Donate Help Contact The AHA Sign In Home
American Heart Association
Arteriosclerosis, Thrombosis, and Vascular Biology
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:897-902
Published online before print February 9, 2006, doi: 10.1161/01.ATV.0000209577.04246.c0
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Data Supplement
Right arrow All Versions of this Article:
26/4/897    most recent
01.ATV.0000209577.04246.c0v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Watanabe, H.
Right arrow Articles by Taskinen, M.-R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Watanabe, H.
Right arrow Articles by Taskinen, M.-R.
Right arrowPubmed/NCBI databases
*Substance via MeSH
Related Collections
Right arrow Lipid and lipoprotein metabolism
(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:897.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Decreased High-Density Lipoprotein (HDL) Particle Size, Preß-, and Large HDL Subspecies Concentration in Finnish Low-HDL Families

Relationship With Intima-Media Thickness

Hiroshi Watanabe; Sanni Söderlund; Aino Soro-Paavonen; Anne Hiukka; Eeva Leinonen; Corradina Alagona; Riitta Salonen; Tomi-Pekka Tuomainen; Christian Ehnholm; Matti Jauhiainen; Marja-Riitta Taskinen

From the Division of Cardiology (H.W., S.S., A.S.-P., A.H., E.L., C.A., M.-R.T.), Department of Medicine, Helsinki University Central Hospital and Biomedicum, Finland; Unita Operativa di Medicina Interna (C.A.), Ospedale Cannizzaro, Universitá di Catania, Catania, Italy; Research Institute of Public Health (R.S., T.-P.T.), University of Kuopio, Finland; and Department of Molecular Medicine (C.E., M.J.), Biomedicum, National Public Health Institute, Helsinki, Finland.

Correspondence to Marja-Riitta Taskinen, MD, Professor of Medicine, Helsinki University Central Hospital Biomedicum, Haartmaninkatu 8, PO Box 700, 00029 Helsinki, Finland. E-mail marja-riitta.taskinen{at}helsinki.fi


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Objective— High-density lipoprotein (HDL) cholesterol correlates inversely with the risk of coronary heart disease (CHD). The precise antiatherogenic mechanisms of HDL subspecies are not thoroughly elucidated. We studied the relationship between carotid intima-media thickness (IMT) and HDL subspecies distribution in Finnish families with low HDL cholesterol and premature CHD.

Methods and Results— Altogether, 148 members of Finnish low-HDL families and 133 healthy control subjects participated in our study. HDL particle size was significantly smaller in affected family members (HDL ≤10th Finnish age-sex specific percentile) compared with unaffected family members and control subjects (9.1±0.04 nm versus 9.5±0.05 nm, P<0.0001, versus 9.8±0.03 nm, P<0.0001 [mean±SE]). Large HDL2b particles as well as preß-HDL concentration were significantly decreased among the affected family members. Mean IMT was significantly higher in the affected family members than in the control subjects (0.85±0.01 mm versus 0.79±0.01 mm; P<0.0001). Age, HDL2b, systolic blood pressure, and preß-HDL were significant independent determinants of mean IMT.

Conclusions— The decreased levels of HDL2b and preß-HDL reflect the potentially efflux-deficient HDL subspecies profile in the affected low-HDL family members. Decreased HDL particle size caused by the decrease of plasma concentration of HDL2b and decreased preß-HDL levels correlate with increased IMT.

The precise antiatherogenic mechanisms of high-density lipoprotein (HDL) subspecies are not thoroughly elucidated. HDL particle size and levels of HDL2b, HDL2a, and preß-HDL were decreased, and intima-media thickness (IMT) was increased in Finnish subjects with familial low HDL. Age, HDL2b, systolic blood pressure, and preß-HDL were significant independent determinants of IMT.


