This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted 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 van Lennep, J. E. R. Articles by van der Wall, E. E. Search for Related Content PubMed PubMed Citation Articles by van Lennep, J. E. R. Articles by van der Wall, E. E. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Lipids Secondary prevention Risk Factors Epidemiology Lipid and lipoprotein metabolism

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:2408.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Apolipoprotein Concentrations During Treatment and Recurrent Coronary Artery Disease Events

Jeanine E. Roeters van Lennep; H. Tineke Westerveld; Henk W. O. Roeters van Lennep; Aelko H. Zwinderman; D. Willem Erkelens; Ernst E. van der Wall

From the Department of Cardiology (J.E.R.v.L., E.E.v.d.W.) and Department of Medical Statistics (A.H.Z.), Leiden University Medical Center, Leiden; Department of Internal Medicine (H.T.W., D.W.E.), University Medical Center Utrecht, Utrecht and Oosterschelde Hospital (H.W.O.R.v.L), Goes, the Netherlands. Correspondence to Ernst E. van der Wall, MD, Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Abstract—The effect of untreated total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) as cardiovascular risk factors in both primary and secondary prevention has been extensively investigated. The predictive value of on-treatment lipid and apolipoprotein levels on subsequent cardiovascular events is as yet uncertain. Eight hundred forty-eight patients (675 men and 173 women) with angiographically proven coronary artery disease (CAD) who received effective statin therapy (30% decrease of baseline TC) were studied. We analyzed the predictive value of on-treatment levels of TC, LDL-C, triglycerides (TG), apolipoprotein A-I (apoA-I) and apolipoprotein B (apoB) on subsequent myocardial infarction (MI) and all cause mortality. On-treatment LDL-C levels were 2.55±0.55 mmol/L and 2.58±0.62 mmol/L for men and women respectively. Age-adjusted Cox regression analysis showed that only on-treatment apoA-I was predictive for future CAD events in both men and women, whereas on-treatment HDL-C was exclusively predictive in women. On-treatment apoB levels were predictive for recurrent CAD events in the total population but not after separate analysis for men and women. On-treatment levels of TC, LDL-C, and TG did not predict subsequent events. Multivariate analysis showed that on-treatment apoA-I and apoB were the only significant predictors for future cardiovascular events. On-treatment levels of TC, LDL-C, and TG were no longer associated with increased risk of recurrent cardiovascular events in CAD patients treated to target levels, which justifies the current guidelines. However, on-treatment levels of apoB and in particular apoA-I (and HDL-C in women) were significantly predictive for MI and all-cause mortality and may therefore be more suitable for cardiovascular risk assessment in this population.

Key Words: lipids • apolipoproteins • risk factors • coronary disease

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Major randomized lipid intervention trials have convincingly demonstrated the clinical benefit of lipid lowering therapy in both primary and secondary prevention.^{1 2 3 4 5} Therefore, elevated levels of total cholesterol (TC), and more specifically elevated levels of low density lipoprotein cholesterol (LDL-C), have become highly modifiable risk factors. Besides TC and LDL-C, elevated triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) levels are other important lipid factors associated with an increased risk on coronary heart disease.^{6 7} Furthermore, apolipoprotein B (apoB) and A-I (apoA-I), the major apolipoproteins of LDL-C and HDL-C particles, have been suggested as better markers than LDL-C and HDL-C in the assessment of risk on coronary artery disease (CAD).^{8 9 10}

Because of their safety and efficacy, statin therapy plays a major role in the management of patients who are at risk for CAD events. An increasing number of patients with hyperlipidemia will therefore achieve target lipid levels as recommended by international guidelines. The National Cholesterol Education Program (NCEP) guidelines recommend target levels of LDL-C of <2.6 mmol/L (100 mg/dL) in patients with established CAD.¹¹ However, the risk on recurrent coronary events in patients with LDL-C levels treated to these targets has never been established. In addition, the predictive value of lipid and apolipoprotein levels during lipid lowering therapy on subsequent cardiovascular events has not sufficiently been investigated.

Accordingly, the aim of this study was to investigate the effect of both lipids and apolipoproteins A-I and B on myocardial infarction (MI) and all-cause mortality in men and women with documented CAD who were adequately treated with lipid lowering therapy.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Patient Population and Follow-Up
The study population derived from a population of 3095 consecutive patients who underwent a first diagnostic coronary angiogram between July 1981 and January 1998 at the Oosterschelde Hospital in Goes, the Netherlands. Patients who were referred for coronary angiography for reasons other than suspicion of CAD (eg, valve pathology, cardiomyopathy) were excluded from analysis (n=365). We next excluded patients without hemodynamically significant coronary artery disease (defined as 60% luminal narrowing, n=682). We then excluded 1200 patients who did not show a 30% reduction of TC by lipid lowering therapy (statin therapy either alone or in combination with cholestyramine or gemfibrozil) or in whom no complete lipid profile was known. As a result 848 patients (675 men and 173 women) could be included for final analysis.

