© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Plasma Sphingomyelin Level as a Risk Factor for Coronary Artery Disease
From the Department of Medicine (X.J., F.P., M.L., L.B., A.R.T.), Columbia University, New York, NY; Bassett Health Care (T.A.P., R.G.R.), Cooperstown, NY; and Harlem Hospital (C.K.F.), New York, NY.
Correspondence to Dr Xian-cheng Jiang, Division of Molecular Medicine, Department of Medicine, Room P&S 8-401, Columbia University, 630 West 168th St, New York, NY 10032. E-mail xcj1{at}columbia.edu
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Abstract |
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Abstract—Only a fraction of the clinical complications of atherosclerosis are explained by known risk factors. Animal studies have shown that plasma sphingomyelin (SM) levels are closely related to the development of atherosclerosis. SM carried into the arterial wall on atherogenic lipoproteins may be locally hydrolyzed by sphingomyelinase, promoting lipoprotein aggregation and macrophage foam cell formation. A novel, high-throughput, enzymatic method to measure plasma SM levels has been developed. Plasma SM levels were related to the presence of coronary artery disease (CAD) in a biethnic angiographic case-control study (279 cases and 277 controls). Plasma SM levels were higher in CAD patients than in control subjects (60±29 versus 49±21 mg/dL, respectively; P<0.0001). Moreover, the ratio of SM to SM+phosphatidylcholine (PC) was also significantly higher in cases than in controls (0.33±0.13 versus 0.29±0.10, respectively; P<0.0001). Similar relationships were observed in African Americans and whites. Plasma SM levels showed a significant correlation with remnant cholesterol levels (r=0.51, P<0.0001). By use of multivariate logistic regression analysis, plasma SM levels and the SM/(SM+PC) ratio were found to have independent predictive value for CAD after adjusting for other risk factors, including remnants. The odds ratio (OR) for CAD was significantly higher for the third and fourth quartiles of plasma SM levels (OR 2.81 [95% CI 1.66 to 4.80] and OR 2.33 [95% CI 1.38 to 3.92], respectively) as well as the SM/(SM+PC) ratio (OR 1.95 [95% CI 1.10 to 3.45] and OR 2.33 [95% CI 1.34 to 4.05], respectively). The findings indicate that human plasma SM levels are positively and independently related to CAD. Plasma SM levels could be a marker for atherogenic remnant lipoprotein accumulation and may predict lipoprotein susceptibility to arterial wall sphingomyelinase.
Key Words: sphingomyelin • risk factors • coronary artery disease
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Introduction |
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The association of lipid abnormalities and coronary atherosclerosis is well established. Case-control and prospective epidemiological studies have shown a direct correlation between coronary artery disease (CAD) and serum levels of total cholesterol and LDL cholesterol (LDL-C) and an inverse relationship between CAD and HDL cholesterol (HDL-C) levels.1 However, compared with plasma cholesterol measurements, very little attention has been given to the relationship between phospholipids and CAD.2 3
Atherogenesis is initiated by the interaction of cholesterol-rich lipoproteins, such as LDL, with the arterial wall.4 5 The uptake of lipoprotein cholesterol by macrophages, leading to foam cell formation, is a central event in the initiation and progression of atherosclerosis.6 However, native LDL is incapable of generating foam cells from macrophages. Thus, it is thought that LDL is modified in the arterial wall by processes such as oxidation, leading to macrophage chemotaxis and the uptake of modified LDL by macrophage foam cells.7 Retention of lipoproteins on the subendothelial matrix, followed by aggregation, has also emerged as a central pathogenic process in macrophage foam cell formation and atherogenesis.8 Lipoprotein aggregation in the vessel wall may result from enzymatic modification of LDL, induced by locally produced sphingomyelinase (SMase).9
It has long been known that sphingomyelin (SM) accumulates in human and animal atheroma and that the major source is plasma lipoproteins.10 Plasma SM levels are increased in human familial hyperlipidemias, especially in familial hypercholesterolemia.11 The concentration of SM relative to total phospholipids (principally phosphatidylcholine [PC] and SM), ie, SM/(SM+PC), is an important determinant of the susceptibility of lipoprotein SM to SMase.8 12 These findings suggest that plasma SM levels and the relative SM concentration might be risk factors for atherosclerosis. However, plasma SM levels have never been systematically assessed as a risk factor for atherosclerosis in humans. This is partly due to the difficulties inherent in the classic method for SM measurement, which involves lipid extraction and thin-layer chromatography.13 14 To overcome this difficulty, we have developed a novel enzymatic method for plasma SM determination and have used this method to test the hypothesis that plasma SM levels are associated with CAD in an angiographic case-control study.
