Published online before print December 17, 2007, doi: 10.1161/CIRCULATIONAHA.107.715698
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(Circulation. 2008;117:176-184.)
© 2008 American Heart Association, Inc.
Epidemiology |
Extreme Lipoprotein(a) Levels and Risk of Myocardial Infarction in the General Population
The Copenhagen City Heart Study
From the Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital (P.R.K., M.B., B.G.N.); Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital (A.T.-H.); and the Copenhagen City Heart Study, Bispebjerg Hospital, Copenhagen University Hospital, University of Copenhagen (A.T.-H., B.G.N.), Copenhagen, Denmark.
Correspondence to Børge G. Nordestgaard, MD, DMSc, Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark. E-mail brno{at}heh.regionh.dk
Received May 21, 2007; accepted October 26, 2007.
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Abstract |
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Background— Elevated lipoprotein(a) levels are associated with myocardial infarction (MI) in some but not all studies. Limitations of previous studies include lack of risk estimates for extreme lipoprotein(a) levels, measurements in long-term frozen samples, no correction for regression dilution bias, and lack of absolute risk estimates in the general population. We tested the hypothesis that extreme lipoprotein(a) levels predict MI in the general population, measuring levels shortly after sampling, correcting for regression dilution bias, and calculating hazard ratios and absolute risk estimates.
Methods and Results— We examined 9330 men and women from the general population in the Copenhagen City Heart Study. During 10 years of follow-up, 498 participants developed MI. In women, multifactorially adjusted hazard ratios for MI for elevated lipoprotein(a) levels were 1.1 (95% CI, 0.6 to 1.9) for 5 to 29 mg/dL (22nd to 66th percentile), 1.7 (1.0 to 3.1) for 30 to 84 mg/dL (67th to 89th percentile), 2.6 (1.2 to 5.9) for 85 to 119 mg/dL (90th to 95th percentile), and 3.6 (1.7 to 7.7) for 
120 mg/dL (>95th percentile) versus levels <5 mg/dL (<22nd percentile). Equivalent values in men were 1.5 (0.9 to 2.3), 1.6 (1.0 to 2.6), 2.6 (1.2 to 5.5), and 3.7 (1.7 to 8.0). Absolute 10-year risks of MI were 10% and 20% in smoking, hypertensive women aged >60 years with lipoprotein(a) levels of <5 and 120 mg/dL, respectively. Equivalent values in men were 19% and 35%.
Conclusions— We observed a stepwise increase in risk of MI with increasing levels of lipoprotein(a), with no evidence of a threshold effect. Extreme lipoprotein(a) levels predict a 3- to 4-fold increase in risk of MI in the general population and absolute 10-year risks of 20% and 35% in high-risk women and men.
Key Words: coronary disease • lipoproteins • myocardial infarction
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Introduction |
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Lipoprotein(a) is composed of a low-density lipoprotein (LDL) particle bound to a plasminogen-like glycoprotein named apolipoprotein(a).1 Previous in vitro, animal, and epidemiological studies suggest that lipoprotein(a) could contribute to the development of atherosclerosis and/or thrombosis and thus myocardial infarction (MI) and ischemic heart disease (IHD).1–16 However, the use of lipoprotein(a) as a risk factor for MI and IHD has not been implemented in clinical practice. Limitations of previous studies include measurements in long-term frozen samples, in which different lipoprotein(a) isoforms may degrade differently,17 and lack of correction for regression dilution bias.18 In addition, only very few studies have provided information on the association between extreme lipoprotein(a) levels and risk of MI and IHD.15,16,19 Finally, we lack absolute risk estimates in the general population to help clinicians use extreme lipoprotein(a) levels in risk assessment of individual patients.
Clinical Perspective p 184
We tested the hypothesis that extreme lipoprotein(a) levels predict risk of MI and IHD in the general population. For this purpose, we used a prospective study of the Danish general population, the Copenhagen City Heart Study, measured lipoprotein(a) levels at baseline shortly after sampling, and corrected for regression dilution bias. Finally, we calculated absolute risk estimates for MI and IHD as a function of extreme lipoprotein(a) levels in the general population.