To acquire mortality data, the computerized hospital system was screened. Subsequently, all family practitioners in the region were asked to verify whether patients who underwent coronary angiography and belonged to their practice were currently alive.

Using this information, we sent a questionnaire containing questions about clinical and lifestyle characteristics to all patients who were known to be alive. Letters were submitted to population registers and family members to obtain information about patients who could not be located or who did not return their questionnaires. Through these procedures, 3084 (99.7%) of all patients could be traced. The questionnaires were returned by 2285 (93.0%) of the 2457 eligible patients. Medical records were consulted to obtain clinical and lifestyle characteristics of the remaining patients. Myocardial infarction was enzymatically diagnosed. The follow-up period of each patient was calculated from the date of the first complete lipid profile that showed a 30% decrease of baseline TC level until death, non-fatal myocardial infarction, or until September 1, 1999.

Coronary Angiography
Coronary angiography was performed according to the standard Judkins technique. An obstruction in 1 of the 3 major epicardial coronary arteries of 60% on visual examination was considered hemodynamically significant.^{8 12} The coronary angiograms were evaluated visually and independently by 2 experienced cardiologists. In case of disagreement, a third observer was consulted to reach consensus.

Lipids and Apolipoproteins
All plasma lipid and apolipoprotein concentrations were determined from overnight fasting blood samples. TC and TG concentrations were measured enzymatically (Vitros analyzer, Johnson & Johnson). HDL-C fractions were prepared by precipitation from plasma of the apoB containing lipoproteins with the use of dextran sulfate and MgCl₂. Plasma LDL-C was calculated with the Friedewald formula (TC-[HDL-C]-[0.45xTG]).¹³ ApoA-I and apoB were measured by immunonephelometry on a Beckman array protein system: Beckman reagents, calibrators, and standards were used. All patients in this study were on statin therapy(simvastatin, atorvastatin, fluvastatin, or pravastatin). For each patient, a baseline TC level without statin therapy was used as reference value. Additionally, baseline HDL-C level was known of 290 men and 81 women, LDL-C level of 270 men and 76 women, TG of 297 men and 80 women, and apoA-I/apoB level of 188 men and 54 women. There were no important differences between baseline total cholesterol levels in patients with or without complete baseline lipid profile. The first complete lipid profile (TC, HDL-C, LDL-C, TG, apoA-I, and apoB) that demonstrated a 30% decrease of baseline TC level was used for analysis. Previous studies have shown that a 30% lowering of TC can be considered effective lipid treatment.^{4 5}

Statistical Analysis
Changes in lipids and apolipoproteins were described as average percent decrease from baseline values. Continuous and categorical variables were analyzed by Student’s t test and 2 analysis respectively. A Cox proportional-hazards regression model was used to estimate the effect of various age-adjusted risk factors as independent predictors of MI and all-cause mortality. A multivariate Cox proportional-hazards regression analysis was performed to measure the combined effect of the variables on MI and all-cause mortality. All lipid and apolipoprotein variables were analyzed as continuous variables unless stated otherwise. Because of interdependency of several lipid factors, LDL-C and HDL-C could not enter the multivariate model.Therefore a ridge regression analysis was performed for these variables. Values were expressed as hazard ratios (HR) with 95% confidence intervals (CI). Cut-off levels for high versus low HDL, apoB, and apoA-I were based to the values that divide the subjects into 2 equal groups. A P value <0.05 was considered statistically significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Baseline Characteristics and Follow-Up
Baseline characteristics of the study population for men and women are shown in Table 1. Age ranged from 33 to 84 years for men and 30 to 87 years for women. Women were older than men (66.9±9.9 years versus 64.2±9.5 years, P<0.001, respectively). Diabetes was more prevalent in women than in men (20.7% versus 11.9%, P=0.005, respectively). Fewer women than men were current smokers (7.1% versus 20.1%, P<0.001, respectively). Results of coronary angiography were similar for men and women in terms of extent of coronary artery disease. Mean follow-up of the 675 men and 173 women was 2.95 years (0–6.61) and 3.03 years (0.1 to 6.55), respectively. The 1-, 2-, and 3-year event-free survival rates were 93.8%, 91.0%, and 88.6% for men and 92.9%, 90.1%, and 87.6% for women.