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Methods |
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Subjects
Subjects were recruited from a patient population scheduled for diagnostic coronary arteriography at either Harlem Hospital Center in New York, NY, or the Mary Imogene Bassett Hospital in Cooperstown, NY. All consecutive patients scheduled for coronary arteriography at the 2 sites between June 1993 and April 1997 were approached. In the present study, 556 patients (341 men and 215 women) ethnically self-identified as African Americans (n=229) or whites (n=327) were enrolled. The mean age was 54.9 and 54.6 years for African American men and women and 56.8 and 56.5 years for white men and women, respectively. Exclusion criteria were as follows: age >70 years, recent (within 6 months) myocardial infarction or thrombolysis, a history of percutaneous transluminal coronary angioplasty, surgery during the previous 6 weeks, a known communicable disease such as hepatitis or AIDS, or current lipid-lowering medication. Information on diabetes mellitus, hypertension, and smoking was obtained by a standardized questionnaire on entry into the study. Among white subjects, 25.6%, 27.3%, and 20.4% of the men and 20.5%, 25.6%, and 20.3% of the women were smokers, had hypertension, and had diabetes, respectively. The corresponding numbers for African Americans were 51.1%, 67.4%, and 24.2% for the men and 42.0%, 78.2%, and 35.6% for the women. The present study was approved by the Institutional Review Boards at Harlem Hospital, Bassett Healthcare, and Columbia University College of Physicians and Surgeons.
Plasma SM Measurement
Enzymatic measurement of plasma SM levels was carried
out by using a novel 4-step procedure. In the first step, bacterial
SMase hydrolyzed SM to phosphorylcholine and
n-acylsphingosine. Thereafter, the addition of
alkaline phosphatase generated choline from phosphorylcholine. The
newly formed choline was used to generate hydrogen peroxide in a
reaction catalyzed by choline oxidase. Finally, with peroxidase as a
catalyst, hydrogen peroxide was used together with phenol and
4-aminoantipyrine to generate a red quinone pigment, with an optimal
absorption at 505 nm. The plasma SM levels were measured in a blinded
fashion. The linear range of plasma SM in this assay was between 10 and
120 µg/dL. The interassay coefficient of variation of the SM assay
was 2.8±0.3%. PC levels did not influence SM measurement (data not
shown). The detailed procedure will be published elsewhere.
To validate our novel SM assay, we compared the results with those obtained by the classic method.13 14 The 2 methods were well correlated (r=0.91, P<0.01; n=60).
Plasma PC Measurement
The total choline-containing phospholipid in plasma
was assayed by an enzymatic method (Wako Pure Chemical Industries Ltd).
PC concentration was obtained by subtracting SM from total phospholipid
concentration.
Lipoprotein and Inflammatory Marker
Measurements
Serum total cholesterol,
triglycerides, and HDL-C were determined by using standard
enzymatic procedures. HDL-C levels were measured after precipitation of
apoB-containing lipoproteins with dextran
sulfate,15 and LDL-C
was calculated by using the Friedewald
formula.16 C-reactive
protein (CRP) was measured by a sensitive
ELISA,17 and
fibrinogen levels were estimated by the clot-rate method of
Clauss.18 Remnant
cholesterol was determined by the method of Nakajima et
al.19 Briefly,
remnant lipoprotein was isolated on the basis of the removal of
apoA-I–containing particles (HDL) and most apoB-containing particles
(LDL, nascent VLDL, and nascent chylomicrons) by use of an
immunoseparation technique, which has been shown to leave remnants of
both intestinal and hepatic origin in the unbound fraction. The
cholesterol concentration in the unbound fraction was
determined by a standard enzymatic assay.
Angiographic Definition of CAD
Coronary angiograms were read by 2
experienced readers who were blinded to patient identity, the clinical
diagnosis, and the lipoprotein results. The readers recorded the
location and extent of luminal narrowing for 15 segments of the major
coronary
arteries.20 The
presence of CAD (ie, case) was defined as the presence of at least 50%
stenosis in any 1 of 15 coronary artery
segments.
