Cholesterol esterification and atherogenic index of plasma correlate with lipoprotein size and findings on coronary angiography
2011; Elsevier BV; Volume: 52; Issue: 3 Linguagem: Inglês
10.1194/jlr.p011668
ISSN1539-7262
AutoresMilada Dobiášová, Jiří Fröhlich, Michaela Šedová, Marian C. Cheung, B. Greg Brown,
Tópico(s)Cardiac Imaging and Diagnostics
ResumoWe 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. Krauss R.M. Ma J. Blanche P.J. Holl L.G. Sacks F.M. Hennekkens C.H. A prospective study of triglyceride level, low-density particle diameter, and risk of myocardial infarction.JAMA. 1996; 276: 882-888Crossref PubMed Google Scholar) and that the distribution of differently sized particles in HDL influences its anti-atherogenic effects (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, 5Drexel H. Aman F.W. Rentsch K. Neunschwander C. Leuthy A. Khan S.I. Relation of high-density lipoprotein subfraction to the presence and extent of coronary artery disease.Am. J. Cardiol. 1992; 70: 436-440Abstract Full Text PDF PubMed Scopus (111) Google Scholar, 6Freedman D.S. Otvos J.D. Jeyarajah E.J. Barboriak J.J. Anderson A.T. Walker J.A. Relation of lipoprotein subclasses as measured by proton nuclear magnetic resonance spectroscopy to coronary artery disease.Arterioscler. Thromb. Vasc. Biol. 1998; 18: 1046-1053Crossref PubMed Scopus (284) Google Scholar, 7Asztalos B.F. Collins D. Cupples L.A. Demissie S. Horvath K.V. Bloomfield H.E. Sander Robins S.J. Schaefer E.J. Value of high-density lipoprotein (HDL) subpopulations in predicting recurrent cardiovascular events in the Veterans Affairs HDL Intervention Trial.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 2185-2191Crossref PubMed Scopus (237) Google Scholar, 8Cheung M.C. Brown B.G. Wolf A.C. Albert J.J. Altered particle size distribution of apolipoprotein A-I-containing lipoproteins in subjects with coronary artery disease.J. Lipid Res. 1991; 32: 383-394Abstract Full Text PDF PubMed Google Scholar). 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 based on existing knowledge about the lipoprotein structure and the link between particle diameter and total core lipid content. Lipoprotein size subpopulations were defined as follows: large VLDL/chylomicrons (>60 nm), medium VLDL (35–60 nm), small VLDL (27–35 nm), large LDL (21.2–23 nm), small LDL (18–21.2 nm), large HDL (8.8–13 nm), medium HDL (8.2–8.8 nm), and small HDL (7.3–8.2 nm). 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, 19Dobiášová M. Frohlich J. Assays of lecithin cholesterol acyltransferase (LCAT).in: Ordovas J.M. Methods in Molecular Biology. Lipoprotein Protocols. Humana Press, Totowa, NJ1998: 217-230Crossref Scopus (25) Google Scholar). Briefly, apoB-containing lipoproteins are precipitated from EDTA plasma (that can be stored at −20°C up to 4 months or at −70°C for up to 6 years without changes in absolute values of FERHDL) by phosphotungstic acid and MgCl2. To the supernatant, which contains plasma with HDL only, is added a filter paper disk containing a trace of 3-H cholesterol. After an overnight incubation at 4°C, the disk is removed and the plasma with labeled HDL is heated to 37°C and incubated for 30 min (the esterification reaction is always linear over this time period). After the incubation, lipids are extracted by ethanol, ethanol evaporated, and with added internal standards of cholesterol and cholesteryl oleate, separated by TLC. Spots of cholesterol and cholesteryl oleate are visualized by iodine, spots cut from TLC plates, and transferred to scintillation vials. The radioactivity is estimated by liquid scintillation counting. The fractional esterification rate is calculated from radioactivity in spots of free and esterified cholesterol as percentages of HDL-C esterified per h. 