© 1999 American Heart Association, Inc.
Original Contributions |
Effect of Lp(a) on the Early Functional and Structural Changes of Atherosclerosis
From the Department of Cardiology (O.T.R., M.R.A., D.S.C.), Royal Prince Alfred Hospital, and The Heart Research Institute (M.R.A., D.S.C.), Sydney, Australia; and the Department of Clinical Physiology (O.T.R.), University Turku, Finland.
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Abstract |
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Abstract—Epidemiologic studies have shown a significant relationship between elevated plasma levels of Lp(a) and increased risk of cardiovascular events; however, the mechanisms by which elevated Lp(a) levels produce this increased risk are not known. To test the hypothesis that high Lp(a) levels might contribute to the development of subclinical atherosclerosis, we examined the influence of Lp(a) levels on early functional and structural atherosclerotic vascular changes. Flow-mediated (endothelium-dependent) and nitrate-mediated (smooth muscle–dependent) arterial dilations were measured by high-resolution ultrasound in 241 normal healthy subjects (aged 15 to 69 years; 116 men). In addition, carotid artery intima-media thickness was measured by ultrasound in 71 subjects. Plasma Lp(a) was measured using a 2-sided immunoradiometric assay (cohort median, 10 mg/dL; interquartile range, 3.9 to 24.4 mg/dL). In these subjects, there were no significant relationships between Lp(a) and arterial endothelial function, smooth muscle responses, or carotid wall thickness (P>0.25). By contrast, other lipid risk factors, such as LDL-cholesterol and LDL-cholesterol/HDL-cholesterol ratio, were significantly correlated with abnormal arterial function and structure (P
0.01). These data suggest that
elevated Lp(a) levels do not confer cardiovascular risk
by contributing to the early functional or structural changes of
atherosclerosis.
Key Words: endothelium • preclinical atherosclerosis • ultrasound • carotid artery
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Introduction |
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Lp(a) was first described by Berg in 1963.1 It differs from LDL by the presence of a glycosylated protein of variable mass, termed apolipoprotein(a), which is linked by a covalent bond to apoB100 and has approximately 80% structural homology with plasminogen, a key protein of the coagulation cascade.2 Most3 4 5 6 7 but not all previous studies8 9 10 have shown that elevated Lp(a) is an independent risk factor for coronary heart disease. The exact mechanism by which Lp(a) confers cardiovascular risk is unknown; however, both proatherogenic and prothrombogenic effects have been hypothesized.2 11 12 13
The early stages of atherosclerosis are associated with changes in arterial function and structure that can now be studied noninvasively using high-resolution ultrasound. A key early event in atherosclerosis is endothelial dysfunction,14 15 which can be detected in systemic conduit arteries by measuring flow-mediated dilation.16 Subtle structural changes, such as thickening of the arterial intima-media complex, also occur early in the atherosclerotic disease process.17 18 Many conventional risk factors, such as smoking, hypercholesterolemia, hypertension, and diabetes, have recently been shown to be significantly associated with impaired arterial endothelial function19 and with increased arterial wall thickness,20 21 22 consistent with their accepted role in atherogenesis. Much less is known, however, about the effects of Lp(a) on these early markers of arterial disease in healthy asymptomatic subjects. The purpose of the present study was therefore to examine the effects of plasma Lp(a) levels on early functional and structural atherosclerotic vascular changes in a cohort of normal healthy subjects.
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Methods |
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Subjects
We studied 241 healthy subjects aged 40±15 years, (range, 15 to 69 years; 116 men, 125 women). None of these subjects had any history or clinical signs of coronary atherosclerosis, diabetes mellitus, familial hypercholesterolemia, or homozygous homocystinuria. All subjects were white. The subjects were recruited from hospital staff and volunteers from the community. None of the subjects was taking any regular cardioactive medications. There were 190 nonsmokers (79%), 40 current smokers (17%) and 11 ex-smokers (4%). Lifetime smoking dose was categorized on basis of self-reported lifetime total pack-years smoked: nonsmokers (0 pack-years), very light (0 to 4 pack-years), light (5 to 9 pack-years), moderate (10 to 19 pack-years), and heavy (
20 pack-years). There were 82 postmenopausal
women and 59 of them (47% of all women) were taking
hormone-replacement therapy: 41 were taking a combination of estrogen
and progestin and 18 were on estrogen only (after hysterectomy). All
studies were approved by the local committees on ethical practice, and
all subjects gave informed consent.
