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J Am Coll Cardiol, 2000; 35:314-320
© 2000 by the American College of Cardiology Foundation
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CLINICAL STUDIES

Lack of association of lipoprotein(a) levels with coronary calcium deposits in asymptomatic postmenopausal women

Masami Nishino, MD* {dagger},1, Mary J. Malloy, MD{dagger}, Josefina Naya-Vigne, MD{dagger}, Julie Russell, RN* {dagger}, John P. Kane, MD, PhD{dagger} and Rita F. Redberg, MD, MSc, FACC* {dagger}

* Division of Cardiology, University of California, San Francisco, California, USA
{dagger} Cardiovascular Research Institute, University of California, San Francisco, California, USA

Manuscript received April 16, 1999; revised manuscript received September 14, 1999, accepted October 21, 1999.


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 Conclusions
 References
 
OBJECTIVES

This study sought to determine the relationship of lipoprotein(a) (Lp(a)) and other cardiac risk factors to coronary atherosclerosis as measured by calcification of coronary arteries in asymptomatic postmenopausal women.

BACKGROUND

Lipoprotein(a) is considered a risk factor for coronary heart disease. Coronary calcium deposition is believed to be a useful noninvasive marker of coronary atherosclerosis in women. However, to our knowledge, there are no reports of the relationship of Lp(a) to coronary calcium in postmenopausal women.

METHODS

In 178 asymptomatic postmenopausal women (64 ± 8 years), we measured Lp(a) and other cardiac risk factors: age, hypertension, diabetes, low-density lipoprotein cholesterol, smoking status, body mass index, physical activity level and duration of hormone replacement therapy. Electron-beam computed tomography was done to measure coronary calcium (calcium score). We analyzed the relationship between calcium score and cardiac risk factors using multivariate analysis.

RESULTS

Although calcium score correlated with traditional risk factors of age, diabetes, hypertension and smoking, it did not correlate with Lp(a) in the asymptomatic postmenopausal women. Similar multivariate analyses were done in the subjects age >60 years and in the subjects with significant coronary calcium deposit (calcium score ≥50). These analyses also have failed to show an association of levels of Lp(a) with coronary calcium deposits.

CONCLUSIONS

We conclude that in asymptomatic postmenopausal women, Lp(a) levels do not correlate with coronary atherosclerosis as measured by coronary calcium deposits.

Abbreviations and Acronyms
  CHD = coronary heart disease
  EBCT = electron beam computed tomography
  HDL = high-density lipoprotein
  HU = Hounsfield Units
  LDL = low-density lipoprotein
  Lp(a) = lipoprotein(a)
  Mets = metabolic equivalents
  UCSF = University of California, San Francisco

Electron-beam computed tomography (EBCT), which allows accurate quantification of coronary calcium (1,2), has been investigated as a tool for noninvasive detection of coronary heart disease (CHD) (3,4) and is considered by some to be a screening method (3–5) predictive of future cardiac events (6). It has been suggested to be especially useful for diagnosis of CHD in women (7), particularly as exercise testing has been shown to be less accurate in women than men for diagnosis of CHD (8). Pathologic studies have documented a close correlation between coronary calcium and atherosclerotic plaque (9–12) with high sensitivity of coronary calcium for predicting advanced lesions. Pathologic studies done in young adults who have died from noncardiac causes show coronary calcium deposits and atherosclerotic plaque, suggesting the potential value of calcium as an early marker of CHD (13).

Lipoprotein(a) (Lp[a]) consists of a low-density lipoprotein (LDL) particle to which the protein (a) moiety is bound by a disulfide bond to apolipoprotein B-100. The (a) protein is a hydrophilic glycoprotein that has considerable sequence homology with plasminogen. These features implicate Lp(a) both directly in atherogenesis and in inhibition of fibrinolysis. A high concentration of Lp(a) is thought to be an independent risk factor for cardiovascular (14–18), cerebrovascular (15,17,19) and thoracic aortic atherosclerosis (20). It is known that Lp(a) levels increase after the menopause (21) and thus may correlate with the higher incidence of atherosclerosis in this age group. As heart disease is the leading cause of death in women, and women have higher mortality after advent of clinical CHD (22–24), it is important to identify all risk factors for CHD in women so that cardiac risk can be more accurately determined and more aggressive prevention strategies can be targeted to high-risk women. The purpose of this study was to determine whether high levels of Lp(a) are associated with coronary calcium deposits, a marker for coronary atherosclerosis, in asymptomatic postmenopausal women. The role of EBCT as a screening tool in asymptomatic patients with conventional risk factors has been of great interest recently, as some studies suggest that EBCT may have a role in detecting early disease (6).


