This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wolfe, M. L. Articles by Rader, D. J. Search for Related Content PubMed PubMed Citation Articles by Wolfe, M. L. Articles by Rader, D. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Coronary Artery Disease Related Collections Chronic ischemic heart disease Genetics of cardiovascular disease Cardiovascular Pharmacology Lipid and lipoprotein metabolism Pathophysiology Risk Factors Related Article

(Circulation. 2004;110:1338-1340.)
© 2004 American Heart Association, Inc.

Editorial

Cholesteryl Ester Transfer Protein and Coronary Artery Disease

An Observation With Therapeutic Implications

Megan L. Wolfe, BS; Daniel J. Rader, MD

From the Center for Experimental Therapeutics and Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa.

Correspondence to Daniel J. Rader, Center for Experimental Therapeutics and Department of Medicine, University of Pennsylvania School of Medicine, 654 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104. E-mail rader{at}mail.med.upenn.edu

Key Words: Editorials • cholesterol • lipoproteins • atherosclerosis • coronary disease

Plasma levels of high-density lipoprotein cholesterol (HDL-C) are strongly inversely associated with risk of atherosclerotic cardiovascular disease (ASCVD). It has been estimated that for every 1-mg increase in HDL-C, there is a 2% to 3% decrease in cardiovascular risk,¹ which suggests that therapy to increase HDL-C levels could be effective in reducing cardiovascular risk. HDL metabolism is therefore a major emerging target for drug discovery.² The finding more than a decade ago that genetic deficiency of the cholesteryl ester transfer protein (CETP) in humans is associated with markedly elevated plasma HDL-C levels led to the concept that CETP inhibition could be a therapeutic strategy for raising HDL.³ Indeed, 2 small-molecule inhibitors of CETP have been shown to raise HDL-C levels in humans,^4–6 and this finding has generated substantial enthusiasm for CETP inhibition as a therapeutic strategy.

See p 1418

Important questions remain about whether CETP inhibition, despite its positive effects on HDL-C levels, will reduce ASCVD. One theoretical concern is that CETP inhibition could slow the rate of reverse cholesterol transport (RCT), the process by which macrophage cholesterol in the vessel wall is returned to the liver for excretion. In studies in humans, radiolabeled cholesteryl esters that originated in HDL ultimately appeared in the bile primarily after their transfer (presumably mediated by CETP) to apolipoprotein B-containing lipoproteins,⁷ which suggests that CETP might play an important physiological role in RCT. Ultimately, randomized controlled trials of CETP inhibitors will definitively address their effect on atherosclerosis and cardiovascular events. In the meantime, observational studies in humans have the potential to provide important insights into this critical question. Such observational studies include careful assessment of cardiovascular risk in CETP-deficient subjects (both homozygous and heterozygous), as well as studies of the association of CETP polymorphisms and plasma CETP levels with cardiovascular outcomes.

Observational Studies of the Relationship Between CETP and Coronary Artery Disease

It has been difficult to establish a consensus about the prevalence of cardiovascular disease in the relatively small number of homozygous CETP-deficient subjects (who are largely limited to Japan) compared with the normal Japanese population. For example, in one report of 29 homozygotes or compound heterozygotes for CETP deficiency, only one had clinical coronary heart disease (CHD), and this patient also was found to have substantially reduced hepatic lipase activity.⁸ Therefore, most efforts to assess the relationship between CETP deficiency and CHD have focused on heterozygotes. In a large population-based study in Japan, CETP gene mutations were identified in 24% of men and more than 30% of women who had HDL cholesterol levels >80 mg/dL, a phenotype that was associated with a low risk of CHD,⁹ but this does not directly indicate that the CETP-heterozygous state is protective. A recent prospective analysis from the Honolulu Heart Study suggested that the risk of CHD might be lower in CETP-deficient heterozygotes, but the trend was not statistically significant.¹⁰ Therefore, the relationship of genetic homozygous or heterozygous CETP deficiency to cardiovascular risk remains unclear.