Lipoprotein Measurements
Fasting serum levels of Lp(a) were determined using commercially
available solid-phase 2-site immunoradiometric assay kits (Mercodia
Apo(a) RIA, Mercodia AB), which measures the apolipoprotein(a)
molecule. Fasting serum total cholesterol and
triglyceride concentrations were measured using standard
enzymatic methods (Boehringer Mannheim GmbH) with a fully
automated analyzer (Hitachi 704 or 747; Hitachi Ltd). HDL
cholesterol (HDL-C) was measured after precipitation with
phosphotungstate-magnesium. The LDL-C concentration was calculated
using the Friedewald formula.23
Ultrasound Studies
Ultrasound study to examine brachial artery flow–mediated
dilation was performed in all subjects, and carotid artery ultrasound
was performed for measurement of mean common carotid artery
intima-media thickness (IMT) in 71 participants (age, 42±13 years;
range, 29 to 69 years), including 62 nonsmokers, 1 current smoker, and
8 ex-smokers. All studies were performed using an Acuson 128XP/10
mainframe (Acuson) with a 7.0-MHz linear array transducer.
Arterial Physiology Testing
The ultrasound method for measuring
endothelium-dependent and smooth muscle–dependent
arterial dilation has been described
previously.16 24 In brief, brachial artery diameter was
measured from B-mode ultrasound images. In all studies, scans were
obtained at rest, during reactive hyperemia, again at rest, and
after sublingual nitrate. The subjects lay quietly for 10 minutes
before the first scan. The brachial artery was scanned in longitudinal
section 2 to 15 cm above the elbow. Depth and gain settings were set to
optimize images of the lumen–arterial wall interface,
images were magnified using a resolution box function, and machine
operating parameters were not changed during any study.
When a satisfactory transducer position was found, the skin was marked
and the arm remained in the same position throughout the study. A
resting scan was recorded, and arterial flow velocity
was measured using a Doppler signal.16 24 Increased
flow was then induced by inflation of a pneumatic tourniquet placed
around the forearm (distal to the scanned part of the artery) to a
pressure of 250 mm Hg for 4.5 minutes, followed by release. A
second scan was taken continuously for 30 seconds before and 90 seconds
after cuff deflation, including a repeat flow velocity
recording for the first 15 seconds after the cuff was released.
Thereafter, 10 to 15 minutes was allowed for vessel recovery, after
which a further resting scan was taken. Sublingual
nitroglycerin in standard antianginal doses (glyceryl
trinitrate spray 400 µg or isosorbide dinitrate spray 2.5 mg) was
then administered, and 3 to 4 minutes later the last scan was
acquired.
