Relationship between cholesteryl ester transfer protein and LDL heterogeneity in familial hypercholesterolemia

Small, dense LDL particles have been associated with an increased risk of coronary artery disease, and cholesteryl ester transfer protein (CETP) has been suggested to play a role in LDL particle remodeling. We examined the relationship between LDL heterogeneity and plasma CETP mass in familial hypercholesterolemia (FH). LDL particles were characterized by polyacrylamide gradient gel electrophoresis in a total of 259 FH heterozygotes and 208 nonFH controls. CETP mass was measured by enzyme-linked immunosorbent assay in a subgroup of 240 participants, which included 120 FH patients matched with 120 controls. As compared with controls, FH subjects had an 11% higher CETP mass. Moreover, LDL-peak particle diameter (LDL-PPD) was significantly smaller in FH heterozygotes than in controls (258.1 ± 4.8 vs. 259.2 ± 4.1 Å; P = 0.01) after adjustment for covariates. There was also an inverse relationship between LDL-PPD and CETP mass (R = −0.15; P = 0.02), and this relationship was abolished by adjustment for the FH/control status, indicating that LDL-PPD changes in FH are mediated, at least in part, by an increase in plasma CETP mass concentrations.These results suggest that increased plasma CETP mass concentrations could lead to significant LDL particle remodeling in FH heterozygotes and could contribute to the pathogenesis of atherosclerosis. Small, dense LDL particles have been associated with an increased risk of coronary artery disease, and cholesteryl ester transfer protein (CETP) has been suggested to play a role in LDL particle remodeling. We examined the relationship between LDL heterogeneity and plasma CETP mass in familial hypercholesterolemia (FH). LDL particles were characterized by polyacrylamide gradient gel electrophoresis in a total of 259 FH heterozygotes and 208 nonFH controls. CETP mass was measured by enzyme-linked immunosorbent assay in a subgroup of 240 participants, which included 120 FH patients matched with 120 controls. As compared with controls, FH subjects had an 11% higher CETP mass. Moreover, LDL-peak particle diameter (LDL-PPD) was significantly smaller in FH heterozygotes than in controls (258.1 ± 4.8 vs. 259.2 ± 4.1 Å; P = 0.01) after adjustment for covariates. There was also an inverse relationship between LDL-PPD and CETP mass (R = −0.15; P = 0.02), and this relationship was abolished by adjustment for the FH/control status, indicating that LDL-PPD changes in FH are mediated, at least in part, by an increase in plasma CETP mass concentrations. These results suggest that increased plasma CETP mass concentrations could lead to significant LDL particle remodeling in FH heterozygotes and could contribute to the pathogenesis of atherosclerosis. Familial hypercholesterolemia (FH) is an autosomal codominant single-gene disorder caused by mutations in the LDL receptor (LDLR) gene that disrupt the normal clearance of LDL (1Goldstein J.L. Hobbs H.H. Brown M.S. Familial hypercholesterolemia.in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic Basis of Inherited Diseases. McGraw-Hill Publishing Co., New York1995: 1981-2030Google Scholar). Phenotypic features characteristic of the disease’s heterozygous form are a 2- to 3-fold rise in plasma LDL-cholesterol (LDL-C) concentrations, tendinous xanthomatosis, and premature atherosclerotic coronary artery disease (CAD), usually occurring between the ages of 35 years and 55 years. Homozygous or compound heterozygous patients have plasma LDL concentrations 6- to 8-fold higher than normal and usually manifest a CAD event before the age of 20 years. FH is also one of the most common inherited diseases in the world, with a frequency of 1 in 500 for heterozygotes and 1 per million for homozygotes (1Goldstein J.L. Hobbs H.H. Brown M.S. Familial hypercholesterolemia.in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic Basis of Inherited Diseases. McGraw-Hill Publishing Co., New York1995: 1981-2030Google Scholar). In the Province of Québec, the homozygote prevalence is 6-fold higher, and the minimal heterozygote frequency ranges from 1:81 to 1:154 (2Moorjani S. Roy M. Gagné C. Davignon J. Brun D. Toussaint M. Lambert M. Campeau L. Blaichman S. Lupien P. Homozygous familial hypercholesterolemia among French Canadians in Quebec Province.Arteriosclerosis. 