The value of measuring apolipoproteins in the risk assessment of cardiovascular disease

In this article, we review evidence which supports a role for apolipoproteins in routine cardiovascular risk assessment. By measuring both apolipoproteins and cholesterol measures in a single assay, there is the potential to signficantly improve cardiovascular risk assessment.

Blood lipid assays are an integral part of the risk assessment of cardiovascular disease. Cholesterol measures - total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol - have traditionally been the main lipid measures used for this purpose. Blood cholesterol tests are considered to be a gold standard in cardiovascular risk assessment but in recent years, studies have shown that apolipoproteins are more effective at assessing cardiovascular risk than traditional cholesterol assays, especially in certain patient groups.


The development of atherosclerosis 


Atherosclerosis is a gradual process whereby bloodstream lipoprotein particles begin to penetrate the arterial wall and leads to the development of a range of cardiovascular diseases. Through inflammatory reactions between cholesterol, white blood cells and connective tissue, atherosclerotic plaques are formed, resulting in the narrowing of arteries. The lipoprotein particles that cause atherosclerosis are called atherogenic particles. The most significant of these are LDL (low-density lipoprotein), VLDL (very low-density lipoprotein) and IDL (intermediate-density lipoprotein) particles. All atherogenic lipoproteins have the same structural protein, apolipoprotein B (ApoB). By contrast, the structural protein of HDL particles (which reduce the risk of atherosclerosis), is apolipoprotein A1 (ApoA1). Whilst traditional cholesterol assays are used to assess cardiovascular risk, these tests do not routinely measure levels of apolipoproteins.


The distinction between apolipoprotein measurements and cholesterol assays


Cardiovascular diseases are among the most prominent preventable causes of morbidity and mortality in the population. The amount of atherogenic lipoprotein particles present in the bloodstream (e.g. LDL-particle concentration) represents a significant cardiovascular risk factor. (1, 2) In Europe, blood cholesterol measurements are the established method of estimating the amount of atherogenic lipoprotein particles present. These assays measure the amount of cholesterol contained in lipoproteins and can be used to estimate the concentrations of harmful LDL and anti-atherogenic HDL particles. (3) LDL-cholesterol concentration is the primary lipid measure that is considered when evaluating cardiovascular risk and monitoring the effect of lipid-lowering medications. (4) However, the size and LDL-cholesterol content of LDL particles can vary significantly between individuals. Therefore, solely measuring LDL-cholesterol concentration is an imprecise method of monitoring the amount of LDL particles in the bloodstream. (5)

Measuring ApoB levels represents a possible alternative to standard blood cholesterol tests, providing us with an indication of the exact number of atherogenic particles present: every LDL particle only has one ApoB protein and ApoB is also the structural protein of IDL and VLDL particles. (6) ApoA1, on the other hand, provides an indication of the amount of anti-atherogenic HDL particles present. Apolipoprotein ratio, ApoB/ApoA1, has been found to associate with risk of myocardial infarction, irrespective of cholesterol levels. (7, 8) Several studies have demonstrated that apolipoprotein measurements are more effective at predicting cardiovascular disease events than routine blood cholesterol measurements. (9-12)


Cholesterol levels do not always reflect the amount of harmful lipoprotein particles


Apolipoproteins are a valuable addition to the risk assessment of cardiovascular disease, especially in those individuals whose LDL cholesterol does not reliably reflect the corresponding number of atherogenic particles. It’s thought that up to 20% of the population have discrepancies between their LDL cholesterol and ApoB levels. In these individuals, LDL-cholesterol provides a false picture of true cardiovascular risk. For those with high levels of ApoB (in relation to LDL), the use of LDL-cholesterol as a risk indicator results in underestimation of the risk. Such an individual’s true risk may in fact be more than two times higher than what would be estimated based on their LDL-cholesterol levels. Conversely, for those with low levels of ApoB (in relation to LDL), the use of LDL-cholesterol in risk assessment may result in an estimation up to three times higher than the true risk. (13) Measuring apolipoproteins, alongside standard blood cholesterol levels, may help clinicians to more accurately target therapeutic interventions to high-risk patients.

Atherogenic dyslipidemia is common in overweight individuals


LDL-cholesterol-based risk assessment tends to consistently underestimate cardiovascular risk in certain groups of individuals. These include individuals who are overweight and obese, suffer from the metabolic syndrome, or have type 2 diabetes. (13, 14) Such individuals commonly have so-called atherogenic dyslipidemia, characterized by an elevated number of triglyceride-rich VLDL particles and small and dense LDL particles. (15) These individuals may have normal (or even low) LDL-cholesterol levels, despite the overall increased number of atherogenic particles. Small and dense LDL particles are believed to be particularly atherogenic, partly because they are, as compared to large LDL particles, more readily oxidized and more prone to penetrate through the vascular endothelium. (16) In spite of normal (or slightly elevated) LDL-cholesterol levels, if a patient is found to have high ApoB levels, it’s likely that they have atherogenic dyslipidemia.

