(Circulation. 1997;95:295-296.)
© 1997 American Heart Association, Inc.
Articles |
Lipoprotein(a), a Clinically Elusive Lipoprotein Particle
the Center for Research in Disease Prevention, Stanford (Calif) University Medical School and the University of Washington, Department of Medicine, Seattle (S.M.M.).
Correspondence to Santica M. Marcovina, PhD, Department of Medicine, University of Washington, 2121 N 35th St, Seattle, WA 98103.
 |
Introduction |
|---|
 Top Introduction References |
|---|
The existence of lipoprotein(a) [Lp(a)] in human plasma was first reported by Berg1 in 1963 as an antigen associated with LDL. Berg and Mohr2 also found in family studies that the presence of Lp(a) was genetically determined by an autosomal mode of inheritance. Later studies provided evidence that Lp(a) is a specific class of lipoprotein particles with a lipid composition very similar to that of LDL. Lp(a) differs from LDL by the presence of a highly glycosylated protein of variable mass, termed apolipoprotein(a) [apo(a)], linked by a covalent bond to apolipoprotein (apo) B-100. The association between Lp(a) and coronary heart disease was first reported in the early 1970s,3 but what triggered a vast train of research on Lp(a) was the discovery in 1987 of the structural homology between apo(a) and plasminogen, a key protein of the coagulation cascade.4 Like plasminogen, apo(a) is composed of a kringle-containing domain and a serine protease domain. Apo(a) kringle domain is formed by one copy of plasminogen-like kringle 5 domain and multiple copies of the plasminogen-like kringle 4 (K4) domain. Ten basic K4 types,5 designated K4 type 1 through 10, are present in apo(a), all as a single copy, except K4 type 2, which is present in a variable number of copies ranging from 3 to >40.6 The varying number of K4 type 2 repeats is the major determinant of apo(a) size heterogeneity,7 giving origin to the large number of apo(a) isoforms detected in human plasma.8 In addition to apo(a) size heterogeneity, Lp(a) is heterogeneous in plasma levels, lysine-binding properties, and lipid, carbohydrate, and apolipoprotein composition, with apo E reported in 20% of plasma Lp(a) particles.9 All these factors may significantly affect the design and interpretation of clinical studies and may at least potentially explain the conflicting results relating Lp(a) to coronary heart disease. Additionally, apo(a) size heterogeneity has posed a major challenge in the development of accurate immunochemical methods for measuring Lp(a) concentration in plasma.
We have recently documented that because of the variable number of apo(a) K4 type 2 repeats, Lp(a) values are underestimated or overestimated, depending on the apo(a) size in the samples, when the analytical methods are based on antibodies recognizing this variable part of the molecule.10 No studies have been performed to evaluate the impact of method inaccuracy on the interpretation of clinical data.
Because of its structural characteristics, apo(a) is part of the plasminogen gene superfamily, which, in addition to plasminogen, includes a large number of other proteins, some of them acting as regulatory proteases in the coagulation pathway. What is the functional rationale for the binding between a protein of the plasminogen gene superfamily and LDL particles whose main physiological role is the transport of cholesterol in human plasma? Structurally, Lp(a) has both thrombogenic and atherogenic potentials, but what are the mechanisms responsible for the pathological effects of Lp(a)? Does the heterogeneity of Lp(a) particles contribute to its pathogenicity? Despite the considerable progress that has been made in our understanding of this complex and elusive lipoprotein particle, both the physiological role and the pathological mechanisms of action of Lp(a) remain unclear.
In this issue, Orth-Gomer and colleagues11 contribute another retrospective, case-control study to the Lp(a) literature and provide significant new information by focusing on women <65 years of age. The case-control method is most useful in the study of uncommon diseases, including coronary disease in young women. Orth-Gomer and colleagues used a sound approach in applying the case-control design, attempting to identify all cases in a defined geographical area and selecting control subjects at random, after appropriate matching, from the same area. Such an approach is most likely to produce representative samples of both cases and noncases, avoiding some of the many biases to which case-control studies are subject. Even though, as stated by the authors, the immunoturbidimetric assay used to quantify Lp(a) has been calibrated by our laboratory, this does not eliminate the effect of apo(a) size heterogeneity on the Lp(a) values measured by this assay. Therefore, in this and most other Lp(a) studies, researchers have to rely on the assumption that apo(a) isoform distribution is similar between cases and control subjects, thus minimizing the potential that method-dependent overestimation or underestimation of Lp(a) values may contribute to the observed difference between cases and control subjects. The study found that the median Lp(a) was 38% higher in cases compared with control subjects, a difference that was very unlikely to be due to chance. This association was independent of other measured cardiovascular risk factors, and there was a stepwise increase in the odds ratio for being a case in subsequent quartiles of Lp(a) concentration compared with the first quartile. In the fourth quartile, the odds ratio was 2.6. The reader should note that the authors' search for a graded increase in risk across quartiles involves an unpaired comparison of cases and control subjects and therefore must be considered exploratory although useful.
