotein(a) and Apolipoprotein(a) Phenotype in Atherogenesis
Prospective Results From the Bruneck Study
From the Institute of Medical Biology and Human Genetics, University of Innsbruck (F.K., E.T., G.U.), and Innsbruck University Hospital, Department of Neurology (M.F.K., S.K., J.W.), Austria, and Bruneck Hospital, Department of Internal Medicine, Italy (P.S., F.O., G.E.).
Correspondence to Dr Florian Kronenberg, Institute of Medical Biology and Human Genetics, Schöpfstraße 41, A-6020 Innsbruck. E-mail florian.kronenberg{at}uibk.ac.at
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Abstract |
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Background—Experimental studies have suggested both atherogenic and thrombogenic properties of lipoprotein(a) [Lp(a)], depending on Lp(a) plasma concentrations and varying antifibrinolytic capacity of apolipoprotein(a) [apo(a)] isoforms. Epidemiological studies may contribute to assessment of the relevance of these findings in the general population.
Methods and Results—This study prospectively investigated the association between Lp(a) plasma concentrations, apo(a) phenotypes, and the 5-year progression of carotid atherosclerosis assessed by high-resolution duplex ultrasound in a random sample population of 826 individuals. We differentiated early atherogenesis (incident nonstenotic atherosclerosis) from advanced (stenotic) stages in atherosclerosis that originate mainly from atherothrombotic mechanisms. Lp(a) plasma concentrations predicted the risk of early atherogenesis in a dose-dependent fashion, with this association being confined to subjects with LDL cholesterol levels above the population median (3.3 mmol/L). Apo(a) phenotypes were distributed similarly in subjects with and without early carotid atherosclerosis. In contrast, apo(a) phenotypes of low molecular weight emerged as one of the strongest risk predictors of advanced stenotic atherosclerosis, especially when associated with high Lp(a) plasma concentrations (odds ratio, 6.4; 95% CI, 2.8 to 14.9).
Conclusions—Lp(a) is one of the few risk factors capable of promoting both early and advanced stages of atherogenesis. Lp(a) plasma concentrations predicted the risk of early atherogenesis synergistically with high LDL cholesterol. Low-molecular-weight apo(a) phenotypes with a putatively high antifibrinolytic capacity in turn emerged as one of the leading risk conditions of advanced stenotic stages of atherosclerosis.
Key Words: atherosclerosis • apolipoproteins • lipoproteins • genetics • carotid arteries
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Introduction |
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Lipoprotein(a) [Lp(a)] consists of 2 components, an LDL particle and an attached apolipoprotein(a) [apo(a)]. The complex structure may explain its atherogenic and thrombogenic properties.1 Lp(a) is believed to contribute to lipid-induced atherogenesis similarly to LDL particles.2 Compared with LDL, however, it contains lower amounts of antioxidants and exhibits a high affinity to extracellular matrix and fibrin(ogen),3 4 5 which prolongs residence time in the subintima. Both properties of Lp(a) facilitate its oxidative modification and may enhance its capacity to cause injury.
Effects on coagulation in turn derive from a high sequence homology of apo(a) with plasminogen.6 Lp(a) competes with plasminogen for binding to plasminogen receptors, fibrinogen, and fibrin,4 5 as well as other cellular binding sites,7 8 but lacks plasmin-like activity. Furthermore, it interferes with plasminogen activation by inhibition of the tissue plasminogen activator9 and by itself enhances the expression of plasminogen activator inhibitor 1.10 In vitro studies on the thrombogenic nature of Lp(a) suggested that this property is defined primarily by the particle size of apo(a) and only secondarily by the Lp(a) concentration.11 12 13 In other words, the same Lp(a) concentrations may be associated with a markedly different atherothrombotic risk, depending on the apo(a) isoform.
Epidemiological studies may help to assess the relevance of these in vitro findings in vivo and for the general population. The current prospective population study attempts to clarify the complex association between Lp(a) and carotid atherosclerosis, with special attention directed to possible differential effects of the apo(a) components of various sizes on different stages of atherosclerotic disease. Interpretation of most previous surveys on this issue is complicated by highly selected study populations, cross-sectional study design, and/or lack of consideration of apo(a) phenotypes.