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 logarithmically transformed ratio of molar concentrations of TG and HDL-C [log (TG/HDL-C)] in plasma (20Dobiášová M. Calculator of atherogenic risk. 1998; (http://www.biomed.cas.cz/fgu/aip)Google Scholar). Statistical analysis was performed using SPSS.15.0 and R (21R Development Core Team A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria2008Google Scholar) software. The data are presented as means ± SD both before and during treatment for the four treatment groups. For descriptive purposes, the differences between measurements taken before and after treatment were tested by paired t-test within the four groups. The effect of treatment on FERHDL and AIP was analyzed by one-way ANOVA. We tested the hypotheses that the mean values after 1 year of treatment are equal against the alternative that they differ at least for one treatment. To investigate the correlations between FERHDL and AIP on one hand and particle sizes and concentrations on the other hand, we calculated bivariate correlation coefficients for basal values of all subjects in the study and partial correlation coefficients for values obtained after treatment to eliminate the influence of the various treatments. To determine the after-treatment relationships between these measurements, we fitted two linear regression models with FERHDL and AIP as the response variables and particle sizes and concentrations as explanatory variables. We assessed association of changes in the coronary artery stenosis with FER-HDL, AIP, and other variables by logistic regression model. The progression of the coronary artery stenosis, defined as positive change versus no change or regression (i.e., dichotomous outcome) was considered as a response variable and the final model was found by the forward selection procedure (21R Development Core Team A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria2008Google Scholar). The initial set of explanatory variables was as follows: AIP, FERHDL, total LDL and HDL cholesterol, triglycerides, apoAI, apoB, HDL, LDL, VLDL particle sizes, and HDL, LDL, and VLDL subpopulations' concentration. All models were adjusted for treatment. Table 1 summarizes the data on lipoprotein subpopulations before and after 1 year of therapy with the four treatment regimens. The table also shows results of paired t-tests between baseline and on treatment values performed for each treatment separately. Although the p-values are not adjusted for multiple comparisons, they indicate that there was a marked 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. Total HDL increased mostly on account of large HDL (from 8.7% to 15.5% of total HDL in S+N, 6.% to 12.5% in S+N+A treatment). LDL decreased on account of small LDL particles whereas the number of large particles was not significantly changed. On the contrary, the treatment by S+N and S+N+A reduced practically all large, medium, and small VLDL particles. The mean particle size of HDL and LDL significantly increased by treatment with S+N and S+N+A. During these treatments, total cholesterol (TC), LDL-C, and TG markedly decreased while HDL-C increased. Placebo treatment had similar even lower significant effects on routine lipid profile with the exception of TG.TABLE 1Effect of therapy on FERHDL, AIP, and lipoprotein specific particles after 12 months of treatmentPLACEBOS+NAS+N+ABase-lineOn treatmentBase-lineOn treatmentBase-lineOn treatmentBase-lineOn treatmentn3333343439394040Biomarkers FERHDL31. 