View this table: [in this window] [in a new window]   Table 1. Clinical Baseline Characteristics in Men and Women

Serum Lipids
Baseline lipids and apolipoprotein levels before lipid lowering therapy for men and women showed that both sexes had similar mean levels of TG and LDL-C (Table 2). Women had significantly higher baseline TC and higher HDL-C levels than men (TC: 7.46±1.19 versus 6.99±1.01 mmol/L, and HDL-C: 1.32±0.31 versus 1.07±0.25 mmol/L, both P<0.0001, respectively). Also, baseline apoA-I and apoB levels were higher for women than for men (apoA-I: 1.55±0.22 versus 1.32±0.21 g/L, P<0.0001, and apoB: 1.64±0.37 versus 1.52±0.28 g/L). On-treatment lipid levels after successful lipid lowering therapy defined as the first complete lipid profile showing a 30% reduction of baseline TC are presented in Table 2. Compared with men, women had higher on-treatment TC levels (4.54±0.71 versus 4.32±0.65 mmol/L, P<0.0001), higher HDL-C levels (1.22±0.31 versus 1.06±0.27 mmol/L, P<0.0001), and higher on-treatment apoA-I levels (1.42±0.26 versus 1.28±0.22 g/L, P<0.0001). However, because of the greater reduction in apoB in women, on-treatment apoB levels reached similar levels for men and women. The effects of lipid treatment showed no major differences between men and women except for the average decrease in apoB, which was somewhat greater in women than in men (-44.00±8.3% versus -40.99±9.6%, P=0.04, respectively). Overall, HDL-C levels did not increase on statin treatment, however a considerable standard deviation was observed. Cox regression analysis adjusted for age showed that of all classical lipid variables (TC, LDL-C, HDL-C, and TG) only on-treatment HDL-C levels were significantly correlated with a decrease in recurrent cardiovascular event-rate (HR 0.37, CI 0.17 to 0.80, P=0.0012). Both on-treatment apoA-I and apoB were significantly associated with the incidence of events in the total study population (P=0.0005 and P=0.033, respectively) (Table 3). This is also illustrated in cumulative events curves that show that patients with low HDL-C (<1.1 mmol/L) (Figure 1), high apoB (0.89 g/L) (Figure 2), and in particular low apoA-I (<1.3 g/L) (Figure 3) had an increased risk on subsequent myocardial infarction or all-cause mortality. The predictive value of lipids and apolipoproteins and the incidence of events as calculated by Cox regression analysis, adjusted for in men and women separately, is shown in Table 3. For both sexes, low levels of on-treatment apoA-I were the most significant predictors for primary events (P=0.026 and P=0.002 for men and women, respectively). The predictive value of HDL-C (P=0.004) was only seen in women. A multivariate Cox regression model was performed to study the effect of individual variables (TC, TG, apoA-I, apoB, male sex, diabetes, age, angiographic results, and smoking status) on all-cause mortality and non-fatal MI, adjusted for concomitant lipid levels and clinical variables (Table 4). Age (P=<0.001), ApoA-I (P=0.044), and apoB (P=0.041) were the only significant predictors for subsequent future events. LDL-C could not be included in the model because of collinearity with TC. The effect of HDL-C could not be estimated due to collinearity between apoA-I and TC. When using a ridge regression approach, the HR of HDL-C was 0.99, CI 0.37 to 2.62 (P=NS).

View this table: [in this window] [in a new window]   Table 2. Baseline and On-Treatment Lipid/Apolipoprotein Levels and Treatment Effects of Statin Therapy on Lipid/Apolipoprotein Levels in Men and Women

View this table: [in this window] [in a new window]   Table 3. Relationship Between On-Treatment Lipid/Apolipoprotein Levels and Clinical Variables on Subsequent Myocardial Infarction/All-cause Mortality by Age-Adjusted Cox Regression Analysis for the Total Population and Men and Women Separately

View larger version (14K): [in this window] [in a new window]   Figure 1. Probability of recurrent cardiovascular events (myocardial infarction or all cause mortality) adjusted for age, from time of 30% decrease of baseline TC level before statin therapy in patients with low HDL-C (<1.1 g/L) (black line) versus higher HDL-C (1.1 g/L) (gray line).

View larger version (14K): [in this window] [in a new window]   Figure 2. Probability of recurrent cardiovascular events (myocardial infarction or all cause mortality) adjusted for age, from time of 30% decrease of baseline TC level before statin therapy in patients with apoB (<0.89 g/L) (black line) versus higher apoB (0.89 g/L) (gray line).