1989; 9: 211-216Crossref PubMed Google Scholar). Nine mutations are responsible for 90% of the heterozygous FH cases in the French-Canadian population, defined on the basis of clinical and biochemical criteria (3Couture P. Vohl M.C. Gagné C. Gaudet D. Torres A.L. Lupien P.J. Després J.P. Labrie F. Simard J. Moorjani S. Identification of three mutations in the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French Canadians.Hum. Mutat. 1998; : S226-S231Crossref PubMed Scopus (27) Google Scholar). Cholesteryl ester transfer protein (CETP) plays a major role in the remodeling of lipoprotein particles by mediating the transfer of cholesteryl ester from HDL to apolipoprotein B (apoB)-containing lipoproteins in exchange for triglycerides, and several lines of evidence support the notion that CETP is linked to LDL size heterogeneity (4Talmud P.J. Edwards K.L. Turner C.M. Newman B. Palmen J.M. Humphries S.E. Austin M.A. Linkage of the cholesteryl ester transfer protein (CETP) gene to LDL particle size: use of a novel tetranucleotide repeat within the CETP promoter.Circulation. 2000; 101: 2461-2466Crossref PubMed Scopus (62) Google Scholar). Small, dense LDL particles have been associated with CAD in a number of studies (5Gardner C.D. Fortmann S.P. Krauss R.M. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women.J. Am. Med. Assoc. 1996; 276: 875-881Crossref PubMed Google Scholar, 6Stampfer M.J. Krauss R.M. Ma J. Blanche P.J. Holl L.G. Sacks F.M. Hennekens C.H. A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction.J. Am. Med. Assoc. 1996; 276: 882-888Crossref PubMed Google Scholar, 7Lamarche B. Tchernof A. Moorjani S. Cantin B. Dagenais G.R. Lupien P.J. Després J.P. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study.Circulation. 1997; 95: 69-75Crossref PubMed Scopus (1013) Google Scholar). These previous results, however, were obtained in nonFH subjects exhibiting lipoprotein profiles very different from the extremely elevated LDL-C seen in FH patients. To date, only a few studies have examined the heterogeneity of LDL particles in FH patients (8Slack J. Mills G.L. Anomalous low density lipoproteins in familial hyperbetalipoproteinaemia.Clin. Chim. Acta. 1970; 29: 15-25Crossref PubMed Scopus (41) Google Scholar, 9Patsch W. Ostlund R. Kuisk I. Levy R. Schonfeld G. Characterization of lipoprotein in a kindred with familial hypercholesterolemia.J. Lipid Res. 1982; 23: 1196-1205Abstract Full Text PDF PubMed Google Scholar, 10Bagnall T.F. Lloyrd J.K. Composition of low-density lipoprotein in children with hyperlipoproteinaemia.Clin. Chim. Acta. 1975; 59: 271-276Crossref PubMed Scopus (9) Google Scholar, 11Teng B. Thompson G.R. Sniderman A.D. Forte T.M. Krauss R.M. Kwiterovich Jr., P.O. Composition and distribution of low density lipoprotein fractions in hyperapobetalipoproteinemia, normolipidemia, and familial hypercholesterolemia.Proc. Natl. Acad. Sci. USA. 1983; 80: 6662-6666Crossref PubMed Scopus (173) Google Scholar), but their limited small sample size precluded any definitive conclusions. As characterization of LDL size could be relevant for the understanding of the variability in CAD risk among FH patients, the objective of the present study was to examine LDL size heterogeneity and its relationship to CETP in a large cohort of genetically-defined FH heterozygotes and controls. A total of 259 FH heterozygotes (122 men and 137 women) from Québec City and Saguenay (Canada) were enrolled. All participants were at least 18 years-of-age. Subjects were excluded if they: had a history of cardiovascular disease; were pregnant or nursing; had acute liver disease, hepatic dysfunction, or persistent elevations of serum transaminases; had plasma triglyceride levels >4.5 mmol/l or homozygous FH; had a secondary hyperlipidemia due to any cause; had a recent history of alcohol or drug abuse; had diabetes mellitus; had a history of cancer; or had hormonal treatment. All FH subjects were carriers of one of the nine previously known French-Canadian mutations in the LDLR gene (3Couture P. Vohl M.C. Gagné C. Gaudet D. Torres A.L. Lupien P.J. Després J.P. Labrie F. Simard J. Moorjani S. Identification of three mutations in the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French Canadians.Hum. Mutat. 