Key Words: HDL particle size • HDL subspecies • preß-HDL • intima-media thickness • atherosclerosis


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Epidemiological studies have shown that low level of high-density lipoprotein (HDL) cholesterol is an independent predictor of coronary heart disease (CHD).1,2 Already, a small 0.03-mmol/L (1 mg/dL) increase in total HDL cholesterol (HDL-C) level is associated with a 2% to 3% decline in cardiovascular risk.3,4 HDL particles are classified into several subspecies differing in their composition, size, charge and function. Based on the electric charge, HDL can be separated into preß-HDL, {alpha}-HDL, and pre{alpha}-HDL. Preß-HDL can be separated into 3 major subspecies, preß1, preß2, and preß3-HDL, whereas {alpha}-HDL can be separated into HDL2b, 2a, 3a, 3b, and 3c according to particle size.5,6 At present, the reverse cholesterol transport (RCT) process, which removes excess cholesterol from peripheral cells to the liver for excretion, is considered one of the most important antiatherogenic functions of HDL.7,8 The initial step of RCT is cholesterol efflux, in which the ATP-binding cassette transporter A1 (ABCA1) mediates efflux of cellular cholesterol to preß-HDL,9 and ATP-binding cassette transporter G1 (ABCG1) stimulates efflux to larger HDL particles, especially to HDL2.10 The discovery of ABCG1 directing cellular cholesterol to large HDL particles10 has focused current attention on the role of HDL subspecies in the prevention of atherosclerosis.

Evaluation of carotid intima-media thickness (IMT) using ultrasonography is a validated quantitative method for assessing the presence and severity of atherosclerosis,11 and a close relationship has been observed between IMT and the incidence of CHD.12–14 To investigate the association of different HDL subspecies with early atherosclerosis in Finnish low-HDL family members, we measured the distribution of HDL subspecies HDL2b, 2a, 3a, 3b, and 3c using polyacrylamide native gradient gel electrophoresis, quantitated proportion of preß-HDL particles by crossed immunoelectrophoresis, and measured carotid IMT by ultrasonography. Altogether, 148 low-HDL family members and 133 normolipidemic control subjects participated in the study.


*    Materials and Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Materials and Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Study Subjects
The study subjects were recruited from multigenerational, carefully characterized pedigrees with low HDL-C and premature CHD. The pedigrees were recruited in Helsinki and Turku University Central Hospitals in Finland as described previously.15,16 For the inclusion criteria of the probands, please see online data supplement I, available at http://atvb.ahajournals.org.

Altogether, 281 subjects participated in the study, including 148 family members from 50 low-HDL families and 133 normolipidemic healthy subjects. The mean number of family members from each participating family was 3 (range 1 to 10); 41 families contributed ≤4 members to this study. Based on their HDL-C level, family members were categorized as affected (HDL-C ≤10th Finnish age-gender specific percentile;17,18 n=83) or unaffected (n=65). In 5 families, we allowed the proband to be hypertriglyceridemic. These families contributed 12 subjects altogether to this study. The control group contained 10 healthy spouses from low-HDL families and 123 healthy volunteers. At the time of the sample collection, 34 affected family members, 4 unaffected family members, and 2 control subjects were using ß-blockers; 19 affected family members and 2 unaffected family members were using statins. Subjects using other medications potentially affecting HDL metabolism were excluded. Each study subject gave written informed consent before participating in the study. All samples were collected in accordance with the Helsinki declaration and the ethics committees of the participating centers approved the study design.

Measurements
Venous blood samples were obtained after an overnight fast. Serum and EDTA plasma were separated by centrifugation and stored at –80°C until analysis. For the measurements of lipids, apolipoproteins and glucose, please see online data supplement II.

We measured the relative distribution of HDL subspecies 2b, 2a, 3a, 3b, and 3c by gradient gel electrophoresis in 78 affected and 59 unaffected low-HDL family members and in 127 control subjects. We used a lipoprotein fraction separated from plasma by ultracentrifugation in density of 1.210 g/mL. Samples of 5 µL were loaded into a native 4% to 22% polyacrylamide gradient gel (10x10.5 cm). All gels were prepared in the laboratory. We used high molecular weight (HMW) calibration kit for native electrophoresis from Pharmacia for standardization. Gels were stained 1 hour with Coomassie blue G-250 and destained overnight with acetic acid. Stained gels were analyzed with ImageMaster 1D software (version 4.00; Amersham Pharmacia Biotech). The diameter of each lipoprotein band was calibrated by computing a log-linear standard curve of the protein-stainable HMW standards as a function of their relative migration distance.5,6

The quantification of preß-HDL was performed by crossed immunoelectrophoresis19 in 63 affected and 46 unaffected family members and in 89 control subjects. Areas under the immunoprecipitate curves were measured after staining. The preß-HDL area is expressed as a percentage of the sum of {alpha}-HDL and preß-HDL areas. Preß-HDL concentration is given in absolute amount (milligrams of apolipoprotein A-I [apoA-I] present in preß-HDL particles per liter serum).