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Methods |
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Study Population
The study design and survey area have been described in detail previously.14 At study entry (year 1990), the study population was composed of an age- and sex-stratified random sample of all inhabitants of Bruneck (Bolzano Province, Italy) 40 to 79 years old (125 women and 125 men in each of the fifth to the eighth decades). There was a participation of 93.6% among individuals invited and complete data assessment in 919 subjects. During the 5-year follow-up period between summer 1990 and summer 1995, 62 individuals died and 1 subject moved away and could not be traced. Follow-up rate was 99.9% with regard to clinical end points (n=918) and 96.5% for sonographic reassessment of survivors (n=826). All participants gave informed consent before enrollment in the study.
Scanning Protocol and Definition of Ultrasound End Points
The internal (bulbous and distal segments) and common (proximal
and distal segments) carotid arteries were scanned by ultrasound on
either side with a 10-MHz imaging probe and a 5-MHz Doppler
probe.14 Atherosclerotic lesions were identified by 2
ultrasound criteria: (1) wall surface (protrusion into the lumen or
roughness of the arterial boundary) and (2) wall texture
(echogenicity). The maximum radial diameter of plaques was assessed in
each of the 8 vessel segments, with the ultrasound beam directed
through the center of the vessel (for details see References 15 through
1915 16 17 18 19 ). Scanning was performed twice, namely in 1990 and 1995, by the same
experienced sonographer, who was blinded to the subjects' clinical and
laboratory characteristics. On the basis of the follow-up evaluation, 2
epidemiologically and etiologically different stages of atherogenesis
were differentiated: (1) early atherogenesis was defined by the
occurrence of new plaques in previously normal segments, and (2)
advanced atherogenesis was assumed whenever the relative increase in
the maximum plaque diameter between 1990 and 1995 exceeded the double
measurement error of the method (distal internal carotid artery, 35%;
bulbous, 30%; common carotid artery, 20%) and a narrowing of the
lumen (stenosis) >40% occurred. As detailed
elsewhere,18 19 the cutoff of 40% appeared to be a
biological threshold in our population, at which marked changes in the
growth kinetics of plaques, in the risk profiles, and in the vascular
remodeling process occurred.
Our ultrasound progression model (person-based approach) was developed and validated before the present study was carried out.18 19
Clinical Evaluation and End Points
All participants underwent a complete clinical examination, with
cardiological and neurological priorities described recently in
detail.14 Cardiovascular disease
(CVD) end points during follow-up were fatal and nonfatal
myocardial infarction according to the World Health Organization
criteria for definite disease status20 and
ischemic stroke and transient ischemic attack according
to the criteria of the National Survey of Stroke.21
Self-reported data were verified from hospital records, death
certificates, and information from general practitioners
and supplemented by a thorough screening of the regional hospital
database for diseases of interest.
Laboratory Measurements
At the 1990 baseline investigation, blood samples were taken
from the antecubital vein after subjects had fasted and abstained from
smoking for 
12 hours. Lp(a) was measured by a double-antibody ELISA
(Immuno) using a polyclonal anti-apo(a) for capture and a monovalent
anti-apo(a) Fab fragment coupled with peroxidase for detection. The
interassay coefficients of variation were 3.5%, 4.6%, and 6.3% for
Lp(a) concentrations of 5, 16, and 54 mg/dL, respectively.
Apo(a) phenotyping was performed by sodium dodecyl sulfate–agarose gel electrophoresis (SDS agarose)22 under reducing conditions, as previously outlined.23 Laboratory investigators were unaware of patient histories and outcomes.