1998; : S226-S231Crossref PubMed Scopus (27) Google Scholar) and were apoE3 homozygotes. Of those 259 heterozygous subjects selected, 123 had the deletion >15 kb at the 5′ end of the gene (12Hobbs H.H. Brown M.S. Russell D.W. Davignon J. Goldstein J.L. Deletion in the gene for the low-density-lipoprotein receptor in a majority of French Canadians with familial hypercholesterolemia.N. Engl. J. Med. 1987; 317: 734-737Crossref PubMed Scopus (210) Google Scholar), 112 had the W66G mutation in exon 3 (13Leitersdorf E. Tobin E.J. Davignon J. Hobbs H.H. Common low-density lipoprotein receptor mutations in the French Canadian population.J. Clin. Invest. 1990; 85: 1014-1023Crossref PubMed Scopus (253) Google Scholar), 13 had the Y468× mutation in exon 10 (14Simard J. Moorjani S. Vohl M.C. Couture P. Torres A.L. Gagné C. Després J.P. Labrie F. Lupien P.J. Detection of a novel mutation (stop 468) in exon 10 of the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French Canadians.Hum. Mol. Genet. 1994; 3: 1689-1691Crossref PubMed Scopus (33) Google Scholar), six had the C646Y mutation in exon 14 (15Hobbs H.H. Brown M.S. Goldstein J.L. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.Hum. Mutat. 1992; 1: PubMed Scopus Google Scholar), one had the mutation in exon (3Couture P. Vohl M.C. Gagné C. Gaudet D. Torres A.L. Lupien P.J. Després J.P. Labrie F. Simard J. Moorjani S. Identification of three mutations in the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French Canadians.Hum. Mutat. 1998; : S226-S231Crossref PubMed Scopus (27) Google Scholar), one had the mutation in exon (15Hobbs H.H. Brown M.S. Goldstein J.L. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.Hum. Mutat. 1992; 1: PubMed Scopus Google Scholar), one had the mutation in exon (3Couture P. Vohl M.C. Gagné C. Gaudet D. Torres A.L. Lupien P.J. Després J.P. Labrie F. Simard J. Moorjani S. Identification of three mutations in the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French Canadians.Hum. Mutat. 1998; : S226-S231Crossref PubMed Scopus (27) Google Scholar), one had the mutation in exon (3Couture P. Vohl M.C. Gagné C. Gaudet D. Torres A.L. Lupien P.J. Després J.P. Labrie F. Simard J. Moorjani S. Identification of three mutations in the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French Canadians.Hum. Mutat. 1998; : S226-S231Crossref PubMed Scopus (27) Google Scholar), and one had the kb deletion in and 3 (15Hobbs H.H. Brown M.S. Goldstein J.L. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.Hum. Mutat. 1992; 1: PubMed Scopus Google Scholar). All FH participants had to for at least before a sample was The study was by the and was obtained from A total of 208 controls men and women) were among the participants of the Québec which was of men and from I. P. C. E. J. Després J.P. of in men in the Quebec with and risk J. Google Scholar). As previously I. P. C. E. J. Després J.P. of in men in the Quebec with and risk J. Google Scholar), the Québec was to relevant on the prevalence and distribution of cardiovascular disease risk in the Québec All controls for the of this study were apoE3 homozygotes. were after a in and A.D. J. of apolipoprotein of plasma low density lipoproteins by and plasma Full Text PDF PubMed Google Scholar). were at for 10 at to plasma and were at and triglyceride levels were in plasma and in lipoprotein fractions by Co., an as previously S. A. Labrie F. Lupien P.J. Brun D. Gagné C. M. A. in plasma lipoprotein in men with 1987; Full Text PDF PubMed Scopus Google Scholar). were by and the HDL obtained after of LDL in the with and The and triglyceride of the were measured before and after the to polyacrylamide gradient gel electrophoresis was as previously Cantin B. Dagenais G.R. Després J.P. B. of of LDL and their relationship to the risk of ischemic heart PubMed Scopus Google Scholar). LDL particle size was on polyacrylamide gradient in in of of plasma were in a with a and and the A at electrophoresis of the plasma at for 3 were for 1 with and in a by the LDL size was from the of plasma of known The diameter for the major in was as the LDL-peak particle diameter LDL diameter was also by a of the by Tchernof A. B. D. A. Moorjani S. Labrie F. Lupien P.J. Després J.P. The dense LDL Association with plasma lipoprotein