B-mode ultrasound imaging was used to measure the intima-media complex of carotid artery wall with a Hewlett Packard Image Point M2410A ultrasound system (Hewlett Packard) as previously described.16,20 IMT was measured in 65 affected and 47 unaffected family members and in 105 control subjects. The Prosound software (Caltech) was used to measure IMTs from ultrasound images.21 Intrareader variability was assessed by reading the scannings of 10 study subjects twice. The coefficient of variation between the mean IMT of the paired scans was 1.0%, and the absolute difference 0.014±0.018 mm, respectively. The readers were blinded for the identities of the study subjects.

Statistical Methods
The statistical comparisons of clinical and biochemical parameters were performed with JMP 5.01 for Windows (SAS Institute Inc.). Results are expressed as mean±SE for continuous variables and as frequencies or percentages for categorical variables. The normality of each variable distribution was tested by Kolmogorov–Smirnov test and variables with skewed distribution were log10 transformed before the analyses, but the values in text, tables, and figure are presented as nontransformed. Continuous variables were compared between control subjects and family members by general linear model, univariate ANCOVA, and between unaffected and affected family members by random effects model to adjust for dependence among the family members. P<0.05 was considered significant (2-tailed). The frequency distribution of the categorical variables was compared between the groups with the {chi}2 test. The relationships of the characteristics were examined by Pearson correlation and Spearman correlation analysis as appropriate. Multivariate stepwise linear regression analysis was performed to determine the relative contribution of different parameters to the mean IMT. Independent variables were removed from the model until the best-fitting model with the maximum adjusted multiple R2 was achieved. All values used in the comparisons with control subjects and in correlation analyses were adjusted for age and gender because of the differences between the study groups.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 *Results
down arrowDiscussion
 down arrowReferences
 
Table 1 shows the biochemical and clinical characteristics of the study subjects. Altogether, 35 family members had CHD. Among these, 33 were affected (31 probands) and 2 were unaffected. The affected family members had significantly higher body mass index (BMI), waist circumference, triglycerides (TGs), and apoB and significantly lower HDL-C, apoA-I, apoA-II, and total cholesterol (TC) than the control subjects. Compared with the unaffected family members, the affected family members were older and had significantly higher BMI, waist circumference, TGs, apoB, and fasting glucose and significantly lower TC, HDL-C, apoA-I, and apoA-II.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Characteristics of the Study Subjects

Table 2 displays the HDL subspecies distribution. HDL particle size was markedly smaller in the affected family members than in the unaffected family members and control subjects. (For a figure, please see online data supplement III.) The amount of protein (as percentage) of integration area of HDL2b was significantly lower, whereas that of HDL3a, HDL3b, and HDL3c was significantly higher in the affected family members than in the unaffected family members and in the control group. The greatest difference was demonstrated in HDL2b, with a reduction of &50% in the affected family members compared with the control group. Interestingly, when the unaffected family members were compared with the control subjects, they had significantly smaller HDL particle size, and their relative amount of HDL2b was significantly reduced. Moreover, the relative amounts of HDL3a, HDL3b, and HDL3c subspecies were significantly increased in the unaffected family members compared with the control subjects.


View this table:
[in this window]
[in a new window]
  		TABLE 2. HDL Species of the Study Subjects

Preß-HDL concentration was significantly lower in the affected family members compared with the levels detected in the unaffected family members and in the control group (Table 2; for a figure, please see online supplement III).

Mean IMT was significantly higher in the affected family members than in the control subjects (0.85±0.01 mm versus 0.79±0.01 mm; P<0.0001). However, no significant difference was observed in mean IMT between the affected and unaffected family members (0.85±0.01 mm versus 0.82±0.02 mm; see the figure in online data supplement III).

