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(Stroke. 1995;26:1582-1587.)
© 1995 American Heart Association, Inc.

Articles

Lipoprotein(a) and Asymptomatic Carotid Artery Disease

Evidence of a Prominent Role in the Evolution of Advanced Carotid Plaques: The Bruneck Study

Johann Willeit, MD; Stefan Kiechl, MD; Peter Santer, MD; Friedrich Oberhollenzer, MD; Georg Egger, MD; Elmar Jarosch, MD Agnes Mair, MD

From the Departments of Neurology (J.W., S.K.) and Laboratory Medicine (E.J.), University Clinic Innsbruck (Austria); and the Departments of Laboratory Medicine (P.S., A.M.) and Internal Medicine (F.O., G.E.), Hospital of Bruneck (Italy).

Correspondence to Johann Willeit, MD, Department of Neurology, University Clinic of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Elevated levels of lipoprotein(a) [Lp(a)] have been reported in association with symptomatic coronary and carotid artery disease. Relevancy of Lp(a) as a risk predictor of presymptomatic atherosclerosis in general populations is not well established.

Methods Serum Lp(a) distribution and its relation to sonographically assessed carotid atherosclerosis were examined in a random sample of 885 men and women aged 40 to 79 years (Bruneck Study).

Results Logistic regression analysis revealed a binary-type association between Lp(a) and carotid artery disease, with the threshold level of Lp(a) for an enhanced atherosclerosis risk defined at 32 mg/dL. The strength of relation increased with advancing severity of carotid atherosclerosis (odds ratios for Lp(a), 1.8 for nonstenotic and 4.7 for stenotic carotid artery disease; P<.001). Lp(a) was unaffected by environmental factors except for a significant decrease in women taking hormone replacement therapy (P<.05). In a multivariate approach, Lp(a) turned out to be an independently significant predictor of carotid atherosclerosis (P<.001). No differential effect of Lp(a) on atherosclerosis (effect modification) was observed for sex, age, low-density lipoprotein cholesterol, apolipoprotein A-I and B, fasting glucose, diabetes, or hypertension. However, the Lp(a)-atherosclerosis relation was significantly modified by fibrinogen (P<.01) and antithrombin III (P<.05).

Conclusions The present study demonstrates a strong and independent association between elevated Lp(a) levels and carotid atherosclerosis in a large randomized population and provides evidence of a potential role of Lp(a) in the evolution of carotid stenosis. Apart from atherogenicity of Lp(a) cholesterol, interference with fibrinolysis of atheroma-associated clots and fibrin deposits in the arterial wall may achieve pathophysiological significance.

Key Words: atherosclerosis • carotid arteries • epidemiology • lipoproteins • ultrasonics

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Serum concentrations of Lp(a) are determined by codominantly inherited apo(a) polymorphism(s) and are only marginally affected by environmental factors.^{1 2 3} Elevated levels of Lp(a) have been reported in association with symptomatic coronary heart disease and ischemic stroke.^{4 5 6 7 8 9 10} Apart from inference with fibrinolysis and promotion of thrombosis, acceleration of atherogenesis is a second proposed mechanism by which Lp(a) may impact cardiovascular disease.^{3 11 12 13} Epidemiological evidence of this pathophysiological pathway is mainly restricted to selected groups of patients.^{14 15 16 17 18 19 20 21 22 23} Clinical application of Lp(a) measurements as a marker of an inherited predisposition to severe atherosclerotic vascular disease, however, requires population-based data derived from healthy subjects from a general population. The investigation reported here was designed to examine the putative relation between Lp(a) and asymptomatic carotid atherosclerosis in a large randomized population with respect to age, sex, severity of atherosclerosis, and underlying pathomechanisms.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Study Population
Population recruitment and baseline examination were performed between July and November 1990. Design and selection of participants in the Bruneck Ischemic Heart Disease and Stroke Prevention Study have been described elsewhere.^{24 25} Briefly, 1000 men and women aged 40 to 79 years were randomly selected (250 subjects of each decade of age) from 4793 white inhabitants of the appropriate age range in the community of Bruneck (province of Bolzano, Italy). Of 936 subjects who agreed to participate, frozen serum samples for the assessment of Lp(a) concentrations were available for 906. To maintain an unselected, representative population, only men and women with incomplete data collection and/or a clinical history of transient ischemic attack and stroke were excluded, which left 885 subjects for analysis.