and in 1996; PubMed Scopus Google Scholar). LDL particle size to the size of LDL in one was as a and was as the of the diameter of LDL by its of plasma that of LDL-PPD was with an of of The of LDL a diameter was by the of the of low-density lipoprotein particle size and of J. 23: PubMed Scopus Google Scholar). The of among particles was by the plasma LDL-C levels by the of LDL with a diameter of low-density lipoprotein particle size and of J. 23: PubMed Scopus Google Scholar). A was to the and concentrations of in particles with a diameter between and or and CETP mass was to plasma CETP are M.C. of hepatic lipoprotein and cholesteryl ester transfer protein to LDL and HDL heterogeneity in PubMed Scopus Google Scholar). sample and the of transfer could have a significant on the relationship between CETP mass and In the present CETP mass was to the of and sample on the of the transfer CETP mass was by a enzyme-linked immunosorbent assay in a subgroup of 240 participants, 120 FH subjects matched for mass and with 120 controls. of was by of a of the exon of the gene with and and of with the of apolipoprotein by gene and with Lipid Res. 1990; Full Text PDF PubMed Google Scholar). from FH patients were compared with from patients for and for were to their were to the of of LDL-PPD and was to the relationship of was to the risk of LDL-PPD on plasma triglyceride levels and CETP mass. All were were from a total of subjects FH heterozygotes and 208 in the study and had The and biochemical of the are in There was significant between the and FH for and The deletion >15 kb and the W66G mutation were the French-Canadian mutations were present in than 90% of the The of was significantly among FH heterozygotes FH heterozygotes had significantly plasma concentrations of total P and LDL-C P and levels P compared with controls. There was significant in plasma triglyceride levels between the = and biochemical of participants to FH/control = = ± ± ± ± ± ± ± ± levels were for and ± ± levels were for and ± ± levels were for and ± ± levels were for and apolipoprotein mass familial LDL LDL are as ± All participants included were apoE3 levels were for and in a apolipoprotein mass familial LDL LDL are as ± All participants included were apoE3 homozygotes. CETP mass and of LDL to FH/control are in CETP mass was measured in a subgroup of 240 120 FH subjects matched for and with 120 controls, and was 11% higher in FH patients than in controls. significant after adjustment for plasma triglyceride levels = CETP mass and of LDL to FH/control = = mass ± ± levels were for plasma triglyceride = = ± ± 4.8 levels were for and plasma triglyceride LDL size ± ± levels were for and plasma triglyceride ± ± levels were for and plasma triglyceride ± ± levels were for and plasma triglyceride ± ± levels were for and plasma triglyceride ± ± levels were for and plasma triglyceride ± ± levels were for and plasma triglyceride ± ± levels were for and plasma triglyceride cholesteryl ester transfer LDL-peak particle are as ± All participants included were apoE3 levels were for plasma triglyceride levels were for and plasma triglyceride in a cholesteryl ester transfer LDL-peak particle are as ± All participants included were apoE3 homozygotes. adjustment for and plasma triglyceride which the diameter of the most of LDL was to be significantly smaller in FH heterozygotes than in subjects (258.1 ± 4.8 vs. 259.2 ± P = that the between LDL-PPD and the LDL which to the size of LDL in was among controls = P than in FH subjects = P that the distribution of LDL particle size between the the of a significantly smaller of LDL with a diameter in FH the LDL size of FH subjects significantly from that of controls ± vs. ± Å; P = is to however, that the smaller of LDL in FH was associated with a increase in the of LDL with a diameter between and significant in the of large LDL was between FH heterozygotes and controls. The distribution of LDL size among FH subjects and controls is in As the and were significantly higher in FH heterozygotes than in of LDL size among controls and FH that LDL-PPD was with plasma triglyceride levels = P = and plasma CETP mass concentrations = −0.15; P = LDL-PPD was to be significantly smaller in than in ± vs. ± P The of the between LDL-PPD and plasma CETP mass concentrations was abolished