Table 3 shows the results of the correlation analyses between mean IMT and clinical parameters in all subjects. Mean IMT showed a significant positive correlation with age, systolic blood pressure (SBP), HDL3a, and HDL3b (Table 3; Figure, D). It correlated inversely with HDL-C, HDL particle size, HDL2b, and preß-HDL level (Table 3; Figure, A through C).


View this table:
[in this window]
[in a new window]
  		TABLE 3. Relationship of IMT With Clinical Parameters by Univariate Regression Analysis


Figure 1
View larger version (13K):
[in this window]
[in a new window]
  		Relationship between mean IMT and HDL particle size, preß-HDL concentration, HDL2b, and HDL3b in low-HDL family members (•) and control group ({circ}). A, Correlation between mean IMT and HDL particle size. B, Correlation between mean IMT and preß-HDL concentration. C, Correlation between mean IMT and HDL2b. D, Correlation between mean IMT and HDL3b.

Stepwise regression analysis was performed in the pooled study sample to test the relative contributions of different variables to IMT. Age, gender, blood pressure, BMI, TC, TGs, HDL-C, preß-HDL, HDL particle size, the amount of protein (as percentage) of integration area of HDL subspecies, low-density lipoprotein (LDL) cholesterol, apoA-I, apoA-II, apoB, and fasting glucose were used for independent variables. The remaining variables in the final model included age, HDL2b, SBP, and preß-HDL concentration, with the adjusted multiple R2 of 0.62 (Table 4).


View this table:
[in this window]
[in a new window]
  		TABLE 4. Relationship of Mean IMT With Clinical Parameters by Multivariate Regression Analysis


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
We measured HDL particle size and the proportions of different HDL subspecies in low-HDL family members and control subjects to clarify the influence of HDL subspecies distribution on the degree of atherosclerosis as measured by IMT. To the best of our knowledge, this is the first study to quantitate specific HDL subspecies, HDL particle size, and preß-HDL concentrations simultaneously in the same cohort. HDL particle size was markedly smaller in the affected family members than in the unaffected family members or control subjects. Preß-HDL concentration and percentage of HDL2b were significantly lower, whereas percentages of HDL3a, HDL3b, and HDL3c were significantly higher in the affected family members compared with the 2 other groups. This is in accordance with previous studies, which have shown that large HDL particles are decreased in subjects with low HDL.22–24 Large HDL particles were also decreased in hypertriglyceridemic subjects.23,25 However, the present affected low-HDL family members showed only a moderate elevation of TGs, suggesting that the changes in HDL subspecies may not be explained by elevation of serum TGs only. This is further supported by the fact that the unaffected family members showed qualitatively similar changes in HDL profile despite a comparable TG level with control subjects. We propose that the observed changes of HDL profile may reflect also an exposure to genetic components regulating the distribution of HDL subspecies. Interestingly, recent data suggest that changes of HDL subspecies may provide better phenotypes than only HDL-C levels.26,27

HDL particle size was markedly smaller in the affected low-HDL family members than in the control subjects. Recently, larger HDL particle size has been shown to associate with exceptional longevity.28 In contrast, reduced HDL particle size is a feature of the high-TG/low-HDL profile in subjects with abdominal obesity.29 Thus, HDL particle size may be a relevant marker of the atherogenic lipid profile.

The most important antiatherogenic function of HDL is considered to be its role in RCT,7,8 in which ABCA1 mediates efflux of cellular cholesterol to preß-HDL9 and ABCG1 stimulates efflux to larger HDL particles, especially to HDL2.10 Wang et al hypothesize that ABCG1-mediated efflux could be more important in preventing CHD because most of the plasma HDL consists of such mature HDL particles.10 Our affected low-HDL family members had decreased proportions of large HDL particles and preß-HDL concentration, supporting the theory of compromised efflux explaining the elevated risk of CHD in subjects with low HDL. Furthermore, the greatest reduction was seen in HDL2b (&50%). This finding further supports the hypothesis of ABCG1-mediated efflux to large HDL species being an important mechanism for the protective action of HDL against atherosclerosis.10 In addition, ABCG1 prevents cellular lipid accumulation in hepatocytes and macrophages in several tissues.30 Thus, RCT-defective HDL subspecies distribution might be associated with increased risk of atherosclerosis in Finnish low-HDL family members.

