(Circulation. 1997;96:1390-1397.)
© 1997 American Heart Association, Inc.
Articles |
Predictive Value of Electrophoretically Detected Lipoprotein(a) for Coronary Heart Disease and Cerebrovascular Disease in a Community-Based Cohort of 9936 Men and Women
From the Division of Endocrinology (T.T.N., H.S.A.-L.), Laboratory Medicine (R.D.E.), Biostatistics (D.O.H., K.R.B.), and Cardiology (T.E.K.), Mayo Clinic and Foundation, Rochester, Minn.
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Abstract |
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Background Elevated lipoprotein(a) [Lp(a)] levels have been associated with the presence of atherosclerotic disease. However, the results of prospective studies of Lp(a) and cardiovascular disease have been contradictory.
Methods and Results From 1968 through 1982, lipoprotein analysis was performed in 11 335 Olmsted County residents. Quantitative cholesterol and triglycerides were obtained along with semiquantitative Lp(a) levels based on electrophoretic pattern. Lp(a) bands were scored from 0 (absent) to 3 (increased). A cohort of 4967 men and 4968 women with no prior history of atherosclerotic disease who had baseline Lp(a) determinations were followed up for 14 years for development of coronary artery disease (CAD) and cerebrovascular disease (CVD). During 131 330 person-years of follow-up, there were 1848 CAD events and 841 CVD events. Age, diabetes, hypertension, cholesterol, and triglycerides were significantly and independently associated with an increased risk of CAD and CVD in men and women. There was a significant increase in the adjusted hazards ratio for CAD with increasing Lp(a) levels for men and women. For Lp(a) level 3, the hazard ratio was 1.9 (range, 1.3 to 2.9) in women and 1.6 (range, 1.0 to 2.5) in men. The adjusted hazard ratio for CVD showed an irregular association with Lp(a) levels in men and no association in women.
Conclusions In this cohort of 9936 men and women initially free of cardiovascular disease who were followed up for 14 years, Lp(a) was a significant predictor of risk of future CAD. Lp(a) was a weak risk factor for CVD in men and was not a significant predictor of CVD risk in women.
Key Words: lipoproteins • coronary disease • risk factors • cerebrovascular disorders
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Introduction |
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Lipoprotein(a) is a lipoprotein fraction with pre-ß or
2
electrophoretic mobility. Its structure, metabolism, and
potential role in atherosclerosis have been reviewed
recently.1 Lp(a) consists of an LDL bound by a disulfide
bond to apo(a). Apo(a) is a hydrophilic glycoprotein of the
plasminogen family. These unique features give Lp(a)
potential atherogenic and thrombogenic roles and have generated
considerable interest in this lipoprotein. A number of recent studies
have shown that increased plasma concentrations of Lp(a) are associated
with atherosclerosis. Most of these studies were
cross-sectional comparisons of patients with atherosclerotic vascular
disease and control subjects and could not differentiate between Lp(a)
being the cause or effect of the disease. To the best of our knowledge,
there have been 10 prospective studies evaluating the role of Lp(a) as
a risk factor for coronary or cerebral
atherosclerosis. Six of these studies2 3 4 5 6 7
confirmed that Lp(a) is an independent risk factor for CAD in men.
However, 4 other studies8 9 10 11 did not confirm the
predictive value of Lp(a) in CAD or in CVD. This discrepancy may be due
to differences in the populations studied and in assay methodology. One
cross-sectional study12 suggested a gender difference in
the significance of Lp(a) for CAD. In that study, Lp(a) protein levels
>30 mg/dL were significantly associated with CAD only in men
younger than 55 years of age. In contrast, Lp(a) appears to be a risk
factor for CAD in women of all ages. There has been only 1 prospective
study in women that showed that Lp(a) was an independent risk factor
for cardiovascular disease.13 In that
study, Lp(a) was assessed qualitatively by electrophoresis after
ultracentrifugation at a density of 1.006. The results
of that study need to be confirmed to provide more insight into the
atherogenic role of Lp(a). Data from the same group also showed that
electrophoretically detected Lp(a) was an independent risk factor for
premature CAD in men.14 From 1967 through 1982, 11 335 Olmsted County residents had analyses of lipoprotein profiles including semiquantitative determinations of Lp(a). Among these were 9936 subjects (4969 women and 4967 men) who were free of clinical cardiovascular disease at the time of Lp(a) assessment. We determined the predictive value of elevated Lp(a) in this cohort by longitudinal follow-up through their medical records for the development of cardiovascular disease.
