Faculty Peer Reviewed
Coronary heart disease (CHD) is the major cause of mortality worldwide. Lipoproteins play a major role in the development of this disease. Current guidelines advocate that low-density lipoprotein (LDL) cholesterol should be the primary target for lipid lowering therapy. However, there is a growing literature on the atherogenic potential of apolipoprotein B (apo B)-containing lipoproteins and the protective effect of apolipoprotein A-one (apo AI)-containing lipoproteins. Many studies suggest that these apolipoproteins be used as markers to evaluate risk of coronary heart disease.
What are apolipoproteins and why are they relevant?
Apolipoproteins are found on the surface of lipoproteins and regulate lipid metabolism. The two apolipoproteins that are of clinical interest are apo B and apo AI. Apo B is found on LDL particles and is responsible for the clearance of LDL cholesterol through the LDL receptor pathway. Overexpression of apo B in transgenic mice increases the levels of LDL, resulting in increased susceptibility to diet-induced atherosclerosis. Apo AI is the structural protein in high-density lipoprotein (HDL) particles. Apo AI also activates lecithin:cholesterol acyltransferase (LCAT), which esterifies free cholesterol on HDL particles. Mutations that lead to apo AI deficiency are characterized by low or absent levels of HDL.
A review of the relevant literature
I. Apolipoprotein-related Mortality RISk (AMORIS) study
The AMORIS study investigated the use of apo B, apo AI, and the apo B:apo AI ratio at predicting fatal myocardial infarction (MI). The study followed 75 553 Swedish men and women from 1985 to 1996. The authors found that apo B and the apo B:apo AI ratio were both strongly predictive of increased risk of fatal MI in both men and women. Furthermore, they found that apo B was a stronger predictor of risk of fatal MI than LDL cholesterol. Apo AI was found to be protective for risk of fatal MI. The authors propose that apo B, apo AI, and apo B:apo AI be used in the evaluation of cardiovascular risk and that this is of greatest benefit in patients with dyslipidemia with normal or low LDL cholesterol.
II. INTERHEART Study
The INTERHEART study compared the apolipoproteins and cholesterol as indices for risk of acute MI. INTERHEART was a standardized case-control study and included 12 461 cases and 14 637 age- and sex-matched controls in 52 countries. Results showed that a high apo B:apo AI ratio had the highest population attributable risk (54%) of acute MI when compared to LDL:HDL cholesterol ratio (37%) and total:HDL cholesterol ratio (32%), and this was a statistically significant difference (p<0.0001). The study concluded that non-fasting apo B:apo AI ratio was superior to any of the cholesterol ratios for estimation of risk of acute MI in all ethnic groups, in both sexes, and at all ages, and it should be introduced into worldwide clinical practice.
III. Copenhagen General Population Study
The Copenhagen General Population study aimed to determine influence of normal food intake on lipid profiles in diabetic and nondiabetic individuals. It included 58 434 individuals, 2270 of whom had diabetes mellitus. The study showed that triglycerides increased and LDL cholesterol decreased after normal food intake in diabetics and nondiabetics. However, no statistically significant differences in postprandial apo B concentrations were found. The authors suggest that this finding may be useful for discussion during revisions of guidelines for lipid measurements in individuals with or without diabetes.[5a]
IV. Québec Cardiovascular Study
The Québec Cardiovascular Study included 2155 men who were followed for a period of 5 years for clinical signs of ischemic heart disease. Study findings showed that apo B was predictive of ischemic heart disease independent of triglycerides, HDL cholesterol, and total:HDL cholesterol ratio. Apo AI was less predictive of ischemic heart disease, and this association was eliminated when controlling for plasma lipid and lipoprotein levels. The authors suggest that apo B is an important tool in the assessment of ischemic heart disease in men because it may provide information that would not be obtained from the conventional lipid-lipoprotein profile.