View larger version (13K): [in this window] [in a new window]   Figure 3. Probability of recurrent cardiovascular events (myocardial infarction or all cause mortality) adjusted for age, from time of 30% decrease of baseline TC level before statin therapy in patients with low apoA-I (<1.3 g/L) (black line) versus higher apoA-I (1.3 g/L) (gray line)

View this table: [in this window] [in a new window]   Table 4. Relationship Between On-Treatment Lipid/Apolipoprotein Levels and Clinical Variables on Subsequent Myocardial Infarction/All-Cause Mortality by Multivariate Cox Regression Analysis

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Our study revealed that only on-treatment levels of apoB and especially apoA-I were significantly predictive for MI and all-cause mortality in CAD patients receiving effective statin therapy, whereas on-treatment HDL-C level was a significant risk factor exclusively for women. On-treatment levels of TC, LDL-C, and TG were no longer associated with increased risk of recurrent cardiovascular events in this population.

LDL Metabolism and Recurrent Cardiovascular Events
Clinical intervention trials have shown that lowering LDL-C plasma levels with statins reduces the relative risk on major coronary events by 30% dependent on baseline risk.¹⁴ The National Cholesterol Education Program (NCEP) guidelines recommend target levels of LDL-C of <2.6 mmol/L (100 mg/dL) in patients with established CAD.¹¹ However, the risk on recurrent coronary events in patients with LDL-C levels treated to these targets have never been established. In our population, patients were on aggressive lipid lowering therapy, resulting in average levels of LDL-C of 2.55 mmol/L for men and 2.58 mmol/L for women. We found that neither TC nor LDL-C levels during statin therapy were predictive for all-cause mortality and non-fatal myocardial infarction. This finding has several implications. First, the value of lipid lowering therapy is once more confirmed, because we showed that effective treatment of elevated LDL-C levels eliminates LDL-C as risk factor for recurrent cardiovascular events. Second, our results imply that it is unlikely that further lowering of LDL-C has any effect when treated to NCEP standards. This is consistent with several previous studies that showed that the magnitude of beneficial clinical effects is diminished^{15 16} or even eliminated^{17 18} at lower LDL-C and TC levels. Results from the Multiple Risk Factor Intervention Trial (MRFIT)¹⁶ and the Scandinavian Simvastatin Survival Study (4S)¹⁵ support a curvilinear model showing a continuous but progressive decrease of benefit on CHD risk with increased reduction of TC levels. The Cholesterol and Recurrent Events (CARE) study¹⁷ demonstrated that no further decline in CHD events was to be expected with LDL-C levels below 3.2 mmol/L (125 mg/dL). Accordingly, our findings along with these the current results provide evidence for justification of the current guidelines.

Nevertheless, as Superko previously emphasized¹⁹ , CAD risk management cannot be simplified to LDL-C reduction. We found that apoB was a better predictor for recurrent coronary events than LDL-C. This finding is biologically plausible. Atherogenic lipoproteins including LDL-C particles and remnants of triglyceride-rich particles each contain 1 molecule of apoB.²⁰ Consequently, apoB gives an accurate estimation of the total number of atherogenic particles.²¹ The composition of LDL-C particles, each containing 1 molecule of apoB, is heterogeneous because of the variable content of cholesterol. Smaller, denser LDL-C are more atherogenic than larger ones.^{22 23} Therefore apoB is superior compared with LDL-C in determining CAD risk. A great number of studies have confirmed that apoB is a better marker for atherogenicity and CAD than LDL-C and TC both in men^{9 10} and women.^{8 10} Recently Gotto et al²⁴ showed in data from the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS) that on-treatment apoB was the only significant predictor for subsequent cardiovascular events for primary prevention. This study²⁴ is as yet the only large study that evaluated the predictive value of on-treatment lipid and apolipoprotein levels. As our study provides information on secondary prevention our data are complementary to their results on primary prevention. In agreement with their findings, we showed that, in patients with effectively treated lipid levels, measurement of apoB seems more appropriate than LDL-C and TC plasma levels as predictor of recurrent cardiovascular events

