Abstract
Background: The apolipoprotein B (apoB)/apoA-I ratio represents the balance of proatherogenic and antiatherogenic lipoproteins. The purpose of this study was to determine whether the apoB/apoA-I ratio was superior to any of the cholesterol ratios – total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C), low-density lipoprotein cholesterol (LDL-C)/HDL-C and non-HDL-C/HDL-C – in predicting the risk of coronary disease. Moreover, we examined whether any lipids, lipoproteins or cholesterol ratios add significant predictive information beyond that provided by the apoB/apoA-I ratio.
Methods: Plasma lipids, lipoproteins, apoB, and apoA-I were measured in 69,030 men and 57,168 women above 40years of age. After a mean follow-up of 98months, 1183 men and 560 women had died from a myocardial infarction in this prospective apolipoprotein-related mortality risk (AMORIS) study.
Results: High apoB and a high apoB/apoA-I ratio were strongly related to increased coronary risk, while high apoA-I was inversely related to risk. The apoB/apoA-I ratio was superior to any of the cholesterol ratios in predicting risk. This advantage was most pronounced in subjects with LDL-C levels <3.6mmol/l. Addition of lipids, lipoproteins or any cholesterol ratio to apoB/apoA-I in risk models did not further improve the strong predictive value of apoB/apoA-I.
Conclusions: These results indicate that the apoB/apoA-I ratio is at present the best single lipoprotein-related variable to quantitate coronary risk. Given the additional advantages apolipoproteins possess – fasting samples are not required, apoB/apoA-I is a better index of the adequacy of statin therapy than LDL-C, and the measurement of apoB and apoA-I are standardized, whereas LDL-C and HDL-C are not – there would appear to be considerable advantage to integrating apolipoproteins into clinical practice.
References
1 Adult Treatment Panel III. Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Final Report. Circulation 2002;106:3144–421.10.1161/circ.106.25.3143Search in Google Scholar
2 Grundy SM. Low-density lipoprotein, non-high-density lipoprotein, and apolipoprotein B as targets of lipid-lowering therapy [editorial]. Circulation 2002;106:2526–9.10.1161/01.CIR.0000038419.53000.D6Search in Google Scholar
3 De Backer G, Ambrosini E, Borch-Johansen K, Brotons C, Cifkova R, Dallongeville J, et al. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 2003; 24:1601–10.10.1016/S0195-668X(03)00347-6Search in Google Scholar
4 Conroy RM, Pyörälä K, Fitzgerald AP, Sans S, Menotti A, De Backer G, et al. Estimation of ten-year risk factor cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003; 24:987–1003.10.1016/S0195-668X(03)00114-3Search in Google Scholar
5 International Atherosclerosis Society. Harmonized Clinical Guidelines on Prevention of Atherosclerotic Vascular Disease. Executive Summary, 2003:1–23 (info@athero.org).Search in Google Scholar
6 Genest J, Frohlich J, Fodor G, McPherson R. Recommendations for the management and treatment of dyslipidemia and the prevention of cardiovascular disease: summary of the 2003 update. Can Med Assoc J 2003; 169:921–4.Search in Google Scholar
7 Swedish–Norwegian guidelines: behandling med lipidsänkande läkemedel vid prevention av hjärt-kärlsjukdom. Uppsala: Läkemedelsverket, 2003 (http://www.mpa.se, Information 2003 14/4).Search in Google Scholar
8 Lamarche B, Moorjani S, Lupien PJ, Cantin B, Bernard P-M, Dagenais GR, et al. Apolipoprotein A-1 and B levels and the risk of ischemic heart disease during a five-year follow-up of men in the Québec Cardiovascular Study. Circulation 1996; 94:273–8.10.1161/01.CIR.94.3.273Search in Google Scholar
9 Moss AJ, Goldstein RE, Marder VJ, Sparks CE, Oakes D, Greenberg H, Weiss HJ, et al. Thrombogenic factors and recurrent coronary events. Circulation 1999; 99:2517–22.10.1161/01.CIR.99.19.2517Search in Google Scholar
10 Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet 2001; 358:2026–33.10.1016/S0140-6736(01)07098-2Search in Google Scholar