Clinical History and Examination
The study protocol included neurological and cardiological examinations.²⁴ A standardized questionnaire on current and past exposure to candidate cardiovascular risk factors, sociodemographic variables, previous disease, and use of medication was completed by each participant. Mean systolic blood pressure was calculated from two independent readings, each of which was taken with the subject in the supine position after 10 minutes of rest. Hypertension was defined as a systolic/diastolic blood pressure >160/95 mm Hg or current use of antihypertensive drugs. Diabetes was diagnosed according to the criteria of the World Health Organization (levels of fasting plasma glucose >7.8 mmol/L [140 mg/dL] and/or 2-hour glucose >11.1 mmol/L [200 mg/dL]).²⁶ Body mass index was determined as body weight (kilograms) divided by height squared (meters squared). Average daily number of cigarettes smoked and years of smoking were assessed. Quantities of alcoholic beverages ingested daily were classified in four categories: (1) no alcohol intake, (2) <50 g/d, (3) 51 to 99 g/d, and (4) >99 g/d ethanol. Coronary artery disease was coded as present if the subject had a documented clinical history of myocardial infarction, self-reported chest pain on effort confirmed as angina pectoris by a cardiologist, and/or ECG Minnesota codes 1.1 to 1.3, 4.1 to 4.3, and 5.1 to 5.3.²⁷

Laboratory Measurements
Blood samples were taken from the antecubital vein after subjects had fasted and abstained from smoking for at least 12 hours. The samples were separated and analyzed immediately or stored at -70°C. Total cholesterol, HDL cholesterol, and triglycerides were determined enzymatically using commercial test kits (CHOD-PAP and GOP-PAP methods, Merck). LDL cholesterol as calculated with the Friedewald equation²⁸ was corrected for the contribution of Lp(a) cholesterol [Lp(a)mass_*0.45].¹³ Fibrinogen was assayed according to the method of Clauss.²⁹ Other parameters were measured by standard laboratory procedures.

Determination of Lipoprotein(a)
Serum samples were kept frozen at -70°C for 3 years, and measurements of Lp(a) concentration were performed immediately after thawing with a double-antibody ELISA (Immuno AG). Lp(a) was captured by a polyclonal anti-apo(a) antibody (microtiter plates) and detected by the second monovalent anti-apo(a)-Fab-fragment coupled with peroxidase. Absorbance of the enzymatic reaction (chromogen, tetramethylbenzidine) was read bichromatically at 450 nm and 620 nm. The assay was calibrated to total Lp(a) mass with standard sera obtained from Immuno. The antibodies used in the assay identify all known isoforms of apo(a) and do not cross-react with plasminogen. The interassay coefficient of variation between 40 duplicate measurements was 3.5%, 4.6%, and 6.3% for Lp(a) levels of 5 mg/dL, 16 mg/dL, and 54 mg/dL, respectively.

Assessment of Carotid Artery Disease
Sonographic assessment of the carotid arteries was performed with a duplex ultrasound system (ATL UM8, Advanced Technology Laboratories) using a 10-MHz imaging probe and 5-MHz Doppler. Carotid stenoses were classified by Doppler criteria or, in the absence of hemodynamic disturbances, as the percentage of maximum diameter reduction in the B mode.³⁰ A systolic peak flow velocity of more than 1.3 m/s was regarded as indicative of stenosis exceeding 50%. Carotid atherosclerosis in the ICA and CCA was quantified by a sensitive and reproducible plaque scoring system, as detailed elsewhere.²⁴ Briefly, the score comprises the sum of 16 different measurements, each of which represents the maximum axial thickness of atherosclerotic lesions (in millimeters) at 16 well-defined imaging sites (near/far wall of right/left proximal CCA, 15 to 30 mm proximal to the carotid bulb; distal CCA, <15 mm proximal to the carotid bulb; proximal ICA, carotid bulb and the initial 10 mm of the ICA; and distal ICA, >10 mm above the flow divider).

