Low-density and high-density lipoprotein subspecies and risk for premature coronary artery disease

Abstract

An approach to diet and drug therapy to treat abnormal lipid levels was developed by the National Cholesterol Education Program (NCEP) based on low-density lipoprotein cholesterol (LDL-C) concentrations. This approach was subsequently modified to include high-density lipoprotein cholesterol (HDL-C) concentrations. Although drug therapy can be recommended for the primary prevention of coronary artery disease (CAD) in many patients with high LDL-C levels, the decision about when to treat borderline-high LDL-C concentrations in the absence of clinical atherosclerosis is more difficult. The NCEP developed a paradigm for the primary prevention of CAD with drug therapy in patients with borderline LDL-C levels of 130 –190 mg/dL, based on an individual patient’s risk factors for CAD and findings on physical examination. A patient with borderlinehigh LDL-C levels would be considered a candidate for lipid-lowering drug therapy in the presence of other risk factors for premature CAD, such as male sex, hypertension, diabetes, obesity, family history of early CAD, and smoking. In addition to recognizing elevated HDL-C levels as a major predisposing factor for CAD, the NCEP added menopause without estrogen-replacement therapy to its risk-factor guidelines. 2 Although these risk factors imply a greater relative risk for a subset of middleaged men and women, the absolute risk for CAD in older individuals is overwhelmed by the effect of age. Recent studies have shown the value of reducing LDL-C levels in the primary prevention of cardiovascular disease (CVD). In the West of Scotland Prevention Study, LDL-C lowering with pravastatin resulted in a 31% reduction in CVD in middle-aged men with LDL-C levels of 155–232 mg/dL. Interestingly, baseline LDL-C levels did not predict a reduction in events. The Air Force/ Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) 5 reported a 37% reduction in primary endpoints over 5 years with lovastatin therapy in middle-aged men and women with borderline-high LDL-C levels, as defined by the NCEP guidelines. This study confirmed that some high-risk patients with borderline-high LDL-C levels benefit from lipid-lowering therapy. However, clinicians are still faced with the challenge of identifying those patients with borderline-high LDL-C concentrations who are at increased risk for CVD and will respond to lipid-lowering therapy. Most atherosclerosis prevention trials have focused on total cholesterol levels or LDL-C levels as the primary target for intervention. It is clear, however, that not all the reductions in coronary events can be attributed to lowering LDL-C concentrations. Evidence indicates that various lipoprotein subspecies may enhance the clinician’s ability to identify patients at high risk for CAD prior to the development of clinical atherosclerosis. In particular, small, dense low-density lipoprotein (sdLDL), intermediate-density lipoprotein (IDL), high-density lipoprotein-2 (HDL2), lipoprotein(a) (Lp[a]), and apolipoprotein(CIII) (apo[CIII]) distribution among lipoproteins have been implicated in the etiology of CAD and may respond to lipid-lowering therapy. LDL-C comprises lipoproteins with hydrated densities of 1.006 –1.063 g/mL. Included in this density range are a number of lipoprotein subspecies, including IDL, sdLDL, and big, buoyant LDL (bbLDL). Indeed, further heterogeneity may exist within each of these major subspecies. IDLs are believed to be particularly atherogenic, and some investigators have attributed a greater atherogenic potential to sdLDL compared with bbLDL. The measurement of plasma lipoprotein apoprotein concentrations can be used to estimate the presence of atherogenic subspecies. A combination of elevated apolipoprotein(B) (apo[B]) levels and borderline-high LDL-C levels reflects an increase in both IDL and sdLDL concentrations. Lowdensity lipoprotein (LDL) compositional abnormalities, combined with decreased HDL2 cholesterol levels, can be estimated by the ratio of apo(B) to apolipoprotein(AI) (apo[AI]) or by the distribution of apo(CIII) between apo(B)-containing particles and high-density lipoprotein (HDL) particles. The association of apo(CIII) with apo(B) particles reflects the presence of increased concentrations of IDL and small very low-density lipoprotein (sVLDL) particles, and often accompanies elevated sdLDL levels. Many of these variations in lipoprotein subspecies occur in patients who have been characterized by the NCEP criteria used to identify individuals with borderline-high LDL-C concentrations at high risk for CAD (Table 1). Central obesity, which commonly occurs in middleFrom the Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition, University of Washington School of Medicine, Seattle, Washington. Supported in part by NIH grants HL-30086, DK-02456, RR-36 (GCRC), and DK-35816 (CNRU). Correspondence should be addressed to John D. Brunzell, MD, University of Washington School of Medicine, Department of Medicine, Box 356178, Seattle, Washington 98195-6178.