Common single-nucleotide polymorphisms (SNPs) in the human CETP gene also have been investigated for their association with cardiovascular disease. Subjects carrying the B2 allele of the Taq1B SNP in intron 1 had lower CETP levels, higher HDL-C levels, and reduced risk of CHD in the Framingham Offspring Study.¹¹ The I405V SNP has been associated with increased HDL-C and increased risk of CHD in women in the Copenhagen City Heart Study.¹² A formal meta-analysis of the Taq1B and I405V SNPs revealed that the Taq1B B2B2 genotype possibly is associated with reduced cardiovascular disease but provided no evidence that the I405V was associated with cardiovascular disease.¹³ Two additional CETP-coding SNPs, A373P and R451Q, are in almost complete linkage disequilibrium. In the Copenhagen City Heart Study, carriers of the rarer 373P/451Q haplotype had reduced levels of HDL-C and a lower CHD risk.¹² A few common promoter SNPs have been studied, including a –629A/C and a variable-number tandem repeat (VNTR) 1946 upstream of the transcription initiation site, and although both are associated with variation in CETP mass and HDL-C levels,^13,14 they have not been shown to be associated with CHD. Thus, the existing data on common genetic variations in CETP are variable and do not definitively resolve the relationship of CETP and ASCVD.

Finally, studies of the association of plasma CETP levels with cardiovascular disease and outcomes have the potential to provide important insight into this issue. There is a surprising dearth of epidemiological data, however, on the association of plasma CETP mass or activity levels with cardiovascular disease. Patients with higher CETP mass had faster progression of angiographic coronary artery disease (CAD)¹⁵ and faster progression of carotid intimal-medial thickness.¹⁶ In a small case-control study (n=82 cases) primarily focused on CETP genetic variation, Blankenberg et al¹⁷ found no difference between CETP activity levels in cases and controls. A small study (n=110) in Japanese patients undergoing angiography found no correlation of CETP mass levels with extent of coronary atherosclerosis.¹⁸ Another small case-control study (n=204) in Chinese found that subjects with myocardial infarction or stroke had higher CETP mass and activity than did controls.¹⁹

Because of the limited and mixed results of studies of the association of CETP levels and cardiovascular disease, the article by Boekholdt et al²⁰ in this issue of Circulation provides important new information. Data are presented from a nested case-control study from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort study, a large prospective study initiated in the mid-1900s. Seven hundred fifty-five originally healthy individuals who developed fatal or nonfatal CAD during follow-up were identified as cases and matched to 1400 controls who remained free of CAD. CETP mass levels were measured in baseline plasma samples by using a commercial ELISA and were assessed for their relationship to CAD. Within the entire cohort, CETP levels were inversely related to HDL-C levels (and directly related to LDL-C levels). Although CETP levels were slightly higher in cases, this difference was not statistically significant. However, subjects in the highest quintile of CETP mass had a nearly 1.5-fold increased risk of future CAD compared with those in the lowest quintile after adjustment for several cardiovascular risk factors but not lipids. It is unfortunate that the results after adjustment for plasma lipids are not provided, but given the strong association of CETP levels with both HDL-C and LDL-C levels, it seems likely that the association of CETP levels with CAD would have been markedly attenuated after adjustment for lipids. Provocatively, a stratified analysis in subjects above or below the median (nonfasting) triglyceride (TG) level showed no association of CETP levels and CAD in those below the TG median but a significant positive association for those above the TG median. This relationship disappeared after adjusting for HDL-C levels, which suggests that if CETP influenced the risk of CAD, it did so by modulating HDL metabolism.

The article by Boekholdt et al²⁰ provides the first prospective epidemiological data on the association of CETP levels and cardiovascular events and has potentially important implications for the development of CETP inhibitors. Given the controversy and uncertainty about cardiovascular disease in CETP-deficient subjects, this prospective study provides assurance that lower levels of CETP mass are in fact associated with both increased HDL-C levels and reduced CAD risk. Therefore, it supports the concept of CETP inhibition not only to raise HDL-C levels but to reduce CAD risk. Interestingly, however, the association of CETP levels and CAD appeared to be confined to those persons with elevated nonfasting TG levels. This is biologically plausible because CETP exchanges cholesteryl esters from HDL to apolipoprotein B-containing lipoproteins in exchange for TGs, and its activity is determined in part by the number of TG-rich lipoproteins. Therefore, for a given amount of CETP mass in plasma, the greater the number of TG-rich lipoproteins, the greater the CETP-mediated transfer of lipids. The implication of this observation is that CETP inhibition may be more effective in reducing cardiovascular risk in patients with elevated TG levels. It will be interesting to determine whether CETP inhibitors have differential effects on lipid levels, atherosclerosis, and clinical events in persons with elevated compared with normal TG levels.