Most of the reported cardioprotective properties of HDL have been associated with HDL2 rather than HDL3 fraction.31,32 Importantly, low levels of HDL2b together with high levels of HDL3b have been reported to associate with high CHD risk.32,33 Thus, changes of specific HDL subspecies may have more significant roles in CHD risk prediction than generally recognized. To investigate the influence of HDL subspecies distribution on the degree of atherosclerosis in Finnish low-HDL families, we measured IMT by ultrasonography. The affected low-HDL family members had significantly higher mean IMT than the control subjects. Mean IMT tended to be higher in the affected family members than in the unaffected family members, but the difference was not significant. Of the traditional risk factors of CHD, age, SBP, and HDL-C appeared to be the most important determinants of IMT. Most important, adding HDL subspecies as independent variables in the stepwise regression analysis, the data demonstrated that among HDL subspecies, HDL2b was the most important determinant of carotid atherosclerosis.

Moreover, stepwise regression analysis showed that preß-HDL is also an important determinant of IMT. As discussed, preß-HDL acts as the primary acceptor of cellular cholesterol in RCT. Decreased preß-HDL concentration is one of the major reasons to diminished cholesterol efflux capacity and thus would promote progression of atherosclerosis.7 Due to the important role of RCT in maintaining the cholesterol homeostasis and lowering the risk of atherosclerosis, the regulation of HDL and HDL subspecies distribution may directly influence the atherogenic process.

One interesting finding was the difference in HDL subspecies between the unaffected low-HDL family members and the control subjects. Although having similar HDL-C levels, the unaffected family members had significantly smaller HDL particle size and less HDL2b. This may reflect their risk of developing the characteristic low-HDL profile later in life. The unaffected family members were younger than the affected members, and thus at least some subjects may have been exposed to the same genotype as the affected members. We speculate that the observed changes in HDL subspecies distribution may be the first changes in the lipoprotein profile leading to the lowering of HDL-C under long-term exposure. In the context of RCT process and HDL subspecies distribution, the next important step will be to measure cholesterol efflux from macrophages to serum withdrawn from low-HDL family members. It would be also interesting to compare serum cholesterol removal capacity between unaffected family members and control subjects having similar HDL-C levels but different HDL subspecies distribution.

One potential limitation of our study is that the correlation analyses as well as the stepwise regression analyses were performed in a pooled study sample. Therefore, these results do not necessarily show the actual causality. On the other hand, the pooling of the different groups together gives us a wider range of these biological parameters, which, in turn, facilitates the interpretation of the outcome in the present study. Another drawback is the relatively small sample size. This is partly because of the exclusion of a large number of women using estrogen. However, the family criteria were strict and the subjects were well characterized and therefore "analysis-wise" behaved similarly.

The effect of distribution of HDL subspecies on the development of atherosclerosis has not been elucidated thoroughly. However, HDL subspecies may become a target in the context of drug development designed to increase the antiatherogenic species of circulating HDL levels. In this context, the discovery of the human genetic cholesterol ester transfer protein (CETP) deficiency typically characterized by markedly increased HDL levels and moderately reduced LDL launched the design of drugs that will inhibit CETP.34–37 A mechanistically interesting result was the observed significant increase in HDL particle size and a decrease in small dense LDL particles in subjects treated with the CETP inhibitor torcetrapib.35 One relevant mechanism to explain the protective effect of large-size HDL particles might be that they act as ideal free cholesterol acceptors mediated by ABCG1.10 This suggests that rising the concentration of large HDL particles might reflect mechanisms that may enhance RCT and consequently reduce the risk of CHD.

In summary, our results suggest that the risk for the development of atherosclerosis in low-HDL family members is increased because of decrease of HDL particle size and a general shift in HDL subspecies distribution toward small-size HDL. The decreased levels of HDL2b and preß-HDL reflect the potentially efflux-deficient HDL subspecies distribution in the affected low-HDL family members. These novel findings support the hypothesis of impaired cholesterol efflux being the mechanism underlying the importance of HDL subspecies in preventing atherosclerosis.


