High-density lipoprotein (HDL) cholesterol is an important molecule in cardiovascular disease. In myocardial infarction (MI) survivors, low levels of HDL are commonly found. For example, in the Prospective Cardiovascular Münster (PROCAM) study, coronary angiography was performed, and HDL and lowdensity lipoprotein (LDL) levels were measured, in 1,293 MI survivors and 11,402 controls. Lipoprotein measurements show that the LDL level was on average 50 mg/dl higher in MI survivors aged 30–39 years as compared to age-matched controls.
On examination of the PROCAM study population, it was apparent that most of the MI survivors in the study experienced their MI at the age of 60 years or older. Among these older individuals the HDL level seemed to have a more pronounced impact than the LDL level: in MI patients the HDL cholesterol level was on average 15 mg/dl lower than in controls, whereas the LDL level was only 3 mg/dl higher.
These findings indicated that the HDL level might have a significant impact on the development of myocardial infarction. Indeed, further research showed that HDL might be important prospectively as a risk factor for MI.
If the frequency distribution of HDL data from the PROCAM study are examined – this included 325 men aged 35–65 years with newly developed fatal or non-fatal MI, with a follow-up period of 10 years – the distribution pattern of HDL cholesterol differs markedly between cases and controls (figure 2). These and other epidemiological data suggest that individuals with low HDL cholesterol concentrations, e.g. below 40 mg/dl, are at particular risk of myocardial infarction. It should be noted, however, that available epidemiological data include only a limited number of individuals with very low (e.g. < 20 mg/dl) or very high (e.g. > 70 mg/dl) HDL cholesterol values. By implication, prognosis for risk of cardiovascular disease should be based upon the family history of such individuals or the identification of the genetic origins rather than on extrapolation of epidemiological data.
In about 95% of cases, those patients with low HDL levels (below 40 mg/dl) will also be found to have high serum triglycerides (TG). The combination of low HDL and high TG may be accompanied by obesity, insulin resistance, diabetes, metabolic syndrome and high global risk of cardiovascular disease (figure 3).
In the more unusual circumstances where the patient has low HDL but normal or only slightly elevated TG (which occurs in about 5%), it is worth making the effort to find the molecular origin of the low HDL, searching for mutations and polymorphisms in candidate genes. Systematic studies among more than 1,000 individuals with very low HDL cholesterol have identified mutations in apo-lipoprotein A-1, LCAT, HTGL, ABCA1 and SR-B1 (figure 3). It is not known exactly how mutations in these candidate genes affect the risk of atherosclerosis.
The significance of low HDL levels in MI can be derived from the PROCAM algorithm (figure 4).3 Examination of the data on 325 fatal and non-fatal MIs shows that age, systolic blood pressure, LDL, HDL, TG, diabetes, smoking, and a family history of MI seem to be independent predictors of future events. They are also significant risk factors, and age is the most important of all on mathematical ranking. In this algorithm, age ranks above LDL, smoking and HDL. In turn, HDL ranks above systolic blood pressure, diabetes, the TG level, and a family history of MI.
Management guidelines suggest that patients with a greater than 20% risk of MI over the next 10 years should be identified. Their LDL levels should be brought to below 100 mg/dl, and perhaps also their levels of HDL and other lipoproteins should be normalised in order to decrease their overall CHD risk.