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