Is lipoprotein(a)-cholesterol a better predictor of vascular disease events than total lipoprotein(a) mass? A nested case control study from the West of Scotland Coronary Prevention Study
Introduction
Elevations of plasma levels of lipoprotein(a) (Lp(a)) (lipoprotein mass over 20–30 mg/dl) have been estimated to confer a 1.5- to 3-fold increased risk of coronary heart disease (CHD) [1], [2], [3], [4], [5]. Several prospective studies have examined the effect of plasma Lp(a) on the incidence of coronary events. In an early uncontrolled study, plasma Lp(a) levels were measured in 232 Swedish males (age 50–53) without overt atherosclerotic disease. The patients were followed for 11 years, and there was a 2–3 fold higher incidence of myocardial infarction (MI) and stroke in those with high plasma concentrations of Lp(a) [6]. A larger prospective case-control study of middle aged men [7] also revealed an association between elevated Lp(a) levels and coronary events.
However, another major prospective study failed to find an association between high plasma levels of Lp(a) and coronary events; in a subgroup analysis of the Helsinki Heart Study, 140 individuals who had suffered an MI during the study were compared with 136 controls [8]. There was no significant difference in the distribution of plasma Lp(a) concentrations in these two populations. Similarly, when plasma Lp(a) levels in Finnish individuals with and without angiographic evidence of CHD were compared, no significant difference was found [9].
Ridker et al. [10] found no evidence of association between plasma Lp(a) concentration and risk of future MI. While this was one of the largest prospective studies to date, its conclusions have been the subject of criticism [11]. A similar sized prospective study of a cohort from the Lipid Research Clinics Coronary Primary Prevention Trial [12] did identify elevated plasma Lp(a) levels as an independent risk factor for CHD in hypercholesterolaemic Caucasian males.
The largest prospective study to date has been the Göttingen Risk Incidence and Prevalence Study (GRIPS) [13]. In this study ∼6000 males aged between 40 and 59.9 years with no overt evidence of CHD were followed for 5 years. The primary end-point in this study was fatal or non-fatal MI. Over the study period, 107 subjects with MI were recorded and compared against a control group of 5364. These groups, as expected, differed significantly in their plasma lipids, but they also exhibited a statistically significant difference in plasma Lp(a) 18 versus 9 mg/dl (P<0.001). Using multivariate logistic regression analysis, the authors were able to rank the different risk factors in order of importance. In this scheme plasma Lp(a) proved to be an important CHD risk factor, ranking fifth behind low density lipoprotein (LDL)-cholesterol, family history of myocardial infarction, fibrinogen, and high density lipoprotein (HDL)-cholesterol.
It must be noted that in all of these studies the total Lp(a) lipoprotein mass has been quantified indirectly using Lp(a) protein assays and to date no information has been presented relating the cholesterol content of Lp(a) to risk of vascular disease.
Estimation of the plasma Lp(a)-cholesterol [Lp(a)-C] concentration is now possible using the LipoPro™ Lp(a)-C assay (Genzyme Corporation, Cambridge, MA). This assay system has been shown to be analytically robust [14] but is only of significant interest if it provides new information over and above that gained from traditional Lp(a) protein mass assays, e.g. a greater ability to discriminate patients at risk of atherosclerotic vascular disease from controls. In this study we measured Lp(a)-C and Lp(a) mass in a nested case control study within the West of Scotland Coronary Prevention Study (WOSCOPS). Samples for the Lp(a) mass estimation were assayed soon after collection, while assays for Lp(a)-C were performed on samples frozen for up to 8 years. The results reinforce the concordance of the two assay systems and confirm that in this population the Lp(a)-C assay provides no added information.
Section snippets
Subjects
The stored plasma samples from 346 participants in the placebo arm of the WOSCOPS were analysed. The baseline characteristics of these subjects are detailed elsewhere [15], [16]. From the study database 108 subjects who had suffered a serious vascular event and 238 controls who had not were identified. A serious vascular event is defined here as the combined end point of CHD death or non-fatal MI (definite or suspect), fatal or non-fatal stroke, silent MI, revascularisation (angioplasty or
Immunoturbidimetric lipoprotein(a) mass assay
Plasma Lp(a)-mass was also measured using the commercially available latex agglutination assay (Bio-Stat Diagnostics Ltd, Stockport, UK) which we have previously evaluated [18]. An anti-Lp(a) antibody is absorbed to latex particles and this antibody-latex suspension is incubated with plasma. The resulting agglutination that occurs when the Lp(a) in the plasma binds to the anti-Lp(a)/latex particle is detected by a change in absorbance. The magnitude of this change is proportional to the
Results
Plasma samples collected at baseline, which had been stored for up to 8 years, were thawed and analysed for Lp(a)-C and Lp(a) mass. A total of 108 patients who had suffered a serious vascular event during the course of the WOSCOPS and 238 controls were examined. In addition the apo(a) isoform sizes of these subjects were measured using a high resolution immunoblotting system. Comparisons of the results from these different assays are shown in Table 1. The median Lp(a)-C concentrations were the
Discussion
The role of Lp(a) in the development of cardiovascular disease remains controversial, with a number of prospective controlled studies showing disparate results. One explanation for these apparent discrepancies may be the different assay methods used to quantify plasma Lp(a).