*    Acknowledgments
 
This work was supported by the International HDL Research Awards (C.E.); Sigrid Juselius Foundation (M.J., M.R.T.); Finnish Foundation for Cardiovascular Research (M.J., M.R.T.); Alumni Association for Hiroshima University Graduate School of Biomedical Science, Department of Molecular and Internal Medicine (H.W.); National Graduate School of Clinical Investigation (S.S.); and the Helsinki University Central Hospital Research Foundation (M.R.T., E.L.). The authors thank the family members and the control subjects for participating in the study. Jari Metso, Helinä Perttunen-Nio, Hannele Hilden, Ritva Nurmi, and Sari Nuutinen are thanked for their excellent technical assistance.


*    Footnotes
 
M.-R.T. received honoraria and consulting fees from Laboratoires Fournier, Merck Sharp and Dome, Pfizer, Bristol-Myers Squibb, Takeda, and Sanofi-Aventis.

H.W. and S.S. contributed equally to this study.

Received September 30, 2005; accepted January 26, 2006.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

  1. Genest J, Jr, Marcil M, Denis M, Yu L. High density lipoproteins in health and in disease. J Investig Med. 1999; 47: 31–42.[Medline] [Order article via Infotrieve]
  2. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977; 62: 707–714.[CrossRef][Medline] [Order article via Infotrieve]
  3. Gordon T, Kannel WB, Castelli WP, Dawber TR. Lipoproteins, cardiovascular disease, and death. The Framingham Study. Arch Intern Med. 1981; 141: 1128–1131.[Abstract]
  4. Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Munster study. Am J Cardiol. 1992; 70: 733–737.[CrossRef][Medline] [Order article via Infotrieve]
  5. Perusse M, Pascot A, Despres JP, Couillard C, Lamarche B. A new method for HDL particle sizing by polyacrylamide gradient gel electrophoresis using whole plasma. J Lipid Res. 2001; 42: 1331–1334.[Abstract/Free Full Text]
  6. Blanche PJ, Gong EL, Forte TM, Nichols AV. Characterization of human high-density lipoproteins by gradient gel electrophoresis. Biochim Biophys Acta. 1981; 665: 408–419.[Medline] [Order article via Infotrieve]
  7. Stein O, Stein Y. Atheroprotective mechanisms of HDL. Atherosclerosis. 1999; 144: 285–301.[CrossRef][Medline] [Order article via Infotrieve]
  8. Assmann G, Nofer JR. Atheroprotective effects of high-density lipoproteins. Annu Rev Med. 2003; 54: 321–341.[CrossRef][Medline] [Order article via Infotrieve]
  9. Wang N, Silver DL, Costet P, Tall AR. Specific binding of ApoA-I, enhanced cholesterol efflux, and altered plasma membrane morphology in cells expressing ABC1. J Biol Chem. 2000; 275: 33053–33058.[Abstract/Free Full Text]
  10. Wang N, Lan D, Chen W, Matsuura F, Tall AR. ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. Proc Natl Acad Sci U S A. 2004; 101: 9774–9779.[Abstract/Free Full Text]
  11. Poli A, Tremoli E, Colombo A, Sirtori M, Pignoli P, Paoletti R. Ultrasonographic measurement of the common carotid artery wall thickness in hypercholesterolemic patients. A new model for the quantitation and follow-up of preclinical atherosclerosis in living human subjects. Atherosclerosis. 1988; 70: 253–261.[CrossRef][Medline] [Order article via Infotrieve]
  12. Davis PH, Dawson JD, Mahoney LT, Lauer RM. Increased carotid intimal-medial thickness and coronary calcification are related in young and middle-aged adults. The Muscatine Study. Circulation. 1999; 100: 838–842.[Abstract/Free Full Text]
  13. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med. 1999; 340: 14–22.[Abstract/Free Full Text]
  14. Hodis HN, Mack WJ, LaBree L, Selzer RH, Liu CR, Liu CH, Azen SP. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med. 1998; 128: 262–269.[Abstract/Free Full Text]