Statistical Evaluation
The relation between Lp(a) and environmental factors was assessed by Pearson correlation coefficients (continuous variables) and ANOVA (categorical variables) and was confirmed by corresponding nonparametric tests. Log_e transformation of Lp(a) [Lp(a)+0.1 in subjects with null alleles, n=8] and other skewed variables was performed to improve approximation to an assumed gaussian distribution. The putative relation between Lp(a) concentrations and carotid atherosclerosis was analyzed by means of unconditional logistic regression analysis, taking into account different stages of atherosclerotic disease. In an attempt to obtain the most suitable parametric scale in the logit, Lp(a) concentrations were categorized in strata of 5% each (n=44±2). Risk estimates of carotid atherosclerosis were calculated for these categories using the lowest quintile (<5.5 mg/dL; n=222) as a reference interval (OR, 1.0). Similar scale fitting was carried out for other risk variables (categorization into quintiles) once the Box-Tidwell approach yielded evidence of nonlinearity in the logit.³¹ The goodness of fit of each model was assessed by the test of Hosmer and Lemeshow.³² Statistical interaction between Lp(a) and significant risk factors was assessed by comparing the relation between Lp(a) and atherosclerosis at different levels of exposure to the variable of interest. The test procedure was accomplished by maximum-likelihood estimation.³² Given the rare occurrence of stenosis (5.3%, n=47), ORs derived from the logistic regression analysis approximated relative risk estimates.³²

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our white population sample exhibited a highly skewed Lp(a) distribution, with a median of 8.8 mg/dL pooled for sexes (range, 0 to 143.2). Serum concentrations were similar in men and women except for a slight divergence in the postmenopausal period (P>.05). The proportion of individuals who lack Lp(a) in serum samples, corresponding to homozygosity of a putative apo(a) null allele, was low at 0.9%. Lp(a) levels by carotid artery disease status are displayed in Fig 1. Sonographic evaluation of the carotid arteries revealed atherosclerotic lesions in 47.6% of men and 36.2% of women. Table 1 depicts a correlation matrix calculated for Lp(a) and selected environmental factors. Cardiovascular risk attributes emerged independent of Lp(a), except for LDL cholesterol (Table 1). When LDL cholesterol was adjusted for the proportion attributable to Lp(a), the association disappeared in men (r=.01) and was substantially lowered in women (r=.10), which underscores the metabolic independence of both lipoproteins.^{1 3 4 33} With regard to behavioral risk conditions, we noted a weak increasing trend of Lp(a) levels across categories of alcohol consumption (P=.14). Lp(a) appeared to be unaffected by other lifestyle variables, including cigarette smoking, physical activity, and social status. Thirty-five women taking hormone therapy (estrogen/gestagen) had a median Lp(a) of 7.8 mg/dL compared with 10.2 mg/dL in the remaining female population (P<.05, ANCOVA with covariate age). Of other drug therapies common in the survey area, only the use of thrombocyte aggregation inhibitors indicated elevated Lp(a) concentrations (median, 15.5 mg/dL; P<.05). The association reflected the introduction of therapy in subjects with clinically overt cardiovascular disease and subsequent higher Lp(a) levels rather than direct drug effects. Finally, the present study failed to find excess Lp(a) in subjects with impaired thyroid function and had insufficient power to lead to a conclusion for renal failure. All above-mentioned environmental factors in concert accounted for less than 3% of Lp(a) variability.