Statistical Analysis
Comparisons between groups were made by the
Wilcoxon test, because plasma SM levels and SM/(SM+PC) ratios
are not normally distributed. The Fisher exact test was used to
calculate the probability value for the odds ratios (ORs) of the
association of univariate categorical data with
case-control status. Stepwise logistic regression was used to assess
association with case-control status for multivariate
models. SAS was used for all
calculations.
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Results |
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Regarding established risk factors, mean total and LDL cholesterol levels were higher among patients with CAD compared with patients without CAD for both African Americans and whites. Also, mean triglyceride levels were higher among patients with CAD in both ethnic groups. Fibrinogen levels were significantly higher among patients with CAD in both ethnic groups, whereas there was no difference in CRP levels between cases and controls. A complete summary of the results for lipid and inflammatory parameters will be published separately (R.G.R., unpublished data, 2000).
For all subjects, patients with CAD had significantly higher
plasma SM concentrations than did controls
(Table 1
). When analyzing the 2 ethnic groups separately,
the plasma SM concentration was significantly increased in African
Americans and whites with CAD (P=0.012 and
P=0.0001, respectively;
Table 1). As seen in the
Figure,
the distribution of plasma SM levels was skewed in cases and controls.
However, a consistent pattern was seen over the entire range of
SM values: CAD cases were found more commonly at higher SM levels than
were controls (panel A of
Figure).
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To evaluate whether the increased plasma SM levels among
cases reflected an overall increase in phospholipid levels or an
increased proportion of SM among total plasma choline–containing
phospholipids, we compared the SM/(SM+PC) ratio (ie, relative
concentration of SM) in case and control groups. The SM/(SM+PC) ratio
was significantly higher for cases than for controls among all subjects
as well as among African Americans and whites when the 2 groups were
analyzed separately
(Table 1
). However, the difference in the SM/(SM+PC) ratio
(
14%) between cases and controls was smaller than the difference in
total SM (22%), indicating that the ratio only partly accounted for
the increase in plasma SM concentrations. Panel B of the
Figure
shows the SM/(SM+PC) ratio distribution in all subjects. Again, the
distribution was skewed, but cases were found to have higher levels
than controls over the entire range of SM/(SM+PC) values.
To investigate the possibility that plasma SM could act as a marker of atherogenic lipoprotein remnants, we measured remnant lipoprotein cholesterol levels. There were moderate but significant correlations between plasma SM levels and remnant cholesterol levels (r=0.51, P<0.0001) and between the SM/(SM+PC) ratio and remnant cholesterol levels (r=0.34, P<0.0001).
To evaluate the risk associated with increasing plasma SM
concentration, we calculated ORs for each quartile relative to the
first. Because African Americans and whites had similar mean and median
values for plasma SM levels and SM/(SM+PC) ratios, we grouped all
subjects together in this analysis. The OR for CAD for the
third and fourth quartiles was significantly higher than the first
quartile for both measurements (Table 2).
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To evaluate whether the plasma concentration of SM and the
SM/(SM+PC) ratio was associated with CAD independent of other known
risk factors, we carried out stepwise multivariate
logistic regression controlling for age, diabetes, smoking,
hypertension, LDL-C, HDL-C, logarithmically transformed
triglycerides, remnant cholesterol, fibrinogen,
and CRP. The OR for CAD increased with increasing quartiles of SM
levels and SM/(SM+PC) ratios. As shown in
Table 3, the OR for CAD in the third and fourth quartiles
of plasma SM levels was significantly higher than in the first quartile
(P=0.0001 and P=0.0015,
respectively), indicating that plasma SM level was an independent risk
factor for CAD in this case-control study. In addition, the OR for CAD
for the relative concentration of SM, ie, the SM/(SM+PC) ratio, was
significantly higher for the third and fourth quartiles compared with
the first quartile (P=0.0218 and
P=0.0028, respectively), indicating that the relative
concentration of SM was also associated with CAD, independent of age,
diabetes, smoking, hypertension, LDL-C, HDL-C, logarithmically
transformed triglycerides, remnant cholesterol,
fibrinogen, and CRP
(Table 3).
