An association between blood serum cholesterol level and the prevalence of coronary artery disease was firmly established more than 60 years ago by epidemiologists such as Keys et al1 and Stamler et al.2 Gofman and associates3 demonstrated that cholesterol is transported in 2 major groups of particles that they called low-density lipoproteins and high-density lipoproteins. Using quantitative analytical ultracentrifugation, Gofman et al3 demonstrated that both lipoprotein groups contained a series of subgroups. The low-density lipoproteins were divided into 4 subgroups now referred to as chylomicrons, very low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs), and low-density lipoproteins (LDLs). High-density lipoprotein (HDL) subgroups were given the names of HDL1, HDL2, and HDL3. Low-density lipoproteins and the HDLs were found to contain 70% to 90% of the cholesterol in the serum of most adults. Triglycerides were primarily in VLDLs unless the individual had recently eaten fat. Triglycerides were then found in chylomicrons as well. Gofman et al3 studied human communities as well as individuals who had blood cholesterol and triglyceride concentrations well outside the normal range of values. He then described variations in the lipoprotein concentrations in a series of clinical syndromes such as familial hypercholesterolemia, xanthomatosis, obesity, diabetes, and hypothyroidism, as well as pregnancy. Most important, he reported that it was the LDLs and VLDLs, not the HDLs, that were associated with coronary heart disease. In the initial studies, the VLDL mass was more strongly associated with vascular disease than the LDL mass. The analytical ultracentrifuge measured the entire mass of the lipoprotein (including proteins and phospholipids), not solely the cholesterol or triglyceride content. In the Framingham Heart Study and other community cohorts, this method was used to assess the associations between these lipoprotein measures and vascular outcome.4 In younger individuals and those with values nearer the mean, LDL level was more associated with future coronary events, but in older patients with elevated triglyceride levels, VLDL level was more strongly associated with future coronary events.5 In later studies, LDL cholesterol (LDL-C) level was also associated with increased risk, but a higher HDL cholesterol (HDL-C) level was associated with lower incidence of vascular events.5
Brown WV. Methods of Calculating Low-Density Lipoprotein Cholesterol Level. JAMA Cardiol. Published online February 26, 2020. doi:10.1001/jamacardio.2020.0042
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