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

We examined the association between rate of cholesterol esterification in plasma depleted of apolipoprotein B-containing lipoproteins (FERHDL), atherogenic index of plasma (AIP) [(log (TG/HDL-C)], concentrations, and size of lipoproteins and changes in coronary artery stenosis in participants in the HDL-Atherosclerosis Treatment Study. A total of 160 patients was treated with simvastatin (S), niacin (N), antioxidants (A) and placebo (P) in four regimens. FERHDL was measured using a radioassay; the size and concentration of lipoprotein subclasses were determined by nuclear magnetic resonance spectroscopy. The S+N and S+N+A therapy decreased AIP and FERHDL, reduced total VLDL (mostly the large and medium size particles), decreased total LDL particles (mostly the small size), and increased total HDL particles (mostly the large size). FERHDL and AIP correlated negatively with particle sizes of HDL and LDL, positively with VLDL particle size, and closely with each other (r = 0.729). Changes in the proportions of small and large lipoprotein particles, which were reflected by FERHDL and AIP, corresponded with findings on coronary angiography. Logistic regression analysis of the changes in the coronary stenosis showed that probability of progression was best explained by FERHDL (P = 0.005). FERHDL and AIP reflect the actual composition of the lipoprotein spectrum and thus predict both the cardiovascular risk and effectiveness of therapy. AIP is already available for use in clinical practice as it can be readily calculated from the routine lipid profile. We examined the association between rate of cholesterol esterification in plasma depleted of apolipoprotein B-containing lipoproteins (FERHDL), atherogenic index of plasma (AIP) [(log (TG/HDL-C)], concentrations, and size of lipoproteins and changes in coronary artery stenosis in participants in the HDL-Atherosclerosis Treatment Study. A total of 160 patients was treated with simvastatin (S), niacin (N), antioxidants (A) and placebo (P) in four regimens. FERHDL was measured using a radioassay; the size and concentration of lipoprotein subclasses were determined by nuclear magnetic resonance spectroscopy. The S+N and S+N+A therapy decreased AIP and FERHDL, reduced total VLDL (mostly the large and medium size particles), decreased total LDL particles (mostly the small size), and increased total HDL particles (mostly the large size). FERHDL and AIP correlated negatively with particle sizes of HDL and LDL, positively with VLDL particle size, and closely with each other (r = 0.729). Changes in the proportions of small and large lipoprotein particles, which were reflected by FERHDL and AIP, corresponded with findings on coronary angiography. Logistic regression analysis of the changes in the coronary stenosis showed that probability of progression was best explained by FERHDL (P = 0.005). FERHDL and AIP reflect the actual composition of the lipoprotein spectrum and thus predict both the cardiovascular risk and effectiveness of therapy. AIP is already available for use in clinical practice as it can be readily calculated from the routine lipid profile. 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 (1Austin M.A. Breslow J.L. Hennekens C.H. Buring J.E. Willett W.C. Krauss R.M. Low-density lipoprotein subclass patterns and the risk of myocardial infarction.JAMA. 1988; 260: 1917-1921Crossref PubMed Scopus (1534) Google Scholar, 2Campos H. Jr. Genest J.J. Blijlevens E. McNamara J.R. Jenner J.L. Ordovas J.M. Wilson P.W. Schaefer E.J. Low density lipoprotein particle size and coronary artery disease.Arterioscler. Thromb. 1992; 12: 187-195Crossref PubMed Google Scholar, 3Stampfer M.J. 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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 (9Brown B.G. Xue-Qiao Z. Chait A. Fisher L.D. Cheung M.C. Morse J.S. Dowdy A.A. Marino E.K. Bolson E.L. Alaupovic P. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.N. Engl. J. Med. 2001; 345: 1583-1592Crossref PubMed Scopus (1779) Google Scholar). 