   Methods
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 Abstract
 Methods
Results
 Discussion
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Subjects.   Between April 1995 and August 1997, 178 asymptomatic postmenopausal women (64 ± 8 years) were enrolled in the Females, Lipids, Activity and Sex Hormones study. Women were recruited by letters to physicians and flyers in the community, medical center, senior centers and private medical practices. Flyers stated that women had to be postmenopausal and have one or more cardiac risk factors (age, hypertension, hypercholesterolemia, smoking, diabetes or low level of physical activity). All women had their last menses ≥1 year before enrollment (46 women had undergone surgical menopause). Women with known CHD were excluded from the study. All study participants gave written, informed consent. The protocol was approved by the Committee on Human Research at the University of California, San Francisco (UCSF).

EBCT.   All studies were performed with a specific scanner (Imatron C-150). Patients were studied in the supine position. After localization of the main pulmonary artery, contiguous slices to the apex of the heart were obtained with ECG-gated triggering at 80% of the RR interval. Coronary foci with a computed tomographic density ≥130 Hounsfield Units (HU) and an area of four or more adjacent pixels (≥1.03 mm2) were determined to represent coronary artery calcium (20). A region of interest was manually selected around each visible lesion within each coronary artery. Computer-acquired measurements of lesion area in square millimeters and the maximal HU number of each region of interest were recorded. A density score was determined based on maximal HU number as follows: 1 = 130 to 199 HU, 2 = 200 to 299 HU, 3 = 300 to 399 HU, 4 ≥ 400 HU. A score for each region of interest was calculated by multiplying density score by area. A calcium score was calculated as the sum of all lesion scores per the protocol of Agatston et al. (25).

Evaluation of cardiac risk factors.   LP(a) assay
Blood was drawn following a 10-h to 12-h fast for assay of Lp(a). The Lp(a) content of serum samples was determined by an ELISA technique developed in the Cardiovascular Research Institute of UCSF to quantify the apolipoprotein B-100 moiety of the Lp(a) lipoprotein. A monoclonal antibody to the protein(a) moiety (Biodesign International, Saco, Maine) is used to coat microtiter plates at 5° for 16 h at a protein content of 10 µg/ml in phosphate-buffered saline 0.05 M phosphate, 0.15 M sodium chloride, pH 7.2. The plates are blocked as above for 1 h at 20° using 200 µl of phosphate-buffered saline, containing 3% bovine serum albumin (Sigma, St. Louis). Serum samples are diluted 200- to 320-fold in phosphate-buffered saline as above, containing 0.1% bovine serum albumin. A standard curve is constructed by diluting ultracentrifugally purified human serum LDL (1.055 > d < 1.020 g/cm3) in the same buffer. After incubation of the samples and standards in the coated plates for 5 h at 37°, they are washed five times with 300 µl of phosphate-buffered saline, as above. A 2000-fold dilution of goat anti-human apolipoprotein B-100 conjugated with horseradish peroxidase is added to each well for 1 h at 37°, followed by a wash as above. Color developed with tetramethyl benzidine is quantified in an automated plate reader (Molecular Devices; Sunnyvale, CA) at 450 nm. The content of Lp(a) is reported in nM/liter of Lp(a)-associated apo B-100.

Other cardiac risk factors
We evaluated cardiac risk factors: age, diabetes, hypertension, smoking and LDL cholesterol, as validated in the Framingham study (26), as well as body mass index and physical activity.

Age was evaluated as a continuous and ordinal variable. Diabetes was considered present if a patient was treated with insulin or oral agents or had a fasting glucose level of ≥126 mg/dl. Hypertension was defined as a blood pressure >140/90 mm Hg or current use of antihypertensive drugs. Smoking was evaluated using the following scoring system: 0, nonsmoker; 1, quit >3 years ago; 2, quit ≤3 years ago; 3, current smoker. As hormone replacement therapy has been shown to affect Lp(a) levels (27), its use and duration were included in the analyses. Hormone replacement therapy was evaluated as the duration of therapy (estrogen or estrogen and progesterone). Body mass index was computed as weight (in kilograms) divided by height (in meters) squared. Physical activity was determined by interview. It was quantified using modified Paffenberger’s method (metabolic equivalents (Mets)·hour/week) (28). This score quantifies maximum metabolic energy intensity x hours duration per week for a wide range of recreational activities that had been maintained during at least 75% of the preceding year.