As for most of the Lp(a) assays, we cannot rule out that the assay we used measured apo(a) isoform-dependently. To test whether this could have influenced our major findings, we repeated the same calculations as presented in the Results section simulating "corrected" Lp(a) levels. Because we used as a reference standard a plasma sample with the same apo(a) isoform as a recent study comparing an isoform-dependent with an isoform-independent assay,24 we were justified in correcting the Lp(a) level of each subject by dividing it by the ratio of these 2 assays (see Reference 2424 ) for each single apo(a) isoform group. In the case of subjects expressing 2 apo(a) isoforms, we first estimated the relation of the 2 isoforms in the SDS agarose electrophoresis and calculated the corresponding amount of Lp(a) for each isoform. These 2 concentrations were divided by the published ratios24 and then finally added again.
LDL cholesterol was calculated by the Friedewald formula, correcting for the contribution of Lp(a) cholesterol.25
Statistical Procedures
Strength and type of association between Lp(a) plasma
concentration/apo(a) phenotype and progression of
atherosclerosis were assessed by logistic regression
analysis. To assess distinct effects of Lp(a) on various stages
in atherogenesis, separate equations were fitted for subjects without
carotid atherosclerosis at the 1990 baseline (no
atherosclerosis versus incident
atherosclerosis during follow-up) and in those with
preexisting lesions (no change versus incidence of stenotic
atherosclerosis). Multivariate
regression models were built with a forward stepwise selection
procedure that allowed for all variables listed in Table 1
. On the basis of experiences
from previous cross-sectional analyses in this
cohort,25 Lp(a) concentrations were dichotomized [Lp(a)
32 versus >32 mg/dL] or treated as a continuous variable.
Likewise, apo(a) phenotypes were divided into 2 subgroups
a priori according to the molecular weight of the smaller apo(a)
isoforms. In analogy to all of our own and some other previous
work,26 27 28 29 the low-molecular-weight (LMW) group included
subjects with 1 apo(a) isoform with 11 to 22 kringle (K)-IV
repeats,23 and the high-molecular-weight (HMW) group
comprised all subjects who had only isoforms with >22 K-IV repeats. In
an attempt to confirm the appropriateness of these preselected
categorizations, separate analyses were fitted with 6 equally
sized categories of Lp(a) concentrations (range, 8 mg/dL each) or K-IV
repeats (steps, 3 repeats each) (scale fitting). Separate equations
that excluded subjects receiving aspirin, anticoagulation, or
antihypertensive or lipid-lowering therapy (in all, n=280) or adjusted
for lifestyle variables confirmed the results of the original
analysis (data not presented). Statistical interaction
between Lp(a) and other variables (eg, LDL cholesterol)
was assessed by comparing the relation between Lp(a) and
atherosclerosis progression at different levels of
exposure to the variable of interest. Finally, crude and adjusted
hazard ratios of incident CVD were calculated by Cox models. The
proportional hazard assumptions were satisfied.
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Results |
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The median Lp(a) level in this white population was 8.8 mg/dL (range, 0.1 to 143.2 mg/dL). Plasma concentrations were similar in men and women except for a slight divergence in the postmenopausal period. Lp(a) plasma concentration emerged as independent of all other vascular risk factors and lifestyle variables.25
Early Atherogenesis
Five hundred individuals were free of carotid
atherosclerosis at the 1990 baseline examination. A
quarter of these individuals (n=125) developed atherosclerotic lesions
during the 5-year follow-up period. These patients with incident
atherosclerosis (early atherogenesis) were older, more
often male, hypertensive, smokers, and heavy drinkers and had higher
ferritin and total and LDL cholesterol concentrations than
those who remained free of atherosclerosis (Table 1
).
Lp(a) plasma concentrations were higher in subjects who developed new
atherosclerotic lesions (Table 1). After adjustment for other
vascular risk factors and potential confounders, Lp(a) was
significantly associated with early atherogenesis in subjects with LDL
cholesterol concentrations above the median of 3.3
mmol/L (Table 2) but not in the
low-LDL-cholesterol group (P<0.05 for effect
modification). The risk of early atherogenesis in the
high-LDL-cholesterol group increased gradually with
increasing Lp(a) concentration (dose-response relation, Figure 1). In contrast, apo(a) phenotype
expressed as the absolute number of K-IV repeats did not show a
significant association with early atherogenesis, nor did predefined
categories of LMW and HMW apo(a) types. This finding applied to
subjects with LDL cholesterol concentrations 3.3
mmol/L and <3.3 mmol/L (Figure 1 and Table 2).