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 (10Dobiasova M. Stribrna J. Pritchard P. Frohlich J. Cholesterol esterification rate in plasma depleted of very low and low density lipoprotein is controlled by the proportion of HDL2 and HDL3 subclasses: study in hypertensive and normal middle aged and septuagenarian men.J. Lipid Res. 1992; 33: 1411-1418Abstract Full Text PDF PubMed Google Scholar, 11Dobiášová M. Frohlich J. Measurement of fractional esterification rate of cholesterol in apoB containing lipoproteins depleted plasma: methods and normal values.Physiol. Res. 1996; 45: 65-73PubMed Google Scholar, 12Dobiášová M. Frohlich J. The plasma parameter log (TG/HDL-C) as an atherogenic index: correlation with lipoprotein particle size and esterification rate in apoB-lipoprotein-depleted plasma (FERHDL).Clin. Biochem. 2001; 34: 583-588Crossref PubMed Scopus (674) Google Scholar, 13Dobiášová M. Urbanová Z. Šamánek M. Relations between particle size of HDL and LDL lipoproteins and cholesterol esterification rate.Physiol. Res. 2005; 54: 159-165PubMed Google Scholar). 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 (10Dobiasova M. Stribrna J. Pritchard P. Frohlich J. Cholesterol esterification rate in plasma depleted of very low and low density lipoprotein is controlled by the proportion of HDL2 and HDL3 subclasses: study in hypertensive and normal middle aged and septuagenarian men.J. Lipid Res. 1992; 33: 1411-1418Abstract Full Text PDF PubMed Google Scholar, 14Fielding C.J. Fielding P.E. Molecular physiology of reverse cholesterol transport.J. Lipid Res. 1995; 36: 211-228Abstract Full Text PDF PubMed Google Scholar). 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 (15Rigotti A. Trigatti B. Babitt J. Fenman M. Xu S. Krieger M. Scavenger receptor BI–a cell surface receptor for high density lipoprotein.Curr. Opin. Lipidol. 1997; 8: 181-188Crossref PubMed Scopus (176) Google Scholar). 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 (16Frohlich J. Dobiášová M. Fractional esterification rate of cholesterol and ratio of triglycerides to HDL-cholesterol are powerful predictors of positive findings on coronary angiography.Clin. Chem. 2003; 49: 1873-1880Crossref PubMed Scopus (207) Google Scholar). The relationships between FERHDL or AIP and CV risk have been well established (12Dobiášová M. Frohlich J. The plasma parameter log (TG/HDL-C) as an atherogenic index: correlation with lipoprotein particle size and esterification rate in apoB-lipoprotein-depleted plasma (FERHDL).Clin. Biochem. 2001; 34: 583-588Crossref PubMed Scopus (674) Google Scholar, 16Frohlich J. Dobiášová M. Fractional esterification rate of cholesterol and ratio of triglycerides to HDL-cholesterol are powerful predictors of positive findings on coronary angiography.Clin. Chem. 2003; 49: 1873-1880Crossref PubMed Scopus (207) Google Scholar, 17Tan M.H. Loh K.C. Dobiasova M. Frohlich J. Fractional esterification rate of HDL particles in patients with type 2 diabetes: relation to coronary heart disease risk factors.Diabetes Care. 1998; 21: 139-142Crossref PubMed Scopus (20) Google Scholar). 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. The rationale, methods, and results of HATS have been described in detail (9Brown B.G. Xue-Qiao Z. Chait A. Fisher L.D. Cheung M.C. Morse J.S. Dowdy A.A. Marino E.K. Bolson E.L. Alaupovic P. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.N. Engl. J. Med. 2001; 345: 1583-1592Crossref PubMed Scopus (1779) Google Scholar). The study tested the hypothesis that a decrease in serum LDL-cholesterol (LDL-C) with a simultaneous increase in HDL-C induced by the statin-niacin combination therapy provides greater benefits than treatment with either placebo or antioxidants. One hundred and sixty patients were divided into four groups and each group was treated with one of four regimens: simvastatin plus niacin (S+N), antioxidants (A), simvastatin, niacin, and antioxidants (S+N+A), or placebos (P). Patients underwent coronary angiography before and after 3 years of treatment. Plasma samples obtained at baseline and at 1 year on therapy were examined in the present analysis. Analyses of plasma lipids and apolipoproteins were previously described (9Brown B.G. Xue-Qiao Z. Chait A. Fisher L.D. Cheung M.C. Morse J.S. Dowdy A.A. Marino E.K. Bolson E.L. Alaupovic P. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.N. Engl. J. Med. 2001; 345: 1583-1592Crossref PubMed Scopus (1779) Google Scholar). The average particle sizes of HDL, LDL, and VLDL subpopulations were determined by NMR spectroscopy (18Jeyarajah E.J. Cromwell W.C. Otvos E.J. Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy.Clin. Lab. Med. 2006; 26: 847-870Abstract Full Text Full Text PDF PubMed Scopus (513) Google Scholar). Particle concentrations (nmol/L for VLDL and LDL; µmol/L for HDL) were calculated for each subclass on the lipoprotein and the between particle and total lipid Lipoprotein size subpopulations were as large medium VLDL small VLDL large LDL small LDL large HDL medium HDL and small HDL Measurement of FERHDL was described in detail previously (4Dobiášová M. Stříbrná J. Sparks D.L. Pritchard P.H. Frohlich J. Cholesterol esterification rates in very low density lipoprotein- and low density lipoprotein- depleted plasma: Relation to high density lipoprotein subspecies, sex, hyperlipidemia and coronary artery disease.Arterioscler. Thromb. 1991; 11: 64-70Crossref PubMed Scopus (81) Google Scholar, 11Dobiášová M. Frohlich J. Measurement of fractional esterification rate of cholesterol in apoB containing lipoproteins depleted plasma: methods and normal values.Physiol. Res. 1996; 45: 65-73PubMed Google Scholar, M. Frohlich J. of cholesterol acyltransferase Ordovas J.M. in Molecular Lipoprotein Scopus Google Scholar). lipoproteins are from plasma can be at to or at for to years changes in values of by and the which plasma with HDL is added a containing a of an at the is and the plasma with HDL is to and for esterification is over this the lipids are by and with added internal standards of cholesterol and cholesteryl by of cholesterol and cholesteryl are by from and to The is by The fractional esterification rate is calculated from in of and cholesterol as of HDL-C AIP (12Dobiášová M. Frohlich J. The plasma parameter log (TG/HDL-C) as an atherogenic index: correlation with lipoprotein particle size and esterification rate in apoB-lipoprotein-depleted plasma (FERHDL).Clin. Biochem. 2001; 34: 583-588Crossref PubMed Scopus (674) Google Scholar) was calculated as ratio of concentrations of TG and HDL-C [log (TG/HDL-C)] in plasma M. of atherogenic 1998; Scholar). analysis was using and A and for statistical for Scholar) The are as both before and treatment for the four treatment the between before and after treatment were tested by within the four The effect of treatment on FERHDL and AIP was by We tested the that the values after 1 year of treatment are the that at for one treatment. the between FERHDL and AIP on one and particle sizes and concentrations on the other we calculated correlation for values of subjects in the study and correlation for values obtained after treatment to the influence of the the relationships between these we two regression with FERHDL and AIP as the and particle sizes and concentrations as We association of changes in the coronary artery stenosis with AIP, and other by regression The progression of the coronary artery as positive or regression was as a and the model was by the A and for statistical for Scholar). The of was as AIP, FERHDL, total LDL and HDL HDL, LDL, VLDL particle and HDL, LDL, and VLDL were for treatment. 1 the on lipoprotein subpopulations before and after 1 year of therapy with the four treatment regimens. The also results of between baseline and on treatment values for each treatment Although the are not for that was a increase in the total HDL particles and decrease in the total LDL and VLDL particles induced by the S+N and S+N+A treatment. HDL increased on of large HDL to of total HDL in to in S+N+A LDL decreased on of small LDL particles the of large particles was not the the treatment by S+N and S+N+A reduced and small VLDL The particle size of HDL and LDL increased by treatment with S+N and these total cholesterol and TG decreased HDL-C treatment had effects on routine lipid with the of of therapy on FERHDL, AIP, and lipoprotein particles after of particles HDL total HDL large HDL small LDL