View larger version (16K): [in this window] [in a new window]   Figure 1. Graph shows cumulative frequency distributions of Lp(a) in subjects with asymptomatic carotid stenosis (dashed line) and a population free of carotid artery disease (solid line).

View this table: [in this window] [in a new window]   Table 1. Mean Values of Potential Cardiovascular Risk Factors and Correlation with Lipoprotein(a)

Logistic regression analysis revealed a significant (P<.001) binary-type association between Lp(a) and carotid artery disease with the threshold level of Lp(a) defined at 32 mg/dL, corresponding to the 85th percentile of its distribution (Fig 2). Regarding carotid stenosis, the OR associated with elevated Lp(a) was 4.7 (95% confidence interval, 2.2 to 9.9), which markedly exceeded those obtained for nonstenotic atherosclerosis of various severity (OR, 1.7 to 2.1; P<.05; for difference, see Fig 3). Assuming causality for the relation between Lp(a) and atherosclerosis, the percentage of carotid stenosis in the general population attributable to Lp(a) can be estimated at 24%. Given its genetic determination, Lp(a) concentration reflected an inherited predisposition for the occurrence of severe atherosclerosis far beyond the information afforded by the clinical history of parental stroke. Separate analyses for sex showed a tendency of ORs for Lp(a) to be greater in the female population. Gender-specific differences, however, were within the range of random variability (P=.18 for effect modification). As expected in view of the lack of correlation between Lp(a) and most exogenous factors, a multivariate model adjusting for age, sex, systolic blood pressure (or hypertension), fibrinogen, HDL cholesterol, adjusted LDL cholesterol, smoking, alcohol consumption, and fasting glucose (or diabetes) yielded risk estimates for Lp(a) similar to those of the univariate approach (Table 2). Substitution of apoA-I and apoB for HDL and LDL cholesterol did not affect the predictive significance of Lp(a). In accordance with previous studies, high Lp(a) levels were more prevalent in subjects suffering from coronary (n=172) and peripheral artery (n=32) disease.^{3 14 34} To rule out the possibility that overrepresentation of these clinical settings among subjects with carotid atherosclerosis had introduced a bias in the Lp(a)-atherosclerosis relation, separate logistic regression models were fitted in subsamples free of cardiovascular disease. Slight deviations in risk estimates for Lp(a) were insufficient to assume relevant confounding (Table 2). Exclusion of patients with advanced renal failure (n=1); subjects taking drug therapy including lipid-lowering agents (n=2), thyroid hormone (n=27), and estrogen medication (n=35); and subjects with triglyceride levels beyond 3.4 mmol/L (300 mg/dL, n=38) had no effect on any conclusion based on the analysis in the entire population sample. Adjustment for hypertriglyceridemia was performed because antigenic determinants of apo(a) in triglyceride-rich Lp(a) particles may be partially masked and Lp(a) levels biased toward lower values.³⁵

View larger version (34K): [in this window] [in a new window]   Figure 2. Bar graphs of odds ratios of Lp(a) categories (5% strata, n=44±2) for carotid stenosis (top) and nonstenotic atherosclerosis (bottom) (reference group, Lp(a) <5.5 mg/dL, n=222). Graphs show a binary-type association with the threshold level defined at 32 mg/dL.

View larger version (17K): [in this window] [in a new window]   Figure 3. Bar graph of odds ratios from logistic regression analysis relating Lp(a) to different manifestations of carotid artery disease. Nonstenotic atherosclerosis (n=325) was divided into three categories corresponding to the tertiles of our atherosclerosis score (B mode): mild atherosclerosis, score <1.75 mm; moderate atherosclerosis, 1.75 mm<score<3.94 mm; and severe atherosclerosis, score >3.94 mm. Stenosis was detectable in 47 subjects.