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Methods |
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Participants
Participants were from the 1991–1994 examination of the Copenhagen City Heart Study, in which participants were drawn randomly from the Copenhagen Central Person Register to represent the adult general population.20 Of the 16 563 invited individuals, 10 135 participated (response rate, 61%). We included 9330 individuals who had lipoprotein(a) levels determined shortly after sampling and who had no prior history of IHD. Hypertension was defined as use of antihypertensive medication, a systolic blood pressure
140 mm Hg, or a diastolic blood pressure 90 mm Hg. Diabetes mellitus was defined as self-reported disease, use of insulin or oral hypoglycemic drugs, or a nonfasting plasma glucose >11 mmol/L. Smokers were active smokers. Body mass index was weight in kilograms divided by height in meters squared. We followed up all individuals from baseline in 1991–1994 until the occurrence of IHD (including MI), death, or beginning of 2004, whichever came first. Follow-up was 100% complete. Approximately half of the participants had a second lipoprotein(a) measurement at the 2001–2003 examination immediately after sampling, allowing correction for regression dilution bias.18
Information on diagnosis of MI and IHD (World Health Organization; International Classification of Diseases, Eighth Edition codes 410 and 410 to 414, respectively, and International Statistical Classification of Diseases, 10th Revision codes I21 to I22 and I20 to I25, respectively) was collected and verified by reviewing hospital admissions and diagnoses entered in the national Danish Patient Registry, causes of death entered in the national Danish Causes of Death Registry, and medical records from hospitals and general practitioners. IHD was defined as the occurrence of MI or characteristic symptoms of angina pectoris based on location, character and duration of pain, and relation of pain to exercise. A diagnosis of MI required the presence of at least 2 of the following criteria: characteristic chest pain, elevated cardiac enzymes, or electrocardiographic changes indicative of MI.
The study was approved by Herlev University Hospital and a Danish ethical committee (No. 100.2039/91, Copenhagen and Frederiksberg committee) and was conducted according to the Declaration of Helsinki. All participants gave written informed consent.
Biochemical Analysis
Colorimetric and turbidimetric assays were used to measure plasma levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and apolipoprotein B at baseline.20 LDL cholesterol was calculated according to the Friedewald formula if triglycerides were <4 mmol/L but measured by a direct method (Thermo Fischer Scientific, Waltham, Mass) at higher levels. With the use of an in-house assay developed by B.G.N., lipoprotein(a) total mass was measured turbidimetrically with a Technicon Axon autoanalyzer (Miles Inc, Diagnostics Division, Tarrytown, NY), rabbit anti-human lipoprotein(a) polyclonal antibodies (Q023, DAKO A/S, Glostrup, Denmark), and a human serum lipoprotein(a) calibrator (DAKO A/S). The antibodies recognize apolipoprotein(a), the apolipoprotein characteristic of lipoprotein(a). The polyclonal antibodies were purified by immunoadsorption against apolipoprotein B and plasminogen, ensuring no cross-reactivity with either of these components, confirmed by immunoelectrophoresis. In addition, the polyclonal antibodies were tested by Western blotting targeting 12 different isoforms of lipoprotein(a) with adequate detection of all isoforms and with no tendency for the larger isoforms to have increased signal intensity. On addition of isolated human very low-density lipoprotein (density <1.006 g/mL) without lipoprotein(a), equivalent to a plasma concentration of triglycerides of 2 to 8 mmol/L, the initial assay measured reduced lipoprotein(a) levels in the samples. We therefore preincubated all samples (25 µL plasma) for 5 minutes with 435 U lipase (catalog No. 414590, Boehringer Mannheim, Mannheim, Germany), 0.29 mg Tween 20 (CIS Bio International, Saclay, France), and 10 mg bovine serum albumin (catalog No. L362064, Behring, Marburg, Germany). After removal of triglycerides from the samples as described, the anti-lipoprotein(a) antibodies were added. Thereafter, there was no interference from triglycerides up to 8 mmol/L or from hemoglobin up to 500 µmol/L or bilirubin up to 400 µmol/L. Samples above a level of lipoprotein(a) 85 mg/dL or of triglycerides >8 mmol/L were diluted 1:5. Lipoprotein(a) levels up to at least 500 mg/dL were within the security range of the assay and would not erroneously be read as a low level due to antigen excess. To improve precision of lipoprotein(a) measurements, all 9330 samples were analyzed by the same technician using only 1 calibration, 1 batch of antibodies, and 1 autoanalyzer: the between-series coefficients of variation at lipoprotein(a) levels of 9, 30, 42, 66, 100, and 127 mg/dL and at triglyceride levels of 1 to 2 mmol/L were 11%, 3%, 2%, 2%, 5%, and 4%, respectively. Equivalent coefficients of variation were 4% in samples with a lipoprotein(a) level of 62 mg/dL and a triglyceride level of 7 mmol/L and 5% in samples with a lipoprotein(a) level of 133 mg/dL and a triglyceride level of 20 mmol/L. Plasma lipoprotein(a) was measured at baseline shortly after sampling (stored at –80°C for 1 to 29 months); storage at –80°C for up to 29 months did not change lipoprotein(a) values at the levels of 20, 52, and 135 mg/dL. In 2001–2003, lipoprotein(a) was measured again on 4609 participants immediately after sampling with the use of a sensitive immunoturbidimetric assay from DiaSys (DiaSys Diagnostic Systems, Holzheim, Germany) containing goat anti-human lipoprotein(a) polyclonal antibodies purified by immunoadsorption against apolipoprotein B and plasminogen. For individuals with both lipoprotein(a) measurements, we observed a minimal bias between the 2 measurements of 1.6 mg/dL and an r2 value of 0.81 (P<0.001) when comparing the 2 measurements by linear regression.