large LDL small VLDL total VLDL large VLDL medium VLDL small size VLDL LDL HDL lipid with NMR TG are as with NMR in a are as 1 that after 1 year of treatment with S+N and FERHDL decreased from and at and to and AIP decreased from and at baseline to and The placebo group also showed a small decrease in FERHDL antioxidants had the four treatment the AIP and FERHDL values after 1 year of treatment were by In both the hypothesis that values are the in groups was (P with antioxidant therapy had S+N and S+N+A treatment decreased AIP and FERHDL We examined the between FERHDL, AIP, and the lipoprotein particles in plasma baseline and on the treatment we used as the values of the patients were The effects of the 1 year therapy were using 2 that values of the correlation before and on treatment very FERHDL and AIP values correlated with each other at baseline (r = the correlation at 1 year of therapy for was = The type of the treatment not have a effect on the relation between other was a correlation between FERHDL and AIP and the of total and small LDL and and size of were in the as large The were seen between LDL particle size and large association was of FERHDL and AIP with atherogenic apoB and between FERHDL, AIP, and lipoprotein subpopulations before and after of particles are in LDL and VLDL particles in of HDL, LDL and VLDL in in a HDL particles are in LDL and VLDL particles in of HDL, LDL and VLDL in The HATS study participants were divided into two groups on changes in coronary artery stenosis after 3 years of treatment to association between plasma lipoproteins and their subpopulations to the changes FERHDL and AIP had values in the group with increased stenosis (P and with increased total particles of LDL (P and VLDL (P small LDL (P and large and medium VLDL (P and Although the total of HDL particles was not in to the changes in the decreased stenosis was by an increase of large HDL particles (P and of large VLDL and small namely and HDL-C has shown in the progression association of FERHDL, AIP, and lipoprotein subpopulations with in coronary artery stenosis = = total large small total large small total large medium small particle lipid in a The regression analysis for of changes in the coronary artery stenosis showed that the probability of progression was in the with AIP, large HDL, total and small LDL particles, total and medium VLDL particles, and sizes of LDL and HDL, this probability was best explained by FERHDL ratio = = 0.005). other was in this FERHDL was not in the of predictors in the model 2 the model for treatment one of probability of which was the concentration of the large HDL ratio = = AIP was tested in the model for its was (P = regression for progression of the coronary artery by of FERHDL, AIP, HDL size), LDL size), VLDL and by the of FERHDL, other the as in are for treatment. in a by of FERHDL, AIP, HDL size), LDL size), VLDL and by the of FERHDL, other the as in are for treatment. The of this study was to the relation between the biomarkers FERHDL and AIP and the distribution of lipoprotein subpopulations before and treatment in patients with coronary low and normal in HATS (9Brown B.G. Xue-Qiao Z. Chait A. Fisher L.D. Cheung M.C. Morse J.S. Dowdy A.A. Marino E.K. Bolson E.L. Alaupovic P. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.N. Engl. J. Med. 2001; 345: 1583-1592Crossref PubMed Scopus (1779) Google Scholar). We also the association between these markers and the changes in coronary artery The treatment the sizes and concentrations of the lipoprotein subpopulations as well as the values of FERHDL and the atherogenic VLDL and LDL and increased the was a decrease in the proportion of large and medium sized VLDL and small dense LDL the other was an increase in the large Treatment with antioxidants not either FERHDL or AIP, or VLDL or LDL subpopulations. However, use of antioxidants either or in combination with S+N to increase small HDL particles treatment had a positive effect on the distribution of the subpopulations for the increase of large was the decrease in FERHDL and of routine lipid profile. effect was related to the with and to the use of simvastatin the of placebo patients with