All assays used so far in these studies have been protein based with calculation of the total Lp(a) lipoprotein mass based on Lp(a) protein immunoassay. It has been proposed that a better way of assaying Lp(a) and
Acknowledgements
We gratefully acknowledge the financial support of the British Hyperlipidaemia Association Parke-Davis/Pfizer Research Award, the British German Academic Research Collaboration Program (100, 313-ARC-6-92-83, and 738), SHHD Grant No. K/MRS/50/C2310, the Medical Research Funds Committee of the University of Glasgow, and the unrestricted research grant from Bristol-Myers Squibb which made WOSCOPS and the follow-up biobank studies possible.
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Cited by (13)
Long-term outcomes of primary cardiovascular prevention: A retrospective study at a referral center in Portugal
2022, Revista Portuguesa de CardiologiaLipoprotein(a) – Marker for cardiovascular risk and target for lipoprotein apheresis
2019, Atherosclerosis SupplementsCitation Excerpt :The polymorphism of Lp(a) particles is a challenge for the immunochemical laboratory measurement of Lp(a) concentration. Deterioration of Lp(a) over time in stored samples is an issue in particular for large genetic studies pooling independent study populations, and can lead to erroneous conclusions [20,21]. To date, Lp(a) determination has been based on Lp(a) mass using appropriate test calibrators.
Lipoprotein(a) and coronary atheroma progression rates during long-term high-intensity statin therapy: Insights from SATURN
2017, AtherosclerosisCitation Excerpt :The relationship between plaque burden and/or MACE with circulating Lp(a) levels may, however, be a function of concomitant LDL-C levels. Prior studies identified correlations between plaque burden (or MACE) with Lp(a) levels essentially in the setting of markedly elevated, but not mild-moderately elevated or normal LDL-C levels [22,23], and not consistently in those who demonstrated significant LDL-C reductions following a range of therapeutic interventions [24,25]. This would support recent and prior clinical observations demonstrating proatherosclerotic effects of elevated Lp(a) levels largely in the presence of higher, but not lower LDL-C levels across a large spectrum of clinical acuity [7–13], suggesting a likely interaction between dual elevations of Lp(a) and LDL-C, particularly in the setting of established coronary disease.
Lipoprotein(a) further increases the risk of coronary events in men with high global cardiovascular risk
2001, Journal of the American College of CardiologyCitation Excerpt :Most prospective data on the role of Lp(a) as a cardiovascular risk factor have been obtained from population and nested case-control studies where Lp(a) was measured in serum or plasma samples that have been stored for several years (7–9,11–16). Because freezing and thawing of serum interferes with the accurate measurement of Lp(a) (25,26), this interference may be responsible for the negative outcome of some prospective studies (13–16,24). In this PROCAM subpopulation the average risk of a 35- to 60-year-old man to suffer from a coronary event was 56 per 1,000 per 10 years.
Lipoprotein (a) as a predictor of myocardial infarction in middle-aged men
2001, American Journal of MedicineCitation Excerpt :Several studies have found no association between Lp(a) and risk of coronary heart disease. For example, the West of Scotland Coronary Prevention Study, which included men who were older and more hyperlipidemic than those in our study, found no association between Lp(a) concentrations and serious cardiovascular events (22). Two other nested case-control prospective studies, the Helsinki Heart Study and the Physicians’ Health Study, did not find that Lp(a) levels were an independent risk factor for coronary heart disease events in middle-aged men (23,24).
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Executive Committee: James Shepherd (chairman), Stuart M. Cobbe, A. Ross Lorimer, James H. McKillop, Ian Ford, Christopher J. Packard, Peter W. Macfarlane, Christopher Isles; Data and Safety Monitoring Committee: Michael F. Oliver (chairman), Anthony F. Lever, Byron W. Brown, John G.G. Ledingham, Stuart J. Pocock, Basil M. Rifkind; Cardiovascular End-points Committee: Stuart M. Cobbe (chairman), Barry D. Vallance, Peter W. Macfarlane; Adverse Events Review Board: A. Ross Lorimer, James H. McKillop, David Ballantyne; Data centre staff: Liz Anderson, David Duncan, Sharon Kean, Audrey Lawrence, June McGrath, Vivette Montgomery, John Norrie; Population screening: Melvyn Percy; Clinical coordination, monitoring, and administration: Elspeth Pomphrey, Andrew Whitehouse, Patricia Cameron, Pamela Parker, Fiona Porteous, Leslie Fletcher, Christine Kilday; Computerised ECG analysis: David Shoat (deceased), Shahid Latif, Julie Kennedy; Laboratory operations: M. Anne Bell, Robert Birrell; Company liaison and general support: Margot Mellies, Joseph Meyer, Wendy Campbell.