HDL Metabolism and Recurrent Cardiovascular Events
Low levels of plasma HDL-C are directly associated with a significantly increased risk of CAD.^{25 26 27} Compared with the knowledge of the LDL-C metabolism, our insight of HDL-C metabolism including reverse cholesterol transport, is incomplete. Judged by the number of recently published studies dedicated to HDL-C, it appears that lipid research has ‘discovered’ HDL-C, due to the remarkable progress in unraveling the HDL-C metabolism. Major breakthroughs include the discovery of the HDL-C receptor, the scavenger receptor B-1 (SR-B1), which is expressed at high levels at the main sites of selective uptake of HDL-C.²⁸ In addition, along with epidemiologic evidence,^{25 29} recent major clinical intervention trials^{3 30} have shown the importance of HDL-C on CAD, in particular in patients without elevated LDL-C levels. Miller et al²⁹ demonstrated the significance of low HDL-C as risk factor on the incidence of recurrent cardiovascular events in a follow-up study of patients with angiographically proven CAD and desirable TC levels. The AFCAPS/TexCAPS study³ showed that, in a population without a history of CAD and with normal TC and LDL-C levels, a below-average HDL-C level (0.94 mmol/L for men and 1.03 mmol/L for women) forms an important risk factor for a first major coronary event. The recently published Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT)³⁰ proved that a modest increase in HDL-C levels in CAD patients with normal LDL-C levels (3.6 mmol/L) resulted in a significant reduction of risk on major cardiovascular events.

In our study, we found that only in women, on-treatment plasma HDL-C was inversely correlated with the risk for recurrent events. This is consistent with some other studies that found that the impact of HDL-C on coronary risk was greater in women than in men.^{26 27}

ApoA-I, the major apolipoprotein of HDL-C, showed a predictive value for CHD events similar to HDL-C in women and was the only significant predictor in men. Similar to our findings, Kwiterovich et al¹⁰ found that the level of apoA-I, but not the level of HDL-C, was an indicator of future CAD for men. ApoA-I has previously been reported as a better indicator of CHD than HDL-C.^{10 31 32} Biologically, this finding can be explained because not all HDL-C particles are equally protective. Two predominant classes of HDL-C can be recognized; HDL-C particles that only contain apoA-I (lipoprotein A-I) and particles that contain both apoA-I and apoA-II (lipoprotein A-I:A-II). In general, lipoprotein A-I is considered to be more protective against CHD than lipoprotein A-I:A-II.³³ Therefore, apoA-I levels may be a better marker for functional reverse cholesterol transport than HDL-C.

Considerations of the Study
Recently it has been stated that clinical investigators should rely on all-cause death as an objective, unbiased end-point, rather than rely on cardiovascular mortality alone. Therefore, we chose to assess total mortality because of the bias existing in the use of cardiovascular mortality, especially in a population with known CAD.³⁴ In our institution, all patients had complete lipid profiles measured after 1993 and we do not expect to create a bias in outcome by excluding patients with incomplete profiles. We analyzed patients with 1 or more significant coronary artery stenosis and, therefore, our results only apply to this group and cannot be generalized. Furthermore, we cannot answer the question whether patients with <30% reduction in total cholesterol should be a given a higher dose of statins as we did not assess these patients. In our opinion, the current guidelines are appropriate as far as it concerns LDL-C target levels as we showed that on-treatment LDL-C levels do not have prognostic relevance anymore. To establish the prognostic value of on-treatment apolipoproteins, large prospective trials are necessary. Therefore, we do not think that the current guidelines should be changed directly as a result of our study.

Conclusion
On-treatment levels of TC, LDL-C, and TG were no longer associated with increased risk of recurrent cardiovascular events in CAD patients treated to target levels, which justifies the current guidelines. However, on-treatment levels of apoB and in particular apoA-I (and HDL-C in women) were significantly predictive for MI and all-cause mortality and may therefore be more suitable for cardiovascular risk assessment in this population.

Received May 4, 2000; accepted August 17, 2000.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349–1357.[Abstract/Free Full Text]

2. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study. N Engl J Med. 1995;333:1301–1307.[Abstract/Free Full Text]

3. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM, Jr. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615–1622.[Abstract/Free Full Text]

4. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389.[Medline] [Order article via Infotrieve]

5. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001–1009.[Abstract/Free Full Text]

6. Harper CR, Jacobson TA. New perspectives on the management of low levels of high-density lipoprotein cholesterol. Arch Intern Med. 1999;159:1049–1057.[Abstract/Free Full Text]

7. Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol. 1998;81:7B–12B.[Medline] [Order article via Infotrieve]

8. Westerveld HT, van Lennep JE, van Lennep HW, Liem AH, de Boo JA, van der Schouw YT, Erkelens DW. Apolipoprotein B and coronary artery disease in women: a cross-sectional study in women undergoing their first coronary angiography. Arterioscler Thromb Vasc Biol. 1998;18:1101–1107.[Abstract/Free Full Text]

9. Lamarche B, Moorjani S, Lupien PJ, Cantin B, Bernard PM, Dagenais GR, Despres JP. Apolipoprotein A-I and B levels and the risk of ischemic heart disease during a five-year follow-up of men in the Quebec cardiovascular study. Circulation. 1996;94:273–278.[Abstract/Free Full Text]