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Exclusion of patients with a neoplasm, renal failure, or manifest CVD
yielded results almost identical to those of the original
analysis. Use of Lp(a) levels corrected for a simulated apo(a)
isoform–dependent measurement of Lp(a) revealed nearly the same odds
ratios as described in Table 2.
Advanced Atherogenesis
Of 326 subjects with preexisting carotid artery disease at the
1990 baseline examination, 92 (28.2%) developed carotid
stenosis >40% (advanced atherogenesis) during follow-up.
These subjects were more often diabetic, smokers, and carriers of the
factor V Leiden mutation and had higher fibrinogen and lower
antithrombin III than those who remained free of advanced
atherosclerosis (Table 1). Lp(a) plasma
concentrations were significantly elevated in those with advanced
atherogenesis (Table 1), and LMW apo(a) phenotypes were
markedly overrepresented (50% versus 32.9%,
P<0.01; Table 3).
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Stepwise logistic regression analysis revealed a binary-type
association between advanced atherogenesis and high Lp(a) plasma
concentrations. Analogous results were obtained for LMW apo(a)
phenotypes (Figure 2). These
associations were not modified by LDL cholesterol levels.
When both Lp(a) concentration and apo(a) phenotype were
considered in a single regression equation, excess risk of
stenosis was confined to the LMW apo(a) phenotype and
was most pronounced in those with both LMW apo(a) phenotype and
high Lp(a) plasma concentrations (OR, 6.4; 95% CI, 2.8 to 14.9; Figure 3 and Table 4). The risk profile of advanced
atherogenesis further included diabetes, smoking, low antithrombin III,
high fibrinogen level, factor V mutation, alcohol consumption, and age.
Again, the above results remained virtually unchanged after subjects
with neoplasms, renal failure, and CVDs had been excluded. Using Lp(a)
levels corrected for a simulated apo(a) isoform–dependent measurement
resulted in only minor changes of the odds ratios without changing the
quintessence.
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Cardiovascular Disease
What has been described for advanced carotid
atherosclerosis applied equally to clinical CVD (n=64).
Lp(a) concentrations conferred an increased risk of fatal and nonfatal
CVD only in subjects with LMW apo(a) phenotypes. Within this
group, the risk for incident CVD increased further when Lp(a)
concentration exceeded the cutoff of 32 mg/dL (Table 4).
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Discussion |
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The present population study may well be the first to systematically and prospectively investigate the influence of Lp(a) plasma concentrations and apo(a) phenotypes on carotid atherosclerosis. The study design permits us to differentiate early from advanced (stenotic) stages of atherogenesis. Notably, the latter process did not rely on conventional risk factors but emerged as a domain of procoagulant risk attributes and most likely arises from plaque thrombosis.18 19 This 2-stage hypothesis is substantiated by pathoanatomic and epidemiological observations.18 19 30
Lp(a) plasma concentrations predicted the risk of early atherogenesis
in a dose-dependent fashion, with this association being confined to
subjects with LDL cholesterol levels 3.3 mmol/L
(median). Apo(a) phenotype, in contrast, distributes similarly
in subjects with and without early carotid
atherosclerosis. A cross-sectional evaluation of the
ARIC study yielded analogous results in that Lp(a) was significantly
elevated in subjects with high intima-media thickness, without any
differences observed in the apo(a) phenotype
distribution.31 Synergistic effects of different
lipoproteins [LDL and Lp(a)] have been observed previously in studies
aimed at investigating risk profiles of coronary artery
disease:Armstrong and colleagues32 reported that the
combination of high Lp(a) plasma concentrations and LDL
cholesterol levels above the group median amplified the
risk of coronary artery disease 6-fold. Therapeutic lowering of
LDL cholesterol by 10% was found to dilute the
predictive value of high Lp(a) for coronary artery
disease.33 Finally, a recent study revealed high Lp(a)
plasma concentrations to increase the risk of familial coronary
artery disease only if the total/HDL cholesterol ratio was
elevated.34 Apparently, the interaction of Lp(a) with
other lipoproteins triggers or enhances its atherosclerotic
properties.