V. Prospective Epidemiological Study of Myocardial Infarction (PRIME)
PRIME was a prospective cohort study conducted in Northern Ireland and France that included 9711 men aged 50 to 59 years free of CHD and stroke at baseline and followed them for 10 years. The study aimed to compare the association of a large panel of lipids with the risk of incident coronary heart disease and ischemic stroke. The results showed that that apo B, apo AI, apo B:apo AI along with total cholesterol, HDL cholesterol, LDL cholesterol, non-HDL cholesterol, and triglycerides were all significantly predictive of future coronary heart disease. The trend was similar for ischemic stroke but with lower strength.
VI. Atherosclerosis Risk in Communities (ARIC) Study
The ARIC study included 12 339 middle-aged participants free of coronary heart disease and followed them for 10 years to evaluate the value of baseline lipoprotein cholesterol levels, triglycerides, lipoprotein-a, apolipoproteins AI and B, and HDL density subfractions in predicting coronary heart disease. The results showed that LDL cholesterol, HDL cholesterol, triglycerides, and lipoprotein-a provided substantial prediction of coronary heart disease and that there was no enhancement in prediction with apolipoproteins.
Smaller studies have shown that measurement of apolipoproteins can be useful in particular instances. A 2010 publication in Metabolic Syndrome Related Disorders showed that in hypertriglyceridemic metabolic syndrome patients, apo B and non-HDL cholesterol are better predictors of significant coronary stenosis than LDL cholesterol. A 2011 publication in Diabetes Care showed that apo B and apo AI are better predictors of diabetic retinopathy than total cholesterol, LDL cholesterol, non-HDL cholesterol, and triglycerides.
What does this mean for clinical practice?
Two large studies, AMORIS and INTERHEART, show that apolipoproteins are useful and even superior to LDL cholesterol in estimating risk of MI. It appears that the apoB:apoAI ratio is the most useful of the apolipoprotein values in predicting this risk. An advantage of using apo B instead of LDL is that apo B levels have been shown to remain stable despite food intake. Despite these promising results, other studies, such as the ARIC study, have shown that apolipoproteins are not useful at predicting CHD.
Despite the promising results on the utility of apolipoprotein levels in predicting CHD as described above, the current National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Cholesterol in Adults (NCEP/ATP III) guidelines do not recommend measurement of apolipoproteins in clinical management.
Apo B: NCEP/ATP III guidelines acknowledge that apo B is a strong predictor of coronary atherosclerosis and CHD events. However, they state that there is not enough evidence to justify apo B replacing LDL cholesterol as the preferred target of therapy.
In patients with hypertriglyceridemia, apo B is a better predictor of coronary heart disease than LDL cholesterol. Due to this difference, NCEP/ATP III guidelines set non-HDL cholesterol as a secondary target in patients with hypertriglyceridemia. The reason for this is that non-HDL cholesterol is significantly correlated with apo B and therefore can serve as a surrogate for it, as apo B measurements are not widely available in clinical practice.
Apo AI: NCEP/ATP III guidelines state that, although low levels of apo AI are associated with increased risk of CHD, this relationship has not been shown to be independent of HDL cholesterol levels. Standardized methods for estimating apo AI are not routinely available and therefore it is not recommended to use apo AI in routine risk assessment of CHD.
The American Diabetes Association (ADA) and American College of Cardiology Foundation (ACCF) consensus panel state that apo B may be a more useful predictor of cardiometabolic risk than LDL cholesterol and might be a more discriminating measure of the adequacy of lipid-lowering therapy. The ADA/ACCF consensus panel concludes that apo B should be measured in patients with cardiometabolic risk on pharmacologic treatment when LDL cholesterol is <130 mg/dl and non-HDL cholesterol is <160 mg/dl because it is a more sensitive index of residual cardiovascular disease. They state that apo B levels should be used to guide adjustments in therapy in these patients.
