The tangled web of coronary risk factors. Although epidemiologic, genetic, and pathophysiologic studies have shown that low-density lipoproteins (LDLs) are involved in the development of coronary artery disease, the standard measurement of LDL cholesterol comprises a number of separate components that may contribute in different ways to the disease process. Some of these components appear to be of particular pathologic importance. Intermediate-density lipoproteins (IDLs) and lipoprotein (a) are highly atherogenic species that each normally account for up to 10% to 15% total LDL cholesterol but may be disproportionately elevated in pathologic states and may therefore contribute disproportionately to coronary disease risk in certain patients. Recently, another subclass of LDL, characterized by relatively small particle size and increased density, also has been found to be associated with relatively increased risk of coronary disease. Furthermore, levels of this subclass, designated LDL-III, are linked to a number of interrelated hormonal and metabolic factors, each of which have also been associated with risk of coronary artery disease. These include male gender, postmenopause, abdominal adiposity, elevated triglyceride levels, increased levels of apolipoprotein B, and reductions in high-density lipoproteins (HDLs), particularly in the HDL2 subclass. Other studies have demonstrated that many of these factors are also commonly associated with relative insulin resistance and hyperinsulinemia. Thus, a lipoprotein profile characterized by a relative increase in LDL-III and a reduction in HDL2 is indicative of a constellation of metabolic features that defines a high-risk state and that makes it extremely difficult to single out one or more factors that are most directly involved in the disease process. Combinations of genetic and environmental factors acting on this "tangled web" of risk factors may account for much of the variation in coronary disease susceptibility found in the general population. 