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Discussion |
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Although traditional measurements have focused on plasma total and LDL cholesterol as indicators of atherogenesis, a body of in vitro and in vivo results11 12 21 has suggested that plasma SM levels could also be related to atherosclerosis. However, this has never been systematically assessed, partly because of the difficulties of measuring SM in large numbers of samples. To overcome this problem, we have developed a simple enzymatic assay to permit the measurement of plasma SM concentrations. In the present study, we demonstrate for the first time that plasma SM levels were higher in cases with CAD than in controls, and this difference was found for African Americans and whites. The increase in plasma SM was in part selective, reflected as an increase in SM concentration relative to other phospholipids, ie, the SM/(SM+PC) ratio, and the relative SM concentration was also independently related to CAD case-control status. Although these findings are biologically plausible,9 22 it will be important to confirm them in other samples and in a prospective study design.
A number of different mechanisms could explain the
relationship between plasma SM and CAD case-control status. Because LDL
is an atherogenic lipoprotein, SM could be a surrogate marker for LDL
cholesterol levels. However, this appears unlikely because
the SM relation to case-control status was independent of LDL-C levels
(Table 3). SM could also be a marker for an inflammatory
effect, and inflammatory markers such as CRP have been shown to be
important risk factors for
atherosclerosis.23
However, in this case-control study, plasma SM levels did not correlate
with 2 well-known inflammatory markers, fibrinogen and CRP (data not
shown), and were independently related to case-control status in a
multivariate analysis that included these
measurements
(Table 3). Thus, it is unlikely that SM is behaving as a
surrogate inflammatory marker.
The hypothesis that we most favor is that plasma SM levels are determined by a unique set of metabolic determinants and that plasma SM, carried by lipoproteins, is directly involved in the atherogenic process subsequent to retention in the artery wall.8 9 24 Thus, we propose that plasma SM levels are directly and causally related to atherogenesis.
Substantial evidence now supports the role of lipoprotein SM and arterial SMase in atherogenesis. SM carried into the arterial wall on atherogenic lipoproteins is acted on by an arterial wall SMase, leading to an increase in ceramide content and promoting lipoprotein aggregation.9 LDL extracted from human atherosclerotic lesions is highly enriched in SM compared with plasma LDL.9 25 Moreover, a significant fraction of LDL extracted from fresh human lesions is aggregated and has a high content of ceramide, indicating that the LDL has been modified by SMase, resulting in aggregation.9 The absolute and relative concentrations of plasma SM are both increased in atherosclerosis-susceptible animal models.12 20 26 In vitro manipulation has shown that the relative SM concentration is an important determinant of susceptibility to SMase-induced aggregation.12 24 Recently, transgenic animals with increased or decreased SMase activity in the arterial wall have been shown to have correspondingly altered atherosclerosis.26
Plasma lipoprotein SM is derived principally from biosynthesis in the liver. The rate-limiting step in SM biosynthesis is the enzyme serine:palmitoyl coenzyme A transferase, and the activity of this enzyme is increased in an atherosclerosis-susceptible animal model.12 Inhibitors of serine:palmitoyl coenzyme A transferase have been described, so there might be some potential for therapeutic modulation of hepatic synthesis. Alternatively, the arterial wall SMase could represent another target for intervention.
Unlike plasma PC, SM is not degraded by plasma enzymes such as lecithin:cholesterol acyltransferase or by lipases.27 28 Thus, SM removal from plasma is absolutely dependent on hepatic clearance mechanisms, such as the LDL receptor, the LDL receptor–related protein, or proteoglycan pathways. Because SM is not degraded in plasma, it becomes enriched in remnants of triglyceride-rich lipoproteins.12 20 Several lines of evidence suggest that such remnants are particularly atherogenic,29 but the relevant fraction of plasma lipoproteins has been difficult to measure. In part, plasma SM measurements may be acting as a marker of atherogenic remnant accumulation. This speculation is supported by the finding that plasma SM levels showed a significant, although moderate, correlation with remnant cholesterol levels. However, in multivariate analysis, plasma SM level remained as a significant predictor of CAD, even after additional adjustment for remnant lipoprotein cholesterol levels.