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Methods |
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Study Population
From 1968 through 1982, serum cholesterol, triglycerides, and lipoprotein electrophoreses were performed in 11 335 Olmsted County residents as part of their general medical examination or for follow-up of abnormal total cholesterol or triglycerides at the Mayo Clinic. Ninety-nine percent of this population was white. From this cohort, we identified 9936 subjects who did not have a diagnosis of cardiovascular disease before the date of lipoprotein analysis.
The diagnostic medical index data were reviewed to identify the presence of other major risk factors for atherosclerosis, ie, hypertension and diabetes mellitus, at the time of lipoprotein measurement. A comprehensive review of 500 randomly selected medical records was done to determine smoking status (ever smoker, never smoker) and BMI at the time of lipoprotein measurement and to assess any confounding interaction between these variables and Lp(a) levels. Hypertension was defined as a blood pressure >160/95 mm Hg or current use of antihypertensive drugs. Diabetes was diagnosed according to the World Health Organization15 or as current use of insulin or oral hypoglycemic agents.
Subjects were followed up for cardiovascular end points using the medical index through the last date of registration or through 1994. End points were total CAD events (angina pectoris, myocardial infarction, and cardiac deaths—HICDA codes 04100 through 04109, 04110, 04120 through 04129, and 04130) and total CVD events (transient ischemic attacks, ischemic strokes, and stroke deaths—HICDA codes 04320 and 04321, 04330 and 04331, 04350 and 04351, 04360 and 04361, 04370, and 04389 through 04431). The medical index of diagnoses includes diagnoses made during outpatient visits as well as diagnoses recorded during hospitalization and at death. The usefulness of this index for population-based studies has been described previously.16 17
Lipoprotein Analyses
Blood samples were collected at baseline by
venipuncture after a 12-hour overnight fast. Lipoprotein
analyses were performed in the Lipids and Lipoprotein
Laboratory at the Mayo Clinic on freshly isolated sera within 3 hours
of venipuncture. The laboratory was standardized for
cholesterol and triglycerides quantitation with
the CDC Lipid Standardization Laboratory in 1974.
Lipoprotein patterns were established by electrophoresis of whole serum, VLDL, and LDL-HDL (VLDL-free) fractions obtained by preparative ultracentrifugation at a density of 1.006 g/mL.18 19 By paper electrophoresis, Lp(a) was detected as the pre-ß migrating component of the VLDL-free fraction. After staining for lipid and electrophoretic separation, semiquantitative Lp(a) levels were all read by a single individual (R.D.E.). Lp(a) levels were coded as follows: 0=absent, 1=trace, 2=small increase, and 3=increase. HDL fractions were also coded according to a semiquantitative scoring system after electrophoresis as low, normal, or high.
