Elsevier

Atherosclerosis

Volume 157, Issue 1, July 2001, Pages 241-249
Atherosclerosis

Lipoprotein (a) and development of intermittent claudication and major cardiovascular events in men and women: The Edinburgh Artery Study

https://doi.org/10.1016/S0021-9150(00)00719-XGet rights and content

Abstract

Lipoprotein (a) may be an important risk factor for atherosclerosis. It is widely accepted that lipoprotein (a) levels are raised in patients with coronary heart disease, but there is some doubt about the causality of the relationship. In addition, little is known about the relationship between lipoprotein (a) and either stroke or peripheral arterial disease, nor about the role of lipoprotein (a) in women. Subjects aged 55–74 years (n=1592) were selected at random from 11 general practices in Edinburgh, Scotland and followed up for 5 years. The incidences of myocardial infarction, intermittent claudication and stroke were 13.4, 9.4 and 3.7%, respectively. Raised lipoprotein (a) levels at baseline were associated with an increased risk (95% confidence interval) of myocardial infarction RR 1.15 (1.00, 1.32), intermittent claudication RR 1.32 (1.10, 1.57) but not significantly for stroke RR 1.24 (0.93, 1.64). This increased risk persisted for intermittent claudication after adjustment for baseline cardiovascular disease and other risk factors RR 1.20 (1.00, 1.43), but for myocardial infarction became non-significant RR 1.06 (0.91, 1.23). The risk of disease associated with raised lipoprotein (a) was slightly higher in women than in men, especially for intermittent claudication (men RR 1.09 (0.87, 1.36) compared to women RR 1.37 (1.01, 1.87)). In conclusion, we found that lipoprotein (a) was an independent predictor of cardiovascular events in both sexes. The association between lipoprotein (a) and cardiovascular events may have been stronger in women than in men, and for peripheral arterial disease than myocardial infarction and stroke.

Introduction

Lipoprotein (a) consists of a large hydrophilic glycoprotein, apolipoprotein (a), linked to a molecule of low density lipoprotein cholesterol. In European populations, the distribution of lipoprotein (a) is positively skewed with levels predominantly genetically determined. Soon after the discovery of lipoprotein (a) in 1963 [1], raised levels were reported in patients with coronary heart disease [2], [3]. Subsequent case control studies confirmed this association [4], [5], [6], [7]. It has since been suggested that lipoprotein (a) may interfere in clot lysis by competing for the same binding sites as plasminogen, with which it has structural homology [8]. Lipoprotein (a) may also assist wound healing by concentrating cholesterol-rich lipoprotein at sites of blood clots [9] or could result in cell proliferation in wounds due to inhibition of transforming growth factor-β, a natural inhibitor of this process [10].

Although it is widely accepted that lipoprotein (a) levels are raised in patients with pre-existing coronary artery disease, results of prospective studies have been inconclusive, raising doubts about the causality of the relationship. Some [11], [12], [13], [14], [15] but not all [16], [17], [18] prospective studies have demonstrated a relationship between raised lipoprotein (a) levels and the subsequent development of coronary artery disease in men. In general, negative studies have tended to exclude subjects with symptomatic cardiovascular disease at baseline, suggesting that raised lipoprotein (a) levels are a response to, rather than a precursor of atherosclerosis. Further prospective studies are required to resolve this issue. In addition, the predominance of studies on coronary artery disease in men means that relatively little is known about the relationship between lipoprotein (a) and either stroke or peripheral arterial disease or about the role of lipoprotein (a) in women.

The Edinburgh Artery Study is a prospective, population-based study, which provided the opportunity to explore the relationship between lipoprotein (a) and a variety of cardiovascular events, including myocardial infarction, stroke and new intermittent claudication in men and women separately. It was also possible to investigate the independence of the relationship with respect to a wide range of potentially confounding factors, including baseline symptomatic and asymptomatic cardiovascular disease. Our aims were to determine whether lipoprotein (a) was an independent risk factor for the development of cardiovascular events in men and/or women, taking into account pre-existing cardiovascular disease and other cardiovascular risk factors.

Section snippets

Baseline study

The Edinburgh Artery Study began in 1988 as a cross-sectional survey of 809 men and 783 women aged 55–74 years. This population, which was almost exclusively Caucasian in origin, was selected at random, in 5-year age bands, from 11 general practices serving a range of socioeconomic and geographic areas throughout the city. The response rate was 65%, and follow-up of a sample of non-responders showed no substantial bias. Details of the study recruitment and examination process have been

Results

After 5 years of follow-up, 297 of the original 1592 Edinburgh Artery Study subjects had had a cardiovascular event (fatal and non-fatal MI, n=166; fatal and non-fatal stroke, n=46; new intermittent claudication, n=116). The 5-year incidence of events by sex is given in Table 1. The incidence of all types of event was higher in men than in women. One thousand two hundred and thirty-seven subjects (588 men and 649 women) did not suffer a new cardiovascular event during follow-up (‘healthy

Discussion

In this prospective study of a large Scottish population, we found that lipoprotein (a) was an independent risk factor for the development of cardiovascular disease (myocardial infarction, stroke or intermittent claudication combined) and for intermittent claudication. The relationship between raised lipoprotein (a) levels and stroke did not reach statistical significance, possibly due to a small number of these events, and that between lipoprotein (a) and myocardial infarction lost

Acknowledgements

We thank the British Heart Foundation for financial support and all participants, staff and general practitioners involved in the Edinburgh Artery Study.

References (43)

  • M.D. Widmann et al.

    Lipoprotein (a): a risk factor for peripheral vascular disease

    Ann. Vasc. Surg.

    (1993)
  • S.W.K. Cheng et al.

    Lipoprotein (a) and its relationship to risk factors and severity of atherosclerotic peripheral vascular disease

    Eur. J. Vasc. Endovasc. Surg.

    (1997)
  • B. Cantin et al.

    Lipoprotein (a) distribution in a French Canadian population and its relation to intermittent claudication (the Quebec Cardiovascular Study)

    Am. J. Cardiol.

    (1995)
  • K. Berg

    A new serum type system in man — the Lp system

    Acta Pathol. Microbiol. Scand.

    (1963)
  • G.H. Dahlen et al.

    Angina of effort and an extra pre-beta lipoprotein fraction

    Acta Med. Scand.

    (1972)
  • G.H. Dahlen et al.

    Myocardial infarction and an extra pre-beta lipoprotein fraction

    Acta Med. Scand.

    (1972)
  • G. Hoefler et al.

    Lipoprotein Lp(a): a risk factor for myocardial infarction

    Arteriosclerosis

    (1988)
  • B.R. Zysow et al.

    The relationship of lipoprotein (a) to haemostasis

    Curr. Opinion Lipidol.

    (1993)
  • M.S. Brown et al.

    Teaching old dogmas new tricks

    Nature

    (1987)
  • A. Rosengren et al.

    Lipoprotein (a) and coronary heart disease: a prospective case-control study in a general population sample of middle-aged men

    Br. Med. J.

    (1990)
  • E.J. Schaefer et al.

    Lipoprotein (a) levels and risk of coronary heart disease in men: the Lipid Research Clinics Coronary Primary Prevention Trial

    J. Am. Med. Assoc.

    (1994)
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