Although presently known risk factors have some
predictive value for CAD, a major part of the variability in this
process remains
unexplained.30 Also,
therapy aimed at lowering LDL cholesterol reduces only a
fraction (30%) of the burden of atherosclerotic
disease.31 Although
our findings that SM is a risk factor for CAD need to be confirmed in
additional studies, they hold the promise of a simple test that may
have independent predictive value for CAD and provide a novel
therapeutic
target.
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Acknowledgments |
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This study was supported by National Institutes of Health grants HL-56984 (SCOR in Arteriosclerosis and Molecular Medicine), HL-64735, and HL-49735. We are indebted to Ira Tabas, MD, PhD, for many stimulating discussions.
Received May 31, 2000; accepted September 21, 2000.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Miller GJ, Miller NE. High-density lipoprotein and atherosclerosis. Lancet. 1975;1:16–19.[Medline] [Order article via Infotrieve]
2.
Gershfeld
NL. Selective phospholipid adsorption and
atherosclerosis. Science. 1979;204:506–508.
3.
Kunz F,
Pechlaner C, Erhart R, Fend F, Muhlberger V. HDL and plasma
phospholipids in coronary artery disease. Arterioscler
Thromb. 1994;14:1146–1150.
4. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–808.[Medline] [Order article via Infotrieve]
5. Havel RJ. Biology of cholesterol, lipoproteins and atherosclerosis. Clin Exp Hypertens. 1989;11:887–900.
6. Libby P, Clinton SK. The role of macrophages in atherogenesis. Curr Opin Lipidol. 1993;4:355–363.
7. Yla-Herttuala S, Palinski W, Rosenfeld ME, Parthasarathy S, Carew TE, Butler S, Witztum JL, Steinberg D. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest. 1989;84:1086–1095.
8.
Schissel
SL, Jiang X, Tweedie-Hardman J, Jeong T, Camejo EH, Najib J, Rapp JH,
Williams KJ, Tabas I. Secretory sphingomyelinase, a product of the
acid sphingomyelinase gene, can hydrolyze atherogenic lipoproteins at
neutral pH. J Biol Chem. 1998;273:2738–2746.
9. Schissel SL, Tweedie-Hardman J, Rapp JH, Graham G, Williams KJ, Tabas I. Rabbit aorta and human atherosclerotic lesions hydrolyze the sphingomyelin of retained low density lipoprotein. J Clin Invest. 1996;98:1455–1464.[Medline] [Order article via Infotrieve]
10. Smith EB. Intimal and medial lipids in human aorta. Lancet. 1960;1:799–803.[Medline] [Order article via Infotrieve]
11. Noel C, Marcel YL, Davignon J. Plasma phospholipids in the different types of primary hyperlipoproteinemia. J Lab Clin Med. 1972;79:611–612.[Medline] [Order article via Infotrieve]
12. Jeong T, Schissel SL, Tabas I, Pownall HJ, Tall AR, Jiang X. Increased sphingomyelin content of plasma lipoproteins in apolipoprotein E knockout mice reflects combined production and catabolic defects and enhances reactivity with mammalian sphingomyelinase. J Clin Invest. 1998;101:905–912.[Medline] [Order article via Infotrieve]
13. Bligh EG, Dyer WJ. A rapid method for total lipid extraction and purification. Can J Biochem Physiol. 1959;37:911–917.
14.
Bartlett
GR. Phosphorus assay in column chromatography.
J Biol Chem. 1959;234:466–468.
15.
Lopes-Virella
MF, Stone P, Ellis S, Colwell JA. Cholesterol determination
in high-density lipoproteins separated by three different methods.
Clin Chem. 1977;23:882–884.
16. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.[Abstract]
17. Myrup B, de Maat M, Rossing P, Gram J, Kluft C, Jespersen J. Elevated fibrinogen and the relation to acute phase response in diabetic nephropathy. Thromb Haemost. 1996;81:485–490.
18. Clauss A. Gerinnugsphysiologische schnellmethode zur bestimmung des fibrinogens. Acta Haematol. 1957;17:237–246.[Medline] [Order article via Infotrieve]
19. Nakajima K, Okazaki M, Tanaka A, Pullinger C, P, Wang T, Nakano T, Adachi M, Havel RJ. Separation and determination of remnant-like particles in human serum using monoclonal antibodies to apo B-100 and apo A-I. J Clin Ligand Assay. 1996;19:177–183.