Assessing the Benefits of HDL-Raising Interventions

The complex relationship of CETP with lipoprotein metabolism and atherosclerosis provides a fascinating opportunity to address the potentially important differences between plasma HDL-C concentrations and HDL function with regard to atherosclerosis. Although it is widely accepted that HDL directly protects against atherosclerosis, the mechanisms by which HDL exerts its protective effect remain uncertain, and the biomarkers and methods for measuring these effects have yet to be developed and validated. For example, the rate of RCT from vessel wall to liver is likely to be more important than the plasma levels of HDL-C, and therefore validated measures of the rate of RCT in humans are sorely needed. Furthermore, HDL has been shown in vitro to have a variety of other properties, such as antiinflammatory, antioxidative, antithrombotic, and nitric oxide-promoting effects, but whether these are relevant in humans in vivo and how best to assess these effects after administration of HDL-raising drugs remain unknown. CETP inhibitors will provide the opportunity to test whether this particular mechanism of HDL-raising has beneficial effects on RCT and other putative HDL functions that ultimately may result in reduced atherosclerotic vascular disease.

In summary, although pharmacological inhibition of CETP in humans clearly increases HDL-C levels, its effect on ASCVD is far from established. Observational studies of the relationships between CETP, lipoprotein metabolism, and ASCVD, such as the study by Boekholdt et al,²⁰ will continue to inform this important issue. Experimental medicine studies of the effects of CETP inhibitors on cholesterol flux and other potential HDL functional effects will constitute a critical component of the understanding of this mechanism of HDL-raising and its biological effects. Ultimately, randomized controlled clinical trials assessing the impact on atherosclerosis will determine whether CETP inhibition will become a new tool in the fight against ASCVD.

Acknowledgments

Dr Rader is the recipient of an American Heart Association Established Investigator Award, a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, and a Doris Duke Distinguished Clinical Investigator Award and also is funded by National Institutes of Health grants from the National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; and National Center for Research Resources.

Footnotes

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

References

1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001; 285: 2486–2497.[Free Full Text]
   
2. Rader DJ. High-density lipoproteins as an emerging therapeutic target for atherosclerosis. JAMA. 2003; 290: 2322–2324.[Free Full Text]
   
3. Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader DJ, Tall AR. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol. 2003; 23: 160–167.[Abstract/Free Full Text]
   
4. 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]
   
5. 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]
   
6. 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]
   
7. Schwartz CC, VandenBroek JM, Cooper PS. Lipoprotein cholesteryl ester production, transfer and output in vivo in humans. J Lipid Res. Published online ahead of print May 16, 2004. DOI: 10.1194/jlr.M300511-JLR200.
   
8. Hirano K, Yamashita S, Kuga Y, Sakai N, Nozaki N, Kihara S, Arai T, Yanagi K, Takami S, Menju M, Ishigami M, Yoshida Y, Kameda-Takemura K, Hayashi K, Matsuzawa Y. Atherosclerotic disease in marked hyperalphalipoproteinemia: combined reduction of cholesteryl ester transfer protein and hepatic triglyceride lipase. Arterioscler Thromb Vasc Biol. 1995; 15: 1849–1856.[Abstract/Free Full Text]
   
9. Moriyama Y, Okamura T, Inazu A, Doi M, Iso H, Mouri Y, Ishikawa Y, Suzuki H, Iida M, Koizumi J, Mabuchi H, Komachi Y. A low prevalence of coronary heart disease among subjects with increased high density lipoprotein cholesterol levels, including those with plasma cholesteryl ester transfer protein deficiency. Prev Med. 1998; 27: 659–667.[CrossRef][Medline] [Order article via Infotrieve]
   
10. Curb JD, Abbott RD, Rodriguez BL, Masaki K, Chen R, Sharp DS, Tall AR. A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly. J Lipid Res. 2004; 45: 948–953.[Abstract/Free Full Text]
    
11. Ordovas JM, Cupples LA, Corella D, Otvos JD, Osgood D, Martinez A, Lahoz C, Coltell O, Wilson PW, Schaefer EJ. Association of cholesteryl ester transfer protein-TaqIB polymorphism with variations in lipoprotein subclasses and coronary heart disease risk. Arterioscler Thromb Vasc Biol. 2000; 20: 1323–1329.[Abstract/Free Full Text]
    
12. Agerholm-Larsen B, Tybjaerg-Hansen A, Schnohr P, Steffensen R, Nordestgaard BG. Common cholesteryl ester transfer protein mutations, decreased HDL cholesterol, and possible decreased risk of ischemic heart disease. The Copenhagen City Heart Study. Circulation. 2000; 102: 2197–2203.[Abstract/Free Full Text]
    