Statistical Analysis
STATA statistical software package was used for analysis. A 2-sided P<0.05 was considered significant. Cumulative incidences were plotted with the use of Kaplan-Meier curves and differences between levels of lipoprotein(a) examined by log-rank tests. Cox proportional hazards regression (age adjusted or multifactorially adjusted) was used to estimate hazard ratios with 95% CIs. We analyzed age at event using left truncation (or delayed entry) and age as time scale. Thus, age is automatically adjusted for, and we take into account that a period of ignorance exists before an individual enters into the study, a period in which the individual may have been subjected to the effects of elevated lipoprotein(a) levels. With age as time scale, we cannot study the effects of age itself. Therefore, for the test of interaction of age with lipoprotein(a) levels, we used years of follow-up as time scale analyzing time to event. The assumption of proportional hazards was tested with the use of Schoenfeld residuals, and no violations were observed. We defined lipoprotein(a) cut points a priori on the basis of percentiles of the distribution (<22nd, 22nd to 66th, 67th to 89th, 90th to 95th, >95th percentile). We compared the reference group (<5 mg/dL; <22nd percentile and equivalent to the detection limit of the assay) with individuals with higher levels of lipoprotein(a) using the prespecified cutoffs at 30 mg/dL (67th percentile), a level previously used for conveying increased risk,1,16,21 and 85 mg/dL and 120 mg/dL, approximately equal to the 90th and 95th percentiles. The lipoprotein(a) groups were coded 1, 2, 3, 4, and 5 for the trend tests in log-rank and Cox analyses. We also examined risk by tertiles of lipoprotein(a) levels. Total cholesterol, LDL cholesterol, and apolipoprotein B levels were adjusted for the lipoprotein(a) contribution,22 according to compositional data in which cholesterol accounts for 
30% and apolipoprotein B for 16% of total lipoprotein(a) mass.23,24 Thus, total lipoprotein(a) mass was multiplied by 0.3, and this value was subtracted from total cholesterol and LDL cholesterol values in all individuals. Similarly, total lipoprotein(a) mass multiplied by 0.16 was subtracted from apolipoprotein B values. On the basis of the second lipoprotein(a) measurement available for approximately half of the cohort reexamined in 2001–2003, hazard ratios were corrected for regression dilution bias by a nonparametric method18; we calculated a regression dilution ratio of 0.77, resulting in 13%, on average (range, –2% to 36%), higher hazard ratios compared with uncorrected values. Interaction of lipoprotein(a) with other risk factors was evaluated by including 2-factor interaction terms between lipoprotein(a) on a continuous scale and other examined risk factors, 1 at a time, in the multifactorial Cox regression model. Absolute 10-year risks of MI and IHD by levels of lipoprotein(a), hypertension no/yes, smoking no/yes, and age 
60 years and >60 years were estimated with the use of the regression coefficients from a Poisson regression model for women and men separately.25 Model calibration for the Poisson regression, that is, agreement between estimated and observed values, was assessed by comparing estimated 1-year occurrence of IHD within each risk factor stratum with observed 1-year occurrence of IHD among 5422 participants in the 2001–2003 examination who all had lipoprotein(a) measurements done (Table in the online-only Data Supplement). We observed good agreement.
The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.
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Results |
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Of the 9330 participants, 57% were women. Age at entry ranged from 21 to 93 years, with a mean of 57 years. Roughly 99% of participants were of Danish descent. During a median follow-up of 10 years, 1142 participants were diagnosed with IHD, including 498 with MI. Characteristics of participants are shown in Table 1.