To determine the reliability of electrophoresis for detecting high concentrations of Lp(a) mass, Lp(a) assessment by electrophoresis and quantitative assessment of Lp(a) by a commercially available ELISA (Strategic Diagnostics, previously Terumo) were simultaneously performed on a separate group of adult subjects (26% women, n=2877 samples) in the same laboratory. The ELISA used a monoclonal antibody against apo(a) for capture and a polyclonal antibody to apo(a) for detection. The antibodies did not cross-react with plasminogen. Mean intra-assay and interassay coefficients of variation were <7% and 8%, respectively. The Lp(a) plasma concentration is reported as milligrams of total Lp(a) mass.20
Statistical Analysis
The overall cumulative probability of developing CAD or CVD was
estimated by use of the Kaplan-Meier method.21 Death not
associated with CAD or CVD is a censoring event in these
analyses. For both the CAD and CVD end points, the follow-up
times were defined independently of the other event. The CAD (or CVD)
end point was defined as time to CAD (or CVD) if an event occurred or
time to last follow-up.22 The relationships of individual
risk factors as well as multivariate predictive
relationships with CAD and CVD were evaluated with the use of the Cox
proportional hazards model.23 Lp(a) measurement was
primarily analyzed as a four-category variable, with
separate hazard ratio estimates (unadjusted or adjusted) for each of
the categories 1, 2, or 3 compared with 0. In addition, hazard ratios
were estimated under the restriction that they were either monotone
nondecreasing or monotone nonincreasing from category 0 through
category 3. The latter analysis was done to smooth the raw
hazard ratios without imposing a strong assumption such as
linearity.
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Results |
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Subject Characteristics
There were 4967 men and 4969 women in our cohort who were free of any cardiovascular disease at the time of Lp(a) determination. The descriptive statistics of the cohort are given in Table 1
. The women were slightly older on
average, had higher mean cholesterol, and had lower mean
triglycerides than the men. Five hundred eighty-eight
subjects (6%) had no follow-up beyond the year of their lipoprotein
assay. In the remaining 9348 subjects, the mean follow-up was 14.1
years in women and 13.9 years in men. Nine percent of the cohort had a
diagnosis of diabetes mellitus at baseline, and the prevalence of
hypertension was higher in women (19%) than in men (14%). During
131 330 person-years of follow-up through 1994, there were 1040 CAD
events in men and 808 in women. There were 413 CVD events in men and
428 in women. In the subgroup of 500 subjects in whom smoking status
and BMI were determined, prevalence of smoking history and BMI were
higher in men than in women.
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Relationship Between Lp(a) Detection by Electrophoresis and
Quantitative Lp(a) Assay
Lp(a) detection by electrophoresis was performed on 2877 samples
simultaneously with a quantitative Lp(a) assay. Lp(a) band
presence on electrophoresis was 59.7% sensitive and 92.5% specific
for Lp(a) of 30 mg/dL, above which there appears to be an
increased risk for CAD.24 25 The sensitivity and
specificity of electrophoresis were very similar to the values reported
by the Framingham Heart Study11 and by Bruckert et
al.26 Fig 1 shows the
frequency distribution of each of the Lp(a) scores by levels of Lp(a)
mass determined by ELISA. The mean Lp(a) level (±SEM) of the group
with an Lp(a) score of 0 (absent) (11.8±0.3 mg/dL) is similar
to that reported in the Framingham study, which used the same
methodology.11 In addition, the distributions and mean
Lp(a) levels increased significantly between Lp(a) scores 0 and 1
(32.9±1.1 mg/dL; P<.0001 by t test),
between scores 1 and 2 (43.1±1.1 mg/dL; P<.0001),
and between scores 2 and 3 (55.3±2.8 mg/dL;
P=.0001).
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Probability of Cardiovascular Disease in Relation
to Lp(a)
Fig 2 shows the Kaplan-Meier
estimates of cumulative probability of CAD and CVD by Lp(a) groups for
men and women. The estimated probability of CAD increased with each
increasing level of Lp(a) in both men and women (Table 2). Proportional hazard models with
monotonicity imposed showed that the increments in hazard were
independently significant when Lp(a) went from 0 to 1
(P<.0001) and from 1 to 2 (P=.13) in men. The
increments in hazard were independently significant at all three
steps—0 to 1 (P=.015), 1 to 2 (P=.001), and 2 to
3 (P=.0015)—in women. The estimated cumulative
probabilities of CVD at Lp(a) levels in men and women are shown in
Table 2. With monotonic proportional hazards, the only significant
increment in hazard in men was observed at the change between Lp(a)
levels 1 and 2 (P=.01). In women, independently
statistically significant hazard increments were observed at the steps
between Lp(a) levels 0 and 1 (P=.014) and levels 2 and 3
(P=.024).
