Using 2-16% gradient gel electrophoresis, we examined low density lipoprotein (LDL) particle size in relation to plasma lipoproteins in 1,168 women and 1,172 men from the Framingham Offspring Study. In addition, we studied the effect of dietary intake on LDL size in a subset of the population. Seven LDL size peaks were identified, with the largest, LDL 1, being found in the density range 1.019-1.033 g/ml; LDL 2 and LDL 3 in d= 1.033-1.038 g/ml; LDL 4 and LDL S in d= 1.038-1.050 g/ml; and the smallest, LDL 6 and 7, in d=1.050-1.063 g/ml. Seventy-seven percent of the population had one major and at least one minor LDL peak. Secondary LDL peaks accounted for 23% of the total LDL relative area, based on laser scanning densitometry. LDL size distribution was skewed toward larger LDL particles in women (prevalence of LDL 1, 30% and of LDL 2, 31%), whereas men exhibited a more symmetric distribution (prevalence of LDL 3, 42%). The prevalence of small (<255 A), dense (d>1.038 g/ml) LDL particles 4-7 was 33% in men, 5% in premenopausal women, and 14% in postmenopausal women. In agreement with previous reports, small, dense LDL particles were significantly (p<0.0001) associated with increased triglyceride and apolipoprotein (apo) B levels and decreased HDL cholesterol and apo A-I levels. In addition, we found a significant (/»< 0.0001) association between LDL cholesterol and LDL size. The highest LDL cholesterol levels were found among women with LDL 4 (148 mg/dl) and men with LDL 3-5 (138 mg/dl). In addition, the presence of LDL 3 or 4 as secondary peaks was significantly associated with higher LDL cholesterol levels, while smaller secondary LDL peaks were associated with higher triglyceride levels. We also found that compared with subjects with optimal LDL cholesterol levels (<130 mg/dl), individuals with high-risk LDL cholesterol levels (a 160 mg/dl) had 1) a higher prevalence of LDL 3 and 4 (women only) and a lower prevalence of LDL 1 and 2 (women only) and 2) 11% higher LDL cholesterol to apo B ratios, even when matched for LDL particle size. Furthermore, low saturated fat and cholesterol intakes were significantly associated (p<0.01) with smaller LDL particles. Therefore, the identification of small, dense LDL particles per se may not be a good indicator of coronary artery disease risk in population studies. Gender differences and environmental factors that affect triglyceride levels and LDL physical and chemical properties should be taken into consideration. In addition, LDL 3-5 particles in men and 4 in women are associated with the highest LDL cholesterol levels.