Apolipoproteins in secondary prevention

Lipid assays are not only used in the primary prevention of cardiovascular disease but also in the monitoring of lipid-lowering medications among high risk patients (e.g. those with known atherosclerotic disease, familiar hypercholesterolemia, or those who have had a myocardial infarction). For these groups of patients, apolipoproteins can also provide valuable information for clinicians. For example, it has been found that some statin-treated patients have high levels of ApoB and an elevated cardiovascular risk, despite having on-target levels of LDL-cholesterol. (2, 17) Identification of such patients enables optimizing their treatment, thereby reducing risk of further illness.

The value of measuring apolipoproteins

Apolipoprotein assays can complement traditional cholesterol assays as they report on the number of lipoprotein particles, whereas standard blood cholesterol tests measure the amount of circulating cholesterol. In terms of cardiovascular disease risk, the concentration of atherogenic particles is more significant than the amount of cholesterol contained in them. This is especially true for overweight people and individuals with metabolic syndrome or type 2 diabetes. For these patient groups, blood cholesterol tests may significantly underestimate the risk of cardiovascular disease. Blood tests that measure apolipoprotein levels may then help clinicians to more accurately identify patients at high risk of disease.

Key points:

  • Blood tests that measure apolipoproteins complement traditional cholesterol assays, as they report on the number of atherogenic particles present, whilst cholesterol assays only indicate the amount of circulating cholesterol. For cardiovascular disease risk, the number of atherogenic particles present is more significant than the amount of cholesterol contained in those particles.
  • In addition to the number of LDLs, ApoB levels also indicate the number of other atherogenic particles.
  • About one-fifth of the population displays a discrepancy between LDL-cholesterol and ApoB levels. For these individuals, ApoB is a better indicator of cardiovascular risk than LDL-cholesterol.
  • Typical patient groups where LDL-cholesterol underestimates the risk of cardiovascular disease include overweight individuals and those with metabolic syndrome or type 2 diabetes.

References

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2. Arsenault BJ, Boekholdt SM, Kastelein JJ. Lipid parameters for measuring risk of cardiovascular disease. Nature reviews Cardiology. 2011;8(4):197-206.

3. Dyslipidemiat (online). Suomalaisen Lääkäriseuran Duodecimin ja Suomen Sisätautilääkärien yhdistys ry:n asettama työryhmä. Helsinki: Suomalainen Lääkäriseura Duodecim, 2013. Saatavilla: www.kaypahoito.fi

4. Leiviskä J, Sundvall J, Jauhiainen M, Laatikainen T. Apolipoproteiinit A-I ja B —Onko määrityksestä enemmän hyötyä dyslipide mioiden diagnostiikassa kuin kolesterolimäärityksistä? Duodecim; lääketieteellinen aikakauskirja. 2014;130(22-23):2331-7.

5. Rizzo M, Berneis K. Low-density lipoprotein size and cardiovascular risk assessment. QJM : monthly journal of the Association of Physicians. 2006;99(1):1-14.

6. Ganda OP. Refining lipoprotein assessment in diabetes: apolipoprotein B makes sense. Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2009;15(4):370-6.

7. McQueen MJ, Hawken S, Wang X, Ounpuu S, Sniderman A, Probst eld J, 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(9634):224-33.

8. 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):2026-33.

9. Sniderman AD, Williams K, Contois JH, Monroe HM, McQueen MJ, de Graaf J, et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circulation Cardiovascular quality and outcomes. 2011;4(3):337-45.

10. Lawler PR, Akinkuolie AO, Ridker PM, Sniderman AD, Buring JE, Glynn RJ, et al. Discordance between Circulating Atherogenic Cholesterol Mass and Lipoprotein Particle Concentration in Relation to Future Coronary Events in Women. Clinical chemistry. 2017;63(4):870-9.

11. Sandhu PK, Musaad SM, Remaley AT, Buehler SS, Strider S, Derzon JH, et al. Lipoprotein Biomarkers and Risk of Cardiovascular Disease: A Laboratory Medicine Best Practices (LMBP) Systematic Review. The journal of applied laboratory medicine. 2016;1(2):214-29.

12. Pischon T, Girman CJ, Sacks FM, Rifai N, Stampfer MJ, Rimm EB. Non-high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men. Circulation. 2005;112(22):3375-83.

13. Mora S, Buring JE, Ridker PM. Discordance of low-density lipoprotein (LDL) cholesterol with alternative LDL-related measures and future coronary events. Circulation. 2014;129(5):553-61.

14. Leiviskä J, Sundvall J, Alfthan G, Jauhiainen M, Salomaa V. Apolipoprotein A-I, apolipoprotein B, and apolipoprotein B/apolipoprotein A-I ratio: reference intervals compared with values in different pathophysiological conditions from the FINRISK 2007 study. Clinica chimica acta; International Journal of Clinical Chemistry. 2011;412(11-12):1146-50.

15. Xiao C, Dash S, Morgantini C, Hegele RA, Lewis GF. Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol. Diabetes. 2016;65(7):1767-78.

16. Diffenderfer MR, Schaefer EJ. The composition and metabolism of large and small LDL. Current opinion in lipidology. 2014;25(3):221-6.

17. Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, LaRosa JC, Nestel PJ, et al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA. 2012;307(12):1302-9.

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