after adjustment for the FH/control status, indicating that the LDL-PPD changes in FH were mediated, at least in part, by were to to the LDL-PPD We that of the variability in LDL-PPD was to plasma triglyceride levels P plasma CETP mass concentrations P = 0.02), and P = and plasma LDL-C contribute significantly to LDL-PPD after adjustment for covariates. The of in plasma CETP mass concentrations and plasma triglyceride levels on the risk of LDL-PPD is in levels mmol/l of the were associated with a significant increase in the risk of LDL-PPD and this risk was increased in subjects with CETP mass The of plasma CETP concentrations was associated with a higher risk of small LDL in subjects with low triglyceride To the of this was the study to examine the role of CETP as the of LDL size heterogeneity in a large cohort of FH heterozygotes and controls. results suggested that LDLR gene mutations to FH are associated with significant in of LDL particle FH heterozygotes smaller LDL-PPD associated with an of LDL particles results also that plasma triglyceride levels and CETP mass concentrations, as as are of LDL-PPD in this cohort of FH and of LDL particles was before in FH patients, in very small and Mills (8Slack J. Mills G.L. Anomalous low density lipoproteins in familial hyperbetalipoproteinaemia.Clin. Chim. Acta. 1970; 29: 15-25Crossref PubMed Scopus (41) Google Scholar) examined LDL particle density in 18 FH heterozygotes compared with 20 controls and higher LDL in FH patients vs. indicating dense LDL W. Ostlund R. Kuisk I. Levy R. Schonfeld G. Characterization of lipoprotein in a kindred with familial hypercholesterolemia.J. Lipid Res. 1982; 23: 1196-1205Abstract Full Text PDF PubMed Google Scholar) also as compared with LDL particles of the LDL of FH heterozygotes were and increased or and Lloyrd T.F. Lloyrd J.K. Composition of low-density lipoprotein in children with hyperlipoproteinaemia.Clin. Chim. Acta. 1975; 59: 271-276Crossref PubMed Scopus (9) Google Scholar) and B. Thompson G.R. Sniderman A.D. Forte T.M. Krauss R.M. Kwiterovich Jr., P.O. Composition and distribution of low density lipoprotein fractions in hyperapobetalipoproteinemia, normolipidemia, and familial hypercholesterolemia.Proc. Natl. Acad. Sci. USA. 1983; 80: 6662-6666Crossref PubMed Scopus (173) Google Scholar) that the LDL particles of FH heterozygotes had an increased and were in The present study the by that the distribution of LDL particle size in FH is characterized by a of small LDL associated with a increase in the of LDL particles with a diameter between and this was the study to that the most of is smaller in FH heterozygotes than in controls. The present study that plasma CETP mass was significantly higher in FH heterozygotes than in controls. We also that the of the inverse between LDL-PPD and plasma CETP mass was abolished by adjustment for the FH/control status, that LDL-PPD changes in FH are mediated, at least in part, by an increase in plasma CETP mass concentrations. has been that CETP plays a major role in the remodeling of HDL have also been to that CETP is an of LDL particle size (4Talmud P.J. Edwards K.L. Turner C.M. Newman B. Palmen J.M. Humphries S.E. Austin M.A. Linkage of the cholesteryl ester transfer protein (CETP) gene to LDL particle size: use of a novel tetranucleotide repeat within the CETP promoter.Circulation. 2000; 101: 2461-2466Crossref PubMed Scopus (62) Google Scholar, L. A. C. P. of plasma cholesteryl ester transfer on the LDL and HDL distribution profiles in PubMed Google Scholar, A. I. D. W. J. W. C. LDL size distribution in to and lipoprotein in and 1998; PubMed Scopus Google Scholar, J.P. F. In of low density lipoproteins and dense low density lipoproteins in role of of transfer and lipoprotein 1998; Full Text Full Text PDF PubMed Scopus Google Scholar), this is a F. P. G. A. Composition of low density of lipoprotein hepatic and cholesteryl ester transfer Full Text PDF PubMed Scopus Google Scholar, M.J. J. J. of LDL distribution and concentrations in 1994; PubMed Scopus Google Scholar). lines of evidence support the that plasma triglyceride levels the role of CETP in lipoprotein LDL remodeling of plasma cholesteryl ester transfer in Clin. Invest. PubMed Scopus Google Scholar, S. A. W. R. plasma cholesteryl ester transfer in with