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Cumulative Incidence
Cumulative incidence of MI and IHD as a function of age increased stepwise with increasing levels of lipoprotein(a) (Figure 1; log-rank tests for trend of P=0.002 and P<0.001).
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Relative Risk
In both genders, increasing levels of lipoprotein(a) were associated with increased risk of MI and IHD (Figure 2; trend tests ranged from P<0.001 to P=0.02). In women, multifactorially adjusted hazard ratios for MI for elevated lipoprotein(a) levels were 1.1 (95% CI, 0.6 to 1.9) for 5 to 29 mg/dL (22nd to 66th percentile), 1.7 (1.0 to 3.1) for 30 to 84 mg/dL (67th to 89th percentile), 2.6 (1.2 to 5.9) for 85 to 119 mg/dL (90 to 95th percentile), and 3.6 (1.7 to 7.7) for 120 mg/dL (>95th percentile) versus levels <5 mg/dL (<22nd percentile). Equivalent values in men were 1.5 (0.9 to 2.3), 1.6 (1.0 to 2.6), 2.6 (1.2 to 5.5), and 3.7 (1.7 to 8.0). Similar but attenuated results were obtained for IHD (Figure 2). Hazard ratios were adjusted for regression dilution bias (unadjusted hazard ratios are displayed in the Figure in the online-only Data Supplement). Noticeably, hazard ratios and tests for trend are more significant in the fully adjusted models than in the age-adjusted models, which is opposite the usual findings in observational studies. We examined how the traditional risk factors affected hazard ratios for lipoprotein(a) levels as predictor of MI by adding them 1 at a time to the age-adjusted model. We found that the following risk factors each slightly increased the lipoprotein(a) hazard ratio estimates: gender, smoking, hypertension, diabetes, total cholesterol, LDL cholesterol, HDL cholesterol, and apolipoprotein B and, for women, menopausal status and hormone replacement therapy.
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On a continuous scale, a 10-mg/dL increase in lipoprotein(a) levels was associated with a multifactorially adjusted hazard ratio of 1.09 (1.06 to 1.12) for MI and 1.06 (1.04 to 1.08) for IHD (Table 2). Likewise, the increase in risk per log increment in lipoprotein(a) concentration after multifactorial adjustment was 1.17 (1.08 to 1.27) for MI and 1.12 (1.07 to 1.18) for IHD. No significant interactions were observed between lipoprotein(a) and gender, age, smoking, hypertension, diabetes mellitus, body mass index, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apolipoprotein B, lipid-lowering therapy, menopause, or use of hormone replacement therapy on risk of MI and IHD (probability values of 0.10 to 0.93 for test of interaction). When we excluded individuals on lipid-lowering therapy, the results were similar to those reported.
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Absolute Risk
Absolute 10-year risk of MI and IHD increased with increasing lipoprotein(a) levels, from women to men, and with smoking, hypertension, and increasing age (Figure 3). In women, the highest absolute 10-year risks of MI of 10% and 20% were found in hypertensive smokers aged >60 years, and with lipoprotein(a) levels <5 mg/dL (<22nd percentile) and 120 mg/dL (>95th percentile), respectively. Equivalent values in men were 19% and 35%. The absolute 10-year risks of IHD were higher than those for MI, but the absolute increase in risk from low to extreme levels of lipoprotein(a) was slightly attenuated compared with that observed for MI.
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Discussion |
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In this study of the adult Danish general population, we observed a stepwise increase in risk of MI with increasing levels of lipoprotein(a) in both genders, with no evidence of a threshold effect. Furthermore, we found that extreme lipoprotein(a) levels >95th percentile predict a 3- to 4-fold increase in risk of MI and absolute 10-year risks of 20% and 35% in high-risk women and men. We observed larger risk estimates for lipoprotein(a) than most previous studies,10,12–14,16,26,27 most likely because we focused on extreme levels, measured levels shortly after sampling, corrected for regression dilution bias, and considered MI rather than IHD. In addition, other studies may have failed to dilute samples sufficiently to get accurate values at the high levels, at which we diluted samples 1:5 at lipoprotein(a) levels >85 mg/dL, and were able to measure levels accurately up to a level of 500 mg/dL. In addition, we designed an assay completely free of interference from triglycerides. Finally, for the first time we provide absolute 10-year risk estimates in the general population for MI and IHD as a function of lipoprotein(a) levels stratified for other risk factors, allowing clinicians to use extreme lipoprotein(a) levels in risk assessment of individual patients.