13. Boekholdt SM, Thompson JF. Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease. J Lipid Res. 2003; 44: 1080–1093.[Abstract/Free Full Text]
    
14. Thompson JF, Lira ME, Durham LK, Clark RW, Bamberger MJ, Milos PM. Polymorphisms in the CETP gene and association with CETP mass and HDL levels. Atherosclerosis. 2003; 167: 195–204.[CrossRef][Medline] [Order article via Infotrieve]
    
15. Klerkx AHEM, de Grooth GJ, Zwinderman AH, Jukema JW, Kuivenhoven JA, Kastelein JJP. Cholesteryl ester transfer protein concentration is associated with progression of atherosclerosis and response to pravastatin in men with coronary artery disease (REGRESS). Eur J Clin Invest. 2004; 34: 21–28.[CrossRef][Medline] [Order article via Infotrieve]
    
16. de Grooth GJ, Smilde TJ, van Wissen S, Klerkx KHEM, Zwinderman AH, Fruchart JC, Kastelein JJP, Stalenfoef AFH, Kuivenhoven JA. The relationship between cholesteryl ester transfer protein levels and risk factor profile in patients with familial hypercholesterolemia. Atherosclerosis. 2004; 173: 261–267.[CrossRef][Medline] [Order article via Infotrieve]
    
17. Blankenberg S, Rupprecht HJ, Bickel C, Jiang XC, Poirier O, Lackner KJ, Meyer J, Cambien F, Tiret L. Common genetic variation of the cholesteryl ester transfer protein gene strongly predicts future cardiovascular death in patients with coronary artery disease. J Am Coll Cardiol. 2003; 41: 1983–1989.[Abstract/Free Full Text]
    
18. Goto A, Sasai K, Suzuki S, Fukutomi T, Ito S, Matsushita T, Okamoto M, Suzuki T, Itoh M, Okumura-Noji K, Yokoyama S. Cholesteryl ester transfer protein and atherosclerosis in Japanese subjects: a study based on coronary angiography. Atherosclerosis. 2001; 159: 153–163.[CrossRef][Medline] [Order article via Infotrieve]
    
19. Zhuang Y, Wang J, Qiang H, Li Y, Liu X, Li L, Chen G. Cholesteryl ester transfer protein levels and gene deficiency in Chinese patients with cardio-cerebrovascular diseases. Chin Med J. 2002; 115: 371–374.[Medline] [Order article via Infotrieve]
    
20. Boekholdt SM, Kuivenhoven JA, Wareham NJ, Peters RJG, Jukema JW, Luben R, Bingham SA, Day NE, Kastelein JJP, Khaw KT. Plasma levels of cholesteryl ester transfer protein and the risk of future coronary artery disease in apparently healthy men and women: the prospective EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk population study. Circulation. 2004; 110: 1418–1423.[Abstract/Free Full Text]
    

Related Article:

Plasma Levels of Cholesteryl Ester Transfer Protein and the Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women: The Prospective EPIC (European Prospective Investigation into Cancer and nutrition)–Norfolk Population Study

S. Matthijs Boekholdt, Jan-Albert Kuivenhoven, Nicholas J. Wareham, Ron J.G. Peters, J. Wouter Jukema, Robert Luben, Sheila A. Bingham, Nicholas E. Day, John J.P. Kastelein, and Kay-Tee Khaw
Circulation 2004 110: 1418-1423. [Abstract] [Full Text]

This article has been cited by other articles:

				M. Cuchel and D. J. Rader Is the Cholesteryl Ester Transfer Protein Proatherogenic or Antiatherogenic in Humans? J. Am. Coll. Cardiol., November 13, 2007; 50(20): 1956 - 1958. [Full Text] [PDF]

				A. Kontush and M. J. Chapman Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis Pharmacol. Rev., September 1, 2006; 58(3): 342 - 374. [Abstract] [Full Text] [PDF]

				D. Duffy and D. J. Rader Emerging Therapies Targeting High-Density Lipoprotein Metabolism and Reverse Cholesterol Transport Circulation, February 28, 2006; 113(8): 1140 - 1150. [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wolfe, M. L. Articles by Rader, D. J. Search for Related Content PubMed PubMed Citation Articles by Wolfe, M. L. Articles by Rader, D. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Coronary Artery Disease Related Collections Chronic ischemic heart disease Genetics of cardiovascular disease Cardiovascular Pharmacology Lipid and lipoprotein metabolism Pathophysiology Risk Factors Related Article