Cholesterol esterification and atherogenic index of plasma correlate with lipoprotein size and findings on coronary angiography

Many anthropometric, clinical, and biochemical factors can influence the composition and size of lipoprotein subpopulations. It has been demonstrated that the prevalence of small dense LDL particles increases cardiovascular (CV) risk (1–3) and that the distribution of differently sized particles in HDL influences its anti-atherogenic effects (4–8). In the HDL-Atherosclerosis Treatment Study (HATS), in which patients with coronary disease and low HDL-cholesterol (HDL-C) were treated with a combinations of simvastatin, niacin, and antioxidants, the therapy had a selective effect on composition of lipoprotein subpopulations and therefore on consequent changes in the coronary artery stenosis (9). Although the composition of lipoprotein subpopulations contributes substantially to plasma atherogenicity, it is impractical to measure its variations as the assays have not been standardized and are expensive and thus not suitable for routine use. We have established that two markers of CV risk, namely cholesterol esterification rate in apolipoprotein (apo)B-depleted plasma (FERHDL) and atherogenic index of plasma [log (TG/HDL-C)] (AIP) reflect the size of LDL and HDL subpopulations and closely correlate with each other over a wide range of plasma lipid values (10–13). AIP is, of course, a transformation of triglyceride (TG)/HDL-C that better meets the assumption of normality of the errors in the statistical model being used to describe the treatment effects than does the untransformed variable. The value of both FERHDL and AIP can be seen in the context of intravascular cholesterol transport: FERHDL measures esterification rate of cholesterol by lecithin: cholesterol acyltransferase within HDL differently sized subpopulations. In small HDLs the esterification rate is high but large particles reduce it (10, 14). The destination of newly produced cholesteryl esters (CEs) is also linked to subpopulations size and with added internal standards of unesterified cholesterol and cholesteryl oleate. Large HDLs reduce esterification rate and serve as the most effective vehicle for delivery of CE via scavenger receptor class B type 1 to catabolic sites in liver and steroidogenic tissues (15). The close association of FERHDL with AIP can be explained by TG participation in the production of large VLDL and small dense LDLs and have also been proposed to be the major determinants of cholesterol esterification/transfer and HDL remodeling in particles that regulate the esterification rate. The potential of FERHDL and AIP to predict CV risk was shown in the study of 1,108 patients who underwent coronary angiography (16). The relationships between FERHDL or AIP and CV risk have been well established (12, 16, 17). However, the changes of these risk biomarkers with different therapies and their relation to treatment outcomes have not been studied. In this study, we related the changes on coronary angiography in HATS to the values of FERHDL and AIP and investigated their relation to lipoprotein subpopulations in patients on different therapeutic regimens.