  15. Soro A, Pajukanta P, Lilja HE, Ylitalo K, Hiekkalinna T, Perola M, Cantor RM, Viikari JS, Taskinen MR, Peltonen L. Genome scans provide evidence for low-HDL-C loci on chromosomes 8q23, 16q24.1–24.2, and 20q13.11 in Finnish families. Am J Hum Genet. 2002; 70: 1333–1340.[CrossRef][Medline] [Order article via Infotrieve]
  16. Alagona C, Soro A, Ylitalo K, Salonen R, Salonen JT, Taskinen MR. A low high density lipoprotein (HDL) level is associated with carotid artery intima-media thickness in asymptomatic members of low HDL families. Atherosclerosis. 2002; 165: 309–316.[CrossRef][Medline] [Order article via Infotrieve]
  17. Vartiainen E, Puska P, Jousilahti P, Korhonen HJ, Tuomilehto J, Nissinen A. Twenty-year trends in coronary risk factors in north Karelia and in other areas of Finland. Int J Epidemiol. 1994; 23: 495–504.[Abstract/Free Full Text]
  18. Vartiainen E, Jousilahti P, Alfthan G, Sundvall J, Pietinen P, Puska P. Cardiovascular risk factor changes in Finland, 1972–1997. Int J Epidemiol. 2000; 29: 49–56.[Abstract/Free Full Text]
  19. van Haperen R, van Tol A, Vermeulen P, Jauhiainen M, van Gent T, van den Berg P, Ehnholm S, Grosveld F, van der Kamp A, de Crom R. Human plasma phospholipid transfer protein increases the antiatherogenic potential of high density lipoproteins in transgenic mice. Arterioscler Thromb Vasc Biol. 2000; 20: 1082–1088.[Abstract/Free Full Text]
  20. Ylitalo K, Syvanne M, Salonen R, Nuotio I, Taskinen MR, Salonen JT. Carotid artery intima-media thickness in Finnish families with familial combined hyperlipidemia. Atherosclerosis. 2002; 162: 171–178.[CrossRef][Medline] [Order article via Infotrieve]
  21. Selzer RH, Hodis HN, Kwong-Fu H, Mack WJ, Lee PL, Liu CR, Liu CH. Evaluation of computerized edge tracking for quantifying intima-media thickness of the common carotid artery from B-mode ultrasound images. Atherosclerosis. 1994; 111: 1–11.[CrossRef][Medline] [Order article via Infotrieve]
  22. Yang Y, Yan B, Fu M, Xu Y, Tian Y. Relationship between plasma lipid concentrations and HDL subclasses. Clin Chim Acta. 2005; 354: 49–58.[CrossRef][Medline] [Order article via Infotrieve]
  23. Xu Y, Fu M. Alterations of HDL subclasses in hyperlipidemia. Clin Chim Acta. 2003; 332: 95–102.[CrossRef][Medline] [Order article via Infotrieve]
  24. Asztalos BF, Lefevre M, Foster TA, Tulley R, Windhauser M, Wong L, Roheim PS. Normolipidemic subjects with low HDL cholesterol levels have altered HDL subpopulations. Arterioscler Thromb Vasc Biol. 1997; 17: 1885–1893.[Abstract/Free Full Text]
  25. Syvanne M, Ahola M, Lahdenpera S, Kahri J, Kuusi T, Virtanen KS, Taskinen MR. High density lipoprotein subfractions in non-insulin-dependent diabetes mellitus and coronary artery disease. J Lipid Res. 1995; 36: 573–582.[Abstract]
  26. Yang Q, Lai CQ, Parnell L, Cupples LA, Adiconis X, Zhu Y, Wilson PW, Housman DE, Shearman AM, D’Agostino RB, Ordovas JM. Genome-wide linkage analyses and candidate gene fine mapping for HDL3 cholesterol: the Framingham Study. J Lipid Res. 2005; 46: 1416–1425.[Abstract/Free Full Text]
  27. Almasy L, Hixson JE, Rainwater DL, Cole S, Williams JT, Mahaney MC, VandeBerg JL, Stern MP, MacCluer JW, Blangero J. Human pedigree-based quantitative-trait-locus mapping: localization of two genes influencing HDL-cholesterol metabolism. Am J Hum Genet. 1999; 64: 1686–1693.[CrossRef][Medline] [Order article via Infotrieve]
  28. Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R, Cheng S, Shuldiner AR. Unique lipoprotein phenotype and genotype associated with exceptional longevity. J Am Med Assoc. 2003; 290: 2030–2040.[Abstract/Free Full Text]