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Association Between Cardiovascular Disease and
Risk Factors
On multivariate analysis, age, diabetes,
hypertension, total cholesterol, and
triglycerides were significantly associated with increased
risk of CAD and CVD in women (Table 3).
The same risk factors were associated with CAD in men except for
triglycerides (Table 4). Only
age, hypertension, and diabetes were independent risk factors for CVD
in men. HDL semiquantitative determinations on electrophoresis were not
significantly associated with CAD or CVD risk. Smoking status was not
entered into the analysis because it was not available in all
subjects.
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Association Between Lp(a) and Other Risk Factors
The relationship of Lp(a) to the other risk factors is shown in
Table 5. Age correlated with Lp(a) levels
for women. This association was also significant for men but was less
consistent across the different Lp(a) groups. Mean total
cholesterol was significantly different among all levels of
Lp(a) in both men and women. Mean triglyceride level was
significantly higher only in the group with an Lp(a) level of 3
compared with the other Lp(a) groups in both men and women. There was a
significant but weaker correlation with hypertension in women, whereas
there was no suggestion of a relationship in men (P=.09).
Diabetes was not significantly related to Lp(a) in either men
(P=.53) or women (P=.57). There was no
significant interaction between sex and Lp(a) for either CAD or CVD end
points. In a subsample of 500 randomly selected subjects in whom
smoking status and BMI were determined, we did not find any association
of these variables with Lp(a). Furthermore, in these 500 subjects,
there was respectively a 98% and 97% agreement rate in the diagnoses
of CAD and CVD as coded in the medical index and by clinical record
review. False-positive diagnoses of CAD and CVD using the medical index
were 4% and 6%, respectively. There was also a 91% and 79%
concordance, respectively, for the diagnoses of diabetes and
hypertension.
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Association Between Cardiovascular Disease, Lp(a),
and Other Risk Factors
CAD
Table 6 shows the crude and adjusted
relative hazards for CAD in men and women, comparing each nonzero Lp(a)
level with the zero level. There was a significant increase in the
adjusted hazard ratio for CAD with increasing Lp(a) levels for both men
and women. After adjustment, the proportional hazard model with
monotonicity imposed showed significant, independent CAD hazard
increments when the Lp(a) level went from 0 to 1 (P=.0012)
and from 1 to 2 (P=.053) in men. In women, when monotonicity
was imposed, significant, independent CAD hazard increments occurred
between levels 1 and 2 (P=.01) and levels 2 and 3
(P=.047).
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CVD
Table 7 shows the crude and adjusted
hazard ratio for CVD. In contrast to what was observed for CAD, the
adjusted hazard ratio for CVD with increasing Lp(a) levels was more
irregular in both men and women. With monotonic proportional hazards,
the adjusted hazard for CVD in men changed significantly between levels
1 and 2 (P=.044). In women, after adjustment, there was an
apparently lower risk associated with Lp(a) level 2. Therefore, when
monotonicity was imposed, the best fit was a single increment in risk
at level 3 (P=.15; hazard ratio of 1.5; CI, 0.86 to
2.65).
