ApoB, Lp(a) and Advanced Cardiovascular Risk Markers

Standard cardiovascular risk assessment, based on age, sex, blood pressure, cholesterol, smoking and diabetes, works well for populations but less well for some individuals. 2 people with the same LDL cholesterol can have very different numbers of atherogenic particles; a person with apparently favourable lipids can carry a high inherited risk from lipoprotein(a); and a person with several risk factors may, or may not, already have measurable coronary disease. Advanced markers help resolve these uncertainties. This article builds on earlier discussions of lipids to examine apoB, lipoprotein(a) and related tools in more depth.

Apolipoprotein B

Why particles matter

Each atherogenic lipoprotein particle, VLDL, IDL, LDL and lipoprotein(a), carries one apoB molecule. Atherosclerosis is driven by the entry and retention of these particles in the artery wall, so particle number, reflected by apoB, is closely linked to risk. Mendelian randomisation studies have suggested that the cardiovascular benefit of lowering triglyceride rich lipoproteins and LDL is proportional to the reduction in apoB, supporting the view that apoB is the fundamental unit of atherogenic risk.

Discordance

LDL cholesterol measures the cholesterol carried in LDL particles, not their number. When particles are small and cholesterol depleted, as commonly occurs in insulin resistance, obesity, type 2 diabetes and high triglycerides, LDL cholesterol can be normal while apoB and particle number are high. Studies of discordance have found that, when LDL cholesterol and apoB disagree, risk tracks apoB more closely.

Using apoB

European guidelines recommend apoB as a risk marker, particularly in people with high triglycerides, diabetes, obesity or very low LDL cholesterol, and suggest apoB targets that correspond to LDL targets for different risk categories. ApoB can be measured without fasting, and assays are well standardised.

Lipoprotein(a)

What it is

Lipoprotein(a) is an LDL like particle with an additional protein, apolipoprotein(a), attached. Its level is determined mainly by genes and is relatively stable through life. It promotes atherosclerosis, inflammation and possibly thrombosis, and is strongly linked to calcific aortic valve stenosis.

Measurement

Lipoprotein(a) is reported either in molar units, nmol/L, reflecting particle number, or in mass units, mg/dL. Because particle size varies between individuals, conversion between the 2 units is not reliable. Laboratories should use assays that minimise sensitivity to particle size, and results should be interpreted in the units reported.

Thresholds and implications

The European Atherosclerosis Society recommends measuring lipoprotein(a) at least once in every adult, noting that risk rises progressively with level and that levels above about 50 mg/dL, or around 105 to 125 nmol/L depending on assay, are associated with meaningfully increased risk. Very high levels confer risk comparable to familial hypercholesterolaemia. Lipoprotein(a) testing is particularly relevant in people with premature cardiovascular disease, a family history of premature disease or high lipoprotein(a), familial hypercholesterolaemia and aortic stenosis.

Management

Diet and exercise have little effect on lipoprotein(a), and statins do not lower it meaningfully. PCSK9 inhibitors lower it modestly. Several therapies designed specifically to lower lipoprotein(a) are being tested in large cardiovascular outcome trials. In the meantime, a high lipoprotein(a) is managed by more intensive control of other risk factors, particularly LDL and apoB, blood pressure, smoking and glucose, and by cascade testing of relatives.

Other advanced tools

Coronary artery calcium scoring

A low dose CT scan quantifies calcium in the coronary arteries, a marker of established atherosclerosis. In people at intermediate risk, a score of zero is associated with low short term event rates, and a high score indicates higher risk than traditional factors suggest. Some guidelines use calcium scoring to help decide on preventive treatment in selected adults when the decision is uncertain. It involves radiation, may identify incidental findings and is not a substitute for risk factor management.

hsCRP

Persistently raised hsCRP is considered a risk enhancing factor in some guidelines.

Family history and other enhancers

Premature cardiovascular disease in first degree relatives, chronic kidney disease, inflammatory diseases, South Asian ancestry, pregnancy complications such as pre eclampsia and gestational diabetes, and premature menopause all increase risk beyond calculator estimates.

Putting it together

1. Calculate risk with a validated calculator appropriate to the population.
2. Identify risk enhancing factors.
3. Measure lipoprotein(a) at least once.
4. Use apoB or non HDL cholesterol, especially with high triglycerides, diabetes or obesity.
5. Consider coronary calcium scoring in selected people when treatment decisions are uncertain.
6. Discuss the overall picture with the patient and prescriber, using absolute risk.
7. Address all modifiable risk factors, whatever the advanced markers show.

2 worked examples

Normal LDL, high apoB

A 48 year old man with central obesity and prediabetes has an LDL cholesterol of 2.8 mmol/L, often considered acceptable, but triglycerides of 2.6 mmol/L and an apoB of 1.3 g/L, indicating a high particle number. His overall risk is higher than his LDL suggests. His plan addresses insulin resistance, and his doctor discusses lipid lowering treatment in light of his apoB and overall risk.

Favourable lipids, very high lipoprotein(a)

A 42 year old woman whose father had a heart attack at 46 has an LDL of 2.9 mmol/L and a lipoprotein(a) of 220 nmol/L. Her risk is substantially higher than her standard lipids suggest. Her doctor discusses more intensive LDL lowering and blood pressure control, and her siblings and children are offered testing.

Precision in prevention

ApoB, lipoprotein(a) and related tools allow cardiovascular risk to be assessed more precisely for individuals. They do not replace established risk factors or the fundamentals of prevention, but they identify people whose risk is hidden by standard tests and help target prevention where it matters most.