Plasma lipoprotein(a) [Lp(a)] concentrations and cardiovascular events in the elderly: evidence from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)
Introduction
Lipoprotein (a) [Lp(a)], a cholesteryl ester-rich lipoprotein, comprises a particle of low density lipoprotein (LDL) to which is attached a large, hydrophilic glycoprotein, apolipoprotein(a) [apo(a)] [1], [2], [3]. Increased plasma levels of 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) [4], [5], [6], [7], [8]. Several prospective studies have examined the effect of plasma Lp(a) on the incidence of coronary events with some studies reporting an association between plasma Lp(a) and coronary risk [9], [10], [11], [12], with others failing to demonstrate any significant association [13], [14], [15].
Controversy also exists over the role of Lp(a) in cerebrovascular disease. Several studies, mostly performed in Japanese cohorts, have shown a positive association [16], [17], [18], [19], but when North American populations are studied there is divided opinion [20], [21], [22]. In the same way, the impact of Lp(a) on cognitive function is hotly debated. Increased plasma Lp(a) concentrations have been reported to increase the risk of Alzheimer's disease [23], but other workers claim the link is with vascular dementia and not Alzheimer's [24]. In contrast, a report from the large Italian Longitudinal Study on Aging concludes that elevated plasma Lp(a) levels do not appear to be a major determinant of cognitive impairment in the elderly at all [25].
The majority of subjects in the studies above were middle-aged, with relatively few over 70 years of age. Recently, Ariyo et al. studied 5888 subjects aged 65 or older and concluded that elevated plasma Lp(a) was an independent predictor of stroke, vascular death and death from any cause in older men, but not women [21]. This raises important questions about the clinical utility of plasma Lp(a) measurements in older adults. Here we examine these in detail from analyses of the large elderly cohort from the prospective study of pravastatin in the elderly at risk (PROSPER) [26], and we test the hypothesis that plasma Lp(a) concentration is an independent predictor of major coronary and cerebrovascular events and cognitive impairment in an elderly population.
Section snippets
Subjects
All subjects studied were participants in PROSPER and their characteristics are summarised in detail elsewhere [27]. Briefly, they were predominantly white Caucasian men and women aged 70–82 years who were recruited if they had either pre-existing vascular disease (coronary, cerebral or peripheral) or elevated cardiovascular risk due to smoking, hypertension, or diabetes. Their plasma total cholesterol was 4.0–9.0 mmol/l (155–348 mg/dl) and their triglycerides <6 mmol/l (<530 mg/dl). The primary
Results
Baseline plasma Lp(a) concentrations were measured in 5732 of the 5804 randomised subjects in PROSPER. Seventy-two samples were insufficient for analysis. The measured values ranged from 0.5 mg/dl (the lower detection limit of the assay) to 277 mg/dl, with a mean value of 27.5 mg/dl and a median value of 13.0 mg/dl. The frequency distribution of plasma Lp(a) concentrations is shown in Fig. 1. As has been repeatedly demonstrated in Caucasian populations throughout the world, the distribution is
Discussion
This study is the first analysis of the association between plasma Lp(a) and a range of cardiovascular endpoints including cognitive function and disability indices in a large elderly population. The main finding of this study is that the plasma Lp(a) level, while influenced by a number of baseline characteristics is not a significant predictor of cognitive function or levels of disability over a 3.2 year follow-up in a large elderly cohort. The association between plasma Lp(a) and risk of
Acknowledgments
PROSPER was originally funded by an unrestricted grant from Bristol-Myers Squibb. The Lp(a) assays were performed with the excellent technical assistance of C. Gourlay, M. Anne Bell, and J. Louden in the Department of Pathological Biochemistry, Glasgow Royal Infirmary.
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Full study group is shown in the Appendix A.