View this table: [in this window] [in a new window]   Table 2. Multiple Logistic Regression Analysis of Carotid Atherosclerosis on Lipoprotein(a) in a Randomized Population: The Bruneck Study

The present analysis obtained a significant synergistic effect of fibrinogen and Lp(a) on the occurrence of carotid atherosclerosis across low-to-medium fibrinogen concentrations. Beyond a fibrinogen level of 3.05 g/L (80th percentile), however, the predictive significance of Lp(a) again decreased, thereby creating a bell-shaped type of interaction (maximum-likelihood estimate, 22.2; P<.01; Fig 4). An increase in antithrombin III was paralleled by a decline in the predictive significance of Lp(a) for carotid atherosclerosis. The trend was significant at a probability level of .02. Apart from these determinants of thrombosis, no meaningful interaction was assessed for other vascular risk attributes (LDL cholesterol, apoA-I and apoB, HDL cholesterol, fasting glucose, fibrinogen, antithrombin III, diabetes mellitus, and hypertension) or any possible combination (higher order interaction).

View larger version (29K): [in this window] [in a new window]   Figure 4. Bar graphs of odds ratios of Lp(a) for carotid stenosis (left) and nonstenotic carotid atherosclerosis (right). Graphs show significant effect modification by fibrinogen quintiles (P<.005).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present analysis is consistent with most previous studies in obtaining a strong relation between elevated Lp(a) levels and risk of atherosclerotic vascular disease, and it is unique in extending these findings to a general, healthy population and asymptomatic carotid stenosis. Past reports have focused on patients with symptomatic cardiovascular disease,^{4 5 6 7 8 9 10 14 15 16 17} hypercholesterolemia,^{20 21 22} end-stage renal disease,²³ or the top decile of the intima-media thickness distribution in a randomized population (matched pairs¹⁸ ). In our study, Lp(a) emerged as the strongest predictor of carotid stenosis (OR, 4.7) among a variety of putative vascular risk factors and showed a moderate relation to nonstenotic atherosclerosis (OR, 1.8) as well. Elevated risk was confined to the upper end of the Lp(a) distribution (>32 mg/dL), which confirms and amplifies previous reports on symptomatic stenosis and clinical end points of atherosclerotic disease.^{4 14 15} The relation was internally consistent for sex and the age range from 40 to 79 years and could not be explained by lifestyle, drug therapy, postmenopausal hormone replacement, or coincidental coronary and peripheral artery disease. A number of mechanism(s) have been proposed by which elevated Lp(a) may promote atherogenesis.

Dysbalance of Thrombosis and Fibrinolysis
Apo(a) shows a high-sequence homology with plasminogen, from which it may have arisen by mutation.³⁶ Whereas the affinity to plasminogen receptor approaches that of the primary ligand, the protease domain has acquired resistance against cleavage by tissue plasminogen activator, thereby losing any plasminlike activity.^{11 12} In vitro, Lp(a) competes in a dose-dependent manner with plasminogen for binding to fibrin clots and endothelial receptors, thus attenuating clot lysis.^{36 37 38 39 40 41 42 43} Stabilization and subsequent incorporation of atheroma-associated clots and fibrin deposits in the arterial wall, however, are important mechanisms in the development and progression of advanced atherosclerotic plaques (stenosis).^{12 44 45} The present study provides indirect support for the hypothesis that Lp(a)-induced promotion of thrombosis occurs clinically: (1) Lp(a) preferentially relates to stenotic carotid artery disease more than to severe nonstenotic atherosclerosis (Fig 3). (2) The strength of the association between Lp(a) and atherosclerosis was significantly modified by major determinants of thrombosis. It was most pronounced in the event of low concentrations of antithrombin III (inhibitor of thrombosis) and medium levels of fibrinogen. One previous study had investigated differential effects of Lp(a) by serum fibrinogen and yielded evidence for a marginally significant effect modification (P=.052).¹⁸ (3) Emergence of a threshold relation between Lp(a) and atherosclerosis corresponds well to the recent experimental observation that interference of Lp(a) with fibrinolysis is restricted to apo(a) phenotypes with low molecular weight [high Lp(a) concentration].⁴⁵