Lipoprotein(a) may contribute to the development of MI and IHD by 2 different mechanisms: lipoprotein(a) consists of an LDL particle that may promote atherosclerosis and a plasminogen-like apolipoprotein(a) particle that may interfere with fibrinolysis and increase the risk of thrombosis.1 Lipoprotein(a) can enter into human atherosclerotic plaques,6 and results from in vitro and animal studies implicate lipoprotein(a) in foam cell formation, smooth muscle cell proliferation, and plaque inflammation and instability.2,7,8 Lipoprotein(a) has also been shown to bind proinflammatory oxidized phospholipids recently associated with coronary artery disease.28 Lipoprotein(a) enters into and leaves the arterial wall by mechanisms similar to LDL3,4 and appears to accumulate more at sites of arterial injury than LDL.5 Mechanisms by which lipoprotein(a) may contribute to thrombus formation include inactivation of tissue factor pathway inhibitor, thus promoting coagulation, and attenuation of fibrinolysis through inhibition of plasminogen activation.2,8
Most but not all prospective studies of lipoprotein(a) and risk of IHD have found positive associations,10–16,26,27 and levels of lipoprotein(a) have also been related to severity of coronary artery disease.29 Our risk estimates are, however, higher than those detected in the majority of previous studies.10,12–14,16,26,27 In contrast to our study, previous studies, with few exceptions,15,16,19 have not explored risk in groups with extreme levels of lipoprotein(a), and most previous studies used the end point IHD rather than MI. A meta-analysis from 2000 including 18 studies found a risk ratio of 1.7 for IHD when comparing individuals in the upper versus lower tertile of the lipoprotein(a) distribution (Figure 4).10 If we likewise in our study consider risk of IHD as a function of the upper versus lower lipoprotein(a) tertile, we arrive at a similar estimate. Among previous studies that evaluated extreme lipoprotein(a) levels, 1 study found a 1.9-fold increase in risk of IHD with lipoprotein(a) levels above the 95th percentile in women16 compared with the 2.4-fold increase in risk of IHD in women and men combined found in our study (Figure 4). The former study used long-term frozen samples16 with a risk of differential degradation of lipoprotein(a) isoforms, resulting in more moderate risk estimates,17 and did not correct for regression dilution bias. Another study, a nested case-control study from 1994 in men,19 also used long-term frozen samples but, like the present study, corrected for regression dilution bias. This study found a 2.3-fold increase in risk of cardiovascular death in individuals with lipoprotein(a) levels >90th percentile, which compares with our finding of a 2.2-fold increase in risk of IHD for those >90th percentile (Figure 4).
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Some previous studies have reported evidence of interaction between lipoprotein(a) levels and LDL cholesterol levels on risk of IHD.13,15,16,21 Our study does not support this finding: Formal testing for interaction was insignificant, and stratifying the cohort by the median LDL cholesterol level yielded similar risk estimates in both strata. Before analyses in our study, LDL cholesterol values were corrected for the lipoprotein(a) contribution, but even without this prior correction, no indication of an interaction between lipoprotein(a) levels and LDL cholesterol was found (data not shown). Some previous studies have also speculated on a threshold effect,15,16 but our study does not support this. We observed a stepwise increase in risk of MI and IHD with increasing levels of lipoprotein(a) in both genders, with no evidence of a threshold effect.
Lipoprotein(a) levels and distributions differ between different ethnic groups,30 and thus results from the present study may not be applicable to other ethnic groups. It is unlikely that our results suffer from selection bias because we selected participants at random from the general population and had 100% follow-up. However, we cannot rule out misclassification of a few cases or controls. Misclassification of either controls or cases will tend to give more conservative risk estimates, and this might be the cause of the more moderate risk estimates obtained for IHD compared with those for MI because a diagnosis of IHD is less certain than a diagnosis of MI.