5 ± 7.527.2 ± 7.2aP < 0.05.30.6 ± 7.418.5 ± 6.4cP < 0.001.30.0 ± 8.127.8 ± 9.532.0 ± 7.521.8 ± 8.6cP < 0.001. AIP0.40 ± 0.230.35 ± 0.250.42 ± 0.210.11 ± 0.24cP < 0.001.0.40 ± 0.250.43 ± 0.290.48 ± 0.240.21 ± 0.31cP < 0.001.Lipoprotein particles HDL total (µmol/L)28.4 ± 3.830.1 ± 3.8bP < 0.01.28.0 ± 3.630.4 ± 5.5cP < 0.001.29.0 ± 3.531.5 ± 4.5cP < 0.001.27.9 ± 4.831.3 ± 5.7cP < 0.001. HDL large (µmol/L)1.8 ± 1.42.4 ± 1.6aP < 0.05.2.5 ± 1.64.7 ± 2.3cP < 0.001.2.2 ± 1.52.2 ± 1.91.8 ± 1.63.7 ± 2.2cP < 0.001. HDL small (µmol/L)23.5 ± 4.224.3 ± 4.623.2 ± 4.722.8 ± 5.023.4 ± 4.326.3 ± 5.8bP < 0.01.22.7 ± 6.525.2 ± 7.1aP < 0.05. LDLtotal (nmol/L)1763 ± 4511694 ± 4471670 ± 4061027 ± 352cP < 0.001.1580 ± 4261668 ± 4511743 ± 5001165 ± 347cP < 0.001. LDL large (nmol/L)277 ± 253309 ± 224347 ± 308327 ± 145272 ± 212270 ± 242313 ± 298271 ± 139 LDL small (nmol/L)1431 ± 5431333 ± 5601275 ± 438673 ± 393cP < 0.001.1260 ± 4831342 ± 5461371 ± 597857 ± 379cP < 0.001. VLDL total (nmol/L)106 ± 45108 ± 4694 ± 2861 ± 28cP < 0.001.107 ± 41108 ± 4597 ± 4060 ± 26cP < 0.001. VLDL large (nmol/L)9.4 ± 8.08.3 ± 7.09.2 ± 8.14.1 ± 3.4cP < 0.001.7.3 ± 7.39.5 ± 10.011.4 ± 8.87.5 ± 6.8bP < 0.01. VLDL medium (nmol/L)50.0 ± 28.349.1 ± 28.444.6 ± 23.624.7 ± 16.8cP < 0.001.48.6 ± 25.953.3 ± 32.848.2 ± 24.730.5 ± 25.7bP < 0.01. VLDL small (nmol/L)46.6 ± 26.550.8 ± 20.240.3 ± 21.531.7 ± 15.751.2 ± 23.145.1 ± 22.337.3 ± 25.027.7 ± 20.5aP < 0.05.Lipoprotein size VLDL (nm)55.2 ± 11.552.9 ± 9.654.5 ± 10.153.6 ± 8.952.7 ± 11.453.6 ± 12.758.4 ± 13.159.8 ± 14.4 LDL (nm)20.2 ± 0.820.3 ± 0.820.3 ± 0.821.0 ± 0.7cP < 0.001.20.3 ± 0.720.2 ± 0.820.3 ± 0.920.7 ± 0.6aP < 0.05. HDL (nm)8.4 ± 0.38.4 ± 0.38.4 ± 0.38.8 ± 0.5cP < 0.001.8.4 ± 0.38.4 ± 0.38.4 ± 0.48.6 ± 0.4cP < 0.001.Routine lipid profiledCurrent data estimated with NMR analyses. TC (mmol/L)5.20 ± 0.794.90 ± 0.60cP < 0.001.5.13 ± 0.933.58 ± 0.63cP < 0.001.4.92 ± 0.614.95 ± 0.585.19 ± 0.903.81 ± 0.84cP < 0.001. LDL-C (mmol/L)3.31 ± 0.673.02 ± 0.54cP < 0.001.3.31 ± 0.881.94 ± 0.54cP < 0.001.3.05 ± 0.672.95 ± 0.593.22 ± 0.782.06 ± 0.59cP < 0.001. HDL-C(mmol/L)0.81 ± 0.110.87 ± 0.13bP < 0.01.0.81 ± 0.121.01 ± 0.24cP < 0.001.0.84 ± 0.120.86 ± 0.160.79 ± 0.110.93 ± 0.14cP < 0.001. TG (mmol/L)2.35 ± 1.052.27 ± 1.052.34 ± 0.991.46 ± 0.76cP < 0.001.2.32 ± 1.292.69 ± 1.982.73 ± 1.31.87 ± 0.16cP < 0.001.Data are presented as mean ± SD.a P < 0.05.b P < 0.01.c P < 0.001.d Current data estimated with NMR analyses. Open table in a new tab Data are presented as mean ± SD. Table 1 shows that after 1 year of treatment with S+N and S+N+A, FERHDL decreased from 30.73 ± 7.05 and 32.0 ± 7.53%/h at baseline, respectively and to 19.53 ± 6.76 (−36%) and 21.96 ± 8.64%/h (−31%,), respectively. AIP decreased from 0.43 ± 0.22 and 0.49 ± 0.24 at baseline to 0.13 ± 0.25 (−71%) and 0.22 ± 0.31 (−51%), respectively. The placebo group also showed a small decrease in FERHDL (−12.1%) whereas antioxidants had negligible effect. For the four treatment groups, the mean AIP and FERHDL values after 1 year of treatment were compared by one-way ANOVA. In both cases, the hypothesis that mean values are the same in all groups was rejected (P < 0.001). Compared with placebo, antioxidant therapy had no effect, whereas S+N and S+N+A treatment decreased AIP and FERHDL significantly. We examined the relationship between FERHDL, AIP, and the lipoprotein particles in plasma baseline and on the various treatment regimens (Table 2). At baseline, we used bivariate analysis, as the starting values of the patients were similar. The possible effects of the 1 year therapy were eliminated using appropriate adjustments. Table 2 shows that values of the correlation coefficients before and on treatment remained very close. FERHDL and AIP values correlated with each other at baseline (r = 0.721); the partial correlation