10. Kwiterovich-PO J, Coresh J, Smith HH, Bachorik PS, Derby CA, Pearson TA. Comparison of the plasma levels of apolipoproteins B and A-1, and other risk factors in men and women with premature coronary artery disease. Am J Cardiol. 1992;69:1015–1021.[Medline] [Order article via Infotrieve]

11. National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation. 1994;89:1333–1445.[Medline] [Order article via Infotrieve]

12. Schweiger MJ, McMahon RP, Terrin ML, Ruocco NA, Porway MN, Wiseman AH, Knatterud GL, Braunwald E. Comparison of patients with <60% to > or=60% diameter narrowing of the myocardial infarct-related artery after thrombolysis. The TIMI Investigators. Am J Cardiol.. 1994;74:105–110.[Medline] [Order article via Infotrieve]

13. 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]

14. Maron DJ, Fazio S, Linton MF. Current Perspectives on Statins. Circulation. 2000;101:207–213.[Abstract/Free Full Text]

15. Pedersen TR, Olsson AG, Faergeman O, Kjekshus J, Wedel H, Berg K, Wilhelmsen L, Haghfelt T, Thorgeirsson G, Pyorala K, Miettinen T, Christophersen B, Tobert JA, Musliner TA, Cook TJ. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation. 1998;97:1453–1460.[Abstract/Free Full Text]

16. Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1986;256:2823–2828.[Abstract/Free Full Text]

17. Sacks FM, Moye LA, Davis BR, Cole TG, Rouleau JL, Nash DT, Pfeffer MA, Braunwald E. Relationship between plasma LDL concentrations during treatment with pravastatin and recurrent coronary events in the Cholesterol and Recurrent Events trial. Circulation. 1998;97:1446–1452.[Abstract/Free Full Text]

18. Fager G, Wiklund O. Cholesterol reduction and clinical benefit. Are there limits to our expectations? Arterioscler Thromb Vasc Biol. 1997;17:3527–3533.[Abstract/Free Full Text]

19. Superko HR. Beyond LDL cholesterol reduction. Circulation. 1996;94:2351–2354.[Free Full Text]

20. Beisiegel U. Lipoprotein metabolism. Eur Heart J. 1998;19 Suppl A:A20–A23.

21. Sniderman AD, Cianflone K. Measurement of apoproteins: time to improve the diagnosis and treatment of the atherogenic dyslipoproteinemias. Clin Chem. 1996;42:489–491.[Free Full Text]

22. Zambon A, Hokanson JE, Brown BG, Brunzell JD. Evidence for a new pathophysiological mechanism for coronary artery disease regression: hepatic lipase-mediated changes in LDL density. Circulation. 1999;99:1959–1964.[Abstract/Free Full Text]

23. Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Despres JP. 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;95:69–75.[Abstract/Free Full Text]

24. Gotto AM, Jr, Whitney E, Stein EA, Shapiro DR, Clearfield M, Weis S, Jou JY, Langendorfer A, Beere PA, Watson DJ, Downs JR, de Cani JS. Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation. 2000;101:477–484.[Abstract/Free Full Text]

25. Jacobs DR, Jr, Mebane IL, Bangdiwala SI, Criqui MH, Tyroler HA. High density lipoprotein cholesterol as a predictor of cardiovascular disease mortality in men and women: the follow-up study of the Lipid Research Clinics Prevalence Study. Am J Epidemiol. 1990;131:32–47.[Abstract/Free Full Text]

26. Stensvold I, Urdal P, Thurmer H, Tverdal A, Lund-Larsen PG, Foss OP. High-density lipoprotein cholesterol and coronary, cardiovascular and all cause mortality among middle-aged Norwegian men and women. Eur Heart J. 1992;13:1155–1163.[Abstract/Free Full Text]

27. Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, Jacobs DR, Jr, Bangdiwala S, Tyroler HA. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989;79:8–15.[Abstract/Free Full Text]

28. Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science. 1996;271:518–520.[Abstract]

29. Miller M, Seidler A, Kwiterovich PO, Pearson TA. Long-term predictors of subsequent cardiovascular events with coronary artery disease and ‘desirable’ levels of plasma total cholesterol. Circulation. 1992;86:1165–1170.[Abstract/Free Full Text]

30. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341:410–418.[Abstract/Free Full Text]