In addition to the lipid pathway, several other mechanisms have been proposed by which Lp(a) may promote early atherosclerosis. High Lp(a) impairs activation of transforming growth factor-ß by downregulation of plasmin generation, thereby contributing to smooth muscle cell proliferation.35 These in vitro findings were confirmed in apo(a) transgenic mouse experiments36 and found an in vivo equivalent in markedly depressed serum concentration of active transforming growth factor-ß in advanced human atherosclerosis.37 Two recent studies demonstrated that Lp(a) induces chemotactic activity to human monocytes in a dose-dependent fashion.38 39 Lp(a) enhances the expression of intercellular adhesion molecule-1.40 Because Lp(a) accumulates in the subendothelial space of the vessel wall, it may act as a potent chemoattractant for monocytes in human atherosclerosis. Preliminary data suggest this property to be independent of apo(a) size.39
Previous cross-sectional reports on effects of Lp(a) on advanced stages
of atherosclerosis are sparse, and most of these did
not consider apo(a) phenotypes. In our study, the apo(a)
phenotype emerged as a particularly strong risk predictor of
incident carotid stenosis >40% (advanced atherogenesis).
Notably, excess risk of advanced atherogenesis was confined to LMW
apo(a) phenotypes, especially when associated with high Lp(a)
plasma concentrations (Figure 3). This finding is
consistent with the theory that plaque-induced thrombosis
probably reflects the main pathogenic mechanism of advanced
atherogenesis; consequently, attenuated fibrinolysis is
crucial in stabilizing atheroma-attached fibrin thrombi.
Hervio and colleagues11 12 observed that the apo(a) size
polymorphism influences the effect of Lp(a) on
fibrinolysis in that only LMW apo(a) isoforms showed
high-affinity binding to fibrin surfaces, thereby acting as a prominent
competitive antagonist to plasminogen. These in
vitro findings suggest that high concentrations of Lp(a) of LMW size
should have the most pronounced influence on
fibrinolysis, which is in close agreement with our
results.
Cross-sectional27 41 and prospective28 29 42 studies revealed strong associations between the apo(a) size polymorphism and CVD.29 A higher frequency of LMW apo(a) phenotypes was observed in men but not in women who experienced incident myocardial infarction or coronary death in the Stanford Five-City Project.28 Two further prospective studies found that LMW apo(a) phenotypes were significantly associated with CVD in men <60 years old29 and in hemodialysis patients.42 In analogy to advanced stenotic atherosclerosis, the risk for incident fatal and nonfatal CVD in our survey was markedly elevated in subjects with LMW apo(a) phenotypes combined with high Lp(a) concentrations.
Conclusions
In this exclusively white study cohort, Lp(a) appears to be
involved in both early and advanced stages of
atherosclerosis, although in distinct ways. On the one
hand, plasma concentration of Lp(a) dose-dependently predicted early
atherosclerosis in subjects with high LDL
cholesterol levels. This effect was independent of the
apo(a) size polymorphism. Conversely, apo(a) polymorphism
emerged as one of the strongest risk predictors of advanced
stenotic atherosclerosis. Only LMW apo(a)
phenotypes with high antifibrinolytic capacity appeared to be
involved in this clinically relevant stage of arterial
disease.
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Acknowledgments |
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This study was supported by grants from the Österreichischer Herzfonds and the Austrian Nationalbank (P-5553) to Dr Kronenberg and from the Austrian Fonds zur Förderung der wissenschaftlichen Forschung to Dr Utermann (P-11695-MED). Dr Kronenberg was supported by the APART program of the Austrian Academy of Science.
Received April 7, 1999; revision received June 1, 1999; accepted June 14, 1999.
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