20. Miller M, Mead LA, Kwiterovich PO, Pearson TA. Dyslipidemias with desirable plasma total cholesterol levels and angiographically demonstrated coronary artery disease. Am J Cardiol. 1990;65:1–5.[Medline] [Order article via Infotrieve]
21. Rodriguez JL, Ghiselli GC, Torreggiani D, Sirtori CR. Very low density lipoproteins in normal and cholesterol-fed rabbits: lipid and protein composition and metabolism. Atherosclerosis. 1976;23:73–83.[Medline] [Order article via Infotrieve]
22.
Williams
KJ, Tabas I. The response-to-retention hypothesis of early
atherosclerosis. Arterioscler Thromb Vasc
Biol. 1995;15:551–561.
23.
Ridker
PM, Cushman M, Stampfer MJ, Tracy RP, Henneken CH. Inflammation,
aspirin, and the risk of cardiovascular disease in
apparently healthy men. N Engl J Med. 1997;336:973–979.
24.
Schissel
SL, Schuchman HE, Williams KJ, Tabas I.
Zn2+-stimulated sphingomyelinase is secreted
by many cell types and is a product of the acid sphingomyelinase
gene. J Biol Chem. 1996;271:18431–18436.
25. Hoff HF, Morton RE. Lipoproteins containing apoB extracted from human aortas: structure and function. Ann N Y Acad Sci. 1985;545:183–194.
26. Marathe S, Tribble DL, Kuriakose G, Williams KJ, Tabas I. Sphingomyelinase (SMase) transgenic and knockout mice: direct evidence that SMase is atherogenic in vivo. Circulation. 1999;100(suppl I):I-695. Abstract.
27.
Subbaiah
PV, Liu M. Role of sphingomyelin in the regulation of
cholesterol esterification in the plasma lipoproteins.
J Biol Chem. 1993;268:20156–20163.
28. Laboda HM, Glick JM, Phillips MC. Hydrolysis of lipid monolayers and the substrate specificity of hepatic lipase. Biochim Biophys Acta. 1986;876:233–242.[Medline] [Order article via Infotrieve]
29. Krauss RM. Atherogenicity of triglyceride-rich lipoproteins. Am J Cardiol. 1998;81:13B–17B.[Medline] [Order article via Infotrieve]
30. Maher V, Sinfuego J, Chao P, Parekh J. Primary prevention of coronary heart disease: what has WOSCOPS told us and what questions remain?: West of Scotland Coronary Prevention Study. Drugs. 1997;54:1–8.
31. Kjekshus J, Pedersen TR. Reducing the risk of coronary events: evidence from the Scandinavian Simvastatin Survival Study (4S). Am J Cardiol. 1995;76:64C–68C.[Medline] [Order article via Infotrieve]
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 J. C. Nelson, X.-C. Jiang, I. Tabas, A. Tall, and S. Shea Plasma Sphingomyelin and Subclinical Atherosclerosis: Findings from the Multi-Ethnic Study of Atherosclerosis Am. J. Epidemiol., May 15, 2006; 163(10): 903 - 912. [Abstract] [Full Text] [PDF]
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J. Rubin, H. J. Kim, T. A. Pearson, S. Holleran, R. Ramakrishnan, and L. Berglund Apo[a] size and PNR explain African American-Caucasian differences in allele-specific apo[a] levels for small but not large apo[a] J. Lipid Res., May 1, 2006; 47(5): 982 - 989. [Abstract] [Full Text] [PDF]
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C. Y. Lee, A. Lesimple, M. Denis, J. Vincent, A. Larsen, O. Mamer, L. Krimbou, J. Genest, and M. Marcil Increased sphingomyelin content impairs HDL biogenesis and maturation in human Niemann-Pick disease type B J. Lipid Res., March 1, 2006; 47(3): 622 - 632. [Abstract] [Full Text] [PDF]
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M. R. Hojjati and X.-C. Jiang Rapid, specific, and sensitive measurements of plasma sphingomyelin and phosphatidylcholine J. Lipid Res., March 1, 2006; 47(3): 673 - 676. [Abstract] [Full Text] [PDF]
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A. Nilsson and R.-D. Duan Absorption and lipoprotein transport of sphingomyelin J. Lipid Res., January 1, 2006; 47(1): 154 - 171. [Abstract] [Full Text] [PDF]
