High density lipoprotein subfractions and the risk of coronary heart disease: 9-years follow-up in the Caerphilly Study
Introduction
High-density lipoprotein (HDL) cholesterol has been shown to be a predictor of subsequent coronary heart disease (CHD) [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]. These studies indicate that HDL cholesterol predicts independently of total cholesterol and low-density lipoprotein cholesterol. High-density lipoprotein can be further divided into two subclasses; HDL2, which has a density range of 1.125–1.063 g ml−1 and HDL3, which represents the range 1.210–1.125 g ml−1 [14]. Different subfractions play different roles in reverse cholesterol transport and represent different stages in the overall metabolism of HDL [15], [16].
What is the effect of HDL2 and HDL3 cholesterol on the risk of incident CHD? and what is the relative importance of the HDL2 and HDL3 subfractions? To date, only six prospective studies [1], [17], [18], [19], [20], [21] have examined the predictive power of HDL subfractions for incident CHD and the results reported have been inconsistent.
In the earliest Livermore study [1], Gofman first suggested that both HDL2 and HDL3 subfractions were significantly lower in the 38 men with CHD than in those without CHD. No multivariate analysis comparing the relative contribution of each subfraction was performed. In the Kuopio study [17], in which 1799 randomly selected Finnish men were recruited during 1984 and 1987, both total HDL and HDL2 cholesterol had inverse associations with the risk of acute myocardial infarction, whereas the role of HDL3 cholesterol remained equivocal after adjustment for HDL2 cholesterol. In the Physician's Health Study [18], Stampfer employed a prospective case/control design for 5 years follow-up (246 cases and 246 controls matched for age and smoking status). Total HDL cholesterol and both HDL2 and HDL3 cholesterol were inversely related to risk of myocardial infarction (MI). The stronger association was with HDL3. In a previous study [19] of the Caerphilly and Speedwell populations, 2512 and 2348 men, respectively were enrolled for a period of 5 years follow-up. Both HDL2 and HDL3 cholesterol were inversely associated with the incidence of CHD, but the association with incident CHD appeared to be stronger for HDL3 cholesterol in both areas. However, the precision or accuracy of the laboratory measurements was poor for the micro method used in this study. Lamarche [20] reported a prospective study between 1980/1981 and 1990 in the Quebec City suburbs, Canada. A total of 1169 French-Canadian men younger than 60 years were followed (944 men with complete follow-up in 1990). After adjustment for other risk factors, men in the fourth quartile of both HDL2 and HDL3 cholesterol distributions were at significantly lower risk of incident CHD than were those in the first quartile. In a multivariate model, HDL2 cholesterol was more closely related to the development of CHD than HDL3 cholesterol. Fujimoto [21] conducted a prospective study in Seattle of 175 Japanese-American men without CHD who were followed for up to 10 years. In univariate analyses, HDL cholesterol and both HDL2 and HDL3 cholesterol were inversely associated with risk of a major incident event. Multiple logistic regression models adjusted for BMI and age showed that intra-abdominal fat accounted for the effect of HDL cholesterol or triglycerides.
In general, whether the protective effect of HDL can be attributed to one or both HDL subfractions still remains controversial [18], as is the evidence on the relative importance of HDL2 and HDL3 cholesterol [19]. In the present report, we consider these important questions using HDL subfractions measured on the Caerphilly cohort alone using fresh plasma samples by a precipitation technique [22] that is more accurate than the micro-centrifugal method that was used in the earlier report from the combined Caerphilly and Speedwell studies [19].
Section snippets
Study population and design
In brief, at the first re-examination of men in the Caerphilly study, the men were invited to attend an afternoon/evening clinic where detailed demographic, medical and lifestyle histories [23], [24], [25] were obtained; the London School of Hygiene and Tropical Medicine (LSHTM) chest pain questionnaire [26] was administered. A full 12-lead electrocardiogram (ECG) was recorded, and height, weight and blood pressure were measured. The men were then invited to return, fasting, to an early morning
Results
Of the total cohort of 2398 men, 282 (12% of all men) developed major new CHD events over the follow-up period of nearly 9 years. Of these, 149 (53%) were fatal and 133 non-fatal (47%). Fasting blood samples were available from 2225 (93%) men, of whom 261 (12%) developed major CHD. Of these 261 events, 125 (48%) were fatal and 136 (52%) non-fatal. HDL cholesterol measurement was missing for 474 (21%) men, either HDL2 or HDL3 cholesterol measurement was missing for 493 (22%) men.
Table 1 shows
Discussion
In this present paper, we are addressing two questions: ‘can we improve the prediction of CHD by replacing HDL cholesterol by some combination of HDL2 and HDL3 cholesterol?’ and ‘is the association between HDL and CHD mediated by HDL2 or HDL3 cholesterol, or both?’ The first question is of practical importance, and the second is relevant to our understanding of the mechanisms of the association between HDL metabolism and CHD.
Our results suggest that (1) we cannot improve prediction of CHD by
Conclusions
We have demonstrated that the prediction of the risk of incident CHD from HDL cholesterol alone could not be improved upon by the linear combination of both the HDL2 and HDL3 subfractions. HDL3 cholesterol is strongly and inversely associated with the risk of incident CHD, whereas HDL2 cholesterol is not significantly associated with risk of subsequent CHD. The HDL3 cholesterol may be the major contributor to the protective effect of elevated plasma HDL cholesterol levels on CHD risk.
Acknowledgements
We thank the British Heart Foundation and the Medical Research Council for financial support. We also thank Dr Keith Davis and Deborah Wheatley for carrying out the HDL measurements; these were made with the assistance of a grant from the South Glamorgan Health Services Research Committee.
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