baseline The correlation between FERHDL and AIP was positive (r = both at baseline and at 1 year on treatment (r = 0.729). FERHDL and AIP correlated with the size and concentration of lipoprotein subpopulations concentration of medium and large VLDL and small LDL particles in FERHDL and AIP the values of these decreased with concentration of large LDL and large HDL subpopulations. the relation between FERHDL, AIP, and particle we used two regression to the potential of the The of AIP was best explained by VLDL concentrations and VLDL size and concentrations of large HDL and large LDL The of was which that the model explained of The of FERHDL was best explained by concentration of large HDL and HDL and VLDL particle sizes with of In the patients with normal and low HDL-C from the combination treatment with simvastatin and niacin that in regression of coronary (9Brown B.G. Xue-Qiao Z. Chait A. Fisher L.D. Cheung M.C. Morse J.S. Dowdy A.A. Marino E.K. Bolson E.L. Alaupovic P. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.N. Engl. J. 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The effect of treatment on high density lipoprotein particle size subclass in Full Text PDF PubMed Scopus Google Scholar). was the combination of niacin and simvastatin in the HATS not decreased the concentration of plasma and increased HDL-C (9Brown B.G. Xue-Qiao Z. Chait A. Fisher L.D. Cheung M.C. Morse J.S. Dowdy A.A. Marino E.K. Bolson E.L. Alaupovic P. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.N. Engl. J. Med. 2001; 345: 1583-1592Crossref PubMed Scopus (1779) Google Scholar) but also the distribution of HDL subpopulations by the proportion of large changes in decreased values of both AIP and also decrease and increase HDL but HDL in to niacin, by the proportion of small HDL and the large HDL B.F. Horvath K.V. McNamara J.R. J.J. Schaefer E.J. the effects of different on the HDL of coronary heart disease Full Text Full Text PDF PubMed Scopus Google Scholar). In the regression model for treatment the probability of progression of the coronary artery stenosis was best explained by changes in FERHDL with other being in this FERHDL was not in the of the model for treatment one namely the concentration of large HDL FERHDL was by AIP in the the for AIP was (P = The effect of large HDL on the of coronary by different methods, was previously (9Brown B.G. Xue-Qiao Z. Chait A. Fisher L.D. Cheung M.C. Morse J.S. Dowdy A.A. Marino E.K. Bolson E.L. Alaupovic P. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.N. Engl. J. Med. 2001; 345: 1583-1592Crossref PubMed Scopus (1779) Google Scholar, M.C. Xue-Qiao Z. Chait A. J.J. Brown B.G. the of HDL to therapy in patients with coronary artery disease and low Thromb. Vasc. Biol. 2001; 21: PubMed Scopus Google Scholar). We that the increased of the large HDL particles, the esterification rate of the of the newly produced CE via scavenger receptor class B type that differently sized HDL particles the of CE produced in plasma to either atherogenic or M. Frohlich J. the of to the high value of cholesterol Res. 1998; Google Scholar) is by the that therapy the regression of coronary by plasma by HDL particle size B.F. E. P.H. Horvath K.V. Schaefer E.J. of the effects of high of on the subpopulations of high-density J. Cardiol. Full Text Full Text PDF PubMed Scopus Google Scholar). we that FERHDL is a measure of the atherogenic It is not that AIP, which is also with the lipoprotein size and with FERHDL, has a predicting potential as results the of not but also changes in HDL that with niacin treatment. Although the of using either AIP or FERHDL in practice have to be a that AIP be of a large study from that AIP was the best of and events A. H. index of high and Lipidol. Full Text Full Text PDF PubMed Scopus Google Scholar). The J. Otvos for the NMR antioxidant atherogenic index of plasma apolipoprotein cholesteryl cardiovascular rate of cholesterol esterification in plasma depleted of apolipoprotein B-containing lipoproteins HDL-Atherosclerosis Treatment Study HDL-cholesterol ratio of concentrations of triglyceride and HDL-cholesterol niacin placebo simvastatin total cholesterol triglyceride