Vessel diameter was measured in every case by independent observers who were blinded to the subject's clinical details and stage of the experiment. The arterial diameter was measured at a fixed distance from an anatomic marker (such as a fascial plane or a vein seen in cross-section) using ultrasonic calipers. Measurements were taken from the anterior to the posterior `m' line at end diastole, incident with the R wave on a continuously recorded ECG. The `m' line represents the edge of the intima-media interface in the ultrasound image of the arterial wall. For the reactive hyperemia scan, diameter measurements were taken 45 to 60 seconds after cuff deflation. Four cardiac cycles were analyzed for each scan, and the measurements for each observer were averaged. The vessel diameter in scans after reactive hyperemia and nitroglycerin administration was expressed as the percentage relative to the average diameter of the artery in the 2 resting (control) scans (100%). Volume flow at baseline and after cuff deflation were calculated from measurements of arterial flow velocity, heart rate, and vessel diameter, as previously described.16 This method has been previously shown to be accurate and reproducible for measurement of small changes in arterial diameter,25 with low interobserver error for measurement of flow-mediated and nitrate-induced arterial dilation.16 25
Carotid Artery Studies
All scans were performed by operators following a predetermined,
standardized scanning protocol for the right and left carotid arteries,
as described by Salonen and Salonen26 and Blankenhorn et
al,27 using images of the far wall of the distal 10
mm of the common carotid arteries. Three scanning angles were used in
each case; anterior oblique, lateral, and posterior oblique. The image
was focused on the posterior (far) wall, and images were recorded
from the angle showing the greatest distance between the lumen-intima
interface and the media-adventitia interface, as described
previously.26 All scans were recorded on super-VHS
videotape for subsequent off-line analysis. Images were
digitized using a video frame-grabber interfaced with a personal
computer and analyzed with custom-made analysis
software. Two end-diastolic frames were selected,
digitized, and analyzed for mean IMT, and the average reading
from these 2 frames was calculated, for both right and left carotid
arteries. We have previously reported good intraobserver and
interobserver repeatability values, and within subject reproducibility,
using this method.28 The interobserver error for mean IMT
was 0.035±0.03 mm (range, 0 to 1.17 mm; coefficient of
variation [CV], 2.5%), and the intrasubject variability was
0.07±0.07 (range, 0 to 0.26 mm; CV, 6%).
Statistical Analysis
Descriptive data are expressed as mean±SD, unless otherwise
stated. Comparisons between groups were performed with independent
samples t tests, nonparametric Mann- Whitney U
tests, or 
2 tests, as appropriate.
Associations were examined by calculating univariate
Spearman's correlation coefficients. Because IMT measurements
correlated linearly with age in this data set, partial correlation
coefficients were also calculated between the measured variables
and age-adjusted IMT. Multivariate linear regression
models were used to study the independent determinants of
arterial function and structure. The values for vascular
parameters were normally distributed. However, because the
distributions for Lp(a) and triglycerides were skewed,
their values were log10-transformed before
regression analyses. Statistical significance was inferred at a
P value 0.05. All statistical analyses were
performed by using the Statistical Analysis
System.29
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Results |
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The study characteristics of the 241 healthy subjects are summarized in Table 1
. As expected, the
distribution of Lp(a) values was skewed toward lower values. The median
Lp(a) value was 10 mg/dL (interquartile range, 3.9 to 24.4 mg/dL,
range, 1 to 125.4 mg/dL). Lp(a) correlated significantly with LDL-C
concentration (r=0.19, P=0.003), but not with the
other measured lipids, subject age (r=0.09,
P=0.18), sex (r=-0.06, P=0.39), or
smoking status (r=-0.11, P=0.10).
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Lp(a) and Arterial Function
The univariate associations between lipid
variables, age, smoking status, and vascular reactivity data are
shown in Table 2. Lp(a) concentration
showed no significant association with flow-mediated dilation (Figure 1) or nitrate-mediated dilation in the
entire cohort, or in either sex (data not shown). Both flow-mediated
and nitrate-mediated dilation were significantly and inversely related
to LDL-C, LDL-C/HDL-C ratio, and triglycerides and directly
to HDL-C concentration. In a multivariate regression
model, the independent determinants of flow-mediated dilation included
LDL-C/HDL-C ratio (P=0.017), smoking (P=0.015),
and vessel size (P<0.001) (Table 3). Independent determinants of
nitrate-mediated dilation included LDL-C/HDL-C ratio
(P<0.001), sex (P<0.001), and vessel size
(P<0.001).
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To examine the influence of extremely high Lp(a) levels on vascular
reactivity, we compared subjects in the highest Lp(a) quintile
(Lp(a)30 mg/dL, n=47) with those in the lowest (Lp(a)3 mg/dL,
n=46). The level of 30 mg/dL represents the atherogenic
threshold of plasma Lp(a) levels in most studies.4 5 6 7
Subjects with high Lp(a) levels had higher LDL-C concentrations
(P=0.012), but otherwise the 2 groups had similar
characteristics and showed no differences in the values for either
flow-mediated or nitrate-mediated dilation (P>0.7).