11 Talmud PJ, Hawe E, Miller GJ, Humphries SE. Non-fasting apoB and triglyceride levels as a useful predictor of coronary heart disease risk in middle-aged UK men. Arterioscler Thromb Vasc Biol 2002; 22:1918–23.10.1161/01.ATV.0000035521.22199.C7Search in Google Scholar
12 Graziani MS, Zanolla L, Righetti G, Marchetti C, Mocarelli P, Marcovina S. Plasma apolipoprotein A-I and B in survivors of myocardial infarction and in a control group. Clin Chem 1998; 44:134–40.10.1093/clinchem/44.1.134Search in Google Scholar
13 Francis MC, Frohlich JJ. Coronary artery disease in patients at low risk – apolipoprotein A-I as an independent risk factor. Atherosclerosis 2001; 155:165–7.10.1016/S0021-9150(00)00528-1Search in Google Scholar
14 Luc G, Bard J-M, Ferrières J, Evans A, Amouyel P, Arveiler D, et al. Value of HDL-C, apolipoprotein A-I, lipoprotein A-I, and lipoprotein A-I/A-II in prediction of coronary artery disease. The PRIME Study. Prospective epidemiological study of myocardial infarction. Arterioscler Thromb Vasc Biol 2002; 22:1155–61.10.1161/01.ATV.0000022850.59845.E0Search in Google Scholar
15 Sniderman AD, Furberg CD, Keech A, Roeters van Lennep JE, Frohlich J, Jungner I, et al. Apolipoproteinsversus lipids as indices of coronary risk and as targets for statin therapy: analysis of the evidence. Lancet 2003; 361:777–80.10.1016/S0140-6736(03)12663-3Search in Google Scholar
16 Marcovina SM, Albers JJ, Kennedy H, Mei JV, Henderson LO, Hannon WH. International Federation of Clinical Chemistry standardization project for measurements of apolipoproteins A-I and B. IV. Comparability of apolipoprotein B values by use of international reference material. Clin Chem 1994; 40:586–92.10.1093/clinchem/40.4.586Search in Google Scholar
17 Otvos JD, Jeyarajah EJ, Cromvell WC. Measurement issues related to lipoprotein heterogeneity. Am J Cardiol 2002; 90:Suppl:22i–29i.10.1016/S0002-9149(02)02632-2Search in Google Scholar
18 Otvos J. LDL particles, but not LDL cholesterol, are highly elevated in the metabolic syndrome: results from the Framingham Offspring Study. AHA 2003 Scientific Sessions Online, Orlando, FL, 2003.Search in Google Scholar
19 Sniderman AD, Scantlebury T, Cianflone K. Hypertriglyceridemic hyperapoB: the unappreciated atherogenic dyslipoproteinemia in type 2 diabetes mellitus. Ann Intern Med 2001; 135:447–59.10.7326/0003-4819-135-6-200109180-00014Search in Google Scholar PubMed
20 Berneis KK, Krauss RM. Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res 2002; 43:1363–79.10.1194/jlr.R200004-JLR200Search in Google Scholar PubMed
21 Marcovina SM, Albers JJ, Henderson LO, Hannon WH. International Federation of Clinical Chemistry standardization project for measurements of apolipoproteins A-I and B. III. Comparability of apolipoprotein A-I values by use of international reference material. Clin Chem 1993; 39:773–81.10.1093/clinchem/39.5.773Search in Google Scholar
22 Bachorik PS, Lovejoy KI, Carroll MD, Johnson CL. Apolipoprotein B and A-I distribution in the United States, 1988–1991: results of the National Health and Nutrition Examination Survey III (NHANES III). Clin Chem 1997; 43:2364–78.10.1093/clinchem/43.12.2364Search in Google Scholar
23 Jungner I, Marcovina S, Walldius G, Holme I, Kolar W, Steiner E. Apolipoprotein B and A-I values in 147576 Swedish males and females, standardized according to the World Health Organization – International Federation of Clinical Chemistry First International Reference Materials. Clin Chem 1998; 44:1641–9.10.1093/clinchem/44.8.1641Search in Google Scholar
24 Jungner I, Walldius G, Holme I, Kolar W, Steiner E. Apolipoprotein B and A-I in relation to serum cholesterol and triglycerides in 43000 Swedish males and females. Int J Lab Res 1992; 21:247–55.10.1007/BF02591655Search in Google Scholar PubMed
25 Friedewald WT, Levy RJ, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18:499–502.10.1093/clinchem/18.6.499Search in Google Scholar
26 Yusuf S, Hawken S, Öunpuu S, Dans T, Avezum A, Lanas F, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364:937–52.10.1016/S0140-6736(04)17018-9Search in Google Scholar