Contribution of Lipoprotein(a) to the Atherogenic Cholesterol Pool
When risk estimates calculated for adjusted LDL cholesterol were applied to Lp(a)-associated cholesterol, less than 10% of the relation between Lp(a) and atherosclerosis was explained by a lipid pathway. In comparison with LDL, however, Lp(a) lacks antioxidants (beta carotene) and exhibits a high affinity to glucosamine and fibrin(ogen), which prolongs the residence time in the arterial subintima.^{46 47} Both properties of Lp(a) may facilitate its oxidative modification and promote the formation of foam cells and fatty streaks. Thus, the above calculations possibly underestimate the significance of a lipid pathway in mediating Lp(a) effects. Armstrong and coworkers¹⁴ reported a synergistic effect of elevated Lp(a) and LDL cholesterol on myocardial infarction. This finding could not be replicated in our study on asymptomatic carotid atherosclerosis or in a previous survey on advanced intima-media thickness.¹⁸

Selected Methodological Issues
Most previous studies agree on the stability of Lp(a) when it is stored at -70°C for up to 6.5 years.^{3 48 49} A recent report revealed a slight but significant decrease in mean Lp(a) concentrations (-7%), which was attributed to the freezing and thawing procedure.⁵⁰ In the present study, uniform duration of storage and a single thawing in all serum samples prevented any differential effect of storage on Lp(a) levels and risk analysis.

Lp(a) differs from other vascular risk factors in its consistency over a broad age range and insusceptibility to most environmental influences.^{3 33 51} Intraindividual and temporal fluctuation are generally considered low.⁵² In our survey, Lp(a) levels were consistent from age 40 to 79 years. Thus, point estimates of Lp(a) in the present study may be used as a surrogate measure for levels in early life before the occurrence of atherosclerotic lesions, and analysis may provide risk calculations for Lp(a) akin to those of a prospectively designed study.

Controversies surround the question of whether apo(a) phenotyping predicts atherosclerosis better than Lp(a) concentrations.^{23 53} A previous study comparatively assessed the relation between both parameters and carotid atherosclerosis; apo(a) polymorphism(s) were marginally related to advanced intima-media thickness (P=.07) and could not substitute for absolute Lp(a) concentrations in the risk prediction of atherosclerosis.⁵³ Similar results were recently obtained in stenotic coronary artery disease.⁵⁴ In the present study, we gave preference to absolute levels of Lp(a) for two main reasons: (1) a commercial and convenient assay as available for Lp(a) concentration is mandatory for any clinical application, and (2) statistical computation of risk estimates associated with Lp(a) polymorphism(s) is complicated by the emerging variety of different phenotypes.⁵³

Clinical Implication
Assessment of Lp(a) permits identification of subjects at high risk (genetic predisposition) for complicated (stenotic) carotid atherosclerosis early in life when preventive measures are most efficient. Close sonographic follow-up, modification of behavioral risk conditions such as cigarette smoking and severe alcohol consumption,⁵⁵ and early drug control of the residual risk profile may improve the management and outcome of these patients. The significance of a therapeutic lowering of elevated Lp(a)^{56 57 58} and its position among other preventive strategies remain to be defined. The present study may assist in establishing a physiologically normal range for Lp(a) and provides a basis for the clinical application of Lp(a) as a risk indicator of (advanced) atherosclerosis in healthy subjects from a general population.

	Selected Abbreviations and Acronyms

 

apo = apolipoprotein CCA = common carotid artery HDL = high-density lipoprotein ICA = internal carotid artery LDL = low-density lipoprotein Lp(a) = lipoprotein(a) OR = odds ratio

	Acknowledgments

 
This study was supported by grants from the Pustertaler Verein zur Prävention der Herz- und Hirngefäßerkrankungen, the Sanitätseinheit Ost, and the Assessorat für Gesundheit, Province of Bolzano, Italy.

Received January 20, 1995; revision received May 16, 1995; accepted June 12, 1995.

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