Risk estimates for lipoprotein(a) were corrected for regression dilution bias on the basis of a second lipoprotein(a) measurement near the end of follow-up. Ideally, correction factors should probably be based on remeasurements midway through the follow-up period,18 but when the remarkable stability of lipoprotein(a) levels is considered, it is not unreasonable to use measurements 10 years apart and far better than not attempting to correct for regression dilution bias. Importantly, however, the absolute 10-year risk estimates given in this article were not corrected for regression dilution bias and therefore underestimate rather than overinflate risk estimates.18
Limitations of lipoprotein(a) assays are well known.31,32 If measurements are affected by apolipoprotein(a) isoform size, concentrations of large isoforms will likely be overestimated and concentrations of small isoforms will likely be underestimated.33 Given the inverse relationship between apolipoprotein(a) isoform size and plasma lipoprotein(a) concentration, that is, small isoform sizes are associated with high concentrations and vice versa, an assay affected by isoform size would tend to underestimate high concentrations and overestimate low concentrations. This would likely lead to risk estimates more conservative than in reality, and thus real effect sizes for risk of MI and IHD by extreme lipoprotein(a) levels may be even larger than those often observed. However, any tendency to overestimate concentrations of large isoforms in our assay is probably modest because characterization of the polyclonal antibodies, including Western blot analysis of different apolipoprotein(a) isoforms, revealed no preferential detection of larger isoforms. In addition, when particles as large as lipoprotein(a) are targeted, turbidimetric assays are not very sensitive to slight variations in the number of antibodies bound per target. Finally, our lipoprotein(a) assay is not standardized internationally for accuracy, and as a consequence the exact cutoff values in milligrams per deciliter may not be directly applicable to other lipoprotein(a) assays. However, this will not change the risk estimates based on percentile cutoff points, particularly because all of our 9330 samples were measured by the same technician, using only 1 calibration, 1 batch of antibodies, and 1 autoanalyzer.
The present study establishes extreme levels of lipoprotein(a) as an important risk factor for MI and IHD in both genders in Europeans. The use of lipoprotein(a) levels in risk assessment could be improved further by development of standardized assays to deliver precise and accurate lipoprotein(a) measurements.32 In particular, our study supports the necessity of developing more careful and accurate measurements of very high levels of lipoprotein(a). Even without such new assays, absolute 10-year risk estimates of MI and IHD, as presented in the present study for extreme lipoprotein(a) levels, can be used directly to advise individual patients. However, this is provided that cut points for the 90th and 95th percentiles of the lipoprotein(a) distribution are used instead of absolute values. Cut points using absolute values may vary between assays because of the current lack of international standardization of lipoprotein(a) assays.
Recent recommendations34 state that lipoprotein(a) screening is not warranted for primary prevention and assessment of cardiovascular risk at present but that lipoprotein(a) measurements can be of use in patients with a strong family history of cardiovascular disease or if risk of cardiovascular disease is judged intermediate on the basis of conventional risk factors. In addition to measurement difficulties, a number of factors contribute to lipoprotein(a) levels not being incorporated into routine cardiovascular risk assessment presently. First, there are no effective drugs that selectively reduce plasma levels of lipoprotein(a). The only well-known means of lowering lipoprotein(a) levels is high doses of niacin,24,35 which affects the levels of many other lipoproteins and is not universally tolerated. No studies have yet documented a reduction in IHD in response to niacin treatment in individuals with elevated lipoprotein(a) levels. Second, the mechanism of action of lipoprotein(a) as a promoter of cardiovascular events is not clear. Finally, plasma levels of lipoprotein(a) have failed to alter the receiver operating characteristic curve independently of traditional risk factors when used for risk prediction36; however, receiver operating characteristic curves focus on the entire range of lipoprotein(a), whereas we demonstrate that particularly extreme values add diagnostic information.
Measurements of lipoprotein(a) levels might help to identify as yet unidentified high-risk individuals who could benefit from other aggressive, prophylactic measures, including statins directed at elevated cholesterol levels. Indeed, the influence of lipoprotein(a) in causing MI and IHD is muted with substantial cholesterol reductions in hypercholesterolemic patients.37
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Acknowledgments |
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The authors thank Preben Galasz for excellent technical assistance and the participants of the Copenhagen City Heart Study for their willingness to participate.
Sources of Funding
The study was supported by Ib Mogens Kristiansen (IMK) Almene Fond and the Danish Heart Foundation.
Disclosures
There are no financial or other conflicts of interest for any of the authors. Børge G. Nordestgaard and Anne Tybjærg-Hansen have previously received lecture honoraria from Merck, Pfizer, and AstraZeneca.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Utermann G. Lipoprotein(a). In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 2001 ed. New York, NY: McGraw-Hill Publishing Co, Medical Publishing Division; 2006: 2753–2787.