Lp(a) and Arterial Structure
The associations between IMT and the measured risk variables
are also shown in Table 2
. Lp(a) concentrations showed no
significant association with IMT in either group (Figure 2). IMT was significantly correlated with
total cholesterol, LDL-C, LDL-C/HDL-C ratio, age, and
triglycerides. Adjustment for age did not change the
overall correlations or significances. For example, the partial
correlation adjusted for age between Lp(a) and IMT remained
nonsignificant (r=0.00, P=0.99). Furthermore,
when the correlation analyses were stratified by age (using the
median value of 37 years as the cut-point), the overall correlations
and significances for IMT remained essentially the same as those shown
in Table 2. In a multivariate regression model,
IMT correlated significantly and directly with age
(P<0.001) and LDL-C/HDL-C ratio (P=0.03).
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Discussion |
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Lp(a) levels in the highest population quintile (greater than
30 mg/dL) appear to be associated with approximately 2 to 3 times
higher relative risk for cardiovascular events,
compared with levels <30 mg/dL. This finding has been observed in men
and women, and in several different regions of the
world.30 Nevertheless, the mechanism of risk conferred by
Lp(a), and its interaction with other traditional atherogenic factors,
remains obscure. In this relatively large study of arterial
function and structure, we have shown that elevated Lp(a) has no
significant association with endothelial dysfunction,
impaired smooth muscle responses, or arterial wall
thickening. By contrast, in the same population, other lipid risk
factors such as elevated LDL-C or LDL-C/HDL-C ratio were significantly
associated with preclinical evidence of arterial damage in
accordance with previous studies.19 20 21 28 The best single
correlate for early functional and structural atherosclerotic changes
in this study was the LDL-C/HDL-C ratio, which has previously been
found to be superior to measurement of serum LDL-C alone, as a
predictor of coronary heart disease risk in epidemiologic
studies.31 Significant associations between risk factors
and impaired nitrate-mediated vasodilation observed here suggest that
early changes in the vessel wall during atherogenesis may not be
limited to the endothelium, and that the reduction in
vasodilation to exogenous sources of nitric oxide may be partly
mediated by changes in vascular smooth muscle
responsiveness.32 Previous results regarding the relationship between Lp(a) and early functional and structural changes of atherosclerosis have been inconsistent. In smaller studies, elevated Lp(a) concentration has been shown to be related to peripheral endothelial dysfunction in children with familial hypercholesterolemia who have markedly elevated LDL-C levels, but not in normocholesterolemic control children,33 healthy adolescents,34 or normal young adults.35 In patients with angiographically normal or minimally diseased coronary arteries, elevated plasma Lp(a) levels have been linked to impaired coronary vasomotion induced by acetylcholine infusion36 37 ; however, coronary vasodilatory response to dipyridamole has not been significantly related to plasma Lp(a) levels in healthy young subjects.38 The results concerning the relationship between high Lp(a) levels and early arterial structural changes are also inconsistent. Elevated serum Lp(a) concentrations have been associated with subclinical carotid atherosclerosis in patients with non–insulin-dependent diabetes mellitus in some studies,39 but not all.40 Furthermore, high Lp(a) has been shown to be a risk factor for increased IMT in patients with severe hypercholesterolemia, but not in normocholesterolemic subjects.41 Lavrencic et al42 found no association between IMT and Lp(a) concentration in a pooled cohort of young patients with familial hypercholesterolemia and controls. By contrast, the large data set from the Atherosclerosis Risk in Communities study has shown that Lp(a) concentration is weakly but significantly correlated with increased IMT values, both in white and African American men and women.43
Mechanisms
Owing to its structural homology with LDL and
plasminogen, Lp(a) has both atherogenic and thrombogenic
potential.44 It is not yet known, however, whether Lp(a)
has a role in the early phases (initiation, development) or late phases
(thrombosis) of occlusive arterial disease, or whether the
associated cardiovascular risk is mediated by some
other mechanism. Several mechanisms have been proposed to explain the
association between Lp(a) and atherosclerosis. In
vitro, Lp(a) migrates to the vessel wall45 binds to
macrophages,12 may be internalized in these cells
after oxidative modification,12 46 and subsequently may be
found in atherosclerotic plaques.11 Lp(a) has also been
shown to promote the proliferation of smooth muscle
cells47 and to enhance the expression of intracellular
adhesion molecule-1 in cultured human umbilical vein
endothelial cells.48 There are fewer in
vivo studies of the potentially proatherogenic effects of Lp(a),
however, and our current data support the suggestion that elevated
Lp(a) levels might confer risk by potential effects on
thrombogenesis,13 49 rather than by promoting early
atherogenic events.