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Discussion |
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Our cohort is unique in the study of the relationship of Lp(a) and the risk of cardiovascular disease. It is a large, prospective study of Lp(a) that includes both men and women. In addition, the lengthy follow-up of this cohort for both men (13.9 years) and women (14.1 years) provides a large number of total CAD and CVD events. We confirm 31 previous reports11 13 25 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 that the detection of Lp(a) as the sinking pre-ß–lipoprotein band during electrophoresis of the d>1.006 g/mL fraction can be used as a very reliable surrogate for Lp(a) excess. In addition, we show that an increase in Lp(a) score as determined by electrophoresis corresponds to an increase in Lp(a) concentrations determined by ELISA. Because total cholesterol is not corrected for Lp(a) cholesterol, it was not surprising that total cholesterol was consistently higher in subjects with higher Lp(a) levels. This relationship has been reported previously when Lp(a) determination was done by electrophoresis.55 Men and women with higher Lp(a) scores were also older. Higher Lp(a) levels have been reported in postmenopausal women than in premenopausal women.56 This rise in Lp(a) levels with age in women has been shown to be associated with a change in their hormonal status.57 The Lp(a) relationship with triglycerides and hypertension was weaker and was not consistent across all the Lp(a) groups. No other interactions were noted.
In the present cohort of nearly 10 000 subjects initially free of
cardiovascular disease who were followed up
prospectively for an average of 14 years, the presence and increasing
degree of Lp(a) was a significant, independent risk factor for CAD in
both men and women, even after multivariate adjustments
of other risk factors for CAD. In men, an Lp(a) level 
2 was
significantly predictive of CVD after multivariate
adjustment, although it was not independently significantly predictive
of CVD in women. By excluding cases with any diagnosis of
cardiovascular disease before Lp(a) and lipoprotein
determination, we avoided possible confounding engendered by the fact
that Lp(a) is an acute-phase reactant. Our study is in agreement with
most prospective studies in middle-aged men that showed that elevated
Lp(a) is a risk factor for CAD3 4 5 6 7 and with the only other
prospective study, the Framingham Heart Study, which showed that Lp(a)
detected by electrophoresis is also an independent risk factor for CAD
in women.13 Unlike the Framingham Heart Study, which
reported the Lp(a) band only as present or absent, Lp(a)
analysis in our study was semiquantitative. This allowed us to
clearly show a gradient in CAD risk with increasing Lp(a) levels, as
determined by the sinking pre-ß assay, both in men and women.
It can be argued that Lp(a) determination in our study is relatively
insensitive compared with the Lp(a) mass quantitative immunoassays that
were introduced in the 1970s. Indeed, electrophoresis detection of
Lp(a) is very specific (92.5%) but is not as sensitive (59.7%) for
Lp(a) mass 30 mg/dL. This cannot be attributed to interference
by triglyceride-rich pre-ß–lipoproteins because in our
study, Lp(a) electrophoretic detection was done on the VLDL-free
fraction. The lower sensitivity may reflect the limits of detection of
Lp(a) by electrophoresis, because it is based on staining for the lipid
content of Lp(a). If anything, the lower sensitivity of our method
would have underestimated the significance of Lp(a) as a predictor for
cardiovascular disease.
Moreover, in our study, as in the Framingham study, this traditional method of detecting Lp(a) as sinking pre-ß lipoprotein provides several advantages. First, it relies on the lipid content of the particle and its electrophoretic mobility, which has been shown to be independent of variations in the apo(a) moiety54 that may influence many of the available Lp(a) quantitation immunoassays.58 Because these latter quantitative methods have not been standardized, they may not all be adequate to assess the potential atherogenicity of Lp(a).59 60 Our study supports the proposition that the traditional method of detecting Lp(a) as sinking pre-ß lipoprotein by electrophoresis can provide useful clinical information even today because it detects high levels of Lp(a).61 It further suggests that measuring Lp(a) by its lipid content may be an alternative method to estimate the risk of CAD. Second, in our study, Lp(a) determination was done on fresh samples, avoiding the problems of Lp(a) degradation during prolonged storage62 that may have led to conflicting results in previous studies. Although freshly isolated serum was used in our Lp(a) determination by electrophoresis, there could still have been some degradation of Lp(a) because no protease inhibitor was added to the serum. However, we have observed that there is no significant loss of Lp(a) band on electrophoresis for 24 hours after serum collection, provided that the serum sample was not at ambient temperature for >4 hours. Even if some Lp(a) degradation did occur in fresh serum, this would have led to underestimation of the risk associated with Lp(a). It is important to note that in the only other three prospective studies7 13 14 in which Lp(a) was determined in fresh plasma or serum samples as in our study, elevated Lp(a), whether determined quantitatively or qualitatively, was consistently shown to be an independent predictor of arteriosclerotic events.