2. Deb A, Caplice NM. Lipoprotein(a): new insights into mechanisms of atherogenesis and thrombosis. Clin Cardiol. 2004; 27: 258–264.[CrossRef][Medline] [Order article via Infotrieve]
3. Nielsen LB, Nordestgaard BG, Stender S, Niendorf A, Kjeldsen K. Transfer of lipoprotein(a) and LDL into aortic intima in normal and in cholesterol-fed rabbits. Arterioscler Thromb Vasc Biol. 1995; 15: 1492–1502.
4. Nielsen LB, Stender S, Jauhiainen M, Nordestgaard BG. Preferential influx and decreased fractional loss of lipoprotein(a) in atherosclerotic compared with nonlesioned rabbit aorta. J Clin Invest. 1996; 98: 563–571.[Medline] [Order article via Infotrieve]
5. Nielsen LB, Stender S, Kjeldsen K, Nordestgaard BG. Specific accumulation of lipoprotein(a) in balloon-injured rabbit aorta in vivo. Circ Res. 1996; 78: 615–626.
6. Nielsen LB, Grønholdt ML, Schroeder TV, Stender S, Nordestgaard BG. In vivo transfer of lipoprotein(a) into human atherosclerotic carotid arterial intima. Arterioscler Thromb Vasc Biol. 1997; 17: 905–911.
7. Nielsen LB, Juul K, Nordestgaard BG. Increased degradation of lipoprotein(a) in atherosclerotic compared with nonlesioned aortic intima–inner media of rabbits: in vivo evidence that lipoprotein(a) may contribute to foam cell formation. Arterioscler Thromb Vasc Biol. 1998; 18: 641–649.
8. Boffa MB, Marcovina SM, Koschinsky ML. Lipoprotein(a) as a risk factor for atherosclerosis and thrombosis: mechanistic insights from animal models. Clin Biochem. 2004; 37: 333–343.[CrossRef][Medline] [Order article via Infotrieve]
9. Craig WY, Neveux LM, Palomaki GE, Cleveland MM, Haddow JE. Lipoprotein(a) as a risk factor for ischemic heart disease: metaanalysis of prospective studies. Clin Chem. 1998; 44: 2301–2306.
10. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease: meta-analysis of prospective studies. Circulation. 2000; 102: 1082–1085.
11. von Eckardstein A, Schulte H, Cullen P, Assmann G. Lipoprotein(a) further increases the risk of coronary events in men with high global cardiovascular risk. J Am Coll Cardiol. 2001; 37: 434–439.
12. Sharrett AR, Ballantyne CM, Coady SA, Heiss G, Sorlie PD, Catellier D, Patsch W. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2001; 104: 1108–1113.
13. Luc G, Bard JM, Arveiler D, Ferrieres J, Evans A, Amouyel P, Fruchart JC, Ducimetiere P. Lipoprotein(a) as a predictor of coronary heart disease: the PRIME Study. Atherosclerosis. 2002; 163: 377–384.[CrossRef][Medline] [Order article via Infotrieve]
14. Ariyo AA, Thach C, Tracy R. Lp(a) lipoprotein, vascular disease, and mortality in the elderly. N Engl J Med. 2003; 349: 2108–2115.
15. Rifai N, Ma J, Sacks FM, Ridker PM, Hernandez WJ, Stampfer MJ, Marcovina SM. Apolipoprotein(a) size and (a) concentration and future risk of angina pectoris with evidence of severe coronary atherosclerosis in men: the Physicians’ Health Study. Clin Chem. 2004; 50: 1364–1371.
16. Danik JS, Rifai N, Buring JE, Ridker PM. Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women. JAMA. 2006; 296: 1363–1370.
17. Kronenberg F, Trenkwalder E, Dieplinger H, Utermann G. Lipoprotein(a) in stored plasma samples and the ravages of time: why epidemiological studies might fail. Arterioscler Thromb Vasc Biol. 1996; 16: 1568–1572.
18. Clarke R, Shipley M, Lewington S, Youngman L, Collins R, Marmot M, Peto R. Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am J Epidemiol. 1999; 150: 341–353.
19. Wald NJ, Law M, Watt HC, Wu T, Bailey A, Johnson AM, Craig WY, Ledue TB, Haddow JE. Apolipoproteins and ischaemic heart disease: implications for screening. Lancet. 1994; 343: 75–79.[CrossRef][Medline] [Order article via Infotrieve]
20. Schnohr P, Jensen G, Lange P, Scharling H, Appleyard M. The Copenhagen City Heart Study: Østerbroundersøgelsen: tables with data from the third examination, 1991–1994. Eur Heart J. 2001; 3 (suppl): H1–H83.[CrossRef]
21. Cantin B, Gagnon F, Moorjani S, Despres JP, Lamarche B, Lupien PJ, Dagenais GR. Is lipoprotein(a) an independent risk factor for ischemic heart disease in men? The Quebec Cardiovascular Study. J Am Coll Cardiol. 1998; 31: 519–525.