We recently completed a prospective, nested case-control study of Lp(a) among participants in the Stanford Five-City Project.12 We used an ELISA method for measuring Lp(a) values, using a detection monoclonal antibody that is specifically directed to an epitope expressed in apo(a) K4 type 9, a method that has been demonstrated to accurately measure Lp(a) independently of apo(a) size polymorphism.10 Lp(a) was determined on plasma samples frozen for 5 to 16 years at -70°C after a pilot test showed no effect of storage time on Lp(a) concentration. Among 90 case-control pairs of men, the Lp(a) concentration was doubled in the cases compared with control subjects, a difference that was statistically significant and independent of other cardiovascular disease risk factors. The odds ratio in the fifth versus the first quintile was 2.4. There were 44 case-control pairs of women in this study; Lp(a) concentration was 34% higher in the female cases compared with control subjects, which was very similar to the difference found by Orth-Gomer.11 However, this difference was not statistically significant in our study, possibly because of the small number of pairs.
The clinical implications of these recent studies, added to the earlier ones, are still limited by several factors. Larger prospective studies that use Lp(a) measurement methods that are not affected by apo(a) size heterogeneity are needed, especially in women and nonwhite ethnic groups, to better characterize the risk relationship between Lp(a) and cardiovascular disease. The role of apo(a) size and other aspects of the pathophysiology of Lp(a) must also be explored, which may suggest the most fruitful therapeutic avenues (eg, anticoagulant, antioxidant, or lipid-lowering therapy). Studies in women are particularly salient because of the finding that postmenopausal women have higher Lp(a) values than premenopausal women, thus suggesting an association between female sex hormones and Lp(a) concentration.13
Even though estrogen, estrogen-progesterone combination, and tamoxifen have been shown to lower Lp(a) in healthy postmenopausal women,14 15 the risk/benefit of a long-term treatment with these agents has not been determined. The same can be said for pharmacological agents like niacin and neomycin, which also have been reported to lower Lp(a) levels.16 17 Additionally, there is a complete lack of data to suggest that lowering Lp(a) levels results in a reduced risk of coronary heart disease. Therefore, interventions directed at lowering Lp(a) level or population screening of Lp(a) values cannot be justified at this time. Is there any situation in which knowing the plasma Lp(a) concentration would be useful? There is evidence that the Lp(a) level loses its predictive power after aggressive LDL lowering,18 and there is considerable need for better individual risk stratification among patients at moderately increased risk of vascular disease with borderline indications for adding pharmacological therapy. In such a patient, an elevated Lp(a) level could indicate a need for a more intensive approach to lipid lowering, the addition of aspirin, or the use of hormone replacement.
To correctly identify these patients, population-based Lp(a) reference values for different ethnic groups should be determined with accurate analytical methods. To enable the physician to estimate a patient's risk, Lp(a) values should be reported with the indication of the corresponding percentile of the general population. On the basis of the outcome of the clinical studies, considering patients with Lp(a) values above the 80th percentile to be at increased risk for coronary heart disease appears reasonable.
|
Footnotes |
|---|
The opinions expressed in this editorial are not necessarily those of the editor or of the American Heart Association.
|
References |
|---|
|
TopIntroductionReferences |
|---|
1. Berg K. A new serum type system in man: the Lp system. Acta Pathol Microbiol Scand.. 1963;59:369-382.[Medline] [Order article via Infotrieve]
2. Berg K, Mohr J. Genetics of the Lp system. Acta Genetica.. 1963;13:349-360.
3. Dahlen GH, Ericson C, Furberg C, Lundvist L, Svardsudd K. Angina of effort and an extra pre-beta lipoprotein fraction. Acta Med Scand.. 1972;531:11-24.
4. McLean JW, Thomlinson JE, Kuang WJ, Eaton DL, Chen EY, Fless GM, Scanu AM, Lawn RM. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature.. 1987;330:132-137.[Medline] [Order article via Infotrieve]
5. Morrisett JD, Gaubatz JW, Knapp RD, Guevara JG Jr. Structural properties of apo(a): a major apoprotein of human lipoprotein(a). In: Scanu A, ed. Lipoprotein(a). San Diego, Calif: Academic Press, Inc; 1990:53-74.
6.
Lackner C, Cohen JC, Hobbs HH. Molecular definition of the extreme size polymorphism in apolipoprotein(a). Hum Mol Genet.. 1993;2:933-940.
7.
van der Hoek YY, Wittekoek ME, Beisiegel U, Kastelein JJ, Koschinsky ML. The apolipoprotein(a) kringle IV repeats which differ from the major repeat kringle are present in variably-sized isoforms. Hum Mol Genet.. 1993;2:361-366.