There are fewer prospective studies on Lp(a) and the risk of CVD. The Framingham Heart Study is the only other prospective study to examine the role of Lp(a) as a risk factor for CVD risk in women. Unlike the Framingham study, we did not find that Lp(a) was a significant predictor of future risk of CVD in women. Duration of follow-up, as well as mean age of the women, was similar in both studies. The number of total CVD events was greater in our study than in the Framingham Heart Study (428 versus 83); however, in our study, these events were documented using the medical index diagnosis (International Classification of Diseases, 9th revision). This may have led to differential misclassification of "softer events" such as transient ischemic attacks and may explain the discordance with the Framingham study.
Although our cohort was not a random population sample, other classic
risk factors were independent predictors of CVD in both women and men
in our study. In particular, total cholesterol was a
significant risk factor for CVD in women. Because total
cholesterol includes Lp(a) cholesterol, it is
possible that the inclusion of total cholesterol in the
multivariate model diluted the CVD risk associated with
Lp(a). However, taking total cholesterol out of the
multivariate model had little impact on the
significance of Lp(a) as a predictor of CVD. On the other hand, age had
a major effect on the significance of Lp(a) in the
multivariate model of CVD in women. This would imply
that in our cohort, the importance of Lp(a) in predicting CVD events in
women is explained by the interaction between Lp(a) and age. In men, an
Lp(a) level 2 was significantly predictive of CVD after
multivariate adjustment. There are only three other
prospective studies on Lp(a) and future CVD risk in men; one showed a
positive association,5 and the other two showed no
association.10 11 More longitudinal studies are needed to
determine the association between elevated Lp(a) levels and CVD risk in
men and women.
Study Limitations
A limitation of our cohort is that it was not a random sample of
the population. However, we believe that the size of our cohort and the
fact that it was composed entirely of members of a community who had a
general medical examination make it unlikely that consistent
selection bias was introduced. In addition, it is reassuring that the
Lp(a) distribution in our cohort is as expected in a white population
and that other classic risk factors (age, hypertension, diabetes, and
lipid fractions) predicted future risk of CAD and CVD. HDL, which was
semiquantitatively determined on electrophoresis, was not a significant
risk factor on multivariate analysis in our
study. This is likely due to the fact that the lipid staining of HDL
with oil red O is not stoichiometric and is more intense for
triglyceride and phospholipids than for
cholesterol. Indeed, Bruckert et al26 have
shown that HDL determined by this method correlates poorly with direct
measurement of HDL cholesterol. Although smoking status and
BMI were not available in all subjects, a review of 500 randomly
selected clinical records did not show any significant relationship
between these variables and Lp(a). Furthermore, we would expect
that in such a large cohort, the different Lp(a) groups would be well
matched for smoking prevalence. Although there are also limitations to
the index diagnoses, a review of 500 randomly selected clinical
records showed good concordance with index diagnoses of
cardiovascular diseases.
In summary, the present study shows that the presence and increasing degree of elevated Lp(a) is a significant independent risk factor for CAD in both men and women. It appears to be a weaker predictor of future risk of CVD in men and was not independently predictive of CVD in women. This study and others suggest the importance of determining Lp(a) in fresh serum or plasma samples and the potential usefulness of Lp(a) semiquantitation by electrophoresis and quantitation by ELISA to estimate arteriosclerotic risk.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grant RR-0585 from the US Public Health Service and by the Mayo Foundation.
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Footnotes |
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Reprint requests to Tu T. Nguyen, MD, Division of Endocrinology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
Received December 12, 1996; revision received March 25, 1997; accepted March 30, 1997.
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