coefficient at 1 year of therapy (adjusted for treatment) was r = 0.729. The type of the treatment did not have a statistically significant effect on the linear relation between other variables. There was a significant correlation between FERHDL and AIP and the number of total and small LDL and total, large, medium, and size of VLDL. Highly significant inverse correlations were observed in the atheroprotective variables such as large HDL. The inverse correlations were seen between LDL particle size and large LDL. Also significant association was found of FERHDL and AIP with atherogenic apoB and atheroprotective apoAI.TABLE 2The correlations (r) between FERHDL, AIP, and lipoprotein subpopulations before and after 12 months of treatmentBefore treatmentOn treatmentBivariate correlationsPartial correlationsFERHDLAIPFERHDLAIPFERHDL0.721ap-value<0.0001.0.729ap-value<0.0001.AIP0.721ap-value<0.0001.0.729ap-value<0.0001.ParticlesHDL total−0.186cp-value<0.01.−0.145−0.077−0.078HDL large−0.536ap-value<0.0001.−0.597ap-value<0.0001.−0.630ap-value<0.0001.−0.598ap-value<0.0001.HDL small−0.227bp-value<0.002.−0.272bp-value<0.002.−0.070−0.004LDL total0.236bp-value<0.002.0.230bp-value<0.002.0.573ap-value<0.0001.0.468ap-value<0.0001.LDL large−0.591ap-value<0.0001.−0.670ap-value<0.0001.−0.505ap-value<0.0001.−0.562ap-value<0.0001.LDL small0.458ap-value<0.0001.0.477ap-value<0.0001.0.497ap-value<0.0001.0.451ap-value<0.0001.VLDL total0.380ap-value<0.0001.0.410ap-value<0.0001.0.592ap-value<0.0001.0.685ap-value<0.0001.VLDL large0.629ap-value<0.0001.0.816ap-value<0.0001.0.560ap-value<0.0001.0.733ap-value<0.0001.VLDL medium0.453ap-value<0.0001.0.556ap-value<0.0001.0.436ap-value<0.0001.0.593ap-value<0.0001.VLDL small−0.072−0.184cp-value<0.01.0.1480.135SizesHDL−0.309ap-value<0.0001.−0.344ap-value<0.0001.−0.491ap-value<0.0001.−0.466ap-value<0.0001.LDL−0.573ap-value<0.0001.−0.620ap-value<0.0001.−0.640ap-value<0.0001.−0.628ap-value<0.0001.VLDL0.481ap-value<0.0001.0.668ap-value<0.0001.0.296ap-value<0.0001.0.425ap-value<0.0001.HDL particles are in µmol/L, LDL and VLDL particles in nmol/L. Sizes of HDL, LDL and VLDL in nm.a p-value<0.0001.b p-value<0.002.c p-value<0.01. Open table in a new tab HDL particles are in µmol/L, LDL and VLDL particles in nmol/L. Sizes of HDL, LDL and VLDL in nm. The HATS study participants were divided into two groups based on changes (negative vs. positive) in coronary artery stenosis after 3 years of treatment to show association between plasma lipoproteins and their subpopulations to the angiographic changes (Table 3). Both FERHDL and AIP had higher values in the group with increased stenosis (P < 0.001 and 0.008), together with increased total particles of LDL (P < 0.007) and VLDL (P < 0.033), small LDL (P < 0.005), and large and medium VLDL (P < 0.044 and 0.036). Although the total number of HDL particles was not significant in relationship to the changes in stenosis, the decreased stenosis was characterized by an increase of large HDL particles (P < 0.001) and reduction of large VLDL and small LDLs. From traditional lipids, namely TC, LDL-C, HDL-C, and TG, only HDL-C has shown significant reduction in the progression group.TABLE 3The association of FERHDL, AIP, and lipoprotein subpopulations with change in coronary artery stenosis (mean ±SD)VariableStenosis ≤ 0n = 50Stenosis > 0n = 95pFERHDL (%/h)20.2 ± 8.425.8 ± 8.6<0.001AIP0.189 ± 0.2970.328 ± 0.2960.008Lipoprotein particlesHDL total (µmol/L)31.80 ± 4.7930.75 ± 4.800.212HDL large (µmol/L)4.1 ± 2.22.8 ± 2.2<0.001HDL small (µmol/L)24.9 ± 5.76124.8 ± 5.90.93LDL total (nmol/L)1228 ± 5151457 ± 4560.007LDL large (nmol/L)323 ± 179277. ±1970.176LDL small (nmol/L)866 ± 5591134 ± 5180.005VLDL total (nmol/L)73.90 ± 46.1291.46 ± 45.730.033VLDL large (nmol/L)5.7 ± 6.48.4 ± 7.90.044VLDL medium (nmol/L)32.5 ± 28.243.3 ± 29.10.036VLDL small (nmol/L)34.8 ± 21.339.8 ± 22.20.198Lipoprotein particle sizesHDL (nm)8.7 ± 0.48.5 ± 0.4 3.5mmol/L. The correlation between FERHDL and AIP was highly positive (r = 0.717) both at baseline and at 1 year on treatment (r = 0.729). FERHDL and AIP strongly correlated with the size and concentration of individual lipoprotein subpopulations (Table 2). Increased concentration of medium and large VLDL and small LDL particles resulted in higher FERHDL and AIP whereas the values of these parameters decreased with increasing concentration of large LDL and large HDL subpopulations. To further investigate the relation between FERHDL, AIP, and particle sizes, we used two linear regression models to assess the potential of the explanatory variables (not shown). The variability of AIP was best explained by all VLDL concentrations and VLDL size (positive effect) and concentrations of large HDL and large LDL (negative effect). The coefficient of determination was 0.75, which means that the model explained 75% variability of AIP. The variability of FERHDL was best explained by concentration of large HDL and HDL and VLDL particle sizes with coefficient of determination 0.62. In the HATS, patients with normal LDL-C and low HDL-C level benefited significantly from the combination treatment with simvastatin and niacin that resulted in regression of coronary atherosclerosis (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). As previously reported, niacin increases the large particle size of HDL (21R Development Core Team A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria2008Google Scholar, 22Cheung M.C. Xue-Qiao Z. Chait A. Albers J.J. Brown B.G. Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary artery disease and low HDL.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1320-1326Crossref PubMed Scopus (154) Google Scholar, 23Shepherd J. Packard C.J. Patsch J.R. Gotto Jr., A.M. Taunton O.D. Effects of nicotinic acid therapy on plasma high density lipoprotein subfraction distribution and composition and on apolipoprotein a metabolism.J. Clin. Invest. 1979; 63: 858-867Crossref PubMed Scopus (209) Google Scholar), and decreases the small HDL subpopulations (22Cheung M.C. Xue-Qiao Z. Chait A. Albers J.J. Brown B.G. Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary artery disease and low HDL.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1320-1326Crossref PubMed Scopus (154) Google Scholar, 23Shepherd J. Packard C.J. Patsch J.R. Gotto Jr., A.M. Taunton O.D. Effects of nicotinic acid therapy on plasma high density lipoprotein subfraction distribution and composition and on apolipoprotein a metabolism.J. Clin. Invest. 1979; 63: 858-867Crossref PubMed Scopus (209) Google Scholar). Statins also increase the large α-1 HDL subpopulation (24Johansson J. Carlson L.A. The effect of nicotinic acid treatment on high density lipoprotein particle size subclass levels in hyperlipidaemic subjects.Atherosclerosis. 1990; 83: 207-216Abstract Full Text PDF PubMed Scopus (17) Google Scholar). That was probably why the combination of niacin and simvastatin in the HATS not only decreased the concentration of plasma LDL-C 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 changed favorably the distribution of HDL subpopulations by increasing the proportion of large HDL. These changes resulted in markedly decreased values of both AIP and FERHDL. Fibrates also decrease TGs and increase HDL but alter HDL distribution, in contrast to niacin, by increasing the proportion of small HDL and decreasing the large HDL (25Asztalos B.F. Horvath K.V. McNamara J.R. Roheim P.S. Rubinstein J.J. Schaefer E.J. Comparing the effects of five different statins on the HDL subpopulation profiles of coronary heart disease patients.Atherosclerosis. 