8. Marcovina SM, Zhang ZH, Gaur VP, Albers JJ. Identification of 34 apolipoprotein(a) isoforms: differential expression of apolipoprotein(a) alleles between American blacks and whites. Biochem Biophys Res Commun.. 1993;191:1192-1196.[Medline] [Order article via Infotrieve]
9. Bard JM, Delattre-Lestavel S, Clavey V, Pont P, Derudas B, Parra HJ, Fruchart JC. Isolation and characterization of two subspecies of Lp(a), one containing apo E and one free of apo E. Biochim Biophys Acta.. 1992;1127:124-130.[Medline] [Order article via Infotrieve]
10.
Marcovina SM, Albers JJ, Gabel B, Koschinsky ML, Gaur VP. The effect of the number of apo(a) kringle 4 domains on the immunochemical measurements of Lp(a). Clin Chem.. 1995;41:246-255.
11.
Orth-Gomer K, Mittleman MA, Schenck-Gustafsson K, Wamala SP, Eriksson M, Belkic K, Kirkeeide R, Svane B, Ryden L. Lipoprotein(a) as a determinant of coronary heart in young women. Circulation.. 1997;95:329-334.
12. Wild SH, Fortmann SP, Marcovina SM. A prospective case-control study of lipoprotein(a) levels and apo(a) size and risk of coronary heart disease in Stanford Five City Project participants. Arterioscler Thromb Vasc Biol. In press.
13.
Brown SA, Hutchinson R, Morrisett J, Boerwinkle E, Davis CE, Gotto AM Jr, Patsch W. Plasma lipid, lipoprotein cholesterol, and apoprotein distributions in selected US communities: the Atherosclerosis Risk in Communities (ARIC) study. Arterioscler Thromb.. 1993;13:1139-1158.
14.
Shewmon DA, Stock JL, Rosen CJ, Heiniluoma KM, Hogue MM, Morrison A, Doyle EM, Ukena T, Weale V, Baker S. Tamoxifen and estrogen lower circulating lipoprotein(a) concentrations in healthy postmenopausal women. Arterioscler Thromb.. 1994;14:1586-1593.
15. Soma MR, Meschia M, Bruschi F, Morrisett JD, Paoletti R, Fumagalli R, Crosignani P. Hormonal agents used in lowering lipoprotein(a). Chem Phys Lipids. 1994;67-68:345-350.
16. Morgan JM, Capuzzi DM, Guyton JR, Centor RM, Goldberg R, Robbins DC, DiPelle D, Jenkins S, Marcovina S. Treatment effect of Niaspan, a controlled-release niacin, in patients with hypercholesterolemia: a placebo-controlled trial. J Cardiovasc Pharmacol Therapeut.. 1996;1:195-202.
17. Gurakar A, Hoeg JM, Kostner G, Papadopoulos NM, Brewer HB Jr. Levels of lipoprotein Lp(a) decline with neomycin and niacin treatment. Atherosclerosis.. 1985;57:293-301.[Medline] [Order article via Infotrieve]
18.
Maher VMG, Brown BG, Marcovina SM, Hillger LA, Zhao Z-Q, Albers JJ. Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a). JAMA.. 1995;274:1771-1774.
This article has been cited by other articles:
 |
|
 |
|
  G. Weidner, C.-W. Kohlmann, M. Horsten, S. P. Wamala, K. Schenck-Gustafsson, M. Hogbom, and K. Orth-Gomer Cardiovascular Reactivity to Mental Stress in the Stockholm Female Coronary Risk Study Psychosom Med, November 1, 2001; 63(6): 917 - 924. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. T. Raitakari, M. R. Adams, and D. S. Celermajer Effect of Lp(a) on the Early Functional and Structural Changes of Atherosclerosis Arterioscler Thromb Vasc Biol, April 1, 1999; 19(4): 990 - 995. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Wehinger, A. Kastrati, S. Elezi, H. Baum, S. Braun, F.-J. Neumann, and A. Schomig Lipoprotein(a) and coronary thrombosis and restenosis after stent placement J. Am. Coll. Cardiol., March 15, 1999; 33(4): 1005 - 1012. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Ribichini, G. Steffenino, A. Dellavalle, A. Vado, V. Ferrero, T. Camilla, S. Giubergia, and E. Uslenghi Plasma Lipoprotein(a) Is Not a Predictor for Restenosis After Elective High-Pressure Coronary Stenting Circulation, September 22, 1998; 98(12): 1172 - 1177. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. W. F. Wilson and W. B. Kannel Should We Measure Lipoprotein Lp(a)? Arch Intern Med, June 9, 1997; 157(11): 1161 - 1162. [Abstract] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||