apolipoprotein lipoproteins and transfer 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). In CETP is to the of small dense LDL to LDL-PPD an of increased of triglyceride transfer from lipoproteins in exchange for cholesteryl ester in LDL and HDL E. L. S. triglyceride in low and density PubMed Google Scholar). examined the to which in plasma triglyceride levels be responsible for the in LDL-PPD between FH subjects and controls. We that the of plasma CETP concentrations were associated with a higher risk of small LDL-PPD in subjects with plasma triglyceride levels that the remodeling of LDL is on the number of plasma results that plasma triglyceride plasma CETP mass concentrations, and were of LDL-PPD and of its that a large of the variability in LDL-PPD by in this cohort of FH and In a number of and have been to be associated with LDL heterogeneity and could also contribute to the variability of LDL-PPD in the present studies on that to of the in LDL-PPD be to M.A. Newman B. Edwards E.J. Krauss R.M. of LDL in and PubMed Scopus Google Scholar, S. D. D. J.M. E.J. The of apolipoprotein and low density lipoprotein and for Full Text PDF PubMed Scopus Google Scholar). a major on LDL-PPD has been L. Després J.P. B. C. Vohl M.C. for a major on low-density lipoprotein particle PubMed Scopus Google Scholar). In of lipoprotein as lipoprotein and hepatic have been to contribute to the of dense LDL particles and could significant of LDL-PPD in FH M.C. of hepatic lipoprotein and cholesteryl ester transfer protein to LDL and HDL heterogeneity in PubMed Scopus Google Scholar). of dense LDL particles have been suggested to be responsible for the risk of In dense LDL particles have been to be to than LDL in lipoprotein PubMed Scopus (62) Google Scholar) and to have a higher to to M. Krauss R.M. in of low density lipoproteins associated with low density lipoprotein Lipid Res. 1990; Full Text PDF PubMed Google Scholar), associated with Moreover, dense LDL particles have been associated with CAD in a number of studies (5Gardner C.D. Fortmann S.P. Krauss R.M. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women.J. Am. Med. Assoc. 1996; 276: 875-881Crossref PubMed Google Scholar, 6Stampfer M.J. Krauss R.M. Ma J. Blanche P.J. Holl L.G. Sacks F.M. Hennekens C.H. A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction.J. Am. Med. Assoc. 1996; 276: 882-888Crossref PubMed Google Scholar, 7Lamarche B. Tchernof A. Moorjani S. Cantin B. Dagenais G.R. Lupien P.J. Després J.P. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study.Circulation. 1997; 95: 69-75Crossref PubMed Scopus (1013) Google Scholar). In the present the in the LDL-PPD between FH heterozygotes and controls was (258.1 ± 4.8 vs. 259.2 ± 4.1 a in LDL-PPD play an role in the of in Cantin B. Dagenais G.R. Després J.P. B. of of LDL and their relationship to the risk of ischemic heart PubMed Scopus Google Scholar) have that the in the LDL-PPD between the subjects and the subjects CAD a was only ± vs. ± in LDL particle and diameter have been to changes of which and changes in LDLR and to E.J. in LDL in and changes in apolipoprotein Lipid Res. 1996; Full Text PDF PubMed Google Scholar, C. M. L. J. Molecular for changes in on changes of the and the of low-density apolipoprotein PubMed Scopus Google Scholar). Moreover, in a recent M.A. dense low-density and the lipoprotein 2000; PubMed Scopus Google Scholar), a 10 in the LDL-PPD was associated with a increase in CAD on the in LDL-PPD between controls and FH subjects in the present study be associated with a increase in the CAD In have that heterozygous FH is associated with increased plasma CETP mass concentrations and changes in the distribution of LDL particle a LDL-PPD and an of LDL that the of LDL and the increased CETP mass concentrations could lead to significant LDL remodeling in FH and could contribute to the pathogenesis of in patients by which the diameter of the most of LDL was by the and The are to the participants for their is of a from the Québec is in and Cardiovascular from the is of and of Cardiovascular which is by and the of the Québec apolipoprotein mass coronary artery disease cholesteryl ester transfer protein familial hypercholesterolemia LDL LDL-peak particle diameter LDL receptor

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