Methodology
Recently, developments in ultrasound have provided methods for the
noninvasive study of the functional and structural changes that occur
in arteries in early atherosclerosis in vivo, and
therefore offer an opportunity to assess the relative importance of
different vascular risk factors in the preclinical stages of
atherosclerosis. In this study, we have used a recently
described and validated test of arterial
endothelial function that reflects mainly the
endothelium-dependent release of nitric oxide in
response to a physical stimulus (shear stress).50 51
Previous in vitro and in vivo data have implicated arterial endothelial dysfunction as a key early event in atherosclerosis,14 15 preceding plaque formation and clinical events. Our current observations about Lp(a) therefore suggest that this factor does not influence endothelial function in otherwise healthy subjects. Endothelial function tested by the currently described method in the brachial artery correlates well with coronary endothelial function52 and with the angiographically determined extent of coronary atherosclerosis.53 Endothelium-independent, smooth-muscle–dependent dilation was studied by measuring the arterial dilator response to sublingual nitrates, which produce vasorelaxation by the cGMP pathway. Early structural changes were studied by measuring the IMT of the common carotid artery. This measurement also correlates significantly with traditional vascular risk factors20 21 22 and the severity and extent of coronary, carotid, and femoral atherosclerotic plaques,28 54 and also predicts the likelihood of future cardiovascular events in at-risk population groups.22 26 Both these surrogate measures of early atherosclerosis may be measured accurately and reproducibly in human subjects.25 28 55
Limitations
The present study examined the relationships between Lp(a) and
arterial reactivity and early
atherosclerosis cross-sectionally. A more ideal
approach would be prospective study of subjects before and after
therapeutic interventions aimed at altering serum Lp(a) levels. Because
Lp(a) levels are mainly determined genetically56 and there
is no effective means to reduce Lp(a) levels without
simultaneously affecting the levels of other
lipoproteins,57 58 59 60 such an interventional study would be
difficult to perform. We have studied only those volunteers approached
and willing to consent to studies on the effects of risk factors on
arterial physiology, and therefore some selection bias may
be present. Nevertheless, the asymptomatic subjects
studied noninvasively presented with a wide range of ages,
cholesterol and blood pressure levels, and smoking
histories, which include the average population values. The number of
subjects with data on arterial structure was limited, and
this subgroup included very few smokers. Nevertheless, significant
associations were present in this group between IMT and lipid risk
factors other than Lp(a).
Conclusions
In summary, we did not find any influence of Lp(a) levels on
either the functional or structural vascular changes associated with
early stages of atherosclerosis in
asymptomatic subjects. These data suggest that elevated
Lp(a) levels do not confer cardiovascular risk by
promoting early atherogenesis in vivo.
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Acknowledgments |
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This study was financially supported by the Academy of Finland (O.T.R.) and by the Medical Foundation of Sydney University, Australia (D.S.C.).
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Footnotes |
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Address correspondence to Olli T. Raitakari, PhD, MD, Department of Cardiology, Royal Prince Alfred Hospital, Missenden Rd, Camperdown 2050, Sydney, Australia.
Received July 17, 1998; accepted September 29, 1998.
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