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P. V. Subbaiah, L. R. Gesquiere, and K. Wang Regulation of the selective uptake of cholesteryl esters from high density lipoproteins by sphingomyelin J. Lipid Res., December 1, 2005; 46(12): 2699 - 2705. [Abstract] [Full Text] [PDF]
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K. J. Williams and I. Tabas Lipoprotein Retention--and Clues for Atheroma Regression Arterioscler Thromb Vasc Biol, August 1, 2005; 25(8): 1536 - 1540. [Abstract] [Full Text] [PDF]
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K. J. Williams, M.-L. Liu, Y. Zhu, X. Xu, W. R. Davidson, P. McCue, and K. Sharma Loss of Heparan N-Sulfotransferase in Diabetic Liver: Role of Angiotensin II Diabetes, April 1, 2005; 54(4): 1116 - 1122. [Abstract] [Full Text] [PDF]
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M. R. Hojjati, Z. Li, H. Zhou, S. Tang, C. Huan, E. Ooi, S. Lu, and X.-C. Jiang Effect of Myriocin on Plasma Sphingolipid Metabolism and Atherosclerosis in apoE-deficient Mice J. Biol. Chem., March 18, 2005; 280(11): 10284 - 10289. [Abstract] [Full Text] [PDF]
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A. Schlitt, M. R. Hojjati, H. von Gizycki, K. J. Lackner, S. Blankenberg, B. Schwaab, J. Meyer, H. J. Rupprecht, and X.-C. Jiang Serum sphingomyelin levels are related to the clearance of postprandial remnant-like particles J. Lipid Res., February 1, 2005; 46(2): 196 - 200. [Abstract] [Full Text] [PDF]
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I. Tabas Sphingolipids and Atherosclerosis: A Mechanistic Connection? A Therapeutic Opportunity? Circulation, November 30, 2004; 110(22): 3400 - 3401. [Full Text] [PDF]
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T.-S. Park, R. L. Panek, S. B. Mueller, J. C. Hanselman, W. S. Rosebury, A. W. Robertson, E. K. Kindt, R. Homan, S. K. Karathanasis, and M. D. Rekhter Inhibition of Sphingomyelin Synthesis Reduces Atherogenesis in Apolipoprotein E-Knockout Mice Circulation, November 30, 2004; 110(22): 3465 - 3471. [Abstract] [Full Text] [PDF]
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W. Khovidhunkit, M.-S. Kim, R. A. Memon, J. K. Shigenaga, A. H. Moser, K. R. Feingold, and C. Grunfeld Thematic review series: The Pathogenesis of Atherosclerosis. Effects of infection and inflammation on lipid and lipoprotein metabolism mechanisms and consequences to the host J. Lipid Res., July 1, 2004; 45(7): 1169 - 1196. [Abstract] [Full Text] [PDF]
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S.-y. Morita, M. Kawabe, A. Sakurai, K. Okuhira, A. Vertut-Doi, M. Nakano, and T. Handa Ceramide in Lipid Particles Enhances Heparan Sulfate Proteoglycan and Low Density Lipoprotein Receptor-related Protein-mediated Uptake by Macrophages J. Biol. Chem., June 4, 2004; 279(23): 24355 - 24361. [Abstract] [Full Text] [PDF]
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N. R. Webb, M. C. de Beer, F. C. de Beer, and D. R. van der Westhuyzen ApoB-containing lipoproteins in apoE-deficient mice are not metabolized by the class B scavenger receptor BI J. Lipid Res., February 1, 2004; 45(2): 272 - 280. [Abstract] [Full Text] [PDF]
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 S. K. Noh and S. I. Koo Egg Sphingomyelin Lowers the Lymphatic Absorption of Cholesterol and {alpha}-Tocopherol in Rats J. Nutr., November 1, 2003; 133(11): 3571 - 3576. [Abstract] [Full Text] [PDF]
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A. R. Leventhal, W. Chen, A. R. Tall, and I. Tabas Acid Sphingomyelinase-deficient Macrophages Have Defective Cholesterol Trafficking and Efflux J. Biol. Chem., November 21, 2001; 276(48): 44976 - 44983. [Abstract] [Full Text] [PDF]
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