31. O’Brien T, Nguyen TT, Hallaway BJ, Hodge D, Bailey K, Holmes D, Kottke BA. The role of lipoprotein A-I and lipoprotein A-I/A-II in predicting coronary artery disease. Arterioscler Thromb Vasc Biol. 1995;15:228–231.[Abstract/Free Full Text]

32. Genest J, Jr, McNamara JR, Ordovas JM, Jenner JL, Silberman SR, Anderson KM, Wilson PW, Salem DN, Schaefer EJ. Lipoprotein cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnormalities in men with premature coronary artery disease. J Am Coll Cardiol. 1992;19:792–802.[Abstract]

33. Colvin PL, Parks JS. Metabolism of high density lipoprotein subfractions. Curr Opin Lipidol. 1999;10:309–314.[Medline] [Order article via Infotrieve]

34. Lauer MS, Blackstone EH, Young JB, Topol EJ. Cause of death in clinical research: time for a reassessment? J Am Coll Cardiol. 1999;34:618–620.[Free Full Text]

This article has been cited by other articles:

				L. Johansson and C. Schmidt Increased apoB/apoA-I Ratio Is Predictive of Peripheral Arterial Disease in Initially Healthy 58-Year-old Men During 8.9 Years of Follow-up Angiology, October 1, 2009; 60(5): 539 - 545. [Abstract] [PDF]

				S. S. Martin, A. N. Qasim, N. N. Mehta, M. Wolfe, K. Terembula, S. Schwartz, N. Iqbal, M. Schutta, R. Bagheri, and M. P. Reilly Apolipoprotein B but not LDL Cholesterol Is Associated With Coronary Artery Calcification in Type 2 Diabetic Whites Diabetes, August 1, 2009; 58(8): 1887 - 1892. [Abstract] [Full Text] [PDF]

				J. H. Contois, J. P. McConnell, A. A. Sethi, G. Csako, S. Devaraj, D. M. Hoefner, and G. R. Warnick Apolipoprotein B and Cardiovascular Disease Risk: Position Statement from the AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices Clin. Chem., March 1, 2009; 55(3): 407 - 419. [Abstract] [Full Text] [PDF]

				J.-C. Fruchart, F. M Sacks, M. P Hermans, G. Assmann, W V. Brown, R. Ceska, M J. Chapman, P. M Dodson, P. Fioretto, H. N Ginsberg, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patients Diabetes and Vascular Disease Research, November 1, 2008; 5(4): 319 - 335. [Abstract] [PDF]

				J. D. Brunzell, M. Davidson, C. D. Furberg, R. B. Goldberg, B. V. Howard, J. H. Stein, and J. L. Witztum Lipoprotein Management in Patients With Cardiometabolic Risk: Consensus Conference Report From the American Diabetes Association and the American College of Cardiology Foundation J. Am. Coll. Cardiol., April 15, 2008; 51(15): 1512 - 1524. [Full Text] [PDF]

				J. D. Brunzell, M. Davidson, C. D. Furberg, R. B. Goldberg, B. V. Howard, J. H. Stein, and J. L. Witztum Lipoprotein Management in Patients With Cardiometabolic Risk: Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation Diabetes Care, April 1, 2008; 31(4): 811 - 822. [Full Text] [PDF]

				K.-L. Chien, H.-C. Hsu, T.-C. Su, M.-F. Chen, Y.-T. Lee, and F. B. Hu Apolipoprotein B and non-high density lipoprotein cholesterol and the risk of coronary heart disease in Chinese J. Lipid Res., November 1, 2007; 48(11): 2499 - 2505. [Abstract] [Full Text] [PDF]

				J. O. Mudd, B. A. Borlaug, P. V. Johnston, B. G. Kral, R. Rouf, R. S. Blumenthal, and P. O. Kwiterovich Jr Beyond Low-Density Lipoprotein Cholesterol: Defining the Role of Low-Density Lipoprotein Heterogeneity in Coronary Artery Disease J. Am. Coll. Cardiol., October 30, 2007; 50(18): 1735 - 1741. [Abstract] [Full Text] [PDF]

				W. A. van der Steeg, S. M. Boekholdt, E. A. Stein, K. El-Harchaoui, E. S.G. Stroes, M. S. Sandhu, N. J. Wareham, J. W. Jukema, R. Luben, A. H. Zwinderman, et al. Role of the Apolipoprotein B-Apolipoprotein A-I Ratio in Cardiovascular Risk Assessment: A Case-Control Analysis in EPIC-Norfolk Ann Intern Med, May 1, 2007; 146(9): 640 - 648. [Abstract] [Full Text] [PDF]

				D.C. Chan and G.F. Watts Apolipoproteins as markers and managers of coronary risk QJM, May 1, 2006; 99(5): 277 - 287. [Abstract] [Full Text] [PDF]

