LDL particle size was smaller in CAD, but other lipid parameters were stronger predictors of CAD
ACP J Club. 1997 Mar-Apr;126:48. doi:10.7326/ACPJC-1997-126-2-048
Related Content in this Issue
• Companion Abstract and Commentary: Triglyceride level but not LDL particle size was an independent risk factor for MI in men
Gardner CD, Fortmann SP, Krauss RM. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA. 1996 Sep 18;276:875-81.
To determine the association between low-density lipoprotein (LDL) particle size and the risk for coronary artery disease (CAD) in men and women.
Nested case-control study (Stanford Five-City Project).
Community study in the United States.
Patients with acute fatal or nonfatal myocardial infarction (MI) or fatal CAD were identified using a community surveillance system. Patients were matched with controls for age, sex, ethnicity, city, and time of initial survey. Potential control participants were excluded if they had symptoms of CAD or cerebrovascular disease. 90 pairs of men and 34 pairs of women were studied.
Assessment of risk factors
LDL particle size was the main risk factor of interest. Other factors were total cholesterol (TC), high-density lipoprotein (HDL) cholesterol and triglyceride levels, smoking, blood pressure, and body mass index. Risk factors were ascertained using data and samples from baseline clinical examinations (plasma samples were frozen for 5 to 10 years).
Main outcome measures
Fatal or nonfatal MI or fatal CAD were the main outcome measures. MI and CAD were validated by nurse and physician review of clinical records using a diagnostic algorithm that included chest pain, electrocardiograms, cardiac enzymes, and autopsy findings.
LDL particle size was smaller for all patients with CAD (case-control difference, -0.51 nm, P < 0.001) and for men with CAD (case-control difference, -0.52 nm, P < 0.001) than for controls. Among women, the case-control difference in LDL particle size was -0.48 nm, and this was not statistically significant (P = 0.06). For men and women combined, the strongest predictors of CAD were LDL particle size (P < 0.001), smoking (P = 0.04), and non-HDL cholesterol levels (P = 0.01). After adjustment for the TC:HDL cholesterol ratio, the particle size was no longer an independent predictor of CAD risk for men or women separately and was a weaker predictor than either the TC:HDL cholesterol ratio or smoking for men and women combined. After the same adjustment among men, the only predictor of CAD was the TC:HDL cholesterol ratio (P < 0.001). For women, independent predictors of CAD were systolic blood pressure (P = 0.004), smoking (P = 0.02), and the TC:HDL cholesterol ratio (P = 0.01).
Low-density lipoprotein particle size was smaller in patients with coronary artery disease, but its predictive properties were markedly decreased after adjustment for other lipid risk factors.
Sources of funding: National Institutes of Health; National Dairy Council; Department of Energy.
For article reprint: Dr. S.P. Fortmann, Stanford Center for Research in Disease Prevention, Stanford University School of Medicine, 1000 Welch Road, Palo Alto, CA 94304-1825, USA. FAX 415-725-6906.
Many studies have shown an association between LDL cholesterol levels and CAD and MI. Several case-control studies have also shown an association between small, dense LDL particles and CAD.
The studies by Gardner and Stampfer and their colleagues show that LDL size abnormalities precede the onset of CAD but do not resolve whether small LDL particles are atherogenic or merely markers for high risk. In both studies, the risk for MI was higher among men who had a higher TC:HDL cholesterol ratio and triglyceride level.
The studies differed in some potentially important respects. Gardner and colleagues studied matched pairs of men and women, whereas Stampfer and colleagues studied men (physicians). In the Gardner study, the outcomes were broader (CAD and definite MI vs MI only) and the men had a cardiovascular mortality that was 15% of that of a comparable population of white men. Potentially important methodologic issues were nonstandardization of meal size and composition; timing of meals relative to blood samples; degradation of samples over time; and in the study by Gardner and colleagues, noninclusion of diabetes as a risk factor.
Small LDL particle size may reflect derangement in the metabolism of triglyceride-rich lipoprotein particles. Triglycerides are readily metabolized by most tissues and do not collect in macrophage cytoplasm or in the extracellular lipid pool that forms the core of the atherosclerotic plaque (LaRosa J. Personal communication). This fact may help explain why triglyceride levels were not consistent independent predictors of atherosclerosis when adjustments were made for cholesterol levels and why the role of hypertriglyceridemia as an independent CAD risk factor is still unresolved (1). Hypertriglyceridemia may indirectly promote atherosclerosis by reducing HDL cholesterol levels and increasing the more atherogenic LDL cholesterol levels (e.g., more easily oxidized, smaller, denser particles) (2) or by facilitating a more hypercoagulable state.
Triglyceride levels increase with age (more in men than women) and are more sensitive than other lipoprotein fractions to diet, exercise, and weight change. Observational studies suggest that the triglyceride level may be especially important as a risk factor for CAD in women and the elderly. However, neither of the studies advanced our understanding about these issues in women, probably because of the small number of women included. The small number may partially explain why LDL particle size and levels of triglyceride and HDL cholesterol did not predict CAD in women.
Studies have shown that lowering cholesterol levels by diet or drugs reduces the risk for CAD and may have beneficial effects on carotid arteries (3). No clinical trial designed predominantly to lower triglyceride levels has yet been done. In the Helsinki study (4), the largest decrease in cardiovascular risk was shown in patients who had the highest triglyceride levels and LDL:HDL cholesterol ratios. A study that used bezafibrate in men who had had an MI (5) showed little LDL cholesterol lowering, a 31% reduction in triglyceride levels, and coronary events and angiographic findings comparable with those in the studies that used statins to lower LDL cholesterol (6).
How should clinicians apply the results of these studies? The use of the more readily available tests, such as measurement of plasma triglyceride, TC, HDL and LDL cholesterol, and the TC:HDL cholesterol ratio, is well established. Measurement of other lipid or lipoprotein moieties, such as very-low-density lipoprotein and apolipoprotein B, may be helpful for specific patients. Until measurement of LDL particle size becomes more widely available at reasonable cost and specific treatment for hypertriglyceridemia is better established bytrials, measurement of particle size should probably remain in the research domain. Vigorous modification of CAD risk factors, including treatment of dyslipidemias, remains the cornerstone of patient management.
Marc D. Meissner, MD
Harper HospitalWayne State UniversityDetroit, Michigan, USA
Marc D. Meissner, MD
Harper HospitalWayne State University
Detroit, Michigan, USA