2002; 164: 361-369Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). In the logistic regression model adjusted (also nonadjusted) for treatment regimens, the probability of progression of the coronary artery stenosis (Table 4) was best explained by changes in FERHDL with no other variable being significant in this model. When FERHDL was not included in the set of initial predictors, the final model adjusted for treatment again contained only one predictor, namely the (−) concentration of large HDL subpopulation. If FERHDL was replaced by AIP in the model, the p-value for AIP was borderline significant (P = 0.055). The effect of large HDL on the change of coronary stenosis, assessed by different methods, was previously reported (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, 22Cheung M.C. Xue-Qiao Z. Chait A. Albers J.J. Brown B.G. Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary artery disease and low HDL.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1320-1326Crossref PubMed Scopus (154) Google Scholar). We hypothesize that the increased number of the large HDL particles, while suppressing the esterification rate of cholesterol, enhances the catabolism of the newly produced CE via scavenger receptor class B type 1. Our idea that differently sized HDL particles may affect the targeting of CE produced in plasma to either atherogenic or atheroprotective targets (26Dobiášová M. Frohlich J. Understanding the mechanism of LCAT reaction may help to explain the high predictive value of LDL/HDL cholesterol ratio.Physiol. Res. 1998; 47: 387-397PubMed Google Scholar) is supported by the recent finding that rosuvastatin therapy may induce the regression of coronary atherosclerosis by raising plasma HDL-C, specifically by increasing HDL particle size (27Asztalos B.F. Le Maulf F. Dallal G.E. Stein E. Jones P.H. Horvath K.V. McTaggart F. Schaefer E.J. Comparison of the effects of high doses of rosuvastatin versus atorvastatin on the subpopulations of high-density lipoproteins.Am. J. Cardiol. 2007; 99: 681-685Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). Thus, we believe that FERHDL is a good measure of the atherogenic (or atheroprotective) pathways. It is not surprising that AIP, which is also associated with the lipoprotein size and correlates highly with FERHDL, has a similar predicting potential as FERHDL. Our results confirm the importance of not only quantitative but also qualitative changes in HDL that occur with niacin treatment. Although the concept of using either AIP or FERHDL in practice will have to be further confirmed, a recent paper suggests that AIP may be of importance: a large study from Turkey found that AIP was the best predictor of hypertension, diabetes, and vascular events (28Onat A. Can G. Kaya H. Hergenc G. “Atherogenic index of plasma” (log10 triglyceride/high-density lipoprotein-cholesterol) predicts high blood pressure, diabetes and vascular events.J. Clin. Lipidol. 2010; 4: 89-98Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). The authors thank Dr. J. Otvos for the NMR analyses. antioxidant atherogenic index of plasma apolipoprotein cholesteryl ester cardiovascular rate of cholesterol esterification in plasma depleted of apolipoprotein B-containing lipoproteins HDL-Atherosclerosis Treatment Study HDL-cholesterol logarithmically transformed ratio of molar concentrations of triglyceride and HDL-cholesterol niacin placebo simvastatin total cholesterol triglyceride
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