In summary, apo B, although a strong predictor of coronary heart disease, is not currently recommended as the primary target of therapy by NCEP/ATP III guidelines. NCEP/ATP III guidelines recommend apo B as the secondary target of therapy in patients with hypertriglyceridemia, but because measurement of apo B is not widely available in clinical practice, non-HDL cholesterol should be used as a surrogate marker. NCEP/ATP III guidelines do not recommend assessment of apo AI, despite its value as a predictor of lower risk of CHD, because of its lack of independent association with CHD and lack of availability. ADA/ACCF consensus guidelines recommend measurement of apo B in patients with cardiometabolic risk on pharmacologic treatment whose LDL cholesterol is <130 mg/dl and non-HDL cholesterol is <160 mg/dl in order to determine residual cardiovascular disease and to titrate medications.
At this time, measurement of apolipoproteins is only recommended in specific situations as described above. With more studies investigating the utility of apolipoproteins at predicting CHD risk, it remains to be seen if future recommendations will call for using apolipoproteins as the primary markers for determining CHD risk and the primary target of therapy.
Commentary by Dr. Arthur Schwartzbard
We have since seen the publication of long-term follow-up of the Québec Heart Study, supporting the role of apo B-containing lipoproteins and their link to increased risk of cardiovascular disease. It is my expectation that more updated guidelines will support the measurement of apo B in assessing cardiometabolic risk. This is likely to be most valuable in patients with diabetes or elevated triglycerides. A subanalysis from the VA-HIT study also suggests some superiority of apo B to non-HDL, though more data are needed on this issue.
Dr. Navya Nair is a recent graduate of NYU School of Medicine
Peer reviewed by Arthur Schwartzbard, MD, Assistant Professor, Department of Medicine, Division of Cardiology, NYU Langone Medical Center
Image courtesy of Wikimedia Commons
1. McQueen MJ, Hawken S, Wang X, et al. Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study. Lancet. 2008;372:224–233. http://www.ncbi.nlm.nih.gov/pubmed/18640459
2. Kappelle PJWH, Gansevoort RT, Hillege JL, Wolffenbuttel BHR, Dullaart RPF. Apolipoprotein B?A-I and total cholesterol?high-density lipoprotein cholesterol ratios both predict cardiovascular events in the general population independently of nonlipid risk factors, albuminuria and C-reactive protein. J Intern Med. 2010;269:232–242. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2010.02323.x/abstract
3. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (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 (Adult Treatment Panel III) final report. Circulation 2002;106:3143–3421.
4. Mahley RW, Weisgraber KH, Bersot TP. Disorders of lipid metabolism. In: Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, eds. Williams Textbook of Endocrinology.11th ed. Philadelphia, PA: Saunders Elsevier; 2008:1589-1631.
5. 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 (9298):2026–2033. http://www.ncbi.nlm.nih.gov/pubmed/11755609
5a. Langsted A, Nordestgaard BG. Nonfasting lipids, lipoproteins and apolipoproteins in individuals with and without diabetes: 58,434 individuals from the Copenhagen General Population Study. Clin Chem. 2010;579(3):482-489.
6. Lamarche B, Moorjani S, Lupien PJ, et al. Apolipoprotein A-I 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(3):273-278.
7. Canouï-Poitrine F, Luc G, Bard JM, et al. Relative contribution of lipids and apolipoproteins to incident coronary heart disease and ischemic stroke: the PRIME Study. Cerebrovasc Dis. 2010;30(3):252–259. http://www.ncbi.nlm.nih.gov/pubmed/20664258
8. Sharrett AR, Ballantyne CM, Coady SA, et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2001;104(10):1108-1113.
9. Boumaiza I, Omezzine A, Rejeb J, et al. Apolipoprotein B and non-high-density lipoprotein cholesterol are better risk markers for coronary artery disease than low-density lipoprotein cholesterol in hypertriglyceridemic metabolic syndrome patients. Metab Syndrome Relat Disord. 2010;8(6):515-522.
10. Sasongko MB, Wong TY, Ngyuen TT, et al. Serum apolipoprotein AI and B are stronger biomarkers of diabetic retinopathy than traditional lipids. Diabetes Care. 2011;34(2):474–479. http://care.diabetesjournals.org/content/34/2/474.full.pdf
11. Brunzell JD, Davidson M, Furberg CD, et al. 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. 2008;51(15):1512-1524. http://www.ncbi.nlm.nih.gov/pubmed/18402913