Total cholesterol and triglyceride levels were measured by automated fluorescence analysis (Hoffmann-La Roche Inc; Nutley, New Jersey). High-density lipoprotein (HDL) cholesterol was measured in like manner after precipitation of apolipoprotein B containing lipoproteins with dextran sulfate and manganese (29). The LDL cholesterol level was computed with the formula of Friedwald et al. (30). Only LDL cholesterol was assessed in data analysis among the four lipid variables (total cholesterol, triglycerides, HDL cholesterol and LDL cholesterol) because multicollinearity can be produced statistically if all four lipid variables were selected. Treatment with any cholesterol-lowering medications was held for at least one week before the blood test.

The number of cardiac risk factors (age, hypertension, hypercholesterolemia, smoking, diabetes, obesity and low level of physical activity) was also calculated in each patient. The following criteria were used to score risk factors. Age >60 years was considered to be risk factor as well as hypertension and diabetes as defined above. Smoking was defined as current smoker or quit ≤3 years ago. Hypercholesterolemia was defined as LDL cholesterol ≥160 mg/dl. Obesity was defined as body mass index >25 kg/m2. Low level of physical activity was defined as Mets·hour/week <15.

Data analysis.   An unpaired Student t test and chi-square analyses were performed to examine differences in mean calcium scores, prevalence of detectable calcium for each age group and Lp(a) level between the patients with and without hormone replacement therapy.

To determine the significant and independent risk factors for coronary calcium in asymptomatic postmenopausal women, all risk factors, including Lp(a), were analyzed by multivariate analysis (general linear models). The dependent variable was the calcium score. Independent variables were as follows: age, Lp(a), LDL cholesterol, hypertension, smoking, diabetes, body mass index, physical activity and duration of hormone replacement therapy. Multivariate analyses also were performed in two subgroups: in women >60 years and in the subjects with significant coronary calcium deposits (calcium score ≥50). Software (SAS for Windows v6.12) was used for these multivariate analyses. All values are expressed as mean ± SD unless otherwise noted. P values <0.05 were considered significant.


   Results
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Discussion
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Patient characteristics.   Age ranged from 36 to 88 years (Table 1). Eighty-seven patients (49%) were taking hormone replacement therapy for a mean of 8.6 ± 9.0 years. In the patients using hormone replacement therapy, 46% used combination therapy (progesterone and estrogen). The mean number of measured cardiac risk factors, in addition to postmenopausal status in this population, was 1.7 ± 0.9.


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  		Table 1 Patient Characteristics

 
Prevalence of coronary calcium.   Calcium scores ranged from 0 to 2,618 with 44% showing no coronary calcium, a calcium score of zero (Table 1). Adequate studies for coronary calcium were obtained in all patients. An increase in the prevalence of detectable calcium deposits was seen with age (Fig. 1). The prevalence of detectable calcium was significantly higher in the 70- to 89-year-old group compared with the younger groups (Fig. 1). Similarly, the total amount of coronary calcium increased with age (Table 2).



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  		Figure 1 Percentage of women with detectable coronary calcium (calcium score greater than zero) by age group. *p < 0.05 vs. 50 to 59 years group.

 

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  		Table 2 Prevalence of Detectable Calcium (score > 0) and Mean Calcium Score

 
Relationship between risk factors, including Lp(a) and coronary calcium in postmenopausal women.   Age (p = 0.006), smoking (p < 0.001), diabetes mellitus (p < 0.001) and hypertension (p = 0.012) were found to be significantly associated with coronary calcium scores in postmenopausal women, whereas Lp(a) (p = 0.480) and the other risk factors analyzed were not correlated with the calcium score. The same associations were found in the subset of women age >60 years (n = 118). In the subset of women with significant calcium deposits (n = 52), age (p = 0.039), smoking (p < 0.001), diabetes mellitus (p = 0.043) and LDL cholesterol (p = 0.018) were found to be associated with coronary calcium score. Lipoprotein(a) (p = 0.117) and the other risk factors analyzed were not correlated with the calcium score.

There were no significant differences in Lp(a) levels between the patients with and without hormone replacement therapy (Table 3).