22. Jenner JL, Ordovas JM, Lamonfava S, Schaefer MM, Wilson PWF, Castelli WP, Schaefer EJ. Effects of age, sex, and menopausal status on plasma lipoprotein(A) levels: the Framingham Offspring Study. Circulation. 1993; 87: 1135–1141.
23. Seman LJ, Breckenridge WC. Isolation and partial characterization of apolipoprotein(a) from human lipoprotein(a). Biochem Cell Biol. 1986; 64: 999–1009.[Medline] [Order article via Infotrieve]
24. Carlson LA, Hamsten A, Asplund A. Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipemic subjects treated with nicotinic-acid. J Intern Med. 1989; 226: 271–276.[Medline] [Order article via Infotrieve]
25. Juul K, Tybjærg-Hansen A, Schnohr P, Nordestgaard BG. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med. 2004; 140: 330–337.
26. Cantin B, Despres JP, Lamarche B, Moorjani S, Lupien PJ, Bogaty P, Bergeron J, Dagenais GR. Association of fibrinogen and lipoprotein(a) as a coronary heart disease risk factor in men (the Quebec Cardiovascular Study). Am J Cardiol. 2002; 89: 662–666.[CrossRef][Medline] [Order article via Infotrieve]
27. Salomaa V, Rasi V, Kulathinal S, Vahtera E, Jauhiainen M, Ehnholm C, Pekkanen J. Hemostatic factors as predictors of coronary events and total mortality: the FINRISK ‘92 Hemostasis Study. Arterioscler Thromb Vasc Biol. 2002; 22: 353–358.
28. Tsimikas S, Brilakis ES, Miller ER, McConnell JP, Lennon RJ, Kornman KS, Witztum JL, Berger PB. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med. 2005; 353: 46–57.
29. Wang XL, Tam C, McCredie RM, Wilcken DE. Determinants of severity of coronary artery disease in Australian men and women. Circulation. 1994; 89: 1974–1981.
30. Utermann G. The mysteries of lipoprotein(a). Science. 1989; 246: 904–910.
31. Tate JR, Rifai N, Berg K, Couderc R, Dati F, Kostner GM, Sakurabayashi I, Steinmetz A. International Federation of Clinical Chemistry standardization project for the measurement of lipoprotein(a): phase I evaluation of the analytical performance of (a) assay systems and commercial calibrators. Clin Chem. 1998; 44: 1629–1640.
32. Marcovina SM, Koschinsky ML, Albers JJ, Skarlatos S. Report of the National Heart, Lung, and Blood Institute Workshop on Lipoprotein(a) and Cardiovascular Disease: recent advances and future directions. Clin Chem. 2003; 49: 1785–1796.
33. Marcovina SM, Albers JJ, Gabel B, Koschinsky ML, Gaur VP. Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a). Clin Chem. 1995; 41: 246–255.
34. American Association for Clinical Chemistry. NACB: emerging CV risk factors. Available at: http://www.aacc.org/AACC/members/nacb/LMPG/OnlineGuide/DraftGuidelines/Emerg_Risk_Factors/default.htm. Accessed October 31, 2007.
35. Rader DJ, Hoeg JM, Brewer HB Jr. Quantitation of plasma apolipoproteins in the primary and secondary prevention of coronary artery disease. Ann Intern Med. 1994; 120: 1012–1025.
36. Chambless LE, Folsom AR, Sharrett AR, Sorlie P, Couper D, Szklo M, Nieto FJ. Coronary heart disease risk prediction in the Atherosclerosis Risk in Communities (ARIC) study. J Clin Epidemiol. 2003; 56: 880–890.[CrossRef][Medline] [Order article via Infotrieve]
37. Maher VM, Brown BG, Marcovina SM, Hillger LA, Zhao XQ, Albers JJ. Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a). JAMA. 1995; 274: 1771–1774.
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The online-only Data Supplement, consisting of a table and a figure, is available with this article at http://circ.ahajournals.org/cgi/ content/full/CIRCULATIONAHA.107.715698/DC1.
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