				T. Pischon, C. J. Girman, F. M. Sacks, N. Rifai, M. J. Stampfer, and E. B. Rimm Non-High-Density Lipoprotein Cholesterol and Apolipoprotein B in the Prediction of Coronary Heart Disease in Men Circulation, November 29, 2005; 112(22): 3375 - 3383. [Abstract] [Full Text] [PDF]

				P. M Ridker, N. Rifai, N. R. Cook, G. Bradwin, and J. E. Buring Non-HDL Cholesterol, Apolipoproteins A-I and B100, Standard Lipid Measures, Lipid Ratios, and CRP as Risk Factors for Cardiovascular Disease in Women JAMA, July 20, 2005; 294(3): 326 - 333. [Abstract] [Full Text] [PDF]

				N. Sattar, K. Williams, A. D. Sniderman, R. D'Agostino Jr, and S. M. Haffner Comparison of the Associations of Apolipoprotein B and Non-High-Density Lipoprotein Cholesterol With Other Cardiovascular Risk Factors in Patients With the Metabolic Syndrome in the Insulin Resistance Atherosclerosis Study Circulation, October 26, 2004; 110(17): 2687 - 2693. [Abstract] [Full Text] [PDF]

				A. M. Wagner, O. Jorba, R. Bonet, J. Ordonez-Llanos, and A. Perez Efficacy of Atorvastatin and Gemfibrozil, Alone and in Low Dose Combination, in the Treatment of Diabetic Dyslipidemia J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3212 - 3217. [Abstract] [Full Text] [PDF]

				A. M. Wagner, A. Perez, E. Zapico, and J. Ordonez-Llanos Non-HDL Cholesterol and Apolipoprotein B in the Dyslipidemic Classification of Type 2 Diabetic Patients Diabetes Care, July 1, 2003; 26(7): 2048 - 2051. [Abstract] [Full Text] [PDF]

				F. F. Ribeiro-Filho, A. N. Faria, N. E.B. Kohlmann, M.-T. Zanella, and S. R.G. Ferreira Two-Hour Insulin Determination Improves the Ability of Abdominal Fat Measurement to Identify Risk for the Metabolic Syndrome Diabetes Care, June 1, 2003; 26(6): 1725 - 1730. [Abstract] [Full Text] [PDF]

				S. Rashid, K. D. Uffelman, P. H. R. Barrett, and G. F. Lewis Effect of Atorvastatin on High-Density Lipoprotein Apolipoprotein A-I Production and Clearance in the New Zealand White Rabbit Circulation, December 3, 2002; 106(23): 2955 - 2960. [Abstract] [Full Text] [PDF]

				S. S. Levinson High Density- and Beta-Lipoprotein Screening for Risk of Coronary Artery Disease in the Context of New Findings on Reverse Cholesterol Transport Ann. Clin. Lab. Sci., April 1, 2002; 32(2): 123 - 136. [Abstract] [Full Text] [PDF]

				P. N. Durrington Can Measurement of Apolipoprotein B Replace the Lipid Profile in the Follow-up of Patients with Lipoprotein Disorders? Clin. Chem., March 1, 2002; 48(3): 401 - 402. [Full Text] [PDF]

				S. Miremadi, A. Sniderman, and J. Frohlich Can Measurement of Serum Apolipoprotein B Replace the Lipid Profile Monitoring of Patients with Lipoprotein Disorders? Clin. Chem., March 1, 2002; 48(3): 484 - 488. [Abstract] [Full Text] [PDF]

				J. Frohlich, A. Sniderman, and R. H. Eckel Familial Combined Hyperlipidemia and Insulin Resistance Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 2100 - 2101. [Full Text] [PDF]

				A. D. Sniderman, T. Scantlebury, and K. Cianflone Hypertriglyceridemic HyperapoB: The Unappreciated Atherogenic Dyslipoproteinemia in Type 2 Diabetes Mellitus Ann Intern Med, September 18, 2001; 135(6): 447 - 459. [Abstract] [Full Text] [PDF]

				J. R. Crouse III and C. D. Furberg Treatment of Dyslipidemia : Room for Improvement? Arterioscler Thromb Vasc Biol, November 1, 2000; 20(11): 2333 - 2335. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted 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 van Lennep, J. E. R. Articles by van der Wall, E. E. Search for Related Content PubMed PubMed Citation Articles by van Lennep, J. E. R. Articles by van der Wall, E. E. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Lipids Secondary prevention Risk Factors Epidemiology Lipid and lipoprotein metabolism