HDL-cholesterol as a marker of coronary heart disease risk: the Québec cardiovascular study

Abstract

Background: Primary as well as secondary prevention trials have shown the relevance of lowering LDL-cholesterol to reduce coronary heart disease (CHD) risk. However, although the association between LDL-cholesterol and CHD is well recognized, there is a considerable overlap in the distribution of plasma LDL-cholesterol levels between CHD patients and healthy subjects. The objective of the present review article is to use data from the Québec cardiovascular study to demonstrate that in men, a low HDL-cholesterol may be even more of a risk factor and a target for therapy than a high LDL-cholesterol. Methods and results: Results of the Québec cardiovascular study, a prospective study of 2103 middle-aged men followed for a period of 5 years, have confirmed results of previous studies in showing that plasma HDL-cholesterol concentration was an independent predictor of a first ischemic heart disease (IHD) event which included typical effort angina, coronary insufficiency, nonfatal myocardial infarction and coronary death. In addition, a reduced plasma HDL-cholesterol concentration was found to have a greater impact than raised LDL-cholesterol on the atherogenic index (total cholesterol/HDL-cholesterol ratio), this ratio being the best variable of the traditional lipid profile for the prediction of IHD events in the Québec cardiovascular study. However, a low HDL-cholesterol concentration is not often observed as an isolated disorder but also includes hypertriglyceridemia, elevated apo B concentration, and an increased proportion of small, dense LDL particles. These abnormalities are features of an insulin resistant-hyperinsulinemic state resulting from abdominal obesity. Conclusions: It is therefore recommended that we need to go beyond LDL-cholesterol measurement lowering therapy for the optimal management of CHD risk. Raising plasma HDL-cholesterol through weight loss and a healthy diet, by an increased physical activity and, if required, by proper pharmacotherapy is therefore a legitimate therapeutic target for the optimal prevention of CHD in a large proportion of high risk patients.

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.