27 O'Keefe JH Jr, Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70mg/dl. Lower is better and physiologically normal. Expedited review. J Am Coll Cardiol 2004; 43:2142–6.Search in Google Scholar
28 Davidson MH. Emerging therapeutic strategies for the management of dyslipidemia in patients with metabolic syndrome. Am J Cardiol 2004; 93:Suppl:3C–11C.10.1016/j.amjcard.2004.02.006Search in Google Scholar PubMed
29 Grundy SM, Cleeman JI, Merz CNB, Brewer HB Jr, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Arterioscler Thromb Vasc Biol 2004; 24:e149–161.10.1161/01.ATV.0000133317.49796.0ESearch in Google Scholar PubMed
30 Gotto AM, Whitney E, Stein EA, Shapiro DR, Clearfield M, Weiss S, et al. 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; 101:477–84.10.1161/01.CIR.101.5.477Search in Google Scholar PubMed
31 Barter PJ, Rye K. Molecular mechanisms of reverse cholesterol transport. Curr Opin Lipidol 1996; 7:82–7.10.1097/00041433-199604000-00006Search in Google Scholar PubMed
32 Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, et al. Effect of recombinant apoA-I Milano on coronary athersclerosis in patients with acute coronary syndromes: a randomized controlled trial. J Am Med Assoc 2003; 290:2322–4.10.1001/jama.290.17.2292Search in Google Scholar PubMed
33 Walldius G, Jungner I. Apolipoprotein B and apolipoprotein A-I: risk indicators of coronary heart disease and targets for lipid-lowering therapy. J Intern Med 2004; 255:188–205.10.1046/j.1365-2796.2003.01276.xSearch in Google Scholar PubMed
34 Williams K, Sniderman AD, Sattar N, D'Agostino R Jr, Wagenknecht LE, Haffner SM. Comparison of the associations of apolipoprotein B and low-density lipoprotein cholesterol with other cardiovascular risk factors in the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2003; 108:2312–6.10.1161/01.CIR.0000097113.11419.9ESearch in Google Scholar PubMed
35 Sniderman AD. Applying apoB to the diagnosis and therapy of the atherogenic dyslipoproteinemias: a clinical diagnostic algorithm. Curr Opin Lipidol 2004; 15:433–8.10.1097/01.mol.0000137220.39031.3bSearch in Google Scholar PubMed
36 Collins-Nakai RL, Daganais GR. The role of the cardiovascular specialist in the prevention of cardiovascular diseases – executive summary. Can J Cardiol 1999;Suppl G:7G–16G.Search in Google Scholar
37 Leiter LA, Mahon J, Chye T. Macrovascular complications, dyslipidemia and hypertension. Can J Diabetes 2003;Suppl 2:S58–65.Search in Google Scholar
38 Scharnagl H, Nauck M, Wieland H, März W. The Friedewald formula underestimates LDL cholesterol at low concentrations. Clin Chem Lab Med 2001; 39:426–31.10.1515/CCLM.2001.068Search in Google Scholar
39 Sniderman AD, Blank D, Zakarian R, Bergeron J, Frohlich J. Triglycerides and small dense LDL; the twin Achilles heels of the Friedewald formula. Clin Biochem 2003; 36:499–504.10.1016/S0009-9120(03)00117-6Search in Google Scholar
40 Otvos JD. Why cholesterol measurements may be misleading about lipoprotein levels and cardiovasculardisease risk – clinical implications of lipoprotein quantification using NMR spectroscopy. J Lab Med 2002; 26:544–50.Search in Google Scholar
41 Miller WG, Waymack PP, Anderson PA, Ethridge SF, Jayne EC. Performance of four homogeneous direct methods for LDL-cholesterol. Clin Chem 2002; 48: 489–98.10.1093/clinchem/48.3.489Search in Google Scholar
42 Usui S, Kakuuchi H, Okamoto M, Mizukami Y, Okazaki M. Differential reactivity of two homogeneous LDL-cholesterol methods to LDL, and VLDL subfractions, as demonstrated by ultracentrifugation and HPLC. Clin Chem 2002; 48:1946–54.10.1093/clinchem/48.11.1946Search in Google Scholar
43 Steinmetz J, Cases E, Couderc R, Beucler I, Legrand A, Henney J. Reference values of apolipoprotein A-I and B. Contribution of international standardization. Ann Biol Clin 1997; 55:451–4.Search in Google Scholar
44 Mendis S, Yach D, Bengoa R, Narvaez D, Zhang X. Research gap in cardiovascular disease in developing countries. Lancet 2003; 361:2246–7.10.1016/S0140-6736(03)13753-1Search in Google Scholar
©2004 by Walter de Gruyter Berlin New York