Review articleHDL-cholesterol as a marker of coronary heart disease risk: the Québec cardiovascular study
Introduction
The relationship between plasma LDL-cholesterol and the risk of coronary heart disease (CHD) is very well established [1], [2], [3], [4]. Furthermore, large randomized primary [5], [6] and secondary [7], [8], [9] prevention trials have shown that reducing plasma LDL-cholesterol levels with the use of statins led to a reduction in the number of CHD events and to a decrease in CHD-related mortality rates. However, although the development of statins has been a remarkable breakthrough regarding our ability to significantly reduce plasma LDL-cholesterol levels and related CHD risk, it is important to recognize that the relative reduction in the number of CHD events achieved with hypolipidemic drugs has been approximately 30% [10]. Thus, CHD patients treated with statins do remain at a high absolute risk for a recurrent CHD event. Furthermore, there is a considerable overlap in the distribution of plasma LDL-cholesterol levels between CHD patients and healthy individuals. Fig. 1 shows the distribution of plasma LDL-cholesterol at baseline in middle-aged men of the Québec cardiovascular study. Although there was a highly significant difference in average plasma LDL-cholesterol levels between the 114 men who developed a first ischemic heart disease (IHD) event (typical effort angina, coronary insufficiency, nonfatal myocardial infarction and coronary death) over the 5-year follow-up period compared with the 1989 men who remained healthy. Indeed, a substantial proportion of patients who developed a first IHD event had plasma LDL-cholesterol concentrations below the average of men who remained IHD-free. Thus, our ability to identify high-risk patients solely on the basis of LDL-cholesterol may be limited [10].
Epidemiological research conducted over the last 40 years has allowed the identification of markers of CHD risk. It is now well established that additional risk factors, such as diabetes, hypertension and smoking substantially increase risk of CHD for any given level of LDL-cholesterol [2], [11]. Furthermore, it is now common practice to measure HDL-cholesterol levels [12], [13], [14], [15] and to compute the LDL-cholesterol/HDL-cholesterol or the cholesterol/HDL-cholesterol ratios for a better assessment of CHD risk [2], [16], [17], [18]. Whether hypertriglyceridemia is an independent risk factor for CHD remains a matter of debate [19], [20], [21], [22], [23], [24], [25], but it is increasingly accepted that the presence of hypertriglyceridemia increases the likelihood of finding related atherothrombotic metabolic abnormalities [26], [27]. It is also well known that a positive family history of early CHD increases risk even in the absence of any dyslipidemia [2], [16], [17], [18]. More recently, new markers of risk have been proposed. They include apolipoprotein (apo) B [28] and elevated Lp(a) levels [29], [30], the presence of small, dense LDL particles [31], [32], [33], hyperinsulinemia as a marker of insulin resistance in non-diabetic subjects [34], [35], elevated homocysteine concentrations [36], [37], renin and aldosterone in hypertensive patients [38], [39], markers of an impaired fibrinolytic capacity and of susceptibility to thrombosis [26], [27], [40], [41] and markers of systemic inflammatory processes [42], [43].
The objective of this review is to discuss work from our laboratory, which emphasizes the importance of HDL as a risk factor for CHD. Results from the prospective Québec cardiovascular study as well as data from our metabolic studies, which are relevant to our understanding of the low HDL syndrome, will be reviewed concurrently. As we have used cumulative IHD end points in the Québec cardiovascular study, we will refer to IHD when discussing our results whereas CHD will be used to globally describe events in other studies.
Section snippets
HDL-cholesterol, triglycerides and CHD risk
The relationship of a low HDL-cholesterol concentration to an increased risk of CHD has become a widely accepted concept. Early data from the Framingham study [12] have shown that low HDL-cholesterol concentration was associated with a substantial increase in the risk of CHD. In a review article on this topic, Austin examined 19 prospective studies with measurements of HDL-cholesterol levels and found that 15 studies reported evidence for a cardio-protective effect of HDL-cholesterol, 3 studies
The low HDL syndrome: the Québec cardiovascular study
The following section describes the evidence from the Québec cardiovascular study that the low HDL syndrome is associated with a substantially increased risk of IHD. In 1985, we had the opportunity to study a sample of 2443 middle-aged men for their IHD risk factors, including the measurement of a fasting lipoprotein-lipid profile. Subjects with IHD or with triglyceride levels greater than 4.5 mmol/l were excluded from follow-up. We were then able to obtain 5-year follow-up data in a sample of
Conclusion
Thus, we need to go beyond LDL-cholesterol measurement and LDL-cholesterol lowering therapy for the proper evaluation and optimal management of CHD risk. Reducing plasma triglyceride levels and raising HDL-cholesterol concentration through weight loss and healthy eating habits, increasing energy expenditure by introducing more physical activity in the patient's lifestyle (or even getting our subjects involved in regular endurance exercise programs), may contribute to improve features of the
Acknowledgements
Jean-Pierre Després is chair professor of human nutrition and lipidology which is supported by Parke Davis/Warner-Lambert and Provigo. Isabelle Lemieux is recipient of a fellowship from the Heart and Stroke Foundation of Canada whereas Benoit Lamarche is a scholar of the Canadian Institute for Health Research (CIHR). This work was supported by the CIHR (MT-14014, MGC-15187) of Canada as well as by an unrestricted grant from Fournier Pharma Inc.
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