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  		Table 3 Relation of Lipoprotein(a) and the Other Variables to Calcium Score

 

   Discussion
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 Abstract
 Methods
 Results
 Discussion
Conclusions
 References
 
In this study, Lp(a) levels did not correlate with calcium score measured by EBCT as a marker for coronary atherosclerosis in asymptomatic postmenopausal women. This lack of an association was consistent in subgroup analysis of only older subjects (age >60 years) or of only subjects with significant coronary calcium deposits (calcium score ≥50). Thus, Lp(a) may not be an independent risk factor for CHD in asymptomatic postmenopausal women.

Lp(a) and atherosclerosis.   Lipoprotein(a) interferes with fibrinolysis. The mechanism is thought to involve competition with plasminogen for binding sites on cells and fibrin because of the structural homology between apolipoprotein(a) and plasminogen (31,32). The clinical correlates of impaired thrombolysis in patients with high levels of Lp(a) include the detection of increased tissue plasminogen activator inhibitor levels, the decreased activity of tissue plasminogen activator in young survivors of myocardial infarction and the detection of increased Lp(a) levels in survivors of myocardial infarction without recanalization of their infarct-related arteries (33). Additionally, Lp(a) is an LDL-like lipoprotein that appears to exert direct atherogenic effect (31,34–36). In histologic studies, Lp(a) and the (a) protein moiety have been identified in atherosclerotic lesions, and elevated levels of Lp(a) in serum have been associated with increased detection of both protein(a) and apolipoprotein B in the arterial wall (31,35,36). Thus, there are at least two possible mechanisms—prothrombotic effects and proatherogenic effects—by which Lp(a) may promote atherosclerosis.

Lp(a) and CHD.   Many studies have reported a relationship between Lp(a) and CHD. The first study to show a significant relationship was performed in 86 women and 216 men by Dahlén et al. (37), using coronary angiography as the end point for CHD. Similar relationships were seen in other studies (38,39). Three large surveys in men showed that higher levels of Lp(a) were correlated with an increase in cardiac events—fatal or nonfatal CHD (37,40,41). Similarly, a recent prospective study of 2,191 young to middle-age men found that elevated plasma Lp(a) was an independent risk factor for the development of premature CHD measured by cardiac events (42). Data from 3,103 women in the Framingham Heart Study showed an increased relative risk for myocardial infarction associated with higher levels of Lp(a). Elevated plasma Lp(a) was a strong, independent predictor of myocardial infarction, intermittent claudication, cerebrovascular disease and total CHD (18). More recently, Schwartzman et al. (43) also reported that higher plasma Lp(a) levels correlated with significant coronary artery disease stenoses.

However, other studies have shown a lack of association between Lp(a) and CHD, as seen in the present study. The Helsinki Heart Study found that Lp(a) did not significantly predict CHD in 4,081 hyperlipidemic men (44). In a large study of 14,916 men, Ridker et al. (45) showed that Lp(a) was unrelated to fatal and nonfatal myocardial infarction. In a cross-sectional analysis of 1,202 men and 1,512 women >60 years of age in Australia, Simons et al. (46) found no significant increase in Lp(a) in patients with CHD. Recently, Cantin et al. (47) reported that Lp(a) is not an independent risk factor for ischemic heart disease in men. They have suggested that elevated Lp(a) may be a risk factor for CHD only in men with elevated LDL cholesterol levels, whereas it is not an independent risk factor in the general population. Using criteria from the Atherosclerosis Risk in Communities (ARIC) study criteria (48), most of our study cohort were in a low-risk lipid group (LDL cholesterol <160 mg/dl or HDL cholesterol >35 mg/dl), and therefore our findings in women are consistent with the report of Cantin et al. (47) in a male population.

Thus, there is conflicting epidemiologic evidence linking Lp(a) to risk of CHD. However, in the previous studies, the definition of CHD was occurrence of events or significant coronary stenosis detected by coronary angiography. Therefore, these patients had relatively advanced coronary disease. In the present study, we used calcium burden measured by EBCT as a marker for atherosclerosis. Electron beam computed tomography is a noninvasive method to identify early coronary atherosclerosis, enabling us to recruit asymptomatic patients. Electron beam computed tomography data have been suggested to be more valuable in women with suspected CHD, because they are gender independent (7), whereas other noninvasive studies such as treadmill testing have been shown to be less accurate in women (8). The relationship of Lp(a) to CHD has been more closely studied in men than women (49). This report offers new insights into the relationship between atherosclerosis measured by coronary calcium deposits and risk factors including Lp(a) in asymptomatic postmenopausal women.