  29. Pascot A, Lemieux I, Prud’homme D, Tremblay A, Nadeau A, Couillard C, Bergeron J, Lamarche B, Despres JP. Reduced HDL particle size as an additional feature of the atherogenic dyslipidemia of abdominal obesity. J Lipid Res. 2001; 42: 2007–2014.[Abstract/Free Full Text]
  30. Kennedy MA, Barrera GC, Nakamura K, Baldan A, Tarr P, Fishbein MC, Frank J, Francone OL, Edwards PA. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell Metab. 2005; 1: 121–131.[CrossRef][Medline] [Order article via Infotrieve]
  31. Lamarche B, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Despres JP. Associations of HDL2 and HDL3 subfractions with ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study. Arterioscler Thromb Vasc Biol. 1997; 17: 1098–1105.[Abstract/Free Full Text]
  32. Johansson J, Carlson LA, Landou C, Hamsten A. High density lipoproteins and coronary atherosclerosis. A strong inverse relation with the largest particles is confined to normotriglyceridemic patients. Arterioscler Thromb. 1991; 11: 174–182.[Abstract/Free Full Text]
  33. Williams PT, Krauss RM, Vranizan KM, Stefanick ML, Wood PD, Lindgren FT. Associations of lipoproteins and apolipoproteins with gradient gel electrophoresis estimates of high density lipoprotein subfractions in men and women. Arterioscler Thromb. 1992; 12: 332–340.[Abstract/Free Full Text]
  34. Brousseau ME, Diffenderfer MR, Millar JS, Nartsupha C, Asztalos BF, Welty FK, Wolfe ML, Rudling M, Bjorkhem I, Angelin B, Mancuso JP, Digenio AG, Rader DJ, Schaefer EJ. Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion. Arterioscler Thromb Vasc Biol. 2005; 25: 1057–1064.[Abstract/Free Full Text]
  35. Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med. 2004; 350: 1505–1515.[Abstract/Free Full Text]
  36. Clark RW, Sutfin TA, Ruggeri RB, Willauer AT, Sugarman ED, Magnus-Aryitey G, Cosgrove PG, Sand TM, Wester RT, Williams JA, Perlman ME, Bamberger MJ. Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib. Arterioscler Thromb Vasc Biol. 2004; 24: 490–497.[Abstract/Free Full Text]
  37. de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, van Tol A, Kastelein JJ. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study. Circulation. 2002; 105: 2159–2165.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Eur J EndocrinolHome page
R. P F Dullaart, A. K Groen, G. M Dallinga-Thie, R. de Vries, W. J Sluiter, and A. van Tol
Fibroblast cholesterol efflux to plasma from metabolic syndrome subjects is not defective despite low high-density lipoprotein cholesterol
Eur. J. Endocrinol., January 1, 2008; 158(1): 53 - 60.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
J. D. Brunzell
Hypertriglyceridemia
N. Engl. J. Med., September 6, 2007; 357(10): 1009 - 1017.
[Full Text] [PDF]

Home page
 J. Lipid Res.Home page
A. Soro-Paavonen, J. Naukkarinen, M. Lee-Rueckert, H. Watanabe, E. Rantala, S. Soderlund, A. Hiukka, P. T. Kovanen, M. Jauhiainen, L. Peltonen, et al.
Common ABCA1 variants, HDL levels, and cellular cholesterol efflux in subjects with familial low HDL
J. Lipid Res., June 1, 2007; 48(6): 1409 - 1416.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Data Supplement
Right arrow All Versions of this Article:
26/4/897    most recent
01.ATV.0000209577.04246.c0v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Watanabe, H.
Right arrow Articles by Taskinen, M.-R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Watanabe, H.
Right arrow Articles by Taskinen, M.-R.
Right arrowPubmed/NCBI databases
*Substance via MeSH
Related Collections
Right arrow Lipid and lipoprotein metabolism

ATVB Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2006 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.