Other studies of healthy populations such as the Physicians’ Health Study also failed to show an association between Lp(a) and CHD (45,50). Perhaps the lack of association of Lp(a) and markers of early CHD can be explained because Lp(a) acts substantially through its antifibrinolytic activity. Thus, it would be expected to correlate best with severe disease involving plaque rupture and thrombotic events.

Coronary calcium deposits.   Studies on the mechanisms of deposition of calcium in atherosclerotic lesions indicate that it is a process analogous to the formation of bone spicules (51,52). Furthermore, it appears that it involves cells of special embryonic lineage. It can be expected that coronary calcification is not merely a direct consequence of atherogenesis but rather may depend on the presence of specific determinants independent of the central processes active in plaque formation. Such determinants may be of much greater importance to the development of coronary calcification than the level of Lp(a), possibly obscuring a contribution by Lp(a) per se.

The prevalence of coronary calcium deposits in our subjects was lower than that in the previous reports (5,53,54). This likely reflects the fact that our population comprised healthy postmenopausal women. However, there was no relationship between Lp(a) and coronary calcium deposits even when the group of women with significant calcium deposits (calcium score ≥50 [5,53,54]) was analyzed separately. Others (5,55) have reported that screening for coronary calcium deposits should be used in older women (>60 years). We analyzed coronary calcium deposits and Lp(a) in this subgroup and found no relationship.

Traditional CHD risk factors.   This study confirms that age, hypertension, smoking and diabetes are independently associated with coronary calcium, consistent with previous reports (5,53,56,57). However, in our study, overall there is no significant correlation between LDL cholesterol and coronary calcium deposits when the entire cohort was analyzed. Other studies have shown significant correlations between hypercholesterolemia and coronary calcium deposits (5,25,41,53). The reasons for this discrepancy may be that our study population had lower calcium scores, lower number of risk factors and presumably less atherosclerosis than patients in previous reports (5,53). In the subgroup with the higher burden of arterial calcium, a significant correlation of LDL cholesterol with calcium deposits was observed. Moreover, although we held treatment with cholesterol-lowering medications for one week before measuring the serum cholesterol level, a longer period of medications might have led to higher levels of LDL, affording a better opportunity to detect a relationship. Most agents used to treat hypercholesterolemia have little effect on levels of Lp(a) (50).

Hormone replacement therapy.   In this study, we found no relationship between use of hormone replacement therapy and coronary calcium. However, McLaughlin et al. (54) recently reported a significant relationship between hormone replacement therapy and coronary calcium deposits estimated by EBCT. The reasons for this discrepancy may be that, in our study, hormone replacement therapy was evaluated by duration of use, whereas the previous study (54) treated hormone replacement therapy as present or absent.

We also found no relationship between the hormone replacement therapy and Lp(a) levels. This differs from the results of the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial (58). In PEPI, Lp(a) levels were significantly decreased (mean reduction of 17% to 23%) in the hormone replacement group compared with the placebo group (27).

Study limitations.   Electron beam computed tomography calcium scores have been shown to be associated with coronary atherosclerosis in studies of predominantly male patients with relatively high risk for CHD (59–61). However, this association may not be present in asymptomatic postmenopausal women. However, EBCT may be clinically more valuable in women with suspected disease because other noninvasive studies have been shown to be less accurate with women than men (7). Thus, we investigated the links between risk factors in women and EBCT calcium scores in this study.

The sample size in our study is relatively small. In addition, we studied asymptomatic postmenopausal women who agreed to undergo a treadmill test, and our conclusions can be applied only to this population. To confirm our findings, large population-based studies should be undertaken.


   Conclusions
Top
 Abstract
 Methods
 Results
 Discussion
 Conclusions
References
 
This study demonstrated a lack of association of Lp(a) with coronary calcium deposits measured by EBCT in asymptomatic postmenopausal women.


   Footnotes
 
These studies were supported by the grants from the National Institute of Health: RO1 HL50772, RO1 HL50782 and RO1 HL50779, and the Drown Foundation, and were performed in part at the General Clinical Research Center, Moffitt Hospital, UCSF, with funds provided by the National Center for Research Resources, 5 MO1 RR-00079, US Public Health Service.

1 Dr Nishino was supported by a grant from the Japanese Labour Welfare Corporation. Back


   References
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